Menter, Alan_ Ryan, Caitriona-Psoriasis, Second Edition-CRC Press (2017)

Psoriasis

Psoriasis

Second Edition

Edited by

M. Alan Menter, M.D.

Chair, Department of Dermatology and Psoriasis Research Institute Baylor University Medical Center Dallas, Texas

Caitriona Ryan M.D., F.A.A.D. Consultant Dermatologist Department of Dermatology St. Vincent’s University Hospital Dublin, Ireland

CRC Press Taylor & Francis Group 6000 Broken Sound Parkway NW, Suite 300 Boca Raton, FL 33487-2742 © 2017 by Taylor & Francis Group, LLC CRC Press is an imprint of Taylor & Francis Group, an Informa business No claim to original U.S. Government works Printed on acid-free paper International Standard Book Number-13: 978-1-4987-0052-8 (Hardback) This book contains information obtained from authentic and highly regarded sources. While all reasonable efforts have been made to publish reliable data and information, neither the author[s] nor the publisher can accept any legal responsibility or liability for any errors or omissions that may be made. The publishers wish to make clear that any views or opinions expressed in this book by individual editors, authors or contributors are personal to them and do not necessarily reflect the views/opinions of the publishers. The information or guidance contained in this book is intended for use by medical, scientific or health-care professionals and is provided strictly as a supplement to the medical or other professional’s own judgement, their knowledge of the patient’s medical history, relevant manufacturer’s instructions and the appropriate best practice guidelines. Because of the rapid advances in medical science, any information or advice on dosages, procedures or diagnoses should be independently verified. The reader is strongly urged to consult the relevant national drug formulary and the drug companies’ and device or material manufacturers’ printed instructions, and their websites, before administering or utilizing any of the drugs, devices or materials mentioned in this book. This book does not indicate whether a particular treatment is appropriate or suitable for a particular individual. Ultimately it is the sole responsibility of the medical professional to make his or her own professional judgements, so as to advise and treat patients appropriately. The authors and publishers have also attempted to trace the copyright holders of all material reproduced in this publication and apologize to copyright holders if permission to publish in this form has not been obtained. If any copyright material has not been acknowledged please write and let us know so we may rectify in any future reprint. Except as permitted under U.S. Copyright Law, no part of this book may be reprinted, reproduced, transmitted, or utilized in any form by any electronic, mechanical, or other means, now known or hereafter invented, including photocopying, microfilming, and recording, or in any information storage or retrieval system, without written permission from the publishers. For permission to photocopy or use material electronically from this work, please access www.copyright.com (http://www.copyright.com/) or contact the Copyright Clearance Center, Inc. (CCC), 222 Rosewood Drive, Danvers, MA 01923, 978-750-8400. CCC is a not-for-profit organization that provides licenses and registration for a variety of users. For organizations that have been granted a photocopy license by the CCC, a separate system of payment has been arranged. Trademark Notice: Product or corporate names may be trademarks or registered trademarks, and are used only for identification and explanation without intent to infringe. Library of Congress Cataloging‑in‑Publication Data Names: Menter, Alan, editor. | Ryan, Caitriona, editor. | Preceded by (work): Menter, Alan. Psoriasis. Title: Psoriasis / [edited by] M. Alan Menter, Caitriona Ryan. Other titles: Psoriasis (Menter) Description: Second edition. | Boca Raton, FL : CRC Press, Taylor & Francis Group, [2017] | Preceded by Psoriasis / Alan Menter, Benjamin Stoff. c2011. | Includes bibliographical references and index. Identifiers: LCCN 2016042175| ISBN 9781498700528 (hardback : alk. paper) | ISBN 9781498700535 (ebook) Subjects: | MESH: Psoriasis Classification: LCC RL321 | NLM WR 205 | DDC 616.5/26—dc23 LC record available at https://lccn.loc.gov/2016042175 Visit the Taylor & Francis Web site at http://www.taylorandfrancis.com and the CRC Press Web site at http://www.crcpress.com

Contents

Preface vii Contributors ix 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20

The history of psoriasis 1 M. Alan Menter and Bobbak Mansouri Epidemiology 5 Yusur Al-Nuaimi and Richard B. Warren Microscopic findings 11 John R. Griffin Genetics 17 Anne M. Bowcock Immunology 31 Jaehwan Kim and James G. Krueger Other environmental risk factors 39 Brian Kirby and Rosalind Hughes Plaque-type psoriasis—Chronic plaque, guttate, and erythrodermic phenotypes 45 Ricardo Romiti Palmoplantar psoriasis 55 Dario Kivelevitch, Bobbak Mansouri, and M. Alan Menter Generalized pustular psoriasis 71 Hervé Bachelez Inverse psoriasis and genital disease 75 Isabel Haugh and Caitriona Ryan Nail psoriasis 79 Phoebe Rich and Racheal Manhart Differential diagnoses of psoriasis 89 Peter Foley Genetics, immunology, and pathogenesis 133 Arthur Kavanaugh and Tristan Boyd Psoriatic arthritis: Clinical manifestations 143 Peter Nash Pediatric psoriasis 149 Jennifer Day and Amy S. Paller Cardiometabolic comorbidities 159 Nehal N. Mehta Psychiatric comorbidities 167 Jessica M. Donigan and Alexa B. Kimball Other disease associations: Liver, gastrointestinal, respiratory, and neoplastic 173 Nancy Podoswa Assessment and measurement of disease 181 Jordan M. Thompson and Abrar A. Qureshi Current and future topical treatments for psoriasis 193 Shivani Nanda and Linda Stein Gold

v

vi Contents 21 22 23 24 25 26 27

Phototherapy and photochemotherapy 203 Farhaad R. Riyaz and Henry W. Lim Traditional systemic therapies and monitoring guidelines 219 Maria Polina Konstantinou and Carle Paul Current biologic therapies (including IL-17) and monitoring guidelines 233 Bruce E. Strober and Jenna M. Wald Current and future oral small molecules 241 Peter Weisenseel and Kristian Reich Biologic therapies in the pipeline 249 Molly Campa, Pablo Michel, and Caitriona Ryan Future directions and personalized medicine 255 Caitriona Ryan and Elliott Call Conclusion 263 Caitriona Ryan

Index 265

Preface

It is with great pleasure that we present the second edition of Psoriasis. With all the advances in the field of immunopathogenesis, genetics, comorbidities, and therapeutic modalities in the field of psoriasis over the past few years, in collaboration with my colleague Dr. Caitriona Ryan, we have significantly expanded the number of chapters with grateful support from multiple colleagues worldwide. This book is written for clinical and research-oriented dermatologists, dermatology registrars, residents and fellows, medical students, and non-physician scientists. The authors also wish to reach general practitioners, such as family and internal medicine specialists and subspecialists. For academic and clinical dermatologists, we believe this book provides a full and thorough review of the evaluation, associated systemic disorders, and treatment of the multiple forms of psoriasis, to help facilitate the evaluation and care of their patients. The text also discusses current concepts in the ever-expanding field of psoriasis pathophysiology, with up-to-date graphic illustrations of key concepts. Emerging concerns, such as systemic disease associations, quality-of-life issues, and psoriatic arthritis, are also reviewed in detail. For research-minded dermatologists, recent advances in basic science and up-to-date clinical trial data particularly relating to the new anti-IL17 and 23 molecules together with new small oral molecules are discussed fully. In addition, examples of well-known and new and old validated assessment tools for psoriasis can be found in Chapter 19. Readers will hopefully find helpful a chapter devoted to differential diagnosis, with juxtaposed images illustrating the main differentiating features between psoriasis and other dermatoses, common and uncommon. For interest, the authors also present a brief historical and epidemiologic discussion of the disease. We hope that non-dermatologists, such as general and family practitioners, internal medicine specialists, rheumatologists, and specialty nurses, will also find the book

valuable, as a substantial number of psoriasis patients continue to visit non-specialists for diagnosis and treatment. New associations between psoriasis and multiple systemic, comorbid conditions have recently been recognized and will play an important role in our further understanding of this complex disease. Knowledge of these will serve all physicians and healthcare professionals involved in the treatment of psoriasis, and their patients, well. For dermatology registrars and residents, this book lays a solid foundation for learning the various aspects of psoriasis, including clinical features, differential diagnoses, laboratory findings, and therapeutic strategies. In addition, the updated sections on immunopathogenesis and genetics will enhance their understanding of the molecular events underlying psoriasis pathophysiology and assist in preparation for their qualifying examinations. For medical students, this book opens a window to the intriguing world of skin disease with specific focus on psoriasis, a condition as pleomorphic and stigmatized as any other in dermatology. We hope to excite and encourage students to pursue further study into this exiting world of psoriasis or even to consider a career in this field. For non-physician scientists, this book bridges the gap between clinical and basic science, relating the pathomechanism of disease to therapeutic targets and systemic disease associations. Our goal is to stimulate their interest in the investigation of inflammatory skin diseases in general and psoriasis in particular. Ultimately, we hope the diverse content within this second edition of Psoriasis will elicit a range of positive responses from the full spectrum of medical professionals whom we believe will find this book, with all the various aspects of psoriasis, interesting, thought-provoking, and enjoyable. We sincerely hope this second edition will help maintain and improve optimal medical practices in the care of our underserved worldwide psoriasis population of approximately 120,000,000 patients.

vii

Contributors

Yusur Al-Nuaimi Department of Dermatology Royal Devon and Exeter Hospital Devon, United Kingdom

Isabel Haugh Department of Dermatology Baylor University Medical Center Dallas, Texas

Hervé Bachelez Department of Dermatology AP-HP Hopital Saint-Louis, Sorbonne Paris-Cité Université Paris-Diderot, NSERM UMR1163 Institut Imagine Paris, France

Rosalind Hughes Department of Dermatology St Vincent’s University Hospital Dublin, Ireland

Anne M. Bowcock National Heart and Lung Institute Imperial College of Science, Technology and Medicine London, United Kingdom Tristan Boyd Department of Medicine Division of Rheumatology Western University London, Ontario, Canada Elliott Call Department of Dermatology Dartmouth-Hitchcock Medical Center Lebanon, New Hampshire Molly Campa Department of Dermatology Case Western Reserve University Cleveland, Ohio Jennifer Day Departments of Dermatology and Pediatrics Feinberg School of Medicine Northwestern University Chicago, Illinois Jessica M. Donigan Department of Dermatology University of Utah Salt Lake City, Utah

Arthur Kavanaugh Professor of Medicine University of California, San Diego San Diego, California Jaehwan Kim Laboratory for Investigative Dermatology The Rockefeller University New York, New York Alexa B. Kimball Clinical Unit for Research Trials and Outcomes in Skin Department of Dermatology Massachusetts General Hospital Boston, Massachusetts and Harvard Medical School Boston, Massachusetts Brian Kirby Department of Dermatology St. Vincent’s University Hospital Dublin, Ireland Dario Kivelevitch Department of Dermatology Baylor University Medical Center Dallas, Texas James G. Krueger The Rockefeller University New York, New York

Peter Foley Foley Dermatology & Associates East Malvern, Victoria, Australia

Henry W. Lim Department of Dermatology Henry Ford Hospital Detroit, Michigan

John R. Griffin Department of Dermatology Baylor University Medical Center Dallas, Texas

Racheal Manhart Clinical Research Oregon Dermatology and Research Center Portland, Oregon ix

x Contributors Bobbak Mansouri Department of Dermatology Texas A&M HSC College of Medicine Scott and White Health Temple, Texas Nehal N. Mehta Section of Inflammation and Cardiometabolic Diseases National Heart Lung and Blood Institute National Institutes of Health Bethesda, Maryland M. Alan Menter Department of Dermatology and Psoriasis Research Institute Baylor University Medical Center Dallas, Texas

Phoebe Rich Department of Dermatology Oregon Health Science University Portland, Oregon Farhaad R. Riyaz Department of Dermatology Henry Ford Hospital Detroit, Michigan Ricardo Romiti Department of Dermatology Psoriasis Clinic University of São Paulo São Paulo, Brazil

Pablo Michel Baylor Institute of Immunology Research Dallas, Texas

Caitriona Ryan Department of Dermatology St. Vincent’s University Hospital Dublin, Ireland

Shivani Nanda Department of Dermatology Henry Ford Hospital Detroit, Michigan

Linda Stein Gold Department of Dermatology Henry Ford Hospital Detroit, Michigan

Peter Nash Department of Medicine University of Queensland Queensland, Australia Amy S. Paller Departments of Dermatology and Pediatrics Feinberg School of Medicine Northwestern University Chicago, Illinois Carle Paul Dermatology Department University and University Hospital of Toulouse Toulouse, France Nancy Podoswa Dermatology Service Regional General Hospital of the Mexican Social Security Institute (IMSS) Mexico City, Mexico Maria Polina Konstantinou Dermatology Department University and University Hospital of Toulouse Toulouse, France Abrar A. Qureshi Department of Dermatology Warren Alpert Medical School Brown University Providence, Rhode Island Kristian Reich Department of Dermatology Dermatologikum Hamburg Hamburg, Germany

Bruce E. Strober Department of Dermatology University of Connecticut Health Center Farmington, Connecticut and Probity Medical Research Waterloo, Ontario, Canada Jordan M. Thompson Warren Alpert Medical School Brown University Providence, Rhode Island Jenna M. Wald Department of Dermatology University of Connecticut Health Center Farmington, Connecticut Richard B. Warren The Dermatology Centre The University of Manchester, Manchester, United Kingdom and Salford Royal NHS Foundation Trust Salford, United Kingdom Peter Weisenseel Department of Dermatology Dermatologikum Hamburg Hamburg, Germany

1 The history of psoriasis M. ALAN MENTER and BOBBAK MANSOURI BIBLICAL TIMES

THE RENAISSANCE PERIOD

Psoriasis is one of the many dermatological conditions, including leprosy, which has been described since Biblical times. In the Hebrew bible, the term “tzaraath,” translated as leprosy, was used as a term of punishment or “ritual uncleanliness.” In the case of Gehazi (2 Kings 5:27), there is a specific biblical reference to psoriasis, “But Naaman’s leprosy will cling to you and your descendants forever. And Gehazi left his presence a leper, white as snow.”1 In addition, ancient Egyptian and neighboring lands’ scrolls frequently mention the term “leprosy”—again, mistaken in many instances for psoriasis. In 550 b.c., Greek athletes used special showers and application of olive oil to heal and protect their skin, whereas ancient poets Aeschylus and Herodotus described “leprosy,” “leuke,” and “psora” as diseases of the skin. Finally, Hippocrates (460–377 b.c.) freed medicine from the realm of superstition and magic with his meticulous descriptions of many disorders, including conditions of the skin. Dry, scaly eruptions were grouped together under the term “lopoi” (meaning epidermis), which likely included both leprosy and psoriasis.1

The “Renaissance” was a time of revival. Classical learning and wisdom brought to the fore the emergence of a more scientific understanding of psoriasis. Medicine experienced a rebirth with the cities of Vienna, Paris, and London becoming the center of the newly found specialty—dermatology. In Vienna, Joseph Jacob Plenck wrote of psoriasis in 1776 as being among the group of desquamative (scaly or scale-like) diseases but did not differentiate it from other dermatoses. Subsequently, in the late eighteenth century, two Yorkshire-born English dermatologists, Robert Willan (1757–1812) and Thomas Bateman (1778–1821), differentiated psoriasis from other skin diseases. Willan is considered to have first described psoriasis and identified two varieties of the disease. “Leprosa Graecorum” was used to describe the condition when scaling of the skin was predominant, whereas the second term, “Psora Leprosa,” described a more eruptive variant of the condition.5 Willan wrote the first textbook entitled Cutaneous Disease (published in 1798), which contained color photographs of psoriasis and established him as the father of modern dermatology. Bateman, on the other hand, was the first to consider a link between psoriasis and arthritic symptoms. Despite these important writings, psoriasis continued to be confused with leprosy until 1841 when the Viennese dermatologist, Ferdinand von Hebra, gave the condition its definitive name “psoriasis,” derived from the Greek word “psora” meaning “to itch,” and eliminated “lepra.”6 Von Hebra improved on Willan’s original system of classification by relating clinical disease to pathologic anatomy. In 1872, Heinrich Koebner (1834–1904) described the induction of lesions of psoriasis within areas of prior trauma in an address delivered to the Silesian Society for National Culture. This has since become known as the “Koebner” phenomenon.7 Subsequently, Heinrich Auspitz (1835–1886) described both the characteristic histological features of psoriasis and the eponymous clinical sign of pinpoint bleeding on the removal of psoriatic scale.8 Finally, in the descriptive era on the origins of psoriasis as a separate disease, Leo

FIRST CENTURY a.d. Cornelius Celsus, the Roman author (25 b.c.–45 a.d.), described psoriasis as the fourth variant of “impetigo” in his work De Re Medica. 2 Thereafter, the Roman physician Galen (133–200 a.d.) first used the term “psoriasis vulgaris” derived from the Greek word “psora” (meaning itch) to describe an affliction of the skin for which he administered arsenic in many different forms as a “cure.”3 However, the confusion between leprosy and psoriasis endured for many centuries with psoriasis patients between the years 1000 and 1400 a.d. receiving brutal treatment, being isolated from both their communities and their church, and even being burned at the stake by Philip the Fair of France in the fourteenth century.4

1

2  The history of psoriasis

Ritter von Zumbusch (1874–1940), a Viennese physician, was the first to document generalized pustular psoriasis in the early 1900s after observing a single male patient through nine hospital admissions over a 10-year period.9

EVOLUTION OF MODERN THERAPIES Arsenic: For centuries arsenic was used to treat psoriasis and other skin diseases with historical records showing its use as far back as Hippocrates. Thomas Fowler developed a treatment that was a solution of potassium arsenite compounded with a tincture of lavender for color and taste. Known as “Fowler’s Solution,” it was “peer reviewed” by Thomas Girdlestone in a paper entitled “Observations on the effects of Dr. Fowler’s Mineral Solution in Lepra and Other Diseases.” Arsenic was actually still used in the treatment of psoriasis as recently as the 1950s. Tars: Tars were also used by Hippocrates. In the late 1800s, tar was used topically in conjunction with arsenic. Coal tar became available with coal gas production in the second half of the nineteenth century and still maintains a role in the treatment of psoriasis. The slogan “The Heartbreak of Psoriasis” originated in the advertising campaign for Tegrin®, which was a coal-tar based ointment. In 1921, Goeckerman initiated the use of coal tar in a hospital-based regimen with phototherapy, 24 hours a day at the Mayo Clinic. Goa Powder or Chrysarobin: Goa Powder was a Chinese remedy, derived originally from the pith of a tree from Goa, a Portugese enclave off India. Goa Powder was mixed with water, lime juice, or vinegar to make a paste that was spread onto the skin. It was often also mixed with cold lard. During World War I, when Goa Powder was difficult to obtain, Bayer synthesized a substitute called dithranol in Europe or anthralin in the United States. After the application of anthralin, patients were wrapped in a dressing for 24 hours, a technique pioneered by Ingram in Leeds, England, in 1948. Although effective, anthralin therapy was time consuming and often caused irritation and/or staining of the skin. These difficulties ultimately led to modifications of the regimen, and by the 1970s, the 24-hour period had been reduced to 6–9 hours a day, similar to the newly developed day care schedule of the Goeckerman regimen. Thereafter, at Stanford, shorter contact anthralian therapy (SCAT), i.e., 1–2 hours application time, was introduced by Eugene Farber in the early 1980s. Folic Acid Antagonists: The folic acid antagonists, aminopterin and amethopterin, were used in dosages from 1.5 to 2 mg daily with improvement in the condition generally observed after 2 weeks. Initial studies were commenced in California in the 1950s under the supervision of Rees B. Rees.10 Toxicity was, however, a constant problem, with aminopterin still being used as late as the 1960s, before being definitively replaced by its metabolite, methotrexate,11 the first oral drug approved by the U.S. Food and Drug Administration (FDA) for the treatment of severe psoriasis in 1971.

Phototherapy and Photochemotherapy: Broadband ultraviolet B (UVB) was initially used in the treatment of psoriasis in the early 1900s, before being replaced by narrowband (NB UVB) phototherapy, initially in Europe over 40 years ago. After almost a century of various forms of UVB therapy, psoralen-ultraviolet light A (PUVA) was finally approved for the treatment of psoriasis in 1976 with the majority of research having been performed by John A. Parrish and his colleagues at Harvard.13 Systemic Retinoids: Etretinate was the first systemic retinoid developed for the treatment of psoriasis being approved by the FDA in 1986.14 Acitretin, a second ­generation systemic retinoid, replaced etretinate shortly thereafter. Retinoic acid acts by modulating and normalizing the proliferation of the otherwise hyperproliferative epidermis in psoriatic lesions by activating retinoic acid nuclear receptors.12 Cyclosporine: Cyclosporine was discovered in the early 1970s and was originally used as an immunosuppressive agent in organ transplantation.17 An anecdotal report of its efficacy in a psoriasis patient in 1979 changed the understanding of psoriasis from what was previously ­ ­considered to be a keratinocyte-driven disorder to that of a T-cell-mediated disease.18 Cyclosporine acts by inhibiting the activity of calcineurin phosphatase by forming a complex with cyclophilin. As a result, important T-cell nuclear transcription factors are not phosphorylated leading to inhibition of the activation of T lymphocytes, natural killer cells, and antigen-presenting cells, depletion of lymphocytes and macrophages in the epidermis, and a host of other effects including inhibition of keratinocyte hyperproliferation.15

Biological agents Over the past 13 years, the advent of biologic agents has revolutionized psoriasis therapy, leading to dramatically improved clinical outcomes in patients with ­moderate-to-severe psoriasis. The first biologic injectable agent approved for ­psoriasis was Alefacept in January 2003. Alefacept inhibits the ­activation of CD4+ and CD8+ T cells by binding with CD2 on the T-cell membrane thereby blocking the ­costimulatory molecule lymphocyte function-associated ­antigen (LFA)-3/CD2 interaction and leading to apoptosis of m ­ emory-effector T lymphocytes.19 Alefacept had limited efficacy in the treatment of psoriasis, and production was discontinued in 2011. Subsequently, a second T-cell biologic agent, efalizumab, was introduced in 2005.20 Efalizumab binds to the CD11a subunit of lymphocyte ­f unction-associated antigen 1 to inhibit lymphocyte activation and cell migration out of blood vessels into tissues. Although efalizumab demonstrated efficacy in psoriasis, particularly in those with palmoplantar disease, it was removed from the market in 2009 due to three fatalities from progressive multifocal leukoencephalopathy (PML).21

References 3

The tumor necrosis factor-alpha (TNF-α) pathway has been an integral pathway targeted by psoriasis, psoriatic and rheumatoid arthritis, and inflammatory bowel disease therapies over the past two decades. Anti-TNF-α agents licensed for the treatment of psoriasis and psoriatic arthritis include adalimumab,22 etanercept,23 and infliximab.24,25 These agents continue to play a major role in the biological therapy of psoriasis. With advances in our understanding of the molecular pathways of psoriasis, newer, more targeted biologic therapies have been developed. The discovery of the critical role of interleukin-23 (IL-23)/Th17 axis in the immunopathogenesis of psoriasis has been the most fundamental advance to date in psoriasis research and has led to the development of many selective biologic agents that target this pathway. Ustekinumab, an antibody to the common p40 subunit of IL-12 and IL-23, has shown considerable efficacy in the treatment of psoriasis and psoriatic arthritis, and it was licensed for use in psoriasis in 2008 in Europe and Canada and in 2009 in the United States.26,27 Finally, the first of the anti-IL-7 molecules, secukinumab and ixekizumab, have been approved for psoriasis in 2015 and 2016, respectively.28,29 The third of these molecules, broadalumb, was approved by the FDA in July. Multiple, new targeted treatments are currently in clinical development for the treatment of psoriasis, including IL-23 inhibitors, and bispecific anti-TNF-α/ IL-17A fusion proteins.

CONCLUSION The history of psoriasis is rich. Much of our early understanding of the disease was guided by observation. More modern therapeutics were guided by serendipitous findings (e.g., cyclosporine). The last two decades have ushered in a new guard, biological therapies, which are the direct result of our improved understanding of the immunopathogenesis of psoriasis and a reminder of the progress we have made in treating this debilitating disease.

REFERENCES 1. Menter MA. Psoriasis: From Leprosy to Biologic Drug Development. Dallas, TX: Baylor University Medical Center Internal Medicine Grand Rounds. 14 October 2003. 2. Celsus AC. De Re Medica, Third Edition, translated by J Grieve. London: E. Portwine, 1837. 3. Glickman FS. Lepra, psora, psoriasis. J Am Acad Dermatol. 1986;14(5 Pt 1):863–866. 4. Bechet PE. Psoriasis, a brief historical review. Arch Dermatol Syph. 1936;33:327–334. 5. Willan R. On Cutaneous Diseases. London: J. Johnson, 1808.

6. Hebra F. On Disease of the Skin, vol. II. London: New Syndenham Society, 1868. 7. Koebner H. Zur Aetiologie der Psoriasis. Vjschr Dermatol. 1876;8:559–561. 8. Pusey WA. History of Dermatology. Springfield, IL: Charles C. Thomas, 1933. 9. von Zumbusch L. Psoriasis and postulöses e­ xanthem. Arch Derm Syph. 1910;99:335. 10. Rees RB, Bennett JH, Bostick WL. Aminopterin for psoriasis. AMA Arch Derm. 1955;72(2):133–143. 11. Rees RB, Bennett JH, Maibach HI, Arnold HL. Methotrexate for psoriasis. Arch Dermatol. 1967;95(1):2–11. 12. Carretero G, Ribera M, Belinchón I, et al. Guidelines for the use of acitretin in psoriasis. Actas Dermosifiliogr. 2013 Sep;104(7):598–616. 13. Parrish JA, Fitzpatrick TB, Tanenbaum L, Pathak MA. Photochemotherapy of psoriasis with oral methoxsalen and longwave ultraviolet light. N Engl J Med. 1974;291(23):1207–1211. 14. Morison WL. Etretinate and psoriasis. Arch Dermatol. 1987 Jul;123(7):879–81. 15. Amor KT, Ryan C, Menter A. The use of cyclosporine in dermatology: Part I. J Am Acad Dermatol. 2010;63(6):925–946. 16. Goldfarb MT, Ellis CN, Gupta AK, Tincoff T, Hamilton TA, Voorhees JJ. Acitretin improves psoriasis in a dose-dependent fashion. J Am Acad Dermatol. 1988;18(4 Pt 1):655–662. 17. Calne RY, White DJ, Thiru S, et al. Cyclosporin A in patients receiving renal allografts from cadaver donors. Lancet. 1978;2(8104–8105):1323–1327. 18. Mueller W, Herrmann B. Cyclosporin A for psoriasis. N Engl J Med. 1979;301(10):555. 19. Lebwohl M, Christophers E, Langley R, et al. An international, randomized, double-blind, placebocontrolled phase 3 trial of intramuscular alefacept in patients with chronic plaque psoriasis. Arch Dermatol. 2003;139(6):719–727. 20. Gordon KB, Papp KA, Hamilton TK, et al. Efalizumab for patients with moderate to severe plaque psoriasis: A randomized controlled trial. JAMA. 2003;290(23):3073–3080. 21. Korman BD, Tyler KL, Korman NJ. Progressive multifocal leukoencephalopathy, efalizumab, and immunosuppression: A cautionary tale for dermatologists. Arch Dermatol. 2009;145(8):937–942. 22. Menter A, Tyring SK, Gordon K, Kimball AB, Leonardi CL, Langley RG, et al. Adalimumab therapy for moderate to severe psoriasis: A randomized, controlled phase III trial. J Am Acad Dermatol. 2008;58(1):106–115. 23. Leonardi CL, Powers JL, Matheson RT, et al. Etanercept as monotherapy in patients with psoriasis. N Engl J Med. 2003;349(21):2014–2022.

4  The history of psoriasis

24. Reich K, Nestle FO, Papp K, et al. Infliximab induction and maintenance therapy for moderateto-severe psoriasis: A phase III, multicentre, doubleblind trial. Lancet. 2005;366(9494):1367–1374. 25. Menter A, Feldman SR, Weinstein GD, et al. A ­randomized comparison of continuous vs. intermittent infliximab maintenance regimens over 1 year in the treatment of moderate-to-severe plaque psoriasis. J Am Acad Dermatol. 2007;56(1):31 e1–15. 26. Leonardi CL, Kimball AB, Papp KA, et al. Efficacy and safety of ustekinumab, a human i­nterleukin-12/23 monoclonal antibody, in patients with psoriasis: 76-week results from a randomised, double-blind, placebo-controlled trial (PHOENIX  1). Lancet. 2008;371(9625):1665–1674.

27. Papp KA, Langley RG, Lebwohl M, et al. Efficacy and safety of ustekinumab, a human interleukin-12/23 monoclonal antibody, in patients with psoriasis: 52-week results from a randomised, double-blind, placebo-controlled trial (PHOENIX 2). Lancet. 2008;371(9625):1675–1684. 28. Langley RG, Elewski BE, Lebwohl M, et al. Secukinumab in plaque psoriasis—Results of two phase 3 trials. N Eng J Med. 2014;371(4):326–338. 29. Gordon KB, Blauvelt A, Papp KA, et al. Phase 3 ­trials of ixekizumab in moderate-to-severe plaque ­psoriasis. N Engl J Med. 2016;375(4):345–356.

2 Epidemiology YUSUR AL-NUAIMI and RICHARD B. WARREN INTRODUCTION Psoriasis is a common, chronic, inflammatory skin disease. A world consortium reported that psoriasis affects 2% of people worldwide.1 The epidemiological study of psoriasis is an essential component of research for this potentially life-ruining condition. Such studies aim to better elucidate population trends and the burden of the disease, and identify factors that may contribute to pathogenesis. Variation in severity, delayed or incorrect diagnosis, types of psoriasis, and heterogeneity in study methodology are some of the factors that make determining the accuracy of epidemiological studies complex. Despite these challenges, valuable insight into psoriasis has been gained through the pursuit of epidemiological study and more recently comprehensive accounts of the epidemiology of psoriasis have come to fruition. Importantly, there is a scarcity in epidemiological data for types of psoriasis other than chronic plaque psoriasis (psoriasis vulgaris) and thus in this chapter, when referring to psoriasis we imply chronic plaque psoriasis. Any data pertaining to the other variants of psoriasis will be appropriately highlighted.

INCIDENCE OF PSORIASIS The incidence of psoriasis (i.e., the number of new cases of psoriasis occurring in a defined time) is low. Several studies have been performed. However in comparison to the number of studies on the prevalence of psoriasis, published work in this particular area is sparse. Studies reporting the incidence of psoriasis have been conducted in the United States and Europe (United Kingdom, Italy, and the Netherlands) (Figure 2.1) with ongoing studies currently underway in Latin America and Asia. A study based in the Mayo Clinic, Rochester, Minnesota (Rochester Epidemiology Study database) reported the ­incidence to be 59.9 per 100,000 people per year.2 Two primary care-based studies from the Netherlands and ­ United Kingdom reported incidences of 120–130 per 100,000 ­person per year3 and 140 per 100,000 person per year, respectively.4 These studies report the incidence in ­persons of all ages.

The incidence of psoriasis in children in the United States was found to be 40.8 per 100,000 people per year.5 Interestingly, girls had a higher incidence (43.9) than boys (37.9). A rise in incidence between 1970 and 2000 was found with 29.6 cases per 100,000 people per year reported between 1970 and1974 and 62.7 cases per 100,000 people per year between 1995 and 1999.5 The incidence of psoriasis in adults alone has been reported in three studies. An Italian study found an incidence rate of 230 per 100,000 person per year,6 whereas the two studies performed in the United States had more similar incidences rate of 78.9 and 82 cases per 100,000 per year.7,8 Incidence of psoriasis was found to have doubled in adults in the 30 years between 1970 and 2000 (Figure 2.1).7 Men had a higher incidence of psoriasis compared with women (85.5 versus 73.2, respectively),7 which is in contrast to the incidence rates reported in children.5 Current evidence highlights an increasing trend in the incidence of psoriasis (Figure 2.1). Whether this trend is due to a true rise in incidence or other factors, such as greater diagnostic rates or awareness of the disease, remains unclear. The contribution of risk factors for psoriasis such as increasing obesity and stress is also thought to be playing a part in this trend. Further studies assessing wider geographical areas and different populations are needed to better characterize the true incidence of this common disease.

PREVALENCE OF PSORIASIS Estimated prevalence (the total number of cases within a defined population) of psoriasis varies worldwide. A systematic review of the epidemiology of psoriasis explored variations in prevalence in terms of age, gender, case definition methods, geography, and study design in 53 population-based studies.9 Populations located further away from the equator seem to have a higher prevalence rate (Figure 2.2).9,10 Psoriasis is more prevalent in adults than in children with a prevalence ranging from 0.91% (United States) to 8.5% (Norway) in adults and 0% (Taiwan) to 2.1% (Italy) in children (Figure 2.3).9 Studies reporting the prevalence of ­psoriasis in persons of all ages, therefore, tend to report lower prevalence 5

6 Epidemiology

300

latitude and prevalence of psoriasis has been studied. No significant correlation was demonstrable; however, a weak relationship was found in the exploration of 22 population-based surveys, case–control studies, and reviews.11 Limitations of this work are the heterogeneity in data, nonstandardized methods between studies, and the potential that prevalence rates differ due to overlying factors such as the possibility of different psoriasis rates in different genetic pools, altitude (ultraviolet [UV] light is directly proportional to altitude), and days of actual sunshine per year, which may vary in different regions regardless of latitude. The speculation that variation in prevalence of psoriasis arises according to different UV wavelengths has been raised; however, altitude and reflection of UV light also contribute to the fluence of UV light.12

100

150

200

250

Children United States (Tollefson et al.5) Adults United States (Icen et al.7) Adults Italy (Vena et al.6) All ages United States (Bell et al.2) All ages The Netherlands (Donker et al.3) All ages United Kingdom (Huerta et al.4)

50

5 00

–2

00

9 20

95

–1

99

4 19

99 –1 90 19

98 9 –1 85 19

80

–1

97 9 19

–1 75 19

–1 70 19

98 4

EFFECTS OF ETHNICITY 97 4

Incidence rate per 100,000 person–years

rates. This is even more apparent in countries where a large proportion of people are young (Figure 2.2). Nations located farther away from the equator exhibit higher prevalence of psoriasis than those closer.9 The geographical variation in prevalence of psoriasis highlights potential factors that may contribute to disease; however, dissecting out the specific roles of factors such as variation in genetics and environment is challenging (Figure 2.4). The relationship between absolute

Epidemiology data on psoriasis in persons of different ethnic backgrounds are limited; however, the

Figure 2.1  The incidence of psoriasis (in population-based studies).

1.1%–1.4% Norway (3 studies)

0.8%–1.87% United Kingdom (4 studies)

2.84% Denmark

0.73% Scotland

2%–2.53% Germany (2 studies)

L

0.72% Russia

A v e

a

r

t i

1.58% Yugoslavia

1.43% Spain

t u

a g 0.12%–0.35% China (2 studies)

2.9% Italy

d e

0.23% Taiwan

0.7%–2.6% United States (3 studies)

e U V I n

0.19% Egypt 0% Andean South Americans

d

0.1% Tanzania

e x 0.44% Sri Lanka

Figure 2.2  World prevalence in population studies performed in people of all ages. Increasing prevalence found with greater distance from the equator. Average ultraviolet (UV) index shows how this may contribute to geographical differences in psoriasis prevalence rates globally. (Data from Parisi R et al., J Invest Dermatol. 2013;133:377–385.)

Effects of ethnicity  7 4.82%–8.5% Norway (2 studies)

1.3%–2.6% United Kingdom (3 studies)

0.30 Sweden

3.73% Denmark

0.91%–3.15% United States (4 studies)

0.71% Germany

1.21% Croatia

5.2% France 2.15% Italy

1.3% United States (African Americans)

0.27% Romania

3.1% Italy

0% Taiwan (2 studies)

2.3%–6.6% Australia (3 studies)

Figure 2.3  World prevalence of psoriasis in children (purple) and adults (dark blue). (Data from Parisi R et al., J Invest Dermatol. 2013;133:377–385.)

Latitude

Triggering environmental agents: streptococcal pharyngitis, stressful life events, low humidity, drugs, HIV infection, trauma, smoking and obesity have been associated with psoriasis and psoriatic arthritis

Ethnicity

Genetics HLA-Cw6

Geoepidemiology of psoriasis

Age UV index

Figure 2.4  Estimated

prevalence of psoriasis varies depending on multiple factors including geographical location, age, ­genetics, ethnicity, UV exposure, and triggering environmental agents.

prevalence of psoriasis is lower in non-Caucasian ­persons.13 In an Australian study, 0% prevalence was found in Aborigines compared with 2.6% of Australian Caucasians.14 Psoriasis is almost half as prevalent in  African-Americans compared with Caucasians.

A  cross-sectional study of 6,216 U.S. adults reported a prevalence of 1.9% in African-Americans and 3.6% in Caucasians.15 Another larger study of over 27,000 people found a 1.3% and 2.5% prevalence in African-Americans and Caucasians, respectively.16 It has been highlighted

8 Epidemiology

that the historical migration pattern of AfricanAmericans originated from West Africa where the prevalence of psoriasis has been reported to be lower than East Africa.17 This suggests that a lower genetic predisposition for psoriasis remains in this population. The associations between psoriasis and human leucocyte antigen (HLA)-Cw6 are recognized. Exploring the frequency of HLA-Cw6 white populations found an average 9.3%. In Northern Chinese Han, it was 4.4%, 2.2% in Southern Chinese Han, 2% in New Guinea, 0% in Taiwanese, 1.0% in Eskimos, 2.9% in North Amerindians, and 0.0% in Brazilian Amerindians. Therefore, a correlation between decline in HLA-Cw6 frequency and lower psoriasis prevalence has been identified. This relationship between low HLA-Cw6 frequency and prevalence does not account for the lower prevalence in black African populations as the allele was common in the population sampled (15.1%).18

GENDER There is conflicting data as to whether prevalence of psoriasis differs between genders.9 Studies have shown that men demonstrate a higher incidence of psoriasis compared with women (85.5 versus 73.2, respectively),7 which is in contrast to the incidence rates reported in children (Figure 2.1).5 The age of onset in females is earlier compared with males. Henseler and Christophers reported an average age of onset of 16 years compared with 22 years in females and men, respectively, likely attributed to hormonal changes associated with puberty.19 The role of hormonal changes such as menarche, postpartum, and menopause have been attributed as triggers for psoriasis flares.20 Conversely, pregnancy has been shown to lead to improvement of ­psoriasis in two-thirds of affected females.21

AGE A bimodal distribution in the age of onset of psoriasis has been demonstrated.19,22 Populations constituting each peak demonstrate distinct genetic and phenotypic associations. The population represented by the first peak has been named “type I” psoriasis and the second “type II.” The type I peak, comprising roughly 75% of patients with psoriasis, occurs before the age of 40. In 35%–50% onset is before the age of 20 years.19,23,24 Type I patients are more likely to have first-degree relatives affected with the disease. Association with class I HLA alleles, namely HLA-Cw6, is observed.18,25-27 In contrast, type II psoriasis is more sporadic with a less than definitive genetic background. Recently, however, a genome-wide study has identified genetic loci exclusively associated with late-onset psoriasis.28

FUTURE DIRECTIONS Psoriasis is a common disease with a profound effect on quality of life and day-to-day function.29 Epidemiological studies have allowed clinicians to better understand groups of people more susceptible to psoriasis and gain insight into the role of both genetics and the environment on the immunopathogenesis of psoriasis. The identification of genetic predisposition to psoriasis has been enabled by epidemiological work, which has highlighted the familial trends of psoriasis as a disease. Identifying distinct phenotypic entities of psoriasis by age of onset has led to genetic studies associating HLA-Cw6 with early onset psoriasis and guttate psoriasis. Dissecting out the influence of multiple factors, such as genetic, epigenetic, and environmental influences on the immunopathogenesis of psoriasis, remains a challenge. Genome-wide association studies (GWAS) have been an essential tool in dealing with the complexity of this polygenic disease.27,30 Future large-scale epidemiological studies, focusing on standardized methodology over wide geographical areas in more diverse populations, are required to better characterize chronic plaque psoriasis. Moreover, the clinical subtypes of psoriasis including nail psoriasis, palmoplantar pustulosis, erythrodermic psoriasis, and inverse psoriasis currently have few definitive epidemiological studies. Measures to improve current data collection and sharing of data may be achieved by standardizing and improving coding of psoriasis through the International Classification of Diseases (ICD), a globally recognized classification system. Further chapters in this book detail the environmental risk factors and genetics that are essential components of understanding the geoepidemiology and genetic epidemiology of psoriasis. In the coming years, we anticipate that genome-wide association analysis with dense marker maps will yield important insights into the many genes that determine the risk of psoriasis, and that identification of these genes, in turn, will allow us to define interactions with specific environmental factors influencing the disease process.

REFERENCES 1. Lima XT, Minnillo R, Spencer JM, Kimball AB. Psoriasis prevalence among the 2009 AAD National Melanoma/Skin Cancer Screening Program participants.JEurAcadDermatolVenereol. 2013;27(6):680–685. 2. Bell LM, Sedlack R, Beard CM, et al. Incidence of psoriasis in Rochester, Minnesota, 1980–83. Arch Dermatol. 1991;127:1184–1187. 3. Donker GA, Foets M, Spreeuwenberg P, van der Werf GT. Management of psoriasis in general ­practice now more in agreement with the guidelines of the Dutch College of General Practitioners (NHG). Ned Tijdschr Geneeskd. 1998;142:1379–1383.

References 9

4. Huerta C, Rivero E, Garcia Rodriguez LA. Incidence and risk factors for psoriasis in the general population. Arch Dermatol. 2007;143:1559–1565. 5. Tollefson MM, Crowson CS, McEvoy MT, Maradit Kremers H. Incidence of psoriasis in children: A population-based study. J Am Acad Dermatol. 2010;62:979–987. 6. Vena GA, Altomare G, Ayala F, et al. Incidence of psoriasis and association with comorbidities in Italy: A 5-year observational study from a national primary care database. Eur J Dermatol. 2010;20:593–598. 7. Icen M, Crowson CS, McEvoy MT, Dann FJ, Gabriel SE, Maradit Kremers H. Trends in incidence of adult-onset psoriasis over three decades: A population-based study. J Am Acad Dermatol. 2009;6:394–401. 8. Setty AR, Curhan G, Choi HK. Obesity, waist circumference, weight change, and the risk of psoriasis in women: Nurses’ Health Study II. Arch Intern Med. 2007;167:1670–1675. 9. Parisi R, Symmons DPM, Griffiths CEM, Ashcroft DM. Global epidemiology of psoriasis: A systematic review of incidence and prevalence. J Invest Dermatol. 2013;133:377–385. 10. Braathen LR, Botten G, Bjerkedal T. Prevalence of psoriasis in Norway. Acta Derm Venereol Suppl. 1989;142:5–8. 11. Jacobson CC, Kumar S, Kimball AB. Latitude and psoriasis prevalence. J Am Acad Dermatol. 2011;65(4):870–873. 12. Enamandram M, Kimball AB. Psoriasis Epidemiology: The Interplay of Genes and the Environment. J Invest Dermatol. 2013;133(2):287–289. 13. Alexis AF, Blackcloud P. Psoriasis in skin of color: Epidemiology, genetics, clinical presentation, and treatment nuances. Desai SR, Alexis A, eds. J Clin Aesthet Dermatol. 2014;7(11):16–24. 14. Farber EM, Nall L. Psoriasis in the tropics. Epidemiologic, genetic, clinical, and therapeutic aspects. Dermatol Clin. 1994;12:805–816. 15. Rachakonda TD, Schupp CW, Armstrong AW. Psoriasis prevalence among adults in the United States. J Am Acad Dermatol. 2014;70:512–516. 16. Gelfand JM, Stern RS, Nijsten T, et al. The prevalence of psoriasis in African Americans: Results from a population-based study. J Am Acad Dermatol. 2005;52:23–26. 17. Chandran V, Raychaudhuri SP. Geoepidemiology and environmental factors of psoriasis and psoriatic arthritis. J Autoimmun. 2010;34:J314–J321.

18. Gudjonsson JE, Elder JT. Psoriasis: Epidemiology. Clin Dermatol. 2007;25:535–546. 19. Henseler T, Christophers E. Psoriasis of early and late onset: Characterization of two types of psoriasis vulgaris. J Am Acad Dermatol. 1985;13:450–456. 20. Xhaja A, Shkodrani E, Frangaj S, Kuneshka L, Vasili E. An epidemiological study on trigger factors and quality of life in psoriatic patients. Mater Sociomed. 2014 Jun;26(3):168–171. 21. Ceovic R, Mance M, Bukvic Mokos Z, et al. Psoriasis: Female skin changes in various hormonal stages throughout life—Puberty, pregnancy, and menopause. Biomed Res Int. 2013;2013:571912. 22. Smith AE, Kassab JY, Rowland Payne CME, Beer WE. Bimodality in age of onset of psoriasis in both patients and their relatives. Dermatology. 1993;186:181–186. 23. Farber EM, Nall ML. The natural history of psoriasis in 5600 patients. Dermatologica. 1974;148:1–18. 24. Raychaudhuri SP, Gross J. A comparative study of pediatric onset psoriasis with adult onset psoriasis. Pediatr Dermatol. 2000;17:174–178. 25. Schmitt-Egenolf M, Eiermann TH, Boehncke WH, Stander M, Sterry W. Familial juvenile onset psoriasis is associated with the human leukocyte antigen (HLA) class I side of the extended haplotype Cw6B57-DRB1*0701-DQA1*0201-DQB1*0303: A population- and family-based study. J Invest Dermatol. 1996;106:711–714. 26. Allen MH, Ameen H, Veal C, et al. The major psoriasis susceptibility locus PSORS1 is not a risk factor for late-onset psoriasis. J Invest Dermatol. 2005;124:103–106. 27. Queiro R, Tejón P, Alonso S, Coto P. Age at disease onset: A key factor for understanding psoriatic disease. Rheumatology. 2014;53(7):1178–1185. 28. Hébert HL, Bowes J, Smith RL, et al. Identification of loci associated with late-onset psoriasis using dense genotyping of immune-related regions. Br J Dermatol. 2015;172(4):933–939. 29. Lebwohl MG, Bachelez H, Barker J, et al. Patient perspectives in the management of psoriasis: Results from the population-based Multinational Assessment of Psoriasis and Psoriatic Arthritis Survey. J Am Acad Dermatol. 2014;70(5):871–881. 30. Julià A, Tortosa R, Hernanz JM, et al. Risk variants for psoriasis vulgaris in a large case-control collection and association with clinical subphenotypes. Hum Mol Genet. 2012;21:4549–4557.

3 Microscopic findings JOHN R. GRIFFIN The microscopic features of psoriasis typically reflect the clinical subtype of disease as well as the stage of development of a particular lesion, allowing for precise clinicopathologic correlation.1,2 The histopathologic findings, therefore, evolve with time just as each individual lesion evolves. It is important to note, however, that the “severity” of the microscopic findings, that is to say, how well developed a particular lesion may be microscopically, does not necessarily reflect the overall clinical severity of the disease as would be measured with clinical scoring systems such as the Psoriasis Area Severity Index (PASI) or Psoriasis Severity Index (PSI).1

THE “EVOLUTION” OF PSORIASIS The earliest features are found at the advancing edge of a plaque or in an early guttate lesion.2,3 In guttate disease, the earliest features consist of focal spongiotic foci in the lower stratum spinosum of the epidermis.3 At this early phase, vascular changes and mast cell degranulation are detectable ultrastructural events, but are not seen by light microscopy. In lesions of several days’ duration, clinically pinheadsized macules at this point, epidermal changes continue with subtle compaction of the stratum corneum, band-like epidermal thickening, and focal spongiosis. The majority of the early changes, however, are noted in the dermis including lymphatic dilatation, a superficial perivascular lymphohistiocytic infiltrate, and edema of the papillary dermis, which is stuffed with capillaries orienting ­t hemselves perpendicularly to the epidermis.2 Once textural changes develop within evolving lesions, clinically represented by a pinhead-sized smooth surfaced papule, microscopic epidermal changes become more prominent. The stratum corneum loses its normal basket weave architecture and becomes compact, with foci of parakeratosis noted. The granular layer is focally lost and subtle hyperplasia of keratinocytes is noted. In the lower half of the epidermis, mitotic figures in keratinocytes are

seen and lymphocytes are noted to collect along the basal layer as well as in small spongiotic foci. The dermis continues to see perivascular lymphocytes and extravasated red blood cells (RBCs) and more edema develops in dermal papillae.2 In fully developed disease, the hallmark features are present and are so characteristic as to have earned the moniker “psoriasiform.” These changes include regular acanthosis with loss of the granular layer and overlying hyperparakeratosis, some of the parakeratotic mounds topped with neutrophils. There is accumulation of intraepidermal and intracorneal neutrophils and thinned suprapapillary plates with dilated capillaries in close apposition to the stratum corneum. Although none of these findings is specific for psoriasis, the sum of the findings is characteristic and only a limited number of mimics exist.

CHRONIC PLAQUE PSORIASIS The prototypical microscopic findings of psoriasis are all present in chronic plaque psoriasis. Acanthosis is noted to be quite regular with uniform-width rete pegs each extending to the same depth, such that the term “psoriasiform acanthosis” has been adapted as a morphologic descriptor of this finding (Figure 3.1). It is reported that an increased number of mitotic figures are observed within the basal layer of the epidermis. Slightly dilated capillaries are present in elongated dermal papillae, which extend to thinned suprapapillary plates (Figure 3.2). The entire superficial portion of the epidermis demonstrates hypogranulosis over which lies confluent parakeratosis with small collections of neutrophils “sandwiched” between abundant layers of stratum corneum (Munro’s microabscesses) (Figure 3.3). Neutrophils may collect within the spinous layer of the epidermis (spongiotic pustules of Kogoj), but these diminish with time. There tends to be a sparse perivascular lymphohistiocytic infiltrate in the superficial dermis. Occasional eosinophils may be noted and do not preclude the diagnosis.

11

12  Microscopic findings

Figure 3.4  Guttate psoriasis 20×. Figure 3.1  Plaque psoriasis 4×.

Figure 3.5  Guttate psoriasis 8×. Figure 3.2  Vessels in plaque psoriasis 40×.

yet developed, such that reliance on other findings is necessary. Dilated, tortuous capillaries are present in edematous dermal papillae and tend to have scattered extravasated erythrocytes and perivascular neutrophils early in the disease (Figure 3.4). Instead of confluent parakeratosis, mounds of parakeratosis are noted (Figure  3.5). Within these mounds are collections of neutrophils, typically “sandwiched” between the layers of parakeratosis. Several findings are distinctly less common in guttate psoriasis when compared with plaque psoriasis: spongiform pustules of Kogoj, dermal edema, and suprapapillary thinning.

ERYTHRODERMIC PSORIASIS

Figure 3.3  Plaque psoriasis 10×. GUTTATE PSORIASIS Guttate disease represents psoriasis at one of its most subtle histopathologic forms and overlaps with that of partially treated disease. Regular acanthosis has not

Rendering a definitive diagnosis on a biopsy from a patient with erythroderma is challenging at best, and potentially dangerous at worst, if a malignant diagnosis is given for a benign process or vice versa. Many biopsies from patients with erythrodermic psoriasis will demonstrate changes of chronic spongiotic dermatitis with mild exocytosis of lymphocytes, which presents a challenge when ­distinguishing these cases from a chronic dermatitis. A study of 45 patients with erythrodermic psoriasis compared the histopathologic findings with other causes of erythroderma. Biopsies

Nail psoriasis  13

from 30% of patients ­ demonstrated findings ­ similar to fully formed plaque psoriasis. Biopsies from 60% of patients with psoriasis demonstrated microscopic changes consistent with early, evolving psoriasis, including slight epidermal hyperplasia with focal ­hypogranulosis, slight spongiosis with a few lymphocytes, and focal parakeratosis. The most constant finding in patients with psoriasis, and arguably only patients with psoriasis, was the dilatation of blood vessels of the superficial plexus spiraling into the dermal papillae with thinned ­suprapapillary plates.4 Unfortunately features of psoriasis that indicate chronicity, such as psoriasiform acanthosis, hypogranulosis, hyperkeratosis, and parakeratosis, may also be present in biopsies from erythrodermic atopic dermatitis.5 In a study of 12 patients with erythroderma definitively diagnosed as secondary to either psoriasis or atopic dermatitis, no single histopathologic feature could distinguish between the two conditions. Findings from this study that did not meet statistical significance but are potentially helpful include the fact that only biopsies from patients with atopic ­dermatitis demonstrated vesiculation, only biopsies from psoriasis demonstrated neutrophilic microabscess formation, and that all biopsies from patients with psoriasis demonstrated perivascular eosinophils.5 The presence of Pautrier’s microabscesses is strongly suggestive of Sezary syndrome or erythrodermic mycosis fungoides and rules out the diagnosis of erythrodermic psoriasis.15 Careful ­clinicopathologic correlation and long-term ­follow-up are necessary to corroborate a diagnosis of erythrodermic psoriasis.

Figure 3.6 

Follicular psoriasis. (From Arps D et al.: Follicular psoriasis. J Cutan Pathol. 2013. 40. 860–862. Copyright WileyVCH Verlag GmbH & Co. KGaA. Reproduced with permission.)

FOLLICULAR PSORIASIS This uncommon form of psoriasis has unique histopathologic features in that the findings are limited to the infundibulum of a follicular unit.6 The subjacent ­epidermis demonstrates psoriasiform hyperplasia while the intervening epidermis is uninvolved. Within a dilated follicular infundibulum, a plug of parakeratotic debris is observed intermixed with neutrophils (Figure 3.6). This is distinct from the follicular plugging noted in lupus and pityriasis rubra pilaris, as each of those entities tend to be plugged with compact orthokeratin. The infundibular epithelium demonstrates hypogranulosis. It may be difficult to distinguish these findings from those of acute folliculitis, particularly when microorganisms are not evident.

INVERSE PSORIASIS Inverse psoriasis may demonstrate spongiosis and serum crust. These features are generally absent in psoriasis unless the sample is obtained from palmoplantar or scalp disease. The acanthosis tends not to be as prominent as in plaque disease and the stratum corneum is frequently quite minimal, with foci of parakeratosis and neutrophils

Figure 3.7  Inverse psoriasis 100×. present, but lacking the thick mounds of stratum corneum seen in classic plaque disease (Figure 3.7).

NAIL PSORIASIS Psoriatic involvement of the nail bed demonstrates f­ eatures quite distinct from other cutaneous surfaces. The healthy nail bed typically lacks a granular layer; in ­psoriasis a granular layer develops in conjunction with acanthosis of the epithelium. Parakeratosis of the nail bed is noted, with neutrophils in the mounds of parakeratotic debris. Spongiosis may be observed, similar to ­ palmoplantar, inverse and scalp psoriasis. Nail plate involvement demonstrates subungual hyperkeratosis, parakeratosis, and collections of neutrophils within parakeratotic debris. Focal spongiosis may also be present (Figure 3.8). It is necessary to rule out a dermatophyte infection with the use of special stains as the appearance is essentially identical.

14  Microscopic findings

Figure 3.8  Nail plate psoriasis 10×.

Figure 3.9  Pustular psoriasis 14.4×.

PSORIATIC ALOPECIA Alopecia is a well-known complication of generalized pustular and erythrodermic psoriasis. In rare cases, ­ ­however, severe inflammatory psoriasis vulgaris can cause alopecia, both nonscarring and scarring. The alopecia is limited to areas involved by psoriasis. In one large series, most patients had psoriasis of the scalp and body, though nearly one-third had scalp-only disease.7 Alopecia was seen more frequently in conjunction with thick hyperkeratosis than in areas with lighter scale. Trichograms from patients with acute hair loss demonstrated an elevated average telogen count of 63%, whereas those with chronic alopecia had an elevated average telogen count of 36%. The histopathology demonstrated a variety of patterns perhaps best considered as being on a spectrum. All biopsies demonstrated features of psoriasis or seborrheic dermatitis involving the epidermis. In patients without features of scarring alopecia, there was a peri-infundibular or periisthmic lymphocytic inflammatory response with dilatation of the follicular infundibulum, an increase in catagen/ telogen hairs, and some follicular plugging with orthokeratin.7–9 Follicular spongiosis was a notable feature though interface dermatitis was not seen. Occasional eosinophils were noted. In addition, a prominent catagen/telogen shift may be seen with a ratio of catagen/telogen hairs to anagen hairs of nearly 1:1 compared to the expected 1:10 ratio (personal observation). In advanced cases, changes ­consistent with a scarring alopecia were present, including perifollicular mucinous fibrosis, thinning of the outer root sheath, and even follicular destruction with free floating hairs and replacement of follicles with thick fibrous tracts. A feature that is characteristic of psoriatic alopecia is a decrease in the number or in the size of sebaceous glands. Interestingly, this feature may also be seen in patients with psoriasis without clinical alopecia.8

PUSTULAR PSORIASIS Pustular psoriasis demonstrates findings quite distinct from other psoriatic subtypes, although if a pustular flare develops on a longstanding lesion of plaque psoriasis, much overlap

Figure 3.10  Pustular psoriasis 13.6×. between the two subtypes is noted. In early disease, neutrophils migrate from dilated capillaries in the dermal papillae into the spinous layer of the epidermis (Figure 3.9). The neutrophils collect in intercellular spaces as neutrophilic “macroabscesses” or large spongiform pustules. Subsequently, the pustule will migrate superficially into a subcorneal location (Figure 3.10). In cases of chronic pustular psoriasis as well as pustular psoriasis that develops on skin previously involved by plaque psoriasis, epidermal changes such as regular acanthosis and parakeratosis are present in addition to the vascular changes of psoriasis.10,11 If a biopsy is taken from a clinical pustule, rather than from erythematous skin without a clinical pustule, elongation of rete ridges is more commonly seen. The pustules contain neutrophils, acantholytic keratinocytes, and, rarely, eosinophils as well.11 Occasionally, the pustule is located even more superficially in a subcorneal location. These cases may be difficult to distinguish from subcorneal pustular dermatosis, pustular impetigo, and the subcorneal pustular dermatosis variant of IgA pemphigus and special studies such as gram staining and immunofluorescence testing may be necessary in addition to clinicopathologic correlation. The generalized form of pustular psoriasis may be difficult to distinguish from acute generalized exanthematous pustulosis (AGEP). Findings that favor AGEP include eosinophils located in the dermis and within pustules, dyskeratotic keratinocytes within the epidermis, a mixed neutrophil-rich d ­ ermal perivascular and interstitial infiltrate, and absence of dilated, tortuous blood vessels in the papillary dermis. Elongated rete ridges may be seen in both pustular psoriasis and AGEP.11

Verrucous psoriasis  15

PALMOPLANTAR PUSTULOSIS Features similar to, but more exaggerated than pustular psoriasis, are seen in fully developed pustular lesions of palmoplantar pustulosis. Early lesions, however, demonstrate spongiosis with lymphocytic exocytosis into the spinous layer where a small vesicle forms. The lymphocytic vesicle will enlarge and subsequently become filled with neutrophils forming a large pustule at which point psoriasiform acanthosis is typically present10 (Figure 3.11). Serum crust in the stratum corneum is not unusual in ­palmoplantar pustulosis.

ANTITUMOR NECROSIS FACTOR ALPHA‑INDUCED PSORIASIS A variety of clinical and microscopic findings have been described related to antitumor necrosis factor-alpha(TNF-α) induced psoriasis including palmo-plantar pustulosis, pustular psoriasis, guttate psoriasis, chronic plaque psoriasis, and anti-TNF-α-induced psoriatic alopecia. The lesions that mimic pustular, guttate, and chronic plaque psoriasis are more likely to demonstrate eosinophils and plasma cells in the dermal infiltrate than de novo psoriasis.12 The psoriatic alopecia induced by antiTNF-α agents resembles the alopecia of psoriasis with a mixed psoriasiform epidermal pattern and a markedly increased catagen/telogen count (Figure 3.12), but also demonstrates an alopecia areata-like peribulbar infiltrate

(Figure 3.13). One feature that may help to distinguish the drug-induced from the de novo form is, again, a prominence of dermal and peribulbar plasma cells and eosinophils.13 Performance of a special stain for Treponema pallidum spirochaetes is recommended in this setting. Occasionally, an interface dermatitis may be observed, favoring the diagnosis of a drug-induced ­psoriasiform eruption (personal observation).

VERRUCOUS PSORIASIS An uncommonly reported clinical and histopathologic variant of psoriasis is that of verrucous or h ­ ypertrophic psoriasis. Lesions tend to localize to extensor skin ­overlying joints and the typical clinical differential diagnoses are lichen simplex chronicus, verruca vulgaris, or psoriasis. Although few cases are reported in the literature, a case series described lesions demonstrating regular psoriasiform hyperplasia with acanthosis, papillomatosis, and an inward pointing of the rete ridges toward the center of the lesion (the authors describe this finding as “buttressing”) (Figure 3.14). Most cases demonstrated spongiform pustules of Kogoj throughout the lesion but

Figure 3.13  Peribulbar lymphocytic inflammation and follicular miniaturization 7.5x. Figure 3.11  Palmoplantar pustulosis 6.2×.

Figure 3.12  Tumor necrosis factor alpha (TNF-α) inhibitor induced scalp psoriasis with alopecia 4x.

Figure 3.14  Verrucous psoriasis 10×.

16  Microscopic findings

Figure 3.15  Verrucous psoriasis 20×. particularly centered upon elongated verrucous papillations (Figure 3.15). One half of the cases in the series also demonstrated Munro’s microabscesses. The authors excluded human papillomavirus (HPV)-induced lesions based on the absence of clumped keratohyaline granules, koilocytic change, and a negative polyclonal anti-bovine papillomavirus (BPV-1) stain for HPV.14

REFERENCES 1. Kim BY, Choi JW, Kim BR, Youn SW. Histopath­ ological findings are associated with the clinical types of p ­ soriasis but not with the corresponding lesional psoriasis severity index. Ann Dermatol. 2015;27(1):26–31. 2. Ragaz A, Ackerman AB. Evolution, maturation, and regression of lesions of psoriasis. Am J Dermatopathol. 1979;1(3):199–207. 3. Brody I. Dermal and epidermal involvement in the evolution of acute eruptive guttate psoriasis vulgaris. J Invest Dermatol. 1984;82(5):465–470. 4. Tomasini C, Aloi F, Solaroli C, Pippione M. Psoriatic erythroderma: A histopathologic study of forty-five patients. Dermatology. 1997;194:102–106.

5. Moy AP, Murali M, Kroshinsky D, Duncan LM, Nazatian RM. Immunologic overlap of helper T-cell subtypes 17 and 22 in erythrodermic psoriasis and atopic dermatitis. JAMA Dermatol. ­ 2015;15(7):753–760. 6. Arps D, Chow C, Lowe, L, Chan MP. Follicular ­psoriasis. J Cutan Pathol. 2013;40(10):860–862. 7. Runne U, Kroneisen-Wiersma P. Psoriatic alopecia: Acute and chronic hair loss in 47 patients with scalp psoriasis. Dermatology. 1992;185:82–87. 8. Silva CY, Brown KL, Kurban AM, Mahalingam M. Psoriatic alopecia—Fact or fiction? A clinicohistopathologic reappraisal. Indian J Dermatol Venereol Leprol. 2012;78(5):611–619. 9. Werner B, Brenner FM, Boer A. Histopathologic study of scalp psoriasis: Peculiar features including sebaceous gland atrophy. Am J Dermatopathol. 2008;59:93–100. 10. Prystowski JH, Cohen PR. Pustular and erythrodermic psoriasis. Dermatol Clin. 1995;13:757–770. 11. Kardaun SH, Kuiper K, Fidler V, Jonkman MF. The histopathological spectrum of acute generalized exanthematous pustulosis (AGEP) and its differentiation from generalized pustular psoriasis. J Cutan Pathol. 2010;37:1220–1229. 12. Laga AC, Vleugels RA, Qureshi AA, Velazquez EF. Histopathologic spectrum of psoriasiform skin reactions associated with tumor necrosis factor-α inhibitor therapy. A study of 16 biopsies. Am J Dermatopathol. 2010;32:568–573. 13. Doyle LA, Sperling LC, Baksh S, et al. Psoriatic alopecia/alopecia areata-like reactions secondary to anti-tumor necrosis factor α therapy: A novel cause of noncicatricial alopecia. Am J Dermatopathol. 2011;32(2):161–166. 14. Khalil FK, Keehn CA, Saeed S, Morgan MB. Verrucous psoriasis: A distinctive clinicopathologic variant of psoriasis. Am J Dermatopathol. 2005;27(3):204–207. 15. Sentis HJ, Willemze R, Scheffer E. Histopathologic studies in Sezary syndrome and erythrodermic mycosis fungoides: A comparison with benign forms of erythroderma. J Am Acad Dermatol. 1986;15:1217–1226.

4 Genetics ANNE M. BOWCOCK INTRODUCTION Psoriasis (Ps) is a complex multifactorial disease, similar to other autoimmune or inflammatory diseases such as type 1 diabetes, Crohn’s disease (CD), and celiac disease. In all of these conditions, susceptibility is influenced by both genetic and environmental factors. The worldwide prevalence of Ps differs. For example, it is 3% in Europeans,1 whereas it is only 0.1% in Asians.2 Ps is a polygenic disease meaning that there are many genetic factors of low risk in the genome that can increase an individual’s risk of developing disease. As with other autoimmune diseases, some of these genetic factors are likely to lead to disease by encoding factors that cumulatively overcome a threshold for immune cell activation.3 There is also overlap between some of these risk factors in the different autoimmune diseases. In the case of Ps, a single genetic mutation can also lead to a strong risk of developing disease. These genetic findings are discussed in the following with particular reference to their altered function.

MODE OF INHERITANCE A genetic basis for Ps is supported by twin studies because there are greater concordance rates for Ps in monozygotic (MZ) than in dizygotic (DZ) twins.4 A recent study on 10,725 twin pairs, aged 20–71 years, from the Danish Twin Registry revealed that the concordance rate of Ps was 0.33 in MZ versus 0.17 in DZ twins. 4.1% of the men and 4.2% of the women had a lifetime history of Ps.5 In this study, genetic factors explained 60%–75% of the variation in the susceptibility to Ps,6 whereas the rest of the variation was explained by nonshared environmental factors.5 Family studies have also supported evidence for a genetic basis for Ps. A few large kindreds provided early evidence that they might harbor a locus conferring Ps susceptibility, with autosomal dominant inheritance and a penetrance of approximately 60%.4 Some rare families are now known to harbor gain-of-function mutations in the caspase recruitment domain family member 14 gene (CARD14)6–8 (discussed further in the following). Genetic linkage studies rely on the availability of single families

with large numbers of affected members or large numbers of small families. In Ps, studies of these types on small families have been inconclusive.9–11 In recent years, with the development of technologies that permit rapid scanning of numerous polymorphic markers in large numbers of individuals, and the identification of millions of base pair changes in the genome (single nucleotide polymorphisms [SNPs]), it has been possible to perform global screens for Ps risk factors (genome-wide association studies [GWAS]). The large numbers of cases and controls used in such studies have enabled the identification of over 50 loci that confer very low risk of developing disease (listed in Table 4.1). This has provided novel insights into Ps pathogenesis, despite the fact that GWAS cannot explain more than ±20% of the heritability of the disease.12,13 However, there is evidence that more individual variants contributing to Ps may be detected if sample sizes in future association studies are increased.13 Only those loci achieving genome-wide significance for association are shown. The chromosomal cytogenetic location is shown, along with the most likely candidate gene/s in the associated interval, the odds ratios (ORs) in each population, and the pathway implicated by the candidate gene. The genetic study leading to the identification of this locus is referenced. In the case of 10 loci, associations are seen in Europeans but not Asians (ELMO1, ERAP2, PRDX5, SOCS1, RNF114, RUNX1, TP63, TRAF3IP2, TYK2, and ZMIZ1; Table 4.1).20 It is suggested that population-specific effects such as these contribute to the ethnic diversity of Ps prevalence.20 With respect to the risk factors shared by both European and Asian populations, there are significant differences in allele frequencies in worldwide populations, and this has been interpreted to be due to selection at these loci.20

PSORIASIS SUSCEPTIBILITY LOCUS 1 In the 1970s, psoriasis case/control studies conducted with classical human leucocyte antigen (HLA) serotyping revealed association with HLA-Cw6.30 In this early study, performed in Finland, the prevalence of HLA-Cw6 was 72.7% in patients with guttate Ps and 45.9% with Ps 17

18 Genetics

Table 4.1  Psoriasis loci in European and Chinese populations. Candidate Chs locus gene in locus Gene name 1p36.23

TNFRSF9

1p36.13

UBR4

1p36.11 1p36.11

IL28RA (IFNLR1) RUNX3

1p31 1q21.3

IL23R LCE3B, LCE3C

2p16.1

REL

2p15

COMMD1

2q24.2 3p24.3

IFIH1 (2 signals) SATB1

3q13.31

ZDHHC23

3q28 5q15

TP63 ERAP1

5q15

ERAP2

5q31.1 5q33.1

IL13 TNIP1,

5q33.3

IL12B (three signals)

6p25.3

IRF4

6p21.33

HLA-C

6q21

OR Caucasian

OR Chinese 1.18

Pathway implicated

Tumor necrosis factor receptor superfamily, member 9 Ubiquitin protein ligase E3 component n-recognin 4

1.160

Interferon (IFN), lambda receptor 1 Runt-related transcription factor 3 Interleukin 23 receptor Late cornified envelope 3B, late cornified envelope 3C v-rel avian reticuloendotheliosis viral oncogene homolog Copper metabolism (Murr1) domain containing 1 IFN induced with helicase C domain 1 SATB homeobox 1

1.160

1.25

1.090

1.16

1.13–1.49 1.250

1.15 1.32

1.200

1.12

Innate immunity, nuclear factor kappa B (NF-κB) subunit19

1.15

1.26

Adaptive immunity, lymphocyte function, NF-κB signaling20 Innate immunity, viral RNA recognition, IFN signaling15,20 Chromatin organizer, T-cell development15

Zinc finger, DHHC-type containing 23 Tumor protein p63 Endoplasmic reticulum aminopeptidase 1 Endoplasmic reticulum aminopeptidase 2 Interleukin 13 TNFAIP3 interacting protein 1, annexin A6 Interleukin 12B

1.12

1.11

1.190, 1.330 1.14, 1.25 1.14

1.17 1.130

Adaptive immunity, generation of CD8+ memory T cells12 Immunity, Signal transducer and activator of transcription 2 (STAT 2) degradation14 Innate immunity, IFN signaling15 Adaptive immunity, T-cell differentiation/ activation12 Inflammatory, Th17 pathway15,16 Epidermal barrier function17,18

21

1.02 1.14

1.15 1.170 1.640

1.13 1.54 1.40

IFN regulatory factor 4

1.20–1.37 (three signals) 1.100

TRAF3IP2

TRAF3 interacting protein 2

3.3 (several signals) 1.200

6q23.3

TNFAIP3

6q25.3

TAGAP

7p14

ELMO1

8p23

CSMD1

9p21.1

DDX58

Tumor necrosis factor, alpha-induced protein 3 T-cell activation RhoGTPase activating protein Engulfment and cell motility 1 CUB and Sushi multiple domains 1 DEAD (Asp–Glu–Ala–Asp) box polypeptide 58

Epidermal differentiation20 Adaptive immunity, trimming of peptides for HLA class I presentation15,22 Adaptive immunity, trimming of peptides for HLA class I presentation20 Adaptive immunity, Th2 signaling23 Innate immunity, NF-κB signaling (inhibitor)18,22,23 Adaptive immunity, interleukin (IL)-23/ Th17 axis15,20,23,24

1.240

Innate immunity, antiviral signaling, IFN signaling12 22.62(several Adaptive immunity, antigen signals) presentation18,23–27 1.02 Innate immunity/NF-κB signaling (inhibitor)15,24 1.29 Innate immunity, inhibition of NF-κB pathway15 1.32 Adaptive immunity, T-cell activation

1.12

Apoptosis, cell motility20

1.240

1.150

1.09

1.09

Keratinocyte differentiation22

1.18

Innate immunity, antiviral signaling (Continued)

Psoriasis susceptibility locus 1  19

Table 4.1  (Continued) Psoriasis loci in European and Chinese populations. Candidate Chs locus gene in locus Gene name

OR Caucasian

OR Chinese

9q31.2

KLF4

Kruppel-like factor 4

1.140

1.11

9q34.13

TSC1, c9Orf9

1.09

10q22.3

ZMIZ1

11q13.1 11q22.3

PRDX5 ZC3H12C

11q24.3

ETS1

12q13

IL23A, STAT2

13q12

GJB2

13q14.11

COG6, FOXO1

13q14.12

14q13.2

KIAA1704 (GPALPP1), TSC22D1, LOC144817 KBIA

Tuberous sclerosis 1, chromosome 9 open reading frame 9 Zinc finger, MIZ-type containing 1 Peroxiredoxin 5 Zinc finger CCCH-type containing 12C v-ets avian erythroblastosis virus E26 oncogene homolog 1 Interleukin 23, alpha subunit p19, signal transducer and activator of transcription 2 Gap junction protein, beta 2 Component of oligomeric Golgi complex 6, forkhead box O1 GPALPP motifs containing 1, TSC22 domain family, member 1

16p13.13

SOCS1

16p11.2

FBXL19

17p11.2

KCNJ12

17q11.2

NOS2

17q21.2

Pathway implicated Innate immunity, epidermal differentiation 23

1.15

1.03

Inflammatory21

1.2 1.100

1.01 1.12

Inflammatory21 Induced by TNF and IL-112

1.130

1.14

Adaptive immunity, keratinocyte and Th17 cell differentiation20

1.550

1.25

Adaptive immunity; IL-23/Th17 axis15,19,23

1.11

Epidermal differentiation22

1.16

1.16

20,28

1.14

1.09

20

Nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor, alpha Suppressor of cytokine signaling 1 F-box and leucine-rich repeat protein 19 Potassium inwardlyrectifying channel, subfamily J, member 12 Nitric oxide synthase 2, inducible

1.160

1.26

Innate immunity, NF-κB signaling15,19

1.16

1.04

Adaptive immunity, Th17 differentiation21

1.150

1.55

Innate immunity19

1.170

1.28

STAT3

Signal transducer and activator of transcription 3

1.150

1.18

17q25.3

CARD14

1.1

1.21

18q21.2

STARD6

1.140

1.29

21

18q22.1

SERPINB8

Caspase recruitment domain family, member 14 StAR-related lipid transfer (START) domain containing 6 Serpin peptidase inhibitor, clade B (ovalbumin), member 8

1.09

Serine protease inhibitor22

1.17

19

Innate immunity (catalyzes the production of nitric oxide for immune defense against pathogens)18 Adaptive immunity, mediation of multiple cytokine signals (IL-6, IL-10, IL-22, and IL-23)20 Innate immunity, NF-κB signaling, epidermal differentiation12,29

(Continued)

20 Genetics

Table 4.1  (Continued) Psoriasis loci in European and Chinese populations. Candidate Chs locus gene in locus Gene name

OR Caucasian

OR Chinese

19p13.2

TYK2

Tyrosine kinase 2

1.130

19q13.41 20q13.13

ZNF816A RNF114

Ring finger protein 114

1.140

0.88 1.30

20q13.12 21q22.12

SDC4, MATN4 RUNX1

1.14 1.17

1.06

22q11.21

UBE2L3

Syndecan 4, matrilin 4 Runt-related transcription factor 1 Ubiquitin-conjugating enzyme E2L 3

1.100

1.16

vulgaris compared with 7.4% in healthy blood donors. Since it was the first psoriasis association, it was termed Ps susceptibility locus 1 (PSORS1). HLA-Cw6 is a member of the HLA class 1 gene family. Epidermal infiltration of predominantly oligoclonal CD8+ T cells, and CD4+ T cells in the dermis, is a striking feature of chronic Ps lesions.31 This suggests that these T cells are responding to specific antigens presented by HLA class 1 alleles. In a more recent and larger study performed on Icelandic Ps patients, 64.2% harbored an HLA-Cw6 allele (termed HLA-C*06:02 when referring to the locus identified with DNA analysis), and 6.8% were homozygous for this allele.32 The presence of one HLA-C*06:02 allele conferred a relative risk of developing Ps of 8.9 compared with 23.1 for the Cw6 homozygous patients. The homozygous patients also had an earlier disease onset (mean 15.0 vs. 17.8 years, p = 0.04). However, the Cw6 homozygotes did not differ from the heterozygotes with respect to disease severity, guttate onset, distribution of plaques, nail changes, or any other recorded clinical parameter.32 Because no clear-cut antigen has been defined that is recognized by this particular allele, it remains unclear exactly how it might predispose to disease. Hence, there have been suggestions that the causative variant may actually reside nearby but regulate the expression of this gene (P. Liu thesis).33 The frequency of HLA-Cw6 varies worldwide from ±16% in Africa and 8.5%–12% in Europe to 3.5%–7.8% in Asia.34 Because the presence of HLA-Cw6 is insufficient for disease development, there is an ongoing GWA search for additional DNA variants that influence Ps susceptibility (discussed more in the following). However, the HLA association with Ps is robust and every Ps GWAS has revealed association with a locus in the major histocompatibility complex (MHC) class I interval (Table 4.1). With respect to the PSORS1 locus, recent studies have explored the association of Ps with alleles from the MHC in depth. Although HLA-C*06:02 demonstrates the greatest statistical correlation with Ps (p = 1.7 × 10 –364 in one study), 25 several HLA-C*06:02-independent risk variants for Ps susceptibility lie in both class I and class II HLA genes.25 These include HLA-B amino acid positions

Pathway implicated Innate immunity, Janus kinase downstream of cytokine receptors, IFN signaling15 Zinc finger protein22 Innate immunity; innate antiviral signaling26 Intracellular signaling, wound healing19 Adaptive immunity, T-cell development/ activation, epidermal development20 Innate immunity, NF-κB signaling (p105)

67 and 9, HLA-A position 95, and HLA-DQA1.25 All of these amino acid sites are located within an HLA-binding pocket suggesting an effect on antigen binding by the predisposing allele. In this study, Ps was also associated with HLA-C*12:03, confirming a smaller earlier study.35 Late-onset Ps is also associated with HLA-C*12:02 allele in Japanese.36 HLA-C*06:02 and HLA-C*12:03 differ by only five amino acid replacements in total and all occur in the alpha-1 domain. However, the alpha-2 domains and the peptide-binding pockets A, D, and E are identical.37 Hence, it is suggested that both HLA-C*06:02 and HLA-C*12:03 could be recognizing the same antigen or set of antigens.35 Some HLA alleles confer Ps risk in one population and not another; for example, HLA-A*02:07 increases Ps risk in Chinese but is very rare or absent in Europeans and HLA-B*07 increases Ps risk in Europeans but is very rare in Chinese. These associations are proposed to have arisen as a result of different selection pressures in the presence of diverse pathogens in the two populations.13 There is also a suggestion that risk heterogeneity between Ps and psoriatic arthritis (PsA) might be driven by HLA-B amino acid position 45 where the Glu amino acid confers risk of psoriatic arthritis.25 Moreover, different HLA susceptibility genes are associated with different forms of PsA.38

VARIANTS DRIVING PSORIASIS GWAS SIGNALS A single associated region identified through GWAS can contain several genes and many base pairs of DNA sequence. The associated SNP is also highly correlated (in linkage disequilibrium) with a number of other SNPs due to the genetic history of the population being examined. If one wants to understand the genetic basis of Ps, it is important to determine what SNP allele or other genomic feature in that interval is causative and in most regions of Ps association, the causative variant/s have not been identified. A  few associations are due to the change of a single amino acid in a peptide encoded by gene residing

Variants driving psoriasis GWAS signals  21

in the GWAS interval (Table 4.1). However, in most intervals, there is no common coding change and the causative variant/s are likely to be within regulatory sequences. For common diseases, the majority of variants identified with GWAS are located in noncoding sequences such as promoters, enhancers, introns or gene deserts. This highlights the fact that these variants may influence diseases or traits by regulating transcript expression levels rather than directly changing protein function.39 The genome has a plethora of regulatory elements that are only now beginning to be identified and characterized through efforts such as the National Institutes of Health (NIH) Roadmap Epigenomics Consortium.40 The identification of such causative variants in common diseases such as Ps is not trivial. The affected gene or alternatively spliced isoform could be expressed at only a specific developmental state or in response to an environmental stimulus. It could also be expressed in a discrete cell type or set of cell types. As genomic analyses on different cell types and their regulatory elements under different conditions are identified, the next few years should see the identity of many of these variants being revealed, including those in Ps. eQTLs in Ps: Expression quantitative trait loci (eQTL) analysis reveals SNPs that potentially affect gene expression (expression SNPs or eSNPs). Identified eSNPs in Ps include variants near TNIP1, IL23A, and IL12B.23 TNIP1: A noncoding variant within or near the TNFAIP3 interacting protein 1 (TNIP1) gene is associated with Ps and as described earlier, this could be affecting its expression level. The region of association harbors both TNIP1 and ANXA6 genes. TNIP1 is involved in regulation of NF-κB signaling.41 It is upregulated in both atopic dermatitis (AD) and psoriatic involved skin compared with healthy skin. However, ANXA6, which encodes a calciumdependent membrane and phospholipid binding protein, is upregulated in atopic skin compared with healthy skin but is downregulated in psoriatic versus healthy skin. It has been suggested that ANXA6 might differentiate AD from psoriatic skin through calcium-dependent effects in keratinocyte differentiation.42 There are a number of similar genes with opposing risk alleles at loci shared by AD and Ps.42 These loci include noncoding alterations in PRKR, the SPRR cluster of genes, and an antisense RNA of filaggrin (FLG-AS1). This is interpreted to be due to distinct genetic mechanisms with opposing effects in shared pathways influencing epidermal differentiation and the immune response. A recent study integrating GWAS evidence in Han Chinese and Caucasians with the signature of eQTL in lymphoblastoid B cells, revealed five additional genes with implied regulatory effect that were associated significantly with the risk of Ps. These had not been identified in earlier GWAS. One of the genes was FAM20B, also known as GXK1, which encodes a kinase that phosphorylates the Glycosaminoglycan (GAG)–protein linkage region of proteoglycans. The others include a number of genes from the HLA class 1 region.43 Interestingly, one SNP allele could regulate several genes, and several genes could share the

same regulatory SNP allele. This reveals the ­complexity of gene regulation effects that contribute to a disease such as Ps.

Protein coding alterations associated with psoriasis Of a handful of genes that are known to harbor a predisposing coding alteration, the interleukin 23 receptor (IL23R) was the first to be described.44 The predisposing polymorphism is a p.R381Q change and the R risk allele is very common in both cases and controls. The same polymorphism is associated with a number of other autoimmune diseases including multiple sclerosis,45 CD, and ankylosing spondylitis.3 Ps and CD are also associated with SNPs near IL12B.44,46 In the case of Ps at least three independent associations exist44 and all are likely to be regulatory because they do not alter the coding sequence of this gene. As with all GWAS findings, the risk conferred by these alleles is low. However, IL12B is undoubtedly an important player in Ps pathogenesis and therapeutic targeting of its protein product (e.g., with ustekinumab) has been remarkably effective in treating the disease.47 IL12B encodes the IL-12-p40 subunit of both IL-12 and IL-23 cytokines. In the skin, IL-12 and IL-23 are produced by Langerhans cells. These are a subset of dendritic cells (DCs) that reside in the epidermis and drive the development of distinct subsets of T cells. IL-12 induces the classic interferon (IFN)-γ–producing T helper (Th) 1 cells, whereas IL-23 drives the expansion and maintenance of effector T helper cells such as Th17 and Th22 cells.48 These T cells produce proinflammatory cytokines such as IL-17 and IL-22, which are important players in various inflammatory diseases. The IL-23–mediated Th17 effector function is affected by the IL-23R p.R381Q polymorphism. Cells transfected with the IL-23R Q nonrisk variant show decreased IL-23–mediated signaling compared with the IL-23R R risk allele.49 Th17 cells from Q allele carriers of IL-23R also have significantly reduced IL-23-induced IL-17A production and signal transducer and activator 3 (STAT3) phosphorylation compared with carriers of the R risk allele.50 Interestingly, the effect of the IL12B and IL23R associations is additive because individuals who are homozygous for both the IL12B and the IL23R predisposing haplotypes have an increased risk of disease (OR = 1.66).44 TRAF3-interacting protein 2 (TRAF3IP2, ACT1) harbors a coding alteration that is associated with both Ps and PsA.24,51 The alteration (p.D10N) exhibits reduced binding to TRAF6, an upstream component of the Rel/nuclear factor-kappaB (NF-κB) transcription factor signaling pathway that lies downstream of the IL-17 receptor (IL-17R).52 A major involvement of the NF-κB pathway in Ps has emerged in recent years.53 This was initially observed on the basis of upregulation of phosphorylated p65, an NF-κB subunit, in both involved and uninvolved psoriatic skin.54

22 Genetics

More recently, GWAS have also implicated the involvement of a number of genes encoding components of this pathway (discussed further in the following). The p.Q144R polymorphism of IL13 is associated with Ps where the R allele confers the risk of disease.55 The same polymorphism, but the opposite risk allele (Q), predisposes to asthma.56 However, the mechanism by which these two alleles lead to these two different diseases is not known. It is also possible that this alteration is not predisposing at all but that a second nearby alteration is causative. Janus kinase (JAK)/tyrosine kinase (TYK) proteins have been proposed as therapeutic targets for the treatment of Ps. An alteration (S684I) within the gene encoding TYK2, a member of the JAK protein family, is associated with disease.15 In Ps, JAK/TYK proteins phosphorylate and activate STAT molecules including STAT3, whose activity is increased in psoriatic lesions.15,57 TYK2 participates in both IL-23 and IL-22 signal transduction to mediate Ps-like skin inflammation and IL-22–dependent epidermal hyperplasia. TYK2(−/−) mice injected with IL-23 show significantly reduced ear skin swelling with epidermal hyperplasia and inflammatory cell infiltration compared with wild-type mice. TYK2 deficiency also reduces the production of proinflammatory cytokines and Ps-relevant antimicrobial peptides. Furthermore, a small-molecule TYK2 inhibitor significantly inhibits IL-23–induced inflammation and cytokine production in the skin.58 The CARD14 (p.W820R) polymorphism is associated with Ps.29 Following its identification, its association with disease was confirmed at genome-wide significance in both European and Asian populations.12,59 Two rare SNPs leading to amino acid alterations p.A946T and p.H848R are found in the IFN induced with helicase C domain 1/melanoma differentiation-associated 5 (IFIH1/MDA5) gene. These rare variants are associated with decreased risk of Ps.60 Rare variants in IFIH1 are also associated with protection from other autoimmune diseases such as type 1 diabetes, systemic lupus erythematosus, multiple sclerosis, and rheumatoid arthritis.61 IFIH1 encodes a cytoplasmic sensor for viral double-stranded RNAs (dsRNAs) and it shares the same domain architecture as the protein encoded by the retinoic acid inducible gene-1 (RIG-1/DDX58). Although MDA5 and RIG-1 recognize distinct groups of viral RNAs, both activate the same IFN signaling pathway through the mitochondria antiviral signaling protein/interferon beta promoter stimulator protein 1 (MAVS/IPS1). Binding to dsRNA activates the IκB kinase (IKK)-related kinases, which induces the production of type I IFN through the activation of interferon regulatory factor 3 (IRF3) in addition to the activation of NF-κB transcription factors. This leads to the production of molecules such as IL-1, IL-6, TNF, type 1 IFN, and IL-9.61 The MDA5/DDX58 gene also lies in a Ps susceptibility interval. With respect to a viral response, the RIG-1-like receptor signaling pathway is also implicated through association with the protein encoded by RNF114,26 which also lies within a GWAS interval. Although the function of RNF114 is poorly understood, it

is a paralog of RNF125, which encodes a Really Interesting New Gene (RING) finger domain E3 ligase (13). RNF125 suppresses dsRNA-induced IFN production by promoting the proteasomal degradation of RNA helicase RIG-I and MDA5 (16). RNF114 is a cytoplasmic protein, which can be upregulated by IFNs and dsRNA, and in a manner similar to RNF125 it associates with ubiquitinated proteins and has ubiquitin ligase activity.62

PATHWAYS TO PSORIASIS IDENTIFIED THROUGH GWAS Of the over 50 GWA loci identified to date (Table 4.1), a large number affect innate immunity. These include responses involving NF-κB signaling (TRAF3IP2,63 TNFAIP3, TNIP1, NF-KBIA [IKBA], REL, COMMD1,64 CARD14); differentiation of T-helper 17 cells (IL23R, IL12B, IRF4, IL23A); and antigen processing, recognition, and response (HLA-C, ERAP1, ERAP2). There are also associations with genes playing important roles in the epidermis (LCE3, GJB2).65 Gene ontology (GO) and kyoto encyclopedia of genes and genomes (KEGG) correlations also revealed significant findings with the genes encoding components of the JAK-STAT (signal transducer and sctivator) signaling pathway (IL28RA, IL23R, IL13, IL12B, IL23A, STAT2, SOCS1, STAT3, TYK2) and defense response to Gram-negative bacteria or viruses/ RIG-1-like receptor signaling (IL-23R, IL-12B, IL-23A, NOS2, IFIH1, DDX58, NF-KBIA, IL-23R).

ALTERATIONS OF COMPONENTS OF THE EPIDERMAL BARRIER IN PSORIASIS Genes of the epidermal differentiation complex Although the Ps associations provide insights into immune cell activation, they do not explain why Ps affects the skin. Hence, the limited number of associations with variants within or near genes encoding epidermal components is important in attempting to explain the skin involvement. Linkage of Ps to a region within the epidermal differentiation complex (EDC) was initially described in Italian families.66 This locus was termed PSORS4. Explanation for this linkage observation was provided by the identification of a common deletion involving the late cornified envelope 3B (LCE3B) and LCE3C genes that were associated with Ps. LCE genes reside within the EDC on chromosome 1q21.17 This locus is comprised of tandemly arrayed gene families encoding proteins involved in skin cell differentiation. LCE genes encode stratum corneum proteins and encompass six different groups. LCE2 protein is restricted to the uppermost granular layer and the stratum corneum. Members of groups 1, 2, 5, and 6 are involved in normal skin barrier function.

Alterations of components of the epidermal barrier in psoriasis  23

Genes  of  the  LCE3 group are upregulated in involved ­psoriatic skin and are induced after superficial injury of normal skin. Conversely, the expression of members of other LCE groups is downregulated under these conditions.67 Thus, it is possible that the deletion of LCE3B and LCEC is sufficient to increase Ps risk by disrupting wound healing. However, an epidermal-specific enhancer has been identified in this deleted region68 and it is possible that deletion of such a critical regulatory element for e­ pidermal regeneration is the causative risk factor.

CARD14 CARD14 encodes a 1004 amino acid scaffold protein involved in NF-κB signaling.69 Unique gain-of-­function mutations segregate with Ps in rare large multiply affected families8 and account for PSORS2. The mutations c.349G>A (p.Gly117Ser) (in a family of European descent) and c.349 + 5G>A (in a Taiwanese family) are rare in the population (present at a frequency of 0.0005 or less). These mutations alter splicing between CARD14 exons 3 and 4, leading to insertion of a novel peptide of 22 amino acids into CARD14. CARD14 activates NF-κB,69 and the disease causing mutations have gain-of-function effects, leading to the upregulation of the NF-κB pathway and the subsequent upregulation of many NF-κB targets involved in proliferation and inflammation. These genes

Epidermis

CARD14 IL36γ IL36RA

TNF

CXCL2/ MIP-2 CCL5 Th1

lL22

Neutrophil

Th1

lL23

Th22

CARD14 IL8 CXCL1

Th17

IL17C

M

T

T cell

M

Monocyte Keratinocyte

CARD14

CARD14 IL8

IL36γ

M

Dermis

lL12

CCL20 lL8 CARD14 lL23

include ­chemokine (C-C motif) ligand 20 (CCL20) and IL-8. CARD14 is localized mainly in the basal and suprabasal layers of healthy skin epidermis, whereas in lesional psoriatic skin, it is reduced in the basal layer and more diffusely upregulated in the suprabasal layers of the epidermis.8 Although CARD14 is expressed mainly in epidermal keratinocytes, it is also expressed in dermal endothelial cells and endothelial cells of other tissues such as the aorta.70 This may provide an explanation for the systemic ­inflammation and cardiovascular comorbidities associated with Ps. It is hypothesized that, after a triggering event that can include epidermal injury, or infection, rare gainof-function mutations in CARD14 initiate a signaling cascade in endothelial cells or keratinocytes. This facilitates recruitment, trafficking, and differentiation of immune cells. Cytokines such as IL-17 and IL-22 produced by these differentiated cells could then set off the vicious cycle of proliferation and inflammation in both cell types, which is the hallmark of this disease.8 Activation of CARD14 in the endothelial cells of the capillaries at entheses could also set off a similar inflammatory/proliferative cycle in the joints, leading to psoriatic arthritis. This is supported by the observation that a switch to a vascular phenotype is found at the enthesis where inflammation occurs.71 This hypothesis, incorporating inflammatory and proliferative events in the endothelial cells and keratinocytes of the skin, is diagrammed simply in Figure 4.1.

Macrophage

IL36RA

CCL20 CXCL10 CCL2 CARD14 M CCL4 CXCL1 lL8

Dendritic cell

Th2

Endothelial cell

CXCL10 CCL5 T

Figure 4.1  Hypothesis for the vicious cycle of psoriasis (Ps) in the presence of caspase recruitment domain family member 14 (CARD14) mutations. Following an assault upon either keratinocytes or endothelial cells such as infection or wounding, individuals with Ps have enhanced or sustained activation of inflammatory and proliferative signaling pathways in these cell types. This leads to the production of cytokines and chemokines, which in turn leads to the recruitment and differentiation of inflammatory cells. Interleukin (IL)-8, IL-36 cytokines, and C-X-C Motif Chemokine Ligand 1 (CXCL1) produced as a result of this altered signaling lead to the recruitment of neutrophils. IL-36Ra, mutated in some forms of pustular Ps, is the natural antagonist for this effect. CXCL10 and chemokine (C–C motif) ligand 5 (CCL5) are involved in recruitment and adhesion of T cells. CXCL10 could recruit macrophages. CCL2, CCL4, and CCL20 could play a role in the differentiation of myeloid dendritic cells. These differentiated cells produce IL-23, which drives the production of T helper (Th)17 and Th22 cells. Cytokines produced by these T cells such as IL-17C and IL-22 help to perpetuate the inflammatory signaling pathways by targeting keratinocytes, endothelial cells, and other cell types still further, leading to the vicious cycle associated with Ps.

24 Genetics

It is worth noting that the initial trigger could be at the level of the epidermis (e.g., wounding, or infection, first activating the keratinocyte) or be systemic (e.g., infection or drugs, first activating the endothelial cell). Ps can occur de novo in patients with no family history. In the same study where PSORS2 was described, a sporadic mutation in the coiled-coil domain of CARD14 leading to a p.E138A alteration triggered generalized ­pustular Ps.8 These type of de novo events could explain some severe cases of disease where there is no family history of Ps. The CARD14 alterations leading to Ps enhance NF-κB activation to different degrees.8,29 The p.Glu138Ala and p.Gly117Ser activate NF-κB eightfold and four- to fivefold, respectively, compared with wild-type CARD14sh.8 A c.526G>C (p.Asp176His) variant present at a frequency of only 0.0006 in the European population activates NF-κB to 2.8-fold levels compared with wild-type CARD1429 and has emerged as a risk factor for generalized pustular psoriasis (GPP) in Japan where it is found in 21% of GPP cases with Ps compared with controls where it is present at a frequency of 3%.72 This allele has also been detected

in some European cases with palmoplantar pustular psoriasis (PPP).73 Mutations in CARD14 can also lead to familial rubra pilaris (PRP),74 a rare inflammatory papulosquamous disorder often misdiagnosed as Ps. CARD14 mutations are also seen in ±12.5% of patients with sporadic PRP.75 As with Ps, these mutations frequently lie in exons 3 or 4 and affect the coiled-coil domain of CARD14. Recent studies have confirmed that these PRP mutations in CARD14 also lead to enhanced NF-κB activation.75 Variants in CARD14 identified to date that are likely to be disease causing, their locations within the CARD14 protein, and their concomitant effect on NF-κB activation are shown in Figure 4.2. It can be seen that some rare variants actually lead to a decrease in NF-κB activation. Whether these effects also lead to Ps remains to be determined. CARD14 is represented by several isoforms.8 ­Full-length CARD14 (CARD14fl, also known as CARD14 isoform 1) encodes both an N-terminal CARD domain necessary for activation of NF-κB and a C-terminal tripartite ­ membrane-associated guanylate kinase (MAGUK) domain (PDZ/SH3/GUK) that is involved in relaying

PRP: p.Glu138Lys^ PRP: p.Glu138del^

PRP: c.349+1G>A

GPP: p.Glu138Ala*

PV: c.349+5G>A*

PV: p.Glu142Lys* PV: p.Glu142Gly*

PV/PA: p.Gly117Ser*/**

PV: p.Leu150Arg* PV: p.Arg151Trp**

PV/GPP: p.Arg69Gln

p.Arg151Gln**

PV/PA: p.Arg69Trp**

PRP: p.Leu156Pro^

PV: p.Arg38Cys* N

PV: p.His171Asn*# CARD

Coiled-coil

PV; PPP; GPP with PV (Japanese); GPP (Chinese); p.Asp176His PV: p.Arg179His* PV; PPP: p.Glu197Lys**>

PDZ

PV; GPP; PPP: p.Ser602Leu** SH3

PV: c.1258A>G**

PRP: p.Leu228Arg+

GUK

C

Common: rs11652075 p.Arg820Trp

PV: p.Ala216Thr** PV; PPP: p.Ser200Asn*>

Figure 4.2  Locations of likely disease-causing rare variants in the CARD14 protein and their effect on nuclear factor kappa B (NF-κB) activation. Protein domains of full-length CARD14 as described in the text are shown. Variants leading to greater than threefold upregulation of NF-κB activation are shown in red and those leading to 1.4- to 3-fold levels of NF-κB activation are shown in orange. The variants leading to <0.6-fold levels are shown in green. The p.H171N founder mutation identified in Newfoundland requires stimulation with tumor necrosis factor (TNF)-alpha to achieve pathogenic NF-κB levels. 29 Those with unknown or negligible effect on NF-κB activation are boxed in black. Variants are described by Jordan et al.*,29 Bensaid et al.**,76 Mossner>,73 Li et al.+,75 and Fuchs Telem et al.,^74 Ps-related disease associated with the variant is also indicated before the amino acid change: GPP, generalized pustular psoriasis; PA, psoriatic arthritis; PPP, palmoplantar pustular psoriasis; PRP, pityriasis rubra pilaris; PV, psoriasis vulgaris. The p.D176H alteration is associated with GPP with PV in the Japanese population,72 with GPP in the Chinese population,77 and with PPP in Germany.73 p.S200N is weakly associated with PV29 and PPP69 and leads to ±0.8-fold downregulation of NF-κB signaling. 29

Generalized pustular psoriasis  25

external signals to the inside of the cell. This is the only isoform that harbors the p.R820W polymorphism. A shorter isoform, CARD14sh, encodes the CARD domain but not the MAGUK domain. CARD14sh is the most abundant isoform in all tissues where it is expressed, including skin. Another isoform, CARD14cl, lacks the CARD and the tripartite domain and is unable to activate NF-κB.8,78CARD14cl has a very restricted pattern of expression, which is confined to the epidermis, thymus, and placenta8 and possibly lung and cervix.78 CARD14induced activation of NF-κB is dependent on TRAF278 and might also require TRAF3 or TRAF6. Moreover, CARD14 may fit into other known Ps associated pathways such as IL-17/Act1. Figure 4.3 provides possible signaling pathways involving CARD14 that are operating in the keratinocyte and endothelial cell in Ps. Genes in regions identified through GWAs are highlighted.

GENERALIZED PUSTULAR PSORIASIS Loss-of-function amino acid substitutions in IL36RN are found in some cases of pustular Ps and behave as recessive traits.79,80 The mutated protein leads to an increased production of proinflammatory cytokines, such as IL-8, from keratinocytes. IL36RN mutations are also found in some patients with severe acute generalized exanthematous pustulosis, palmar–plantar pustulosis, and acrodermatitis continua of hallopeau.81 The protein encoded by IL36RN directly opposes the activity of IL-36γ and also intersects with the NF-κB pathway. As described earlier, a sporadic mutation in the coiled-coil domain of CARD14, leading to a p.E138A alteration, triggered generalized pustular Ps.8 Determining whether and where activation pathways for CARD14 and IL-36RN intersect requires further evaluation.

Figure 4.3  CARD14 signaling pathway. The known components of the CARD14 signaling pathway that are likely to be operating in the keratinocyte and endothelial cell are shown. Steps that have been confirmed to be involved in CARD14 signaling are indicated with solid lines. Signaling steps that might be involved but have not been confirmed are indicated with dotted lines. Components of the pathways encoded by genes in Ps-associated loci are shown in red. CARD14 is known to bind B-Cell CLL/Lymphoma 10 gene (BCL10) and is likely to bind MALT1 Paracaspase as part of the CARD-BCL10-MALT1 (CBM) complex, but other binding partners have not yet been identified. CARD14 is also known to activate canonical signaling of NF-κB, but it might also be involved in noncanonical signaling. Possible pathways leading to IFN and activator protein-1 (AP-1) signaling are also shown. The following abbreviations not described elsewhere in the text are used: TLR, Toll-like receptor; TNFR, TNF-α receptor; IL-1R, interleukin-1 receptor; IL-17R, interleukin-17 receptor; IL-22R, interleukin-22 receptor; IL-10R2, interleukin 10 receptor 2; ITCH, itchy E3 ubiquitin protein ligase; RNF11, ring finger protein 11; NEMO, NF-κB essential modifier; IKKβ, inhibitor of nuclear factor kappa-B kinase subunit beta; IKKα, inhibitor of nuclear factor kappa-B kinase subunit alpha; IKBβ, inhibitor of NF-kappaB beta; XIAP1, X-linked inhibitor of apoptosis; RIPK1, receptor-interacting serine/threonine-protein kinase 1; IKBalpha, inhibitor of NF-kappaBalpha; RELA, nuclear factor NF-kappa-B p65 subunit; REL (c-rel), v-rel reticuloendotheliosis viral oncogene homolog; p50 (derived from nuclear factor of kappa light polypeptide gene enhancer in B-cells 1 [NFKB1]); p52 (NFKB2 derived); MAPK, mitogen-activated kinase; AP-1, activator protein 1; IFN, Interferon; Ub, ubiquitin; P, phosphate; GCPR, G-coupled protein receptor; CYLD, cylindromatosis (turban tumor syndrome); TAX1BP1, Tax1 (human T-cell leukemia virus type I) binding protein 1.

26 Genetics

RARE VARIANTS LEADING TO PSORIASIS GWAS have been disappointing in that they explain little of the genetic contribution to Ps and usually less than 20%, although as described earlier, they can provide essential insights into disease pathogenesis. Nevertheless, the identification of the cause of the remaining genetic heritability is axiomatic if genetic findings are to be translated into personalized medicine. To try to identify this, researchers have also looked for rare disease-causing coding variants that could contribute to disease heritability. In a large study from China, sequencing of 1326 candidate genes revealed two independent missense single nucleotide variants (SNVs) in IL23R and GJB2 of low frequency and novel common missense SNVs in LCE3D, ERAP1, and ZNF816A. Rare missense SNVs in FUT2 and TARBP1 were also observed with suggestive evidence of association. However, overall the conclusion from this study was that coding variants in the 1326 genes selected for follow-up sequencing contributed only a limited fraction of the overall genetic risk for Ps.83

GENETIC CONTRIBUTION TO DISEASE SEVERITY AND AGE AT ONSET The age of onset of Ps has been used for decades as a descriptor to define two subpopulations of psoriatic patients. Patients who are HLA-Cw6 positive in general have a lower age at onset with the guttate-type onset of Ps mostly being confined to this group. The HLA-Cw6–­ positive patients have more extensive plaques on their arms, legs, and trunk, more severe disease, higher incidence of Koebner’s phenomenon, reported more often that their Ps became worse during or after throat infections, and more often have a favorable response to sunlight.83 In contrast, dystrophic nail changes are more common in the HLA-Cw6–negative patients who are also more likely to have psoriatic arthritis. However, this is not clear-cut because there are a substantial number of patients in the earlier category without HLA-Cw6 alleles, and a substantial number in the older category with the HLA-Cw6 alleles. It is worth noting that in the case of the families harboring CARD14 mutations, disease severity can range from mild to severe.84 Approximately 30% of patients with the CARD14 p.G117S alteration also develop psoriatic arthritis. However, in patients with this mutation, and even within the same family, disease severity and age at onset can vary considerably (infancy to 83 years).6,84 Hence, other factors, including genetic modifiers, are likely to also be at play in determining age at onset and severity of Ps. These could include the common p.CARD14 R820W predisposing variant, the HLA class 1 variant, or other potential modifiers. With respect to the different CARD14 alterations, severity appears to correlate with the level at which they lead to activation of the NF-κB signaling pathway, with the p.E138A alteration found in the sporadic GPP

patient leading to the highest levels of NF-κB activation, the greatest production of chemokines such as IL-8, and the most severe disease. Moreover, response to treatment seemed to be dictated by the level to which the mutation (or possibly combination of genetic risk factors) activates NF-κB. For example, patients with a p.G117S mutation where NF-κB is upregulated four- to fivefold respond to conventional Ps therapies including methotrexate and cyclosporine, but the patient with the p.E138A mutation which upregulates NF-κB to the same degree as TNFα stimulation does has the most severe disease and did not respond to TNF inhibitors. However, this patient did respond to the anti-p40 antibody (ustekinumab) that blocks IL-12 and IL-23.85 The risk allele of TNFAIP3 is also associated with the clinical severity of Ps86 and response to TNF blockers in both Europeans and Asians.86,87 With respect to response to other Ps therapies, a more rapid response to ustekinumab was achieved in HLA-Cw6–positive than negative patients.88 Moreover, a case–case study comparing severe and mild Ps phenotypes, controlling for age at disease onset and gender, has revealed significant differences between the two groups for SNPs in IL-23R, NF-KB1, IL-21, IL-12B, NF-KBIL1, and IL-23A. Although in this study the HLA class 1 association was similar in the mild and severe disease cohorts, the addition of IL-23A, IL-23R, IL-12B, NF-KB1, or TNIP1 was restricted to the severe cohort.89 No protective gene was identified in the mild cohort, leading to the suggestion that current GWAS screens have primarily identified Ps variants associated with a more severe phenotype.

CONCLUSION Genetic studies have identified a substantial number of genetic risk factor for Ps, but each of these contributes a relatively small genetic risk to the eventual development of the disease. It is hypothesized that susceptibility to inflammatory diseases such as Ps is due to a lowering of the threshold required for activation of inflammatory and proliferative pathways in the skin. Rare variants such as those in CARD14 can operate independently to affect this threshold, or an accumulation of common variants could conceivably do the same thing. In the next few years, additional Ps risk factors will be identified through larger GWAS. At the same time, the contributing variants in the regions of association will be identified, providing further insights into Ps ­pathogenesis. However, GWAS is unlikely to explain all of disease heritability. Some of this could come through the identification of less common variants, or gene–gene i­ nteractions. To identify less common variants, one can sequence large cohorts of cases or controls, or screen for association with rare variants that have been already been identified. Population-specific exome arrays harbor a subset of rare variants existing in the population that have been identified through genome sequencing of ±1000 i­ndividuals. A  study from China, where DNA

References 27

samples from over 40,000 psoriatics were interrogated with an Asian exome array, revealed 16 rare variants in 15 new genes/loci associated with Ps. These variants collectively accounted for 1.9% of the Ps heritability.90 Further analyses of European cohorts interrogated with the European exome chip are currently ongoing through the International Psoriasis Council and should reveal additional rare variants contributing to Ps in that population. It is worth noting, however, that even in the case of rare variants it is only possible to obtain statistical evidence for association with disease if single genes harbor statistically more variants in cases than controls, or if rare variants are sufficiently common to be observed in a sufficient number of cases versus controls so that statistical evidence for association with disease is obtained. It is not clear at present what proportion of heritability will be explained by these types of additional genetic data. An investigation into genetic interactions could also be fruitful if the problems associated with multiple testing could be overcome. Findings from complete genomic sequencing of large numbers of cases will also help to illuminate additional genetic causes of this disease in concert with epigenetic analyses. Some variants will also help to stratify patients and be associated with treatment response, eventually facilitating personalized treatment of Ps in all of its forms.

ACKNOWLEDGMENTS This work was supported in part by NIH grant AR050266. Drs. Ashleigh Howes and Michael Lovett provided critical comments on this chapter.

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51. Huffmeier U, Uebe S, Ekici AB, et al. Common variants at TRAF3IP2 are associated with susceptibility to psoriatic arthritis and psoriasis. Nat Genet. 2010 Nov;42(11):996–999. 52. Boele J, Persson H, Shin JW, et al. PAPD5-mediated 3’ adenylation and subsequent degradation of miR-21 is disrupted in proliferative disease. Proc Natl Acad Sci U S A. 2014 Aug 5;111(31):11467–11472. 53. Goldminz AM, Au SC, Kim N, Gottlieb AB, Lizzul PF. NF-kappaB: An essential transcription factor in psoriasis. J Dermatol Sci. 2013 Feb;69(2):89–94. 54. Lizzul PF, Aphale A, Malaviya R, et al. Differential expression of phosphorylated NF-kappaB/RelA in normal and psoriatic epidermis and downregulation of NF-kappaB in response to treatment with etanercept. J Invest Dermatol. 2005 Jun;124(6):1275–1283. 55. Chang M, Li Y, Yan C, et al. Variants in the 5q31 cytokine gene cluster are associated with psoriasis. Genes Immun. 2008 Mar;9(2):176–181. 56. Li X, Ampleford EJ, Howard TD, et al. Genomewide association studies of asthma indicate opposite immunopathogenesis direction from autoimmune diseases. J Allergy Clin Immunol. 2012 Oct;130(4):861–868.e7. 57. Andres RM, Hald A, Johansen C, Kragballe K, Iversen L. Studies of Jak/STAT3 expression and signalling in psoriasis identifies STAT3-Ser727 phosphorylation as a modulator of transcriptional activity. Exp Dermatol. 2013 May;22(5):323–328. 58. Ishizaki M, Muromoto R, Akimoto T, et al. Tyk2 is a therapeutic target for psoriasis-like skin inflammation. Int Immunol. 2014 May;26(5):257–267. 59. Cheng H, Li Y, Zuo XB, et al. Identification of a missense variant in LNPEP that confers psoriasis risk. JInvest Dermatol. 2014 Feb;134(2):359–365. 60. Li Y, Liao W, Cargill M, et al. Carriers of rare missense variants in IFIH1 are protected from psoriasis. J Invest Dermatol. 2010 Dec;130(12):2768–2772. 61. Del Toro Duany Y, Wu B, Hur S. MDA5-filament, dynamics and disease. Curr Opin Virol. 2015 Feb 9;12C:20–25. 62. Bijlmakers MJ, Kanneganti SK, Barker JN, Trembath RC, Capon F. Functional analysis of the RNF114 psoriasis susceptibility gene implicates innate immune responses to double-stranded RNA in disease pathogenesis. Hum Mol Genet. 2011 Aug 15;20(16):3129–3137. 63. Sonder SU, Saret S, Tang W, Sturdevant DE, Porcella SF, Siebenlist U. IL-17-induced NF-kappaB ­activation via CIKS/Act1: Physiologic significance and signaling mechanisms. J Biol Chem. 2011 Apr 15;286(15):12881–12890. 64. Bartuzi P, Hofker MH, van de Sluis B. Tuning NF-kappaB activity: A touch of COMMD proteins. Biochim Biophys Acta. 2013 Dec;1832(12):2315–2321. 65. Puig L, Julia A, Marsal S. The pathogenesis and genetics of psoriasis. Actas Dermosifiliogr. 2014 Jul–Aug;105(6):535–545.

66. Capon F, Novelli G, Semprini S, et al. Searching for psoriasis susceptibility genes in Italy: Genome scan and evidence for a new locus on chromosome 1. J Invest Dermatol. 1999 Jan;112(1):32–35. 67. Bergboer JG, Tjabringa GS, Kamsteeg M, et al. Psoriasis risk genes of the late cornified envelope-3 group are distinctly expressed compared with genes of other LCE groups. Am J Pathol. 2011 Apr;178(4):1470–1477. 68. de Guzman Strong C, Conlan S, Deming CB, Cheng J, Sears KE, Segre JA. A milieu of regulatory elements in the epidermal differentiation complex syntenic block: Implications for atopic dermatitis and psoriasis. Hum Mol Genet. 2010 Apr 15;19(8):1453–1460. 69. Bertin J, Wang L, Guo Y, et al. CARD11 and CARD14 are novel caspase recruitment domain (CARD)/membrane-associated guanylate kinase (MAGUK) family members that interact with BCL10 and activate NF-kappa B. J Biol Chem. 2001 Apr 13;276(15):11877–11882. 70. Harden JL, Lewis SM, Pierson KC, et al. CARD14 expression in dermal endothelial cells in psoriasis. PLoS One. 2014 Nov 4;9(11):e111255. 71. Aydin SZ, Ash ZR, Tinazzi I, et al. The link between enthesitis and arthritis in psoriatic arthritis: A switch to a vascular phenotype at insertions may play a role in arthritis development. Ann Rheum Dis. 2013 Jun;72(6):992–995. 72. Sugiura K, Muto M, Akiyama M. CARD14 c.526G>C (p.Asp176His) is a significant risk factor for generalized pustular psoriasis with psoriasis vulgaris in the Japanese cohort. J Invest Dermatol. 2014 Jun;134(6):1755–1757. 73. Mossner R, Frambach Y, Wilsmann-Theis D, et  al. Palmoplantar pustular psoriasis is associated with missense variants in CARD14, but not with loss-offunction mutations in IL36RN in European patients. J Invest Dermatol. 2015 May 19;135(10):2538–2541. 74. Fuchs-Telem D, Sarig O, van Steensel MA, et al. Familial pityriasis rubra pilaris is caused by mutations in CARD14. Am J Hum Genet. 2012 Jul 13;91(1):163–170. 75. Li Q, Jin Chung H, Ross N, et al. Analysis of CARD14 Polymorphisms in pityriasis rubra pilaris: Activation of NF-kappaB. J Invest Dermatol. 2015 Mar 3;135(7):1905–1908. 76. Ammar M, Jordan CT, Cao L, et al. CARD14 alterations in Tunisian psoriasis patients and further characterization in European cohorts. Br J Dermatol. 2016 Feb;174(2):330–337. 77. Berki DM, Liu L, Choon SE, et al. Activating CARD14 mutations are associated with generalized pustular psoriasis but rarely account for familial recurrence in psoriasis vulgaris. J Invest Dermatol. 2015 Jul 23;135(12):2964–2970. 78. Scudiero I, Zotti T, Ferravante A, Vessichelli M, Vito P, Stilo R. Alternative splicing of CARMA2/ CARD14 transcripts generates protein variants with

30 Genetics

differential effect on NF-kappaB activation and endoplasmic reticulum stress-induced cell death. J Cell Physiol. 2011 Dec;226(12):3121–3131. 79. Marrakchi S, Guigue P, Renshaw BR, et al. Interleukin-36-receptor antagonist deficiency and generalized pustular psoriasis. N Engl J Med. 2011 Aug 18;365(7):620–628. 80. Onoufriadis A, Simpson MA, Pink AE, et al. Mutations in IL36RN/IL1F5 are associated with the severe episodic inflammatory skin disease known as generalized pustular psoriasis. Am J Hum Genet. 2011 Sep 9;89(3):432–437. 81. Sugiura K. The genetic background of generalized pustular psoriasis: IL36RN mutations and CARD14 gain-of-function variants. J Dermatol Sci. 2014 Jun;74(3):187–192. 82. Tang H, Jin X, Li Y, et al. A large-scale screen for coding variants predisposing to psoriasis. Nat Genet. 2014 Jan;46(1):45–50. 83. Gudjonsson JE, Karason A, Antonsdottir AA, et al. HLA-Cw6-positive and HLA-Cw6-negative patients with psoriasis vulgaris have distinct clinical features. J Invest Dermatol. 2002 Feb;118(2):362–365. 84. Bhalerao J, Bowcock AM. The genetics of psoriasis: A complex disorder of the skin and immune system. Hum Mol Genet. 1998;7(10):1537–1545.

85. Almeida de Jesus A, Goldbach-Mansky R. Monogenic autoinflammatory diseases: Concept and clinical manifestations. Clin Immunol. 2013 Jun;147(3):155–174. 86. Zhang C, Zhu KJ, Liu H, et al. The TNFAIP3 polymorphism rs610604 both associates with the risk of psoriasis vulgaris and affects the clinical severity. Clin Exp Dermatol. 2014 Dec 12; 40(4):426–430. 87. Tejasvi T, Stuart PE, Chandran V, et al. TNFAIP3 gene polymorphisms are associated with response to TNF blockade in psoriasis. J Invest Dermatol. 2012 Mar;132(3 Pt 1):593–600. 88. Talamonti M, Botti E, Galluzzo M, et al. Pharmacogenetics of psoriasis: HLA-Cw6 but not LCE3B/3C deletion nor TNFAIP3 polymorphism predisposes to clinical response to interleukin 12/23 blocker ustekinumab. Br J Dermatol. 2013 Aug;169(2):458–463. 89. Nikamo P, Lysell J, Stahle M. Association with genetic variants in the IL-23 and NF-kappaB pathways discriminates between mild and severe psoriasis skin disease. J Invest Dermatol. 2015 Mar 19;135(8):1969–1976. 90. Zuo X, Sun L, Yin X, et al. Whole-exome SNP array identifies 15 new susceptibility loci for psoriasis. Nat Commun. 2015 Apr 9;6:6793.

5 Immunology JAEHWAN KIM and JAMES G. KRUEGER INTRODUCTION Psoriasis is a chronic inflammatory skin disease ­mediated by the cells and molecules of both the innate and ­ adaptive immune systems. The innate immune response, represented by the activity of neutrophils, macrophages, natural killer (NK) T cells, and plasmacytoid dendritic cells (pDCs), recruits T cells to the skin, which then play key roles in sustaining psoriasis disease activity.1 Interleukin (IL)-17–producing T helper (Th)17 cells, Th1 cells, and Th22 cells, which are activated by IL-23 and IL-12 released from inflammatory myeloid DCs, produce psoriatic cytokines IL-17, interferon (IFN)-γ, tumor necrosis factor (TNF)-α, and IL-22. 2,3 These cytokines mediate effects on keratinocytes to amplify psoriatic inflammation. In many ways, the immune pathways that become activated in psoriasis represent amplifications of background immune circuits that exist as constitutive or inducible pathways in normal human skin. 2

T CELLS IN PSORIASIS Integral role of T cells in psoriasis pathogenesis The evidence for the integral role of T cells in psoriasis has come from extensive translational research involving human subjects. The general hypothesis that psoriasis is a disease mediated by activated T cells was first confirmed by clinical trials of DAB389 IL-2 (denileukin diftitox or Ontak®) in 1995.4 This lymphocyte-selective fusion protein, consisting of IL-2 and fragments of diphtheria toxin, selectively blocked activated lymphocytes without having effects on keratinocytes. Treatment with two doses of DAB389 IL-2 resulted in clinical and histological resolution of psoriasis in 8 of 10 patients.4 Since then, a series of immune-targeted drugs have been tested in psoriasis patients, solidifying the major role of activated T cells in psoriasis pathogenesis.5

The hypothesis that only specific subsets of T cells could play critical roles in psoriasis was also confirmed by translational approaches. When psoriasis patients were treated with Cytotoxic T-Lymphocyte Associated Protein 4 (CTLA-4-Ig) (abatacept or Orencia®), which blocks B7-mediated costimulation of T cells, improvements in psoriasis correlated with a decrease of T-cell subsets from diseased skin regions. Subsequently, multiple biologics targeting primarily the T-cell activation pathway have been Food and Drug Administration (FDA)-approved therapeutics for psoriasis, and the roles of different T-cell subsets in psoriasis, including Th1 (IFN-γ), Th17 (IL-17), and Th22 (IL-22), have been dissected through the testing of a range of cytokine antagonists.6

T cells in normal skin Healthy skin contains abundant resident T cells and the capacity to recruit additional circulating T cells. Skinhoming T cells are cutaneous lymphocyte antigen (CLA)+ T cells, which bind to dermal venules of the skin through the interaction of CLA on the T cells and E-selectin on  the endothelial cells.7 Approximately 10% of T cells in the peripheral circulation of adults become differentiated for skin homing immunity through expression of CLA.2 Besides those CLA+ recirculating T cells, normal human skin also contains CLA+ noncirculating resident memory T cells that mediate protective immunity in the skin.2,8–10

T cells in psoriatic lesion Psoriatic lesions contain increased number of T-cell subsets, which discretely produce IFN-γ (Th1), IL-17 (Th17), and IL-22 (Th22).2,11 Th1, Th17, and Th22 cells are included in both CD4+ and CD8+ T-cell populations. Also, both αβ T cells and γδ T cells are increased in numbers and can produce IL-17 in psoriatic skin.12 Innate lymphoid cells, immune cells that lack a specific antigen receptor, can

31

32 Immunology

produce an array of effector cytokines, and are another potential source of IL-17 in psoriasis.13,14

Regulatory T cells Regulatory T cells (Tregs) are a heterogeneous group of cells that maintain antigen-specific self-tolerance and are one immune mechanism to prevent tissue damage due to inflammation.2 Tregs use diverse pathways to maintain immune tolerance, including release of inhibitory cytokines, induction of apoptosis, and inhibition of IL-2 secretion.15 Dysregulation of T-cell expansion mediated by downregulation of Tregs could also be an important pathway in the immunopathogenesis of psoriasis. Previous studies have found that suppressor activity of CD4+ CD25high Tregs was deficient in the skin and blood of psoriasis patients, associated with an accelerated proliferation of CD4+ responder T cells.16 Also, the CD4+ CD25+ FoxP3+ Treg versus activated effector T-cell ratio in psoriatic skin was considerably lower than the ratio in normal human skin. There have been conflicting reports, however, describing a similar frequency of FoxP3+ T cells in normal and psoriatic skin, and a positive correlation between disease severity and FoxP3+ Tregs in both skin and blood.17,18 Further studies are needed to elucidate the function of skin-derived Tregs and their contribution to psoriasis.

DENDRITIC CELLS INTERPLAYING WITH T CELLS Dendritic cells (DCs) may be central pathogenic players in psoriasis, both by activating T cells and by producing amplifying cytokines and chemokines during inflammation.19 In the skin, the main DC populations include dermal DCs (myeloid DCs and pDCs) and epidermal DCs (Langerhans cells).

Dermal myeloid dendritic cells The α x integrin CD11c has been found to be the specific marker of myeloid DCs and a panel of blood dendritic cell antigen (BDCA) antibodies was developed to stratify human myeloid DCs, as BDCA-3 (CD141) and BDCA-1 (CD1c), identifying distinct circulating myeloid DC subsets.20,21 The major subpopulation of myeloid DCs consists of BDCA-1+ cells in healthy skin, and BDCA-1 expression is used to distinguish two distinct populations of dermal myeloid DCs: BDCA-1+ “resident” DCs and BDCA1- “inflammatory” DCs.22 Although there is a 30-fold increase in CD11c+ myeloid DCs in the dermis of psoriatic skin lesions compared with uninvolved psoriatic or normal skin, this increase is in the BDCA-1- inflammatory DCs, not the BDCA-1+ resident DCs.3,23 Furthermore,

effective treatment of psoriasis is correlated with decreased ­numbers of BDCA-1- inflammatory myeloid DCs in psoriatic lesions.24 Psoriatic BDCA-1+ DCs express markers of DC maturity, such as DC-lysosomal-associated membrane protein (DC-LAMP/CD208) and CD205 (DEC-205), in contrast to BDCA-1− DCs, which show increased expression of CD209 (DC-SIGN).2 BDCA-3+ DCs, the minor CD11c+ DC subset in healthy skin, are suggested to have a role in acute response to injury, because they are increased twofold after exposure to acute narrow-band ultraviolet B (NB-UVB) radiation.25

Plasmacytoid dendritic cells pDCs are a rare cell population characterized by a plasma cell-like morphology and a unique surface phenotype.26,27 In contrast to myeloid DCs, pDCs can mount rapid and robust type 1-IFN responses to viral and other microbial infections. They normally do not respond to self-DNA, but pDCs can sense and respond to self-DNA in psoriasis and other autoimmune diseases.26,28 As a stimulating factor that triggers pDCs, LL-37, an antimicrobial peptide in psoriatic skin, converts otherwise nonstimulatory self-DNA into a potent trigger of pDCs to produce IFN-α.29 When stimulated, pDCs induce an IFN-α–dependent maturation of bystander myeloid DCs with the ability to drive Th1 responses.30 It has been shown that pDCs infiltrate psoriatic skin and their activation to produce IFN-α is a key upstream event that initiates the activation of T cells.27 In a xenograft model of psoriasis, inhibiting the ability of pDCs to produce IFN-α prevented the T-cell–dependent development of psoriasis.27

Langerhans cells Langerhans cells are a type of immature conventional DC that reside in the epidermis.7 They are actively phagocytic and contain large granules known as Birbeck granules. CD1a and langerin (CD207) are used as specific markers to distinguish Langerhans cells from other DC subsets. The main role of Langerhans cells is to take up and process antigens and migrate to local skin-draining lymph nodes where they present to antigen-specific T cells.2 However, the role of Langerhans cells in psoriasis immunopathogenesis is still unclear.3 Recently, attention has focused on the potential importance of Langerhans cells in uninvolved skin sites of psoriasis patients, and it has been demonstrated that Langerhans cell migration is impaired in early onset psoriasis (onset before 40 years of age).31,32 Also, the treatment with TNF-α inhibitors (adalimumab, etanercept) and anti-IL-12p40 antibody (ustekinumab) significantly restored epidermal Langerhans cell migration in uninvolved skin.33 Although the influence of impaired Langerhans cell mobilization on the pathogenesis of psoriasis is uncertain, the loss of Langerhans cell motility may have an impact on the ability of these cells to sense the

Psoriatic cytokines  33

local antigenic microenvironment and regulate cutaneous immune responses.

INNATE IMMUNE CELLS IN PSORIASIS Neutrophils As a first line of defense against an immune attack, neutrophils have many intracellular antimicrobial peptides. In psoriatic skin, the presence of neutrophils in the epidermis and the formation of Munro,s microabscesses are histological hallmarks of psoriasis. There is also an abundant expression of neutrophil chemokines, such as CXCL1, CXCL2, and CXCL8/IL-8, in psoriatic skin. However, neutrophils are inconsistently found in chronic psoriatic lesions and are absent from some mouse models of psoriasis.2 Neutrophils have been also suggested as a source of IL-17, potentially having another role in psoriasis pathophysiology.34 It has been suggested that a ­neutrophil– keratinocyte­cross talk is an early target of IL-17 inhibitory treatment for psoriasis.35 However, it is unclear whether cutaneous neutrophils in psoriatic skin synthesize new IL-17 or if neutrophils containing preformed IL-17 are entering the skin.

Macrophages Macrophages are phagocytic cells that participate in ­tissue homeostasis, the clearance of erythrocytes, and the removal of cellular debris generated during tissue remodeling.36 There is a threefold increase in macrophages in psoriatic lesional skin with a return to nonlesional skin levels after effective treatment.37 Macrophages have long been recognized as antigen-presenting cells, capable of activating memory T cells during stimulation of the adaptive arm of the immune response. However, they are unable to polarize allogeneic T cells to produce IL-17 in psoriasis.19 Although the function of macrophages in psoriasis is not yet fully understood, they are likely to contribute to the pathogenic inflammation in psoriasis by releasing key inflammatory products.38

Natural killer and NKT cells NK cells are a specialized subset of CD56+ CD16+ cells with the ability to kill cancer and virally infected cells in a ­non-major histocompatibility complex (MHC)–dependent manner.39 Natural killer T (NKT) cells are a heterogeneous group of innate cells that share some features of both NK cells and T cells.40 NKT cells are distinct from NK cells in that they express a T-cell receptor (TCR) but also express certain C-type lectin NK receptors such as CD94 and CD161.41 CD1d, an invariant stimulator of NKT cells, is abundantly expressed in the epidermis of psoriasis lesions.42 NK cells have been suggested to play a role in psoriasis by releasing

cytokines such as IFN-γ, TNF, and IL-22.2 NKT cells may also play a role in psoriasis by releasing cytokines such as IFN-γ. However, the function of NK and NKT cells is not yet fully understood, and further studies are required to evaluate their contributions to psoriasis.

PSORIATIC CYTOKINES IL-17 Clinical studies have shown that blockade of IL-17A or the IL-17 receptor A subunit can reverse the clinical, histologic, and molecular features of psoriasis in approximately 80% of psoriasis patients.43–46 The strong effect of IL-17 antagonists even raise questions about the pathogenic functions of Th1 and Th22 cell subsets in chronic disease, although there are clear molecular pathways in psoriasis that can be traced to the individual cytokines of each T-cell class.2 Keratinocytes are the main cell type expressing the receptors for IL-17 (IL-17R) in psoriasis. Recent studies have found that IL-17 can upregulate the expression of 419 gene probes and downregulate the expression of 216 gene probes using the reconstructed human epidermis model.47 Furthermore, IL-17 stabilizes the transcription of chemokines, such as CXCL1, and synergistic effects exist between IL-17 and TNF-α, as a combination of the two cytokines induces greater changes in gene expression than either alone.48,49 IL-17 also induces IL-19 and IL-36γ in psoriatic lesions, which may then lead to proliferative responses in keratinocytes.2 Overall, IL-17 is the most important pathogenic stimulant of keratinocytes in psoriasis.

IL-23 IL-23 is composed of two chains: the unique p19 (IL-23R) chain and the p40 (IL-12Rβ1) chain which is shared with IL-12. IL-23p19 and IL-12/23p40 messenger RNA (mRNA) are strongly unregulated in psoriatic lesions, and variants in the genes for the IL-23 receptor and the p19 subunit are linked to psoriasis susceptibility in genome-wide association studies.2,50,51 IL-23 induces differentiation of Th17 cells and Th22 cells, and abundant IL-23 is produced by both BDCA-1- inflammatory DCs and BDCA-1+ resident DCs, as well as macrophages in psoriatic lesions.2,38,52 In recent clinical trials, administration of an a­ nti-IL-23A monoclonal antibody has been associated with rapid and substantial clinical improvement in patients with ­moderate-to-severe psoriasis.53,54 The speed and sustained duration of clinical improvement after even single doses of the anti-IL-23A monoclonal antibody provided strong evidence that IL-23 plays a central role in the pathogenesis of psoriasis. Importantly, FoxP3 mRNA levels remained relatively high in posttreatment biopsy specimens, indicating some long-term effect of inhibiting IL-23A on increasing relative regulatory T-cell levels or function in resolved psoriatic lesions.54

34 Immunology

IFN-γ

DCs.19,61,62 A key effect of TNF-α is regulation of a­ ntigen presenting cells, and TNF-α inhibitors can impair DC– T-cell interactions, resulting in decreased epidermal stimulation by T-cell cytokines.63,64 In addition, TNF-α is an activator of IL-23 synthesis in DCs, and the clinical benefit seen with TNF-α blockade is linked to suppression of the IL-23/Th17 axis.39 As a result, serum TNF-α levels correlate with disease severity and are reduced by effective therapy in psoriasis.65,66

In the past, overactivity of the Th1 cell subset was ­considered to be the dominant pathogenic pathway for psoriasis.55 Th1 cells, producing IFN-γ, are abundant in psoriatic lesions and blood, and are reduced with successful therapy. However, the dominant role of IFN-γ in psoriasis is now less clear, as selective blockade of IL-23 without effects on IFN-γ leads to full resolution of psoriasis based on clinical, histologic, and molecular disease markers.53,54 Also, direct blockade of IFN-γ with a neutralizing antibody in psoriasis patients was shown to have little or no therapeutic benefit, suggesting that this cytokine does not directly drive the psoriasis phenotype in chronic lesions.56 Instead of having a direct impact on psoriasis pathogenesis, it is likely that the main effect of IFN-γ is activating antigen-presenting cells early in the psoriatic cascade.57 It has been shown that the IL-12/IFN-γ axis potentially acts to suppress IL-17–modulated tissue injury.58–60 Hence, theoretically, continued expression of the IL-12/IFN-γ axis in psoriasis while Th17 responses are inhibited via IL-23 or IL-17 blockade might lead to better treatment and suppression of disease, compared with combined blockade of IL-12 and IL-23.

IMMUNE PATHWAY MODELS OF PSORIASIS Models of immunogenic pathways in psoriasis are summarized in Figure 5.1. Keratinocytes take part in both innate and adaptive immune responses of psoriasis. They participate in innate immune responses by synthesizing antimicrobial peptides, such as LL-37, defensins, and S100 proteins. In adaptive immunity, keratinocytes participate in directing the migration of new T-cell subsets into the skin through cytokine production.2,67 The antimicrobial peptide, LL-37, has been proposed as an antigenic peptide, triggering T-cell activation in psoriasis.68 LL-37 is expressed not only by k­ eratinocytes in the epidermis, but also by infiltrating neutrophils in the dermis.29,69–71 It is recognized by circulating T cells of psoriasis patients, and the presence of circulating LL-37-specific T cells correlates significantly with disease activity.68 LL-37 is also produced by keratinocytes in response to skin injury by triggering factors.

TNF-α TNF-α can be produced by many cell types including keratinocytes, T cells, and psoriatic BDCA-1- inflammatory

lL-22* (TNF) Th22 3 lL-2

CCL20

Possible autoantigen

LL-37

+RNA

Myeloid DCs

+DNA Keratinocytes

Neutrophils hl

lL-23

TLR8

TLR7

Th17

lL-

12

lFN-α/β Th1

TLR9 pDCs lFN-γ (TNF) lL-17 (TNF)

Figure 5.1  The immune pathway model of psoriasis. Keratinocytes activate myeloid dendritic cells (DCs) through antimicrobial peptide LL-37, plasmacytoid DCs (pDCs), and Toll-like receptors (TLRs). Keratinocytes also produce CCL20, which attracts myeloid DCs and Te helper (Th)17. Myeloid DCs stimulate psoriatic T cells producing interleukin (IL)-17 (Th17), interferon gamma (IFN)-γ (Th1), and IL-22 (Th22). The cytokines released by these cells further stimulate keratinocytes, and the immune circuit is amplified by the feedback cytokine production. The IL-23/Th17 axis is the dominant pathogenic pathway in psoriasis (marked in red). Of note, the IL-12/IFN-γ axis potentially suppresses the IL-23/Th17 axis (marked in blue). *IL-19, IL-20, and IL-24 are upregulated in psoriatic lesions and have biological effects similar to IL-22.

References 35

LL-37/DNA complexes then activate pDCs by binding to intracellular Toll-like receptor9 (TLR9), and LL-37/RNA complexes activate pDCs through TLR7.29,72,73 Activated pDCs produce type I IFNs, IFN-α and IFN-β, which activate myeloid DCs. In addition, LL-37/RNA complexes can directly activate myeloid DCs through TLR8. Injured keratinocytes produce high levels of the chemokine C-C Motif Chemokine Ligand 20 (CCL20), which functions to recruit both myeloid DCs and Th17 cells into active psoriatic skin.2,73,74 Skin infection activates immune pathways leading to the production of TNF in the skin, which also induces CCL20 and mediates recruitment of neutrophils by stimulating keratinocyte-derived CXCL chemokines, such as CXCL8. The following part in this immune pathway is mediated by activated myeloid DCs. These cells can drive T-cell activation and cytokine production through the production of IL-23 and IL-12.2 They also produce IL-20 in psoriatic lesions, which could be a driver of epidermal hyperplasia.75 In the next steps in the central pathogenic psoriatic pathway, IL-23 is required for expansion and survival of the Th17 and Th22 subsets, which produce IL-17 and IL-22, respectively. It is important to note that IL-17 and IL-22 modulate distinct keratinocyte-response pathways. IL-17 is a strong inducer of antimicrobial peptide synthesis in keratinocytes, and IL-22 is a strong inducer of keratinocyte hyperplasia.76,77 The immune circuit described is amplified by further activation of keratinocytes and myeloid DCs. In response to cytokines from each of T-cell subsets, keratinocytes upregulate mRNAs for a range of inflammatory products, which feedback on immune cells in the skin such that chronic T-cell activation persists.2

CONCLUSIONS IL-23/Th17 is now recognized as the major axis of the psoriatic immune pathway, and antagonists of IL-23 or IL-17 result in the ability to control most of the signs and symptoms of clinical disease in up to 90% of psoriasis patients. However, antigens that drive T-cell response have yet to be elucidated, and further research is needed to better understand mechanisms of tolerance that might be defective in psoriatic skin lesions. We expect that we can overcome these hurdles through clinical and translational studies and, in doing so, take necessary steps toward an ultimate cure for psoriasis.

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3. Perera GK, Di Meglio P, Nestle FO. Psoriasis. Annu Rev Pathol. 2012;7:385–422. 4. Gottlieb SL, et al. Response of psoriasis to a ­lymphocyte-selective toxin (DAB389IL-2) suggests a primary immune, but not keratinocyte, pathogenic basis. Nat Med. 1995;1(5):442–447. 5. Lebwohl M. Biologics for psoriasis: A t­ranslational research success story. J Invest Dermatol. 2015;135(5):1205–1207. 6. Nograles KE, Krueger JG. Anti-cytokine therapies for psoriasis. Exp Cell Res. 2011;317(9):1293–1300. 7. Murphy K. Janeway’s Immunobiology. New York, NY: Garland Science, 2011. 8. Streilein JW. Skin-associated lymphoid tissues (SALT): Origins and functions. J Invest Dermato. 1983;80 Suppl:12s–16s. 9. Egawa G, Kabashima K. Skin as a peripheral lymphoid organ: Revisiting the concept of skinassociated lymphoid tissues. J Invest Dermatol. 2011;131(11):2178–2185. 10. Di Meglio P, Perera GK, Nestle FO. The multitasking organ: Recent insights into skin immune function. Immunity. 2011;35(6):857–869. 11. Bos JD, et al. Immunocompetent cells in psoriasis. In situ immunophenotyping by monoclonal antibodies. Arch Dermatol Res. 1983;275(3):181–189. 12. Cai Y, Fleming C, Yan J. New insights of T cells in the pathogenesis of psoriasis. Cell Mol Immunol. 2012;9(4):302–309. 13. Spits H, Cupedo T. Innate lymphoid cells: Emerging insights in development, lineage relationships, and function. Annu Rev Immunol. 2012;30:647–675. 14. Villanova F, et al. Characterization of innate lymphoid cells in human skin and blood demonstrates increase of NKp44+ ILC3 in psoriasis. J Invest Dermatol. 2014;134(4):984–991. 15. Goodman WA, Cooper KD, McCormick TS. Regulation generation: The suppressive functions of human regulatory T cells. Crit Rev Immunol. 2012;32(1):65–79. 16. Sugiyama H, et al. Dysfunctional blood and target tissue CD4+CD25high regulatory T cells in psoriasis: Mechanism underlying unrestrained pathogenic effector T cell proliferation. J Immunol. 2005;174(1):164–173. 17. de Boer OJ, et al. Immunohistochemical analysis of regulatory T cell markers FOXP3 and GITR on CD4+CD25+ T cells in normal skin and inflammatory dermatoses. J Histochem Cytochem. 2007;55(9):891–898. 18. Zhang L, et al. Increased Th17 cells are accompanied by FoxP3(+) Treg cell accumulation and c­ orrelated with psoriasis disease severity. Clin Immunol. 2010;135(1):108–117. 19. Zaba LC, et al. Psoriasis is characterized by accumulation of immunostimulatory and Th1/Th17 cell-polarizing myeloid dendritic cells. J Invest ­ Dermatol. 2009;129(1):79–88.

36 Immunology

20. Zaba LC, et al. Normal human dermis contains ­distinct populations of CD11c+BDCA-1+ dendritic cells and CD163+FXIIIA+ macrophages. J Clin Invest. 2007;117(9):2517–2525. 21. Dzionek A, et al. BDCA-2, BDCA-3, and BDCA-4: Three markers for distinct subsets of dendritic cells in human peripheral blood. J Immunol. 2000;165(11):6037–6046. 22. Hyder LA, et al. TREM-1 as a potential therapeutic target in psoriasis. J Invest Dermatol. 2013;133(7):1742–1751. 23. Johnson-Huang LM, et al. Cytokine-producing dendritic cells in the pathogenesis of inflammatory skin diseases. J Clin Immunol. 2009;29(3):247–256. 24. Johnson-Huang LM, Lowes MA, Krueger JG. Putting together the psoriasis puzzle: An update on developing targeted therapies. Dis Model Mech. 2012;5(4):423–433. 25. Kennedy Crispin M, et al. Gene profiling of narrowband UVB-induced skin injury defines cellular and molecular innate immune responses. J Invest Dermatol. 2013;133(3):692–701. 26. Liu Y-J. IPC: Professional type 1 ­interferon-producing cells and plasmacytoid dendritic cell precursors. Annu Rev Immunol. 2005;23:275–306. 27. Nestle FO, et al. Plasmacytoid predendritic cells initiate psoriasis through interferon-α production. J Exp Med. 2005;202(1):135–143. 28. Krieg AM. CpG motifs in bacterial DNA and their immune effects. Annu Rev Immunol. 2002;20:709–760. 29. Lande R, et al. Plasmacytoid dendritic cells sense selfDNA coupled with antimicrobial peptide. Nature. 2007;449(7162):564–569. 30. Blanco P, et al. Induction of dendritic cell differentiation by IFN-alpha in systemic lupus erythematosus. Science. 2001;294(5546):1540–1543. 31. Cumberbatch M, et al. Impaired Langerhans cell migration in psoriasis. J Exp Med. 2006;203(4):953–960. 32. Shaw FL, et al. Langerhans cell mobilization distinguishes between early-onset and late-onset ­ psoriasis. J Invest Dermatol. 2010;130(7):1940–1942. 33. Shaw FL, et al. Treatment-related restoration of Langerhans cell migration in psoriasis. J Invest Dermatol. 2014;134(1):268–271. 34. Lin AM, et al. Mast cells and neutrophils release IL-17 through extracellular trap formation in psoriasis. J Immunol. 2011;187(1):490–500. 35. Reich, K, et al. Evidence that a neutrophil-keratinocyte crosstalk is an early target of IL-17A inhibition in psoriasis. Exp Dermatol. 2015;24(7):529–535. 36. Mosser DM, Edwards JP. Exploring the full spectrum of macrophage activation. Nat Rev Immunol. 2008;8(12):958–969. 37. Zaba LC, et al. Amelioration of epidermal h ­ yperplasia by TNF inhibition is associated with reduced Th17 responses. J Exp Med. 2007;204(13):3183–3194. 38. Fuentes-Duculan J, et al. A subpopulation of ­CD163-positive macrophages is classically activated in psoriasis. J Invest Dermatol. 2010;130(10):2412–2422.

39. Dunphy S, Gardiner CM. NK cells and psoriasis. J Biomed Biotechnol. 2011;2011:248317. 40. Simoni Y, et al. Therapeutic manipulation of natural killer (NK) T cells in autoimmunity: Are we close to reality? Clin Exp Immunol. 2013;171(1):8–19. 41. Gaspari AA. Innate and adaptive immunity and the pathophysiology of psoriasis. J Am Acad Dermatol. 2006;54(3):S67–S80. 42. Bonish B, et al. Overexpression of CD1d by keratinocytes in psoriasis and CD1d-dependent IFNgamma production by NK-T cells. J Immunol. 2000;165(7):4076–4085. 43. Krueger JG, et al. IL-17A is essential for cell activation and inflammatory gene circuits in subjects with psoriasis. J Allergy Clin Immunol. 2012;130(1):145–154 e9. 44. Papp KA, et al. Brodalumab, an anti-interleukin17-receptor antibody for psoriasis. N Engl J Med. 2012;366(13):1181–1189. 45. Papp KA, et al. Anti-IL-17 receptor antibody AMG 827 leads to rapid clinical response in subjects with moderate to severe psoriasis: Results from a phase I, randomized, placebo-controlled trial. J Invest Dermatol. 2012;132(10):2466–2469. 46. Leonardi C, et al. Anti-interleukin-17 monoclonal antibody ixekizumab in chronic plaque psoriasis. N Engl J Med. 2012;366(13):1190–1199. 47. Chiricozzi A, et al. IL-17 induces an expanded range of downstream genes in reconstituted human epidermis model. PLoS One. 2014;9(2):e90284. 48. Datta S, et al. IL-17 regulates CXCL1 mRNA stability via an AUUUA/tristetraprolin-independent sequence. J Immunol. 2010;184(3):1484–1491. 49. Chiricozzi A, et al. Integrative responses to IL-17 and TNF-alpha in human keratinocytes account for key inflammatory pathogenic circuits in psoriasis. J Invest Dermatol. 2011;131(3):677–687. 50. Cargill M, et al. A large-scale genetic association study confirms IL12B and leads to the identification of IL23R as psoriasis-risk genes. Am J Hum Genet. 2007;80(2):273–290. 51. Nair RP, et al. Genome-wide scan reveals association of psoriasis with IL-23 and NF-kappaB pathways. Nat Genet. 2009;41(2):199–204. 52. Zaba LC, et al. Identification of TNF-related apoptosis-inducing ligand and other molecules ­ that distinguish inflammatory from resident dendritic cells in patients with psoriasis. J Allergy Clin Immunol. 2010;125(6):1261–1268 e9. 53. Sofen H, et al. Guselkumab (an IL-23–specific mAb) demonstrates clinical and molecular response in patients with moderate-to-severe psoriasis. J Allergy Clin Immunol. 2014;133(4):1032–1040. 54. Krueger JG, et al. Anti-IL-23A mAb BI 655066 for treatment of moderate-to-severe psoriasis: Safety, efficacy, pharmacokinetics, and biomarker results of a single-rising-dose, randomized, double-blind, placebo-controlled trial. J Allergy Clin Immunol. 2015;136(1):116–124.

References 37

55. Lew W, Bowcock AM, Krueger JG. Psoriasis ­v ulgaris: Cutaneous lymphoid tissue supports T-cell activation and “Type 1” inflammatory gene expression. Trends Immunol. 2004;25(6):295–305. 56. Harden J, et al. Humanized anti-IFN-gamma (HuZAF) in the treatment of psoriasis. J Allergy Clin Immunol. 2015;135(2):553–556. 57. Kryczek I, et al. Induction of IL-17+ T cell ­trafficking and development by IFN-gamma: Mechanism and pathological relevance in psoriasis. J Immunol. 2008;181(7):4733–4741. 58. Zhang J. Yin and yang interplay of IFN-gamma in inflammation and autoimmune disease. J Clin Invest. 2007;117(4):871–873. 59. Cua DJ, et al. Interleukin-23 rather than ­interleukin-12 is the critical cytokine for ­autoimmune inflammation of the brain. Nature. 2003;421(6924):744–748. 60. Becher B, Durell BG, Noelle RJ. Experimental autoimmune encephalitis and inflammation in the absence of interleukin-12. J Clin Invest. 2002;110(4): 493–497. 61. Lowes MA, et al. Increase in TNF-alpha and inducible nitric oxide synthase-expressing dendritic cells in psoriasis and reduction with efalizumab (anti-CD11a). Proc Natl Acad Sci U S A. 2005;102(52):19057–19062. 62. Zaba LC, Krueger JG, Lowes MA. Resident and “inflammatory” dendritic cells in human skin. J Invest Dermatol. 2009;129(2):302–308. 63. Lowes MA, et al. The IL-23/T17 pathogenic axis in psoriasis is amplified by keratinocyte responses. Trends Immunol. 2013;34(4):174–181. 64. Summers deLuca L, Gommerman JL. Fine-tuning of dendritic cell biology by the TNF superfamily. Nat Rev Immunol. 2012;12(5):339–351. 65. Arican O, et al. Serum levels of TNF-α, IFN-γ, IL-6, IL-8, IL-12, IL-17, and IL-18 in patients with active psoriasis and correlation with disease severity. Mediators Inflamm. 2005;2005(5):273–279.

66. Mussi A, et al. Serum TNF-alpha levels correlate with disease severity and are reduced by effective therapy in plaque-type psoriasis. J Biol Regul Homeost Agents. 1996;11(3):115–118. 67. Nestle FO, et al. Skin immune sentinels in health and disease. Nat Rev Immunol. 2009;9(10):679–691. 68. Lande R, et al. The antimicrobial peptide LL37 is a T-cell autoantigen in psoriasis. Nat Commun. 2014;5:5621. 69. Giacometti A, et al. Cathelicidin peptide sheep myeloid antimicrobial peptide-29 prevents endotoxin-induced mortality in rat models of septic shock. Am J Respir Crit Care Med. 2004;169(2):187–194. 70. Ganguly D, et al. Self-RNA-antimicrobial peptide complexes activate human dendritic cells through TLR7 and TLR8. J Exp Med. 2009;206(9):1983–1994. 71. Chamilos G, et al. Cytosolic sensing of extracellular self-DNA transported into monocytes by the antimicrobial peptide LL37. Blood. 2012;120(18):3699–3707. 72. Gilliet M, Lande R. Antimicrobial peptides and selfDNA in autoimmune skin inflammation. Curr Opin Immunol. 2008;20(4):401–407. 73. Martin DA, et al. The emerging role of IL-17 in the pathogenesis of psoriasis: Preclinical and clinical findings. J Invest Dermatol. 2013;133(1):17-26. 74. Kennedy-Crispin M, et al. Human keratinocytes’ response to injury upregulates CCL20 and other genes linking innate and adaptive immunity. J Invest Dermatol. 2012;132(1):105–113. 75. Wang F, et al. Prominent production of IL-20 by CD68+/CD11c+ myeloid-derived cells in psoriasis: Gene regulation and cellular effects. J Invest Dermatol. 2006;126(7):1590–1599. 76. Nograles KE, et al. Th17 cytokines interleukin ­(IL)-17 and IL-22 modulate distinct inflammatory and keratinocyte-response pathways. Br J Dermatol. 2008;159(5):1092–1102. 77. Eyerich S, et al. Th22 cells represent a distinct human T cell subset involved in epidermal immunity and remodeling. J Clin Invest. 2009;119(12):3573–3585.

6 Other environmental risk factors BRIAN KIRBY and ROSALIND HUGHES

INFECTION Psoriasis may be triggered or aggravated by a number of environmental factors. The association of guttate psoriasis (GP) and streptococcal throat infection has been recognized since the beginning of the last century.1 Streptococcal infection may trigger the onset of GP in individuals and may be accountable for guttate flares in those with chronic plaque psoriasis (CPP).2 Streptococcal organisms are internalized into tonsilar epithelia cells, where they remain protected from antibiotic treatment and immune defense mechanisms.3 Here, they persevere, acting as a reservoir of disease-stimulating antigens. Evidence of identical T-cell clones within the tonsils, psoriatic plaques, and peripheral blood strongly supports this concept.4 Numerous other infectious organisms have been associated with exacerbations of psoriasis, including herpes simplex, varicella zoster, cytomegalovirus, and parvovirus B19. The true role of these organisms in triggering psoriasis remains unclear, and large studies examining their roles have been inconclusive. The association between human immunodeficiency virus (HIV) infection is well established. Psoriasis may be worsened by or detected for the first time, following HIV infection.5 It is paradoxical that psoriasis most commonly occurs with increasing immune dysfunction, contrary to our understanding of psoriasis as a CD4+ T-lymphocyte–mediated disease, which responds to T-cell suppressing treatments. It is proposed that profound immune dysregulation associated with HIV may lead to cytotoxic CD8+ T cells crossreacting with HLACw0602.6 Highly active antiretroviral therapies appear most effective in treating HIV-associated psoriasis.5

MEDICATION Numerous drugs have been implicated in the precipitation or exacerbation of psoriasis. The strength of evidence implicating different medications with psoriasis flares varies greatly. Those drugs with most evidence of culpability

include lithium salts,7 antimalarials,8 interferon alpha,9 and tumor necrosis factor (TNF)-alpha inhibitors.10 Rapid withdrawal of systemic or superpotent topical steroids can induce pustular psoriasis in addition to flaring CPP. Lithium has been reported to both exacerbate preexisting psoriasis and to induce psoriasis in previously unaffected individuals.7 Lithium has been shown to downregulate keratinocyte proliferation via glycogen synthase kinase-3 and nuclear factor of activated T cells.11 Hydroxychloroquine and chloroquine have also been reported to both exacerbate and, less commonly, induce psoriasis. Antimalarial exacerbation of existing disease is common, with an incidence of up to 41% reported in one series.12 Hydroxychloroquine-induced psoriatic erythroderma has also been reported.8 Worsening of psoriasis during the course of interferon alpha therapy for hepatitis C or multiple sclerosis is widely reported. Exacerbations are typically responsive to psoriasis treatments and rarely require cessation of interferon therapy.9 TNF-alpha antagonist–induced psoriasis may occur at any time throughout treatment and may be morphologically atypical. In most patients, however, it does not require cessation of therapy.13 Eruptions are most often pustular and occur more commonly on the palms or soles.14 An increased incidence is reported in females and in current or previous smokers.13 The combination of antiTNF alpha therapy plus immunosuppressants may reduce the risk of paradoxical psoriasis.15 A large UK-based case-control study of the association between beta-blockers and psoriasis did not find an increased incidence of psoriasis with beta-blocker therapy.16 Previous reports of psoriasiform eruptions in individuals receiving beta-blocker therapy are limited to small series and case reports. The evidence linking Ace inhibitor therapy and exacerbation of psoriasis is restricted to small case series and a case-crossover study.17 Furthermore, a large case-controlled analysis did not find increased risk of psoriasis with Aceinhibitor or other antihypertensive medication use.16 39

40  Other environmental risk factors

Nonsteroidal anti-inflammatory drugs (NSAIDs) are perhaps one of the most commonly prescribed medications worldwide. Despite their widespread use, only a limited number of reports implicate them in the exacerbation of psoriasis. Topical indomethacin was reported to exacerbate psoriasis in 14 of 20 patients.18 In a subsequent double-blind crossover study, oral indomethacin exacerbated psoriasis in only two of five patients.19 A large cohort study assessing risk of psoriasis and psoriatic arthritis (PsA) with use of aspirin, NSAIDs, and acetaminophen found a marginally significant hazards ratio (HR) for PsA and NSAIDS. No association between aspirin use and either PsA or psoriasis was found and the HR for psoriasis and NSAIDs, aspirin, and acetaminophen were not statistically significant.20 Both rebound and tachyphylaxis phenomena can occur with corticosteroid use. Abrupt withdrawal of corticosteroid treatment can destabilize psoriasis and as such gradual withdrawal of treatment is preferable.21

PSYCHOLOGICAL DISTRESS In 1977, Seville et al. identified that 41% of psoriasis patients in a prospective cohort study reported a specific stress event before recurrence of their skin disease.22 Psychological distress is now well known to be associated with psoriasis both as a consequence of the disease and as a potential aggravating influence. The underlying pathophysiological mechanisms responsible are not fully understood. Approximately 80% of patients with psoriasis report stress as a trigger of their skin disease.23 Gupta et al. identified that certain individuals appear to be “highstress reactors,” whereas others are “low-stress reactors.” Those identified as high-stress reactors tended to have more severe psoriasis and suffered more from psoriasisassociated daily stress.24 Patients with moderate to severe psoriasis have an increased risk of depression, anxiety, and suicidality compared with the background population.25 Increasing research suggests that inflammatory responses have an important role in the pathophysiology of depression. Depressed patients have been found to have higher levels of proinflammatory cytokines, acute phase proteins, chemokines, and cellular adhesion molecules.26 Both the innate and adaptive cutaneous immune responses may be impacted by psychological stress. Evidence that the cutaneous peripheral nervous system plays a crucial role in skin hemostasis27,28 has led to the concept of a neurocutaneous axis. Kleyn et al. demonstrated a significant reduction in epidermal Langerhans cell frequency, modulated neuropeptide gene product expression, and calcitonin gene-related peptide in subjects subjected to acute social stress.29 Psychological stress has been shown to markedly decrease the percentages of leukocytes in the blood30 and lead to immunosuppression in a number of systems, including skin graft rejection.31 Psoriasis patients who report stress-exacerbated flares have been shown to have

reduced levels of cortisol and epinephrine, suggesting that the response of the hypothalamic–pituitary–adrenal axis is blunted in psoriatics sensitive to psychological stressors.32 Harvima et al. evaluated involved and uninvolved skin from stressed and nonstressed patients using immunohistochemistry. Increased neuropeptides, calcitonin gene-related peptide, and substance P and vasoactive intestinal peptide nerve fibers were detected in the papillary dermis of the skin in stressed patients, whereas these nerve fibers were only weakly detected in nonstressed individuals. In addition, reduced concentrations of neuropeptide degrading enzymes were decreased in stressed patients, compared with nonstressed psoriatic controls.33 Psychological distress may affect treatment outcomes in psoriasis.34 By contrast, the current evidence to support stress reduction techniques to improve patients’ psoriasis is of insufficient quality to interpret.35

Cigarette smoking The association between palmoplantar pustular psoriasis and smoking was first noted in 1985.36 Increased rates of smoking among psoriasis patients, compared with the normal population, are now well established. Although smoking behavior is closely linked to alcohol consumption, evidence controlling for alcohol suggests that smoking is an independent risk factor for the development of psoriasis.37 Smoking confers an increased risk up to 3.3fold of developing psoriasis and increasing pack-years escalates that risk.38 Furthermore, increased risk of greater disease severity and of PsA is identified in smokers.39

Sunshine Sunlight is a continuous spectrum of electromagnetic ­radiation comprising visible light, ultraviolet light (UV), and infrared radiation. The ultraviolet component of sunlight induces cell-mediated immunosuppression.40 The beneficial effect of sunlight on skin conditions including vitiligo and psoriasis has been acknowledged for centuries. The majority of psoriasis patients enjoy improvement of their skin condition with sunlight exposure. It is estimated, however, that between 5% and 20% of psoriasis patients have photosensitive psoriasis.41 The exact mechanism underlying this is unclear. Köebnerization of psoriasis following sunburn42 or following polymorphic light eruption43 and the coexistence of other photosensitive disorders44 have been proposed as underlying mechanisms. Rutter et al. found that patients may have normal monochromator photosensitivity testing to narrowband UVB, UVA, and visible radiation, whereas broadband UVA provocation produces an abnormal clinical response.41 The group also suggested that photoaggravated psoriasis had a female predominance and strong association with Human Leukocyte Antigen (HLA)-Cw6.

References 41

Alcohol misuse

REFERENCES

Alcohol consumption is higher in psoriasis patients than the in the general population.45 A higher prevalence and incidence of psoriasis in a population of patients with alcoholic liver disease has been shown previously.46 Strong evidence of a positive association between alcohol consumption and psoriatic risk exists.47 The exact mechanisms responsible are yet to be elucidated. Once consumed, alcohol is rapidly absorbed into the blood stream and measurable quantities of ethanol are excreted through the skin. It is suggested that the impaired barrier function in psoriatic skin may lead to increased antigen absorption, possibly initiating keratinocyte hyperproliferation and a proinflammatory cytokine release characteristic of psoriasis.48 Psoriasis in heavy drinkers is typically more severe and more extensive.49 In a study of the compliance of medical treatment for psoriasis, the mean medication adherence for patients who declared themselves as nondrinkers of alcoholic beverages was 91.5%, whereas it was 53.4% for those who consumed alcohol. Drinking alcohol was the major reason reported for missing doses of treatment.50

1. Winfield JM. Psoriasis as a sequel to acute inflammations of the tonsils: A clinical note. J Cutan Dis. 1916;34:441–443. 2. Gudjonsson JE, Thorarinsson AM, Sigurgeirsson B, Kristinsson KG, Valdimarsson H. Strepto­ coccal throat infections and exacerbation of chronic plaque psoriasis: A prospective study. Br J Dermatol. 2003;149(3):530–534. 3. McFadden JP, Baker BS, Powles AV, Fry L. Psoriasis and streptococci: The natural selection of psoriasis revisited. Br J Dermatol. 2009;160(5):929–937. 4. Diluvio L, Vollmer S, Besgen P, Ellwart JW, Chimenti S, Prinz JC. Identical TCR beta-chain rearrangements in streptococcal angina and skin lesions of patients with psoriasis vulgaris. J Immunol. 2006;176(11):7104–7111. 5. Morar N, Willis-Owen SA, Maurer T, Bunker CB. HIV associated psoriasis: Pathogenesis, clinical features, and management. Lancet Infect Dis. 2010;10(7):470–478. 6. Mallon E, Bunker CB. HIV-associated psoriasis. AIDS Patient Care STDS. 2000;14(5):239–246. 7. Sarantidis D, Waters B. A review and controlled study of cutaneous conditions associated with lithium carbonate. Br J Psychiatry. 1983;143(1):42–50. 8. Kuflik EG. Effect of antimalarial drugs on psoriasis. Cutis. 1980;26(2):153–155. 9. Afshar M, Martinez AD, Gallo RL, Hata TR. Induction and exacerbation of psoriasis with interferon-alpha therapy for hepatitis C: A review and analysis of 36 cases. J Eur Acad Dermatol Venereol. 2013;27(6):771–778. 10. Collamer AN, Guerrero KT, Henning JS, Battafarano DF. Psoriatic skin lesions induced by tumor necrosis factor antagonist therapy: A literature review and potential mechanisms of action. Arthritis Rheum. 2008;59(7):996–1001. 11. Hampton PJ, Jans R, Flockhart RJ, Parker G, Reynolds NJ. Lithium regulates keratinocyte proliferation via glycogen synthase kinase 3 and NFAT2 (nuclear factor of activated T cells 2). J Cell Physiol. 2012;227(4):1529–1537. 12. Arenbergerova M, Gkalpakiotis S, Arenberger P. Pharmacology and therapeutics effective long-term control of refractory hidradenitis suppurativa with adalimumab after failure of conventional therapy. Pharmacol Ther. 2010;49(12):1445–1449. 13. Guerra I, Pérez-Jeldres T, Iborra M, et al. Incidence, clinical characteristics, and management of psoriasis induced by anti-TNF therapy in patients with inflammatory bowel disease: A nationwide cohort study. Inflamm Bowel Dis. 2016;22(4):894–901. 14. Joyau C, Veyrac G, Dixneuf V, Jolliet P. Anti-tumour necrosis factor alpha therapy and increased risk of de novo psoriasis: Is it really a paradoxical side effect? Clin Exp Rheumatol. 2012;30(5):700–6.

Trauma The Köebner phenomenon (KP), whereby psoriatic lesions developed in uninvolved skin of psoriatic patients as a consequence of trauma was first described in 1876.51 Up to 25% of patients report exacerbation of psoriasis in areas of trauma.52 Provoking factors include burns, friction, insect bites, surgical incision, herpes zoster, syphilis, and UVB treatment.53,54 KP can develop in any anatomic site. The duration from insult to occurrence of KP may vary from 3 days to years, but is typically between 10 and 20 days55 (see Figure 6.1).

Figure 6.1  The Köebner phenomenon.

42  Other environmental risk factors

15. Pugliese D, Guidi L, Ferraro PM, et al. Paradoxical psoriasis in a large cohort of patients with inflammatory bowel disease receiving treatment with anti-TNF alpha: 5-year follow-up study. Aliment Pharmacol Ther. 2015;42(7):880–888. 16. Brauchli YB, Jick SS, Curtin F, Meier CR. Association between beta-blockers, other antihypertensive drugs and psoriasis: Population-based case-control study. Br J Dermatol. 2008;158(6):1299–1307. 17. Cohen AD, Bonneh DY, Reuveni H, Vardy DA, Naggan L, Halevy S. Drug exposure and psoriasis vulgaris: Case-control and case-crossover studies. Acta Derm Venereol-Stockholm. 2005;85(4):299. 18. Ellis CN, Fallon JD, Heezen JL, Voorhees JJ. Topical indomethacin exacerbates lesions of psoriasis. J Invest Dermatol. 1983;80:362. 19. Powles AV, Griffiths CEM, Seifert MH, Ffry L. Exacerbation of psoriasis by indomethacin. Br J Dermatol. 1987;117(6):799–800. 20. Wu S, Han J, Qureshi AA. Use of aspirin, non-steroidal anti-inflammatory drugs, and acet­ aminophen (paracetamol), and risk of psoriasis and psoriatic arthritis: A cohort study. Acta Derm Venereol. 2015;95(2):217–223. 21. Boxley JD, Dawber RP, Summerly R. Generalized pustular psoriasis on withdrawal of clobetasol propionate ointment. Br Med J. 1975;2(5965):255–256. 22. Seville RH. Psoriasis and stress. Br J Dermatol. 1977;97(3):297–302. 23. Fortune DG, Richards HL, Griffiths CEM. Psychologic factors in psoriasis: Consequences, mechanisms, and interventions. Dermatol Clin. 2005;23(4):681–694. 24. Gupta MA, Gupta AK, Kirkby S, et al. A psychocutaneous profile of psoriasis patients who are stress reactors. Gen Hosp Psychiatry. 1989;11(3):166–173. 25. Kurd SK, Troxel AB, Crits-Christoph P, Gelfand JM. The risk of depression, anxiety, and suicidality in patients with psoriasis: A population-based cohort study. Arch Dermatol. 2010;146(8):891–895. 26. Raison CL, Capuron L, Miller AH. Cytokines sing the blues: Inflammation and the pathogenesis of depression. Trends Immunol. 2006;27(1):24–31. 27. Roosterman D, Goerge T, Schneider SW, Bunnett NW, Steinhoff M. Neuronal control of skin function: The skin as a neuroimmunoendocrine organ. Physiol Rev. 2006;86(4):1309–1379. 28. Arck PC, Slominski A, Theoharides TC, Peters EMJ, Paus R. Neuroimmunology of stress: Skin takes center stage. J Invest Dermatol. 2006;126(8):1697–1704. 29. Kleyn CE, Schneider L, Saraceno R, et al. The effects of acute social stress on epidermal Langerhans’ cell frequency and expression of cutaneous neuropeptides. J Invest Dermatol. 2008;128(5):1273–1279. 30. Dhabhar FS, Miller AH, Stein M, McEwen BS, Spencer RL. Diurnal and acute stress-induced changes in ­distribution of peripheral blood leukocyte subpopulations. Brain Behav Immun. 1994;8(1):66–79.

31. Dhabhar FS. A hassle a day may keep the pathogens away: The fight-or-flight stress response and the augmentation of immune function. Integr Comp Biol. 2009;49(3):215–236. 32. Buske-Kirschbaum A, Ebrecht M, Kern S, Hellhammer DH. Endocrine stress responses in TH1-mediated chronic inflammatory skin disease (psoriasis ­vulgaris)—Do they parallel stress-induced endocrine changes in TH2-mediated inflammatory dermatoses (atopic dermatitis)? Psychoneuroendocrinology. 2006;31(4):439–446. 33. Harvima IT, Viinamäki H, Naukkarinen A, et al. Association of cutaneous mast cells and sensory nerves with psychic stress in psoriasis. Psychother Psychosom. 1993;60(3–4):168–176. 34. Fortune DG, Richards HL, Kirby B, et al. Psychological distress impairs clearance of psoriasis in patients treated with photochemotherapy. Arch Dermatol. 2003;139(6):752–756. 35. Fordham B, Griffiths CEM, Bundy C. Can stress reduction interventions improve psoriasis? A review. Psychol Health Med. 2013;18(5):501–514. 36. O’Doherty CJ, MacIntyre C. Palmoplantar pustulosis and smoking. BMJ. 1985;291(6499):861–864. 37. Shahrad MB, Shahdad EB, John YK. Smoking and psoriasis. Skinmed. 2005;4(3):174–176. 38. Li W, Han J, Choi HK, Qureshi AA. Smoking and risk of incident psoriasis among women and men in the United States: A combined analysis. Am J Epidemiol. 2012;175(5):402–413. 39. Tobin A-M, Veale DJ, Fitzgerald O, et al. Cardiovascular disease and risk factors in patients with psoriasis and psoriatic arthritis. J Rheumatol. 2010;37(7):1386–1394. 40. Beissert S, Schwarz T. Mechanisms involved in ultraviolet light-induced immunosuppression. J Investig Dermatol Symp Proc. 1999;4(1):61–64. 41. Rutter KJ, Watson REB, Cotterell LF, Brenn T, Griffiths CEM, Rhodes LE. Severely photosensitive psoriasis: A phenotypically defined patient subset. J Invest Dermatol. 2009;129(12):2861–2867. 42. Frain-Bell W. What is that thing called light? Clin Exp Dermatol. 1979;4(1):1–29. 43. Ros A-M, Eklund G. Photosensitive psoriasis: An epidemiologic study. An epidemiologic study. J Am Acad Dermatol. 1987;17(5):752–758. 44. Doyle JA. Photosensitive psoriasis. Australas J Dermatol. 1984;25(2):54–58. 45. Brenaut E, Horreau C, Pouplard C, et al. Alcohol consumption and psoriasis: A systematic literature review. J Eur Acad Dermatol Venereol. 2013;27(Suppl 3): 30–35. 46. Tobin A-M, Higgins EM, Norris S, Kirby B. Prevalence of psoriasis in patients with alcoholic liver disease. Clin Exp Dermatol. 2009;34(6):698–701. 47. Zhu K-J, Zhu C-Y, Fan Y-M. Alcohol consumption and psoriatic risk: A meta-analysis of case-control studies. J Dermatol. 2012;39(9):770–773.

References 43

48. Farkas Á, Kemény L. Alcohol, liver, systemic inflammation and skin: A focus on patients with psoriasis. Skin Pharmacol Physiol. 2013;26(3):119–126. 49. Higgins EM, du Vivier AW. Invited review: Alcohol and the skin. Alcohol Alcohol. 1992;27(6):595–602. 50. Zaghloul SS, Goodfield MJD. Objective assessment of compliance with psoriasis treatment. Arch Dermatol. 2004;140(4):408–414. 51. Köebner H. Zur aetiologie der psoriasis. Vjschr Dermatol. 1876;3:1876. 52. Weiss G, Shemer A, Trau H. The Köebner phenomenon: Review of the literature. J Eur Acad Dermatol Venereol. 2002;16(3):241–248.

53. Zhao Y-K, Zhang Y-Q, Wang F, et al. Developing shingles-induced köebner phenomenon in a patient with psoriasis: A case report. Medicine (Baltimore). 2015;94(26):e1009.doi:10.1097/MD.0000000000001009. 54. Arias-Santiago S, Espiñeira-Carmona MJ, AneirosFernández J. The Köebner phenomenon: Psoriasis in tattoos. CMAJ. 2013;185(7):585. doi:10.1503/ cmaj.111299. 55. Sagi L, Trau H. The Köebner phenomenon. Clin Dermatol. 2011;29(2):231–236.

7 Plaque-type psoriasis—chronic plaque, guttate, and erythrodermic phenotypes RICARDO ROMITI PLAQUE-TYPE PSORIASIS Introduction Plaque-type psoriasis, also known as psoriasis vulgaris, represents the most common variant of psoriasis and comprises over 90% of cases.1–3 The primary lesion is an erythematous plaque of variable thickness covered with adherent silvery white scales (Figure 7.1). Plaque-type psoriasis is also the most common form of psoriasis in childhood and adolescence (Figure 7.2).4,5 The clinical presentation may vary considerably from patient to patient. In some cases, almost all of the body surface may be involved (erythrodermic psoriasis), whereas other cases may present with generalized small papules and plaques (guttate psoriasis). Different manifestations may coexist in a particular individual and one single lesion may eventually change its pattern over time.6 In most cases, the diagnosis of psoriasis is dependent primarily on pattern recognition: the morphologic evaluation of skin lesions and assessment for nail and joint involvement. Occasionally, dermatopathologic evaluation may be helpful in confirming the diagnosis of psoriasis or to exclude differential diagnoses.7 Time-honored clinical features are useful in confirming the diagnosis of psoriasis, but no clinical characteristic is absolutely specific for psoriasis8 Candle sign: when scales are scratched away from the plaques, they tend to fall off as tiny flakes that resemble scrapings from a candle. Auspitz sign: punctuate bleeding from enlarged capillaries when scales are removed to expose the hypervascular dermal papillae. A further well-characterized sign in psoriasis patients is the Köebner phenomenon, described as the appearance

of psoriatic lesions in the uninvolved skin of psoriatic patients as a consequence of trauma (Figure  7.3). This phenomenon was originally described by Heinrich Köebner in 1876.9 Now it is known that several other dermatological conditions may also demonstrate the Köebner phenomenon. Other causes of cutaneous injury can lead to Köebnerization, including sunburn, tattoos, and drug reactions. Studies have shown that approximately 25% of psoriasis patients will Köebnerize on external stimulation of the skin.10 More recently, the Renbök phenomenon has been coined to describe the opposite of the Köebner phenomenon, designating the withdrawal of a lesion with the appearance of another one.11 It was originally described in 1991 by Happle et al. in alopecia areata patients experiencing hair growth in psoriatic lesions.12 Although psoriasis can often coexist with alopecia areata, reports on this psoriasis-induced Renbök phenomenon in alopecia areata have been exceedingly sparse. The disease spectrum or clinical phenotypes of psoriasis have been classified based on various features such as the age of onset, degree of skin involvement, morphologic p ­ attern, and predominant involvement of specific ­anatomic sites.7,13

CHRONIC PLAQUE PSORIASIS Psoriatic plaques are generally oval or discoid and present with sharp borders distributed symmetrically over the body surface (Figures 7.4 and 7.5). Initially, wellcircumscribed erythematous macules with varying degrees of scaling may appear as isolated or widespread lesions further progressing to form infiltrated and hyperkeratotic plaques (Figures 7.6 and 7.7).1,3 The combination of peripheral spread and central resolution can sometimes produce artistic patterns such as annular, gyrate,

45

46  Plaque-type psoriasis—chronic plaque, guttate, and erythrodermic phenotypes

Figure 7.3  Köebner phenomenon occurring in an appendectomy scar.

Figure 7.1  Classic plaque psoriasis with silver scales.

Figure 7.4  Symmetric psoriatic plaques.

Figure 7.2  Plaque psoriasis affecting a child.

and serpiginous psoriasis (Figures 7.8 and 7.9). Secondary infection of psoriasis lesions is extremely rare, in contrast to atopic dermatitis, where superinfection and colonization of lesional skin is common. This is due to upregulation of antimicrobial peptides in the cutaneous lesions of psoriasis.14 Psoriatic plaques tend to present in a symmetric distribution in varying patterns. Sites of predilection include the extensor surfaces of the limbs, scalp, lumbar

Chronic plaque psoriasis  47

Figure 7.5  Generalized plaque psoriasis.

Figure 7.8  Annular psoriatic lesions with complete central regression.

Figure 7.6  Erythematous patches of psoriasis with minor scaling.

Figure 7.9  Serpiginous and symmetric psoriasis lesions.

Figure 7.7  Predominantly scaly and infiltrated plaques. region, and the gluteal cleft and genital area. The size of a lesion may vary considerably from punctiform papules to widespread plaques measuring over 30 cm

in diameter (Figures 7.10 and 7.11). The outline of the lesions is sharply demarcated and usually oval, circular, or polycyclic. A pale blanching ring surrounding the lesions may be observed and is referred to as Woronoff,s ring (Figure 7.12).6 The scalp is a very common site of involvement in psoriasis. Typically, the frontal hair line and the temporal regions are involved and pruritus can be severe and

48  Plaque-type psoriasis—chronic plaque, guttate, and erythrodermic phenotypes

Figure 7.10  Small plaque psoriasis.

Figure 7.12  Woronoff,s ring.

Figure 7.13  Scalp psoriasis.

Figure 7.11  Extensive psoriatic plaque. recalcitrant (Figure 7.13). Although hair loss is unusual in psoriasis, nonscarring alopecia may occur in areas of intense inflammation and continuous manipulation of psoriatic scales may eventually lead to cicatricial alopecia (Figure 7.14).15 The appearance of plaque psoriasis may be modified depending on the site of psoriasis. Flexural psoriasis, which is also known as inverse or intertriginous psoriasis,  refers to plaque psoriasis of the submammary,

inguinal, axillary, genital, and natal cleft regions, and often lacks scale. Seborrheic psoriasis, “sebopsoriasis,” is similar in appearance and distribution to seborrheic dermatitis (hence the name) and may occur in isolation or associated with plaque psoriasis elsewhere.16 Rare patterns of psoriasis include ostraceus or ­rupioid psoriasis and linear or follicular variants (Figures 7.15 and 7.16). During exacerbations of the disease, new lesions may be characterized by an active edge with an inflammatory border and tend to coalesce (Figure 7.17). In contrast, areas of regression may present as normochromic or postinflammatory hypo- or hyperpigmented spots that may persist for months (Figure 7.18). Occasionally, well-demarcated dark lentigines have been reported in regressing psoriasis plaques that are not associated with phototherapy treatment. Dark lentigines have also been attributed to the application of tar products in psoriasis lesions and a postinflammatory hypothesis has been ­suggested (Figure 7.19).17–19

Chronic plaque psoriasis  49

Figure 7.14  Cicatricial psoriatic plaque affecting the scalp.

Figure 7.16  Rupioid plantar psoriasis.

Figure 7.17  Confluent plaques of psoriasis. Figure 7.15  Follicular pattern of psoriasis. Psoriasis follows a variable course depending on many factors, such as age, localization, exacerbating factors, and treatment. Individual plaques may remain unchanged for months, may slowly progress and coalesce with peripheral lesions forming geographic patterns, or can acutely transform into more inflammatory stages with rapid dissemination to other skin sites. In some cases, new lesions replace older regressing ones, and in rare cases, the patient remains clear for long periods of time.

Clinical symptoms Pain, itching, burning, and irritation are common symptoms of psoriasis. Although in the past, psoriasis was ­recognized ­as a nonitchy skin disorder, available literature data show that this symptom may even concern up to 84% of psoriatic patients and severely affects their q ­ uality of life.20,21 In a study by Sampogna et al. evaluating the prevalence of symptoms associated with different clinical types of psoriasis, the proportions of patients experiencing

50  Plaque-type psoriasis—chronic plaque, guttate, and erythrodermic phenotypes

symptoms often or always in the 4 weeks before hospitalization were 63.8% itching, 59.7% irritation, 46.1% burning/stinging, 39% sensitivity, 26% pain (from 10% in guttate psoriasis to 50% in those with joint involvement), and 25.4% bleeding. The prevalence of all symptoms was significantly higher in women and tended to increase with clinical severity.22

GUTTATE PSORIASIS

Figure 7.18 

Peripheral regression with hyperpigmentation.

Figure 7.19  Multiple lentigines in a plaque of psoriasis.

Guttate psoriasis is a distinctive form of psoriasis that ­characteristically occurs in children and young adults. It may arise on its own (acute guttate psoriasis) or may complicate existing, often quite limited, chronic plaque psoriasis (guttate flare of chronic plaque psoriasis). Typically, guttate plaques erupt explosively over large areas of the skin surface 1–2 weeks after an episode of acute tonsillitis or pharyngitis.23 The clinical picture is characterized by a sudden onset of diffuse red and scaling papules generally measuring between 1 and 2 cm mostly affecting sun-protected areas (Figure 7.20). These lesions usually resolve spontaneously after a few months or may progress to plaque psoriasis, and most individuals who have been affected by guttate psoriasis eventually develop psoriasis vulgaris. The etiopathogenesis of the disease is still largely unknown but studies indicate that it is caused by an interaction of multiple genetic components and environmental factors including β-hemolytic

Figure 7.20  Detail of guttate lesions of psoriasis.

Erythrodermic psoriasis  51

streptococci.24 It was first reported in 1916 that the onset of guttate psoriasis is often preceded by throat infections with b-hemolytic streptococci.25 The pathogenic role of M  protein-positive b-hemolytic streptococci resulting in the development of guttate psoriasis has been further confirmed in several studies.26,27 The paradoxical development of guttate psoriasis in the setting of Crohn,s disease patients treated with infliximab has also been reported.28 It is generally accepted that guttate psoriasis has a better prognosis than other types of psoriasis because it may clear spontaneously after a period of months and usually has a longer remission period. However, the eruption may progress into chronic plaque psoriasis or recur even after spontaneous involution.29,30

ERYTHRODERMIC PSORIASIS Erythrodermic psoriasis represents one of the most severe and life-threatening variants of psoriasis. This form affects greater than 90% of the body surface area and presents as large coherent sheets of stratum corneum or fine scales over a predominant dusky red color reflecting the great degree of cutaneous inflammation (Figure 7.21). It is also one of the rarest forms of psoriasis, with an estimated prevalence of 1%–2.25% of patients with psoriasis.31–33

Figure 7.21  Erythrodermic psoriasis.

Erythrodermic psoriasis can manifest with ­cutaneous signs of bright erythema, edema, superficial desquamation, hair loss, or nail dystrophy, and with systemic manifestations such as fever, chills, fatigue, or malaise, or h ­igh-output congestive heart failure. Patients are at an increased risk of superinfection and sepsis from skin pathogens, particularly Staphylococcus aureus and Streptococcus species. Hospitalization should be considered for severely ill patients, as erythroderma can lead to substantial water loss and electrolyte imbalance, and the high rate of skin cell turnover places a large metabolic demand on the patient. Concurrent infections can precipitate or exacerbate erythrodermic psoriasis and pose substantial risk to the patient. It is essential to identify and treat such bacterial pathogens appropriately.32,33 This form of psoriasis can arise in patients with longstanding psoriasis vulgaris or it can occur de novo as the initial presentation of psoriasis. It generally develops if there is poor control of a patient,s existing psoriasis; abrupt withdrawal of systemic medication, such as corticosteroids (Figure 7.22); as a response to a drug reaction, such as lithium and beta-blockers; or due to an underlying systemic infection.7 There is a wide range of severity and acuity in patients with erythrodermic psoriasis. Some may present with a rapid course that may require aggressive systemic therapy to achieve disease control, whereas others may experience a more prolonged course of chronic erythroderma and experience frequent relapses.34 In rare instances, both the erythrodermic and the generalized pustular variants of psoriasis have been associated with acute noncardiogenic pulmonary edema with hypoxemia attributed to pulmonary capillary leak syndrome. Skin manifestations include diffuse edema, purpuric lesions, livedo, and eruptions in sun-exposed areas. The condition is caused by increased capillary permeability resulting in accumulation of fluids and proteins in the interstitial or extravascular space with subsequent hypovolemic shock. It is a serious condition and can be potentially fatal if not treated in a timely manner and with appropriate intensive therapy.35–37

Figure 7.22  Acute exacerbation of psoriatic lesions after corticosteroid withdrawal.

52  Plaque-type psoriasis—chronic plaque, guttate, and erythrodermic phenotypes

It is important to distinguish erythrodermic psoriasis from other inflammatory skin conditions that can present with generalized erythroderma, such as pityriasis rubra pilaris, severe cases of atopic dermatitis, generalized drug eruptions, and the erythrodermic stage of ­cutaneous lymphoma. Overall, 25% of cases of erythroderma are caused by psoriasis. Although controversy exists, one or more biopsies of representative areas can occasionally be useful in differentiating the underlying cause of erythroderma.34

REFERENCES   1. Griffiths CE, Barker JN. Pathogenesis and clinical features of psoriasis. Lancet. 2007;370:263–271. 2. Levine D, Gottlieb A. Evaluation and management of psoriasis: An internist,s guide. Med Clin North Am. 2009 November;93(6):1291–1303. 3. Naldi L, Gambini D. The clinical spectrum of psoriasis. Clin Dermatol. 2007;25(6):510–518. 4. Raychaudhuri SP, Gross J. A comparative study of pediatric onset psoriasis with adult onset psoriasis. Pediatr Dermatol. 2000;17(3):174–178. 5. Romiti R, Maragno L, Arnone M, Takahashi MD. Psoriasis in childhood and adolescence. An Bras Dermatol. 2009;84(1):9–20. 6. Kerkhof PCM, Schalkwijk J. Psoriasis. In Dermatology, Second Edition, edited by JL Bolognia, JL Jorizzo RP Rapini, pp. 115–136. Madrid: Mosby Elsevier, 2008. 7. Raychaudhuri SK, Maverakis E, Raychaudhuri SP. Diagnosis and classification of psoriasis. Autoimmun Rev. 2014;13(4–5):490–495. 8. Braun-Falco O, Plewig G, Wolff HH, Burgdorf WHC. Erythemato-papulo-squamous diseases. Dermatology, Second Edition, pp. 571–648. Berlin/ Heidelberg/New York: Springer Verlag, 2000. 9. Köbner H. Zur Aethiologie der Psoriasis. Viertel­ jahresschr Dermatol Syph. 1876;8:559–561. 10. Weiss G, Shemer A, Trau H. The Köebner phenomenon: Review of the literature. J Eur Acad Dermatol Venereol. 2002;16:241–248. 11. Criado PR, Valente NY, Michalany NS, et al. An unusual association between scalp psoriasis and ophiasic alopecia areata: The Renbök phenomenon. Clin Exp Dermatol. 2007;32(3):320–321. 12. Happle R, Van Der Steen P, Perret C. The Renbök phenomenon: An inverse Köebner reaction observed in alopecia areata. Eur J Dermatol. 1991;1:39–40. 13. Henseler T, Christophers E. Psoriasis of early and late onset: Characterization of two types of psoriasis vulgaris. J Am Acad Dermatol. 1985;13:450–456. 14. Lande R, Gregorio J, Facchinetti V, et al. Plasma­ cytoid dendritic cells sense self-DNA coupled with antimicrobial peptide. Nature. 2007 October 4;449(7162):564–569.

15. Almeida MC, Romiti R, Doche I, Valente NY, Donati  A. Psoriatic scarring alopecia. An Bras Dermatol. 2013;88(6 Suppl 1):29–31. 16. National Clinical Guideline Centre (UK). Psoriasis: Assessment and Management of Psoriasis. London: Royal College of Physicians (UK), 2012 October. 17. Burrows NP, Handfield-Jones S, Monk BE, Sabroe RA, Geraghty JM, Norris PG. Multiple lentigines confined to psoriatic plaques. Clin Exp Dermatol. 1994;19:380. 18. Kirby B, Sheehan K, Cattell D, Rogers S. Multiple lentigines arising in resolving psoriatic plaques: A histological, immunohistochemical and ultrastructural study. Abstract from Section of Dermatology Meeting. London: The Royal Society of Medicine, 1998. 19. Rogers M. Multiple lentigines confined to a resolving psoriatic plaque, treated without phototherapy. Clin Exp Dermatol. 1995;20:446. 20. Szepietowski JC, Reich A, Wisnicka B. Pruritus and psoriasis. Br J Dermatol. 2004;151:1272–1288. 21. Yosipovitch G, Goon A, Wee J, Chan YH, Goh CL. The prevalence and clinical characteristics of pruritus among patients with extensive psoriasis. ­ Br J Dermatol. 2000;143:969–973. 22. Sampogna F, Gisondi P, Melchi CF, et al. Prevalence of symptoms experienced by patients with different clinical types of psoriasis. Br J Dermatol. 2004;151:594–599. 23. Chalmers RJ, O,sullivan T, Owen CM, Griffiths CEM. A systematic review of treatments for guttate psoriasis. Br J Dermatol. 2001;145:891–894. 24. Gudjonsson JE, Thorarinsson AM, Sigurgeirsson B, Kristinsson KG, Valdimarsson H. Streptococcal throat infections and exacerbation of chronic plaque psoriasis: A prospective study. Br J Dermatol. 2003;149:530–534. 25. Winfield JM. Psoriasis as a sequel to acute inflammations of the tonsils: A clinical note. J Cutan Dis. 1916;34:441–443. 26. Whyte JH, Baughman RD, Hanover NH. Acute guttate psoriasis and streptococcal infection. Arch Dermatol. 1964;89:350–356. 27. Telfer NR, Chalmers RJ, Whale K, Colman G. The role of streptococcal infection in the initiation of guttate psoriasis. Arch Dermatol. 1992;128:39–42. 28. Costa-Romero M, Coto-Segura P, Suarez-Saavedra S, Ramos-Polo E, Santos-Juanes J. Guttate psoriasis induced by infliximab in a child with Crohn’s disease. Inflamm Bowel Dis. 2008;14:1462–1463. 29. Farber EM, Nall ML. The natural history of psoriasis in 5,600 patients. Dermatologica. 1974;148:1–18. 30. Owen CM, Chalmers RJ, O’sullivan T, Griffiths CE. A systematic review of antistreptococcal interventions for guttate and chronic plaque psoriasis. Br J Dermatol. 2001;145:886–890. 31. Boyd AS, Menter A. Erythrodermic psoriasis: Precipitating factors, course, and prognosis in 50 patients. J Am Acad Dermatol. 1989;21:985–991.

References 53

32. Farber EM, Nall L. Erythrodermic (exfoliative) psoriasis. Cutis. 1993;51(2):79–82. 33. Balasubramaniam P, Berth-Jones J. Erythroderma: 90% skin failure. Hosp Med. 2004;65(2):100–102. 34. Rosenbach M, Hsu S, Korman NJ, et al. Treatment of erythrodermic psoriasis: From the medical board of the National Psoriasis Foundation. J Am Acad Dermatol. 2010;62(4):655–656. 35. Sadeh JS, Rudikoff D, Gordon ML, Bowden J, Goldman BD, Lebwohl M. Pustular and erythrodermic psoriasis complicated by acute respiratory distress syndrome. Arch Dermatol. 1997;133(6):747–750.

36. O’Donnell PG, Hughes JR, Higgins EM, Groves RW, Pembroke AC. A fatal case of capillary leak syndrome in erythrodermic psoriasis. Br J Dermatol. 1995;132(1):160–161. 37. Bressan AL, Gripp A, Oliveira EF, Silva RS. Systemic capillary leak syndrome. An Bras Dermatol. 2011;86(3):593–595.

8 Palmoplantar psoriasis DARIO KIVELEVITCH, BOBBAK MANSOURI, and M. ALAN MENTER Palmoplantar psoriasis refers to a spectrum of rare p ­ soriasis variants that affect the palms of the hands and/or soles of the feet. These variants include palmoplantar plaque psoriasis, palmoplantar pustular psoriasis (PPP), also referred to as palmoplantar pustulosis, and acrodermatitis continua of Hallopeau (ACH). Although these conditions are considered to be separate clinical entities, overlap between them is common.1,2 In a study of 150 patients with a history of palmoplantar psoriasis, 52% were classified as having purely palmoplantar plaque psoriasis, 16% had purely PPP, 18% had a mixed phenotype, and 20% were classified as indeterminate (i.e., had features of both palmoplantar psoriasis and palmoplantar eczema/dermatitis).2 Palmoplantar psoriasis also causes significant qualityof-life (QOL) impairment with over 80% of patients having moderate to severe disease based on the modified Palmar– Plantar QOL Index, even with less than 5% of the total body surface being involved.2,3 Furthermore, patients with palmoplantar psoriasis have a greater impairment of QOL compared with moderate to severe psoriasis3 and overall more physical disability and discomfort than patients with other forms of psoriasis.4 The first section of this chapter will review localized pustular psoriasis, which includes both PPP and ACH. The second section will review the hyperkeratotic form of PPP, also referred to as palmoplantar plaque psoriasis.

LOCALIZED PUSTULAR PSORIASIS Palmoplantar pustular psoriasis INTRODUCTION

PPP is a chronic and relapsing inflammatory skin disease characterized by eruptions of sterile pustules on the palms and/or soles. Despite the relatively small surface area affected, it can have a major impact on patients’ QOL with appropriate therapeutic control being frequently difficult. Due to genetic and epidemiologic differences with chronic plaque psoriasis, PPP has to be considered as a separate entity.5

EPIDEMIOLOGY

PPP is a rare condition. Although the exact incidence worldwide is not known, a recent Japanese study of 565,903 patients found the prevalence of PPP to be 0.12%.6 Females are more likely to be affected than males, with variations in the reported literature showing 58%–94% female predominance.1 A family history of psoriasis exists in 1­ 0%–43% of PPP patients.1 The onset of PPP is most common after the age of 30 years.7 ETIOPATHOGENESIS

The etiology of PPP is not completely understood. Its genetic background does differ from that of chronic plaque psoriasis. Human leukocyte antigen (HLA) association studies have found an increased frequency of HLA-B8 and HLA-Bw35 alleles among Caucasian PPP patients.8,9 PPP has also been associated with the absence of HLA-Cw*0602 with a Japanese study suggesting that HLA-DR molecules (specifically HLA-DR9) are likely to be involved in PPP pathogenesis.10,11 Interestingly, none of these studies found an increased frequency of the known psoriasis-associated HLA antigens in PPP. Furthermore, allelic variation in three genes located in the PSORS1 region (HLA-Cw*6, HCR*WWCC, and CDSN*5) was associated with guttate psoriasis but not PPP.12 Although tumor necrosis factor (TNF)-α plays a key role in the pathogenesis of chronic plaque psoriasis, it likely plays a less defined role in PPP. Genetic studies have linked TNF-α promoter polymorphisms to plaque psoriasis and psoriatic arthritis but not to PPP,13,14 whereas a polymorphism in the TNF B (TNF-β) gene was found to be associated with PPP in the Japanese population.15 A recent study in European patients found missense variants of CARD14 associated with PPP. In contrast with generalized pustular psoriasis (GPP) no association was found with interleukin (IL)-36RN mutations.16,17 Additionally, genetic studies on cytokines of the IL-10 family found that certain variants of genes encoding for IL-19/IL-20 increased the risk of developing PPP, whereas other gene variants encoding for IL-20 and IL-24 decreased the risk of developing the disease.18 55

56  Palmoplantar psoriasis

PPP can also be associated with tonsillitis in certain patients. However, in those PPP patients without this particular association, the TNF-β2 allele and the TNF-α B allele were significantly more prevalent than in the controls.19 The pathophysiology of PPP is also not entirely understood. Recent studies have pointed to the acrosyringium as the initial site of PPP inflammation.20 The peripheral part of the eccrine gland duct shows loss of its normal structure in PPP.21 Lesional PPP skin has increased numbers of Langerhans cells and higher amounts of IL-17 at or near the acrosyringium compared with nonlesional skin or skin from healthy donors.22 A study with 48 PPP patients found IL-17A, 17C, 17D, 17F, IL-22, IL-23A, IL-23 receptor, IL-8, IL-10, IFN-γ, and TNF-α mRNAs overexpressed in PPP lesional skin compared with healthy controls, whereas TNF-α, IL-17, IL-22, and IFN-γ serum concentrations were also increased in PPP patients compared with healthy controls.23 The antimicrobial peptide LL-37 and its precursor hCAP-18 are present in higher concentrations in early PPP vesicle fluid (PPP-VF) compared with healthy sweat fluid.24 Poteinase-3, which converts hCAP-18 into LL-37, was also present in PPP-VF. Furthermore, PPP-VF induced the expression of IL-17C, IL-8, IL-1α, and IL-1β mRNAs in skin equivalents.24 Smoking is the modifiable risk factor that has most commonly been linked with PPP. Ninety-five percent of PPP patients surveyed in a Swedish study were smokers at the onset of their disease,25 PPP onset and exacerbation have been associated with smoking,26 and smoking cessation has also been shown to lead to significant disease improvement.27 Although the mechanism by which smoking can affect PPP severity is not completely elucidated, available data suggest that nicotine may contribute to the interplay between the eccrine sweat gland and the immune infiltrate. Interestingly, normal eccrine sweat contains IL-1α, IL-1β, and IL-31, which could stimulate keratinocytes in case of skin barrier dysfunction.28 A possible mechanism for skin barrier disruption in PPP could be linked to decreased levels of antileukoprotease (SKALP) activity found in pustular psoriasis29 or other imbalances within the skin’s protease/antiprotease system. The mechanism by which smoking causes or exacerbates PPP also likely relates to the activity of nicotine on the nicotinic acetylcholine (ACh) receptors. ACh is the main stimulus for palmar eccrine sweating. However, both adrenaline and nicotine can also induce palmar eccrine sweating.30,31 It has been shown that neutrophils infiltrating sweat glands and ducts of PPP patients express choline acetyl ­transferase—the ACh synthesizing enzyme.32 Furthermore, nicotinic ACh receptors are distributed differently in lesional PPP skin compared with healthy smokers and healthy nonsmokers,33 and the highest concentration of ACh esterase—the enzyme that degrades ACh—in the acrosyringium unit was located at the lower part of the stratum corneum, the typical location of pustules in PPP.33 These data suggest

imbalances in neurotransmitter homeostasis, which may play a role in disease pathogenesis. The skin neuroendocrine system is also altered in PPP. Certain molecules, such as chromogranins, synaptophysin,34 and somatostatin receptors,35 are differentially expressed in PPP skin compared with healthy controls. PPP exacerbations have also been observed after skin exposure to metals and were accompanied by elevated leukotriene B4 levels in plasma and pustules.36 The relationship between tonsillitis and PPP onset or its worsening is not entirely clear. Japanese studies have found varying degrees of therapeutic success, ranging from 16.7% to over 75% improvement for PPP patients following tonsillectomy. 37,38 A randomized controlled trial on the effect of tonsillectomy in PPP patients showed that 86% of patients who underwent a tonsillectomy had a sustained response with significant reduction in the Palmoplantar Psoriasis Area and Severity Index (PPPASI) score, ranging from 30% to 90% reduction. Nevertheless, some patients experienced psoriasis relapse after initial improvement. 39 Histologically, the tonsils of PPP patients show significantly increased numbers of lymphoid follicles surrounded by reticular crypt epithelial cells compared with controls. IL-6 concentrations were higher in PPP patients’ tonsils than in controls.40 IL-6 has also been found significantly elevated in PPP serum. Furthermore, after tonsillectomy there was a significant reduction in the serum concentration of IL-6 that paralleled a PPP improvement.41 In vitro stimulation with streptococcal antigens on PPP tonsillar and peripheral blood T cells showed a significant upregulation of IL-6, IFN-γ, TNF-α, and CCR6.42–44 CCL20, CCR6 ligand, mediates recruitment of lymphocytes and is overexpressed in PPP lesions. Tonsillectomy of PPP patients resulted in a decreased CCR6 expression on blood T cells.44 New onset PPP has been reported as a result of the use of TNF-α inhibitor agents in nonpsoriasis patients (i.e., Crohn’s disease and rheumatoid arthritis). This paradoxical effect is thought to be caused by a shift in the immune response toward one that is interferon mediated.45 Of interest, several cases of TNF-α inhibitor–induced PPP have been treated successfully with IL-6 inhibitors.46–48 However, plaque psoriasis has been triggered by the use of IL-6 inhibitors,49 providing another example of the heterogeneity of these psoriasis vulgaris variants and the complex interplay of cytokines within the immune systems of these patients. CLINICAL PRESENTATION

Physical exam: The primary lesions in PPP are pustules measuring from 1 to 10 mm in diameter, with frequent coalescence to form larger lesions (Figure 8.1). Recurring crops of pustules usually erupt on healthy-appearing palmar and plantar skin. Erythema can either surround the lesions or may involve larger areas of the palms and soles (Figures 8.2 and 8.3). Although the distribution of lesions

Localized pustular psoriasis  57

Figure 8.1 

Hand with multiple pustules in various stages of development, some coalescing into larger lesions.

Figure 8.3 Soles with pustules in various stages of ­evolution in association with localized hyperkeratotic plaques.

Figure 8.2  Palm with multiple scattered pustules with an erythematous halo in different stages of evolution. Coalescence evident plus resolving brown-colored lesions. is usually seen on both palms and/or soles, u ­ nilateral involvement has also been noted on occasional patients presenting with only one to two pustules. The most common sites affected are the thenar eminence on the palms and the instep, the medial and/or lateral borders of the foot as well as the sides and/or back of the heel on the feet. In severe cases of PPP, the entire palm and/or sole surfaces can be affected. Lesions may also extend to the flexor surface of the wrists and dorsa of the fingers and feet. Although lesions can occasionally be seen on other anatomical locations in a patient with PPP,50 the diagnosis of GPP should only be considered in a patient who is found to have spreading “pustulosis” involving larger areas of the body surface. New eruptions and recurrences of PPP frequently tend to affect sites of prior involvement. Resolving PPP lesions have a distinctive change in color and substance, from pale yellowish pustules to dark brown macules (Figures 8.4 and 8.5) over the course of several

days with residual scaling, hyperkeratosis, and prominent hyperpigmentation being noted. Nails can also be affected in up to 30% of the patients with the most common finding being subungual pustulation.51 Onycholysis, pitting, onychodystrophy, or discoloration of the nail plate may also be seen. Symptoms: Pain, burning, or a stinging sensation and itching is associated with PPP eruptions. PPP is frequently a disabling disease, preventing patients from walking or utilizing their hands normally due to pain and discomfort. Clinical course: PPP usually is a recurring, remitting, and totally unpredictable condition. Response to all forms of therapy is unpredictable, being often resistant to multiple treatments including combination therapies. Some patients enjoy relatively long (weeks–months) pustule-free periods, whereas others have a continuous eruptions of new lesions.52 PPP coexists infrequently with other forms of psoriasis, including chronic plaque psoriasis. COMORBIDITIES

Psoriatic arthritis is found in approximately 25% of patients with PPP.1 The presence of antithyroglobulin antibodies as well as hyper- and hypothyroidism have been associated with PPP.21,53,54 Interestingly, there is a structural homology between thyroglobulin and ACh esterase,55 which is present in higher concentrations at the acrosyringium in PPP. Glucose intolerance was more prevalent in PPP patients in a Japanese study.56 The association of arthropathies with PPP may present as a part of the synovitis, acne, pustulosis, hyperostosis, and o ­ steitis

58  Palmoplantar psoriasis

and elongation of the rete ridges). Areas of spongiosis can also be identified. Neutrophils, eosinophils, and mast cells are increased in PPP lesional skin with dilatation of the superficial dermal capillaries in all lesions. The acrosyringium and its relation with the pustule cannot be seen in affected skin (Figure 8.6).21 DIFFERENTIAL DIAGNOSIS

The main diagnoses to be distinguished from PPP are

• Acute palmoplantar eczema/dyshidrotic eczema (pompholyx) where pustules similar to PPP, due to secondary infection are not infrequently noted ACH Pustular variants of tinea pedis or tinea manum

• • Figure 8.4  Hand lesions in various stages of development, some coalescing into larger lesions with patchy hyperkeratosis.

Less common conditions to be considered are variants of pemphigus vulgaris, vesiculopustular mycosis fungoides, and localized pustular vasculitis. TREATMENT

Multiple clinical trials have been performed investigating an array of treatment modalities for PPP. However, most studies have been small with an absence of appropriate controls.52 Treatment response for PPP is highly variable and unpredictable with high rates of recurrence noted. In patients with mild, limited disease, therapy with high potency topical corticosteroids with or without occlusion is the usual treatment of choice with responses to occlusion usually preferable.64 There are no randomized controlled trials (RCTs) and few studies to support the efficacy of topical retinoids, tar, anthralin, or calcipotriol, although these agents are sometimes used in the clinical setting. In those cases in which topical steroids are not effective or PPP affects larger areas of palms and/or soles with concomitant increase in symptomatology, more active intervention

Figure 8.5  Foot lesions in various stages of development, some coalescing into larger lesions with patchy hyperkeratosis. (SAPHO) ­syndrome.57 PPP-associated arthropathies include infectious and noninfectious inflammatory bone lesions, among which are recurrent multifocal osteomyelitis,58 pustular arthro-osteitis,59 axial and peripheral arthritis,60 and sternocostoclavicular involvement, which can affect up to 22% of PPP patients.61 A recent study also found anti-gliadin and anti-transglutaminase antibodies in 18% and 10% of PPP patients, respectively. Only 6% of the patients were diagnosed with celiac disease, although those patients with positive titers of any of the antibodies showed significant improvement after following a gluten-free diet.62 In contrast, a German study was unable to find the same gluten intolerance association.63 DERMATOPATHOLOGY

PPP is characterized by the presence of subcorneal intraepidermal pustules and psoriasiform changes (parakeratosis

Figure 8.6 

Histopathology of pustular psoriasis: ­epidermal acanthosis with hypogranulosis, thinning of supra papillary plates, and overlying parakeratosis. Intraepidermal c­ ollections of neutrophils coalescing into pustules. Accentuated ­papillary dermal capillaries with perivascular lymphocytic ­ infiltrate. (Courtesy of Dr. Clay Cockerell.)

Localized pustular psoriasis  59

should be considered with or ­without c­oncomitant ­topical therapy. Treatment guidelines set forth by the medical board of the National Psoriasis Foundation in 2012 suggest acitretin, cyclosporine, topical or systemic psoralen with ultraviolet A (PUVA), or retinoid-PUVA (Re-PUVA) combination as therapeutic options.65 Data from four RCTs with etretinate showed good or excellent responses in 39% of PPP compared with 17% of the placebo group.66 Etretinate is no longer available in the United States, but acitretin has been shown to have similar efficacy to etretinate.67 An RCT with cyclosporine for treatment of PPP showed it was significantly more effective than placebo in achieving at least 50% of clinical improvement (89% vs. 27%).68 Oral PUVA has been reported to be effective in the treatment of PPP,69 as has topical PUVA,69 although a RCT failed to prove superior efficacy over placebo.70,71 Re-PUVA has shown increased efficacy compared with either a retinoid or PUVA alone.52,66 Anti-TNF-α agents may be used in patients who fail to respond appropriately to the aforementioned topical and/ or systemic therapies.65 Despite the fact that these agents have been shown to induce PPP, there is evidence to support the use of TNF-α inhibitors to treat PPP as well. In an RCT with etanercept, significant improvement was shown after 24 weeks, although in some patients it appeared to worsen the disease.72 Similarly, infliximab has shown benefit for some patients while worsening others.73,74 Adalimumab has shown efficacy in a small open-label study.75 Other potential therapeutic options include methotrexate (MTX), fumaric acid esters (FAE), itraconazole, other lightbased therapies, and IL-1 antagonists. Evidence supporting the use of MTX is limited. In a retrospective study 57% of patients on MTX improved significantly.76 The use of FAEs for the treatment of PPP in an open-label study resulted in a mean improvement of the PPPASI of 49% in palms and 44% in soles at 24 weeks.77 Oral itraconazole improved PPP in two open-label studies. All patients relapsed after cessation of therapy.78,79 Excimer laser has shown to be effective in PPP treatment in open-label studies,80,81 whereas photodynamic therapy has also been reported to be effective in several case reports.82 There has also been a case report of a patient with severe, recalcitrant PPP showing partial response to the IL-1 inhibitor anakinra.83 The use of colchicine and ustekinumab are not recommended. An open label trial with 52 patients found acitretin as the most effective system followed by colchicine and MTX.76 However, in an RCT, colchicine did not show good clinical results.84 Similarly, ustekinumab failed to show higher effectiveness than placebo in an RCT.85 MANAGEMENT

Patients should be strongly encouraged to cease smoking. Tonsillectomy may help to prevent new eruptions of PPP in some patients. Patients with positive titers of antigliadin and/or tissue transglutaminase antibodies or with celiac disease should be advised to initiate a gluten-free diet with clinical response appropriately assessed.

Acrodermatitis continua of Hallopeau INTRODUCTION

ACH is considered a rare form of localized pustular ­psoriasis. It presents as chronic, relapsing pustular eruptions affecting the tips of the fingers or toes and nails.86 It can present as a singular clinical finding or as a fresh finding in a patient with preexisting PPP. ACH is the most uncommon variant of PPP. EPIDEMIOLOGY

Although rarely seen in children, ACH most frequently occurs in middle-aged women. There are no specific data on prevalence or incidence of the disease.86,87 ETIOPATHOGENESIS

The etiopathogenesis of ACH remains unclear. The onset of the disease occasionally follows trauma or even infection of a finger or a toe.86 A few patients with ACH have shown mutations in the IL36RN gene, the same gene affected in a familial form of GPP.16 These findings suggest that some cases of ACH may be part of the clinical spectrum of deficiency of the IL-36 receptor antagonist (DITRA).88 A recent study linked mutations in AP1S3 with various forms of pustular psoriasis—PPP, GPP, and ACH.89 The mutations described are associated with impaired Tolllike receptor 3 trafficking and decreased IFN-β, which possess an anti-inflammatory effect and could explain the immune system dysregulation.89 CLINICAL PRESENTATION

Physical exam: Initially, ACH invariably affects the tips of only one or two digits. Finger involvement is more common than toe involvement.86 The primary lesions are individual pustules that may coalesce to form larger pus-filled lesions. Pustules often rupture to form an ­erythematous, hyperkeratotic area with subsequent new pustules appearing. The nail folds are compromised early in the disease. Chronic involvement of the nail apparatus can lead to onychodystrophy and anonychia90 (Figures 8.7 and 8.8). ACH may on occasion progress to affect all 10 digits and, in severe cases, extend proximally to involve the hand, foot, or dorsum of the forearm with more than one extremity being affected, including the distal phalanx. Areas of atrophy may be noted with long standing involvement. Clinical course: ACH follows a chronic course. Its lesions tend to spread proximally, with repetitive cycles of fresh pustular eruptions and minimal improvement if left untreated. ACH can also lead to irreversible loss of the nail apparatus. ACH has rarely been reported to progress to GPP.91 Radiological/laboratory findings: In severe, advanced cases, atrophy of the distal phalanx and arthropathy of the interphalangeal joints can be seen radiographically. Laboratory values are usually within normal limits.92

60  Palmoplantar psoriasis

(a)

Figure 8.7 

Hand with severe acropustulosis of fingers with erythema and hyperkeratosis. Major onychodystrophy and anonychia.

(b)

Figure 8.8  Hand with distal involvement of finger pulps with erythema and hyperkeratosis. DERMATOPATHOLOGY

Biopsies of ACH lesional skin resemble pustular psoriasis (Figure 8.9). There are subcorneal pustules filled with neutrophils. The zones adjacent to the pustule show groups of leukocytes forming spongiform pustules in the upper epidermis. The upper dermis shows a lymphohistiocytic infiltrate and focal edema. Long-standing lesions may show thinning of the epidermis and severe atrophy of the papillary dermis.86 DIFFERENTIAL DIAGNOSIS

Early disease should be distinguished from the following:

• Acute paronychia (bacteria or fungi) • Herpetic whitlow • Dyshidrotic eczema

Figure 8.9  (a) Clinical presentation of acropustulosis of Hallopeau and (b) histopathology: acral skin with intraepidermal spongiform pustules and variable neutrophils, psoriasiform epidermal acanthosis, and moderate perivascular dermal inflammation, histologically indistinguishable from acral pustular psoriasis. (Courtesy of Dr. Clay Cockerell.) TREATMENT

Treatment success is difficult to achieve and sustain with ACH recurrences frequent after treatment withdrawal. Available data on treatment of ACH are mostly limited to case reports. Topical steroids with or without occlusion can be used with relative benefit, although cautious use in atrophic areas is recommended. Topical calcipotriol (alone or in combination with topical corticosteroids or topical tacrolimus), topical tacrolimus,93 topical fluorouracil, topical and systemic PUVA, and narrowband UVB are some of the local treatments that have been reported to be effective in ACH.86 Systemic therapies that may yield some ­benefit include oral retinoids, cyclosporine, MTX, systemic ­ g lucocorticoids, etanercept, adalimumab, infliximab94 (Figures 8.10 and 8.11), and

Palmoplantar plaque psoriasis  61

PALMOPLANTAR PLAQUE PSORIASIS Introduction Palmoplantar plaque psoriasis is similar in phenotype to chronic plaque psoriasis presenting on other areas of the body surface.

Epidemiology

Figure 8.10  Acropustulosis continua of Hallopeau before treatment with infliximab.

Palmoplantar plaque psoriasis has been reported to affect up to 41% of psoriasis patients,97 with 7.5%–70% of patients having only palmoplantar involvement.2,98,99 In a study of 3065 patients with psoriasis who were screened over a 7-year period, 17.4% were found to have PPP, whereas 70% of those patients with palmoplantar plaque psoriasis presented with only isolated palmoplantar disease.98 The disease appears to have no male or female predominance. The estimated overall prevalence of palmoplantar plaque psoriasis is 0.12%–0.36%.1,98

Etiopathogenesis The etiology of palmoplantar plaque psoriasis is not fully understood, though the basic pathomechanisms of the disease are thought to be shared with classic plaque psoriasis. IL-23, Th17 cells, IL-17, and TNF-α likely play important roles in its pathogenesis.100 In fact, immunohistochemical analyses have shown that there are increased levels of IL-23 in palmoplantar plaque psoriasis as opposed to normal skin.101 However, most studies examining the immunopathogenesis of PPP have been focused on PPP rather than on palmoplantar plaque psoriasis. Additional factors that have been shown to exacerbate PPP include manual trauma,102,103 the Köebner phenomenon,98 contact sensitivity,104 and smoking.105

Clinical presentation

Figure 8.11  Acropustulosis

continua of Hallopeau after 1 year of treatment with infliximab.

anakinra. Combination therapy is frequently ­necessary to sustain treatment response, with a combination of systemic acitretin and local calcipotriol showing good results in a case report.95 Dapsone has also been tried in recalcitrant cases.96

Physical exam: Palmoplantar plaque psoriasis presents in a similar fashion to chronic plaque psoriasis lesions observed on other areas of the body. It is characterized by sharply demarcated erythema and thick keratotic plaques, overlying silvery scale or discrete plaques that affect the palms and/or soles with frequent extension to the wrists and margins of the plantar surfaces of the feet (Figures 8.12–8.14). Additionally, fissures both small and large are a common finding, producing a significant impact on a patient’s QOL2,106 (Figures 8.15 and 8.16). Palmoplantar plaque psoriasis is mainly differentiated from PPP by its lack of pustules and warty plaques. It can present as a singular finding or in association with psoriasis elsewhere.2,98 Patients who do have psoriatic lesions outside the palmoplantar area tend

62  Palmoplantar psoriasis

Figure 8.12  Hand with localized hyperkeratotic plaque on mid palm with few fissures.

Figure 8.13  Foot with large hyperkeratotic plaque with underlying erythema and fissuring affecting the posterior two-thirds of the sole and heel with extension to the instep. to have less severe involvement.1 Interestingly, patients with palmoplantar plaque psoriasis have been found to have inverse (or flexural) psoriasis five times more frequently than patients with chronic plaque psoriasis.107 Symptoms: Itching is a common symptom. In addition, pain and burning are frequent complaints in patients with skin fissures.

Figure 8.14  Foot with large hyperkeratotic, erythematous plaque with coarse scaling affecting the heel and extending to the medial ankle.

Figure 8.15  Foot with large hyperkeratotic plaque with scaling, erythema, and multiple fissures affecting the sole. Clinical course: This form of psoriasis is a chronic r­ecalcitrant, relapsing condition, particularly in those patients with no clinical evident disease elsewhere.1 Palmoplantar plaque psoriasis can be exacerbated by stress, contact irritants, or infection.

Palmoplantar plaque psoriasis  63

Dermatopathology Distinguishing palmoplantar plaque psoriasis from other hand and foot dermatoses, including atopic eczema, irritant/contact dermatitis, dyshidrotic or nummular eczema, -id reactions, or tinea infections, can be difficult to make based solely on histologic findings.108,109 Biopsies of palmoplantar plaque psoriasis share a number of histologic features with eczematous dermatitis, such as prominent epidermal spongiosis109 (Figure 8.17). Cribier states that the key to diagnosis is the presence of tortuous papillary vessels, neutrophils in the spinous layer, or relative decrease of granular layer thickness in the suprapapillary areas.108 Aydin et al. showed that, in a study of 42 patients (17 with psoriasis and 25 with

eczematous dermatitis), vertically situated multiple foci of p ­arakeratosis, a­lternating with orthokeratosis, were the only significant feature distinguishing palmoplantar plaque psoriasis within its differential diagnosis.109 Nonsignificant findings more common to PPP included multiple foci of parakeratosis, loss of granular layer at least in focal areas, presence of neutrophils at the summits of parakeratosis, presence of neutrophils and/or plasma in the parakeratotic foci, psoriasiform epidermal hyperplasia, spongiosis restricted to the lower parts of the epidermis, dyskeratotic cells, thinning of the suprapapillary plate, edema of the papillary dermis, presence of tortuous and dilated capillaries in the papillary dermis, and extravasated erythrocytes.

Differential diagnosis Differential considerations within the spectrum of PPP include the following:

• Palmoplantar eczema/dermatitis • ACH • PPP • Tinea pedis or manum Treatment

Figure 8.16  Foot

with large hyperkeratotic plaque with deep fissures on the sole.

Figure 8.17  Histopathology of hyperkeratotic palmoplantar psoriasis: acral skin with thick, parakeratotic scale overlying epidermal acanthosis, thinning of the suprapapillary plates, and a mild perivascular inflammation. (Courtesy of Dr. Clay Cockerell.)

The treatment of palmoplantar plaque psoriasis, like PPP and ACH, is challenging. Conventional treatments for chronic plaque psoriasis are less effective and because it is less common than classic plaque psoriasis, few definite clinical studies exist for its specific treatment. Treatment of palmoplantar plaque psoriasis is approa­ ched in a similar way as chronic plaque psoriasis. There is an early emphasis on topical therapy, with or without occlusion. First-line options for treating palmoplantar plaque psoriasis based on expert opinion and higher levels of evidence include high potency corticosteroids110,111 (as monotherapy or in combination with calcipotriol),112 topical coal tar and salicylic acid under occlusion,113 topical PUVA (oral, paint, or soak),114–118 and topical calcipotriol with or without occlusion.112,119 Other options include topical tazarotene,111 topical calcineurin inhibitors,120 narrowband UVB,114,121 and intralesional triamcinolone injection for individual small lesions.112 A significant number of patients will require systemic therapy to maintain adequate long-term control of their disease and QOL with oral acitretin commonly used as a first-line drug.122–124 Additional oral s­ ystemic therapeutic options include both cyclosporine76 and MTX.125 These oral agents can also be used cautiously in combination. Biological therapeutic options include adalimumab,126,127 etanercept,128 infliximab,129 secukinumab,130,131 or ustekinumab132 with less optimal results usually seen as compared with classic plaque psoriasis elsewhere on the body. Other potential systemic

64  Palmoplantar psoriasis

options include FAE, apremilast, or hydroxyurea often in combination with acitretin. In clinical practice, systemic therapies are generally used in combination with topical therapies, with or without occlusion. Furthermore, appropriate counseling of patients relating to care of their hands and feet and use of appropriate gloves with manual labor is essential.

SUMMARY

• PPP is a spectrum of disease which includes palmoplantar plaque psoriasis, PPP, and ACH. • PPP is a separate disease entity. • PPP has a significant effect on a patient’s quality of life. • PPP variants generally have a chronic, relapsing course. • PPP can be exacerbated by smoking, contact irritants, stress, or infections. • Diagnosing PPP relies heavily on the clinical picture.

Palmoplantar plaque psoriasis resembles chronic plaque psoriasis lesions whereas PPP presents as crops of subcorneal pustules on the palms and/or soles. ACH presents as pustular eruption confined to the distal ends of the fingers and toes with nail involvement. Histopathology is frequently of minimal help in differentiating PPP from other entities, specifically hand and foot eczema. Treatment of PPP can be challenging. Initial therapy includes topical medications with or without occlusion, and the addition of systemic/biologic therapies is frequently necessary for more recalcitrant cases, despite less than optimal outcomes. As a general rule, frequent use of skin moisturizers can help reduce the discomfort associated with fissures in skin and should be recommended for all patients with PPP. Avoidance of irritants by the use of gloves is recommended as exacerbations of PPP are seen in many cases, mediated by contact irritants.

• • •

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32. Hagforsen E. The cutaneous non-neuronal ­cholinergic system and smoking related dermatoses: Studies of the psoriasis variant palmoplantar pustulosis. Life Sci. 2007;80(24–25):2227–2234. 33. Hagforsen E, Edvinsson M, Nordlind K, Michaelsson G. Expression of nicotinic receptors in the skin of patients with palmoplantar pustulosis. Br J Dermatol. 2002;146(3):383–391. 34. Hagforsen E, Michaelsson G, Stridsberg M. Normal and PPP-affected palmoplantar sweat gland express neuroendocrine markers chromogranins and synaptophysin differently. Arch Dermatol Res. 2010;302(9):685–693. 35. Hagforsen E, Michaelsson G, Stridsberg M. Somatostatin receptors are strongly expressed in palmoplantar sweat glands and ducts: Studies of normal and palmoplantar pustulosis skin. Clin Exp Dermatol. 2011;36(5):521–527. 36. Nakamura K, Imakado S, Takizawa M, et al. Exacerbation of pustulosis palmaris et plantaris after topical application of metals accompanied by elevated levels of leukotriene B4 in pustules. J Am Acad Dermatol. 2000;42(6):1021–1025. 37. Tsubota H, Kataura A, Kukuminato Y, et al. Efficacy of tonsillectomy for improving skin lesions of Pustulosis palmaris et plantaris—Evaluation of 289 cases at the Department of Otolaryngology of Sapporo Medical University. Nihon Jibiinkoka Gakkai kaiho. 1994;97(9):1621–1630. 38. Ozawa A, Ohkido M, Haruki Y, et al. Treatments of generalized pustular psoriasis: A multicenter study in Japan. J Dermatol. 1999;26(3):141–149. 39. Thorleifsdottir RH, Sigurdardottir SL, Sigurgeirsson B, et al. Improvement of psoriasis after tonsillectomy is associated with a decrease in the frequency of circulating T cells that recognize streptococcal determinants and homologous skin determinants. J Immunol. 2012;188(10):5160–5165. 40. Koshiba S, Ichimiya S, Nagashima T, et al. Tonsillar crypt epithelium of palmoplantar pustulosis secretes interleukin-6 to support B-cell development via p63/p73 transcription factors. J Pathol. 2008;214(1):75–84. 41. Nakamura T, Oishi M, Johno M, Ono T, Honda M. Serum levels of interleukin 6 in patients with pustulosis palmaris et plantaris. J Dermatol. 1993;20(12):763–766. 42. Murakata H, Harabuchi Y, Kukuminato Y, Yokoyama Y, Kataura A. Cytokine production by tonsillar lymphocytes stimulated with alpha-streptococci in patients with pustulosis palmaris et plantaris. Acta oto-laryngol Suppl. 1996;523:201–203. 43. Murakata H, Harabuchi Y, Kataura A. Increased interleukin-6, interferon-gamma and tumour necrosis factor-alpha production by tonsillar mononuclear cells stimulated with alpha-streptococci in patients with pustulosis palmaris et plantaris. Acta Otolaryngol. 1999;119(3):384–391.

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85. Bissonnette R, Nigen S, Langley RG, et al. Increased expression of IL-17A and limited involvement of IL-23 in patients with palmo-plantar (PP) pustular psoriasis or PP pustulosis; results from a randomised controlled trial. J Eur Acad Dermatol Venereol. 2014;28(10):1298–1305. 86. Sehgal VN, Verma P, Sharma S, et al. Acrodermatitis continua of Hallopeau: Evolution of treatment options. Int J Dermatol. 2011;50(10):1195–1211. 87. Griffits CEM, Barker JNWN. Psoriasis. In Burns T, Rook A, Rook’s Textbook Of Dermatology, 4 Volume Set [e-book]. Chichester, UK: Wiley-Blackwell, 2010. 88. Abbas O, Itani S, Ghosn S, et al. Acrodermatitis c­ontinua of Hallopeau is a clinical phenotype of DITRA: Evidence that it is a variant of pustular psoriasis. Dermatology. 2013;226(1):28–31. 89. Setta-Kaffetzi N, Simpson MA, Navarini AA, et al. AP1S3 mutations are associated with pustular psoriasis and impaired Toll-like receptor 3 trafficking. Am J Hum Genet. 2014;94(5):790–797. 90. Naldi L, Gambini D. The clinical spectrum of psoriasis. Clin Dermatol. 2007;25(6):510–518. 91. Ranugha PS, Kumari R, Thappa DM. Acrodermatitis continua of Hallopeau evolving into generalised pustular psoriasis. Indian J Dermatol. 2013;58(2):161. 92. Mrowietz U. Pustular Eruptions of Palms and Soles. In Goldsmith LA, Katz SI, Gilchrest BA, Paller AS, Leffell DJ, Wolff K. eds, Fitzpatrick’s Dermatology in General Medicine, 8e. New York, NY: McGraw-Hill, 2012. 93. Wilsmann-Theis D, Hagemann T, Dederer H, Wenzel J, Bieber T, Novak N. Successful treatment of acrodermatitis continua suppurativa with topical tacrolimus 0.1% ointment. Br J Dermatol. 2004;150(6):1194–1197. 94. Puig L, Barco D, Vilarrasa E, Alomar A. Treatment of acrodermatitis continua of Hallopeau with TNF-blocking agents: Case report and review. Dermatology. 2010;220(2):154–158. 95. Kuijpers AL, van Dooren-Greebe RJ, van de Kerkhof PC. Acrodermatitis continua of Hallopeau: Response to combined treatment with acitretin and calcipotriol ointment. Dermatology. 1996;192(4):357–359. 96. Nikkels AF, Nikkels-Tassoudji N, Pierard GE. Breaking the relentless course of Hallopeau’s acrodermatitis by dapsone. Eur J Dermatol. 1999;9(2):126–128. 97. Farber EM, Nall ML. The natural history of psoriasis in 5,600 patients. Dermatologica. 1974;148(1):1–18. 98. Kumar B, Saraswat A, Kaur I. Palmoplantar lesions in psoriasis: A study of 3065 patients. Acta DermVenereol. 2002;82(3):192–195. 99. Sampogna F, Gisondi P, Melchi CF, et al. Prevalence of symptoms experienced by patients with different clinical types of psoriasis. Br J Dermatol. 2004;151(3):594–599.

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with involvement of hands and/or feet: Subanalysis of a randomized, double-blind, placebo-controlled, phase 2 dose-ranging study. J Eur Acad Dermatol Venereol. 2014;28(8):1127–1129. 132. Au SC, Goldminz AM, Kim N, et al. Investigatorinitiated, open-label trial of ustekinumab for the treatment of moderate-to-severe palmoplantar psoriasis. J Dermatolog Treat. 2013;24(3):179–187.

9 Generalized pustular psoriasis HERVÉ BACHELEZ INTRODUCTION Psoriasis is a common, chronic inflammatory skin disease, which has a heterogeneity of clinical presentations and phenotypes, of which the plaque-type variant dominates in terms of prevalence. At the other extremity of the psoriasis spectrum lies a variant called generalized pustular psoriasis, initially described by von Zumbusch in 1910 in a patient also affected by psoriasis vulgaris, and then further described in cohorts studies.1,2 Although the inclusion of generalized pustular psoriasis (GPP) in the psoriasis spectrum has been, and still is, questioned, many epidemiological, clinical, physiopathological, and therapeutic parameters indicate that it should be maintained in this ensemble of psoriasis or psoriasis-like entities, notably due to its association with plaque psoriasis in roughly 25% to 30% of cases.1

DEFINITION, CLINICAL PRESENTATION, HISTOPATHOLOGICAL, AND BIOLOGICAL FINDINGS In its typical form, GPP is a severe cutaneous and multisystemic inflammatory disease with life-threatening potential characterized by sudden, repeated episodes of a generalized eruption of disseminated aseptic pustules, associated with high fever, and general symptoms such as asthenia and polymyalgia. Characteristic histopathological findings consist of a dense, pleomorphic dermal infiltrate of innate immune cells, where neutrophils and monocytes predominate, along with a significant T lymphocytic component.3 The typical intraepidermal afflux of neutrophils leads to the typical spongiform Kogoj pustule. Marked hyperleukocytosis with peripheral blood neutrophilia is observed, with striking systemic inflammation demonstrated by a high serum level of C-reactive protein (CRP). The frequency of these attacks greatly varies between patients and even in a given patient over time. Aside from the typical acute generalized form described by von Zumbusch, other clinical presentations include palmo-plantar pustulosis (PPP),

annular and circinate forms, juvenile and infantile GPP, and acrodermatitis ­continua of Hallopeau (ACH), a variant of pustulosis confined to the nails and distal ­digits.1–4 (see Figures 9.1 and 9.2). Triggering events reported and/ or identified to date include infection, withdrawal of systemic steroid therapy, stress, and pregnancy. The variant in pregnancy previously known as “impetigo herpetiformis” has now been replaced by the term “GPP of pregnancy.” Occasional cases of paradoxical GPP following treatment with tumor necrosis factor-alpha (TNF-α) inhibitors have been also reported. Although clinically distinct from the most frequent form of psoriasis, psoriasis vulgaris (PV)/plaque type, GPP may be associated with plaque lesions in approximately 30% of cases.1,5 This legitimates the inclusion of GPP in the wide spectrum of psoriasis.

EPIDEMIOLOGY There are very few studies that have investigated the incidence and/or prevalence of GPP at a population level. A retrospective survey conducted in dermatology centers in France estimated the minimal prevalence and annual incidence to be 0.64 and 1.76/million, respectively.6,7 Another epidemiological survey performed in Japanese dermatological institutions reported that GPP represented 1.3% of all 11,631 patients recorded with any form of psoriasis. Taking these figures together, GPP may certainly be considered as a rare, orphan disease. It is more common in females than in males.

PHYSIOPATHOLOGY In 2011, a major achievement in understanding the etiology of GPP was the identification of homozygous or composite heterozygous loss-of-function mutations of interleukin (IL)-36RN, a gene belonging to the IL-1 family encoding the IL-36 receptor antagonist (IL-36Ra), through studies of familial or sporadic GPP cases.4,8 This IL-36Ra protein is responsible for tight control of the 71

72  Generalized pustular psoriasis

Figure 9.1  Erythroderma with erythematous and micropustular lesions of the trunk in a young patient with deficiency of interleukin (IL)-36 receptor antagonist (deficiency of IL-36 receptor antagonist or DITRA). Superficial yellow crusts are also visible.

chain common to the IL-1 receptor called IL-1RacP. The IL-36RN mutations described so far lead to the absence or at least to major alterations in the production of functional IL-36Ra protein, and then to subsequent uncontrolled activation of the nuclear factor kappa B (NF-κB) signaling pathway and further production and release of inflammatory mediators, including IL-8/CXCL8 (a neutrophil-recruiting chemokine), TNF-α, and IL-6. Of note, the IL-36 receptor is heavily expressed in keratinocytes, dendritic cells, and monocytes, all cellular subtypes that are highly represented in the skin. The identification of IL-36 dysregulation in GPP led to the acronymous definition of deficiency of IL-36 receptor antagonist (DITRA). Since its initial description, IL-36RN mutations have been reported not only in sporadic cases of GPP, but also in subsets of patients with palmoplantar pustulosis (PPP), ACH, and acute exanthematous generalized pustulosis (AGEP), but not in isolated plaque psoriasis.9 There is, however, clear evidence that IL-36 agonist cytokines, especially IL-36γ, are consistently upregulated in plaque psoriasis lesions, making this pathway an appealing therapeutic target across different psoriasis subtypes.10 Rare GPP cases have been associated with heterozygous mutation of the CARD14 gene,11 or AP1S3 innate immune response genes.12 Altogether, even if IL-36 appears to be the dominant dysregulated pathway in GPP, there is evidence for genetic heterogeneity, as only a small proportion of patients have homozygous mutations for IL-36RN.

CLINICAL COURSE, COMPLICATIONS, PROGNOSIS

Figure 9.2  Annular lesions with peripheral pustules and superficial desquamation of the leg and foot in a patient with GPP.

inflammatory cascade resulting from the interaction of three i­ nflammatory IL-36 cytokines (Il-36α, β, and γ) with a specific, common receptor called IL-1Rp2, which subsequently leads to the recruitment of an accessory receptor

The typical evolutive profile of GPP is intermittent, marked by sudden attacks separated by phases of remission that may last from weeks to several years. The best identified triggering factors of attacks are infections, pregnancy, and to a lower extent, psychological stress.4 The age of disease onset varies greatly from one patient to the other and has been shown to be lower in patients with DITRA compared with those lacking IL-36RN genetic abnormalities.13 Also, the frequency of GPP attacks and the duration of remission intervals between flares vary considerably from one patient to another, even in patients from the same family (consanguineous) carrying the same mutation. The GPP attack duration is typically a few weeks, and although some patients will enter into complete clinical remission thereafter, others will exhibit chronic pustular and/ or plaque lesions between GPP flares. This latter characteristic should be very carefully taken into account in investigations of the efficacy of any therapeutic intervention. Finally, some patients display chronic PPP and ACH between GPP attacks, even in DITRA.4 Aside from pustular enanthema of the buccal mucosa during flares, geographic tongue is a frequent finding in GPP patients and persists over time. The most critical,

References 73

potentially life-threatening systemic manifestations include cardiovascular collapse or even aseptic shock due to the release of high amounts of inflammatory mediators and rarely acute respiratory distress syndrome. Uveitis, arthritis, or aseptic osteomyelitis has also been reported.2,3 More recently, a high frequency of cholestasis and sometimes mild cytolysis during GPP flares led to the identification of direct involvement of biliary ducts that exhibit neutrophilic cholangitis. This manifestation and its consequences have been proven by liver biopsy and by magnetic resonance cholangiopancreatography (MRCP), the latter revealing alternating strictures and dilatations of biliary ducts.14

TREATMENT There are several challenges when assessing efficacy of any therapeutic intervention in GPP: (1) disease flares are selfremitting within various time periods, (2) the rarity and intermittent disease characteristics are serious limitations for the design of any controlled trial, and (3) the scores used to assess plaque psoriasis severity are not relevant for GPP. Some acknowledgeable attempts by Japanese authors led to the design of a severity assessment tool combining clinical and biological parameters for the existence or absence of extra-dermatological complications, but this latter score remains to be validated and a practical, while clinically meaningful score has yet to be designed.3 All of these aforementioned issues explain why current therapeutic guidelines rely on weak evidence, e.g., expert consensus in virtually all cases. With all of these caveats in mind, it is still possible to define a hierarchy of therapeutic interventions across different clinical situations on the basis of the disease severity and clinical features and patient’s characteristics. Likewise, the use of highdose systemic steroids is only justified in life-threatening emergencies like shock and/or pulmonary distress syndrome, and it seems reasonable to combine them with steroid-sparing agents in anticipation of the maintenance treatment phase, i.e., therapeutic intervention with the objective of preventing further relapse. In non-lifethreatening situations, the best rationale for the induction phase, based on case series and most of all for rapid onset of action, is the use of cyclosporine and TNF-α inhibitors, particularly infliximab, whereas high-dose acitretin may be of use in less severe cases, both as induction and maintenance strategy.15 On the other hand, the efficacy of methotrexate when indicated makes sense as maintenance therapy, but again there is very limited evidence for its efficacy in preventing or attenuating further flares. Recently, a retrospective study of the efficacy of TNF-α inhibitors established their efficacy, with heavily  biased usage of infliximab.16 Other therapeutic interventions that have been reported to show efficacy are anakinra (a recombinant IL-1Ra),17 and the depletion of peripheral blood leukocytes using adsorptive granulocyte and monocyte apheresis in a limited prospective trial.18 Finally, in a

prospective 52-week study investigating in 12 patients the efficacy of secukinumab, an anti-IL17 monoclonal antibody showed evidence for sustained success in 10 cases.19 Given the genetic heterogeneity of GPP on one hand and the heterogeneity and biased reporting of success on the other hand, it is quite clear that targeting the IL-36 pathway is a very appealing strategy in patients with DITRA, whereas its impact on patients without IL-36RN mutations is more uncertain, but warrants investigation. With all of the limitations of currently available treatments for GPP, more recent series suggest a reduced mortality ­compared with older studies.1,2,16

CONCLUSION Recent genetic discoveries led to the inclusion of GPP in the range of autoinflammatory syndromes, a spectrum of genetically inherited, innate immune-mediated disorders. These major advances are likely to lead to the development of truly tailored therapies in the very close future.

REFERENCES 1. Baker H, Ryan TJ. Generalized pustular psoriasis. A clinical and epidemiological study of 104 cases. Br J Dermatol. 1968;80:771–793. 2. Zelickson BD, Muller SA. Generalized pustular psoriasis. A review of 63 cases. Arch Dermatol. 1991;127:1339–1345. 3. Umezawa Y, Ozawa A, Kawasima T, et al. Therapeutic guidelines for the treatment of generalized pustular psoriasis (GPP) based on a proposed classification of disease severity. Arch Dermatol Res. 2003;295:S43–S54. 4. Marrakchi S, Guigue P, Renshaw BR, et al. Interleukin36-receptor antagonist deficiency and generalized pustular psoriasis. N Engl J Med. 2011;365:620–628. 5. Sugiura K, Takemoto A, Yamaguchi M, et al. The majority of generalized pustular psoriasis without psoriasis vulgaris is caused by deficiency of interleukin-36 receptor antagonist. J Invest Dermatol. 2013;133:2514–2521. 6. Augey F, Renaudier P, Nicolas JF. Generalized pustular psoriasis (Zumbusch): A French epidemiological survey. Eur J Dermatol. 2006;16:669–673. 7. Takahashi H, Nakamura K, Kaneko F, Nakagawa H, Iizuka H, Japanese Society For Psoriasis Research. Analysis of psoriasis patients registered with the Japanese Society for Psoriasis Research from 2002– 2008. J Dermatol. 2011;38:1125–1129. 8. Onoufriadis A, Simpson MA, Pink, AE, et al. Mutations in IL36RN/IL1F5 are associated with the severe episodic inflammatory skin disease known as gener­alized pustular psoriasis. Am J Hum Genet. 2011;89:432–437.

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9. Navarini AA, Valeyrie-Allanore L, Setta-Kaffetzi N, et al. Rare variations in IL36RN in severe adverse drug reactions manifesting as acute generalized exanthematous pustulosis. J Invest Dermatol. 2013;133:1904–1907. 10. Lowes MA, Suárez-Fariñas M, Krueger JG. Immunology of psoriasis. Annu Rev Immunol. 2014;32:227–255. 11. Ammar M, Jordan CT, Cao L, et al. CARD14 alterations in Tunisian psoriasis patients and further characterization in European cohorts. Br J Dermatol. 2015 September 11. doi:10.1111/bjd.14158. [Epub ahead of print] 12. Setta-Kaffetzi N, Simpson MA, Navarini AA, et al. AP1S3 mutations are associated with pustular psoriasis and impaired toll-like receptor 3 trafficking. Am J Hum Genet. 2014;94:790–797. 13. Hussain S, Berki DM, Choon S-E, et al. IL36RN mutations define a severe autoinflammatory phenotype of generalized pustular psoriasis. J Allergy Clin Immunol. 2015;135:1067–1070. 14. Viguier M, Allez M, Zagdanski AM, et al. High frequency of cholestasis in generalized pustular psoriasis: Evidence for neutrophilic involvement of the biliary tract. Hepatology. 2004;40:452–458.

15. Robinson A, van Voorhees AS, Hsu S, et al. Treatment of pustular psoriasis: From the medical board of the National Psoriasis Foundation. J Am Acad Dermatol. 2012;67:279–288. 16. Viguier M, Aubin F, Delaporte E, Pagès C, et al. Efficacy and safety of tumor necrosis factor alpha inhibitors in generalized pustular psoriasis. Arch Dermatol. 2012;148:1423–1425. 17. Viguier M, Guigue P, Pagès C, Smahi A, Bachelez H. Successful treatment of generalized pustular psoriasis with the interleukin-1-receptor antagonist Anakinra: Lack of correlation with IL1RN ­mutations. Ann Intern Med. 2010;153:66–67. 18. Ikeda S, Takahashi H, Suga Y, et al. Therapeutic depletion of myeloid lineage leukocytes in patients with generalized pustular psoriasis indicates a major  role for neutrophils in the immunopathogenesis of psoriasis. J Am Acad Dermatol. 2013;68:609–617. 19. Imafuku S, Honma M, Okubo Y, Komine M, et al. Efficacy and safety of secukinumab in patients with generalized pustular psoriasis: A 52-week analysis from phase III open-label multicenter Japanese study. J Dermatol Sci. 2016 February 26. doi:10.1111/13468138.13306. [Epub ahead of print]

10 Inverse psoriasis and genital disease ISABEL HAUGH and CAITRIONA RYAN Inverse psoriasis refers to a variant of the disease that affects flexural and intertriginous skin and can have a profound impact on quality of life. Reports show that up to 36% of psoriasis patients have flexural disease and that 2%–7% of psoriasis patients present with this primary pattern of lesions in isolation.1–4 Due to the infrequency of this variant, it is often misdiagnosed and mistreated.

CLINICAL PRESENTATION Unlike plaque psoriasis that commonly affects the extensor surfaces, inverse psoriasis may manifest over any area of skin where two surface areas meet. It most commonly affects the inguinal folds, the axillae, and the external genitalia.4 The lesions are smooth, well demarcated, and are typically less scaly and more erythematous than the lesions of classic plaque psoriasis.5,6 The skin surface often appears atrophic with a slightly shiny or moist appearance. Patients often experience symptoms of pruritus, irritation, and burning that are exacerbated by friction, perspiration, fissures, and maceration. In childhood, inverse psoriasis that presents as shiny well-demarcated plaques in the folds of the diaper area may mimic diaper dermatitis.

GENITAL PSORIASIS Inverse psoriasis affecting the genital skin folds is seen in up to 79% of patients with inverse psoriasis2 and is one of the most commonly seen dermatoses of this region in both females and males.7 Typically, genital psoriasis accompanies psoriasis lesions on other parts of the body, but may also be isolated to the genital skin. Approximately two-thirds of patients with psoriasis of all types will experience genital involvement at some point in their disease course.8 Psoriasis of all forms can have a negative impact on social functioning, relationships, and sexual health,9 but psoriasis involving the genital region has been shown to be the most stigmatizing area of involvement independent of overall disease

severity.10 This can have a profound effect on quality of health. In females, genital psoriasis often presents as symmetrical plaques of the vulva and perineum. Rarely, the vaginal mucosa can be compromised with exudative and bright erythematous plaques. 5,11 Symptoms associated with genital psoriasis include itch, pain, dyspareunia, a worsening of their genital psoriasis after intercourse, and a decreased frequency of sexual intercourse. Irritation and trauma caused by intercourse, urine, feces, underwear, clothes, and local infections can worsen genital involvement and perpetuate the process through the Köebner phenomenon.6 Genital psoriasis usually does not produce scarring but one case report of two patients has described atrophic scarring of the labia minora, mimicking the scarring caused by genital lichen sclerosus.12 A study characterizing factors associated with the development of genital psoriasis showed associations with a younger age of onset of psoriasis, male sex, more severe disease, and involvement of the scalp, flexures, or nails.8

DIFFERENTIAL DIAGNOSES Due to its atypical presentation, inverse psoriasis can sometimes be difficult to differentiate from other dermatological conditions that affect intertriginous skin. In particular, the absence of scale may cause confusion. Cutaneous candidiasis also commonly presents in a flexural distribution, particularly in the genital region, but unlike in inverse psoriasis, satellite pustular lesions are often observed. Contrary to common belief, research has shown that the frequency of Candida is not increased in patients with inverse psoriasis when compared with healthy patients.8,9 Other differentials that may be considered include tinea corporis, bacterial infection, Paget’s disease, Langerhans cell histiocytosis, and necrolytic migratory erythema in patients with glucagonoma. Microscopic examination of skin scrapings using potassium hydroxide, fungal, and bacterial cultures, and occasionally a skin biopsy may be

75

76  Inverse psoriasis and genital disease

necessary to exclude or confirm these alternate etiologies. Cases of inverse psoriasis triggered by the medications infliximab, terbinafine, and etretinate have been described.13–15 Efalizumab-associated papular psoriasis of the flexural areas was a potential adverse event observed with efalizumab therapy, a biologic therapy formerly available to treat psoriasis.16

IMMUNOPATHOLOGY Comparison of immunohistochemical testing from skin samples of inverse psoriasis and regular plaque psoriasis shows identical profiles of T-cell subsets, epidermal proliferation, and keratinization patterns but a reduction in CD161+ cells in the dermis of inverse psoriasis lesions.17 It is suggested that the decreased quantity of lesional CD161+ cells in the dermis of flexural psoriatic lesions may reflect chronic microbial challenge in inverse psoriasis.17 Studies investigating microorganisms in inverse psoriasis show that untreated inverse psoriasis patients are colonized by Staphylococcus aureus more frequently than healthy patients.18 There is a potential role for microorganisms triggering an inflammatory reaction in some cases of inverse psoriasis and decolonizing agents and antimicrobial therapy should be considered in certain individuals.19

TREATMENT OF INVERSE AND GENITAL PSORIASIS When compared with common plaque psoriasis, inverse psoriasis has both similar and unique characteristics in terms of response to treatments. Topical corticosteroids remain the first-line therapy for most forms of inflammatory skin disease. As intertriginous skin is thinner, it is more sensitive to irritation by most topical therapies and allows increased penetration of topical treatments.20 These regions are particularly vulnerable to the adverse effects of steroid use and so corticosteroid-induced skin atrophy and striae tend to be more pronounced.21,22 Limited application of low-potency topical corticosteroid over a short period of time has been shown to be effective in treating inverse psoriasis without causing adverse effects in moderate-tosevere cases.23 Guidelines for the treatment of intertriginous psoriasis from the Medical Board of the National Psoriasis Foundation (NPF) recommend low- to mid-potency topical steroids as first-line, short-term treatment.19 It is recommended that their use should either be of limited duration (<2–4 weeks) or that the lowest effective strength be used intermittently for long-term care to minimize the potential for side effects in this vulnerable zone.19 Tacrolimus ointment 0.1% has been shown to successfully treat inverse psoriasis in both adults and children.24–27 Pimecrolimus cream 1% has also been shown to be an efficacious and welltolerated treatment.28 The vitamin D analogs, calcipotriene and calcipotriol, are alternative topical treatment options. It

has been recommended that calcipotriene be used with care in intertriginous regions and diluted in petrolatum20,29 as it can cause skin irritation particularly in the genital region.30 Calcipitrol does not cause irritation to the same extent.31 The NPF advises that although calcipotriene, calcipotriol, pimecrolimus, and tacrolimus are not as efficacious as topical corticosteroids, they are associated with fewer risks, in particular, a lower rate of skin atrophy, and are preferred for long-term therapy when feasible.19 It is also important that irritants and friction are avoided and that gentle cleansers are used in affected areas. The use of phototherapy is limited in the treatment of inverse psoriasis due to the physical location of these lesions. Light treatment with the 308 nm excimer laser as well as the excimer laser in combination with topical tacrolimus, however, has been shown to clear lesions in inverse psoriasis.32,33 The use of traditional systemic and biologic pharmacotherapies for inverse psoriasis has not been studied in randomized controlled trials. Typically, these treatments are used when psoriasis is refractory to topical therapy. A case report describing dapsone as an effective and convenient alternative for the treatment of inverse psoriasis in genital skin folds has been published.34 In terms of evidence for the treatment of inverse psoriasis with biologic therapies, only two cases are found in the literature. The first case describes successful treatment with the monoclonal antibody ­adalimumab.35 The second reported the effective use of another monoclonal antibody, efalizumab, to treat inverse psoriasis; however, this has since been withdrawn from the market due to its association with progressive multifocal leukoencephalopathy.36 Another therapy described in the literature is the use of botulinum toxin type-A.37,38 It has been suggested that its use in inverse psoriasis results in an improvement in patient symptomatology, erythema, and maceration.37 It is postulated that since this neuromodulator acts at the neuroglandular junction level, the reduction in local sweating decreases skin maceration and secondary infection.37 Botulinum toxin type A may also inhibit the release of neuropeptides and other proalgogenic substances responsible for inflammation, hyperkeratosis, and the transmission of pain.37

CONCLUSION Inverse psoriasis has unique characteristics in terms of presentation, treatment, and symptomatology ­compared with chronic plaque psoriasis. In light of these d ­ ifferences, inverse psoriasis should be treated as a distinct entity in terms of management. It is a skin disease that causes great discomfort and has profound effects on quality of life and so it is vitally important to include examination of the flexural and genital regions as the standard of care for all psoriasis patients. Few studies have examined the treatment of inverse psoriasis as a separate entity to classic plaque psoriasis. Randomized control trials are needed to investigate the use of topical, systemic, and biologic treatments

References 77

in inverse psoriasis to ensure that this subpopulation of patients receives optimal care.

REFERENCES 1. Van De Kerkhof PCM. Clinical features. In Textbook of Psoriasis, Second Edition, pp. 3–29. Oxford: Blackwell, 2003. 2. Wang G, Li C, Gao T, Liu Y. Clinical analysis of 48 cases of inverse psoriasis: A hospital-based study. Eur J Dermatol. 2005;15(3):176–178. 3. Kundakci N, Türsen Ü, Babiker MOA, Gürgey E. The evaluation of the sociodemographic and clinical features of Turkish psoriasis patients. Int J Dermatol. 2002;41(4):220–224. 4. Van de Kerkhof PCM, Murphy GM, Austad J, Ljungberg A, Cambazard F, Duvold LB. Psor­ iasis of the face and flexures. J Dermatol Treat. 2007;18(6):351–360. 5. Varghese M, Kindel S. Pigmentary disorders and inflammatory lesions of the external genitalia. Urol Clin North Am. 1992;19(1):111–121. 6. Farber EM, Nall L. Genital psoriasis. Cutis. 1992;50(4):263–266. 7. Meeuwis KAP, de Hullu JA, Massuger LFAG, van de Kerkhof PCM, van Rossum MM. Genital psoriasis: A systematic literature review on this hidden skin disease. Acta Derm-Venereol. 2011;91(1):5–11. 8. Ryan C, Sadlier M, de Vol E, et al. Genital psoriasis is associated with significant impairment in quality of life and sexual functioning. J Am Acad Dermatol. 2015;72(6):978–983. 9. Flytström I, Bergbrant IM, Bråred J, Brandberg LL. Microorganisms in intertriginous psoriasis: No evidence of candida. Acta Derm-Venereol. 2003;83(2):121–123. 10. Schmid-Ott G, Kuensebeck HW, Jaeger B, et al. Validity study for the stigmatization experience in atopic dermatitis and psoriatic patients. Acta DermVenereol. 1999;79(6):443–447. 11. Salim A, Wojnarowska F. Skin diseases affecting the vulva. Curr Obstet Gynaecol. 2002;12(2):81–89. 12. Albert S, Neill S, Derrick EK, Calonje E. Psoriasis associated with vulval scarring. Clin Exp Dermatol. 2004;29(4):354–356. 13. Peramiquel L, Puig L, Dalmau J, Ricart E, Roé E, Alomar A. Onset of flexural psoriasis during infliximab treatment for Crohn’s disease. Clin Exp Dermatol. 2005;30(6):713–714. 14. Pauluzzi P, Boccucci N. Inverse psoriasis induced by terbinafine. Acta Derm-Venereol. 1999;79(5):389. 15. Shelley ED, Shelley WB. Inframammary, intertriginous, and decubital erosions due to etretinate. Cutis. 1990;45(2):111–113.

16. Antonucci A, Bardazzi F, Balestri R, Patrizi A. Efalizumab-associated papular psoriasis: An adverse reaction to efalizumab in three cases. J Dermatolog Treat. 2009;20(1):61–62. 17. Vissers WHPM, Roelofzen J, de Jong EMGJ, van Erp PEJ, Van De Kerkhof PCM. Flexural ­versus plaque  lesions in psoriasis: An immunohistochemical ­d ifferentiation. Eur J Dermatol. 2005;15(1):13–17. 18. Flytström I, Bergbrant IM, Bråred J, Brandberg LL. Microorganisms in intertriginous psoriasis: No evidence of Candida. Acta Derm-Venereol. 2003;83(2):121–123. 19. Kalb RE, Bagel J, Korman NJ, et al. Treatment of intertriginous psoriasis: From the Medical Board of the National Psoriasis Foundation. J Am Acad Dermatol. 2009;60(1):120–124. 20. Lebwohl MG, Heymann WR, Berth-Jones J, Coulson I. Treatment of Skin Disease: Compre­ hensive Therapeutic Strategies. St. Louis, MO: Mosby, 2002. 21. Stoughton RB, Cornell RC. Corticosteroids. In: Dermatology in General Medicine, edited by TB Fitzpatrick, AZ Eisen, K Wolff, IM Freedberg, KF Austen, pp. 2846–2850. New York, NY: McGraw-Hil, 1993. 22. Mills CM, Marks R. Side effects of topical glucocorticoids. Curr Probl Dermatol. 1993;21:122–131. 23. Lebwohl MG, Tan M-H, Meador SL, Singer G. Limited application of fluticasone propionate ointment, 0.005% in patients with psoriasis of the face and intertriginous areas. J Am Acad Dermatol. 2001;44(1):77–82. 24. Rallis E, Nasiopoulou A, Kouskoukis C, et al. Successful treatment of genital and facial psoriasis with tacrolimus ointment 0.1%. Drugs Exp Clin Res. 2005;31(4):141–145. 25. Bissonnette R, Nigen S, Bolduc C. Efficacy and tolerability of topical tacrolimus ointment for the treatment of male genital psoriasis. J Cutan Med Surg. 2008;12(5):230–234. 26. Brune A, Miller DW, Lin P, Cotrim-Russi D, Paller AS. Tacrolimus ointment is effective for p ­ soriasis on the face and intertriginous areas in pediatric patients. Pediatr Dermatol. 2007;24(1):76–80. 27. Martín Ezquerra G, Sánchez Regaña M, Herrera Acosta E, Umbert Millet P. Topical tacrolimus for the treatment of psoriasis on the face, genitalia, intertriginous areas and corporal plaques. J Drugs Dermatol. 2006;5(4):334–336. 28. Gribetz C, Ling M, Lebwohl M, et al. Pimecrolimus cream 1% in the treatment of intertriginous psoriasis: A double-blind, randomized study. J Am Acad Dermatol. 2004;51(5):731–738. 29. Kragballe K. Treatment of psoriasis with calcipotriol and other vitamin D analogues. J Am Acad Dermatol. 1992;27(6 Pt 1):1001–1008.

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30. Kienbaum S, Lehmann P, Ruzicka T. Topical calcipotriol in the treatment of intertriginous psoriasis. Br J Dermatol. 1996;135(4):647–650. 31. Ortonne JP, Humbert P, Nicolas JF, et al. Intraindividual comparison of the cutaneous safety and efficacy of calcitriol 3 μg g-1 ointment and calcipotriol 50 μg g-1 ointment on chronic plaque psoriasis localized in facial, hairline, retroauricular or flexural areas. Br J Dermatol. 2003;148(2):326–333. 32. Mafong EA, Friedman PM, Kauvar ANB, Bernstein LJ, Alexiades-Armenakas M, Geronemus RG. Treatment of inverse psoriasis with the 308 nm excimer laser. Dermatol Surg. 2002;28(6):530–532. 33. Carrascosa JM, Soria X, Domingo H, Ferrándiz C. Treatment of inverse psoriasis with excimer therapy and tacrolimus ointment. Dermatol Surg. 2007;33(3):361–363.

34. Guglielmetti A, Conlledo R, Bedoya J, Ianiszewski F, Correa J. Inverse psoriasis involving genital skin folds: Successful therapy with dapsone. Dermatol Ther. 2012;2(1):1–9. 35. Ješe R, Perdan-Pirkmajer K, Dolenc-Voljč M, Tomšič M. A case of inverse psoriasis successfully treated with adalimumab. Acta Dermatovenerol Alp Pannonica Adriat. 2014;23(1):21–23. 36. George D, Rosen T. Treatment of inverse p ­ soriasis with efalizumab. J Drugs Dermatol. 2009;8(1):74–76. 37. Zanchi M, Favot F, Bizzarini M, Piai M, Donini M, Sedona P. Botulinum toxin type-A for the treatment of inverse psoriasis. J Eur Acad Dermatol Venereol. 2008;22(4):431–436. 38. Saber M, Brassard D, Benohanian A. Inverse psoriasis and hyperhidrosis of the axillae responding to botulinum toxin type A. Arch Dermatol. 2011;147(5):629–630.

11 Nail psoriasis PHOEBE RICH and RACHEAL MANHART INTRODUCTION Nail psoriasis occurs in up to 80% of patients with plaque psoriasis and is more prevalent in patients with psoriatic arthritis. Nail psoriasis is far more than just a cosmetic problem. Psoriasis of the fingernails is psychologically distressing and can cause pain, functional deficits in fine motor manipulation of small objects, and when toenails are involved, it can cause difficulty with ambulation. Although nail psoriasis can be extensively destructive to the nail plate, it is a nonscarring process. If treated effectively, nails with psoriasis can return to a normal or close to normal condition. Nail psoriasis takes a vast toll on patients, but with treatment and hopefully clearing of nail psoriasis the quality of life can greatly increase.

EPIDEMIOLOGY AND PREVALENCE Nearly 2% of the population suffers from psoriasis. Psoriasis affects the scalp, palms, soles, mucous membranes, and nails.1,2 Nearly 80% of patients with plaque psoriasis and 90% of patients with psoriatic arthritis have nail involvement at some time during their life.3–5 Nail psoriasis is more common in adults than in pediatric populations. In pediatric populations, nail psoriasis is relatively uncommon with a prevalence of 7%–13%.6–8 Often, the severity of nail and plaque psoriasis parallels each other in individual patients. Interestingly, approximately 5% of patients with psoriasis have the disease limited to the nail at the time of initial presentation. However, in many of these cases, the psoriasis will develop elsewhere on the body.6–9

QUALITY OF LIFE The negative impact of nail psoriasis on a patient’s quality of life is well documented. In a large sample of 1369 patients with nail psoriasis, 90% reported that nail psoriasis was cosmetically distressing, caused pain, and resulted in restrictions in activities of daily living. Psoriasis of highly

visible areas of the body (including face, hands, scalp, and nails) affects patients’ quality of life sometimes more compared with other chronic diseases.7,10–12 Nail psoriasis can have a significant negative impact on a patient’s quality of life (QOL), causing physical impairment and pain.3,10–12

CLINICAL FEATURES OF NAIL PSORIASIS The nail unit is composed of four specialized epithelial structures: the nail matrix, nail bed, hyponychium, and nail folds. The science behind our current understanding of the clinical pathophysiology of psoriatic nails comes from the work of Nardo Zaias. Zaias characterized the clinical features of nail disorders, including nail psoriasis.13,14 The appearance of any feature of a nail disorder depends upon which part(s) of the nail unit is affected by the pathologic processes (Figure 11.1). The nail has a limited number of responses to disease, and, as a result, none of the features of psoriatic nails are unique to nail psoriasis. All features of nail psoriasis occur in dystrophies of other etiologies. It is the collection of the nail features that enables the differentiation of nail psoriasis from nail dystrophy in the absence of concomitant plaque psoriasis. In nails, the psoriatic inflammation occurs primarily in the nail matrix, nail bed, and, less commonly, in the hyponychium or nail folds. On the basis of the pathology of the nail matrix, psoriatic inflammation within the nail matrix can result in the “nail matrix pitting complex.” This complex includes nail plate pitting and the related findings of nail crumbling, psoriatic leukonychia, and red dots in the lunula (Table 11.1). Occurrence of these features depends on the duration and location of psoriasis within the distal or proximal matrix. Similarly, the “nail bed onycholysis complex” occurs when psoriatic inflammation affects the nail bed. This results in oil drop dyschromia, splinter hemorrhages, and subungual hyperkeratosis, all of which evolve into onycholysis (Table 11.2) (Figures 11.2 and 11.3).

79

80  Nail psoriasis 1. Pitting

2. Crumbling

3. Leukonychia

Proximal nail fold

Matrix

Nail bed

Figure 11.1  Sagittal section of a nail demonstrating the nail plate, nail bed, and nail matrix and proximal nail fold showing the mechanism of pitting crumbling and psoriatic leukonychia. (1) Nail pit that results from parakeratotic cells in the proximal matrix, which fall away after the nail grows past the proximal nail fold. (2) Crumbling due to a larger area of inflammation over a longer span of time. (3) Leukonychia is due to cells from the distal matrix that are trapped in the nail plate and cannot escape. These deep cells appear white and the nail surface is smooth. (Modified from Zaias N, Arch Dermatol, 99, 567–579, 1969.)

Table 11.1  Clinical features of nail matrix psoriasis. Appearance

Location of pathologic changes

Pitting (Figure 11.2a through c)

Small focal or punctate depressions, “pits,” on the surface of the nail plate. In the absence of damaging inflammation, pits will continue to be seen on the surface of the nail plate until either the nail grows out and is clipped off or the pit is superficial enough to be removed over time by normal wear.

Proximal nail matrix

Psoriatic leukonychia (Figure 11.2a through e)

White, punctate macules in the deep layers of the nail plate appear as smooth white spots on the surface of the nail. Psoriatic leukonychia is easily distinguished from punctate leukonychia, which is commonly due to mild trauma to the matrix.

Distal nail matrix

Pathophysiology Inflammation/damage/cellular changes can occur at a single or multiple locations within the proximal nail matrix. The frequency and duration of this damage are reflected in the number and position of pits in relation to the proximal nail fold (PNF) and cuticle. As the nail grows past the PNF and cuticle, pits develop due to shedding of parakeratotic cells from the surface of the nail plate. Changes are similar to pitting but occur in the distal nail matrix. Unlike pitting, the surface of the nail plate is smooth, due to the parakeratotic cells being trapped deeper in the layers of the nail plate.

(Continued)

Management of nail psoriasis  81

Table 11.1  (Continued) Clinical features of nail matrix psoriasis. Appearance

Location of pathologic changes

Nail crumbling (Figure 11.2b, d, and e)

Broad areas of nail plate destruction.

Proximal and/or distal nail matrix

Red dots in the lunula (Figure 11.2e)

Red spots in the lunula, some of which grow out and remain as red dots in the nail plate. Rarely an isolated finding, which is useful in combination with other features.

Deep, distal nail matrix

Pathophysiology Crumbling depends on the magnitude, duration, and location of the inflammatory damage in the nail matrix. Crumbling develops from confluent areas of pitting and/or leukonychia in the nail plate. Unknown.

Table 11.2  Clinical features of nail bed psoriasis. Appearance

Location of pathologic changes

Oil drop/salmon patch dyschromia (Figure 11.3b and c)

Orange-brown discolored patches.

Usually begins in proximal nail bed and migrates distally with nail growth.

Splinter hemorrhages (Figure 11.3d)

Small, thin dark lines oriented parallel to the longitudinal ridges of the nail bed, seen with other features of nail bed psoriasis.

Usually distal nail bed, and can migrate as the nail grows.

Nail bed hyperkeratosis (Figure 11.3e)

Thick white scale under the free edge of the nail plate.

Usually distal nail bed and hyponychium.

Onycholysis (Figure 11.3a through e)

The nail plate is lifted and separated from the nail bed and appears white due to air under the nail plate.

Any location in the nail bed. It is usually distal and connected to the free edge.

Pathophysiology Due to glycoprotein deposits in the nail bed that migrate distally with nail growth and either coalesce with existing onycholysis or become onycholytic when they reach the free edge. Pinpoint bleeding in the longitudinal ridges of the nail bed, analogous to the Auspitz sign in cutaneous psoriasis. As they migrate distally with the nail bed, the blood dries and creates a space that becomes onycholytic as it grows toward the free edge of the nail. Thickening of the nail bed analogous to thick scale on psoriatic lesional skin. The thickened scale under the free edge of the nail plate can fall away and result in onycholysis. Onycholysis is the end result of oil drop dyschromia, splinter hemorrhages, and nail bed hyperkeratosis.

82  Nail psoriasis

(a)



(b)

(c)



(d)

(e)

Figure 11.2  Clinical

features of nail matrix psoriasis: (a) pitting and leukonychia; (b) leukonychia, pitting, and crumbling; (c) ­crumbling due to confluent pitting and psoriatic leukonychia; (d) crumbling; (e) red dots in lunula, and leukonychia.

Management of nail psoriasis  83

(a)



(b)

(c)



(d)

(e)

Figure 11.3  Clinical features of nail bed psoriasis: (a) onycholysis, (b) oil drop dyschromia and onycholysis, (c) oil drop dyschromia and onycholysis, (d) splinter hemorrhages and onycholysis, (e) nail bed hyperkeratosis, evolving into onycholysis.

84  Nail psoriasis

ASSESSMENT OF NAIL PSORIASIS SEVERITY It is a challenge to objectively grade nail psoriasis due to the idiosyncrasies of nail structure and growth kinetics. As such, psoriatic nail disease severity is only visible as the nail grows; instantaneous assessment of psoriatic nail disease activity is nearly impossible. Fingernails grow at a rate of 0.1 mm daily. This translates to 5–6 months for fi ­ ngernail turnover and 10–12 months for toenail turnover. Thus, the appearance of the nail on the day of assessment reflects events that happened in the nail’s matrix in prior months. There are many good nail severity assessment scales including the NAPSI, modified NAPSI, Target NAPSI, Baran, N-Nail, Cannavo, PNSS, NASS, and others, but none of these scales are perfect. An excellent review by Klaassen et al. summarizes and compares these methods of nail psoriasis assessment in detail.12 For over a decade, NAPSI has been the standard nail psoriasis assessment measure

used in hundreds of published clinical trials, abstracts, and posters. NAPSI is based on the research done in 1969 by Nardo Zaias.13 Zaias is credited with the discovery of the pathophysiology of nail psoriasis, which is the science on which our current understanding of nail psoriasis is based. NAPSI divides the nail into imaginary quadrants and records the number of quadrants in which any of the interchangeable features of nail matrix psoriasis (pitting, psoriatic leukonychia, crumbling, red dots in lunula) and any of the features of nail bed psoriasis (onycholysis, oil drop dyschromia, nail bed hyperkeratosis, and splinter hemorrhages) are seen. The composite score for each nail is 0–8.15

MANAGEMENT OF NAIL PSORIASIS The initial step in management of nail psoriasis is to provide education for patients. Patients need to understand the importance of routine nail care and protection,

Table 11.3  Management of nail psoriasis. 1. Patient education a. Avoidance of minor repetitive nail trauma to prevent Koebner (isomorphic) reactions that may exacerbate nail psoriasis b. Educate the patient on the expected time necessary to see nail improvement c. Discuss prevention and treatment of concomitant fungal infection in psoriatic nails d. Discuss nail cosmetics and other factors that may interfere with therapy 2. Topical products applied to the involved nails a. Pharmaceutical creams, solutions, ointments, and combination therapies i. Calcipotriol ii. Topical calcipotriol + betamethasone53,54 iii. Tazarotene55 iv. Tacrolimus ointment 0.1%56 v. Topical clobetasol lacquer 0.05%, 1%, 8%57 vi. Topical cyclosporine A (CsA) 70% in corn oil58 vii. Topical calcipotriol + betamethasone + salicylic acid59 b. Botanical topical agents such as indigo naturalis (Lindioil)60 3. Devices and procedural interventions a. Light energy–based devices i. Excimer laser61 ii. Pulse dye laser (PDL)62 iii. Grenz ray63 iv. Intense pulse light (IPL)64 v. Photodynamic therapy (PDT), PDL, plus methyl aminolevulinate (MAL)65 b. Procedural interventions: intralesional (IL) triamcinolone 3–5 mg/cc, when single or few nails are involved66,67 c. Combination therapies i. Phototherapy with psoralen + acitretin19 ii. PDL + 0.1% tazarotene68 4. Systemic therapy a. Oral treatments i. Traditional agents: methotrexate,18,19,22–24 acitretin,19,24,25 CsA,18,19,20,21 leflunomide26 ii. Newer agents: apremilast,69 tofacitiniba,70 b. Biologic agents i. Tumor necrosis factor alpha (TNF-ɑ), adalimumab (ADA)21,24,29–36; etanercept (ETN)24,27–31; infliximab (IFN),19,24,29–31 golimumab,71,72 certolizumab pegol (CZP)43 ii. IL-17, ixekizumaba (IXE)49,51; secukinumab (SEC)50,52 iii. IL-12/IL-23, ustekinumab (UST)56–60 iv. IL-23, on the horizon, tildrakizumab,a guselkumab,a BI 655066a a

Not yet approved by U.S. Food and Drug Administration.

References 85

and factors that may exacerbate nail psoriasis. Koebner ­reactions from minor repetitive trauma to the nail during daily activities should be avoided when possible by protecting with gloves. The patient should understand that nail growth determines the rate of nail improvement and the nail may take 6 months or more to clear. Approximately 30% of patients with nail psoriasis additionally have onychomycosis, therefore, discussions of nail fungus diagnosis, prevention, and treatment are prudent. The selection of pharmacologic interventions available for nail psoriasis depends on many factors such as severity of the nail dystrophy, cost, availability of medications, and adherence, as well as the overall severity of cutaneous and joint involvement. There are currently no medications approved specifically for nail psoriasis in the United States. However, clinical trials are working to address the need for nail psoriasis medications. The impact of the pain and psychological distress of nail psoriasis on a patient’s quality of life may dictate the level of therapy prescribed. Generally, topical therapies such as corticosteroids, calcipotriol, tazarotene, and tacrolimus in the form of creams, ointments, foam, or solutions may be helpful in mild or early nail psoriasis. Botanical agents such as Indigo Naturalis (Lindioil), a Chinese botanical, are a novel topical treatment for psoriatic nails.16 The next treatment options, before systemic medications, include intralesional triamcinolone and light-based devices such as the excimer and pulse dye lasers; these can be useful in cases of nail psoriasis when one or few nails are involved. If nail psoriasis is accompanied by concomitant extensive plaque psoriasis, or psoriatic arthritis, systemic treatment is usually recommended. Traditional small molecules such as cyclosporine A (CsA),17–21 methotrexate (MXT),14,20–24 acitretin,14,19,21,24–26 and leflunomide26 (European trial) are sometimes helpful, although it appears that these drugs are more beneficial for psoriasis involving the skin rather than the nails (Table 11.3). Biologics are an effective treatment option for moderate to severe psoriatic disease, especially in cases of nail psoriasis previously unresponsive to other therapeutic options. Numerous clinical trials of biologic agents for moderate to severe plaque psoriasis measured nail psoriasis efficacy as a secondary endpoint. Therefore, some data exist regarding the effect of biologics on nail psoriasis from these large clinical trials. In addition, there have been numerous small trials evaluating the efficacy of various investigational products for the treatment of nail psoriasis. The uncommon nail-specific trials generally have low enrollment and are not always blinded or controlled; thus data are limited. Many of these trials involve a combination therapy. Excellent recent publications review these nail psoriasis trials in great detail; the references to these publications appear as part of Table 11.3. A plethora of data exists that demonstrates the superior efficacy of biologic medication use for the treatment of nail psoriasis. The tumor necrosis factor alpha (TNF-α) antagonists have good data supporting the improvement

of nail psoriasis including etanercept,19,24,27–31 adalimumab,19,21,24,31,32 infliximab,17,19,24,29–42 and cergtolizumab pegol.43 Ustekinumab is a weight-based anti-interleukin 12 (IL-12)/23 biologic therapy that is very effective in treating nail psoriasis.44–48 Considerable nail improvement was observed in the phase 3 trials of secukinumab and phase 2 studies of ixekizumab.49–52 Ongoing trials with other new biologics and biosimilars will hopefully provide favorable nail psoriasis data in the future.

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86  Nail psoriasis

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88  Nail psoriasis

68. Huang YC, Chou CL, Chiang YY. Efficacy of pulsed dye laser plus topical tazarotene versus topical tazarotene alone in psoriatic nail disease: A single-blind, intrapatient left-to-right controlled study. Lasers Surg Med. 2013;45:102–107. 69. Papp K, Reich K, Leonardi C, et al. Apremilast, and oral phosphodiesterase 4 inhibitor, in nail, and scalp psoriasis: 52-week results from the ESTEEM 1 study [abstract 203]. Paper presented at: European Academy of Dermatology & Venereology. 2–6 October, Istanbul, Turkey, 2013. 70. Papp KA, Menter A, Abe M. et.al Tofacitinib, an oral Janus Kinase inhibitor, for treatment of chronic plaque psoriasis: Results from 2 phase three trials. Br J Dermatol. 2015 October;173(4):949–961.

71. Kavanaugh A, McInnes I, Mease P, Krueger GG, Gladman D, Gomez-Reino J, et al. Golimumab, a new human tumor necrosis factor alpha antibody, administered every four weeks as a subcutaneous injection in psoriatic arthritis: Twenty-four-week efficacy and safety results of a randomized, placebocontrolled study. Arthritis Rheum. 2009;60:976–986. 72. Kavanaugh A, van der Heijde D, McInnes IB, Mease P, Krueger GG, Gladman DD, et al. Golimumab in psoriatic arthritis: One-year clinical efficacy, radiographic, and safety results from a phase III, randomized, placebo-controlled trial. Arthritis Rheum 2012;64:2504–2517.

12 Differential diagnoses of psoriasis PETER FOLEY INTRODUCTION

CHRONIC PLAQUE PSORIASIS

The clinical presentation of psoriasis varies according to form and location, which can pose a difficult diagnostic dilemma.1 There are many other dermatological presentations that may be confused with psoriasis. The differential diagnoses are dependent on the morphological pattern and distribution of lesions. The most characteristic lesions consist of red, sharply demarcated, indurated plaques with a silvery scale, present particularly over extensor surfaces (Figure 12.1) and the scalp.2 The disease is enormously variable in duration, extent, and distribution. Clues to the diagnosis include common comorbidities such as psoriatic arthritis, Crohn’s disease, depression, metabolic syndrome, hypertension, nonalcoholic fatty liver disease, and positive family history of psoriasis.1–3 Possible triggers, which may provide clues to the diagnosis, include drugs, trauma, sunburn, infection, alcohol, and stress.1,2 The clinical and histological aspects of psoriasis are generally sufficient to make the diagnosis; however, doubt may arise in several clinical variants and atypical cases or when the psoriatic lesions are localized in particular sites.4 The d ­ ifferential diagnoses are discussed as follows:

Chronic plaque psoriasis (psoriasis vulgaris) is the most common form of psoriasis (Figure 12.2) and accounts for approximately 90% of all cases. Males and females are affected equally. The age of onset is usually between 15 and 30 years, but the first manifestation may occur at any age. The clinical presentation is of well-demarcated symmetrical erythematous plaques with overlying scale. Lesions can vary in size from pinpoint papules to plaques covering large areas.1,2 The amount of scaling is variable, but most psoriatic lesions are covered with a characteristic silvery white scale that varies in thickness.2 The removal of psoriatic scale usually reveals an underlying smooth glossy red membrane with small bleeding points (Auspitz’s sign).2 Typically, psoriasis is symmetrical in distribution, involving the extensor aspects of the extremities, particularly elbows and knees, trunk, scalp, sacrum (Figure 12.3), buttocks, and genitals.1 Plaques may form at sites of trauma, termed the isomorphic or Koebner phenomenon.2 Patients usually report a chronic long-standing nature with associated flares and varying symptoms of pain, itch, and burning.4 Family history

Forms

• Chronic plaque psoriasis • Guttate psoriasis • Pustular psoriasis • Erythrodermic psoriasis • Flexural psoriasis Localized sites

• Palmoplantar • Nails • Genitals • Scalp • Ears • Face

Figure 12.1  Chronic plaque psoriasis including elbow.

89

90  Differential diagnoses of psoriasis

of psoriasis is common. Lesions may remit and recur spontaneously or with associated triggers. The typical histopathological features of psoriasis include acanthosis (psoriasiform hyperplasia), parakeratosis, suprapapillary thickening, papillary elongation, mitoses in basal keratinocytes, dilated vessels in dermal papillae, and thinning of the suprapapillary epidermis.5 Two other changes are diagnostic: the Munro microabscesses and the spongioform pustule of Kogoj, due to the small accumulation of neutrophils, respectively, within the parakeratotic stratum corneum and spongiotic epidermis.4 There is often overlying basket-weave type orthokeratosis and loss of the underlying granular layer.2 The dermal inflammatory cell infiltrate in developing lesions includes activated T lymphocytes, fewer Langerhans cells than in earlier lesions, and very occasional neutrophils.2 A subset of spindle-shaped macrophages along the basement membrane has been described as a characteristic feature.2 Plasma cells and eosinophils are usually absent.

Figure 12.2  Lower legs male.

Figure 12.3  Chronic plaque psoriasis.

Later lesions show orthokeratosis, an intact granular layer and some thickening of the suprapapillary plates.2 The differential diagnoses of chronic plaque psoriasis include tinea corporis, discoid eczema, lichen planus, cutaneous T-cell lymphoma, and subacute cutaneous lupus erythematosus (SCLE). If localized to a small area, the differential diagnoses include superficial basal cell carcinoma (sBCC), Bowen’s disease, actinic keratosis, contact dermatitis, and Paget’s disease.

Tinea corporis Tinea corporis is the cutaneous manifestation of dermatophyte infection of the skin (Figure 12.4). The most common pathogen is Trichophyton rubrum.6 The clinical appearance of tinea corporis is quite variable depending on the species of fungus, the site of infection (Figure 12.5), the immunological status of the patient, and the prior use of topical steroids (Figure 12.6). The clinical presentation is characteristically

Figure 12.4  Tinea corporis.

Figure 12.5  Tinea corporis—buttock.

Chronic plaque psoriasis  91

a progressively enlarging erythematous plaque with peripheral scale and central clearing (Figure 12.7). Less commonly vesicles, pustules (see Figure 12.6), or large blisters may be clinically evident.7 Characteristic lesions are circular, ­usually sharply marginated with a raised edge (Figure 12.8; see also Figure 12.4). Single lesions typically occur or there

may be multiple plaques that remain discrete or become confluent. Central clearing is a common but not ­reliable feature of tinea corporis (Figure 12.9).6 The degree of inflammation is variable depending on the species of

Figure 12.8  Tinea corporis. Figure 12.6  Tinea incognito with pustules.

Figure 12.7  Tinea corporis.

Figure 12.9  Tinea corporis.

92  Differential diagnoses of psoriasis

fungus and the clinical pattern can be modified in immunodeficiency.6 Tinea corporis can affect all ages and can occur in any location, although it typically occurs on exposed sites. Tinea corporis elicits a reaction pattern that may be difficult to distinguish from psoriasis in cases where the distribution is not typical. Special stains and correlation with skin scrapings are sometimes required. Presence of plaques on the knees, elbows, scalp, and associated psoriatic nail changes is helpful.6 Histopathological changes typically demonstrate foci of parakeratosis with epidermal acanthosis, spongiosis, and collections of neutrophils in the upper layers of the epidermis along with presence of hyphae in the stratum corneum. The dermis may show mild edema and a sparse perivascular infiltrate, which includes lymphocytes and occasionally eosinophils or neutrophils.8 Histological clues include the presence of neutrophils, compact orthokeratosis, and the “sandwich sign” (presence of hyphae “sandwiched” between an upper layer of normal basket-weave stratum corneum).8

Discoid eczema Discoid eczema (nummular eczema) is characterized by circular or oval plaques with a clearly demarcated edge (Figure 12.10), although the demarcation between involved and uninvolved skin may not be as sharply defined as in a classic psoriasis plaque (Figure 12.11).9 Some cases are associated with Staphylococcus aureus infection.10 Discoid eczema can affect children and adults but predominantly affects adults with a peak incidence of 50–65 years of age.10 It is slightly more prevalent in males than in females.9 It can be seen in elderly people, often with dry skin exacerbated by low humidity and central heating.9 The pathogenesis is unknown; most patients do not have a history of atopy, and immunoglobulin E (IgE) levels are often within the normal range.9 The clinical presentation is of well-demarcated coin-shaped annular plaques (Figure  12.12) with coalescing papules and papulovesicles on an erythematous base.9 Pinpoint oozing and crusting are distinctive.9 Scaling is usually less marked than in psoriasis. These lesions arise quite rapidly, ranging in size from 1 to 3 cm.9 The surrounding skin is generally normal but may be xerotic.9 In the acute phase, the lesions are dull red, very exudative or crusted (Figure 12.13), and highly pruritic.9 They progress toward a less vesicular and more scaly stage, often with central clearing, and peripheral extension, causing ring-shaped or annular lesions.9 Distribution is usually on the extensor surface of the extremities more than the trunk but can become widespread.9 Females tend to have more involvement of the upper extremities compared with the lower extremities in men (Figure 12.14).10 The clinical course tends to be chronic with relapses and most are worse during the colder months of the year.10 Some cases clear within 1 year and others may persist for many years.

Figure 12.10  Discoid eczema.

Figure 12.11  Discoid eczema.

Chronic plaque psoriasis  93

Figure 12.12  Discoid eczema.

Figure 12.14  Discoid eczema—leg.

Figure 12.13  Crusted discoid eczema. Histopathology shows a subacute dermatitis indistinguishable from other forms of eczema, with spongiotic vesicles and a predominantly lymphocytic infiltrate.9 Parakeratosis containing plasma cells and neutrophils and psoriasiform epidermal hyperplasia with spongiosis are present, with a superficial dermal perivascular infiltrate of lymphocytes, macrophages, and eosinophils.10 In psoriasis, the lesions are dry with more prominent silver scaling and less itch.

Mycosis fungoides Mycosis fungoides (MF) is the most common form of cutaneous T-cell lymphoma.11 Lesions are often less symmetrical with an associated itch (although often asymptomatic) and there is usually less scaling than psoriasis (Figure 12.15).12 MF is characterized by cutaneous stages of disease, consisting of patches and plaques. In plaque

Figure 12.15 Mycosis

fungoides

(cutaneous

T-cell

lymphoma).

stage MF, the patches become thickened and may resemble psoriasis (Figure 12.16). Stage IA involves less than 10% of the body surface area, stage IB more than 10% of the body surface area, stage IIB tumors, and stage III erythrodermic disease.12 The clinical features of MF vary a­ ccording to the clinical stage.12 Stage IA MF is ­characterized by subtle fine scaly and often slightly atrophic erythematous patches (Figure 12.17) on the trunk, usually involving the limb girdle area, breast, and buttocks.12 In Stage IB, plaques are more obvious, persistent, and polymorphic

94  Differential diagnoses of psoriasis

Figure 12.18 Mycosis

fungoides

(cutaneous

T-cell

lymphoma).

Figure 12.16 Mycosis

fungoides

(cutaneous

T-cell

lymphoma).

and border definition.12 Striking psoriasiform scaling can sometimes be a feature.12 Stage IIB is characterized by the development of tumors, which show considerable variation in shape and size (see Figure 12.18). Many patients with stage IA/IB disease do not progress but rarely patients may gradually become erythrodermic (stage III), which is associated with severe pruritus.12 The histological features of MF vary according to the clinical stage.13 MF may show significant hyperkeratosis and parakeratosis mimicking psoriasis.14 Often multiple biopsies are required to make a diagnosis.14 Clues to diagnosis include Pautrier’s microabscesses (clusters of atypical lymphocytes in the epidermis), prominent epidermotropism, band-like infiltrate of lymphocytes aligned within the basal layer, papillary dermal fibrosis and variable cytological atypia of lymphocytes with hyperchromatic nuclei, a cerebriform appearance, and a characteristic halo, which extends upward into the papillary dermis.5 Any patient with persistent polymorphic plaques, particularly in the pelvic girdle area, should have a skin biopsy to confirm the diagnosis.

Subacute cutaneous lupus erythematosis Figure 12.17  Mycosis

fungoides

(cutaneous

T-cell

lymphoma).

(Figure 12.18) with a similar distribution, but there is usually involvement of the head, neck, and limbs, as well as the trunk.12 Individual plaques may become very large and demonstrate some degree of regression, giving rise to arcuate-shaped lesions (see Figure 12.18) that can show considerable variation in color, degree of scaling,

Subacute cutaneous lupus erythematosis (SCLE) is a specific form of lupus characterized by mainly cutaneous disease and antibodies to Ro/SS-A antigen. SCLE predominantly affects adults and usually has a good prognosis.15 SCLE is characterized by recurring, photodistributed, nonscarring erythematous plaques, which may be annular, polycyclic, or papulosquamous (Figures 12.19 and 12.20).15 Lesions usually occur above the waist. The typical distribution involves the face, neck, upper trunk (Figure 12.21), and extensor surfaces of the arms (Figure  12.22) and lesions

Chronic plaque psoriasis  95

Figure 12.21  Upper trunk lupus erythematosus. Figure 12.19  Subacute

cutaneous lupus erythematosus

(SCLE).

Figure 12.22  Forearm lupus erythematosus. exacerbate SCLE.15 The histopathology shows a lichenoid reaction pattern with basal vacuolar change, epidermal atrophy, hyperkeratosis, dermal edema with occasional Civatte bodies, follicular plugging, and basement membrane thickening. The inflammatory infiltrate is confined to the upper dermis.16

Figure 12.20  Subacute cutaneous lupus erythematosus (SCLE).

Lichen planus

are usually not pruritic.15 The  borders may show vesiculation and crusting and occasionally bullae.15 Follicular ­plugging and hyperkeratosis are not a prominent feature. Lesions resolve leaving hypopigmentation and telangiectasia. Diffuse nonscarring alopecia and photosensitivity occur in approximately 50% of patients.15 Other clinical features include mouth ulcers, reticular livedo, periungual telangiectasia, and Raynaud’s phenomenon.15 Fever, malaise, and central nervous system (CNS) involvement may occur, but renal disease is mild and infrequent. A history of Sjogren’s syndrome or calcifying lupus panniculitis may be reported.15 SCLE may occur in the course of psoralen ultraviolet light A (PUVA) treatment for psoriasis. A number of drugs have been implicated to precipitate or

Lichen planus is a common inflammatory disorder that affects the skin, mucous membranes, nails, and hair, with a worldwide incidence of 1% of the population. Two-thirds of cases occur between the ages of 30 and 60 years.17 Males and females are affected equally.17 An association with hepatitis C infection has been identified.17 Characterized by shiny violaceous, flat-topped polygonal papules, lesions can remain discrete or occur in clusters, linear (Figure 12.23), or an annular formation (Figure 12.24).17,18 Fine white reticulated networks, known as Wickham’s striae, are present over the surface of many well-developed papules.18 These are considered highly characteristic. Lichen planus can affect any part of the body surface but it is most often seen on the volar aspects of the wrists

96  Differential diagnoses of psoriasis

Figure 12.23  Linear lichen planus.

Figure 12.26  Lumbar lichen planus.

Figure 12.24  Annular lichen planus.

Figure 12.27  Ankle and feet lichen planus.

Figure 12.25  Volar wrist lichen planus. (Figure 12.25), the lumbar region (Figure 12.26), and the ankles (Figure 12.27). Pruritus is a common feature of lichen planus, ranging from mild to continuous severe itching.17 The onset can be rapid but is usually insidious. In most cases papules flatten after a few months, often replaced with an area of hyperpigmentation that persists for months to years.17 Mucous membrane lesions are

common (Figures 12.28 and 12.29), occurring in 30%–70% of cases.17 Nail involvement occurs in up to 10% of cases with fingernails more often affected than toenails (Figure 12.30).17 The most common nail changes include exaggerated longitudinal lines and linear depressions due to thinning of the nail plate.17 Two major pathologic findings are seen in lichen planus: basal epidermal keratinocyte damage and lichenoid-interface lymphocytic reaction.16,18 The epidermal changes include hyperkeratosis, wedge-shaped areas of hypergranulosis, and elongation of rete ridges that

Localised plaque psoriasis  97

the epidermis.16,18 Many histiocytes and few plasma cells are seen. Separation of the epidermis in small clefts (Max Joseph cleft formation) is occasionally seen.18

LOCALISED PLAQUE PSORIASIS Superficial basal cell carcinoma Basal cell carcinoma (BCC) is found predominantly on areas of skin exposed to the sun, but can appear anywhere on the body, particularly in fair skinned ­individuals (Figures 12.31 and 12.32).19,20 More c­ommon in older

Figure 12.28  Mucosal lichen planus.

Figure 12.29  Mucosal lichen planus.

Figure 12.31  Superficial basal cell carcinoma.

Figure 12.30  Nail lichen planus. resemble a sawtooth pattern.16,18 Multiple apoptotic cells or colloid-hyaline (Civatte) bodies are seen at the dermal– epidermal junction.16,18 Eosinophilic colloid bodies are present in the papillary dermis. A band-like lymphocytic infiltrate is seen in the papillary dermis that abuts

Figure 12.32  Superficial basal cell carcinoma.

98  Differential diagnoses of psoriasis

patients, BCC can be seen in young adults. Clinically, sBCCs appear as erythematous slow-­g rowing scaly irregular plaques with visible telangiectasia (Figure 12.33). Lesions are usually less than 1 cm in diameter but may slowly grow larger (Figure 12.34). Etiology is predominantly solar damage but immunosuppression and exposure to ionizing radiation have been implicated.19,20 Histopathology demonstrated islands or nests of basaloid

cells with palisading of the cells at the periphery and a haphazard arrangement of those at the center of the islands.20 The tumor cells have hyperchromatic nucleus with poorly defined cytoplasm.20

Bowen’s disease Bowen’s disease is also known as squamous cell carcinoma in situ of the skin. 20,21 It presents as an asymptomatic well-defined erythematous scaly plaque (Figure 12.35), which expands centrifugally. Bowen’s disease has a predilection for sun-exposed sites of fair-skinned older individuals (Figure 12.36). Several factors are implicated in the etiology of Bowen’s disease: solar damage, arsenic, immunocompromise, and human papillomavirus infection. 20,21 Lesions most commonly occur on the lower legs (Figure 12.37) but may develop on the trunk, vulva, nail bed, lip, nipple, palm, sole, and eyelid. 20,21 Bowen’s disease occasionally mimics psoriasis. There is usually less scale than in psoriasis. 20 Histopathology demonstrates full thickness involvement of the epidermis by atypical keratinocytes, disordered maturation of the epidermis with mitoses at different levels, multinucleate keratinocytes, and dyskeratotic cells. 20 Usually there is loss of the granular layer, with overlying parakeratosis and sometimes hyperkeratosis.20 In the psoriasiform pattern there is regular acanthosis with thickening of the rete ridges and overlying parakeratosis. 20

Figure 12.33  Superficial basal cell carcinoma.

Figure 12.34  Superficial basal cell carcinoma.

Figure 12.35  Bowen’s disease.

Localised plaque psoriasis  99

Figure 12.38  Actinic keratosis.

Figure 12.36  Bowen’s disease.

Figure 12.39  Actinic keratosis.

Figure 12.37  Bowen’s disease. Actinic keratosis Actinic (solar) keratoses are superficial cutaneous lesions consisting of localized proliferations of atypical epidermal keratinocytes.20,21 Actinic keratoses develop commonly as a consequence of cumulative ultraviolet radiation.20,21 The clinical presentation is typically erythematous scaly macules or papules from 2 mm to 1 cm in diameter (Figure 12.38). They occur predominantly on chronically sun-exposed sites, in fair-skinned individuals.20,21 The face, ears, scalp, hands, and forearms are common sites of involvement (Figures 12.39 and 12.40). Histopathology shows focal parakeratosis, with loss of the underlying granular layer and slightly thickened epidermis with some irregular downward buds.

Figure 12.40  Actinic keratosis. Dermal changes include actinic elastosis, and usually a mild chronic inflammatory cell infiltrate.20

Contact dermatitis Allergic contact dermatitis is an inflammatory disorder that is initiated by contact with an allergen to which the person has previously been sensitized. The

100  Differential diagnoses of psoriasis

prevalence of allergic contact dermatitis is about 7% of the general population. 22 It is uncommon in children. Clinically, there may be erythematous papules, small vesicles, or weeping plaques, which are usually pruritic (Figure  12.41 and 12.42). The lesions usually develop 12–48 hours following exposure to the allergen. 22 Lesions may extend beyond the zone of contact. 23,24 Causative agents may include cosmetics, fragrance, foods, plants, topical medicaments, and industrial chemicals (Figures 12.43 through 12.46). 23 Allergic contact dermatitis is characterized in the very early stages by spongiosis, which is most marked in the lower epidermis. 24 This is followed by the formation of spongiotic vesicles at different levels. The upper dermis contains a mild to moderately heavy infiltrate of lymphocytes, macrophages, and Langerhans cells, with accentuation around the superficial plexus. 24 There is exocytosis of lymphocytes and sometimes eosinophils. 24 Chronic lesions may show

little spongiosis but prominent epidermal hyperplasia of psoriasiform type. 24 Mild fibrosis may develop in the papillary dermis.

Figure 12.43 Allergic

contact dermatitis to metal in

underwired bra.

Figure 12.41  Allergic contact dermatitis face mask. Figure 12.44  Allergic contact dermatitis to formaldehyde in nail polish.

Figure 12.42  Allergic contact dermatitis face to plant.

Figure 12.45  Allergic contact dermatitis to accelerants in gloves.

Guttate psoriasis  101

papules (and plaques) (Figure 12.47), which are widely disseminated, particularly on the trunk (Figure 12.48) and proximal part of the extremities (Figure 12.49).4 The face may also be involved. The lesions typically appear 1–2 weeks following a streptococcal infection of the upper respiratory tract.4 The lesions tend to persist for 2–3 months then spontaneously resolve. A third of

Figure 12.46  Allergic

contact dermatitis to belt buckle

(nickel).

Figure 12.47  Guttate psoriasis.

Irritant contact dermatitis is an inflammatory condition of the skin produced in response to the direct contact of an irritant substance. Irritant contact dermatitis is more common than allergic contact dermatitis.24,25 The clinical presentation varies according to body site and cutaneous response. Lesions can vary from erythematous plaques to vesiculobullous lesions.24,25 Itch is an important clinical feature. Lesions are confined to the area of contact. Histopathology shows ballooning of keratinocytes in the upper dermis with variable necrosis. Neutrophils are seen in areas of ballooning and necrosis and mild spongiosis in the adjacent epithielium.24

Extramammary Paget’s disease Extramammary Paget’s usually affects sites with a high density of apocrine glands, such as the anogenital region and the axilla.26 It has also rarely been reported to occur in the external auditory canal, buttocks, thigh, knee, umbilicus, abdomen, and chest. Extramammary Paget’s disease presents as an erythematous, eczematous, and slowly spreading plaque.26,27 Histopathology demonstrates tumor cells with an abundant pale cytoplasm and large pleomorphic nuclei.27 Occasional cells have an eccentric nucleus and the appearance of a signet ring.27 Further discussion is provided under the differential diagnoses of genital psoriasis.

Figure 12.48  Guttate psoriasis.

GUTTATE PSORIASIS Guttate psoriasis is the most frequent form of psoriasis observed in children and young adults.4 It is characterized by an acute eruption of numerous, small (0.5– 1.5 cm), round or slightly oval, erythematous, and scaly

Figure 12.49  Guttate psoriasis.

102  Differential diagnoses of psoriasis

children with guttate psoriasis go on to develop plaque psoriasis in later life.1 This pattern of psoriasis can also occur in patients with established chronic plaque disease. 3 The histological features of guttate psoriasis are the same as seen in chronic plaque type psoriasis.5 The differential diagnoses of guttate psoriasis include pityriasis rosea, pityriasis versicolor, secondary syphilis, pityriasis lichenoides, and cutaneous T-cell lymphoma (MF).

Pityriasis rosea Pityriasis rosea is a common, acute, self-limited ­dermatosis characterized by the development of oval, salmon-pink, papulosquamous lesions. Like guttate psoriasis, pityriasis rosea occurs predominantly on the trunk (Figures 12.50 and 12.51), although the neck and proximal extremities may also be involved. 28 In pityriasis rosea the lesions are usually a paler color, more oval in shape, and have centripetal fine scaling. 28 A sharply defined, scaly plaque 2–10 cm in diameter, called the “herald patch,” may develop on the torso 5–15 days prior to other lesions. 5,28 History of herald patch is a strong diagnostic clue. Occasionally, the lesions are predominantly papular and the diagnosis may depend on the herald patch. 28 The majority of patients are between 10 and 35 years of age, similar to guttate psoriasis, although pityriasis rosea has been

Figure 12.51  Pityriasis rosea. reported at all ages. 28 Clinical variants include acral or facial involvement, oral lesions, or the presence of pustular, purpuric, or vesicular lesions. 5 The etiology is uncertain, but reactivation of human herpes virus HHV-6 and HHV-7 has been implicated. 5,28 A preceding viral infection, such as an upper respiratory tract infection or inf luenza, may trigger pityriasis rosea. Patients are generally asymptomatic, although pruritus can be reported. The lesions typically fade and resolve over 3–6 weeks. 28 Although the lesions are clinically papulosquamous, histopathology shows a spongiotic tissue reaction. 5 There is focal parakeratosis, sometimes with the formation of parakeratotic mounds. 5 There is diminution of the granular layer and focal spongiosis with lymphocyte exocytosis. 5 Small spongiotic vesicles, sometimes simulating Pautrier’s microabscesses, are a characteristic feature and are present in most cases. 5 Dyskeratotic cells may be seen at all levels of the epidermis. Multinucleate epidermal cells are uncommon. 5 The herald patch may show a psoriasiform tissue reaction. 5

Pityriasis versicolor

Figure 12.50  Pityriasis rosea.

Pityriasis versicolor is a relatively common noncontagious superficial yeast infection.29,30 Often confined to the upper trunk, neck, and abdomen, lesions can spread down the arms (Figure 12.52) and occasionally involve the face.29,30 Lesions in the axilla, groin, thighs, and genitalia can occur.29 It may be both chronic and recurrent. The causative organism is yeast from the genus Malessezia.29,30 Typically lesions are sharply demarcated red-brown macules and patches, slightly scaly, and may be macular, nummular, or confluent (Figure 12.53).29,30 Variations in skin

Guttate psoriasis  103

Figure 12.52  Pityriasis versicolor.

color are seen from darker patches where skin is involved in paler skin types to hypopigmented patches in more tanned skin types.29 Infections are slightly more common in patients with seborrheic dermatitis and psoriasis, and more common in temperate climates. Patients are usually asymptomatic.29 Histopathology shows slight to moderate hyperkeratosis and acanthosis.29 The dermis contains a mild, superficial perivascular inflammatory infiltrate that includes lymphocytes, histiocytes, and occasional plasma cells.29 In the stratum corneum there are numerous round budding yeasts and short septate hyphae, giving a so-called “spaghetti and meat balls” appearance on microscopy.29

Secondary syphilis The great imitator, syphilis can sometimes present lesions in the second phase with a psoriasiform pattern. Syphilis is an infectious disease caused by the spirochete Treponema palladum.31 The mode of infection is almost always through sexual contact. Untreated cases progress to secondary syphilis 4–8 weeks after the development of the chancre. There may be constitutional symptoms including fever, lymphadenitis, and hepatitis.31,32 The cutaneous lesions of secondary syphilis are usually maculopapular or erythrosquamous, but multiple other forms may develop including lichenoid, nodular, corybose, annular, bullous, follicular, pustular, rupial, and ulcerative lesions.32 A sudden eruption in adults with involvement of palm, soles, and face is common.32 There is considerable variation in the histopathological appearances of secondary syphilis. The epidermis is frequently involved and may show acanthosis with spongiosis, psoriasiform hyperplasia, and spongioform pustulation, with considerable exocytosis of neutrophils.32 Psoriasiform hyperplasia is more often seen in late lesions of secondary syphilis.32 A lichenoid tissue reaction may also be present and this combination of tissue reactions is very suggestive of syphilis, particularly if the infiltrate in the dermis forms in both the superficial and deep parts.32 Plasma cells are often present, but they are not invariable.32 T. palladium can be detected using polymerase chain reaction (PCR).32

Pityriasis lichenoides

Figure 12.53  Pityriasis versicolor.

Pityriasis lichenodes is an uncommon, self-limiting dermatosis with a spectrum of clinical changes.33 There is both an acute and a chronic form. The acute form, pityriasis lichenoides et varioliformis acuta (PLEVA), is characterized by a generalized eruption of acute onset, consisting of papular lesions that may develop into blisters, become hemorrhagic or crusted, and evolve into redbrown plaques with central necrosis that heal to leave a

104  Differential diagnoses of psoriasis

superficial varioliform scar (Figure 12.54). The lesions appear in crops, which heal in several weeks. New lesions may continue to appear for many months or even years, with varying periods of remission.34 Lesions can be painful or itchy. The chronic form known as pityriasis lichenoides chronica (PLC) (Figure 12.55) is characterized by the gradual development of symptomless, small scaly red-brown papules and macules (Figure 12.56), which are more scaly and less hemorrhagic; they spontaneously flatten and regress over a period of weeks and do not evolve into necrotic lesions.33,34 The scale in pityriasis lichenoides is more adherent, with a characteristic, centrally adherent “mica” scale that is easily detached.34,35 Lesions, which vary in number from 20 to several hundred, are most common on the anterior aspect of the trunk (Figure 12.57) and the flexor surface of the proximal parts of the extremities, followed by the head and acral areas.33 Pityriasis lichenodes most often affects adolescents and young adults

before the age of 30 years.34 It is slightly more common in males. The pathogenesis is unknown but it has been suggested that three main features are present: evidence of an infective trigger, cytotoxic CD8+ T-cell proliferation, and lymphocytic vasculitis.34 Associated infections include Toxoplasma gondii, Epstein–Barr virus, human immunodeficiency virus (HIV), cytomegalovirus, parvovirus, S. aureus, and group A beta-hemolytic streptococcus.34 In PLC, patients can have relapses of the condition for months to years.34,35 Histopathology demonstrates a lymphocytic vasculitis in which the associated inflammatory cell infiltrate shows exocytosis into the epidermis

Figure 12.56  Pityriasis lichenoides.

Figure 12.54  Pityriasis lichenoides.

Figure 12.55  Pityriasis lichenoides.

Figure 12.57  Pityriasis lichenoides.

Erythrodermic psoriasis  105

with obscuring of the dermoepidermal interface.35 There is variable death of keratinocytes that may involve single cells or sheets of cells resulting in confluent necrosis of the epidermis.35 The inflammatory infiltrate and the degree of epidermal changes are more prominent in PLEVA. Both are lichenoid (interface) dermatitides with lymphocytic vasculitis. In PLC, the epidermis shows variable acanthosis and is sometimes vaguely psoriasiform.35

Mycosis fungoides As described in the preceding section under chronic plaque psoriasis, cutaneous T-cell lymphoma may present as patches and plaques.35 A potentially prelymphomatous condition, chronic superficial scaly dermatitis (CSSD), also known as “chronic superficial dermatitis,” “small plaque parapsoriasis,” or “digitate dermatosis,” is characterized by round or oval red, pink, brown, or slightly yellow, slightly scaly patches, about 2.5 cm across, on the trunk and limbs.37,38 It is rarely present on the face, palms, or soles. The condition mostly affects adults and is more common in men. CSSD commences as one or more red, slightly scaly patches that are generally round or oval, although it may present as fingerlike processes, especially on the abdomen, accounting for the alternative name digitate dermatosis.37,38 The individual patches are often slightly wrinkled and described as appearing like cigarette paper.37

Figure 12.58  Erythrodermic psoriasis.

ERYTHRODERMIC PSORIASIS Erythrodermic psoriasis represents a generalized form that involves more that 90% of the skin surface area.3 All body sites including face, hands, feet, nails, trunk (Figure 12.58), and extremities (Figure 12.59) are involved.3 Erythema is the most prominent feature with superficial scale. Erythrodermic psoriasis can have a gradual or sudden onset of diffuse erythema; it usually develops in patients with active plaque psoriasis but may arise de novo.3,39 Precipitating or trigger factors include withdrawal of systemic glucocorticosteroids, infections, and less commonly discontinuation of methotrexate.3 In some cases, crops of pustules may develop and evolution to pustular psoriasis may occur.38 Histopathology findings are variable and often nonspecific; psoriasiform hyperplasia, sometimes accompanied by mild spongiosis, may be present.5 Histopathology may resemble early lesions of psoriasis.5 Dilation of the superficial vessels is usually prominent, typically with absence of a cornified layer.5 Sometimes the histological changes do not resemble those of psoriasis at all.5 There are many clinical presentations of erythroderma that are often challenging to differentiate.5,39 The differential diagnosis of erythrodermic psoriasis includes pityriasis rubra pilaris, atopic dermatitis, contact dermatitis, chronic actinic dermatitis (CAD), Sezary syndrome, and drug eruption.

Figure 12.59  Erythrodermic psoriasis.

Pityriasis rubra pilaris Pityriasis rubra pilaris (PRP) is an idiopathic erythematous scaling eruption that can be difficult to distinguish from psoriasis.40 PRP is characterized by one or more of circumscribed follicular keratotic papules (Figure 12.60), palmoplantar keratoderma (Figure 12.61), and a desquamating orange-hued erythematous eruption (Figure 12.62) that follows a cephalocaudal progression to erythroderma with islands of sparing.40 A variable degree of pruritus is often present.40 PRP may occur

106  Differential diagnoses of psoriasis

Figure 12.60  Pityriasis rubra pilaris close up.

in adults or children.40 It shares clinical features with psoriasis, making its distinction difficult in some cases.40 The presence of follicular, horny plugs on the knees and elbows and on the dorsal surface of the fingers and toes is distinctive.40,41 In many cases, islands of normal skin persist in the erythrodermic regions, and horny plugs may be evident around their margins.41 These normal pale “islands” are very suggestive of the diagnosis and the skin on the palms and soles often has an orange discoloration.41 Histopathology shows alternating orthokeratosis and parakeratosis, vertically and horizontally. Follicular plugging with perifollicular parakeratosis, mild to moderate epidermal hyperplasia, without neutrophil exocytosis.5 PRP shares with psoriasis regular epidermal hyperplasia and hyperkeratosis.5 Distinguishing features between PRP and psoriasis include acantholysis, an increased granular layer, follicular plugging, and the absence of psoriatic capillary alterations, granular layer diminution, and epidermal pustulation.3,5 Histopathological distinction between these two conditions is nonetheless problematic.3

Allergic contact dermatitis

Figure 12.61  Pityriasis rubra pilaris palms and abdomen.

Irritant and allergic contact dermatitis can rarely precipitate exfoliative dermatitis.41 In allergic contact dermatitis it can occur following previous sensitization to an allergen in which the dermatitis becomes generalized.41 Exfoliative dermatitis has been reported as an unusual manifestation of acute irritant contact dermatitis, in the setting of widespread exposure to the irritant.41 Clinically it presents as a widespread exfoliative erythroderma-like eruption with generalized erythema and scaling of the skin following contact with the causative agent.41 Preceding history of eczema helps to confirm the diagnosis. Features of allergic contact dermatitis on histopathology include a mild to moderately heavy infiltrate of lymphocytes, macrophages, and Langerhans cells, with accentuation around the superficial plexus within the upper dermis contains. 24 There is exocytosis of lymphocytes and sometimes eosinophils. 24 Chronic lesions may show little spongiosis but prominent epidermal hyperplasia of psoriasiform type. 24 Mild fibrosis may develop in the papillary dermis. 24

Atopic dermatitis

Figure 12.62  Pityriasis rubra pilaris legs.

Generalization of atopic dermatitis occurs most frequently in the sixth and seventh decades but may occur at any age.39 Exacerbation of existing lesions usually precedes the generalization, which follows the usual pattern.39 Pruritus is often intense. Some patients have elevated serum IgE and lactate dehydrogenase (LDH) levels with eosinophilia.38 Erythroderma developing in primary eczema is often of sudden onset.39 Patchy erythema, which rapidly

Erythrodermic psoriasis  107

Figure 12.63  Erythrodermic eczema. generalizes, may be accompanied by fever and malaise (Figure 12.63).39 The erythema extends rapidly and may be universal in 12–48 hours. Scaling appears after 2–6 days, often first appearing in the flexures.39 A preceding history of eczema helps to confirm the diagnosis. Histopathology demonstrates spongiosis and spongiotic vesiculation, exocytosis of lymphocytes, perivascular infiltrate of lymphocytes, and macrophages around vessels of the superficial plexus.24 Mast cells in different stages of degranulation, and occasional eosinophils, may be present.24 Lesions may show hyperkeratosis and moderate to marked psoriasiform hyperplasia.24

Figure 12.64  Chronic actinic dermatitis.

Chronic actinic dermatitis CAD is a rare photosensitive eczema of exposed and nonexposed skin.42–44 It is one of the most frequently encountered photodermatoses in patients over 50 years of age.42,43 CAD is often associated with, but must be differentiated from, photocontact allergy and contact dermatitis, most commonly airborne contact sensitivity.42,44 It is generally worse in summer.42–44 CAD typically affects older males, but also rarely individuals with atopic dermatitis.42 Exposed sites are predominantly affected, particularly the face, scalp, back, and sides of the neck, upper chest, and dorsal aspects of the forearms or hands (Figures 12.64 and 12.65).42,44 There are often sharp demarcations at lines of clothing, and sparing of the skin creases, upper eyelids, finger web spaces, and postauricular spaces.42 Palmoplantar eczema is not uncommon and erythroderma may occasionally develop.42 CAD is eczematous, severely pruritic, often lichenified, and can be patchy or confluent.42 In severe cases, it characteristically shows scattered or widespread, erythematous, shiny, infiltrated, psuedolymphomatous papules or plaques, arising on a background of erythema, eczema, or normal skin.42 Erythrodermic CAD can be confirmed by phototesting of clear areas.42 Histopathology shows epidermal

Figure 12.65  Chronic actinic dermatitis. spongiosis and acanthosis, sometimes with hyperplasia, and a usually deep dermal, predominantly perivascular dense lymphohistiocytic infiltrate, sometimes with large hyperchromatic, convoluted nuclei or mitotic figures.42,45 In addition there may be macrophages, eosinophils, and plasma cells. In florid cases, the appearance may resemble erythrodermic psoriasis.42,45

108  Differential diagnoses of psoriasis

Cutaneous T-cell lymphoma (Sezary syndrome) Cutaneous T-cell lymphoma is the most common malignancy to cause erythroderma (Figure 12.66), followed by Hodgkin’s disease. 39 Sezary syndrome is a clinical triad of erythroderma, peripheral lymphadenopathy, and atypical mononuclear cells (Sezary cells) comprising 5% or more of the peripheral blood lymphocytes. 39,46 The majority of patients are elderly males. Sezary syndrome may develop de novo or as progression of a form of classic MF. 39,46 The erythema is universal; rubbing and scratching may produce secondary lichenification. 39 Pruritus is often severe. Enlargement of the lymph nodes may be considerable, even if they are histologically not involved by the lymphoma. 39 There is great variability in the histological findings. Biopsy of involved skin may show only nonspecific features initially. 39,47 In many cases the findings are similar to MF. In the most frequently observed pattern, there is a band-like cellular infiltrate involving the papillary dermis and sometimes the upper reticular dermis as well.47 Epidermotropism is present in some of these cases and Pautrier’s abscesses may be found.47 The infiltrate is of varying density and is composed of small lymphocytes admixed with some larger cells with indented nuclei.47 These changes occur in a background of irregular acanthosis of the epidermis with orthokeratosis and focal parakeratosis.47 Spongiosis is sometimes present although usually mild.47 The papillary dermis is fibrotic with thickened collagen bundles and scattered melanophages.47

Figure 12.66 Cutaneous fungoides).

T-cell lymphoma (mycosis

Drug eruption A wide range of drugs can cause erythroderma. Among the more commonly implicated are antibiotics, nonsteroidal anti-inflammatories, beta blockers, carbamazepine, cimetidine, and lithium.39 The eruption has an acute onset beginning as a generalized eczema with associated fevers and skin irritation increasing in severity.39 Erythema may first appear in the flexures or be generalized involving the whole skin.39 This group has the best prognosis of all the causes of erythroderma, often resolving in 2–6 weeks.39 However, it is important to remember that drug hypersensitivity may involve other organs, for example hematological abnormalities, hepatitis, or nephritis.39 Exposure to the causative agent may occur 2 weeks to several months before the onset of symptoms emerge.39 Clues to a drug eruption on histopathology include superficial dermal edema, activated lymphocytes, the presence of eosinophils and/or plasma cells, red cell extravasation, and endothelial swelling of vessels with exocytosis of lymphocytes.39,45 A characteristic feature is the presence of rare apoptotic keratinocytes (Civatte bodies) in the basal layer.45

PUSTULAR PSORIASIS Pustular psoriasis is characterized by coalescing sterile pustules on an erythematous background (Figure 12.67). There are clinical variants of pustular psoriasis: generalized pustular psoriasis (Figure 12.68) and localized forms (Figure 12.69).4 Generalized pustular psoriasis is a distinctive acute variant of psoriasis, which may be

Figure 12.67  Pustular psoriasis palm.

Pustular psoriasis  109

Figure 12.70  Pustular palmar psoriasis.

Figure 12.68  Generalized pustular psoriasis.

in patches that then progress to become confluent leading to erythroderma. 3 Characteristically the disease occurs in waves of fever and pustules. 3 The etiology is unknown; various provoking factors include infections, hypocalcaemia, irritating topical treatments (Koebner phenomenon), and withdrawal of oral corticosteroids. 3 Histopathology shows a lymphocytic infiltrate and spongiform pustule formation. 3 Localized forms of pustular psoriasis are typically confined to the hands and feet including psoriasis pustulosa palmoplantaris (Figure 12.71) and acrodermatitis continua suppurativa (Figure 12.72). 2,3 Palmoplantar pustulosis is a common condition in which erythematous and scaly plaques are studded with sterile pustules on the palms and soles of the feet (Figure 12.73). 2 It is a chronic condition and may be very treatment resistant.2 It typically occurs in adults 50–60 years of age and is rare in children. 2 Acrodermatitis continua is characterized by a chronic sterile pustular eruption of the fingertips and/or toes (see Figure 12.72) that slowly extends and may evolve into generalized pustular psoriasis. 2 Acrodermatitis continua is more common in females and can occur at any age. 2 Histopathology shows psoriatic changes with a neutrophilic accumulation of pustules in the epidermis. 2 The differential diagnosis of pustular psoriasis includes acute generalized exanthematous pustulosis, drug eruption, and tinea pedis.

Acute generalized exanthematous pustulosis Figure 12.69  Localized pustular psoriasis. preceded by plaque psoriasis or arise de novo, classically after withdrawal of systemic glucocorticosteroids.1,3 It is characterized by explosive onset of widespread erythematous patches and sterile pustules, which coalesce to form large lakes of pus (Figure 12.70).1,3 Attacks are characterized by fever that lasts several days along with a sudden generalized eruption of sterile pustules 2–3 mm in diameter. 3 The pustules arise on erythematous skin

Acute generalized exanthematous pustulosis (AGEP) is an uncommon, rapidly evolving pustular eruption characterized by the development of sterile nonfollicular-based pustules occurring on a diffuse erythematous background.50,51 The lesions may have a targetoid appearance. Distribution is mainly seen in the flexures and on the face. Mucous membrane involvement may occur in about 20% of cases but usually is mild and remains limited to one location, most commonly the oral mucosa.50 The eruption occurs within hours to days of ingestion of certain drugs and

110  Differential diagnoses of psoriasis

Figure 12.71  Plantar pustular psoriasis.

Figure 12.73  Pustular drug eruption. Drug eruption

Figure 12.72  Acrodermatitis continua. resolves spontaneously within 5–15 days after cessation of the offending agent.50 In some cases, a viral infection has been implicated.50 Some patients have a history of underlying psoriasis, ulcerative colitis, or thyroiditis.50–52 Patients often describe a burning or itching sensation.51,52 Fever and elevated neutrophils are common. Lymphadenopathy has been reported in some cases.50 Numerous drugs have been implicated including but not limited to antibiotics, carbamazepine, frusemide, paracetamol, allopurinol, itraconazole, diltiazem, nystatin, terbinafine, phenytoin, olanzapine, and antimalarials.51,52 Histopathology typically shows spongiform subcorneal and/or intraepidermal pustules, edema of the papillary dermis, and perivascular infiltrates with neutrophils and exocytosis of eosinophils.50,52 Vasculitis and keratinocyte necrosis may be present.52 Psoriatic changes such as acanthosis and papillomatosis are usually absent.50 AGEP can be difficult to differentiate from generalized pustular psoriasis; features that may help to distinguish the two include the presence of eosinophils in the pustules or dermis, necrotic keratinocytes, a mixed neutrophil interstitial and mid-dermal infiltrate, and the absence of tortuous, dilated blood vessels.53

Pustular drug reactions have been reported in association with a number of medications.53 They can easily be clinically confused with generalized pustular psoriasis.54 Pustulosis often develops within 24 hours of drug administration, often beginning on the face (see Figure 12.73) or in flexural areas, rapidly becoming disseminated with associated fever.54 Causative agents frequently include antibiotics (usually penicillins and macrolides), terbinafine, diltiazem, carbamazepine, frusemide, azathioprine, chemotherapy agents, morphine, paracetamol, and nonsteroidal anti-­inflammatories.54 Two histological patterns may be seen: (1) a toxic pustuloderma with spongioform intraepidermal pustules, papillary edema, and a mixed upper dermal perivascular inflammatory infiltrate; or (2) a leukocytoclastic vasculitis with neutrophil collections both below and within the epidermis, suggesting passive neutrophil elimination via the overlying epidermis.49 The presence of eosinophils in the inflammatory infiltrate is a helpful clue to a drug cause.49

Tinea pedis Tinea pedis is the most common regional dermatophytosis in adolescents and adults.6,8 The appearance is often modified by maceration and fissuring, but the sharp scaling border is usually preserved.8 Tinea pedis has various patterns including clusters of blisters or pustules (Figure 12.74) on the sides and soles of the feet, which can commonly confused with pustular psoriasis (usually Trichophyton mentagrophytes var. interdigitale).6 Tinea pedis affects all ages but is more common in adults than in children.6 Some factors that can make individuals more prone to tinea pedis include occlusive footwear, hyperhidrosis, immunodeficiency, and use of communal showers.6 Tinea pedis is often seen in combination with onychomycosis.6 This can make the distinction between localized pustular psoriasis and tinea pedis with onychomycosis difficult. In some cases, both pustular psoriasis and dermatophyte infection can coexist.6,8 Skin scrapings and nail clippings can help to confirm the diagnosis. In some cases, the clinical picture of tinea pedis can be modified by the use of topical corticosteroids (tinea incognito).6 In this instance, the diagnosis can be even more problematic.

Flexural psoriasis  111

Figure 12.75  Flexural psoriasis.

Figure 12.74  Pustular tinea pedis.

FLEXURAL PSORIASIS Flexural (inverse) psoriasis is a rare variant that occurs in the flexural skin folds. 55 It affects between 3% and 7% of all patients with psoriasis and is characterized by well-defined plaques confined to the flexural areas. Flexural psoriasis can be localized to the axillae (Figure 12.75), groin, genital area, umbilicus, postauricular area, intergluteal cleft (Figure 12.76), inframammary creases (Figure 12.77), antecubital fossae, and popliteal fossae. 55 The sites most commonly affected include the groin. 55 Plaques are thin, and have minimal scale and a shiny nonscaly surface (Figure 12.78) commonly accompanied by secondary fissuring and/or maceration. 3,55 Clinical diagnosis of flexural psoriasis can be difficult. 3 A full body examination, in particular, the anogenital, peri-umbilical, and retroauricular areas, scalp, and nails should be included to look for psoriasis. 3,56 Flexural psoriasis is slightly more common in patients with nail involvement. 56 Characteristic features on histopathology include reduced epidermal hyperplasia and more pronounced spongiosis than chronic plaque psoriasis. 56 The differential diagnosis of inverse psoriasis includes intertrigo, candida, erythrasma, tinea cruris, contact dermatitis, and Hailey–Hailey disease.

Figure 12.76  Flexural psoriasis (gluteal cleft). Intertrigo Intertrigo is a generic name for an inflammatory dermatosis involving the body folds (Figure 12.79), notably the submammary (Figure 12.80) and genitocrural regions, usually seen in neonates and older individuals.57 Physiological factors such as obesity, sweating, friction, and incontinence may cause inflammation, erythema,

112  Differential diagnoses of psoriasis

Figure 12.77 

Flexural psoriasis (breast fold with secondary

candidiasis).

Figure 12.79  Intertrigo.

Figure 12.78  Flexural psoriasis. and fissuring, and render the skin more vulnerable to secondary bacterial or fungal infections.57 There may be tenderness, itching, and a superficial erythema. Secondary infectious organisms include candida, erythrasma, and dermatophyte.57 Intertrigo can be differentiated from flexural psoriasis by bacterial and fungal cultures as well as skin biopsy, which does not show a psoriasiform reaction pattern.57 Candida infection is common.57

Candidosis Candidosis clinically presents as an intertrigo with coalescent erythematous patches or plaques involving the skin folds (Figure 12.81), often with superficial erosions.6 Satellite pustulosis may extend onto the skin of the abdomen, buttocks, and thighs (Figure 12.82).6 It is seen commonly in pregnancy and infants.6 Immunosuppression, occlusion, obesity, diabetes, and systemic antibiotic treatment are risk factors.6 Symptoms of burning and soreness are more common than itch.6 Psoriasiform epidermal hyperplasia may be present in lesions of chronic candidosis.5,8 The rete ridges are not usually long in the

Figure 12.80  Intertrigo. psoriasiform hyperplasia of chronic candidosis.5,8 There are usually a few neutrophils and some serum in the overlying parakeratotic scale. Fungal elements may be sparse and difficult to identify.5,8

Erythrasma Erythrasma is a common genitocrural infection, especially in males, caused by chronic superficial infection of the skin by Corynebacterium minutissimum, a commensal organism normally found as part of the skin flora.58,59 Typically, irregular erythematous to brown slightly scaly macules with well-defined borders are seen on the upper inner thighs. More chronic lesions can be slightly scaly and lichenified.58,59 Lesions may also be seen in the axillae and the web spaces of the toes. In the inguinal folds,

Flexural psoriasis  113

confirmed by the demonstration of coral pink fluorescence under Wood’s light due to porphyrin produced by the bacterium.58

Tinea cruris Tinea cruris is a common disease of the groin (Figure 12.83) and is usually caused by T. rubrum.6 It is less common in females and occurs frequently in hot humid climates.6 Typical lesions are erythematous plaques, curved with sharp margins (Figure 12.84), and a fine peripheral scale, extending from the groin down the thighs (Figure 12.85).6 Central clearance is usually present but is often incomplete.6 Satellite lesions if present are few and relatively large.6 Spread to the scrotum is common, but scaling is minimal.6 Itch is a predominant feature. Diabetes, obesity, and excessive sweating are predisposing factors. Skin scrapings confirm the diagnosis.6

Contact dermatitis

Figure 12.81  Flexural candida.

Irritant contact dermatitis of the genitocrural region is common and is caused by excessive use of soap and toiletries.25 Allergic contact dermatitis of the genitocrural folds may present suddenly with pruritus, edema, and erythema or insidiously as a gradual intensification of a preexisting dermatitis.23 Medicament sensitization is common in the anogenital region. Common allergens include fragrance, antiseptics, local anesthetics, Balsam of Peru, corticosteroids, antifungals, neomycin, and more recently methylisothazolinone found in moist toilet tissues and wipes.23,60

Hailey–Hailey disease

Figure 12.82  Flexural candida. erythrasma may present as an intertrigo and can be macerated and eroded.58,59 It is not usually very itchy, but can be slightly tender.58 It may coexist with T. rubrum and candidosis. Erythrasma can occur at any age but is more common in adults. Warmth and humidity are the ideal predisposing factors. Erythrasma is a clinical diagnosis

Hailey–Hailey disease is a rare late onset intraepidermal blistering disease of the flexures that has an autosomal inheritance. It is due to a defect in keratinocyte adhesion as a consequence of APT2 C1 gene mutation.61 The condition usually presents by 30–40 years of age.61 The lesions tend to have a history of appearing as vesicles, blisters, or flaccid vesiculopustules and usually have a fissured appearance with some overlying crust.55,61 Crusted erosions or expanding circinate plaques appear in areas exposed to friction.62 Hailey–Hailey disease appears mostly in the same distribution as flexural psoriasis. Common sites include the armpits, groin, neck, submammary region, and buttocks.62 Lesions extend peripherally with h ­ ealing in the center.62 Flexural disease may be hypertrophic and ­ malodorous with soft flat moist vegetations and ­fissures.61 Itch and pain are common. Mucosal involvement is uncommon but has been reported.61 Nail involvement occurs in some patients (longitudinal white bands).61 Lesions tend to affect the skin folds in the axilla, groin, perianal regions, and neck.62 Longitudinal whitening of the nails can be seen. Primary lesions are loose blisters on

114  Differential diagnoses of psoriasis

Figure 12.83  Tinea cruris.

Figure 12.85  Tinea cruris. SCALP PSORIASIS

Figure 12.84  Tinea cruris. an erythematous background. Secondary infections can occur.62 Histopathology shows suprabasal acantholysis and formation of epidermal bullae.62,63 In the epidermis, a partial acantholysis that has the appearance of a dilapidated brick wall is observed.52,62,63 Epidermal hyperplasia, parakeratosis, and perivascular lymphocytic infiltration are observed in the upper dermis.52,62

The scalp is the most common anatomical site to be involved by psoriasis and frequently the site of initial presentation.3 Clinically the morphology of scalp psoriasis can range from discrete erythematous plaques (Figure 12.86) with silverywhite scale to total scalp involvement (Figure 12.87) with either thick plaques or scaly nonthickened areas similar to seborrheic dermatitis.3 Sites of predilection include the immediate postauricular area (Figure 12.88) and occiput (Figure 12.89).3 Scalp involvement is frequently asymmetrical and rarely extends more than 2 cm beyond the hairline (Figure 12.90).3 Hair loss is not a common feature of psoriasis.2 The histopathology features are similar to chronic plaque psoriasis.2 The differential diagnosis of scalp psoriasis includes contact dermatitis, atopic dermatitis, and seborrheic dermatitis.

Contact dermatitis Although exposed to many potential allergens, allergic contact dermatitis of the scalp is rare and in the main, the scalp usually tends to be spared from involvement

Scalp psoriasis  115

Figure 12.86  Scalp psoriasis.

Figure 12.87  Occipital scalp psoriasis.

Figure 12.88  Scalp psoriasis.

Figure 12.89  Scalp and ear psoriasis.

116  Differential diagnoses of psoriasis

Figure 12.90  Scalp psoriasis. by allergic contact dermatitis.23 This may be an inherent property of the scalp. Contact dermatitis of the scalp tends to present as pruritus with erythema. Vesicles seen with allergic contact dermatitis elsewhere are typically not seen. There may be exudation and crusting of the skin. Geometric areas of dermatitis are an indication of contact dermatitis. Allergic reactions to hair care products are largely not restricted to the scalp but will also involve the face, eyelids, ear, and neck (Figure 12.91).

Figure 12.91  Allergic contact dermatitis scalp.

Atopic dermatitis Atopic dermatitis of the scalp clinically presents as a d ­ iffuse erythema with fine adherent scale. Signs of e­ xcoriation, lichenification, crusting, and secondary infection may be seen. Atopic dermatitis of the scalp rarely ­presents in ­isolation.24 A clue to the diagnosis is the presence of eczema elsewhere on the body, particularly involving the face, trunk, and flexural surfaces.24 Differentiating features from scalp psoriasis include the diffuse nature, fine scale, and less well-defined edges.24 Patients usually report a personal or family history of atopy.24 Histopathology shows spongiosis, spongiotic vesiculation, exocytosis of lymphocytes, perivascular infiltrate of lymphocytes, and macrophages around vessels of the superficial plexus.24 Mast cells present in different stages of degranulation, and occasional eosinophils may be present.24 Chronic lesions may show hyperkeratosis, moderate to marked psoriasiform hyperplasia.24

Seborrheic dermatitis Seborrheic dermatitis is a chronic dermatitis with distinctive morphology and distribution in sebaceous areas.64 It is characterized by red sharply marginated plaques covered in a greasy yellow scale typically on the scalp, nasolabial folds, ears, eyebrows, and chest (Figures 12.92 through 12.94).64 Seborrheic dermatitis affects all age groups; however, it is more common in infants and young

Figure 12.92  Seborrhoeic dermatitis. adults.64 Seborrheic dermatitis occurs more frequently in males and individuals with HIV infection.64 Yeast of the genus Malessezia, a commensal organism of the skin flora, is thought to be important in the etiology.64 Involvement of the frontal hairline is more common in psoriasis than seborrheic dermatitis.65 Otitis externa may accompany seborrheic dermatitis or may occur alone. The typical ­histological features are of both psoriasis and chronic dermatitis.64 Most of the stratum corneum is lost in

Nail psoriasis  117

NAIL PSORIASIS

Figure 12.93  Seborrhoeic dermatitis.

Psoriatic dystrophy of the nails is the most common disorder affecting fingernails (Figure 12.95).66 Nail ­ involvement occurs in 40%–50% of patients with psoriasis. It may also occur in up to 5% of patients without cutaneous disease.66,67 History of cutaneous psoriasis, p ­ soriatic arthritis, and family history are clues to the ­diagnosis. Arthritis of the interphalangeal joint may suggest a psoriatic cause.66 Nail morphology in psoriasis depends upon the a­ natomical location of the disease process and may involve ­single or multiple nails.67 Nail matrix signs include pitting (Figure 12.96), leukonychia, red spots in the lunula, and nail plate crumbling (Figure 12.97). Nail bed signs include ­onycholysis (Figure 12.98), salmon patches or the “oil drop” sign (see Figure 12.95), subungual hyperkeratosis, and splinter hemorrhages.66,68 Nail folds may also be affected by psoriasis and may show papulosquamous (Figure 12.99) or pustular lesions (Figure 12.100).66 When nail psoriasis is present, it often affects multiple nails. It is important to exclude onychomycosis.66,67 Pitting in the fingernails and subungual hyperkeratosis in the toenails is the most common finding.67 Nail psoriasis can be painful and limit activities of daily living and may be a marker for ­psoriatic arthritits.3,66 Occasionally, there is complete destruction of the nail unit. Characteristic histological features include varying degrees of psoriasiform hyperplasia, loss of the granular layer in the hyponychium, spongioform pustules, parakeratosis with neutrophils, and prominent granular layer in the nail bed epidermis along with spongiosis.66,67 Diagnosis of nail unit disorders can be challenging because of multiple overlap of clinical features.66 Psoriasis of the nails is often difficult to distinguish from other causes of dystrophic nails, especially onychomycosis.67 Histological features of psoriasis and onychomycosis are similar except for the presence of fungal hyphae.67 The differential diagnosis of nail psoriasis includes onychomycosis, lichen planus, alopecia areata, and contact dermatitis.

Onychomycosis

Figure 12.94  Seborrhoeic dermatitis chest. processing.64 There is slight to moderate acanthosis, with slight spongiosis.24,64 Spongiosis is the major histological feature distinguishing seborrheic dermatitis from psoriasis.64 The dermis shows a mild, chronic inflammatory infiltrate.24,64

Onychomycosis is a fungal infection of the nails (Figure 12.101) caused by dermatophytes, yeasts, and molds. Onychomycosis most commonly affects adults. It is typically limited to one or a few digits, whereas psoriasis is usually more widespread.6 Toenails (Figure 12.102) are more commonly affected than fingernails (Figure 12.103). Clinically, onychomycosis presents as a thickened nail plate with subungual hyperkeratosis, which can lead to total nail dystrophy.6 Patients may have coexisting ­dermatophyte infection, usually tinea pedis or tinea cruris.6 Differentiation between psoriasis of the nails and onychomycosis is often difficult.6 In onychomycosis the features usually present in the toes (Figure 12.104), whereas ­ fingernails are more commonly affected in

118  Differential diagnoses of psoriasis

Figure 12.95  Nail psoriasis pits, onycholysis, oil drop sign.

Figure 12.98  Nail psoriasis onycholysis.

Figure 12.96  Psoriatic nail pits. Figure 12.99 

Nail psoriasis severe with periungual disease.

Figure 12.100 Nail Figure 12.97 

psoriasis with periungual pustular

disease. Nail psoriasis periungual and nail crumbling.

­ soriasis.6 Many of the histological features of psoriasis p may be seen in ­onychomycosis including psoriasiform hyperplasia, thinned rete ridges, thinned suprapapillary plates, dilated capillaries, parakeratosis, and neutrophils within the nail bed.6,69

Lichen planus Lichen planus is an inflammatory mucocutaneous d ­ isease often with a relapsing and remitting course.17,70 Nail involvement (see Figure 12.30) is seen in 2%–16% of all patients with lichen planus.66 Onset is most often seen in

Nail psoriasis  119

Figure 12.101  Onychomycosis great and third toes.

Figure 12.104  Onychomycosis multiple toes.

Figure 12.102 

Onychomycosis with orange pigmentation.

Figure 12.105  Nail lichen planus.

Figure 12.103  Onychomycosis thumb. patients 50–60 years of age and affects men and women equally but has been reported in children.66 Typically nail lichen planus is asymptomatic though acute onset can be painful.66 It typically involves multiple nails (Figure 12.105), with fingernails more often involved than ­toenails.17,66,70 Lichen planus isolated to the nails occurs in 1%–2% of cases.66 The most common clinical features are nail plate thinning, longitudinal ridging, and distal splitting.17,66,70 Nail bed lichen planus causes erythronychia, hyperpigmentation, hyperkeratosis, and onycholysis.66 On occasion, there may be almost complete destruction of the entire nail unit (Figure 12.106). A classic feature of

Figure 12.106  Nail lichen planus. nail bed lichen planus is the “pup-tent sign,” which is a centrally peaked split nail that angles downward toward the lateral nail folds (see Figure 12.105).66 Histologically, the findings in nail lichen planus are similar to cutaneous disease.66 In active lesions, there is a band-like inflammatory infiltrate of lymphocytes in the superficial dermis.66

120  Differential diagnoses of psoriasis

Within the inflammatory infiltrate may be scattered eosinophils and plasma cells.66 There is elongation of rete ridges that resemble a sawtooth pattern, hypergranulosis, and ­dyskeratotic keratinocytes.1 Typically, the hypergranulosis is more diffuse with more epithelial spongiosis than seen in cutaneous lichen planus.66

Alopecia areata Nail changes are present in 10%–66% of patients with ­alopecia areata.70,71 Many types of nail changes are ­possible; however, the most common clinical features include p ­ itting, trachyonychia (longitudinal ridging), onychorrhexis (longitudinal riding and grooving), brittle nails, spotting of the lunula, onycholysis, and onychomadesis.71 Pitting in alopecia areata is generally more shallow and uniform when compared with nail psoriasis.72 Trachyonychia is more common in males than in females and is more frequently observed in children.73 Histopathology demonstrates a mild to moderately dense lymphocytic infiltrate associated with exocytosis and spongiosis of the proximal nail fold, matrix, nail bed, and hyponychium.73,74

often associated hand dermatitis and typically an eczematous reaction elsewhere, most often involving the face and neck.75,76 Clues to the diagnosis include acute onset, vesicles surrounding the proximal nail fold, itch, periungual swelling, and paronychia. Associated hand dermatitis may show vesicles, scaling, erythema, fissures, swollen fingers, and lichenification.70 Nail matrix disease shows thickening nail plate, pits, nail loss, transverse ridges, and furrows. Nail bed disease can produce subungual hyperkeratosis, splinter hemorrhages, onycholysis, and pain.70

PALMOPLANTAR PSORIASIS Palmoplantar psoriasis is characterized by hyperkeratotic, discrete plaques on palms (Figure 12.109) and/ or soles (Figure 12.110) that tend to become confluent (Figures 12.111 and 12.112).2 Mixed forms may occur

Contact dermatitis Allergic contact dermatitis of the nails (Figure 12.107) can occur with nail products such as acrylates and formaldehydes in nail polishes.70,75 It often presents as a painful and sometimes itchy dermatitis of the proximal nail fold, with associated nail dystrophy (Figure 12.108). There is

Figure 12.109  Palmar psoriasis, plaque type.

Figure 12.107  Allergic contact dermatitis fingertips with nail dystrophy.

Figure 12.108  Allergic contact dermatitis fingertips with associated nail dystrophy.

Figure 12.110  Plantar psoriasis.

Figure 12.111  Plantar psoriasis.

Palmoplantar psoriasis  121

Figure 12.113  Plantar psoriasis with pustules. Figure 12.112  Plantar psoriasis, plaque type with pustules. with pustulosis (Figure 12.113).2 It can be difficult to distinguish palmoplantar psoriasis from eczema. Sharply demarcated edges at the wrist (see Figure 12.112) and absence of vesicles may be helpful.2 Palmoplantar psoriasis may have different features compared with psoriasis at other sites.2 Classic histological features include mounds of parakeratosis with neutrophils at their summits, confluent parakeratosis, loss of the granular layer of the epidermis, psoriasiform epidermal hyperplasia, thinned suprapapillary plate, spongiosis, dyskeratotic cells within the epidermis, dilated capillaries, and edema of the papillary dermis.2,5,77 These features may not all be present.77 Many histological features of palmoplantar psoriasis overlap with those of eczema.77 Clues to differentiating psoriasis from eczema include multiple parakeratotic foci, placed vertically, alternating with othohyperkeratosis.77 The differential diagnosis of palmoplantar psoriasis includes pityriasis rubra pilaris, tinea pedis, contact dermatitis, Bazex syndrome, lichen planus, Darier’s disease, porokeratosis of Mibelli, and juvenile plantar dermatosis.

Figure 12.114  Palmar pityriasis rubra pilaris.

Pityriasis rubra pilaris Pityriasis rubra pilaris (PRP) is an idiopathic disorder of keratinization of unknown cause.40 It may occur in adults or children.40 Palms and soles become hyperkeratotic and develop an orange hue, and painful fissures may develop (Figure 12.114; see also Figure 12.61).40 PRP shares clinical features with psoriasis, making its distinction difficult in some cases.40 Histopathology is described under erythroderma.

Figure 12.115  Tinea pedis.

Tinea pedis Tinea pedis (Figure 12.115) is an infection of the feet with a dermatophyte fungus.6 It is more common in adults than in children and more common in males.6 Predisposing factors include occlusive footwear, excessive sweating, or hyperhidrosis.6 Clinical features of tinea pedis include peeling, maceration, and fissuring of the lateral toe clefts (Figure 12.116), sometimes spreading to involve the

Figure 12.116  Tinea pedis interdigital maceration.

122  Differential diagnoses of psoriasis

plantar surface of the toes.6 Vesicles and pustules may be seen and are more common in infections with T. mentagrophytes var. interdigitale.6 The dorsal surface of the feet is not commonly involved (Figure 12.117).6 The reaction may occasionally spread to involve the entire sole (and rarely dorsum, see Figure 12.117).6 Associated onychomycosis is common (see Figures 12.102 and 12.104). Patients typically complain of itch. An id reaction may develop on the unaffected hands (Figure 12.118).6

Contact dermatitis Palmoplantar eczema (Figure 12.119) may be a combination of both contact allergic and irritant dermatitis.78 It may present as an acute or chronic eruption of

Figure 12.117  Tinea pedis et unguium.

erythematous scaly plaques with crops of vesicles on the palms (Figure 12.120), the sides of the fingers, and/or central part of the soles and sides of the toes.78 Irritant contact dermatitis is the most common cause of hand eczema, typically caused by wet work.79 Irritant contact dermatitis may lead to allergic contact dermatitis due to the loss of barrier function leading to increased penetration by irritants and allergens.79

Acrokeratosis neoplastica (Bazex syndrome) Bazex syndrome is a rare disease associated with squamous cell carcinoma of the upper respiratory or gastrointestinal tracts.80 It is more common in males than in females.80 The cutaneous features are predominantly acral in distribution (Figure 12.121). An underlying malignancy is an essential criteria of the diagnosis.80 More than 60% of the tumors arise in the oropharynx and larynx; often metastases are found in the cervical lymph nodes.80 Rare associations with metastatic adenocarcinoma of the prostate and transitional cell carcinoma of the bladder have been reported.80 Hands, feet, helices of the ears, and tip of nose are involved. Initially, Baxez syndrome presents with violaceous erythema and scaling, which then develops to hyperkeratotic lesion on the hands and feet.80 The acral changes are psoriasiform. Nail dystrophy and paronychia are often present (Figure 12.122).80 The histological changes are not diagnostic but reflect the clinical appearance with

Figure 12.118  Vesicular hand dermatitis id reaction.

Figure 12.120  Irritant hand dermatitis.

Figure 12.119  Palmar hand dermatitis.

Figure 12.121  Bazex syndrome.

Palmoplantar psoriasis  123

Figure 12.122  Bazex syndrome.

Figure 12.123  Palmar lichen planus.

hyperkeratosis, parakeratosis, acanthosis, focal spongiosis, and a mixed inflammatory cell infiltrate.48,80 Patients may also report nonspecific symptoms such as weight loss and fatigue due to underlying malignancy.80

Lichen planus Involvement of the palms and soles in lichen planus is rare.81 Several different morphological patterns have been described: erythematous plaques, punctate keratosis, d ­ iffuse keratoderma (Figure 12.123), and ulcerated lesions.81 The most common presentation is of erythematous scaly, hyperkeratotic plaques, most frequently on the soles of the feet.17,81 Itch is commonly reported. Palmoplantar lichen planus shows histological f­eatures similar to other sites: focal parakeratosis, irregular e­ pidermal hyperplasia, wedged shaped hypergranulosis and spongiosis, vacuolar degeneration, Max–Joseph spaces, and a band-like lymphohistiocytic infiltrate.16,17,81

Figure 12.124  Darier’s disease.

Darier’s disease Darier’s disease is an autosomal dominantly inherited condition characterized by a persistent eruption of hyperkeratotic papules (Figure 12.124).61 It usually appears in childhood, but lesions may present in young adults, most often affecting the limbs, hands, and feet. Darier’s disease is caused by a mutation in the ATP2A2 gene at chromosome 12q24.1.61 The distinctive lesions of Darier’s disease are firm, rough brown to skin-colored papules.61 It can involve seborrheic areas on the trunk (Figure 12.125), face, scalp margins, temples, ears, hands, and feet.61 On the dorsa of the hands and feet, discrete papules and minute pits can be seen.61 In severe cases, palmoplantar hyperkeratosis may occur.61 Hemorrhagic macules are occasionally seen on the hands and feet.61 Characteristic nail changes are seen (Figure 12.126). Histopathology shows suprabasal acantholysis with a distinctive overlying dyskeratosis.61,63

Figure 12.125  Darier’s disease.

Figure 12.126  Darier’s disease nails.

124  Differential diagnoses of psoriasis

Porokeratosis of Mibelli Porokeratosis of Mibelli is characterized by annular ­erythematous scaly plaques surrounded by a raised fine keratotic margin.82,83 The center is usually atrophic but may be hyperkeratotic. Lesions are most common on the limbs and can involve hands and feet.82 Histology is characteristic, demonstrating coronoid lamella, a column of closely stacked parakeratotic cells that appear homogenous and possess basophilic nuclei.82,83 The central lesion shows parakeratosis and psoriasiform acanthosis in the epidermis.82

Juvenile plantar dermatosis Juvenile plantar dermatosis is specific to children mainly in children aged 3–14 years, characterized by dermatitis of weight-bearing areas of the soles of the feet.9,84 Slightly more males are affected than females.9,84 The etiology is unknown; friction and pressure are thought to play a part.9 The presenting complaint is redness and tenderness of the plantar surface of the forefoot.9 Clinically it is characterized by shiny, dry, fissured dermatitis of the plantar surface of the forefoot.9,84 Histopathology shows a mild, nonspecific eczematous reaction.9 The condition is always symmetrical and most severe on the ball of the foot and toe pads, usually sparing the nonweight baring instep.9,84 Occasionally, the condition affects the hands resulting in tender shiny fissured palms and/or fingertips.9

GENITAL PSORIASIS Psoriasis frequently involves the genitals.57 It commonly affects the anogenital region especially the natal/gluteal cleft (see Figure 12.76), the penis, and vulva.26,57,85 Genital psoriasis can occur in isolation or as part of more widespread psoriasis (Figure 12.127). Lesions on the glans penis of the uncircumcised male lack scale but the color is a rich red with well-defined margins (Figure 12.128).26,57,68 In females, genital psoriasis most frequently involves the genitocrural folds, mons pubis, and outer aspects of the labia majora, the perianal skin, and the natal cleft.57,85 Clinically, genital psoriasis presents with well-demarcated bright red plaques, most often without scale.57,85 Direct

Figure 12.127  Genital and groin psoriasis.

extension is often seen from the natal cleft to the perianal skin.57 Clues to the diagnosis include signs of other cutaneous involvement.26,68 Histology in genital psoriasis is not always typical and there may be marked spongiosis and papillary edema.26,57 The differential diagnosis of genital psoriasis includes seborrheic dermatitis, contact dermatitis, lichen planus, lichen sclerosis, plasma cell balanitis, Bowen’s disease, erythroplasia of Queyrat, and extramammary Paget’s disease.

Seborrheic dermatitis Genital involvement with seborrheic dermatitis is ­common.26,57 Genitocrural folds, labia majora, mons pubis, and perianal skin are the usual sites involved26,57,85 Involvement of other sites is common and gives a clue to the diagnosis.57 Diagnosis is often made on clinical grounds.57 Histology is typically not helpful as there may be features of both psoriasis and eczema.57 Histopathology shows moderate acanthosis with slight spongiosis and mild dermal inflammatory infiltrate.57

Contact dermatitis Due to a thin epidermal barrier and a tendency for ­irritant/allergen retention, the anogenital region is prone to irritation and sensitization. Unlike other areas of skin, the anogenital skin is exposed to friction, heat, and ­moisture. Contact dermatitis in this area may be secondary to treatment of genital dermatoses, which have lowered the threshold for irritation and sensitization. Contact ­dermatitis is typically pruritic. The rash is erythematous and may show scaling, crusting, or vesiculation. More chronic forms may show lichenification. Contact dermatitis in the genital region frequently spares the depths of creases or folds unless directly applied to the area.26,85

Lichen planus Lichen planus can present and remain localized to the genitals.26,57,85 Clinically, it presents as itchy, red or purple papules, plaques, annular, hypertrophic, and erosive lesions.26,57,85 It may occur on the penis, vulva, anogenital

Figure 12.128  Penile psoriasis.

Genital psoriasis  125

region, and oral mucosa (see Figure 12.28). 26,57,85 Lichen planus can affect the vulva in isolation or at the same time as a generalized eruption.17,57,85,86 Vulval lesions are erythematous to violaceous papules or annular plaques, and erosions with or without Wickham’s striae. 57 Lesions may ulcerate.17,57,85,86 In males, lichen planus may present as phimosis.26,57 The male genitalia is the most frequently reported site for the annular subtype of lichen planus.17,57 Occasionally an erosive form is seen. 26,57,85 In most cases, genital lichen planus is self-limiting, although some patients may remit and relapse. 26,57 Postinflammatory hyperpigmentation may be seen and can persist for months to years. 57 Chronic mucosal erosive lichen planus is associated with a risk of progression to squamous cell carcinoma.26,57 Histopathology characteristically demonstrates hyperkeratosis, irregular acanthosis with typical saw-tooth appearance of the rete pegs, an increased granular layer, and disruption of the basal layer with a closely apposed dermal band-like lymphocytic infiltrate. 57

Lichen sclerosus Lichen sclerosus is a chronic skin condition that most often affects the genital and perianal areas.26,57,85 Lichen sclerosus is 10 times more common in females than in males and can affect females at any age.26,57 The majority are prepubertal or menopausal.57,85 The etiology is unknown.26,57,85 The presenting symptom is usually itch, which can be severe. It is a chronic skin condition persisting for many years that may cause scarring.26,57,85 In women, lichen sclerosus can affect the genitocrural folds, inner aspect of the labia majora, labia minora, clitoris, and clitoral hood.57,85 Vestibular involvement is rare and vaginal lesions do not occur.57,85 Perianal lesions occur in 30% of women but do not usually develop in males.57,85 The classical lesions seen on the extragenital skin in 10% of women with lichen sclerosus are ivory white papules and plaques with follicular delling on the trunk, upper back, wrists, buttocks, and thighs.57,85,87 Anogenital disease tends to be characterized by flatter lesions of atrophic whitened epithelium, which may extend around to the vulva in a figure-of-eight pattern.57,85,87 There may be edema, erosions, and ulceration.57,85,87 Lichen sclerosis is a scarring dermatosis and can cause loss of the labia minora, sealing over the clitoral hood, introital narrowing, and labial fusion.57,85,87 In males, lichen sclerosus usually affects the glans and foreskin, and can lead to phimosis and meatal stenosis.57,86 The development of secondary phimosis in school aged boys is highly suggestive of lichen sclerosis.57,85 Oral involvement is very rare and occurs on the tongue.57 Histopathology shows a thinned epidermis with flattening of the rete pegs.26,57,85 Established lesions are characterized by hyperkeratosis, follicular plugging, and basal layer vacuolar change.88 The underlying dermis is hyalinized. There is a band-like zone of chronic inflammatory cells and absence of elastic fibers in the upper dermis.26,57,85,88

Plasma cell balanitis (Zoon’s balanitits, balanitis circumscripta plasmacellularis) Plasma cell balanitis is an inflammatory condition of the glans penis.26,57 The etiology is unknown; it is thought to be a chronic reactive disorder caused by a dysfunctional prepuce.26,57 It affects middle aged and older uncircumcised men.26,57 It is often asymptomatic but may cause localized irritation. Plasma cell balanitis may occur secondary to psoriasis, seborrheic dermatitis, lichen sclerosus, lichen planus, or contact dermatitis.57 Clinically, it is characterized by a usually solitary well-demarcated shiny, glistening, bright red patch on the glans penis and visceral prepuce with sparing of the keratinized penile shaft and foreskin.26,57 Histopathology shows epidermal attenuation with absent granular layer and horny layers, diamondshaped basal cell keratinocytes with sparse dyskeratosis and spongiosis.26,57,89 There is a band of dermal infiltration with plasma cells.86,89

Plasma cell vulvitis (vulvitis circumscripta plasmacellularis) A similar condition may be seen in women with several well-defined red patches most commonly found on the inside of the vulva at the entrance to the vagina (vestibule).85

Bowen’s disease Bowen’s disease of the penis characteristically affects the keratinized surfaces of the penis, in males over 50 years of age.26,57 Clinically, it presents as erythematous plaques, which may be smooth, scaly, or eroded.26,57 Bowen’s disease of the vulva is termed vulvar intraepithelial neoplasia (VIN).57,85 VIN can occur in women of all ages. Clinically, it presents with pruritus and/or burning with an irregular red to pale white plaque on the vulva.57,85 Untreated cases can progress to invasive squamous cell carcinoma.57 Histology confirms the diagnosis showing intraepithelial carcinoma.57

Erythroplasia of Queyrat Erythroplasia of Queyrat is a clinical variant of carcinoma in situ of the penis.26,57 It is found most commonly on the glans penis of uncircumcised males.26,57 Clinically, it presents as well-circumscribed, asymptomatic red shiny plaques.26,57 It may also arise on the coronal sulcus or the inner surface of the prepuce.26 The histological features are those of carcinoma in situ, as in Bowen’s disease.20 There are said to be fewer multinucleate and dyskeratotic cells than in Bowen’s disease. The accompanying inflammatory cell infiltrate in the dermis is often rich in plasma cells.20

126  Differential diagnoses of psoriasis

Extramammary Paget’s disease Extramammary Paget’s disease is an intraepithelial adenocarcinoma arising in the epidermis or the epithelium. It is more common in elderly patients.26,57,90 There is a female predominance with the vulva, a common site of involvement.90 Intractable pruritus is a common presenting symptom.85,90 Extramammary Paget’s disease presents as an erythematous, eczematous, slowly enlarging plaque involving the anogenital region.26,85,90 The size of the lesion usually correlates with its duration. Extramammary Paget’s disease is often associated with underlying malignancy.26,57,85,90 The most common tumors associated are anorectal adenocarcinoma and carcinoma of the bladder or urethra.26 Less frequently, the underlying malignancy may be of cervix, endometrium, or ovary.57,85 Histopathology shows epidermal hyperplasia with overlying hyperkeratosis and parakeratosis, and infiltration with pale-staining Paget’s cells; mitoses are usually present.26,57,85,90

EXTERNAL EAR PSORIASIS The retroauricular folds (see Figure 12.89), which extend into the scalp margin, are a common site of psoriatic involvement.91 Both guttate and plaque psoriasis can involve the external ear (Figures 12.129 and 12.130); this may be by extension from the scalp.91 Psoriasis often involves the concha and distal part of the external auditory canal (Figure 12.131).91

The differential diagnosis of external ear psoriasis includes seborrheic dermatitis, atopic dermatitis, contact dermatitis, and otitis externa.

Seborrheic dermatitis Seborrheic dermatitis is a chronic dermatitis with distinctive morphology: red sharply marginated plaques covered in a greasy yellow scale, and distribution in sebaceous areas, most commonly the scalp, nasolabial folds, ears, eyebrows, beard area in males, and chest (see Figure 12.94).64 Seborrheic dermatitis of the ear (see Figure 12.92) clinically presents with scaling and inflammation at the entrance to the external auditory meatus, the concha, or the auricular folds.91 When severe, the whole pinna may be affected and there may be coexistent otitis externa.91 With the ears involved, seborrheic dermatitis is often seen at other sites such as the scalp and face.91 The typical histological features are of both psoriasis and chronic dermatitis, and are described under scalp seborrheic dermatitis.64

Atopic dermatitis The ears are commonly involved in atopic dermatitis.91 Usually this is in combination with atopic dermatitis of the scalp and/or face.91 A crusted eczematous fissure, often present at the junction of the earlobe and the face, is a diagnostic clue of atopic dermatitis.91 The tragal notch and sometimes the whole pinna may be involved.91

Figure 12.129  Psoriasis external ear plus scalp.

Figure 12.130  Psoriasis external ear.

Figure 12.131  Psorisis conchal bowl and external auditory canal.

Facial psoriasis  127

Contact dermatitis Contact dermatitis of the external ear is commonly seen secondary to medicament use.60 A localized dermatitis involving the ear may be due to allergy to nickel or chromate in mobile phones. The absence of rash elsewhere raises the possibility of a contact reaction. The localized erythema and scale may be lichenified, crusted, or exudative, without scale typical of psoriasis, and typically is pruritic.

Otitis externa Otitis externa is characterized by inflammation of the external ear canal epithelium.91 It is usually multifactorial.91 Clinically, it presents as inflammation of the external ear with varying degrees of pain, erythema, edema, itch, hearing loss, and discharge.91 It may be acute or chronic and not unusually occurs in patients with coexisting eczema, psoriasis, or seborrheic dermatitis, or as a result of an infection with bacteria or fungi.91,92 Environmental factors such as humidity and moisture may be predisposing factors.91 Otitis externa is commonly observed in swimmers (Swimmer’s ear).91,92 It can also be seen secondary to trauma from scratching and aggressive ear cleaning.91 Histopathology shows acanthosis, elongation of rete ridges, and an increase in orthokeratosis and parakeratosis.91 Spongiosis occurs in eczematous and seborrheic forms.91

FACIAL PSORIASIS Involvement of the face is not uncommon.93 Scaling, ­erythema, and plaque formation can be seen on the cheeks, eyebrows (Figure 12.132), nasolabial folds, forehead, and beard area in men.93 Facial involvement (particularly central) in psoriasis may be associated with early onset disease and increased severity (extent) of disease, along with nail disease and psoriatic arthritis.93 Involvement of the forehead and peripheral face is usually associated with extensive scalp psoriasis.93

Figure 12.132  Psorisis forehead and eyebrow.

The differential diagnosis of facial psoriasis includes seborrheic dermatitis, lupus erythematosus, contact dermatitis, atopic dermatitis, and rosacea.

Seborrheic dermatitis On the face seborrheic dermatitis characteristically involves the medial part of the eyebrows, the glabella, and the nasolabial folds.64 It is usually in association with involvement of the scalp or other sites.64 In males facial seborrheic dermatitis often involves the beard area.64 Clinically, there are erythematous plaques covered with a variable amount of greasy scale.64,94 Histopathology demonstrates the same features as other sites.24,64

Lupus erythematosus Lupus erythematosus often presents with facial involvement, which varies according to subtype.15,95 Systemic lupus erythematosus most frequently presents with a typical malar eruption termed “butterfly rash.”15,95 This is characterized by an erythematous and slightly edematous eruption across both cheeks and nasal bridge. It commonly presents following sun exposure.95 An important clue to the diagnosis is the lack of involvement of the nasolabial folds.95 The main histological features are thinning of the epidermis, degradation of the basal layer, dermal edema with a sparse lymphocytic infiltrate, and fibrinoid degradation of connective tissue.16,95 Following sun exposure SCLE can present with an erythematous eruption of the face resembling a malar rash.15,95 Discoid lupus often presents with facial lesions: characteristically discoid, erythematous papules covered with silvery scales and follicular keratosis.15,95 Atrophy and scarring can occur following resolution of active disease (Figure 12.133).15,95

Figure 12.133  Facial lupus erythematosus.

128  Differential diagnoses of psoriasis

Histopathology shows atrophy of the epidermis, compact hyperkeratosis with follicular plugging, and dilation of blood vessels with dense lymphocytic infiltrate.16,95 Erythema perstans faciei is a form of chronic cutaneous lupus that appears on the face. It is superficial with little inflammation.95 The typical appearance is erythematous macules or plaques with little scaling and edema that resolve without atrophy or scaring.95 Lupus tumidis also frequently involves the face; it is characterized by erythematous, edematous plaques, without follicular plugging.15,95

Contact dermatitis Dermatitis of the face (see Figure 12.42) may occur alone or in association with eczema elsewhere.23 The face is exposed to the environment and is frequently touched by the hands. Consequently, contact dermatitis on the face may be from a causative agent that has had direct, indirect, or airborne contact. The face is also the most common site of photocontact dermatitis. Allergic contact dermatitis due to fragrances, preservatives, hair dyes, and nail products typically involves the face and neck. Allergens applied to the scalp may cause a “rinse-off” or “drip” pattern with well-demarcated, relatively linear streaking dermatitis of the preauricular face and lateral neck.23 Nail polish and acrylate allergy often affects the face and may be associated with eyelid dermatitis (Figure 12.134) and more extensive involvement of the neck and chest.23 Sunscreens may cause contact allergic reactions as well as photoallergic contact dermatitis at the sites of application.23,42,96 Spectacle frames containing nickel may cause dermatitis on areas of contact with the nasal bridge, cheeks, and ears.23 The patterns of airborne contact dermatitis caused by airborne allergens such as wood, cement, and plant dusts can be distinguished by involvement of the eyelids and by triangles of spared skin below the chin and behind and below the ear lobes, as well as a relatively sharp cut-off at the collar.23,96 Facial dermatitis in bilateral, symmetrical geometric patterns can also be caused by allergens and irritants in face masks (see Figure 12.41).23

Figure 12.134  Facial allergic contact dermatitis.

Atopic dermatitis Atopic dermatitis often involves the face. Characteristically it presents as a diffuse erythema of the face involving the cheeks, forehead, chin, and nasolabial folds.97 Papules and vesicles may be seen, sometimes with crusting and secondary infection, particularly in children (Figure 12.135).97 Pruritic dry, scaly erythematous lesions can occur around the eyelids.97 Dry lichenified skin and chelitis are common.97,98 There is usually evidence of eczema elsewhere along with a history of atopy.97

Rosacea Rosacea is a chronic inflammatory disorder of the facial skin characterized by transient or persistent facial flushing, erythema, telangetasia, and often papules and pustules, typically involving the central face (nose, forehead, cheeks, and chin).99 Subtypes of rosacea include erythematotelangiectatic rosacea, papulopustular rosacea, phymatous rosacea, and ocular rosacea.99 Rosacea is a common disease, considered more common in fair-skinned individuals.100 Women are more affected than men. It is most common from 30 to 50 years of age, but can be seen in all ages.100 The development of rhinophyma is more common in men.100 Etiology remains unknown. Patients often report burning and erythema is triggered by irritants such as heat, sun exposure, alcohol, emotion, stress, hot drinks, and spicy food.99,100 Histopathology shows dilated superficial capillaries, solar elastosis with variable inflammation from mild perivascular lymphohistiocytic infiltrate to perifollicular, and perivascular infiltrate in papular rosacea.100,101 Foreign-body giant cells may be observed.100,102 Some lesions can contain granulomas which can be epitheliod, elastolytic, or palisaded around altered collagen.100–102 Demodex folliculorum is often observed.100

Figure 12.135  Facial atopic dermatitis.

References 129

FINAL COMMENTS/CONCLUSION Psoriasis in its classic presentation is predominantly a clinical diagnosis. However, there are many variants of psoriasis and if the condition is early in its evolution or limited in extent, a number of alternative diagnoses need to be entertained. With a careful history, thorough and complete skin examination, and on occasion histological evaluation, the diagnosis can usually be determined.

REFERENCES 1. Boehncke WH, Schon MP. Psoriasis. Lancet. 2015;386:983–994. 2. Burden AD, Kirby B. Psoriasis and related disorders. In: Rook’s Textbook of Dermatology, Ninth Edition, edited by CEM Grifiths, J Barker, T Bleiker, R Chalmers, D Creamer, pp. 35.1–35.48. West Sussex: Blackwell Publishing Ltd, 2016. 3. Griffiths CEM, Christophers E, Barker JNWN, et al. A classification of psoriasis vulgaris according to phenotype. Br J Dermatol. 2007;156:258–262. 4. Lisi P. Differential diagnosis of psoriasis. Br J Dermatol. 2015;173:610–630. 5. Weedon DA. The psoriasiform reaction pattern, Chapter 4. In: Skin Pathology, Third Edition, pp. 71– 92. China: Churchill Livingstone Elsevier, 2010. 6. Hay RJ, Ashbee HR. Fungal infections. In: Rook’s Textbook of Dermatology, Ninth Edition, Edited by CEM Grifiths, J Barker, T Bleiker, R Chalmers, D Creamer, pp. 32.1–32.96. West Sussex: Blackwell Publishing Ltd, 2016. 7. Hoss D, Berke A, Kerr P, Grant-Kels J, Murphy M. Prominent papillary dermal edema in dermatophytosis (tinea corporis). J Cutan Pathol. 2010;37:237–242. 8. Weedon DA. Mycoses and algal infections, Chapter 25. In: Skin Pathology, Third Edition, pp. 581–606. China: Churchill Livingstone Elsevier, 2010. 9. Ingram JR. Eczematous disorders. In: Rook’s Textbook of Dermatology, Ninth Edition, edited by CEM Grifiths, J Barker, T Bleiker, R Chalmers, D Creamer, pp. 39.1–39.36. West Sussex: Blackwell Publishing Ltd, 2016. 10. Burgin S. Nummular eczema, lichen simplex chronicus, and prurigo nodularis. In: Fitzpatrick’s Dermatology in General Medicine, Eighth Edition, edited by A Lowell, LA Goldsmith, I Stephen, et al., pp. 158–159. New York, NY: McGraw Hill Professional, 2012. 11. Furmanczyk PS, Wolgamot GM, Kussick SJ, Sabath DE, Olerud JE, Argenyi ZB. Diagnosis of mycosis fungoides with different algorithmic approaches. J Cutan Pathol. 2010;37:8–14. 12. Whittaker SJ, Child F. Cutaneous lymphomas. In: Rook’s Textbook of Dermatology, Ninth Edition, edited by CEM Grifiths, J Barker, T Bleiker, R Chalmers, D Creamer, pp. 140.1–140.58. West Sussex: Blackwell Publishing Ltd., 2016.

13. Strutton G. Cutaneous infiltrates—Lymphomatous and leukemic. In: Skin Pathology, Third Edition, Chapter 41, edited by Weedon DA, pp. 971–1006. China: Churchill Livingstone Elsevier, 2010. 14. Barr RJ, Young EM. Psoriasiform and related papulosquamous disorders. J Cutan Pathol. 1985;12:412–425. 15. Goodfield M, Dutz J, McCourt C. Lupus erythematosus. In: Rook’s Textbook of Dermatology, Ninth Edition, edited by CEM Grifiths, J Barker, T Bleiker, R Chalmers, D Creamer, pp. 51.1–51.39. West Sussex: Blackwell Publishing Ltd., 2016. 16. Weedon DA. The lichenoid reaction pattern (‘interface dermatitis’), Chapter 3. In: Skin Pathology, Third Edition, pp. 35–70. China: Churchill Livingstone Elsevier, 2010. 17. Piguet V, Breathnach SM, Le Cleach L. Lichen planus and lichenoid disorders In: Rook’s Textbook of Dermatology, Ninth Edition, edited by CEM Grifiths, J Barker, T Bleiker, R Chalmers, D Creamer, pp. 37.1– 37.20. West Sussex: Blackwell Publishing Ltd., 2016. 18. Shiohara T, Kano Y. Lichen planus and lichenoid dermatoses. In: Dermatology, Third Edition, edited by JL Bolognia, JL Jorizzo, JV Schaffer, pp. 183–202. China: Elsevier Saunder, 2012. 19. Madan V, Lear JT. Basal cell carcinoma. In: Rook’s Textbook of Dermatology, Ninth Edition, edited by CEM Grifiths, J Barker, T Bleiker, R Chalmers, D Creamer, pp. 141.1–141.22. West Sussex: Blackwell Publishing Ltd., 2016. 20. Weedon DA. Tumours of the epidermis, Chapter 31. In: Skin Pathology, Third Edition, pp. 668–708. China: Churchill Livingstone Elsevier, 2010. 21. Gupta G, Madan V, Lear JT. Squamous cell carcinoma. In: Rook’s Textbook of Dermatology, Ninth Edition, edited by CEM Grifiths, J Barker, T Bleiker, R Chalmers, D Creamer, pp. 142.1–142.42. West Sussex: Blackwell Publishing Ltd., 2016. 22. Toholka R, Wang Y, Tate B, et al. The first Australian baseline series: Recommendations for patch testing in suspected contact dermatitis. Australas J Dermatol. 2015;56:107–115. 23. Wilkinson M, Orton, D. Allergic contact dermatitis. In: Rook’s Textbook of Dermatology, Ninth Edition, edited by CEM Grifiths, J Barker, T Bleiker, R Chalmers, D Creamer, pp. 128.1–128.87. West Sussex: Blackwell Publishing Ltd., 2016. 24. Weedon DA. Skin pathology. In: The Spongiotic Reaction Pattern, Third Edition, Chapter 5; pp. 93– 122. China: Churchill Livingstone Elsevier, 2010. 25. White JML. Irritant contact dermatitis. In: Rook’s Textbook of Dermatology, Ninth Edition, edited by CEM Grifiths, J Barker, T Bleiker, R Chalmers, D Creamer, pp. 129.1–129.13. West Sussex: Blackwell Publishing Ltd., 2016. 26. Bunker CB, Porter WM. Dermatoses of the male genitalia. In: Rook’s Textbook of Dermatology, Ninth Edition, edited by CEM Grifiths, J Barker, T Bleiker,

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R Chalmers, D Creamer, pp. 111.1–111.41. West Sussex: Blackwell Publishing Ltd., 2016. 27. Weedon DA. Tumours of cutaneous appendages, Chapter 33. In: Skin Pathology, Third Edition, pp. 757– 807. China: Churchill Livingstone Elsevier, 2010. 28. Sterling JC. Viral infections. In: Rook’s Textbook of Dermatology, Ninth Edition, edited by CEM Grifiths, J Barker, T Bleiker, R Chalmers, D Creamer, pp. 25.89–25.92. West Sussex: Blackwell Publishing Ltd., 2016. 29. Weedon DA. Mycoses and algal infections, Chapter 25. In: Skin Pathology, Third Edition, pp. 590–592. China: Churchill Livingstone Elsevier, 2010. 30. Hay RJ, Ashbee HR. Fungal infections. In: Rook’s Textbook of Dermatology, Ninth Edition, edited by CEM Grifiths, J Barker, T Bleiker, R Chalmers, D Creamer, pp. 32.10–32.13. West Sussex: Blackwell Publishing Ltd., 2016. 31. Kinghorn GR, Omer R. Syphillis and Congenital Syphilis. In: Rook’s Textbook of Dermatology, Ninth Edition, edited by CEM Grifiths, J Barker, T Bleiker, R Chalmers, D Creamer, pp. 29.1–29.35. West Sussex: Blackwell Publishing Ltd., 2016. 32. Weedon DA. Spirochetal infections, Chapter 24. In: Skin Pathology, Third Edition, pp. 574–580. China: Churchill Livingstone Elsevier, 2010. 33. Wahie A, Hiscutt E, Natarajan S, Taylor A. Pityriasis lichenoides: The differences between children and adults. Br J Dermatol. 2007;157:941–945. 34. Child F, Whittaker SJ. Lymphocytic infiltrates. In: Rook’s Textbook of Dermatology, Ninth Edition, edited by CEM Grifiths, J Barker, T Bleiker, R  Chalmers, D Creamer, pp. 135.3–135.6. West Sussex: Blackwell Publishing Ltd., 2016. 35. Weedon DA. The vasculopathic reaction pattern, Chapter 8. In: Skin Pathology, Third Edition, pp. 230–232. China: Churchill Livingstone Elsevier, 2010. 36. Whittaker SJ, Child F. Cutaneous lymphomas. In: Rook’s Textbook of Dermatology, Ninth Edition, edited by CEM Grifiths, J Barker, T Bleiker, R  Chalmers, D Creamer, pp. 140.4–140.15. West Sussex: Blackwell Publishing Ltd., 2016. 37. Ingram JR. Eczematous disorders. In: Rook’s Textbook of Dermatology, Ninth Edition, edited by CEM Grifiths, J Barker, T Bleiker, R Chalmers, D Creamer, pp. 39.26–39.27. West Sussex: Blackwell Publishing Ltd., 2016. 38. Child F, Whittaker SJ. Lymphocytic infiltrates. In: Rook’s Textbook of Dermatology, Ninth Edition, edited by CEM Grifiths, J Barker, T Bleiker, R  Chalmers, D Creamer, pp. 135.6–135.7. West Sussex: Blackwell Publishing Ltd., 2016. 39. Ingram JR. Eczematous disorders. In: Rook’s Textbook of Dermatology, Ninth Edition, edited by CEM Grifiths, J Barker, T Bleiker, R Chalmers, D Creamer, pp. 39.30–39.35. West Sussex: Blackwell Publishing Ltd., 2016.

40. Magro CM, Crowson AN. The clinical and histomorphologial features of pityriasis rubra pilaris. J Cutan Pathol. 1997;24:416–424. 41. Mose M, Sommerlund M, Koppelhus U. Severe acute irritant contact dermatitis presenting as exfoliative erythroderma. Contact Dermatitis. 2013;69:118–127. 42. Ibbotson S, Dawe R. Cutaneous photosensitivity diseases. In: Rook’s Textbook of Dermatology, Ninth Edition, edited by CEM Grifiths, J Barker, T Bleiker, R Chalmers, D Creamer, pp. 127.1–127.36. West Sussex: Blackwell Publishing Ltd., 2016. 43. Norris PG, Hawk JLM. Chronic actinic dermatitis—A unifying concept. Arch Dermatol. 1990;126(3):376–378. 44. Roelandts R. Chronic actinic dermatitis. J Am Acad Dermatol. 1993;28:240–249. 45. Weedon DA. Reactions to physical agents, Chapter 21. In: Skin Pathology, Third Edition, pp. 525–540. China: Churchill Livingstone Elsevier, 2010. 46. Whittaker SJ, Child F. Cutaneous lymphomas. In: Rook’s Textbook of Dermatology, Ninth Edition, edited by CEM Grifiths, J Barker, T Bleiker, R Chalmers, D Creamer, pp. 140.18–140.20. West Sussex: Blackwell Publishing Ltd., 2016. 47. Strutton G. Skin pathology. In: Cutaneous Infiltrates— Lymphomatous and Leukemic, Third Edition, Chapter 41, pp. 971–1004. China: Churchill Livingstone Elsevier, 2010. 48. Weedon DA. Miscellaneous conditions, Chapter 19. In: Skin Pathology, Third Edition, pp. 502–509. China: Churchill Livingstone Elsevier, 2010. 49. Weedon DA. Cutaneous drug reactions, Chapter 20. In: Skin Pathology, Third Edition, pp. 512–523. China: Churchill Livingstone Elsevier, 2010. 50. Sidoroff A, Halevy S, Bavinck JNB, Vaillant L, Roujeau JC. Acute generalized exanthematous pustulosis (AGEP)—A clinical reaction pattern. J Cutan Pathol. 2001;28:113–119. 51. Walsh S, Lee HY, Creamer D. Severe cutaneous adverse reactions to drugs. In: Rook’s Textbook of Dermatology, Ninth Edition, edited by CEM Grifiths, J Barker, T Bleiker, R Chalmers, D Creamer, pp. 119.1–119.123. West Sussex: Blackwell Publishing Ltd., 2016. 52. Weedon DA. The vesiculobullous reaction pattern, Chapter 6. In: Skin Pathology, Third Edition, pp. 123– 168. China: Churchill Livingstone Elsevier, 2010. 53. Kardaun SH, Kuiper H, Fidler V, Jonkman MF. The histopathological spectrum of acute generalized exanthematous pustulosis (AGEP) and its differentiation from generalized pustular psoriasis. J Cutan Pathol. 2010;37:1220–1229. 54. Breathnach SM. Drug reactions. In: Rook’s Textbook of Dermatology, Eighth Edition, edited by DA Burns, SM Breathnach, NH Cox, CEM Grifiths, 75.1–75.177. West Sussex: Blackwell Publishing Ltd., 2010. 55. Syed ZU, Khachemoune. Inverse psoriasis. Am J Clin Dermatol. 2011;12:143–146.

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56. Omland SH, Gniadecki R. Psoriasis inversa: A separate identity or a variant of psoriasis vulgaris? Clin Dermatol. 2015;33:456–461. 57. Bunker CB, Neill SM. The genital, perianal and umbilical regions. In: Rook’s Textbook of Dermatology, Eighth Edition, edited by DA Burns, SM Breathnach, NH Cox, CEM Grifiths, pp. 71.1–71.102. West Sussex: Blackwell Publishing Ltd., 2010. 58. Hay RJ, Morris-Jones R. Bacterial infections. In: Rook’s Textbook of Dermatology, Ninth Edition, edited by CEM Grifiths, J Barker, T Bleiker, R Chalmers, D Creamer, pp. 26.1–26.87. West Sussex: Blackwell Publishing Ltd., 2016. 59. Tüzün Y, Wolf R, Engin B, Kecici AS, Kutlubay Z. Bacterial infections of the folds (intertriginous areas). Clin Dermatol. 2015;33:420–428. 60. Veien NK. General aspects. In: Contact Dermatitis, Fourth Edition, edited by PJ Frosch, T Menne, JP  Lepoittevin, pp. 201–254. Germany: Springer, 2006. 61. Zamiri M, Munro CS. Inherited acantholytic disorders. In: Rook’s Textbook of Dermatology, Ninth Edition, edited by CEM Grifiths, J Barker, T Bleiker, R Chalmers, D Creamer, pp. 66.1–66.14. West Sussex: Blackwell Publishing Ltd., 2016. 62. Engin B, Kutlubay Z, Çelik U, Serdaroğlu S, Tüzün Y. Hailey–Hailey disease: A fold (intertriginous) dermatosis. Clin Dermatol. 2015;33:452–455. 63. Weedon DA. Disorders of epidermal maturation and keratinization, Chapter 9. In: Skin Pathology, Third Edition, pp. 248–279. China: Churchill Livingstone Elsevier, 2010. 64. Wakelin S. Seborrhoeic dermatitis. In: Rook’s Textbook of Dermatology, Ninth Edition, edited by CEM Grifiths, J Barker, T Bleiker, R Chalmers, D Creamer, pp. 40.1–40.6. West Sussex: Blackwell Publishing Ltd., 2016. 65. Kim GW, HJ Jung, MB Ko m, WJ Lee, SJ Lee, DW Kim, BS Kim. Dermoscopy can be useful differentiating scalp psoriasis from seborrhoeic dermatitis. Br J Dermatol. 2011;164:652–656. 66. Hinshaw W, Rubin A. Inflammatory diseases of the nail unit. Semin Cutan Med Surg. 2015;34:109–116. 67. Grover C, Reddy BSN, Chaturvedi KU. Diagnosis of nail psoriasis: Importance of biopsy and histopathology. Br J Dermatol. 2005;153:1153–1158. 68. Burden AD, Kirby B. Psoriasis and related disorders. In: Rook’s Textbook of Dermatology, Ninth Edition, edited by CEM Grifiths, J Barker, T Bleiker, R Chalmers, D Creamer, pp. 35.1–35.4. West Sussex: Blackwell Publishing Ltd., 2016. 69. Kouskoukis CE, Scher RK, Ackerman AB. What histologic finding distinguishes onychomycosis and psoriasis? Am J Dermatopathol. 1983;5:501–504. 70. de Berker DAR, Bertrand Richert B, Baran R. Acquired disorders of the nails and nail unit. In: Rook’s Textbook of Dermatology, Ninth Edition, edited by CEM Grifiths, J Barker, T Bleiker,

R Chalmers, D Creamer, pp. 95.1–95.65. West Sussex: Blackwell Publishing Ltd., 2016. 71. Kasumagic-Halilovic E, Prohic A. Nail changes in alopecia areata: Frequency and clinical presentation. J Eur Acad Dermatol Venereol. 2009;23:240–241. 72. Dotz WI, Lieber CD, Vogt PJ. Leukonychia punctate and pitted nails in alopecia areata. Arch Dermatol. 1985;121:1452–1454. 73. Tosti A, Fanti PA, Morelli R, Bardazzi F. Trachonychia associated with alopecia areata: A clinical and pathologic study. J Am Acad Dermatol. 1991;25:266–270. 74. Andre J, Sass U, Richert B, Theunis A. Nail pathology. Clin Dermatol. 2013;31:526–539. 75. Le Q, Cahill J, Palmer-Le A, Nixon R. The rising trend in allergic contact dermatitis to acrylic nail products. Australas J Dermatol. 2015;56:221–223. 76. Mestach L, Goossens A. Allergic contact dermatitis and nail damage mimicking psoriasis caused by nail hardeners. Contact Dermatitis. 2016;74:112–114. 77. Aydin O, Engin B, Oğus O, Ilvan Ş, Demirkesen C. Non-pustular palmoplantar psoriasis: Is histologic differentiation from eczematous dermatitis possible? J Cutan Pathol. 2008;35:169–173. 78. Veien NK. Hand eczema. In: Contact Dermatitis, Fourth Edition, edited by PJ Frosch, T Menne, JP Lepoittevin, pp. 335–342. Germany: Springer, 2006. 79. Rietschel RL, Fowler JF. Fisher’s contact dermatitis, Chapter 18. In: Hand Dermatitis due to Contactants: Special Considerations, Fifth Edition, pp. 261–278. Philadelphia, PA: Lippincott Williams & Wilkins, 2001. 80. Emtestam L, Sartorius K. Cutaneous markers of internal malignancy. In: Rook’s Textbook of Dermatology, Ninth Edition, edited by CEM Grifiths, J Barker, T Bleiker, R Chalmers, D Creamer, pp. 147.1–147.27. West Sussex: Blackwell Publishing Ltd., 2016. 81. Sánchez-Pérez J, Buceta LR, Fraga J, García-Díez A. Lichen planus with lesions on the palms and/or soles: prevalence and clinicopathological study of 36 patients. Br J Dermatol. 2000;142:310–314. 82. Oji V, Metze D, Traupe H. Inherited disorders of cornification. In: Rook’s Textbook of Dermatology, Ninth Edition, edited by CEM Grifiths, J Barker, T Bleiker, R Chalmers, D Creamer, pp. 65.1–65.75. West Sussex: Blackwell Publishing Ltd., 2016. 83. Yazkan F, Turk BG, Dereli T, Kazandi AC. Porokeratosis of Mibelli induced by topical corticosteroid. J Cutan Pathol. 2006;33:516–518. 84. Reider N, Fritsch PO. Other eczematous eruptions. In: Dermatology, Third Edition, edited by JL Bolognia, JL Jorizzo, JV Schaffer, pp. 219–231. China: Elsevier Saunder, 2012. 85. Lewis F. Dermatoses of the female genitalia. In: Rook’s Textbook of Dermatology, Ninth Edition, edited by CEM Grifiths, J Barker, T Bleiker, R Chalmers, D Creamer, pp. 112.1–112.45. West Sussex: Blackwell Publishing Ltd., 2016.

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86. Andreassi L, Bilenchi R. Non-infectious inflammatory genital lesions. Clin Dermatol. 2014;32:307–314. 87. Fischer G. The commonest causes of symptomatic vulvar disease: A dermatologist’s perspective. Australas J Dermatol. 1996;37:12–18. 88. Weedon DA. Disorders of collagen, Chapter 11. In: Skin Pathology, Third Edition, pp. 304–329. China: Churchill Livingstone Elsevier, 2010. 89. Weedon DA. Cutaneous infiltrates—Non-lymphoid, Chapter 40. In: Skin Pathology, Third Edition, pp. 938– 970. China: Churchill Livingstone Elsevier, 2010. 90. Weedon DA. Tumours of cutaneous appendages, Chapter 33. In: Skin Pathology, Third Edition, pp. 757– 807. China: Churchill Livingstone Elsevier, 2010. 91. Kennedy C. Dermatoses of the external ear. In: Rook’s Textbook of Dermatology, Ninth Edition, edited by CEM Grifiths, J Barker, T Bleiker, R Chalmers, D Creamer, pp. 108.1–111.30. West Sussex: Blackwell Publishing Ltd., 2016. 92. Öztürkcan S, Öztürkcan S. Dermatologic diseases of the external ear. Clin Dermatol. 2014;32:141–152. 93. Woo SM, Choi JW, Yoon HS, Jo SJ, Youn JI. Classification of facial psoriasis based on the distributions of facial lesions. J Am Acad Dermatol. 2008;58:959–963. 94. Ramos-e-Silva M, Sampaio AL, Carneiro S. Red face revisited: Endogenous dermatitis in the form of

atopic dermatitis and seborrhoeic dermatitis. Clin Dermatol. 2014;32:109–115. 95. Kazandjieva J, Tsankov N, Pramatarov K. The red face revisited: Connective tissue disorders. Clin Dermatol. 2014;32:153–158. 96. Dooms-Goossens A. The red face: Contact and photocontact dermatitis. Clin Dermatol. 1993;11:289–295. 97. Mirensky YM. The red face: Atopic dermatitis. Clin Dermatol. 1993;11:235–242. 98. Ardern-Jones MR, Flohr C, Reynolds NJ, Holden CA. Atopic eczema. In: Rook’s Textbook of Dermatology, Ninth Edition, edited by CEM Grifiths, J Barker, T Bleiker, R Chalmers, D Creamer, pp. 41.1–41.34. West Sussex: Blackwell Publishing Ltd., 2016. 99. İkizoğlu G. Red face revisited: Flushing. Clin Dermatol. 2014;32:800–808. 100. Powell F. Rosacea. In: Rook’s Textbook of Dermatology, Ninth Edition, edited by CEM Grifiths, J Barker, T  Bleiker, R Chalmers, D Creamer, pp. 91.1–91.19. West Sussex: Blackwell Publishing Ltd., 2016. 101. Weedon DA. Diseases of cutaneous appendages, Chapter 15. In: Skin Pathology, Third Edition, pp. 397–440. China: Churchill Livingstone Elsevier, 2010. 102. Weedon DA. The granulomatous reaction pattern, Chapter 7. In: Skin Pathology, Third Edition, pp.  169– 194. China: Churchill Livingstone Elsevier, 2010.

13 Genetics, immunology, and pathogenesis ARTHUR KAVANAUGH and TRISTAN BOYD EPIDEMIOLOGY Psoriatic arthritis (PsA) is a chronic systemic inflammatory disease that affects approximately 0.3% of the general population and up to 20%–30% of patients with skin psoriasis.1 PsA has an equal distribution among men and women and can occur at any age, with a peak age of onset between 30 and 50 years.2 In patients with a history of psoriasis, the onset of skin disease precedes the onset of musculoskeletal manifestations in over 80% of patients, often by more than a decade.3

ETIOLOGY As with many autoimmune diseases, the precise cause of PsA remains unknown. The disease is thought to potentially arise in genetically susceptible individuals as a result of an aberrant immune response after exposure to some environmental or other stimulus. The temporal association of PsA with skin psoriasis suggests that the initiating events may occur in the skin and subsequently spread to the joints and other tissues. PsA is a heterogeneous disease with diverse musculoskeletal manifestations, including peripheral arthritis, axial arthritis, enthesitis, and dactylitis, as well as extra-articular manifestations, including uveitis and gut inflammation. To what extent distinct or overlapping immunopathogenic mechanisms underlie each of the various clinical manifestations remains to be determined.

Genetic susceptibility Many lines of evidence, including familial aggregation, disease concordance in twins, and genome-wide association studies (GWAS), suggest a strong genetic component in PsA. The high occurrence of PsA and psoriasis within families indicates a significant genetic predisposition to developing these diseases, with first-degree relatives having a 30-fold increased risk of developing PsA compared with the general population.4 Twin studies in psoriasis

patients reveal an increased rate of concordance in monozygotic versus dizygotic twins (72% versus 15%–23%, respectively).5 In contrast, no large twin cohort studies have been conducted to date in PsA. One twin study in PsA did not demonstrate a significant genetic effect, with almost identical concordance rates observed in monozygotic and dizygotic twins.6 Difficulty in differentiating PsA from other forms of inflammatory arthritis and inclusion of psoriasis patients without true inflammatory articular and periarticular disease in PsA cohorts has likely complicated the study of PsA, as their inclusion introduces a lack of uniformity. The ClASsification of Psoriatic Arthritis (CASPAR) criteria should help create a more uniform patient population for future studies.7 Genome-wide scans have identified the contribution of several susceptibility genes, indicating that psoriasis and PsA are polygenic disorders. Of the many genes proposed, the most relevant appear to be certain class I human leukocyte antigen (HLA) genes occurring within the major histocompatibility complex (MHC) region on chromosome 6p, which account for roughly 30% of genetic susceptibility.8 Polymorphisms of class I HLA alleles that are associated with PsA include HLA-B7, HLA-B27, HLA-B38, and HLA-B39 (see Table 13.1).9 Although HLA-B alleles seem to confer increased risk for articular manifestations, HLA-C alleles confer greater susceptibility to cutaneous manifestations: HLA-Cw6 is associated with early-onset skin psoriasis, with a more severe and extensive presentation, but appears to have less of an association with articular symptoms.10 In addition to influencing disease ­phenotype, certain HLA antigens confer increased risk for disease progression (e.g., H ­ LA-B39 alone and ­ H LA-B27 in the  presence of HLA-DR7), whereas o ­ thers may reduce the risk of disease progression (e.g., HLA-B22 may be  protective).11 Other genes, such as the shared epitope HLADRB1, when found in linkage disequilibrium with the aforementioned alleles, confer a worse radiological outcome (i.e., more erosive disease in peripheral joints) in PsA.12 Other susceptibility genes identified by genome-wide scans that are associated with an increased risk of psoriasis 133

134  Genetics, immunology, and pathogenesis

and PsA includes polymorphisms of the tumor necrosis ­factor-alpha (TNF-α) promoter region (TNFA) and the MHC class I chain–related A gene (MICA-A9).13,14 NonMHC susceptibility regions conferring increased risk for psoriasis have also been identified (e.g., the PSORS1 [psoriasis susceptibility 1]-9 loci); however, r­elevant candidate genes have not yet been identified.15 Thus, although high rates of familial aggregation occur in PsA and psoriasis, the ­disease phenotype can vary widely depending on the presence or absence of various s­ usceptibility genes.

Environmental factors Environmental factors appear to play a role in the development of PsA among some individuals. Evidence for the role of environmental factors in the pathogenesis

Table 13.1  Proposed genetic and environmental risk factors that may lead to increased susceptibility for psoriatic arthritis. Type Genetic MHC region alleles

Non-MHC alleles Environmental Trauma

Infection

RFs in patients with psoriasis

Trigger HLA-Cw6 (skin > joint) HLA-B7 HLA-B13 (shared with psoriasis) HLA-B17 (shared with psoriasis) HLA-B22 (protective) HLA-B27 (axial disease) HLA-B38 HLA-B39 HLA-DRB1 (polyarticular disease) MICA-A9 polymorphism TNF-α polymorphism PSORS regions Joint injury Vaccination Recurrent oral ulceration Heavy lifting Infection requiring antibiotics Bacterial (e.g., streptococcal) Viral (e.g., HIV) Body surface area Skin lesions at specific sites Obesity

Abbreviations:          HLA, human leukocyte antigen; MICA, MHC class I chain–related A gene; TNF-α, tumor necrosis factoralpha; HIV, human immunodeficiency virus.

of psoriasis and PsA comes largely from observational ­studies. The two most commonly reported associations are infection and trauma; however, the mechanism underlying how these processes contribute to disease pathogenesis remains poorly understood. There is a strong association of streptococcal pharyngitis preceding an acute form of guttate psoriasis in children.15 Similarly, human immunodeficiency virus (HIV) infection, particularly before the introduction of antiretroviral therapy, has been associated with a more aggressive form of psoriasis and PsA.16 Thus, certain prior infections may confer an increased risk of developing PsA.17 Of note, this is not the case for most patients, as antecedent infections typically do not seem to initiate PsA. There is some evidence for the role of trauma in skin psoriasis and possibly PsA. The Koebner phenomenon is an uncommon but well-described occurrence in psoriasis wherein skin plaques develop at sites of trauma to nonlesional skin. Trauma or biomechanical stress has been proposed as a potential cause of enthesitis and joint inflammation in PsA, sometimes referred to as “deep Koebner phenomenon.”18 Interestingly, a history of trauma preceding the onset of peripheral arthritis was reported in 8%–9% of patients with newly diagnosed PsA.19,20 Case–control studies have suggested several other potential causative factors, including joint injury, vaccination, recurrent oral ulceration, repetitive heavy lifting, and infections requiring treatment with antibiotics.18,21 In patients with nail dystrophy, repetitive microtrauma has been hypothesized to play a role in the pathogenesis of distal interphalangeal (DIP) joint involvement by eliciting an aberrant immune response that results in persistent inflammation of the adjacent enthesis and synovium (see Figure 13.1).22

Risk factors in patients with skin psoriasis In patients with a history of skin psoriasis, several factors have been associated with a risk for developing articular disease. For example, patients with a greater extent of skin involvement (i.e., higher body surface area) may have an increased risk of developing PsA, although there is certainly the possibility of channeling bias in these series.23–25 In addition, psoriatic skin lesions in certain locations have been suggested to be associated with a higher likelihood of developing PsA. These include scalp lesions (3.75-fold increased risk), nail dystrophy (2.24fold increased risk), and intergluteal or perianal lesions (1.95-fold increased risk).23 Finally, psoriasis patients who are overweight or obese are at increased risk of developing PsA.26 Interestingly, patients with elevated body mass index who develop PsA may also respond less efficaciously to disease-modifying therapies.27 Other proposed risk f­ actors include stress, tobacco use, and alcohol consumption.

Immunology 135 1. Nail dystrophy Pittting onycholysis leukonychia ridging Terminal extensor tendon

Synovium

Nail bed

2. Repetitive microtrauma

Nail

3. Enthesitis Terminal phalanx 4. Synovitis Enthesis Distal interphalangeal (DIP) joint

Figure 13.1  Schematic representation of the proposed pathogenesis of distal interphalangeal (DIP) joint synovitis in psoriatic arthritis. A patient with preexisting nail dystrophy subject to repetitive microtrauma develops an aberrant immune response resulting in the production of proinflammatory cytokines. The adjacent enthesis and synovium become inflamed producing a characteristic pattern of synovitis affecting the DIP joints. IMMUNOLOGY Aberrations in both innate and adaptive immunity occur in PsA, resulting in a chronic systemic inflammatory process.28 The disease is characterized by cellular infiltration, with substantial accumulation of T lymphocytes and macrophages among other cells in the synovial tissue along with prominent new vessel formation.13 A complex interaction between T cells, dendritic cells, keratinocytes, and synoviocytes results in a self-perpetuating loop of sustained inflammation in the skin and synovium.29 Some of the most pivotal cells and inflammatory mediators involved in the disease process, along with characteristic histopathologic findings in PsA, are discussed in the following.

Cellular involvement Psoriatic arthritis appears to be a predominantly T-cell– mediated disease. This concept is supported by several lines of evidence, including the effectiveness of medications (e.g., cyclosporine) that inhibit the activation of T cells. Also, a prominent lymphocytic infiltrate, composed of CD4+ and CD8+ T cells as well as neutrophils, has been identified in the skin and joints of patients with psoriatic disease.30 These cell types localize to different areas with CD4+ T cells found predominantly in dermal papillae of skin and sublining stroma of the joint, whereas CD8+ T cells are more prominent in the epidermis, inflamed enthesis, and synovial fluid. In addition, increased numbers of Th17 cells have been detected in

the serum and synovial fluid of PsA patients and in the skin plaques of patients with psoriasis.31–33 These cells can mediate chronic inflammation through production of proinflammatory cytokines, such as IL-17. Other cells that play a prominent role in PsA pathogenesis including plasmacytoid and myeloid dendritic cells, CD14+ monocytes, and CD163+ macrophages. Dendritic cells act as a bridge between the innate and adaptive immunity: they recognize foreign antigen and present it to T cells resulting in their activation and proliferation. Dendritic cells can also secrete cytokines that promote inflammation and help dictate the phenotype of T cells involved in the immune response. The monocyte–macrophage system plays an important role in the initiation and maintenance of joint inflammation in PsA. CD14+ monocytes are increased in the circulation of PsA patients; these osteoclast precursors differentiate into osteoclasts after exposure to monocyte colony stimulating factor (M-CSF) and receptor activator of nuclear factor kappa B (NF-κB) ligand (RANKL), which are expressed by synovial cells in the inflamed psoriatic synovium.34 Osteoclasts mediate osteolysis at the bone–pannus junction and are responsible for bone erosions.35 CD163+ macrophages release cytokines, growth factors, and proteinases, which are involved in several aspects of the immunopathogenesis of PsA, such as synovial inflammation and cartilage degradation. A number of other cells are also involved, including neutrophils, natural killer cells, B cells, plasma cells, fibroblasts, osteoblasts, osteoclasts, and others. The exact role of these diverse cell types in the immunopathogenesis of PsA is still being elucidated.

136  Genetics, immunology, and pathogenesis

Inflammatory cytokines Methods used to help determine upregulation of ­particular cytokines and other inflammatory mediators in autoimmune diseases include immunohistochemical and gene expression techniques, as well as monitoring clinical response to targeted therapies. As discussed above, psoriasis and psoriatic arthritis are T-cell–­mediated diseases. Evidence for a T-helper cell type 1 (Th1) biased profile, characterized by increased production of interleukin-2 (IL-2) and interferon-gamma (IFN-γ) by T lymphocytes, has been observed in psoriasis and PsA.36,37 A number of other proinflammatory cytokines are also upregulated in PsA that contribute to disease pathogenesis, including predominantly macrophage-derived cytokines (e.g., TNF-α, IL-1α, and IL-6), dendritic cell-derived cytokines (e.g., IL-12 and IL-23), and IL-17A that is produced by Th17 cells and other cells. These cytokines are involved in the recruitment of other immune cells as well as the activation of genes whose products can help perpetuate and sustain the aberrant immune response in PsA. TUMOR NECROSIS FACTOR-ALPHA

TNF-α is upregulated in the psoriatic synovium and skin and mediates a number of processes involved in disease pathogenesis.37 TNF-α stimulates epidermal proliferation and increases the expression of vascular endothelial growth factor (VEGF) in psoriatic skin and synovium. This can lead to increased vascular leakage and also the formation of new blood vessels.38 The resulting long and tortuous vessels are characteristic in psoriatic synovium. TNF-α, along with IL-1β, increases the production of degradative enzymes including matrix metalloproteinases by macrophages, which can result in cartilage degradation.39,40 TNF-α also promotes the differentiation of osteoclast precursors that migrate to the inflamed synovium and subchondral bone to mediate bone resorption.35 Together, these processes cause cartilage degradation and bone erosion resulting in joint damage and, ultimately, causing impaired physical function. Clinical response to TNF inhibitors (TNFi) illustrates the importance of this inflammatory mediator in PsA. Therapy with TNF inhibitors is associated with a marked reduction in the T-cell infiltrate in psoriatic skin lesions, as well as decreased matrix metalloproteinase (MMP) expression and macrophage infiltration in synovial tissue.41,42 TNFi have been notably effective in treating all of the diverse domains of disease activity in PsA, including peripheral arthritis, axial arthritis, enthesitis, dactylitis, skin psoriasis, and nail disease.3,43 In addition, TNFi inhibit radiographic progression in peripheral joints.44–47

Th1-dominant immune responses were once considered to be predominant in PsA and psoriasis, it now appears that the IL-23/Th17 axis may assume an even greater role in this disease. Expression of IL-23 is increased in psoriatic skin lesions and increased levels of the p19 subunit of IL-23 have been detected in psoriatic synovium.49,50 Ustekinumab is a monoclonal antibody directed against the common p40 subunit of IL-12 and IL-23. Data from phase III clinical trials have shown significant improvement in psoriatic skin disease, peripheral arthritis, enthesitis, dactylitis, and physical function with ustekinumab therapy.51 Ustekinumab has also demonstrated efficacy in decreasing progression of radiographic damage.52 It is approved as a treatment for both skin psoriasis and PsA in many countries worldwide. INTERLEUKIN-17

Elevated levels of IL-17 have been detected in the skin, synovium, and synovial fluid of PsA patients.53 The expression of IL-17A in skin lesions correlates with disease activity in psoriasis.30 IL-17A acts on a variety of cells with proinflammatory effects: it increases the production of chemokines and angiogenic factors resulting in a self-sustaining feedback loop that sustains chronic inflammation in the synovium, enthesis, and skin.54 IL-17A also acts on osteoblasts and osteoclast precursors that could help promote bone resorption and thus result in radiologic damage in PsA.55,56 Monoclonal antibodies that inhibit IL-17A (e.g., secukinumab and ixekizumab) or the IL-17 receptor (i.e., brodalumab) are promising new therapies in psoriatic disease. Available data suggest significant improvement in skin psoriasis, as well as peripheral and axial arthritis, with IL-17 inhibitors.57

Other mediators Infiltrating cells release a number of other inflammatory mediators that play a role in recruiting immune cells and perpetuating inflammation. Chemokines and MMPs are upregulated in the psoriatic synovium.58 RANKL is upregulated in PsA synovium and contributes to increased osteoclastogenesis and eventual bone erosion mediated by osteoclasts at the bone–pannus junction. Bone morphogenic proteins (BMPs) are increased in areas of new bone formation (e.g., periostitis and ankylosis).59 In addition, IL-22 may also mediate bone formation in spondyloarthropathies, as demonstrated in an animal model.60 Finally, a number of growth factors (e.g., M-CSF, VEGF, and platelet-derived growth factor) are produced that are responsible for some of the characteristic histopathologic findings seen in PsA.

INTERLEUKIN-23

IL-12 and IL-23 also appear to be involved in the immunopathogenesis of psoriasis and PsA.48 These cytokines are secreted predominantly by myeloid dendritic cells and can help direct the differentiation of naïve T cells into Th1 cells (IL-12) or Th17 cells (IL-23). Whereas IL-12 and

Immunohistopathology Characteristic microscopic features are seen in psoriatic skin and also in the synovium of patients with PsA. The epidermis in psoriasis is characterized by

Pathogenesis 137

proliferation of immature keratinocytes with retained nuclei (parakaratosis), cellular infiltration, and tortuous and dilated blood vessels (see Chapter 3 for more details). PSORIATIC SYNOVIUM

Like psoriatic skin, the synovium in PsA is characterized by overexpression of multiple cytokines (TNF-α, IFN-γ, IL-1β, IL-6, IL-10, IL-17, and IL-23).61 Histologic features are similar to those seen in psoriatic skin with lining layer hyperplasia, neovascularization, and cellular infiltration by T lymphocytes and macrophages. Both CD8+ T cells and CD4+ T cells are present in the cellular infiltrate, with preference for certain locations as listed above. Studies comparing the synovial histopathology of PsA to other rheumatic diseases have found a closer resemblance to spondyloarthropathy than to that seen in rheumatoid arthritis (RA).62 Some differences from RA include increased vascularity with a distinctive “corkscrew” appearance, and infiltration by polymorphonuclear cells. These differences have helped establishing PsA as a distinct condition, with semblance to spondylitis, rather than simply the co-occurrence of RA in patients who also have psoriasis. ENTHESIS

One of the characteristic findings of PsA is inflammation of the entheses, or attachments of tendons or ligaments to bone. It has been proposed that enthesitis may be a unifying lesion that could explain some of the varied clinical manifestations seen in PsA. Enthesitis is often associated with inflammation in the adjacent bone and synovium. The concept of a “synovioentheseal complex” has been proposed, whereby an environmental stimulus triggers the release of focal proinflammatory mediators from entheseal sites causing an immune response with resulting synovitis in the contiguous joint.63 CARTILAGE AND BONE

PsA can be characterized by extensive bone erosion. Although some bony damage in PsA resembles that seen in RA (e.g., periarticular erosions), other destructive phenotypes are much more commonly seen in PsA (e.g., pencil-in-cup deformities and arthritis mutilans). In addition to bony erosion, concomitant new bone formation underlies certain radiographic manifestations of PsA, such as periostitis and ankylosis.64 The two processes (bony erosion and new bone formation) occurring together are considered a radiographic hallmark of PsA.2 Biopsies of psoriatic joints demonstrate large numbers of multinucleated osteoclasts in resorption pits at the bone– pannus junction.35 TNF-α, M-CSF, and RANKL promote osteoclastogenesis and osteolysis resulting in bone erosion. Meanwhile, synovial lining cells release proteinases that can degrade cartilage, resulting in loss of cartilage

and joint space narrowing. Together, these processes lead to joint damage and impaired function. Simultaneously, new bone formation results from the upregulation of BMP and other growth factors, such as VEGF. This disordered pattern of bone remodeling is characteristic of PsA. The importance of TNF-α in these processes is implicated by the decreased radiographic progression observed with TNFi therapy.

PATHOGENESIS The precise immunopathogenic mechanisms in PsA remain incompletely understood, but they are thought to share some of the same disease mechanisms seen in psoriasis. As mentioned, a genetically susceptible individual exposed to some environmental or other stimulus may develop an aberrant immune response of both innate and adaptive immunity that leads ultimately to a chronic systemic inflammatory process that causes the clinical manifestations of PsA. On a histopathologic level, the sequence may occur as follows (see Figure 13.2)65: (1) A genetically ­susceptible host is exposed to an environmental stimulus (e.g.,  trauma or infection). (2) Damage to keratinocyte results in release of antigenic material (e.g., antimicrobial ­peptides) that activates the innate immune response, possibly via binding to Toll-like receptors. (3) P ­ lasmacytoid dendritic cells and other innate cells located in the epidermis are activated and produce proinflammatory cytokines (e.g., IFN-α, TNF-α). (4) These cytokines stimulate myeloid dendritic cells (CD83+) located in the dermis, which ­subsequently migrate to lymph nodes and present antigen to T cells. (5) T cells are activated by antigen presentation and subsequently proliferate (adaptive immunity). The cytokine milieu favors increased production of Th17 and Th1 cells resulting in an inflammatory response. (6) T cells migrate to the tissues (e.g., skin and synovium) where they perpetuate a chronic inflammatory immune response (e.g.,  keratinocyte hyperproliferation and synovitis). (7) The overexpression of proinflammatory cytokines results in activation of transcription factors and upregulation of proinflammatory genes. (8) A ­self-sustaining loop results in a chronic ­systemic inflammatory process. The inf lammatory response varies depending on the structures affected but includes the following ­processes that result in the characteristic clinical manifestations seen in PsA (see Table 13.2): (1) ­s ynovial cell ­hyperplasia results in synovitis; (2) vascular remodeling produces long and tortuous blood vessels in skin and synovium, producing characteristic red, scaly plaques; (3) c­ artilage degradation is mediated by proteinases (e.g., MMPs), resulting in joint space narrowing of affected joints; (4)  osteoclastogenesis and osteolysis cause bone resorption and erosive changes; and (5)  simultaneously, new bone formation yields periostitis and ankylosis.

138  Genetics, immunology, and pathogenesis 2.

4.

Environmental stimulus

Damage

Chronic inflammatory process

Psoriasis

Psoriatic arthritis

Skin Proinflammatory cytokines

Keratinocytes

Synovium enthesis

Plasmacytoid Antigenic dendritic cell peptides Activated T cells Epidermis

Activated T cells

Dermis

Myeloid dendritic cell

1.

3. Aberrant immune response (innate + adaptive)

Genetically susceptible host

CD4+ T cells CD8+ T cells Th17 cells

Skin-draining lymph node T cell activation + proliferation

Figure 13.2  Hypothetical model of the pathogenesis of psoriatic arthritis. An environmental stimulus (e.g., trauma or infection) causes damage to keratinocytes in a genetically susceptible host. Antigenic peptides released from the damaged area activate the innate immune system, resulting in the release of proinflammatory cytokines. Myeloid dendritic cells subsequently migrate to skindraining lymph nodes, where they cause T-cell activation and proliferation. These activated T cells migrate to the tissues (e.g., skin, synovium, or entheses) and mediate a chronic inflammatory process. Table 13.2  Histopathologic disease processes that result in characteristic clinical and radiographic manifestations in psoriatic arthritis. Some of the most common inflammatory mediators involved in each process are listed. Disease process

Inflammatory mediators

Clinical/radiographic manifestation

Synovial cell hyperplasia Vascular remodeling Cartilage degradation Osteoclastogenesis/osteolysis New bone formation

TNF-α, IL-a7A, IL-23 TNF-α, VEGF, PDGF, MMPs TNF-α, IL-1β, MMPs TNF-α, RANKL, M-CSF BMP, VEGF

Synovitis Tortuous blood vessels (erythema) Joint space narrowing Bone erosion Periostitis and ankylosis

Abbreviations:        TNF-α, tumor necrosis factor-alpha; IL, interleukin; VEGF, vascular endothelial growth factor; PDGF, platelet-derived growth factor; MMPs, matrix metalloproteinases; RANKL, receptor activator of nuclear factor kappa-B ligand; M-CSF, monocyte colony-stimulating factor; BMPs, bone morphogenic proteins.

SUMMARY Our growing knowledge of the pathogenesis of PsA comes from a variety of sources, including animal models, familial aggregation, and twin concordance studies, genetic studies (e.g., GWAS and gene expression

studies), immunohistochemical analysis, and clinical observation of targeted immunotherapies. Although the process continues to be better defined in skin, more uniform populations of PsA patients resulting from updated classification criteria will hopefully help shed light on the disease mechanisms of this heterogeneous

References 139

inflammatory arthropathy. Significant progress in our understanding has been made with the implementation of novel therapies (e.g., TNFi, IL-12/23 inhibitors, and IL-17 inhibitors) that effectively treat and ultimately improve clinical outcomes in PsA.

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treatment on synovial tissue. Ann Rheum Dis. 2009;68:1303–1309. 43. Mease P. Management of psoriatic arthritis: The therapeutic interface between rheumatology and dermatology. Curr Rheumatol Rep. 2006;8:348–354. 44. Mease PJ, Kivits AJ, Burch FX, et al. Etanercept treatment of psoriatic arthritis: Safety, efficacy, and effect on disease progression. Arthritis Rheum. 2004;50:2264–2272. 45. Kavanaugh A, Antoni CE, Gladman D, et al. The Infliximab Multinational Psoriatic Arthritis Controlled Trial (IMPACT): Results of radiographic analyses after 1 year. Ann Rheum Dis. 2006;65:1038–1043. 46. Mease PJ, Ory P, Sharp JT, et al. Adalimumab for longterm treatment of psoriatic arthritis: 2-year data from the adalimumab effectiveness in psoriatic arthritis trial (ADEPT). Ann Rheum Dis. 2009;68:702–709. 47. Kavanaugh A, Van Der Heijde D, McInnis IB, et al. Golimumab in psoriatic arthritis: One-year clinical efficacy, radiographic, and safety results from a phase III, randomized, placebo-controlled trial. Arthritis Rheum. 2012;64:2504–2517. 48. Filer C, Ho P, Smith RL, et al. Investigation of association of the IL12B and IL23R genes with psoriatic arthritis. Arthritis Rheum. 2008;58:3705–3709. 49. Lee E, Trepicchio WL, Oestreicher JL, et al. Increased expression of interleukin 23 p19 and p40 in lesional skin of patients with psoriasis vulgaris. J Exp Med. 2004;199:1908–1915. 50. Celis R, Plannel N, Fernandez-Sueiro JL, et al. Synovial cytokine expression in psoriatic arthritis and associations with lymphoid neogenesis and clinical features. Arthritis Res Ther. 2012;14:R93. 51. McInnes IB, Kavanaugh A, Gottlieb AB, et al. Efficacy and safety of ustekinumab in patients with active psoriatic arthritis: 1 year results of the phase 3, multicenter, double-blind, placebo-controlled PSUMMIT 1 trial. Lancet. 2013;382:780–789. 52. Kavanaugh A, Ritchlin C, Rahman P, et al. Ustekinumab, an anti-IL-12/23 p40 monoclonal antibody, inhibits radiographic progression in patients with active psoriatic arthritis: Results of an integrated analysis of radiographic data from the phase 3, multicenter, randomized, double-blind, placebo-controlled PSUMMIT-1 and PSUMMIT-2 trials. Ann Rheum Dis. 2014;73:1000–1006. 53. Frieta M, Siebert S, McInnes IB. The interleukin-17 pathway in psoriasis and psoriatic arthritis: Disease pathogenesis and possibilities of treatment. Curr Rheumatol Rep. 2014;16:414. 54. Martin DA, Towne JE, Kricorian G, et al. Emerging role of IL-17 in the pathogenesis of psoriasis: Preclinical and clinical findings. J Invest Dermatol. 2013;133:17–26. 55. Sato K, Suematsu A, Okamoto K, et al. Th17 functions as an osteoclastogenic helper T cell subset that links T cell activation and bone destruction. J Exp Med. 2006;203:2673–2682.

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14 Psoriatic arthritis: Clinical manifestations PETER NASH INTRODUCTION

CLINICAL CONCEPTS

The association between psoriasis and arthritis has been known for more than a century,1 but it was the publications of Verna Wright and John Moll that proposed psoriatic arthritis (PsA) as a unique entity. Their clinical descriptions of the disease include the following:

Over the past 25 years, two important developments have been described adding to the understanding of the clinical manifestations of PsA. First, PsA is now classified a member of the “seronegative spondylarthropathies” (SpA), a group of disorders characterized by shared genetics (particularly HLA B27), overlapping clinical features, common synovial ­histology, and common imaging characteristics.4 The role of the gut microbiome is under intense investigation in this group.5 The grouped diseases are

• Almost equal distribution between males and females • Peripheral arthritis involving few small joints in asymmetrical fashion • Involvement of distal interphalangeal joint (DIP) joints • Sausage digits • Arthritis mutilans • Ankylosing spondylitis • Gout-like onset • Higher incidence than occurs in uncomplicated psoriasis • Rash may present with arthritis, or, equally, may precede or succeed joint involvement

Their writings highlight the key features of this disease which are

• Asymmetry—a single wrist or a single digit involved

and not their counterpart, which contrasts with the typical symmetry of rheumatoid arthritis (RA) for example Pauci-arthropathy— a small number of joints, often less than five, are involved DIP joint involvement—with associated psoriatic nail disease—only osteoarthritis commonly involves this joint Axial involvement—spinal inflammation with inflammation of sacroiliac joints (sacroileitis) Dactylitis—inflammation with marked swelling of an entire digit finger or toe An evanescent psoriatic rash

• • • • •

• Ankylosing spondylitis (either “nonradiographic” when

magnetic resonance imaging but not plain x-ray shows sacroileitis, and “radiographic” when typical x-ray changes of sacroileitis are present) PsA The arthritis of inflammatory bowel disease, i.e., Crohn’s disease and ulcerative colitis Reactive arthritis—postenteritic, posturethritis Anterior uveitis Juvenile SpA—typical SpA pattern of involvement in juveniles Undifferentiated SpA—a few of the clinical ­features stron­ gly suggesting SpA, e.g., SpA in evolution (Figure 14.1)

• • • • • •

Second, PsA is hypothesized to commence not in joint lining (synovium) as seen typically in RA but as an enthesopathy, i.e., the primary inflammation arises at tendon and ligament insertions (the “entheses”), the sites of mechanical musculoskeletal stress, with secondary spread of inflammation to neighboring joints—a musculoskeletal equivalent of the cutaneous Koebner phenomenon.6 The nail bed has been shown on imaging to have features of an enthesis and nail bed involvement in patients with ­psoriasis significantly increases a patient’s risk of ­developing PsA and should be a red flag to examine for inflammatory joint disease of the adjacent DIP joint as well as in other joint areas.7

143

144  Psoriatic arthritis: Clinical manifestations Spondylarthropathies (SpA) Ankylosing spondylitis

Psoriatic arthritis Juvenile SpA

Undifferentiated SpA

Arthritis associated ulcerative colitis Crohn’s disease

Anterior uveitis

Figure 14.2  Deforming psoriatic arthritis of hands.

Reactive arthritis

Figure 14.1 The

spondylarthropathy group. (Adapted from Assessment of SpondyloArthritis International Society [ASAS] educational slide set.)

CLINICAL MANIFESTATIONS The clinical manifestations of PsA are highly variable. PsA is a multisystem disorder, not limited to joints but also affecting eyes (uveitis), arteries (premature atherosclerosis), bowel (associations with inflammatory bowel disease), and the liver (associated nonalcoholic hepato-steatosis), so that the term “psoriatic disease” is frequently used as a descriptor. Common comorbidities add to the complex picture. Increased comorbid associations include the following8:

• Depression • Alcohol abuse • Smoking • Obesity • Type 2 diabetes • Metabolic syndrome • Hypertension • Dyslipidaemia

Thus, clinicians should recommend weight control, monitor blood pressure, check lipid profile, emphasize nonsmoking, and assess depression and substance abuse in their PsA patients. A positive family history of psoriasis is common; indeed it increases the likelihood of PsA by a factor of 6.9

TYPES OF ARTHROPATHY An important clue for the clinician assessing patients with an inflammatory arthropathy [especially when seronegative for rheumatoid factor antibodies, i.e., rheumatoid factor and anti-citrullinated cyclic peptide antibodies (anti-CCP)] is nail involvement, especially nail pitting,

Figure 14.3  Deforming psoriatic arthritis of feet. which increases the likelihood the diagnosis is PsA by a factor of 59.9 On the contrary, a study by the International Psoriasis Council (IPC) did not show this relationship except for DIP joints with anatomical relationship to the nail.10 Occult psoriatic rash particularly in the scalp and ears, intergluteal as well as other body folds plus the genital regions is often missed and the diagnosis not entertained. In 20% of patients, arthritis preceeds skin involvement adding further diagnostic difficulty.9 Adding the arthritis component to psoriasis adds cost, increased severity of skin symptoms, reduced quality of life, a greater impairment of productivity, and increased morbidity and mortality, especially cardiovascular disease.11 The arthritis of PsA should not be considered benign when compared to other diseases such as RA. Mortality is increased compared with the general population; 20% of patients develop severe disabling disease with clinical deformities and joint damage. Patients show significant progression over time with greater than 5 irreversibly damaged joints over 5 years in up to 22% and 55% over 10 years8,9 (Figure 14.2 and 14.3).

Types of arthropathy  145

Table 14.1  Established inflammatory musculoskeletal disease (joint, spine, or entheseal) with three or more of the following five categories. 1. Psoriasis

(a) Current (b) History (c) Family history

2. Nail changes 3. A negative test for RF 4. Dactylitis 5. Radiological evidence of juxta-articular new bone formation

(a) Current (b) History

Psoriatic skin or scalp disease present today as judged by a qualified health professional (two points) A history of psoriasis that may be obtained from the patient, or a qualified health professional A history of psoriasis in a first- or second-degree relative according to patient report Typical psoriatic nail dystrophy including onycholysis, pitting, and hyperkeratosis observed on current physical examination By any method except latex but preferably by ELISA or nephlemetry, according to the local laboratory reference range Swelling of an entire digit A history of dactylitis recorded by a qualified health professional Ill-defined ossification near joint margins (but excluding osteophyte formation) on plain x-rays of hand or foot

Figure 14.4  Pauciarthritis. The classification criteria for the psoriatic arthritis CASPAR criteria for PsA have recently been developed for clinical trials as inclusion criteria rather than diagnostic criteria, with high sensitivity and specificity when ­clinical, radiological, and laboratory criteria are utilized (Table 14.1). The arthropathy of PsA is typically described in five distinct, but overlapping patterns. The typical ­patterns of joint involvement in PsA are

Figure 14.5  Pauciarthritis.

Pauciarthritis This occurs in 20%–40% of patients (Figure 14.4 and 14.5). Involvement is asymmetrical, a mixture of one to five joints both large and small joints, including uncommonly involved joints like the sternoclavicular joints, DIP joints, temporomandibular joints, and manubrosternal joints. Common presentations include one large joint such as a knee, or one or two MTP joints of one foot or a single dactylitic digit. The diagnosis of PsA is often missed at a primary physician level as blood tests are generally negative, leading to inappropriate referrals to exclude infection in a reddened painful and swollen joint, which leads to unnecessary investigations, intervention, and the likelihood incorrect therapy.

Figure 14.6  Polyarthritis. Polyarthritis This is seen in 30%–60% of patients (Figure 14.6). Symmetrical involvement is typical, affecting multiple small joints like fingers and toes, as well as larger joints

146  Psoriatic arthritis: Clinical manifestations

like shoulders, wrists, and ankles in a “rheumatoid” pattern but seronegative with psoriatic nail changes and rash.

DIP disease This is present in 5%–20% of patients (Figure 14.7). DIP joints are involved generally beneath a nail with psoriatic

Figure 14.7  Distal interphalangeal joint (DIP) disease.

changes of pitting, onycholysis, leuconychia, dyschromia, or nail bed hyperkeratosis. It is important to distinguish this from osteoarthitis (OA) affecting the DIP joint (with Heberden’s nodes) (Figure 14.8 and Table 14.2). OA joints do not have associated psoriatic nail involvement, and are associated with briefer morning stiffness and pain with use rather than at rest. Symptoms, which often settle over time, are associated with typical OA changes at PIP joints (Bouchard’s nodes), involvement at the thumb base (first carpo-metacarpal joint), and often a positive family history of OA hand involvement. The presence of DIP involvement increases the likelihood of PsA sixfold.

Figure 14.8 Osteoarthitis affecting the DIP joint (with Heberden’s nodes).

Table 14.2  Distinguishing characteristics PsA compared to other common arthropathies. Arthritis Spinal disease Morning stiffness Joint swelling Gender Enthesitis Nail lesions Psoriasis Joint pain Inflammatory markers Rheumatoid antibodies— RhF, Anti-CCP Plain radiograph

PsA

Osteoarthritis

RA

Asymmetric Common Prolonged Prominent soft tissue Equal Common Common Common At rest High (in 50%) Negative

Asymmetric Absent Brief Prominent bony Female (hands) Absent Absent Absent With use Normal Negative

Symmetric Absent Prolonged Prominent soft tissue Female Absent Absent Absent At rest High Positive (in 80%)

Erosions and bony hyperproliferation, ankylosis

Sclerosis, cartilage loss, usually no erosions, bone hypertrophy

Periarticular osteoporosis, marginal erosions, cartilage loss, subluxation

Types of arthropathy  147

Axial disease

Enthesitis

Depending on how it is defined, i.e., the presence of clinical symptoms or the requirement for definite radiographic changes, axial involvement occurs in 5%–30% of PsA patients (Figure 14.9). Inflammatory back pain has a characteristic features that allow its differentiation from mechanical back pain. It is associated with prolonged morning stiffness, improvement with exercise rather than rest, night pain typically in the second half of the night improved by movement rather than lying still, insidious onset rather than acute onset, alternating buttock pain, compared with unilateral pain, and onset prior to age 40 lasting more than 3 months. Sacroileitis (inflammation of sacroiliac joints), often unilateral, is typical as are bridging syndesmophytes (bony bridges between vertebrae due to ossification of the anterior spinal ligament). HLA-B27 is positive in up to 50% of patients.

The inflammation of tendons and ligaments at their insertions to bone adds a widespread element of soft-tissue pain (Figure 14.11). Commonly affected areas include plantar fascial insertions with heel pain, trochanters producing lateral hip pain, lateral epicondyles elbow pain, shoulder pain from rotator cuff involvement, and anterior knee pain from tibial tuberosity enthesitis. The presence of chronic enthesitis increases the ­likelihood of PsA fourfold.9

Arthritis mutilians This is a rare (<5%) form of arthritis leading to rapid bone and joint destruction of a finger or toe, with collapse and telescoping of that digit associated with erosions and bony lysis with deformity and significant functional disability (Figure 14.10).

Figure 14.10  Arthritis mutilans.

Figure 14.9  Axial disease.

Figure 14.11  Enthesitis.

148  Psoriatic arthritis: Clinical manifestations

mimics such as osteoarthritis and mechanical back pain, are imperative if long-term patient outcomes and quality of life are to be improved.

REFERENCES

Figure 14.12  Dactylitis. Dactylitis Dactylitis is an inflammation of an entire digit including interphalangeal joints, periosteum, and tendon sheaths of a finger and toe, creating a sausage-like appearance of the entire digit (Figure 14.12). This is strongly suggestive of PsA, increasing the likelihood by 20-fold. It is associated with erosive disease.

OTHER CLINICAL FEATURES Tenosynovitis, inflammation of tendon sheaths such as Achilles tendon and flexor tendons of fingers bursitis and bursitis, inflammation of bursal sacs are commonly found in PsA contributing to soft-tissue pain. Extra-articular manifestations which include ocular involvement with conjunctivitis (20%), uveitis (5%–10%) often unilateral, insidious in onset so readily missed and often chronic is particularly common in the HLA-B27 positive population as well as patients with inflammatory bowel disease.

CONCLUSION Biological therapies have revolutionized the management of PsA and a window of opportunity has been proven, so that therapeutic delay leads to worsened physical function and irreversible accumulated joint damage.12-14 Psoriasis rash preceds inflammatory joint disease often by decades. Therefore, awareness of the clinical manifestations of PsA, particularly in the general psoriasis population, the use of validated diagnostic criteria, and the awareness of

1. Alibert JL. Precis Theorique et Pratique Sur les maladies de la Peau Paris Caille et Ravier 1818, 21. 2. Moll J, Wright V. Psoriatic arthritis. Semin Arthritis Rheum. 1973;3(1):55–78. 3. Wright V. Psoriatic arthritis. A comparative radiographic study of rheumatoid arthritis and arthritis associated with psoriasis. Ann Rheum Dis. 1961;20:123–132. 4. Rudwaleit M, Van Der Heijde D, Landewe R, et al. The ASAS classification criteria for peripheral spondylitis and spondylitis in general. Ann Rheum Dis. 2011;70:25–31. 5. Gill T, Asquith M, Rosenbaum J, Colbert R. The intestinal microbiome in spondylarthritis. Curr Opin Rheum. 2015;4:319–325. 6. McGonagle D, Lories R, Tan A, Benjamon M. The concept of a “synovio-entheseal complex” and its implications for understanding joint inflammation & damage in psoriatic arthritis and beyond. Arthritis Rheum. 2007;56:2482–2491. 7. McGonagle D, Benjamin M, Tan A. The pathogenesis of psoriatic arthritis and associated nail disease: Not autoimmune after all? Curr Opin Rheum. 2009; 21:340–347. 8. Strohal R, Kirby B, Puig L, et al. Psoriasis beyond the skin: An expert group consensus on the management of psoriatic arthritis and common co-morbidities in patients with moderate-to-severe psoriasis. JEADV. 2014;28:1661–1669. 9. Taylor W, Gladman D, Helliwell P, et al. Classification criteria for PsA. Arthritis Rheum. 2006;54:2665–2673. 10. Wittkowski KM, Leonardi C, Gottlieb A, et al. Clinical symptoms of skin, nails, and joints manifest independently in patients with concomitant soriasis and psoriatic arthritis. PLoS One. 2011;6(6):e20279. 11. Polachek A, Touma Z, Anderson M, Eder L. Risk of cardiovascular morbidity in patients with psoriatic arthritis: A meta-analysis of observational studies. Arthritis Care Res. 2016. 12. Gladman D, Shuckett R, Russell M, et al. Psoriatic arthritis (PsA)—An analysis of 220 patients. Quart J Med. 1987;62(238): 127–141. 13. Torre Alonso JC, Rodriguez Perez A, Arribas Castrillo JM, et.al. Psoriatic patients: A clinical, immunological & radiological study of 180 patients. Brit J Rheum. 1991;30(4):245–250. 14. Haroon M, Gallagher P, FitzGerald O. Diagnostic delay of more than 6 months contributes to poor radiographic and functional outcome in psoriatic arthritis. Ann Rheum Dis. 2015;74(6):1045–1050.

15 Pediatric psoriasis JENNIFER DAY and AMY S. PALLER Children with psoriasis present unique challenges for providers. These include under-recognition by primary care providers, unusual presentations, and a­ ccessibility to effective, safe medication since few intervention ­studies are performed in children and no systemic m ­ edications are currently approved by the U.S. Food and Drug Administration (FDA).

EPIDEMIOLOGY Psoriasis occurs in 0.5%–0.8% of pediatric patients, with a prevalence that increases with age, from 0.2% at 2 years to 1.2% at 18 years.1–6 About one-third of adults with psoriasis report onset during the first two decades of life.7–9 Among the pediatric psoriasis population, females (slightly) and Caucasians predominate.7,10,11 Development of psoriasis involves complex genetic and environmental factors. About 30% of pediatric patients have an immediate family history of psoriasis. The lifetime risk of developing psoriasis if no parent, one parent, or two parents have psoriasis is 4%, 28%, and 65%, respectively,12 and the risk is two- to threefold greater in monozygotic versus dizygotic twins.4 Human leukocyte antigen (HLA) types Cw6 and DR713 and caspase recruitment domain family, member 14 (CARD14) mutations, which lead to familial psoriasis and autosomal dominant pityriasis rubra pilaris, are linked to early-onset psoriasis (Chapter 4).14 Environmental factors well known to trigger psoriasis include skin injury, the Koebner phenomenon (reaction to skin trauma), and streptococcal infections.9 Psoriasis flares have also been linked to staphylococcal infections,15 varicella zoster,16 Kawasaki disease,17,18 certain medications and psychological or physical stress.

CLINICAL PRESENTATION The diagnosis of psoriasis in children is based on clinical features, and rarely requires confirmation with a biopsy. Approximately 5% of pediatric patients show an atopic

dermatitis/psoriasis overlap, with characteristic lesions of both or intermediate lesions,10 making diagnosis more challenging. Plaque psoriasis is most common, particularly affecting the elbows and knees (Figure 15.1).2,4,9,10,19 Inverse psoriasis is more common in children than adults,20 but pustular and erythrodermic presentation are far less common. The Koebner phenomenon is described in 50% of pediatric patients and only 39% of adult patients7 and is an explanation for psoriasis of the diaper region and around enteral feeding tubes. Guttate psoriasis (Chapter 7) develops in up to 44% of pediatric patients9,10,19 and is often the first clinical presentation of psoriasis (Figure 15.2).4 Several infectious triggers have been implicated, most commonly group A streptococcus9,21,22 and one-third of patients describe upper respiratory symptoms within 3 weeks before the onset of guttate lesions.8 Up to 40% of patients with guttate psoriasis go on to develop chronic plaque psoriasis,23,24 which has been associated with greater eventual severity than having plaque psoriasis initially.25 Children experience facial psoriasis more commonly than adults (38%–46% of children)9,10,26 and as the sole manifestation in 4%–5%.10,27 Plaques tend to be periorificial (especially periorbital) (Figure 15.3). Psoriatic facial plaques tend to be less pruritic and more clearly delineated than atopic dermatitis. Geographic tongue is an oral feature. Scalp involvement occurs in 40%–79%,27,28 especially in girls.29 Lesions are typically well demarcated, e­ rythematous plaques with thick adherent silvery scale (Figure 15.4). Sebopsoriasis involves salmon-colored patches with a greasy scale, especially on the scalp, eyebrows, and ears. Extension beyond the hairline and failure to respond to antiseborrheic shampoos distinguish sebopsoriasis from seborrheic dermatitis. Pityriasis amiantacea is a variant in school-aged children in which the scaling adheres to the hair and is often complicated by focal alopecia30; only 2.5%–15% of patients develop psoriasis.31,32 Psoriatic diaper rash is the presenting manifestation in 13% of pediatric patients10 and must be differentiated from irritant or candidal diaper dermatitis and seborrheic 149

150  Pediatric psoriasis

Figure 15.1  Plaque psoriasis. Well demarcated, erythematous, scaling plaques on knees.

Figure 15.3  Facial psoriasis in an adolescent. Regions were originally on the medial cheeks and perinasal area, leading to a misdiagnosis of seborrheic dermatitis.

Figure 15.4  Scalp psoriasis. Thick white plaques overlying erythema on the scalp.

Figure 15.2 Guttate

psoriasis. This girl had very small plaques on the trunk and extremities, but clustering was seen on the elbows and knees.

dermatitis. Well-demarcated bright red plaques often lack visible scale because of high regional moisture, but gentle scraping reveals the scale (Figure 15.5). Psoriatic lesions may be present elsewhere. Diaper area involvement often clears with toilet training. However, genital psoriasis accounts for 17% of genital complaints in prepubescent

girls.33 The vulva, perineum, and often natal cleft, but not the vagina, can be involved. Plaques involving the inguinal area may also occur. Nail manifestations occur in up to 40% of pediatric psoriasis patients, more commonly in boys.9,26,29,34 The most common characteristic is nail pitting, but discoloration, onycholysis, and subungual hyperkeratosis may also occur (Figure 15.6). There is an increased frequency of secondary infections. Pustular and erythrodermic psoriasis are rare but severe variants of pediatric psoriasis,35 occurring in about 1% of pediatric cases.8 Erythrodermic psoriasis involves greater than 90% of the total body surface area. Pustular psoriasis has a mean onset at 6 years of age.36–39 In children (vs. adults), pustular psoriasis is often the first manifestation of disease. Generalized pustular psoriasis is often

Comorbidities 151

Figure 15.5 Diaper

(napkin) psoriasis. Well-demarcated erythematous plaques most prominent on the convex surfaces. Note the minimal scale due to chronic occlusion of the area from the diaper. Diagnosis in this patient was facilitated by having psoriatic plaques elsewhere.

­interleukin-1 receptor antagonist (DIRA), which results from inappropriate activation of interleukin-1. Sterile multifocal osteomyelitis or periostitis, joint swelling, stomatitis, and pyoderma gangrenosum are other features.41 Patients respond rapidly to subcutaneous administrations of anakinra 2–4 mg/kg/day. Deficiency of interleukin-36 receptor antagonist (DITRA) is the major known genetic cause of generalized pustular psoriasis in patients of any age without initial plaque psoriasis. DITRA is associated with irritability, tender skin, diarrhea, dysphagia, and failure to thrive. Laboratory evaluation may reveal neutrophilia and thrombocytosis. Skin biopsies in DIRA and DITRA show features similar to those seen in pustular psoriasis.42 A genetic variant of psoriasis seen in patients with CARD14 mutations may also present with pustules overlying erythroderma. Typical presentation for patients with CARD14 mutation is a recalcitrant plaque-type psoriasis or pityriasis rubra pilaris, with onset during infancy or early childhood. Patients may be fairly recalcitrant to systemic medications but respond rapidly to ustekinumab.

COMORBIDITIES Obesity and cardiovascular risk

Figure 15.6  Nail psoriasis. Onycholysis and trachyonychia in this adolescent with psoriasis. Tinea unguium is the most frequent misdiagnosis. annular (60%) and is more common than pustulosis palmaris et plantaris (limited to the palms and soles).36,38,40 Pustules in infancy can begin in intertriginous areas, especially the neck fold, and is misdiagnosed as dermatitis, bacterial, or candida infection.38 Pustules are sterile unless secondarily infected. Biopsy shows parakeratosis, elongated rete ridges, spongiotic pustules and Munro’s abscesses, and can confirm the clinical diagnosis. Patients often have fever, malaise, and anorexia, and require hospitalization. Courses may be complicated by cutaneous infection and bacterial septicemia. Relapses are common, and frequent recurrences can be associated with failure to thrive. The onset of psoriasiform pustules during the first year of life raises concern about deficiency of

Obesity is the most common pediatric comorbidity, with most children exhibiting excess adiposity [overweight (>85th to <95th percentile body mass index or BMI) or obesity (>95th percentile BMI)] at least 2 years prior to onset of psoriasis.43,44 The odds ratio of being overweight or obese in pediatric psoriasis is 2.65 (95% CI, 1.70–4.15) globally and 4.22 (2.05–8.67) in the United States. There is even a higher risk of excess adiposity in mild-to-moderate psoriasis, although obesity, increased waist circumference percentile, and waist-to-height ratio are correlated with greater severity of disease. Pediatric patients with psoriasis have an elevated risk of hyperlipidemia, hypertension, and diabetes.43 In a study of 20 children, criteria for the metabolic syndrome were found in 30% of psoriatic children, compared to 5% of control children (p < .05).45 Having psoriasis has also been associated with higher apolipoprotein B concentrations, decreased large high-density lipoprotein particles, and reduced cholesterol efflux capacity.46 The possibility that early, aggressive treatment with lifestyle modification and anti-inflammatory therapy may decrease long-term cardiovascular risk deserves testing in children with pediatric psoriasis.

Joint complaints In the United States, 10% of children with moderate-tosevere psoriasis experience joint pain, in contrast with less than 5% in European countries.43,47 The diagnostic criteria of psoriatic arthritis (juvenile idiopathic arthritis, psoriatic type), defined by the International League of Associations for Rheumatology (ILAR),48–50 includes

152  Pediatric psoriasis

arthritis with psoriasis, or arthritis and (1) a family history of confirmed psoriasis in a parent or sibling, (2) dactylitis,51 or (3) nail pitting or onycholysis.51 The diagnosis is excluded if the patient has a positive rheumatoid factor titer or signs of systemic disease (daily fever, evanescent erythematous eruption, generalized adenopathy, hepatomegaly or splenomegaly, or serositis). The presentation of pediatric psoriatic arthritis generally depends on the age of the child. Younger patients tend to present with dactylitis (blunt “sausage-shaped” digits) and have a progressive and persistent course.50 Polyarthritis develops in about 30% of these patients,48 which can result in severe bone destruction. Older affected children present with enthesitis and axial joint involvement.50 Either joint symptoms or skin lesions may come first, but skin manifestations are present at diagnosis of psoriatric arthritis in about 60% of patients.

about disease chronicity, the Koebner phenomenon, and potential trigger factors, including medications and streptococcal infections. Families should understand the rationale for therapeutic decisions, potential risks of intervention, and the precise manner of administration.7,57

Topical therapy (see Chapter 21)

In addition to examination, a directed review of s­ ystems addressing symptoms of inflammatory bowel disease (weight loss, decreased growth rate, gastrointestinal symptoms), uveitis (eye pain, redness, photophobia, blurry vision), and arthritis (joint pain or edema, joint stiffness, inflammation of digits, limping) may reveal the need for referral to other specialists. In addition, it is advisable to determine a body mass index (based on weight and height), take a blood pressure measurement, determine fasting lipid levels if not done by a primary care physician (screening studies routinely done at 9–11 years old), and consider whether the patient has issues with depression or anxiety. For overweight/obese adolescents with psoriasis, especially moderate to severe, it might be appropriate to obtain (or request through the primary care physician) fasting glucose and hepatic ­transaminases to consider the possibility of early type 2 diabetes and nonalcoholic fatty liver disease, respectively.

Topical corticosteroids are frequently used as monotherapy. Class II–IV topical steroids applied twice daily often improve milder disease on the trunk and extremities. Ointments more effectively penetrate thick scales, but oils and solutions are available for the scalp. Class I steroids may be used for up to 2 weeks and then more intermittently (e.g., weekend therapy). Use of halogenated mid- to potent steroids should be avoided in the diaper area, intertriginous areas, and on the face. Addition of 6% salicylic acid for thick lesions enhances penetration, but increases potency. When acute lesions are well controlled, a lower potency option or emollients alone may provide sufficient maintenance. Topical treatment of the scalp and nails, including with topical steroids, is similar to treatment in adults.58 The vitamin D3 analogues calcipotriene (cream, ointment, foam, or solution) and calcitriol (ointment) have a slow onset of action (6–8 weeks) when used as monotherapy twice daily, but are more effective in combination with topical steroids.59 Irritant dermatitis, particularly on the face and intertriginous areas, occurs in up to 20% of patients. Calcineurin inhibitors, particularly tacrolimus ointment 0.1%, are steroid-sparing agents, which can be applied twice daily and are helpful for facial and intertriginous lesions within 1–2 months.60,61 Tar-based topical therapy is an effective anti-­ inflammatory and antiproliferative option. Tar (as 1%–10% crude coal tar or 5%–10% liquor carbonis detergens) may be compounded with steroids and/or salicylic acid, used in the bath, or as a foam. Tar products are also available overthe-counter. Anthralin, also called dithranol, has antiinflammatory and antiproliferative characteristics and staining is less than seen with tar. Anthralin is applied for 5 minutes initially and the length of exposure is increased as tolerated to minimize irritation.62 Tazarotene has been used as monotherapy and in combination with topical steroids, particularly for nail treatment, but is often too ­irritating for routine use.63

THERAPEUTIC OPTIONS

Phototherapy (see Chapter 22)

Therapeutic options for pediatric psoriasis are similar to options for adults, although relatively few trials have been conducted in children. Providers should select approaches optimized for the individual patient to increase compliance. Patients and families should be introduced to national patient support groups (such as the National Psoriasis Foundation in the United States) and educated

Regular exposure to sunlight may alleviate psoriasis during the summer months, but families must be advised to use precautions against sunburn, which may lead to a flare because of the Koebner phenomenon. Artificial ultraviolet therapy may also be appropriate for children with 12%–20% body surface area, involvement of palms and soles, or resistance to topical therapy.59,64 With two to

Other complaints Affected children have an increased risk of developing Crohn’s disease,43 anterior uveitis,52,53 anxiety,54 and depression.54,55 In one study, 65% of children with psoriasis experienced stigmatization and 43% complained about fatigue.56

Screening for comorbidities

Therapeutic options  153

three treatments of narrow band ultraviolet B (nbUVB) weekly, greater than 90% of treated children improve by more than 75%.65–68 NbUVB therapy is best initiated in an outpatient setting and patients may then be transitioned to home phototherapy as families show proficiency in increasing the doses of UV light gradually, judging effects of the daily treatment, and practicing preventive eye care. Young children may have difficulty tolerating phototherapy. However, tricks such as singing or word games can serve as distractions during treatment. Theoretical longterm risks of phototherapy include increased risk of cutaneous carcinomas and premature aging. The excimer laser (~308 nm), a fiber optic, targeted form of UVB for localized lesions, is another option but has limited data available regarding use in children.59,69–71 Oral psoralens and ultraviolet A light (PUVA) (320–400 nm) are used rarely in children due to possible ocular toxicity, generalized photosensitivity, and the increased risk of actinic changes and cutaneous carcinomas.72 Topical PUVA therapy is occasionally used for recalcitrant hand/ foot psoriasis.

Systemic therapy (see Chapters 23 and 24) Systemic therapy should be reserved for children with severe forms of psoriasis or moderate to severe plaque psoriasis that is recalcitrant to topical therapy due to potential side effects. In general, systemic therapy options for children are the same as for adults, although none of the options are approved for use in pediatric psoriasis by the FDA. Major categories of systemic therapy include traditional immunosuppressants (e.g. methotrexate, cyclosporine, dimethylfumarate), retinoids, and biologics. Oral corticosteroids are best avoided, since their use predisposes to severe, rebound flares when withdrawn. The choice of systemic therapy must take into account patient preference, cost, tolerance, adverse effects, dosing schedule, and mode of administration. For example, the cost of biologics is significantly higher than other options. Recent studies have suggested that methotrexate is the most commonly prescribed of these medications in the United States,73 although in a study in France acitretin was preferentially used for pediatric plaque psoriasis.74 For flares, particularly guttate flares, streptococcal pharyngitis or perianal cellulitis may be the trigger and culture should be considered if there are clinical signs of infection. Antibiotics can eliminate triggering infections, but often not improve psoriasis. Recurrent positive cultures likely indicate a carrier state and trials of antibiotics are not recommended for those who fail to improve.75 Tonsillectomy for chronic and recurrent streptococcal infections may improve refractory psoriasis.76 Methotrexate is indicated for severe unresponsive psoriasis, exfoliative erythrodermas, pustular psoriasis, psoriatic arthritis, and occasionally nail psoriasis (Table 15.1).77–80 Subcutaneous administration may

improve systemic levels and alleviate gastrointestinal upset. Concomitant folic acid 1–5 mg daily reduces gastrointestinal side effects; dosing of the folate varies, but administration daily or daily except for on the day when methotrexate is administered is most common. While on methotrexate, children should avoid live vaccines and sulfa medications. Optimal improvement typically occurs between 2 and 6 months after initiation.81 Once lesions clear, the dose of methotrexate should be gradually decreased in the subsequent months with recurrence the endpoint for dose reduction. Cyclosporine may be used in children with severe refractory psoriasis, exfoliative erythroderma, or pustular psoriasis79,82 (Table 15.1). In addition to immunosuppression, the risks of renal and hepatotoxicity, hypertension, and future neoplasia limits its use to 12 months in the United States and 24 months in Europe. Patients should avoid live vaccines and macrolide antibiotics, which can increase cyclosporine levels. Dimethylfumarate, a fumaric acid ester, is an immunosuppressant available outside of the United States for moderate to severe psoriasis.83 Side effects include abdominal cramps, diarrhea, and flushing, and transient mild transaminitis and leukopenia occur in one-third of children. Retinoids tend to be more effective in combination with topical ointments, phototherapy, or systemic medications than as monotherapy. They are commonly used for exfoliative erythrodermas and pustular psoriasis unresponsive to compresses and topical corticosteroids alone (Table 15.1).77,84 Due to the additional risk of teratogenicity, alternate therapeutic options are preferred for girls of child-bearing potential. Biological agents are highly effective options for recalcitrant psoriasis through inhibition of tumor ­ necrosis factor-alpha (TNF-α; adalimumab, e­ tanercept, infliximab), interleukin-12 /23 (ustekinumab), 85 or ­i nterleukin-17 (secukinumab) (Table 15.1). Only etanercept has undergone a double-blind, randomized trial in U.S. children (n = 211)47; 57% of children receiving etanercept 0.8 mg/kg subcutaneously once weekly achieved 75% improvement in 12 weeks of therapy, compared to 11% receiving vehicle control. Five-year follow-up has shown safety and continued efficacy.86 Although primarily used for plaque psoriasis, TNF inhibitors have led to improvement for recalcitrant palmoplantar pustular and erythrodermic psoriasis. Other biologic agents have been described in trials outside the United States.87–96 Standard dosing of adalimumab is more efficacious than low dose (0.1–0.4 mg/kg/week) methotrexate over 16 weeks.94 Ustekinumab led to a PASI90 reduction of 61% after 12 weeks in a recent blinded, randomized trial in adolescents.95 Ustekinumab may also be the optimal therapy for CARD14-related psoriasis and pityriasis rubra pilaris. To date, secukinumab has not been tested in children. Serious adverse events are rare in children. Patients may be at risk for mycobacterial and salmonella  infections97

154  Pediatric psoriasis

Table 15.1  Dosing, screening, monitoring, and side effects for systemic agents commonly used in pediatric psoriasis or at least testing in clinical trials. Medication Methotrexate (MTX)

Cyclosporine

Dosing recommendations Initial dose: 0.3–0.5 mg/ kg/week, oral Maximum dose: 0.6 mg/ kg/week or 20–25 mg/ week78–80 Can be given s.c. Initial dose: 4–5 mg/kg daily, oral (3 mg/kg daily if microemulsion)77 Dose adjustments may be guided by cyclosporine troughs

Acetretin

Initial dose: 0.5–1.0 mg/ kg daily, oral Titrate dose to effect77

TNF inhibitors Etanercepta Adalimumaba

0.8 mg/kg/week to maximum of 50 mg/wk 0.8 mg/kg/every other week after loading dose to maximum of 40 mg/wk 0.75 mg/kg (≤60 kg), 45 mg (>60 to ≤100 kg), 90 mg (>100 kg)

Ustekinumaba

Screening

Monitoring

Side effects

Blood count (CBC) Hepatic panel Tuberculosis (TB) testing Pregnancy test

CBC and hepatic panel monthly for 6 months and then every 3 months* Yearly TB testing

CBC Comprehensive metabolic panel (CMP) Uric acid Fasting lipid panel Serum magnesium TB testing CBC Hepatic panel Fasting lipid profile Pregnancy test At a minimum, TB testing At a minimum, TB testing

Blood pressure, CBC, CMP, uric acid, fasting lipid panel, and magnesium every 2 weeks for 3 months and then monthly Yearly TB testing

Nausea Abdominal discomfort Fatigue Headache Infections Bone marrow suppression Hypertension Renal toxicity Hepatic toxicity Hypertrichosis Infections Bone marrow suppression

At a minimum, TB testing

CBC, hepatic panel, fasting lipid profile monthly for first months, then every 6 months Annual TB testing Annual TB testing

Xerosis of skin and mucous membranes Hypertriglyceridemia Bone toxicity if long term Injection site reactions Injection site reactions

Annual TB testing

Injection site reactions

Note: None of the listed medications are approved for use in pediatric patients with psoriasis by the U.S. Food and Drug Administration. a Approved for use in pediatric subjects with psoriasis by the European Medicines Agency. * Avoid testing within 72 hours of MTX administration due to transient transaminase elevation

and baseline and annual tuberculosis (TB) testing (by PPD, quantiferon-gold, or Interferon-gamma release assay) is recommended. The long-term side effects in children are unknown and adverse effects on immune system development and an increased risk of lymphoma are theoretical concerns. Although TNF inhibitors carry a black box warning for an increased risk of malignancy, no cases of lymphoma have been reported in pediatric psoriasis. TNF inhibitors can show loss of efficacy with time; in adults, the 4-year drug survival for etanercept or adalimumab is approximately 40%.98 Should a TNF inhibitor lose its efficacy, an alternative TNF inhibitor (or different class of medication) can significantly improve psoriasis severity. Therapy for Psoriatic Arthritis. Many patients with psoriatic arthritis require only nonsteroidal anti-inflammatory drugs, maintenance of joint position, functional splinting, and physiotherapy. Methotrexate and biologic agents (but not ustekinumab) are popular choices for cases requiring more aggressive therapy.

REFERENCES 1. Patel S, Paller AS. Pediatric psoriasis. In: Psoriasis, edited by JY Yoo, CS Lee, MG Lebwohl, et al., pp. 219–238. New York: Informa Healthcare, 2009. 2. Rogers M. Childhood psoriasis. Curr Opin Pediatr. 2002;14(4):404–409. 3. Lehman JS, Rahil AK. Congenital psoriasis: Case report and literature review. Pediatr Dermatol. 2008; 25(3):332–338. 4. Fan X, Xiao FL, Yang S, et al. Childhood psoriasis: A study of 277 patients from China. J Eur Acad Dermatol Venereol. 2007;21(6):762–765. 5. Nair RP, Duffin KC, Helms C, et al. Genomewide scan reveals association of psoriasis with IL-23 and NF-kappaB pathways. Nat Genet. 2009;41(2):199–204. 6. Cai YH, Lu ZY, Shi RF, et al. Enhanced proliferation and activation of peripheral blood mononuclear cells in patients with psoriasis vulgaris mediated by

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streptococcal antigen with bacterial DNA. J Invest Dermatol. 2009;129(11):2653–2660. 7. Raychaudhuri SP, Gross J. A comparative study of pediatric onset psoriasis with adult onset psoriasis. Pediatr Dermatol. 2000;17(3):174–178. 8. Farber EM, Nall ML. The natural history of psoriasis in 5600 patients. Dermatologica. 1974;109:207–211. 9. Nyfors A, Lemholt K. Psoriasis in children. A short review and a survey of 245 cases. Br J Dermatol. 1975;92:437–442. 10. Morris A, Rogers M, Fischer G, et al. Childhood psoriasis: A clinical review of 1262 cases. Pediatr Dermatol. 2001;18:188–198. 11. Wu JJ, Black MH, Smith N, et al. Low prevalence of psoriasis among children and adolescents in a large multiethnic cohort in southern California. J Amer Acad Dermatol. 2011;65(5):957–964. 12. Swanbeck G, Inerot A, Martinsson T, et al. Genetic counseling in psoriasis: Empirical data on psoriasis among first-degree relatives of 3095 psoriatic probands. Br J Dermatol. 1997;137:939–942. 13. Henseler T. The genetics of psoriasis. J Am Acad Dermatol. 1997;37:S1–S11. 14. Fuchs-Telem D, Sarig O, van Steensel MA, et al. Familial pityriasis rubra pilaris is caused by mutations in CARD14. Am J Hum Genet. 2012;91(1):163–170. 15. Pouessel G, Ythier H, Carpentier O, et al. Childhood pustular psoriasis associated with Panton-Valentine leukocidin-producing Staphylococcus aureus. Pediatr Dermatol. 2007;24(4):401–404. 16. Ito T, Furukawa F. Psoriasis guttate acuta triggered by varicella zoster virus infection. Eur J Dermatol. 2000;10(3):226–227. 17. Ergin S, Karaduman A, Demirkaya E, et al. Plaque  psoriasis induced after Kawasaki disease. Turk J Pediatr. 2009;51(4):375–377. 18. Nestle FO, Kaplan DH, Barker J. Psoriasis. N Engl J Med. 2009;361(5):496–509. 19. Menter MA, Whiting DA, McWilliams J. Resistant childhood psoriasis: An analysis of patients seen in a day-care center. Pediatr Dermatol. 1984;2:8–12. 20. Benoit S, Hamm H. Childhood psoriasis. Clin Dermatol. 2007;25(6):555–562. 21. Patrizi A, Costa AM, Fiorillio L, et al. Perianal streptococcal dermatitis associated with guttate psoriasis and/or balanoposthitis. Pediatr Dermatol. 1994;11(2):168–171. 22. Seyhan M, Coskun BK, Saglam H, et al. Psoriasis in childhood and adolescence: Evaluation of demographic and clinical features. Pediatr Int. 2006;48(6):525–530. 23. Ko HC, Jwa SW, Song M, et al. Clinical course of guttate psoriasis: Long-term follow-up study. J Dermatol. 2010;37(10):894–899. 24. Martin BA, Chalmers RJ, Telfer NR. How great is the risk of further psoriasis following a single episode of acute guttate psoriasis?. Arch Dermatol. 1996;132(6):717–718.

25. Schachner L, Ling MS, Press S. A statistical analysis of a pediatric dermatology clinic. Pediatr Dermatol. 1983;1:157–164. 26. Nanda A, Kaur S, Kaur I, et al. Childhood psoriasis: An epidemiologic survey of 112 patients. Pediatr Dermatol. 1990;7:19–21. 27. Farber EM. Facial psoriasis. Cutis. 1992;50:25–28. 28. Farber EM, Nall L. Natural history and treatment of scalp psoriasis. Cutis. 1992;49(6):396–400. 29. Mercy K, Kwasny M, Cordoro KM, et al. Clinical manifestations of pediatric psoriasis: Results of a multicenter study in the United States. Pediatr Dermatol. 2013;30(4):424–428. 30. Abdel-Hamid IA, Agha SA, Moustafa YM, et al. Pityriasis amiantacea: A clinical and etiopathologic study of 85 patients. Int J Dermatol. 2003;42(4): 260–264. 31. Hersle K, Lindholm A, Mobacken H, et al. Relationship of pityriasis amiantacea to psoriasis: A  follow-up study. Dermatologica. 1979;159: 245–250. 32. Hansted B, Lindskov R. Pityriasis amiantacea and psoriasis. Dermatologica. 1983;166:314–315. 33. Fischer G, Rogers M. Vulvar disease in children: A clinical audit of 130 cases. Pediatr Dermatol. 2000; 17(1):1–6. 34. Farber EM, Nall L. Nail psoriasis. Cutis. 1992;50: 174–178. 35. Xiao T, Li B, He CD, et al. Juvenile generalized pustular psoriasis. J Dermatol. 2007;34(8):573–576. 36. Zelickson BD, Muller SA. Generalized pustular psoriasis. A review of 63 cases. Arch Dermatol. 1991;127(9):1339–1345. 37. Zelickson BD, Muller SA. Generalized pustular psoriasis in childhood. J Am Acad Dermatol. 1991;24:186–194. 38. Bellet JS, Chamlin SL, Yan AC, et al. Intertriginous pustular psoriasis. J Am Acad Dermatol. 2009;60(4):679–683. 39. Ivker RA, Grin-Jorgensen CM, Vega VK, et al. Infantile generalized pustular psoriasis associated with lytic lesions of the bone. Pediatr Dermatol. 1993;10:277–282. 40. Liao PB, Rubinson R, Howard R, et al. Annular pustular psoriasis—Most common form of pustular psoriasis in children: Report of three cases and review of the literature. Pediatr Dermatol. 2002;19(1):19–25. 41. Aksentijevich I, Masters SL, Ferguson PJ, et al. An autoinflammatory disease with deficiency of the interleukin-1-receptor antagonist. N Engl J Med. 2009;360(23):2426–2437. 42. Reddy S, Jia S, Geoffrey R, et al. An autoinflammatory disease due to homozygous deletion of the IL1RN locus. N Engl J Med. 2009;360(23):2438–2444. 43. Augustin M, Glaeske G, Radtke MA, et al. Epidemiology and comorbidity of psoriasis in children. Br J Dermatol. 2010;162(3):633–666.

156  Pediatric psoriasis

44. Boccardi D, Menni S, La Vecchia C, et al. Overweight and childhood psoriasis. Br J Dermatol. 2009;161(2):484–486. 45. Au SC, Goldminz AM, Loo DS, et al. Association between pediatric psoriasis and the metabolic syndrome. J Am Acad Dermatol. 2012;66(6):1012–1013. 46. Tom WL, Playford MP, Admani S, et al. Characterization of lipoprotein composition and function in pediatric psoriasis reveals a more atherogenic profile. J Invest Dermatol. 2016;136(1): 67–73. 47. Paller AS, Siegfried EC, Langley RG, et al. Etanercept treatment for children and adolescents with plaque psoriasis. N Engl J Med. 2008;358(3):241–251. 48. Stoll ML, Lio P, Sundel RP, Nigrovic PA. Comparison of vancouver and International League of Associations for rheumatology classification criteria for juvenile psoriatic arthritis. Arthritis Rheum. 2008; 59(1):51–58. 49. Flatø B, Lien G, Smerdel-Ramoya A, Vinje O. Juvenile psoriatic arthritis: Longterm outcome and differentiation from other subtypes of juvenile idiopathic arthritis. J Rheumatol. 2009;36(3):642–650. 50. Stoll ML, Zurakowski D, Nigrovic LE, et al. Patients with juvenile psoriatic arthritis comprise two distinct populations. Arthritis Rheum. 2006;54(11):3564–3572. 51. Butbul YA, Tyrrell PN, Schneider R, et al. Comparison of patients with juvenile psoriatic arthritis and nonpsoriatic juvenile idiopathic arthritis: How different are they? J Rheumatol. 2009;36(9):2033–2041. 52. Niccoli L, Nannini C, Cassarà E, et al. Frequency of iridocyclitis in patients with early psoriatic arthritis: A prospective, follow up study. Int J Rheum Dis. 2012;15(4):414–418. 53. Rosenbaum JT. Uveitis in spondyloarthritis including psoriatic arthritis, ankylosing spondylitis, and inflammatory bowel disease. Clin Rheumatol. 2015;34(6):999–1002. 54. Kimball AB, Wu EQ, Guerin A, et al. Risks of developing psychiatric disorders in pediatric patients with psoriasis. J Am Acad Dermatol. 2012;67(4):651–657. e1–2. 55. Bilgic A, Bilgic O, Akis HK, et al. Psychiatric symptoms and health-related quality of life in children and adolescents with psoriasis. Pediatr Dermatol. 2010;27(6):614–617. 56. de Jager ME, de Jong EM, Evers AW, et al. The burden of childhood psoriasis. Pediatr Dermatol. 2011;28(6):736–737. 57. Cordoro KM. Topical therapy for the management of childhood psoriasis: Part I. Skin Therapy Lett. 2008;13(3):1–3. 58. Lara-Corrales I, Ramnarine S, Lansang P. Treatment of childhood psoriasis with phototherapy and photochemotherapy. Pediatrics. 2013;7:25–33. 59. Van Geel MJ, Mul K, Oostveen AM, et al. Calcipotriol/betamethasone dipropionate ointment in mild-to-moderate paediatric psoriasis: Long-term

daily clinical practice data in a prospective cohort. Br J Dermatol. 2014;171(2):363–369. 60. Trueb R. Therapies for childhood psoriasis. Curr Probl Dermatol. 2009;38:137–159. 61. Brune A, Miller DW, Lin P, et al. Tacrolimus ointment is effective for psoriasis on the face and intertriginous areas in pediatric patients. Pediatr Dermatol. 2007;24(1):76–80. 62. Oostveen AM, Beulens CA, van de Kerkhof PC, et al. The effectiveness and safety of short-contact dithranol therapy in paediatric psoriasis: A prospective comparison of regular day care and day care with telemedicine. Br J Dermatol. 2014;170(2):454–457. 63. Diluvio L, Campione E, Paterno EJ, et al. Childhood nail psoriasis: A useful treatment with tazarotene 0.05%. Pediatr Dermatol. 2007;24(3):332–333. 64. Ersoy-Evans S, Altaykan A, Sahin S, Kölemen F. Phototherapy in childhood. Pediatr Dermatol. 2008;25(6):599–605. 65. Jain VK, Bansal A, Aggarwal K, Jain K. Enhanced response of childhood psoriasis to narrow-band UV-B phototherapy with preirradiation use of mineral oil. Pediatr Dermatol. 2008;25(5):559–564. 66. Pavlovsky M, Baum S, Shpiro D, et al. Narrow band UVB: Is it effective and safe for paediatric psoriasis and atopic dermatitis? J Eur Acad Dermatol Venereol. 2011;25(6):727–729. 67. Zamberk P, Velazquez D, Campos M, et al. Paediatric psoriasis—Narrowband UVB treatment. J Eur Acad Dermatol Venereol. 2010;24(4):415–419. 68. Tan E, Lim D, Rademaker M. Narrowband UVB phototherapy in children: A New Zealand experience. Australas J Dermatol. 2010;51(4):268–273. 69. Menter A, Korman NJ, Elmets CA, et al. Guidelines of care for the management of psoriasis and psoriatic arthritis Section 5. Guidelines of care for the treatment of psoriasis with phototherapy and photochemotherapy. J Am Acad Dermatol. 2010;62:114–135. 70. Cordisco MR. An update on lasers in children. Curr Opin Pediatr. 2009;21(4):499–504. 71. Gattu S, Rashid RM, Wu JJ. 308-nm excimer laser in psoriasis vulgaris, scalp psoriasis, and palmoplantar psoriasis. J Eur Acad Dermatol Venereol. 2009;23(1):36–41. 72. Stern RS, Nichols KT. Therapy with orally administered methoxsalen and ultraviolet A radiation during childhood increases the risk of basal cell carcinoma. The PUVA Follow-up Study. J Pediatr. 1996;129(6):915–917. 73. Garber C, Creighton-Smith M, Sorensen EP, et al. Systemic treatment of recalcitrant pediatric psoriasis: A case series and literature review. J Drugs Dermatol. 2015;14(8):881–886. 74. Charbit L, Mahé E, Phan A, et al. Systemic treatments in childhood psoriasis: A French multicentre study on 154 children. Br J Dermatol. 2016;174(5):1118–1121

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75. Owen CM, Chalmers R, O’Sullivan T, Griffiths CEM. Antistreptococcal interventions for guttate and chronic plaque psoriasis. Cochrane Database Syst Rev. 2000;(2):CD001976. 76. Wilson JK, Al-Suwaidan SN, Krowchuk D, et al. Treatment of psoriasis in children: Is there a role for antibiotic therapy and tonsillectomy?. Pediatr Dermatol. 2003;20(1):11–15. 77. Lebwohl M, Ali S. Treatment of psoriasis. Part  2. Systemic therapies. J Am Acad Dermatol. 2001;45:649–661. 78. Bright RD. Methotrexate in the treatment of psoriasis. Cutis. 1999;64:332–334. 79. Cordoro KM. Systemic and light therapies for the management of childhood psoriasis: Part II. Skin Therapy Lett. 2008;13(4):1–3. 80. Collin B, Vani A, Ogboli M, Moss C. Methotrexate treatment in 13 children with severe plaque psoriasis. Clin Exp Dermatol. 2009;34(3):295–298. 81. Van Geel MJ, Oostveen AM, Hoppenreijs EP, et  al. Methotrexate in pediatric plaque-type psoriasis: Long-term daily clinical practice results from the Child-CAPTURE registry. J Dermatolog Treat. 2015;26:406–412. 82. Pereira TM, Vieira AP, Fernandes JC, SousaBasto A. Cyclosporin A treatment in severe childhood psoriasis. J Eur Acad Dermatol Venereol. 2006;20(6):651–656. 83. Reich K, Hartl C, Gambichler T, Zschocke I. Retrospective data collection of psoriasis treatment with fumaric acid esters in children and adolescents in Germany (KIDS FUTURE study). J Dtsch Dermatol Ges. 2016;14(1):50–57. 84. Brecher AR, Orlow SJ. Oral retinoid therapy for dermatologic conditions in children and adolescents. J Am Acad Dermatol. 2003;49(2):171–182. 85. Krueger GG, Langley RG, Leonardi C, et al. A human interleukin-12/23 monoclonal antibody for the treatment of psoriasis. N Engl J Med. 2007;356(6):580–592. 86. Paller AS, Siegfried EC, Pariser DM, et al. Long-term safety and efficacy of etanercept in children and adolescents with plaque psoriasis. J Am Acad Dermatol. 2016;74(2):280–287. 87. Farnsworth N, George SJ, Hsu S. Successful use of infliximab following a failed course of etanercept in a pediatric patient. Dermatol Online J. 2005;11(3):11.

88. Menter MA, Cush JM. Successful treatment of pediatric psoriasis with infliximab. Pediatr Dermatol. 2004;21:87–88. 89. Luu M, Cordoro KM. The evolving role of biologics in the treatment of pediatric psoriasis. Skin Therapy Lett. 2013;18(2):1–4. 90. Pereira TM, Vieira AP, Fernandes JC, Antunes H, Basto AS. Anti-TNF-alpha therapy in childhood pustular psoriasis. Dermatology. 2006;213(4):350–352. 91. Weishaupt C, Metze D, Luger TA, et al. Treatment of pustular psoriasis with infliximab. J Dtsch Dermatol Ges. 2007;5(5):397–399. 92. Alvarez AC, Rodriguez-Nevado I, de Argila D, et al. Recalcitrant pustular psoriasis successfully treated with adalimumab. Pediatr Dermatol. 2011;28(2):195–197. 93. Callen JP, Jackson JH. Adalimumab effectively controlled recalcitrant generalized pustular psoriasis in an adolescent. J Dermatolog Treat. 2005;16(5–6):350–352. 94. Efficacy and Safety of Adalimumab versus Methotrexate Treatment in Pediatric Patients with Severe Chronic Plaque Psoriasis: Results from the 16-Week Randomized, Double-Blind Period of a Phase 3 Study. Abstract #2970552. 23rd World Congress of Dermatology (WCD 2015), Vancouver, Canada, 2015 95. Landells I, Marano C, Hsu MC, et al. Ustekinumab in adolescent patients age 12 to 17 years with moderateto-severe plaque psoriasis: Results of the randomized phase 3 CADMUS study. J Am Acad Dermatol. 2015 October;73(4):594–603. 96. Kim IH, West CE, Kwatra SG, et al. Comparative efficacy of biologics in psoriasis: A review. Am J Clin Dermatol. 2012;13(6):365–374. 97. Van de Vosse E, van Dissel JT, Ottenhoff TH. Genetic deficiencies of innate immune signalling in human infectious disease. Lancet Infect Dis. 2009;9(11):688–698. 98. Gniadecki R, Kragballe K, Dam TN, et al. Comparison of drug survival rates for adalimumab, etanercept and infliximab in patients with psoriasis vulgaris. Br J Dermatol. 2011;164(5):1091–1096.

16 Cardiometabolic comorbidities NEHAL N. MEHTA CARDIOMETABOLIC DISEASES: OVERVIEW

Dysglycemia

Psoriasis is associated with an increased prevalence of atherosclerotic cardiovascular disease (CVD), diabetes, obesity, and future vascular events.1–7 Cardiometabolic disease is a broad term used to describe a constellation of maladaptive responses to excess caloric energy. Components of cardiometabolic disease include obesity, dysglycemia, dyslipidemia, and atherosclerotic CVDs. These CV and metabolic derangements individually and collectively lead to a substantial increase in CVD and diabetes, and represent potent risk factors for premature myocardial infarction and stroke.4,8,9 Preclinical models, human studies, and epidemiology reveal that lack of physical activity, weight gain, and poor control of known CV risk factors contribute to the increasing prevalence of cardiometabolic diseases among the U.S. population. As per a recent report from the World Health Organization,10 cardiometabolic disease prevalence has increased threefold in the past decade and is now recognized as a serious disease entity by most professional medical societies.

Dysglycemia is a term used for when fasting blood sugar is elevated, or there are problems with peripheral (skeletal muscle or adipose tissue) insulin sensitivity, commonly referred to as insulin resistance. Several human translational and epidemiological studies have demonstrated that psoriasis is related to a peripheral insulin resistance as measured by HOMA-IR or the hyperinsulinemic–­ euglycemic clamp.16 The mechanisms by which this is governed are not entirely worked out; however, they may be a consequence of inflammatory cytokines modulating peripheral insulin metabolism of glucose or associated adipose tissue inflammation observed in psoriasis.

Obesity Obesity has been noted to be highly prevalent in people with psoriasis.11 The definition of obesity is based on body mass index (BMI) categorized as ideal <25, overweight as 25–29, and obesity as >30. Epidemiological studies have demonstrated that there is a dose–response relationship between psoriasis severity and increasing obesity.12 Studies in humans have demonstrated that this obesity may be in fact related to adipose tissue inflammation either directly due to psoriatic plaques or because of the inflammatory cytokine milieu observed in psoriasis.13 Furthermore, studies of blood biomarkers secreted by adipocytes called adipokines have demonstrated that psoriasis modulates the adipokines in a fashion similar to diabetes.14,15

Dyslipidemia Dyslipidemia, commonly referred to as high cholesterol, is highly prevalent in people with psoriasis. Dyslipidemia is based on measurement of serum or plasma cholesterol concentration, which is then fractionated for the commonly reported elements. Total cholesterol, triglycerides (TGs), and high-density lipoprotein (HDL) are directly measured in most clinical laboratories. This then permits calculation of low-density lipoprotein (LDL) by the Friedewald formula. LDL total cholesterol and TGs contain apolipoprotein B, which is atherogenic. HDL contains apolipoprotein A and has been referred to as “good cholesterol” due to its beneficial activity of removing cholesterol from the body in a process called “reverse cholesterol transport.” In psoriasis, dyslipidemia also remains one of the most underdiagnosed CV risk factors,17 which is highly modifiable by lifestyle changes and medical therapy. Patterns of dyslipidemia observed in psoriasis resemble diabetes, whereby HDL is low, TGs are high, and LDL particles are small and dense.18,19 Finally, recent efforts have demonstrated that psoriasis severity directly relates to a decrement in the ability of HDL to perform “reverse cholesterol transport,” which may accelerate atherosclerosis in these patients.20

159

160  Cardiometabolic comorbidities

ATHEROSCLEROTIC CARDIOVASCULAR DISEASES Atherosclerosis, a process that hardens the arteries due to lipid deposition following blood vessel injury, remains the most common cause of mortality and morbidity in people with psoriasis.6 By definition, atherosclerosis is both a component and a complication of having cardiometabolic diseases. The presence of atherosclerotic CVDs is generally termed subclinical if there are no manifestations or clinical signs such as chest pain or shortness of breath. When atherosclerosis leads to myocardial infarction, peripheral arterial disease or stroke, it is called clinical CVD. Both of these entities have been demonstrated to be increased in psoriasis.4,6,8 An entire section of this chapter is devoted to atherosclerosis and psoriasis.

state ­transiently emerges 6 hours following injection.23 This insulin ­resistance coincides with the development of adipose inflammation with an increased infiltrate of inflammatory cell cytokines,24 which has been observed in psoriasis as well.25 In addition to the insulin resistance following LPS injection, lipid composition and function change to resemble a metabolic dyslipidemia consisting of low HDL, decreased HDL function, and increased TGs.26 These changes are also observed in human psoriasis, whereby the lipid concentrations of HDL are low and TGs are high.18,19

CHRONIC SYSTEMIC INFLAMMATION IN PSORIASIS Skin inflammation

THE ROLE OF INFLAMMATION IN CARDIOMETABOLIC DISEASES There are several lines of evidence that inflammation in humans predisposes to cardiometabolic diseases. Much of this literature is derived from preclinical animal m ­ odels, in vitro cellular studies, human translational studies, and human epidemiological studies in nonpsoriasis populations. Animal models have demonstrated that induction of inflammation via bolus of an inflammatory cytokine such as tumor necrosis factor (TNF) alpha or interleukin (IL)-6, both implicated in psoriasis pathogenesis and ­progression, resulting in peripheral insulin resistance and glucose abnormalities in mice. Furthermore, use of antiinflammatory medicines including aspirin abrogates these metabolic changes, suggesting that inflammation is critical to the development of these.21 From large prospective human epidemiological studies involving healthy individuals followed over 10 years, chronic low-grade systemic inflammation assessed by high-sensitivity C-reactive protein (hs-CRP) demonstrates that the presence of an elevated hs-CRP, suggesting increased systemic inflammation, relates strongly to future CV events.22 For example, in a study of 20,000 healthy women followed for 10 years in the Women’s Health Initiative, a high hs-CRP was associated with a fourfold risk of future events. In this same cohort, an elevated LDL cholesterol increased future CV events by twofold. Highsensitivity CRP has been noted to be elevated in psoriatic diseases and correlated to skin and joint disease severity thereby calling into question whether this marker accurately quantifies CV risk in inflammatory populations. Findings from human translational studies support a temporal relationship between inflammation and development of cardiometabolic diseases. When humans are given a single injection of lipopolysaccharide (LPS), which s­timulates innate immune activation consisting of a surge of IL-6 and TNF-alpha, an insulin-resistant

There are many lines of evidence that there is chronic lowgrade systemic inflammation present in people with psoriasis. This inflammation is thought to originate from the skin including keratinocyte production of inflammatory cytokines and the ensuing immune infiltration consisting of neutrophils, dendritic cells, macrophages, and T cells.27 All of the cells produce inflammatory proteins, which in turn affect remote sites in the body, a concept termed the “psoriatic march.”13 Recently, positron emission tomography/computed tomography (PET/CT) has demonstrated the presence of increased inflammation in the skin of patients with psoriasis after injection with radiolabeled glucose ([18F]-fluorodeoxyglucose [18-FDG]) (Figure 16.1).28

Blood inflammation The deleterious effects of this chronic low-grade skin inflammation have been associated with increase in markers of systemic inflammation in the blood including an elevated erythrocyte sedimentation rate, elevated high-sensitivity CRP, elevated markers of innate immune activation such as IL-6 and TNF-α, as well as numerous interleukins associated with T cells and neutrophils. Interestingly, these markers have also been demonstrated to be elevated in patients with diabetes, coronary artery disease, and other cardiometabolic disorders, including the metabolic syndrome demonstrating a shared potential disease pathophysiology.29–31

Adipose inflammation Recent evidence suggests that there is presence of adipose inflammation in people with psoriasis. This adipose inflammation has been documented following transient injections of LPS into humans as previously noted. 24 After an injection of LPS, healthy human volunteers were noted to have infiltration of macrophages as

Psoriasis and cardiovascular diseases  161 Healthy control

Psoriasis patient

injection of the tracer. Furthermore, this increase in glucose uptake within the blood vessels has been shown in patients with inflammatory diseases such as rheumatoid arthritis (RA) and psoriasis, 28,33 both diseases which have increased CVD in large population-based studies. In psoriasis, this vascular inflammation has been shown to be dose-dependently related to the severity of skin disease, 34 further suggesting that skin disease may drive remote atherosclerotic processes.

PSORIASIS AND CARDIOVASCULAR DISEASES Epidemiological studies

(a)

 

(b)

Figure 16.1 

Planar reconstructed [18F]-fluorodeoxyglucose (18F-FDG) positron emission tomography/computed tomography (PET/CT) images from (a) psoriasis patient and (b) healthy control depicting increased uptake of a radiolabeled tracer 18F-FDG in the skin affected by psoriatic plaques (a: solid black arrows), which is absent in the control (b: solid black arrows). (Courtesy of Dr. Aditya Joshi from the Mehta Lab, National Institutes of Health, Bethesda, MD.)

well as T cells into subcutaneous adipose tissue. A recent study of psoriasis patients demonstrated an infiltration of the cell types in the adipose tissue, supporting the notion that chronic low-grade systemic inflammation may induce adipose inflammation. 25 Whether the significance of this adipose inflammation relates directly to the metabolic syndrome or diabetes has yet to be determined; however, this does support the hypothesis of inflammatory metabolic adipose dysfunction in people with psoriasis.

Vascular inflammation The findings of elevated blood biomarkers of inflammation and adipose inflammation observed in human psoriatic diseases also have been associated with an increase in inflammation noted in the blood vessels measured by nuclear imaging techniques. This “vascular inflammation” is reliably assessed by FDG PET/CT. Vascular uptake of FDG by PET/CT has been associated with future CV events in nonpsoriasis patients, 32 and this FDG uptake in the blood vessels represents macrophage uptake when scanned 60–120 minutes following

CVD can be broadly defined as any abnormalities of blood vessel anatomy (atherosclerotic vascular disease) or function (endothelial dysfunction), myocardial abnormalities including congestive heart failure, and rhythm disturbances including arrhythmias like atrial fibrillation. All of these aforementioned outcomes have been noted epidemiologically to be increased in prevalence in patients with psoriasis.35–37 However, the focus of the remaining section will be on atherosclerotic CVDs because these portend the greatest adverse prognosis on morbidity and mortality in patients with psoriasis. Large-scale, population-based, epidemiological studies have demonstrated that psoriasis is associated with an increased risk of atherosclerotic CVDs beyond traditional risk factors including hypertension, hyperlipidemia, tobacco use, diabetes, and BMI. The most serious life-threatening complication of atherosclerotic CVDs is myocardial infarction, when plaque rupture leads to superimposing thrombosis in a coronary artery. In seminal work performed in the early 2000s, patients with severe psoriasis were shown to have an elevation of 60% risk for experiencing the first myocardial infarction.4,9,38 Furthermore, there was also a dose–response relationship noted with severity of psoriasis whereby patients with more severe disease had higher odds of having the first myocardial infarction (MI). These findings suggest that skin disease severity may have direct adverse effects on atherosclerotic processes. Following this work, other serious CV outcomes such as stroke, angina, and severity of angiographic coronary disease were all shown to be increased in patients with psoriasis. Additionally, a composite outcome called major adverse CV events, which includes a combination of incident stroke, angina, myocardial infarction, and CV death, is the major outcome used in CV risk scoring, called the Framingham Risk Score. Psoriasis has been noted to augment this risk score by approximately 6% beyond the traditionally calculated score.39 This increase in risk should alert clinicians to screen for CV risk factors when patients present with psoriatic diseases and is similar to recommendations by the European League Against Rheumatism (EULAR) for calculating risk in patients with rheumatoid arthritis. It is worthy of mention that not all studies have found that psoriasis is not an independent risk

162  Cardiometabolic comorbidities

factor for these outcomes and that severe psoriasis may be the only risk.40–43 These studies, however, tended to be ­underpowered and done in smaller populations.35–37

Translational studies To better understand the relationship between psoriasis and CVDs, recent studies have focused specifically on potential mechanisms at play to better understand inflammatory atherogenesis. These studies are called translational studies because they involve both laboratory sciences and clinical research and have focused on understanding how the skin may drive these processes. Generally speaking, the studies have incorporated some type of imaging modality for the blood vessels including cardiac CT, electron beam CT for coronary artery calcium score, ultrasound for intimal medial thickness, or aortic stiffness called pulse wave velocity. The exposures in the studies beyond psoriasis have explored three general spheres of important potential contributors to the accelerated atherogenesis observed: cholesterol markers, inflammatory proteins/immunologic phenotyping, and metabolic dysregulation. The results of these translational studies have demonstrated that psoriasis leads to an increase in LDL particle number and decrease in size,18 both of which have been shown to increase first MI in nonpsoriasis patients. Furthermore, psoriasis has been found to have poor HDL function, which leads to an increase in noncalcified burden of coronary artery disease.44 The amount of inflammatory proteins detected in the blood of psoriatic patients has been shown to directly relate to subclinical atherosclerosis by ultrasound as well as by CT.44 Markers of immunologic dysregulation including generation of microparticles from macrophages, T cells, platelets, and endothelial cells have been shown to be upregulated and psoriasis.45 Proteins secreted by the adipose tissue including adiponectin and leptin have been shown to be modulated in psoriasis in a manner similar to diabetes,14 and these adipokines have been related to the presence of cardiometabolic disease as assessed by the metabolic syndrome presence in psoriasis.5 These findings suggest that there are several potential pathways leading to cardiometabolic diseases in psoriasis and that human translational studies complement findings from epidemiological studies. Studies focused on the pathogenesis to understand deeper mechanisms need to be completed to have a better understanding of whether treatment of psoriatic diseases ameliorates cardiometabolic diseases.

PSORIASIS, OBESITY AND DIABETES Epidemiological studies One of the most prevalent comorbid diseases observed in psoriasis is obesity. Several studies in the United States,

United Kingdom, and Asia have demonstrated that the prevalence of obesity in psoriasis exceeds 50%. Using U.S. survey data, a recent study demonstrated that there was a dose–response relationship between psoriasis severity and the presence of obesity as measured by BMI. Furthermore, a UK-based study demonstrated that this dose-dependent increase in BMI by psoriasis severity space was associated with a dose-dependent increase in metabolic syndrome, diabetes, and features of the metabolic syndrome including dysglycemia and hypertriglyceridemia.5 Another study from the Netherlands demonstrated that as psoriasis severity increased, there was an increase in diabetes prevalence and diabetes complications.46 Furthermore, the authors demonstrated that the percentage of patients who did not receive optimal control of their diabetes was higher than in those without psoriasis. Another study, which looked at a clinical trial population, demonstrated that impaired fasting glucose, insulin resistance, and diabetes were all highly undiagnosed in patients with psoriasis as they entered the clinical trial.17 These findings collectively suggest that in addition to adipose inflammation, which is observed in psoriasis, obesity and diabetes have a dose-dependent increase with psoriasis severity.

Translational studies To better understand how this epidemiological increase in obesity and diabetes is occurring, a few translational studies have been performed to understand the nature of this association. Adipose inflammation was recently demonstrated to be present in psoriasis regardless of psoriasis severity, suggesting that immune hyperfunction may be leading to either peripheral insulin resistance or central decrease in secretion of insulin from the pancreatic beta cells. Elegant work before and after treatment of psoriasis using an anti-TNF drug demonstrated that insulin sensitivity improved with a direct relationship with psoriasis improvement.47 Another study demonstrated that as patients had decreasing scores of psoriasis severity, markers of insulin resistance, dyslipidemia, and even metabolic syndrome features decreased.48 More efforts are needed to understand the metabolic this regulation in psoriasis because it does represent the most prevalent abnormality observed for cardiometabolic diseases in psoriasis.

PSORIASIS TREATMENT AND EFFECT ON CARDIOMETABOLIC DISEASES Epidemiological studies Whether treatment of skin disease in psoriasis leads to improvement of cardiometabolic disease has not been tested as of yet in a randomized clinical trial and is the topic of intense investigation. However, findings from epidemiological studies done in other inflammatory diseases such

References 163

as rheumatoid arthritis show that treatment of r­ heumatoid arthritis with aggressive biologic therapy does in fact reduce future CV events.49 In psoriasis, there have been studies done retrospectively to understand treatment effects. For example, using a Veterans Affairs cohort of patients, it was shown that treatment of psoriatic skin disease with systemic agents such as methotrexate reduced heart attack risk by approximately 40%.50 Using large representative population-based data sets in the Netherlands as well as in the United States, anti-TNF therapy, systemic therapy for treatment of psoriatic skin disease, was shown to decrease future risk of myocardial infarction by approximately 40%–50%.51,52 Both of these studies were done as retrospective cohort studies and included several years of follow-up time (8 and 10 years, respectively). Whether or not treatment of joint disease in psoriatic arthritis will be of benefit to cardiometabolic disease amelioration is unknown; however, it is also the topic of intense investigation.

Ongoing studies Open label studies using anti-TNF therapy have shown improvement of markers of CVDs. For example, a recent open label study using an anti-TNF drug in severe psoriatic patients for 1 year demonstrated a reduction in vascular inflammation by FDG PET CT.53 Because this study was small and underpowered, it did not meet its primary outcome, but did show a strong trend toward reducing vascular inflammation following treatment. Furthermore, currently there is an ongoing randomized controlled clinical trial testing on whether use of anti-TNF versus ultraviolet light therapy versus placebo will reduce vascular inflammation in severe psoriatic patients using FDG PET CT, and this study should move our understanding forward of whether treatment of skin disease will improve vascular inflammation and CV biomarkers. Of note, to best understand whether or not aggressive treatment of psoriatic skin disease will reduce future CV events, a large prospective outcome study needs to be planned so that firm evidence can be established for whether or not treatment of skin disease will ameliorate cardiometabolic disease risk in psoriasis.

RECOMMENDATION FOR SCREENING AND TREATMENT OF CARDIOMETABOLIC DISEASES IN PSORIASIS The current American College of Cardiology/American Heart Association guidelines for CV risk screening do not recognize psoriasis as a risk factor for CVDs. Furthermore, the National Cholesterol Education Program/Adult Treatment Panel guidelines54 note that inflammatory diseases may be considered as emerging risk factors and added to the traditional risk score similar to what EULAR recommends for RA.55 In the updated guidelines from

the American College of Cardiology/American Heart Association for training in prevention, psoriasis was noted to be a potential risk factor for heart disease with recommendations that patients should be counseled, educated, and screened per current, age-appropriate guidelines at this time. Therefore, although there are no consensus statements for current recommendations for patients with psoriasis in the United States, the United Kingdom, and Europe, the weight of evidence suggests performing the following in each patient with psoriasis once before the age of 18, every 5 years between the ages of 18 and 35 years of age, and then annually after 35 years of age: 1. Obtain a seated, resting blood pressure with the goal that the reading be less than 130/80. 2. Perform a height and weight measurement to assess for obesity by calculating a BMI with the ideal goal that the measurement be less than 25. 3. Send blood for measurement of cholesterol concentration and glucose to assess for dyslipidemia and this glycemia.

CONCLUSIONS Inflammation in humans has been tightly linked to the development of atherosclerosis and metabolic dysregulation, termed cardiometabolic diseases. This systemic inflammation observed in psoriasis is increasingly being recognized as a risk factor for the development of cardiometabolic diseases. It is of utmost importance that patients as well as providers are educated of this increased risk so as to screen for and appropriately treat the ­conditions ­associated with morbidity and mortality. This public health awareness is critically needed, as the field understands whether treatment ameliorates cardiometabolic disease development and progression in psoriasis. Finally, providers should be educated to convey the message of heightened risk of cardiometabolic comorbid disease incidence and ensure that it is a topic of discussion with every patient with psoriasis.

REFERENCES 1. Armstrong AW, Harskamp CT, Armstrong EJ. Psoriasis and the risk of diabetes mellitus: A systematic review and meta-analysis. JAMA Dermatol. 2013;149(1):84–91. 2. Armstrong AW, et al. Coronary artery disease in patients with psoriasis referred for coronary angiography. Am J Cardiol. 2012;109(7):976–980. 3. Azfar RS, Gelfand JM. Psoriasis and metabolic disease: Epidemiology and pathophysiology. Curr Opin Rheumatol. 2008;20(4):416–422. 4. Gelfand JM, et al. Risk of myocardial infarction in patients with psoriasis. JAMA. 2006;296(14): 1735–1741.

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5. Langan SM, et al. Prevalence of metabolic syndrome in patients with psoriasis: A population-based study in the United Kingdom. J Invest Dermatol. 2012;132(3 Pt 1):556–562. 6. Mehta NN, et al. Patients with severe psoriasis are at increased risk of cardiovascular mortality: Cohort study using the General Practice Research Database. Eur Heart J. 2010;31(8):1000–1006. 7. Yeung H, et al. Psoriasis severity and the prevalence of major medical comorbidity: A population-based study. JAMA Dermatol. 2013;149(10):1173–1179. 8. Gelfand JM, et al. The risk of stroke in patients with psoriasis. J Invest Dermatol. 2009;129(10):2411–2418. 9. Prodanovich S, et al. Association of psoriasis with coronary artery, cerebrovascular, and peripheral vascular diseases and mortality. Arch Dermatol. 2009;145(6):700–703. 10. Kassi E, et al. Metabolic syndrome: Definitions and controversies. BMC Med. 2011;9:48. 11. Armstrong AW, Harskamp CT, Armstrong EJ. The association between psoriasis and obesity: A systematic review and meta-analysis of observational studies. Nutr Diabetes. 2012;2:e54. 12. Fleming P, et al. The relationship of obesity with the severity of psoriasis: A systematic review. J Cutan Med Surg. 2015;19(5):450–456. 13. Boehncke WH, et al. The ‘psoriatic march’: A concept of how severe psoriasis may drive cardiovascular comorbidity. Exp Dermatol. 2011;20(4):303–307. 14. Li RC, et al. Psoriasis is associated with decreased plasma adiponectin levels independently of cardiometabolic risk factors. Clin Exp Dermatol. 2014;39(1):19–24. 15. Qasim A, et al. Adipokines, insulin resistance, and coronary artery calcification. J Am Coll Cardiol. 2008;52(3):231–236. 16. Gyldenlove M, et al. Patients with psoriasis are insulin resistant. J Am Acad Dermatol. 2015;72(4):599–605. 17. Kimball AB, et al. Underdiagnosis and undertreatment of cardiovascular risk factors in patients with moderate to severe psoriasis. J Am Acad Dermatol. 2012;67(1):76–85. 18. Mehta NN, et al. Abnormal lipoprotein particles and cholesterol efflux capacity in patients with psoriasis. Atherosclerosis. 2012;224(1):218–221. 19. Yu Y, et al. Aortic vascular inflammation in psoriasis is associated with HDL particle size and concentration: A pilot study. Am J Cardiovasc Dis. 2012;2(4):285–292. 20. Mehta NN, Gelfand JM. High-density lipoprotein cholesterol function improves after successful treatment of psoriasis: A step forward in the right direction. J Invest Dermatol. 2014;134(3):592–595. 21. Kim JK, et al. Prevention of fat-induced insulin resistance by salicylate. J Clin Invest. 2001;108(3):437–446. 22. Ridker PM. High-sensitivity C-reactive protein, inflammation, and cardiovascular risk: From concept to clinical practice to clinical benefit. Am Heart J. 2004;148(1 Suppl):S19–S26.

23. Anderson PD, et al. Innate immunity modulates adipokines in humans. J Clin Endocrinol Metab. 2007;92(6):2272–2279. 24. Mehta NN, et al. Experimental endotoxemia induces adipose inflammation and insulin resistance in humans. Diabetes. 2010;59(1):172–181. 25. Rose S, et al. Characterization of immune cells in psoriatic adipose tissue. J Transl Med. 2014;12:258. 26. Basciano H, Federico L, Adeli K. Fructose, insulin resistance, and metabolic dyslipidemia. Nutr Metab (Lond). 2005;2(1):5. 27. Nestle FO, Kaplan DH, Barker J. Psoriasis. N Engl J Med. 2009;361(5):496–509. 28. Mehta NN, et al. Systemic and vascular inflammation in patients with moderate to severe psoriasis as measured by [18F]-fluorodeoxyglucose positron emission tomography-computed tomography (FDG-PET/CT): A pilot study. Arch Dermatol. 2011;147(9):1031–1039. 29. de Lemos JA, et al. Association between plasma levels of monocyte chemoattractant protein-1 and longterm clinical outcomes in patients with acute coronary syndromes. Circulation. 2003;107(5):690–695. 30. Hansson GK. Inflammation, atherosclerosis, and coronary artery disease. N Engl J Med. 2005; 352(16):1685–1695. 31. Mehta NN, et al. Modulation of cardiometabolic pathways in skin and serum from patients with psoriasis. J Transl Med. 2013;11:194. 32. Figueroa AL, et al. Measurement of arterial activity on routine FDG PET/CT images improves prediction of risk of future CV events. JACC Cardiovasc Imaging. 2013;6(12):1250–1259. 33. Rose S, et al. A comparison of vascular inflammation in psoriasis, rheumatoid arthritis, and healthy subjects by FDG-PET/CT: A pilot study. Am J Cardiovasc Dis. 2013;3(4):273–278. 34. Naik HB, et al. Severity of psoriasis associates with aortic vascular inflammation detected by FDG PET/CT and neutrophil activation in a prospective observational study. Arterioscler Thromb Vasc Biol. 2015;35(12):2667–2676. 35. Gelfand JM, Azfar RS, Mehta NN. Psoriasis and cardiovascular risk: Strength in numbers. J Invest Dermatol. 2010;130(4):919–922. 36. Gelfand JM, Mehta NN, Langan SM. Psoriasis and cardiovascular risk: Strength in numbers, part II. J Invest Dermatol. 2011;131(5):1007–1010. 37. Ogdie A, et al. Psoriasis and cardiovascular risk: Strength in numbers Part 3. J Invest Dermatol. 2015;135(9):2148–2150. 38. Brauchli YB, et al. Psoriasis and risk of incident myocardial infarction, stroke or transient ischaemic attack: An inception cohort study with a nested case-control analysis. Br J Dermatol. 2009;160(5):1048–1056. 39. Mehta NN, et al. The impact of psoriasis on 10-year Framingham risk. J Am Acad Dermatol. 2012;67(4):796–798.

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40. Stern RS. Psoriasis is not a useful independent risk factor for cardiovascular disease. J Invest Dermatol. 2010;130(4):917–919. 41. Stern RS, Nijsten T. Going beyond associative studies of psoriasis and cardiovascular disease. J Invest Dermatol. 2012;132(3 Pt 1):499–501. 42. Dowlatshahi EA, et al. Psoriasis is not associated with atherosclerosis and incident cardiovascular events: The Rotterdam Study. J Invest Dermatol. 2013;133(10):2347–2354. 43. Wakkee M, Herings RM, Nijsten T. Psoriasis may not be an independent risk factor for acute ischemic heart disease hospitalizations: Results of a large population-based Dutch cohort. J Invest Dermatol. 2010;130(4):962–967. 44. Salahuddin T, et al. Cholesterol efflux capacity in humans with psoriasis is inversely related to noncalcified burden of coronary atherosclerosis. Eur Heart J. 2015;36(39):2662–2665. 45. Takeshita J, et al. Endothelial cell-, platelet-, and monocyte/macrophage-derived microparticles are elevated in psoriasis beyond cardiometabolic risk factors. J Am Heart Assoc. 2014;3(1):e000507. 46. Khalid U, et al. Psoriasis and new-onset diabetes: A Danish nationwide cohort study. Diabetes Care. 2013;36(8):2402–2407. 47. Boehncke S, et al. Effective continuous systemic therapy of severe plaque-type psoriasis is accompanied by amelioration of biomarkers of cardiovascular risk: Results of a prospective longitudinal observational study. J Eur Acad Dermatol Venereol. 2011;25(10):1187–1193. 48. Boehncke S, et al. Systemic therapy of plaque-type psoriasis ameliorates endothelial cell function: Results of a prospective longitudinal pilot trial. Arch Dermatol Res, 2011;303(6):381–388.

49. Morgan CL, et al. Treatment of rheumatoid arthritis with etanercept with reference to disease-modifying anti-rheumatic drugs: Long-term safety and survival using prospective, observational data. Rheumatology (Oxford). 2014;53(1):186–194. 50. Prodanovich S, et al. Methotrexate reduces incidence of vascular diseases in veterans with psoriasis or rheumatoid arthritis. J Am Acad Dermatol. 2005;52(2):262–267. 51. Ahlehoff O, et al. Cardiovascular disease event rates in patients with severe psoriasis treated with systemic anti-inflammatory drugs: A Danish real-world cohort study. J Intern Med. 2013;273(2):197–204. 52. Wu JJ, et al. Association between tumor necrosis factor inhibitor therapy and myocardial infarction risk in patients with psoriasis. Arch Dermatol. 2012;148(11):1244–1250. 53. Bissonnette R, et al. Effects of the tumor necrosis factor-alpha antagonist adalimumab on arterial inflammation assessed by positron emission tomography in patients with psoriasis: Results of a randomized controlled trial. Circ Cardiovasc Imaging. 2013;6(1):83–90. 54. Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. Executive summary of the third report of the National Cholesterol Education Program (NCEP) expert panel on detection, evaluation, and treatment of high blood cholesterol in adults (Adult Treatment Panel III). JAMA. 2001;285(19):2486–2497. 55. Peters MJ, et al. EULAR evidence-based recommendations for cardiovascular risk management in patients with rheumatoid arthritis and other forms of inflammatory arthritis. Ann Rheum Dis. 2010;69(2):325–331.

17 Psychiatric comorbidities JESSICA M. DONIGAN and ALEXA B. KIMBALL

INTRODUCTION Psoriasis has been associated with multiple comorbidities including cardiovascular disease, hypertension, hyperlipidemia, and diabetes mellitus. In addition to these physical illnesses, psoriasis also has substantial psychiatric comorbidities. The appearance of psoriatic lesions and the associated social stigma have been suggested as a major precipitant of psychiatric symptoms.1,2 Psoriasis can interfere with activities of daily living, athletic activities, social and romantic relationships, and employment, which all have an impact on psychological well-being.3 The effect that psoriasis can have on mental functioning is comparable to arthritis, cancer, and heart disease,4 and is not necessarily dependent on the severity of the skin disease.5 In fact, the effects of psoriasis on quality of life can be a stronger predictor of psychiatric morbidity than the clinical severity.6 The degree to which age, gender, and socioeconomic status impact psychological sequelae is controversial.1,7 Increased psychological morbidity has been associated with a sense of a lack of control over psoriasis, and the knowledge that it is an incurable disease.1 Some medications used to treat psoriasis (e.g., systemic corticosteroids) can also cause psychiatric disturbances.2 This chapter focuses on the psychological comorbidities most commonly associated with psoriasis, with mention of some less frequently associated conditions.

PSYCHOSOCIAL STRESS Psoriasis can cause significant stress for patients, some of which is secondary to the appearance of skin lesions and stigma surrounding the disease.8,9 Frequent visits to physicians’ offices, and the potential inconvenience of treatments such as traveling for light therapy, likely also contribute to stress. The physical symptoms of psoriasis, namely pruritus, can contribute to diseaserelated psychosocial stress,10 although its role may be less prominent than other features.1 Psoriasis-induced stress

can lead to a self-perpetuating problem as stress has been suggested to precipitate psoriasis flares.11–14 In one study, patients who associated their psoriasis with stress had more cosmetically disfiguring psoriasis, a greater tendency to want the approval of others, and a greater difficulty with expression of anger.8 Stress reduction interventions such as relaxation techniques and mindfulness meditation may help to reduce the distress associated with psoriasis. Small studies have shown improved response to phototherapy and increased remission duration when phototherapy is combined with a mindfulness meditation-based stress reduction intervention and cognitive behavioral therapy (CBT), respectively.15–17 Furthermore, large-scale studies are currently underway. Short-term treatment of stress with benzodiazepines has been suggested18; however, one must take caution as these medications can be habit forming.

ANXIETY AND SOCIAL PHOBIA Along with psychosocial stress, psoriasis can also induce anxiety. The prevalence of anxiety in psoriasis patients has been reported to range from 11% to 58%,19,20 values higher than those seen in patients with other medical conditions.21 Embarrassment, shame, and s­ elf-consciousness over appearance are common,3,22 and a correlation between anxiety and the presence of psoriasis plaques in visible areas, particularly the face or hands, has been noted.23 Stigmatization of psoriasis and misconceptions of contagion can give patients a sense that others are scrutinizing and judging them based on the appearance of their skin leading to avoidance and social phobia.1 This leads to decreased involvement in social activities with some patients not even going out in public at all.3 Avoidance may contribute to the difficulty that patients with psoriasis have establishing social contacts and relationships22 and may paradoxically perpetuate anxiety.24 Again, short-term treatment of anxiety and social phobia with benzodiapezines has been suggested,18 but it may be prudent to refer 167

168  Psychiatric comorbidities

patients who have symptoms to a provider who specializes in the treatment of these conditions.25

DEPRESSION Embarrassment over the appearance of lesions, social avoidance, and subsequent feelings of isolation can contribute to depressed mood in patients.1,26 Psoriasis is associated with higher depression scores than other dermatologic conditions.27 The prevalence of depression in psoriasis has been reported to range from 7.7%7 to 62%.28 This wide range in prevalence is likely due to differences in study design, such as the criteria used to measure depression or the patient population examined (e.g., inpatients versus outpatients).29 Depressive symptoms are more prevalent among women with psoriasis.27,28 Level of education has also been associated with an increased risk of depression with a greater prevalence in patients with only primary or secondary education.28 Quality of life issues are most frequently associated with depression,29 but physical symptoms of psoriasis can also contribute. A direct relation between the severity of pruritus and depression has been reported and improvement in pruritus is associated with improvement in depressive symptoms and vice versa.10 Reports of the correlation between psoriasis severity and depression have been conflicting; however, the correlation with self-rated psoriasis severity may be stronger than what is seen with clinician-rated severity.30 Similarly to the circular phenomenon of stress and psoriasis, premorbid depression can predispose to developing more severe psoriasis, whereas coping with psoriasis can result in depression.30 Feelings of helplessness fueled by a sense of incurability are a prominent feature of depression in patients with psoriasis.1 Treatment with antidepressant medications may be beneficial not only in the treatment of depression but also in the management of psoriasis,31 particularly as depression can affect treatment adherence.7 Caution must be exercised when choosing which antidepressant to prescribe, as some (e.g., fluoxetine and lithium) can precipitate or aggravate psoriasis.32–34 Escitalopram may be a good choice as it has been shown to cause a significant reduction in pruritus scores.35 Because increased levels of proinflammatory cytokines have been associated with depression,36 anti-inflammatory agents may lead to improvement in both psoriasis lesions and depressive symptoms.37 Antitumor necrosis factor alpha (anti-TNF-α) agents including adalimumab and etanercept have been shown to improve symptoms of depression.38,39 As with anxiety and social phobia, patients with symptoms of depression may warrant a referral to psychiatry.

SUICIDAL IDEATION Depressive symptomatology may include suicidal ideation. The prevalence of suicidal ideation has been reported to

range from 2.5% to 10%,27,40 with 1.6% of patients noting they had tried to hurt or kill themselves in the past because of their disease.3 The prevalence of suicidal ideation is higher in psoriasis than other skin conditions40 and is consistent with the frequency seen in other chronic illnesses.41 Assessing for thoughts of suicidal ideation is important, with prompt referral to psychiatry or emergency medicine if there is any evidence of suicidality.

ALEXITHYMIA Alexithymia is a personality construct characterized by difficulty experiencing, identifying, and expressing feeling24 leading to a deficit in the self-regulation of affect.42 The rate of alexithymia in psoriasis has been reported to range from 25% to 39%.43 It has been suggested that the higher rate of alexithymia may account for a decreased ability for psychological adjustment.24 In fact, alexithymia has been reported to be a risk factor for anxiety and, to a lesser extent, depression and stress in psoriasis.24 Reports of the association between anxiety and alexithymia, ­however, are conflicting.43 The impact that alexithymia has on disability in those with psoriasis is also controversial with some reporting no significant relation24 and others suggesting higher rates of unemployment, and decreased work productivity and activity in psoriatic patients with alexithymia.44 Alexithymia has not been related to clinical severity of psoriasis.45

SUBSTANCE USE Psoriasis is associated with increased alcohol consumption and smoking. In one study, nearly 40% of patients noted that their psoriasis resulted in increased consumption of alcohol or tobacco.46

Alcohol The prevalence of alcoholism in psoriasis has been reported to be as high as 18%, greater than that of healthy controls47,48 as well as other dermatological conditions.18 However, study results have been conflicting, likely due to a heterogeneous definition of increased alcohol consumption. Some patients self-medicate with alcohol to decrease anxiety during social situations.1 This can have a further negative impact on patients as excessive alcohol consumption can worsen anxiety and depression. Additionally, excessive alcohol intake can increase pruritus and have a negative impact on sleep quality which can precipitate or worsen psoriasis.29 Once again, this leads to a self-perpetuating problem. Excessive alcohol intake can potentially worsen psoriasis and it also can interact with psoriasis treatments and increase the risk of hepatotoxicity, particularly in the case of methotrexate. It is important to encourage abstinence from alcohol, or at least minimal intake, in

Eating disorders  169

these patients. Additionally, the negative impact that alcohol can have on psoriasis in general should be discussed with all patients. It is recommended that patients with a score of two or greater on the CAGE questionnaire (a four question screening test for alcohol abuse) be referred for suspected excessive alcohol consumption.25

Smoking Yet another circular phenomenon is the association between smoking and psoriasis. Nicotine leads to the overproduction of inflammatory mediators and can thus participate in the pathogenesis of psoriasis. A 70% increased risk of psoriasis has been reported in smokers,49 with the strongest association observed in palmoplantar pustulosis (a localized type of pustular psoriasis).48 The risk of developing psoriasis is higher in current smokers than in past smokers and declines with longer periods of cessation.50 An increased number of pack-years and intensity of smoking are associated with an increased risk of psoriasis in both current and past smokers.50 Despite the increased risk of psoriasis due to smoking, the prevalence of tobacco use in psoriatic patients has been reported to be as high as 48.9%.51 As with alcohol, it is important to discuss the negative effect of smoking on psoriasis and to encourage smokers to quit or reinforce the decision in those who have already done so.25

SEXUAL DYSFUNCTION Up to 71.3% of patients report that psoriasis adversely affects their sexual function.52 Shame and embarrassment over appearance and lack of confidence may inhibit intimacy.17,53 Higher depression scores have been associated with sexual dysfunction.54 Physical symptoms of psoriasis including pruritus, scaling, and joint involvement can also affect sexual functioning.54 The presence of genital psoriasis can cause dyspareunia, worsening of genital psoriasis after intercourse (likely due to the Köebner effect), and a decreased frequency of intercourse. Furthermore, patients with genital involvement have been shown to have more impairment in quality of life and sexual health as determined by the Dermatology Life Quality Index, the Center for Epidemiological Studies-Depression Scale, and the Relationship and Sexuality Scale, even after correcting for overall psoriasis severity.55 Reports describing an association between sexual dysfunction and marital status, age, sex, and severity of disease have been inconsistent.52,54 Cardiovascular comorbidity can contribute to impaired sexual functioning in patients with psoriasis as atherosclerosis can lead to erectile dysfunction.56

SCHIZOPHRENIA A higher prevalence of schizophrenia in patients with psoriasis has been suggested.7 In a study that looked at the

prevalence of psoriasis among patients with s­ chizophrenia, a 1.2-fold higher risk of psoriasis was reported, with a higher risk in females. Similarly to the association with depression, it has been suggested that the link in pathogenesis between psoriasis and schizophrenia may be systemic inflammation, including increased levels of TNF-α.57,58 Caution must be taken in choosing treatment agents in psoriasis patients who also have schizophrenia as there has been a report of exacerbation of schizophrenic symptoms with cyclosporine therapy, believed to be due to decreased interleukin (IL)-2 production.59 Etanercept was found to be a suitable replacement therapy without psychiatric side effects. Conversely, care must also be taken when choosing the appropriate antipsychotic as olanzapine can induce or exacerbate psoriasis.60,61

OBSESSIVE-COMPULSIVE DISORDER Symptoms of obsessionality are increased in patients with psoriasis.62 Obsessions related to skin care or appearancechecking behaviors can be present.1

PERSONALITY DISORDERS Studies aiming to identify personality variables in psoriasis patients have had inconsistent findings,63 but a higher prevalence of personality disorders has been reported.7 Avoidant personality disorder may be the most common subtype due to fears of rejection resulting from the appearance of psoriasis lesions, social stigma, and misperceptions of contagion. Other personality disorders including schizoid, schizotypal, paranoid, borderline, antisocial, dependent, and obsessive-compulsive personality disorder have also been suggested to be more prevalent in psoriasis patients,64 although this study lacked a healthy control group. Rates of dependent, obsessive-compulsive, and borderline personality disorders have been reported to be higher in psoriasis than in chronic urticaria.65

SOMATIZATION AND SOMATOFORM DISORDERS Physical symptoms that cause distress and cannot be fully explained by a general medical condition, a phenomenon known as somatization, has also been reported to be increased in patients with psoriasis.7 Similarly, body dysmorphic disorder, an excessive concern for a defect in appearance even if slight, can be prevalent in patients with psoriasis.18

EATING DISORDERS A higher prevalence of binge eating, anorexia, and bulimia has been suggested in patients with psoriasis. These conditions may be found in conjunction with depression,

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but binge eating is also frequently seen in patients with psoriasis who have the metabolic syndrome.66

CONCLUSION Because psoriasis develops before the age of 30 in the majority of patients, it can play a large role in psychosocial development. The effect of psoriasis on body image should be assessed in context of the stage of development as younger patients may have greater difficulty adjusting to its effect on their appearance.27 Additionally, better education of the lay public is important to try to reduce the social stigmatization of psoriasis to reduce anxiety, social phobia, and avoidance that negatively impact social relationships in patients with psoriasis.3 One possible forum is health education classes that are part of school curricula. The incorporation of chronic, disfiguring diseases into the curricula could help reduce stigmatization of school children with psoriasis67 and would be knowledge that may hopefully be taken home and shared with parents and sibling, and could be carried into adulthood. Dermatologists need to be aware of the psychiatric comorbidities of psoriasis and take them into consideration when making management decisions as psychological interventions can have beneficial effects on both mental health and psoriasis.3 An assessment of the psychological aspects of psoriasis including mood, suicidal ideation, substance use, and sexual function should be performed along with the physical examination. If there is evidence of psychological morbidity, particularly depression or suicidal ideation, a referral to psychiatry should be made.5  Interventions including support groups, counseling, relaxation techniques, mindfulness meditation, CBT, and psychotropic medications can be beneficial for some patients.16,68,69 A multidisciplinary approach with a psychiatry liaison should be considered as this tactic has been shown to cause more pronounced improvements in psoriasis-related quality of life than dermatology care alone.35,70

REFERENCES 1. Magin P, Adams J, Heading G, Pond D, Smith W. The psychological sequelae of psoriasis: Results of a qualitative study. Psychol Health Med. 2009;14(2):150–161. 2. Hughes JE, Barraclough BM, Hamblin LG, White JE. Psychiatric symptoms in dermatology patients. Br J Psychiatry. 1983;143:51–54. 3. Rapp SR, Exum ML, Reboussin DM, Feldman SR, Fleischer A, Clark A. The physical, psychological and social impact of psoriasis. J Health Psychol. 1997;2(4):525–537. 4. Rapp SR, Feldman SR, Exum ML, Fleischer AB Jr, Reboussin DM. Psoriasis causes as much disability as other major medical disease. J Am Acad Dermatol. 1999;41:401–407.

5. Russo PA, Ilchef R, Cooper AJ. Psychiatric morbidity in psoriasis: A review. Australas J Dermatol. 2004;45(3):155–159. 6. Kirby B, Richards HL, Woo P, Hindle E, Main CJ, Griffiths CE. Physical and psychologic measures are necessary to assess overall psoriasis severity. J Am Acad Dermatol. 2001;45(1):72–76. 7. Schmitt J, Ford DE. Psoriasis is independently associated with psychiatric morbidity and adverse cardiovascular risk factors, but not with cardiovascular events in a population-based sample. J Eur Acad Dermatol Venereol. 2010;24(8):885–892. 8. Gupta MA, Gupta AK, Kirkby S, et al. A psychocutaneous profile of psoriasis patients who are stress reactors: A study of 127 patients. Gen Hosp Psychiatry. 1989;11:166–173. 9. Ginsburg IH, Link BG. Feelings of stigmatization in patients with psoriasis. J Am Acad Dermatol. 1989;20:53–63. 10. Gupta MA, Gupta AK, Kirkby S, et al. Pruritus in psoriasis. A prospective study of some psychiatric and dermatologic correlates. Arch Dermatol. 1988;124(7):1052–1057. 11. Ingram JT. The significance and management of psoriasis. Br Med J. 1954;2(4892):823–828. 12. Seville RH. Psoriasis and stress. Br J Dermatol. 1977;97(3):297–302. 13. Seville RH. Stress and psoriasis: The importance of insight and empathy in prognosis. J Am Acad Dermatol. 1989;20(1):97–100. 14. Kimball AB, Jacobson C, Weiss S, Vreeland MG, Wu  Y. The psychosocial burden of psoriasis. Am J Clin Dermatol. 2005;6(6):383–392. 15. Kabat-inn J, Wheeler E, Light T, et al. Influence of a mindfulness meditation-based stress reduction intervention on rates of skin clearing in patients with moderate to severe psoriasis undergoing phototherapy (UVB) and photochemotherapy (PUVA). Psychosom Med. 1998;60(5):625–632. 16. Fortune DG, Richard HI, Kirby B, Bowcock S, Main CJ, Griffiths CEM. A cognitive-­behavioural ­symptom management programme as an adjunct in  ­psoriasis   therapy. Br J Dermatol. 2002;146: 458–465. 17. D’Alton P. Psoriasis, mindfulness. ClinicalTrials.gov. Available from https://clinicaltrials.gov/ct2/show/ NCT02122978?term=psoriasis%2C+mindfulness&r ank=1. Accessed November 22, 2015. 18. Gupta MA, Gupta AK. Psychodermatology: An update. J Am Acad Dermatol. 1996;34:1030–1046. 19. Schneider G, Hockmann J, Ständer S, Luger TA, Heuft G. Psychological factors in prurigo nodularis in comparison with psoriasis vulgaris: Results of a case-control study. Br J Dermatol. 2006;154(1):61–66. 20. Jowett S, Ryan T. Skin disease and handicap: An analysis of the impact of skin conditions. Soc Sci Med. 1985;20:425–429.

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21. Richards HL, Fortune DG, Griffiths CE, Main CJ. The contribution of perceptions of stigmatisation to disability in patients with psoriasis. J Psychosom Res. 2001;50(1):11–15. 22. Jobling RG. Psoriasis—A preliminary questionnaire study of sufferers’ subjective experience. Clin Exp Dermatol. 1976;1(3):233–236. 23. Kent G, Keohane S. Social anxiety and disfigurement: The moderating effects of fear of negative evaluation and past experience. Br J Clin Psychol. 2001;40(Pt 1):23–34. 24. Fortune DG, Richards HL, Griffiths CE, Main CJ. Psychological stress, distress and disability in patients with psoriasis: consensus and variation in the contribution of illness perceptions, coping and alexithymia. Br J Clin Psychol. 2002;41(Pt 2):157–174. 25. Daudén E, Castañeda S, Suárez C, et al. Clinical practice guideline for an integrated approach to comorbidity in patients with psoriasis. J Eur Acad Dermatol Venereol. 2013;27(11):1387–1404. 26. Henley LA. Dealing with the disadvantaged: Psoriasis. Br Med J. 1981;282;1851–1852. 27. Gupta MA, Gupta AK. Depression and suicidal ideation in dermatology patients with acne, alopecia areata, atopic dermatitis and psoriasis. Br J Dermatol. 1998;139(5):846–850. 28. Esposito M, Saraceno R, Guinta A, Maccarone  M, Chimenti S. An Italian study on psoriasis and depression. Dermatology. 2006;212(2):123–127. 29. Hayes J, Koo J. Psoriasis: Depression, anxiety, smoking, and drinking habits. Dermatol Ther. 2010;23(2):174–180. 30. Gupta MA, Schork NJ, Gupta AK, Kirkby S, Ellis CN. Suicidal ideation in psoriasis. Int J Dermatol. 1993;32(3):188–190. 31. Gupta MA, Gupta AK. The use of antidepressant drugs in dermatology. J Eur Acad Dermatol Venereol. 2001;15:512–518. 32. Hemlock C, Rosenthal JS, Winston A. Fluoxetineinduced psoriasis. Ann Pharmacother. 1992; 26: 211–212. 33. Tamer E, Gur G, Polat M, Alli N. Flare-up of pustular psoriasis with fluoxetine: possibility of a serotoninergic influence? J Dermatolog Treat. 2009;20(3):1–3. 34. Gupta AK, Sibbald RG, Knowles SR, Lynde CW, Shear NH. Terbinafine therapy may be associated with the development of psoriasis de novo or its exacerbation: Four case reports and a review of drug-induced psoriasis. J Am Acad Dermatol. 1997;36:858–862. 35. D’Erme AM, Zaniere F, Campolmi E, et al. Therapeutic implications of adding the psychotropic drug escitalopram in the treatment of patients suffering from moderate-severe psoriasis and psychiatric comorbidity: A retrospective study. J Eur Acad Dermatol Venereol. 2014;28(2):246–249.

36. O’Brien SM, Scott LV, Dinan TG. Cytokines: Abnormalities in major depression and implications for pharmacological treatment. Hum Psychopharmacol. 2004;19:397–403. 37. Bassukas ID, Hyphantis T, Gamvroulia C, Gaitanis  G, Mavreas V. Infliximab for patients with plaque psoriasis and severe psychiatric comorbidity. J Eur Acad Dermatol Venereol. 2008;22(2): 257–258. 38. Menter A, Augustin M, Signorovitch J, et al. The effect of adalimumab on reducing depression symptoms in patients with moderate to severe psoriasis: A randomized clinical trial. J Am Acad Dermatol. 2010;62(5):812–818. 39. Tyring S, Gottlieb A, Papp K, et al. Etanercept and clinical outcomes, fatigue, and depression in psoriasis: Double-blind placebo-controlled randomised phase III trial. Lancet. 2006;367(9504):29–35. 40. Picardi A, Mazzotti E, Pasquini P. Prevalence and correlates of suicidal ideation among patients with skin disease. J Am Acad Dermatol. 2006;54(3): 420–426. 41. Cooper-Patrick L, Crum RM, Ford DE. Identifying suicidal ideation in general medical patients. JAMA. 1994;272:1757–1762. 42. Taylor GJ, Bagby RM, Parker JDA. Disorders of Affect Regulation. Cambridge: Cambridge University Press, 1997. 43. Torres-Hernández M, L ópez-García S, PedrozaEscobar D, Escamilla-Tilch M. The role of alexithymia as a psychosomatic factor in psoriasis. Rev Med Inst Mex Seguro Soc. 2015;53(3):268–272. 44. Paul C, Girolomoni G, Radtke Ma, et al. Impact of alexithymia and disease characteristics on work productivity and activity in psoriasis patients with short disease duration: Epidepso Multicentre Study. Value Health. 2015;18(7):A425–A426. 45. Richards HL, Fortune DG, Griffiths CE, Main CJ. Alexithymia in patients with psoriasis: Clinical correlates and psychometric properties of the Toronto Alexithymia Scale-20. J Psychosom Res. 2005;58(1):89–96. 46. Finlay AY, Coles EC. The effect of severe psoriasis on the quality of life of 369 patients. Br J Dermatol. 1995;132:236–244. 47. Poikolainen K, Reunala T, Karvonen J, Lauharanta J, Kärkkäinen P. Alcohol intake: A risk factor for psoriasis in young and middle aged men? BMJ. 1990;300(6727):780–783. 48. Naldi L, Peli L, Parazzini F. Association of early-stage psoriasis with smoking and male alcohol consumption: Evidence from an Italian case-control study. Arch Dermatol. 1999;135(12):1479–1484. 49. Poikolainen K, Karvonen J, Pukkala E. Excess mortality related to alcohol and smoking among hospital-treated patients with psoriasis. Arch ­ Dermatol. 1999;135(12):1490–1493.

172  Psychiatric comorbidities

50. Setty AR, Curhan G, Choi HK. Smoking and the risk of psoriasis in women: Nurses’ Health Study II. Am J Med. 2007;120(11):953–959. 51. Zhang X, Wang H, Te-Shao H, Yang S, Wang F. Frequent use of tobacco and alcohol in Chinese psoriasis patients. Int J Dermatol. 2002;41(10):659–662. 52. Sampogna F, Gisondi P, Tabolli S, Abeni D. Impairment of sexual life in patients with psoriasis. Dermatology. 2007;214(2):144–150. 53. Magin P, Heading G, Adams J, Pond D. Sex and the skin: A qualitative study of patients with acne, psoriasis and atopic eczema. Psychol Health Med. 2010;15(4):454–462. 54. Gupta MA, Gupta AK. Psoriasis and sex: A study of moderately to severely affected patients. Int J Dermatol. 1997;36:259–262. 55. Ryan C, Sadlier M, De Vol E, et al. Genital psoriasis is associated with significant impairment in quality of life and sexual functioning. J Am Acad Dermatol. 2015;72(6):978–983. 56. Goulding JM, Price CL, Defty CL, Hulangamuwa CS, Bader E, Ahmed I. Erectile dysfunction in patients with psoriasis: Increased prevalence, an unmet need, and a chance to intervene. Br J Dermatol. 2011;164(1):103–109. 57. Yang YW, Lin HC. Increased risk of psoriasis among patients with schizophrenia: A nationwide population-based study. Br J Dermatol. 2012;166(4):899–900. 58. Naudin J, Capo C, Guisano B, Merge JL, Azorin JM. A differential role of interleukin-6 and tumor necrosis factor-alpha in schizophrenia? Schizophr Res. 1997;26:227–233. 59. Di Nuzzo S, Zanni M, De Panfilis G. Exacerbation of paranoid schizophrenia in a psoriatic patient after treatment with cyclosporine A, but not with etanercept. J Drugs Dermatol. 2007;6(10): 1046–1047.

60. Ascari-Raccagni A, Baldari U, Rossi E, Alessandrini F. Exacerbation of chronic large plaque psoriasis associated with olanzepine therapy. J Eur Acad Dermatol Venereol. 2000;14(4):315–316. 61. Latini A, Carducci M. Psoriasis during therapy with olanzapine. Eur J Dermatol. 2003;13(4):404–405. 62. Hardy GE, Cotterill JA. A study of depression and obsessionality in dysmorphophobic and psoriatic patients. Br J Psychiatry. 1982;140:19–22. 63. Fukunishi I, Berger D. Comment on “Personality disorders and psychiatric symptoms in psoriasis”: A critical analysis. Psychol Rep. 1996;78(3 Pt 2):1265–1266. 64. Rubino IA, Sonnino A, Pezzarossa B, Ciani N, Bassi R. Personality disorders and psychiatric symptoms in psoriasis. Psychol Rep. 1995;77(2):547–553. 65. Rubino IA, Zanna V. Further comments on psoriasis and personality disorders. Psychol Rep. 1996;79(3 Pt 2):1248–1250. 66. Altunay I, Demirci GT, Ates B, et al. Do eating disorders accompany metabolic syndrome in psoriasis patients? Results of a preliminary study. Clin Cosmet Investig Dermatol. 2011;4:139–143. 67. Ryan C, Korman NJ, Gelfand JM, et al. Research gaps in psoriasis: Opportunities for future studies. J Am Acad Dermatol. 2014;70(1):146–167. 68. Abel E, Moore US, Glathe JP. Psoriasis patient support group and self-care efficacy as an adjunct to day care center treatment. Int J Dermatol. 1990;29:640–643. 69. Barankin B, DeKoven J. Psychosocial effect of common skin diseases. Can Fam Physician. 2002;48:712–716. 70. Schmitt J, Wozel G, Garzarolli M. Effectiveness of interdisciplinary vs. dermatological care of moderate-to-severe psoriasis: A pragmatic ran­ domised controlled trial. Acta Derm Venereol. 2014;94(2):192–197.

18 Other disease associations: Liver, gastrointestinal, respiratory, and neoplastic NANCY PODOSWA INTRODUCTION Over the last decade, the concept of psoriasis has evolved from being considered a pure cutaneous disease to a chronic inflammatory skin disease with a risk of systemic comorbidities. A wide constellation of comorbid conditions virtually affecting every system has been reported. In this chapter, we review the comorbidities affecting the gastrointestinal system, the liver, the lung, and finally, the association of psoriasis with neoplastic disorders.

the clinical variants of psoriasis have presented the abovementioned association, particularly the pustular forms, and some authors have postulated that psoriasis is associated with IBD and constitutes a different clinical group in which the disease presents distinctive characteristics as more severe cutaneous forms, higher prevalence of psoriatic arthritis, high titers of systemic inflammatory markers, and an increased risk of autoimmune comorbidity.

Genetic correlations GASTROINTESTINAL COMORBIDITY

Different lines of evidence including observational and genetic studies have demonstrated an epidemiological, genetic, environmental, and immunological relation between psoriasis and inflammatory bowel disease (IBD).

Data from genome-wide association studies (GWAS) have identified several susceptibility loci and genes that are shared by both diseases. The most important correlations described so far include polymorphisms at loci 6p22, 16q, Ip31, and 5q33. Some of the genes in these loci are involved in the regulation of the innate immune responses and may be associated with other diseases also prevalent in psoriasis and IBD-like type II diabetes mellitus.13–15

Epidemiological correlation

Pathologic correlations

Both diseases can present more often in the same person than would be expected if the diseases were mutually exclusive. Several studies from different countries have reported a marked increase (four to six times) in the prevalence of psoriasis in patients with IBD compared with the general population.1–8 This association has also been described in children9,10 and even in Asia, where the prevalence of both psoriasis and IBD is very low, the correlation between psoriasis and IBD has been documented.11 Also a higher incidence of psoriasis is reported in first-degree relatives of patients with IBD. This association is stronger between psoriasis and Crohn’s disease than in psoriasis and ulcerative colitis.9 Conversely patients with psoriasis and psoriatic arthritis present an increased prevalence of IBD and families of psoriatic patients are more likely to be affected by psoriasis, IBD, or different autoimmune diseases.3,12 All

Psoriasis and IBD share several immune pathogenic mechanisms that include dysregulation of innate and adaptive immune responses with activation of different effector cells and release of multiple cytokines, and chemokines that trigger and sustain pathological processes at cutaneous and intestinal levels. Both present with some similarities in regards to flare ups, and the wide therapeutic overlap between them supports the concept of a strong pathophysiological link between psoriasis and IBD.16,17

Inflammatory bowel disease

CELIAC DISEASE Numerous studies have demonstrated an association between celiac disease and psoriasis, reporting a higher prevalence of celiac disease among psoriatic patients 173

174  Other disease associations: Liver, gastrointestinal, respiratory, and neoplastic

compared with controls.18–22 Furthermore, there are also reports of a higher prevalence of serological markers of celiac disease in patients with psoriasis including antigliadin, antitransglutaminase, and antiendomyseal antibodies. Some studies have reported a correlation between the presence of higher titers of these antibodies and the severity of the disease, and an improvement of the disease on gluten-free diets.23–31 Also, as would be expected, there have been reports on the co-occurrence of dermatitis herpetiformis and psoriasis.32,33

MICROSCOPIC COLITIS The term “microscopic colitis” was initially coined in the 1980s to describe a noninfectious chronic diarrheal disease characterized by histological changes in the presence of endoscopically normal or near normal mucosa. It is an inflammatory condition of the colon of unknown etiology and currently includes two histologically distinct entities, termed lymphocytic colitis and collagenous colitis. The disease is presented clinically with watery diarrhea, crampy abdominal pain, nausea, and weight loss, and, as mentioned, it requires histological demonstration of specific abnormalities of the endothelial colonic mucosa for its diagnosis. As opposed to what is seen in IBD, extraintestinal manifestations are rare in microscopic colitis. 34,35 Of particular interest and clinical importance is the association between microscopic colitis and celiac sprue and other autoimmune diseases like rheumatoid arthritis, thyroiditis, polymyalgia rheumatic, and spondyloarthropathies. In recent years, there have been several reports on the association of microscopic colitis, either lymphocytic or collagenous, with psoriasis and psoriatic arthritis.36–40

ALTERATIONS IN INTESTINAL STRUCTURE AND PERMEABILITY It has been postulated that alterations in intestinal structure and function in psoriasis play an important role in the physiopathology of the disease. Some studies have demonstrated structural abnormalities in the intestinal tract as well as increased intestinal permeability in patients with psoriasis and psoriatic arthritis. Among the structural abnormalities reported are thinning of the mucosa and atrophy of the villi as well as an increase in intraepithelial cellularity with lymphocytic and eosinophilic infiltrates.41–45 Based on these findings, a hypothesis has emerged stating that alterations in intestinal epithelium of psoriatic patients lead to increased intestinal permeability allowing large molecules to be absorbed and gain access to the circulation through the lymphatic system. These molecules will be deposited in the skin and will act as antigens triggering an immune response that culminates in the production of cutaneous lesions. Subclinical gut inflammation has also been specifically cited as a likely causative

factor in spondyloarthropaties and certain forms of psoriatic arthritis.46–49

LIVER Nonalcoholic fatty liver disease Regarded as the hepatic manifestation of the metabolic syndrome, and an independent risk factor for cardiovascular disease, nonalcoholic fatty liver disease (NAFLD) is defined as the excessive accumulation of fatty deposits in the liver in the absence of a history of excessive alcohol intake. The term encompasses a broad spectrum of liver pathology that ranges from a harmless fatty deposit (steatosis simplex) to a progression of steatosis associated with inflammatory changes (nonalcoholic steatohepatitis [NASH]), and finally the development of potentially lethal conditions such as hepatic fibrosis, cirrhosis, and hepatic carcinoma. NAFLD is the most common cause of abnormal serum liver enzymes in Western countries and affects up to one-third of the general population. It is estimated that by 2020 it will be the leading cause for hepatic transplants.50–54 Several case reports and observational studies have reported a marked increase in the prevalence of NAFLD in patients with psoriasis versus controls, and this d ­ ifference has remained significant after controlling for confounding factors, such as body mass index (BMI), gender, sex, and alcohol consumption. A positive correlation has been established between the prevalence of NAFLD and disease severity, presence of psoriatic arthritis and higher disease activity scores. The prevalence of NAFLD was also higher among psoriatic patients who presented with the metabolic syndrome.55–60 Another study demonstrated a higher prevalence of NAFLD even in milder forms of the disease.61 This increased prevalence might explain the propensity of psoriatic patients to develop methotrexate-induced hepatotoxicity. To date, with this information, it is advisable to include a liver ultrasound in the diagnostic work-up previous to treatment with potentially liver hepatotoxic drugs of patients with moderate-to-severe psoriasis.62

CHOLANGITIS AND CHOLESTASIS A series of cases of liver involvement with altered liver function tests, cholestasis, jaundice, and neutrophilic cholangitis have been reported in association with generalized pustular psoriasis, von Zumbusch type, usually paralleling the severity and the course of the skin disease.63–67

PSORIASIS AND LUNG COMORBIDITY Although not very common, several reports have demonstrated an association between psoriasis and many different lung diseases.

Psoriasis and cancer  175

INFECTIOUS PNEUMONIA Few studies have explored the relationship between psoriasis and acute infections. These studies have shown that psoriatic patients are more likely to acquire infectious diseases and have excess rates of bacterial and viral infection including pneumonia. A recent study has shown that patients with psoriasis were 1.5 times more likely to be hospitalized for pneumonia than controls. The higher risk was positively correlated to psoriasis severity, and these observations have been explained by dysregulation of the immune system with increased serum levels of multiple proinflammatory cytokines that have been associated with the incidence of pneumonia, the use of systemic therapy, and the presence of comorbidities that may affect susceptibility to infections.68–70

INTERSTITIAL LUNG DISEASE The term interstitial lung disease (ILD) comprises many different lung conditions that affect the lung interstitium causing it to thicken and impairing gas exchange. Some forms of ILD are short lived; others are chronic and irreversible. Interstitial pneumonia, nonspecific interstitial pneumonitis, and organizing pneumonia are some of the types of ILD. Although infections, drugs, environmental factors, and autoimmune disease can cause ILD, the cause of most ILD is unknown. ILD is an increasingly recognized complication of chronic inflammatory diseases including psoriasis. Diagnosis of these diseases can be challenging since many diseases such as infection, drugs, and so on can mimic ILD, creating diagnostic dilemmas. Generally, a biopsy is necessary to confirm the diagnosis and many of them require administration of systemic steroids. ILD is a debilitating disease with a high morbidity and mortality and strong negative impact on the quality of life.71–75

PULMONARY FIBROSIS Pulmonary fibrosis is a well-known complication  of the s­pondyloarthropathies, particularly ankylosing ­spondylitis,76,77 and it is thought that its development is related to an altered immune response present in chronic immune diseases that activate profibrotic pathways. Although few cases of apical pulmonary fibrosis have been reported in psoriasis, a psoriatic arthritis it is important to consider this occurrence, especially in the context of the work-up for biologic treatment where ruling out latent tuberculosis is mandatory.78

CHRONIC OBSTRUCTIVE PULMONARY DISEASE Large population-based studies have demonstrated an increase in prevalence of chronic obstructive pulmonary disease (COPD) in psoriatic patients. This increase has been shown to be independent of the presence of psoriatic

arthritis and has been demonstrated even in mild forms of the disease. Also an increase in the future risk for development of COPD has been demonstrated in patients with psoriasis with significant lower COPD-free survival rates compared with controls. Of note are the limitations in these studies that did not control for other confounding factors that can influence the development of COPD like the presence of the metabolic syndrome. Dermatologists caring for patients with psoriasis should be aware of this association, approach these patients in a multidisciplinary manner by consulting an internist or pulmonologist, and advise the patients to stop smoking and reduce additional risk factors for COPD in order to potentially reduce comorbidity and mortality.79–82

PULMONARY HYPERTENSION An increased incidence in mild pulmonary hypertension has been reported in patients with psoriasis and an inflammatory/autoimmune pathogenesis with increased BMI, endothelial dysfunction, increased in procoagulant activity, and platelet activation has been suggested.83

ACUTE RESPIRATORY DISTRESS SYNDROME Acute respiratory distress syndrome, also known as sterile pneumonitis or acute interstitial pneumonia, refers to the development of a noncardiogenic pulmonary edema associated with hypoxia. The syndrome is attributed to increased capillary permeability and has been associated with the severe forms of psoriasis (erythrodermic and generalized pustular forms). Dermatologists should be aware of this condition as it is potentially lethal, must be differentiated from other diseases (infections, congestive heart failure, hypersensitivity drug reaction), and requires early treatment with high-dose systemic corticosteroids.

PSORIASIS AND CANCER The association between psoriasis and cancer has been studied for a long time. Numerous studies have been conducted addressing this relation and the majority of them have encountered a positive correlation between psoriasis and an increased risk of developing different neoplasms, including cutaneous, hematological, and solid cancers.84–89 Also a link between a longer duration, severe forms of the disease, and the risk of development of certain cancers has been suggested.90,91 However, many of these studies present different biases including short periods of follow-up, small size samples, selection of subgroups, and no adjustment for several confounding factors such as smoking, alcohol consumption, other health-related habits and lifestyles, BMI, exposition to environmental factors, and so on. Evidence is convincing for nonmelanoma skin cancer, especially for squamous cell carcinoma, and the increased incidence is related mainly to treatments. Lower incidence

176  Other disease associations: Liver, gastrointestinal, respiratory, and neoplastic

for basal carcinomas have been reported and the studies have not shown an increased incidence of melanoma.92–94 Of note is the fact that the incidence of cutaneous cancers is far less than expected, despite the fact that psoriatic plaques are continually exposed to numerous topical and systemic carcinogens. This has resulted in a hypothesis that psoriasis might present a cancer-resistant factor.95,96 Regarding hematological neoplasm, only a small positive correlation has been reported with non-Hodgkin lymphoma.97–99 Increased prevalence of different solid cancers has been reported in association with psoriasis but after controlling for confounding factors, only a small but statistically significant correlation has been reported between psoriasis and colon cancer.100–107

CONCLUSIONS Comorbid diseases are common in psoriatic patients and have important clinical implications as they may pose unique challenges in differential diagnosis, and in designing proper care, surveillance, and treatment. Physicians taking care of these patients have a unique opportunity in making early diagnosis of these comorbidities as well as in taking actions aimed at reducing risks, improving clinical outcomes and quality of life.

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gliadin results in decreased expression of tissue transglutaminase and fewer Ki 67*+ cells in the dermis. Acta Derm Venereol. 2003;83:425. 28. Addolorato G, Pariente A, de lorenzi G, et al. Rapid regression of psoriasis in a coeliac patients after gluten free diet. Digestion. 2003;68:9–12. 29. Michaëlsson G, Gerden B, Hagforsen E, et al. Psoriasis patients with antibodies to gliadin can be improved by a gluten-free diet. Br J Dermatol. 2000;142:44–51. 30. Wolters M. Diet and psoriasis: Experimental data and clinical evidence. Br J Dermatol. 2005;153:706–714. 31. Woo W, Mc Millan S, Watson R, et al. Coeliac ­disease-associated antibodies correlate with psoriasis activity. Br J Dermatol. 2004;151:891–894. 32. Agusti-Mejiasa A, Messeguerb F, García-Ruiza R, et  al. Concomitant dermatitis herpetiformis and plaque psoriasis: Possible skin manifestations of celiac disease. Actas Dermosifiliog. 2011;102:471–473. 33. Gkalpakiotis S, Sticova E Arenbergerova M, et al. Dermatitis herpetiformis Duhring as a rare comorbidity of psoriasis in a patient on biologic therapy. J Am Acad Dermatol. 2013;68(Suppl1):AB196. 34. Parkes M. Microscopic colitis. Medicine. 2015; 43:291–292. 35. Pardi DS. Microscopic colitis. Clin Ger Med. 2014;30:55–65. 36. Wiedermann CJ, Zelger A. Lymphocytic colitis in a patient with psoriasis responsive to budesonide. Scand J Gastroenterol. 2007;42:538–539. 37. Azzouz D, Gargouri A, Hamdi V, et al. Coexistance of psoriatic arthritis and collagenous colitis with inflammatory nervous system disease. Join Bone Spine. 2008;75:624–625. 38. Wiedermann CJ, Zagler B. Reduced watery diarrhea during pregnancy in a psoriasis patient with lymphocytic colitis. Z Gastroenterol. 2008;46:1275–1277. 39. Taccari E, Spada S, Giuliani A, et al. Co-occurrence of psoriatic arthritis with collagenous colitis: Clinicopathologic findings of a case. Clin Rheumatol. 2002:21:335–338. 40. Scarpa R, Manguso F, D’Arienzo A, et al. Microscopic inflammatory changes in colon of patients with both active psoriasis and psoriatic arthritis without bowel symptoms. J Rheumatol. 2000;27:1241–1246. 41. Shuster S, Marks J. Psoriatic enteropathy, a new cause of steatorrhoea. Lancet. 1965;1:1367–1368. 42. Barry RE, Salmon PR, Read AE, Warin RP. Mucosal architecture of the small bowel in cases of psoriasis. Gut. 1971;12:873–877. 43. Barry RM, Salmon PR, Read AE. Small bowel mucosal changes in psoriasis. Gut. 1971;12:495. 44. Schatteman L, Mielants H, Veys EM, et al. Gut inflammation in psoriatic arthritis: A prospective ileocolonoscopic study. J Rheumatol. 1995;22:680–683. 45. Lindqvist U, Kristjánsson G, Pihl-Lundin I, et al. Patients with psoriatic arthritis have an increased number of lymphocytes in the duodenal mucosa in

comparison with patients with psoriasis vulgaris. J Rheumatol. 2006;33:924–927. 46. Hamilton I, Fairris GM, Rothwell J, et al. Small intestinal permeability in dermatological disease. Ann Dermatol Venereol. 2012;139 (Suppl 2):S46–D52. 47. Humbert P, Bidet A, Treffel P, et al. Intestinal permeability in patients with psoriasis. J Dermatol Sci. 1991;2:324–326. 48. Hendel L, Hendel J, Johnsen A, Gudmand-Hoyer E. Intestinal function and methotrexate absorption in psoriatic patients. Clin Exp Dermatol. 1982;7:491–498. 49. Mcmillin DL, Richards DG, Mein EA, Nelson CD. Systemic aspects of psoriasis. An integrative model based on intestinal etiology. Integr Med. 2000; 2:105–113. 50. Hamaguchi M, Kojima T, Takeda N, et al. The metabolic syndrome as a predictor of nonalcoholic liver disease. Ann Intern Med. 2005;143:722–728. 51. Adams LA, Angulo P, Lindor KD. Nonalcoholic fatty liver disease. CMAJ. 2005;172:899–905. 52. de Alwis NM, Day CP. Non-alcoholic fatty liver disease: The mist gradually clears. J Hepatol. 2008;48:S104–S112. 53. Marchesini G, Marzocchi R, Agostini F, Bugianesi E. Nonalcoholic fatty liver disease and the metabolic syndrome. Curr Opin Lipidol. 2005;16:421–427. 54. Kotronen A, Yki-Ja¨rvinen H. Fatty liver: A novel component of the metabolic syndrome. Arterioscler Thromb Vasc Biol. 2008;28:27–38. 55. Gisondi P, Del Giglio M, Cozzi A, Girolomoni G. Psoriasis, the liver, and the gastrointestinal tract. Dermatol Ther. 2010;23:155–159. 56. Candia R, Ruiz A, Torres Robles R, et al. Risk of nonalcoholic fatty liver disease in patients with psoriasis: A systematic review and meta-analysis. J Eur Acad Dermatol Venereol. 2015;29:656–662. 57. Roberts KK, Cochet AE, Lamb PB, et al. The prevalence of NAFLD and NASH among patients with psoriasis in a tertiary care dermatology and rheumatology clinic. Aliment Pharmacol Ther. 2015;41:293–300. 58. Wenk KS, Arrington KC, Ehrlich A. Psoriasis and non-alcoholic fatty liver disease. J Eur Acad Dermatol Venereol. 2011;25:383–391. 59. Leonardo A, Loria P, Carulli N. Concurrent nonalcoholic steatohepatitis and psoriasis. Report of three cases from the POLI.ST.E.N.A. study. Dig Liver Dis. 2001;33:86–87. 60. Matsumoto T, Suzuki N, Watanabe H, et al. Nonalcoholic steatohepatitis associated with psoriasis vulgaris. J Gastroenterol. 2004;39:1102–1105. 61. Van der Voort EAM, Koehler EM, Dowlatshahi EA, et al. Psoriasis is independently associated with nonalcoholic fatty liver disease in patients over 55 years old or older: Results from a population-based study. J Am Acad Dermatol. 2014;70:517–524. 62. Langman G, Hall PM, Todd G. Role of non-alcoholic steatohepatitis in methotrexate-induced liver injury. J Gastroenterol Hepatol. 2001;16:1395–1401.

178  Other disease associations: Liver, gastrointestinal, respiratory, and neoplastic

63. Viguier M, Allez M, Zagdanski AM, et al. High frequency of cholestasis in generalized pustular psoriasis: Evidence for neutrophilic involvement of the biliary tract. Hepatology. 2004;40:452–458. 64. Allez M, Roux ME, Bertheau P, et al. Recurrent cholestatic jaundice associated with generalized pustular psoriasis: Evidence of a neutrophilic colangitis. J Hepatol. 2000;33:160–162. 65. Aronsson A, Nilsson A. Pustular psoriasis of v. Zumbusch type associated with recurring cholestatic jaundice. Acta Dermato-venereologica. 1986;66(2):164–167. 66. Nisha SC, Chong W-S. A dramatic response to a single dose of infliximab as rescue therapy in acute generalized pustular psoriasis of von Zumbusch associated with a neutrophilic colangitis Australas. J Dermatol. 2010;51:29–31. 67. Li SP, Tang WY, Lam WY, Wong SN. Renal failure and cholestatic jaundice as unusual complications of childhood pustular psoriasis. Br J Dermatol. 2000;143:1292–1296. 68. Lindegard B. Diseases associated with psoriasis in a general population of 159,200 middle-aged, urban, native Swedes. Dermatologica. 1986;172:298–304. 69. Wakkee M, de Vries E, van den Haak P, et al. Increased risk of infectious diseases requiring hospitalization among patients with psoriasis: A population-based cohort. J Am Acad Dermatol. 2011;65:1135–1144. 70. Kao L-T, Lee C-Z, Liu S-P, et al. Psoriasis and the risk of pneumonia: A population-based study. PLoS One. 2014;9:e116077. 71. Jürgen B. Approach to diagnosis of interstitial lung disease. Clin Chest Med. 2012;33:1–10. 72. Travis W, Costabel U, Hansell D, et al. An official American Thoracic Society/European Respiratory Society statement: Update of the international multidisciplinary classification of the idiopathic interstitial pneumonias. Am J Respir Crit Care Med. 2013;188:733. 73. Penizzotto M, Retegui M, Arrien-Zucco MF. Organizing pneumonia associated with psoriasis. Arch Bronconeumol. 2010;46:206–212. 74. Weber NK, Elston CM, O’Toole EA. Generalized pustular psoriasis and cryptogenic organizing pneumonia. Br J Dermatol. 2008;158:853–854. 75. Tokunaga T, Ohno S, Tajima S, et al. Usual interstitial pneumonia associated with psoriasis vulgaris. Nihon Kokyuki Gakkai Zasshi. 2002;40:692–696. 76. Quismorio F. Pulmonary involvement in ankylosing spondylitis. Curr Opin Pul Med. 2006;12:342. 77. Kanathur N, Lee-Chiong T. Pulmonary manifestations of ankylosing spondylitis. Clin Chest Med. 2010;3:547–554. 78. Bourke S, Campbell J, Henderson AF, et al. Apical fibrosis in psoriasis. Br J Dis Chest. 1988;82:444–446. 79. Dreiher J, Weitzman D, Shapiro J, et al. Psoriasis and chronic obstructive pulmonary disease: A case–­ control study. Br J Dermatol. 2008;159:956–960.

80. Chiang Y-Y, Lin H-W. Association between psoriasis and chronic obstructive pulmonary disease: A ­population-based study in Taiwan. J Eur Acad Dermatol Venereol. 2012;26:59–65. 81. Kim N, Thrash B, Menter A. Comorbidities in psoriasis patients. Semin Cutan Med Surg. 2010; 29(1):10–15. 82. Al-Mutairi N, Al-Farag S, Al-Mutairi A, Al-Shiltawy M. Comorbidities associated with psoriasis: An experience from the Middle East. J Dermatol. 2010 Feb;37(2):146–155. 83. Gunes Y, Tuncer M, Calka, et al. Increased frequency of pulmonary hypertension in psoriasis patients. Arch Dermatol Res. 2008;300:435–440. 84. Lindelof B, Eklund G, Linden S, Stern RS. The prevalence of malignant tumors in psoriasis. J Am Acad Dermatol. 1990;22:1056–1060. 85. Olsen JH, Moller H, Frentz G. Malignant tumor in patients with psoriasis. J Am Acad Dermatol. 1992;27:716–722. 86. Stern RS, Vakeva LH. Noncutaneous malignant tumors in the PUVA follow-up study: 1975–1996. J Invest Dermatol. 1997;108:897–900. 87. Frentz G, Olsen J. Malignant tumors and psoriasis: a follow-up study. Brit Assoc Dermatol. 1999;140:237–242. 88. Hannuksela-Svahn A, Pukkala E, Laara E, et al. Psoriasis, its treatment, and cancer in a cohort of Finnish patients. J Invest Dermatol. 2000;114: 587–590. 89. Boffetta P, Gridley G, Lindelöf B. Cancer risk in a population based cohort of patients hospitalized for psoriasis in Sweden. J Invest Dermatol. 2001;117:1531–1537. 90. Margolis D, Bilker W, Hennessy S, et al. The risk of malignancy associated with psoriasis. Arch Dermatol. 2001;137:778–783. 91. Brauchli YB, Jick SS, Miret M, Meier CR. Psoriasis and risk of incident cancer: An inception cohort study with a nested case control analysis. J Invest Dermatol. 2009;129.2604–2612. 92. Stern RS, Nichols KT, Vakeva LH. Malignant melanoma in patients treated for psoriasis with methoxsalen (psoralen) and ultraviolet A radiation (PUVA). The PUVA Follow-Up Study. N Engl J Med. 1997;336:1041–1045. 93. Stern RS, Liebman EJ, Vakeva LH. Oral psoralen and ultraviolet-A light (PUVA) treatment of psoriasis and persistent risk for nonmelanoma skin cancer, PUVA Follow-Up Study. J Natl Cancer Inst. 1998;90:1278–1284. 94. Naldi L, Malignancy concern with psoriasis treatments using phototherapy, methotrexate, cyclosporine, and biologics: Facts and controversies. Clin Dermatol. 2010;28:88–92. 95. Shuster S, Chapman PH, Rawlings MD. Psoriasis and cancer. Br Med J. 1979;1:941–942.

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96. Nickoloff BJ. Creation of psoriatic plaques: The ultimate tumor suppressor pathway. A new model for an ancient T-cell mediated skin disease. Viewpoint. J Cutan Pathol. 2001;28:57–64. 97. Gelfand JM, Shin DB, Neimann AL, et al. The risk of lymphoma in patients with psoriasis. J Invest Dermatol. 2006;126:2194–2201. 98. Gelfand JM, Berlin J, Van Voorhees A, Margolis DJ. Lymphoma rates are low but increased in patients with psoriasis: Results from a population-based cohort study in the United Kingdom. Arch Dermatol. 2003;139:1425–1429. 99. Stern RS. Lymphoma risk in psoriasis: Results of the PUVA Follow-Up Study. Arch Dermatol. 2006;142:1132–1135. 100. Chen Y-J, Wu Y, Chen T-J, et al. The risk of cancer in patients with psoriasis: A population-based cohort study in Taiwan. J Am Acad Dermatol. 2011;65:84–91. 101. Rokehar S, Tom BDM, Hassa A, et al. Prevalence of malignancy in psoriatic arthritis. Arthritis Rheum. 2008;58:82–87.

102. Alderson MR, Clarke JA. Cancer incidence in patients with psoriasis. Br J Cancer. 1983;47:857–859. 103. Prinzment AE, Alonso A, Folson AR, et al. Association between psoriasis and incident cancer: The Iowa´s Women’s Health Study. Cancer Causes Control. 2011;22:1003–1010. 104. Maleszka R, Paszkowka-Szczur K, Soczawa W, et  al. Psoriasis vulgaris and familial cancer risk: A ­population-based study. Her Cancer Clin Practice. 2013; 11:6. 105. Ji J, Shu X, Sundqvist K, et al. Cancer risk in hospitalized psoriasis patients: A follow up study in Sweden. Brit J Can. 2009;100:1499–1502. 106. Pouplard C, Brenaut E, Horreau C, et al. Risk of cancer in psoriasis: A systematic review and meta-­ analysis of epidemiological studies. J Eur Acad Dermatol Venereol. 2013;27:36–46. 107. Beyaert R, Beaugerie L, Van Assche G, et al. Cancer risk in immune-mediated inflammatory diseases. Mol Cancer. 2013;12:98.

19 Assessment and measurement of disease JORDAN M. THOMPSON and ABRAR A. QURESHI INTRODUCTION Psoriasis is extraordinarily variable in presentation, both within and between patients. As such, the assessment and measurement of disease presents a challenge to both clinicians and researchers. Psoriasis can present with different areas of bodily involvement, different levels of severity, distinct responses to treatment, and variable degrees of impact on a patient’s quality of life (QoL). Assessment of these many aspects is of great importance, as the implications on treatment and prognosis are significant, most importantly for the patient, but also for the allocation of progressively rationed resources within today’s health care economy. Both our understanding and definitions of burden and severity of disease have significantly evolved in the past 50 years, giving rise to an exceptional number of formal clinical measurement instruments. This chapter provides a focused overview of the most significant developments in psoriatic disease assessment and measurement and will begin with a discussion of the most essential components of disease assessment for the practicing clinician.

A brief but thorough assessment of the physical components is then combined with a general inquiry on the impact of disease on a patient’s physical, emotional, and professional well-being, all in efforts to determine the severity of a given patient’s disease, and to then guide the decision of treatment modality. With future visits, it is especially important to characterize these variables by way of change over time and in response to treatment. Thus, the clinician can determine patient satisfaction with current treatment and whether any changes are needed in the regimen. Although most of today’s treating clinicians take this less formal subjective approach, we should note that many of the previous and new formal disease measurement tools are being streamlined and could be used in clinical practice. Furthermore, new approaches to the assessment of physical disease are moving toward truly objective quantitative measurement. These noninvasive tools include high-frequency ultrasound and optical coherence tomography among many others.2 These tools remain a topic of research though some have promise as potentially efficient and cost-effective tools that might eventually find their way into routine clinical practice.

Assessment in day-to-day practice Practicing clinicians are well acquainted with the increasing importance of time efficiency in a busy clinic. It deserves mention then, that while we provide in this chapter a discussion of complex tools of disease assessment, the typical assessment of a psoriatic patient in the clinic might not make use of all such tools. Instead, the experienced clinician less formally assesses many of the same formal graded elements appearing in these measurement tools and thus makes an overall subjective global assessment of disease. A detailed history of the patient’s disease, with onset, history of flares, and symptom severity is essential. Then, estimates and descriptions should be made of body surface area (BSA) and locations of involvement, of the degree of scaling, erythema, plaque thickness, and itching, and of the presence or absence of psoriatic arthritis (PsA).1

The importance of thorough measurement and assessment Proper disease measurement has an essential role in diagnosis and initial assessment, but also for the selection of psoriasis therapeutics. In fact, a recent survey of over 5000 psoriatic patients revealed that over 50% were dissatisfied with treatment, and 49% of mild psoriatic patients were completely untreated.3 The therapeutic ladder for psoriasis is complex with topical corticosteroids, retinoids, vitamin D analogs, phototherapy, and systemic and biologic agents. The ideal choice among these or even combination, thereof, is especially predicated on a thorough assessment and measurement of disease involvement. To illustrate this point, an extensive area of involvement might obviate phototherapy as an ideal treatment 181

182  Assessment and measurement of disease

modality. On the other hand, a particular area of surface involvement, such as the face or genitals, might steer the clinician away from high-potency corticosteroids. Additionally, should psoriasis in that area become particularly painful, or burdensome, systemic treatment might be considered, even though a small area is involved. Not only is it clinically reasonable to consider measurement of disease in designing treatment regimens, clinicians are often economically bound to such assessments by third-party payers. For example, prior authorization forms from health insurers require certain degrees of BSA involvement for the use of specific therapies, such as 10% BSA for biologic agents. Moreover, insurance companies are also interested in improvements in BSA in their approvals of payment for continued treatment. Considering a total yearly estimated cost of $35.2 billion, or $6422 per patient attributed to psoriasis, it is economically prudent for patients, insurance companies, and society at large to use informed disease assessments to guide care.4,5 Thorough assessment of disease is not only important for currently available therapeutics, but also for the design of new drugs. Indeed, this was the initial impetus for the design of the Psoriasis Area Severity Index (PASI) scoring system, and many scoring systems to follow. These more formal tools of measurement allow for detailed, quantitative scoring and observation of response to change with a new drug both alone, and in comparison with current treatments.

Body surface area: A misunderstood variable of assessment BSA is one of the most commonly utilized elements of disease measurement and assessment, but unfortunately it is plagued by inconsistencies in implementation. For psoriasis, BSA is usually estimated using the hand of the patient to represent a percentage of BSA involvement. Confusion arises, though, as to whether one should use the palm surface alone, or to also include the finger surfaces. A survey of surgery residents in the United Kingdom illustrated the confusion, with significant inconsistencies among respondents.6 Much of the confusion is owed to contradictory teachings in the literature, with some works professing the entire hand surface as 1% BSA, with others insisting the palm alone as 1% BSA.7,8 The truth is that neither represents 1% BSA. A recent meta-analysis sought to clarify the confusion once and for all. Using 14 studies of hand surface area (HSA) and correlating them with strict objective BSA calculations, authors determined that palm surface area, not including the fingers, is the most reliable method, equating to 0.5% of BSA. Total hand surface was less reliable, but equated to 0.9% for men and 0.85% for women, with significant variability depending on body mass index (BMI) and race. Not only then does use of HSA as 1% overestimate BSA, but if erroneously used for the palm alone, as recommended by past authorities, overestimations of disease involvement

are even greater.9 The other most commonly used estimate of BSA is known as the “rule of nines.” This system assigns 9% BSA to each of the head and neck, arm, anterior leg, posterior leg, trunk quadrants, and 1% for the genitalia.10

CLINICIAN-ASSESSED MEASUREMENT TOOLS An impressive number of clinical severity and outcome measures exists for psoriasis. A recent review identified some 53 separate measures.11 No one tool is capable of assessing each and every aspect of disease, though as we will discuss, new tools seek a more comprehensive approach combining clinician assessment and patientreported outcomes. However, given the complexity of psoriasis, an inherent compromise will always exist between creation of a tool that is thorough, yet simplistic and administered in a practical time frame. Because of inherent time compromises, each psoriasis assessment tool tends to have a particular focus, and therefore, a specific application—for example, in measuring current disease, or in response to change. Therefore, some are more clinic friendly, whereas others find use primarily in the research setting. The ideal measurement tool should demonstrate strong reliability, validity, as well as a sensitivity to change over time.12 In Table 19.1, we discuss a selection of the most common tools to equip clinicians with a framework for the interpretation of literature and clinical trial data, or potentially for use in suitable clinical settings.11,13,14–27

Psoriasis area and severity index The first and most well-known measurement tool, the PASI, debuted in 1978 to assess retinoid treatment for psoriasis. This tool has become quintessential measurement tool, through its use in countless clinical trials. Given its historical use, the PASI allows for comparison of new therapeutics against decades of past data. When administering the PASI, four regions including the head, upper limbs, trunk, and lower limbs including buttocks are each assessed by way of a 0–4 severity scale, for each of erythema, induration, and scaling. The sum of these three scores for each body area is then multiplied by the surface area represented by that region of the body (0.1, 0.2, 0.3, and 0.4, respectively). Next, the summative score is multiplied by a 0–6 score, used to estimate percentage involvement in that specific area (e.g., 1 = 1%–9%, 2 = 10%–29%, 3 = 30%– 49%). Finally, each of the four quadrant scores is summed to give the total PASI score ranging from 0 to 72.11,13 Initially, both through historical serendipity as well as formal deliberations between the Food and Drug Administration (FDA) and Dermatology Advisory Committee, a reduction of PASI ≥75% or “PASI 75” emerged as the primary endpoint for assessing new therapies.28 However, because the elements of the PASI system

Clinician-assessed measurement tools  183

Table 19.1  Summary of common measures of physical disease. Elements of assessment

Notable aspects of this tool

Clinician-assessed tools (primarily plaque psoriasis) Psoriasis Area and Severity Index (PASI)11,13 • Severity of disease based on erythema, • 50% reduction in PASI is clinically meaningful improvement14 induration, scaling, and body surface area (BSA) involvement • Does not assess quality-of-life (QoL) • Relies on clinician estimates of BSA • Not sensitive for mild disease or disease subtypes Self-administered PASI (SAPASI)15 • Patient shades a body surface diagram and marks a visual analog scale for erythema, induration, and scale Psoriasis Assessment Severity Score • BSA, erythema, desquamation, and • BSA assessed by “rule of nines” (PASS)16 induration • Induration has greater weight; reflects greater severity with greater induration 17 Simplified PASI (SPASI) • Sum of average redness, thickness, and scaling multiplied by %BSA involved • Same as the PASI • Uses more granular BSA Psoriasis Log-Based Area and Severity groupings for better sensitivity in Index (PLASI)18 mild disease • More subjective, intuitive tool Physician’s Global Assessment (PGA)19 • Typically seven-level scale (clear-to• No quantitative assessments other severe), based on plaque elevation, than seven-point severity scaling, and/or erythema • Exists in multiple slightly different forms Lattice System Physician’s Global • Lower intra-, interrater variation than • Similar to PGA but incorporates BSA; Assessment (LS-PGA)20 PASI clinician assessments are input into • Does not vary based on clinician lattice algorithm for final score experience Clinician-assessed tools (psoriasis subtypes) Palmoplantar Pustular Psoriasis Area and • Modification of the PASI score • Erythema, number of pustules, and Severity Index (PPPASI) 21 desquamation involving the hands and feet Palmoplantar Physician’s Global • Modification of the plaque-type Physicians’ Global Assessment Assessment22 Nail Psoriasis Severity Index (NAPSI)23 • Nail changes such as pitting or leukonychia and degree of surface area involved • More patient-oriented based on QoL • Three questionnaires covering QoL, Nail Assessment in Psoriasis and Psoriatic assessment treatment benefits, and clinical Arthritis (NAPPA)24 severity Genital PASI (gPASI)25 • PASI-like assessment of disease subtypes Comprehensive Assessment of the Psoriasis • Uses patient-reported outcomes and clinician-assessed severity Patient (CAPP)27 • PASI-like assessment of genital disease subtypes • Originally designed for males; a corresponding but not yet validated scale exists and has been used for females26

are ­nonlinear and do not account for quality-of-life (QoL) or histological improvement, the PASI can easily underestimate clinically meaningful improvements. In 2004, Carlin et al. professed that a 50% reduction in the PASI score is a better endpoint, allowing a lower hurdle for new therapies that might provide true benefit. They noted that the bulk of QoL improvements occurs between PASI 50 and PASI 70, that PASI 50 allows statistical differentiation from placebo in trials, and that treatment with highly

regarded methotrexate often results in PASI 50 but not PASI 75.14 It is important to note that the PASI system does not directly assess impact on patient QoL, an essential element of thorough assessment of this potentially debilitating disease. The tool has other limitations including reliance on notoriously inaccurate clinician estimates of surface area involvement.10 With this tool and any other clinicianassessed tool that depends on visual appraisal, the

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validity of measurement is only as good as the clinician conducting the assessment, as shown by increasing reliability with increasing experience of the assessing clinician.20 Furthermore, the PASI has been criticized for lacking sensitivity for less severe disease, and it also fails to characterize subtypes of disease including pustular, nail, or scalp psoriasis. Poor response distribution is also noted, as scores over 40 are quite rare.12 Despite these shortcomings, the PASI remains widely used and has been shown to have substantial inter- and intrarater reliability.29 Notable variations on the PASI have emerged to address the shortcomings of the original tool. The self-­ administered PASI (SAPASI) mirrors the PASI, but uses the patient’s own assessment of disease variables, by way of shading areas on a body diagram, and completing visual analog scales for extent of erythema, induration, and scaling.15 The Psoriasis Assessment Severity Score (PASS) uses BSA by way of the “rule of nines,” three-point scoring for each of erythema and desquamation, and a four-point score for induration. A complex formula then yields a score between 0 and 140, allowing for greater sensitivity.16 Finally, the simplified PASI (SPASI) uses a simple sum of average redness, thickness, and scaling of all lesions multiplied by total percentage BSA involved, whereas the Psoriasis Log-Based Area and Severity Index (PLASI) uses more granular BSA groupings to allow for better sensitivity for patients with less area of involvement.17,18

Physician’s global assessment The “Physician’s Global Assessment” (PGA), sometimes known as “Investigator’s or Psoriasis Global Assessment,” serves as a more intuitive and subjective tool compared with the PASI and its offspring.19 The PGA exists in many iterations, but typically uses a seven-level scale graded from clear to severe, based on plaque elevation, scaling, and/or erythema, but with no quantitative assessments by the clinician. For example, BSA is not formally assessed, and a patient with one plaque that is very thick, red, and scaly would be considered to have severe disease. Succeeding the PGA, the Lattice System Physician’s Global Assessment (LS-PGA) shares features with the PASI and PGA. Like the PGA, an overall intuitive description of severity is assessed but then a BSA of involvement is also incorporated. Thickness, erythema, and scale are assessed globally and each is assigned a description of “none,” “mild,” “moderate,” or “marked.” Finally, the BSA and average plaque qualities are combined in a lattice via a computerized algorithm.20 More weight is given to plaque elevation than to scale or erythema reflecting the greater clinical significance of this sign. An overall degree of clinical severity is assigned on an eight-point scale from “clear” to “very severe.” Both the PGA and LS-PGA have been noted for their overall high reliability. Both have shown lower intra- and interrater variation than PASI, and neither showed variation based on clinician’s experience.20

PSORIASIS SUBTYPES Nonplaque psoriasis subtypes Multiple phenotypic subtypes of psoriasis exist, each with likely unique aspects of underlying pathophysiology. To ­better study these subtypes and their response to the therapy, a number of assessment tools have emerged (Table 19.1). Palmoplantar pustular psoriasis (PPPP) is a particularly debilitating subtype, often causing significant limitation of a patient’s activities of daily living.30 Many of the previously mentioned tools have been modified for PPPP and have been used to determine outcomes in clinical trials. The Palmoplantar Pustular Psoriasis Area and Severity Index (PPPASI) scores severity for erythema, number of pustules, and desquamation.21 Similarly, a modified Palmoplantar PGA has been developed.22 QoL is an especially important variable for this phenotype of disease. Recently, the Palmoplantar Quality-of-Life Instrument (PPPQoLI) was developed by dermatologists and experienced hand and foot surgeons. This tool queries patients on their disease-induced limitations of hand and foot specific activities, such as performing household chores, or opening a jar.30 For disease affecting the nails, the Nail Psoriasis Severity Index (NAPSI) is assessed by scoring nail changes such as pitting or leukonychia and the degree of area involvement.23 The Nail Assessment in Psoriasis and Psoriatic Arthritis (NAPPA) is a more patient-relevant tool, using three separate questionnaires to assess QoL, relevant treatment benefits, and a clinical assessment of severity.24 The modified genital PASI was designed to address this psychologically debilitating subtype and does so via judgment of erythema, scaling, and thickness for genital lesions.25 Finally, as we will later discuss in detail, the Comprehensive Assessment of the Psoriasis Patient (CAPP) tool27 is a new instrument aimed at assessing all subtypes of psoriasis, incorporating both physicianassessed and patient-reported outcomes.

Psoriatic arthritis Persistent attention to joint health is extremely important in the care of a patient with psoriasis. Diagnostic delays of a mere 6 months have been associated with the development of peripheral joint erosions and worse Health Assessment Questionnaire scores.31 Psoriasis treating clinicians are at a particular advantage to monitor for joint disease, as skin disease usually precedes joint symptoms by an average of 8.5 years.32 An impressive number of disease assessment tools have been developed to specifically characterize PsA (Table 19.2).33–40 SCREENING TOOLS

Screening tools seek to identify individuals most likely to have PsA, who should then be referred for rheumatology specialty care, or these tools can also be used to determine prevalence of disease on an epidemiological scale. Notably,

Psoriasis subtypes  185

Table 19.2  Summary of common psoriatic arthritis (PsA)-specific tools. Elements of assessment

Notable aspects of this tool

Psoriatic Arthritis Screening and Evaluation Tool (PASE)33 Toronto Psoriatic Arthritis Screen (ToPAS)35

• Symptoms of joint disease and effects on function • Psoriatic skin and nail photos and questions assessing past skin lesions, joint pain, and stiffness

Psoriasis Epidemiology Screening Tool (PEST)37

• Stick figure joints marked by patients as causing discomfort; “yes/no” questions about joints and nails

• Score cutoff of 47 is 93% sensitive and 80% specific34 • Lacks function questions • Does not require baseline psoriasis diagnosis • Score cutoff of 8 is 87% sensitive and 93% specific36 • Score cutoff of 3 is 92% sensitive and 78% specific37

PsA screening tools

PsA measurement tools American College of Rheumatology 20 (ACR20)38

Sharp assessment for PsA39

• Swollen and tender joints • Global patient and physician assessments • Acute phase reactants • Patient’s pain Visual Analogue Scale • Health Assessment Questionnaire Score • Joint erosion and joint space narrowing for numerous hand and foot joints

these screening tools differ from all other tools discussed in this chapter, as they are not meant to aid in the determination of total disease burden, or in the comparison of patients before and after treatment.36 The Psoriatic Arthritis Screening and Evaluation Tool (PASE) debuted in 2007 as one of the first screening tools. It was developed with the goal of aiding dermatologists in the identification of PsA in currently diagnosed psoriatic patients. The PASE is a one-page, self-administered tool consisting of 15 questions assessing symptoms and function on five-point Likert scales, jointly developed by dermatologists and rheumatologists. The PASE is able to distinguish PsA from other arthritic conditions and can distinguish severe PsA subtypes.33 In a validation study, PASE showed strong test–retest reliability, was sensitive to change after treatment, and after excluding patients with quiescent disease, a PASE score of 47 was 93% sensitive and 80% specific for detecting PsA.34 The Toronto Psoriatic Arthritis Screen (ToPAS) was developed to screen patients for PsA regardless of whether they are followed for psoriasis, and consists of 12 items with psoriatic skin and nail photos, and questions about past skin lesions, joint pain, and stiffness.35,36 ToPAS differs from the PASE in that it does not feature questions on function and answers are provided in a binary “yes or no” fashion. Upon validation, it was shown to be 87% sensitive and 93% specific. The Psoriasis Epidemiology Screening Tool (PEST) is a unique screening tool featuring a stick figure diagram upon which patients mark any joint that has caused

• Appraisal of improvement from baseline during treatment • Especially valuable in interpreting clinical trials

• Sensitive to change in clinical trials40

discomfort. It also features 5 “yes or no” questions about joints and nails, with a score of 3 or more yielding a 92% sensitive and 78% specific score for identification of PsA.37 Head-to-head studies have shown little difference in the sensitivity and specificity of the PASE, ToPAS, and PEST tools, though they have shown significantly lower sensitivities as compared with original validation studies, possibly due to poor detection of nonpolyarticular (oligoarticular, spinal, and entheseal) disease.41,42 ASSESSMENT TOOLS

Clinical classification criteria for PsA often depend on a physical examination by rheumatology physicians. The Classification of Psoriatic Arthritis (CASPAR) criteria are the widely used clinical criteria for diagnosing PsA, encompassing indicators such as nail dystrophy and radiological evidence of juxta-articular new bone formation.43 Once PsA is diagnosed, numerous potential tools can be used for the detailed assessment and measurement of disease. An in-depth review of these tools has been undertaken in the rheumatology community.44 Two PsA-specific assessment tools are especially notable. The American College of Rheumatology 20 (ACR20) was initially developed as a standardized outcome measure for patients with rheumatoid arthritis, to describe improvement from initial assessment. It is now used for those with PsA, and provides especially useful information when interpreting results of clinical drug trials. The ACR20 describes at least 20% improvement in a

186  Assessment and measurement of disease

count of swollen and tender joints, and 20% improvement in three of the following: global patient assessment, global physician assessment, acute phase reactants (erythrocyte sedimentation rate or c-reactive protein), patient’s pain Visual Analogue Scale, and Health Assessment Questionnaire Score.38 Another tool known as the Sharp scoring method was modified for PsA from its original use for rheumatoid arthritis. The Sharp method was developed by rheumatologists and radiologists and scores numerous hand and foot joints for joint erosion, and joint space narrowing separately. Assessments are made radiographically, and assigned a 0–7 score for erosion and 0–5 score for joint space narrowing for each joint. Other more specific attributes are noted as well, such as pencil-in-cup deformities or periostitis in the wrist.39 This method has been used in clinical trials, for example, with etanercept, with the Sharp tool demonstrating sensitivity to change.40

PATIENT-REPORT MEASUREMENT TOOLS In today’s modern era of evidence-based, patient-centered care, clinically meaningful outcomes are more important than ever. The assessment of patient health-related QoL (HRQoL) has emerged as an integral component of clinical outcome. HRQoL refers to a patient’s QoL associated with disease and its treatment, and generally encompasses physical, psychological, social, and cognitive function, as well as general well-being. HRQoL is especially important and complex in psoriasis, where the same patterns of disease can be experienced in drastically different ways depending on the life experience, coping skills, responsibilities, and concerns of patients.45,46

Many of the early clinical tools, such as the PASI, are devoid of HRQoL measures. This has initially biased drug development and prescribing practices based on a narrow definition of severe disease. Patient recruitment for clinical trials as well as preauthorization requirements for current drugs often require a threshold of BSA involvement. This remains a poor indicator of severe disease if taken in isolation. For example, one patient with <10% BSA but severe involvement of a dominant hand might have severe disease, as compared with one who has 40% BSA but thin and unexposed plaques. In fact, one study revealed no relationship between QoL and overall area of disease involvement.47 Fortunately, the importance of HRQoL has been increasingly acknowledged and studied in recent years, with some proclaiming that psoriasis is, “first and foremost, a QoL issue.”48 This has helped to bring awareness not only to clinicians but also to some third-party payers and has begun to influence drug development in the direction of more patient-centered outcomes. Thankfully, a diverse array of patient-centered tools has emerged to address this important element of patient experience. These HRQoL tools generally assess ­f unctional impairment vs. psychosocial stress and anxiety outcomes and can be grouped into psoriasis-specific, general dermatologic, and general QoL assessment tools. Each tool type exhibits different advantages. For ­example, p ­ soriasis-specific tools assess elements unique only to psoriasis patients while generic QoL assessments allow score comparison across many different, even ­nondermatologic diseases. In Table 19.3, we highlight some of the most widely known tools in each of these ­c ategories. 30,49–62

Table 19.3  Summary of common patient-report and QoL tools. Elements of assessment

Notable aspects of this tool • Scores correlate with BSA involvement • Sensitivity is lacking for mild disease

Psoriasis Life Stress Inventory (PLSI) 51

• Daily activities at home, work, or school, personal relationships, leisure, and treatment • Stress, social stigma, and anxiety

Psoriasis Index of Quality of Life (PSORIQoL)54,55 Palmoplantar Quality of Life Instrument (PPPQoLI)30

• Self-consciousness, physical contact, and intimacy • Activities requiring use of hands or feet

Psoriasis-specific tools Psoriasis Disability Index (PDI)49,50

General dermatologic tools Dermatology Life Quality Index (DLQI)56

• Feelings, daily activities, leisure, work, school, personal relationships, and treatment side effects

• Correlates with self-reported physical psoriasis severity but not with Psoriasis Area Severity Index (PASI) scores52,53 • Valid and reliable; response to change not well-assessed • Developed by dermatologists and hand/ foot surgeons • Well-studied; correlates with generic, dermatologic, and disease-specific measures of health-related quality of life (HRQoL)57 • Requires only 1–2 minutes • Responsive to change before and after treatment (Continued)

General dermatologic and generic HRQoL assessment tools  187

Table 19.3  (Continued) Summary of common patient-report and QoL tools. Skindex58,59 Generic QoL tools Short-Form 3661

Elements of assessment

Notable aspects of this tool

• Three domains: symptoms, emotions, and functions

• Exists in 29- and 16-item formats • Reliable and valid for psoriasis58–60

• Eight concepts: physical activity, social activity, work or other rolerelated activity, pain, general mental health, emotion, vitality, and general health perceptions

• Linearly associated with SAPASI scores62

PSORIASIS-SPECIFIC TOOLS Psoriasis disability index The Psoriasis Disability Index (PDI), one of the first psoriasis-specific HRQoL tools, has been widely used since its inception in 1985, with translation into at least 16 different languages.49,50 Fifteen questions assess patients’ daily activities at home, work, or school, personal relationships, leisure, and treatment. Boxes are ticked indicating the extent of interference with HRQoL over the previous month, including “not at all,” “a little,” “a lot,” and “very much,” scored 0–4 with maximum possible score of 45. In a study of 1196 U.S. patients, the PDI score correlated with a global “problem in everyday life” question, and also correlated with clinical BSA involvement, supporting it as a valid tool. However, the sensitivity of the tool was questioned, especially for those with less severe disease, as over 80% of patients responded “not at all” to at least half of the PDI questions.63 The PDI has been used in numerous clinical trials to assess HRQoL outcomes, for example, with calcipotriol and narrowband ultraviolet B (UVB) treatments.64

Psoriasis life stress inventory The Psoriasis Life Stress Inventory (PLSI) is a 15-item tool, assembled from the survey of 217 psoriasis patients, focusing on psoriasis-associated stress, social stigma, and anxiety. Like the PDI, the PLSI asks patients to rate stress on a four-point scale, for example, based on “feeling selfconscious among strangers” or “fear of having serious side-effects from medical treatments.” Authors found that a score of 10 or greater was significantly associated with selfreported physical psoriasis severity, number of flare-ups, and pruritus, though another study found that PLSI scores were independent of PASI assessed clinical severity.51–53

Psoriasis index of quality of life The Psoriasis Index of Quality of Life (PSORIQoL) was introduced in 2003 after interviews with European psoriasis patients. Upon multiple iterations, a 25-item tool was

developed to measure similar psychosocial aspects as that of the PLSI, including self-consciousness, physical contact and intimacy, and emotional stability among others. In this way, the PSORIQoL does not test functional impairment directly as in the PDI, but instead assesses the downstream psychological outcomes of disease. This tool has been found to be both valid and reliable, though responsiveness to change with therapy has been minimally assessed with this tool.54,55

GENERAL DERMATOLOGIC AND GENERIC HRQOL ASSESSMENT TOOLS The following tools were designed to assess HRQoL more generically. They include tools for either patients with dermatologic disease or more generically, patients with any health condition. They make up the most frequently used tools of their type in the assessment of psoriasis.

Dermatology life quality index The Dermatology Life Quality Index (DLQI) is one of the most frequently used general dermatologic tools, with use in hundreds of studies, and versions in over 50 different languages.54,65 Patients respond on a 0–3 Likert scale to 10 questions regarding the impact of skin problems on feelings, daily activities, leisure, work, school, personal relationships, and treatment side effects.56 Over 30 studies have highlighted the DLQI’s validity by demonstrating correlation with generic, dermatologic, and disease specific measures of HRQoL. For example, one study showed comparable changes in the DLQI and the more clinical, psoriasis-specific SAPASI tool.57 The DLQI is championed for its ease of use, requiring only 1–2 minutes for completion, and most clinical trials using the DLQI have shown its responsiveness to change before and after treatment.65 The DLQI has been used in studies of over 30 different specific skin diseases but most frequently for psoriasis. Of particular importance for the DLQI, and for all psoriasis measurement tools, is the application of clinical meaning for given scores. A study of 1993 patients led to the development of a banding of DLQI scores. For example, scores of 2–5 mean “small effect,” whereas 10 and above signify

188  Assessment and measurement of disease

a very large effect on a patient’s life, therefore potentially guiding treatment decisions such as indications for systemic therapy.66 Interestingly, one study strongly highlighted the importance of HRQoL tools in clinical practice, showing that in patients with no treatment changes on consultation, an impressive 36% still had DLQI scores greater than 10, suggesting significant unmet treatment needs.67

Skindex Skindex-29 was developed by Chren and colleagues as a general dermatologic QoL assessment, evaluating three domains: symptoms, emotions, and functions. Patients are queried regarding how often they experience a given effect in the previous 4 weeks, and scores are reported separately for each domain.58 Authors later developed Skindex-16 as a shorter, one-page instrument that queries patients slightly differently, asking “in the past week,” how often have you been “bothered by” a given aspect of disease, with a seven-point scale from “never bothered” to “always bothered.” Authors suggest Skindex-16 might better assess effects on QoL by asking about bother, rather than frequency of experience. Both Skindex-29 and Skindex-16 have been found as reliable and valid tools for assessing QoL in skin disease, including psoriasis.58–60 As with the DLQI, Skindex has been used to assess QoL burden in a variety of dermatologic diseases, and therefore, allows comparison of burden from psoriasis with burden from, for example, acne vulgaris or eczematous dermatitis.68

Short-Form 36 Unlike the many tools discussed up to this point, the Medical Outcomes Study 36-item Short-Form Health Survey, or Short-Form 36 (SF-36), was designed to assess any and all health problems. It is a 36-item instrument that assesses eight concepts including physical activity, social activity, work or other role-related activity, pain, general mental health, emotion, vitality, and general health perceptions. These eight components are then grouped into a physical and mental component summary score.61 The SF-36 is the most frequently used general health questionnaire when assessing psoriasis.69 For example, one study of over 300 patients revealed worse QoL in psoriatic patients than in the

general population on all eight scales, and a ­linear ­association between SA-PASI scores and SF-36 subscale scores.62,70 Both the SF-36 and the dermatology-specific Skindex have been used to assess QoL outcomes following psoriasis treatments, as for example in scalp psoriasis treatments with calcipotriol/betamethasone dipropionate formulations.71 A review of QoL measures in psoriasis noted, though, that when considering general health versus dermatology-specific measures of QoL, dermatology-specific measures are likely to be more sensitive to subtle effects of disease and for those with mild psoriasis. Authors also championed the concurrent use of both a generic and dermatology-specific questionnaire to make use of the merits of both scales.69 Finally, one recent study compared Skindex-29 against the DLQI, PDI, and SF-36, and found that Skindex-29 has better sensitivity to clinical severity and covers the same main domains as the other QoL instruments particularly for patients with mild-to-severe psoriasis.72

COMBINED MEASUREMENT TOOLS Salford psoriasis index As patient-centered QoL outcomes continue to gain their deserved notoriety in assessments of disease, recent tools (Table 19.4) have combined this all-important measure with clinician-assessed clinical scoring systems.73–75 The Salford Psoriasis Index (SPI) is one of the betterknown combinatorial tools comprising a score based on PASI, a score for psychosocial disability, and a score for past severity based on treatment history, allowing for a more holistic assessment of burden of disease.73 The SPI has since been modified to the “Simplified Psoriasis Index” where the PASI component is replaced with a clinical severity score weighted to reflect functional or psychosocially important sites.74

Koo–Menter psoriasis instrument The Koo–Menter instrument was designed with the overarching goal to identify patients most likely to benefit from systemic treatments. This tool comprises a patient

Table 19.4  Combined measurement tools. Elements of assessment Psoriasis-specific tools Salford Psoriasis Index (SPI)73 Simplified Psoriasis Index74

• PASI-based score, psychosocial disability, past severity based on treatment history • Same as the Salford Psoriasis Index but PASI component is replaced with clinical score weighted for functionally and psychosocially important body sites Koo–Menter Psoriasis Instrument (KMPI)75 • Patient and physician assessments incorporating HRQoL as well as physical disease assessment aimed to determine suitability for systemic treatment Comprehensive Assessment of the Psoriasis • Clinical signs and patient-reported outcomes for all subtypes of psoriasis Patient (CAPP)27

References 189

self-assessment and physician assessment. Patients first complete a QoL questionnaire grading psoriasis-induced life-quality limitations on a 0–10 scale. Next are questions regarding psoriasis symptoms, a body diagram ticked by patients to indicate areas of involvement, and finally a set of questions to assess joint involvement or PsA symptoms. The physician appraisal incorporates BSA and a number of yes/no questions such as presence of serious subtypes and effects on daily activities. A series of questions aimed to determine phototherapy feasibility are then answered. Ultimately, the tool yields a final answer as to whether the patient is a candidate for systemic therapy. The Koo– Menter Psoriasis Instrument (KMPI) was designed for ease of use, is contained on two sides of a single page, and requires only 5 minutes for completion. Not only does it facilitate treatment decisions for the clinician but it can also be used to justify treatment decisions to third-party payers.75

The comprehensive assessment of the psoriasis patient: A comprehensive measurement tool The Comprehensive Assessment of the Psoriasis Patient (CAPP)27 is a new tool developed to provide a more inclusive, global assessment of psoriatic disease. This tool is aimed at classifying all subtypes of disease, including those often overlooked clinically and in trials, including plaque, scalp, nail, inverse, genital, and palmoplantar psoriasis. These disease subtypes can have especially profound effects on QoL, for example, nail psoriasis can severely limit one’s livelihood. Clinician scoring of clinical severity and area of involvement are added to patient-reported outcomes scores for each disease subtype. The two highest summative scores are then added to give a final CAPP score, estimating overall severity of disease. A recent survey conducted by the authors revealed that both dermatologists and rheumatologists agree that the CAPP should also include questions to identify PsA. Once this measure is added, the CAPP will be a truly comprehensive tool highlighting the evolution of psoriasis assessment tools from the PASI to the more comprehensive patient-oriented tools of modern psoriasis care.

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Psoriasis area and severity index, physician’s global assessment and lattice system physician’s global assessment. Br J Dermatol. 2006 Oct;155(4): 707–713. 30. Farley E, Masrour S, McKey J, Menter A. Palmoplantar psoriasis: A phenotypical and clinical review with introduction of a new quality-of-life assessment tool. J Am Acad Dermatol. 2009 Jun;60(6):1024–1031. 31. Haroon M, Gallagher P, FitzGerald O. Diagnostic delay of more than 6 months contributes to poor radiographic and functional outcome in psoriatic arthritis. Ann Rheum Dis. 2015 Jun;74(6): 1045–1050. 32. Gelfand JM, Gladman DD, Mease PJ, et al. Epidemiology of psoriatic arthritis in the population of the United States. J Am Acad Dermatol. 2005 Oct;53(4):573. 33. Husni ME, Meyer KH, Cohen DS, Mody E, Qureshi  AA. The PASE questionnaire: Pilot-testing a psoriatic arthritis screening and evaluation tool. J Am Acad Dermatol. 2007 Oct;57(4):581–587. 34. Dominguez PL, Husni ME, Holt EW, Tyler S, Qureshi AA. Validity, reliability, and sensitivity-tochange properties of the psoriatic arthritis screening and evaluation questionnaire. Arch Dermatol Res. 2009 Sep;301(8):573–579. 35. Gladman DD, Schentag CT, Tom BDM, et al. Development and initial validation of a screening questionnaire for psoriatic arthritis: The Toronto Psoriatic Arthritis Screen (ToPAS). Ann Rheum Dis. 2009 Apr;68(4):497–501. 36. Dominguez P, Gladman DD, Helliwell P, Mease PJ, Husni ME, Qureshi AA. Development of screening tools to identify psoriatic arthritis. Curr Rheumatol Rep. 2010 Aug;12(4):295–299. 37. Ibrahim GH, Buch MH, Lawson C, Waxman R, Helliwell PS. Evaluation of an existing screening tool for psoriatic arthritis in people with psoriasis and the development of a new instrument: The psoriasis epidemiology screening tool (PEST) questionnaire. Clin Exp Rheumatol. 2009 May;27(3):469–474. 38. Felson DT, Anderson JJ, Boers M, et al. American College of Rheumatology. Preliminary definition of improvement in rheumatoid arthritis. Arthritis Rheum. 1995 Jun;38(6):727–735. 39. van der Heijde D, Sharp J, Wassenberg S, Gladman DD. Psoriatic arthritis imaging: A review of scoring ­methods. Ann Rheum Dis. 2005 Mar;64 (Suppl 22):ii61–64. 40. Mease PJ, Kivitz AJ, Burch FX, et al. Etanercept treatment of psoriatic arthritis: Safety, efficacy, and effect on disease progression. Arthritis Rheum. 2004 Jul;50(7):2264–2272. 41. Coates LC, Aslam T, Balushi Al F, et al. Comparison of three screening tools to detect psoriatic arthritis in patients with psoriasis (CONTEST study). Br J Dermatol. 2013 Apr;168(4):802–807.

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42. Haroon M, Kirby B, FitzGerald O. High prevalence of psoriatic arthritis in patients with severe psoriasis with suboptimal performance of screening questionnaires. Ann Rheum Dis. 2013 May;72(5):736–740. 43. Taylor W, Gladman D, Helliwell P, et al. Classification criteria for psoriatic arthritis: Development of new criteria from a large international study. Arthritis Rheum. 2006 Aug;54(8):2665–2673. 44. Mease PJ. Measures of psoriatic arthritis: Tender and Swollen Joint Assessment, Psoriasis Area and Severity Index (PASI), Nail Psoriasis Severity Index (NAPSI), Modified Nail Psoriasis Severity Index (mNAPSI), Mander/Newcastle Enthesitis Index (MEI), Leeds Enthesitis Index (LEI), Spondyloarthritis Research Consortium of Canada (SPARCC), Maastricht Ankylosing Spondylitis Enthesis Score (MASES), Leeds Dactylitis Index (LDI), Patient Global for Psoriatic Arthritis, Dermatology Life Quality Index (DLQI), Psoriatic Arthritis Quality of Life (PsAQOL), Functional Assessment of Chronic Illness TherapyFatigue (FACIT-F), Psoriatic Arthritis Response Criteria (PsARC), Psoriatic Arthritis Joint Activity Index (PsAJAI), Disease Activity in Psoriatic Arthritis (DAPSA), and Composite Psoriatic Disease Activity Index (CPDAI). Arthritis Care Res (Hoboken). 2011 Nov;63(Suppl 11):S64–S85. 45. Mckenna KE, Stern RS. The outcomes movement and new measures of the severity of psoriasis. J Am Dermatol. 1996 Mar;34(3):534–538. 46. Revicki DA. Health-related quality of life in the evaluation of medical therapy for chronic illness. J Fam Pract. 1989 Oct;29(4):377–380. 47. Heydendael VM, de Borgie CA, Spuls PI, Bossuyt PM, Bos JD, de Rie MA. The burden of psoriasis is not determined by disease severity only. J Investig Dermatol Symp Proc. 2004 Mar;9(2):131–135. 48. Krueger GG, Feldman SR, Camisa C, et al. Two considerations for patients with psoriasis and their clinicians: What defines mild, moderate, and severe psoriasis? What constitutes a clinically significant improvement when treating psoriasis? J Am Dermatol. 2000 Aug;43(2 Pt 1):281–285. 49. Lewis VJ, Finlay AY. Two decades experience of the psoriasis disability index. Dermatology. 2005;210(4):261–268. 50. Finlay AY, Kelly SE. Psoriasis-an index of disability. Clin Exp Dermatol. 1987 Jan;12(1):8–11. 51. Gupta MA, Gupta AK. The psoriasis life stress inventory: A preliminary index of psoriasis-related stress. Acta Derm Venereol. 1995 May;75(3):240–243. 52. Ashcroft DM, Li Wan Po A, Williams HC, Griffiths CE. Quality of life measures in psoriasis: A critical appraisal of their quality. J Clin Pharm Ther. 1998 Oct;23(5):391–398. 53. Fortune DG, Main CJ, O’Sullivan TM, Griffiths CE. Assessing illness-related stress in psoriasis: The psychometric properties of the psoriasis life stress inventory. J Psychosom Res. 1997 May;42(5):467–475.

54. Bronsard V, Paul C, Prey S, et al. What are the best outcome measures for assessing quality of life in plaque type psoriasis? A systematic review of the literature. J Eur Acad Dermatol Venereol. 2010 Apr;24 (Suppl 2):17–22. 55. McKenna SP, Cook SA, Whalley D, et al. Development of the PSORIQoL, a psoriasis-specific measure of quality of life designed for use in clinical practice and trials. Br J Dermatol. 2003 Aug;149(2):323–331. 56. Finlay AY, Khan GK. Dermatology life ­quality index (DLQI)—A simple practical measure for routine clinical use. Clin Exp Dermatol. 1994 May;19(3):210–216. 57. Mazzotti E, Picardi A, Sampogna F, et al. Sensitivity of the dermatology life quality index to clinical change in patients with psoriasis. Br J Dermatol. 2003 Aug;149(2):318–322. 58. Chren MM, Lasek RJ, Flocke SA, Zyzanski SJ. Improved discriminative and evaluative capability of a refined version of Skindex, a quality-of-life instrument for patients with skin diseases. Arch Dermatol. 1997 Nov;133(11):1433–1440. 59. Chren MM, Lasek RJ, Sahay AP, Sands LP. Measurement properties of Skindex-16: A brief quality-of-life measure for patients with skin ­ ­diseases. J Cutan Med Surg. 2001 Mar;5(2):105–110. 60. Chren MM, Lasek RJ, Quinn LM, Mostow EN, Zyzanski SJ. Skindex, a quality-of-life ­measure for patients with skin disease: Reliability, v­ alidity, and responsiveness. J Invest Dermatol. 1996  Nov;107(5): 707–713. 61. Ware JE, Sherbourne CD. The MOS 36-item shortform health survey (SF-36). I. Conceptual framework and item selection. Med Care. 1992 Jun;30(6):473–483. 62. Rapp SR, Feldman SR, Exum ML, Fleischer AB, Reboussin DM. Psoriasis causes as much disability as other major medical diseases. J Am Dermatol. 1999 Sep;41(3 Pt 1):401–407. 63. Nijsten T, Whalley D, Gelfand J, Margolis D, McKenna SP, Stern RS. The psychometric properties of the psoriasis disability index in United States patients. J Invest Dermatol. 2005 Oct;125(4):665–672. 64. Takahashi H, Tsuji H, Ishida-Yamamoto A, Iizuka H. Comparison of clinical effects of psoriasis treatment regimens among calcipotriol alone, narrowband ultraviolet B phototherapy alone, combination of calcipotriol and narrowband ultraviolet B phototherapy once a week, and combination of calcipotriol and narrowband ultraviolet B phototherapy more than twice a week. J Dermatol. 2013 Jun;40(6):424–427. 65. Basra MKA, Fenech R, Gatt RM, Salek MS, Finlay AY. The dermatology life quality index 1994–2007: A comprehensive review of validation data and clinical results. Br J Dermatol. 2008 Nov;159(5):997–1035. 66. Hongbo Y, Thomas CL, Harrison MA, Salek MS, Finlay AY. Translating the science of quality of life into practice: What do dermatology life quality index scores mean? J Invest Dermatol. 2005 Oct;125(4):659–664.

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67. Katugampola RP, Hongbo Y, Finlay AY. Clinical management decisions are related to the impact of psoriasis on patient-rated quality of life. Br J Dermatol. 2005 Jun;152(6):1256–1262. 68. Chren M-M. The Skindex instruments to measure the effects of skin disease on quality of life. Dermatol Clin. 2012 Apr;30(2):231–236, xiii. 69. de Korte J, Mombers FMC, Sprangers MAG, Bos JD. The suitability of quality-of-life questionnaires for psoriasis research: A systematic literature review. Arch Dermatol. 2002 Sep;138(9):1221–7–discussion1227. 70. O’Neill P, Kelly P. Postal questionnaire study of disability in the community associated with psoriasis. BMJ. 1996 Oct 12;313(7062):919–921. 71. Ortonne J-P, Ganslandt C, Tan J, Nordin P, Kragballe K, Segaert S. Quality of life in patients with scalp psoriasis treated with calcipotriol/betamethasone dipropionate scalp formulation: A randomized controlled trial. J Eur Acad Dermatol Venereol. 2009 Aug;23(8):919–926.

72. Fernandez-Peñas P, Jones-Caballero M, Espallardo O, García-Díez A. Comparison of skindex-29, dermatology life quality index, psoriasis disability index and medical outcome study short form 36 in patients with mild to severe psoriasis. Br J Dermatol. 2012 Apr;166(4):884–887. 73. Kirby B, Fortune DG, Bhushan M, Chalmers RJ, Griffiths CE. The Salford Psoriasis Index: An holistic measure of psoriasis severity. Br J Dermatol. 2000 Apr;142(4):728–732. 74. Chularojanamontri L, Griffiths CEM, Chalmers RJG. The Simplified Psoriasis Index (SPI): A practical tool for assessing psoriasis. J Invest Dermatol. 2013 Aug;133(8):1956–1962. 75. Feldman SR, Koo JYM, Menter A, Bagel J. Decision points for the initiation of systemic treatment for psoriasis. J Am Acad Dermatol. 2005 Jul;53(1):101–107.

20 Current and future topical treatments for psoriasis SHIVANI NANDA and LINDA STEIN GOLD INTRODUCTION Psoriasis is a chronic dermatologic disease characterized by erythematous plaques with overlying micaceous scale (Figure 20.1). Topical therapy is the cornerstone of treatment for psoriasis. For approximately 80% of patients who have mild to moderate psoriasis, topical agents are often sufficient to control symptoms.1 For those with severe psoriasis, topical modalities can be used adjunctively with systemic agents or ultraviolet (UV) light therapy. Various topical agents exist for the treatment of psoriasis and include topical corticosteroids, vitamin D analogs, tazarotene, calcineurin inhibitors, anthralin, coal tar, and combination therapies. Just as the topical treatment options are numerous, so too are the choices of vehicle. The choice of the vehicle often impacts efficacy, penetration, and adherence to the treatment regimen. Multiple new topical options are also on the horizon.

TOPICAL CORTICOSTEROIDS Corticosteroids remain the most commonly used topical medications in the treatment of psoriasis.2 By regulating the gene transcription of proinflammatory cytokines, topical corticosteroids exert anti-inflammatory, antiproliferative, and immunosuppressive effects on target tissues.3 Topical corticosteroids are divided into seven classes according to the Stoughton–Cornell classification system (Table 20.1), ranging from superpotent formulations (Class I) to weak preparations (Class VII).4 To minimize local cutaneous side effects such as striae, purpura, and atrophy, the use of Class VI–VII steroids is recommended on the face, intertriginous areas, and infants. Class I–II steroids are used in the treatment of other anatomic sites on adults and for the treatment of thick psoriatic plaques. Typical treatment regimens recommend twice daily use of topical steroids. The duration of use for class I corticosteroids should not generally exceed 2 weeks so as to minimize local side effects. Clobetasol spray and desoximethasone

spray are the only Class I corticosteroids that have a 4-week ­indication. Efficacy rates for superpotent steroids after 2–4 weeks of treatment range from 58%5 to 92%.6 Lower potency steroids achieve efficacy rates ranging from 41%7 to 83%.8 Novel delivery vehicles, such as foams and sprays, which enhance penetration and ease of application to large body surface areas,9 have improved overall clinical efficacy in part by enhancing patient compliance.10 Once clinical improvement is achieved, gradual reduction in the frequency of application of topical steroids should be pursued. Various maintenance regimens have been studied. Katz et al. studied the use of betamethasone propionate ointment twice daily for 2–3 weeks followed by weekend only use for the duration of the 12-week study. Results revealed that 74% of patients maintained remission on this regimen compared with only 21% of patients in the vehicle group.11 Similar findings were reported with 2 weeks of twice daily clobetasol propionate ointment followed by twice weekly applications at 4 months.12 Despite their efficacy in the treatment of psoriasis, topical steroids should be used judiciously in the longterm treatment of chronic conditions such as psoriasis due to their cutaneous and systemic side effect profiles. Cutaneous side effects including atrophy (Figure 20.2), purpura (Figure  20.3), striae distensiae (Figure 20.4), periorificial dermatitis, and acne may limit treatment duration, especially in the treatment of steroid-sensitive anatomic sites such as the face, groin, or skin folds. Although much less common, systemic steroid side effects can occur when potent or superpotent topical steroids are used over large body surface areas for prolonged periods of time. Disturbance of the hypothalamic–pituitary axis, Cushing’s syndrome, osteonecrosis of the femoral head, cataracts, and glaucoma have all been reported.13–17 Several innovative methods to reduce the potential for these serious adverse events have been implemented. These include “weekend-only” steroid regimens and combination therapies with noncorticosteroid topical formulations. In addition, although there have been reports of rebound18,19 following discontinuation of topical steroids, this is not 193

194  Current and future topical treatments for psoriasis

Figure 20.1  Erythematous plaques with overlying micaceous scaling on the knees in a patient with psoriasis. (Courtesy of Dr. Joseph Bikowski.)

Table 20.1  Stoughton–Cornell classification system. Class I (superpotent)

II–III (high potency)

IV–V (moderate potency)

VI–VII (low potency)

Figure 20.2  Cutaneous atrophy in a patient treated with topical steroids. (Courtesy of Dr. Joseph Bikowski.)

Name Clobetasol 0.05% ointment, cream, lotion, spray, solution, shampoo, foam Betamethasone dipropionate 0.05% ointment Halobetasol propionate 0.05% cream/ ointment Fluocinonide 0.1% cream Diflorasone diacetate 0.05% ointment Desoximetasone 0.25% spray Betamethasone dipropionate 0.05% cream Betamethasone valerate 0.12% foam Mometasone furoate 0.1% ointment Halocinonide 0.1% ointment, cream Fluocinonide 0.05% ointment, cream, gel Diflorasone diacetate 0.05% cream Desoximetasone 0.05% gel Desoximetasone 0.25% ointment, cream Flurandrenolide 0.05% ointment, cream, lotion, tape Mometasone furoate 0.1% cream Triamcinolone 0.1% ointment, cream, spray Fluocinolone acetonide 0.03% ointment, cream Fluocinolone 0.01% cream, shampoo Desoximetasone 0.05% ointment, cream Hydrocortisone valerate 0.2% ointment, cream Desonide 0.05% ointment, cream, lotion Fluocinolone acetonide 0.01% solution, oil Desonide 0.05% gel, foam Hydrocortisone 0.5%, 1.0%, 2.5% ointment, cream, lotion, spray

Note:  In the United States, the potency of topical corticosteroids is subdivided into seven classes.

Figure 20.3 Purpura in a patient treated with topical steroids. (Courtesy of Dr. Joseph Bikowski.)

Figure 20.4  Striae distensiae in a patient treated with topical steroids. (Courtesy of Dr. Joseph Bikowski.)

Vitamin D analogs  195

generally seen in practice. Last, fear of the d ­ evelopment of tachyphylaxis, or a progressive loss in efficacy of topical corticosteroids with continued use, can limit longterm use of topical corticosteroids. It should be noted that conflicting reports exist regarding the true validity of this phenomenon. Some argue that the long-term decline in efficacy is in fact a result of decreased adherence with prolonged use and not a true loss of efficacy.20,21

VITAMIN D ANALOGS At this time, three vitamin D analogs, calcipotriene (calcipitriol), calcitriol, and tacalcitol, exist for the treatment of psoriasis. Vitamin D analogs result in keratinocyte differentiation and inhibition of keratinocyte proliferation that is mediated by binding of intracellular vitamin D receptors and subsequent gene regulation.22 Calcipotriene is available as a cream, solution, foam, and ointment. When used as monotherapy, calcipotriene ointment was found to result in greater than 75% improvement in patients with chronic plaque-type psoriasis compared with a 19% improvement in patients treated with vehicle alone.23 When compared with potent topical corticosteroids such as betamethasone dipropionate, no significant differences in efficacy were seen in the treatment of psoriatic plaques on the body.24 However, studies have shown that calcipotriene in solution is inferior in treatment of scalp psoriasis when compared with potent or superpotent topical steroids.25 Calcitriol is another synthetic vitamin D analog that is approved for use in the United States and is available as an ointment. Calcitriol has been shown to be as effective in the treatment of psoriasis as calcipotriene. However, calcitriol appears to be better tolerated in sensitive areas such as the face or intertriginous folds.26 Tacalcitol is available for use outside of the United States but has not yet been approved for use in the United States. Unlike calcipotriene, which is approved for once or twice daily dosing, and calcitriol, which is approved for twice daily dosing, tacalcitol is designed to be used once daily. Although its efficacy for the treatment of psoriasis has been established in vehicle-controlled studies,27

tacalcitol appears to be less efficacious than potent topical ­corticosteroids in the treatment of scalp psoriasis.28 As a class, vitamin D analogs are generally welltolerated. Local side effects, including burning, pruritus, edema, peeling, and erythema, are among the most common to occur and can affect up to 25% of patients.1 The risk of more serious systemic adverse events including hypercalcemia and impaired parathyroid hormone regulation is rare and can be avoided if patients do not exceed the maximum allotted doses of the vitamin D analogs (Table 20.2). Patients with chronic kidney disease or on medications that can concurrently result in hypercalcemia, such as thiazide diuretics, are at increased risk of hypercalcemia. 29 Most commonly vitamin D analogs are used in ­combination with other topical or systemic treatments for psoriasis. Care must be taken in using combination topical therapy and phototherapy with vitamin D analogs as vitamin D analogs are inactivated by acidic compounds and UV radiation.30 A fixed dose combination product containing calcipotriene and betamethasone dipropionate is now available in an ointment suspension for once daily use. As with other regimens combining vitamin D analogs and potent topical corticosteroids,31 this fixed drug ointment preparation was shown to be more effective than either agent used alone. The fixed combination was also better tolerated than calcipotriene alone. Specifically, after 4 weeks of treatment the fixed drug combination in the ointment formulation achieved “absent” or “very mild” disease in 71.2% of patients compared with 64% of patients treated with betamethasone dipropionate ointment and 36.8% of patients treated with calcipotriol ointment.32 The fixed drug combination product in the suspension formulation is approved for both scalp and body psoriasis for up to 8 weeks. In a randomized, double-blinded, four-arm clinical trial for body psoriasis, the fixed drug combination of calcipotriene 0.005% plus betamethasone dipropionate 0.064% topical suspension achieved controlled disease in 29% of subjects compared with 21.5%, 14.6%, and 6.3% for the betamethasone dipropionate suspension, calcipotriene suspension, and vehicle groups, respectively.33 Recently, the fixed combination of calcipotriene 0.005% plus betamethasone dipropionate 0.064% topical suspension was Food and Drug Administration (FDA) approved for use

Table 20.2  Maximum weekly dosages for vitamin D analogs. Vitamin D analog

Maximum recommended weekly dosage

Calcitriol 3 µg/g Tacalcitol 4 µg/g Calcipotriol 50 µg/g Calcipotriol 50 ug/g + betamethasone diproponate 0.5 mg/g ointment or solution Calcipotriol 50 µg/g + betamethasone diproponate 0.5 mg/g suspension for ages 12–17 years Note:  The maximum weekly dosages (in grams) are listed for each of the vitamin D analogs.

200 g 70 g 100 g 100 g 60 g

196  Current and future topical treatments for psoriasis

in adolescents (ages 12–17 years) for the treatment of scalp psoriasis. In an open-label, single-arm multicenter trial, this fixed drug topical suspension was well tolerated and achieved treatment success by the end of the 8-week trial in 55% of adolescents.34 In a Phase II, multicenter, investigator-blind, 4-week trial, adult patients with psoriasis vulgaris Cal/BD aerosol foam was studied against Cal/ BD ointment, aerosol foam vehicle or ointment vehicle (3:3:1:1). In total, 376 patients were r­ andomized. At week 4, significantly more patients using Cal/BD aerosol foam achieved treatment success (54.6% versus 43.0% [ointment]; p = 0.025).35 In addition, vitamin D analogs can be combined with phototherapy. The use of twice daily regimens of calcipotriene with twice weekly narrowband ultraviolet B (UVB) phototherapy resulted in greater reductions in Psoriasis Area and Severity Index (PASI) scores than with either therapy alone.36

Table 20.3  Pregnancy categories for topical psoriasis treatments. Name

Pregnancy category

Topical corticosteroids

C (mild to moderate potency preferred) C X C C C C

Vitamin D analogs Tazarotene Calcineurin inhibitors Anthralin Coal tar Salicylic acid

Tazarotene is a synthetic retinoid that exerts its antiproliferative and anti-inflammatory effects through the binding of nuclear retinoid acid receptors (RARs). It is the only topical retinoid approved for use in psoriasis and is available at concentrations of either 0.05% or 0.1% in both cream and gel preparations. Two large, vehiclecontrolled, randomized trials conducted over 12 weeks reported success rates of 49%–59% with tazarotene 0.1% cream versus 42%–48% with tazarotene 0.05% cream when compared with 37% success with the vehiclecontrolled groups. 37 When compared with twice daily application of fluocinonide cream, once daily use of tazarotene gel was found to be similar in its efficacy profile but resulted in prolonged maintenance of results after cessation of therapy. 38 Unfortunately, use of tazarotene is often limited by local irritation, characterized by erythema, burning, and stinging. Irritation can be mitigated by use of the cream formulation, use of the 0.05% concentration, and short-contact (30–60 minutes) treatment.39 The concomitant use of tazorotene with a potent topical steroid not only improves tolerability but has also been shown to result in efficacy rates as high as 95%.40 In addition, although the combination of tazarotene and phototherapy provides enhanced efficacy,41 UV light doses should be decreased to avoid burning.42 Tazarotene is pregnancy Category X (Table 20.3). Caution is advised in the use of this medication in women of child-bearing age given the potential for systemic absorption and subsequent teratogenicity.

pimecrolimus 1% cream and tacrolimus 0.1% ointment. By their inhibition of calcineurin, they prevent the production of TH2 cytokines that play an essential role in the pathogenesis of psoriasis. Initial studies revealed that topical calcineurin inhibitors were ineffective in the treatment of psoriasis.43 However, subsequent studies applied these preparations under occlusion to enhance penetration and found a decrease in erythema and induration of psoriatic plaques on the body after 2 weeks of treatment.44 In addition, studies have shown that both tacrolimus and pimecrolimus are effective at treatment of psoriatic plaques on the face and intertriginous areas. In a doubleblind, randomized, vehicle-controlled study, 71% of the patients with intertriginous psoriasis treated with twice daily pimecrolimus 0.1% cream without occlusion were clear or almost clear after 8 weeks of treatments compared with 21% of patients treated with placebo.45 The topical calcineurin inhibitors are advantageous in the treatment of psoriasis in these areas as they do not result in the development of cutaneous atrophy as is seen with long-term topical steroid use in these regions. The most common side effects reported with the use of the topical calcineurin inhibitors include burning and itching at the sites of application. These local skin reactions resolve with time and can be minimized by applying to dry skin.1 In addition, all patients should be counseled on the “black box” warning placed on these medications in 2005 by the FDA due to potential for development of lymphoma and skin cancer seen in animal models. Fortunately, no studies to date have been able to establish a causal relationship between the use of topical calcineurin inhibitors and subsequent development of malignancies in humans.46,47 The topical calcineurin inhibitors are pregnancy category C and should be used only when the benefits of their use outweigh the risks. They are approved for use in children 2 years of age or older for atopic dermatitis.

CALCINEURIN INHIBITORS

ANTHRALIN/DITHRANOL

Calcineurin inhibitors are not FDA approved for the treatment of psoriasis; however, they have been used for this indication off-label. Topical calcineurin inhibitors include

Anthralin has been a principal treatment modality for psoriasis since the early 20th century. Due to significant skin irritation as well as red-brown staining that occurs upon

TAZAROTENE

Salicylic acid  197

application, its use has declined in recent years as numerous more acceptable alternatives have been developed. In the United States it is currently available as 1% or 1.2% cream or a 1% shampoo. However, anthralin may be compounded in a desired vehicle to any strength ranging from 0.1% to 4%. Although its exact mechanism of action is not fully understood, anthralin has been shown to normalize keratinocyte differentiation and prevent T-cell activation.48 Anthralin is used in the day-care setting typically combined with phototherapy (Ingram method) or in the inpatient setting with application of titrating concentrations of anthralin for up to 24 hours at a time for the treatment of severe plaque-type psoriasis. In the outpatient setting, anthralin is prescribed as a short-contact regimen (<2 hours of exposure) that is slowly titrated up in concentration and time of exposure based on patient tolerance. Studies have shown that higher concentrations of anthralin (1%–3%) applied for 10–20 minutes at a time have been more effective than lower concentrations applied for prolonged periods of time.49 Efficacy of anthralin in patients with moderate to severe psoriasis with inpatient regimens appears to be higher when compared with outpatient short-contact therapy alone.50 However, when compared with calcipotriol ointment applied twice daily for 8 weeks, short-­contact anthralin 1% cream therapy for 30 minutes daily for ­ 8 weeks was less effective at reducing PASI scores.51 The most common adverse effects of anthralin include skin irritation, which begins shortly after initiation of treatment. Even at low concentrations of anthralin, irritation has been reported to occur in as many as 85% of patients.52 As mentioned earlier, short-contact regimens can help ameliorate skin irritation and zinc oxide paste can also be applied to unaffected skin to limit irritation. Redbrown staining of clothing, nails, and items that come in contact with anthralin also limit its use. Anthralin is pregnancy category C and considered safe to use in children.53

COAL TAR Coal tar is a distillation product of coal that is composed of various chemicals that may vary from one preparation to the next. Like anthralin, it was more commonly used in the past before the advent of more cosmetically pleasing alternatives. It is thought to suppress DNA synthesis and subsequently result in antiproliferative effects.1 Coal tar is available in various vehicles including shampoos, creams, lotions, ointments, oils, solutions, and foams. With regards to efficacy, a preparation of 5% coal tar was able to achieve an improvement of 48% at 4 weeks versus only a 35% improvement with vehicle in a small study of 18 patients.54 Interestingly, 1% coal tar lotion in a liposomal base resulted in greater improvement at 12 weeks compared with a conventional 5% coal tar extract. It is thought that the improved efficacy with the liposomal formulation is due to enhanced penetration.55 Coal tar is also a safe and cost-effective treatment for scalp psoriasis.56

­ ar-containing shampoo can result in up to 8 months of T remission when used for the treatment of scalp psoriasis.57 Coal tar 2% foam, a novel coal tar formulation, has been shown to be efficacious in the treatment of “difficult-totreat” areas of psoriasis, which were defined in one study as the scalp, palmoplantar surfaces, and intertriginous folds. In this study, the foam vehicle was shown to be well tolerated without the common adverse effects of unpleasant odor and staining associated with other formulations of coal tar.58 Similarly, coal tar 15% solution is another novel formulation that, when used twice daily for 12 weeks, was well tolerated and resulted in greater mean reductions in PASI scores when compared with calcipotriene 0.005% cream (58% versus 37%).59 Combination therapies with coal tar have also been effective in the treatment of psoriasis. In particular, the Goeckerman regimen, which involves the combined use of coal tar and phototherapy, has been found to be effective in the treatment of even widespread psoriatic lesions.60 In one study, patients who had previously failed to improve on biologic therapy were treated for an average of 28 days with the Goeckerman regimen. Forty percent of these patients had greater than 80% clearance of their psoriatic lesions.61 Other commonly used combination therapies with coal tar include the use of coal tar with topical corticosteroids. The combination with low-potency topical corticosteroids is less effective at achieving clearance when compared with vitamin D analogs, although tolerability profiles are similar.62 Prior to prescribing this medication, prescribers should warn patients about the potential for staining of hair, clothes, and skin as well as an unpleasant odor that has been associated with the use of coal tar. Use of coal tar can also result in the development of an irritant contact dermatitis,63 folliculitis of the legs,64 and occasional exacerbations of psoriasis at sites of application.55 Furthermore, patients should be made aware of conflicting data linking the use of coal tar with malignancy. It is thought that the potential for carcinogenicity associated with coal tar is due to the presence of polyaromatic hydrocarbons.65 Studies assessing occupational exposure to coal tar have shown an increased risk of developing nonmelanoma skin cancers.66 In addition, animal studies have confirmed an increased risk of development of cutaneous malignancies with the use of coal tar, especially in conjunction with UV radiation exposure.67 However, human studies on dermatologic use of coal tar have failed to verify these claims.65 Studies on the safety of coal tar preparations in pregnancy and in children have not been conducted and its use in these populations should be undertaken with caution.68

SALICYLIC ACID Salicylic acid is a topical keratolytic agent that reduces scaling of psoriatic plaques by potentially disrupting keratinocyte–keratinocyte binding and altering the pH of

198  Current and future topical treatments for psoriasis

the stratum corneum.1 Because of its ability to decrease scaling and enhance penetration, salicylic acid is often used in combination with other topical psoriatic treatments. Treatment with combinations of salicylic acid and topical steroid69 and calcineurin inhibitors70 led to greater improvements when compared with either component alone. These combination therapies are not FDA approved for the treatment of psoriasis. Salicyclic acid should not be used in combination with oral salicylate drugs due to risk of systemic salicylism. Salicylism is characterized by nausea, vomiting, tinnitus, confusion, psychosis, coma, and even death.71 Furthermore, because percutaneous absorption of salicylic acid does occur, it should not be applied to over 20% body surface area.1 This risk is heightened with application to areas of skin breakdown.71 Caution should also be used with the combined use of salicylic acid and narrowband-UVB (NBUVB) phototherapy. Because salicylic acid prevents NBUVB penetration, it decreases the efficacy of NBUVB and, thus, should only be applied after NBUVB treatment.72 Due to the risk of systemic absorption, salicylic acid should not be used in children. It is, however, considered safe to use for localized psoriasis in pregnancy.

NOVEL THERAPIES WBI-1001 WBI-1001 (2-isopropyl-5-[(E)-2-phenylethenyl]benzene-1, 3-diol) is an emerging nonsteroidal, anti-inflammatory topical treatment for psoriasis. It has been shown to inhibit the production of proinflammatory cytokines, including tumor necrosis factor alpha (TNF-α) and interferon-γ, and decrease in T-cell viability. In a phase IIa, randomized, double-blinding, vehicle-controlled trial, 61 patients with psoriasis affecting less than 10% body surface area were randomized to receive either WBI-1001 in a 1% cream formulation or in a vehicle, applied twice daily for 12 weeks. At week 12, improvement in physician global assessment scores was 62.8% in patients randomized to WBI-1001 and 13% in the vehicle-controlled group. Adverse reactions observed in the WBI-1001 group included hyperpigmentation, dermatitis, folliculitis, and papules at application sites. Adverse events ranged from mild to moderate and were generally well tolerated.73 Although long-term studies are needed to assess the safety and efficacy of WBI1001, preliminary studies support the use of WBI-1001 for the treatment of mild to moderate psoriasis.

E804 E804 is an indirubin derivative that has been shown to block  constitutive signal transducer and activator of transcription 3 (STAT3) signaling.74 STAT3 is p ­ roduced by interleukin (IL)-22 and appears to be responsible for epidermal proliferation and impaired epidermal

­ ifferentiation.75 Preliminary animal studies on transd genic mice that exhibited constitutive keratinocyte activation of STAT3 and were treated with topical E804 for 8 weeks revealed a marked inhibition in the development of psoriasis-like lesions.76 E804 has not yet been tested in clinical trials for the treatment of psoriasis.

Crisaborole Crisaborole is a topical, boron-containing, a­ ntiinflammatory compound that is a phosphodiesterase 4 (PDE4) inhibitor resulting in suppression of TNF-α, IL-23, IL-12, and various other downstream cytokines via an increase in intracellular cyclic adenosine monophosphate (cAMP) ­levels.77 It is currently under review by the FDA for the t­reatment of atopic dermatitis. In a randomized, double-blinded bilateral trial, 35 patients were randomized to receive either Crisaborole 5% ointment applied twice daily or vehicle. Assessment at day 28 revealed that 40% of plaques were clear or almost clear in those receiving Crisaborole versus 6% in those receiving vehicle.78 A subsequent doseranging study found 2% Crisaborole ointment applied twice daily to be the most effective dose with an improvement compared with vehicle.78 Furthermore, Crisaborole appears to be well tolerated with only mild to moderate application sites and initial studies suggest that it is well tolerated even in the intertriginous areas.78

INC8018424 INCB018424 is a Janus kinase 1/2 (JAK 1/2) inhibitor that is being studied in a topical cream formulation. JAKs are involved in signal transduction and lead to the production of many of the proinflammatory cytokines implicated in psoriasis. In a vehicle-controlled, phase IIb study, INCB018424 cream in three different strengths (0.5%, 1.0%, 1.5%) was applied twice daily for 28 days. A dose– response curve was seen with the best improvement with the 1.5% concentration used twice daily. Mild to moderate local irritation reactions were seen in 20% of patients treated with INCB018424 compared with 28% of patients treated with vehicle.79

Tofacitinib Tofacitinib is a JAK 1/3 inhibitor that is being evaluated in an ointment formulation. In a phase IIa, randomized, double-blinded, vehicle-controlled study, 71 patients were randomized to receive tofacitinib 2% ointment, tofacitimib ointment with a penetration enhancer, or either vehicle. At week 4, improvement in plaque severity scores in the formulation with the penetration enhancer was statistically superior to vehicle. Adverse events were mild to moderate and consisted of mainly local application site reactions.80 Although larger studies assessing long-term outcomes need to be conducted, tofacitinib appears to be a promising emerging topical treatment modality for psoriasis.

Conclusion 199

CT327 CT327 is a tropomyosin-receptor kinase A (TrkA) inhibitor that has been found to be effective in the treatment of pruritus in patients with mild to moderate psoriasis. TrkA is a component of the nerve growth factor (NGF) pathway. Increased local concentrations of NGF have been noted to be present in psoriatic plaques when compared with normal subjections. There appears to be a correlation of pruritus severity and expression levels of TrkA.81 In a phase IIb randomized, double-blind, vehicle-controlled trial on 160  patients with mild to moderate psoriasis, topical formulations of CT327 at three different concentrations (0.05%, 0.1%, 0.5%) were applied twice daily and compared with vehicle. Although no clinical improvements were noted in psoriasis severity with use of CT327, there was a statistically significant decrease in pruritus severity with use of all the tested concentrations of CT327 in patients who had moderate baseline pruritus when compared with placebo. CT327 was well tolerated by all patients.82

with calcipitriol monotherapy. Reported mild to moderate adverse effects were similar to vehicle.83

CONCLUSION Topical therapy continues to be the cornerstone for the treatment of psoriasis. Various topical therapies are efficacious, both alone and as combination therapy (Table 20.4). Further understanding of the pathogenesis of the disease has led to the development of new topical modalities (Table 20.5) that will continue to provide dermatologists

Table 20.4  Strength of recommendations for topical treatments for psoriasis. Strength of recommendation A

DPS-101 DPS-101 is a steroid-sparing drug combination containing calcipotriol and niacinamide. In a randomized, ­placebo-controlled, double-blind, phase IIb study, patients were divided into one of seven treatment arms, consisting of placebo, calcipotriol 0.005%, nicotinamide 1.4%, and four DPS-101 arms with varying doses of nicotinamide (0.05%, 0.1%, 0.7%, 1.4%) and a fixed dose of calcipotriol 0.005%. At the end of 12 weeks, patients applying the DPS-101 combination containing the highest dosage of nicotinamide and calcipotriol showed statistically significant efficacy rates compared with placebo and nicotinamide monotherapy alone and a trend toward statistical significance

B

C

Topical treatment Class 1, III, IV, V, VI, VII corticosteroids Vitamin D analogs Tazarotene Combination corticosteroid + Vitamin D analog Combination of corticosteroid and tazarotene Class II corticosteroids Calcineurin inhibitors Coal tar Combination corticosteroid and salicylic acid Combination tacrolimus and salicylic acid Anthralin

Source:  D  ata adapted from Menter A et al., J Am Acad Dermatol, 60, 643–659, 2009.

Table 20.5  Future topical therapies for psoriasis. Stage of development

Novel therapy

Vehicle

Mechanism of action

Animal studies Phase 2

E804 WBI-1001 AN-2728 INCB018424 Tofacitinib CT327 DPS-101 AS101 IDP-118

– Cream Ointment Cream Ointment Cream, Ointment Cream Cream Lotion

STAT3 inhibitor Anti-inflammatory PDE4 inhibitor JAK 1/2 inhibitor JAK 1/3 inhibitor Tropomyosin-receptor kinase A inhibitor Vitamin D analog + nicotinamide Integrin inhibitor Topical corticosteroid + retinoid

MQX-5902 PH-10 MOL4239 LAS41004 MOL4249 M518101

Not disclosed Aqueous hydrogel Ointment Ointment Not disclosed Not disclosed

Dihydrofolate reductase inhibitor Xanthine dye p-STAT3 inhibitor Topical corticosteroid + retinoid p-STAT3 inhibitor Vitamin D analog

Phase 3

Source:  Data adapted from Feely MA et al., Cutis, 95, 164–168, 170, 2015.

200  Current and future topical treatments for psoriasis

with a plethora of options by which to individually tailor treatment plans for patients with psoriasis.

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15. Kubo T, Kojima A, Yamazoe S, Ueshima K, Yamamoto T, Hirasawa Y. Osteonecrosis of the femoral head that developed after long-term topical steroid application. J Orthop Sci. 2001;6:92–94. 16. Katz HI, Hien NT, Prawer SE, Mastbaum LI, Mooney JR, Samson CR. Superpotent topical steroid treatment of psoriasis vulgaris—Clinical efficacy and adrenal function. J Am Acad Dermatol. 1987;16:804–811. 17. Munro DD. The effect of percutaneously absorbed steroids on hypothalamic–pituitary–adrenal function after intensive use in in-patients. Br J Dermatol. 1976;94:67–76. 18. Baker H, Ryan TJ. Generalised pustular psoriasis. Br J Dermatol. 1968;80:771–793. 19. Baker H. Corticosteroids and pustular psoriasis. Br J Dermatol. 1976;94:83–88. 20. Ponec M, de Hass C, Bachra BN, Molano MK. Effects of glucocorticosteroids on cultured human skin fibroblasts. Arch Dermatol Res. 1979;265:219–227. 21. Miller JJ, Rolling D, Margolis D, Guzzo C. Failure to demonstrate therapeutic tachyphylaxis to topically applied steroids. J Am Acad Dermatol. 1999;41: 546–549. 22. Hansen CM, Mathiasen IS, Binderup L. The antiproliferative and differentiation-induced effects of vitamin D analogs are not determined by the binding affinity for the vitamin D receptor alone. J Invest Dermatol Symp Proc. 1996;1:44–48. 23. Highton A, Quell J. Calcipotriene ointment 0.005% for psoriasis: A safety and efficacy study. Calcipotriene Study Group. J Am Acad Dermatol. 1995;32:67–72. 24. Cunliffe WJ, Berth-Jones J, Caudy A, et al. Comparative study of calcipotriol (MC 903) ointment and betamethasone 17-valerate ointment in patients with psoriasis vulgaris. J Am Acad Dermatol. 1992;26:736–743. 25. Mason A, Mason J, Cork M, Hancock H, Dooley G. Topical treatments for chronic plaque psoriasis: An abridged Cochrane Systematic Review. J Am Acad Dermatol. 2013;69:799–807. 26. Dubertret L, Wallach D, Souteyrand P, et al. Efficacy and safety of calcipotriol (MC 903) ointment in psoriasis vulgaris. A randomized, double-blind, right/ left comparison, vehicle-controlled study. J Am Acad Dermatol. 1992;27: 983–988. 27. Scarpa C. Tacalcitol ointment is an efficacious and well tolerated treatment for psoriasis. J Eur Acad Dermatol Venereol. 1996;6:142–146. 28. Ruzicka T, Trompke C. Treatment of scalp psoriasis: An effective and safe tacalcitol emulsion. Hautarzt. 2004;55:165–170. 29. Braun GS, Witt M, Mayer V, Schmid H. Hypercalcemia caused by vitamin D3 analogs in psoriasis treatment. Int J Dermatol. 2007;46:1315–1317. 30. Patel B, Siskin S, Krazmien R, Lebwohl M. Compatibility of various topical preparations with calcipotriene ointment. J Invest Dermatol. 1997;108:658.

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44. Mrowietz U, Graeber M, Brautigam M, et al. The novel ascomycin derivative SDZ ASM 981 is effective for psoriasis when used topically under occlusion. Br J Dermatol. 1998;139:992–996. 45. Gribetz C, Ling M, Lebwohl M, et al. Pimecrolimus cream 1% in the treatment of intertriginous psoriasis: A double-blind, randomized study. J Am Acad Dermatol. 2004;51:731–738. 46. Siegfried EC, Jaworski JC, Hebert A. Topical calcineurin inhibitors and lymphoma risk: Evidence update with implications for daily practice. Am J Clin Dermatol. 2013;14:163–178. 47. Tennis P, Gelfand JM, Rothman KJ. Evaluation of cancer risk related to atopic dermatitis and use of topical calcineurin inhibitors. Br J Dermatol. 2011;165:465–473. 48. McGill A, Frank A, Emmett N, Turnbull DM, BirchMachin, MA, Reynolds NJ. The anti-psoriatic drug anthralin accumulates in keratinocyte mitochondria, dissipates mitochondrial membrane potential, and induces apoptosis through a pathway dependent on respiratory competent mitochondria. FASEB J. 2005;19:1012–1014. 49. Runne U, Kunze J. Short-duration (minutes) therapy with dithranol for psoriasis: A new out-patient regimen. Br J Dermatol. 1982;106:135–139. 50. Sminkels OQ, Prins M, Veeniiuis RT, et al. Effectiveness and side effects of UVB-phototherapy, dithranol inpatient therapy and a care instruction programme of short contact dithranol in moderate to severe psoriasis. Eur J Dermatol. 2004;14:159–165. 51. Berth-Jones J, Chu AC, Dodd WA. A multicentre, parallel-group comparison of calcipotriol ointment and short-contact dithranol therapy in chronic plaque psoriasis. Br J Dermatol. 1992;127:266–271. 52. Kucharekova M, Lieffers L, van de Kerkhof PC, Van Der Valk PG. Dithranol irritation in psoriasis treatment: A study of 68 inpatients. J Eur Acad Dermatol Venereol. 2005;19:176–179. 53. de Jager ME, van de Kerkhof PC, de Jong EM, Seyger MM. Dithranol therapy in childhood psoriasis: Unjustifiably on the verge of falling into oblivion. Dermatology. 2010;220: 329–332. 54. Kanzler MH, Gorsulowsky DC. Efficacy of topical 5% liquor carbonisdetergens vs. its emollient base in the treatment of psoriasis. Br J Dermatol. 1993;129:310–314. 55. Goodfield M, Kownacki S, Berth-Jones J. Doubleblind, randomized, multicenter, parallel group study comparing a 1% coal tar preparation (Exorex) with a 5% coal tar preparation (Alphosyl) in chronic plaque psoriasis. J Dermatolog Treat. 2004;15:14–22. 56. Paghdal KV, Schwartz RA. Topical tar: Back to the future. J Am Acad Dermatol. 2009;61:294–302. 57. Langner A, Wolska H, Hebborn P. Treatment of psoriasis of the scalp with coal tar gel and shampoo preparations. Cutis. 1983;32:290–291, 295–296.

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58. Zelchner JA. Use of topical coal tar foam for the treatment of psoriasis in difficult-to-treat areas. J Clin Aesthet Dermatol. 2010;3:37–40. 59. Alora-Palli MB, Perkins AC, VanCott A, Kimball AB. Efficacy and tolerability of a cosmetically acceptable coal tar solution in the treatment of moderate plaque psoriasis: A controlled comparison with calcipotriene (calcipotriol) cream. Am J Clin Dermatol. 2010;11:275–283. 60. Serrao R, Davis M. Goeckerman treatment for remission ofpsoriasis refractory to biologic therapy. J Am Acad Dermatol. 2009;60:348–349. 61. Fitzmaurice S, Bhutani T, Koo J. Goeckerman regimen for management of psoriasis refractory to biologic therapy: The University of California San Francisco experience, J Am Acad Dermatol. 2013;69: 648–649. 62. Hendriks AG, Keijsers RR, de Jong EM, Seyger MM, Van de Kerkhof PC. Combinations of classical time-honouredtopicals in plaque psoriasis: A systematic review. J Eur Acad Dermatol Venereol. 2013;27:399–410. 63. Sutton RL. Diseases of the Skin, Fifth Edition. St Louis, MO: CV Mosby, 1923. 64. Arnold WP. Tar. Clin Dermatol. 1997;15:739–744. 65. Pion IA, Koenig KL, Lim HW. Is dermatologic usage of coal tar carcinogenic? A review of the literature. Dermatol Surg. 1995;21:227–231. 66. Kubasiewicz M, Starzynski Z. Cancer of the skin in Poland related to occupational factors. Med Pr. 1987;38:441–446. 67. Mukhtar H, Link CM, Cherniack E, Kushner DM, Bickers DR. Effect of topical application of defined constituents of coal tar on skin and liver aryl hydrocarbon hydrolase and 7-ethoxycoumarin diethylase activities. Toxicol Appl Pharmacol. 1982;64: 541–549. 68. Roelofzen J, Aben K, Khawar A, van de Kerkhof PC, Kiemeney LA, Van Der Valk PG. Treatment policy for psoriasis and eczema: A survey among dermatologists in the Netherlands and Belgian Flanders. Eur J Dermatol. 2007;17:416–421. 69. Katz HI, Tanner DJ, Cuffie CA. A comparison of the efficacy and safety of the combination mometasone furoate 0.1%–salicylic acid 5% ointment with each of its components in psoriasis. J Dermatolog Treat. 1998;9:151–156. 70. Carroll CL, Clarke J, Camacho F, Balkrishnan R, Feldman SR. Topical tacrolimus ointment combined with 6% salicylic acid gel for plaque psoriasis treatment. Arch Dermatol. 2005;141:43–46. 71. Madan RK, Levitt J. A review of toxicity from topical salicylic acid preparation. J Am Acad Dermatol. 2014;70:788–792. 72. Asztalos ML, Heller MM, Lee ES, Koo J. The impact of emollients on phototherapy: A review. J Am Acad Dermatol. 2013;68:817–824.

73. Bissonnette R, Bolduc C, Maari C, et al. Efficacy and safety of topical WBI-1001 in patients with mild to moderate psoriasis: Results from a randomized double-blind placebo-controlled, phase II trial. J Eur Acad Dermatol Venereol. 2012;26:1516–1521. 74. Nam S, Buettner R, Turkson J, et al. Indirubin derivatives inhibit Stat3 signaling and induce apoptosis in human cancer cells. Proc Natl Acad Sci USA. 2005;102:5998–6003. 75. Boniface K, Bernard FX, Garcia M, Gurney AL, Lecron JC, Morel F. IL-22 inhibitsepidermal differentiation and induces proinflammatory gene expression and migration of human keratinocytes. J Immunol. 2005;174:3695–3702. 76. Miyoshi K, Takaishi M, Digiovanni J, Sano S. Attenuation of psoriasis-like skin lesion in a mouse model by topical treatment with indirubin and its derivative E804. J Dermatol Sci. 2012;65:70–72. 77. Nazarian R, Weinberg JM. AN-2728, a PDE4 inhibitor for the potential topical treatment of psoriasis and atopic dermatitis. Curr Opin Investig Drugs. 2009;10:1236–1242. 78. Beutner, K. 2012. AN2728 Clinical Data in Psoriasis. http://www.files.shareholder.com /ANAC_Investor_ Day_Part_3b_minimized.pdf 79. Punwani N, Scherle P, Flores R, et al. Preliminary clinical activity of a topical JAK1/2 inhibitor in the treatment of psoriasis. J Am Acad Dermatol. 2012;67:658–664. http://www.ncbi.nlm.nih.gov/pub med/?term=J+Am+Acad+Dermatol+10.1016%2Fj. jaad.2011.12.018 80. Ports WC, Khan S, Lan S, et al. A randomized phase 2a efficacy and safety trial of the topical Janus kinase inhibitor tofacitinib in the treatment of chronic plaque psoriasis. Br J Dermatol. 2013;169:137–145. 81. Nakamura M, Toyoda M, Morahashi M. Pruritogenic mediators in psoriasis vulgaris: Comparative evaluation of itch-associated cutaneous factors. Br J Dermatol. 2003;149:718–730. 82. Roblin D, Yosipovitch G, Boyce B, et al. Topical TrkA kinase inhibitor CT327 is an effective, novel therapy for the treatment of pruritus due to psoriasis: Results from in vitro and tissue experimental studies, and efficacy and safety of CT327 in a phase 2b, randomised, double-blind, vehicle-controlled clinical trial in patients with psoriasis. Acta Derm Venereol. 2015;95(o5):542–548. http://www.ncbi.nlm.nih.gov/ pubmed/?term=ct327 [Epub ahead of print] 83. Pipeline in Review. 2015. Dermipsor Reports Positive Phase 2b Results Showing Efficacy and Synergy of its Leading Product DPS-101, a Non-Steroidal Combination Drug to Treat Psoriasis. http://www .pipelinereview.com/index.php/2008102923043/ Small-Molecules/Dermipsor-Reports-PositivePhase-2b-Results-Showing-Efficacy-and-Synergyof-its-Leading-Product-DPS-101-a-Non-SteroidalCombination-Drug-to-Treat-Psoriasis.html.

21 Phototherapy and photochemotherapy FARHAAD R. RIYAZ and HENRY W. LIM OVERVIEW Sunlight has been used in the treatment of psoriasis for hundreds of years. The Dead Sea Depression is an area of land below sea level along the Israeli–Jordanian border that, for centuries, has been a place of pilgrimage for patients with psoriasis seeking a natural remedy for their disease. Four hundred meters below sea level, it is believed that the sun,s rays are filtered on their descent and those rays that reach ground level are effective for treating psoriasis. Scientific investigation of phototherapy began in the late 1800s with Niels Ryberg Finsen, a Faroese– Danish physician of Icelandic descent, who won the Nobel Prize in Medicine in 1903 for his work using refractive sunlight to treat cutaneous tuberculosis. It is now known that the ultraviolet (UV) light spectrum contains two distinct regions of biologic and therapeutic significance, UVB (290–320 nm) and UVA (320–400 nm). UVB is now the most widely used form of phototherapy. In the 1920s, William Goeckerman at the Mayo Clinic began administering UV therapy using b ­ road-spectrum quartz mercury vapor lamps.1 Narrowband UVB (NB-UVB, 311–313 nm) was introduced in 1988 when the Philips TL-01 lamp was shown to be effective and superior to the broadband UVB (BB-UVB) Philips TL-12 lamp, requiring fewer treatments and producing less erythema.2 Figure 21.1 shows where UV light falls on the electromagnetic spectrum, and Figure 21.2 shows how different wavelengths of UV light have different depths of penetration into the skin. UVA is used in combination with topical and systemic photosensitizers to treat psoriasis. Psoralen coadministered with UVA light (PUVA) was first studied in 1974 by John Parrish and his colleagues, who demonstrated its efficacy, leading to its approval by the U.S. Food and Drug Administration (FDA) in 1982.3 Although PUVA is a form of photochemotherapy, for simplicity, the term “phototherapy” will be used in this chapter to refer to both UVB and PUVA therapy. Table 21.1 shows characteristics of

the different phototherapeutic modalities used in the treatment of psoriasis. In the era of biologics and targeted immune modulators, NB-UVB remains one of the most cost-effective treatments for moderate to severe psoriasis.5 It can be used in most patients safely, including in children and during pregnancy, and it works well for scalp and palmoplantar disease. Phototherapy can be performed in the office or at home and can be effective even in patients who have failed systemic therapies.6 In a study published in 2012, NB-UVB is the dermatologists’ preferred firstline treatment for moderate to severe psoriasis in healthy adult patients.7

MECHANISM OF ACTION It was originally thought that the activity of UV light in treating psoriasis was due to alteration of DNA and subsequent inhibition of cellular replication. Recent evidence has emerged showing that psoriasis is an immunologic disease and the immunosuppressive effects of UV light have become better appreciated. Both UVA and UVB are immunosuppressive in the skin by their direct effects on antigen-presenting Langerhans cells, decreasing the migration of these cells and the cell surface expression of major histocompatibility and costimulatory molecules. UV light also has indirect effects on cytokines and adhesion molecules, causing changes in T regulatory cells and leading to a switch from a T-helper 1 to a T-helper 2 phenotype, as well as inducing direct apoptosis in T effector cells.8,9 BB-UVB, NB-UVB, and PUVA can all induce apoptosis of T lymphocytes.10–12

General contraindications Table 21.2 outlines the relative and absolute contraindications to delivering phototherapy. Because the action spectrum of almost all photosensitizing medications is in the UVA range, PUVA should be used with caution

203

204  Phototherapy and photochemotherapy

in patients taking these medications. The photocarcinogenic effect of PUVA is well established; as such, in those younger than 18 years, other treatment options should be explored before deciding on PUVA therapy. The total number of treatment sessions with PUVA should be monitored, as it is known that greater than 200 PUVA treatments is associated with increased photocarcinogenicity, especially in fair-skinned individuals. Although psoralens have not been shown to be teratogenic, it is common practice not to administer PUVA to women who are pregnant or nursing. In addition, patients who are claustrophobic, unable to stand, unable to regularly attend treatment sessions, or cannot comply with keeping their goggles on while in the phototherapy booth are poor candidates for phototherapy. A clear treatment protocol should be established and a well-trained nurse or technician should closely monitor each patient’s treatment. Any abnormal findings should be communicated to the supervising dermatologist. X-rays

10−2

UVC

200

UVB

280

UVA

320

Infrared rays

Visible light

400

700

106

λ (wavelength, nm)

Figure 21.1  The light spectrum. UVA

UVB

UVC

UVB PHOTOTHERAPY The modern era of phototherapy started with William H. Goeckerman, who first described the use of artificial UV light in combination with crude coal tar for the treatment of psoriasis, delivered as an inpatient procedure.2 Later it was found that clear emollients improve the optical properties of the skin and enhance the efficacy of UVB,13,14 and this helped shift UVB phototherapy to an outpatient modality.15–17 In 1981, it was conclusively shown that the most effective wavelength in clearing psoriasis was 313 nm and that suberythemogenic doses of 313 nm light were sufficient to produce significant improvement of psoriasis.18,19 Irradiation with UVB results in the formation of pyrimidine dimers, membrane lipid peroxidation, decreased numbers of Langerhans cells, alteration of the secretion of cytokines by macrophages, and generation of transcriptional factors.9,20,21 Th17 cells, now understood to play a central role in psoriasis, are also decreased by exposure to UVB.22 Last, UVB irradiation triggers a decrease in the rate of differentiation of keratinocytes by interfering with the synthesis of proteins and nucleic acids.

Indications UVB therapy is an appropriate option for patients with an inadequate response to topical treatments, or those with involvement of a large body surface area. It is also useful in patients with guttate psoriasis. It is effective for plaques of minimal to moderate thickness; however, because of limited penetration, it does not work well as monotherapy on very thick plaques.

Efficacy

Figure 21.2  Penetration of ultraviolet light into the skin.

BB-UVB has been known to be effective in the treatment of psoriasis. Early studies showed resolution of psoriasis in >70% of patients treated with erythemogenic doses of outpatient or home UVB therapy,23,24 and Levine and Parrish combined petrolatum with BB-UVB showing complete clearance in 26 outpatients.17 A randomized double-blind trial comparing PUVA and NB-UVB in 93 patients showed that 65%

Table 21.1  General characteristics of ultraviolet (UV)A and UVB for the treatment of psoriasis. Wavelength (nm)

Onset of erythema (hours)

Depth of penetration

Frequency of visits per week

Efficacy4

BB-UVB

290–320

12–24

2–3

+

NB-UVB

311–313

12–24

2–3

++

PUVA

320–400

24–96+

Lower epidermis to upper dermis Lower epidermis to upper dermis Into mid-dermis

2–3

+++

Modality

Abbreviations: 

BB-UVB, broadband UVB; NB-UVB, narrowband UVB; PUVA, psoralen coadministered with UVA light.

UVB phototherapy  205

Table 21.2  Contraindications to phototherapy. Relative

Absolute

Intake of photosensitizing medications (especially for PUVA therapy) or immunosuppressive medications

Xeroderma pigmentosum

History of skin cancer (melanoma or nonmelanoma)

Lupus erythematosus

History of atypical nevi, or multiple risk factors for melanoma

Pregnancy or nursing (for PUVA only)

History of arsenic ingestion

–

Prior ionizing radiation therapy

–

Age <18 years (for PUVA only)

–

Abbreviation:  PUVA, Psoralen coadministered with UVA light.

of patients achieved clearance in 30 treatments.25 Remission times are prolonged with maintenance therapy.26–28 NB-UVB is now established to be superior to BB-UVB therapy.2,29–32 One study demonstrated that 40% of patients treated with one modality to each arm of their body had superior results on the arm treated with NB-UVB.29 Other studies have determined that NB-UVB results in more rapid clearing.2,33 NB-UVB treatment is also more likely than BB-UVB to lead to histopathological resolution of psoriasis lesions (88% compared with 59%).34 Finally, NB-UVB is associated with long disease remission; in one study of 101 cases (63 patients, some with more than 1 cycle of phototherapy) treated with NB-UVB and a mean follow-up period of 9.5 months, psoriatic re-exacerbation occurred in 65% of patients after 9.2 months, with a range of 1–35 months of remission.35

Dosage and scheduling The initial dose of UVB may be based on the minimal erythema dose (MED) or the Fitzpatrick skin type of the patient,36 with subsequent doses adjusted based upon the patient’s tolerance for the treatment. Although there are minor variations in the treatment protocols used at different phototherapy centers and offices, Table 21.3 shows dosing guidelines for NB-UVB according to Fitzpatrick skin type. For MED-based dosing, the initial dose is 50%–70% of the MED, and one may increase the dose by 5%–10% per treatment as tolerated. Maximal doses are identical to those of the skin type-based protocol. Table 21.4 explains how to adjust dosing if a patient misses treatment sessions, based upon treatment guidelines at the Henry Ford Hospital. Newer UVB phototherapy devices are equipped with an internal dosimeter that calculates the amount of time that a prescribed does is delivered. As the output from the lamps decreases over time, the treatment duration needed to deliver the appropriate dose increases proportionally. It is recommended that lamps should be replaced once their output has dropped to <50% of their original output. To avoid unevenness in the radiation

Table 21.3  Dosing guidelines for narrowband UVB. According to skin type Skin type I II III IV V VI

Initial UVB dose, mJ/cm2

UVB increase after each treatment, mJ/cm2

Maximum dose, J/cm2

100 220 260 330 350 400

15 25 40 45 60 65

2 (body), 1 (face) 2 (body), 1 (face) 3 (body), 1 (face) 3 (body), 1 (face) 5 (body), 1 (face) 5 (body), 1 (face)

Source: Adapted from Menter A et al., J Am Acad Dermatol, 62,114– 135, 2010. Note:  Administered 3×/wk.

Table 21.4  Dose adjustments for missed UVB treatments. If patient misses treatment Amount of time missed

Dose adjustment

1–3 treatments Miss 1–2 weeks Miss 2–3 weeks Miss 4 weeks

Hold dose Decrease dose by 25% Decrease dose by 50% Restart at initial dose

Source: Derived from treatment protocol used at Henry Ford Hospital, Department of Dermatology, Detroit, MI.

delivered to the skin, all lamps in a booth should be replaced at the same time. Once a satisfactory response has been achieved, it is common practice to taper phototherapy rather than to abruptly discontinue treatment. After 12 weeks of NB-UVB, patients who received NB-UVB twice weekly for 4 weeks and then NB-UVB once weekly for 4 weeks were 22% more likely to be in remission at 1 year compared with patients who did not receive tapering of phototherapy.23

206  Phototherapy and photochemotherapy

Toxicity Acute side effects of UVB therapy include sunburn-like erythema, pruritus, burning, stinging, and blistering. 37 Reactivation of herpes simplex virus infection is also possible. Patients with known photosensitivity (e.g., lupus erythematosus) are poor candidates for UVB therapy (Table  21.2). Caution should be exercised in patients with history of multiple nonmelanoma skin cancers or melanoma. Because NB-UVB has been shown to decrease serum folic acid levels, and folic acid deficiency is known to be associated with the development of neural tube defects, serum folic acid levels should be measured in pregnant patients (especially in the first trimester) who are receiving phototherapy. Supplementation with 0.5 mg/day of folic acid is the general recommendation; alternately, there should be consultation with the patient’s obstetrician. 38 It should be noted that the action spectrum of the vast majority of oral medications is in the UVA range; because NB-UVB lamps emit negligible amount of UVA, it is safe for patients on most oral photosensitizing medications to receive NB-UVB therapy. The use of goggles is recommended to decrease the risk of cataract formation. Standard practice involves covering the face and genitals in men as long as there is no active psoriasis in these areas. Minimizing facial exposure by delivering lower doses of UVB is another common practice, as lesions on the face tend to respond to lower doses of UVB. Long-term side effects are those of photoaging, including wrinkling, lentigines, and telangiectasias. Photocarcinogenesis is a theoretical adverse effect of UVB phototherapy, but studies have failed to show this effect. 39–41 Some studies show NB-UVB to be as phototoxic as BB-UVB, 34,42 but others report conflicting data. 29,31 Because NB-UVB is more efficacious, patients receive lower total MED equivalent NB-UVB doses compared with BB-UVB doses, hence they are likely to be at a lower risk of photocarcinogenesis.40 In a review of 3867 patients treated with NB-UVB, 352 patients received >100 treatments and there was no significant association found with basal cell carcinoma, squamous cell carcinoma (SCC), or melanoma with a median follow-up period of 5.5 years.41

Special populations who may benefit from NB-UVB UVB therapy is not known to have teratogenicity and has been used successfully in the treatment of psoriasis in pregnant women.43–46 The dosing schedule usually does not require modification. Pregnant patients should be counseled about the possibility of developing melasma.

No studies have documented the long-term safety of UVB phototherapy in childhood psoriasis, but it is generally accepted as nonimmunosuppressive and safe to use as a second-line therapy in children after failure of topical treatments. It is important that the patient is able to follow proper instruction while receiving treatment, especially keeping their goggles in place and not touching the lamps. In a retrospective review of 77 children treated with NB-UVB, phototherapy was well tolerated. Clearance was observed in 63% of the 35 children with psoriasis.47 The elderly population is another patient group in which phototherapy is a viable option. Phototherapy reduces the burden of the treatment regimen at home and minimizes the need for systemic treatment; there is also less concern for long-term carcinogenicity in seniors. Limitations of phototherapy for elderly patients include difficulty standing for the duration of treatment and inability to travel to frequent appointments. These patients should be advised to moisturize aggressively, as initially phototherapy can exacerbate xerosis and pruritus, which are already common in the elderly.

Home UVB Home UVB has been available for many years and is now even available in combs and brushes for targeted delivery to the scalp. 23 A single-blinded randomized clinical trial from the Netherlands of 196 patients demonstrated that home NB-UVB was as effective as clinicadministered NB-UVB, with about 70% of patients in each group reaching PASI 50.48 Quality of life improved equally between the groups but patients using home NB-UVB rated their experience more positively than those coming to clinic. Home UVB is appropriate for select patients: those known to respond to UV therapy from prior sessions in the office, those able to follow the instructions of selfadministered phototherapy, and those who are compliant with follow-up visits. The standard and least expensive home phototherapy unit consists of a flat panel with four 6-foot lamps, though more sophisticated units are available having additional lamps that are housed in multiple panels, which can be positioned to encircle the body. Newer units come with an internal dosing meter, allowing the patient to set a specified UVB dose and be sure they are receiving the correct dose. Furthermore, almost all units are programed to deliver only a given number of treatments. After a number of treatments have passed, the patient is required to contact the physician to obtain a code that allows the unit to deliver additional treatments. These two practical improvements allow the dermatologist to know the precise treatment doses that the patient has been receiving and prevent the delivery of long-term, unsupervised home phototherapy (Figure 21.3).

UVB combination therapy  207

calcipotriol in combination with UVB required fewer UVB exposures (twice weekly UVB rather than thrice weekly)59,60; in contrast, earlier studies did not show this benefit.61,62 Topical retinoids, such as tazarotene, have also been used in combination with UVB. They may improve the therapeutic efficacy and reduce the cumulative UVB dose necessary—albeit with an increased risk of irritation. A randomized study of 40 patients treated with UVB and 0.1% tazarotene revealed a 75% improvement in the plaques at a median of 28 days earlier than that with UVB monotherapy.63

Combination UVB with PUVA UVB has been combined with PUVA to bring more rapid clearing. One study of 42 patients showed that when treated with both modalities together, patients cleared with 18% of the UVB dose normally required for clearance.64 However, this combination of therapies is not frequently used due to the known carcinogenic effects of PUVA and the concern for additive or synergistic effects with added UVB radiation.

Figure 21.3  A narrowband UVB therapy unit.

Combination UVB with traditional systemic therapies

UVB COMBINATION THERAPY

Systemic agents have been used in conjunction with UVB in the treatment of psoriasis. The most commonly used traditional systemic treatments include methotrexate, cyclosporine, and acitretin. Methotrexate is thought to have a synergistic effect with UVB, allowing for lower doses of UV radiation and quicker clearance of lesions but with the risk of having a flare in activity once phototherapy is stopped.65,66 The duration of methotrexate combined with UVB should be kept at a minimum as the potential for increased carcinogenicity is unknown. UVB is not commonly used in combination with cyclosporine due to the increased frequency of skin cancer seen in patients treated with cyclosporine. One study has shown that cyclosporine may decrease the number of UVB treatments and total UVB dose during treatment.67 Although cyclosporine has been used in combination with UVB safely for short periods of time, there are no studies documenting the long-term safety of this combination. When combined with phototherapy, retinoids such as acitretin grant clearance of disease with lower doses of both UVB and acitretin compared with these therapies alone.68 This is the case when acitretin is used with either NB-UVB or BB-UVB.69,70 This combination is frequently beneficial in patients with thick lesions. If UVB dosing is being performed by skin type rather than MED, or if the oral retinoid is added while the patient is already receiving phototherapy, a 25%–33% reduction in UVB dose is

Combination of UVB with topical modalities Goeckerman therapy1 and the Ingram regimen49 combine UV therapy with topical tar and anthralin, respectively. The observation that suberythemogenic doses of UVB therapy are effective when used in combination with crude coal tar50 paved the way for the use of less aggressive UVB therapy regimens by using a combination of treatments. An emollient is typically applied before UV exposure based on the understanding that it enhances the UV penetration on the skin by minimizing the reflection and scattering of photons by psoriatic scales. Topical corticosteroids, though effective in psoriasis, do not provide any extra benefit when administered concomitantly with UVB when compared with UVB monotherapy. Patients may experience more rapid clearing of psoriasis initially,51 but with no higher clearance rate in the end. Furthermore, they may be at higher risk of relapse with a shorter time to relapse.52–55 Vitamin D analogs such as calcipotriol have also been combined with UVB. As some vitamin D analogs are photolabile,56,57 they should be applied after UV exposure rather than before. In a study comparing UVB given with calcipotriol to each therapy alone, a reduction in relapse rate was reported with combination therapy.58 Two randomized controlled trials showed that patients using

208  Phototherapy and photochemotherapy

recommended to account for the thinning of epidermis caused by the retinoid; the dose may then be increased based on the protocol used.

Combination UVB with biologic agents Large studies that compare the effectiveness of biologics and phototherapy used concomitantly against the effectiveness of each therapy used alone do not exist.71 In studies involving small numbers of patients, NB-UVB appears to increase the efficacy of etanercept, adalimumab, and ustekinumab when used as an adjunct. The combination of etanercept and thrice weekly NB-UVB appears well tolerated and effective at bringing PASI 75 or greater in studies of 25–86 patients.72–74 NB-UVB was also shown to bring additional benefit in a study of 75 patients not reaching PASI-90 after 12 weeks of etanercept therapy.75 A study of 20 patients showed the combination of NB-UVB and adalimumab to be effective in achieving a PASI 75 response or greater,76 and a half-body study assessing the combination of NB-UVB with adalimumab showed a benefit of the addition of NB-UVB in four patients.77 NB-UVB administered with ustekinumab in a half-body study of nine patients showed that the combination may bring quicker PASI reduction than ustekinumab alone.78 Studies that evaluate the long-term safety of combining phototherapy with biologic agents are still needed.

TARGETED PHOTOTHERAPY When the 308-nm monochromatic and coherent xenonchloride excimer laser became available in 1997, it became possible to administer phototherapy to treat confined psoriatic lesions.79 The excimer laser has the inherent advantage of decreasing collateral damage to surrounding normal skin. Therefore, its dose can be tailored to the patient’s constitutive skin phototype, the thickness and scaliness of their lesions, and the body site being treated. The chromophore of this laser is cellular DNA; the laser induces expression of proteins related to cell death and causes physical breakage of DNA strands in T lymphocytes.80,81 This leads to a decrease in epidermal proliferation and a decrease in T-cell populations as deep as the reticular dermis (Figure 21.4).82

Indications Excimer laser therapy is an appropriate option for patients with limited disease or hard-to-expose areas, such as the skin folds or scalp.83–93 It can be used as a supplement for patients with residual limited disease after other treatments. It also works moderately well for palmoplantar psoriasis.86 It does not have any contraindications beyond the general precautions for UV light therapy.

Figure 21.4  An excimer laser unit. Efficacy A number of studies have shown impressive results with use of the 308-nm excimer laser. In one study, 84% of patients achieved greater than 75% clearance after just two treatments87; multiple other studies have shown almost complete clearance with as few as 6–10 treatment sessions or 3–4 weeks of treatment.88,89 With as little as one treatment, it is possible to clear psoriasis with moderate remission, though this is uncommon.90 An incoherent 308-nm lamp, known as the excimer lamp, is also available. Incoherent light sources have lower costs than laser sources and can treat larger areas more easily. A study of 31 patients showed improvements that were not statistically different between those treated with excimer laser and those treated with excimer lamp.91 Most patients have some sustained results up to 1 year after termination of treatment,92 but mean disease remission appears to be around 3–4 months after stopping light delivery.88

Dosage and scheduling There is a paucity of evidence regarding the optimal dosing and scheduling of excimer laser treatment sessions. Most protocols call for twice weekly dosing; a review of seven protocols showed that excimer treatments were

PUVA photochemotherapy  209

Table 21.5  Dosing guidelines for excimer laser. According to skin type Skin type I II III IV V VI

Initial dose for thin plaque, mJ/cm2

Initial dose for moderately thick plaque, mJ/cm2

150 200 250 300 350 400

200 300 400 500 600 700

Initial dose for severely thick plaque, mJ/cm2 300 450 600 750 900 1050

Source:  Derived from treatment protocol used at Henry Ford Hospital, Department of Dermatology, Detroit, MI. Note:  Administered 3×/wk.

effective regardless of the initial dosage, the dose fluency, or the number of treatments, reflecting the need for more study in this area.92 Doses in the 1–3 MED range are normally used as starting doses with subsequent dose adjustment based on the patient’s response. Rather than using the MED to guide dosing, most providers determine dosing by using the Fitzpatrick skin type and plaque thickness. A dosing guideline implemented at the Henry Ford Hospital using this strategy is shown in Table 21.5. As with NB-UVB therapy, at least 24 hours should be left between treatments to properly evaluate the UVB-induced erythema, which peaks at 24 hours; ideally patients should be scheduled for two or three sessions weekly. An increase of 5%–15% of the dose with each subsequent visit is recommended to account for photoadaptation as long as there is only mild asymptomatic erythema between treatments. The maximum dose per session is 3 J/cm2 for the body and 1 J/cm2 for the face. Most treatment plans last 15–20 sessions. There are no studies evaluating whether there is a benefit to tapering the treatment frequency before discontinuing excimer laser therapy. Most centers and practitioners abruptly discontinue excimer laser without tapering it.

Toxicity Adverse effects of excimer laser are fortunately limited to the treated area due to the spot size of 1–3 cm. At higher doses, excimer laser is more efficacious but also more likely to cause erythema, blistering, and erosions.90,93 Another commonly reported side effect is hyperpigmentation, especially in perilesional areas.87–89 Excimer laser is safe in pregnancy and in the pediatric population. No data are available on the long-term safety of the excimer laser, although the potential carcinogenic risk is very low due to the limited area treated and the short duration of therapy, as most treatments are completed in 15–20 sessions.

PUVA PHOTOCHEMOTHERAPY PUVA is an acronym standing for psoralen (P) and UVA. It is the term applied to the group of therapeutic techniques that use psoralens (natural and synthetic furocoumarins,

found in foods such as figs and celery) to presensitize skin cells to the effects of 320–400 nm light. Ancient Egyptians knew that natural photosensitizing compounds found in vegetables could be combined with exposure to natural sunlight for the successful treatment of vitiligo. Trimethylpsoralen, a synthetically produced psoralen, was first used for the treatment of vitiligo in combination with sunlight. In the 1970s, oral ingestion of 8-methoxypsoralen (8-MOP) combined with high-intensity UVA was shown to be effective for the treatment of psoriasis3; in 1982, this treatment was FDA approved for psoriasis. PUVA has since been used to successfully treat many other inflammatory photoresponsive diseases such as cutaneous T-cell lymphoma, atopic dermatitis, and lichen planus.94 The only oral psoralen available in the United States is 8-MOP; in Europe, the less phototoxic 5-methoxypsoralen is also available. The latter causes less nausea. 8-MOP solution is used for topical PUVA (mostly for palmar and plantar psoriasis). In Europe, psoralens dissolved in water are also used for bath PUVA. Psoralens work by intercalating into DNA and linking the strands together when exposed to UVA, resulting in the formation of cross-links and cyclobutane adducts that impair DNA synthesis. PUVA also promotes the formation of reactive oxidation species, induces apoptosis, and reduces the production of cytokines and the expression of intercellular adhesion molecules.9 UVA light has similar epidermal effects to those of UVB but in addition penetrates deeper into the dermis to affect dendritic cells, fibroblasts, endothelial cells, mast cells, and inflammatory cells.95 Despite its efficacy, PUVA currently is not commonly used due to the intermittent availability and cost of 8-MOP, and because of its known photocarcinogenic effect. Furthermore, there are advantages posed by NB-UVB: ease of administration, efficacy that is almost similar to PUVA, and a better long-term safety profile.

Indications Because UVA penetrates deeper than UVB, PUVA is useful for patients with darker skin types and those with thick plaques. Topical PUVA is an excellent treatment option for diffuse palmar plantar psoriasis.

210  Phototherapy and photochemotherapy

Efficacy PUVA is well known to be highly efficacious and has the potential to achieve remission of disease. Systematic reviews of studies examining the efficacy of PUVA demonstrate that between 70% and 100% of patients achieve clearance of lesions usually in less than 12 weeks and stay in remission for 3–6 months.96,97 There are two large studies that show the efficacy of oral PUVA in psoriasis, one using the minimal phototoxic dose for initial dosing and the other using the Fitzpatrick skin type.98,99 The two studies vary in their protocols for stepwise dosage increases, yet 89% of patients in both studies achieved skin clearing, although with a difference in overall UVA dose. Similar to UVB phototherapy, once clearance has been achieved, PUVA is often decreased from thrice weekly to twice weekly for 4 weeks, and then to once weekly for 4 weeks. The UVA dose is not increased once the patient is on this once-weekly regimen. If the patient continues to do well, treatment can then be discontinued. Two forms of PUVA exist: systemic treatment (oral PUVA) and localized treatment (topical and bath PUVA). Topical PUVA therapy consists of the application of 1% 8-MOP solution compounded in a hydrophilic lotion to achieve a final concentration of 0.1% to the skin followed by exposure to UVA 10–15 minutes later. Bath PUVA consists of a 30-minute bath in 2 L of warm water that contains 1 mL of 10 mg/mL of 8-MOP in ethanol. Several studies show that bath PUVA works as well as oral PUVA but with much lower required cumulative UVA doses.100–103 Because of the resources involved in delivering bath PUVA, it is rarely used in the United States. Topical PUVA avoids many of the side effects of oral psoralens; however, it has a narrow safety window and hence a higher probability of causing significant phototoxicity, including blisters (Figure 21.5).

PUVA compared with NB-UVB Several studies have shown the superior efficacy of PUVA compared with NB-UVB in the treatment of psoriasis,25,104,105 although studies exist that show no difference in time to clearance or remission duration.106 Unfortunately, these studies used varying treatment protocols for both PUVA and NB-UVB. PUVA shows better rates of clearance than NB-UVB in larger studies and one meta-analysis.107,108 PUVA demonstrates clearance in more patients with fewer treatment sessions, and with a higher probability of remission at 6 months compared with NB-UVB.25

Dosing 8-MOP should be taken 1 hour prior to UVA radiation exposure, as its peak serum concentration is around 1–1.5 hours after ingestion. It is given as 0.4–0.5 mg/kg of ideal body weight; the dose may be increased up to 0.6 mg/kg

Figure 21.5  A

hand/foot psoralen coadministered with

UVA light unit.

in resistant cases. The maximum recommended dose is 70 mg, regardless of body weight. The greatest absorption of 8-MOP occurs on an empty stomach, but better tolerance of 8-MOP occurs when patients take it with small meal, such as a light breakfast of a piece of toast and a glass of milk. This minimizes the nausea experienced by many patients. It is suggested that this meal be consistent in size, type, and timing from day to day to minimize variations in 8-MOP absorption. 8-MOP is metabolized in the liver. Treatments are given two to three times weekly, but not on successive days as the peak of PUVA-induced erythema occurs 48–72 hours after exposure. UVA dosing guidelines, based on the Fitzpatrick skin types, are provided in Table 21.6. The dose should not increase if there is transient erythema from the prior treatment. The next session should be skipped if there is persistent erythema from the last treatment.109 General guidelines regarding UVA phototherapy are found in Table 21.7.

Toxicity Studies have found slightly higher rates of acute toxicity with PUVA compared with NB-UVB.110 Acute cutaneous toxicities caused by PUVA include erythema, exanthems, pruritus, xerosis, friction blisters, Köebnerization, development of polymorphous light eruptions, herpes simplex virus reactivation, photo-onycholysis, dyspigmentation, and melanonychia.

PUVA photochemotherapy  211

Table 21.6  Dosing of UVA for oral psoralen coadministered with UVA light (PUVA). Skin type I II III IV V VI

Initial UVA dose, J/cm2

Dosage increase per treatment, J/cm2

Maximum dose per treatment, J/cm2

1–1.5 2–2.5 3–3.5 4–4.5 5–5.5 6–6.5

0.5–1.5 0.5–1.5 1.0–2.5 1.0–2.5 1.5–3.5 1.5–3.5

8 (body), 4 (face) 8 (body), 4 (face) 12 (body), 4 (face) 12 (body), 4 (face) 20 (body), 4 (face) 20 (body), 4 (face)

Source:  Adapted from Menter A et al., J Am Acad Dermatol, 62,114–135, 2010.

Table 21.7  General guidelines for administration of UVA phototherapy. Dose modifications Circumstance

Dose adjustment

Patient starts new medication with photosensitizing potential (e.g., thiazide diuretic, doxycycline, minocycline) Mild redness develops Severe redness develops

Decrease dose by 30%, then increase again per protocol Hold dose for 1–2 treatments, then increase again per protocol Decrease dose by 10%, hold decreased dose for 1–2 treatments, and then increase by 5% as tolerated

Source:  Derived from treatment protocol used at Henry Ford Hospital, Department of Dermatology, Detroit, MI.

8-MOP (oxsoralen) is known to cause central nausea in 20%–30% of patients that correlates with its peak serum levels. Nausea can be managed by the consumption of food containing milk or ginger, anti-emetics or reduction in the 8-MOP dose. Spacing the doses apart by 30 minutes can also be helpful. Psoralens are reported to rarely cause hepatitis and bronchoconstriction in some patients. Chronic effects of PUVA include the development of acquired widespread dark brown macules (also known as PUVA lentigines) and less commonly, hypertrichosis.98 Psoralens are thought to increase the risk of cataract formation, therefore patients undergoing PUVA must wear UV-protective sunglasses when outdoors on the day of treatment after the ingestion of psoralen.111 The most significant chronic effect is a dose-related increase in cutaneous SCC development in Caucasian patients who receive oral PUVA,112–115 although this has not been shown in those who undergo bath PUVA.116,117 This risk is much higher in patients who receive high doses of PUVA: after 200 treatments, 50% of patients will develop at least one SCC and 33% will develop at least one basal cell carcinoma.118 Men are recommended to cover their genitals during irradiation to mitigate the known increased risk of SCC of the genitalia.119 There is a controversial association between the use of oral PUVA and melanoma development. Data from Europe suggest that there is no increased risk,120,121 but studies from the United States indicate a possible latent risk.122–125

Pregnancy Oral psoralen has been given a pregnancy category of C. Studies have shown that women who are receiving PUVA around the time of conception or during the first trimester do not have a higher rate of congenital anomalies in their children, but do have a higher risk of delivering a lowbirthweight infant.126 The effects of topical PUVA on infants of women with psoriasis have not been studied. A study that attempted to measure plasma psoralen concentrations after topical paint PUVA administration could not detect plasma psoralen 1, 5, or 24 hours after topical PUVA.127

Pediatric use Oral PUVA is not recommended in the pediatric population because of its photocarcinogenicity. One of the five pediatric patients who received greater than 200 treatments with PUVA in the original United States cohort study developed basal cell carcinomas by the age of 17.128 Topical PUVA may be better for this group of patients, but remains a second- or third-line option.129

Contraindications PUVA requires precautions additional to those suggested for other phototherapy modalities. Patients with severe liver disease are at risk of accumulation of toxic levels of

212  Phototherapy and photochemotherapy

psoralens. Those who have previously been treated with methotrexate and cyclosporine are not ideal candidates for PUVA due to the potential increased risk for photocarcinogenesis. Patients with cataracts or uremia should also be treated with caution. Psoralen may be secreted in the breast milk of nursing mothers, causing photosensitivity in children. Drugs that cause interference with PUVA therapy include those with photosensitizing properties, including NSAIDs, statins, diuretics, antifungals, retinoids, neuroleptics, tetracyclines, sulfonamides and fluoroquinolones.130 Because the action spectrum of photosensitizing medications is in the UVA range, it is recommended that the dose of UVA be decreased by at least 30% if a patient starts a new medication that has photosensitizing potential while on treatment. Other relative and absolute contraindications to PUVA are shown in Table 21.2.

PUVA COMBINATION THERAPY Due to the long-term toxicity of PUVA, it has been administered at lower total doses alongside other medications in the hopes of a synergistic effect.131 Topical corticosteroids may help clear patients faster but may also lead to faster relapse132,133; topical calcipotriol given with PUVA appears to allow for a decrease in the duration of PUVA treatment134–136 and topical retinoids may act synergistically with PUVA.137,138 The combination of PUVA with oral acitretin is more effective than monotherapy with either agent.139–141 This combination allows for a lower number of PUVA treatments and decreased total UVA exposure.141,142 Another benefit of retinoids is that they are protective against the development of skin cancer and patients demonstrate a lower incidence of SCC when given retinoids with PUVA.143 There are no studies evaluating the combination of biologic agents with PUVA. The safety of PUVA with methotrexate is uncertain due to risk of carcinogenicity.144 PUVA should also be avoided in patients who have used cyclosporine, as both of these treatments lead to an increased risk of SCC development.145

LIMITATIONS OF PUVA Some small studies have shown that PUVA only partially improves nail psoriasis. Onycholysis, onychorrhexis, nail plate crumbling, “oil spots,” subungual hyperkeratosis, and proximal nailfold psoriasis can at least partially respond to oral PUVA, although nail pitting does not.146 The UVA used in PUVA is unable to sufficiently reach the nail bed or matrix. A study on human cadaveric fingernail plates showed that UVB light is unable to penetrate the human nail plate and only a minimal amount of UVA adequately penetrates the nail.147 There is no evidence to suggest that PUVA is helpful in psoriatic joint disease.

SUMMARY UV light therapy is efficacious, cost-effective, and well tolerated as a treatment for psoriasis; the risks and side effects are well known. UV light appeals to patients interested in avoidance of systemic and immunosuppressive agents. The major limitations are related to access: the inconvenience of travel to phototherapy treatment sites and the time commitment necessary to complete a treatment course of up to 30–60 treatments. Continued research is necessary to further elucidate mechanisms of action, optimal dosimetry, and treatment regimens of UV light in the treatment of psoriasis.148

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138. Behrens S, Grundmann-Kollmann M, Peter RU, Kerscher M. Combination treatment of psoriasis with photochemotherapy and tazarotene gel, a receptor-selective topical retinoid. Br J Dermatol. 1999;141:177. 139. Lauharanta J, Geiger JM. A double-blind comparison of acitretin and etretinate in combination with bath PUVA in the treatment of extensive psoriasis. Br J Dermatol. 1989;121:107–112. 140. Saurat JH, Geiger JM, Amblard P, et al. Randomized double-blind multicenter study comparing acitretin-PUVA, etretinate-PUVA and placebo-PUVA in the treatment of severe psoriasis. Dermatologica. 1988;177:218–224. 141. Tanew A, Guggenbichler A, Hönigsmann H, Geiger JM, Fritsch P. Photochemotherapy for severe psoriasis without or in combination with acitretin: A randomized, double-blind comparison study. J Am Acad Dermatol. 1991;25:682–684. 142. Lebwohl M. Acitretin in combination with UVB or PUVA. J Am Acad Dermatol. 1999;41:S22–S24. 143. Nijsten TE, Stern RS. Oral retinoid use reduces cutaneous squamous cell carcinoma risk in patients with psoriasis treated with psoralen-UVA: A nested cohort study. J Am Acad Dermatol. 2003;49:644–650. 144. MacKie RM, Fitzsimons CP. Risk of carcinogenicity in patients with psoriasis treated with methotrexate or PUVA singly or in combination. J Am Acad Dermatol. 1983;9:467–469. 145. Marcil I, Stern RS. Squamous-cell cancer of the skin in patients given PUVA and cyclosporin: Nested cohort crossover study. Lancet. 2001;358:1042–1045. 146. Marx JL, Scher RK. Response of psoriatic nails to oral photochemotherapy. Arch Dermatol.  1980; 116:1023–1024. 147. Stern DK, Creasey AA, Quijije J, Lebwohl MG. UV-A and UV-B penetration of normal human cadaveric fingernail plate. Arch Dermatol. 2011;147:439–441. 148. Lim HW, Silpa-archa N, Amadi U, Menter A, van Voorhees AS, Lebwohl M. Phototherapy in dermatology: A call for action. J Am Acad Dermatol. 2015;72:1078–1080.

22 Traditional systemic therapies and monitoring guidelines MARIA POLINA KONSTANTINOU and CARLE PAUL There is no commonly accepted definition of limited (mild) versus moderate or severe psoriasis. In a consensus statement from the National Psoriasis Foundation, a group of North American experts divided plaque psoriasis patients into “candidates for localized therapy” with a body surface area (BSA) <5% and “candidates for systemic and/or phototherapy” (BSA ≥5%).1 Finlay proposed the rule of tens to differentiate patients with mild psoriasis from patients with moderate to severe psoriasis, integrating BSA >10%, Psoriasis Area and Severity Index (PASI) >10, and dermatology life quality index (DLQI) >10 as the relevant criteria.2 In clinical practice estimation of psoriasis severity is a multidimensional concept taking into account patientcentered factors, disease presentation, course-related factors, and comorbidities (see Table 22.1). Patient surveys have identified pruritus as the number one bothering factor in patients with psoriasis and joint pain as the number one bothering symptom in patients with psoriatic ­arthritis.3 Currently, three conventional systemic agents— cyclosporine, methotrexate, acitretin—are approved worldwide for chronic plaque psoriasis. Their use in therapy varies from country to country based on regulatory and economic constraints. The exact choice among them is individualized and may vary according to patient, disease, and physician-associated factors.

METHOTREXATE Methotrexate is the gold standard traditional systemic treatment of psoriasis. There is considerable variation in the dosing, treatment scheme, and surveillance in the different countries worldwide.4

Mechanism of action Methotrexate is an inhibitor of the enzyme dihydrofolate reductase. Methotrexate inhibits pyrimidine and purine nucleotide synthesis and targets rapidly dividing cells. For the treatment of autoimmune and inflammatory diseases

methotrexate has an immunomodulatory effect on a­ ntigen presenting cells and T lymphocytes.

Dosing Initiation of methotrexate by oral route is preferred. Parenteral administration, at the same dose, should be considered if there is inadequate clinical response, gastrointestinal intolerance, or risk of poor compliance.5 Methotrexate should be started at 5–10 mg/week the first week. Depending on the presence of risk factors for toxicity, a rapid dose escalation over 4 weeks is recommended to reach a target therapeutic dose between 15 and 25 mg/week. The weekly doses may be lower in the elderly or in patients with slightly impaired kidney function. Prescription of folic acid supplementation is recommended to reduce methotrexate toxicity. Folic acid is prescribed at a dose of 5–15 mg/week, to be taken 48 hours after the methotrexate dose. The days on which methotrexate and folic acid are administered must be specified on the prescription to avoid confusion.

Efficacy There is limited data on the efficacy of methotrexate from randomized controlled studies. A recent systematic review indicated that 40%–45% of patients treated with methotrexate achieved PASI 75 at 16 weeks.6 However, the heterogeneity between studies was high. The efficacy is dependent upon the speed of dose escalation and upon the maintenance dose used. In patients with suboptimal responses, changing the route of administration, i.e., switching to the parenteral route, may improve the therapeutic effect.

Adverse events and management The prevalence and severity of methotrexate-induced adverse events, depending on the dosing and the dosing regimen. Minor and common toxicities such as nausea, 219

220  Traditional systemic therapies and monitoring guidelines

Table 22.1 

Parameters influencing decision to use a systemic treatment in psoriasis.

Skin symptoms

Pruritus, pain

Lesions severity and extend Quality of life Involvement of “high impact body location” Joint involvement Resistance to therapy

BSA >10%, PASI >10, PGA ≥3 DLQI >10 Face, hands, palms and soles, nail, genitalia Axial or peripheral psoriatic arthritis, enthesitis Psoriasis uncontrolled by topical therapy and photo (chemo) therapy Stigmatization at work, emotional distress

Psychosocial impact

Abbreviation:  BSA, body surface area; DLQI, dermatology life quality index; PASI, psoriasis area and severity index; PGA, physicians’ global assessment.

fatigue, and anorexia can be managed by changing the route of administration, dose splitting, and administration with food or at bedtime. Major toxicities of greatest concern are myelosuppression, hepatotoxicity, and pulmonary fibrosis (see Table 22.2). Myelotoxicity occurs mostly in patients with impaired renal function, hypoalbuminemia, advanced age, and greater than moderate alcohol intake. For these patients, the administration of an initial test dose of 2.5–5 mg, with a control of the blood count a week after to detect leucopenia nadir, is recommended. In case of early signs of bone marrow toxicity such as an increase in mean corpuscular volume or presence of mild leucopenia and/or thrombopenia, it is advised to decrease doses. Increasing the dose of folic acid supplementation can be efficacious as well. In the absence of improvement, methotrexate must be discontinued. The literature does not provide accurate estimates of the incidence of liver fibrosis attributable to methotrexate as relevant studies rarely consider potential confounders common in psoriasis population, such as metabolic syndrome or alcohol consumption.7,8 This incidence, however, seems low.9 In general, clinicians should consider all psoriasis patients taking methotrexate to be at a potential risk of liver fibrosis and screening for additional risk factors should be adopted before prescription (see Table 22.3). Furthermore, during treatment, appropriate monitoring for early detection of fibrosis provides an opportunity to reverse the disease progression. There is uncertainty about the best monitoring method and clinical practice varies.10 The procollagen3N-terminal peptide (PIIINP) is currently used in Europe11,12 reducing by sevenfold the need for liver biopsies. PIIINP dosing is recommended every 3 months. In case of persistent abnormalities, i.e., PIINP > 4.2 µg/L in at least three samples over a 12-month period, a hepatologist opinion may be taken and a liver biopsy may be considered. Other noninvasive methods are becoming increasingly popular such as fibroscan and fibrotest but they remain to be fully validated. Pulmonary toxicity must be ruled out in patients with new symptoms such as cough. The prevalence of methotrexate-related lung interstitial disease remains ­ unknown and large observational studies are lacking. In a recent meta-analysis in psoriatic patients, however, no increase in respiratory adverse events was found.13

Table 22.2 

Overview of important side effects of

methotrexate. Very frequent Nausea, malaise, hair loss, anorexia Frequent Elevated liver function tests, bone marrow suppression, gastrointestinal ulcers Occasional Fever, chills Rare Nephrotoxicity, liver fibrosis, and cirrhosis Very rare Interstitial pneumonia, alveolitis

Table 22.3  Risk factors for methotrexate hepatotoxicity. History of or current greater than moderate alcohol consumption Abnormal liver function tests History of liver disease including chronic hepatitis B or C Family history of inheritable liver disease Diabetes mellitus Obesity History of significant exposure to hepatotoxic drugs or chemicals Hyperlipidemia

Recommended monitoring Baseline monitoring should include a physical examination and a thorough history taking to identify previous and concomitant diseases and concomitant medication. Physicians should assess disease severity (PASI, PGA, BSA), signs of articular involvement, and the effect of psoriasis on patient’s quality of life (DLQI). Laboratory tests and imaging ­methods that should be performed at baseline and during follow-up are summarized in Table 22.4. Further tests may be necessary based on clinical findings and patient’s history. Live vaccines are contraindicated during treatment.

Contraindications Contraindications for methotrexate are summarized in Table 22.5.

Methotrexate 221

Table 22.4  Recommended lab controls/other procedures for methotrexate. Laboratory parameters

Baseline

Blood count

x

Liver function tests

x

Serum creatinine

x

Blood urea nitrogen

x

Pregnancy testa HBVb/hepatitis C virus/human immunodeficiency virus serology PPDc Chest radiographd Procollagen-3N-terminal peptide (PIIINP) or fibroscan/fibrotest when available

x x

a b c d

x x x

Follow-up frequency In a week, then every other week for 2 months and then every 3 months Monthly for 6 months and then every 3 months Every other week for 2 months and then every 3 months Every other week for 2 months and then every 3 months

Every 3 months for PIIINP

Reliable contraception is necessary for women of child-bearing age. When screening for hepatitis B virus (HBV) the following serologic markers should be determined: anti-HB core, anti-HBs, and HBsAg.14 Purified protein derivative (PPD) or other screening test for latent tuberculosis particularly if the patient’s history indicates risk. If the patient has history of underlying pulmonary disease.

Table 22.5  Contraindications for methotrexate. Absolute

Relative

Hypersensitivity to methotrexate Pregnancy and breastfeeding Alcoholic liver disease or cirrhosis Excessive alcohol consumption Immunodeficiency syndromes Renal failure Bone marrow dysfunction Acute peptic ulcer Significant reduction in lung function

Old age Obesity Diabetes mellitus Unreliable patient Abnormalities in renal function, liver function History of hepatitis Ulcerative colitis Active infection

Pharmacokinetics In adults, oral absorption is dose proportional and oral bioavailability is 70%. Peak serum levels are reached within 1–2 hours. Food has been shown to delay absorption. Methotrexate is completely absorbed from parenteral routes of injection. After intramuscular injection, peak serum concentrations occur in 30–60 minutes. Methotrexate in serum is approximately 50% protein bound. It undergoes hepatic and intracellular metabolism to polyglutamated forms. The terminal half-life reported is approximately 3–10 hours for low-dose regimens. Renal excretion is the primary route of elimination.

Interactions Methotrexate interacts with numerous medications by various mechanisms:

1. Decrease in intestinal absorption of methotrexate or interference with the enterohepatic circulation: tetracycline, chloramphenicol, and nonabsorbable broad spectrum antibiotics. 2. Antagonists for albumin binding: salicylates, non steroidal anti-inflammatory drugs (NSAIDs), sulfonamides, diphenylhydantoin, antibiotics (penicillin, minocycline, chloramphenicol, trimethoprim). 3. Decrease in renal tubular excretion and renal elimination: colchicine, cyclosporine, probenecid, salicylates, sulfonamides, and NSAIDs. 4. Increase in hepatotoxicity: ethanfol, leflunomide, retinoids, tetracyclines, statins, and azathioprine. NSAIDs that may lead to elevation of serum methotrexate levels include ibuprofen, salicylates, and naproxen. Other NSAIDs such as ketoprofen, flurbiprofen, piroxicam, meloxicam, lumiracoxib, rofecoxib, and celecoxib do not interact with methotrexate.

Pregnancy and breastfeeding Methotrexate is abortifacient and teratogen. It is U.S. Food and Drug Administration (FDA) pregnancy category X. It can provoke fetal death or teratogenic effects including cardiac, skeletal, and central nervous system abnormalities. It is widely distributed in maternal tissues and may persist in the liver for up to 3 months after exposure. Thus, contraception is mandatory during treatment with a washout period of 3 months before pregnancy for females. Breastfeeding is contraindicated. Methotrexate is not mutagenic but toxic to cell division. One cycle of spermatogenesis requires 74 days thus a washout period of 3 months is necessary before conceiving for males.

222  Traditional systemic therapies and monitoring guidelines

Pediatric population Evidence on effectiveness of methotrexate in pediatric psoriasis is lacking. In a systematic review by De Jager et al., methotrexate was considered to be the systemic treatment of choice in severe childhood plaque psoriasis, recalcitrant to local therapies (0.1–0.41 mg/kg/week).15 In a recent observational daily practice cohort of pediatric patients, methotrexate was efficacious in terms of PASI, PGA score, and improvement of quality of life, with a reasonable safety profile. Twenty-five children were treated and PASI 75 was achieved in 4.3% and 33.3% of them at weeks 12 and 24, respectively.16 The most frequent side effects in children are elevated liver tests, stomatitis, nausea, and vomiting.17 It is noteworthy that PIIINP, widely used in adults for early detection of liver fibrosis (see “Recommended monitoring” section), is not useful in children due to the confounding effect of growth and puberty on serum levels.18

Overdose Overdose in psoriasis patients can result from an accidental daily administration. Clinical manifestations include myelosuppression, mucosal ulceration (particularly of the oral mucosa), cutaneous necrolysis, and neurological symptoms such as headaches, nausea, vomiting, and seizures. Folinic acid is a fully reduced folate coenzyme that ­bypasses the action of methotrexate. When overdose is clinically suspected, serum levels of methotrexate should be measured. Subsequently folinic acid is administered intravenously or intramuscularly at 20 mg (or 10 mg/m²) along with alkaline hyperhydration. Doses should be given at 6-hour intervals until serum methotrexate concentration is <10−8 M. In the absence of methotrexate levels, folinic acid should be continued until the blood count has returned to normal and the mucosae have healed.

CYCLOSPORINE Mechanism of action Cyclosporine belongs to the family of immunosuppressant drugs known as calcineurin inhibitors. T-helper cells are the main target and, to a lesser extent, T-suppressor cells. Cyclosporine is inactive until it binds with a cytoplasmic receptor, cyclophilin. This complex inhibits the enzyme calcineurin leading to lower levels of dephosphorylated nuclear factor of activated T cells (NFAT). Normally, dephosphorylated NFAT reaches the nuclei inducing the transcription of proinflammatory genes such as interleukin (IL)-2, IL-4, interferon-gamma.

Hence, cyclosporine blocks the intracellular components of T-cell activation.

Dosing Different therapeutic regimens have been proposed. Cyclosporine can be prescribed as a short-term induction therapy of approximately 10–16 weeks. This regimen is suitable for crisis intervention and reflects current clinical practice. The initial dosing is 2.5–3 mg/kg/day in two divided doses. This dosing is maintained for 4 weeks and then increased by increments of 0.5 mg/kg/day until achievement of disease control. The recommended maximal dose is 5 mg/kg/day, in the absence of comorbidities such as obesity and older age. Another approach is to initiate treatment at the highest dosage of 5 mg/kg/day for a rapid onset of action, followed by decrease in dosage after achievement of disease control. When necessary, treatment can be stopped abruptly.19 For obese patients, dose calculation is being made according to ideal weight (see Table 22.6). For some patients, however, maintenance therapy is required. This maintenance therapy can be prescribed either as long-term continuous therapy at the minimal effective dose or as intermittent short courses. In the first case, the maintenance dosage varies from 0.5 to 3.0 mg/kg/day. It is admitted that long-term treatment should not be pursued beyond 2 years without a nephrologist opinion due to the significant risk of renal toxicity. In the intermittent short courses regimen, patients can receive, after the induction therapy and upon relapse, additional 12-week courses of cyclosporine, for up to eight times, for a total duration of 2 years. The main purpose of this intermittent regimen is to diminish the cumulative exposure over time and hence minimize side effects.19,21 In transplantation medicine, levels 2 hours after a cyclosporine dose (C2 monitoring) are considered reflective of drug exposure22 and essential for the optimization of efficacy and safety with regards to nephrotoxicity. Nevertheless, in a recent systematic review, Knight and Morris failed to confirm a significant benefit of dose adjustments based on C2 monitoring in organ transplantation.23 C2 monitoring is not recommended systematically for psoriasis patients (see the “Recommended monitoring” section).

Table 22.6  Ideal weight calculation. Men: 50 + 2.3 [Height(in) – 60] Women: 45.5 + 2.3 [Height(in) – 60] For adults >18 years old. For patients with a height between 55 and 87 inches (140–220 cm). 1 inch = 2.54 cm. According to Devine formula,20 Pai MP, Paloucek FP, Ann Pharmacother., 34, 1066–1069, 2000.

Cyclosporine 223

Efficacy Cyclosporine is ideally suited for crisis intervention. Efficacy is dose dependent, with a tendency of higher doses of 5 mg/kg to produce a higher percentage of remission.24 The efficacy is evaluated at 2 months. The rate of remission with cyclosporine at doses 2.5 mg/kg/day and 5 mg/ kg/day matches the results obtained with methotrexate24 and is significantly superior to etretinate25 for plaque psoriasis. In a meta-analysis by Schmitt et al., cyclosporine 2.5 mg/kg/day was superior to placebo, in terms of induction of remission, with an absolute risk difference of 25% (95% confidence interval [CI] 10%–40%).6 Two randomized controlled trials (RCTs) compared long-term continuous with intermittent maintenance cyclosporine therapy and showed that overall control of psoriasis was better with continuous therapy.26,27 Low-dose cyclosporine for palmo-plantar pustulosis was found more efficacious than placebo in the induction and maintenance of remission.28–30 Furthermore, cyclosporine is a valuable therapeutic option for erythrodermic (recommended dose 3–5 mg/kg/day) and nail psoriasis, in particular, for women of childbearing age. There is no evidence for its efficacy in generalized pustular psoriasis and guttate psoriasis.

Adverse events and management The rate of adverse effects with cyclosporine ­demonstrates a clear dose dependency.31 The majority of common ­toxicities is reversible after drug discontinuation. Major toxicities are nephrotoxicity, hypertension, and an increase on the risk of nonmelanoma skin cancer (see Table 22.7).

Table 22.7  Overview of important side effects of cyclosporine. Frequent

Irreversible renal damage (long-term therapy), renal failure, hypertension, gingival hyperplasia, hepatogastric complaints, tremor, headache, paresthesia, musculoskeletal pain, elevated blood lipids, hypertrichosis Occasional Seizures (lowers seizure threshold), gastrointestinal ulcerations, weight gain, hyperglycemia, hyperuricemia, hyperkalemia, hypomagnesemia, acne Rare Ischemic heart disease, pancreatitis, motor polyneuropathy, impaired vision, defective hearing, central ataxia, myopathy, itching, leucopenia, thrombocytopenia Very rare Microangiopathic hemolytic anemia, colitis, papillary edema, idiopathic intracranial hypertension

Cyclosporine nephrotoxicity is due to vasoconstriction of renal arterioles. Patients should be screened for risk factors of renal toxicity prior to treatment initiation32 (see Table 22.8). Treatment-related risk factors include larger cumulative dose, higher daily dose (>5 mg/kg/day), and the occurrence of acute increases in creatinine levels.24 There is no firm evidence that the scheme of administration of maintenance therapy (continuous/intermittent) influences kidney toxicity.24 Changes are usually functional and rapidly reversed after treatment cessation. Structural damage can be expected in a patient in whom serum creatinine does not decrease upon cessation of cyclosporine therapy. Chronic cyclosporine nephropathy is characterized p ­ rimarily by focal interstitial fibrosis with tubular atrophy and arteriolar alterations.33 In a recent review, Maza et al. demonstrated that the best predictive factor of structural kidney damage is an increase in serum creatinine above 30% of the baseline value.24 The algorithm of cyclosporine dose adjustments according to the elevation of serum creatinine levels is summarized in Figure 22.1. Hypertension develops in 2%–15% of patients. If hypertension develops, i.e., systolic blood pressure ≥160 mmHg and/or diastolic blood pressure ≥90 mmHg in two consecutive measurements, an antihypertensive therapy should be initiated or intensified. The use of calcium channel blockers is advised, i.e., isradipine or amlodipine. If blood pressure remains high, a dosage decrease of 25% is necessary. In a prospective cohort study, 1252 psoriasis patients treated with cyclosporine were followed for malignancies for 5 years (mean length of treatment 1, 9 years; mean dose 2.7–3.1 mg/kg/day). The incidence of skin malignancies, mainly squamous cell carcinoma, was sixfold higher compared with the general population. Multivariable analysis identified as risk factors a cumulative treatment duration of more than 2 years, exposure to psoralen, ultraviolet A (UVA), and other immunosuppressants.34 Cyclosporine should be avoided immediately prior to and especially following psoralen and ultraviolet A (PUVA) therapy. Cyclosporine prescription should be limited in patients with a high cumulative exposure to PUVA (>200 sessions, >1000 J/cm²) and history of skin cancer.32

Table 22.8  Patient-related risk factors for cyclosporine nephrotoxicity. Cumulative exposure of more than 3 years Age older than 65 years Obesity (body mass index [BMI] >30) Arterial hypertension Diabetes Concomitant nephrotoxic medication Renal inflammatory condition

224  Traditional systemic therapies and monitoring guidelines Elevation of serum creatinine compared to baseline

≤30%

>30% and ≤50%

>50%

Check of fluid intake

Dose reduction of 25% and check within 30 days

Dose reduction of 50% and check within 30 days

If increase of >30% persists, discontinuation

If increase of >30% persists, discontinuation

Figure 22.1  Algorithm of management of cyclosporine-induced renal toxicity. (Adapted from Pathirana D et al., J Eur Acad Dermatol Venereol, 23, 1–70, 2009.) Early studies from transplant patients mentioned the increased risk of lymphoma after the long-term use of immunosuppressants such as cyclosporine.35–37 These data were not confirmed in a prospective cohort study in psoriasis patients.34 Furthermore, in a retrospective cohort study of 272 patients with inflammatory skin diseases, all of whom had received at least 1 month of cyclosporine treatment (median 8 months), the overall risk of cancer was almost identical to that expected in the general population (standardized incidence ratios [SIR] = 1.31, 95% CI = 0.70–2.23). The median follow-up time was 10.9 years.38

Recommended monitoring Baseline monitoring should include a physical examination, and a thorough history taking to identify previous and concomitant diseases and concomitant medication. Physicians should assess the disease severity (PASI, PGA, BSA), the signs of articular involvement, and the effect of psoriasis on patient’s quality of life (DLQI). Laboratory tests and procedures that should be performed at baseline and during follow-up are described in Table 22.9. Further tests may be necessary based on clinical findings and patient’s history. Patients should be advised to follow national recommendations for cancer screening (cervix, breast, prostate) and should be seen for dental examination at least yearly because of the risk of gingival hyperplasia. The necessity of photoprotection and sun avoidance should be explained upon prescription and regularly during follow-up. Studies conducted in transplant excipients have shown that influenza vaccination given concomitantly with cyclosporine therapy may be less efficacious.39 Live vaccines are contraindicated.

Contraindications Contraindications for cyclosporine are summarized in Table 22.10.

Pharmacokinetics Oral absorption of cyclosporine is incomplete, depending on the individual patient, the patient population, and the formulation. There is a linear correlation between administered dose and exposure (area under the concentration versus time curve) within the therapeutic dose range. The terminal half-life is variable and estimated at approximately 8.4 hours (range 5–18 hours). Cyclosporine is metabolized by the cytochrome P-450 3A enzyme system in the liver and is a substrate of the intestinal P-glycoprotein, an adenosine triphosphate–dependent efflux pump. Elimination is primarily biliary with only 6% of the dose excreted in the urine.

Interactions Cyclosporine interacts with various mechanisms with other medication mostly because of its metabolism by the cytochrome P-450 3A enzyme system in the liver, and its P-glycoprotein–mediated transport. Medications that increase cyclosporine levels (P450 inhibitors): calcium antagonists: diltiazem, nicardipine, nifedipine, verapamil, mibefradil; antifungals: ketoconazole, fluconazole, itraconazole; antibiotics: macrolides, doxycycline, gentamicin, amikacin, tobramycin, ticarcillin, quinolones; oral contraceptives and androgenic steroids (norethisterone, levonorgestrel, methyl testosterone,

Cyclosporine 225

Table 22.9  Recommended lab controls/other procedures for cyclosporine. Laboratory parameters

Baseline

Blood count

x

Liver function tests

x

Electrolytes

x

Serum creatinine

x

Blood urea nitrogen

x

Uric acid Pregnancy test (urine)a Cholesterol, triglycerides Magnesiumb HBVc/hepatitis C virus/human immunodeficiency virus serology C2 monitoringd Blood pressure measurement

x x x x x

a b c d

Follow-up frequencies Every other week for 2 months and then monthly Every other week for 2 months and then monthly Every other week for 2 months and then monthly Every other week for 2 months and then monthly Every other week for 2 months and then monthly Monthly

x x

Reliable contraception is necessary for women of child-bearing age. There is a risk of reduced efficacy of progesterone containing contraceptives. In case of muscle cramps. When screening for hepatitis B virus (HBV) the following serologic markers should be determined: anti-HB core, anti-HBs, HBsAg.14 May be required in selected patients that take more than 3 mg/kg/day over the long term, take concomitant medication interfering with cyclosporine metabolism, have liver disease, or to confirm adherence.

Table 22.10  Contraindications for cyclosporine. Absolute Hypersensitivity to cyclosporine Impaired renal function Uncontrolled arterial hypertension Uncontrolled severe infections History or current malignancya Simultaneous phototherapy a

Relative High cumulative exposure to psoralen and ultraviolet A (PUVA) therapy (>200 sessions, >1000 J/cm²) Immunodeficiency Chronic liver disease Pregnancy and breastfeeding Concomitant medications interacting with cyclosporine (see “Interactions” section) Epilepsy

Except for nonmelanoma skin cancer (basal cell carcinoma, squamous carcinoma in situ).

ethinyl estradiol); statins: lovastatin, simvastatin, atorvastatin, pravastatin, fluvastatin; protease inhibitors: saquinavir; others: allopurinol, methylprednisolone (high doses), ranitidine, cimetidine, metoclo-pramide, acetazolamide, grapefruit juice, amiodarone, acitretin. Medications that decrease cyclosporine levels (P450 inducers): antiepileptics: carbamazepine, phenytoin, barbiturates; antibiotics: rifampicin, nafcilin; hypericum perforatum; others: octreotide, ticlopidine. Medications with increased plasma levels when used concomitantly with cyclosporine: calcium channel blockers: diltiazem, nicardipine, verapamil; statins: atorvastatin, lovastatin, simvastatin; benzodiazepines; others: prednisolone, digoxin, diclofenac, colchicine.

Medications that may potentiate nephrotoxicity: aminoglycosides: gentamicin, tobramycin; NSAIDs: diclofenac, naproxen, sulindac; fibrates: bezafibrate and fenofibrate; antibiotics: trimethoprim and sulfamethoxazole, vancomycin, ciprofloxacin; others: amphotericin B, aciclovir, melphalan.

Pregnancy and breastfeeding Current experience from cyclosporine use during pregnancy is extrapolated from organ transplant patients. Low birth weight and premature birth have been reported as well as exacerbation of maternal hypertension.40 However,

226  Traditional systemic therapies and monitoring guidelines

in a meta-analysis by Bar Oz et al., calculated odds ratio for malformations, overall prevalence of major malformations, and prematurity did not achieve statistical significance.41 Cyclosporine is FDA pregnancy category C. It should be prescribed, for women of childbearing age, after a negative pregnancy test and adequate contraception should be ensured during treatment. Progesterone-containing contraceptives should not be used, their efficacy being reduced by cyclosporine. Nevertheless, if we take into account that most systemic medications used to treat psoriasis are teratogenic and contraindicated during pregnancy, only cyclosporine should be considered in pregnant women with severe psoriasis when the benefits outweigh potential risks.42 Cyclosporine is present in small amounts in breast milk (less than 1% of the maternal dose). Breastfeeding should be avoided. The alcohol content of cyclosporine oral (12% ethanol, i.e., 500 mg per dose) should be taken into consideration in pregnant and breastfeeding women.

Pediatric population Besides the paucity of data concerning the efficacy and tolerability cyclosporine in pediatric psoriatic patients,14,43 in a multicenter audit conducted recently in the United Kingdom, physicians reported the prescription of cyclosporine in 4% of the 285 children treated for moderate to severe psoriasis.44 The most notable side effects are nausea, vomiting, hypertrichosis, mild hypertension, and moderate but within normal changes in renal function.17

ACITRETIN Retinoids are vitamin-A derivatives that have been used as topical and systemic treatments in psoriasis for more than 30 years. Etretinate was the first oral agent introduced and it was replaced, in the early nineties, by its main active metabolite, acitretin.

Mechanism of action Acitretin activates the retinoic acid receptors (RAR α, β, γ), a member of the steroid/thyroid superfamily of nuclear hormone receptors. The complex then binds to nuclear receptors of genes, modulating their expression. Acitretin has antiproliferative action and modifies epidermal differentiation. It has, also, immunomodulatory actions inhibiting neutrophil migration and antigen presentation from Langerhans cells and keratinocytes.

Dosing Acitretin is administered orally, preferably with food to enhance absorption. The recommended initial dose is between 10 and 25 mg/day, in a single or twice-daily dose. Then the dose should be increased gradually every 2 weeks until xerosis and cheilitis appear (clinical indicators of sufficient bioavailability). Optimal dose is 0.3–0.5 mg/kg/ day.45 Higher doses of 0.5–1 mg/kg/day are more effective at the expense of increased mucocutaneous side effects and are currently only recommended for the treatment of generalized flares of pustular psoriasis. Depending on the clinical context, a combination of lower doses ≤25 mg/day of acitretin with phototherapy can be envisaged resulting in a reduction in side effects and a better maintenance of clinical response.

Efficacy Acitretin belongs to the group of less effective systemic agents, although very few trials have directly compared acitretin with other antipsoriatic agents.46,47 It is not s­ uggested as first choice monotherapy. The efficacy of acitretin is dose dependent. A 3- to 6-month period is required to achieve maximum response. In some patients, psoriasis may worsen after the beginning of treatment. Acitretin was found less efficacious than etanercept 25 and 50 mg twice per week.46,47 Etretinate was less efficacious than 2.5 mg/kg/day of cyclosporine.48 Acitretin monotherapy is recommended as first-line systemic treatment (excluding phototherapy) for palmoplantar pustulosis.45 It is, similarly, recommended for generalized pustular psoriasis, at a dose of 0.5–1 mg/kg/ day, provided the flare is not life threatening.49 Acitretin monotherapy is not suitable for the treatment of nail psoriasis49 and psoriatic arthritis. It is not an immunosuppressant and thus the treatment of choice for psoriatic patients with cancer and for immunocompromised patients (human immunodeficiency virus infection).50

Adverse events and management Most of the adverse effects are dose dependent (see Table 22.11).12,51 The toxic dose and the therapeutic dose are very close. Hence, most patients experience some adverse effects that are generally mucocutaneous at treatment initiation while the does is being adjusted. Elderly patients are more susceptible to cutaneous and mucosal xerosis at lower doses. In the case of hypertriglyceridemia, dietary and lifestyle interventions are an effective first-line management. If this intervention is insufficient triglyceride lowering

Acitretin 227

therapy should be prescribed and if triglyceride level is >5 mmol/L discontinuation should be considered. Liver enzyme elevations are often transient. Acitretin is not preferred in women of c­hild-bearing potential due to the risk of teratogenicicty. This risk is higher during the first trimester of pregnancy.52 Retinoids’ embryopathy results from its deleterious effect on cephalic neural-crest cell activity during embryogenesis (see Table 22.12).53 Double contraception is mandatory for all female patients of child-bearing potential 1 month before, during, and 3 years after discontinuation of

acitretin therapy (2 years in Europe). The ­re-esterification of a­ citretin to etretinate is enhanced in women consuming ethanol during therapy. Etretinate is more lipophilic and is sequestrated in adipose tissue with a subsequent slower elimination than acitretin (half-life of 120 days vs. 49 hours). Thus, the 2-year posttherapy contraception requirement is the time required for elimination of more than 98% of etretinate that may have formed. A year is added for an increased margin of safety in the United States. Retinoid-induced skeletal toxicity has been the subject of controversy.45 In a case–control study, 124,655 adult patients with fractures were matched for age and gender to 373,962 controls. No increased risk of fracture was found in adult patients undergoing retinoid therapy.54 Diffuse idiopathic hyperostosis induced by acitretin has been rarely described.

Table 22.11  Overview of important side effects of acitretin. Very frequent Frequent

Occasional Rare Very rare

Xerosis, cheilitis (vitamin A toxicity) Conjunctival inflammation (may prohibit use of contact lenses), alopecia, photosensitivity, hyperlipidemia Muscle, joint, and bone pains, retinoid dermatitis, rigors Gastrointestinal complaints, hepatitis, paronychia Pseudotumor cerebri, decreased color vision, and impaired night vision

Recommended monitoring Baseline monitoring should include a physical examination and a thorough history taking to identify previous and concomitant diseases and concomitant medication. Physicians should assess the disease severity (PASI, PGA, BSA), the effect of psoriasis on patient’s quality of life (DLQI), and exclude articular involvement. Laboratory tests that should be performed at baseline and d ­ uring ­follow-up are described in Table 22.13. Further tests may be necessary based on clinical findings and patient’s ­history. Patients can be vaccinated with toxoids and live attenuated vaccines.

Table 22.12  Retinoic acid teratogenicity. Craniofacial dysmorphia: microtia, anotia, stenosis of the external ear canal, micrognathia, cleft palate, ocular hypertelorism Skeletal abnormalities: syndactyly, multiple synostoses Thymic aplasia Cardiovascular abnormalities: transposition of the great vessels and tetralogy of Fallot Central nervous system: hydrocephalus, learning disabilities, optic nerve abnormalities

Contraindications Contraindications for acitretin are summarized in Table 22.14.

Table 22.13  Recommended lab controls for acitretin. Laboratory parameters Blood count Liver function tests Serum creatinine Pregnancy testa

Baseline X X X Two negative testsb

Lipid profile

X

Fasting blood glucose

X

a b

Follow-up frequencies Every 3 months Every other week for 2 months and then every 3 months Every 3 months Every month during treatment and then every 3 months for at least 3 years after treatment discontinuation Every other week for 2 months and then every 3 months

Women of child-bearing age must use two effective forms of contraception. The first pregnancy test should be done when the decision of acitretin therapy is made. The second test should be performed during the first 5 days of the menstrual period preceding immediately the beginning of acitretin.

228  Traditional systemic therapies and monitoring guidelines

Table 22.14  Contraindications for acitretin. Absolute

Relative

Hypersensitivity to acitretin Pregnancy and breastfeeding Women of child bearing age noncompliant with contraceptive measures Alcohol abuse Severe renal and hepatic dysfunction Blood donationa

Severe hyperlipidemia Hepatitis B and/or C Contact lenses Metabolic syndrome

a

Blood donation is prohibited during treatment and up to 1 year after.

Table 22.15  Drugs that potentially interact with acitretin. Cyclines Phenytoin Methotrexate Imidazoles Lipid-lowering drugs Ethanola Microdosed progesterone pills Vitamin A and other retinoids Cyclosporine a

Risk of idiopathic intracranial hypertension Protein plasma displacement Risk of hepatotoxicity Risk of hepatotoxicity Risk of myotoxicity Reesterification of acitretin to etretinate; subsequently stockage in the subcutaneous tissue Insufficient contraceptive effect Risk of hypervitaminosis A Competition for cytochrome P450 (inactivation)

During treatment and 2 months after its discontinuation.

Pharmacokinetics

Pediatric population

The oral absorption of acitretin is linear and proportional. Peak serum levels are reached within 2–5 hours. Acitretin in serum is more than 99.9% protein bound, primarily with albumin. Following oral absorption, it undergoes extensive metabolism and is isomerized to its 13-cis form (cis-acitretin).The metabolites of acitretin and cis-acitretin are excreted in the feces and urine. Its terminal elimination half-life is 49 hours (range: 33–96 hours), and that of cis-acitretin is 63 hours (range: 28–157 hours).

Effectiveness and safety of acitretin in childhood psoriasis have not been sufficiently investigated.15 Skeletal alterations have been reported after long-term treatment with etretinate in childhood, including premature epiphyseal closure, skeletal hyperostosis, and extra osseous calcification. This raises special concerns due to the implications for growth potential. It is advisable to monitor growth at regular intervals under treatment.12 Short-term therapy should be preferred, whereas long-term therapy, if necessary, should be prescribed at the lowest possible dosage.56

Interactions Interactions for acitretin are summarized in Table 22.15.

Pregnancy and breastfeeding Acitretin is FDA pregnancy category X (see Table 22.10). Double contraception is mandatory a month before initiating treatment, during, and for 2 years in Europe and 3 years in the United States after its discontinuation (see the “Adverse events and management” section). Mothers receiving acitretin should not breastfeed. Small amounts of acitretin of unknown significance are found in the semen of male patients.55

COMBINATION THERAPIES Methotrexate should not be associated with acitretin due to the increased risk of hepatotoxicity.57,58 Methotrexate serum levels may be increased in case of concomitant use with cyclosporine due to their common renal tubular excretion. Furthermore, this association enhances immunosuppression. Fraser et al. randomized patients with psoriatic arthritis and psoriasis to receive either methotrexate and placebo or methotrexate and cyclosporine. There was a statistically significant difference between groups with regards to efficacy in both skin and articular involvement in favor of the combination therapy. There were more drug-related adverse events such as nausea, headache, and

References 229

higher discontinuation rates in the combination group confirming the increased toxicity.59 The combination of low-dose methotrexate with biologic therapies in psoriasis is currently commonplace. These associations are likely sufficient to reduce formation of antidrug antibodies, increasing ­biologics through levels and thus their efficacy.60 Etanercept prescription in patients not adequately controlled on methotrexate monotherapy results in significant clinical improvement in terms of PASI 75, PASI 90, and PGA, without any statistically significant safety issues.61,62 The use of infliximab and adalimumab in conjunction with methotrexate has not been as extensively studied as with etanercept.63 The association of cyclosporine and phototherapy is contraindicated (see the “Contraindications” section for cyclosporine) due to the significant increase in the risk of skin cancer. A combination of oral retinoids with cyclosporine increases the risk of hyperlipidemia. Controlled data are scarce on concomitant use of cyclosporine and biologics in the treatment of psoriasis. The synergistic effect of phototherapy and retinoids is well known. This combination is more effective than monotherapy, allowing a reduction in the number of phototherapy sessions and in the dose of acitretin required, thereby improving tolerance. The preferred schedule is acitretin monotherapy for 2 weeks followed by the addition of phototherapy. Acitretin can also be added to increase efficacy in patients already receiving UVB phototherapy with suboptimal responses. At that moment, it is prudent to decrease the UVB dose by 30%–50% for 1 week due to risk of acitretin-induced photosensitivity. The UVB dose can be subsequently increased gradually as tolerated by the patient.52 A 2011 meta-analysis evaluated the association of retinoids with PUVA (re PUVA) compared with PUVA monotherapy in plaque psoriasis. The pooled effect size provided an odds ratio of 3.1 (95% CI 1.11–8.66) in favor of re PUVA.45 In a randomized blinded controlled study by Gisondi et al. of 60 patients, a combined therapeutic regimen with etanercept 25 mg once weekly and acitretin 0.4 mg/kg/ day was as effective as etanercept 25 mg twice weekly, and more effective than acitretin alone. All three groups had similar safety profiles.47 Based on the expert opinion by the Medical Board of the National Psoriasis Foundation, the addition of acitretin to biologics can be marginally beneficial to increase efficacy.63

REFERENCES 1. Pariser DM, Bagel J, Gelfand JM, et al. National Psoriasis Foundation clinical consensus on disease severity. Arch Dermatol. 2007 Feb;143(2):239–242. 2. Finlay AY. Current severe psoriasis and the rule of tens. Br J Dermatol. 2005 May;152(5):861–867.

3. Lebwohl MG, Bachelez H, Barker J, et al. Patient perspectives in the management of psoriasis: Results from the population-based Multinational Assessment of Psoriasis and Psoriatic Arthritis Survey. J Am Acad Dermatol. 2014 May;70(5):871–81. e1–30. 4. Gyulai R, Bagot M, Griffiths CEM, et al. Current practice of methotrexate use for psoriasis: Results of a worldwide survey among dermatologists. J Eur Acad Dermatol Venereol. 2015 Feb;29(2): 224–231. 5. Paul C, Gallini A, Maza A, et al. Evidence-based recommendations on conventional systemic treatments in psoriasis: Systematic review and expert opinion of a panel of dermatologists. J Eur Acad Dermatol Venereol. 2011 May;25 (Suppl 2):2–11. 6. Schmitt J, Rosumeck S, Thomaschewski G, Sporbeck B, Haufe E, Nast A. Efficacy and safety of systemic treatments for moderate-to-severe psoriasis: Meta-analysis of randomized controlled trials. Br J Dermatol. 2014 Feb;170(2):274–303. 7. Poikolainen K, Karvonen J, Pukkala E. Excess ­mortality related to alcohol and smoking among hospital-treated patients with psoriasis. Arch ­ Dermatol. 1999 Dec;135(12):1490–1493. 8. Stern RS, Lange R. Cardiovascular disease, cancer, and cause of death in patients with psoriasis: 10 years prospective experience in a cohort of 1,380 patients. J Invest Dermatol. 1988 Sep;91(3):197–201. 9. Maybury CM, Jabbar-Lopez ZK, Wong T, Dhillon AP, Barker JN, Smith CH. Methotrexate and liver fibrosis in people with psoriasis: A systematic review of observational studies. Br J Dermatol. 2014 Jul;171(1):17–29. 10. Maybury CM, Samarasekera E, Douiri A, Barker JN, Smith CH. Diagnostic accuracy of noninvasive markers of liver fibrosis in patients with psoriasis taking methotrexate: A systematic review and meta-analysis. Br J Dermatol. 2014 Jun;170(6):1237–1247. 11. Montaudié H, Sbidian E, Paul C, et al. Methotrexate in psoriasis: A systematic review of treatment modalities, incidence, risk factors and monitoring of liver toxicity. J Eur Acad Dermatol Venereol. 2011 May;25 (Suppl 2):12–18. 12. Pathirana D, Ormerod A, Saiag P, et al. European S3-Guidelines on the systemic treatment of psoriasis vulgaris. J Eur Acad Dermatol Venereol. 2009 Oct;23:1–70. 13. Conway R, Low C, Coughlan RJ, O’Donnell MJ, Carey JJ. Methotrexate use and risk of lung disease in psoriasis, psoriatic arthritis, and inflammatory bowel disease: Systematic literature review and meta-analysis of randomised controlled trials. BMJ. 2015;350:h1269.

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14. Motaparthi K, Stanisic V, Van Voorhees AS, Lebwohl MG, Hsu S, Medical Board of the National Psoriasis Foundation. From the Medical Board of the National Psoriasis Foundation: Recommendations for screening for hepatitis B infection prior to initiating anti-tumor necrosis factor-alfa inhibitors or other immunosuppressive agents in patients with psoriasis. J Am Acad Dermatol. 2014 Jan;70(1):178–186. 15. De Jager MEA, de Jong EMGJ, van de Kerkhof PCM, Seyger MMB. Efficacy and safety of treatments for childhood psoriasis: A systematic literature review. J Am Acad Dermatol. 2010 Jun;62(6): 1013–1030. 16. Geel MJ van, Oostveen AM, Hoppenreijs EP, et al. Methotrexate in pediatric plaque-type psoriasis: Long-term daily clinical practice results from the Child-CAPTURE registry. J Dermatol Treat. 2014 Dec;1–7. 17. Dadlani C, Orlow SJ. Treatment of children and adolescents with methotrexate, cyclosporine, and etanercept: Review of the dermatologic and rheumatologic literature. J Am Acad Dermatol. 2005 Feb;52(2):316–340. 18. Wootton CI, Murphy R. Type III procollagen amino terminal propeptide: What does it measure in children? Br J Dermatol. 2012 Dec;167(6): 1391–1392. 19. Ho VC, Griffiths CE, Albrecht G, et al. Intermittent short courses of cyclosporin (Neoral(R)) for psoriasis unresponsive to topical therapy: A 1-year multicentre, randomized study. The PISCES Study Group. Br J Dermatol. 1999 Aug;141(2):283–291. 20. Pai MP, Paloucek FP. The origin of the ‘ideal’ body weight equations. Ann Pharmacother. 2000 Sep;34(9):1066–1069. 21. Ho VC, Griffiths CE, Berth-Jones J, et al. Intermittent short courses of cyclosporine microemulsion for the long-term management of psoriasis: A 2-year cohort study. J Am Acad Dermatol. 2001 Apr;44(4): 643–651. 22. Thervet E, Pfeffer P, Scolari MP, et al. Clinical outcomes during the first three months posttransplant in renal allograft recipients managed by C2 monitoring of cyclosporine microemulsion. Transplantation. 2003 Sep;76(6):903–908. 23. Knight SR, Morris PJ. The clinical benefits of cyclosporine C2-level monitoring: A systematic review. Transplantation. 2007 Jun;83(12):1525–1535. 24. Maza A, Montaudié H, Sbidian E, et al. Oral cyclosporin in psoriasis: A systematic review on treatment modalities, risk of kidney toxicity and evidence for use in non-plaque psoriasis. J Eur Acad Dermatol Venereol. 2011 May;25 Suppl 2:19–27. 25. Faerber L, Braeutigam M, Weidinger G, et al. Cyclosporine in severe psoriasis. Results of a meta-analysis in 579 patients. Am J Clin Dermatol. 2001;2(1):41–47.

26. Chaidemenos GC, Mourellou O, Avgoustinaki N, Papakonstantinou M, Karakatsanis G, Katsambas A. Intermittent vs. continuous 1-year cyclosporin use in chronic plaque psoriasis. J Eur Acad Dermatol Venereol. 2007 Oct;21(9):1203–1208. 27. Ohtsuki M, Nakagawa H, Sugai J, et al. Long-term continuous versus intermittent cyclosporin: Therapy for psoriasis. J Dermatol. 2003 Apr;30(4):290–298. 28. Erkko P, Granlund H, Remitz A, et al. Double-blind placebo-controlled study of long-term low-dose cyclosporin in the treatment of palmoplantar pustulosis. Br J Dermatol. 1998 Dec;139(6):997–1004. 29. Sevrain M, Richard M-A, Barnetche T, et al. Treatment for palmoplantar pustular psoriasis: Systematic literature review, evidence-based recommendations and expert opinion. J Eur Acad Dermatol Venereol. 2014 Aug;28 (Suppl 5):13–16. 30. Reitamo S, Erkko P, Remitz A, Lauerma AI, Montonen O, Harjula K. Cyclosporine in the treatment of palmoplantar pustulosis. A randomized, double-blind, placebo-controlled study. Arch Dermatol. 1993 Oct;129(10):1273–1279. 31. Ellis CN, Fradin MS, Messana JM, et al. Cyclosporine for plaque-type psoriasis. Results of a multidose, double-blind trial. N Engl J Med. 1991 Jan;324(5):277–284. 32. Griffiths CEM, Dubertret L, Ellis CN, et al. Ciclosporin in psoriasis clinical practice: An international consensus statement. Br J Dermatol. 2004 May;150 (Suppl 67):11–23. 33. Feutren G, Mihatsch MJ. Risk factors for cyclosporine-induced nephropathy in patients with autoimmune diseases. International kidney biopsy registry of cyclosporine in autoimmune diseases. N Engl J Med. 1992 Jun;326(25):1654–1660. 34. Paul CF, Ho VC, McGeown C, et al. Risk of malignancies in psoriasis patients treated with cyclosporine: A 5 y cohort study. J Invest Dermatol. 2003 Feb;120(2):211–216. 35. Penn I. Cancers following cyclosporine therapy. Transplantation. 1987 Jan;43(1):32–35. 36. Penn I, First MR. Development and incidence of cancer following cyclosporine therapy. Transplant Proc. 1986 Apr;18(2 Suppl 1):210–215. 37. Cockburn IT, Krupp P. The risk of neoplasms in patients treated with cyclosporine A. J Autoimmun. 1989 Oct;2(5):723–731. 38. Väkevä L, Reitamo S, Pukkala E, Sarna S, Ranki A. Long-term follow-up of cancer risk in patients treated with short-term cyclosporine. Acta Derm Venereol. 2008;88(2):117–120. 39. Kumar B, Dhar S, Handa S, Kaur I. Methotrexate in childhood psoriasis. Pediatr Dermatol. 1994 Sep;11(3):271–273. 40. Armenti VT, Radomski JS, Moritz MJ, et al. Report from the National Transplantation Pregnancy Registry (NTPR): Outcomes of pregnancy after transplantation. Clin Transpl. 2005;69–83.

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41. Bar Oz B, Hackman R, Einarson T, Koren G. Pregnancy outcome after cyclosporine therapy during pregnancy: A meta-analysis. Transplantation. 2001 Apr;71(8):1051–1055. 42. Paul C, Bachelez H, Pour groupe de recherche sur psoriasis. [Choice of therapy based on clinical setting]. Ann Dermatol Vénéréologie. 2011 Dec;138(12):821–825. 43. Burden-Teh E, Lam ML, Taibjee SM, et al. How we use systemic drugs to treat psoriasis in children? An insight into current UK practice. Br J Dermatol. 2015 Jan; 173(2):614–618. 44. Lam ML, Burden-Teh E, Taibjee SM, et al. A U.K. multicentre audit of the assessment and management of psoriasis in children. Br J Dermatol. 2015 Mar;172(3):789–792. 45. Sbidian E, Maza A, Montaudié H, et al. Efficacy and safety of oral retinoids in different psoriasis subtypes: A systematic literature review. J Eur Acad Dermatol Venereol. 2011 May;25 (Suppl 2):28–33. 46. Caproni M, Antiga E, Melani L, Volpi W, Del Bianco E, Fabbri P. Serum levels of IL-17 and IL-22 are reduced by etanercept, but not by acitretin, in patients with psoriasis: A randomized-controlled trial. J Clin Immunol. 2009 Mar;29(2):210–214. 47. Gisondi P, Del Giglio M, Cotena C, Girolomoni G. Combining etanercept and acitretin in the therapy of chronic plaque psoriasis: A 24-week, randomized, controlled, investigator-blinded pilot trial. Br J Dermatol. 2008 Jun;158(6):1345–1349. 48. Mahrle G, Schulze HJ, Färber L, Weidinger G, Steigleder GK. Low-dose short-term cyclosporine versus etretinate in psoriasis: Improvement of skin, nail, and joint involvement. J Am Acad Dermatol. 1995 Jan;32(1):78–88. 49. Paul C, Gallini A, Maza A, et al. Evidence-based recommendations on conventional systemic treatments in psoriasis: Systematic review and expert opinion of a panel of dermatologists. J Eur Acad Dermatol Venereol. 2011 May;25(Suppl 2):2–11. 50. Buccheri L, Katchen BR, Karter AJ, Cohen SR. Acitretin therapy is effective for psoriasis associated with human immunodeficiency virus infection. Arch Dermatol. 1997 Jun;133(6):711–715. 51. Katz HI, Waalen J, Leach EE. Acitretin in psoriasis: An overview of adverse effects. J Am Acad Dermatol. 1999 Sep;41(3 Pt 2):S7–12. 52. Menter A, Korman NJ, Elmets CA, et al. Guidelines of care for the management of psoriasis and psoriatic arthritis: Section 4. Guidelines of care for

the management and treatment of psoriasis with ­traditional systemic agents. J Am Acad Dermatol. 2009 Sep;61(3):451–485. 53. Lammer EJ, Chen DT, Hoar RM, et al. Retinoic acid embryopathy. N Engl J Med. 1985 Oct;313(14):837–841. 54. Vestergaard P, Rejnmark L, Mosekilde L. High-dose treatment with vitamin A analogues and risk of fractures. Arch Dermatol. 2010 May;146(5):478–482. 55. Geiger J-M, Walker M. Is there a reproductive safety risk in male patients treated with acitretin (neotigason/soriatane?). Dermatol Basel Switz. 2002;205(2):105–107. 56. Brecher AR, Orlow SJ. Oral retinoid therapy for dermatologic conditions in children and adolescents. J Am Acad Dermatol. 2003 Aug;49(2):171–182; quiz 183–186. 57. Zachariae H. Dangers of methotrexate/etretinate combination therapy. Lancet. 1988 Feb;1(8582):422. 58. Zachariae H. Methotrexate and etretinate as concurrent therapies in the treatment of psoriasis. Arch Dermatol. 1984 Feb;120(2):155. 59. Fraser AD, van Kuijk AWR, Westhovens R, et al. A randomised, double blind, placebo controlled, multicentre trial of combination therapy with methotrexate plus ciclosporin in patients with active psoriatic arthritis. Ann Rheum Dis. 2005 Jun;64(6): 859–864. 60. St Clair EW, van Der Heijde DMFM, Smolen JS, et al. Combination of infliximab and methotrexate therapy for early rheumatoid arthritis: A randomized, controlled trial. Arthritis Rheum. 2004 Nov;50(11):3432–3443. 61. Zachariae C, Mørk N-J, Reunala T, et al. The combination of etanercept and methotrexate increases the effectiveness of treatment in active psoriasis despite inadequate effect of methotrexate therapy. Acta Derm Venereol. 2008;88(5):495–501. 62. Gottlieb AB, Langley RG, Strober BE, et al. A randomized, double-blind, placebo-controlled study to evaluate the addition of methotrexate to etanercept in patients with moderate to severe plaque psoriasis. Br J Dermatol. 2012 Sep;167(3):649–657. 63. Armstrong AW, Bagel J, van Voorhees AS, Robertson AD, Yamauchi PS. Combining biologic therapies with other systemic treatments in psoriasis: Evidence-based, best-practice recommendations from the medical board of the national psoriasis foundation. JAMA Dermatol. 2015 Apr;151(4):432–438.

23 Current biologic therapies (including IL-17) and monitoring guidelines BRUCE E. STROBER and JENNA M. WALD Currently, there are five biologic therapies approved by the U.S. Food and Drug Administration (FDA) for the treatment of moderate-to-severe plaque psoriasis. These drugs can be classified as (1) tumor necrosis factor-alpha (TNF-α) inhibitors, (2) interleukin (IL)-12/23 inhibitors, and (3) IL-17 pathway inhibitors. As the number of targets of biologic therapies continues to broaden, it is important that practitioners follow both the FDA and specialtyspecific recommendations for screening and monitoring patients on long-term treatment. This chapter will review the efficacy and adverse effects of each drug (and its class) and suggest pretreatment screening tests and ongoing monitoring that should be considered for each biologic therapy. Efficacy of treatments is described as the reduction of Psoriasis Area and Severity Index (PASI) score as reported in phase 3 clinical trials. The three TNF-α inhibitors approved for psoriasis are adalimumab, etanercept, and infliximab. Adalimumab is a fully human monoclonal antibody for both soluble and membrane-bound TNF-α. After 16 weeks of treatment with adalimumab, 71% of patients achieved a PASI 75 (indicating a reduction in PASI scoring greater than or equal to 75%) versus 7% of placebo-treated patients; PASI 90 and 100 scores were achieved by 45% and 20%, respectively.1 The most common adverse effects (incidence >10%) are infections, injection site reactions, headache, and rash.2 Infliximab is a chimeric monoclonal antibody for both soluble and membrane-bound TNF-α. After 10 weeks of infliximab therapy, 80% of patients achieve PASI 75 and 57% PASI 90, versus 3% and 1% of placebo-treated patients. Similarly, at 24 weeks of treatment, PASI 75 and PASI 90 were achieved by 82% and 61%, respectively.3 The most common adverse effects (incidence >10%) are infections, infusion-related reactions, headache, and abdominal pain.4 Etanercept is a dimeric fully human receptor fusion protein. Phase 3 testing of etanercept at the FDAapproved loading dose of 50 mg twice weekly for 12 weeks demonstrated 49% of patients achieving PASI 75 and

21% achieving PASI 90, versus the 3% of placebo-treated patients and 34% of patients receiving 25 mg twice weekly. A maintenance dose of 25 mg twice weekly (to both groups treated with both loading doses) through week 24 demonstrated a PASI 75 in 54% of the 50 mg twice weekly group and 45% of patients from the 25 mg twice weekly group.5 The most common adverse effects (incidence >5%) are infection and injection site reaction.6 Well-established risks associated with TNF-α inhibitors as a class include new or reactivation of latent opportunistic infections, lupus-like reactions, nonmelanoma skin cancers (NMSCs), and development or progression of demyelinating diseases and congestive heart failure. Other adverse events including malignancies such as lymphoma have been reported in patients; however, this may be due to combination therapy with other immunosuppressive medications or associated with the inflammatory disease being treated. Ustekinumab is currently the only IL-12/23 inhibitor FDA approved for the treatment of psoriasis. It is a fully human monoclonal antibody that binds the shared p40 subunit of both IL-12 and IL-23, thus preventing the activation of both T-helper (TH)-1 and TH-17 pathways, respectively. After 12 weeks of treatment with 45 or 90 mg of ustekinumab, PASI 75 was achieved in 66.7%–67.1% and 66.4%–75.7% of patients, respectively, versus 3.1%–3.7% of placebo; PASI 90 was achieved in between 41.6%–42.3% and 36.7%–50.9% of patients. At 28 weeks of treatment with 45 of 90 mg, PASI 75 was achieved by 69.5%–71.2% and 78.5%–78.6% of patients, and PASI 90 by 44.8%–49.2% and 54.3%–55.6% of patients, respectively.7,8 The most common adverse effects (incidence ≥3%) are nasopharyngitis, upper respiratory tract infection, headache, and fatigue.9 Secukinumab is currently the only FDA-approved IL-17 inhibitor. Secukinumab is a fully human monoclonal antibody that binds to IL-17A, a cytokine produced by TH17 cells, blocking inflammation that is highly specific for psoriasis. After 12 weeks of the FDA-approved dose of secukinumab, depending on the study, between

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77.1% and 81.6% of patients demonstrated PASI 75, 54.2%–59.2% PASI 90, and 24.1%–28.6% PASI 100 versus 4.5%–4.9% of placebo-treated patients. Similarly, maintenance of PASI 75 at 24 weeks of treatment was achieved by 80.5%–84.3% of patients.10 The most common adverse effects (­incidence  >1%) are candidiasis, nasopharyngitis, ­diarrhea, and upper respiratory tract infection.11

TUBERCULOSIS Baseline screening for latent tuberculosis is recommended for all patients starting immunosuppressive therapy. Specifically, the Th1 cell subset and TNF-α play a central role in patient defenses against initial Mycobacterium tuberculosis infection and maintaining a latent (or inactive) state. Inhibiting these host defenses leads to reactivation and atypical presentations of tuberculosis (TB) at a higher rate than in control populations. All patients starting a TNF-α inhibitor should be screened for latent tuberculosis (LTB) by obtaining a thorough history, examination, and testing prior to initiation of treatment.2,12 The risk of TB reactivation has been noted to be lower in studies of patients treated with ustekinumab compared with TNF-α inhibitors; this may be due to either IL-12 or IL-23 being less relevant to maintaining TB latency, or a heightened awareness and screening initiated prior to the drug’s development.13 Caution should be exercised, however, as IL-12 is an important cytokine in the expansion of the Th1 cell subset and inhibition of its effects may diminish the host response to TB. Additionally, there have been no documented cases of reactivation of LTB in patients treated with secukinumab. Nevertheless, in the absence of a thorough understanding of this risk, all patients starting an immunosuppressive therapy should receive screening for LTB before initiation of biologic therapy and should be monitored for clinical signs or symptoms throughout therapy.14–17 Traditionally, screening for LTB was performed via tuberculin skin test (TST); however, this is being replaced with the more sensitive and specific interferon gamma release assay (IGRA), also known as the QuantiFERON-TB Gold test.18,19 The IGRA test allows for a more accurate interpretation in patients who have received Bacille– Calmette–Guerin vaccination (where the test would be negative), it does not depend on provider interpretation or patient independent factors, and is more convenient as it can be completed in a single visit with results obtained within 24 hours.18,19 At the initial screening IGRA may be preferable as an uncontrolled inflammatory disease state that can lead to a false-positive TST.18,19 If either method of testing is found to be positive, in an asymptomatic patient with a negative chest x-ray, guidelines recommend at least 1 month of LTB treatment before initiation of TNF-α inhibitors.12 The risk for reactivation of TB during TNF-α inhibitor treatment is not transient.20 Consequently, the current recommendation for patients is annual monitoring

via TST or IGRA testing.12,18,19 Reactivation of LTB is seen at increased rates in all patients on TNF-α inhibitors, but is greater with the TNF-α inhibiting antibodies, adalimumab and infliximab, compared with etanercept.21 The 2010 Center for Disease Control (CDC) recommendations suggest that routine monitoring in low-risk populations may be of limited utility due to the rate of false positives, but it additionally states that patients on TNF-α inhibitors are considered immunocompromised and may benefit from surveillance testing as they are at an increased risk for progression to active TB if infected.18,20 This is in contrast to the American College of Rheumatology that recommends annual screening only in patients with a personal history suggesting increased risk.22 Some have suggested that prescreening and annual testing are not necessary, but rather a physical examination and history are sufficient and more cost effective.14,22 Importantly, in the setting of ongoing immunosuppressive therapy both tests display a greater risk for false-negative results (TST greater than IGRA), thus emphasizing the need for a thorough history of exposure and review of symptoms.2,18,19 Additional testing only occurs in patients with evidence of new infection.19

HEPATITIS Screening for hepatitis B virus (HBV) and hepatitis C virus (HCV) should be performed prior to initiation of any biologic therapy. 22–24 The recommended screening includes testing for hepatitis B surface (HBs) antigen and anti-hepatitis B core (anti-HBc) antibodies, with or without anti-hepatitis B surface (anti-HBs) antibodies.15,23–28 Testing for anti-HBs antibodies is part of the traditional triple test and is usually positive in cases of vaccination and prior exposure. Although it may be useful in verifying vaccination, the presence of anti-HBs antibodies does not eliminate the risk of reactivation of HBV in previously infected individuals. Reactivation can occur in up to 5% of patients receiving TNF-α inhibitors; however, the effect of ustekinumab and secukinumab in reactivation is unknown. 24 Patients with acute HBV infection should not receive immunosuppressive treatment. However, patients with chronic or resolved HBV may be considered for treatment with a TNF-α inhibitor or other biologic therapy after consultation with a hepatologist and consideration of concomitant antiviral treatment. 23,24,26–29 Prophylactic antiviral therapy has been associated with up to an 80% decrease in reactivation of HBV. 30 If negative, regular clinical monitoring should be performed for signs and symptoms of pathology. Although not an absolute requirement, vaccination prior to the initiation of therapy should be considered for uninfected and unvaccinated individuals. 23 The risk of HCV during treatment with biologic therapy is unclear and thus baseline screening is recommended.15,23,26–28 Positive results are not an absolute contraindication to biologic treatment and patients should

Other adverse events  235

be referred to hepatologist for consideration of concomitant antiviral therapy or treatment prior to initiation of therapy.27–29 There is supportive evidence that both etanercept and adalimumab can be safely used in HCV patients without adverse events.13,26 If negative, repeated tests for infection during therapy need only be guided by the onset of suggestive signs and symptoms, or abnormal laboratory results (elevated liver function tests [LFTs]). TNF-α inhibitors very rarely have been implicated in liver pathology ranging from transient LFT abnormalities to significant hepatic injury; therefore, baseline LFTs should be obtained prior to initiation of therapy.15,23,31 If the patient is at risk for liver damage due to concomitant therapies, alcohol abuse, fatty liver, or history of nonalcoholic fatty liver disease, the clinician should consider monitoring LFTs at regular intervals, such as every 12–24 weeks. For low-risk patients with normal baseline values, no further monitoring is necessary unless warranted by signs or symptoms.

MALIGNANCIES Baseline screening should include a thorough history for previous cancers, baseline hematologic labs, and routine clinical monitoring for new symptoms or signs that suggest malignancy, such as unexplained weight loss and fatigue. It should be emphasized that a baseline history of malignancy does not exclude the use of biologic medications, as supported by more recent registry data.32 The risk of treating patients with a prior malignancy has not been quantified. However, often this scenario arises and a thorough risk and benefit discussion may lead to a decision for or against biologic therapy. The risk of NMSCs may be higher in patients on longterm therapy with TNF-α or IL-12/23 inhibitors.13,17,33,34 These data may be confounded by the fact that many psoriasis patients have an extensive history of both natural and in-office ultraviolet phototherapy.35 Regardless, the data warrant higher risk patients receiving full skin examinations at regular (every 6- to 12-month) intervals.33,35 Other than NMSC there are no conclusive data indicating an increased risk of malignancy in psoriasis patients treated with any of the approved biologics as a monotherapy.13,26,33,34,36,37 Although biologics as a monotherapy likely pose no increased risk for psoriasis patients, some data, particularly from the rheumatoid arthritis (RA) and inflammatory bowel disease (IBD) populations, suggest that the use of a TNF-α inhibitor with additional disease-modifying immunosuppressive agents (such as methotrexate, cyclosporine, 6-mercaptopurine, and azathioprine) may lead to an increased risk of malignancy such as lymphoma. 33,38 For example, the use of TNF-α inhibitors in combination with thiopurines (azathioprine or 6-mercaptopurine) may increase a patient’s risk of T-cell non–Hodgkin’s lymphoma; this risk is found most notably in patients with IBD treated

with combination immunosuppression that developed ­hepatosplenic T-cell lymphoma. 38–40

OTHER INFECTIONS Treatment with TNF-α inhibitors leads to an increased risk of a panel of rare opportunistic infections including Listeria monocytogenes, Pneumocystis jirovecii (formerly, Pneumocystis carinii), Histoplasma capsulatum, candidiasis, and aspergillosis.41,42 Pretreatment tests for the causative pathogens are not indicated. Patients in regions with known opportunistic fungi should be counseled on the increased risk and the symptoms of infection, and patients should be screened and monitored using a complete review of systems and appropriate laboratory testing.41 IL-17 is a cytokine that functions in the innate immune response against extracellular bacteria, parasites, and fungus; additionally, it is important in mucocutaneous immunity. There are no pretreatment tests indicated before starting secukinumab, but patients should be counseled on the increased risk of oral candidal infections.10,43,44 A theoretical risk that is gaining merit also includes an increased risk of Staphylococcus aureus infections.44,45 There is no evidence of increased risk of opportunistic infections in ustekinumab-treated patients; however, all patients should be clinically monitored for evidence of such infections.

OTHER ADVERSE EVENTS Hematologic effects Secukinumab trials saw a grade 3 neutropenia in 1.0% of patients, and hematologic abnormalities have rarely been reported in patients treated with TNF-α inhibitors.10 Although a direct correlation cannot be established with TNF-α inhibitors, it is still recommended that a baseline complete blood cell count be performed before starting any biologic therapy.15,36 In addition it is recommended that all patients starting a biologic therapy have a baseline chemistry performed.15,16 The role of laboratory monitoring is unclear, but for additional monitoring of blood dyscrasias the authors usually perform follow-up laboratory testing of the complete blood cell count every 6 months, and sooner if symptoms or signs warrant.

Cardiovascular effects Prescribing TNF-α inhibitors in patients with congestive heart failure (CHF) remains controversial, and some data suggest that treatment may lead to CHF exacerbation.16,35,46 Patients should be screened by history and

236  Current biologic therapies (including IL-17) and monitoring guidelines

review of systems prior to initiation of, and during therapy. In patients with New York Heart Association class III or IV CHF, it is recommended that TNF-α inhibitors be avoided.16,22 Although caution should be exercised in all TNF-α inhibitors, infliximab may demonstrate a higher risk than either adalimuamb or etanercept.46 Ustekinumab does not appear to worsen CHF, but there is conflicting evidence as to whether it increases or decreases major adverse cardiovascular events (MACE) with long-term use.36,37,46 Although IL-12/23 inhibitors present a therapeutic alternative to TNF-α inhibitors, caution should be exercised until further data support or refute the risk of MACE in high-risk psoriatic patients with uncontrolled cardiometabolic disease (diabetes, hypertension, and hypercholesterolemia) treated with this drug. There are currently no data supporting or against the use of secukinumab in patients with CHF, but clinical trials for this drug revealed no consistent cardiovascular adverse event signal.

Demyelinating neurologic diseases TNF-α is known to play a role in the pathogenesis of demyelinating neurologic disorders. Although initially considered as a potential treatment for multiple sclerosis (MS), data have shown that there is a connection between TNF-α inhibitors and the development or progression of demyelinating disorders such as MS, optic neuritis, Guillain–Barre syndrome, transverse myelitis, chronic inflammatory demyelinating polyradicularneuropathy, and multifocal motor neuropathy.47–50 As such, patients should be screened for a personal and family history of such disorders. If a personal history is present, treatment with a TNF-α inhibitor is contraindicated. If personal history is questionable, a neurological referral should be arranged. If a family history exists, although the risk is likely much lower, patients should be counseled about this risk. If symptoms develop while on a TNF-α inhibitor, treatment should be immediately stopped and the patient referred to a neurologist. Unlike TNF-α inhibitors ustekinumab is safe to use in patients with MS.36,37 Although their causal relationship to ustekinumab therapy is unclear, there have been isolated cases of reversible posterior leukoencephalopathy syndrome.17,43

Autoimmunity Patients who initially screen negative may develop positive antinuclear antibodies (ANAs), including anti–doublestranded DNA (anti-dsDNA), anti-histone, anti-Sm, and anti-ribonucleoprotein antibodies, after treatment with TNF-α inhibitors.15,16,51 Some patients treated with TNF-α inhibitors will develop a lupus-like reaction, which usually resolves with treatment cessation.15,16 A positive baseline

low titer positive test for ANA does not correlate with a greater risk of a lupus-like reaction during therapy, nor is seroconversion while on therapy indicative of an ongoing or incipient lupus-like reaction.15,51 Therefore, a baseline ANA is not necessary but may be performed at the discretion of the provider solely to be used as a comparison in patients who develop symptoms of a lupus-like reaction while on therapy.15,16,51 Regardless of the baseline test result, follow-up monitoring is not recommended unless a patient develops signs and symptoms to suggest a lupuslike reaction.15,51 Over the course of treatment with TNF-α inhibitors some patients demonstrate a diminished response over time. The mechanism of secondary loss of efficacy is not entirely clear, although, in part, it may relate to the development of antidrug antibodies.52 Testing for specific antidrug antibodies is not readily available. However, the development of ANA appears to also coincide with secondary treatment failure and may potentially represent a surrogate marker for secondary failure.52,53 After initially screening negative, 17% of patients will become positive for ANA while on their first TNF-α inhibitor, 54% after failing to respond to the first TNF-α inhibitor, 78% of patients after failing to respond to the second, and 83% after failing three TNF-α inhibitors; similarly positive anti-dsDNA antibodies can be seen in 2%, 27%, 33%, and 83% of patients from the same respective treatment points during treatment with TNF-α inhibitors.52 When accounting for all autoantibodies, newly positive or an increased antibody titer can be observed in 29% of patients on TNF-α inhibitors.54 As loss of response is clinically obvious, the monitoring of ANA level for this purpose is not recommended.52 Although antidrug antibodies have also been observed with ustekinumab and secukinumab treatment, they have not been shown to correlate with decreased efficacy and the correlation with ANA titers has yet to be assessed.10,36

CONCLUSIONS Biologics provide a safe and effective treatment option for most psoriasis patients. As a general rule, all patients starting a biologic therapy should have baseline testing including complete blood cell count, chemistry, LFTs, and screening for hepatitis B, C, and latent tuberculosis. Special considerations and more fastidious on-treatment monitoring should be given to patients with preexisting risks associated with any specific biologic therapy.

UPDATE While this chapter was in production, Ixekizumab (a humanized monoclonal antibody targeting IL-17A) became the sixth biologic therapy FDA approved for the treatment of moderate-to-severe plaque psoriasis.55

References 237

REFERENCES 1. Menter A, Tyring SK, Gordon K, et al. Adalimumab therapy for moderate to severe psoriasis: A randomized, controlled phase III trial. J Am Acad Dermatol. 2008;58(1):106–115. 2. National Food and Drug Administration. Access Data. FDA Approved Humira® Label updated 09/2014. Available from: http://www.accessdata.fda. gov/drugsatfda_docs/label/2011/125057s0215lbl.pdf 3. Reich K, Nestle FO, Papp K, et al. Infliximab induction and maintenance therapy for moderateto-severe psoriasis: A phase III, multicentre, doubleblind trial. Lancet. 2005;366:1367–1374. 4. National Food and Drug Administration. Access data. FDA Approved Remicade® Label updated 01/2015. Available from: http://www.accessdata. fda.gov/drugsatfda_docs/label/2015/103772s537 0lbl.pdf 5. Papp KA, Tyring S, Lahfa M, et al. A global phase III randomized controlled trial of etanercept in psoriasis: Safety, efficacy, and effect of dose reduction. Br J Dermatol. 2005 Jun;152(6):1304–1312. 6. National Food and Drug Administration. Access data. FDA Approved Enbrel® Label updated 03/2015. Available from: http://www.accessdata.fda.gov/ drugsatfda_docs/label/2015/103795s5548lbl.pdf 7. Leonardi CL, Kimball AB, Papp KA, et al. Efficacy and safety of ustekinumab, a human interleukin-12/23 monoclonal antibody, in patients with psoriasis: 76-week results from a randomized, double-blind, placebo-controlled trial (PHOENIX 1). Lancet. 2008 May 17;371 (9625):1665–1674. 8. Papp KA, Langley RG, Lebwohl M, et al. Efficacy and safety of ustekinumab, a human interleukin-12/23 monoclonal antibody, in patients with psoriasis: 52-week results from a randomized, double-blind, placebo-controlled trial (PHOENIX 2). Lancet. 2008 May 17;371(9625):1675–1684. 9. National Food and Drug Administration. Access data. FDA Approved Stelara® Label updated 03/2014. Available from: http://www.accessdata.fda.gov/ drugsatfda_docs/label/2014/125261s114lbl.pdf 10. Langley R, Elewski B, Lebwohl M, et al. Secukinumab in plaque psoriasis—Results of two Phase 3 trials. N Eng J Med. 2014;371(4):326–338. 11. National Food and Drug Administration. Access data. FDA Approved Cosentyx® Label updated 01/2015. Available from: http://www.accessdata. fda.gov/drugsatfda_docs/label/2015/125504s000 lbl.pdf 12. Doherty S, van Voorhees A, Lebwohl M, Korman N, Young M, Hsu S. National Psoriasis Foundation consensus statement on screening for latent tuberculosis infection in patients with psoriasis treated with systemic and biologic agents. J Am Acad Dermatol. 2008;59(2):209–217.

13. Caso F, Cantarini L, Morisco F, et al. Current ­evidence in the field of the management with TNF-α inhibitors in psoriatic arthritis and concomitant hepatitis C virus infection. Expert Opin Biol Ther. 2015;15(5):641–650. 14. Huang W, Cordoro K, Taylor S, Feldman S. To test or not to test? An evidence-based assessment of the value of screening and monitoring tests when using systemic biologic agents to treat psoriasis. J Am Acad Dermatol. 2008;58(6):970–977. 15. Lebwohl M, Bagel J, Gelfand J, et al. From the Medical Board of the National Psoriasis Foundation: Monitoring and vaccinations in patients treated with biologics for psoriasis. J Am Acad Dermatol. 2008;58(1):94–105. 16. Menter A, Gottlieb A, Feldman S, et al. Guidelines of care for the management of psoriasis and psoriatic arthritis; Section 1. Overview of psoriasis and guidelines of care for the treatment of psoriasis with biologics. J Am Acad Dermatol. 2008;58(5):826–850. 17. Gordon K, Papp K, Langley R, et al. Long-term safety experience of ustekinumab in patients with moderate to severe psoriasis (Part II of II): Results from analyses of infections and malignancy from pooled phase II and III clinical trials. J Am Acad Dermatol. 2012;66(5):742–751. 18. Mazurek G, Jereb J, Vernon A, LoBue P, Goldberg S, Castro K; IGRA Expert Committee; Centers for Disease Control and Prevention (CDC). CDC updated guidelines for using interferon gamma release assays to detect Mycobacterium tuberculosis infection—United States, 2010. MMWR Recomm Rep. 2010 Jun 25;59 (RR-5):1–25. 19. Sivamani R, Goodarzi H, Garcia M, Raychaudhuri S, Wehrli L, Ono Y, et al. Biologic therapies in the treatment of psoriasis: a comprehensive evidence-based basic science and clinical review and a practical guide to tuberculosis monitoring. Clin Rev Allergy Immunol. 2012;44(2):121–140. 20. Dixon W, Hyrich K, Watson K, et al. Drug-specific risk of tuberculosis in patients with rheumatoid arthritis treated with anti-TNF therapy: Results from the British Society for Rheumatology Biologics Register (BSRBR). Ann Rheum Dis. 2009;69(3):522–528. 21. Tubach F, Salmon D, Ravaud P, et al. Risk of tuberculosis is higher with anti-tumor necrosis factor monoclonal antibody therapy than with soluble tumor necrosis factor receptor therapy: The threeyear prospective French research axed on tolerance of biotherapies registry. Arthritis Rheum. 2009;60(7):1884–1894. 22. Singh J, Furst D, Bharat A, et al. 2012 Update of the 2008 American College of Rheumatology recommendations for the use of disease-modifying antirheumatic drugs and biologic agents in the treatment of rheumatoid arthritis. Arthritis Care Res. 2012;64(5):625–639.

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23. Motaparthi K, Stanisic V, van Voorhees A, Lebwohl M, Hsu S. From the Medical Board of the National Psoriasis Foundation: Recommendations for screening for hepatitis B infection prior to initiating anti-tumor necrosis factor-alfa inhibitors or other immunosuppressive agents in patients with psoriasis. J Am Acad Dermatol. 2014;70(1):178–186. 24. Perrillo R, Martin P, Lok A. Preventing hepatitis B reactivation due to immunosuppressive drug treatments. JAMA. 2015;313(16):1617. 25. Weinbaum C, Williams I, Mast E . Recommendations for identification and public health management of persons with chronic hepatitis B virus infection. MMWR Recomm Rep. 2008 Sep 19;57(RR-8):1–20. 26. Rustin M. Long-term safety of biologics in the treatment of moderate-to-severe plaque psoriasis: Review of current data. Br J Dermatol. 2012;167:3–11. 27. Navarro R, Vilarrasa E, Herranz P, et al. Safety and effectiveness of ustekinumab and antitumour necrosis factor therapy in patients with psoriasis and chronic viral hepatitis B or C: A retrospective, multicentre study in a clinical setting. Br J Dermatol. 2013;168(3):609–616. 28. Chiu H, Chen C, Wu M, Cheng Y, Tsai T. The safety profile of ustekinumab in the treatment of patients with psoriasis and concurrent hepatitis B or C. Br J Dermatol. 2013;169(6):1295–1303. 29. Steglich R, Meneghello L, Carvalho A, Cheinquer H, Muller F, Reginatto F. The use of ustekinumab in a patient with severe psoriasis and positive HBV serology. An Bras Dermatol. 2014;89(4):652–654. 30. Loomba R. Systematic review: The effect of preventive lamivudine on hepatitis B reactivation during chemotherapy. Ann Intern Med. 2008;148(7):519. 31. Björnsson E, Gunnarsson B, Gröndal G, et al. Risk of drug-induced liver injury from tumor necrosis factor antagonists. Clin Gastroenterol Hepatol. 2015;13(3):602–608. 32. Strangfeld A, Hierse F, Rau R, et al. Risk of incident or recurrent malignancies among patients with rheumatoid arthritis exposed to biologic therapy in the German biologics register RABBIT. Arthritis Res Ther. 2010;12(1):R5. 33. Dommasch E, Abuabara K, Shin D, Nguyen J, Troxel A, Gelfand J. The risk of infection and malignancy with tumor necrosis factor antagonists in adults with psoriatic disease: A systematic review and metaanalysis of randomized controlled trials. J Am Acad Dermatol. 2011;64(6):1035–1050. 34. Dommasch E, Gelfand J. Is there truly a risk of lymphoma from biologic therapies? Dermatol Ther. 2009;22(5):418–430. 35. Semble A, Davis S, Feldman S. Safety and tolerability of tumor necrosis factor-α inhibitors in psoriasis: A narrative review. Am J Clin Dermatol. 2013;15(1):37–43.

36. Toussirot E, Michel F, Bereau M, Binda D. Ustekinumab in chronic immune-mediated diseases: A review of long term safety and patient improvement. Patient Prefer Adherence. 2013;369. 37. Sorenson E, Koo J. Evidence-based adverse effects of biologic agents in the treatment of moderate-tosevere psoriasis: Providing clarity to an opaque topic. J Dermatol Treat. 2015;1–9. 38. Deepak P, Sifuentes H, Sherid M, Stobaugh D, Sadozai Y, Ehrenpreis E. T-cell non-Hodgkin’s lymphomas reported to the FDA AERS with tumor necrosis factor-alpha (TNF-α) inhibitors: Results of the REFURBISH study. Am J Gastroenterol. 2012;108(1):99–105. 39. Kotlyar D, Osterman M, Diamond R, et al. A systematic review of factors that contribute to hepatosplenic T-cell lymphoma in patients with inflammatory bowel disease. Clin Gastroenterol Hepatol. 2011;9(1):36–41.e1. 40. Parakkal D, Sifuentes H, Semer R, Ehrenpreis E. Hepatosplenic T-cell lymphoma in patients receiving TNF-α inhibitor therapy. Eur J Gastroenterol Hepatol. 2011;23(12):1150–1156. 41. Murdaca G, Spanò F, Contatore M, et al. Infection risk associated with anti-TNF-α agents: A review. Expert Opin Drug Saf. 2015;14(4):571–582. 42. Tsiodras S, Samonis G, Boumpas D, Kontoyiannis D. Fungal infections complicating tumor necrosis factor α blockade therapy. Mayo Clin Proc. 2008;83(2):181–194. 43. Gratton D, Szapary P, Goyal K, Fakharzadeh S, Germain V, Saltiel P. Reversible posterior leukoencephalopathy syndrome in a patient treated with ustekinumab. Arch Dermatol. 2011;147(10):1197. 44. Gisondi P, Dalle Vedove C, Girolomoni G. Efficacy and safety of secukinumab in chronic plaque psoriasis and psoriatic arthritis therapy. Dermatol Ther (Heidelb). 2014;4(1):1–9. 45. Baeten D, Baraliakos X, Braun J, et al. Antiinterleukin-17A monoclonal antibody secukinumab in treatment of ankylosing spondylitis: A randomised, double-blind, placebo-controlled trial. Lancet. 2013;382(9906):1705–1713. 46. Hugh J, van Voorhees A, Nijhawan R, et al. From the Medical Board of the National Psoriasis Foundation: The risk of cardiovascular disease in individuals with psoriasis and the potential impact of current therapies. J Am Acad Dermatol. 2014;70(1):168–177. 47. Seror R, Richez C, Sordet C, et al. Pattern of demyelination occurring during anti-TNF- therapy: A French national survey. Rheumatology. 2013;52(5):868–874. 48. Theibich A, Dreyer L, Magyari M, Locht H. Demyelinizing neurological disease after treatment with tumor necrosis factor alpha-inhibiting agents in a rheumatological outpatient clinic: Description of six cases. Clin Rheumatol. 2014;33(5):719–723.

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49. Solomon A, Spain R, Kruer M, Bourdette D. Inflammatory neurological disease in patients treated with tumor necrosis factor alpha inhibitors. Mult Scler J. 2011;17(12):1472–1487. 50. Hare N, Hunt D, Venugopal K, et al. Multiple sclerosis in the context of TNF blockade and inflammatory bowel disease. QJM. 2014;107(1):51–55. 51. van Lümig P, Driessen R, Roelofs-Thijssen M, Boezeman J, van de Kerkhof P, de Jong E. Relevance of laboratory investigations in monitoring patients with psoriasis on etanercept or adalimumab. Br J Dermatol. 2011;165(2):375–382. 52. Pink A, Fonia A, Allen M, Smith C, Barker J. Antinuclear antibodies associate with loss of response to antitumour necrosis factor-α therapy in

psoriasis: A retrospective, observatonal study. Br J Dermatol. 2009;162(4):780–785. 53. Hoffmann J, Hartmann M, Enk A, Hadaschik E. Autoantibodies in psoriasis as predictors for loss of response and anti-infliximab antibody induction. Br J Dermatol. 2011;165(6):1355–1358. 54. Bardazzi F, Odorici G, Virdi A, Antonucci V, Tengattini V, Patrizi A et al. Autoantibodies in psoriatic patients treated with anti-TNF-α therapy. J Dtsch Dermatol Ges. 2014;12(5):401–406. 55. National Food and Drug Administration. Access data.  FDA Approved Taltz label 03/2016. Available from:  http://www.accessdata.fda.gov/drugsatfda_ docs/label/2016/125521s000lbl.pdf.

24 Current and future oral small molecules PETER WEISENSEEL and KRISTIAN REICH FUMARIC ACID ESTERS Fumaric acid esters (FAEs) are a group of small molecules that were introduced into psoriasis therapy by the German chemist Walter Schweckendiek in the late 1950s.1 Schweckendiek suffered from psoriasis and experimented on himself with fumaric acid in different oral and topical formulations. Along with the German physician Schaefer, he developed several esters of fumaric acid that exhibited much better oral bioavailability than unmodified fumaric acid. Fumaric acid is part of the citric acid cycle in human cells and can also be found in certain plants, e.g., Fumaria officinalis, from which the name fumaric acid was derived. However, it took more than another three decades before the first fumarate-based drug was approved in Germany (Fumaderm intial®/Fumaderm® by Fumapharm AG, Switzerland). Fumaderm® was approved in 1994 and is a combination of different FAEs: dimethylfumarate (DMF)—that is currently regarded as the crucial component—and three salts of ethyl hydrogenfumarate. The use of Fumaderm initial®/Fumaderm® was initially restricted to severe psoriasis and limited to 6 months according to the Summary of Product Characteristics (SmPC). The time restriction was waived in 2003 and the label was extended to moderate psoriasis in 2008. Fumaderm® for psoriasis is still approved in Germany, where it is the most frequently prescribed systemic antipsoriatic therapy. Fumarates are widely used in other European countries, but rarely in non-European countries. In the Netherlands, pharmacy-made products are available, which mainly contain DMF.

Mode of action DMF is a pro-drug that is converted to the active monomethylfumarate inside cells. The mode of action has not been completely elucidated, but there is increasing in vitro and in vivo evidence that FAEs foster the production of type II dendritic cells through the depletion of intracellular glutathione levels.2 This leads to increased hemoxygenase-1 (HO-1) expression and impaired signal

transducer and activator of transcription (STAT1) phosphorylation. Type I dendritic cells produce interleukin (IL)-12 and IL-23 and induce differentiation of naïve T cells into pathogenic Th1 and Th17 cells. In contrast, type II dendritic cells produce IL-10 and Th2 cells, which produce IL-4. Upregulation of IL-4 and IL-10 and downregulation of IL-12 and IL-23 enhance Th1- and Th17-mediated autoimmune inflammatory disorders, such as psoriasis or multiple sclerosis (MS).

Clinical efficacy in psoriasis FAEs exhibit a relatively slow onset of action in psoriasis. Clear clinical improvement is typically not seen before week 4. Maximum clinical efficacy is expected at week 24, but some patients may show further clinical improvement beyond week 24.3–5 Only a few randomized clinical trials have been performed on the use of fumarates in the treatment of psoriasis. In an open-label prospective multicenter study in Germany with 101 patients, two measures of efficacy— Psoriasis Area and Severity Index (PASI)—improved after 4 months of FAE therapy. In another German study with 124 patients, the mean PASI reduction after 13 weeks of FAE therapy was about 52%. In the second arm, additional topical therapy with calcipotriol ointment increased the mean PASI reduction to 76% within the same time frame.2 An open-label prospective study showed a psoriasis global assessment (PGA) response of <1 (clear or almost clear) of about 80% at week 24.6 FAEs exhibit higher efficacy than placebo in the induction phase, as assessed by the PASI 75 response rate or PGA <1 (=clear/almost clear), but the FAE treatment is accompanied by a higher rate of adverse events. On the other hand, the withdrawal rates in the induction phase due to adverse events (AEs) were comparable in FAE and placebo-treated patients.7 For FAEs and methotrexate (MTX), efficacy rates based on PASI 75, PASI 90, and PGA <1 response rates are comparable in the induction phase until week 12.8 MTX gave a 241

242  Current and future oral small molecules

slightly better outcome with respect to the final PASI score. AE rates and discontinuation due to AEs were similar. The 4-year drug survival rate is about 60%, which is high compared with the published data of biologicals such as etanercept and adalimumab (each about 40%).9

Psoriatic arthritis FAEs do not show relevant efficacy in psoriatic arthritis (PsA), though a clinical response may be seen.10

FAEs in MS The clinical efficacy of oral dimethyl fumarate (DMF) in the treatment of MS has been demonstrated in two pivotal phase III studies. Dimethyl fumarate reduced relapse rates by about 50% compared with placebo.11 Reduction in disability progression was significant in only one of the two studies. The formulation and dosing of FAEs for MS differ from Fumaderm. The approved dosing of dimethyl fumarate for MS is 240 mg, two or three times per day (SmPC Tecfidera).

Dosing in psoriasis Fumaderm initial/Fumaderm for psoriasis is administered as tablets one to three times per day. The starter kit (Fumaderm initial) contains 30 mg tablets of DMF and is used for the first 3 weeks. The dose is increased from one tablet per day in the first week to three tablets per day in the third week. The treatment is then switched to Fumaderm, which contains 120 mg DMF per tablet. In accordance with the SmPC, the dose is increased in weekly steps from one tablet per day up to 3 × 2 tablets per day (maximum dose). In case of relevant side effects, the dose should not be increased further or decreased until the side effects have substantially improved. In daily practice, the maximum dose of six tablets per day is rarely targeted, as the majority of patients can be adequately

treated with a maximum dose of three to four tablets per day. When the maximum clinical response is achieved, the dose can be tapered slowly (e.g., monthly) to an individual maintenance dose, usually one to three tablets (=120–360 mg DMF) per day.5 Temporary dose increases to cut psoriasis flares are possible.

Side effects, safety, and monitoring The most common side effects are “flushing” and gastrointestinal (GI) symptoms—diarrhea, increased stool frequency, nausea, and abdominal cramps, which occur in up to twothirds of patients, predominantly in the first 2–3 months after initiation of therapy. GI tolerance may be improved by taking the tablets with dairy products and ingesting the main dose in the evening. Flush symptoms may present as temporary facial reddening, along with a feeling of warmth or headache lasting for minutes to hours. If this is bothering the patient, flush symptoms may be blocked/decreased by intake of acetylsalicylic acid after the FAE intake. Hematological side effects are also common and have to be monitored closely (see Table 24.1). Leucopenia or lymphopenia may occur during induction and maintenance therapy. Eosinophilia is usually temporary, occurs during early induction therapy, and can be a surrogate parameter for the subsequent onset of clinical improvement. Longlasting lymphopenia may increase the risk of opportunistic infections. Up to now, at least 11 cases of progressive multifocal leukencephalopathy (PML) have been published worldwide during therapy with FAEs (including patients with Fumaderm for psoriasis, pharmacy-made FAEs for psoriasis, and Tecfidera for MS). PML is a serious infection of the central nervous system caused by reactivation of John Cunningham (JC) polyoma virus. PML is very rare and mainly occurs in immunocompromised patients (e.g., human immunodeficiency virus [HIV], treatment with immunosuppressants). The PML cases reported under FAE therapy affected patients with lymphocyte counts <500/µL for at least several months.

Table 24.1  Relevant side effects of oral fumaric acid esters (FAEs) and possible actions to be taken. Side effect

Frequency

Possible/recommended action

Diarrhea, abdominal cramps, flatulence, nausea Flush symptoms

Occasional–very frequent Very frequent

Mild leukopenia and lymphopenia Transient eosinophilia

Very frequent Frequent

Severe lymphopenia Dizziness, headache, fatigue Increase in serum creatinine, proteinuria, increase in liver enzymes

Frequent Occasional Occasional

Intake with milk (dairy products), intake in the evening (expert opinion) Acetyl salicylic acid (ASS), administered orally (per os [p.o.] (expert opinion)) Dose reduction/lab control Usually transient, lab control, dose reduction only if eosinophilia 25% Dose reduction or discontinuation/lab control Intake in the evening (expert opinion) Check for other reasons (e.g., concomitant medication), dose reduction/lab control (expert opinion)

Apremilast 243

According to European and German guidelines and the SmPC of Fumaderm, FAE therapy has to be discontinued at lymphocytes <500/μL. In rare patients, FAE may induce tubular resorption insufficiency, presenting as proteinuria, which usually disappears after dose reduction or discontinuation of treatment. For this reason, urine should be checked regularly for protein. An isolated increase in alanine transaminase (ALT) or bilirubin may be detected in occasional patients. Data from retrospective and prospective open-label studies with psoriasis patients under long-term FAE treatment (>1 year) showed sustained efficacy and no increase in AEs. Some psoriasis patients in retrospective studies have received FAE treatment continuously for up to 14 years. There were no signals for an increased risk of malignancies or infections (except for patients with drug-induced substantial lymphopenia—see previous discussion). No dose adjustments are required in elderly patients. As FAEs are metabolized and eliminated via unspecific and ubiquitous esterases; drug interactions do not occur. Combination with other systemic antipsoriatic substances is not recommended, but is very occasionally used in selected patients.12 Care must be taken when combining FAEs with nephrotoxic drugs. Combination with ultraviolet (UV) therapy during the induction phase is possible, and may improve the time to response and minimize the daily and maximum FAE dose.13 There have been no published reports on the use of FAEs during pregnancy or breastfeeding. The manufacturers have reported that they have about 40 cases on file of pregnancies during FAE treatment, without any signals of teratogenic or mutagenic effects (personal communication).

Monitoring According to the SmPC, blood and urine should be monitored every 4 weeks. The German guideline recommends blood and urine testing every 4 weeks in the first 4 months and every 8 weeks thereafter (see Table 24.2). Absolute contraindications: Severe disease of the GI tract, including liver and/or the kidneys, pregnancy or breastfeeding (lack of experience). Relative contraindications: Hematological disease.

FAE summary FAEs are recommended by the European and German guidelines for long-term treatment of moderate to severe psoriasis. The therapy exhibits a relatively slow onset of action but shows sustained safety and efficacy over time. The most common side effects are GI symptoms and flush symptoms in the induction phase, which usually decrease over time. It is essential to monitor blood and urine. An international approval for a new DMF formulation for psoriasis is exptected for 2017.

APREMILAST Apremilast is a novel oral small molecule that inhibits phosphodiesterase 4 (PDE4). It has been approved for the treatment of moderate to severe psoriasis vulgaris and PsA in the United States (since 2014) and in Europe (since 2015). According to the U.S. label, apremilast is indicated for the treatment of patients with moderate to severe plaque psoriasis who are candidates for phototherapy or systemic therapy. According to the European label, apremilast can be used after the failure of or contraindications against conventional systemic therapy, namely cyclosporine, MTX, or psoralen and ultraviolet A (PUVA) therapy.

Mode of action Phosphodiesterase inhibitors—of which 11 families are known—increase the level of intracellular cyclic adenosine monophosphate (cAMP) by inhibiting its degradation and inactivation. Cyclic AMP converts protein kinase A from its inactive form into its active form. Protein kinase A is a key regulator of cytokine gene transcription. Increased cAMP levels in leukocytes decrease the expression of proinflammatory cytokines, such as tumor necrosis factor alpha (TNF-α) and IL-12, as well as proinflammatory leukotrienes, and increase the level of anti-inflammatory cytokines such as IL-10. Certain phosphodiesterases are tissue specific. PDE4 has four subtypes (A, B, C, D) and is ubiquitously expressed in various cell types, including

Table 24.2  Recommended monitoring according to Summary of Product Characteristics (SmPC) and German guideline. SmPC Fumaderm® Parameter Liver enzymes Serum creatinine Full blood counta Urine status a

Every 4 weeks X X X X

German guideline Baseline until month 3, every 4 weeks X X X X

>Month 4, every 8 weeks (if values are normal) X X X X

If leukocytes are <3000/μL, fumarate therapy has to be discontinued/interrupted. If lymphocytes are <700/μL, the dose should be reduced to 50%; therapy needs to be discontinued if lymphocytes remain below 700/μL despite dose reduction for >4 weeks. If lymphocytes are <500/μL, treatment has to be discontinued.

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immune cells, such as T cells, dendritic cells, macrophages, and monocytes. It is also present in different cutaneous cells, including keratinocytes. PDE4 is considered a crucial checkpoint of inflammatory cell functions. In particular, PDE4 promotes a proinflammatory state by decreasing cAMP levels, which is a unique property of PDE4. Other PDEs regulate different functions and pathways, e.g., PDE5, which inactivates cGMP and is targeted by the group of PDE5 inhibitors for the treatment of erectile dysfunction.

Clinical efficacy in psoriasis vulgaris In previous dose finding studies, 30 mg apremilast b.i.d. (bis in die, twice daily) has been superior to 20 mg b.i.d. with respect to PASI 75 response and patient reported outcomes, including improvement in the Dermatology Life Quality Index (DLQI) and a pruritus Visual Analog Scale (VAS) score. Two main pivotal phase III trials with apremilast have been conducted in psoriasis vulgaris. Efficacy and Safety Trial Evaluating the Effects of Apremilast in Psoriasis (ESTEEM) 1 was a randomized, placebo-controlled, clinical phase III trial with 844 randomized patients.14 In the first study period (weeks 0–16), patients were randomized to apremilast 30 b.i.d. per os or placebo (2:1). At week 16, 33.1% of the apremilast treated patients achieved a PASI 75 response, compared with 5.3% in the placebo arm. Between weeks 16 and 32, patients were either maintained on apremilast or switched from placebo to apremilast. At week 32, patients who received apremilast from baseline and who achieved at least PASI 75 response at week 32 were randomized to continue apremilast or to receive placebo (blinded withdrawal period) through week 52. Patients re-­ randomized to placebo at week 32 resumed apremilast if they lost the PASI 75 response. At week 52, 61% of the patients re-randomized to apremilast at week 32 and achieved a PASI 75 response, in contrast to 11.7% patients re-randomized to placebo. ESTEEM 2 generally confirmed the results of ESTEEM 1; PASI 75 response rates at week 16 were 28.8% in the apremilast 30 mg b.i.d. compared with 5.8 in the placebo arm. In a randomized placebo-controlled trial with three arms (1:1:1 apremilast, placebo, and etanercept 50 mg QOW as an active comparator) PASI 75 response rates at week 16 were 39.8% for apremilast 30 mg b.i.d. and 48.2% for etanercept. At week 16, patients were switched from placebo or etanercept to apremilast 30 mg b.i.d.. At 32 weeks, patients who initially received apremilast showed a PASI 75 response rate of 53.0%.

Clinical efficacy in PsA The efficacy and safety of apremilast in PsA have been investigated in two main pivotal trials: PALACE 1 and 2. The ACR 20 response rate at week 16 was 40% (in the

30  mg b.i.d. arm) vs. 19% in the placebo arm. Clinical efficacy continued to improve beyond week 16. There was also a significant improvement in dactylitis and enthesitis compared with placebo.

Dosing The approved dose for psoriasis and PsA is 30 mg apremilast b.i.d. (60 mg/day), preceded by an initial 6-day titration period (stepwise dose increase from 10 once daily to 30 mg b.i.d.).

Metabolism The half-life is 6–9 hours. The drug is metabolized via CYP pathways (predominantly CYP3A4); additional metabolic pathways include hydrolysis and glucuronidation. Accordingly, drug–drug interactions may occur with drugs metabolized by CYP3A4, such as rifampicin, ketoconazole, or carbamazepine.

Side effects, safety, and monitoring In the pooled safety analysis of the ESTEEM 1 and 2 and PALACE 1 and 2 studies, the overall safety profile of apremilast did not show any relevant patterns of events of interest. In the first weeks of treatment, up to 20% of patients may develop GI symptoms such as nausea, loose stools, or diarrhea. These symptoms are usually mild to moderate and do not lead to premature treatment discontinuation. The main finding during longer-term therapy was weight loss occurring independently of GI side effects and baseline weight. In the pooled analysis of the ESTEEM studies, 19.2% of the patients lost >5% body weight through week 52. No relevant changes in laboratory parameters were observed during the induction phase or during the maintenance phase of treatment. According to the label, no testing for latent tuberculosis or specific laboratory monitoring is required. The dose should be reduced by 50% in patients with a glomerular filtration rate lower than 30 mL/min. More detailed recommendations are still pending on the use and monitoring of apremilast by national or international treatment guidelines for psoriasis or PsA. Our personal recommendation is to monitor serum chemistry and red and white blood cells at baseline, after 4 weeks and then every 12 weeks, especially in elderly comorbid patients, patients with concomitant medication likely to interact with apremilast, and patients with more pronounced GI side effects. Stricter monitoring may also be required in patients with reduced renal function. As certain patients may lose weight during the therapy, body weight should be assessed and documented at least twice per year.

Janus kinase inhibitors  245

In november 2016 a European wide “dear doctor letter” addressed a potential associaton of suicidal ­ideation and depression with the intake of apremilast. In patients with preexisting psychiatric disorders risks and benefits should be weighed carefully before initiating apremilast therapy. In case of new onset or worsening of psychiatric disorders or suicidal ideation apremilast therapy should be discontinued.

Apremilast summary Apremilast is approved for the treatment of moderate to severe plaque-type psoriasis and for the treatment of PsA. The U.S. and European labels differ with respect to prior therapies. The data in psoriasis indicate moderate efficacy combined with a favorable safety profile. There is as yet no published longer-term data beyond 1 year.

JANUS KINASE INHIBITORS A number of small molecules that block Janus kinase (JAK) pathways are under investigation for the treatment of psoriasis. JAKs belong to the tyrosine kinase family. Four JAK subtypes are known: JAK1, JAK2, JAK3, and TYK2.

JAK–STAT signaling If activated by certain cytokines on the cell surface, JAKs bind in pairs to the intracellular receptors and are activated by autophosphorylation. Activated JAKs modify the receptors and enable the binding of STAT. The phosphorylated and activated STATs dimerize, translocate into the cell nucleus, and modify DNA transcription and gene expression. Different JAK pairs activate one of six different STAT proteins. In this way, the JAK–STAT pathway can regulate expression of a variety of genes, which are important for cell growth or apoptosis. As the activation of JAKs is based on specific cytokine receptors expressed on immune cells, the function and activation of those immune cells can be influenced by blocking the JAK–STAT pathway. JAK1 can be activated via IFN, IL-6, IL-10 receptors, and receptors containing common γ chains. JAK2 is associated with hematopoietic receptors and IL-12 and IL-23. The pair JAK3 and JAK1 is associated with receptors containing the common γ chain, such as IL-2, IL-4, IL-7, IL-9, IL-15, and IL-21, all of which regulate lymphocyte function. The pair TYK2/JAK2 is regulated by IFN, IL-12, and IL-23 receptors. Dysfunctions of the JAK–STAT pathway are associated with various inflammatory autoimmune disorders, including psoriasis. Selective inhibition of certain JAK–STAT pathways is therefore a promising approach to treat immune-­mediated diseases.

Oral JAK inhibitors in advanced clinical study phases Three oral JAK inhibitors have already been studied quite extensively in psoriasis: tofacitinib, baricitinib, and GSK2586184.

Tofacitinib Tofacitinib inhibits JAK1 and JAK3 and is being investigated in oral and topical formulations. Oral tofacitinib has been approved in the United States and Japan for the treatment of rheumatoid arthritis since 2012. MODE OF ACTION

In animal models, tofacitinib inhibits the expression of various proinflammatory cytokines and receptors, which are known to play essential roles in the inflammatory cascade of psoriasis, including, but not limited to, the IL-23 receptor, IL-17A, IL-17F, IL-22, and IL-15 (…). IL-23 and the IL-17 receptor family are well-established targets for treating psoriasis.

Tofacitinib in psoriasis Here we summarize the clinical results of the published data of tofacitinib in clinical trials in psoriasis. In a phase II study (197 patients with moderate to severe psoriasis), the PASI 75 response rates of oral tofacitinib 2 mg b.i.d., 5 mg b.i.d., or 15 mg b.i.d. were 25.0% (2 mg; p < 0.001), 40.8% (5 mg; p < 0.0001), and 66.7% (15 mg; p < 0.0001), respectively, versus 2.0% in the placebo group at week 12. Significant clinical improvement compared with placebo was seen from week 4 onwards. Upper respiratory tract infections, nasopharyngitis, and headache were the most common adverse effects reported by the patient cohort. Three patients experienced five serious adverse events, including angina pectoris, pyelonephritis, urosepsis, and atrial fibrillation. Discontinuation from the study was reported in 2.0%, 4.1%, and 6.1% of patients in the 2, 5, and 15 mg b.i.d. groups, respectively, versus 6.0% of patients in the placebo group. Serum creatinine increased (mean 0.04 mg/dL) in the 15 mg b.i.d. group at week 12 compared with the baseline. One case of alanine aminotransferase elevation greater than 2.5 times the upper limit of normal was documented in the 15 mg b.i.d. group. Tofacitinib treatment was associated with mild, dose-dependent decreases in hemoglobin of 0.15, 0.20, 0.14, and 0.71  g/dL for placebo and tofacitinib 2, 5, and 15 mg b.i.d. groups, respectively, at week 12. In addition, mean absolute neutrophil counts decreased at higher doses of tofacitinib, with a maximum mean decrease of 0.9 × 103 mm−3 in patients receiving 15 mg b.i.d. at week 4. However, these values began to return to baseline values from weeks 4–8. Tofacitinib improved both physician- and patient-reported outcomes. In a double-blind, double-dummy, placebo-controlled phase III study with 1106 patients with moderate to severe

246  Current and future oral small molecules

psoriasis, oral tofacitinib at 10–20 mg/day was compared with etanercept. At week 12, PASI 75 response rates with tofacitinib at 5 mg b.i.d, 10 mg b.i.d., etanercept 50 mg biweekly (b.i.w.), and placebo were 63.6%, 39.5%, 58.8%, and 5.6%, respectively. Safety profiles and the assessment of patient satisfaction with tofacitinib and etanercept were comparable up to week 12. In a pooled analysis of two placebo-controlled phase III studies with tofacitinib in 1861 patients with moderate to severe psoriasis, the PASI 75 response rates for 10 mg b.i.d., 5 mg b.i.d., and placebo at week 16 were 59.4 %, 43.1%, and 8.9%, respectively. A substantial improvement in nail psoriasis as assessed by the mean change of NAPSI was demonstrated in both dose groups up to week 16. The rate of serious infection events in both dosing groups was comparable to placebo. In the active treatment arms, several cases of herpes zoster (0.8% in each group) were documented vs. no cases in the placebo group. In the active treatment arms, a total of three MACE were documented compared with none in the placebo group.15 Randomized withdrawal of patients with a very good clinical response (PASI 75 and PGA ≤ 1) revealed that of patients who relapsed, only up to 60% retained a response to tofacitinib on restarting the drug. There are several phase III trials of the efficacy and safety of tofacitinib in psoriasis patients. One phase III trial compared oral tofacitinib 5 mg or 10 mg b.i.d. versus etanercept 50 mg twice weekly for 12 weeks for patients with moderate-to-severe psoriasis, and the results are pending at the time of writing. Another study is examining the efficacy and safety of tofacitinib in patients with PsA. This phase III study began recruiting participants for tofacitinib in PsA patients with inadequate response to at least one TNF inhibitor. SPECIAL SAFETY ASPECTS OF TOFACITINIB

Tofacitinib can induce (temporary) dose-dependent decreases in neutrophil counts and hemoglobin levels and increases in low-density lipoprotein (LDL), triglycerides, total cholesterol, high-density lipoprotein (HDL), and transaminases in selected patients. These changes are mainly mild to moderate and do not usually require intervention or discontinuation of drug treatment. The cause remains unclear. The European Medical Agency (EMA) refused the approval for rheumatoid arthritis in 2013. The Committee for Medicinal Products for Human Use (CHMP) had major concerns about the overall safety profile of the drug, stating that “There were significant and unresolved

concerns about the risk and type of serious infections seen with tofacitinib, which are related to the immunosuppressant action of the medicine.” In a vehicle-controlled phase II trial with 71 mild-tomoderate psoriasis patients (two different 2% ointments), topical tofacitinib was applied b.i.d. on a target plaque within a fixed defined area for 2 weeks. Only one of the ointments showed statistically superior clinical efficacy compared with its vehicle after 4 weeks. Systemic concentrations were detected in up to 60% of patients. Serological levels were 40-fold lower than the systemic concentration achieved at the lowest oral dose tested.

Baricitinib Baricitinib is a selective JAK1/JAK2 inhibitor that is still in clinical studies for psoriasis and other immune-­mediated diseases. In a placebo-controlled phase II trial, once daily oral doses of barcitinib from 2 to 10 mg showed dosedependent PASI 75 response rates of up to 54% for the 10 mg dose group at week 12. The 8 and 10 mg dose groups met the primary endpoint, whereas the 2 and 4 mg dose groups were not statistically superior to placebo. Lymphopenia, neutropenia, and anemia were observed in the 8 and 10 mg dose groups, but not in the 2 and 4 mg dose groups or in the placebo-treated patients.

ASP015K ASP015K is an oral JAK inhibitor with moderate selectivity for JAK3 over JAK1 and JAK2. In a placebo-controlled phase II study, 124 patients with moderate to severe psoriasis were treated in four, twicedaily dosing groups (10, 25, 60, 100 mg) and in one, oncedaily dosing group (50 mg) for 6 weeks. The primary efficacy endpoint, the mean change in PASI score, was met, with more pronounced clinical response in the higher dosing groups. The tolerability and safety of ASP015K were reported to be good, with no serious AEs occurring during the study period.13

Oral JAK inhibitor summary Several oral JAK inhibitors are being investigated for psoriasis and PsA and have shown moderate to good clinical efficacy in clinical studies in both indications (Table 24.3).

Table 24.3  Clinical stage of oral Janus kinase (JAK) inhibitors for psoriasis (May 2015). Investigational product/drug name

Target

Stage of clinical development for psoriasis

Tofacitinib/Xeljanz® Baricitinib GSK2586184 ASP015K

JAK 1 and JAK 3 JAK 1 and JAK2 JAK1 JAK1, JAK2, and JAK3

Phase III Phase II Phase II Phase II

Suggested readings  247

Tofacitinib is the first approved oral JAK inhibitor in the United States and Japan for the treatment of rheumatoid arthritis. The approval for psoriasis is pending. The EMA has raised certain safety concerns regarding the use of rheumatoid arthritis and therefore has not approved tofacitinib yet.

REFERENCES 1. Schweckendiek W. Treatment of psoriasis vulgaris. Med Monatsschr. 1959 Feb;13(2):103–104. 2. Ghoreschi K, Brück J, Kellerer C, et al. Fumarates improve psoriasis and multiple sclerosis by inducing type II dendritic cells. J Exp Med. 2011 Oct 24;208(11):2291–303. 3. Mrowietz U, Christophers E, Altmeyer P. Treatment of psoriasis with fumaric acid esters: Results of a prospective multicentre study. German Multicentre Study. Br J Dermatol. 1998 Mar;138(3):456–60. 4. Gollnick H, Altmeyer P, Kaufmann R, et al. Topical calcipotriol plus oral fumaric acid is more effective and faster acting than oral fumaric acid monotherapy in the treatment of severe chronic plaque psoriasis vulgaris. Dermatology. 2002;205(1):46–53. 5. Reich K, Thaci D, Mrowietz U, Kamps A, Neureither M, Luger T. Efficacy and safety of fumaric acid esters in the long-term treatment of psoriasis—A retrospective study (FUTURE). J Dtsch Dermatol Ges. 2009 Jul;7(7):603–611. 6. Thaci D. A prospective, non-interventional study to evaluate the long-term outcomes of treatment with fumaric acid ester in patients with plaquetype psoriasis in daily practice (ADHERENCE study), Poster AAD. J Amer Acad Dermatol. 2012;66(4):AB182. 7. Nugteren-Huying WM, Van Der Schroeff JG, Hermans J, Suurmond D. Fumaric acid therapy for psoriasis: a randomized, double-blind, placebocontrolled study. J Amer Acad Dermatol. 1990 Feb;22(2 Pt 1):311–312. 8. Fallah Arani S, Neumann H, Hop WC, Thio HB. Fumarates vs. methotrexate in moderate to severe chronic plaque psoriasis: A multicentre prospective randomized controlled clinical trial. Br J Dermatol. 2011 Apr;164(4):855–861. 9. Ismail N, Collins P, Rogers S, Kirby B, Lally A. Drug survival of fumaric acid esters for psoriasis: A retrospective study. Br J Dermatol. 2014 Aug;171(2):397–402. 10. Peeters AJ, Dijkmans BA, van der Schroeff JG. Fumaric acid therapy for psoriatic arthritis. A randomized, double-blind, placebo-controlled study. Br J Rheumatol. 1992 Jul;31(7):502–504. 11. Fox RJ, Miller DH, Phillips JT, et al. Placebo-controlled phase 3 study of oral BG-12 or glatiramer in multiple sclerosis. N Engl J Med. 2012 Sep 20;367(12): 1087–1097.

12. Wilsmann-Theis D, Frambach Y, et al. Systemic ­antipsoriatic combination therapy with fumaric acid esters for plaque-type psoriasis: Report on 17 cases. Dermatology. 2015;230(2):119–127 13. Weisenseel P et al. Efficacy, safety and dosage of fumaric acid esters in combination with phototherapy in patients with moderate to severe plaque-type psoriasis (FAST), accepted for publication in JDDG Aug 2015. 14. Papp K, Reich K, Leonardi CL, et al. Apremilast, an oral phosphodiesterase 4 (PDE4) inhibitor, in patients with moderate to severe plaque psoriasis: Results of a phase III, randomized, controlled trial (Efficacy and Safety Trial Evaluating the Effects of Apremilast in Psoriasis [ESTEEM] 1). J Am Acad Dermatol. 2015 Jul;73(1):37–49. 15. Papp K, Pariser D, Catlin M, et al. Phase 2a randomised, double-blind, placebo-controlled, sequential dose-escalation study to evaluate the efficacy and safety of ASP015K, a novel Janus kinase (JAK) inhibitor, in patients with moderate to severe psoriasis. Br J Dermatol. 2015 Feb 21. doi:10.1111/bjd.13745. [Epub ahead of print].

SUGGESTED READINGS Altmeyer PJ, Matthes U, Pawlak F, et al. Antipsoriatic effect of fumaric acid derivatives. Results of a multicenter double-blind study in 100 patients. J Am Acad Dermatol. 1994 Jun;30(6):977–981. Boy MG, Wang C, Wilkinson BE, et al. Double-blind, placebo-controlled, dose-escalation study to evaluate the pharmacologic effect of CP-690,550 in patients with psoriasis. J Invest Dermatol. 2009;129(9):2299–2302. Fridman JS, Scherle PA, Collins R, et al. Preclinical evaluation of local JAK1 and JAK2 inhibition in cutaneous inflammation. J Invest Dermatol. 2011;131(9):1838–1844. Ghoreschi K, Gadina M. Jakpot! New small molecules in autoimmune and inflammatory diseases. Exp Dermatol. 2014 Jan;23(1):668–677. Ghoreschi K, Jesson MI, Li X, et al. Modulation of innate and adaptive immune responses by tofacitinib (CP690,550). J Immunol. 2011;186(7):4234–4243. Gold R, Kappos L, Arnold DL, Bar-Or A, et al. Placebocontrolled phase 3 study of oral BG-12 for relapsing multiple sclerosis. N Engl J Med. 2012 Sep 20;367(12):1098–1107. Gottlieb AB, Matheson RT, Menter A, et al. Efficacy, tolerability, and pharmacodynamics of apremilast in recalcitrant plaque psoriasis: A phase II open-label study. J Drugs Dermatol. 2013 Aug;12(8):888–897. Gottlieb AB, Strober B, Krueger JG, et al. An open-label, single-arm pilot study in patients with severe plaquetype psoriasis treated with an oral anti-inflammatory agent, apremilast. Curr Med Res Opin. 2008 May;24(5):1529–1538.

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Hoefnagel JJ, Thio HB, Willemze R, Bouwes Bavinck JN. Long-term safety aspects of systemic therapy with fumaric acid esters in severe psoriasis. Br J Dermatol. 2003 Aug;149(2):363–369. Kavanaugh A, Mease PJ, Gomez-Reino JJ, et al. Longterm (52-week) results of a phase III randomized, controlled trial of apremilast in patients with psoriatic arthritis. J Rheumatol. 2015 Mar;42(3):479–488. Kavanaugh A, Mease PJ, Gomez-Reino JJ, et al. Treatment of psoriatic arthritis in a phase 3 randomised, placebo-controlled trial with apremilast, an oral phosphodiesterase 4 inhibitor. Ann Rheum Dis. 2014 Jun;73(6):1020–1026. Liu Y, Zhou S, Nissel J, Wu A, Lau H, Palmisano M. The pharmacokinetic effect of coadministration of apremilast and methotrexate in individuals with rheumatoid arthritis and psoriatic arthritis. Clin Pharmacol Drug Dev. 2014 Nov;3(6):456–465. Epub 2014 May 8. Liu Y, Zhou S, Wan Y, Wu A, Palmisano M. The impact of co-administration of ketoconazole and rifampicin on the pharmacokinetics of apremilast in healthy volunteers. Br J Clin Pharmacol. 2014 Nov;78(5):1050–1057. Loveland MA, Gilhar A, Cheung YF, et al. Apremilast, a cAMP phosphodiesterase-4 inhibitor, demonstrates anti-inflammatory activity in vitro and in a model of psoriasis. Br J Pharmacol. 2010 Feb;159(4):842–855. Mamolo C, Harness J, Tan H, Menter A. Tofacitinib (CP690,550), an oral Janus kinase inhibitor, improves patient-reported outcomes in a phase 2b, randomized, double-blind, placebo-controlled study in patients with moderate-to-severe psoriasis. J Eur Acad Dermatol Venereol. 2014;28(2):129–203. Mrowietz U, Reich K, Spellman MC. Efficacy, safety, and quality of life effects of a novel oral formulation of dimethyl fumarate in patients with moderate to severe plaque psoriasis: Results of a phase 3 study (Abstract P2816). American Academy of Dermatology 64th Annual Meeting, March 3–7, 2006. J Am Acad Dermatol. 2006;54(3 Suppl):Ab202. Mrowietz U, Spellman M. Dimethyl fumarate (BG00012) as an oral therapy for moderate to severe psoriasis: Results of a multicenter, randomized, double-blind, placebo-controlled trial. Abstract 406. 35th Annual ESDR Meeting 22–24th September 2005, Tübingen, Germany. J Invest Dermatol. 2005;125(Suppl 1):A69. Nast A, Boehncke WH, Mrowietz U, et al. S3—Guidelines on the treatment of psoriasis vulgaris (English version). Update. J Dtsch Dermatol Ges. 2012 Mar;10 (Suppl 2):S1–95. Papp K, Cather JC, Rosoph L, et al. Efficacy of apremilast in the treatment of moderate to severe psoriasis: A randomised controlled trial. Lancet. 2012 Aug 25;380(9843):738–746. Papp K, Pariser D, Catlin M, Wierz G, Ball G, Akinlade B, Zeiher B, Krueger JG. Phase 2a randomised, doubleblind, placebo-controlled, sequential dose-escalation study to evaluate the efficacy and safety of ASP015K, a Novel Janus Kinase (JAK) inhibitor, in patients with

moderate to severe psoriasis. Br J Dermatol. 2015 Feb 21. doi: 10.1111/bjd.13745. [Epub ahead of print]. Papp K, Reich K, Leonardi CL, et al. Apremilast, an oral phosphodiesterase 4 (PDE4) inhibitor, in patients with moderate to severe plaque psoriasis: Results of a phase III, randomized, controlled trial (Efficacy and Safety Trial Evaluating the Effects of Apremilast in Psoriasis [ESTEEM] 1). J Am Acad Dermatol. 2015 Jul;73(1):37–49. Papp KA, Kaufmann R, Thaçi D, Hu C, Sutherland D, Rohane P. Efficacy and safety of apremilast in subjects with moderate to severe plaque psoriasis: Results from a phase II, multicenter, randomized, doubleblind, placebo-­ controlled, parallel-group, dosecomparison study. J Eur Acad Dermatol Venereol. 2013 Mar;27(3):e376–383. Papp KA, Menter A, Strober B, et al. Efficacy and safety of tofacitinib, an oral Janus kinase inhibitor, in the treatment of psoriasis: A Phase 2b randomized placebo-controlled dose-ranging study. Br J Dermatol. 2012;167(3):668–677. Ports WC, Khan S, Lan S, et al. A randomized phase 2a efficacy and safety trial of the topical Janus kinase inhibitor tofacitinib in the treatment of chronic plaque psoriasis. Br J Dermatol. 2013;169(1):137–145. Reich K. Oral presentation. J Am Acad Dermatol. 2015. Schafer PH, Chen P, Fang L, Wang A, Chopra R. The pharmacodynamic impact of apremilast, an oral phosphodiesterase 4 inhibitor, on circulating levels of inflammatory biomarkers in patients with psoriatic arthritis: Substudy results from a phase III, randomized, placebo-controlled trial (PALACE 1). J Immunol Res. 2015;2015:906349. doi:10.1155/2015/906349. Epub 2015 Apr 20. Schafer PH, Day RM. Novel systemic drugs for psoriasis: Mechanism of action for apremilast, a specific inhibitor of PDE4. J Am Acad Dermatol. 2013 Jun;68(6):1041–1042. Strand V, Fiorentino D, Hu C, Day RM, Stevens RM, Papp KA. Improvements in patient-reported outcomes with apremilast, an oral phosphodiesterase 4 inhibitor, in the treatment of moderate to severe psoriasis: Results from a phase IIb randomized, controlled study. Health Qual Life Outcomes. 2013 May 10;11:82. Strober B, Buonanno M, Clark JD, et al. Effect of tofacitinib, a Janus kinase inhibitor, on haematological parameters during 12 weeks of psoriasis treatment. Br J Dermatol. 2013;169(5):992–999. Tan H, Gupta P, Harness J, et al. Dose response and pharmacokinetics of tofacitinib (CP-690,550), an oral Janus kinase inhibitor, in the treatment of chronic plaque psoriasis. CPT: Pharmacometrics Systems Pharmacol. 2013;2:e44. Thaçi D, Weisenseel P, Philipp S, et al. Efficacy and safety of fumaric acid esters in patients with psoriasis on medication for comorbid conditions—A retrospective evaluation (FACTS). J Dtsch Dermatol Ges. 2013 May;11(5):429–435.

25 Biologic therapies in the pipeline MOLLY CAMPA, PABLO MICHEL, and CAITRIONA RYAN The advent of biologic therapies has revolutionized the treatment of moderate-to-severe psoriasis. With the approval of several tumor necrosis factor-alpha (TNF-α) inhibitors, interleukin 12/23 (IL-12/23) inhibitors, and IL-17 inhibitors, physicians now have multiple options when choosing which drug to prescribe to psoriasis patients. As we further our understanding of the complex pathogenesis of psoriasis, new classes of biologic therapies continue to emerge. These new biologic drugs, in various phases of development, add to the growing armamentarium of psoriasis therapy. New biologic drug candidates aim to be more effective, easier to use, or more targeted than existing biologic therapies. There are several biologic drugs in the pipeline targeting TNF-α, the p19 subunit of IL-23, IL-17, and IL-17 receptor A. Furthermore, there are bispecific antibodies in development with multiple simultaneous targets. In addition to these novel biologic drugs, there are numerous biosimilar drugs in the pipeline. Biosimilars aim to have near-identical safety and efficacy profiles compared with their reference bio-originator products, while decreasing the overall cost. Biosimilar versions of infliximab and etanercept have been approved by the European Medicines Agency (EMA), biosimilars have been approved by Health Canada for infliximab, and the U.S. Food and Drug Administration (FDA) approved a biosimilar for infliximab in April 2016.1–3 Due to the impending expiration of the Humira (adalimumab, AbbVie, North Chicago, Illinois) patent, there are multiple adalimumab biosimilars in the pipeline.

DRUGS TARGETING TNF-α Certolizumab pegol Certolizumab pegol (UCB, Brussels, Belgium) is a monoclonal Fab fragment antibody conjugated to polyethylene glycol (PEG) targeting soluble and transmembrane ­TNF-α. It is currently approved for psoriatic arthritis but not plaque psoriasis. In phase II studies, a Psoriasis Area and Severity Index 75 (PASI 75) response was seen in

74.6% of patients receiving a 200 mg dose and 82.8% of patients receiving a 400 mg dose.4 Phase III trials evaluating the efficacy and safety of certolizumab pegol compared with placebo and with etanercept in plaque psoriasis are ongoing.5,6 Certolizumab does not have an Fc portion and so Fc receptor–mediated transcytosis does not occur. As a result, studies are also underway to examine the placental transfer of certolizumab in pregnant females and its excretion in breastmilk.7

DRUGS TARGETING THE P19 SUBUNIT OF IL-23 Guselkumab Guselkumab (Janssen, Beerse, Belgium) is a fully human immunoglobulin G (IgG)1λ monoclonal antibody targeting the unique p19 subunit of IL-23. A multicenter, phase II, double-blind, placebo-controlled, a­ ctive-comparator trial comparing guselkumab, adalimumab, and placebo found guselkumab to be superior to placebo and superior to adalimumab at higher doses.8 Patients were randomized to one of seven treatment groups: 5 mg guselkumab every 12 weeks, 15 mg guselkumab every 8 weeks, 50  mg guselkumab every 12 weeks, 100 mg guselkumab every 8  weeks, 200 mg guselkumab every 12 weeks, 80 mg adalimumab every other week, and placebo.8 The percentage of patients achieving a Physician Global Assessment (PGA) score of 0 or 1 (the primary end point) was significantly higher in all guselkumab groups than in placebo and significantly higher than the adalimumab group with 50, 100, and 200 mg doses of guselkumab: 34% in the 5 mg group, 61% in the 15 mg group, 79% in the 50 mg group, 86% in the 100 mg group, 83% in the 200 mg group, and 7% in the placebo group, compared with 58% in the adalimumab group.8 At week 16, the PASI 75 response rates were significantly greater at every dose of guselkumab compared with placebo: 44% at 5 mg dose, 76% at 15 mg dose, 81% at 50 mg dose, 79% at 100 mg dose, and 81% at 200 mg dose versus 5% in the placebo group.8 Seventy percent 249

250  Biologic therapies in the pipeline

of the adalimumab-treated patients achieved a PASI 75 response but the statistical significance compared with guselkumab-treated patients was not reported.8 Phase III trials are ongoing to assess the response of patients with moderate-to-severe psoriasis to guselkumab compared with ustekinumab and adalimumab.9–11

Risankizumab (BI-655066) Risankizumab (Boehringer Ingelheim, Ingelheim am Rhein,  Germany), a fully human IgG1 monoclonal antibody specific for the IL-23 p19 subunit, is in development for moderate-to-severe psoriasis and other inflammatory diseases.12 Phase II clinical trial data comparing the efficacy and safety of risankizumab to ustekinumab demonstrated the superiority of risankizumab over ustekinumab with a PASI 90 response achieved in 77.1% of patients in the risankizumab group versus 40% of patients in the ustekinumab group (p < .0001).12 Several phase III studies are currently ongoing for psoriasis and psoriatic arthritis, including studies comparing risankizumab to ustekinumab and adalimumab.13–17

Tildrakizumab Tildrakizumab (MK-3222) (Merck, Kenilworth, New Jersey) is a humanized IgG1k, anti-IL-23p19 monoclonal antibody.18 A three-part, randomized, double-blind, phase IIb trial demonstrated that tildrakizumab was superior to placebo in treating moderate-to-severe plaque psoriasis. Participants were randomized to receive subcutaneous tildrakizumab (5, 25, 100, or 200 mg) or placebo at weeks 0 and 4 and then every 12 weeks until week 52.18 At week 16, the PASI 75 response rate was significantly greater for all doses of the tildrakizumab group compared with placebo: 33.3% on 5 mg, 64.4% on 25 mg, 66.3% on 100 mg, and 74.4% on 200 mg, versus 4.4% in the placebo group.18 The drug was withdrawn at week 52, and subjects were followed until week 72. Tildrakizumab showed a low rate of relapse during the 20-week nontreatment period, with only 3.6% of responders relapsing before week 72.18

DRUGS TARGETING IL-17 BCD-085 JCS BIOCAD (Saint Petersburg, Russia) completed an open label, phase I, dose escalating study of the tolerability, safety, pharmacokinetics, and immunogenicity of a single subcutaneous injection of the humanized anti-IL-17 monoclonal antibody, BCD-085.19 The results have not been published. If results are positive, the company plans to continue to phase II trials with psoriasis as a potential indication.19

Bimekizumab Bimekizumab (UCB 4940) is an anti-IL-17A/F humanized monoclonal antibody with phase I trials completed in both psoriasis and psoriatic arthritis.20,21 The molecule is currently undergoing phase II trials, including the addon use of bimekizumab to certolizumab-pegol in rheumatoid arthritis patients and another study in chronic plaque ­psoriasis.22,23 Results from these studies are pending.

Brodalumab Brodalumab is a fully human monoclonal antibody that blocks IL-17 receptor A (IL-17RA), resulting in a decrease in IL-17A, IL-17C, and IL-17F.24,25 A phase III clinical trial was initiated with an initial 12-week induction period of 210 mg brodalumab, 140 mg brodalumab, or placebo every 2 weeks, followed by 52 weeks of withdrawal and retreatment.26 At 12 weeks, 83% of subjects on 210 mg, 60% on 140 mg, and 3% on placebo achieved a PASI 75 response.26 Additionally, 76% of patients on 210 mg, 54% on 140 mg, and 3% on placebo achieved a static Physician Global Assessment (sPGA) score of 0 (clear) or 1 (almost clear).26 Of the patients in the study who had brodalumab withdrawn and experienced a return psoriasis (sPGA ≥ 3), 97% of those given 210 mg and 84% of those given 140  mg recaptured a sPGA of 0 or 1 after 12 weeks of retreatment.26 In two additional phase III clinical trials, patients achieved the following PASI 75 response rates: 85%–86% on 210 mg brodalumab, 67%–69% on 140  mg brodalumab, and 6%–8% on placebo.27 Seventy-nine to eighty percent of those on 210 mg, 58%–60% of those on 140 mg, and 4% of those on placebo achieved a sPGA score of 0 or 1.27 Brodalumab was demonstrated to be superior to ustekinumab in achieving complete clearance (PASI 100) with the 210 mg dose, but not significantly different from the 140 mg dose: 37%–44% on the 210 mg dose, 26%–27% on 140 mg dose, 0.3%–1% on placebo, and 19%–22% in patients treated with ustekinumab.27 Although Phase III trials demonstrated the efficacy of brodalumab, there has been concern over suicide and suicidal ideation in patients treated with brodalumab. Four suicides occurred during or after participation in a brodalumab clinical trial including one suicide in the placebo group during the induction phase, one suicide 27 days after the last dose of brodalumab in a patient who received placebo followed by 210 mg brodalumab, one in the openlabel extension phase in a patient receiving placebo in the induction phase and 210 mg brodalumab in the withdrawalretreat phase, and one 19 days after the last dose in the open label extension phase in a patient who received 210 mg of brodalumab every 2 weeks.26,27 Due to concerns over these suicides, Amgen announced in May 2015 that it would no longer partner with AstraZeneca in the development of brodalumab.28 AstraZeneca is now partnering with Valeant Pharmaceuticals in the further development of this drug.

Biosimilar drugs  251

CJM112 Novartis (Basel, Switzerland) has completed phase I and II clinical trials in psoriasis for CJM112, a fully human IgG1 IL-17 monoclonal antibody, but results have not been published. 29,30 Phase II studies analyzing its use in hidradenitis suppurativa are ongoing, and phase II ­clinical trials for multiple sclerosis are scheduled for 2016. 31,32

Ixekizumab Ixekizumab (Taltz, Eli Lilly, Indianapolis, Indiana) is a recently FDA approved (March 2016), humanized monoclonal antibody specific for IL-17A for moderate-to-severe psoriasis. In two phase III tri­ als for m ­ oderate-to-severe psoriasis participants were assigned to receive subcutaneous placebo, etanercept 50 mg twice weekly, or ixekizumab 80 mg every 2 weeks or every 4 weeks following a 160 mg starting dose. 33 At 12 weeks, 76.9%–77.5% of those receiving 80 mg every 4 weeks and 87.3%–89.7% of those receiving 80 mg every 2 weeks achieved a PASI 75, compared with 41.6%–53.4% in the etanercept group. 33 Furthermore, 30.8%–40.5% of the patients achieved PASI 100 (complete clearance) at 12 weeks with high levels of sustained response through 60 weeks of treatment. 33 The most common adverse events were nasopharyngitis and injection site reactions, with serious adverse events reported in 1.9% of the patients, rates comparable to etanercept. 33

MSB0010841 (ALX-0761) MSB0010841 (Merck, Kenilworth, New Jersey) is a trivalent, bispecific nanobody blocking both IL-17A and IL-17F. It consists of a C terminal moiety that binds both IL-17A and IL-17F, an N-terminal IL-17F specific moiety, and a central portion that binds to albumin to increase its plasma half-life.34 The moieties are fused head-to-tail with a nine amino acid glycine/serine linker. A preclinical proof-of-concept study in a collagen-induced animal arthritis model showed improved x-ray findings and improved arthritis scores.34 A phase I, randomized, double-blind, placebo-controlled trial in patients with moderate-to-severe plaque psoriasis has been completed, but the results are not yet published.35

BISPECIFIC DRUGS TARGETING TNF-α/IL-17A COVA322 COVA322 (Covagen, Zurich, Switzerland) is a fully human, divalent anti-TNF/IL-17A Fynom antibody, composed of an anti-TNF-α domain identical to adalimumab and two anti-IL-17A Fynomers fused to the C-terminal

light chains.36 A phase I/II clinical trial for moderate-tosevere plaque psoriasis was terminated by Covagen based on the observed safety profile.37 It is unknown if the company will proceed with further studies.

ABT-122 Abbvie (North Chicago, Illinois) is developing an immunoglobulin targeting both TNF-α and IL-17.38 In a phase I study of single dose administration of ABT-122 and placebo, up to 10 mg/kg intravenous (IV) and up to 3 mg/kg subcutaneous (SC) in 64 healthy volunteers, no significant differences were seen between adverse events in the two groups.38 The most common reported adverse events were upper respiratory infections.38 Currently, the antibody is being studied in phase II clinical trials for moderate-to-severe psoriatic arthritis and rheumatoid arthritis.39,40

LY3114062 Eli Lilly (Indianapolis, Indiana) is developing LY3114062, a TNF/IL-17 bispecific antibody. A phase I study to evaluate safety and tolerability after single SC and IV injections in subjects with inflammatory arthritis has been completed, but the results have not been published.41 It is expected that this molecule may be considered for psoriasis depending on results from early studies.

BISPECIFIC BAFF/IL-17 MONOCLONAL ANTIBODY Eli Lilly (Indianapolis, Indiana) is developing a tetravalent antibody targeting both B-cell activating factor (BAFF) (a member of the TNF superfamily) and IL-17.42 Using recombinant DNA, a single change fragment variable antibody is fused to a complete antibody having a different specificity. It is currently undergoing phase I clinical trials.42

BIOSIMILAR DRUGS Although biologic drugs have revolutionized the ­treatment of psoriasis, they are expensive, averaging approximately $34,550 per patient annually.43 There is a great need for less expensive psoriasis drugs with similar efficacy. Due to the complexity of biologic drugs, specifically monoclonal antibodies, it is not possible to produce true generic forms of these medications. In Europe, where several biosimilars have been approved for psoriasis, these drugs cost up to 30% less than their respective reference drugs, with similar projections being made for

252  Biologic therapies in the pipeline

the U.S. market.43 Some of the biologic drugs used in the treatment of psoriasis will soon reach the expiration of their patents.44–46 Although  no biosimilars have been approved for the treatment of psoriasis in the United States, several biosimilars have been approved for other indications.47 Unlike generics, biosimilars are not absolutely identical in chemical composition to the reference drug (approved, brand-name biologic drug) on which they are designed and must meet numerous requirements set forth by regulatory agencies to establish adequate similarity.47 The amino acid sequence must be nearly identical, and only minor modifications that do not affect drug efficacy and safety profiles are acceptable.48 The dosage and route of administration must be identical, and the biosimilar can only be approved for indications for which the reference drug is already approved.49 Minor clinically insignificant differences, such as device delivery systems, container closures, and variations in the inactive components, are generally allowed.50 Biosimilar drugs undergo a somewhat streamlined process for FDA approval but still require clinical trials.43,50,51 To demonstrate adequate similarity between biosimilars and their reference compounds, head-tohead active comparator noninferiority or equivalence trials with prespecified inferior and superior margin limits must be undertaken.48,49 The goal of these studies is to demonstrate that the biosimilar is neither inferior nor superior to the reference drug. Biosimilar clinical trials must also include both pharmacokinetic and pharmacodynamics studies, with results falling within a prespecified margin.49 In addition to similar efficacy, biosimilars must also demonstrate a similar safety profile during these clinical trials. Despite the likely decreased price of biosimilars, there are several controversial issues surrounding their development including extrapolation, interchangeability, and substitution. Extrapolation refers to the approval of the biosimilar for other indications for which the reference product is approved, once it has been approved for one indication.52 Interchangeability is the ability to switch between the reference drug and the biosimilar without any clinically significant changes to the patient, with regard to efficacy, safety, or immunogenicity of the drug.46,50 Substitution is allowing a pharmacist (with or without a physician,s direct authorization) to substitute a biosimilar for the reference drug at the time of prescription or vice versa.49 It is unclear how these issues will be addressed once biosimilars are available for the treatment of psoriasis.

CONCLUSION Despite the efficacy and safety of the six approved biologic drugs for moderate-to-severe psoriasis, there are many novel biologic and biosimilar drugs in the pipeline.

Once  the aforementioned drugs are demonstrated to be effective and safe, they will provide additional therapeutic options for our psoriasis patients.

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(NCT02430909). Available from: https://clinicaltrials. gov/ct2/show/NCT02430909. Accessed March 28, 2016. 24. Papp KA, Leonardi C, Menter A, et al. Brodalumab, an anti-interleukin-17-receptor antibody for psoriasis. N Eng J Med. 2012 Mar 29;366(13):1181–1189. 25. Russell CB, Rand H, Bigler J, et al. Gene expression profiles normalized in psoriatic skin by treatment with brodalumab, a human anti-IL-17 receptor monoclonal antibody. J Immunol. 2014 Apr 15;192(8):3828–3836. 26. Papp KA, Reich K, Paul C, et al. A prospective phase 3, randomised, double-blind, ­placebo-controlled study of brodalumab in patients with moderate-to-severe plaque psoriasis. Br J Dermatol 2016;175(2):273–286. 27. Lebwohl M, Strober B, Menter A, et al. Phase 3 studies comparing brodalumab with ustekinumab in psoriasis. N Eng J Med. 2015 Oct;373(14):1318–1328. 28. Amgen. Amgen to Terminate Participation in ­Co-development and Commercialization of Brodalumab. Thousand Oaks, CA: PRNewswire; 2015. 29. Novartis pipeline 2015 annual report. Available from: https://www.novartis.com/sites/novartisemea.prod. acquia-sites.com/files/novartis-pipeline-2015-annualreport.pdf. Accessed March 17, 2016. 30. Single and multiple dose escalation study to assess the safety and tolerability of CJM112 in psoriasis (NCT01828086). Available from: https://clinicaltrials. gov/ct2/show/NCT01828086. Accessed March 17, 2016. 31. Efficacy, safety, and pharmacokinetics study of CJM112 in hidradenitis suppurativa patients (NCT02421172). Available from: https://­clinicaltrials. gov/ct2/show/record/NCT02421172. Accessed March 17, 2016. 32. Wiendl HDF, Bennett D, Rosenkranz G, Wold C, Bar-Or A. IL-17 neutralization by subcutaneous CJM122, a fully human anti-IL-17A monoclonal antibody fo r the treatment of relapsing-remitting multiple sclerosis: study design of a phase 2 trial. 31st Congress of the European Committee for Treatment and Research in Multiple Sclerosis. Barcelona, Spain 2015. 33. Griffiths CE, Reich K, Lebwohl M, et al. Comparison of ixekizumab with etanercept or placebo in moderate-to-severe psoriasis (UNCOVER-2 and UNCOVER-3): Results from two phase 3 randomised trials. Lancet. 2015 Aug 8;386(9993):541–551. 34. Vanheusden KLD, Hemeryck A, Vicari A, Grenningloh R, Poelmans S, Wouters H, Stohr T. Preclincial proof-of-concept of ALX-0761, a nanobody (R) neutralizing both IL-17A and F in a cynomolgus monkey collage induced arthritis model. Annual Meeting of the American College of Rheumatology. San Diego, CA 2013. 35. Multiple ascending dose trial of MSB0010841 (Anti-IL17A/F nanobody) in psoriasis subjects (NCT02156466). Available from: https://clinicaltrials. gov/ct2/show/NCT02156466. Accessed March 11, 2016. 36. Covagen Pipeline. Available from: http://covagen. com/pipeline/cova322/. Accessed March 11, 2016.

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37. Safety and tolerability of COVA322 in patients with stable chronic moderate-to-severe plaque psoriasis (NCT02243787). Available from: https://clinicaltrials. gov/ct2/show/NCT02243787. Accessed March 11, 2016. 38. Mansikka H RM, Hugunin M, Ivanov A, et al. Safety, tolerability, and functional activity of ABT-122, a dual TNF- and IL-17A-targeted DVD-Ig™, following single-dose administration in healthy subjects. American College of Rheumatology 2014 Annual Meeting. Boston, Massachusetts 2014. 39. A phase 2 study to investigate the safety, tolerabiity and efficacy of ABT-122 in subjects with active psoriatic arthritis who have an inadequate response to methotrexate (NCT02349451). Available from: https://clinicaltrials.gov/ct2/show/NCT02349451. Accessed March 16, 2016. 40. Phase 2, multicenter, open-label extension (OLE) study with ABT-122 in rheumatoid arthritis subjects who have completed the preceding M12-963 study (NCT02433340). Available from: https://clinicaltrials. gov/ct2/show/NCT02433340. Accessed March 16, 2016. 41. Safety study to evaluate LY3114062 in participants with inflammatory arthritis (NCT02144272). Available from: https://clinicaltrials.gov/ct2/show/ NCT02144272. Accessed March 18, 2016. 42. Eli Lilly clinical development pipeline. Available from: https://www.lilly.com/_Assets/SiteCollection Documents/Pipeline/Clinical-Development-Pipeline/ index.html. Accessed March 18, 2016. 43. Blackstone EA, Fuhr JP, Jr. Innovation and Competition: Will Biosimilars Succeed?: The creation of an FDA approval pathway for biosimilars is complex and fraught with hazard. Yes, innovation and market

competition are at stake. But so are efficacy and patient safety. Biotechnol Healthc. 2012 Spring;9(1):24–27. 44. Strober BE, Armour K, Romiti R, et al. Biopharmaceuticals and biosimilars in psoriasis: What the dermatologist needs to know. J Am Acad Dermatol. 2012 Feb;66(2):317–322. 45. Tsiftsoglou AS, Ruiz S, Schneider CK. Development and regulation of biosimilars: Current status and future challenges. BioDrugs. 2013 Jun;27(3):203–211. 46. Li EC, Abbas R, Jacobs IA, et al. Considerations in the early development of biosimilar products. Drug Discovery Today 2015 May;20 Suppl 2:1–9. 47. Blackstone EA, Joseph PF. The economics of biosimilars. Am Health Drug Benefits. 2013 Sep;6(8):469–478. 48. USFDA. Scientific considerations in demonstrating biosimilarity to a reference product. Available from: http://www.fda.gov/downloads/Drugs/Guidance ComplianceRegulatoryInformation/Guidances/UCM 291128.pdf. Accessed April 18, 2016. 49. Mysler E. Biosimilars: Clinical interpretation and implications for drug development. Curr Rheumatol Rep. 2015 Feb;17(2):8. 50. USFDA. Biosimilars: Questions and answers regarding implementation of the Biologics Price Competition and Innovation Act of 2009. Available f rom: ht tp://w w w.fda.gov/dow n loads/Dr ugs/ GuidanceComplianceRegulator yInformation/ Guidances/UCM444661.pdf. Accessed April 18, 2016. 51. Challand R, Gorham H, Constant J. Biosimilars: Where we were and where we are. J Biopharm stat. 2014;24(6):1154–1164. 52. Feagan BG, Choquette D, Ghosh S, et al. The challenge of indication extrapolation for infliximab biosimilars. Biologicals. 2014 Jul;42(4):177–183.

26 Future directions and personalized medicine CAITRIONA RYAN and ELLIOTT CALL INTRODUCTION Psoriasis has become a common paradigm of autoimmune disease in modern medicine. In the last two decades, significant progress has been made in understanding the complex cellular and molecular pathways of inflammation that contribute to psoriasis pathogenesis.1 These pathways have proven fundamental in the shift from therapies borne from mere pharmacological serendipity to evidence-based targeted biologic therapies. The anti-tumor necrosis factor-alpha (TNF-α) therapies paved the way for the era of biologic therapies for psoriasis, and now several biologic agents targeting both the innate and adaptive immune systems, angiogenesis, and cell adhesion are now in the late stages of development for use in psoriasis. Despite these revolutionary pharmacological advances, there is still limited understanding of how these targeted therapies will subsequently interact with the unique genetic expression of each psoriasis patient. To realize the future of psoriasis care, these novel treatments must go beyond a generalized therapeutic approach and transition into more personalized care medicine that interprets individual immunological and genetic variations to drive therapeutic decision-making. One of the most promising future directions in the study of psoriasis may well be the field of pharmacogenomics. Friedrich Vogel first described pharmacogenetics in 1959 as the study of relationships between genetic polymorphisms and drug response.2 These polymorphisms, or variant forms of a gene, can be involved in multiple cellular mechanisms. Examples can be seen in the alteration of expression and/or function of drug metabolizing enzymes, drug transporters, or psoriasis susceptibility genes and cytokines—each of which are known to be important in the immunopathogenesis of psoriasis. In elucidating the genetic architecture and identifying predictive biomarkers, clinicians would have the capacity to better predict treatment responses for each patient. Efforts in the identification of biomarkers would not only allow better response rates but would assist in recognizing those who may experience significant side effects. In doing so,

pharmacogenetics could minimize or avoid unnecessary exposure to unwanted drug reactions and evade considerable health-care expense. This would generate increased patient safety, potential long-term remission, and patient compliance. Thus, the study of pharmacogenetics can clearly aid in the development of individually tailored therapy and be a catalyst toward the beginnings of personalized psoriasis care.

TOPICAL TREATMENTS Topical vitamin D analogs are also known to improve psoriasis. By activating the vitamin D receptor, topical treatments suppress pathogenic T-cell activation, regulate TNF-α secretion, and prevent the maturation, differentiation, and migration of dendritic cells.3 Despite the convenience of topical therapies, a significant proportion of patients show no response to topical vitamin D3 analogs. This discrepancy in responsiveness of psoriasis patients was evaluated by Chen et al. who showed that the clinical response correlated with the induction of vitamin D receptor (VDR) mRNA expression in psoriatic plaques, with no increase in receptor mRNA level in nonresponders.4 This suggests that the cutaneous response to vitamin D3 is determined by the ability to upregulate transcription, which in turn could potentially be influenced by underlying polymorphisms. However, studies of VDR gene polymorphisms and response to topical vitamin D analogs have shown conflicting results. In one study by Halsall et al., patients with multiple distinct alleles were shown to have a positive response to topical calcipotriol; however, no association between VDR genotype and response to calcipotriol was represented in three other studies.5–8 Regardless of the dissimilarity, the relatively quick response and economic preparation of topical D3 analogs render the utilization of pharmacogenetic predictors impractical. However, by identifying genetic markers that account for variability in treatment response, further progress can be made in the understanding of the molecular mechanism of vitamin D analogs in the treatment of psoriasis.

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Phototherapy Phototherapy has long been a mainstay in the treatment of psoriasis and showcases an interesting example of how pharmacogenetics can be utilized going forward. Dating back over 20 years ago, increased knowledge of the most efficient spectrum of ultraviolet radiation led to the development of a fluorescent lamp emitting a narrowband of ultraviolet B (NB-UVB).9–10 Since then, up to 80% of patients with chronic plaque psoriasis have found effective relief with NB-UVB therapy.11–16 Although this phototherapy is beneficial for many, unfortunately NB-UVB treatment is time consuming, expensive, and potentially carcinogenic. Apart from this, many patients are faced with uncertainty regarding their potential duration of remission posttherapy.17 By incorporating pharmacogenetics, recent studies have shown promising results in identifying distinct polymorphisms to create a strong predictive power regarding the response to NB-UVB. This enables improved therapy, targeting those who would benefit most from this potentially dangerous and time-consuming treatment. In one prospective study of 93 patients with chronic plaque psoriasis treated with NB-UVB, genomic DNA was collected and the frequency of the Fok1, Apa1, Bsm1, and Taq1 polymorphisms of the VDR gene was analyzed.17 It was found that the Taq1 VDR polymorphism (rs731236) significantly predicted remission duration (p = 0.038). The Taq1 polymorphism results in a silent T to C transition in exon 9 at the 3ʹ region of the VDR gene leading to decreased VDR activity and consequently reduced remission duration. Moreover, patients homozygous for the C allele had shorter remission duration compared with those homozygous for the T allele (p = 0.013) or heterozygous for the allele (0.026). Patients homozygous for the T allele were additionally only 48% as likely as those homozygous for the C allele to relapse. These results show a significant predictive potential in NB-UVB targeted therapy for the future. However, the routine testing for VDR polymorphisms is likely to be too expensive for use in current clinical practice. Nonetheless, this study provides a paradigm for other studies, highlighting the need to assess genetic factors when determining treatment outcomes in psoriasis.

Methotrexate Dating back over 50 years, methotrexate remains a firstline systemic agent with approximately 60% of patients achieving a Psoriasis Area and Severity Index 75 (PASI 75) response with methotrexate monotherapy.18–21 By inhibiting key formulary purine synthesis pathways methotrexate can inhibit both DNA and RNA synthesis and produce key anti-inflammatory effects in the pathogenesis of psoriasis. The use of methotrexate is limited by its unpredictable response and toxicity. Studies have shown that up to 30% of patients experience adverse effects necessitating discontinuation of therapy, including gastrointestinal side effects, bone marrow suppression, hepatotoxicity,

pneumonitis, neuropathy, and alopecia.21 This drug is an example of a long established therapy whose use could be optimized with the use of pharmacogenetics. In an effort to better predict treatment response and avoid potential toxicity, phamacogenetic studies have been used to evaluate several polymorphisms believed to be involved in the metabolic pathway of drugs.22,23 Using a tagging method, one study involved 374 patients screened for variations in several sets of single nucleotide polymorphisms (SNPs) across 10 genes relevant to methotrexate metabolism. The key findings suggested that SNPs in efflux transporter genes, specifically the adenosine triphosphate (ATP)– binding cassette, subfamily C, member 1 (ABCC1), and ATP-binding cassette, subfamily G, member 2 (ABCG2), were associated with a positive response to methotrexate therapy in patients with psoriasis. An SNP of the ABCC1 gene, rs246240, was identified that predicted toxicity to methotrexate with an odds ratio (OR) of 2.2 (95% confidence interval: 1.3–3.6; p = 0.001). A smaller study (n = 203) found that an SNP in the reduced folate carrier (RFC), a transporter involved in intracellular folate transportation, was associated with methotrexate-induced toxicity as well.24 These data support the concept of incorporating pharmacogenetic studies involving methotrexate metabolism into the clinical picture of relevant therapy both within psoriasis and across other indications.

Acitretin Acitretin is a retinoid vitamin A derivative, which has been used to treat psoriasis since the early 1980s. Although its mechanisms of action are not fully understood, acitretin᾽s therapeutic effects are thought to be mediated by binding to nuclear receptors, influencing genes that regulate cellular proliferation, decreasing epidermal proliferation, keratinization, and further inflammation.25 As a monotherapy, acitretin has proven to be less effective than other systemic agents, with approximately only one quarter of patients achieving PASI 75.26 Response rates are significantly higher, however, in patients with the severe generalized pustular variant of psoriasis with up to 84% of patients showing a significant response.26 In an effort to improve the efficacy of acitretin in psoriasis, studies have investigated polymorphisms on chromosome 6 close to the locus PSORS1.27,28 These polymorphisms influence the expression of vascular endothelial growth factor (VEGF), a potent angiogenic growth signal associated with the pathogenesis of psoriasis. One specific polymorphism, VEGF 460, was shown to influence the response to acitretin.29,30

Cyclosporine The serendipitous discovery of the effectiveness of cyclosporine for psoriasis in 1979 radically advanced the understanding of the immunopathogenesis of the disease. This calcineurin antagonist redefined the etiology of

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psoriasis from what was thought to be a hyperproliferative, ­keratinocyte-driven disorder to that of an immune-driven disease. Calcineurin activates nuclear factor of activated T cells (NFAT), a transcription factor that regulates the transcription of interleukin-2 (IL-2). This cytokine facilitates further activation of T cell, natural killer cell, and monocyte pathways, all contributing toward the immunogenesis of psoriasis.31 At a dose of 3 mg/kg/day, cyclosporine rapidly produces a PASI 75 response in up to 70% of patients, with increased response rates seen at higher doses.26 However, like many other immunosuppressants there is a narrow therapeutic index and an extensive side effect profile, including possible nephrotoxicity, hypertension, hyperlipidemia, and neurological effects. Due to the drug’s extensive side effect profile, it is limited in its clinical use. Pharmacogenetic studies of cyclosporine in psoriasis patients are lacking. Much of the existing knowledge on the effects of genetic polymorphisms comes through transplantation research focusing on the variability in pharmacokinetics and pharmodynamics of cyclosporine. Studies have shown three distinct P450 isoenzymes that control the systemic clearance and oral bioavailability of cyclosporine: cytochrome P450 3A4 (CYP3A4), cytochrome P450 3A5 (CYP3A5), and the efflux p ­ -glycoprotein pump (PGP). All three enzymes are encoded by genes that incorporate several SNPs thought to account for the variability in pharmacokinetics.32–36 For example, in the CYP3A enzyme group, the specific gene (and its accompanying enzyme) CYP3A5 has been shown to represent up to 50% of the total CYP3A content.34 In healthy volunteers carrying this CYP3A5 gene with the A6986 allele (CYP3A5*1) polymorphism, patients showed a lower total drug concentration over time and a higher clearance of cyclosporine.35 Similarly in another study of the pharmacokinetics, a lower serum ­cyclosporine concentration was observed in 103 renal transplant patients homozygous for the CYP3A4*18B allele SNP.37 Many of the these studies have been disputed in successive research, having failed to demonstrate a valid relationship between cyclosporine pharmacokinetics and isoenzyme polymorphisms.38–40 Two pharmacogenomic studies have demonstrated the effect of cyclosporine treatment on genetic expression in moderate-to-severe psoriasis.41,42 The first study investigated the genetic expression of 11 patients actively responding to cyclosporine therapy.41 RNA microarray analysis was performed on both blood and skin (lesional and nonlesional) samples at baseline and following 14 days of treatment. Cyclosporine downregulated the expression of 220 genes by 1.5-fold in the skin, more than 95% of which were associated with proinflammatory cells, keratinocytes, and fibroblasts. By contrast, there were no changes in the genetic expression in the peripheral blood at day 14. The expression of proinflammatory genes in skin lesions of the 11 patients was also analyzed using real-time polymerase chain reaction (RT-PCR) at baseline and periodically over 56 days. At day 14 of the treatment, there was downregulation of expression in genes coding for the type 1 helper T cell (Th1) pathway (p40, IFN-g Signal transducer and activator of transcription

1 [STAT1], Interferon regulatory factor 1, Chemokine [C-X-C motif] ligand 9 [CXCL9], interferon γ-induced protein 10, Interferon-induced GTP-binding protein Mx1) and the Th17 pathway (p19, IL-17, and IL-22 and downstream genes such as macrophage inflammatory protein-3 [MIP-3a], DefensinB-2 [DEFB-2], IL-1b, serpin family B member 3 [SERPINb3], and S100A12) in the skin.41 There was also a decrease in the production of TNF-α and inducible nitric oxide synthase (iNOS) from dendritic cells. When expression of genes in the skin was correlated to overall clinical score (using epidermal thickness, PASI, and K16 expression), IL-17 expression correlated best with the activity at day 14, whereas iNOS correlated best with long-term response. The second study examined the expression levels in genes upregulated in the skin of psoriasis patients following treatment with cyclosporine or recombinant IL-11.42 Microarray was used to compare genetic expression in lesional and nonlesional skin of eight patients compared with normal skin, showing 159 differentially expressed genes. Upregulation of genes encoding S100A12, ID4, metaxin [MTX], and heparinbinding protein17 [HBP17] occurred within 1 week of treatment, often preceding clinical improvement. Consequently cyclosporine, although potentially devastating in its side effects, could better be curtailed to patients whose genetic architecture affords them the benefits and response of cyclosporine without the associated toxicity.

TNF-α inhibitors The advent of anti-tumor necrosis factor alpha (anti-TNF-α) therapies with their unique biological structure has transformed pharmacological treatment of both psoriasis and psoriatic arthritis (PsA). These therapies have become first-line agents in the treatment of moderate-to-severe ­ psoriasis offering efficacy and relief for many. Despite the improved prognosis these therapies can offer, TNF-α inhibitors are expensive, have potentially severe side effects, and exhibit a heterogeneous response with up to 50% of patients not responding satisfactorily.43 Among the foremost antiTNF-α therapies, infliximab, etanercept, and adalimumab, inadequate response or loss of initial response occurs in 20%–50% of patients.43 With such therapeutic variability, it is important to identify pharmacogenetic markers to aid in the understanding of the complex genetic heterogeneity seen in each individual psoriasis patient. Several recent pharmacogenetic studies have examined the link between genetic markers and response to drug treatment. One study investigated the potential influence of both TNF-α and accompanying TNF receptor (TNFRSF1A and TNFRSF1B) polymorphisms on infliximab, etanercept, and adalimumab.44 Numerous SNPs in TNF (−238G>A, −308G>A, −857C>T), TNFRSF1A (36A>G), and TNFRSF1B (676T>G) were sequenced by PCR restriction fragment length polymorphism assays in 80 patients who were treated for 6 months. Sixty-three (78.8%) of the patients were classified as responders to one of the three biologics, based on achieving a PASI 75 response.

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There was a significant association between response to ­etanercept and carriage of the TNF-857C or TNFRSF1B 676T alleles (p = 0.002 and p  =  0.001, respectively). No other allele was associated with treatment response to any of the agents. In another study of 90 patients receiving TNF inhibitors for psoriasis, next generation sequencing (NGS) was used to identify nucleotide variants in TNFRSF1A and TNFRSF1B and TNF-α.45 Carriers of allele G (p.196R) carriers were more likely to be in the nonresponder group (56%) (p = 0.05). In a recent study of 116 patients, Batalla et al. examined the impact of carriage of the human leukocyte antigen (HLA)-Cw6 allele and late-cornified envelope (LCE) polymorphism deletions in response to anti-TNF-α therapy.46 This study demonstrated a nonsignificant trend of treatment response (≥PASI 75 response after 24 weeks) in patients who were HLA-Cw6 positive. Patients with the LCE-DD polymorphism were more likely to be nonresponders (p = 0.028; OR = 2.45). Patients who were both HLA-Cw6 positive and LCE-I carriers (ID/II) were more likely to respond than those who were HLA Cw6 negative and LCE-DD (p = 0.034; OR = 3.14). Several studies have failed to show a lack of association between specific polymorphisms and treatment response to TNF inhibitors. One study showed no association among genotypes of HLA-C, VDR, and killer immunoglobulin receptor (KIR) in 138 patients with severe chronic plaque psoriasis who were treated with etanercept or adalimumab.47 Studies have also examined predictors of treatment response in patients with PsA. One study assessed soluble biomarkers in 40 patients with PsA before and during TNF-α inhibitor therapy.48 Enzyme-linked immunosorbent assay (ELISA) was used to measure specific biomarkers including TNF superfamily 14, matrix metalloprotease-3 (MMP-3), receptor activator of nuclear factor κ-B ligand, osteoprotegerin, cartilage oligomeric matrix protein (COMP), and highly sensitive C-reactive protein. Both baseline and reduction in MMP-3 increased the OR of achieving response (OR 1.067 and OR 1.213, respectively). A reduction in COMP decreased the OR of treatment response. Because of the unique anti-immune mechanism of biologic therapy, the clinical implications reach far past the disease of psoriasis. A significant research effort has undertaken further investigation into TNF-α antagonists in both rheumatoid and Crohn’s disease.49,50 In a study of 1050 rheumatoid arthritis patients treated with TNF-α antagonists, the AA genotype of the −308 polymorphism was associated with a poor response compared with the GG genotype in etanercept, whereas the GA genotype at −238 was associated with a poorer response to infliximab.50 Additional studies have also shown the −308 allele to be a predictor of response to infliximab, etanercept, and adalimumab, whereas others have shown no relationship between this allele and treatment response.51–57 There are a number of difficulties in identifying biomarkers of response to TNF inhibitors in psoriasis,

including limitations in statistical power and issues surrounding secondary failure to drugs, which cannot be accounted for by genetic factors alone.47 With time, more robust and comprehensive analysis strategies may guide further studies and enhance genomic-based therapy for individually tailored therapy.

Ustekinumab One of the most fundamental advances in psoriasis research has been the discovery of the role of Th17 cells in disease pathogenesis. Formerly considered to be purely a Th1-cell–mediated disease, the central function of Th17 cell/IL-17 paradigm in the immunopathogenesis of psoriasis has been much researched over the past decade. The expansion of Th17 cells is mediated by IL-23. Ustekinumab is a fully human IgG1/κ monoclonal antibody to the shared p40 subunit of IL-12 and IL-23. Inhibition of these cytokines results in the inhibition of Th1 and Th17 cell activity. Several studies have examined possible biomarkers to predict response to ustekinumab, in particular, the influence of HLA-Cw6 polymorphisms on the treatment response.58–59 In the first, 51 psoriasis patients underwent genotyping and treatment response was observed over a 40-week period. HLA-Cw6–positive patients demonstrated a superior response with 96.4% achieving PASI 75 by week 12 compared with only 65.2% of Cw6-negative patients (p = 0.008). These Cw6-positive patients also responded more quickly with 89.3% achieving a PASI 50 response at week 4 compared with only 60.9% of the Cw6negative cohort.58 A second study of 66 Chinese patients confirmed a positive correlation between ustekinumb response and HLA-Cw6 positivity. Those patients who carried the HLA-Cw6 polymorphism were more likely to achieve a PASI 75 response after 4 weeks of treatment compared with those who were negative for the allele (38% vs. 9%, respectively, p = 0.019).59 HLA-Cw6 carriers were also more likely to have maintained a PASI 90 response at week 28 (63% vs. 26%, p = 0.035). These studies offer a potential biomarker of treatment response to ustekinumab. Another study took a more functional approach by measuring mRNA expression levels of specific inflammatory targets of the drug, specifically IL-20, IL-21, and p40 in skin biopsies from 18 psoriasis patients.60 PCR showed a significant increase in IL-20, IL-21, and p40 in nonresponders compared with that of responders.

CONCLUSION Although the use of pharmacogenomics in psoriasis treatment is an exciting concept, its clinical utility and feasibility in individualized health care is still in question. Current pharmacogenetic studies have shown limitations in statistical power being unable to establish reliable and reproducible objective results regarding treatment response. Before a more individualized approach into

References 259

psoriasis care can develop, distinct studies must first demonstrate and validate statistically significant results concerning the identification of pharmacogenetic biomarkers and their benefit in predicting patient treatment response. Once proven advantageous, compilations of biostatistical data can be collected using RNA microarray analysis and other genome sequencing technologies. Captured data including individual genotype expression profiling, polymorphisms, and epigenetic/proteomic studies can all then be combined with current phenotypic presentation and demographics to create patient registries. Such registries ultimately can be analyzed and used in longitudinal studies as a model to predict both systemic and biological treatment responses in future psoriasis patients and help direct clinical decision-making. Although visionary, the concept of genome-wide registries could play a valuable role in the field of pharmacogenetics—an exciting prospect and goal in the future of biomedical research and psoriasis care in the twenty-first century.

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11. Markham T, Rogers S, Collins P. Narrowband UV-B (TL-O1) phototherapy vs oral 8-methoxypsoralen psoralen UVA for treatment of chronic plaque psoriasis. Arch Dermatol. 2003;139:325–328. 12. Green C, Lakshmipathi T, Johnson BE, Ferguson   J. A comparison of the efficacy and relapse rates of narrowband UVB (TL01) monotherapy vs. etretinate ­(re-TL-01) vs. etretinate-PUVA (re-PUVA) in the treatment of psoriasis patients. Br J Dermatol. 1992;127:5–9. 13. Kirke S, Lowder S, Lloyd JJ, et al. A randomized comparison of selective broadband UVB and narrowband UVB in the treatment of psoriasis. J Invest Dermatol. 2007;127:1641–1646. 14. Kleinpenning MM, Smits T, Boezeman J, et al. Narrowband ultraviolet B therapy in psoriasis: Randomized double-blind comparison of high-dose and low-dose irradiation regimens. Br J Dermatol. 2009;161:1351–1356. 15. Ibbotson SH, Bilsland D, Cox NH, et al. An update and guidance on narrowband ultraviolet B phototherapy: A British Photodermatology Group Workshop Report. Br J Dermatol. 2004;151:283–297. 16. Cameron H, Dawe RS, Yule S, et al. A randomized, observer-blinded trial of twice versus three times weekly narrowband ultraviolet B phototherapy for chronic plaque psoriasis. Br J Dermatol. 2002;147:973–978. 17. Ryan C, Renfro L, Collins P, Kirby B, Rogers S. Clinical and genetic predictors of response to narrowband ultraviolet B for the treatment of chronic plaque psoriasis. Br J Dermatol. 2010;163(5):1056–1063. 18. Edmundson WF, Guy WB. Treatment of psoriasis with a folic acid antagonist. Arch Dermatol. 1958;78:200–203. 19. Heydendael VM, Spuls PI, Opmeer BC, et al. Methotrexate versus cyclosporine in moderateto-severe chronic plaque psoriasis. N Engl J Med. 2003;349:658–665. 20. Flytstrom I, Stenberg B, Svensson A, Bergbrant  IM. Methotrexate vs cyclosporin in psoriasis: Effectiveness, quality of life and safety. A randomized controlled trial. Br J Dermatol. 2008;158:116–121. 21. Van Dooen-Greebe R, Kuijpers A, Mulder, et al. Methotrexate revisited: Effects of long-term treatment in psoriasis. Br J Dermatol. 1994;130:204–210. 22. Warren RB, Smith RL, Campalani E, et al. Genetic variation in efflux transporters influences outcome to methotrexate therapy in patients with psoriasis. J Invest Dermatol. 2008;128:1925–1929. 23. Warren RB, Smith RL, Campalani E, et al. Outcomes of methotrexate therapy for psoriasis and relationship to genetic polymorphisms. Br J Dermatol. 2009;160:438–441. 24. Campalani E, Arenas M, Marinaki AM, et al. Polymorphisms in folate, pyrimidine, and purine metabolism are associated with efficacy and toxicity of methotrexate in psoriasis. J Invest Dermatol. 2007;127:1860–1867.

260  Future directions and personalized medicine

25. Pang ML, Murase JE, Koo J. An updated review of acitretin—A systemic retinoid for the treatment of psoriasis. Expert Opin Drug Metab Toxicol. 2008 Jul;4(7):953–964. 26. Menter A, Korman NJ, Elmets CA, et al. Guidelines of care for the management of psoriasis and psoriatic arthritis: Section 4. Guidelines of care for the management and treatment of psoriasis with traditional systemic agents. J Am Acad Dermatol. 2009; 61:451–485. 27. Wongpiyabovorn J, Yooyongsatit S, Ruchusatsawat K, et al. Association of the CTG (-278/-460/405) haplotype within the vascular endothelial growth factor gene with early-onset psoriasis. Tissue Antigens. 2008;72:458–463. 28. Wang Z, Liang W, Zhang B, et al. Single nucleotide polymorphisms of VEGF gene and psoriasis risk. J Dermatol Sci. 2008;49:263–265. 29. Young HS, Summers AM, Read IR, et al. Interaction between genetic control of vascular endothelial growth factor production and retinoid responsiveness in psoriasis. J Invest Dermatol. 2006;126:453–459. 30. Lee JH, Cho EY, Namkung JH, et al. Single-nucleotide polymorphisms and haplotypes in the VEGF receptor 3 gene and the haplotype GC in the VEGFA gene are associated with psoriasis in Koreans. J Invest Dermatol. 2008;128:1699–1703. 31. Stein CM, Murray JJ, Wood AJ. Inhibition of stimulated interleukin-2 production in whole blood: A practical measure of cyclosporine effect. Clin Chem. 1999;49:1477–1484. 32. Lamba JK, Lin YS, Schuetz EG, et al. Genetic contribution to variable human CYP3A-mediated metabolism. Adv Drug Deliv Rev. 2002;54:1271–1294. 33. Marzolini C, Paus E, Buclin T, et al. Polymorphisms in human MDR1 (p-glycoprotein): Recent advances and clinical relevance. Clin Pharmacol Ther. 2004;75:13–33. 34. Kuhl P, Zhang J, Lin Y, et al. Sequence diversity in CYP3A promoters and characterization of the genetic basis of polymorphic CYP3A5 expression. Nat Genet. 2001;27:383. 35. Min DI, Elingrod VL, Marsh SP, et al. CYP3A5 polymorphism and the ethnic differences in cyclosporine pharmacokinetics in healthy subjects. Ther Drug Monit. 2004;26:524–528. 36. Haufroid V, Mourad M, van Kerckhove V, et al. The effect of CYP3A5 and MDR1 (ABCB1) polymorphisms on cyclosporine and tacrolimus dose requirements and trough blood levels in stable renal transplant patients. Pharmacogenetics. 2004;14: 147–154. 37. Qiu XY, Jiao Z, Zhang M, et al. Association of MDR1, CYP3A4*18B, and CYP3A5*3 polymorphisms with cyclosporine pharmacokinetics in Chinese renal transplant recipients. Eur J Clin Pharmacol. 2008;64:1069–1084.

38. Hesselink DA, van Schaik RH, Van Der Heiden IP, et  al. Genetic polymorphisms of the CYP3A4, CYP3A5, and MDR-1 genes and pharmacokinetics of the calcineurin inhibitors cyclosporine and tacrolimus. Clin Pharmacol Ther. 2003;74:245–254. 39. Zhao Y, Song M, Guan D, et al. Genetic polymorphisms of CYP3A5 genes and concentration of cyclosporine and tacrolimus. Transplant Proc. 2005;37:178–181. 40. Anglicheau D, Thervet E, Etienne I, et al. CYP3A5 and MDR1 genetic polymorphisms and cyclosporine pharmacokinetics after renal transplantation. Clin Pharmacol Ther. 2004;75:422–433. 41. Haider AS, Lowes MA, Suárez-Fariñas M, et al. Identification of cellular pathways of “Type 1,” Th17 T cells and TNF- and inducible nitric oxide synthaseproducing dendritic cells in autoimmune inflammation through pharmacogenomic study of cyclosporine A in psoriasis. J Immunol. 2008;180:1913–1920. 42. Oestreicher JL, Walters IB, Kikuchi T, et al. Molecular classification of psoriasis disease-associated genes through pharmacogenomic expression profiling. Pharmacogenomics J. 2001;1:272–287. 43. Ryan C, Kelleher J, Collins P, et al. A study to examine if the HLA Cw*0602 allele is a predictor of response to TNF-a inhibitors in the treatment of psoriasis [abstract]. Br J Dermatol. 2009;161 (Suppl 1):28. 44. Vasilopoulos Y, Manolika M, Zafiriou E, et al. Pharmacogenetic analysis of TNF, TNFRSF1A, and TNFRSF1B gene polymorphisms and prediction of response to anti-TNF therapy in psoriasis patients in the Greek population. Mol Diagn Ther. 2012;16(1):29–34. 45. González-lara L, Batalla A, Coto E, et al. The TNFRSF1B rs1061622 polymorphism (p.M196R) is associated with biological drug outcome in Psoriasis patients. Arch Dermatol Res. 2015 Jul;307(5):405–412. 46. Batalla A, Coto E, González-fernández D, et al. The Cw6 and late-cornified envelope genotype plays a significant role in anti-tumor necrosis factor response among psoriatic patients. Pharmacogenet Genomics. 2015. 47. Ryan C, Kelleher J, Fagan MF, et al. Genetic markers of treatment response to tumour necrosis factor-α inhibitors in the treatment of psoriasis. Clin Exp Dermatol. 2014;39(4):519–524. 48. Chandran V, Shen H, Pollock RA, et al. Soluble biomarkers associated with response to treatment with tumor necrosis factor inhibitors in psoriatic arthritis. J Rheumatol. 2013;40(6):866–871. 49. Taylor KD, Plevy SE, Yang, et al. ANCA pattern and LTA haplotype relationship to clinical responses to anti-TNF antibody treatment in Crohn’s disease. Gastroenterology. 2001;120:1347–1355. 50. Maxwell JR, Potter C, Hyrich KL, et al. Association of the tumour necrosis factor-308 variant with differential response to anti-TNF agents in the treatment of rheumatoid arthritis. Hum Mol Genet. 2008;17:3532–3538.

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51. Mugnier B, Balandraud N, Darque A, et al. Polymorphism at postion −308 of the tumour necrosis factor alpha gene influences outcome of inlisimab therapy in rheumatoid arthritis. Arthritis Rheum. 2003;48:1849–1852. 52. Fonseca JE, Carvalho T, Cruz M, et al. Polymorphism at postion −308 of the tumour necrosis factor alpha gene and rheumatoid arthritis pharmacogenetics. Ann Rheum Dis. 2005;64:793–794. 53. Seitz M, Wirthmuller U, Moller B, Villiger PM. The −308 tumour necrosis factor alpha gene polymorphism predicts therapeutic response to TNF alphablockers in rheuamtoid arthitis an spondyloarthritis patients. Rheumtology. 2007;46:93–96. 54. Guis S, Balandraud N, Bouvenot J, et al. Influence of −308A/G polymorphism in the tumour necrosis factor alpha gene on etanercept treatment in rheumatoid arthritis. Arthritis Rheum. 2007;57:1426–1430. 55. Martinez A, Salido M, Bonilla G, et al. Association of the major histocompatibility complex with response to infliximab therapy in rheumatoid arthritis patients. Arthritis Rheum. 2004;50:1077–1082. 56. Marotte H, Pallot-Prades B, Grange L, et al. The shared epitope is a marker of severity associated with

selection for, but no with response to, infliximab in a large rheumatoid arthritis population. Ann Rheum Dis. 2006;65:342–347. 57. Criswell LA, Lum RF, Turner KN, et al. The influence of genetic variation in the HLA-DRB1 and LTA-TNF regions on the response to treatment of early rheumatoid arthritis with methotrexate or etanercept. Arthritis Rheum. 2004;50:2750–2756. 58. Talamonti M, Botti E, Galluzzo M, et al. Pharmacogenetics of psoriasis: HLA-Cw6 but not LCE3B/3C deletion nor TNFAIP3 polymorphism predisposes to clinical response to interleukin 12/23 blocker ustekinumab. Br J Dermatol. 2013;169(2):458–463. 59. Chiu HY, Wang TS, Chan CC, Cheng YP, Lin SJ, Tsai TF. Human leucocyte antigen-Cw6 as a predictor for clinical response to ustekinumab, an interleukin-12/23 blocker, in Chinese patients with psoriasis: A retrospective analysis. Br J Dermatol. 2014;171(5):1181–1188. 60. Gedebjerg A, Johansen C, Kragballe K, Iversen L. IL20, IL-21 and p40: Potential biomarkers of treatment response for ustekinumab. Acta Derm Venereol. 2013;93(2):150–155.

27 Conclusion CAITRIONA RYAN The future for psoriasis patients is bright, with considerable advances in our understanding of disease pathogenesis and drug development over the past two decades. With the advent of the biologic era, we have had a dramatic growth in the therapeutic armamentarium at our disposal to treat patients with moderate-to-severe psoriasis. Deconvolution of the complex molecular basis of psoriasis has driven pharmacologic development, and patients can look forward to an even greater array of more targeted therapeutic options that are currently in the late stages of clinical development. With increasing efficacy of these newer therapies, Psoriasis Area and Severity Index (PASI) 90 and PASI 100 are soon becoming the new measures of optimal treatment response. Continued research is required to fully elucidate the complex immunopathogenesis of psoriasis, in particular, studies to examine the role of environmental factors in the development and exacerbation of psoriasis, the function of psoriasis susceptibility genes, and factors associated with spontaneous remission. There is growing evidence to support an association between moderate-to-severe psoriasis and cardiovascular risk.1,2 Further guidelines are needed to appropriately screen for and optimally manage cardiovascular comorbidities in patients with moderate-to-severe psoriasis. Increased research to define the molecular pathways leading to increased cardiovascular risk in psoriasis patients may allow the development of new approaches to reduce cardiovascular inflammation while treating psoriasis. Studies are ongoing to identify reliable biomarkers of systemic inflammation and cardiovascular risk in psoriasis patients. It has been shown that children with psoriasis are at increased risk for metabolic and psychiatric comorbidities. 3,4 There is an urgent need for clinical randomized controlled trials (RCTs) of systemic and biologic agents in pediatric patients with severe psoriasis, to circumvent potential devastating psychosocial effects in this patient subpopulation. The reluctance of drug regulatory agencies to approve the use of immunosuppressant drugs for pediatric psoriasis has had a deleterious impact on the management of pediatric psoriasis, as many dermatologists are reluctant to prescribe drugs off-label for

children and pharmaceutical companies are discouraged from pursuing approval of new biologic agents for this population.5 There is a wide variation in the reported frequency of joint involvement in psoriasis.6 Large cohort studies are needed to determine the true incidence of psoriatic arthritis (PsA) and the rate of joint destruction. Examining the differences in genotype, immunophenotype, and environmental influences between patients with and without joint involvement may allow the identification of patients at a higher risk of developing PsA and facilitate the development of targeted therapies that specifically treat joint involvement.7–11 Growing evidence has shown that the early diagnosis of PsA and early intervention with immune-modulating therapies may alter the clinical course of joint disease.12 Longterm, prospective studies are needed to examine the influence of systemic and biologic treatments on the natural progression of PsA. Close collaboration with our rheumatology colleagues is also necessary for the development of appropriate screening tools and biomarkers to diagnose early PsA. As discussed in Chapter 26, the identification of biomarkers of treatment response as part of drug registries or large-scale RCTs may facilitate advances in the personalized treatment of psoriasis.13 The recent advent of biosimilar drugs may also change the landscape of psoriasis therapy, with decreasing cost allowing increased access of patients to biologic therapies.14 It is essential, however, that the quality of drug delivery is not compromised in any way, and that rigorous assessment of the efficacy and safety of biosimilar drugs is performed on a continual basis.14 Despite a rapid rate of growth in the array of systemic and biologic treatments for moderate-to-severe psoriasis in recent years, there is a relative dearth of new topical agents for the treatment of milder disease. There is a great need for more effective topical therapies to serve the great majority of psoriasis patients who have mild-to-moderate disease.15 As discussed in Chapter 21, several new exciting classes of molecules are currently in development for topical use that will hopefully expand our topical treatment options for the treatment of mild-to-moderate psoriasis. 263

264 Conclusion

Despite radical advances in the therapy of psoriasis, long-term safety data are still essential with newly developed drugs. The short duration of the placebo-controlled phase in RCTs may not allow the detection of rare or longterm adverse events. Regulatory agencies have mandated open-label extension studies of new drugs in development for up to 5 years to address this need. Data collected from established psoriasis drug registries will be a valuable source of information to examine the long-term safety and efficacy of biologic and systemic agents. Large prospective studies are also needed to determine the effect of systemic and biologic therapies on cardiovascular events and metabolic comorbidities. Although the number of psoriasis treatments in development has expanded exponentially over the past 5 years, the biological market for moderate-to-severe psoriasis has experienced relatively little growth worldwide over the same timeframe. Through patient surveys, it is estimated that less than a fifth of patients with moderate-to-severe psoriasis worldwide are treated with appropriate systemic or biologic therapies.16 This is likely due to a multitude of factors, including the reluctance of a considerable proportion of dermatologists worldwide to use newer biologic therapies coupled with a lack of awareness among patients of the availability of these newer agents and of the systemic inflammatory nature of psoriasis. More concerning, however, is the lack of access of patients to newer therapies, due to their prohibitive cost, combined with the restrictions imposed by insurance companies, third-party payers, and governmental agencies. The continued collaboration of dermatologists, rheumatologists, scientists, patient support groups, pharmaceutical companies, drug regulatory agencies, and national health care systems is essential to optimize the management of psoriasis patients of all ages worldwide.

REFERENCES 1. Gelfand JM, Neimann AL, Shin DB, Wang  X, Margolis DJ, Troxel AB. Risk of myocardial infarction in patients with psoriasis. JAMA. 2006;296(14):1735–1741. 2. Ryan C, Kirby B. Psoriasis is a systemic disease with multiple cardiovascular and metabolic comorbidities. Dermatol Clin. 2015;33(1):41–55. 3. Paller AS, Mercy K, Kwasny MJ, et al. Association of pediatric psoriasis severity with excess and central adiposity: An international cross-sectional study. JAMA Dermatol. 2013;149(2):166–176.

4. Kimball AB, Wu EQ, Guérin A, et al. Risks of developing psychiatric disorders in pediatric patients with psoriasis. J Am Acad Dermatol. 2012;67(4):651–657. e651–652. 5. Gorman RL. The march toward rational therapeutics in children. Pediatr Infect Dis J. 2003; 22(12):1119–1123. 6. Gottlieb A, Korman NJ, Gordon KB, et al. Guidelines of care for the management of psoriasis and psoriatic arthritis: Section 2. Psoriatic arthritis: Overview and guidelines of care for treatment with an emphasis on the biologics. J Am Acad Dermatol. 2008;58(5):851–864. 7. Chandran V. Familial aggregation of psoriatic arthritis. Ann Rheum Dis. 2009;68:664–667. 8. O’Rielly DD, Rahman, P. Genetics of susceptibility and treatment response in psoriatic arthritis. Nat Rev Rheumatol. 2011;7:718–732. 9. Stuart PE. Genome-wide association analysis identifies three psoriasis susceptibility loci. Nat Genet. 2010;42:1000–1004. 10. Ellinghaus E, Ellinghaus D, Stuart PE, Nair RP, et al. Genome-wide association study identifies a psoriasis susceptibility locus at TRAF3IP2. Nat Genet. 2010;42:991–995. 11. Nograles KE, Brasington RD, Bowcock AM. New insights into the pathogenesis and genetics of psoriatic arthritis. Nat Clin Pract Rheumatol. 2009;5(2):83–91. 12. Kirkham B, de Vlam K, Li W, et al. Early treatment of psoriatic arthritis is associated with improved patient-reported outcomes: Findings from the etanercept PRESTA trial. Clin Exp Rheumatol. 2015;33(1):11–19. 13. Ryan C, Menter A, Warren RB. The latest advances in pharmacogenetics and pharmacogenomics in the treatment of psoriasis. Mol Diagn Ther. 2010;14(2):81–93. 14. Blauvelt A, Cohen AD, Puig L, Vender R, Van Der Walt J, Wu JJ. Biosimilars for psoriasis: Preclinical analytical assessment to determine similarity. Br J Dermatol. 2016;174(2):282–286. 15. Menter A, Korman NJ, Elmets CA, et al. Guidelines of care for the management of psoriasis and psoriatic arthritis. Section 3. Guidelines of care for the management and treatment of psoriasis with topical therapies. J Am Acad Dermatol. 2009;60(4):643–659. 16. Lebwohl MG, Bachelez H, Barker J, et al. Patient perspectives in the management of psoriasis: Results from the population-based Multinational Assessment of Psoriasis and Psoriatic Arthritis Survey. J Am Acad Dermatol. 2014;70(5):871–881.e871–830.

Index

A ABT-122, 251 Ace inhibitor therapy, 39 ACH, see Acrodermatitis continua of Hallopeau Acitretin, 207, 229, 256 adverse events and management, 226–227 contraindications for, 227–228 dosing, 226 drugs interacting with, 228 ACR20, see American College of Rheumatology 20 Acrodermatitis continua of Hallopeau (ACH), 59–61, 71 Acrokeratosis neoplastica, see Bazex syndrome Actinic keratosis, 99 Acute generalized exanthematous pustulosis (AGEP), 14, 109–110 Acute guttate psoriasis, 50 Acute palmoplantar eczema, 58 Acute respiratory distress syndrome, 175 AD, see Atopic dermatitis Adalimumab, 233, 235 Adaptive immunity, 34 Adipose inflammation, 160–161 AGEP, see Acute generalized exanthematous pustulosis Age, psoriasis, 8 Alcohol, 168–169 misuse, 41 Alefacept, 3 Alexithymia, 168 Allergic contact dermatitis, 106, 114, 116, 120 Alopecia areata, 120 American College of Rheumatology 20 (ACR20), 185 ANA, see Antinuclear antibodies Anthralin, 152, 196–197 Antidepressant medications, 168 Anti–double stranded DNA (antidsDNA), 236 Antinuclear antibodies (ANA), 236 Anti-tumor necrosis factor alpha (anti-TNF-α), 15, 257, 258 Anxiety, 167–168 Apremilast clinical efficacy in psoriasis vulgaris, 244 mode of action, 243–244 side effects, safety, and monitoring, 244–245

Arsenic, 2 Arthritis mutilians, 147 Arthropathy axial disease, 147 dactylitis, 148 distal interphalangeal joint disease, 146 pauciarthritis, 145 polyarthritis, 145–146 ASP015K, 246 Atherosclerotic cardiovascular diseases, 160 Atopic dermatitis (AD), 21, 106–107, 116, 126, 128 Auspitz’s sign, 45, 89 Autoimmunity, 236 Axial disease, 147 B Balanitis circumscripta plasmacellularis, see Plasma cell balanitis Baricitinib, 246 Basal cell carcinoma (BCC), 97–98 Bateman, Thomas, 1 Bath psoralen ultraviolet light A, 210 Bazex syndrome, 122–123 BB-UVB, see Broadband UVB BCC, see Basal cell carcinoma BCD-085, 250 BDCA, see Blood dendritic cell antigen Bimekizumab, 250 Biologic therapies cardiovascular effects, 235–236 demyelinating neurologic diseases, 236 hepatitis, 234–235 malignancies, 235 in pipeline, see Pipeline, biologic therapies in tuberculosis, 234 Biosimilar drugs, 251–252 Birbeck granules, 32 Blood biomarkers, 159 Blood dendritic cell antigen (BDCA), 32 Blood inflammation, 160 BMI, see Body mass index Body mass index (BMI), 159 Body surface area (BSA), 182 Botulinum toxin type-A, 76 Bowen’s disease, 98–99, 125 Broadband UVB (BB-UVB), 203, 204 Brodalumab, 250 Buccal mucosa, 72 Butterfly rash, 127

C CAD, see Chronic actinic dermatitis Calcineurin inhibitors, 196 Calcipotriene, 76, 152, 195 Calcipotriol, 60, 76, 207 Calcitriol, 152, 195 cAMP, see Cyclic adenosine monophosphate Cancer, psoriasis and, 175–176 Candidosis, 112 Candle sign, 45 CAPP, see Comprehensive assessment of the psoriasis patient CARD14, see Caspase recruitment domain family member 14 Cardiometabolic comorbidities, 159–163 Cardiometabolic diseases, 159 psoriasis treatment and effect on, 162–163 role of inflammation in, 160 screening and treatment of, 163 Cardiovascular diseases (CVD), 161–162 risk, 151 Cartilage, 137 Caspase recruitment domain family member 14 (CARD14), 17, 23–25 Celiac disease, 173–174 Central pathogenic psoriatic pathway, 35 Certolizumab pegol, 249 Chemokines, 33 CHF, see Congestive heart failure Chloroquine, 39 CHMP, see Committee for Medicinal Products for Human Use Cholangitis, 174 Cholestasis, 174 Chronic actinic dermatitis (CAD), 107 Chronic cyclosporine nephropathy, 223 Chronic inflammatory skin disease, 31, 71 Chronic obstructive pulmonary disease (COPD), 175 Chronic plaque psoriasis (CPP), 5, 11–12, 39, 89–90 discoid eczema, 92–93 lichen planus, 95–97 mycosis fungoides, 93–94 plaque-type psoriasis, 45–50 subacute cutaneous lupus erythematosis, 94–95 tinea corporis, 90–92

Chronic superficial scaly dermatitis (CSSD), 105 Chronic systemic inflammation, in psoriasis, 160–161 Chrysarobin, 2 Cigarette smoking, 40 CJM112, 251 CLA+, see Cutaneous lymphocyte antigen Clinical cardiovascular diseases, 160 Coal tar, 197 Combination therapies, 228–229 Committee for Medicinal Products for Human Use (CHMP), 246 Comorbidities, screening for, 152 Comprehensive assessment of the psoriasis patient (CAPP), 184, 189 Congestive heart failure (CHF), 235–236 Contact dermatitis, 99–101, 124, 127, 128 COPD, see Chronic obstructive pulmonary disease Corticosteroids, 60, 193–195 Corynebacterium minutissimum, 112 COVA322, 251 CPP, see Chronic plaque psoriasis C-reactive protein (CRP), 71 Crisaborole, 198 CSSD, see Chronic superficial scaly dermatitis CT327, 199 CTLA-4-Ig, see Cytotoxic T-Lymphocyte Associated Protein 4 Cutaneous candidiasis, 75 Cutaneous lymphocyte antigen (CLA)+, 31 Cutaneous T-cell lymphoma, 108 CVD, see Cardiovascular diseases Cyclic adenosine monophosphate (cAMP), 243 Cyclosporine, 2, 153, 207, 212, 256–257 adverse events and management, 223–224 dosing, 222 interactions with other medication, 224–225 pediatric population, 226 pharmacokinetics, 224 and phototherapy, 229 Cytokines, genetic studies on, 55 Cytotoxic T-Lymphocyte Associated Protein 4 (CTLA-4-Ig), 31

265

266 Index D Dactylitis, 148 Dapsone, 61 Darier’s disease, 123 Deficiency of interleukin-1 receptor antagonist (DIRA), 151 Deficiency of interleukin-36 receptor antagonist (DITRA), 151 Demyelinating neurologic diseases, 236 Dendritic cells, interplaying with T cells, 32–33 Depression, 168 Dermal myeloid dendritic cells, 32 Dermatology Life Quality Index (DLQI), 187–188 Diabetes, 162 Dimethyl fumarate (DMF), 242 DIP, see Distal interphalangeal joint DIRA, see Deficiency of interleukin-1 receptor antagonist Discoid eczema, 92–93 Distal interphalangeal joint (DIP), 134, 135, 146 Dithranol, 152, 196–197 DITRA, see Deficiency of interleukin-36 receptor antagonist DLQI, see Dermatology Life Quality Index DMF, see Dimethyl fumarate Double-blind crossover study, 40 DPS-101, 199 Drug eruption, 108, 110 Dysglycemia, 159 Dyshidrotic eczema, 58 Dyslipidemia, 159 E E804, 198 Eating disorders, 169–170 Efalizumab, 3, 76 8-methoxypsoralen (8-MOP), 209–211 ELISA, see Enzyme-linked immunosorbent assay Enthesis, 137 Enthesitis, 147 Enzyme-linked immunosorbent assay (ELISA), 258 Epidemiology, of psoriasis difference between genders, 8 effects of ethnicity, 6–8 incidence, 5 prevalence, 5–6 Epidermal barrier, in psoriasis, 22–25 Epidermal differentiation complex (EDC), genes of, 22–23 eQTL, see Expression quantitative trait loci Erythrasma, 112–113 Erythrodermic eczema, 107 Erythrodermic psoriasis, 12–13, 51–52, 105, 150 allergic contact dermatitis, 106 atopic dermatitis, 106–107 chronic actinic dermatitis, 107 cutaneous T-cell lymphoma, 108 pityriasis rubra pilaris, 105–106

Erythroplasia of Queyrat, 125 Etanercept, 233, 235 Etretinate, 76 EULAR, see European League Against Rheumatism European League Against Rheumatism (EULAR), 161 European Medical Agency (EMA), 246 Exacerbation of psoriasis, 39 Excimer laser therapy, 208, 209 Expression quantitative trait loci (eQTL), 21 External ear psoriasis contact dermatitis, 127 seborrheic dermatitis, 126 Extramammary Paget’s disease, 101, 126 F Facial psoriasis, 149 contact dermatitis, 128 lupus erythematosus, 127–128 seborrheic dermatitis, 127 Flexural candida, 113 Flexural psoriasis, 111 candidosis, 112 erythrasma, 112–113 Hailey–Hailey disease, 113–114 intertrigo, 111–112 tinea cruris, 113 fluorouracil, 60 Folic acid antagonists, 2 Folinic acid, 222 Follicular psoriasis, 13 “Fowler’s solution,” 2 Framingham Risk Score, 161 Fumaderm®, 241 Fumaderm initial®, 241 Fumaric acid esters (FAEs), 153 clinical efficacy in psoriasis, 241–242 dosing in psoriasis, 242 mode of action, 241 monitoring, 243 side effects, safety, and monitoring, 242–243 G Gastrointestinal comorbidity, 173 Gender, of psoriasis, 8 Generalized pustular psoriasis (GPP), 71–73 Genetics Caspase recruitment domain family member 14, 23–25 epidermal differentiation complex, 22–23 generalized pustular psoriasis, 25 genome-wide association studies signals, 20–22 mode of inheritance, 17 pathways to psoriasis, 22 psoriasis susceptibility locus 1, 17–20 rare variants leading to psoriasis, 26 Genital psoriasis, 75, 124, 150 extramammary Paget’s disease, 126 lichen planus, 124–125 plasma cell balanitis, 125 Genome-wide association studies (GWAS), 8, 17, 20–22, 173 Goa powder, 2 “Good cholesterol,” 159

GP, see Guttate psoriasis GPP, see Generalized pustular psoriasis Guselkumab, 249–250 Guttate psoriasis (GP), 12, 39, 50–51, 101–102, 149 mycosis fungoides, 105 pityriasis lichenodes, 103–105 pityriasis versicolor, 102–103 secondary syphilis, 103 H Hailey–Hailey disease, 113–114 Hand surface area (HSA), 182 HDL, see High-density lipoprotein Health-related QoL (HRQoL), 186–187 Hepatitis B virus (HBV), 234 Hepatitis C virus (HCV), 234–235 Hepatotoxicity, for methotrexate, 220 High-density lipoprotein (HDL), 159 Histoplasma capsulatum, 235 History, of psoriasis Biblical times, 1 biological agents, 2–3 evolution of modern therapies, 2 renaissance period, 1–2 HLA-Cw6, see Human leukocyte antigen Home ultraviolet B, 206 HPV, see Human papillomavirus HRQoL, see Health-related QoL Human leukocyte antigen (HLA)-Cw6, 8, 17–20, 26, 258 Human papillomavirus (HPV), 16 Human translational studies, 160 Hydroxychloroquine, 39 Hyperinsulinemic–euglycemic clamp, 159 Hyperpigmentation, 50 I IBD, see Inflammatory bowel disease ILD, see Interstitial lung disease IL23R, see Interleukin 23 receptor IL-1RacP, 72 IL36RN mutations, 25 Immune circuit, 35 Immune pathway models, of psoriasis, 34–35 Immunologic dysregulation, markers of, 162 Immunology dendritic cells interplaying with T cells, 32–33 immune pathway models of psoriasis, 34–35 innate immune cells in psoriasis, 33 psoriatic cytokines, 33–34 T cells in psoriasis, 31–32 Immunopathology, inverse psoriasis, 76 INC8018424, 198 Indomethacin, 40 Inducible nitric oxide synthase (iNOS), 257 Infectious pneumonia, psoriasis, 175 Inflammatory bowel disease (IBD), 173 Inflammatory cytokines, 136 Infliximab, 73, 76, 233, 236

Innate immune cells, in psoriasis, 33 iNOS, see Inducible nitric oxide synthase Interferon-γ, 34 Interferon gamma release assay (IGRA), 234 Interleukin-2 (IL-2), 257 Interleukin-17 (IL-17), 33, 136 Interleukin-23 (IL-23), 3, 33, 136 Interleukin 23 receptor (IL23R), 21 International Psoriasis Council (IPC), 144 Interstitial lung disease (ILD), 175 Intertriginous psoriasis, see Inverse psoriasis Intestinal permeability, 174 Intestinal structure, 174 Inverse psoriasis, 13, 48 clinical presentation, 75 differential diagnoses, 75–76 treatment of, 76 Irritant contact dermatitis, 113 Irritant hand dermatitis, 122 Ixekizumab, 236, 251 J JAK proteins, see Janus kinase proteins JAK–STAT signaling, 245 Janus kinase (JAK) proteins, 22 baricitinib, 246 JAK–STAT signaling, 245 tofacitinib, 245–246 Joint complaints, 151–152 Juvenile plantar dermatosis, 124 K Keratinocytes, 33, 34 KMPI, see Koo–Menter psoriasis instrument Köebner phenomenon (KP), 26, 41, 45 Koo–Menter psoriasis instrument (KMPI), 189 KP, see Köebner phenomenon L Langerhans cells, 32–33 Latent tuberculosis (LTB), 234 Lattice system physician’s global assessment (LS-PGA), 184 LDL, see Low-density lipoprotein “Leprosa Graecorum,” 1 Lesional palmoplantar pustular psoriasis skin, 56 LFTs, see Liver function tests Lichen planus, 95–97, 124–125 Lichen sclerosus, 125 Lipopolysaccharide (LPS), 160 Listeria monocytogenes, 235 Lithium, 39 Liver, 174 Liver function tests (LFTs), 235 Local calcipotriol, 61 Localised plaque psoriasis actinic keratosis, 99 allergic contact dermatitis, 99–101 Bowen’s disease, 98 extramammary Paget’s disease, 101 guttate psoriasis, 101–102 mycosis fungoides, 105 pityriasis lichenodes, 103–105 pityriasis rosea, 102 pityriasis versicolor, 102–103

Index 267 secondary syphilis, 103 superficial basal cell carcinoma, 97–98 Localized pustular psoriasis, 55–59 Low-density lipoprotein (LDL), 159 LPS, see Lipopolysaccharide LS-PGA, see Lattice system physician’s global assessment Lung comorbidity, psoriasis and, 174 Lupus erythematosus, 127–128 LY3114062, 251 M Macrophages, 33 Major adverse cardiovascular events (MACE), 236 Malessezia, 102, 116 Measurement, of psoriasis assessment tools, 185–186 body surface area, 182 Comprehensive Assessment of the Psoriasis Patient, 189 dermatology life quality index, 187–188 importance of thorough assessment, 181–182 Koo–Menter psoriasis instrument, 188–189 patient-report measurement tools, 186–187 physician’s global assessment, 184 psoriasis area and severity index, 182–184 psoriasis disability index, 187 Salford Psoriasis Index, 188 screening tools, 184–185 Methotrexate (MTX), 153, 256 adverse events and management, 219–220 combination therapies, 228, 229 combined with ultraviolet B, 207 contraindications for, 220–221 dosing, 219 efficacy rates, 241–242 interactions with other medication, 221 pediatric population, 222 MF, see Mycosis fungoides Microscopic colitis, 174 M protein-positive b-hemolytic streptococci, 51 MSB0010841, 251 MTX, see Methotrexate Multisystemic inflammatory disease, 71 Munro’s microabscesses, 33 Mycobacterium tuberculosis, 234 Mycosis fungoides (MF), 93–94, 105 Myelotoxicity, 220 N NAFLD, see Nonalcoholic fatty liver disease Nail assessment in psoriasis and psoriatic arthritis (NAPPA), 184 Nail bed psoriasis, 81, 83 Nail lichen planus, 118–120 Nail manifestations, 150 Nail matrix psoriasis, 80–82 Nail psoriasis, 13, 14, 117

alopecia areata, 120 assessment of, severity, 84 clinical features of, 79–83 epidemiology and prevalence of, 79 lichen planus, 118–120 management of, 84–85 onychomycosis, 117–118 Nail psoriasis severity index (NAPSI), 84, 184 NAPPA, see Nail assessment in psoriasis and psoriatic arthritis NAPSI, see Nail psoriasis severity index Narrowband ultraviolet B (NB-UVB), 60, 198, 208, 256 psoralen with ultraviolet A compared with, 210 for special population, 206 treatments for psoriasis, 203, 205 National Institutes of Health (NIH), 21 Natural killer (NK) cells, 33 Natural killer T (NKT) cells, 33 NB-UVB, see Narrowband ultraviolet B Nerve growth factor (NGF), 199 Neutrophils, 33 NFAT, see Nuclear factor of activated T cells NF-κB transcription factor, see Nuclear factorkappaB transcription factor NIH, see National Institutes of Health NK cells, see Natural killer cells NKT cells, see Natural killer T cells NMSCs, see Nonmelanoma skin cancers Nonalcoholic fatty liver disease (NAFLD), 174 Noncoding sequences, 21 Nonmelanoma skin cancers (NMSCs), 233, 235 Nonplaque psoriasis subtypes, 184 Nonsteroidal anti-inflammatory drugs (NSAIDs), 40, 221 Novel therapies, for psoriasis, 198–199 Nuclear factor-kappaB (NF-κB) transcription factor, 21, 23 Nuclear factor of activated T cells (NFAT), 222, 257 Nummular eczema, see Discoid eczema O Obesity, 151, 159, 162 Obsessive-compulsive disorder, 169 Occipital scalp psoriasis, 115 Onychomycosis, 110, 117–119 Oral small molecules apremilast, 243–245 fumaric acid esters, 241–243 Janus kinase inhibitors, 245–247 Osteoarthitis affecting distal interphalangeal joint, 146 Otitis externa, 116, 127

P Palmar hand dermatitis, 122 Palmar lichen planus, 123 Palmoplantar eczema, 107, 122 Palmoplantar plaque psoriasis, 61–64 Palmoplantar psoriasis, 120–121 Bazex syndrome, 122–123 contact dermatitis, 122 lichen planus, 123 pityriasis rubra pilaris, 121 porokeratosis of Mibelli, 124 tinea pedis, 121–122 Palmoplantar pustular psoriasis (PPP), 24, 40, 55–56, 58, 184 Palmoplantar pustular psoriasis area and severity index (PPPASI), 184 Palmoplantar pustulosis, 15 Palmoplantar quality-oflife instrument (PPPQoLI), 184 Paradoxical development, of guttate psoriasis, 51 PASE, see Psoriatic arthritis screening and evaluation tool PASI, see Psoriasis area and severity index PASI 75, see Psoriasis area and severity index 75 Pauciarthritis, 145 pDCs, see Plasmacytoid dendritic cells PDE4, see Phosphodiesterase 4 PDI, see Psoriasis disability index Pediatric psoriasis clinical presentation, 149–151 comorbidities, 151–152 epidemiology, 149 therapeutic options for, 152–154 Pediatric psoriatic arthritis, 152 Penile psoriasis, 124 Peripheral regression, with hyperpigmentation, 50 Personality disorders, 169 PEST, see Psoriasis epidemiology screening tool Phagocytic cells, 33 Phosphodiesterase 4 (PDE4), 243–244 Photochemotherapy, 2, 203 psoralen and ultraviolet A, 209–212 Phototherapy, 2, 76, 203 pediatric psoriasis, 152–153 targeted, 208–209 in treatment of psoriasis, 256 ultraviolet B, 204–207 Physician’s global assessment (PGA), 184 PIINP, see Procollagen-3Nterminal peptide Pimecrolimus, 76 Pipeline, biologic therapies in biosimilar drugs, 251–252 bispecific drugs targeting TNF-α/IL-17A, 251 drugs targeting IL-17, 250–251 drugs targeting TNF-α, 250 Pityriasis lichenoides, 103–105 Pityriasis rosea, 102 Pityriasis rubra pilaris (PRP), 105–106, 121 Pityriasis versicolor, 102–103 Plaque psoriasis, 149, 219 Plaque-type psoriasis, 45

Plasma cell balanitis, 125 Plasma cell vulvitis, 125 Plasmacytoid dendritic cells (pDCs ), 32 PLSI, see Psoriasis life stress inventory PML, see Progressive multifocal leukoencephalopathy Pneumocystis jirovecii, 235 Polyarthritis, 145–146, 152 Polygenic disease, 17 Pompholyx, 58 Porokeratosis of Mibelli, 124 Poteinase-3, 56 PPP, see Palmoplantar pustular psoriasis PPPASI, see Palmoplantar pustular psoriasis area and severity index PPPP, see Palmoplantar pustular psoriasis PPPQoLI, see Palmoplantar quality-of-life instrument Predisposing polymorphism, 21 Prevalence, of psoriasis, 5–7 Procollagen-3N-terminal peptide (PIIINP), 220 Progressive multifocal leukoencephalopathy (PML), 3, 242 Prophylactic antiviral therapy, 234 Protein coding alterations, associated with psoriasis, 21–22 PRP, see Pityriasis rubra pilaris PsA, see Psoriatic arthritis Psoralen-ultraviolet light A (PUVA), 2, 59, 203–204 combination therapy, 212 combination ultraviolet B with, 207 photochemotherapy, 209–212 “Psora leprosa,” 1 Psoriasiform acanthosis, 11, 13, 15 Psoriasis area and severity index 75 (PASI 75), 233, 244, 256 Psoriasis area and severity index (PASI), 182–184, 233–234, 241–242 Psoriasis assessment severity score (PASS), 184 Psoriasis disability index (PDI), 187 Psoriasis epidemiology screening tool (PEST), 185 Psoriasis index of quality of life (PSORIQoL), 187 Psoriasis life stress inventory (PLSI), 187 Psoriasis log-based area and severity index (PLASI), 184 Psoriasis susceptibility locus 1 (PSORS1), 17, 20 Psoriasis vulgaris, 45 Psoriatic alopecia, 14 Psoriatic arthritis (PsA), 20, 57, 184–186, 242, 257, 263 cellular involvement, 135 clinical concepts of, 143–144 clinical features, 148 environmental factors, 134 epidemiology, 133 genetic susceptibility, 133–134

268 Index immunohistopathology, 136–137 inflammatory cytokines, 136 pathogenesis, 137–138 therapy for, 154 types of arthropathy, see Arthropathy Psoriatic arthritis screening and evaluation tool (PASE), 185 Psoriatic cytokines, 33–34 Psoriatic diaper rash, 149–150 Psoriatic inflammation, 79 Psoriatic lesions, T cells in, 31–32 “Psoriatic march,” 160 Psoriatic plaques, 45–49 Psoriatic synovium, 137 PSORIQoL, see Psoriasis index of quality of life PSORS1, see Psoriasis susceptibility locus 1 Psychiatric comorbidities, 167–170 Psychological distress, 40 Psychosocial stress, 167 Pulmonary fibrosis, 175, 220 Pulmonary hypertension, 175 “Pup-tent sign,” 119 Pustular psoriasis, 14, 25, 108–109 acute generalized exanthematous pustulosis, 109–110 drug eruption, 110 tinea pedis, 110–111 PUVA, see Psoralen-ultraviolet light A Q Quality-of-life (QoL), 79, 181, 183 R RA, see Rheumatoid arthritis Randomized controlled trials (RCTs), 263, 264 RBCs, see Red blood cells RCTs, see Randomized controlled trials Red blood cells (RBCs), 11 Regulatory T cells (Tregs), 32 Retinoid-PUVA (Re-PUVA), 59 Retinoids, 153, 212 “Reverse cholesterol transport,” 159 Rheumatoid arthritis (RA), 161 Risankizumab, 250 Roadmap epigenomics consortium, 21

Rosacea, 128 Rupioid plantar psoriasis, 49 S Salford psoriasis index (SPI), 188 Salicylic acid, 197–198 Scaffold protein, 23 Scalp psoriasis, 48, 114, 149 atopic dermatitis, 116 contact dermatitis, 114–116 seborrheic dermatitis, 116–117 Schizophrenia, 169 SCLE, see Subacute cutaneous lupus erythematosis Sebopsoriasis, 48, 149 Seborrheic dermatitis, 116–117, 124, 126, 127 Seborrheic psoriasis, 48 Secondary infection, of psoriasis lesions, 46 Secondary syphilis, 103 Secukinumab, 233, 235 Sexual dysfunction, 169 Sezary syndrome, see Cutaneous T-cell lymphoma Short-Form 36 (SF-36), 188 Signal transducer and activator of transcription (STAT), 241, 245 Single genetic mutation, 17 Single nucleotide polymorphisms (SNPs), 17, 22, 256 Skindex-29, 188 Skin inflammation, 160 Skin neuroendocrine system, 56 Skin psoriasis, patients with, 134 Small plaque psoriasis, 48 Smoking, 169 SmPC, see Summary of product characteristics SNPs, see Single nucleotide polymorphisms Social phobia, 167–168 Somatization, 169 Somatoform disorders, 169 SPI, see Salford psoriasis index Spondylarthropathy, 144 Staphylococcus aureus, 51, 76, 92, 235 STAT, see Signal transducer and activator of transcription Steroids, 60 Stigmatization of psoriasis, 167 Stoughton–Cornell classification system, 194 Streptococcal throat infection, 39

Stress reduction interventions, 167 Subacute cutaneous lupus erythematosis (SCLE), 94–95 Suicidal ideation, 168 Summary of product characteristics (SmPC), 241–243 Sunlight, 40 Systemic retinoids, 2 Systemic therapy, 153, 189, 243 T Tacalcitol, 195 Tachyphylaxis, 40 Tacrolimus, 60, 76, 152 Tar-based topical therapy, 152 Targeted phototherapy, 208–209 Tars, 2 Tazarotene, 152, 196 T-cell receptor (TCR), 33 T cells dendritic cells interplaying with, 32–33 in psoriasis, 31–32 TCR, see T-cell receptor Tenosynovitis, 148 Terbinafine, 76 Tildrakizumab, 250 Tinea corporis, 90–92 Tinea cruris, 113, 114 Tinea pedis, 110, 121–122 TNF-α inhibitors, see Tumor necrosis factor-α inhibitors TNFAIP3 interacting protein 1 (TNIP1) gene, 21 TNF-alpha antagonist–induced psoriasis, 39 TNF inhibitors (TNFi), 136 TNIP1 gene, see TNFAIP3 interacting protein 1 gene Tofacitinib, 198, 245–247 ToPAS, see Toronto Psoriatic Arthritis Screen Topical PUVA therapy, 210 Topical treatments, for psoriasis anthralin/dithranol, 196–197 coal tar, 197 corticosteroids, 152, 193–195 crisaborole, 198 CT327, 199 salicylic acid, 197–198 tazarotene, 196 vitamin D analogs, 195–196 Toronto Psoriatic Arthritis Screen (ToPAS), 185

TRAF3-interacting protein 2 (TRAF3IP2), 21 TRAF3IP2, see TRAF3interacting protein 2 Translational studies, 162 Tregs, see Regulatory T cells Treponema pallidum, 15, 103 Trichophyton rubrum, 90 Trimethylpsoralen, 209 Tropomyosin-receptor kinase A (TrkA), 199 Tuberculin skin test (TST), 234 Tuberculosis (TB), 234 Tumor necrosis factor-α (TNF-α) inhibitors, 3, 34, 55, 85, 136, 233–236, 255, 257–258 TYK proteins, see Tyrosine kinase proteins Tyrosine kinase (TYK) proteins, 22 U Ultraviolet (UV) A, 203, 204, 211 Ultraviolet (UV) B, 2, 196, 203, 204 combination therapy, 207–208 phototherapy, 204–207 Ustekinumab, 3, 85, 233, 236, 258 V Vascular endothelial growth factor (VEGF), 256 Vascular inflammation, 161 VDR, see Vitamin D receptor VEGF, see Vascular endothelial growth factor Verrucous psoriasis, 15–16 VIN, see Vulvar intraepithelial neoplasia Vitamin D analogs, 76, 195–196, 207 Vitamin D receptor (VDR), 255 Vulvar intraepithelial neoplasia (VIN), 125 Vulvitis circumscripta plasmacellularis, see Plasma cell vulvitis W WBI-1001, 198 Woronoff’s ring, 48 Worsening of psoriasis, 39 Z Zoon’s balanitits, see Plasma cell balanitis