Um1pq.recent.advances.in.Dermatology.volume.1

Recent Advances in DERMATOLOGY

Disclaimer As medicine is an everyday-changing science with newer researches and refined clinical experiences, and, also in view of the possibility of human error, neither the editors nor the authors nor the publisher warrant that the information contained in the book is in every respect accurate or complete, and they disclaim all responsibility for any errors or omissions or for the results obtained from use of the information presented in this work.

Recent Advances in

DERMATOLOGY

Editor-in-Chief Sanjay Ghosh Consultant Dermatologist AMRI-Apollo Hospital Kolkata Associate Editors Dinesh Hawelia Consultant Dermatologist Suraksha Hospital Kolkata Susmit Haldar Consultant Dermatologist Calcutta Skin Institute Kolkata

JAYPEE BROTHERS MEDICAL PUBLISHERS (P) LTD New Delhi

Published by Jitendar P Vij Jaypee Brothers Medical Publishers (P) Ltd EMCA House, 23/23B Ansari Road, Daryaganj New Delhi 110 002, India Phones: 23272143, 23272703, 23282021, 23245672, 23245683 Fax: +91-11-23276490 e-mail: [email protected] Visit our website: http://www.jpbros.20m.com Branches • 202 Batavia Chambers, 8 Kumara Krupa Road Kumara Park East, Bangalore 560 001 Phones: 2285971, 2382956 Tele Fax : 2281761 e-mail: [email protected] • 282 IIIrd Floor, Khaleel Shirazi Estate, Fountain Plaza Pantheon Road, Chennai 600 008 Phone: 28262665 Fax: 28262331 e-mail: [email protected] • 4-2-1067/1-3, 1st Floor, Balaji Building Ramkote Cross Road, Hyderabad 500 095 Phones: 55610020, 24758498 Fax: 24758499 e-mail: [email protected] • 1A Indian Mirror Street, Wellington Square Kolkata 700 013, Phone: 22451926 Fax: 22456075 e-mail: [email protected] • 106 Amit Industrial Estate, 61 Dr SS Rao Road Near MGM Hospital, Parel, Mumbai 400 012 Phones: 24124863, 24104532 Fax: 24160828 e-mail: [email protected] Recent Advances in Dermatology © 2004, Sanjay Ghosh All rights reserved. No part of this publication should be reproduced, stored in a retrieval system, or transmitted in any form or by any means: electronic, mechanical, photocopying, recording, or otherwise, without the prior written permission of the Editor-in-Chief and the publisher. This book has been published in good faith that the material provided by contributors is original. Every effort is made to ensure accuracy of material, but the publisher, printer and Editor-in-Chief will not be held responsible for any inadvertent error(s). In case of any dispute, all legal matters are to be settled under Delhi jurisdiction only. First Edition : 2004 ISBN 81-8061-306-2 Typeset at JPBMP typesetting unit Printed at Gopsons Papers Ltd., A-14, Sector 60, Noida

To all the past dermatologists of India, whose footprints are showing path in our derma-trek

Contributors A.K. Bajaj Formerly Professor and Head Dept. of Dermatology and STD MLN Medical College Allahabad Anil H. Patki Consultant Dermatologist Skin Clinic, Runwal Plaza 41/12, Karve Road Pune A. Vilas Consultant Dermatologist Hyderabad Belinda Vaz Consultant Dermatologist 42A, Luis Apartments College Street, Dadar Mumbai Debabrata Bandyopadhyay Associate Professor and Head Dept. of Dermatology STD and Leprosy RG Kar Medical College Kolkata Deepa Sachdev Lecturer Dept. of Dermatology KEM Hospital and Seth GS Medical College Mumbai Devinder Mohan Thappa Professor and Head Dept. of Dermatology and STD JIPMER Pondicherry

Dinesh Hawelia Consultant Dermatologist Suraksha Hospital Kolkata Jayakar Thomas Senior Consultant Dermatologist Kanchi Kamakoti CHILDS Trust Hospitals Chennai and Apollo Hospitals, Chennai Formerly Professor and Head Dept. of Dermatology Thanjavur Medical College Thanjavur Kaushik Nandy Consultant Plastic, Reconstructive and Esthetic Surgeon AMRI-Apollo Hospital Kolkata K.K. Raja Babu Consultant Dermatologist A-62, Road No.12 Film Nagar, Jubilee Hills Hyderabad M. Ramam Additional Professor Dept. of Dermatology and Venereology All India Institute of Medical Sciences, New Delhi Nilay Kanti Das Postgraduate Trainee (Dermatology), Dept. of Dermatology, IPGME & R, Kolkata

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Recent Advances in Dermatology

Sanjay Ghosh Consultant Dermatologist AMRI-Apollo Hospital 27/2C Bakultala Lane Kasba Kolkata Sujit Ranjan Sengupta Professor Dept. of Dermatology IPGME & R Kolkata

Susmit Haldar Consultant Dermatologist Calcutta Skin Institute 169 VI M CIT Scheme Kolkata Uday Khopkar Professor and Head Dept. of Dermatology KEM Hospital and Seth GS Medical College Mumbai

Foreword The science of dermatology is rapidly advancing and it is essential for every practitioner to keep abreast of the latest advances in the subject. With the advent of Information Technology, medical information is rapidly dissipated with just the click of a button. However, with volumes of information that is available, one has to weed out well-researched information and the practicability of this information in everyday practice. It is very difficult for a busy practitioner to scan through and refer to the enormous amount of literature that is available. With this in mind, the editors have computed advances in various aspects of dermatology that have been authored by well-known dermatologists in the field. This update discusses many subjects of current interests. Narrowband UV-B light is a new modality for treating vitiligo. It is gaining popularity as this is safe and does not require any systemic medication. These aspects have made this form of therapy as a treatment of choice for children in vitiligo. Computers and digital photography are absolute “Must know” for all dermatologists. The Internet is a goldmine of information waiting to be tapped, and also a means of sharing information as computers connect you easily and fast to your areas of interest. Digital photography as well facilitates pictorial record of interesting cases and of the effect of therapy. The update also includes subjects of contemporary interest as apoptosis and cell markers in dermatology. Scleroderma and leukocytoclastic vasculitis have always been enigmatic problems that have been aptly updated. Other subjects of interest are emergencies in pediatric dermatology, recently introduced systemic and topical drugs in dermatology as well as drug eruptions to new systemic agents. This book of recent updates in dermatology covers a wide variety of topics and would be of immense interest and utility to the consultant dermatologist in practice as well as students of dermatology. Dr. Rui Fernandez

Preface “Who can utter the last words of one which has no end?” —Rabindranath Tagore I felt somewhat hesitant to accept the proposal given by Jaypee Brothers, the reputed medical publisher of New Delhi to become the Editor-inChief of such a volume under the title ‘Recent Advances in Dermatology’. The underlying reason was nothing but that it seemed to me a very difficult task to get writings from the busy dermatologists, who can perform this only by stealing time from their hectic academic, hospital or practising schedules. However, later, my fear-complex got completely erased when I received prompt response from most of them whom we approached, including some of the senior and eminent dermatologists of the country. I hereby convey my deepest regards to all the authors and co-authors for their sincere co-operation with this project. This book was designed as an academic project with the target readers as both postgraduate students and practising dermatologists; we, therefore, desired that the chapters would encompass glimpses of existing knowledge in the light of recent advances in the field. So, we invited articles from dermatologists staying at different parts of the country, both seniors for their retrospective analysis with vast experience and comparatively younger for their enthusiastic and prospective views on the subjects. I sincerely apologize to those numerous academic dermatologists of the country who could be the eligible contributory authors of this collection but have not been included due to the dearth of space. However, we firmly believe that we would be able to include them in rotation in the subsequent editions of this title. I also acknowledge my heartfelt respect to Dr. R. Fernandez and Dr. B. Haldar as they kindly agreed to write the ‘Foreword’ and ‘Introduction’ respectively for this volume. I must thank and pay regards especially to Mr Tarun Duneja, General Manager (Publishing), Jaypee Brothers for his constant help and cooperation in this project. At the same time, I give my personal thanks and regards to all the staff of Jaypee Brothers, both New Delhi and Kolkata Branch. My offer of earnest regards should not have an end without giving this to Mr. Subhrajyoti Bose, who on behalf of me, has taken the burden of painstaking job of DTP and all other computer works of this issue. Last but not the least, no language can express my gratefulness to my associate editors who have walked beside me constantly from the beginning to the end of the present journey. Sanjay Ghosh

Contents 1. Apoptosis : Its Role in Different Dermatoses Anil H. Patki

1

2. Cell Markers in Dermatology Uday Khopkar, Deepa Sachdev

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3. Cutaneous Tuberculosis: Recent Perspective M. Ramam 4. The Spectrum of Leukocytoclastic Vasculitis: Etiology, Classification and Approach to Management Debabrata Bandyopadhyay 5. Emergencies in Pediatric Dermatology Jayakar Thomas 6. Cutaneous Adverse Drug Reactions to Systemic Drugs: Recent Update Sujit Ranjan Sengupta, Nilay Kanti Das

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31 56

88

7. The Scleroderma Disorders: An Update Sanjay Ghosh

115

8. Patch Testing: An Overview A.K. Bajaj

136

9. Laboratory Diagnosis and Treatment of Common Sexually Transmitted Diseases: An Update Devinder Mohan Thappa 10. Narrowband UV-B Phototherapy: A Newer Advance in the Treatment of Vitiligo K.K. Raja Babu, A. Vilas

147

171

11. Newer Drugs in Dermatology: Systemic Dinesh Hawelia

180

12. Newer Drugs in Dermatology: Topical Susmit Haldar

204

13. Wound Dressings: Newer Concepts Kaushik Nandy

234

14. Computer and Digital Photography: Newer Tools in Dermatological Practice Belinda Vaz Index

242 255

B Haldar

Introduction Clinical Dermatology: Its Past, Present and Future Diagnosis and treatment for the community are the two watch-words of every branch of medicine, be it dermatology or any other speciality. Admittedly, there has been a phenomenal development in medicine over the past two decades or so. ‘Even though we can now comprehend many skin disorders at a molecular level and have advanced our therapeutic realm to include laser technology and immunobiology, the cornerstone of all dermatological endeavours will always be a careful clinical observation.’1 While for professional safeguard ‘evidence-based medicine’ has been a crying need of the day, the importance of clinical dermatology can neither be underestimated nor ignored. If we look at the history of growth and development of medicine in totality, along with the benefits the community had obtained thereby, the role played by clinical medicine had been of vital importance. It would indeed constitute a great danger to the wider community if ‘evidence-based diagnosis’ outweighs the ‘clinical’ one where the diagnosis is written large on the face. One should not forget that the base of diagnosis is essentially clinical and that it is the clinical findings that dictate the necessary tests to confirm or reject the diagnosis. There is also another aspect that cannot be dispensed with outright. Community is a complex structure, the complexity varying from country to country—over-rich, rich and utterly poverty-stricken; over-developed, developed and under-developed. High-skilled investigative facilities are neither uniformly available everywhere nor every community can afford to bear the cost thereof. These are naked truths that can hardly be brushed aside. Cost-benefit analysis is, therefore, equally pertinent. Some instances may enlighten the matter. For treating scabies, the demonstration of Sarcoptes scabiei or eggs from the burrows is seldom, if at all, done in India in spite of the fact that it is considered as a

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pathognomonic sign. Similarly, in pure neuritic leprosy, the finding of AFB in nerve biopsy is not routinely made. It is also difficult to locate the offending drug in dermatitis medicamentosa, and challenging the patient with suspected offending drug runs the risk of flaring up the eruption severely. In chronic urticaria, often the causative agent cannot be pinpointed and is termed ‘idiopathic’. In clinically obvious tinea cruris or corporis, rarely the causative fungus is identified. In various eczemas, the treatment is, more often than not, based on clinical judgement. In treating a vitiligo patient, empirical treatment is still followed. In trichotillomania and neurotic excoriation, an in-depth psychological analysis is mostly not done. The above narration of the Indian scene and, for the matter, a common scene of all developing countries only shows that what ‘Haves’ can afford, the ‘Have-nots’ unfortunately cannot. Let the ‘Haves’ have both the examinations—clinical and high-tech one, and the rest be satisfied with the clinical one unless highly imperative. And here lies the importance of clinical medicine and clinical dermatology. One is happy to note that the American Journal of Clinical Dermatology claims to ‘promote rational therapy and effective patient management within the disciplines of dermatology and appearance medicine’.2 Happily, all recently published books, including textbooks, provide a good number of excellent coloured clinical photographs to emphasize on the clinical aspects of the described diseases. This, in fact, goes a long way to bedside clinical teaching in internal medicine, the importance of which can hardly be overlooked. The colour and smell of sputum, stool and urine give us a lot of prima facie information and provide important clues towards diagnosis. There are records that in ancient India, a careful examination of pulse could give enough information regarding the condition of the patient so as to provide even the prognosis. Clinical judgement gives the solid data-base which one can ill-afford to neglect in dermatology, particularly when even histological diagnosis is not always infallible. Histology depicts only a particular stage of evolution of the disease. Every disease has a characteristic pattern of clinical evolution and rarely the same could be followed accurately even by having a series of temporal histological specimens. Even spongiosis, the hallmark sign or eczema, may not be found in the very early stage. But symptoms and signs in dermatology are of great diagnostic value. The pruritus and its intensity can be judged only by applying the mind and not by any instrument. The diagnosis of scabies (the itch) mainly depends on the symptoms and signs which must be allowed to speak for themselves. Just as a skilful statistician finds from the apparent mess

Introduction xvii

of figures facts of significance, a good clinician may also bag useful information for diagnostic purpose by applying his eyes (physical and mental) to see the signs and his ears to hear the symptoms. Another feature of importance in clinical dermatology is the psychological aspect and is particularly felt in case of vitiligo. No amount of evidence that it is just a cosmetic disorder can help remove the patient’s mental depression. What is needed most to do good to the patient is a skilled reassurance by the physician. And here lies the importance of patient-doctor relationship. In conclusion, the scientific value of clinical dermatology in diagnosis of disorders is convincingly clear and it is not possible to dislodge it from its unique position of importance. The edifice of ‘evidence-based dermatology’ can only be built on the sure foundation of clinical dermatology. Its importance is all the more glaringly established in the perspective of developing nations. In the final analysis, however, there is no inherent quarrel between clinical dermatology and evidence-based dermatology. They are not antagonistic but complementary to each other—a relationship of symbiosis. While we shall not be blind to science and its development, we shall not also be blinded by it. A torch-light is focussed only at night in the dark and not in daytime when the sun steadily shines. We must appear logically sensible. No microscope, simple or compound, polarising or electron, is of any avail without our physical eyes. Let not our ‘clinical eyes’ be allowed to get lost. REFERENCES 1. Heymann RW. Foreword, Goodhearts Photoguide of common skin disorders, 2nd ed, Lippincott Williams and Wilkins, Philadelphia, 2003; XIII. 2. Cochrane D. Aim and Scope, Am J Clin Dermatol 2001; 2: 389-406.

Recent Advances in DERMATOLOGY

JAYPEE BROTHERS MEDICAL PUBLISHERS (P) LTD EMCA House, 23/23B Ansari Road, Daryaganj New Delhi 110 002, India

Apoptosis: Its Role in Different Dermatoses 1

1

Anil H. Patki

Apoptosis: Its Role in Different Dermatoses INTRODUCTION There are two ways in which an eukaryotic cell can die: necrosis and programmed cell death. Apoptosis represents an important type of programmed cell death.1 Since necrosis occurs as a result of some external insult and apoptosis occurs due to an innate cellular programme, they may as well be described as ‘cell murder’ and ‘cell suicide’ respectively. The term ‘apoptosis’, which is pronounced with a short ‘a’ and a silent second ‘p’, is a Greek word literally meaning falling of leaves from a tree or of petals from a flower (Apo = away, ptosis = to droop). It was first used by Kerr et al2 in 1972 to describe the mechanism of controlled cell deletion little described till that time. The process of apoptosis is important in both physiological and pathological contexts. During the embryonic life, various organs and limbs are carved by controlled death of certain cells. In adult life, apoptosis is necessary to maintain the homeostasis by a balance with mitosis. The size of organs like liver remains the same as the number of cells produced by mitosis are balanced by the number of cells eliminated by apoptosis.3 Also, autoimmune responses are normally prevented by apoptotic death of auto-reactive lymphocyte clones. Thus, apoptosis is important in eliminating the unnecessary or senescent cells without causing any damage to the surrounding normal cells. Necrosis, by contrast, attracts inflammatory cells which lead to tissue damage. Apoptosis, if gone awry, can lead to certain disorders. If auto-reactive immune cells or cancer cells are not eliminated, an autoimmune or malignant disorder may be the result. Also, excessive and uncontrolled apoptosis may lead to disorders like Parkinsonism, Alzheimer’s disease and amyotrophic lateral sclerosis.4,5 It has also been found that certain viral infections like that due to the human immunodeficiency virus [HIV] induce apoptosis in CD4 lymphocytes.6 Thus, apoptosis is an important phenomenon in both health and disease. This essay will discuss the mechanisms of apoptosis and the importance of apoptosis in different dermatoses.

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MORPHOLOGY OF APOPTOSIS As opposed to necrosis, where the cell swells up and lyses, apoptosis involves reduction in volume, blebbing of the cell membrane and the margination of chromatin along the nuclear membrane.2 This is followed by the collapse of the nucleus into apoptotic bodies surrounded by a membrane. The cytoplasmic organelles are much less affected during this process. An important difference between necrosis and apoptosis is that apoptotic cells do not invoke any inflammatory reaction unlike the necrotic cells which release chemotactic cell contents. The apoptotic bodies consist of membrane bound fragments of nucleus and cell organelles. They are phagocytosed by surrounding cells or macrophages. In case of tubular organs, the apoptotic bodies are released in the lumina. Thus, apoptosis is a special type of programmed cell death which can occur in health or disease. The death of keratinocytes in the stratum corneum is also an example of programmed cell death which is slightly different from apoptosis and is termed ‘differentiation to death’.1 PATHOMECHANISMS OF APOPTOSIS To die actively, a cell must receive some ‘message’ to initiate the process. This message or death signal is received by some transmembrane proteins of the TNF (Tumor necrosis factor) family of the receptors called the death receptors. Each death receptor has two or four cysteine-rich extracellular domains and a cytoplasmic sequence termed ‘death domain’. Six human death receptors have been identified along with their respective ligands which bring the death signal (Table 1.1).7 When a death ligand combines with a death receptor, a signal is transmitted in the cytoplasm to a system of enzymes called caspases. Initially, caspase 8 and 10, which are initiator caspases, are activated and later, akin to the complement cascade, the effector caspases viz., caspases 3,6, and 7 are activated. The caspases in turn activate a variety of endonucleases and proteases which cause breakdown of cellular contents and ultimately apoptosis. Besides the death receptor pathway, there is another pathway inducing apoptosis can be: mitochondrial pathway.8 Triggered by factors like radiation, withdrawal of growth factors and cytotoxic drugs, release of cytochrome C from the mitochondria activates caspase 9 with further activation of downstream caspases and finally leads to apoptosis. Thus, apoptosis is a process by which a cell dies through activating its own system of serine proteases and endonucleases which breakdown cellular contents. The nuclear DNA is broken down into various fragments. This phenomenon is useful in the detection of apoptosis, as agarose gel electrophoresis reveals a ‘ladder’ pattern as different DNA fragments move at different rates.

Apoptosis: Its Role in Different Dermatoses 3 Table 1.1: Death receptors and ligands7 Death receptors

Death ligands

1. Fas (CD 95, Apo 1)

Fas-L (CD 95L) (Fas ligand) TNF Apo 3 L, TWEAK (TNF-like weak inducer of apoptosis) TRAIL

2. TNF-R1 (Tumor necrosis factor receptor 1) 3. TRAMP (Apo 3) (TNF related apoptosis mediating protein) 4. TRAIL-R1 (TNF–related apoptosis inducing ligand receptor 1) 5. TRAIL-R2 6. DR 6

TRAIL ?

GENES AND APOPTOSIS Several genes are important in either promoting or inhibiting apoptosis. Amongst them, the p53 gene and those of Bcl-2 (B cell lymphoma) family are important. The p53 gene is a tumor suppressor gene whose product, the p53 phosphoprotein, has a molecular weight of 53000 and is important in protection against malignancy.9 It acts in two ways. Whenever there is a mild damage to the cellular DNA, the p53 protein arrests the cell in G1 phase, allowing the cell to repair the damage before it proceeds to the S phase. If the damage to the DNA is irrepairable, the p53 protein eliminates that cell by inducing apoptosis. Thus it is a guardian of the genome. Absence or abnormalities of the p53 gene are found in almost 50 percent malignancies found in man. p53 mutations are associated with aggressive malignancies and poor prognosis. The Bcl family of genes consists of about 20 members, some of which are pro-apoptotic and the rest anti-apoptotic. The products of these genes can form either homodimers or heterodimers in the cytoplasm and can exert their control on apoptosis at the level of release of cytochrome C from the mitochondria.10 APOPTOSIS AND SKIN DISORDERS Excessive or defective apoptosis of epidermal cells or those of the immune system is an important feature of many dermatological conditions. The dyskeratotic and eosinophilic keratinocytes, seen in the epidermis after exposure to ultraviolet radiation (UVB and UVC), are apoptotic cells.11 These, so called ‘sunburn cells’, appear in the epidermis within 30 minutes of the exposure and reach their maximum number in 24 hours. These cells then move upwards within the epidermis to be shed off. Another

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common physiological example of apoptosis in the skin is that of the regression of the portion of hair follicle during catagen.12 Besides these common examples, apoptosis is an important feature of many hypersensitivity reactions, autoimmune disorders, malignancies and graft-versus-host disease. Toxic Epidermal Necrolysis Toxic epidermal necrolysis (TEN) is a severe drug reaction resulting in extensive epidermal damage and separation of sheets of epidermis from the underlying dermis. The common drugs causing TEN are antibiotics and antibacterials, non-steroidal anti-inflammatory drugs and anticonvulsants. Some cases of TEN also show lesions suggestive of erythema multiforme and this group of patients is considered to have an overlap of TEN and Stevens-Johnson syndrome (SJS). The keratinocyte death in TEN and TEN-SJS overlap conditions was shown to be due to apoptosis by Paul et al in 1996.13 They demonstrated the apoptosis of keratinocytes by electron microscopy which revealed the typical changes of apoptosis; by DNA-nick end labeling which stained apoptotic cells and by agarose gel electrophoresis of DNA extracted from the epidermis which revealed the ladder pattern due to DNA fragmentation. TEN is a life-threatening condition with a high mortality rate and requires intensive care. Paul et al conjectured that agents inhibiting apoptosis may play an important part in management of TEN.13 Subsequently, an important advance in the therapy of TEN was reported by Viard et al in 1998.14 It was known that keratinocytes normally express Fas (CD 95) receptor on their surfaces. Viard et al showed that in TEN, keratinocytes also express Fas ligand which is lytically active and induces apoptosis in Jurkat cells (a T-lymphocyte line) in vitro. Intravenous immunoglobulin (IVIG), prepared from multiple donors, contains naturally occurring anti-Fas antibodies. If keratinocytes are treated with IVIG (leading to blockade of Fas receptors), futher exposure to Fas ligand does not lead to apoptosis. Armed with this knowledge, Viard et al treated 10 patients of TEN with high doses of IVIG (0.2 to 0.75 gm/kg per day) for 4 successive days. The disease process halted in 1-2 days and epidermal regeneration was complete in 7-12 days with a favourable outcome in all patients.14 In a subsequent study, Stella et al treated 9 patients of TEN with high doses of IVIG (0.6 to 0.7gm/ kg per day) for 4 days out of which 8 healed and survived.15 However, whether systemic problems in TEN (hepatitis, pancreatitis, hematological abnormalities, lung involvement) also involve apoptosis is not known. Treatment of TEN with IVIG denotes a very good example of


development of a treatment modality on the basis of understanding the pathomechanisms of apoptosis. Lichen Planus and Lichenoid Tissue Reaction (LTR) The lichenoid tissue reaction (LTR) is characterized by damage to basal cells in the epidermis associated with a massive infiltrate of mononuclear cells in the upper dermis.16 Many clinically diverse skin disorders ranging from lichen planus to lupus erythematosus have in common lichenoid histopathological features. The epidermal cell death, usually found in the LTR, results from apoptosis. The mode of cell death mediated by cytotoxic T cells and natural killer cells represents apoptosis. Cytotoxic T cells mediate apoptosis by atleast 2 ways: i) by perforin and serine proteases (Granzyme A and B), ii) by interaction of Fas receptors on the target cells and Fas ligand on the cytotoxic cells.17 The formation of colloid bodies, also referred to as hyaline, cytoid or Civatte bodies in the lower epidermis and upper dermis is a characteristic histological feature of LTR and is commonly seen in lichen planus. The colloid bodies are nothing but apoptotic cells. Bloor et al have shown that in oral lichen planus, approximately one apoptotic cell is detected per mm of basal layer and the number of apoptotic cells is proportional to the density of the lymphocytic infiltrate.18 Bcl-2 expression (which is anti-apoptotic) is weak or absent in the lesions and Bax expression is localized to the upper prickle cell layer. Neppelberg et al19 using a different method have found a higher number of apoptotic cells than Bloor et al.18 The apoptotic cells in oral lichen planus are mostly confined to the basal layer. Fas and Fas-L are expressed by the basal keratinocytes as well as by majority of the mononuclear cells in the subepithelial infiltrate.19 In cutaneous lichen planus lesions, granzyme pathway seems to be at work. Shimuzu et al have shown that granzyme-B-positive CD8 cells induce keratinocyte apoptosis in cutaneous lichen planus.20 Perforin and granzymes are the main constituents of the granules of cytotoxic T cells and natural killer cells. Perforin is a pore forming protein which drills a hole in the cell membrane of the target cell through which granzyme B is injected in the cytoplasm of the target cell. Granzyme, a serine protease, activates or subsitutes for interleukin1-alpha-converting enzyme (ICE) and promotes apoptosis. Shimuzu et al have shown by immunoelectron microscopy that granzyme B molecules are secreted from a lymphocyte to an apoptotic keratinocyte. They also found the infiltrate to consist of CD4, CD8 cells as well as a few natural killer cells.20 Apoptosis is thus an important feature of lichen planus and lichenoid tissue reaction.

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Graft-Versus-Host Disease (GVHD) GVHD occurs as a result of bone marrow transplantation and an attack by the donor’s immunocompetent lymphocytes on the host tissue. The skin, the intestines and the liver are the tissues mostly involved. In the acute phase of GVHD and lichenoid type of chronic GVHD, apoptotic cells are observed in the epidermis.21 These dyskeratotic cells with eosinophilic cytoplasm and small pyknotic nuclei were termed ‘mummified’ cells by earlier workers.22 Various studies have shown that lymphocyte Fas-L, induced during acute GVHD, is involved in inducing Fas mediated apoptosis in the target organs viz., skin, liver and gut. Malignancies Malignant cells expressing Fas are normally eliminated through apoptosis by cytotoxic T cells expressing Fas-L. However, absence of Fas receptors on the malignant cells allows them to escape Fas-Fas-L mediated apoptosis. This phenomenon is found in basal cell carcinoma and melanoma.23,24 Thus, defective apoptosis is a feature of these malignant conditions. Reinduction of Fas expression on tumor cells of basal cell carcinoma by intralesional injection of interferon-alpha causes regression of tumour by apoptosis.23 Primary cutaneous T cell lymphoma (CTCL) represents a group of T cell neoplasm of skin-homing, CD 4-positive T cells. All the successful therapies in the treatment of CTCL like radiotherapy, electron beam therapy, topical chemotherapy, psoralen and UVA therapy (PUVA) and topical steroids, work by inducing apoptosis of neoplastic T cells.25 Loss of Fas expression on neoplastic cells is found in aggressive types of CTCL but not in indolent types.26 Thus, loss of Fas expression allows tumor cells to escape an effective immune response and may contribute to unfavourable prognosis in some types of CTCL. Autoimmune Disorders During the development of T cells, the autoreactive T cells are eliminated in the thymus by a process involving apoptosis. Any defect in this process results in persistence of autoreactive immune competent cells which may be an etiological factor in autoimmune disorders of the skin.27 Phototherapy: Underlying Mechanism The narrowband UVB phototherapy of psoriasis has been shown to be causing apoptosis of T cells in the lesions of psoriasis.28 Even UVA phototherapy is known to induce apoptosis of T helper lymphocytes.29


CONCLUSIONS In conclusion, apoptosis is an important phenomenon both in health and disease. Excessive and abnormal apoptosis is a feature of disorders like TEN and LTR while defective apoptosis is a feature of conditions like malignancies and autoimmune disorders. Since its description more than 30 years ago, apoptosis has, during the last few years, become one of the hottest topics in biomedical research. REFERENCES 1. Bowen ID, Bowen SM, Jones AH. Matters of life and death. In: Mitosis and Apoptosis. London: Chapman and Hall, 1998; 1-16. 2. Kerr JFR, Wyllie AH, Currie AR. Apoptosis: a basic biological phenomenon with wide ranging implications in tissue kinetics. Br J Cancer 1972; 26: 23957. 3. Bowen ID, Bowen SM, Jones AH. The structural and physiological basis of apoptosis and mitosis. In: Mitosis and Apoptosis. London: Chapman and Hall, 1998; 17-27. 4. Gibson RM. Does apoptosis have a role in neurodegeneration? Br Med J 2001; 322: 1539-40. 5. Barinaga M. Is apoptosis key in Alzheimer’s disease ? Science 1998; 281: 130912. 6. Patki AH, Lederman MM. HIV-I Tat protein and its inhibitor Ro 24-7429 inhibit lymphocyte proliferation and induce apoptosis in peripheral blood mononuclear cells from healthy donors. Cell Immunol 1996; 169: 40-6. 7. Wehrli P, Viard I, Bullani R, et al. Death receptors in cutaneous biology and disease. J Invest Dermatol 2000; 115: 141-8. 8. Green DR, Reed JC. Mitochondria and apoptosis. Science 1998; 281: 1309-12. 9. Ko LJ, Prives C. P 53: Puzzle and paradigm. Genes Dev 1996; 10: 1054-1572. 10. Wang HG, Reed JC. Mechanism of Bcl-2 protein function. Histol Histopathol 1998; 13: 521-30. 11. Wolff K, Kiffi AG, Mihm MC. Basic pathological reactions of the skin. In: Fitzpatrick TB, Eisen AZ, Wolff K, et al (Eds) Dermatology in General Medicine. 4th ed. New York: Mc Graw Hill Inc., 1993: 66-84. 12. Bertolino AP, Klein LM, Freedberg IM: Biology of hair follicles. In: Fitzpatrick TB, Eisen AZ, Wolff K, et al (Eds) Dermatology in General Medicine. 4th ed. New York: Mc Graw Hill Inc., 1993: 289-93. 13. Paul C, Wolkenstein P, Adle H, et al. Apoptosis as a mechanism of keratinocyte death in toxic epidermal necrolysis. Br J Dermatol 1996; 134: 710-14. 14. Viard I, Wehrli P, Bullani R, et al. Inhibition of toxic epidermal necrolysis by blockade of CD 95 with human intravenous immunoglobulin. Science 1998; 282: 490-3. 15. Stella M, Cassano P, Bollero D, et al. Toxic epidermal necrolysis treated with intravenous high-dose immunoglobulin: Our experience. Dermatol 2001; 203: 45-9. 16. Shiohara T, Moriya N, Nagashima M. The lichenoid tissue reaction. Int J Dermatol 1998; 27: 365-74.

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Recent Advances in Dermatology 17. Kagi D, Vignaux F, Lederman B, et al. Fas and perforin pathways as major mechanisms of T-cell-mediated cytotoxicity. Science 1994; 265: 528-30. 18. Bloor BK, Malik FK, Odell EW, et al. Quantitative assessment of apoptosis in oral lichen planus. Oral Surg Oral Med Oral Pathol 1999; 88: 187-95. 19. Neppelberg E, Johannessen AC, Jonssan R. Apoptosis in oral lichen planus. Eur J Oral Science 2001; 109: 361-4. 20. Shimuzu M, Higaki Y, Higaki M, et al. The role of granzyme-B expressing CD8 positive cells in apoptosis of keratinocytes in lichen planus. Arch Dermatol Res 1997; 289: 527-32. 21. Gilliam AC, Whitaker Menezes D, Kamgold R, et al. Apoptosis is the predominant form of epithelial target cell injury in acute experimental graftversus-host disease. J Invest Dermatol 1996; 107: 377-83. 22. Slavin RE, Santos GW. The graft-versus-host reaction in man after bone marrow transplantation: pathology, pathogenesis, clinical features and implications. Clin Immunol Immunopathol 1973; 1: 472-98. 23. Buechner SA, Wernii M, Harr T, et al. Regression of basal cell carcinoma by intralesional interferon-alpha treatment is mediated by CD 95 (Apo-1/Fas) CD95 ligand-induced suicide. J Clin Invest 1997; 100: 2691-2726. 24. Hahne M, Rimoldi D, Schroter M, et al. Melanoma cell expression of Fas (Apo1/CD 95) ligand: implications for tumor immune escape. Science 1996; 274: 1363-6. 25. Kacinski BM, Flick M. Apoptosis and cutaneous T cell lymphoma. Ann NY Acad Sci 2001; 941: 194-9. 26. Zio-Toli O, Vermeer MH, D-Vries E, et al. Expression of Fas and Fas ligand in primary cutaneous T-cell lymphoma (CTCL): association between lack of Fas expression and aggressive types of CTCL. Br J Dermatol 2000; 143: 3139. 27. Cohen JJ. Programmed cell death in the immune system. In: Dixon FJ (Ed). Recent Advances in Immunology. Vol 50. San Diego: Academic Press Inc. 1991: 55–85. 28. Kruegaer JG, Wolfe JT, Nabeya RJ, et al. Successful ultraviolet B treatment of psoriasis is accompanied by a reversal of keratinocyte pathology and by selective depletion of intraepidermal T cells. J Exp Med 1995; 182: 2057-68. 29. Morita A, Werfel T, Stege H, et al. Evidence that singlet oxygen-induced human T helper cell apoptosis is the basic mechanism of ultraviolet-A radiation phototherapy. J Exp Med 1997; 186: 1763-8.

Cell Markers in Dermatology

2

9

Uday Khopkar, Deepa Sachdev

Cell Markers in Dermatology INTRODUCTION An average dermatologist rarely deals with a report of cell marker studies in his or her clinical practice. However, access to knowledge about them is handy at times to understand one’s patient’s condition as well as to explain him or her prognosis and the course of action to be followed. For the pathologists and dermatopathologists, the subject is of interest for pinpointing the differentiation of various neoplasms and at times, to reach a specific diagnosis. WHAT ARE CELL MARKERS? These are functional molecules reflecting the state of cellular differentiation, expressed on the outer cell surface membrane. Monoclonal and polyclonal antibodies directed to the surface molecules on B cells, T cells, macrophages and natural killer cells are now available. When a cluster of monoclonal antibodies is found to be reactive to the same surface molecule, it clearly represents a series of reagents defining a given marker (cell surface molecule). The cell marker is then assigned a CD number, 1 i.e. cluster designation (also known as cluster differentiation) number meaning that a known cluster of antibodies bind to this known antigen/molecule. HOW ARE CELL MARKER STUDIES DONE? Immunophenotyping is a technique of identifying surface molecules that are associated with the tumor cells and that help to characterize them. The molecules are then identified by using specific antibodies that bind to them. Use of monoclonal antibodies is preferred to polyclonal antibodies as the former are more sensitive and do not have risk of cross-reacting antibodies. The only disadvantage of monoclonal antibodies is that the majority of them require frozen sections. PROCEDURE The serum (containing antibodies) is poured over the tumor cells, which may be present in the tissue section. If the tumor cells bear the surface

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markers for which the antibodies are specific, the antibodies will bind to the cells. These antibodies bound to the cells are then detected by one of the following ways: Immunofluorescence The tissue section when examined under a fluorescent microscope reveals the cell-bound antibodies as glowing areas. Flow Cytometry In a flow cytometer, the cells in suspended liquid are exposed to a beam of laser light. If the specific antibodies are bound to their surface, they will fluoresce and the cytometer will record the signal. Immunohistochemistry It is a procedure that enables the identification of cells in a tissue section by means of antibodies that have attached enzymes. Immunoperoxidase techniques are widely used, e.g. peroxidase enzyme in peroxidase antiperoxidase, i.e. PAP technique. On exposure of tissue to chromogenic substrate, the enzyme on the bound antibody will cause the substrate to change color and precipitate on the cells. WHAT ARE THE COMMON MARKERS USED IN DERMATOLOGY? The cell markers are needed in dermatopathology mainly to pinpoint the diagnosis in an undifferentiated or poorly differentiated neoplasm, to confirm the diagnosis of an amelanotic melanoma, and for classifying lymphoproliferative disorders. Some of the commonly used cell markers in dermatology are listed in Table 2.1. Antibodies against Cytoskeletal Antigens The cell cytoskeleton consists of microfilaments, intermediate filaments and microtubules. Antibodies directed against cytofilaments help to identify the differentiation of neoplastic cells. It has been found that primary and secondary malignant tumors retain the intermediate filament-type characteristic of the cell towards which they differentiate.2 There are five types of intermediate filaments: i. Cytokeratins—characteristic for true epithelia ii. Vimentin—found in mesenchymal cells and melanocytes iii. Desmin—found in muscle cells


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Table 2.1: Commonly used cell markers Antigen/Cell marker

Normal tissue

Tumors

Cytokeratins*

Epidermis and its appendages Mesenchymal cells, melanocytes, lymphocytes Smooth and skeletal muscle Neurons, endocrine system

Epidermal and appendageal tumors Sarcomas, lymphomas and melanomas Muscle tumors Neuroectodermal and neuroendocrine tumors Rhabdomyosarcomas, leiomyosarcomas Rhabdomyomas, rhabdomyosarcomas Epithelial tumors, some mesenchymal tumors Melanomas, liposarcomas, histiocytosis X Melanomas, junctional nevi, dysplastic nevi Paget cells, tumors of eccrine and apocrine glands Hematopoietic tumors

Vimentin* Desmin* NSE Actin* Myoglobin

Smooth and skeletal muscle, myofibroblasts Striated muscle

EMA

Fetal skin, adult sweat glands

S-100 protein*

Melanocytes, Langerhans cells, eccrine and apocrine glands

HMB-45

Fetal and neonatal melanocytes

CEA

Eccrine and apocrine glands

LCA*

Histiocytes, lymphocytes, granulocytes Histiocytes

α1-antitrypsin, α1-antichymotrypsin Factor VIII-related antigen (FVIII-RA)*

Endothelium

Ulex europaeus Endothelial cells, keratinocytes Agglutinin-1 (UEA-1)

Fibrohistiocytic neoplasms Endothelial-derived tumors, e.g. angiosarcomas Angiosarcomas, Kaposi’s sarcoma

*Standard panel of antibodies

iv. Neurofilaments—found in neuronal cells v. Glial filaments—found in astrocytes Cytokeratins/Prekeratins These are a family of heterogenous proteins with molecular weight varying from 40,000 to 68,000.3 Keratin is present in all epithelial cells. The high molecular weight keratins are present in the more differentiated cells of the epidermis, while the low molecular weight keratins are

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found in simple epithelia and non-keratinising squamous epithelia.4 Thus antikeratin antibodies help to differentiate epithelial tumors from non-epithelial (melanocytic, mesenchymal and hematopoietic) tumors. A mixture of low and intermediate keratins such as AE1 and AE3 is commonly used.5 CK20 is a keratin marker specific for Merkel cell carcinoma. However, it has been observed that certain non-epithelial tumors like leiomyosarcomas, rhabdomyosarcomas and plasmacytomas can react with cytokeratin antibodies. Vimentin It is an intermediate filament expressed by a number of different cell types such as lymphocytes, melanocytes, macrophages, endothelial cells, fibroblasts and smooth muscle cells. Because of its nonspecific nature, it is useful only as a panel approach to support mesenchymal or melanocytic differentiation. Thus, it is a valuable tool in differentiating sarcomas from carcinomas, and malignant melanomas from carcinomas. When used in combination with cytokeratin markers in spindle cell tumors, it helps to make a definite histopathological diagnosis.6 Moreover, it has been found to be the only intermediate filament present in certain soft tissue tumors, e.g. malignant fibrous histiocytomas. Desmin It is an intermediate filament expressed by smooth, skeletal and cardiac muscle cells. Its main diagnostic application is in the differential diagnosis of soft tissue tumors as its presence establishes the myogenic nature of any neoplasm.7 Thus, it is positive in leiomyomas, rhabdomyomas, leiomyoblastomas, leiomyosarcomas and rhabdomyosarcomas. Neurofilaments Neuron-specific enolase (NSE) is an enzyme found in neurons, neuroendocrine cells, and tumors derived from them. However, it has low specificity, as it is detectable in a variety of tumors like Merkel cell carcinoma and malignant melanoma. Actin It is a contractile protein present in smooth and striated muscle, myoepithelial cells of salivary gland, breast and the sweat gland. Tumor cells of a number of muscular and nonmuscular neoplasms also stain positive for actin.


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Epithelial Membrane Antigen (EMA) It is a glycoprotein isolated from human milk fat globule membrane. EMA is detectable in the majority of carcinomas, mesotheliomas, and synovial and epitheloid sarcomas.8 However, basal cell carcinomas do not express EMA.9 Thus EMA is neither sensitive nor specific as an epithelial cell marker as is keratin. Carcinoembryonic Antigen (CEA) Ordinarily present in gastrointestinal malignancies, it has been found in normal eccrine and apocrine units as well as benign and malignant sweat gland tumors, and in mammary and extra-mammary Paget’s disease of the skin.10 It may help in distinguishing Paget’s disease from pagetoid melanoma. Miscellaneous Involucrin It is present in the maturing stratified squamous epithelia. It has been detected in the majority of reactive hyperplasias and condylomata of the cervix, whereas cervical dysplasias do not express this protein. Chromogranin and Synaptophysin These are neuroendocrine antigens found in normal endocrine glands and neuroendocrine tumors such as Merkel cell carcinoma.11 Antibodies against Lysozyme, α-1-antitrypsin and α-I-antichymotrypsin These are regarded as markers of ‘mononuclear’ phagocytic cells. They help in the diagnosis of fibrohistiocytic neoplasms but are not specific markers as they have also been detected in carcinomas and melanomas. WHAT ARE THE SITUATIONS WHERE CELL MARKER STUDY IS REQUESTED? 1. 2. 3. 4. 5.

Diagnosis of a poorly differentiated neoplasm Classifying spindle cell neoplasms Suspected malignant melanoma that lacks pigment Diagnosis of histiocytic disorders Classifying vascular neoplasms

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Recent Advances in Dermatology Table 2.2: Panel for basophilic small cell tumors5

Diagnosis Lymphoma Merkel cell carcinoma Melanoma Carcinoma

Keratin

LCA

S100

Synaptophysin

– + – +

+ – – –

– – + +/–

– + – –

This table is adapted from Lever’s Histopathology of Skin

6. Diagnosing and classifying lymphoma 7. Diagnosing and classifying leukemias 8. As a research tool Diagnosis of a Poorly Differentiated Neoplasm In the diagnosis of a poorly differentiated neoplasm (including metastases), a standard panel of antibodies is done. This usually includes the antibodies marked with an asterisk in Table 2.1. They help in deciding whether the neoplasm is epithelial, mesothelial, melanocytic or lymphoreticular. Additional antibodies may be included in the panel depending on clinical and histopathological inputs. Immunohistochemistry plays a vital role in the diagnosis of poorly differentiated basophilic small cell neoplasms in the skin. The panel used and its interpretation is mentioned in Table 2.2. Classifying Spindle Cell Neoplasms Cell marker studies are crucial in the diagnosis of poorly differentiated spindle cell neoplasms in the skin. The panel used and its interpretation is mentioned in Table 2.3. Table 2.3: Panel for malignant spindle cell tumors5 Diagnosis Squamous cell carcinoma Melanoma Angiosarcoma Leiomyosarcoma

Keratin

Vimentin

Desmin

S-100

+ – – –

– + – +

– – – +

– + – –

This table is modified from Lever’s Histopathology of Skin

HMB-45 Factor VIIIrelated antigen – + – –

– + –


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Suspected Malignant Melanoma that Lacks Pigment S 100 Protein S 100 protein is an acidic protein present in a large variety of cells such as the melanocytes, Langerhans cells, histiocytes, eccrine and apocrine gland cells, Schwann cells, myoepithelial cells, nerves, muscles, chondrocytes and their malignant counterparts.12-14 It has a high sensitivity but low specificity that restricts its utility to the following indications: 1. Diagnosis of “spindle cell” and “desmoplastic” melanoma 2. Diagnosis of poorly differentiated cutaneous metastases. HMB-45 HMB-45 is an antigen expressed only by melanocytes. However, its sensitivity is only about 70 percent. It mainly helps to differentiate melanoma from carcinoma.15 However, it cannot differentiate between a benign nevus and a malignant melanoma. Recently, a new panel consisting of Melan-A, Tyrosinase, and MiTF (microphthalmia gene) has been recommended for melanocytic neoplasms. Studies have shown that monoclonal antibody to MiTF is a sensitive and specific marker for epitheloid melanomas.16-17 Rarely carcinomas are S-100 positive and sometimes melanomas, unlike carcinomas, express an intermediate filament vimentin. Diagnosis of Histiocytic Disorders It is important to distinguish Langerhans cell histiocytosis from other histiocytoses by presence of Birbeck granules and S-100 and CD 1a positivity. Table 2.418 summarizes the characteristics of all histiocytoses. Table 2.4: Cell markers in histiocytic disorders18 Disease

S-100

CD-1a

KP 1

MAC 387

LCH CSHRH ICH XD JXG VX

+ + + – – –

+ + + – – –

– – – + + +

— — — — — +

* Abbreviations- LCH: Langerhans cell histiocytosis; CSHRH: Congenital selfhealing reticulohistiocytosis; ICH: Indeterminate cell histiocytosis; XD: Xanthoma disseminatum; JXG: Juvenile xanthogranuloma; VX: Verruciform xanthoma This modified table is adapted from Lever’s Histopathology of Skin

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Langerhans cells stain positive also with CD45, S100 and are negative for HMB-45. Classification of Vascular Neoplasms Classifying vascular tumors is of prognostic significance, as several low grade variants of angiosarcoma have a distinctly different prognosis as compared to classical angiosarcoma. The various markers used for vascular tumors include Factor VIII related antigen (FVIII-RA), Ulex europaeus agglutinin-1 (UEA-1), CD31 and CD34. Individual vascular proliferations have specific pattern of positivity. i. Granuloma pyogenicum shows positive staining of the endothelial cells for FVIII-RA, UEA-1 and Vimentin. ii. Reactive angioendotheliomatosis differs from malignant angioendotheliomatosis by its universal reactivity for endothelial markers and negativity for LCA, proving that the proliferating cells are endothelial cells. iii. Kaposi’s sarcoma has spindle cells that are of endothelial origin labeling positive with newer endothelial cell markers CD31 and CD34.19,20 iv. Angiosarcomas are usually negative for FVIII-RA. UEA-1 is often positive but has a very low specificity. The newer markers CD31 and CD34 are more sensitive and specific for endothelial cells. v. Tumors of lymphatic vessels (lymphangiomas) are for the most part negative for FVIII-RA. This is in contrast to UEA-1, which is positive in endothelial cells of both hemangiomas and lymphangiomas. vi. Glomus tumor cells stain positive for smooth muscle actin, musclespecific actin, and myosin. Staining for desmin is only focally positive. Diagnosing and Classifying Lymphomas Leucocyte Common Antigen (LCA, CD45) LCA, also known as CD45, is expressed on all leucocytes, lymphocytes, monocytes, macrophages, mast cells, and Langerhans cells. Lymphocytes and neoplastic cells derived from lymphocytes stain with greatest intensity. Reactivity of macrophages, granulocytes, and plasma cells is variable. It helps to differentiate lymphoreticular malignancies from undifferentiated carcinomas, melanomas and sarcomas.21


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T Cell Lymphomas Although T and B lymphocytes are indistinguishable by light microscopy, T cells can be detected by a series of monoclonal antibodies against various T cell antigens. The diagnosis of T-cell lymphoma is based on: • Histological features, e.g. epidermotropism. • Pan T cell markers: CD2, CD3, CD5 and CD7 are present on almost all the T cells. • Gene rearrangement studies: Use of PCR to look for a unique, clonal rearrangement of T cell receptor gene. In most of the peripheral T cell lymphomas, it has been observed that one or more T cell antigens may be aberrantly clonally deleted. CD7 is often found to be negative. Also some lymphomas can express unnatural combination of antigens, such as co-expression of CD4 and CD8, or expression of neither. T Cell Pseudolymphoma/Lymphocytoma Cutis This presents clinically as nodules or plaques and histologically as band like or nodular infiltrates. The cells show convoluted nuclei with immunophenotypic pattern similar to mycosis fungoides, i.e. CD3, CD4 and CD45RO positivity.22 Pagetoid Reticulosis It is an indolent form of T cell lymphoma. The localized variant (known as Woringer-Kolopp disease) is clinically characterized by verrucous scaly plaques on the acral region. The disseminated form (also known as Ketron-Goodman variant) clinically resembles with the patch or plaque stage of mycosis fungoides.23 CD4 positivity is common, while CD7 is mostly absent or diminished. Besides, there is a lack of expression of CD45 and CD45RO. Granulomatous Slack Skin This rare form of T cell lymphoma, in the early stages, resembles clinically and histologically with the patch stage of mycosis fungoides. However, with evolution, the affected skin becomes lax, clinically presenting as patches resembling anetoderma or plaques with loose hanging skin involving the axillae or groins. Histopathology shows a granuloma with numerous giant cells in the dermis. The neoplastic cells are positive for CD3 and CD4 markers, while they are negative for CD7.24

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Lymphomatoid Papulosis This is clinically characterized by papules that evolve into papulovesicular, papulopustular, hemorrhagic or necrotic papules. It is associated with lymphoma in about 10-20 percent cases. The associated lymphoma is most commonly mycosis fungoides (40%), a CD30-positive T-cell lymphoma (30%) or Hodgkin’s disease (25%). Lymphomatoid papulosis shows two types of histopathology and the atypical lymphocytes stain for the activation marker ki-1 or CD30.25 Anaplastic Large Cell Lymphoma (ALCL) These were once called Ki-1 lymphomas after antibody to CD30. CD30 antigen is a lymphocyte activation marker that can be identified on either B or T cells. CD30 positivity is seen in LyP, regressing atypical histiocytosis and ALCL. ALCL clinically presents as cutaneous nodules, ulcerated or crusted tumors on the extremities. Primary cutaneous ALCLs are positive for CD30 antigen and other T cell markers. Systemic ALCLs are often reactive for EMA. Some ALCLs are non-reactive for LCA or Tlineage markers. Cases that lack lymphoid lineage markers are called “null-cell” type. CD30 positive ALCL is reported to be the most common cutaneous lymphoma in HIV patients.26-27 Rarely, ALCLs may be positive for keratin, which can lead to misdiagnosis of carcinoma. Angiocentric Lymphomas These commonly present as subcutaneous or dermal nodules or ulcerated tumors. The tumor cells can be of T cell or NK-cell lineage. Those of T cell lineage often show aberrant T cell phenotypes with loss of CD3, CD5 and CD7 antigens. Those of NK-cell lineage express CD16 and CD56 antigen. Mycosis Fungoides Cell markers are important to diagnose mycosis fungoides in the patch stage. Immunophenotyping is invaluable in these cases to prove or support the diagnosis. The cells are positive for CD2, CD3, CD4 and sometimes CD8.23 When CD4 and CD8 are simultaneously expressed by the T cells, it indicates a neoplastic infiltrate. Recently gene rearrangement studies28,29 have shown that all mycosis fungoides lesions including early macules are produced by single clones of neoplastic T cells. The immunophenotypic profile of T cell and NK-cell neoplasms is summarized in Table 2.5.30


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Table 2.5: Cell markers in T cell and NK-cell neoplasms30 Lymphoma type

Positive markers on neoplastic cells

Expected negative T markers helping the diagnosis

T-PLL (Peripheral T cell lymphoepitheloid lymphoma)

CD2, CD3, CD4, CD5, CD7

T-large granular lymphocytic leukemia(T-LGL)

1-Tcell: CD3, CD57(+/-) 2-NK cell: CD56(+/-), CD57(+/-)

1- CD56 2- CD3

Adult T cell leukemia/ lymphoma (HTLV-1+)


CD7

Mycosis fungoides


CD7, CD8 (+/-)

Anaplastic large cell lymphoma

1-CD3, CD30, 2-CD3 EMA (T cell) 2-CD30, EMA (Null cell)

This modified table is adapted from http:/ www.thd.org.tr/sub/eng/lymphoid.php

B Cell Lymphomas The diagnosis of a lymphoid tumor of B cells is made on the basis of: 1. Presence of surface immunoglobulin specific for B cells. The demonstration of J-chain establishes the B cell nature of any given cell population, whether benign or malignant. 2. CD19, which is both sensitive and specific for B cells 3. Rearranged immunoglobulin genes Most B cell lymphomas express the pan-B cell antigens: CD19, CD20 and CD22. However, as the B cells mature into plasma cells, they tend to lose their markers. Hence, multiple myeloma cells are negative for these antigens. Hodgkin’s Lymphoma (HL) Skin involvement by Hodgkin’s lymphoma clinically presents as papules, plaques or nodules and signifies a poor prognosis.31 Reed-Sternberg cells are mostly CD30-positive. CD15 is also positive in Hodgkin’s disease except in nodular lymphocyte-predominant variety.32 Gene rearrangement studies are helpful to differentiate HL from CD30+ cutaneous lymphoproliferative disorders though these conditions can coexist.33 Non-Hodgkin’s Lymphoma (NHL) Differentiating reactive lymphoreticular hyperplasia from malignant lymphoma is a common diagnostic dilemma for pathologists. In such

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Recent Advances in Dermatology Table 2.6: Differential diagnosis of HL and some of the NHL subtypes30

Lymphoma type

Immunophenotypic profile of malignant cells

Lymphocytic predominance HL

Positive: CD45, CD20, CD79a Negative: CD30(+/-), CD15

Classical HL

Positive: CD30, CD15, CD20(+/-)

1. Nodular sclerosis 2. Mixed cellularity 3. Lymphocyte depleted

Can be positive: EMA Negative: CD45, CD79a

T cell histiocyte rich B cell lymphoma

Positive: CD45, CD20, CD79a Negative: CD15, CD3

Anaplastic large cell lymphoma

Positive: CD30, CD45(+/-), EMA(+/-) Negative: CD20, CD15

This modified table is adapted from http:/ www.thd.org.tr/ sub/ eng/ lymphoid.php

situations, monoclonal staining for light chain or heavy chain immunoglobulin constitutes a firm indication of the neoplastic nature of the lesion, while a polyclonal reaction for two or more classes of immunoglobulins indicates a non-neoplastic process. The most practical approach to the demonstration of monoclonal lymphoid cells is to perform staining for kappa and lambda light chains. In case of well-differentiated lymphomas that are associated with monoclonal gammopathy (Waldenström’s macroglobulinemia), the cytoplasmic immunoglobulin of plasmacytoid lymphocytes can be readily demonstrated. The detailed cell marker profile in HL and NHL is discussed in Table 2.6.30 Large cell lymphoma (immunoblastic sarcoma) has been shown to arise from immunoblastic lymphadenopathy and has predominantly biclonal staining for kappa and lambda light chains. Diagnosing and Classifying Leukemias Leukemia Cutis The identification of leukemic infiltrate is based on the histochemical and immunophenotypic studies. No single reagent is sensitive or specific. Therefore, it has been recommended to use a panel of at least 3 antisera. CD45, CD45RO, CD3, CD20, CD43, CD68, lysozyme, chloroacetate esterase are the commonly used markers.34 CD99 is another sensitive but non-specific marker useful in acute myelogenous leukemia.35Positive staining for immunoglobulin establishes the lymphoreticular nature of the neoplasm.


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Table 2.7: Diagnostic dilemmas assisted by immunocytochemistry1 Differential diagnosis

Cell markers used

Carcinoma vs lymphoma

LCA, T and B cell markers, keratin, CEA

Melanoma vs carcinoma

Keratin, CEA(carcinoma), S-100, HMB-45 (melanoma)

Sarcoma vs carcinoma

Keratin, CEA, EMA(carcinoma), vimentin, desmin

Carcinoma vs mesothelioma CEA, CD15 (carcinoma), EMA (mesothelioma) This modified table is adapted from textbook of ‘Diagnostic cytology and its histopathologic bases’

SUMMARY The cytologic diagnosis of malignancy is primarily based on the histologic findings, in conjunction with patient’s history and clinical examination. In situations, where the histopathological features are inconclusive, the use of cell marker studies can help to achieve a definitive diagnosis. However, it is essential to select the ‘appropriate panel’ of antibodies. Selection of an appropriate cell marker as an aid in the diagnosis of a tumor of uncertain histogenesis depends on various factors, such as the patient’s clinical presentation, laboratory and radiographic findings, the histologic features of the tumor, the skill and experience of the examining pathologist, the differential diagnosis entertained and the availability of specific markers. Recently with the availability and application of PCR technique to the analysis of immunoglobulin and T cell receptor gene rearrangements, it is possible to arrive at an accurate diagnosis and also detect minimal residual disease in hematologic malignancies.36 In conclusion, immunocytochemistry is gradually gaining wider recognition for its role in solving certain diagnostic dilemmas (discussed in Table 2.7) as well as to decide prognosis and therapy especially for lymphoreticular malignancies. REFERENCES 1. Margaret B Listrom, Cecilia M Fenoglio-Preiser. Immunocytochemistry in tumor diagnosis. In: Leopold G Koss, (Ed). Diagnostic cytology and its histopathologic bases. 4th ed. Philadelphia: J.B.lippincott company, 1992:1532-71. 2. Osborn M. Component of the cellular cytoskeleton: A new generation of markers of histogenetic origin. J Invest Dermatol 1984; 82: 443. 3. Frank WW, Schiller DL, Moll R, et al. Diversity of cytokeratins. Differentiation specific expression of cytokeratin polypeptides in epithelial cells and tissues. J Mol Biol 1981; 153:933-59. 4. Sun TT, Eichner R, Nelson WG, et al. Keratin classes:Molecular markers for different types of epithelial differentiation. J Invest Dermatol 1983; 81 (suppl): 109-15.

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5. Rosalie E, Patricia Van Belle, David E. Laboratory methods. In: David E, Rosalie E, Christine J, et al. (Eds). Lever’s Histopathology of the Skin. 8th ed. Philadelphia: Lippincott-Raven: 1997: 51-60. 6. Leader M, Collins M, Patel J, et al. Vimentin: An evaluation of its role as a tumor marker. Histopathology 1987; 11: 63-72. 7. Denk H, Krepler R, Artlieb U, et al. Proteins of intermediate filaments. An immunochemical and biochemical approach to the classification of soft tissue tumors. Am J Pathol 1983; 110: 193-208. 8. Heyderman E, Steele K, Ormerod MG. A new antigen on the epithelial membrane: Its localization in normal and neoplastic tissue. J Clin Pathol 1979; 32: 35-9. 9. Pinkus GS, Kurtin PJ. Epithelial membrane antigen—a diagnostic discriminant in surgical pathology: Immunohistochemical profile in epithelial, mesenchymal and hematopoietic neoplasms using paraffin sections and monoclonal antibodies. Hum Pathol 1985; 16:929-40. 10. Nadji M, Morales AR, Girtanner RE, et al. Paget’s disease of skin. A unifying concept of histogenesis. Cancer 1982; 50: 2203-6. 11. Lloyd RV, Cano M, Rosa P, et al. Distribution of chromogranin A and Chromogranin I (chromogranin B) in neuroendocrine cells and tumors. Am J Pathol 1988; 130: 296. 12. Kahn HJ, Baumal R, Marks A. The value of immunohistochemical studies using antibody to S-100 protein in dermatopathology.Int J Dermatol 1984; 23: 38-44. 13. Nakajima T, Watanabe S, Sato Y, et al. An immunoperoxidase study of S-100 protein distribution in normal and neoplastic tissues. Am J Surg Pathol 1982; 6: 715-27. 14. Kahn HJ, Marks A, Thom H, et al. Role of antibody to S 100 protein in diagnostic pathology. Am J Clin Pathol 1983; 79: 341-7. 15. Wick MR, Swanson PE, Rocamora A. Recognition of malignant melanoma by monoclonal antibody HMB-45. An immunohistochemical study of 200 paraffinembedded cutaneous tumors. J Cut Pathol 1988; 15: 201-7. 16. O’Reilly FM, Brat DJ, McAlpine BE, et al. Microphthalmia transcription factor immunohistochemistry: a useful diagnostic marker in the diagnosis and detection of cutaneous melanoma, sentinel lymph node metastases, and extracutaneous melanocytic neoplasms. J Am Acad Dermatol 2001; 9: 29-34. 17. King R, Weilbaecher KN, McGill G, et al. Microphthalmia transcription factor: a sensitive and specific melanocyte marker for melanoma diagnosis. Am J Pathol 1999;155: 731-8. 18. Burgdorf WHC. The Histiocytoses. In: David E, Rosalie E, Christine J, et al. (Eds). Lever’s Histopathology of the Skin. 8th ed. Philadelphia: LippincottRaven: 1997: 591-616. 19. Orchard GE, Wilson Jones E, Russel Jones R. Immunocytochemistry in the diagnosis of Kaposi’s sarcoma and angiosarcoma. Br J Biomed Sci 1995; 52: 35. 20. Nickoloff BJ. The human progenitor cell antigen (CD34) is localized on endothelial cells, dermal dendritic cells, and perifollicular cells in formalinfixed normal skin, and on proliferating endothelial cells and stromal spindleshaped cells in Kaposi’s sarcoma. Arch Dermatol 1991; 127:523. 21. Battifora H, Trowbridge IS. A monoclonal antibody useful for the differential diagnosis between malignant lymphoma and nonhematopoietic neoplasm. Cancer 1983; 51: 816-21.


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22. Rijlaarsdam JU, Scheffer E, Meijer CJ, et al. Cutaneous pseudo-T-cell lymphomas: A clinicopathologic study of 20 patients. Cancer 1992; 69: 717. 23. LeBoit PE, McCalmont TH. Cutaneous lymphomas and leukemias. In: David E, Rosalie E, Christine J, et al. eds. Lever’s Histopathology of the Skin. 8th ed. Philadelphia: Lippincott-Raven: 1997: 805-46. 24. LeBoit PE. Granulomatous slack skin. Dermatol Clin.1994; 12: 375. 25. Karp DL, Horn TD. Lymphomatoid papulosis. J Am Acad Dermatol1994; 30: 379. 26. LeBoit PE. Lymphomatoid papulosis and cutaneous CD30+ lymphoma. Am J Dermatopathol 1996; 18: 221. 27. Kerschmann RL, Berger TG, Weiss LM, et al. Cutaneous presentation of lymphoma in human immunodeficiency virus disease: Predominance of T cell lineage. Arch Dermatol 1995; 131: 1281. 28. Weiss LM, Hu E, Wood GS, et al. Clonal rearrangements of T cell receptor genes in mycosis fungoides and dermatopathic lymphadenopathy. N Engl J Med 1985; 313: 539. 29. Wood GS. Using molecular biologic analysis of T cell receptor gene rearrangements to stage cutaneous T cell lymphoma. Arch Dermatol 1998; 134: 221. 30. Lymphoid markers used for the diagnosis of lymphomas according to the REAL or WHO classification, 13/3/2001, http:/ www.thd.org.tr/ sub/ eng/ lymphoid.php, 27/8/2003. 31. White RM, Patterson JW. Cutaneous involvement in Hodgkin’s disease. Cancer 1985; 55: 1136. 32. Moretti S, Pimpinelli N, Di Lollo S, et al. In situ immunologic characterization of cutaneous involvement in Hodgkin’s disease. Cancer 1989; 63: 661. 33. Willenbrock K, Ichinohasama R, Kadin ME, et al. T cell variant of classical Hodgkin’s lymphoma with nodal and cutaneous manifestations demonstrated by single-cell polymerase chain reaction. Lab Invest 2002; 82: 1103-9. 34. Ratnam KV, Su WPD, Ziesmer SC, et al. Value of immunohistochemistry in the diagnosis of leukemia cutis: Study of 54 cases using paraffin-section markers. J Cutan Pathol 1992; 19: 193-200. 35. Dorfman DM, Kraus M, Perez-Atayde AR, et al. CD99 (p30/32 MIC2) immunoreactivity in the diagnosis of leukemia cutis. Mod Pathol 1997; 10: 2838. 36. van der Velden VH, Hochhaus A, Cazzaniga G, et al. Detection of minimal residual disease in hematologic malignancies by realtime quantitative PCR: principles, approaches, and laboratory aspects. Leukemia 2003; 17: 1013-34.

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3

M. Ramam

Cutaneous Tuberculosis: Recent Perspective METHODOLOGY The definition of “recent” can be flexible; I have chosen a cut-off of 5 years from the time of writing this account. The primary source of information for this chapter was PubMed, the online retrieval system for digital biomedical archives maintained by the National Center for Biotechnology Information at the U.S. National Library of Medicine. A search was conducted with the term “cutaneous tuberculosis” NOT “lupus erythematosus”. All citations from 1998 onwards were screened and the abstracts available perused. When further details were required, the full article was consulted. In addition, we searched IndMed, the online site of the National Informatics Center, New Delhi which contains a database of 75 medical journals including the Indian Journal of Dermatology, Venereology and Leprology (IJDVL) and the Indian Journal of Dermatology. A hand search of all copies of the IJDVL received by the author in the last 5 years was also conducted to look for relevant articles. From among all these sources, information judged to be new and/or relevant was included in this account. EPIDEMIOLOGY AND CLINICAL FEATURES Three hospital-based studies of cutaneous tuberculosis were published. Dr Bhushan Kumar’s group from Chandigarh reported their experience with cutaneous tuberculosis at a teaching hospital between 1975 and 1995.1 Lupus vulgaris was the commonest variant seen. An interesting finding was the association of regional lymphadenopathy at the site of the cutaneous lesion with disseminated disease in other organ systems. The Chandigarh group also reported their experience in 75 children with cutaneous tuberculosis.2 Scrofuloderma was the commonest presentation, followed by lupus vulgaris and tuberculosis verrucosa cutis; tubercular gummata and tuberculids were rare. Regional lymphadenopathy was noted more frequently in patients with disseminated disease. The Mantoux test was positive in 91.8 percent with

Cutaneous Tuberculosis: Recent Perspective

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localized disease and 50 percent with disseminated disease. Skin biopsy showed characteristic tubercular changes in 80 percent of patients with lupus vulgaris and in 47.5 percent of patients with scrofuloderma. The lung, bone and abdomen were the sites of extracutaneous tuberculosis in 21.3 percent of patients. A report from New Delhi described 63 children with cutaneous tuberculosis.3 Culture was positive in only 3 children. Regional lymphadenopathy with lupus vulgaris was commoner than in adults. No difference in the clinical presentation was seen between children who were vaccinated with BCG and those who were not. Some reports of unusual clinical manifestations have appeared. Proptosis was described in a child who had facial lesions of scrofuloderma associated with an intraorbital abscess. Both cutaneous and orbital lesions subsided with antitubercular therapy.4 Oral ulcers are not generally recognized by dermatologists as a manifestation of tuberculosis. A study of 42 cases with orofacial tuberculosis revealed oral ulcers in 70 percent of cases. Other manifestations included bony lesions and involvement of the salivary glands and lymph nodes.5 Inoculation tuberculosis has been described following nose piercing6 and tattooing.7 A report from Turkey states that the ear lobe is a relatively common site of lupus vulgaris occurring in about 12 percent of patients.8 Could this also be related to piercing? Cutaneous tuberculosis has also been described following injury to the skin and corticosteroid injections.9 Tuberculous gumma developed at the site of venepuncture in a man who had had pulmonary tuberculosis in the past. It was postulated that endogenous tuberculosis had localized to the site of a sterile injury.10 A recent report describes a patient who developed lupus vulgaris at the site of previously healed scrofuloderma.11 This is not a particularly novel or rare phenomenon in our experience. The rare presentation of lupus vulgaris in a sporotrichoid pattern was reported.12 Tuberculosis has been reported at the sites of ports used for laparoscopic surgery.13 We have also observed draining sinuses at these sites in a few patients. However, the diagnosis of tuberculosis is difficult to establish and patients usually receive a trial of antitubercular therapy which may not always be successful. The possibility of a foreign body leading to a persistent infection or of another non-tuberculous infection must be kept in mind in such patients. Tuberculosis is not usually considered as a cause of lymphedema. A case with nodules on the leg followed by lymphedema was reported. Biopsy of the nodules revealed granulomas and a Mantoux test was positive. The nodules subsided with antitubercular therapy, though the lymphedema was unchanged.14 As dermatologists, we look for evidence of tuberculosis in other systems in patients who present to us with cutaneous tuberculosis. One study turned that question around and asked what proportion of patients

26


with tuberculosis in other organs have cutaneous tuberculosis? Cutaneous tuberculosis was seen in 7 (2.6%) of patients with tuberculosis in other organs, viz. lymph node and lung.15 Sexual transmission of tuberculosis was described in an Indian man who had penile tuberculosis that was confirmed by culture. A year later, his wife developed endometrial tuberculosis. The organism grown from the woman was identical on molecular typing to that grown from her husband providing strong evidence of sexual transmission in this couple.16 TUBERCULIDS Lichen scrofulosorum was noted to develop in 2 children after initiation of therapy for tuberculosis. The pathogenesis was ascribed to an improvement in cell-mediated immunity similar to type I reaction developing after the initiation of antileprosy treatment. The skin lesions of lichen scrofulosorum subsided on continuation of therapy.17 Papulonecrotic tuberculids and a sterile, symmetric arthritis (Poncet’s arthritis) developed in an HIV-positive patient. Both skin and joint lesions improved after anti-tubercular therapy.18 Arthritis, like tuberculids, is a rare hypersensitivity response to tuberculosis that dermatologists should be aware of. Nodular tuberculid has been suggested as a designation for subcutaneous, non-ulcerated nodules that showed granulomatous inflammation in the deep dermis and adjacent fat. The biopsies also showed vasculitis in 2 out of 4 cases. The Mantoux test was positive in all and there was a good response to antituberculous therapy.19 This entity shows features of erythema induratum though the changes are not confined to the panniculus. A new term for these lesions does not appear to be justified.20 Multiple episodes of Sweet’s syndrome during treatment were reported in 5 out of 18 patients with scrofuloderma due to atypical mycobacteria and M. tuberculosis. This association has recently been highlighted.21 This probably represents a hypersensitivity phenomenon similar to the tuberculids. CUTANEOUS TUBERCULOSIS IN THE IMMUNOSUPPRESSED HOST Cutaneous tuberculosis was described in immunosuppressed hosts. A study from Mumbai reported the histopathological analysis of cutaneous lesions in 195 patients with HIV/AIDS which revealed cutaneous tuberculosis in 13 patients.22 A report from Thailand described 3 patients with HIV/AIDS who had cutaneous tuberculosis.23 One patient presented


27

with a nodule on the forearm while 2 had generalized erythematous papules and vesicopustules. The latter is an unusual presentation and may represent miliary tuberculosis of the skin in these immunosuppressed patients. Four patients with HIV/AIDS and cutaneous miliary tuberculosis were described in another report. All patients also had miliary lesions in other organs. Skin biopsies revealed no or ill-formed granulomas, extensive necrosis and many acid-fast bacilli. Three patients had multidrug resistant organisms and all these patients had a rapid downhill course.24 PATHOGENESIS A woman with tuberculosis of the axillary lymph nodes and erythema induratum was found to have circulating T cells that were stimulated by purified protein derivative (PPD). These T cells produced interferon gamma in response to PPD. It is possible that these cells mediated the development of erythema induratum at skin sites where mycobacterial antigen was present.25 The tissue levels of collagen, elastin, fibronectin, transforming growth factor-beta (TGF-beta) was higher in active lesions compared to healed lesions of cutaneous tuberculosis indicating that effective chemotherapy reduces the fibrosis that accompanies active infection.26 DIAGNOSIS A study from Mumbai reported the growth of mycobacteria in 29 (56.9%) out of 51 cases of cutaneous tuberculosis. Twenty-six of the isolates were M. tuberculosis.27 This is a much higher isolation rate than is usually reported from our country. PCR is yet to find a definite place in the diagnosis of cutaneous tuberculosis. Different studies provide conflicting evidence of its value. In a study that did not include controls and did not specify a gold standard, 18 (56.2%) of 34 cases of granulomatous inflammation were considered to have tuberculosis or atypical mycobacterial infection based on the results of PCR analysis.28 A study of 10 patients with cutaneous tuberculosis and 20 controls from Chandigarh showed a positive PCR result in 6 (60%) of cases and in none of the controls.29 In another study using controls, 1 out of 23 cases of cutaneous tuberculosis and 1 out of 22 healthy controls showed amplification of M. tuberculosis DNA.30 This indicates a poor sensitivity and specificity of the test. In a study from Taiwan, 12 cases were diagnosed to have erythema induratum based on the findings of tender subcutaneous nodules on the legs, granulomatous panniculitis with vasculitis and a therapeutic response to antitubercular

28


therapy. PCR for M. tuberculosis DNA was positive in 9 cases.31 A study from Singapore found that PCR was highly sensitive and specific in immunocompromised patients who had multibacillary disease and showed acid-fast bacilli on biopsy. The sensitivity was considerably less in paucibacillary diseae: lupus vulgaris (55%), tuberculosis verrucosa cutis (60%) and erythema induratum (54%). The authors suggest that the clinical decisions in paucibacillary cutaneous tuberculosis should not be based on PCR results alone.32 The same group had reported their findings earlier using another PCR technique which was less sensitive.33 However, their conclusions about the value of PCR remained unchanged. A similar conclusion was reached by another group who performed PCR in facial lesions.34 Mycobacterial DNA was detected in 16 (80%) out of 20 cases of cutaneous sarcoidosis indicating that mycobacteria may play a role in the development of sarcoidosis.35 It also indicates that PCR for mycobacterial DNA is not a reliable way to differentiate cutaneous tuberculosis from sarcoidosis. TREATMENT Standard treatment regimens consisting of isoniazid 300 mg daily and rifampicin 450 mg daily for 6 months along with pyrazinamide 1500 mg daily and ethambutol 800 mg daily for the first 2 months are used for cutaneous tuberculosis. Some workers use only 3 drugs if there is no evidence of extracutaneous tuberculosis. These schedules are effective. A recent retrospective analysis found that nearly all patients show a clinical response within 4 weeks of starting treatment. By extension, it was suggested that when a therapeutic trial of the diagnosis is undertaken in cutaneous tuberculosis, a period of 6 weeks is enough to decide whether the patient has tuberculosis (or not). Longer durations of therapy do not appear to be justified in those who have not responded within this period.36 The bad news is that two culture-documented cases of drug resistant tuberculosis were reported from Delhi.37,38 One patient had tuberculous gummata while the other had scrofuloderma. The patients were treated with second-line drugs with improvement. This is a serious development that bodes ill for patients. So far, reports of drug resistance in cutaneous tuberculosis were rare. The situation may change for the worse in the future and require the use of expensive, less effective medication to treat these patients.


29

REFERENCES 1. Kumar B, Muralidhar S. Cutaneous tuberculosis: A twenty-year prospective study. Int J Tuberc Lung Dis 1999;3:494-500. 2. Kumar B, Rai R, Kaur I, et al. Childhood cutaneous tuberculosis: A study over 25 years from northern India. Int J Dermatol 2001;40:26-32. 3. Ramesh V, Misra RS, Beena KR, et al. A study of cutaneous tuberculosis in children. Pediatr Dermatol 1999;16:264-9. 4. Sardana K, Koranne RV, Langan U, et al. Ocular scrofuloderma with unilateral proptosis. J Dermatol 2002;29:232-4. 5. Mignogna MD, Muzio LL, Favia G, et al. Oral tuberculosis: A clinical evaluation of 42 cases.Oral Dis 2000;6:25-30. 6. Kaur C, Sarkar R, Kanwar AJ. How safe is nose-piercing? Inoculation cutaneous tuberculosis revisited. Int J Dermatol 2003;42:645-6. 7. Ghorpade A. Lupus vulgaris over a tattoo mark - inoculation tuberculosis. J Eur Acad Dermatol Venereol. 2003;17:569-71. 8. Ozkaya-Bayazit E, Baykal C, Buyukbabani N, et al. Earlobe dermatitis.Arch Dermatol 2002;138: 1607-12. 9. de Jong JW, van Altena R. Non-respiratory tuberculosis with Mycobacterium tuberculosis after penetrating lesions of the skin: five case histories. Int J Tuberc Lung Dis. 2000;4:1184-7. 10. Vidal D, Barnadas M, Perez M, et al. Tuberculous gumma following venepuncture. Br J Dermatol 2001;144:601-3. 11. Motta A, Feliciani C, Toto P, et al. Lupus vulgaris developing at the site of misdiagnosed scrofuloderma.J Eur Acad Dermatol Venereol 2003;17:313-5. 12. Khandpur S, Nanda S, Reddy BS. An unusual episode of lupus vulgaris masquerading as sporotrichosis. Int J Dermatol 2001; 40:336-9. 13. Jagdish N, Sameer R, Omprakash R. Port-site tuberculosis: A rare complication following laparoscopic cholecystectomy. Scand J Infect Dis 2002;34:928-9. 14. Gangopadhyay AK. Tuberculosis lymphedema cutis. Ind J Dermatol 2001; 46: 50-1. 15. Kivanc-Altunay I, Baysal Z, Ekmekci TR, et al. Incidence of cutaneous tuberculosis in patients with organ tuberculosis.Int J Dermatol 2003; 42: 197200. 16. Angus BJ, Yates M, Conlon C, et al. Cutaneous tuberculosis of the penis and sexual transmission of tuberculosis confirmed by molecular typing. Clin Infect Dis 2001;33:E132-134. Epub 2001 Oct 22. 17. Thami GP, Kaur S, Kanwar AJ, et al. Lichen scrofulosorum: A rare manifestation of a common disease. Pediatr Dermatol 2002;19:122-6. 18. Cuende E, Almeida V, Portu J, et al. Poncet’s disease and papulonecrotic tuberculid in a patient infected with the human immunodeficiency virus. Arthritis Rheum 1998; 41: 1884-8. 19. Jordaan HF, Schneider JW, Abdulla EA. Nodular tuberculid: A report of four patients. Pediatr Dermatol 2000; 17:183-8. 20. Kumar B, Parsad D. Is ‘nodular tuberculid’ a distinct entity? Pediatr Dermatol 2001; 18: 164-7. 21. Mahaisavariya P, Chaiprasert A, Manonukul J, et al. Scrofuloderma and Sweet’s syndrome.Int J Dermatol 2002; 41:28-31. 22. Lanjewar DN, Bhosale A, Iyer A. Spectrum of dermatopathologic lesions associated with HIV/AIDS in India. Indian J Pathol Microbiol 2002;45:293-8.

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23. Chiewchanvit S, Mahanupab P, Walker PF. Cutaneous tuberculosis in three HIV-infected patients. J Med Assoc Thai 2000;83:1550-4. 24. Daikos GL, Uttamchandani RB, Tuda C, et al. Disseminated miliary tuberculosis of the skin in patients with AIDS: report of four cases.Clin Infect Dis 1998; 27:205-8. 25. Koga T, Kubota Y, Kiryu H, et al. Erythema induratum in a patient with active tuberculosis of the axillary lymph node: IFN-gamma release of specific T cells. Eur J Dermatol 2001; 11:48-9. 26. Jayasankar K, Shakila H, Umapathy KC, et al. Biochemical and histochemical changes pertaining to active and healed cutaneous tuberculosis. Br J Dermatol 2002;146: 977-82. 27. Gopinathan R, Pandit D, Joshi J, et al. Clinical and morphological variants of cutaneous tuberculosis and its relation to mycobacterium species. Indian Journal of Medical Microbiology 2001; 19: 193-6. 28. Hsiao PF, Tzen CY, Chen HC, et al. Polymerase chain reaction based detection of Mycobacterium tuberculosis in tissues showing granulomatous inflammation without demonstrable acid-fast bacilli. Int J Dermatol 2003;42:281-6. 29. Arora SK, Kumar B, Sehgal S. Development of a polymerase chain reaction dot-blotting system for detecting cutaneous tuberculosis. Br J Dermatol 2000;142:72-6. 30. Senturk N, Sahin S, Kocagoz T. Polymerase chain reaction in cutaneous tuberculosis: Is it a reliable diagnostic method in paraffin-embedded tissues? Int J Dermatol 2002;41:863-6. 31. Chen YH, Yan JJ, Chao SC, et al. Erythema induratum: a clinicopathologic and polymerase chain reaction study. J Formos Med Assoc 2001;100:244-9. 32. Tan SH, Tan HH, Sun YJ, et al. Clinical utility of polymerase chain reaction in the detection of Mycobacterium tuberculosis in different types of cutaneous tuberculosis and tuberculids. Ann Acad Med Singapore 2001; 30: 3-10. 33. Tan SH, Tan BH, Goh CL, et al. Detection of Mycobacterium tuberculosis DNA using polymerase chain reaction in cutaneous tuberculosis and tuberculids. Int J Dermatol 1999;38:122-7. 34. Ferrara G, Cannone M, Scalvenzi M, et al. Facial granulomatous diseases: A study of four cases tested for the presence of Mycobacterium tuberculosis DNA using nested polymerase chain reaction. Am J Dermatopathol 2001; 23:8-15. 35. Li N, Bajoghli A, Kubba A, et al. Identification of mycobacterial DNA in cutaneous lesions of sarcoidosis.J Cutan Pathol 1999;26:271-8. 36. Ramam M, Mittal R, Ramesh V. How soon does cutaneous tuberculosis respond to treatment? Implications for a therapeutic trial of diagnosis. Int J Dermatol In press. 37. Sharma N, Kumar P, Mantoo S, et al. Primary multi-drug resistant tuberculous gumma. J Commun Dis 2001;33:170-3. 38. Ramesh V, Murlidhar S, Kumar J, et al. Isolation of drug-resistant tubercle bacilli in cutaneous tuberculosis. Pediatr Dermatol 2001;18:393-5.

The Spectrum of Leukocytoclastic Vasculitis

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31

Debabrata Bandyopadhyay

The Spectrum of Leukocytoclastic Vasculitis: Etiology, Classification and Approach to Management BACKGROUND Vasculitis is a clinicopathological process characterized by inflammation of and damage to blood vessels.1 Compromise of vascular lumen occurs and the resultant ischaemia causes damage to the organs in which the vasculitic process takes place. Since vessels of any calibre in any organ may be affected, vasculitis can result in a wide variety of clinical entities. The pathogenic mechanisms largely remaining uncertain, vasculitic disorders continue to be defined and categorized according to their clinical and pathological findings. Leukocytoclastic vasculitis (LV) is a category of vasculitis that includes clinicopathological entities characterized by inflammation of small blood vessels (mainly post-capillary venules, also small arterioles and capillaries) with neutrophilic infiltration in and around vessel walls, and fragmentation of nuclei of neutrophils (leukocytoclasis). Fibrinoid changes of vessel walls and extravasation of red blood cells also occur.2 LV is not a disease in itself, but rather a pathologic process associated with diseases of diverse causes.3 LV has many synonyms, and the term has been used interchangeably with nomenclatures such as allergic vasculitis, allergic angiitis, hypersensitivity vasculitis, hypersensitivity angiitis, necrotizing venulitis, and others. Palpable purpura is the hallmark lesion of LV. This term appropriately describes the elevated, firm, hemorrhagic, non-blanchable lesions most commonly seen on the lower limbs, often appearing in crops. Generally asymptomatic, the lesions may be pruritic or tender. Other types of lesions associated with LV include urticarial wheals, papules, plaques, pustules, nodules, blisters, necrotic ulcerations and livedo reticularis.4 General symptoms of fever, malaise, arthralgia and myalgia are often present. LV may be associated with systemic involvements. The common sites of visceral affection include kidney, joints, lung, gastrointestinal tract, and nervous system. Cutaneous LV may result from, or associated

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with a variety of causes like drugs, infections, connective tissue diseases, malignancies, systemic vasculitic syndromes, and other underlying systemic diseases. The pathologic links of these causes with the development of LV remain largely speculative or unknown, but immune mechanisms are believed to play important roles.5 However, no aetiological factors can be demonstrated despite thorough clinical and laboratory investigations in about one-third to half of the patients with LV.6,7 Although LV usually follows a benign course limited to the skin in most of the patients,8 the importance of cutaneous LV lies in the fact that the skin lesions may provide with the dermatologists a window to the early diagnosis of serious life-threatening systemic vasculitic disorders. In this context, the recently described antineutrophil cytoplasmic antibodies may provide important input for the diagnosis and categorizations of systemic small-vessel vasculitides. Management of LV requires a rational diagnostic approach that takes into consideration the possibilities of various etiological factors that may give rise to this disorder. ETIOPATHOGENESIS Leukocytoclastic vasculitis is a heterogenous group of disorders having the unifying features of histological evidence of inflammation and necrosis of small blood vessels and a neutrophilic infiltrate in and around vessel walls. Although the pathomechanisms leading to this vascular damage are not fully elucidated, various immune-mediated tissue reactions are generally implicated.5 There is compelling animal and human experimental evidence that leukocytoclastic vasculitis results from a hypersensitivity reaction similar in nature to the experimental Arthus reaction, the essential elements of which include antigen, complement-fixing antibodies, intact complement pathway and an adequate number of neutrophils.5 The initiating event at the level of the vasculature is deposition of circulating immune complexes, formed in situations of antigen excess. This leads to a sequence of tissue reactions. Complement is activated and activated complement components (C5a and C3a) then attract neutrophils to the site. Phagocytosis of immunecomplexes by infiltrating neutrophils is associated with the release of neutrophil granules containing proteolytic enzymes like collagenase and elastase and production of oxygen free radicals that damage the vessel wall and surrounding tissue. The membrane attack complex of the complement also plays a role in the mechanisms of endothelial cell damage.9 Expression of adhesion molecules, which are present on cell surfaces and mediate cell-cell interaction, are upregulated on activated neutrophils and endothelial cells and play a crucial role in the processes


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of neutrophil margination along vessel wall and their migration outside the vessel lumen into the extravascular space.10 Cytokines such as interleukins (like IL-1, IL-6, IL-8), tumor necrosis factor-alpha (TNFalpha) and granulocyte monocyte colony-stimulating factor (GM-CSF) are synthesized by activated endothelial cells and act as mediators of inflammation in the vasculitic process.5,11 Apart from neutrophils and endothelial cells, other cell types also takes part in the inflammatory reaction. Mast cells, by releasing histamine, chemoattractants and proteolytic enzymes, participate in the inflammatory process and cause tissue damage.12 Formation of platelet aggregates and release of secretory products from platelets also contribute to the inflammatory response and tissue damage in vasculitis.13 A variety of mechanisms involving antibodies like antineutrophil cytoplasmic antibodies (ANCA), anti-endothelial antibodies, and anticardiolipin antibodies are believed to contribute to the pathogenesis of LV.5 ANCAs are antibodies directed against specific cytoplasmic proteins of neutrophils and are present mainly in the sera of patients with systemic vasculitides and certain other systemic disorders like connective tissue disorders, inflammatory bowel diseases and autoimmune liver diseases. In the indirect immunofluorescence test, alcohol-fixed indicator neutrophils are treated with patients’ sera and examined for patterns of immunofluorescence. Two main types of fluorescence patterns are recognized, a diffuse staining pattern of the cytoplasm (cytoplasmic ANCA, cANCA), and a staining around the nucleus (perinuclear ANCA, pANCA). The specific protein recognized by cANCA is nearly always proteinase 3, a serine proteinase present in the primary granules of neutrophils, while the pANCAs are directed mainly against myeloperoxidase as well as other proteins present in the cytoplasm of neutrophils, like elastase, cathepsin and lactoferrin. cANCAs against proteinase 3 are commonly designated as PR3 ANCA while pANCAs against myeloperoxidase are called MPO ANCA. Although their pathogenetic role remains to be fully elucidated, detection of ANCAs has important diagnostic and prognostic roles in systemic small vessel vasculitides like Wegener’s granulomatosis and microscopic polyangiitis.14 What brings about or initiate the above-mentioned tissue reactions may remain undetermined in most patients, but etiological factors (Table 4.1) like infections, drugs, food and food additives,15 connective tissue disorders, malignant disease processes, and a number of various underlying systemic diseases may be responsible in a large proportion of cases. Drug-induced vasculitis is a common cause of LV. In a retrospective study of an unselected population of adults with LV, 23.9 percent of 138

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Recent Advances in Dermatology Table 4.1: Etiological factors in cutaneous LV

1. 2. 3. 4. 5. 6.

Infections Connective tissue diseases Malignancies Drugs Foods and food additives Systemic vasculitic syndromes Henoch-Schönlein purpura, mixed cryoglobulinemia, Wegener’s granulomatosis, Churg-Strauss syndrome, microscopic polyangiitis 7. Other systemic diseases Alpha1-antitrypsin deficiency, Behcet’s disease, congenital deficiency of complement components, chronic active hepatitis, cystic fibrosis, inflammatory bowel disease, intestinal bypass surgery, primary biliary cirrhosis, relapsing polychondritis, sarcoidosis, Wiskott-Aldrich syndrome

patients were diagnosed with drug-induced vasculitis.16 Drugs from almost every pharmacologic class have been implicated in causing vasculitis in sporadic cases (Table 4.2). The level of certainty and quality of evidence for these associations between specific agents and vasculitis varies greatly.17 Drug-induced vasculitis develops within 7 to 21 days after treatment begins.14 Drugs that have been commonly implicated include penicillins, aminopenicillins, sulphonamides, allopurinol, thiazides, pyrazolones, retinoids, quinolones, hydantoin and nonsteroidal anti-inflammatory drugs.12 Some recent reports of drug-induced vasculitis have incriminated such varied agents as clarithromycin,18 naproxen,19 omeprazole,20 glyburide,21 celecoxib,22 losartan,23 zafirlukast,24 ibuprofen,25 methotrexate,26 infliximab,27 efavirenz28 and influenza vaccinations29 among others. The pathologic mechanisms of drug-induced vasculitis remain to be defined and appear to be multifactorial with humoral and cell-mediated immune mechanisms playing important roles.30 Some drugs such as penicillins, cause vasculitis by conjugating to serum proteins and mediating immune-complex vasculitis. Other drugs that cause immune-complex formation are foreign proteins, such as streptokinase, cytokines, and monoclonal antibodies.14 Drugs such as propylthiouracil and hydralazine appear to cause vasculitis by inducing ANCA.15,31 In a study of 56 patients with Graves’ disease receiving treatment with propylthiouracil, 37.5 percent developed MPOANCA positivity.32 There are no significant differences in clinical presentation, serologic abnormalities, and pathologic findings of druginduced vasculitis with the idiopathic forms of vasculitis.30 However, it is extremely important to identify the offending drug because the discontinuation of the agent is often followed by a rapid improvement of the underlying vasculitic disorder.30


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Table 4.2: List of drugs causing LV Antibacterials Ciprofloxacin Cefaclor Clarithromycin Clindamycin Minocycline Penicillins Sulphonamides

Biological response modifiers Granulocyte colony stimulating factor (G-CSF) Infliximab Interferon-alpha

Anticonvulsants Barbiturates Diphenylhydantoin Gabapentin

Diuretics Thiazides

Antidiabetic Glyburide Anti-gout Allopurinol Antipsychotic Phenothiazines Antiretrovirals Indinavir Efavirenz Anti-thyroid Propylthiouracil Methimazole Anti-ulcer Cimetidine Omeprazole

Disease-modifying antirheumatic Leflunomide

Immunosuppressive Methotrexate Gold salts Leukotriene inhibitor Zafirlukast Non-steroidal anti-inflammatory drugs Aspirin Ibuprofen Phenylbutazone Naproxen Celecoxib Vaccines Hepatitis B Influenza Measles Typhoid Miscellaneous Bupropion Iodides Radiocontrast media Streptokinase

Infections may precipitate LV (Table 4.3). The pathogenic mechanisms appear to be complex and may include immune complex formation to microbial antigens, damage to vessels directly mediated by pathogens and humoral or cellular immune response. The most commonly recognized infectious agents are group A hemolytic streptococci, Staphylococcus aureus, Mycobacterium leprae, and hepatitis B virus.12 Leprosy is perhaps the commonest cause of vasculitis in the world.4 An immune-complex mediated vasculitis in multibacillary leprosy causes

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Recent Advances in Dermatology Table 4.3: Infections associated with LV

Bartonella henselae infection

HIV infection

Brucellosis

Leprosy

Candidiasis

Meningococcosis

Chlamydia pneumoniae infection

Parvovirus B19 infection

Cytomegalovirus infection

Rickettsioses

Ehrlichiosis

Staphylococcal infection

Epstein-Barr virus infection

Streptococcal infection

Gonorrhoea

Syphilis

Helicobacter pylori infection

Tuberculosis

Hepatitis A, B and C infection

Varicella

Herpes simplex

the clinical syndrome of erythema nodosum leprosum. Hepatitis C virus (HCV) infection runs a chronic course in a large majority of the affected individuals involving many extra-hepatic organ systems including the skin. HCV-induced mixed cryoglobulinemia is a frequently recognized cause of cutaneous vasculitis.14,33 Polymerase chain reaction analyses could detect HCV RNA expression in endothelia and perivascular inflammatory cells.34 It was postulated that viral infection of endothelia, cross-reactivity between endogenous and viral antigens leading to immune reactions, viral tropism to B lymphocytes resulting in B cell proliferation and resultant autoantibody production, and circulating immune complexes containing cryoglobulins could all be of pathogenic significance.34 Other infections reported to be associated with LV include human immunodeficiency virus (HIV) infection,35,36 hepatitis A virus infection,37,38 Epstein-Barr virus infection,39 and Chlamydia pneumoniae infection.40 Parvovirus B 19 infection has been reported to be associated with LV in a number of reports.41 Infections with cytomegalovirus,42 Mycoplasma pneumoniae,43 and Bartonella henselae44 were also implicated in a number of cases. Pulmonary tuberculosis,45 brucellosis,46 bacterial endocarditis, and meningococcemia were also among the infective diseases reported to have caused LV. A number of connective tissue diseases are sometimes associated with cutaneous leukocytoclastic vasculitis. Autoimmunity and formation of immune complex are believed to be the usual pathomechanism. Systemic lupus erythematosus (SLE), Sjögren’s syndrome, and rheumatoid arthritis (RA) are the commonly implicated disorders among this group of patients. LV occurs rarely in patients with scleroderma and mixed connective tissue disease.12 In a retrospective study of 186 patients with


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LE, 13.7 percent was found to have cutaneous LV. Cutaneous LV, like some other LE-nonspecific skin lesions, were detected only in patients with SLE and usually in the active phase of the disease.47 LV with the clinical feature of a figurate erythema mimicking erythema gyratum repens has been described in SLE.48 LV in rheumatoid arthritis may present clinically with palpable purpura, maculopapular erythema, erythema elevatum diutinum, and hemorrhagic blisters.49 In patients with RA, development of vasculitis is related to the severity of the disease.12 Vasculitis is commoner in children than in adults in dermatomyositis. In adult patients, features of LV in lesional skin biopsy have a predictive value for the presence of underlying malignancy.50 LV occurring in association with various malignant conditions is termed paraneoplastic vasculitis. Neoplasia is a relatively rare cause of LV. In a study of 222 cases of vasculitis, only 11 had associated malignancies.51 Paraneoplastic vasculitis is usually described in association with hematologic malignancies and rarely, solid organ tumors.52,53 Hematologic malignancies described in association with cutaneous LV include various forms of leukemia, Hodgkin’s and non-Hodgkin’s lymphoma,54 multiple myeloma,55 Waldenstrom’s macroglobulinemia,56 and myelodysplastic syndrome.57 Among the solid organ malignancies reported in association with LV are carcinomas of prostate, breast, and colon,53 ovarian carcinoma,58 squamous cell carcinoma of the lung59 and renal cancer.60 In most of the cases, manifestations of vasculitis appeared before or concurrent with the initial recognition or the relapse of the tumor.53 Besides infections, connective tissue diseases, and malignancies, other underlying systemic diseases may also be associated with cutaneous LV. Among the various diseases described in the literature1,61-63 are Behcet’s disease, inflammatory bowel disease, autoimmune liver diseases, cystic fibrosis, relapsing polychondritis, sarcoidosis and Wiskott-Aldrich syndrome. CLASSIFICATION Vasculitides constitute the myriad clinicopathologic entities resulting from a multitude of etiological factors and range in severity from inconsequential skin rashes to life-threatening multisystem diseases, the disorders sharing the common feature of injury to blood vessels with resultant tissue damage. For accurate diagnosis, rational management and prognostication, as well as for the purpose of studying uniform populations of patients for clinical trials, there is a need for an allencompassing classification system with clearly defined diagnostic

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criteria. But lack of knowledge about etiopathogenesis of individual disorders, compounded by confusing terminology, imprecise case definitions and overlapping clinicopathologic and laboratory features, has rendered the classification of vasculitis a taxonomist’s nightmare. Pending a fuller understanding of the pathogenic mechanisms, classification of vasculitic syndromes will continue to be based on clinical and histological findings. Depending on the chosen perspectives, vasculitic disorders can be classified according to the calibre of the blood vessels involved, nature of the infiltrate, presence or absence of systemic involvement, serologic markers and the presumed etiology. For example, the case of a child who presents, after an attack of upper respiratory streptococcal infection, with abdominal pain, renal manifestations and palpable purpuras that on histology shows features of small-vessel vasculitis with neutrophilic infiltrate and is ANCA-negative, may be variously classified as having infection-associated vasculitis, leukocytoclastic vasculitis, systemic small-vessel vasculitis, or ANCA-negative vasculitis and so on. The case would usually, however, be classified as having the distinctive syndrome of Henoch-Schönlein purpura. Zeek64 developed the first classification system of vasculitis in 1952; the classification included the terms hypersensitivity vasculitis, polyarteritis nodosa, granulomatous vasculitis, rheumatic vasculitis, and large vessel vasculitis. Decades later, the American College of Rheumatology published a classification system65 with criteria that separated Henoch-Schönlein purpura from hypersensitivity vasculitis and subdivided granulomatous vasculitis into Wegener’s granulomatosis and Churg-Strauss syndrome. These criteria were meant for homogenous grouping of patients for clinical trials, and not designed for diagnosis of individual patients, although they are widely used for this purpose. The criteria were not adequate for differentiating among the various clinicopathological expressions of small-vessel vasculitis.14 Moreover, this system lacked input from dermatological community, explaining the difficulty for dermatologists in placing a patient into one group or another66. The Chapel Hill International Consensus Conference in 1994 tried to address this problem and proposed names and definitions for categories of vasculitis67 without suggesting diagnostic criteria. This system classified vasculitis into 3 major subtypes, depending on the calibre of blood vessels involved: (1) Large vessel vasculitis (Giant cell arteritis and Takayasu’s arteritis), (2) Medium-sized vessel vasculitis (polyarteritis nodosa and Kawasaki’s disease) and (3) Small vessel vasculitis (Wegener’s granulomatosis, Churg-Strauss syndrome, microscopic polyangiitis, Henoch-Schönlein purpura, cryoglobulinemic


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Table 4.4: Classification of diseases associated with LV I. Systemic small-vessel vasculitis A. ANCA-associated: Wegener’s granulomatosis Churg-Strauss syndrome Microscopic polyangiitis B. Non-ANCA associated: Henoch-Schönlein purpura Mixed cryoglobulinemia II. Predominantly cutaneous vasculitis A. Idiopathic B. Drug-induced (Table 4.2) C. Infection-mediated (Table 4.3) D. Connective tissue disease-associated E. Paraneoplastic F. Associated with other diseases (Table 4.1) G. Miscellaneous syndromes: Acute hemorrhagic oedema of infancy Cutaneous polyarteritis nodosa Erythema elevatum diutinum Granuloma faciale Neutrophilic dermatosis of dorsal hands Serum sickness Urticarial vasculitis

vasculitis, and cutaneous vasculitis). This widely accepted classification system is also fraught with problems from a dermatological viewpoint, since patients with cutaneous LV with systemic manifestations may be placed in more than one category. Fauci’s classification of vasculitic syndromes, popular among internists, included the term ‘predominantly cutaneous vasculitis’ in place of cutaneous LV or hypersensitivity vasculitis for conditions where skin involvement generally dominate the clinical picture but skin is not the exclusive organ involved.1 From a dermatological perspective and using one common denominator - the presence of leukocytoclastic vasculitis on histologic examination of skin biopsy specimens, vasculitic disorders can be classified as given in Table 4.4. Disorders like Wegener’s granulomatosis and Churg-Strauss syndrome, which are generally classified on histologic ground as ‘granulomatous vasculitis’, are included in the territory of leukocytoclastic vasculitis as these disorders frequently produce skin lesions that on histology shows LV. This will help dermatologists appreciate the fact that cutaneous lesions of LV, notably palpable purpuras, can actually have more sinister implications than the innocuous-looking rashes suggest.

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A QUICK OVERVIEW OF SYNDROMES ASSOCIATED WITH LEUKOCYTOCLASTIC VASCULITIS Wegener’s Granulomatosis Wegener’s granulomatosis (WG) is characterized by granulomatous inflammation of the respiratory tract, necrotizing vasculitis affecting small to medium sized arteries and necrotizing glomerulonephritis.67 Upper respiratory tract disease occurs in more than 90 percent of cases and includes sinusitis, nasal crusting, bleeding, obstruction, otitis media and conductive deafness and tracheal stenosis.68 Pulmonary involvement manifests with cough, hemoptysis, and dyspnea. Proteinuria, hematuria, and urinary casts are signs of renal involvement. Renal failure may develop rapidly. Other systemic involvements include ocular, neurological and coronary heart diseases. Cutaneous manifestations are reported in 14 to 50 percent of cases in different series and may be the presenting feature in a significant proportion of cases.69-71 Palpable purpura was found to be the commonest cutaneous manifestation, and leukocytoclastic vasculitis the commonest pathology. Papular, plaque-like, ulcerated lesions, vesicles, urticarial lesion, subcutaneous nodules and panniculitis have all been described.69-71 Although, in its classical form, WG is a multisystem disease with protean manifestations, there can actually be a spectrum of clinical manifestations and the disease may present with limited organ involvement.12 WG can affect patients at any age with a peak incidence during fourth decade of life and is slightly more common in men.72 Serum antiproteinase3 ANCA (cANCA) is positive in 75 to 90 percent, although 20 percent may have positive pANCA.72 The classic triad of respiratory tract granulomatous inflammation, systemic small-vessel vasculitis, and necrotizing glomerulonephritis readily suggest the diagnosis, but in atypical cases a positive ANCA test is helpful in substantiating a case of WG.14 Churg-Strauss Syndrome Churg-Strauss syndrome (CSS) is also known as allergic granulomatosis. CSS is a systemic disorder characterized by asthma, pulmonary infiltrates, peripheral blood as well as tissue hypereosinophilia and systemic vasculitis. The etiology of CSS is uncertain; however, allergic and autoimmune processes are suspected. Drug sensitivity to leukotriene inhibitors (used in the treatment of asthma) has been implicated in the aetiology of CSS in some recent reports.73,74 A perinuclear antineutrophilic cytoplasmic antibody (pANCA) directed predominantly against a myeloperoxidase


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is detected in up to 75 percent of patients with CSS. Antineutrophil cytoplasmic antibody (cANCA) directed against serine proteinase 3 is positive in about 10 percent of cases of CSS. Evolution of CSS occurs in 3 distinct phases. The first phase is characterized by asthma and allergic rhinitis. The second phase is marked by a peripheral blood eosinophilia and eosinophilic tissue infiltration, eosinophilic pneumonia, or eosinophilic gastroenteritis. The third phase is characterized by a systemic vasculitis. The three phases may or may not be sequential. The organs that may be involved include the heart, lung, central nervous system, kidney, muscle, and skin. In contrast to Wegener’s granulomatosis and microscopic polyangiitis, CSS causes much less frequent and less severe renal disease, but more frequent neuropathy and cardiac disease. Coronary arteritis and myocarditis are the principal causes of morbidity and mortality accounting for approximately 50 percent of deaths.14 Skin involvement occurs in more than two-thirds of patients75 and may be the initial manifestation of this multisystem disease. The lesions consist of palpable purpura and large ecchymoses often with necrosis. Cutaneous and subcutaneous nodules may also occur.76 The histology of purpuric lesions typically shows features of LV,76 but eosinophils may be conspicuous.2 Microscopic Polyangiitis Microscopic polyangiitis (MPA) is the most common ANCA-associated small vessel vasculitis. MPA is characterized by necrotizing vasculitis with few or no immune deposits affecting small vessels, necrotizing glomerulonephritis, and pulmonary capillaritis.67 MPA is differentiated from classic polyarteritis nodosa by the absence of small vessel vasculitis (venulitis) in the latter. MPA is commoner in men and involves people in the age group 40 to 60. MPA has the same spectrum of manifestations of small-vessel vasculitis as Wegener’s granulomatosis, but does not include granulomatous inflammation.14 Approximately 90 percent of patients have glomerulonephritis, which is accompanied by a variety of other organ involvement. Patients present with the variable combinations of renal manifestations, abdominal pain, palpable purpura, cough and hemoptysis.72 Most patients have MPO ANCA (pANCA) although PR3 ANCA (cANCA) may also be present in 40 percent of patients.72 Henoch-Schönlein Purpura Henoch-Schönlein purpura (HSP) is an immunoglobulin A-mediated LV that predominantly affects children but is also seen in adults. Immune

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complexes containing IgA and C3 have been found in the skin, kidney, intestinal mucosa, and synovia, thus explaining the major organ site involvement seen in HSP. HSP is the commonest form of systemic vasculitis encountered during childhood. Seventy five percent of cases occur between two and 11 years of age, with a peak incidence at five years of age.77 In the Indian population, the age of onset of disease, however, is higher than that in the west.78,79 HSP can occur in response to infectious agents such as group A streptococci, mycoplasma, EpsteinBarr virus and varicella virus. Parvovirus B19,41,80 campylobacter,81 and Bartonella henselae44 infections have been implicated in the causation of HSP. Cases of HSP following vaccinations for typhoid, measles, cholera and yellow fever have also been reported82. The disease often begins after an upper respiratory tract infection. The dominant clinical features of HSP, in descending order of frequency, are cutaneous purpura, arthritis, abdominal pain, nephritis and gastrointestinal bleeding. Pulmonary disease and peripheral neuropathy occur rarely. Scrotal involvement with severe pain may occur. Scrotal sonographic findings are sufficiently characteristic to allow distinction from torsion in most cases.83 The rash occurs in 100 percent of cases. The lesions occur predominantly on the lower limbs and buttock, but may involve other areas of the body. The classic lesions consist of palpable purpura and urticarial wheals. Necrotic and bullous hemorrhagic lesions may also occur. HSP is generally benign and self-limited in children and more severe in adults.84 The most serious manifestation of HSP is renal involvement which occurs in 50 percent of older children but in only 25 percent of children younger than two years. The main long-term morbidity is from progressive renal disease. End-stage renal disease develops in approximately 5 percent of patients.14 Diagnosis of HSP depends on clinical findings and history. According to the diagnostic criteria proposed by Michel et al,85 three or more of the following six features should be present to diagnose HSP: palpable purpura, bowel angina, gastrointestinal bleeding, hematuria, age of onset younger than twenty years, and no medications as a precipitating agent. Since renal manifestation may follow the development of the rash by up to three months, monthly urinalysis should be done for a few months following resolution of the condition. Cryoglobulinemic Vasculitis Cryoglobulins are circulating immunoglobulins or complexes containing immunoglobulins that precipitate in the cold and dissolve on rewarming. Cryoglobulins are classified according to their constituents. Type I cryoglobulins are monoclonal immunoglobulins associated with multiple


43

myeloma or other paraproteinemias. Type II and type III are mixed cryoglobulins. Type II is the complex of a monoclonal component with polyclonal immunoglobulins while type III is a heterogenous mixture of polyclonal immunoglobulins that sometimes contain non-immunoglobulin molecules like complement or lipoproteins. Type III mixed cryoglobulinemia is the commonest variety encountered in patients. Mixed cryoglobulinemia is associated with autoimmune diseases, lymphoproliferative diseases, liver disorders, and various chronic infections among which hepatitis C has a central role. Mixed cryoglobulins were demonstrated in 40 percent of a series of 1202 patients with chronic hepatitis C infection.86 Patients with cryoglobulinemia occasionally develop a vasculitic syndrome which features skin manifestations, arthralgia, nephritis, and hepatitis. In some patients, the syndrome may progress to life-threatening renal or pulmonary disease. Palpable purpura that typically shows histologic features of LV is the hallmark of cryoglobulinemic vasculitis. This is present in 100 percent of cases. Cryoglobulins were demonstrated in 25.4 percent of a series of 160 patients of LV in whom it was found to be a risk factor for the chronicity of skin lesions.87 Acute Hemorrhagic Edema of Childhood Acute hemorrhagic edema of childhood, also known as acute infantile hemorrhagic edema, is a cutaneous LV clinically characterized by an acute illness consisting of a symptom triad of fever, large purpuric skin lesions and peripheral edema.88 It usually involves children younger than two years of age. The disease follows a short, benign course with spontaneous complete recovery usually within one to three weeks without recurrence or long-term complications. In most cases, the origin is not clear, but underlying infections are assumed to play a causative role. Cytomegaloviral infection,89 hepatitis A infection,90 and drugs91 have been implicated in the etiology. This disease is considered by many to be a variant of HenochSchönlein purpura because of similarities in cause and histopathology. However, because of the benign nature of the condition and frequent absence of IgA associated with HSP, it may be sensible to consider as a distinct variety of cutaneous LV.92 Cutaneous Polyarteritis Nodosa Cutaneous polyarteritis nodosa is characterized by the appearance of crops of nodules predominantly affecting the lower limbs and occasionally elsewhere. Livedo reticularis is also a feature of this benign

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disorder.4,93 Apart from local neuromuscular involvement in some cases, no visceral manifestations are seen. Cutaneous biopsy shows a segmentary LV in the arteries of the deep dermis and/or hypodermis.93 The relationship of this disorder with systemic polyarteritis is so remote that some authors prefer the term ‘livedo with nodules’.4 Erythema Elevatum Diutinum Erythema elevatum diutinum (EED) is a rare form of LV characterized clinically by chronic papules, plaques, and nodules that occur symmetrically over the extensor surface of the body, mainly over the joints. The lesions are initially soft, red to violaceous in color, later becoming brown to yellowish and acquire a firm to hard consistency owing to fibrosis. The disease may persist for years, but spontaneous resolution may occur. EED is probably not a distinct disease entity, but rather a clinicopathologic reaction pattern that can be seen in a number of different disease processes.2 EED may be associated with HIV infection,94,95 rheumatoid arthritis,96 inflammatory bowel disease,97 IgA paraproteinemias and myelodysplastic syndrome.98 Histopathology of EED in its early phase shows features of LV. Older lesions show formation of granulation tissue and fibrosis, but even in later stages, neutrophil predominates the infiltrate and capillaries may still show deposits of fibrinoid material.2 Granuloma Faciale Granuloma faciale is a rare disease of unknown cause that typically presents with soft, brownish red, slowly growing, asymptomatic papules or plaques occurring on the face. Extrafacial lesions may rarely occur.99,100 Other than the involvement of upper respiratory tract mucosa,101 no other systemic affection has been reported. Histology of granuloma faciale shows a dense polymorphous infiltrate beneath a narrow sub-epidermal ‘grenz’ zone. The infiltrate is composed of neutrophils, eosinophils, mononuclear cells, plasma cells and mast cells. Features of LV may be detected within the infiltrate.99 Immunofluorescence studies also support vascular etiology of the disease by showing deposits of immunoglobulins and complement components around the blood vessels and along the dermo-epidermal junction.4 Neutrophilic Dermatosis (pustular vasculitis) of the Dorsal Hands Neutrophilic dermatosis of the dorsal hands, also known as pustular vasculitis of the dorsal hands, is a recently described entity, which may


45

clinically resemble a localized variant of Sweet’s syndrome.102 The disorder was first reported in 1995 in six patients who had an eruption involving the dorsa of hands.103 The lesions clinically resembled Sweet’s syndrome and showed similar histologic feature of a dense dermal neutrophilic infiltrate. In contrast to Sweet’s syndrome, however, the lesions were limited almost exclusively to the dorsal hand and definite LV was evident on histologic examinations. More similar cases were subsequently described.104-6 Although originally described as ‘pustular vasculitis of dorsal hands’, due to absence of vasculitis in some of the latter cases, the term neutrophilic dermatosis of the dorsal hands was proposed by authors who consider the disorder to be a subset of Sweet syndrome.106 Similarity in location and histology has led others to suggest that this disorder may in fact be a variant of erythema elevatum diutinum.107 Thus, the nosologic position of this clinical entity has remained uncertain. The condition is characterized by102-6 predominant involvement of middleaged to elderly women with erythematous plaques and nodules with pustules and occasional ulceration on the surface, limited to the dorsal hands. Other anatomical sites are minimally involved. Skin biopsy specimens show dense dermal infiltration with leukocytoclasis and fibrinoid vascular necrosis. Vasculitis may, however, be absent.106 The importance of this entity lies in its liability to be misdiagnosed as cutaneous infective diseases. As relatively few cases have been reported till date, the possible systemic associations are less clear. Associations of uncertain significance have included a history of breast cancer,103 metastatic renal adenocarcinoma,104 Raynaud’s disease with arthritis,106 and concurrent bowel disorders.102 Most cases have responded to dapsone and systemic corticosteroids therapy.102-6 Subsequent relapse has been reported.102 Serum Sickness Serum sickness is an acute hypersensitivity reaction which was originally defined to occur in association with administration of heterologous serum. Serum sickness or serum sickness-like reactions (SSLR) usually occur now in the context of chronic hepatitis B virus infection or drug administration. The most frequently described drugs in recent reports include oral penicillins,108 streptokinase,109 cefaclor,110 minocycline,111 and bupropion.112 The syndrome is characterized by the symptom complex of fever, arthralgia, skin rashes in the form of urticaria, angioedema, palpable purpura, and lymphadenopathy. The symptoms of SSLR typically begin six to 21 days after administration of the causative agents and they are usually self-limiting, lasting 4 to 14 days.

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Urticarial Vasculitis Urticarial vasculitis (UV) is a clinicopathologic entity typified by recurrent episodes of urticaria that have the histopathologic features of LV. The condition is idiopathic in many patients but can also occur in the context of autoimmune disorders, infections, drug reactions, or as a paraneoplastic syndrome.113 Clinical features include12,113 pruritic, painful, or burning urticarial lesions, which, in contrast to allergic urticaria, usually persist longer than 24 hours and may show pronounced central clearing of lesions often leaving residual hyperpigmentation. However, because clinical characteristics of urticarial vasculitis may overlap with those of allergic urticaria, confirmation of diagnosis requires lesional skin biopsy.113 Systemic features may include fever, malaise, lymphadenopathy, hepatosplenomegaly, arthralgia, renal, gastrointestinal, or ocular manifestation.12 Urticarial vasculitis typically affects young women and usually pursues a chronic course. Patients with UV can be divided into two types, those with normal complement levels and those with hypocomplementemic UV.114 The latter condition has a strong association with SLE and is commonly associated with angioedema, ocular inflammation, obstructive lung disease, and glomerulonephritis.114,115 APPROACH TO DIAGNOSIS AND TREATMENT Leukocytoclastic vasculitis presents a diagnostic and therapeutic challenge to the physicians. Appreciation of the fact that, LV is only a non-specific reaction pattern and its significance ranges from a selflimiting mild rash to life-threatening multisystem diseases, is crucial to the diagnosis and management principles. Since cutaneous lesions are very common manifestations of nearly all vasculitic syndromes, dermatologists are often the first contact-points for patients affected with such disorders. It is the onus of the physician to evaluate the patients thoroughly in order to confirm the diagnosis, search for etiological factors, and identify the organs involved. In most cases, dermatologists will be required to treat the patients and, if serious systemic involvements are detected, to refer them to appropriate specialists. The first step in the diagnosis of LV is to suspect that a rash and its accompanying symptoms are features of a vasculitic process. While palpable purpura is the most easily recognizable sign of LV, other lesions which are suggestive of LV include persistent urticarial wheals, hemorrhagic pustules, livedo reticularis, subcutaneous nodules, and cutaneous infarcts. The clinical diagnosis of cutaneous LV is confirmed by histopathological examination of biopsy specimens. The unequivocal


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histologic evidence of LV is provided by fibrinoid degeneration of vessel walls together with a neutrophilic infiltrate and fragmentation of nuclei of leukocytes (leukocytoclasis). It is important to appreciate the dynamic nature of the infiltrate in LV, which, in older lesions may show a lymphocytic predominance.116 Hence, a fresh lesion should be selected for biopsy. Once the diagnosis of LV is made, emphasis should be on the search for causative factors and detection of systemic involvements. The role of detailed history taking and a thorough physical examination for this purpose cannot be over-emphasized. Details of medications used during the few weeks preceding the rash should be enquired about. A check-list of enquiry about indicators of systemic affection should include features like joint pain, abdominal pain, gastrointestinal bleeding, upper and lower respiratory symptoms like nasal stuffiness, discharge or bleeding, cough, hemoptysis, and breathing difficulties, urinary symptoms, muscular weakness and paresthesia and ocular complaints. Presence of features of general illness like fever, malaise, bodyache, anorexia, and weight loss should also be looked into. Laboratory workup in a patient with LV has basically two goals. First, to detect underlying causative factors or disease associations, and secondly, to identify or exclude systemic involvements. However, in a developing country setting, the extent and range of laboratory tests ordered are often subject to financial and infrastructural constraints. The initial screening tests should include routine hemogram, urinalysis, examination of stools for occult blood, erythrocyte sedimentation rate, blood biochemistry panel for hepatic or renal involvement, ASO titre, and a chest X-ray. The nature of further lab tests advised will depend on the indications obtained from physical examination and routine tests. Table 4.5: Steps in the diagnosis and management of LV I. Suspect diagnosis of LV II. Confirm diagnosis by histology III. Detailed clinical evaluation to detect underlying diseases and systemic involvement IV. Laboratory workup: A. Initial screen B. Focussed tests V. Syndrome recognition VI. Appropriate referral if necessary VII. Treatment: A. Elimination of underlying cause B. Treatment of underlying disease C. Treatment of vasculitis VIII. Follow-up

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Recent Advances in Dermatology Table 4.6: Laboratory workup in patients of LV

Initial screening: Complete blood count ESR C-reactive protein Urinalysis Stool guaiac Focussed tests: ANA Rheumatoid factor ANCA Hepatitis B, C serology HIV testing CH 50, C3, C4 Cryoglobulins Throat swab Blood culture

Blood urea, creatinine LFT X-ray chest ECG ASO titre Bone marrow exam Tissue biopsy Visceral angiography Creatine kinase EMG, MCV Mantoux test Serum protein electrophoresis Sinus X-ray, CT scan Other appropriate tests for suspected systemic diseases/infections

Hence, the next level of laboratory tests is more focussed and directed at diagnosing specific vasculitic disease entities (Table 4.6). These often include tests for antinuclear antibodies and rheumatoid factor for detecting connective tissue disorders; serologic tests for hepatitis B and C viruses; an ANCA profile for systemic small-vessel vasculitis and appropriate tests to detect any infective disorders, malignancies, and other underlying diseases if clinical suspicion so directs. Cryoglobulins are looked for if hepatitis C virus infection is present. Once evaluations are completed and systemic affections, if present, are clearly identified, it is imperative to recognize the specific vasculitic syndrome from the characteristic combinations of clinical and laboratory features. This is extremely important from the point of view of treatment and prognosis. For example, the same combination of palpable purpura, arthritis, and renal involvement have a much better prognosis when they occur as components of Henoch-Schönlein purpura than as components of Wegener’s granulomatosis. After recognition of the syndrome as one of the systemic vasculitides with prominent visceral involvement, referral to appropriate specialities like rheumatology, nephrology, gastroenterology or neurology is imperative for proper management of the case. Treatment of vasculitis depends on the identified causative factors, the nature of the syndrome, and more importantly, the degree and extent of systemic involvement. If drug-induced vasculitis is suspected, withdrawal of the drug results in rapid improvement of symptoms and


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Table 4.7: Drugs used in the treatment of LV For mild/skin-limited disease Antihistaminics Non-steroidal anti-inflammatory drugs Antimalarials Dapsone Colchicine Thalidomide Potassium iodide For systemic disease/severe cutaneous disease Systemic corticosteroids Cyclophosphamide Azathioprine Methotrexate Cyclosporine

complete recovery without sequelae.16,30 Treatment of infections and underlying systemic diseases is undertaken in appropriate cases. Mild affection limited to the skin may not require anything more than rest, antihistaminics, and non-steroidal antiinflammatory agents. In moderately severe cutaneous LV and in skin-limited vasculitic syndromes, dapsone, colchicine, and antimalarials frequently control the disease. Thalidomide is the drug of choice in erythema nodosum leprosum. Thalidomide was also used successfully in refractory Henoch-Schönlein purpura.117 Treatment of ANCA-associated systemic vasculitic syndromes needs a multidisciplinary approach. Treatment of Wegener’s granulomatosis and microscopic polyangiitis are similar and undertaken in three phases: induction of remission, maintenance of remission, and treatment of relapse.14 Current induction therapy uses high-dose systemic steroids in combination with cyclophosphamide. Once remission is achieved, it is maintained by cyclophosphamide or azathioprine. Methotrexate may also be used for maintenance of remission in relatively less severe disease.117 Severe or chronic and disabling cutaneous disease may also need treatment with systemic steroid and immunosuppressive agents. Mixed cryoglobulinemia due to hepatitis C infection may be treated with a combination of interferon-alpha and ribavirin.119 Finally, there is also a place for physical modalities of treatment like liquid nitrogen cryotherapy in cutaneous disease like granuloma faciale.120 REFERENCES 1. Fauci AS. The vasculitis syndromes. In: Fauci AS, Braunwald E, Isselbacher K, et al (Eds). Harrison’s Principles of Internal Medicine. 14th ed. New York: McGraw Hill, 1998: 1910-22.

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2. Elder D, Elenitsas E, Jaworsky C, et al (Eds). Lever’s Histopathology of the Skin. 8th edn. Philadelphia: Lippincot Raven. 1997. 3. Sanches NP, Van HHM, Su WP. Clinical and histopathologic spectrum of necrotizing vasculitis: Report of findings in 101 cases. Arch Dermatol 1985; 121:220-4. 4. Ryan TJ. Cutaneous vasculitis. In: Champion RH, Burton JL, Burns DA, et al (Eds) Textbook of Dermatology. 6th ed. Oxford, Blackwell Science, 1998: 21552225. 5. Claudy A. Pathogenesis of leukocytoclastic vasculitis. European J Dermatol 1998; 8:75-9. 6. Sais G, Vidaller A, Jucgla A, et al. Prognostic factors in leukocytoclastic vasculitis. A clinicopathologic study of 160 patients. Arch Dermatol 1998; 134:309-315. 7. Gyselbrecht L, De Keyser F, Ongenae K, et al. Aetiological factors and underlying conditions in patients with leukocytoclastic vasculitis. Clin Exp Rheumatol 1996; 14:665-8. 8. Garcia-Porrua C, Llorca J, Gonzalez-Louzao C, et al. Hypersensitivity vasculitis in adults: A benign disease usually limited to skin. Clin Exp Rheumatol 2001; 19:85-8. 9. Kawana S. The membrane attack complex of complement alters the membrane integrity of cultured endothelial cells: A possible pathophysiology for immune complex vasculitis. Acta Derm Venereol 1996; 76:13-6. 10. Sais G, Vidaller A, Jucgla A, et al. Adhesion molecule expression and endothelial cell activation in cutaneous leukocytoclastic vasculitis. An immunohistologic and clinical study in 42 patients. Arch Dermatol 1997; 133:443-50. 11. Besbas N, Saatci U, Ruacan S, et al. The role of cytokines in Henoch-Schönlein purpura. Scand J Rheumatol 1997; 26:456-60. 12. Soter NA. Cutaneous necrotizing venulitis. In: Fitzpatrick TB, Eisen AZ, Wolff K, et al (Eds). Dermatology in General Medicine. 4th ed. New York: McGraw Hill,1993; 1501-10. 13. Meijer-Jorna LB, Mekkes JR, van der Wal AC. Platelet involvement in cutaneous small vessel vasculitis. J Cutan Pathol 2002; 29:176-80. 14. Jennette JC, Falk RJ. Small-vessel vasculitis. N Engl J Med 1997; 337:1512-23. 15. Businco L, Falconieri P, Bellioni-Businco B, et al. Severe food-induced vasculitis in two children. Pediatr Allergy Immunol 2002; 13:68-71. 16. Garcia-Porrua C, Gonzalez-Gay MC, Lopez-Lazaro L. Drug associated cutaneous vasculitis in adults in northwestern Spain. J Rheumatol 1999; 26: 1942-4. 17. Merkel PA. Drug-induced vasculitis. Rheum Dis Clin North Am 2001; 27: 849-62. 18. Gavura SR, Nusinowitz S. Leukocytoclastic vasculitis associated with clarithromycin. Ann Pharmacother 1998; 32:543-5. 19. Schapira P, Balbir-Gurman A, Nahir AM. Naproxen-induced leukocytoclastic vasculitis. Clin Rheumatol 2000; 19:242-4. 20. Odeh M, Lurie M, Oliven A. Cutaneous leukocytoclastic vasculitis associated with omeprazole. Postgrad Med J 2002; 78:114-5. 21. Bukhalo M, Zeitouni NC, Cheney RT. Leukocytoclastic vasculitis induced by use of glyburide: a case of possible cross-reaction of a sulphonamide and a sulphonylurea. Cutis 2003; 71:235-8. 22. Gscheidel D, Daspet MK, Le Coz CJ, et al. Allergic vasculitis following ingestion of celecoxib? Hautarzt 2002; 53:488-91.


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23. Pierard FC, Henry F, Pierard GE. Severe pustular and plymorphous vasculitis caused by losartan. Ann Dermatol Venereol 2001; 128:1040-2. 24. Soy M, Ozer H. Canatarglu A, et al. Vasculitis induced by Zafirlukast therapy. Clin Rheumatol 2002; 21: 328-9. 25. Davidson KA, Ringpfeil F, Lee JB. Ibuprofen-induced bullous leukocytoclastic vasculitis. Cutis 2001; 6:303-7. 26. Borman P, Boden H, Gulec AT, et al. Atypical methotrexate dermatitis and vasculitis in a patient with ankylosing spondylitis. Rheumatol Int 2000; 19:1913. 27. Devos SA, Van ben Bossche N, Vos M, et al. Adverse skin reactions to antiTNF-alpha monoclonal antibody therapy. Dermatology 2003; 44:42-4. 28. Domingo P, Barcelo M. Efavirenz-induced leukocytoclastic vasculitis. Arch Intern Med 2002; 162:355-6. 29. Tavadia S, Drummond A, Evans CD, et al. Leukocytoclastic vasculitis and influenza vaccination. Clin Exp Dermatol 2003; 28:154-6. 30. Cueller ML. Drug-induced vasculitis. Curr Rheumatol Rep 2002; 4:55-9. 31. Morita S, Ueda Y, Eguchi K. Anti-thyroid drug-induced ANCA-associated vasculitis: A case report and review of the literature. Endocr J 2000; 47:467-70. 32. Sera N, Ashizawa K, Ando T, et al. Treatment with propylthiouracil is associated with appearance of antineutrophil cytoplasmic antibodies in some patients with Graves disease . Thyroid 2000; 10:595-9. 33. Agnello V, Chung RT, Kaplan LM. A role for hepatitis C virus infection in type LL cryoglobulinemia. N Engl J Med 1992; 327:1490-5. 34. Crowson AN, Nuovo G, Ferri C, et al. The dermatopathologic manifestations of hepatitis C infection: A clinical, histological, and molecular assessment of 35 Case. Hum Pathol 2003; 34:573-9. 35. Watkins KV, Ittman MM. Necrotizing vasculitis in a patient with acquired immunodeficiency syndrome. J Oral Maxillofac Surg, 1992; 50:1003. 36. Fakhiri A, Gupta SM, White SM, et al. Erythema elevatum diutinum in a patient with human immunodeficiency virus. Cutis 2001; 41:55. 37. Kuroda K, Yabunami H, Hisanaga Y. Henoch-Schönlein purpura associated with hepatitis A infection. Pediatr Int 2003; 45:114-6. 38. Bozaykut A, Atay E, Atay Z et al. Acute infantile haemorrhagic oedema associated with hepatitis A. Ann Trop Paediatr 2002; 22:59-61. 39. Leukocytoclastic vasculitis neuropathy associated with chronic Epstein-Barr virus infection. Muscle Nerve 2003, 27:113-6. 40. Cascina A, Marone Bjanco A, Mangiarotti P, et al. Cutaneous vasculitis and reactive arthritis following respiratory infection due to chlamydia pneumoniae. Report of a case. Clin Exp Rheumatol 2002; 20:845-7. 41. Cioc AM, Sedmac DD, Nuovo GJ, et al. Parvovirus B19 associated adult HenochSchönlein purpura. J Cutan Pathol 2002; 29:602-7. 42. Acute haemorrhagic oedema of infancy associated with cytomegalovirus infection. Br J Dermatol 2002; 147:1254-7. 43. Perez C, montes M. Cutaneous leukocytoclastic vasculitis and encephalitis associated with mycoplasma pneumoniae infection. Arch Intern Med 2002; 162:352-4. 44. 44.Ayoub EM, McBride J, Schmiederer M, et al. Role of Bartonella henselae in the etiology of Henoch-Schönlein purpura. Pediatr Infect Dis J 2002; 21:28-31. 45. Minguer P, Pintor E, Buron R, et al. Pulmonary tuberculosis presenting with leukocytoclastic vasculitis. Infection 2000;28:55-7.

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46. Nagore E, Sanchez-Motilla JM, Navarro V, et al. Leukocytoclastic vasculitis as a cutaneous manifestation of systemic infection caused by Brucella melitensis. Cutis 1999; 63:25-7. 47. Cardinali C, Caproni M, Brnacchi E, et al. The spectrum of cutaneous manifestations in lupus erythematosus – the Italian experience. Lupus 2000; 9:417-23. 48. Pique E, Palacios S, Santana Z. Leukocytoclastic vasculitis presenting as an erythema gyratum repens-like eruption on a patient with systemic lupus erythematosus. J Am Acad Dermatol 2002; 47:S254-6. 49. Chen KR, Toyohara A, Suzuki A, et al. Clinical and histopathological spectrum of cutaneous vasculitis in rheumatoid arthritis. Br J Dermatol 2002;147:905-13. 50. Hunger RE, Durr C, Brand CU. Cutaneous leukocytoclastic vasculitis in dermatomyositis suggests malignancy. Dermatology 2002; 202:123-6. 51. Sanchez-Guerrero, Gutierrez-Urena S, Vidaller A, et al. Vasculitis as a paraneoplastic syndrome. Report of 11 cases and review of the literature. J Rheumatol 1990; 17:1458-62. 52. Paydas S, Zorludemir S: Leukaemia cutis and leukaemic vasculitis. Br J Dermatol 2000; 143:773-9. 53. Kurzrock R, Cohen PR, Markowitz A. Clinical manifestations of vasculitis in patients with solid tumors. A case report and review of the literature. Arch Intern Med 1994; 154:334-40. 54. Wilson D, McCluggage WG, Wright GD. Urticarial vasculitis: A paraneoplastic presentation of B-cell non-Hodgkin’s lymphoma. Rheumatology 2002; 41:4767. 55. Bayer-Garnez IB, Smoller BR. The spectrum of cutaneous disease in multiple myeloma. J Am Acad Dermatol 2003; 48:497-507. 56. Cho S, Chang SE, Kim KR, et al. Waldenstrom’s macroglobulinaemia presenting as reticulate purpura and bullae in a patient with hepatitis B virus infection. Clin Exp Dermatol 2001; 26:513-7. 57. Blanco R, Gonzalez-Gay, Ibanez D, et al. Henoch-Schönlein purpura as clinical presentation of myelodysplastic syndrome. Clin Rheumatol 1997; 16:626-8. 58. Stashower ME, Rennie TA, Turiansky GW, et al. Ovarian cancer presenting as leukocytoclastic vasculitis. J An Acad Dermatol 1999; 40:287-9. 59. Odeh M, Misselevich I, Oliven A. Squamous cell carcinoma of the lung presenting with cutaneous leukocytoclastic vasculitis: A case report. Angiology 2001; 52:641-4. 60. Lacour JP, Castanet J, Perrin C, et al. Cutaneous leukocytoclastic vasculitis and renal cancer: two cases. Am J Med 1993; 94:104-8. 61. Gyselbrecht L, De Keyser F, Ongenae K, et al. Etiological factors and underlying conditions in patients with leucocytoclastic vasculitis. Clin Exp Rheumatol 1996; 14:665-8. 62. Aractingi S, Cadranel J, Milleron B, et al. Sarcoidosis associated with leucocytoclastic vasculitis. A case report and review of the literature. Dermatology 1993; 187:50-3. 63. Dupuis-Girod S, Medioni J, Haddad E, et al. Autoimmunity in Wiskott-Aldrich syndrome: risk factors, clinical features, and outcome in a single center cohort of 55 patients. Pediatrics 2003; 111:622-7. 64. Zeek PM. Periarteritis nodosa: a critical review. Am J Clin Pathol 1952; 22:77792 cited in ref. no. 63.


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65. Hunder GG, Arend WO, Bloch DA, et al. The American College of Rheumatology 1990 criteria for the classification of vasculitis. Arthritis Rheum 1990; 33:1065-1144. 66. Callen JP. Cutaneous vasculitis. What have we learned in the past thirty years? Arch Dermatol 1998; 134:355-7. 67. Jennette JC, Falk RJ, Andrassy K, et al. Nomenclature of systemic vasculitides: proposal of an international consensus conference. Arthritis Rheum 1994; 37:18792. 68. Savage COS, Harper L, Cockwell P, et al. ABC of arterial and vascular diseases: Vasculitis. BMJ 2000; 320: 1325-8. 69. Hoffman GS, et al: Wegener granulomatosis: An analysis of 158 patients. Ann Intern Med 1992; 116: 448-98. 70. Daoud MS, Gibson LE, et al. Cutaneous Wegener’s granulomatosis: Clinical, histopathologic, and immunopathologic features of thirty patients. J Am Acad Dermatol 1994;31:605-12. 71. Patten SF, Tomecki KJ. Wegener’s granulomatosis: cutaneous and oral mucosal disease. J Am Acad Dermatol 1993, 28:710-8. 72. Mansi IA, Opran A, Rosner F. ANCA associated small-vessel vasculitis. Am Fam Physician 2002; 65: 1615-20. 73. Mukhopadhyay A, Stanley NN. Churg-Strauss syndrome associated with montelukast. Postgrad Med J 2001; 77:390-1. 74. Tang MBY, Yosipovitch G. Acute Churg-Strauss syndrome in an asthmatic patient receiving montelukast therapy. Arch Dermatol 2003; 139: 715-8. 75. Vogel PS, Nemer J, Sau P, et al. Churg-Strauss syndrome. J Am Acad Dermatol 1992; 27: 821-4. 76. Davis MD, Daoud MS, McEvoy MT, et al. Cutaneous manifestations of ChurgStrauss syndrome: A clinicopathologic correlation. J Am Acad Dermatol. 1997:37:199-203. 77. Amitai Y, Gillis D, Wasserman D, et al. Henoch-Schönlein purpura in infants. Pediatrics 1993; 92:865-7. 78. Murali NS, George R, John GT, et al. Problems of classification of Henoch Schönlein purpura: An Indian perspective. Clin Exp Dermatol 2002; 27:260-3. 79. Bagga A, Kabra SK, Srivastava RN, et al. Henoch-Schönlein syndrome in Northern Indian children. Indian Pediatr 1991; 28:1153-7. 80. Finkel TH, Torok TJ, Ferguson PJ, et al. Chronic parvovirus B19 infection and systemic necrotizing vasculitis: opportunistic infection or aetiological agent? Lancet 1994; 343:1255-8. 81. Lind KM, Gaub J, Pedersen RS. Henoch-Schönlein purpura associated with Campylobacter jejuni enteritis. Scand J Urol Nephrol 1994; 28:179-81. 82. Szer IS. Henoch-Schönlein purpura. Curr Opin Rheumatol 1994; 6:25-31. 83. Ben-Sira L, Laor T. Severe scrotal pain in boys with Henoch-Schönlein purpura: Incidence and sonology. Pediatr Radiol 2000; 30:125-8. 84. Garcia-Porrua C, Calvino MC, Llorca J, et al. Henoch-Schonlein purpura in children and adults: Clinical differences in a defined population. Semin Arthritis Rheum 2002; 32:149-56. 85. Michel BA, Hunder GG, Bloch DA. Hypersensitivity vasculitis and HenochSchönlein purpura: A comparison between the 2 disorders. J Rheumatol 1992; 19:721-8. 86. Cacoup P, Poynard T, Ghillani P, et al. Extrahepatic manifestations of chronic hepatitis C. Arthritis Rheum 1999; 42:2204-12.

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87. Sais G, Vidaller A, Jucgia A, et al. Prognostic factors in leukocytoclastic vasculitis. A clinicopathologic study of 160 patients. Arch Dermatol 1998; 134: 309-15. 88. Caksen H, Odabas D, Kosem M, et al. Report of eight infants with acute infantile hemorrhagic oedema and review of the literature. J Dermatol 2002; 29:290-5. 89. Kuroda K, Yabunami H, Hisanaga Y. Acute haemorrhagic oedema of infancy associated with cytomegalovirus infection. Br J Dermatol 2002;147:1254-7. 90. Bozaykut A, Atay E, Atay Z, et al. Acute infantile haemorrhagic oedema associated with hepatitis A. Ann Trop Paediatr 2002; 22:59-61. 91. Paradisi M, Annessi G, Corrado A. Infantile acute hemorrhagic oedema of the skin. Cutis 2001;68:127-9. 92. Millard R, Harris A, Macdonald D. Acute infantile hemorrhagic oedema. J Am Acad Dermatol 1999; 41:837-9. 93. Bauza A, Espana A, Idoate M. Cutaneous polyarteritis nodosa. Br J Dermatol 2002; 146: 694-9. 94. Muratori S, Carrera C, Gorani A, et al. Erythema elevatum diutinum and HIV infection: A report of five cases. Br J Dermatol 1999; 141:335-8. 95. Johnson RM, Barbarini G, Barbaro G. Kawasaki-like syndromes and other vasculitic syndromes in HIV-infected patients. AIDS 2003; (Suppl1): S77-82. 96. Chen KR, Toyohara A, Suzuki A, et al. Clinical and histopathological spectrum of cutaneous vasculitis in rheumatoid arthritis. Br J Dermatol 2002; 147:90513. 97. Buahene K, Hudson M, Mowat A, et al. Erythema elevatum diutinum: An unusual association with ulcerative colitis. Clin Exp Dermatol 1991; 16: 2046. 98. Yiannias JA, Ez-Azhary RA, Gibson LE. Erythema elevatum diutinum: a clinical and histopathological study of 13 patients. J Am Acad Dermatol 1992; 26:3844. 99. Castellano-Howard L, Fairbee SI, Hogan DJ, et al. Extrafacial granuloma faciale: report of a case and response to treatment. Cutis 2001; 67: 413-5. 100. Roustan G, Sanchez Yus E, Salas C, et al. Granuloma faciale with extrafacial lesions. Dermatology 1999; 198:79-82. 101. Burns BV, Roberts PF, De Carpentier J, et al. Eosinophilic angiocentric fibrosis affecting the nasal cavity. A mucosal variant of the skin lesion granuloma faciale. J Laryngol Otol 2001 115(3):223-6. 102. DiCaudo DJ, Connolly SM. Neutrophilic dermatosis (pustular vasculitis) of the dorsal hands. A report of seven cases and review of the literature. Arch Dermatol 2002; 138:361-5. 103. Strutton G, Weedon D, Robertson I . Pustular vasculitis of the dorsal hands. J Am Acad Dermatol 1995; 32:192-8. 104. Curco N, Pagerols X, Tarroch X, et al. Pustular vasculitis of the hands: report of two men. Dermatology 1996; 196:346-7. 105. Hall AP, Goudge RJ, Ireton HJC, et al. Pustular vasculitis of the hands. Australas J Dermatol 1999; 40:204-7. 106. Galaria NA, Junkins-Hopkins JM, Kligman D, et al. Neutrophilic dermatosis of the dorsal hands: Pustular vasculitis revisited. J Am Acad Dermatol 2000, 43: 870-4. 107. Ayoub N, Tomb R. Neutrophilic dermatosis of dorsal hands: a variant of erythema elevatum diutinum? Arch Dermatol 2003; 139:102.


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108. Tatum AJ, Ditto AM, Patterson R. Severe serum sickness-like reaction to oral penicillin drugs. Three case reports. Ann Allergy Asthma Immunol 2001; 86: 330-4. 109. Creamer JD, McGrath JA, Webb-Peploe M, et al. Serum sickness-like illness following streptokinase therapy. A case report. Clin Exp Dermatol 1995; 20:46870. 110. Sanklecha MU. Cefaclor-induced serum sickness-like reaction. Indian J Paediatr 2002;69:921. 111. Harel L, Amir J, Livni E, et al. Serum sickness-like reaction associated with minocycline therapy in adolescents. Ann Pharmacother 1996; 30:481-3. 112. McCollom RA, Elbe DH, Ritchie AH. Bupropion-induced serum sickness-like reaction. Ann Pharmacother 2000; 34:471-3. 113. Venzor J, Lee WL, Huston DP. Urticarial vasculitis. Clin Rev Allergy Immunol 2002; 23:201-16. 114. De Amicis T, Mofid MZ, Cohen B, et al. Hypocomplementemic urticarial vasculitis: Report of a 12-year-old girl with systemic lupus erythematosus. J Am Acad Dermatol 2002; 47:273-4. 115. Wisnieski JJ, Baer NN, Christensen J, et al. Hypocomplementemic urticarial vasculitis syndrome. Clinical and serologic findings in 18 patients. Medicine 1995; 74:24-41. 116. Zax RH, Hodge SJ, Callen JP. Cutaneous leukocytoclastic vasculitis: Serial histopathologic evaluation demonstrates the dynamic nature of the infiltrate. Arch Dermatol 1990; 126:69-72. 117. Choi SJ, Park SK, Uhm WS, et al. A case of refractory Henoch-Schönlein purpura treated with thalidomide. Korean J Intern Med 2002; 17:270-3. 118. Sneller MC, Hoffman GS, Talar-Williams C, et al. An analysis of 42 Wegener’s granulomatosis patients treated with methotrexate and prednisolone. Arthritis Rhem 1995; 38:608-13. 119. Zuckerman E, Keren D, Siobodin G, et al. Treatment of refractory, symptomatic, hepatitis C virus related mixed cryoglobulinemia with ribavirin and interferonalpha. J Rheumatol 2000; 27:2172-8. 120. Dowlati B, Firooz A, Dowlati Y. Granuloma faciale: successful treatment of nine cases with a combination of cryotherapy and intralesional corticosteroid injection. Int J Dermatol 1997; 36:548-51.

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5

Jayakar Thomas

Emergencies in Pediatric Dermatology INTRODUCTION The word ‘emergency’ means sudden happening that needs immediate and quick attention. It was something that was never thought of earlier in the speciality of dermatology. But today we know that the reality is far from this and current dermatological practice has undergone tremendous change in the direction of crisp, comprehensive, and critical care being offered to various conditions ranging from urticaria through gangrenous conditions to vesiculo-bullous disorders. There are several studies on the subject of ‘emergency dermatology’ in terms of the nature of consultations, direct or referrals, in an emergency setting and in terms of evaluation of the same in tertiary care centres. Some of the common dermatological emergencies seen in the pediatric age group will be discussed and brief description of the condition and steps involved in management of the conditions are provided in this article. Novel concepts of ‘acute skin failure’ (ASF) like cardiac, renal or respiratory failures and ‘intensive skin care unit’ (ISCU) put forward by Rene Touraine in 19761 will also be described briefly. PEDIATRIC SIGNIFICANCE These concepts of ASF and ISCU have to be perceived with more seriousness from the pediatric point of view. The reasons for such significance in children include: • Improper development of barrier function in children skin. • Lack of fully formed immunological role. • Both of the above leading to increased susceptibility to infection. • Increased metabolic rates in children leading to increase in energy expenditure and these in turn demand more of fluid and nutrition supplement. • Impaired thermoregulatory function of skin in children requiring better management of ambience.

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• The different proportion of body weight and body surface area of a child’s skin in comparison to the adult (almost three times) making it difficult to evaluate the dosage of medication to be used. • Easy hemodynamic instability resulting from increased cutaneous blood flow. • More percutaneous absorption of topically used drugs making the physician to be more alert about side effects. • All of the above heightening the chances of multi-organ and multisystem failures. CLASSIFICATION For the purposes of orderly thinking and for the ease of presentation, the following classification of pediatric dermatological emergencies might prove helpful: Infections: Cellulitis, Staphylococcal scalded skin syndrome, Neonatal herpes, Neonatal candidiasis Toxic erythemas: Urticaria and angioedema, Drug eruptions, Kawasaki syndrome, Exfoliative dermatitis Drug reactions: Erythema multiforme, Stevens Johnson syndrome, Toxic epidermal necrolysis Keratinization disorders: Collodion baby, Harlequin fetus Purpuric and hemorrhagic disorders: Meningococcal disease, Graft versus host disease Vesiculo-bullous disorders: Pemphigus, Epidermolysis bullosa, Linear IgA disease Proliferative disorders: Hemangiomas, Histiocytosis, Mastocytosis Miscellaneous: Acrodermatitis enteropathica, Sclerema, Leiner’s disease, etc. PEDIATRIC DERMATOLOGICAL EMERGENCIES As a complete description of all the conditions included in this group of dermatoses is not within the scope of this article, the more important one will be discussed. Cellulitis2 Streptococcus pyogenes (group A-hemolytic streptococcus) is the most common cause of superficial cellulitis; diffuse infection occurs because

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streptokinase, DNase, and hyaluronidase enzymes produced by the organism break down cellular components that otherwise would contain and localize the inflammation. Group B, C, D, or G-hemolytic streptococci are less common causes. Staphylococcus aureus occasionally produces a superficial cellulitis typically less extensive than that of streptococcal origin and usually only in association with an open wound or cutaneous abscess. Superficial cellulitis caused by other organisms, primarily aerobic gram-negative bacilli, occurs rarely (generally in special circumstances). With granulocytopenia, diabetic foot ulcers, or severe tissue ischemia, aerobic gram-negative bacilli (e.g., Escherichia coli, Pseudomonas aeruginosa) may be responsible. Unusual bacteria may cause cellulitis occurring after animal bites, especially Pasteurella multocida from dogs and cats. Immersion injuries in fresh water may result in cellulitis caused by Aeromonas hydrophila; in warm salt water, Vibrio vulnificus may cause cellulitis. Infection is most common in the lower extremities. A cutaneous abnormality (e.g., skin trauma, ulceration, tinea pedis, dermatitis) often precedes the infection; areas of lymphedema or other edema seem to be especially susceptible. Frequently, however, no predisposing condition or site of entry is evident. The major findings are local erythema and tenderness, frequently with lymphangitis and regional lymphadenopathy. The skin is hot, red and edematous, often with an infiltrated surface resembling the skin of an orange (peau d’orange). The borders are usually indistinct, except in erysipelas, a type of cellulitis in which the raised margins are sharply demarcated. Petechiae are common; large areas of ecchymosis are rare. Vesicles and bullae may develop and rupture, occasionally with necrosis of the involved skin. Systemic manifestations (fever, chills, tachycardia, headache, hypotension, delirium) may precede the cutaneous findings by several hours, but many patients do not appear ill. Leukocytosis is common, but not constant. The diagnosis usually depends on the clinical findings. Unless pus has formed or an open wound is present, the responsible organism often is difficult to be isolated, even on aspiration or skin biopsy. Blood cultures are occasionally positive. Serologic tests, especially measurement of rising titers of anti-DNase B, confirm a streptococcal cause, but are usually unnecessary. Although cellulitis and deep vein thrombosis usually are easily differentiated clinically, many physicians confuse these entities when edema occurs in the lower extremities. Local abscesses form occasionally, requiring incision and drainage. Serious but rare complications include severe necrotizing subcutaneous infection and bacteremia with metastatic foci of infection. Even without antibiotics, most cases of superficial cellulitis resolve spontaneously; however, recurrences in the same area are common, sometimes causing serious damage to the lymphatics,


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chronic lymphatic obstruction, marked edema, and rarely, elephantiasis. With antibiotics, such complications are uncommon. Symptoms and signs of superficial cellulitis usually resolve after a few days of antibiotic therapy. For streptococcal cellulitis, penicillin is the drug of choice: For mild outpatient cases, penicillin V in the dose of 15-30 mg/kg/24 hr, divided, every 6-8 hours is adequate. For severe infections, which require hospitalization, aqueous penicillin G 25,000-50,000 units/kg/24 hr is indicated. In penicillin-allergic patients, erythromycin 30-50 mg/kg/ 24 hr, divided, every 6 hr is effective for mild infections, and parenteral gentamicin for severe infections. Although S. aureus rarely causes typical cellulitis, many clinicians prefer using antibiotics also active against this organism: cloxacillin 50-100 mg/kg/24 hr, divided, every 6 hr qid for mild infections, or cefotaxime 100-150 mg/kg/24 hr, divided, every 4-6 hr IV for severe infections. For penicillin-allergic patients or those with suspected methicillin-resistant S. aureus infection, vancomycin 45-60 mg/kg/24 hr, divided, every 6-8 hr is the drug of choice. When pus or an open wound is present, results of a Gram stain should dictate antibiotic choice. Immobilization and elevation of the affected area help reduce edema, and cool, wet dressings relieve local discomfort. Cellulitis in a neutropenic patient requires antibiotics effective against aerobic gram-negative bacilli until culture results are available. Penicillin is the drug of choice for P. multocida, an aminoglycoside (e.g., gentamicin) is effective against A. hydrophila, and tetracycline is the preferred antibiotic for V. vulnificus. Treating concomitant tinea pedis, which often eliminates the source of bacteria residing in the inflammed, macerated tissue prevents recurrent leg cellulitis. If such therapy is unsuccessful or not indicated, recurrent cellulitis sometimes can be prevented by benzathine penicillin 1.2 million U IM monthly, or penicillin V or erythromycin for 1 week every month. Staphylococcal Scalded Skin Syndrome3 (Ritter-Lyell Syndrome) Staphylococcal scalded skin syndrome (SSSS) almost always occurs in infants and in children below 6 years. Epidemics may occur in nurseries, presumably transmitted by the hands of personnel in contact with an infected infant. However, nursery personnel may be nasal carriers of S. aureus. Sporadic cases also occur. Group II coagulase-positive staphylococci, usually phage type 71 and often resistant to penicillin, elaborate exfoliatin (also called epidermolysin), an epidermolytic toxin that splits off the upper part of the epidermis just beneath the granular cell layer. The inciting infection

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may be on the skin but usually is in the eye or nasopharynx. The toxin enters the circulation and affects the skin systemically, as in scarlet fever. In infants, illness often begins during the first few days of life with a localized crusted infection (often impetigo-like), most often at the umbilical stump or in the diaper area. Sporadic cases often start with a superficial crusted lesion, frequently around the nose or ear. Within 24 hours, tender scarlet areas appear around the crusted area and may become painful and generalized. Large, flaccid blisters arise on the erythematous skin and quickly break to produce erosions. The epidermis peels off easily, often in large sheets, when the red areas are rubbed (Nikolsky’s sign). Widespread desquamation of the skin occurs within 36 to 72 hours, and patients may become very ill with systemic manifestations (e.g., malaise, chills, fever). Loss of the protective skin barrier can lead to sepsis and fluid and electrolyte imbalance. Symptoms and signs are indistinguishable clinically from toxic epidermal necrolysis; yet SSSS must be distinguished rapidly from TEN because therapy is different. Cultures should be obtained from the skin and nasopharynx. Diagnosis is confirmed by skin biopsy and examination of frozen tissue sections or exfoliative cytology, showing epithelial cells. Although final biopsy results may be available until well after treatment has been started, frozen tissue sections and cytology can provide rapid confirmation. Differential diagnosis includes drug hypersensitivity (most notably, TEN), viral exanthems and scarlet fever, but none of these causes a painful rash. Bullae, erosions, and an easily loosened epidermis occur in thermal burns, genetic bullous diseases (e.g., some types of epidermolysis bullosa) and acquired bullous diseases (e.g., pemphigus vulgaris, bullous pemphigoid). With prompt diagnosis and therapy, death rarely occurs. Systemic penicillinase-resistant antistaphylococcal antibiotics (e.g., cloxacillin, cephalexin) must be started as soon as the clinical diagnosis is made, without waiting for culture results. In early-stage disease, oral cloxacillin 12.5 mg/kg q 6 h (for infants and children weighing <=20 kg) and 250 to 500 mg q 6 h (for older children) may be given; in severe disease, gentamicin IV in 4 divided doses should be additionally given until improvement is noted, followed by oral cloxacillin 25 mg/kg/day up to 100 mg/kg/day for >=10 days. Corticosteroids are contraindicated, and topical therapy and patient handling must be minimized. If the disease is widespread and the lesions are weeping, the skin should be treated as if it were burned. Hydrolyzed polymer gel dressings may be very useful, and the number of dressing changes should be minimized. Because the split is high in the epidermis, the stratum corneum is quickly replaced


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and healing is usually within 5 to 7 days after the start of treatment. Steps to detect carriers and prevent or treat nursery epidemics are to be taken. Neonatal Herpes Simplex Virus Infection4 Infection with herpes simplex virus is usually transmitted during parturition, typically causing vesicular eruption and subsequent disseminated disease. Neonatal herpes simplex virus (HSV) infection has high mortality and significant morbidity. Incidence estimates range from 1/3,000 to 1/20,000 live deliveries. HSV type 2 causes about 80 percent of cases; 20 percent are caused by HSV type 1. HSV type 2 is usually transmitted to the newborn during delivery by passage through an infected maternal genital tract. Transplacental transmission of virus and nosocomial spread from one newborn to another by hospital personnel or family has also been implicated in about 15 percent of cases. Mothers of newborns with HSV infection tend to have no history or symptoms of genital infection at the time of delivery. Manifestations generally occur between the 1st and 2nd week of life; however, symptoms may not appear until as late as the 4th week. The hallmark of infection is skin vesicles, which, if untreated, frequently lead to progressive or more serious froms of disease within 7 to 10 days. However, up to 45 percent of infected newborns initially have no skin vesicles; usually these newborns have localized CNS disease. Other signs of infection, which can occur singly or in combination, include temperature instability, lethargy, hypotonia, respiratory difficulty (apnea or pneumonia), convulsions, hepatitis, and disseminated intravascular coagulation (DIC). Newborns with disseminated disease and visceral organ involvement have hepatitis, pneumonitis, and/or DIC with or without encephalitis or skin disease. Newborns with localized disease can be subdivided into two groups. The first group has encephalitis manifested by neurologic findings, CSF pleocytosis and elevated protein concentration, with or without concomitant involvement of the skin, eyes, and mouth. The second group has only skin, eye, and mouth involvement and no evidence of CNS or organ disease. Rapid and specific diagnosis of neonatal HSV infection is essential. Infection can be confirmed by isolating virus in tissue culture, using vaious cell lines of human or nonhuman origin. The most common site of retrieval is a skin vesicle; the mouth, eye, and CSF are also high-yield sites. In some newborns presenting with encephalitis, virus is found only in the brain; however, accurate testing (such as HSV polymerase

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chain reaction) is available in only a few research and specialized laboratories. Cytopathologic effects usually can be demonstrated in tissue culture within 24 to 48 h after inoculation. The diagnosis can also be confirmed by neutralization with appropriate high-titer antiserum; immunofluorescence of lesion scrapings, particularly with use of monoclonal antibodies and electron microscopy. If no diagnostic virology facilities are available, a Leishman smear of the lesion base may show characteristic histopathologic evidence (multinucleated giant cells and intranuclear inclusions), but this is less sensitive than culture and falsepositive results occur. The mortality rate of newborns with untreated disseminated disease is 85 percent; of those with untreated local disease and encephalitis, about 50 percent. At least 95 percent of the survivors have severe neurologic sequelae. Death is uncommon in those with local (skin, eyes, mouth) disease having without CNS or organ disease, except as the result of concomitant medical problems, but about 30 percent develop neurologic impairment, which may not manifest until 2 to 3 years of age. Morbidity in each group parallels mortality and is directly proportional to disease extent. About 90 percent of infants with viscerally disseminated neonatal HSV infection have subsequent sequelae. Only 5 percent of those with CNS infection return to normal. Therapy with acyclovir decreases the mortality rate by 50 percent and increases the percentage that develops normally from 10 to 50 percent. Acyclovir 30 mg/kg/day in standard IV fluid is given q 8 h in divided doses for 10 to 14 days. Vigorous supportive therapy is required, including appropriate IV fluids, alimentation, respiratory support, correction of clotting abnormalities, and control of seizure disorders. Herpes keratoconjunctivitis requires concomitant systemic acyclovir and topical therapy with a drug such as trifluridine. Neonatal Candidiasis5 Systemic or cutaneous candidiasis presenting within 12 hours of birth are classified as congenital candidal infection. It is an intrauterine infection acquired by ascending or cervical infection. Oral mucosa and diaper areas are not involved. The presentation is initially as a morbiliform eruption, erythematous macules, papulo-vesicles, or pustules. The condition is best treated with ketoconazole in a dosage of 3 mg/kg/day for 7 to 10 days. Urticaria and Angioedema6 Acute urticaria and angioedema are essentially anaphylaxis limited to


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the skin and subcutaneous tissues and can be due to drug allergy, insect stings or bites, desensitization injections, or ingestion of certain foods (particularly eggs, shellfish, or nuts). Some reactions occur explosively after ingestion of minute amounts. Others (e.g., reactions to strawberries) may occur only after overindulgence and possibly result from direct (toxic) mediator liberation. Urticaria may accompany or even be the first symptom of several viral infections, including hepatitis, infectious mononucleosis, and rubella. Some acute reactions are unexplained, even when recurrent. If acute angioedema is recurrent, progressive, painful rather than pruritic and not associated with urticaria, a hereditary enzyme deficiency should be considered (see Hereditary Angioedema, below). Chronic urticaria and angioedema lasting more than 6 weeks are more difficult to explain and only in exceptional cases can a specific cause be found. The reactions are rarely IgE-mediated. Occasionally, chronic ingestion of an unsuspected drug or chemical is responsible; e.g., from penicillin in milk; from the use of nonprescription drugs; or from preservatives or other food additives. Chronic underlying disease (SLE, polycythemia vera, lymphoma, or infection) should be ruled out. Though often suspected, controllable psychogenic factors are rarely identified below. A few patients with intractable urticaria have thyroid disease. Occasionally, urticaria may be the first or only visible sign of cutaneous vasculitis. In urticaria, pruritus (generally the first symptom) is followed shortly by the appearance of wheals that may remain small (1 to 5 mm) or enlarge. The larger ones tend to be clear in the center and may be noticed first as large rings (> 20 cm across) of erythema and edema. Ordinarily, crops of hives appear and subside; a lesion may remain in one site for several hours and then disappear, only to reappear elsewhere. If a lesion persists >=24 h, the possibility of vasculitis should be considered. Angioedema is characterized by a more diffuse and painful swelling of loose subcutaneous tissue, dorsum of hands or feet, eyelids, lips, genitalia and mucous membranes. Edema of the upper airways may produce respiratory distress and the stridor may be mistaken for asthma. The cause of acute urticaria or acute angioedema is usually obvious. Even when it is not, diagnostic tests are seldom required because of the self-limited, nonrecurring nature of these reactions. In chronic urticaria, an underlying chronic disease should be ruled out by a detailed history and physical examination and routine screening tests. Eosinophilia is uncommon in urticaria. Other tests (e.g., stool examination for ova and parasites, serum complement, antinuclear antibody, and sinus or dental X-rays) are not helpful without additional clinical indications. Since acute urticaria generally subsides in 1 to 7 days, treatment is

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chiefly palliative. If the cause is not obvious, all non-essential drugs should be stopped until the reaction has subsided. Symptoms usually can be relieved with an oral antihistamine, such as diphenhydramine 5 mg/kg/24 hr, divided, every 6-8 hr, hydroxyzine 2 mg/kg/24 hr, divided, every 6-8 hr, or cyproheptadine 2 mg/dose (children 2-6 yr) and 4 mg/dose (children > 7 yr) every 8-12 hr. If these cause drowsiness (which occurs in a majority of patients), one of the nonsedating antihistamines should be used. A glucocorticoid (e.g., prednisolone 2 mg/kg/24 hr, divided, every 6-8 hr may be needed for more severe reactions, especially when associated with angioedema. Topical glucocorticoids are of no value. Epinephrine 1:1000, 0.3 ml sc, should be the first treatment for acute pharyngeal or laryngeal angioedema. This may be supplemented with topical treatment; e.g., a nebulized adrenergic agent and an IV antihistamine (e.g., diphenhydramine). This usually prevents airways obstruction, but intubating or performing a tracheostomy and administering O2 might be necessary. In chronic urticaria, spontaneous remissions occur within 2 yr in about half of cases. Control of stress often helps reduce the frequency and severity of episodes. Hereditary Angioedema7 It is a form of angioedema transmitted as an autosomal dominant trait and associated with a deficiency of serum inhibitor of the activated first component of complement. In 85 percent of cases, the deficiency is due to a lack of the CI esterase inhibitor; in 15 percent, to malfunction of CI esterase inhibitor. A positive family history is the rule with some exceptions. Edema is typically unifocal, indurated, painful rather than pruritic and unaccompanied by urticaria. Attacks are often precipitated by trauma or viral illness and are aggravated by emotional stress. The GI tract is often inolved, with nausea, vomiting, colic and even signs of intestinal obstruction. The condition may cause fatal upper airway obstruction. Diagnosis may be made by measuring C4, which is low even between attacks, or more specifically by showing C1 inhibitor deficiency by immunoassay, and a functional assay if the immunoassay results are unexpectedly normal. An acquired form of C1-inhibitor deficiency secondary to neoplastic diseases such as lymphoma is distinguished by low C1 levels and by depressed C4 levels. For short-term prophylaxis of the previously untreated patient (as before a dental procedure, endoscopy, or surgery), 2 U of fresh frozen plasma can be given. Although theoretically a complement substrate in the plasma might provoke an attack, this has not been observed in


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symptom-free patients. Recently, a partially purified C1 esterase inhibitor fraction of pooled plasma has been shown to be safe and effective for prophylaxis, but it is unavailable for general use. If time permits, the patient should be treated for 3 to 5 days with an androgen. For long-term prophylaxis, androgens are effective. One of the impeded androgens should be used. Treatment is begun with oral stanozolol 2 mg tid or danazol 200 mg tid. Stanozolol is less expensive. Once control is achieved, the dosage should be reduced as much as possible to reduce the cost and, in women, to minimize masculinizing side effects. These drugs not only are effective but also have been shown to raise the low C1 esterase inhibitor and C4 toward normal. The edema progresses until complement components have been consumed. Acute attacks that threaten to produce airways obstruction, therefore, should be treated promptly by establishing an airway. The use of fresh frozen plasma is controversial. Epinephrine, an antihistamine and a glucocorticoid should be given, but there is no proof that these drugs are effective. Drug Eruptions8 (Dermatitis Medicamentosa) Although the mechanisms of most drug eruptions are unknown, many are allergic. Specific antibodies or sensitized lymphocytes to the drug may develop as soon as 4 to 5 days after initial drug exposure. A later eruption caused by re-exposure to the drug may appear within minutes, but may be delayed for days or longer. Other reactions may be caused by accumulation of a drug (e.g., pigmentation from silver), pharmacologic action of a drug (e.g., striae or acne from systemic corticosteroids, purpura from excessive anticoagulation), or interaction with genetic factors (e.g., porphyria cutanea tarda from estrogens, which induce an enzyme involved in porphyrin metabolism). Drug eruptions vary from a mild rash to toxic epidermal necrolysis. Onset may be sudden (e.g., urticaria or angioedema from penicillin) or delayed for hours or days (morbilliform or maculopapular eruptions from penicillin or sulfonamides) or for years (exfoliation or pigmentation from arsenic). The lesions may be localized (fixed drug eruptions, oral ulcers, dermatitis in light-exposed areas), but many are generalized. Reactions may be characteristic of certain drugs or may imitate practically features of any dermatosis. The drugs added to therapy most recently are most likely to be the cause, but drugs taken for long periods must also be suspected. Identification of the causative agent is essential. A detailed history is often required, with persistent inquiry about all drugs, including OTC drugs for sleep, pain, colds, constipation, headache, eyedrops, nose drops

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and suppositories. Some eruptions start after the drug has been stopped (e.g., ampicillin) or continue for weeks or months; minute amounts of some drug may produce a reaction. However, most drug reactions resolve when the offending drug is stopped and require no further therapy. Often, especially in hospitalized patients, all but lifesustaining dugs can be discontinued and each reinstituted at weekly intervals in order of importance. A physician well versed in the incidence and types of drug eruptions can often withhold the most likely offender while continuing all other drugs. When suspected offending drugs are necessary, chemically unrelated compounds should be substituted when possible. No laboratory tests are available to aid diagnosis, although lymphocyte transformation and penicillin skin tests are under study. Biopsy of affected skin may be helpful. Sensitivity can be definitively established only by readministration of the drug, but this may be hazardous or unethical. A lubricant (e.g., white petrolatum) may provide symptomatic relief for a dry, itching maculopapular eruption. A fluorinated corticosteroid ointment may be applied in a small area initially and, if effective, applied to the entire eruption. Acute urticaria may be a sign of anaphylaxis and may require aqueous epinephrine (1:1000) 0.2 ml sc or IM or the sloweracting but more persistent soluble hydrocortisone 100 mg IV, which may be followed by an oral corticosteroid for a short period. Kawasaki Syndrome9 A syndrome, occurring usually in infants and children less than 5 years, characterized by prolonged fever, exanthem, conjunctivitis, mucous membrane inflammation, cervical lymphadenopathy and polyarteritis of variable severity. Its etiology is unknown, but the epidemiology and clinical presentation suggest an infection or an abnormal immunologic response to an infection. Since the syndrome was first described in Japan in the late 1960s, thousands of cases have been reported worldwide in diverse racial and ethnic groups, although children of Japanese descent have a higher incidence. The male: female ratio is about 1.5 : 1. Eighty percent of patients are less than 5 years (median, 2 years); true cases in teenagers or adults are rare. Cases occur year-round, but most often in spring or winter. Clusters have been reported in communities without clear evidence of person-to-person spread. Recurrences occur in about 1 percent of patients. The pathology is nearly identical to infantile periarteritis nodosa, with vasculitis primarily affecting the coronary arteries, but also other medium-sized and large arteries. The illness tends to progress in stages,


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beginning with fever, usually remittent and > 39°C (> 102.2°F), which is associated with irritability, often extreme, and occasional lethargy or intermittent colicky abdominal pain. Fever lasts 1 to 2 weeks or more in untreated patients. Usually within a day or two of fever onset, bilateral bulbar conjunctival injection without exudate appears. Within 5 days, a polymorphous, erythematous macular rash appears, primarily over the trunk, often with accentuation in the perineal region. The rash may be urticarial, morbilliform, or scarlatiniform and is accompanied by injected pharynx; reddened, dry, fissured lips; and a red strawberry tongue. During the first week, pallor of the proximal portion of the fingernails or toenails (leukonychia partialis) may occur. Erythema or a purple-red discoloration and variable edema of the palms and soles usually appear on about the third to fifth day. Although edema may be slight, it is often tense, hard, and nonpitting. Periungual, palmar, and plantar desquamation begins on about the 10th day after onset. The superficial layer of the skin sometimes comes off in large casts, revealing new normal skin. Tender, nonsuppurative cervical lymphadenopathy (>=1 node, >= 1.5 cm in size) is present throughout the course in about 50 percent of patients; the other findings each are present in about 90 percent of patients. The illness may last from 2 to 12 weeks or longer. Other less specific findings indicate involvement of many systems. Arthritis or arthralgias (mainly involving large joints) occur in about 1/3 of patients. Other clinical features may include urethritis, aseptic meningitis, diarrhea, hydrops of the gallbladder, and anterior uveitis. The most important complications are those of cardiac inflammation, most notably coronary arteritis. Cardiac manifestations usually begin on about the 10th day, as the rash, fever, and other early acute clinical symptoms begin to subside; i.e., in a subacute phase of the syndrome. Inflammation of the coronary arteries with dilation and aneurysm formation occurs in 5 to 20 percent of all cases, sometimes associated with acute myocarditis with heart failure, arrhythmias, and pericarditis and rarely with cardiac tamponade, thrombosis, or infarction. Leukocytosis, often with a marked increase in immature cells, is common in the acute phase of the illness. Other hematologic findings include a mild anemia, thrombocytosis (>= 500,000/uL) in the second or third week of illness and elevated ESR (often strikingly so). Other abnormalities, depending on the organ systems involved, may include pyuria, proteinuria, CSF pleocytosis and ECG changes (arrhythmias, decreased voltage, or left ventricular hypertrophy). Echocardiography should be performed in all patients at diagnosis (for establishing a baseline and detecting coronary artery aneurysms, pericarditis, or myocarditis); at 3 to 4 weeks after onset; at 6 to 8 weeks

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after onset; and perhaps at 6 to 12 months after onset. Coronary arteriography is occasionally useful in patients with aneurysms and abnormal stress testing. ECGs are often repeated along with echocardiograms. Diagnosis is based on the clinical findings and on exclusion of other diseases. Results of cultures for bacteria and viruses as well as serologic tests for evidence of infection are negative, but may be useful for diagnosing other illnesses with similar presentations. Differential diagnosis includes bacterial diseases (especially scarlet fever, staphylococcal exfoliative syndromes, and leptospirosis), viral exanthems (e.g., measles, viral hemorrhagic fever), toxoplasmosis, acrodynia (caused by mercury poisoning), Stevens-Johnson syndrome and juvenile RA. The mortality rate is 0.1 percent with adequate therapy; without therapy, mortality may approach 1 percent. Deaths most commonly result from cardiac complications, but can be sudden and unpredictable; 50 percent occur within 1 month of onset, 75 percent within 2 months and 95 percent within 6 months, but may occur as long as 10 years later. Effective therapy reduces acute symptoms and, more importantly, reduces the incidence of coronary artery aneurysms from 20 percent to < 5 percent. In the absence of coronary artery disease, the prognosis for complete recovery is excellent. About 2/3 of coronary aneurysms regress within 1 year, although it is unknown whether residual coronary stenosis remains or not. Giant coronary aneurysms (> 8 mm internal diameter on echocardiogram) are less likely to regress and require more intensive follow-up and therapy. Children with Kawasaki syndrome should be treated by or in close consultation with an experienced pediatric cardiologist or pediatric infectious disease specialist. Therapy is started as soon as possible, optimally within the first 10 days of illness, with a combination of highdose immune globulin intravenous (IGIV-a single dose of 2 g/kg given over 10 to 12 h) and oral high-dose aspirin (80 to 100 mg/kg/day in 4 divided doses). The aspirin dose is reduced to 3 to 5 mg/kg/day as a single dose when the child becomes afebrile. (Some authorities prefer to continue high-dose aspirin until the 14th day of illness.) Aspirin metabolism is erratic during acute Kawasaki syndrome, which partially explains the reason for the high dose requirements. Some authorities monitor serum aspirin levels during high-dose therapy, especially if therapy is given for 14 days. Most patients have a brisk response over the 24 hours after therapy begins; a small fraction continue to be ill with fever for several days and require repeat dosing with IGIV. An alternative regimen, which may lead to slightly slower resolution of symptoms but may benefit those with cardiac dysfunction who could not tolerate the volume of a 2 g/kg IGIV infusion, is 400 mg/kg/day of IGIV daily over


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4 days (again in combination with high-dose aspirin). The efficacy of IGIV/aspirin therapy, when begun more than 10 days after onset of illness, is unknown, but therapy should still be considered. After the child has improved, aspirin 3 to 5 mg/kg/day is continued for at least 8 weeks until repeat echocardiographic testing is completed. If there are no coronary artery aneurysms and signs of inflammation are receding (demonstrated by normalization of ESR and platelets), aspirin may be discontinued. Because of its antithrombotic effect, aspirin is continued indefinitely for children with coronary artery abnormalities. Children with giant coronary aneurysms may require additional anticoagulant therapy (e.g., coumarin or dipyridamole). Children who receive IGIV therapy may have a lower response rate to live viral vaccines. Thus, measles-mumps-rubella vaccine should generally be delayed 11 months after IGIV administration and varicella vaccine should be delayed for at least 5 months. If the risk of measles exposure is high, vaccination should proceed, but revaccination (or serologic testing) should be performed 11 months later. A small risk of Reye’s syndrome exists in children receiving longterm aspirin during outbreaks of influenza or varicella. Parents of children receiving aspirin should be instructed to contact their child’s physician promptly if the child is exposed to or develops symptoms of influenza or varicella. Temporary interruption of aspirin may be considered (with substitution of dipyridamole for children with documented aneurysms). Annual influenza vaccination is indicated for children receiving longterm aspirin therapy. Generalized Exfoliative Dermatitis10 Usually no cause is found. Some cases are secondary to certain dermatitis (e.g., atopic, psoriatic, pityriasis rubra pilaris, contact dermatitis); others may be induced by a systemic drug (e.g., penicillin, sulfonamides, isoniazid, phenytoin, barbiturates) or a topical agent. Exfoliative dermatitis may also be associated with mycosis fungoides or lymphoma. The onset may be insidious or rapid. The entire skin surface becomes red, scaly, thickened, and occasionally crusted. Pruritus may be severe or absent. The characteristic appearance of any primary dermatitis is usually lost. Localized areas of normal skin may be seen when the exfoliative dermatitis is caused by such conditions as psoriasis, mycosis fungoides, or pityriasis rubra pilaris. Generalized superficial lymphadenopathy is frequent, but biopsy usually shows benign lymphadenitis, The child may feel cold and have an elevated temperature caused by excessive heat loss from increased blood flow to the skin. Generalized

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exfoliative dermatitis may also cause weight loss, hypoproteinemia, hypocalcemia, iron deficiency or (in patients with borderline cardiac compensation) high-output heart failure. Every attempt must be made to determine the cause. A history or signs of a primary dermatitis may be helpful. Biopsy is usually not helpful, but pemphigus foliaceus or mycosis fungoides may be diagnosed by skin biopsy, or lymphoma by a lymph node biopsy. Sezary syndrome may be diagnosed by a blood smear. The disease may be life-threatening and hospitalization is often necessary. Because drug eruptions and contact dermatitis cannot be ruled out by history alone, all drugs should be stoped, if possible, or essential systemic drugs should be changed to chemically dissimilar ones. Petrolatum applied after tap-water baths gives temporary relief. Oral corticosteroids should be used only when other measures fail. Prednisolone 40 to 60 mg/day is given; after about 10 days, the drug is given on alternate days. Usually the dose can be further decreased, but if an underlying cause is not eliminated, long-term prednisolone will be required. Erythema Multiforme11 An inflammatory eruption characterized by symmetric erythematous, edematous, or bullous lesions of the skin or mucous membranes. No cause of erythema multiforme can be found in over 50 percent of cases. Most other cases are due to infectious diseases (e.g., herpes simplex [probably most common], coxsackie viruses and echoviruses, Mycoplasma pneumoniae, psittacosis, histoplasmosis) or drug therapy. Almost any drug can cause erythema multiforme; penicillin, sulfonamides and barbiturates are the most likely. Vaccinia, Bacille Calmette-Guerin (BCG) and poliomyelitis vaccines have also induced erythema multiforme. The mechanism by which infectious agents, drugs or vaccines cause erythema multiforme is unknown, but it is generally considered a hypersensitivity reaction. Onset is usually sudden, with erythematous macules, papules, wheals, vesicles and sometimes bullae appearing mainly on the distal portion of the extremities (palms, soles) and on the face. Hemorrhagic lesions of the lips and oral mucosa can also occur. The skin lesions (target or iris lesions) are symmetric in distribution and often annular, with concentric rings, central purpura and grayish discoloration of the epidermis or vesicle. Itching is variable. Systemic symptoms vary; malaise, arthralgia and fever are frequent. Attacks sometimes last 2 to 4 weeks and recur in the fall and spring for several years. Stevens-Johnson syndrome is a severe form of erythema multiforme (erythema multiforme major) characterized by bullae on the oral mucosa,


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pharynx, anogenital region and conjunctiva, target-like lesions and fever. The patient may be unable to eat or properly close the mouth. The eyes may become very painful; purulent conjunctivitis may make it impossible for the patient to open them. Symblepharon production, keratitis with corneal ulceration, iritis, and uveitis may occur. The conjunctival lesions may leave resistant corneal opacity and synechia. The condition is occasionally fatal. The skin lesions of erythema multiforme must be distinguished from bullous permphigoid, urticaria and dermatitis herpetiformis; the oral lesions from aphthous stomatitis, pemphigus and herpetic stomatitis. Hand, foot and mouth disease produced by coxsackieviruses A5, A10 and A16 must also be considered. Pneumonia should be treated with tetracycline. Local treatment depends on the type of lesion. Vesicles and bullous or erosive lesions can be treated with intermittent Burrow’s solution, saline, or tap-water compresses. Cheilitis and stomatitis of erythema multiforme require special care. Use of systemic corticosteroids is controversial; some patients, especially those with severe mouth and throat lesions, seem to succumb more readily to fatal respiratory complications. The cause, if found, should be treated, eliminated, or avoided. Simple erythema multiforme often needs no treatment. Systemic antibiotics (as indicated by culture and sensitivity) and fluid and electrolyte replacement may be lifesaving in childen with extensive mucous membrane lesions. If frequent or severe erythema multiforme is preceded by herpes simples, acyclovir 200 mg orally five time daily may prevent attacks. Toxic Epidermal Necrolysis12 Toxic epidermal necrolysis (TEN) more often occurs in adults. Sulfonamides, barbiturates, NSAIDs, phenytoin, allopurinol and penicillin are most frequently associated, but numerous other drugs have been less commonly implicated. Intake of drugs is denied by about 1/5 of patients. In about 1/3 of cases, the cause is unclear because of concomitant serious disease and drug treatment. TEN is one of the few true dermatologic emergencies; the mortality rate is 61 percent. TEN typically begins with painful localized erythema that disseminates rapidly. At the sites of erythema, flaccid blisters occur or the epidermis peels off in large sheets with gentle touching or pulling (Nikolsky’s sign). Malaise, chills, myalgias and fever accompany the denudation. Widespread areas of erosion, including all mucous membranes (eyes, mouth, genitalia), occur within 24 to 72 h and the patient may become gravely ill. Affected areas of skin often resemble seconddegree burns. Death is caused by fluid and electrolyte imbalance and

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multiorgan sequelae (e.g. pneumonia, GI bleeding, glomerulonephritis, hepatitis, infection). Rapid diagnosis is important so that a possibly offending drug can be stopped. Before widespread erythema and epidermal denudation occur, it may be difficult to distinguish TEN from morbilliform drug eruptions or erythema multiforme minor and the Stevens-Johnson syndrome (erythema multiforme major). TEN is often thought to be a continuum of the latter two diseases. Although TEN closely resembles staphylococcal scalded skin syndrome, these disorders can be differentiated by the patient’s age, the clinical setting, and the level of the epidermal split seen on biopsy. Patient should be hospitalized; excellent nursing care and close observation are essential. Suspected drugs should be stopped immediately. Patients should be isolated to minimize exogenous infection and treated as are those with severe burns by protecting the skin and denuded areas from trauma and infection and by replacing fluid and electrolyte losses. Although controversial, systemic corticosteroid use has been successful when initiated early in the course of disease. The idea is to stop further immunologic injury to the skin, but systemic corticosteroids will not breathe life into dead keratinocytes or reverse programmed death of skin. Some severe cases require high-dose parenteral corticosteroids for several days; most authorities recommend prednisolone 80 to 200 mg/ day IV (or equivalent), although some recommend 500 to 1000 mg/day IV. This type of corticosteroid therapy has been associated with many adverse effects and should be given under well-controlled conditions. Corticosteroids often seem to enhance the propensity to gram-negative or other sepsis and increase the mortality rate; thus, if these drugs are used, a short course is safer. Septicemia, the most common cause of death, often occurs with pulmonary infections and must be recognized and treated promptly. Ophthalmologic consultation is often required because there may be considerable crusting of the conjunctiva. To prevent phimosis, urologic consultation may be necessary. Collodion Baby13 Autosomal recessive lamellar ichthyosis manifest as collodion babies. These babies are born with a thick armour-like collodion membrane around them that is replaced much later by essentially normal skin. Such babies are at a high risk of dehydration, sepsis, and temperature lability. Emollients such as liquid paraffin are the best topical agents helpful along with control of infection. Topical salicylic acid should never be used because of the danger of salicylism and likewise topical steroids are to be avoided to prevent rapidly developing adrenal


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suppression. Meningococcal Disease14 Meningococcal disease is an illness caused by the bacteria Neisseria meningitides. The two common presentations of meningococcal infection are meningococcal meningitis and meningococcemia. An infected individual may suffer one or both of these diseases. Meningococcal disease is a medical emergency and patients showing signs and symptoms suspicious of meningococcal infection need to seek medical advice from their doctor or a hospital immediately. A delay of even hours can be fatal. Most patients with meningococcal disease are otherwise healthy individuals. However, there are some patient groups who are at an increased risk for developing meningococcal infection. • Children 6 months to 4 years—until about 6 months immunity from the mother is present. Beyond 4 years many children have developed immunity to many strains of Neisseria meningitides. • Individuals with complement deficiencies. Complement is a part of the immune system required for the breakdown of meningococcal bacteria. • Individuals without spleens (asplenic). • Individuals taking immunosuppressive drugs such as prednisolone or cyclosporine. • Individuals with a current viral infection. The most common signs and symptoms of meningococcal disease are listed in the Table 5.1. If an individual has both meningococcal meningitis and meningococcemia, they may present with a mixture of symptoms and signs characterisic to each of the diseases. Meningococcal meningitis and meningococcemia is often suspected from the history and physical examination. Blood culture and/or lumbar puncture are used to confirm diagnosis. A lumbar puncture involves putting a needle in the lower back to obtain some spinal fluid. An increased number of white cells are seen under the microscope. Early recognition of meningococcal infection is critical as meningococcemia spreads so quickly that with hours of symptoms appearing, a patient may rapidly die. Patients may initially just have a rash and not be particularly unwell. Meningococcemia can kill more rapidly than any other infectious disease. Patients with either meningococcemia or meningococcal meningitis must be hospitalized and treatment with antibiotics and supportive care instituted immediately. Many patients

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Recent Advances in Dermatology Table 5.1: Clinical features for meningococcal diseases

Meningococcal meningitis Children >1 year and adults • Neck stiffness • Headache • Nausea and vomiting • Neck and/or back pain • Fever and chills • Increased sensitivity to light • Irritability, confusion Infants • Refusing feeds • Increased irritability • Sleeping all the time • Fever • Bulging fontanelle (soft spot on the top of the head) • Inconsolable crying • Epileptic fits (seizures)

Meningococcemia Signs on the skin • Petechie (rash of small red or purple spots that do not disappear when pressure is applied to the skin) occur in 50-75 percent of cases • Rash may progress to larger red patches or purple lesions (similar to bruises) • Most often found on the trunk and extremities but may progress to involve any part of the body • In severe cases lesions may burst and lead to necrosis. Other signs and symptoms • Acute fever and chills • Headache • Neck stiffness • Low back and thigh pain • Nausea and vomiting • Confusion or unconsciousness • Epileptic fits (seizures) • Unstable vital signs, e.g. very low blood pressure, reduced blood flow, low urine output • Collapse from septic shock

are admitted to an intensive care unit. Penicillin is the drug of choice. Some strains of Neisseria meningitides resistant to penicillin have been isolated; in these cases, third-generation cephalosporins are a suitable alternative. Very sick patients are often treated with both penicillin and cephalosporins prior to obtaining the laboratory results. Other treatments may include: • intravenous fluids to treat shock and prevent organ damage • medications such as noradrenaline for patients with very low blood pressure • blood products such as platelets and fresh frozen plasma • oxygen and ventilation to assist with breathing Patients who survive very severe cases of meningococcemia may have suffered severe necrosis of skin and underlying tissue. Skin grafts and amputation may be necessary. Complications from meningococcal


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disease may occur at the time of the acute disease or during the recovery period. Some complications are so severe that they may reduce the chances of survival. • Massive hemorrhage of the adrenal glands • Disseminated intravascular coagulopathy (DIC), which prevents blood clotting • Arthritis • Heart problems, e.g. pericarditis • Neurological problems, e.g. deafness or peripheral neuropathy (damage to the nerves in feet and hands) • Permanent musculoskeletal problems • Amputation Graft Versus Host Disease15 Graft versus host disease (GVHD) is a condition where, following transplantation, the donor’s immune cells in the transplant (graft) make antibodies against the patient’s tissues (host) and attack vital organs. Organs most often affected include the skin, gastrointestinal (GI) tract and the liver. Ninety percent of bone marrow transplants lead to GVHD. Solid organ transplantation, blood transfusions and maternal-fetal transfusions have also been reported to cause GVHD less frequently. There are two forms of GVHD: 1. Acute GVHD • Early form of GVHD that occurs within the first 3 months of transplantation. • First sign is usually a skin rash appearing on the hands, feet and face. • Gastrointestinal and liver dysfunction symptoms may follow. 2. Chronic GVHD • Late form of GVHD that develops 3 months post-transplantation. • Usually evolves from acute GVHD but occurs de novo in 20-30 percent of patients. • Cutaneous (skin) reactions resemble those of autoimmune disorders such as lupus, lichen planus and especially systemic sclerosis. Acute GVHD and chronic GVHD are distinct diseases. One common factor is that they both increase the patient’s susceptibility to infection. The features of acute and chronic GVHD have been enumerated in Table 5.2.

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Recent Advances in Dermatology Table 5.2: Features of acute and chronic GVHD

Acute GVHD • Tender, red spots usually appear 10-30 days post-transplantation • Face, hands and feet affected first then spreading to whole body (erythroderma) • Spots may coalesce to form widespread red rash • Rash may develop into raised spots or blisters that resemble toxic epidermal necrolysis • Fever may be present • Watery or bloody diarrhea with stomach cramps indicates GI involvement • Jaundice (yellowing of the skin and eyes) indicates liver involvement • Abnormal liver function tests Chronic GVHD • Dry, itchy raised rash develops over whole body • Dry mouth and sensitivity to spicy or acid foods leading to mouth lesions • Dry eyes causing irritation and redness • Skin thickening, scaling, hyper or hypopigmentation (resembling lichen planus) • Hardening of skin (scleroderma) may interfere with joint mobility • Hair loss or premature graying • Decreased sweating • Liver involvement causing jaundice • Lung and GI disorders may occur

Patients recovering from bone marrow transplantation are usually hospitalized for several weeks following transplant and are monitored closely for signs of developing GVHD or infection. The best treatment for GVHD is prevention. This consists of a cocktail of immunosuppressive drugs such as cyclosporine, methotrexate, cyclophosphamide, mycophenolate, tacrolimus and sirolimus with or without prednisolone. The combination of cyclosporine and methotrexate has been found to significantly decrease the severity of GVHD. These drugs weaken the ability of the donor’s immune cells to launch an attack on the patient’s organs. Treatment for patients who do develop GVHD depends on the severity of the disease. Mild cases with only skin involvement of acute GVHD may settle without treatment. More severe acute or chronic GVHD predisposes the patient to infection and overwhelming sepsis is the main cause of death in patients with GVHD. The aim is to treat GVHD before life-threatening sepsis occurs. High dose corticosteroids are usually added to the immunosuppressive regime. New monoclonal antibodies appear very effective, but are very costly. Photochemotherapy (PUVA) and high dose long wave ultraviolet radiation (UVA1) may reduce the severity of the skin problems.


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Epidermolysis Bullosa16 Several forms are described of this disease, but only the major lifethreatening forms are discussed here. Junctional Epidermolysis Bullosa (JEB) JEB Subtypes

Features

Herlitz (JEB letalis or lethal JEB)

Generalized and most severe form of JEB where blisters appear all over the body and often involve mucous membranes and internal organs May only present at birth with small single blister but becoming more widespread soon after Hoarse cry or cough is indicative of internal organ involvement Complications such as infection, malnutrition and dehydration usually lead to early death in infancy

JEB mitis or non-lethal JEB

Generalized blistering and mucosal involvement present at birth or soon after Scalp, nails and tooth more involved Complications such as infection, malnutrition and dehydration may cause death in infancy, but those who survive clinically improve with increasing age

Generalized atrophic benign EB

Mild generalized blistering present at birth, usually with scalp, nail and teeth involvement Blisters heal with a distinctive atrophic appearance Blisters worsen in warmer climates

Dystrophic Epidermolysis Bullosa (DEB) DEB Subtypes Dominant DEB

Recessive DEB

Features Generalized blistering present at birth Blistering becomes localized to hands, feet, elbow or knees as child grows older and in response to friction Small white spots called milia are often present at healed but scarred sites May be mild or severe presentations Generalized severe blistering is more common and involves large areas of skin and mucous membranes Blisters heal but with scarring and deformity causing limited movement, as fingers and toes may be fused

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together Complications such as infection, malnutrition and dehydration may cause death in infancy and those who survive are at great risk of developing squamous cell carcinoma There is no cure for EB. Treatment is symptomatic and the primary aim is to protect the skin and stop blister formation, promote healing and prevent complications. Because EB can affect so many different parts of the body, a team of medical specialists is usually required for overall care. When necessary, treatment with oral and topical medications may be prescribed to assist healing or prevent complications. The following are some general measures used in caring for a patient with EB. • Maintain a cool environment and avoid overheating • Use foam padding or sheepskins to help reduce friction on furniture such as beds, chairs and infant car seats • Wear clothing made of soft non-irritating fabrics • Pierce, drain and dress blisters to promote healing (this should be done only by the people who have received training on wound care) • Try to avoid using nappies in infants with severe EB, instead place child on a clean pad. Linear IgA Disease17 Linear IgA disease is a rare blistering disorder. It is nearly identical to a similar condition that affects children, chronic bullous disease of childhood. Chronic bullous disease of childhood usually presents before puberty with an abrupt onset of blistering in the genital region, later affecting hands, feet and face. In adults with linear IgA disease, the limbs are more often the first sites, although any area of the body may be affected later. Clear round or oval blisters may arise from normal-looking or red skin. Red flat or elevated patches may arise, studded with small blisters (vesicles) or large ones (bullae), often target-shaped. The tendency for new blisters to arise in a ring around an old one is called the string of beads sign and groups of small blisters may be described as a cluster of jewels. Crusts, scratch-marks, sores and ulcers may arise. The lesions can resemble other uncommon blistering skin diseases especially erythema multiforme, bullous pemphigoid and dermatitis herpetiformis. The intensity of itching is variable. Blisters and ulceration on the lips and inside the mouth affect about 50 percent. Eye involvement may result in irritation, dryness, light sensitivity and blurred vision. Biopsy shows


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a subepidermal blister. Direct immunofluorescence reveals the immunoglobulin IgA along the basement membrane of the epidermis in a linear pattern. Sometimes these IgA antibodies can be detected in the blood (indirect immunofluorescence). Research indicates that the antibodies are directed against various basement membrane components (target antigens). Most children with Linear IgA disease improve or clear with Dapsone 50-100 mg daily. Other helpful medications include corticosteroids (prednisolone) and erythromycin. Although the condition may eventually be cured, many patients require long-term treatment as a reduction in dose of medication results in further blistering. Pemphigus18 An uncommon, potentially fatal autoimmune skin disease characterized by intraepidermal bullae and extensive erosions on apparently healthy skin and mucosa, pemphigus usually occurs in middle-aged or elderly persons and is rare in childen. In active pemphigus, the serum and skin show readily demonstrable IgG antibodies that bind at the site of epidermal damage. The primary lesions are flaccid bullae of various sizes, but often the skin or mucosae just shear off, leaving painful erosions. Lesions typically occur first in the mouth where they rupture and remain as chronic, often painful, erosions for variable periods before the skin is affected. The bullae typically arise from healthy-appearing skin, rupture and leave a raw area and crusting. Any area of stratified squamous epithelium may be affected, but the extent of skin and mucosal involvement varies (e.g., lesions may occur in the oropharynx and upper esophagus). Pemphigus should be suspected in any bullous disorder or chronic mucosal ulceration. It must be differentiated from other chronic oral ulcers and from other bullous dermatoses (e.g., bullous pemphigoid, benign mucosal [cicatricial] pemphigoid, drug eruptions, toxic epidermal necrolysis, erythema multiforme, dermatitis herpetiformis, bullous contact dermatitis). In pemphigus vulgaris, the epidermis is easily detached from the underlying skin (Nikolsky’s sign) and biopsy usually shows typical suprabasal epidermal cell separation. In pemphigus foliaceus, the separation does not occur in the suprabasal region but rather in the upper layers of the stratum spinosum or stratum granulosum. A Tzanck test is frequently diagnostic when Wright’s or Giemsa stain is used on a smear of cells obtained by scraping the base of a lesion. The acantholytic cells typical of pemphigus are unattached and basal cell-like, with large centrally placed nuclei and peripherally condensed cytoplasm. Direct immunofluorescence tests of perilesional skin or mucous membranes

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are most reliable and invariably show IgG on the epidermal or epithelial cell surfaces. Indirect tests of immunofluorescence usually show pemphigus antibodies in the patient’s serum, even when the lesions are localized in the mouth. The antibody titer may correlate with disease severity. Pemphigus is a serious disease with an inconsistent and unpredictable response to therapy. The aim of treatment, both immediate and subsequent, is to stop the eruption of new lesions. Specific therapy depends on the extent and severity of disease. The mainstay is systemic corticosteroids. Some patients with few lesions may respond to lowdose oral prednisolone (e.g., 20 to 30 mg/day), but most require much higher doses. Hospitalization and high-dose corticosteroids are indicated for children with widespread disease, which may be fatal if inadequately treated. The initial dose of oral prednisolone, 30 to 40 mg bid (or equivalent), should be repeatedly doubled if new lesions continue to appear after 5 to 7 days. Very high doses may be necessary. Corticosteroid dose should be tapered if no new lesions appear for 7 to 10 days, with the total daily dose given every morning at first, then every other morning. The maintenance dose should be as low as possible. Many patients require maintenance therapy, which can usually be discontinued after months or years if no new lesions appear during a trial of several weeks without treatment. Methotrexate, cyclophosphamide, azathioprine, gold, or cyclosporine used alone or with corticosteroids reduces the need for corticosteroids and thus minimizes the undesirable effects of long-term corticosteroid use, but the aforementioned drugs also carry serious risks. Plasmapheresis combined with an immunosuppressive drug to reduce antibody titers has also been effective. Active skin infections are treated with systemic antibiotics. Reverse isolation procedures may be required. Generous use of talc on the patient and sheets may prevent oozing skin from adhering; hydrocolloid dressings may be useful. Silver sulfadiazine cream used on erosions can prevent secondary infection. Hemangiomas19 These vascular proliferations or ectasias are grouped as superficial, deep and mixed. Infants are at a great risk during the first 6 months of age. However, the danger is governed by factors such as site and size of the angioma. Vascular malformations have to be distinguished from hemangiomas. A vascular malformation is almost always present from birth, remians stable or might progress very slowly. The absence of brisk proliferative response in vascular malformations is due to the absence of endothelial cell proliferation. Unlike hemangiomas, they do not resolve spontaneously. Hemangiomas will need early treatment when alteration


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to vital functions can occur (like around the eye, nose, ear, throat) or with Kasabach-Merritt syndrome or congestive heart failure. When treatment is required, oral prednisolone 1 to 3 mg/kg bid or tid should be given as soon as possible and for about 2 weeks. If resolution starts, the prednisolone should be decreased slowly; if not, the drug should be stopped. Interferon alfa is an antiangiogenic drug that inhibits epithelial cell proliferation and motility and is the first line of therapy in KasabachMerritt syndrome. Histiocytosis X20 Langerhans cell granulomatosis (histiocytosis X) is a group of disorders (Letterer-Siwe disease, Hand-Schuller-Christian disease, pulmonary histiocytosis X) in which histiocytes and eosinophils proliferate, especially in the skin, bone and lung, often causing scarring. The cause of these disorders is not known. They all start with infiltration of the lung (and other tissues) by histiocytes, which are cells that scavenge for foreign materials, and to a lesser extent by eosinophils, which are cells that are normally involved in allergic reactions. Letterer-Siwe disease starts before age 3 and is usually fatal without treatment. The histiocytes damage not only the lungs but also the skin, lymph glands, bones, liver and spleen. A small portion of the lung may rupture into the pleural space (a condition called pneumothorax). Hand-Schuller-Christian disease usually begins in early childhood but can start in late middle age. The lungs and bones are most frequently affected. Rarely, damage to the pituitary gland causes diabetes insipidus, a condition in which large quantities of urine are produced, leading to dehydration. Some people develop bulging eyes (exophthalmos) because the bones of the eye sockets are affected. Pulmonary histiocytosis X (eosinophilic granuloma) is a rare, smokingrelated lung disease. The disease occurs more often in men than in women. Symptoms usually start between the ages of 20 and 40. About 16 percent of people have no symptoms, but the rest develop coughing, shortness of breath, fever, chest pain and weight loss. Pneumothorax is a common complication due to rupture of a lung cyst. Scarring makes the lungs stiff and impairs their ability to transfer oxygen into and out of the blood. Chest X-rays show nodules, small lung cysts (honeycombing) and other changes that are typical of these diseases. X-rays may also show that the bones are affected. Pulmonary function tests show reduced function. Hemoptysis and diabetes insipidus are rare complications. People with Hand-Schuller-Christian disease may recover spontaneously. Most people with pulmonary histiocytosis X have persistent or progressive disease. Death usually results from respiratory failure or cor

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pulmonale, although when people with pulmonary histiocytosis X stop smoking, improvement occurs in about one-third of cases. All three disorders may be treated with corticosteroids and immunosuppressant drugs such as cyclophosphamide, although no therapy is clearly beneficial. The treatment for affected bones is similar to that for bone tumors. Mastocytosis21 A condition of unknown etiology is characterized by excessive accumulation of mast cells in various body organs and tissues. Tissue mast cells may contribute to host defense by releasing potent preformed mediators (e.g., histamine) from their granules and by generating newly formed mediators (e.g., leukotrienes) from membrane lipids. Normal tissue mast cells also mediate the symptoms of common allergic reactions by means of IgE antibodies attached to specific surface receptors. Mastocytosis can occur in three forms: mastocytoma (a benign cutaneous tumor); urticaria pigmentosa (multiple small cutaneous collections of mast cells that develop as salmon-colored or brown macules and papules which urticate when stroked and may become vesicular or even bullous) and systemic mastocytosis (mast cell infiltrates in the skin, lymph nodes, liver, spleen, GI tract and bones). Patients with systemic mastocytosis have arthralgias, bone pain and anaphylactoid symptoms. Other symptoms (increased gastric acid and mucus secretion) are caused by stimulation of H2 receptors. Thus, peptic ulcer disease and chronic diarrhea are common problems. The histamine content of tissue biopsies can be extremely high, commensurate with the elevated mast cell concentration. The urinary excretion of histamine and its metabolites is high in systemic mastocytosis and plasma histamine may be elevated. Increased plasma levels of tryptase, heparin and prostaglandin D2 have also been reported. Cutaneous disease involutes spontaneously; urticaria pigmentosa either clears completely or is substantially improved before adolescence. These conditions rarely progress to systemic mastocytosis. Usually, only treatment of pruritus with H1 blocker is needed. The symptoms of systemic mastocytosis should be treated with H1 and H2 blocker. Because prostaglandins, especially prostaglandin D2, may contribute to mast cell-related symptoms, aspirin therapy may be tried cautiously. While inhibiting prostaglandin synthesis, aspirin and similar drugs may enhance leukotriene production. If GI symptoms are not controlled, oral cromolym 100 mg qid for children 2 to 12 yr old (not to exceed 40 mg/kg/day) should be given. No effective treatment is available to reduce the number


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of tissue mast cells. The solitary mastocytoma should be surgically excised. Acrodermatitis Enteropathica22 Acrodermatitis enteropathica is a rare congenital disorder characterized by diarrhea, an inflammatory rash around the mouth and/or anus and hair loss. The inheritance is autosomal recessive. Symptoms usually occur within the first few months after birth. Both males and females are equally affected. In some cases, discontinuation of breastfeeding appears to trigger the disease. This has led researchers to believe that human milk may affect zinc bioavailability. However, the disease is also found in healthy breast-fed infants, thus the exact mechanism of the metabolic defect remains unclear. An acquired form, although extremely rare, is also possible in children who are on total parenteral nutrition (TPN). For the last few years since the disease has been recognized, TPN has included zinc supplementation. Clinical features include: • Red and inflammed patches of dry and scaly skin, particularly around body openings such as the mouth, anus and eyes, and the skin on elbows, knees, hands and feet. It may look like atopic dematitis. • Patches evolve into crusted, blistered, pus-filled and eroded lesions. • There is usually a sharp demarcation between the affected area and normal skin. • Skin around nails becomes inflamed and there may be abnormal nail growth. • Hair loss on the scalp, eyebrows and eyelashes. • Conjunctivitis. • Sensitivity to light. • Loss of appetite. • Diarrhea, mild or severe. • Irritability and withdrawal. • Blood zinc level is abnormally low. Acrodermatitis enteropathica is easily and effectively treated with zinc supplementation. Daily oral zinc supplementation will need to be continued for life. Secondary bacterial and/or fungal infection of lesions require appropriate antibiotic therapy. If acrodermatitis enteropathica is left untreated, symptoms of zinc deficiency progress further and may even result in death. Sclerema Neonatorum23

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It is seen in a preterm, ill neonate. Almost always associated with metabolic acidosis, hypothermia and infection; the mortality rate of this condition is around 60 percent. The disease presents as woody induration of the skin and subcutis over the buttocks, cheeks, thighs, and lowe legs. Histopathology helps to differentiate it from subcutaneous fat necrosis that has a good prognosis. Sclerema does not show necrosis, but shows cleft-filled fat cells that contain triglyceride crystals. The presence of erythema, bluish discoloration of the skin, focal distribution and the histologic presence of inflammatory cells, giant cells and calcium crystals may differentiate subcutaneous fat necrosis. Children with sclerema may respond to corticosteroids with packed cells transfusion. Leiner’s Disease24 Leiner’s disease occurs in infants and is characterized by severe generalized seborrheic dermatitis, recurrent diarrhea, recurrent skin and internal infections and failure to thrive. It may be present at birth, but more commonly develops within the first few months of life. It appears to be more common in females than males and in breast-fed infants. The precise cause of Leiner’s disease remains unknown, but it is known that a defect in the body’s complement system has a major role to play in its development. The complement system is a vital part of the body’s immune system and in Leiner’s disease, an inherited dysfunction or deficiency in the C5 component of complement alongside other factors have been implicated. Other immune deficiencies may present in an identical fashion in infancy. The condition usually starts off as a scaly rash on the scalp, face or napkin area. Very rapidly it spreads to other parts of the body. The affected area is bright red and may look swollen. Infants appear uncomfortable but do not itch. Other symptoms include recurrent diarrhea, infant not thriving or gaining weight and local skin infections. There is also a risk of developing more severe infections that may lead to pneumonia, meningitis and septicemia. Initially affected babies may need to be hospitalized to manage fluid and heat loss. Bland emollients may be used to treat the rash. Providing adequate nutrition is also an essential part of treatment. Biotin, a water-soluble vitamin that is found naturally in foods such as liver, kidney, meat, milk, egg yolks and vegetables, appears to be useful in treating Leiner’s disease. ACUTE SKIN FAILURE25 What are the Consequences of ASF?


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These include the following: • Loss of barrier function • Loss of immunological function • Loss of fluids • Increased cutaneous blood flow • Increase in energy expenditure • Impaired thermoregulation • Increased susceptibility to infections • Increased percutaneous absorption • Development of multi-organ failure Management of ASF The principles of managment are as follows: • Fluid and electrolytes balance • Hemodynamic balance • Prevention of sepsis • Treatment of infection • Nutritional supplementation • Maintenance of environmental temperature • Anticoagulant therapy in cases of DIC • Skin grafting in conditions such as TEN Criteria for Poor Prognosis of ASF • • • • • • • •

Younger children, particularly the neonate Extension of skin involvement Altered states of consciousness Increased respiratory rate Increased cardiac rate Drop in systolic blood pressure Reduced neutrophil counts Decreased urinary output

Monitoring of Children with ASF26 Centers specialized in management of ASF have created what is known as ‘Simplified Acute Physiological Scores’ (SAPS), a scoring system builtup in order to predict the outcome of severe skin disorders. This system takes into consideration a combination of several clinical and biological parameters following admission of the patient into the ward. The parameters include • Hourly recording of respiratory rate, pulse rate, blood pressure, and

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urine output volume • Four hourly observation of body temperature, consciousness and gastric emptying • Daily monitoring of body weight, extension of skin involvement, fluid losses, blood chemistry and blood gas analysis. The urine is examined for glycosuria • Bacteriology of skin lesions at least once every other day INTENSIVE SKIN CARE UNITS (ISCU) From the brief description of the disease entities mentioned above and the concept of ASF, it is needless to say that there is a definite need for specialized ISCUs in every teaching hospital and tertiary health care centers. However, in countries such as India, the economics of such ISCUs do not work out to be a feasible project. This should not deter our enthusiasm. But the emphasis should be on building the perception of teamwork that is the key to the successful outcome of pediatric dermatological emergencies. There is always scope for innovation, indigenization and improvisation. They are the determinants that drive us through our search for excellence. CONCLUSION Unsurprisingly intensive care is absolutely necessary in a wide range of dermatoses. Acute skin failure often leads to several changes such as fluid loss, electrolyte imbalance, infections, etc. Cardiac or renal failure may be the terminal eventuality of acute skin failure. Diseases such as toxic epidermal necrolysis have to be managed just as a case of extensive burns. Precise watching of hemodynamic and cutaneous bacteriological data help in the assessment of prognosis. The guidelines of treatment include careful attention to electrolyte equilibrium, nutrition, aseptic precautions, energy expenditure and environmental temperature. All these therapeutic measures should best be given in specialized wards that will get to be known as ‘intensive skin units’ in future. REFERENCES 1. Roujeau JC, Revuz J. Intensive care in dermatology. In: Champion RH, Pye RJ, eds. Recent advances in dermatology. No. 8. London: Churchill Livingstone, 1990:85-99. 2. Feingold DS. Gangrenous and crepitant cellulitis. J Am Acad Dermatol 1982; 6: 289-99. 3. Snyder RA, Eliaz PM. Toxic epidermal necrolysis and staphylococcal scalded skin syndrome. Dermatol Clin 1988; 235-48.


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4. Whitley RJ, Namiaz AJ, Soong SJ, et al. Therapy of Neonatal Herpes simplex virus infection. Paediatr 1980; 66: 495-501. 5. Jacobs MI, Magid MS, Jarowski CT. Disseminated Candidiasis. Arch Dermatol 1980; 116: 1277-99. 6. Beltrani VS. Urticaria and Angioedema. Dermatol Clin 1996; 171-98 7. Rosen FS, Charache P, Pensky J, et al. Angioedema-2 genetic variants. Science 1964; 148: 957-8. 8. Kramer MS, Leventhal JM, Hutchinson TA, et al. Adverse drug reactions. JAMA 1979; 242: 623-68. 9. Kawasaki T, Kosaki F. A new infantile acute febrile mucocutaneous lymph node syndrome (MLNS) in Japan. Paediatr 1974; 54: 271. 10. Ramsay DL, Hurley HJ. Papulosquamous eruptions and exfoliative dermatitis. In: Moschella SL, Hurley HJ, eds. Dermatology. WB Saunders. 11. Tonnesen MG, Soter NA. Erythema multiforme. J Am Acad Dermatol 1978; 1: 357-64. 12. Heinbeck DM, Hengrave LH, Marvin JA, et al. Toxic epidermal necolysis. A step forward in the treatment. JAMA 1985; 257: 2171-5. 13. Lentz CL, Altman J. Lamellar ichthyosis. The natural history of collodion babies. Arch Dermatol 1968; 97: 3-5. 14. Ognibene AJ, Dito WR. Chronic meningococcemia: further comments on the pathogenesis of associated skin lesions. Arch Intern Med 1964; 114: 29. 15. Grogen TM, Odom RB, Bargeta JH. Graft versus host reaction. Arch Dermatol 1977; 113: 806-12. 16. Briggaman RA. Hereditary epidermolysis bullosa with special emphasis on newly recognized syndromes and complications. Dermatol Clin 1983; 1: 26380. 17. Chorzelski TP, Jablonska S. IgA linear dermatosis of childhood. Br J Dermatol 1979; 101: 535-42. 18. Ahmed RA, Moy R. Death in pemphigus. J Am Acad Dermatol 1982; 7: 2218. 19. Lang PG. Dubin HV. Hemangioma-thrombocytopenia syndrome: A disseminated intravascular coagulopathy. Arch Dermatol 1975; 111: 105-7. 20. Vogel JM, Vogel P. Idiopathic histiocytosis: A discussion of eosinophilic granuloma, the Hand-Schuller-Christian disease and Letterer-Siwe syndrome. Semin Hematol 1972; 9: 3-19. 21. Demis DJ. The mastocytosis syndrome. Ann Intern Med 1963; 59: 194-206. 22. Moynahan EL. Acrodermatitis enteropathica: A lethal inherited human zincdeficiency disorder. Lancet 1974; 2: 399-400. 23. Kellum RE, Ray TL, Brown GR. Sclerema neonatorum. Arch Dermatol 1968; 97: 372-5. 24. Miller ME, Koblenzer PJ. Leiner’s disease and C5 dysfunction. J Paediatr 1972; 80: 879-81. 25. Shuster S. Systemic effects of skin disease. Lancet 1967; 1: 907-12. 26. LeGall JR, Loirat P, Alperovitch A, et al. A simplified acute physiological score for intensive care unit patients. Critical Care Medicine 1984; 12: 975-7.

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6


Sujit Ranjan Sengupta, Nilay Kanti Das

Cutaneous Adverse Drug Reactions to Systemic Drugs: Recent Update The field of medicine is broadening with the passage of time along with the list of drugs in the pharmacopeia. Every month a few new drugs gain its entry in the market and many remain in the pipeline for introduction. It is quite common to find new dangers of the marketed drugs, with more than half of the approved drugs having serious side effects that were not detected before approval.1 Any adverse drug reaction is described as “an appreciably harmful or unpleasant reaction, resulting from an intervention related to the use of a medicinal product, which predicts hazard from future administration and warrants prevention or specific treatments or alteration of the dosage regimen or withdrawal of the product”.2 Studies have documented that approximately 14 percent of such adverse drug reactions in hospital care are cutaneous or allergic in nature,3 amongst which the ‘exanthematous drug reaction’ is the commonest.4 Pattern of the cutaneous adverse drug reaction (CADR) varies among various drugs, hence understanding the precise nature of CADR helps to narrow down the search for the incriminating drugs. This chapter attempts to highlight the features of CADR though presenting the entire catalogue of all the drugs used in the past or the present is beyond the scope of this article. The aim will be to describe the CADR of the recently introduced non-dermatological drugs, newly described CADR of longknown drugs (many of which are yet to find its place in the textbooks) with the exclusion of topical medicaments from this review. SOURCES OF INFORMATION The sources of information regarding the side effects of the drugs5 are enlisted in Table 6.1 along with their merits and demerits. The MEDLINE database was searched for the studies that contain information regarding the various forms of CADR. The bibliographies of the retrieved articles were also searched to find relevant information.

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Table 6.1: Sources of information on adverse drug reaction Source

Merits

Demerits

1. Clinical trial

• Study group designed • Sample size too small to to show efficacy of some detect uncommon serious drug may also document reaction. common side effects during the course of • Short duration of trial not trial. sufficient to document the late-onset side effects.

2. Case reports

• First line of defense in the detection of unanticipated drug reaction.

• No comparison group to allow for a quantitation estimation of risk.

• Invaluable function of • Incidence rate cannot be raising suspicions that assessed due to lack of can be assessed in more reliable denominator. formal research. 3. Epidemiological • Only practical option in • Needs prolonged time and studies post-marketing situation enough funding to conduct (Case-control to have the real estimate the study. studies or of ‘relative and absolute Cohort studies) risk’ and ‘incidence rate. • Best source of information on adverse drug reaction.

NATURE OF THE CUTANEOUS ADVERSE DRUG REACTION Adverse reaction to drugs involves different systems of the body, of which cutaneous reactions are the most frequent. They manifest with varied and diverse morphological pattern starting from trivial urticaria to severe form of vasculitis or toxic epidermal necrolysis and cutaneous necrosis or gangrene. The wide array of its clinical presentation mimics innumerable dermatological disorders and often poses a serious diagnostic problem. It is an utmost necessity for an internist or a dermatologist to have a comprehensive understanding of the cutaneous and histological spectra of the drug reactions as well as the knowledge of the drugs incriminated for such adverse reactions. It helps to lower or minimize the incidence of iatrogenic morbidity or mortality. Untoward reaction to drugs can arise as a result of immunologic as well as non-immunologic mechanism. The immunologic mechanisms primarily thought to be responsible in cutaneous drug reaction include, immediate hypersensitivity reaction (type I), cellular cytotoxic reaction (type II) immune-complex reaction (type III), or delayed type of T-cell

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mediated immune response (type IV). Non-immunologic cutaneous reactions occur due to several unrelated mechanisms like immunologic activation of effector pathway, synergistic or cumulative toxicity, overdose, drug interaction, metabolic alteration, inherited enzyme and protein deficiency. It is not often possible to specify the offending drugs or the exact underlying pathogenetic mechanism as some common reaction patterns are elicited by a variety of stimuli. To attribute a drug as a causal factor in a specific cutaneous drug reaction, one has to establish a temporal relationship with ingestion of the incriminating drug and appearance of the lesion as well as reappearance of the lesion on rechallenge.6 Patch test is generally satisfactory and well-tolerated method7 in establishing a diagnosis, but oral rechallenge is not without risk and often not performed. Radio-allergosorbent testing (RAST), lymphocyte transformation assays, assay of drug specific antibodies7 are of limited value to the clinician because of low sensitivity. Exanthematous/Morbillform/Maculopapular Drug Eruption It is the most common form of CADR constituting 90 percent4 of all skin eruptions. The patient usually presents with an acute onset of symmetrically distributed erythematous maculo-papular lesions, starting most commonly on the trunk, which may then involve the extremities but usually spares the face. The lesions are extremely pruritic and often mimic viral exanthem; withdrawal of the drug is helpful in differentiating the two conditions. The lesions usually resolve within 7-12 days but may lead to erythroderma if offending drug is not withdrawn. It is proposed that the lesional skin shows up-regulation of intercellular adhesion molecule 1 (ICAM-1) or CD54 along with the up-regulated corresponding lymphocyte function antigens, which play a role in the pathogenesis of the disease.8 Histopathology of the lesional skin shows vascular interface dermatitis with dyskeratotic cells and lymphocytes along dermo-epidermal junction. Sparse superficial perivascular infiltrate may also be found along with papillary dermal edema. Tissue eosinophilia, which is present in some cases helps to differentiate it from viral exanthems. The drugs commonly involved for causing exanthematous drug eruption include aminopenicillins (penicillin), sulfonamides, antiepileptics and the non-nucleoside reverse transcriptase inhibitors (nevirapine). Lamotrigine, a newer antiepileptic, is also implicated9,10 along with the anti-cancer drug, docataxel11 in causing such reaction. Thalidomide is shown to cause exanthematous reaction and it is reported that such


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reaction can be suppressed if methylprednisolone is concomitantly used.12 Celecoxib, a COX II inhibitor13 and the contrast agent sodium ioxaglic acid meglumine14 are also known to cause maculo-papular exanthem. Hypersensitivity Syndrome Reaction It is one of the severe forms of CADR, which begins as a widespread morbilliform eruption that may become indurated and infiltrated, and may progress to exfoliative dermatitis later. Mucus membrane is seldom involved and necrolysis of skin is never present. It is associated with fever, lymphadenopathy and visceral involvements, which differentiate it from exanthematous reaction. Eosinophilia (in about 90%) or mononucleosis-like atypical lymphocytes (in about 40%) are the hematological hallmark of this syndrome. Hence the acronym DRESS15 (Drug Rash with Eosinophilia and Systemic Symptoms) has been proposed for this clinical variant. This syndrome is thought to be the result of immunologic mechanism. Histopathology reveals dense lymphocytic with occasional eosinophilic infiltrate of the papillary dermis along with epidermotropism. Aromatic anticonvulsants (phenytoin, phenobarbital, carbamazepine), sulfonamide, dapsone, minocycline and allopurinol are the drugs responsible for this disorder. Exfoliative Dermatitis/Erythroderma It is one of the severe forms of CADR, which may follow exanthematous drug reaction. Patient presents with an abrupt onset of erythema, edema, tenderness of skin with scaling involving more than 90 percent of body surface area (BSA), often associated with intense pruritus. It may start even several weeks after the drug exposure. Drug induced erythroderma represents the extension of the same pathogenetic mechanism as of exanthematous drug reaction and is histopathologically characterized by psoriasiform hyperplasia of epidermis with adherent parakeratotic scales and loss of granular cell layer. It is distinguished histologically from other causes of erythroderma by the presence of architectural disarray, dysmaturation, scattered necrotic keratinocytes and tissue eosinophilia. Absence of epidermotropism, supra-papillary thinning with dilated capillaries in dermal papillae and neutrophil-imbued parakeratosis help to differentiate drug induced erythroderma from erythroderma due to mycosis fungoides, psoriasis and seborrheic dermatitis respectively. The drugs that are known to cause erythroderma include acetylsalicylic acid, allopurinol, captopril, cefoxitine, clofazimine,

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cotrimoxazole, diltiazem, etretinate, fenbufen, gentamicin, GM-CSF, ketoconazole, lithium, minoxidil, methotrexate, nystatin, oxytetracycline, phenobarbital, quinidine, sulfonamide, thalidomide and timolol. Recently it has been reported that continuous therapy with epoprostenol (PGI2), which is used for preventing platelet aggregation and damage during hemodialysis and cardiopulmonary bypass, may also lead to exfoliative dermatitis.16 Bupropion,17 an antidepressant and the proton pump inhibitors18,19 like omeprazole and lansoprazole are also being reported along with calcitonin20 as a cause of erythroderma. Other drugs implicated in causing exfoliative dermatitis include erythropoietin,21 lipid lowering agent-pentostatin, 22 cyanamide,23 indinavir24 and ticlopidine.25 Urticaria, Angioedema and Serum Sickness Urticaria is the second most common type of CADR, next to exanthematous drug reaction, accounting for about 6 percent of drug reaction.26 It appears within 36 hours of drug administration but on rechallenge the lesions may develop within minutes. Angioedema however, is rarely seen as a CADR and accounts for less than 1 percent of the patients receiving a particular drug. Serum sickness has a distinctive clinical findings with erythema first appearing on the sides of the fingers, toes and hands later turning into extensive morbilliform rash (in two-third of the patient) sometimes with urticaria.27 Immediate (type I) hypersensitivity reaction leading to degranulation of mast cells with the release of histamine plays the key role in urticaria and angioedema. Cross linking of cell bound IgE or high affinity Ig receptors either by immunologic or non-immunologic mechanism is the basis for mast cell degranulation. Serum sickness is a type III hypersensitivity reaction that is mediated by the deposition of immune complexes in the small vessels, activating the complement system and recruiting the granulocytes. Histology of urticaria shows dermal edema and sparse perivascular infiltrate consisting of lymphocytes and eosinophils whereas in angioedema, the edema and infiltrate extend into the sub-cutaneous tissue. Serum sickness shows leucocytoclastic vasculitis (LCV) with no other remarkable features on histology. Urticaria/angioedema is commonly caused by ACE inhibitors, antifungals (ketoconazole, fluconazole), antibiotics (penicillins, cephalosporins), aspirin, codeine, food additives, hydantoin, hydralazine, NSAIDs, quinidine and radiologic contrast media. The additions to this list include interferon-beta la,28 interferon beta lb,29 the heparin substitute-danaparoid, steroid analogue-deflazacort,30


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muscle relaxant-carisoprodol.31 The antihistaminic cetirizine is also documented in causing urticaria32,33 as also intra-articular injection of mehyl-prednisolone.34 Though NSAIDs are responsible in causing urticaria, the newer COX II inhibitors, such as rofecoxib, are relatively safe in NSAID-sensitive patients with urticaria or angioedema.35 The drugs implicated in causing serum sickness include bupropion, cefaclor, cephalexin, cefprozil, minocycline, propranolol and streptokinase. Eczematous Drug Eruption The persons who are previously sensitized to a drug may develop eczematous lesion on ingestion, inhalation or topical application of that particular compound. Following ingestion, the lesions typically develop within 2 to 24 hours and over the site which previously showed contact dermatitis. The pathology is similar to that of allergic contact dermatitis and the skin biopsy shows spongiosis with exocytosis of lymphocytes and eosinophils, edema of the papillary dermis and perivascular lymphohistiocytic and eosinophilic infiltrate. The drugs commonly implicated in causing eczematous drug reaction are antibiotics, aminophylline, antihistaminics containing ethylene diamine and oral hypoglycemic agents. Other agents that are recently documented in causing eczematous reaction include heparin alternative-danaparoid,36 phenobarbitone,37 synergistins,38 hepatitis B vaccine39 and anthrax vaccine.40 Photosensitive Drug Eruption Photosensitivity causes cutaneous eruptions on the sun-exposed areas with sparing of retro-auricular folds, upper eyelids and submental region. It accounts for about 8 percent of all CADRs. 41 Drug induced photosensitivity may be either photoallergic or phototoxic drug eruption (it may sometimes coexist). Photoallergic reactions are a form of delayed hypersensitivity reaction where the hapten or the avidity with which the hapten binds with the carrier is altered by light, leading to the formation of photoantigen. Phototoxic reaction, on the other hand, is due to reactive oxygen species resulting from the dissipation of the absorbed solar energy by the drug. Photoallergic dermatitis presents within 24 hours of sun exposure and is clinically manifested by acute, subacute or chronic dermatitis and occasionally with lichenoid papules. In a few cases, the photoallergic lesions may become generalized due to autosensitization phenomenon and can involve covered area of the body.

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On the other hand, the phototoxic reaction is sunburn reaction usually appearing within hours of sun exposure on the exposed parts of the body. It is clinically characterized by erythema, edema, vesiculation, peeling or desquamation. Chronic exposure for a long time produces scaling and lichenification; the severity of clinical manifestation depends on the combined effects of concentration of the drugs and duration of sun exposure. Histopathology of photoallergic dermatitis is that of allergic contact dermatitis which shows spongiosis of the epidermis, angiocentric lymphocytic and eosinophilic iniltrate, exocytosis, microvesiculation and papillary dermal edema. In phototoxic dermatitis, necrotic keratinocytes in all layer of epidermis with architectural disarray and dismaturity is found in acute stage. Both vacuolated keratinocytes (sunburn cells) or dyskeratotic keratinocytes may be found. Over time, photo adaptive changes occur and hyperkeratosis, hypergranulosis, melanocytic hyperplasia, epidermal architectural disarray and dysmaturity are found on histopathology. Drugs frequently associated with photosensitivity are amiodarone, NSAIDs, nalidixic acid, phenothiazine, psoralens, sulfonamide, tetracyclines, thiazides. Other systemic drugs associated with photosensitivity include ampicillin, antidepressants, antifungals (griseofulvin, ketoconazole), beta-blocker, carbamazepine, cimetidine, cytotoxic agents, diazepam, fluoroquinolones, furosemide, oral contraceptives, quinine, quinidine, sulphonylurea. Recently, this list is further lengthened by inclusion of new drugs. Triflusal, a fluorinated aspirin derivative with antiplatelet properties, is reported to be associated with photosensitivity.42-44 Anti-HIV drugs ribavirin,45 efavirenz46 and the anti-neoplastic agent capecitabine47 are also reported to cause photosensitivity. Other agents include antiandrogen flutamide,48 newer quinolone lomefloxacine,49 itraconazole,50 paroxitine.51 Photosensitivity is also noted with lipid lowering agent simvastatin,52 anti-thrombotic agent clopidogrel.53 Hydroxychloroquine, which is a systemic photo-protective agent, is reported to cause photosensitivity in 4 cases.54 Erythema Multiforme, Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis Erythema multiforme (EM), Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are often considered to be the part of the same disease spectrum. Some authors believe that EM represents a separate clinical entity from that of SJS/TEN.55 A consensus agreement


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was made on the three-grade classification of SJS/TEN spectrum of disorder.55 EM represents a self-limiting acute onset dermatosis where target lesions with peripheral rim of erythema, a central zone of pallor and sometimes dusky or violaceous macular blister arise, preferentially on the distal extremities. SJS includes the cases that are manifested clinically as small blisters or dusky purpuric macules or a typical target rarely. The areas of confluence/detachment do not exceed 10 percent of BSA and there are usually more than two areas of mucosal erosion.56 TEN represents those cases where individual lesions resemble SJS but in addition have large sheets of necrotic epidermis which peel off easily with pressure, and the total detachment exceeds 30 percent of BSA.56 In cases where the detachment is between 10 to 30 percent of BSA, SJS and TEN are thought to overlap and represent ‘Transitional SJS-TEN’.55 It has been hypothesized that EM is mediated by type III hypersensitivity phenomenon where impaired histamine metabolism is thought to play a role.57 Further immuno-pathologic studies have found that epidermis of the lesional skin are infiltrated by activated lymphocytes, mainly CD8+ cells and macrophages,58 which suggests cell-mediated cytotoxic reaction against the epidermal cells playing the vital role in this disease spectrum. The cytotoxic T-cells, apart from causing direct damage, also release cytokines, tumor necrosis factor a (TNF α) and interleukin 6 (IL 6), all of which also play a damaging role in SJS/TEN.59 Recently, the role of FAS (CD 95)—FAS ligand (CD 95 L) interaction in cell necrosis in TEN has been described and it has been found that epidermal keratinocytes in TEN express a large amount of FAS ligand (CD 95 L) on their surface.60 EM, SJS and TEN display the vacuolar form of interface dermatitis with orthokeratotic stratum corneum, mild spongiosis with exocytosis, tagging of lymphocytes along the dermo-epidermal junction. Early lesions show sparse lymphocytic infiltrates and scattered or grouped dyskeratotic (apoptotic) keratinocytes, whereas in advanced lesion the whole of the epidermis shows necrosis with detachment from a seemingly normal dermis.61 Satellite cell necrosis, characterized by intra-epidermal lymphocytes surrounding necrotic keratinocytes are often found in this group of disorders. Drugs commonly incriminated in causing EM, SJS/TEN include anticonvulsants (including lamotrigine), allopurinol, NSAIDs, sulfonamides and dapsone. Other drugs including penicillin, barbiturates, dilantin, sulfonamides, phenothiazines, griseofulvin, phenolphthalein, nitrogen mustard, codeine, tetracycline, minocycline, cotrimoxazole, glutethimide, cimetidine, methotrexate, prazosin, ethinyl estradiol, ketoconazole,

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sulfasalazine, cefaclor, methazualone, furosemide, aminopenicillins, streptomycin are also implicated in this group of disorder. The additions to this long list include aceclofenac (Beofenac),62 ofloxacin,63 Fenoterol, 64 bupropion,65,66 sestamibi,67 vancomycin, 68 granulocyte colony-stimulating factor, 69 Bufexamac,70 roxatidine,71 pyrazolon derivatives,72 celecoxib,73 and 5-fluorouracil.74 Apart from the above drugs, there are reports of SJS caused by cefotazime,75 azithromycin,76 ranitidine,77 celocoxib,78 methotrexate,79 nevirapine,80,81 imatinib (or ST 1571),82,83 bromhexine,84 hydroxychloroquine,85 leflunomide,86 rituximab,87 bezafibrate.88 SJS/TEN are also reported with amifostine, a phosphorylated aminothiol prodrug, that can selectively protect normal tissues against the toxic effects of chemotherapy and radiotherapy, 89,90 and also with cytosine arabinoside.91 Fixed Drug Eruption Fixed drug eruption (FDE) is clinically manifested as sharply marginated pruritic dusky erythema or violaceous macules which usually start within minutes to hours of drug intake, may evolve into a vesicle and heal with hyperpigmentation. The lesions more commonly involve acral skin or genitalia and perianal skin and characteristically show recurrence in the same area(s) with or without appearance of new lesion on rechallenge. Up-regulation of the expression of ICAM 1 (or CD 54) of the keratinocytes as well as endothelial expression of E-selectin and vascular adhesion molecule are thought to represent the pathogenetic mechanism of FDE.92,93 Histologically, it is characterized by interface dermatitis with vasculopathy, dyskeratotic keratinocytes (civatte bodies) in the epidermis, pigmentary incontinence, tissue eosinophilia and neutrophilia and presence of intra-epithelial granulocytic abscess. Histologically it mimics erythema multiforme except for the presence of acanthosis, hypergranulosis, hyperkeratosis and which help to differentiate the two. The common offending drugs causing FDE are oral contraceptives, opiates, barbiturates, benzodiazepine, anticonvulsants, phenolphthalein, phenacetin, salicylates, sulindac, naproxen, ibuprofen, paracetamol, indomethacin, tolmetin, nystatin, tetracycline, minocycline, sulfonamides, metronidazole, antifungals, dapsone, clindamycin, antimalarials. Newer drugs, also reported to cause FDE, include nimesulide,94 rofecoxib,95 ticlopidine,96,97 lamotrigine,98 ciprofloxacin,99 paclitaxel,100 phenylpropanolamine hydrochloride,101 tosufloxacin tosilate,102 atenolol,103 metamizole,104 interleukin-2105 and cetirizine.106 Apart from the usual clinical type, other variants of FDE are also known. Non-pigmenting FDE is reported to result from eperisone


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hydrochloride107 and after skin testing and intra-articular injection of triamcinolone acetonide.108 Rifampicin109 and influenza vaccination110 are reported to result in bullous FDE. Acetaminophen111 is reported to give rise to papular fixed drug eruption which resembles folliculitis. There are reports of fixed plaque of erythrodysesthesia resulting from docetaxel112 and daunorubicin.113 Lichenoid Drug Eruption Lichenoid drug eruptions clinically manifest as extensive papular skin eruptions which resemble classic lichen planus. In contrast to classic lichen planus, it is more psoriasiform and rarely involve oral mucosa. It usually develops weeks to months following initiation of therapy and initially may present as eczematous lesion. The lag period between the commencement of therapy and onset of the lesions along with the slow resolution following withdrawal of the drug points towards the role of delayed type hypersensitivity in its pathogenesis. Histologically, it is manifested by a band shaped infiltrate in upper dermis with vacuolar degeneration of basal cell, dyskeratosis, effete keratinocyte in papillary dermis (manifested as colloid-body accumulation) and perivascular infiltrate comprising of lymphocyte with scattered eosinophils, plasma cells and histiocytes. The drugs incriminated in the causation of lichenoid drug eruption are beta-blockers, ACE inhibitors, thiazides, furosemide, methyldopa, antimalarials, oral hypoglycemic agents, penicillamine, phenytoin, carbamazepine, phenothiazine, lithium, antihistaminics. Among the newer agents, lichenoid drug eruption is reported to result from the leflunomide,114 clopidogrel,115 imatinib,116 sildenafil,117 ursodeoxycholic acid,118 granulocyte colony stimulating factor.119 Apart from these newer agents, sparfloxacin120 and amlodipine121 are also reported to cause lichenoid drug eruption. Psoriasiform Drug Reaction This variant of drug reaction manifests clinically as classic papulosquamous lesions of psoriasis. The only clue to the diagnosis being the temporal association of the drug with the lesion. Histopathology reveals psoriasiform epidermal hyperplasia, hypogranulosis, foci of neutrophil-imbued parakeratosis sometimes associated with interface dermatitis and eczematous epithelial changes. Absence of tortuous capillary in the dermal papillae in apposition to the supra-papillary thinned epidermis helps to differentiate the drug reaction from psoriasis.

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Drugs that are implicated in precipitating or aggravating psoriasiform lesion include aspirin, morphine, NSAIDs, ampicillin, antimalarials, ACE inhibitors, quinidine, terbinafine, beta-blockers, lithium, cyclosporine, penicillamine, interleukins, interferon and methoxypsoralen. Recently, there has been three case reports of psoriasiform skin lesion in patients on dialysis receiving icodextrin.122 Drug Induced Pustular Eruption Drug induced pustular eruption may manifest itself as a mild form of acneiform eruption to the severe CADR, acute generalized exanthematous pustulosis. Acute generalized exanthematous pustulosis (AGEP) is a form of pustular eruption where widespread non-follicular pustules develop over diffuse total body erythema usually within hours of administration of the implicated drug and is associated with constitutional symptoms and leucocytosis. AGEP can be differentiated from pustular psoriasis based upon more acute onset, temporal relationship with the drug and rapid resolution (within 10-15 days) following drug withdrawal. The precise nature of AGEP is not known, but the patch test with the offending drugs is more frequently positive in this disorder than in any other CADR,123 suggesting immunologic background. Histopathology shows spongiform subcorneal pustulation, which may manifest follicular and/or acrosyringeal accentuation. It can be differentiated from pustular psoriasis by the presence of papillary edema, angiocentric neutrophillic and some eosinophilic infiltrate, LCV or sometimes by focal necrosis of keratinocytes. The common incriminating agents causing AGEP include calcium channel blockers, NSAIDs, anticonvulsants, antibiotics (especially betalactum and macrolide), antifungals (itraconazole, terbinafine). In recent years numerous other drugs are implicated in causing AGEP which includes sertraline,124 hydrochlorothiazide,125 imatinib (ST 1571),126 mexiletine,127 methylprednisolone,128 teicoplanin,129 dextropropoxyphene,130 clindamycin,131 sulfamethoxazol,132 famotidine,133 bamifylline,134 cytarabine,135 allopurinol,136 meladinine,137 icodextrin138 and furosemide.139 Vasculitis Drug-induced vasculitis (DIV) clinically manifests itself as palpable purpuric papule,56 which is its hallmark, or sometimes as purpuric maculo-papular rash classically involving the lower extremities within 7-21 days of starting the drug. Hemorrhagic blisters, urticaria, ulcers,


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nodules, Raynaud’s phenomenon and digital necrosis may be less frequent accompaniments of DIV.56 The persons developing vasculitis following drug ingestion have an underlying immune-dysregulatory state. Reports of cases where antineutrophilic cytoplasmic antibody (ANCA) associated vasculitis developed following intake of certain drugs,140 support the fact that DIV is manifested in predisposed individuals. DIV is a sub-type of hypersensitivity vasculitis involving the small vessels.141-143 It is thought that antibodies against drug-related hapten result in DIV but substantial proof is lacking.144 Alternative mechanisms of DIV which are also being proposed include direct drug toxicity against vessel walls, autoantibodies reacting with endothelial cells and cell mediated cytotoxic reactions against blood vessels.145,146 Mild leukocytoclastic vasculitis (LCV) is the prototype of DIV where sparse, superficial perivascular and interstitial leukocytoclasis is found along with fibrin deposit and hemorrhage. It can be differentiated from systemic vasculitis by the absence of pandermal severe LCV. Druginduced lymphocytic vasculitis is also observed in some instances where lymphocytic vascular reaction with hemorrhage and tissue eosinophilia is present in the absence of luminal thrombosis, a feature of lymphocytic vasculitides of collagen vascular disease. Eosinophilia is a common feature of systemic DIV (79%) though it is only present in 29 percent of cutaneous DIV. The pustular variant of drug-induced hypersensitivity vasculitis shows vascular deposition of IgA.147 The drugs associated with LCV include phenylbutazone, indomethacin, allopurinol, penicillins, erythromycin, sulfonamides, thiazide and hydantoin. The pustular vasculitis can result from the use of naproxen, penicillins, furosemide, diltiazem and carbamazepine. Recent, ibuprofen-induced bullous vasculitis148 and vasculitis resulting from the use of COX II inhibitor, celecoxib149 are described. Churg-Strauss syndrome, which is a form of necrotizing eosinophilic vasculitis inolving predominantly the small and medium sized vessels, is reported to result from the use of zafirlucast150 in asthma patients. Drug Induced Pseudolymphoma Syndrome The cutaneous manifestations in pseudolymphoma may range from a few erythematous plaques or nodules to generalized maculo-papular eruption and rarely exfoliative dermatitis. Generalized lymphadenopathy, hepatosplenomegaly, fever, arthralgia and eosinophilia are characteristically present in this disorder. All the cases improve completely following the withdrawal of the incriminating drug. Histopathology is indistinguishable from ‘mycosis fungoides’ (hence also termed as ‘pseudomycosis fungoides’) with pautrier’s micro-abscess

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in the epidermis and cerebriform nuclei in the dermal infiltrate. Large masses of atypical lymphocytes may also be found in the dermis. The offending drugs causing pseudolymphoma include phenytoin, phenothiazine, barbiturates, beta-blockers, ACE inhibitors, calcium channel blockers, H1 and H2 blockers, benzodiazepine and antidepressants. Drug Induced Erythema Nodosum It usually presents as tender erythematous nodules of acute onset with size varying from 1-5 cm on the anterior surface of the lower limb, though calves, thighs, forearms may also be involved. The lesions involute spontaneously with desquamation and pigmentary change. Paucity of immune complex suggests type IV hypersensitivity reaction. Histopathology shows changes predominantly in the subcutaneous tissue where there is septal inflammation together with inflammation of septal blood vessels. The infiltrate mainly consists of lymphocytes and histiocytes with a few neutrophils and eosinophils. Extravasations of RBCs are found mostly near the septa. Drugs implicated in causing erythema nodosum include sulfonamides, analgesics, antipyretics, oral contraceptive pills as well as granulocyte colony stimulating factor. Recently, panniculitis mimicking erythema nodosum is described in a patient of asthma who received leukotriene modifying agents.151 Blistering Drug Eruption Blistering drug eruption may be of varied etiologies and clinical manifestations as described below: Linear IgA Bullous Dermatosis The clinical manifestations of drug induced linear IgA bullous dermatosis (LAD) may vary from tense vesicles on erythematous base resembling bullous pemphigoid (BP), grouped papulovesicular lesions like dermatitis herpetiformis (DH) to urticaria or EM like lesion. Mucosal involvement is absent in case of drug-induced LAD which differentiate it from the idiopathic LAD. The antibodies are either produced against lamina lucida (laminin 5) or against anchoring fibrils (collagen IV), determining the localization of the bullae. The histopathology shows interface dermatitis with the formation of micro-abscess in dermal papillae and subsequent subepidermal blister. The infiltrate consists of neutrophils around the


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superficial vascular plexus. The direct immunofluorescence (DIF) shows deposition of IgA along the dermo-epidermal junction.152 The main offending drugs are amiodarone, ampicillin, cephalosporins, captopril, diclofenac, interferon-gamma, interleukin-2, lithium, phenytoin and vancomycin. Recently, atorvastatin, a lipid lowering agent, has also been documented to cause LAD.153 Drug Induced Pemphigus The drug-induced pemphigus usually starts with some prodromal features which may be either morbilliform rash or urticarial lesion, following which the blisters develop. These features help to differentiate the drug-induced variety from the idiopathic pemphigus state. It is postulated that the offending drugs bind to the disulfide bond on the inter-cellular junction and render them antigenic. Some drugs, however, may cause direct toxic effect on inter-cellular junction leading to blister formation. The antibodies are either against desmoglein I or desmoglein III except the cases of direct toxicity where no antibodies are found. The skin biopsy shows features similar to pemphigus foliaceous or vulgaris. The early lesion may show parakeratosis, eosinophilic spongiosis and variable dermal infiltrate. DIF shows pericellular deposition of IgG in about 90 percent of cases. Indirect immunofluorescence may show circulating antibodies in about 70 percent of cases. Drugs implicated include thiol group containing drug captopril, penicillamine, and non-thiol drugs penicillins, cephalosporins, phenylbutazone etc. Drug-induced pemphigus is also reported to result from carbamazepine,154 indapamide,155 Quinolones,156 fosinopril157 interferon alpha2a,158 fludarabine,159 bucillamine,160 quinapril161 and also following tetanus and diphtheria vaccination.162 Drug Induced Pemphigoid The clinical manifestation of drug-induced pemphigoid varies widely. It may resemble BP and sometimes may present with EM or pemphigus like picture. The antibodies found in this group of disorder are of IgG class and are directed against 230-Kda and 180-Kda antigens of hemidesmosomes. Histopathology mimics BP with eosinophil-rich subepidermal blister. Among the drugs related to the development of drug-induced pemphigoid are diuretics (furosemide), neuroleptic agents, phenacetin, penicillamine, penicillin and sulfasalazine.

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Other new introductions to this list include gabapentin,163 spironolactone,164 and cephalexin.165 Lichen planus pemphigoides, a condition which shares the features of both lichen planus and BP, is reported to be induced by the lipid lowering agent-simvastatin.166 The anti-neoplastic agent, azathioprine is implicated in the development and exacerbation of lesions of cicatricial pemphigoid. 167 Drug Induced Pseudo-porphyria Drug-induced pseudo-porphyria presents with discrete blisters on the face and dorsal surface of the hands, like that of porphyria cutanea tarda (PCT), though the other cutaneous manifestations of PCT are absent. The pathogenesis of drug-induced pseudo-porphyria is largely unknown and unlike PCT, no abnormality is found in porphyrin metabolism. The skin biopsy shows pauci-inflammatory sub-epidermal blisters like that of PCT. Drugs associated with the development of pseudo-porphyria are NSAIDs (naproxen), chlorthalidone, thiazides, furosemide and tetracycline. Many new drugs added to the list include flutamide,168 relafen,169 and nabumetone. 170 Apart from these drugs porphyria cutanea tarda is related to imatinib and tamoxifen.171,172 Drug Induced Lupus Erythematosus The subset of patients developing systemic lupus erythematosus following ingestion of drug are more likely to have systemic involvement (esp. pulmonary manifestation) than cutaneous and renal features. The drugs causing lupus erythematosus (LE) inhibit T-cell DNA methylation, thereby provoking autoreactivity and generating antibodies against histone-DNA complex (anti-histone antibodies). Drug induced LE is histologically indistinguishable from spontaneously arising LE. Among the drugs incriminated in the development of LE are acebutalol, procainamide, hydralazine, isoniazide, chlorpromazine, dilantin, diltiazem, hydrochlorthiazide, penicillamine, sulfonylurea, betablocker, griseofulvin, NSAIDs and minocycline. Reports suggesting the role of other drugs in the development of LE endorse the names of amiodarone,173 etanercept,174 infliximab,175 antiTNF-alpha,176 propylthiouracil177 and ticlopidine178 Drug-induced subacute lupus erythematosus (SCLE) is a newly described entity which is associated with the calcium channel blocker, diltiazem. Such SCLE like lesions are also reported to result from the use of antifungal agent, terbinafine.179


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Scleromatoid Tissue Reaction Drug may provoke scleromatous tissue reaction, which may be either confined to skin or associated with systemic involvements. Typically the plaques affect the thighs bilaterally and are found to have an erythematous rim. The pathogenesis of such reaction is not yet clearly known. Abnormality of the vascular supply is an accompaniment in this disorder. Drugs causing scleromatoid tissue reaction with systemic involvement include serotonin, methysergide, hydralazine and practolol; while bromocriptine, lithium, valproate, hydantoin and L-tryptophan leads to tissue reaction confined to the skin. Recently, paclitaxel, the anti-tumor drug, is also documented to cause scleroderma-like skin condition.180-182 CADR TO ANTI-RETROVIRAL THERAPY The review is incomplete without a comprehensive outline of the CADR to anti-retroviral therapy in this era of AIDS. The drugs used are classified in three broad categories, namely: protease inhibitors (PIs), nonnucleoside reverse transcriptase inhibitor (NNRTIs) and nucleoside reverse transcriptase inhibitor (NRTIs). The PIs include indinavir, ritonavir, saquinavir and nelfinavir which increase the CD4 count and reduce the viral load rapidly. In general the CADR to PIs are lipodystrophy, hypersensitivity and AGEP. The NNRTIs, which acts by inhibiting the enzyme reverse transcriptase by binding with the enzyme and altering its structure, include nevirapine, delavir-dine and loviride. The major toxicity of NNRTIs are rash, SJS and hypersensitivity syndorme. The NRTIs are nucleoside analogue, which get incorporated in the DNA of virus impending the process of replication. Important NRTIs are zidovudine, didanosine, lamivudine, zalcitabine and stavudine. The anti-retroviral drugs can be used alone, but in ‘highly active antiretroviral therapy (HAART)’ they are used in combination (PIs in combination with nucleoside analogue). The CADR to individual drugs are enlisted in Table 6.2. CONCLUSION The article makes an attempt to bring forth the CADR which the dermatologists might encounter in their clinical practice. With the advancement of medical science, many new diseases are likely to be identified and many new drugs are going to be introduced in the market.

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Recent Advances in Dermatology Table 6.2: CADR associated with anti-retroviral agents

Anti-retroviral drugs

Side-effects

Indinavir

• • • • • • • •

Ritonavir Nelfinavir Saquinavir Nevirapine Zidovudine

Didanosine Lamivudine Zalcitabine

• • • • • • • • • • • • • • • • • • •

Acute porphyria183 Hypersensitivity syndrome24 SJS184 Maculopapular drug eruption185 Gynecomastia186,187 Alopecia188,189 Paronychia and Pyoderma gangrenosum190 Spontaneous bleeding hematoma formation (especially in hemophiliac)191 Morbilliform eruption192 Urticaria193 Fixed drug eruption194 Gynecomastia195 SJS80,81,196,197 Hypersensitivity syndrome198,199 Nail pigmentation200 Cutaneous pigmentation201 Vasculitis202 Hypertrichosis (including eye-lash hypertrichosis)203,204 Paronychia with nail fold pyoderma gangrenosum205 Hypersensitivity syndrome206 Heightened reaction to mosquito bite207 Vasculitis208 SJS209 Papuloerythroderma of Ofuji210 Paronychia211 Hypersensitivity syndrome212 Morbilliform eruption213

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113. Hui YF, Cortes JE. Palmar-plantar erythrody sensthesia syndrome associated with liposomal daunorubicin. Pharmacotherapy 2000; 20:1221-3. 114. Canonne Courivaud D, Carpentier O, Dejobert Y, et al. Lichenoid drug reaction to leflunomide. Ann Dermatol Venereol 2003; 130(4): 435-7. 115. Guijarro B, Lopez A. Lichenoid reaction caused by Clopidogrel, a new antiplatelet drug. Med Oral 2003; 8(1): 33-7. 116. Lim DS, Muir J. Oral lichenoid reaction to imatinib (STI 571, Gleevec). Dermatology 2002; 205(2): 169-71. 117. Goldman BD. Lichenoid drug reaction due to sildenafil, Cutis 2000; 65(5):2823. 118. Buyukgebiz B, Arslan N, Ozturk Y, et al. Drug reaction to ursodeoxycholic acid: lichenoid drug eruption in an infant using ursodeoxycholic acid for neonatal hepatitis. Pediatr Gastroenterol Nutr 2002; 35(3): 384-6. 119. Viallard AM, Lavenue A, Balme B, et al. Lichenoid cutaneous drug reaction in injection sites of granulocyte colony-stimulating factor (Filgrastim). Dermatology. 1999; 198(3): 301-3. 120. Hamanaka H, Mizutani H, Shimizu M. Sparfloxacin-induced photosensitivity and the occurrence of a lichenoid tissue reaction after prolonged exposure. J. Am Acad Dermatol 1998: 38 (6 Pt 1): 945-9. 121. Swale VJ, McGregor JM. Amlodipine associated Lichen Planus. Br. J. Dermatol 2001; 144: 920-1. 122. Valance A, Lebrum-Vignes B, Descamps V, Icodextrin cutaneous hypersensitivity: report of 3 psoriasiform cases. Arch Dermatol 2001; 137(3): 309-10. 123. Woikenstein P, Chosidow O, Flechet ML, et al. Patch testing in severe cutaneous adverse drug reactions including Stevens-Johnson syndrome and toxic epidermal necrolysis. Contact Dermatitis 1996; 35: 234-6. 124. Thedenat B, Loche F, Albes B, et al. Acute generalized exanthematous pustulosis with photodistribution pattern induced by sertraline. Dermatology 2001; 203(1): 87-8. 125. Petavy-Catala C, Martin L, Fontes V, et al. Hydrochlorothiazide-induced acute generalized exanthematous pustulosis. Acta Derm Venereol 2001; 81(3): 209. 126. Brouard MC, Prins C, Mach-Pascual S et al. Acute generalized exanthematous pustulosis associated with ST1571 in a patient with chronic myeloid leukemia. Dermatology 2001; 203(1):57-9. 127. Sasaki K, Yamamoto T, Kishi M, et al. Acute exanthematous pustular drug eruption induced by mexiletine. Eur J Dermatol 2001; 11(5):469-71. 128. Mussot-Chia C, Flechet ML, Napolitano M. et al. Methylprednisolone induced acute generalized exanthematous pustulosis Ann Dermatol Venereol 2001; 128 (3 Pt 1): 241-3. 129. Chu CY, Wu J, Jean SS, et al. Acute generalized exanthematous pustulosis due to teicoplanin. Dermatology 2001; 202(2): 141-5. 130. Machet L, Martin L, Machet MC et al. Acute generalized exanthematous pustulosis induced by dextropropoxyphene and confirmed by patch testing. Acta Derm Venereol 2000; 80(3):224-5. 131. Schwab RA, Vogel PS, Warschaw KE. Clindamycin-induced acute generalized exanthematous pustulosis. Cutis 2000; 65(6): 391-3. 132. Anliker MD, Wuthrich B. Acute generalized exanthematous pustulosis due to sulfamethoxazol with positive lymphocyte transformation test (LTT) J Investig Allergol Clin Immunol 2003; 13(1): 66-8.


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133. Scheinfeld N, Wesson K, Perry P. Acute generalized exanthematous pustulosis resembling toxic epidermal necrolysis caused by famotidine. Acta Derm Venereol 2003; 83(1):76-7. 134. Galvao C, Criado RF, Criado PR, Acute generalized exanthematous pustulosis induced by ingestion of bamifylline J Eur Acad Dermatol Venereol 2002; 16(6): 634-7. 135. Chiu A, Kohler S, McGuire J, et al. Cytarabine-induced acute generalized exanthematous pustulosis. J Am Acad Dermatol 2002; 47(4): 633-5. 136. Lun K, Harley W. Allopurinol-induced pustular eruption: an unusually mild case. Australas J Dermatol 2002; 43(2): 140-3. 137. Moorant C, Devis T, Alcaraz I, et al. Acutre generalized exanthematous pustulosis due to meladinine with positive patch tests. Ann Dermatol venereal 2002; 129(2):234-5. 138. Al-Hoqail Ia, Crawford RI. Acute generalized exanthematous pustulosis induced by icodextrin. Br J Dermatol 2001; 145(6): 1026-7. 139. Noce R, Paredes BE, Pichler WJ, et al. Acute generalized exanthematous pustulosis (AGEP in a patient with furosemide. Am J Med Sci 2000; 320: 3313. 140. Merkel PA. Drug induced vasculitis. Rheum Dis Clin North Am 2001; 27:84962. 141. Calabrese LH, Michel Ba, Bloch DA, et al, the American college of rheumatology 1990 criteria for the classification of hypersensitivity vasculitis. Arhritis Rheum 1990; 33:1108-13. 142. Callen JP. Cutaneous vasculitis: relationship to systemic disease and therapy. Curr Probl Dermatol 1993 5: 45. 143. Jennette JC. Vasculitis affecting the skin. Arch Dermatol 1944; 130: 899. 144. Wintroub BU, Stern R. Cutaneous drug reaction: pathogenesis and clinical classification. J Am Acad Dermatol 1985 13: 167-79. 145. Dubost JJ, Souteyraud P, Sauvezie B. Drug induced vasculitis. Baillieres Clin Rheumatol 1991; 119-38. 146. Brasil L, Kremer JM, Clarke JL, et al. Identification of an autoantibody to vascular endothelial cell specific antigen in patients with systemic vasculitis. Am J Med 1989; 87: 74-80. 147. Kaneko K, Igarashi J, Suzuki Y, et al. Carbamazepine induced thrombocytopenia and leucopenia complicated by Henoch-Schonlein purpura symptoms. Eur J Pediatr 1993; 52:769-70. 148. Davidson KA, Ringpfeil F, Lee JB. Ibuprofen-induced bullous leukocytoclastic vasculitis. Cutis 2001; 67(4): 303-7. 149. Schneider F, Meziani F, Chartier C, et al. Fetal allergic vasculitis associated with celecoxib. Lancet 2002; 359(9309): 852-3. 150. Green RL, Vayonis AG. Churg-Stauss syndrome after zafirlucast in two patients not receiving systemic steroid treatment. Lancet 1999; 353:725-6. 151. Dellaripa PF, Wechsler ME, Roth ME. Recurrent panniculitis in a man with asthma receiving treatment with leukotriene-modifying agents. Mayo Clin proc 2000; 75(6): 643-5. 152. Kuechle MK, Stegemeir E, Maynard B, et al. Drug induced linear IgA bullous dermatosis. Report of 6 cases and review of the literature. J Am Acad Dermatol 1994; 30: 187-92. 153. Konig C, Eickert A, Scharfelter-Kochanek K, et al. Linear IgA bullous dermatosis induced by Atarvastatin J Am Acad Dermatol 2001; 44: 689-92.

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154. Patterson CR, Divies MG. Carbamazepine-induced pemphigus. Clin Exp Dermatol 2003; 28(1):98-9. 155. Bayramgurler D, Ercin C, Apaydin R, et al. Indapamide-induced pemphigus foliaceus. J. Dermatolog Treat 2001; 12(3): 175-7. 156. Anadolu RY, Birol A, Bostanci S, et al. A case of pemphigus vulgaris possibly triggered by quinolones. J Eur Acad Dermatol Venereol 2002; 16(2): 152-3. 157. Parodi A, Cozzani E, Milesi G. et al. Fosinopril as a possible pemphigusinducing drug. Dermatology 2002; 204(2):139-41. 158. Marinho RT, Johnson NW, Fetela NM, et al. Oropharyngeal pemphigus in a patient with chronic hepatitis C during interferon alpha-2a therapy. Eur J Gastroenterol Hepatol 2001; 13(7): 869-72. 159. Gooptu C, Littlewood TJ, Frith P, et al. Para-neoplastic pemphigus: An association with fludarabine? Br J Dermatol 2001; 144: 1255-61. 160. Ogata K, Nakajima H, Ikeda M, et al. Drug induced pemphigus foliaceus with features of pemphigus vulgaris Br. J Dermatol 2001; 144: 421-2. 161. Ong CS, Cook N, Lee S. Drug related pemphigus and angiotensin converting enzyme inhibitors. Australas J Dermatol 2000; 41: 242-6. 162. Cozzani E, Cacciapuoti M, Parodi A, et al. Pemphigus following tetanus and diphtheria vaccination. Br. J. Dermatol. 2002; 147(1): 188-9. 163. Zachariae CO. Gabapentin-induced bullous pemphigoid. Acta Derm Venereol 2002; 82(5): 396-7. 164. Modeste AB, Cordel N, Courville P. et al. Bullous pemphigoid induced by spironolactone. Ann Dermatol Venereol 2002; 129 (1 Pt 1): 56-8. 165. Czechowicz RT, Reid CM, Warren LJ et al. Bullous pemphigoid induced by cephalexin. Australas J. Dermatol 2001; 42(2): 132-5. 166. Stoebner PE, Michot C, Ligeron C, et al. Simvastatin-induced lichen planus pemphigoides. Ann. Dermatol Venereol 2003; 130(2 Pt 1): 187-90. 167. Burgess MJA, Fivenson DP. Generalisation of cicatricial pemphigoid during azathioprine therapy, Arch Dermatol 2000; 136: 1274. 168. Mantoux F, Bahadoran P, Perrin C, et al. Flutamide-induced late cutaneous pseudoporphyria. Ann Dermatol Venereol 1999; 126(2): 150-2. 169. Magro CM, Crowson AN. Pseudoporphyria associated with Relafen therapy. J Cutan pathol 1999; 26(1): 42-7. 170. Krischer J, Scolari F, Kondo-Oestreicher M. et al. Pseudoporphyria induced byt nabumetone. J. Am Acad Dermatol 1999; 40(3): 492-3. 171. Ho AY, Deacon A, Osborne G, et al. Precipitation of porphyria cutanea tarda by imatinib mesylate? Br J Haematol 2003; 121(2):375. 172. Agarwal R, Peters TJ, Coombes RC et al. Tamoxifen-related porphyria cutanea tarda. Med Oncol 2002; 19(2) 121-3. 173. Kundu AK. Amiodarone-induced systemic lupus erythematosis. J Assoc Physician India. 2003; 51: 216-7. 174. Carlson E, Rothfield N. Etanercept-induced lupus-like syndrome in a patient with rheumatoid arthritis. Arthritis Rheum 2003; 48(4): 1165-6. 175. Favalli EG, Sinigaglia L, Varenna M. Drug-induced et al. lupus following treatment with infliximab in rheumatoid arthritis. Lupus 2002; 11(11):753-5. 176. Debandt M, Vittecoq O, Descamps V, et al. Anti-TNF-alpha-induced systemic lupus syndrome. Clin Rheumatol 2003; 22(1): 56-61. 177. Yamada A, Sato K, Hara M, et al. Propylthiouracil-induced lupus-like syndrome developing in a Graves patient with a sibling with systemic lupus erythematosus. Intern Med 2002; 41 (12): 1204-8.


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178. Spiera RF, Berman RS, Werner AJ, et al. Ticlopidine-induced lupus: a report of 4 cases. Arch Intern Med. 2002, 162 (19): 2240-3. 179. Bonsmann G, Schuller M, Luger Ta, et al. Terbinafin induced sub-acute lupus erythematosus. J Am Acad Dermatol 2001; 44: 925-31. 180. Kupfer I, Balguerie X, Courville P, et al. Scleroderma-like cutaneous lesions induced by paclitaxel: a case study. J Am Acad Dermatol 2003; 48(2): 279-81. 181. De Angelis R, Bugatti L, Cerioni A, et al. Diffuse Scleroderma occurring after the use of paclitaxel for ovarian cancer. Clin Rheumatol 2003; 22(1): 49-52. 182. Lauchli S, Trueb RM, Fehr M. et al. Scleroderma-like drug reaction to paclitaxel (Taxol). Br. J Dermatol 2002; 147(3): 619-21. 183. Fox PA, Boang FC, Hawkins DA, et al. Acute porphyria following commoncement of indinavir. AIDS 1999; 13: 622-3. 184. Teira R, Zubero Z, Munoz J, et al. Stevens-Johnson syndrome caused by indinavir. Scand J Infect Cis 1998: 30: 634-5. 185. Fung HB, Pecini RA, Brown ST, et al Indinavir associated maculopapular eruption. J Clin Immunol 1991; 11: 52-64. 186. Toma E, Therrien R. Gynecomastia during antiretroviral therapy in HIV infection. AIDS 1998. 12:681-2. 187. Herry I. Hypertrophy of breast in a patient treated with indinavir. Clin Infect Dis 1997; 25: 937-8. 188. Bouscarat F, Prevot MH, Matheron S, Alopecia associated with indinavir therapy. N. Eng J Med 1999; 8: 618. 189. Monforte A, Testa L, Gianotto M, et al. Indinavir related alopecia. AIDS 1998; 338: 1776-7. 190. Bouscant F, Bouchard C. Paronychia and pyogenic granuloma of the great toe in patients treated with indinavir. N Eng J Med 1998; 338: 1776-7. 191. Hagerty SL, Asher DP. Spontaneous bleeding associated with the use of the protease inhibitor ritonavir in a hemophiliac patient with HIV infection. Pediatr Infect Dis 1998: 17: 929-30. 192. Vicant MA, Medina MM, Gonzalez-Ensenat A. Rash as a side effect of nelfinavir in children. AIDS 2000; 114: 335-6. 193. Demoly P, Messad D, Trylesinski A, et al. Nelfinavir induced urticaria and successful desensitization. J Allergy Clin Immunol 1998; 102: 875-6. 194. Smith KJ, Yeager J, Skelton H. Fixed drug eruption to HIV-I protease inhibitor. Cutis 2000; 66: 29-32. 195. Chopra K, Tyring SK. Current antiretroviral therapy in the treatment of HIV infection Semin Cutan Med Surg 1997; 16: 224-34. 196. Barner A, Myers M. Nevirapine and rashes. Lancent 1998; 351:1133. 197. Warren KJ, Boxwell DE, Kim NY et al Nevirapine associated Stevens-Johnson syndrome. Lancet 1998; 351: 567. 198. Bourezane Y, Salard D, Hoen B, et al. DRESS (drug rash with eosinophilia and systemic symptom) syndrme associated with nevirapine therapy. Clin Infect Dis 1998; 27: 1321-2. 199. Callot V, Roujeau JC, Bagot M, et al. Drug induced pseudo –lymphoma and hypersensitivity syndrome. Arch Dermatol 1996; 132: 1315-21. 200. Fisher CA, Mc Poland PR. Azidothymidine induced nail pigmentation. Cutis 1988; 43: 552-4. 201. Obuch ML, Baker C, Roth Ri, et al Selective cutaneous hyperpigmentation in mice following zidovudine administration. Arch Dermatol 1992: 28: 508-13.

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202. Torres RA, Lin RY, Lee M, et al. Zidovudine induced leucocytoclastic vasculitis. Arch Intern Med. 1992; 152: 850-1. 203. Sahai J, Conway B, Cameron D, et al. idovudine associated hypertrichosis and nail pigmentation in a HIV-infected patient. AIDS 1991; 5: 1995. 204. Kintman NE, Hinthorn DR. Excessive growth of eyelashes in a patient with AIDS being trated with zidovudine. N Eng J Med 1991: 324: 1896. 205. Russo F, Collantes C, Guerren J. Severe paronychia due to zidovudine neutropenia in neonate. J Am Acad Dermatol 1999. 40: 322-4. 206. Jacobson MA, McGarth MS, Joseph P. et al. Zidovudin induced fever. J. Acquir Immune Defic Syndr 1984; 100: 495-9. 207. Diven DG, Newton RC, Ramsey KM. Heightened cutaneous reaction to mosquito bites in patients with acquired immuno-deficiency syndrome receiving zidovudine. Arch Intern Med. 1988; 148: 2296. 208. Herranz P, Fernandez-Diaz ML, Lucas R, et al. Cutaneous vasculitis associated with didanosine. Lancet 1994; 344: 680. 209. Parneix Spake A, Bastuji-Garin S, Levy Y. et al Didanosine as a probable cause of Stevens-Johnson syndrome. Lancet 1992; 340: 857-8. 210. Just M, Carrascosa JM, Ribera M, et al. Dideoxyinosine associated Ofuji ppuloerythroderma in a HIV infected patient. Dermatology 1997; 1995; 4101. 211. Zerboni R, angins AG, Cusini M, et al. Lamivudine induced paronychia. Lancet 1998; 351 1256. 212. Tancred-Bohin E. Grange F, Bournerios I et al. Hypersensitivity syndrome associated with zalcitabine. Lancet 1996: 347: 971. 213. Yarchoan R, Thomas RV, Allain JP, et al. Phase I studies of 2,3-dideoxycytidine in severe human immuno deficiency virus infection as a single agent and alternating with zidovudine. Lancent 1988; 1: 76-81.

The Scleroderma Disorders: An Update

7

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Sanjay Ghosh

The Scleroderma Disorders: An Update The scleroderma disorders encompass a group of heterogeneous disorders representing sclerosis of skin as the linking clinical feature.1 The dust of controversies regarding many facts of these disorders are yet to settle. However, recent researches have thrown some scattered light in the different misty corners of these disorders, which have led to better understanding of their pathogenesis and thus more rational approach in their management. The detailed description of every aspect of these disorders is beyond scope of the present article which will mainly highlight certain intriguing facts as well as some recent informations about the disorders. CLASSIFICATION The scleroderma-related disorders have been primarily classified into two basic types: localized and systemic. These localized and systemic forms have again been subdivided into different subtypes (Tables 7.1 and 7.2).2,3 The term ‘systemic sclerosis’ seems to be preferable over ‘systemic scleroderma’, as the former denotes the frequent occurrence of internal manifestations seen in these disorders.4 Inclusion of lichen sclerosus et atrophicus (LSA) into the localized scleroderma group has been questioned, but certain rational facts may firmly support this view: (i) guttate morphea and LSA clinically resemble each other quite often; (ii) co-existence of LSA and morphea has been well documented both clinically and histopathologically;5 (iii) in partially treated morphea with intralesional corticosteroid, LSA types of lesions appeared5 and (iv) Borrelia burgdorferi has been detected both in morphea and LSA patients of Europe and Asia by PCR analysis.6 Severe generalized morphea may mimick diffuse systemic sclerosis but the former always spares the hands and face and does not present with manifestations of major vascular or visceral involvement.4 Morphea patch may simulate Hansen’s patch because both may show diminished sensation as depicted by quantitative thermal test,7 diminished sweating response and absence of hairs. Histopathology may ultimately solve this dilemma.

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Recent Advances in Dermatology Table 7.1: Classification of localized scleroderma (morphea) (proposed)2 •

• • •

•

•

Plaque morphea • Morphea en plaque • Guttate morphea • Atrophoderma of Pasini and Pierini • Keloid morphea (nodular morphea) [Lichen Sclerosus et atrophicus] Generalized morphea Bullous morphea Linear morphea • Linear morphea (linear scleroderma) • En coup de sabre • Progressive hemifacial atrophy Deep morphea • Subcutaneous morphea • Eosinophilic fascitis • Morphea profunda Disabling pansclerotic morphea of children

Table 7.2: Classification of systemic sclerosis3

Systemic Sclerosis (SSc)

Limited cutaneous (lcSSc)

Diffuse cutaneous (dcSSc)

Related forms • Prescleroderma • Overlap syndrome • Environment-induced scleroderma • Systemic sclerosis sine scleroderma

Systemic sclerosis sine scleroderma, a rare form of disorder, shows features of typical vascular and visceral involvement without having any skin sclerosis. Overlap syndromes represent the disease where systemic sclerosis coexists with features of other rheumatic disorders. Prescleroderma denotes the subjects with definite Raynaud’s phenomenon (RP) who also shows positivity to one of the hallmark autoantibodies of SSc, like anticentromere, antitopoisomerese I or anti-RNA polymerase I or II antibodies. Systemic sclerosis is usually subdivided into limited (lcSSc) and diffuse cutaneous (dcSSc) subsets. These two subsets are basically differentiated


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Table 7.3: Two subsets of SSc: Salient features Type

Limited (lcSSc)

Diffuse (dcSSc)

Years

Less than 1 year

2. Involvement a. Skin b. Systemic c. Vascular d. Fibrosis

Acral Late, uncommon Predominant Less

Truncal + Acral Early, common Less Predominant

3. Nailfold capillary

No drop out

Drop out

4. Antibodies

Anticentromere antibodies (ACA) (40%)

Scl-70 (30%)

5. Prognosis

Less gloomy

Gloomy

1. Interval between Raynaud’s phenomenon and appearance of skin changes

by the extent of the skin sclerosis: lcSSc is restricted to the hands, and to some extent, the face and neck, whereas dcSSc extends proximal to the wrists and involves proximal limbs and trunk but commonly sparing the upper back. The salient features of the two subsets have been enumerated in the Table 7.3. Drawbacks of Current Classification System The present two subset classification system is of some definite practical value as working classification but possesses some inherent flaws: (1) Clinical outcomes within each major subset are so diverse, (2) Prognosis remains unpredictable; although overall survival is graver for dcSSc than for lcSSc, certain patients with lcSSc may also show high mortality rate, e.g., lcSSc patients showing pulmonary hypertension, lung fibrosis or acute renal failure, (3) Genetic and serological predictors of end-organ involvement have not been accounted into the present classification system: antibodies to topoisomerase-I (Scl-70) are associated with increased risk of pulmonary fibrosis both in lcSSc and dcSSc,8 anticentromere antibodies (ACA) are almost always sign of lcSSc and are especially associated with the classical CREST variants of this disorder, anti-histone antibodies (AHA) are associated with cardiac, pulmonary and renal involvement, and (4) Racial factors and HLA types have also not been considered into this system; HLA-DR52a is associated with an increased risk of lung fibrosis in Caucasians, but not in the other racial groups.10

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Thus, it is expected that in future the classification system would be increasingly supported by genetic and immunological markers, which may give vital clue to identify the risk of serious complications like pulmonary hypertension, lung fibrosis, and renal failure, ultimately predicting the prognosis of the disorders.11 PATHOGENESIS The complex and yet incompletely understood pathogenesis of systemic sclerosis depends on three basic underlying factors: (a) vascular damage, (b) immune activation, and (c) increased synthesis of extracellular matrix with deposition of excessive amounts of structurally normal collagen. These patho-mechanisms result from cell-cell, cell-cytokine and cellmatrix interactions. The heterogeneous nature of the clinical presentations of the disorder probably represents the variable contributions from each of these pathogenic factors.12 Current hypotheses regarding the pathogenesis of scleroderma mainly pay attention to the interplay between early immunological events and vascular changes, yielding the generation of a population of activated fibrogenic fibroblasts, considered to be the effector cell in the disease.13,14 Recent investigations have solved a much hotly debated ‘egg before? hen before?’ mystery regarding systemic sclerosis (which one is earlier? vascular changes or fibrosis?) that vascular changes precede fibrosis in its pathogenesis. The observations which have proved this fact include: (1) markers of vascular damage like endothelin-1,15 von Willebrand-factor antigen etc. appear early in the disease process, (2) Raynaud’s phenomenon frequently starts early, (3) photoplethysmographic (PPG) studies in systemic sclerosis16 have shown early vascular changes, and (4) digital arteriography17 has shown narrowing of digital arteries in systemic sclerosis. Vascular Changes Vascular and endothelial changes, predominantly affecting vascular tone, as discussed above, appear to precede other features of scleroderma. Endothelins, nitric oxide and superoxide anions are the most significant inflammatory mediators whose derangements are currently thought to be associated with altered vascular tone in scleroderma.18 Endothelin (ET), the most potent vasoconstrictor known, contributes to both vascular dysfunction and the development of the fibrotic lesion in systemic sclerosis.19 The basal secretion of ET-1 from the endothelial cells may provide an important early link between endothelial cell damage and fibroblast activation.12 Levels of circulating ET-1 have been found to be


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significantly raised in both lcSSc having primarily vascular involvement as well as in dcSSc having widespread fibrosis as the predominant feature.20 Nitric oxide (NO) counteracts the vasoconstrictive action of ET-1 in normal blood vessels whereas an alteration in the relative amount of these two mediators has been postulated to play a pathogenic role in scleroderma.12 Superoxide anions liberated from the endothelium may damage the endothelium by neutralizing NO and oxidizing circulating low-density lipoproteins (LDL). Oxidized LDL may be cytotoxic for endothelial cells.21 Studies have documented that LDLs in patients with scleroderma are much more susceptible to oxidations (perhaps via free radical attack) than those from patients with primary Raynaud’s phenomenon or other rheumatic diseases.22 The scleroderma patients’ sera possess certain factors which are cytotoxic to endothelial cells. Twenty to thirty percent of scleroderma patients have circulating anti-endothelial cell antibodies which, however, may be found in the sera of patients suffering from other rheumatic diseases. These antibodies can upregulate the expression of adhesion molecules on endothelial cells and induce apoptosis of these cells.23 The vascular cytotoxicity in some scleroderma patients has been documented to be attributed by tumor necrosis factor-alpha and -beta, proteases or complement membrane attack complex (C 5b-C9).24,25 Scleroderma patients have increased endothelial cell surface expression of adhesion molecules like ICAM-1 and E-selectin.26 Elevated levels of soluble VCAM-1, E-selectin and ICAM-1 have been shown in certain group of scleroderma patients,27 especially in scleroderma renal-crisis but not in scleroderma-associated pulmonary disease.12 One study has depicted a correlation between changes in soluble VCAM-1 and soluble E-selectin and clinical deterioration or improvement of systemic sclerosis.28 Immunologic Activity The continuing activation of endothelial cells, leading to upregulation of adhesion molecules, leukocyte adhesion and leukocyte leaking out of the vasculature plays an underlying factor in the pathogenesis of systemic sclerosis.12 The expression of ELAM-1 on endothelial cells correlates with the degree of mononuclear cell infiltration in the early inflammatory lesion of scleroderma.28 In scleroderma patients, subpopulations of lymphocytes, namely activated/cytotoxic/inducer T-cells, natural killer cells and some helper T-cells acquire a significantly increased ability to adhere to endothelium.29 The mononuclear cells in systemic sclerosis patients which migrate into the extracellular matrix express differentiation markers of activated T-cells including CD3, CD4, CD45, HLA-DR and

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LFA-1 (lymphocyte function associated antigen-1).30 The surface of these cells also possesses subsets of integrin molecules including those of beta 1 and beta 2 class, which facilitate binding to other cells including fibroblasts and tissue components like types I and IV collagens, fibronectin, and laminin.31 Circulating autoantibodies directed against a variety of antigens are found in about 75 percent of systemic sclerosis patients which include topoisomerase I (formerly called Scl-70) (15 to 20%), centromere antigens (25 to 30 percent), fibrillin-1, and RNA I, II and III (20 percent).12 The provocative stimulus for the production of these antibodies is yet unknown. One hypothesis is that these autoantibodies are targeted against those autoantigens who have been fragmented via reactive oxygen species and specific metals such as copper or iron.32 Another theory has explained that these antibodies are produced as a result of infection (e.g., cytomegalovirus) and via molecular mimicry, crossreact with a native antigen.33 Autoantibodies interacting with fibroblasts may have some potential pathogenic role in systemic sclerosis. One study has shown significantly elevated levels of anti-fibroblast antibodies of IgG and IgMclass in systemic sclerosis, both limited and diffuse types.34 Interplay between a number of cytokines and growth factors seems to contribute significantly to the pathogenesis of systemic sclerosis. Increased levels of circulating IL-1, IL-2, IL-2R, IL-4, IL-8, IL-17, TNFalpha and interferon, and antibodies to IL-6 and IL-8 have been found in patients with systemic sclerosis.35 The marked matrix stimulatory properties of the transforming growth factors, particularly TGF-beta, have implicated these proteins as potentially important mediators in systemic sclerosis. Increased expression of endoglin, a non-activated TGF beta receptor occurs in sclerodermatous skin and these levels increase with the duration of the disease. Although high level of a particular cytokine does not necessarily imply a causative role, the increased levels of various cytokines support a cellular immune mechanism in systemic sclerosis and an on-going expression of T-cells and their secreted products.12 Increased Fibroblast Activity and Collagen Synthesis The development of the fibroblast capable of excess matrix production and deposition is the hallmark of systemic sclerosis. The scleroderma fibroblasts have been clearly shown to be the effector cells which, as activated fibroblasts, mediate the fibrogenic pathway. The theory put forward to unify several of the different pathogenic events seen in systemic sclerosis tells that the development of the activated fibroblast places the initiating event in the vascular bed, leading to growth factor


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and cytokine production with resulting fibroblast activation and subsequent fibrosis. However, this cannot explain adequately the abnormal phenotype of scleroderma fibroblast.12 The missing link between the systemic autoimmunity and fibrosis in the pathogenesis of systemic scleroderma has been attempted to be searched in a recent study.36 The net accumulation of extracellular matrix depends on the balance between the synthesis and degradation of extracellular matrix components, the latter process being regulated by matrix metalloproteinases. Matrix metalloproteinase-1 (interstitial collagenase-1) can initiate degradation of collagen types I-III, that are major extracellular matrix constituents of affected skin of systemic sclerosis. The hypothesis that systemic autoimmunity in systemic sclerosis induces anti-matrix metalloproteinase-1 autoantibodies which inhibit matrix metallo-proteinase-1 activity, resulting in collagen accumulation has been proved by the following observations: (1) IgG anti-matrix metalloproteinase-1 auto-antibody levels were significantly elevated in sera of the patients with SSc but not with SLE or dermatomyositis, (2) the same autoantibody levels were significantly high in dcSSc as compared with those in lcSSc, (3) these autoantibody levels significantly correlate with the extent of fibrosis in the skin, lung and renal blood vessels in SSc. Thus the presence of anti-matrix metalloproteinase-1 autoantibody in SSc confirms the link between systemic autoimmunity and fibrosis.36 ETIOLOGY Although we had already deposited a lot of informations in our knowledge–bank regarding the pathogenesis of scleroderma, it is not fully clear to us, till date, how these pathogenic pathways are initially switched on. However, certain possible etiological and risk factors37 have been enumerated below. No single gene or environmental factor is likely to be the sole contributory factor for this disorder. Genetic Factors Genetic factors clearly affect both disease susceptibility and patterns of disease expression. The presence of antitopoisomerase antibodies have been strongly linked with HLA haplotype DQ7, DR2 (DRB1 1602).38 Recently, the fibrillin 15 gene located on human chromosome 15q has been found to be strongly linked to scleroderma.39 The beneficial effects of angiotensin converting enzyme (ACE) inhibitors in scleroderma renal disease have led to search the role of ACE in the pathogenesis of scleroderma. An insertion/deletion polymorphism of the ACE gene has

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been indentified and carriage of one or two alleles with deletion genotype has been associated with increased risk of developing scleroderma. A single nucleotide polymorphism in the gene for endothelial nitric oxide synthase (eNOS) has similarly got increased risk of developing scleroderma.40 Infectious Agents An infectious agent may trigger autoimmune and other events in a genetically susceptible host, resulting in scleroderma. Infection with a virus containing a similar amino acid sequence to that of a host protein may precipitate scleroderma. This phenomenon, although not unique to scleroderma, is called molecular mimicry. Such a shared epitope between topoisomerase I and certain retroviruses has been found.37 Latent viral infection may also augment or promote disease expression in the susceptible host. Cytomegalovirus may thus alter the vascular, fibrotic and immunologic features of systemic sclerosis. 41 Recent investigations33 have shown that the autoantibodies in SSc react with the UL94 human cytomegalovirus protein. These auto-antibodies also induce endothelial cell apoptosis. Morphea/LSA: Borrelia Controversy The hypothesis that morphea is caused by infection with Borrelia burgdorferi has been challenged repeatedly. The following facts may be noteworthy: (1) morphea shares many clinico-pathological features of acrodermatitis chronica atrophicans caused by Borrelia burgdorferi;42 (2) Borrelia burgdorferi DNA was detected in morphea and LSA patients of Europe and Asia but not of North America,43 (3) geographical differences exist between different species of Borrelia; Borrelia burgdorferi has three geno species namely, B. garinii and B. afzelli (in Europe and Asia) and B. sensu stricta (in North America). Thus, it can be concluded that a subset of morphea/LSA, not all, especially among patients in Euope and Asia but not in North America may be caused by special subspecies of Borrelia burgdorferi.44 Non-infectious Environmental Agents A number of environmental agents have been incriminated in the etiology of systemic sclerosis. Exposure to silica has been suspected for long period, but recent epidemiological studies have uniformly failed to support a causative relationship.45 Scleroderma-like diseases clearly appear to occur among individuals exposed to manufacturing process


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of vinyl chloride polymer but not in connection with any finished product.37 Other contributing agents include epoxy resins, pesticides and a number of organic solvents used in paints. Ingestion of contaminated rapeseed oil may lead to an epidemic of toxic oil syndrome, which was characterized by acute myalgia, fever, neuropathy, sclerodermalike skin disease and pulmonary hypertension.46 Another clinically similar syndrome called eosinophilia-myalgia syndrome with fascitis and dermal induration has been found in individuals consuming the nutritional supplement L-trytophan.47 Drugs Some drugs, particularly bleomycin, have been implicated in the genesis of scleroderma-like syndrome. Bleomycin may induce chromosomal break which may lead to formation and release of unique autoantigens responsible for development of scleroderma. The other drugs incriminated in causing scleroderma-like syndromes are pentazocine and cocaine.37 Microchimerism Normal women harbor viable immunologic stem cells of fetal origin for long years following pregnancy. Women with scleroderma, who have been pregnant, possess much greater number of fetal cells as compared to those without scleroderma. Such persistent fetal cell may mount an immune response against the mother or the maternal response to the fetal cells may subsequently be directed against ‘self’ leading to autoimmunity. A graft-versus-host disease type of mechanism may originate from the persistent fetal cells to induce sclerodermatous disease process, since both disorders share many clinical features. In men with scleroderma and women who have never been pregnant, their maternal cells crossing the placenta and then carried by the fetus may play the immunomodulatory role.48 A recent study has shown that in SSc patients, cellular microchimerism is accounted for by a lage number of cells that have the characteristics of T lymphocytes specific for maternal allogenic antigens.49 Why Scleroderma Common in Female? There exist two possible explanations for female predominance of scleroderma: (1) IL-1, TNF, and IFN gamma have been shown to modulate the expression of ICAM-1 by scleroderma fibroblasts, an effect enhanced by the female sex hormone beta-estradiol,50 and (2) microchimerism as discussed above.

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MANIFESTATIONS AND DIAGNOSIS Skin involvement in the scleroderma-related disorders includes: sclerosis or thickening of the skin, pruritus, calcinosis, edema, telangiectasia, sclerodactyly, and digital ulcers and infection. Ultrasonography can definitely determine skin thickness and durometer can assess skin hardness.51 Among vascular manifestations of scleroderma, Raynaud’s phenomenon has been classically viewed as reversible vasospasm; many patients, however, develop structural changes in the vessels with permanently impaired flow. Episodes of Raynauds’ phenomenon may be prolonged and lead to digital ulcers or infarcts.51 Photoplethysmographic (PPG) studies16 in systemic sclerosis (lcSSc) has demonstrated diminished digital flow in all the extremities irrespective of clinical findings. Some digits even showed ‘critical flow’ (almost zero) without having any external sign of digital gangrene. This is in contrast to PPG studies in SLE patients,52 where not all the extremitis showed such diminshed digital flow and not a single digit had depicted ‘critical flow’. Organ involvement in scleroderma frequently affects the kidneys, gastrointestinal tract and lungs. Severe and life-threatening renal disease termed scleroderma renal-crisis which develops in approximately 10 to 15 percent of patients is manifested by: (1) the acute onset of renal failure, (2) the sudden onset of moderate to marked hypertension (some subject may remain normotensive), and (3) a urine sediment that usually reveals only mild proteinuria with few cells or casts. Esophageal hypomotility and incompetence of the lower esophageal sphincter represent the earliest visceral manifestation described and remains the most common source of gastrointestinal symptoms in scleroderma. Symptoms usually arise from gastroesophageal reflux, stricture formation, and abnormal motility. The two chief clinical presentations of lung involvement are interstitial lung disease (also termed fibrosing alveolitis or pulmonary fibrosis) and pulmonary vascular disease leading to pulmonary hypertension.51 Diagnosis The diagnosis of the scleroderma group of disorders depends mainly on the presence of characteristic clinical features. As an example, localised scleroderma and lcSSc can usually be diagnosed clinically. However, there underly certain fallacies in the diagnosis: (a) morphea may sometimes mimic tuberculoid leprosy lesions,7 (b) generalised morphea may simulate dcSSc,4 or (c) early diagnosis of dcSSc can sometimes be


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missed during the first few months of disease as arthralgia and soft tissue swelling may be the most prominent clinical features in this phase rather than skin sclerosis.51 Certain organ specific investigations and serological tests are also required for confirmation of diagnosis and for correct classification. In a patient of Raynaud’s phenomenon, for example, abnormal esophageal motility by scintigraphy or barium swallow may aid in the diagnosis of scleroderma. Abnormal nailfold capillaroscopy also confirms a diagnosis of secondary Raynaud’s in case of diagnostic dilemma.51 The combination of sclerodermatous skin changes plus one or more of the following features point towards the diagnosis of systemic sclerosis: 1. The abrupt onset of renal insufficiency plus hypertension in the absence of significant urine pathology 2. Dyspnea due to pulmonary interstitial fibrosis 3. Pulmonary hypertension 4. Diarrhea with malabsorption51 Serological Tests Scleroderma or an overlap syndrome may be associated with the presence of characteristic autoimmune antibodies: anticentromere, antitopoisomerase-I (Scl 70), anti-RNA polymerase, or U3-RNP antibodies. A positive antinuclear staining pattern, seen in most of the SSc patients, has much less sensitivity and specificity than previously thought.51 Some important observations regarding autoantibodies in systemic sclerosis are as follows: 1. Anticentromere antibodies favour a diagnosis of lcSSc (especially CREST) 2. Antitopoisomerase I (Scl 70), although not very sensitive, are highly specific for dcSSc. 3. Anti-RNA polymerase I and III are only seen in systemic sclerosis; Anti-RNA polymerase II are found only in systemic sclerosis or SLE.53 4. Antibodies to U3-RNP (fibrillarin) are found in systemic sclerosis, especially those with pulmonary hypertension.51 In a patient suspected to be suffering from scleroderma should undergo a baseline antibody profile test including ANA, anti-Scl 70 and anti-centromere antibodies (ACA). However, a diagnosis of scleroderma cannot be excluded by a negative serological test due to the low sensitivity of these antibodies.54 Anti PM-Scl antibodies are associated with myositis and the presence of high titers of rheumatoid factor, anti U1-RNP antibodies or lupusassociated antibodies suggests overlap syndromes. These syndromes

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present with more prominent arthritis than seen in systemic sclerosis alone and may be associated with features of systemic lupus erythematous.51 Antineutrophil cytoplasmic antibodies (ANCA) are found to be not associated with systemic sclerosis.55 PROGNOSIS The prognosis for patients with scleroderma depends on the extent of skin involvement. Patients having diffuse skin disease have poorer survival rate than those with limited scleroderma.56 Four other adverse prognostic factors were identified: 1. Visceral involvement (cardiac, pulmonary, renal) 2. Presence of antibodies to topoisomerase I (anti-Scl 70) 3. Elevated ESR (> 25 mm/hr) 4. Anemia.56 MANAGEMENT Optimal management of scleroderma varies with the subset and stage of the disease (see Table 7.4). In lcSSc, effective therapies are primarily targeted at the vasculature, including Raynaud’s phenomenon and later in the course of the disease, pulmonary hypertension. In early diffuse cutaneous scleroderma, immune-mediated therapy followed quickly by antifibrotic agents should be the rational choice, whereas in late stage, Table 7.4: Systemic sclerosis: management approach Systemic sclerosis Limited cutaneous (lcSSc)

Diffuse cutaneous (dcSSc)

Vascular therapy Early Immunomodulatory quickly followed by antifibrotic agents NonPharmacological pharmacological

Surgical

Late Antifibrotic agents


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where inflammatory phase has already subsided, therapy with only antifibrotic agents would be more effective.57 Vascular Therapy The vasospasm associated with SSc may be controllable, but the proliferative structural vascular changes, playing more significant role in its pathogenesis, have not been yet successfully prevented or cured. Therapeutic options in treating vascular changes in SSc depends on three modalities: nonpharmacological, pharmacological and surgical.57,58 Nonpharmacological ways predominantly include prevention of vasospasm induced by cold and other precipitating factors. Patients should have warm-water bath and avoid cold contact and exposure especially in winter. They should wear woollen gloves and socks particularly during winter morning and evening. Smoking and drugs inducing vasospasms (like beta-blockers) should be strictly restricted. Whirling of arms and other biofeedback measures may help in the acute episodes. 57,58 Pharmacological therapies are indicated in patients with frequent episodes, prolonged functional impairment, severe pain or digital ischemia. Calcium channel blockers like long-acting nifedipine at doses of 30 to 90 mg/day may be beneficial. Some patients intolerant or nonresponding to nifedipine have been managed successfully by nicardipine (30 to 60 mg BID). Selective alpha-blockers such as prazosin have been effective only in primary Raynaud’s phenomenon (RP) but not in scleroderma. The fact that platelet serotonin (5HT) may be a contributory factor for triggering RP has prompted the use of agents affecting platelet serotonin either by blocking serotonin receptors (ketanserin 40 mg TID)59 or inhibiting serotonin reuptake (SSRIs: fluoxetin 20 mg/day).60 Combination of pentoxiphylline (400 mg BID) which improves digital perfusion by increasing the deformability of RBC plasma membranes and antiplatelet agent like low dose aspirin (75 mg daily) have also been quite effective in preventing and amelioration of digital gangrenous changes (personal observation). The nonselective endothelin antagonist, bosentan, which has been approved for treatment of pulmonary hypertension in patients with scleroderma, may be beneficial upon digital ischemia and may decrease the incidence of digital ulceration. The role of bosentan (62.5 mg BID with dose escalation to 125 mg BID as tolerated), which although prevents new ulcer formation, in healing of establisted digital ulceration is not certainly known. Iloprost, the synthetic analogue of prostacyclin, given parenterally at doses of 0.5 to 2 ng/kg per min, is a potent vasodilator which inhibits platelet aggregation and adhesion, increases RBC’s deformability, alters neutrophilic functions including

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free radical formation and probably helps in repairing of damaged endothelium. It also reduces the production and release of the profibrotic cytokine, connective tissue growth factor from fibroblasts, and thus lessening its concentration in sclerodermatous skin.62 Considerable side effects, however, have limited its use only in short-term palliation of severe RP in SSc, especially in helping to avoid amputation of the distal tip of a digit.63 Oral prostaglandin analogue, beraprost, which is comparatively safer, has been evaluated recently in some trials for patients with SSc and digital necrosis.64 Surgical manoeuvre includes different forms of sympathectomy in severe RP in SSc. While cervical sympathectomy provides only shorttime benefit, lumbar sympathectomy leads to long-term beneficial effects for severe RP of feet. The reason of this discrepancy between the upper and lower limbs has yet not been explained. In some of our SSc patients with impending toe gangrene lumbar sympathectomy has been able to reverse the digital ischemic process and prevent severe RP in followup for long period.58 Recently radical microarteriolysis (digital sympathectomy) or vein by-pass have been effectively performed to minimize severe pain, augment feeling of digital ulcer and prevent severe, acute episode of RP.65 Immuno-Modulation Therapy Activation of immune system may be major provocating factor for both the vascular and fibrotic lesion in SSc, whose maximum damaging effect occurs in the early stage of the disease. This initial immune activation, by producing cytokines and growth factors, could create autocrine loops which, however, do not require further stimulus to perpetuate the vascular and fibrotic lesions. Due to these autocrine loops formation, immuno-suppressive therapy, showing good response in the early phase of SSc, is not that effective in the late phase.57 The role of cyclophosphamide as a single agent in scleroderma remains uncertain. It is mainly useful in patients with fibrosing alveolitis in combination with corticosteroids but not in the cases of advanced fibrosis.57 Corticosteroids in high-dose for long period have potential toxicity and may precipitate normotensive renal crisis.66 Steroids should therefore be better restricted only in patients having myositis, active fibrosing alveolitis, symptomatic serositis and tenosynovitis. Moreover, the lowest possible effective dose should only be used in these conditions, preferably below 20 mg/day.57 Cyclosporine, which acts as both suppressor of cell mediated immunity and reducer of collagen synthesis has the limitation of using


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in scleroderma by its significant nephrotoxicity.67 Other cyclophilins, such as rapamycin, may provide more targeted immunosuppression, improved efficacy, and reduced toxicity.57 Other immunosuppressive drugs have been employed in scleroderma with varying degree of success. The role of azathioprine, however, is anecdotal. Methotrexate, that although corrects the skin induration, has shown conflicting results in randomised double-blind trials.68 An uncontrolled study has shown promising result in early stage diffuse cutaneous disease by anti-thymocyte globulin followed by mycophenolate mofetil.69 Antifibrotic Therapy The management of established fibrosis still remains a therapeutic challenge due to paucity of safe and effective agents which can remove excess insoluble cross-linked collagen fibers without destroying structural framework of the body and individual organs.57 The major drawbacks of the antifibrotic drugs are that they are slow to act and not powerful enough to prevent rampant fibrosis. Such agents are unnecessary for cutaneous manifestations in patients with lcSSc. However, they are indicated in cases of lcSSc when associated with visceral fibrosis.57 D-penicillamine can reduce collagen biosynthesis as well as suppress immune disorders. Autoantibodies in scleroderma are produced against autoantigens that have been fragmented via reactive oxygen species and specific metals such as copper or iron.70 Penicillamine, as a chelator of metals, may thus reduce the formation of these autoantigens in systemic scleroderma. The precise role of penicillamine, however, in the treatment of scleroderma has yet not been defined.57 High dose of penicillamine (750-1000 mg/day) seems to possess no advantage over low dose (125 mg every other day).71 Even with penicillamine therapy skin sclerosis worsens during the first four to six months of therapy which indicates the need of quickly effective antifibrotic agents. Penicillamine has been recommended for use in comparatively stable patients with established diffuse scleroderma or as a follow-up to more aggressive agents (e.g., anti-thymocyte globulin) in more active scleroderma.57 Interferon gamma (IFN-gamma), a more potent inhibitor of collagen synthesis in vitro as compared to IFN-alpha, may be effective in the treatment of scleroderma. IFN-gamma may, however, cause aberrant cellular activation in SSc and considerable vascular side effects, including renal hypertensive crisis.72 Iloprost, mentioned earlier in the vascular therapy of scleroderma, has also some antifibrotic properties. Five days of iloprost infusion among

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six patents of dcSSc reduced concentration of the profibrotic cytokine, connective tissue growth factor (CTGF) in the dermal interstitial fluid.73 However, clinically significant efficacy of iloprost as antifibrotic agent could not be ascertained. Relaxin, a natural antifibrotic protein, produced by the uterus and corpus luteum during pregnancy, enhances the degradation of collagen and suppresses the formation of new collagen by fibroblasts. A placebocontrolled trial74 showed reduction in mean skin thickness in SSc by human recombinant relaxin (25 microg/kg per day by continuous subcutaneous infusion). A subsequent larger multicenter study, however, could not confirm the said benefit.57 Other Therapeutic Agents Due to paucity of specific medication in systemic sclerosis and difficulties in conducting double-blind trials in these disorder, anecdotal evidences of effectivity of some agents have been claimed. Minocycine, in an open trial of eleven patients in the early diffuse scleroderma, but without having any affection of internal organ system, has shown some benefit.75 The drug may act as a disease-modifying agent.76 Stem cell transplantation, showing some benefit in other auto-immune diseases, has been attempted in some patients of SSc. In majority of the patients skin diseases responded but the mortality rate during the first year of post-transplantation period was as high as 27 percent.77 High dose immunosuppression (total body irradiation, cyclophosphamide, and anti-thymocyte globulin) followed by autologous stem cell support have been tried in diffuse disease with visceral involvement. Such attempt has shown slightly lower mortality in the follow-up period.78 Another multicenter study 79 used cyclophosphamide or melphalan for immunosuppression and peripheral stem cell support or bone marrow transplantation for hematopoietic reconstitution. Most patients demonstrated some initial benefit in skin scores and disability along with the cardiac and renal function of survivors remained at or near baseline. Long-term follow-up, however, showed relapse in some survivors. Thus, high dose immunosuppression with autologous stem cell rescue till date remains as an experimental therapeutic option. In Europe a trial has begun to compare this mode of therapy with cyclophosphamide alone.57 Better understanding of pathogenesis has revealed that the key mediators like cytokines play a definite role in the evolution of systemic sclerosis. Combinations of anticytokine therapies like agents directed against both TGF–beta and CTGF (connective tissue growth factors) are being investigated recently for their potentiality as clinically effective


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regimens.80 Parenteral prostacycline-like iloprost, already mentioned, represents significant example of anticytokine therapy as it suppresses CTGF.57 Therapy for Cutaneous Involvement Localised scleroderma seems to soften with topical intralesional corticosteroids, topical calcipotriene,81 and UVA-182 therapy. Widespread morphea was treated with oral methotrexate 15 mg/week for a 24-week period which showed some benefit.83 Telangiectasia, which may induce more cosmetic problem especially when on face, may be covered with camouflage make-up or treated with laser therapy.84 Calcinosis, that may cause considerable distress, may be surgically removed if present in a suitable location, occasionally with the help of a dental drill which creates less tissue damage than the conventional ways.57 While pharmacological attempts with probenecid, colchicine or warfarin have failed to reduce calcinosis, diltiazem, in an anecdotal study, has shown some promise.85 REFERENCES 1. Black CM. Scleroderma—clinical aspects. J Intern Med 1993; 234: 114-6. 2. Peterson LS, Nelson AM, Su WP. Classification of morphea (localised scleroderma). May Clin Proc 1995; 70: 1068-76. 3. LeRoy EC, Black CM, Fleischmajer R, et al. Scleroderma (systemic sclerosis): Classification, subsets and pathogenesis. J Rheumatol 1988; 15: 201-4. 4. Black CM, Denton CP. Classification of scleroderma. www. Up To Date.com. 2000, Dec: 9.1. 5. Ghosh S, Haldar B. Coexistence of lichen sclerosus et atrophicus and morphoea. Ind J Dermatol Ven Leprol 1987; 53: 369-70. 6. Ozkan S, Atabey N, Fetil E, et al. Evidence of B. burgdorferi in morpha and lichen sclerosus. Int J Dermatol 2000; 39: 278-83. 7. Ghosh S, Haldar B. Quantitative evaluation of cutaneous thermal sensation in psoriasis, morphea and vitiligo. Ind J Dermatol Ven Leprol 1989; 55: 30-2. 8. Kuwana M, Medsger Jr TA, Wright TM. T cell proliferative response induced by DNA topoisomerase1 in patients with systemic sclerosis and healthy donors. J Clin Invest 1995; 96: 586-8. 9. Hesselstrand R, Scheja A, Shen GQ, et al. The association of antinuclear antibodies with organ involvement and survival in systemic sclerosis. Rheumatology 2003; 42: 534-40. 10. Altmann RD, Medsger JA Jr, Bloch DA, et al. Predictors of survival in systemic sclerosis (scleroderma). Arthritis Rheum 1990; 34: 401-3. 11. Denton CP, Black CM, Korn JH, et al. Systemic sclerosis: Current pathogenetic concepts and future prospects for targeted therapy. Lancet 1996; 347: 1452-4. 12. Block CM, Denton CP. Pathogenesis of scleroderma-I and II. www. Up To Date. com, 2003, April: 11.2

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13. Piela-Smith TH, Korn JH. Lymphocyte modulation of fibroblast function in systemic sclerosis. Clin Dermatol 1994; 12: 368-9. 14. Sollberg S, Mauch C, Eches B, et al. The fibroblast in systemic sclerosis. Clin Dermatol 1994; 12: 378-9. 15. Vancheeswarah R, Azam A, Black C, et al. Localisation of endothelin-1 and its binding sites in scleroderma skin. J Rheumatol 1994; 21: 1267-9. 16. Ghosh S, Biswas A. Digital blood flow in systemic sclerosis. Ind J Dermatol Venereol Leprol 1992; 58: 169-72. 17. Dobich L, Bookstein JJ, Zweiffer A, et al. Digital arteries in patients with scleroderma. Arch Intern Med 1972; 130: 708-14. 18. Flavahan NA, Flavahan S, Liu Q, et al. Increased alpha 2-adrenargic constriction of isolated arterioles in diffuse scleroderma. Arthritis Rheum 2000; 43: 1884-6. 19. Kahaleh MB. Endothelin: An endothelial-dependent vasoconstrictor in scleroderma. Arthritis Rheum 1991; 34: 97-8. 20. Vancheswaron R. Magoulas T, Etrat G, et al. Circulating endothelin-1 levels in systemic (SSc) subsets—A marker of fibrosis or vascular dysfunction? J Rheumatol 1994; 21: 1837-9. 21. Blake DR, Winyard P, Scott D GL, et al. Endothelial cell cytoxicity in inflammatory vascular diseases—the possible role of oxidised lipoproteins. Ann Rheum Dis 1985; 44: 176-7. 22. Bruckdorfer KR, Hilary JB, Bunce T, et al. Increased susceptibility to oxidation of low-density lipoproteins isolated from patients with systemic sclerosis. Arthritis Rheum 1995; 38: 1060-1. 23. Sgonc R, Gruschwitz MS, Boeck G, et al. Endothelial cell apoptosis in systemic sclerosis is induced by antibody-dependent cell-mediated cytotoxicity via CD95. Arthritis Rheum 2000; 43: 2550-2. 24. Kahaleh MB, Fan PS. Mechanism of serum-mediated endothelial injury in scleroderma: identification of a granular enzyme in scleroderma skin and sera. Clin Immunol Immunopathol 1997; 83: 32-4. 25. Sprott H, Muller-Ladner U, Distler O, et al. Detection of activated complement complex C5b-9 and complement receptor C5a in skin biopsies of patients with systemic sclerosis (scleroderma). J Rheumatol 2000; 27: 401-3. 26. Gruschwitz M, Driesch P, Kellner I, et al. Expression of adhesion proteins involved in cell-cell and cell-matrix interactions in the skin of patients with progressive systemic sclerosis. J Am Acad Dermatol 1992; 27: 168-70. 27. Sfikakis PP, Tesar J, Baraf H, et al. Circulating intercellular adhesion molecule1 in patents with systemic sclerosis. Clin Immunol Immunopathol 1993; 68: 87-9. 28. Denton CP, Bickerstaff MCM, Shoiwen X, et al. Serial circulating adhesion molecule levels reflect disease severity in systemic sclerosis. Brit J Rheumatol 1995; 34: 1047-9. 29. Rudnicka L, Majewski S, Blaszcyk M, et al. Adhesion of peripheral blood mononuclear cells to vascular endothelium in patients with systemic sclerosis (scleroderma). Arthritis Rheum 1992; 35: 770-3. 30. Prescott RJ, Freemont AJ, Jones CJP, et al. Sequential dermal microvasculature and perivascular changes in the development of scleroderma. J Pathol 1992; 166: 254-6. 31. Hynes RO. Interins: Versatility, modulation, and signaling in cell adhesion. Cell 1992; 69: 11-3.


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32. Cascolo-Rosen L, Wighlay F, Rosen A. Scleroderma autoantigens are uniquely fragmented by metal-catalyzed oxidation reactions: Implications. J Exp Med 1997; 185: 71-3. 33. Lunard C, Beson C, Navone R, et al. Systemic sclerosis immunoglobulin G autoantibodies bind the human cytomegalovirus late protein UL94 and induce apoptosis in human endothelial cells. Nat Exed 2000; 6: 1182-4. 34. Chizzolini C, Raschi E, Rezzonico R, et al. Autoantibodies to fibroblasts induce a proadhesive and proinflammatory fibroblast phenotype in patients with systemic sclerosis. Arthritis Rheum 2002; 46: 1601-3. 35. Kwcasawa K, Hirose K, Sani H, et al. Increased interleukin-17 production in patients with systemic sclerosis. Arthritis Rheum 2000, 43: 2454-6. 36. Sato S, Hayakawa I, Hasegawa M, et al. Function blocking autoantibodies against matrix metaloproteinase-1 in systemic sclerosis. J Invest Dermatol 2003; 120: 542-7. 37. Korn J. Risk factors for and possible causes of scleroderma. www. UpTo Date. com. 2002; August: 10.3. 38. Tan FK, Stivers DN, Arnett FC, et al. HLA haplotypes and micosatellite polymorphisms in and around the major histocompatibility complex region in Native American population with a high prevalence of scleroderma (systemic sclerosis). Tissue Antigens 1999; 53: 73-5. 39. Tan FK, Stivers DN, Foster MW, et al. Association of microsatellite markers near the fibrillin 1 gene on human chromosomes 15q will scleroderma in a Native American population. Arthritis Rheum 1998; 41: 1728-31. 40. Fatini C, Gensini F, Sticchi E, et al. High prevalence of polymorphisms of angiotensin-converting enzyme (I/D) and endothelial nitric oxide synthase (Glu 298 Asp) in patients with systemic sclerosis. Am J Med 2002;112: 539-42. 41. Pandey JP, Leroy EC. Human cytomegalovirus and the vasculopathies of autoimmune disease (especially scleroderma), allograft rejection and coronary restenosis. Arthritis Rheum. 1998; 41: 9-11. 42. Aberer E, Neumann R, Stanek G. Is localised scleroderma a Borrelia infection? (letter) Lancet 1985; ii: 278. 43. Weide B, Walz T, Garbe C. Is morphea caused by B. burgdorferi? A review. Br. J Dermatol 2000; 142: 636-44. 44. Bajaj AK. Morphea and Borrelia burgdorferi: Causal or casual relationship? What’s New? In Dermatology, Sexually transmitted diseases and Leprosy. 2001; 28: 11-3. 45. Janowsky EC, Kupper LL, Hulka BS. Meta-analysis of the relation between silicone breast implants and the risk of connective tissue diseases. N Eng J Med 2000, 342; 780-3. 46. Tabuenca JM. Toxic-allergic syndrome caused by ingestion of rapeseed oil denatured with antiline. Lancet 1981; 2: 565-8. 47. Silver RM, Heyes MP, Maize JC, et al. Scleroderma, fascitis and eosinophilia associated with the ingestion of tryptophan. N Eng J Med 1990; 322; 873-6. 48. Johnson KL, Nelson JL, Furst DE, et al. Fetal cell microchimerism in tissue from multiple sites in women with systemic sclerosis. Arthritis Rheum 2001; 44: 1846-9. 49. Burasteno SE, Galbiati S, Vassollo A, et al. Cellular microchimerism as a lifelong physiological status in parous women: an immunologic basis for its amplification in patients with systemic sclerosis. Arthritis Rheum 2003; 48: 1109-16.

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50. Shi-Wen X, Panesar M, Vancheeswaran R, et al. Expression and shedding intercellular adhesion molecule 1 and lymphocyte function associated antigen 3 by normal and scleroderma fibroblasts. Effects of interferon. gamma, tumor necrosis factor alpha, and estrogen. Arthritis Rheum 1994; 37: 1688-91. 51. Korn JH. Overview of the manifestations and diagnosis of scleroderma. www. UpToDate.com 2003 April; 11.2 52. Ghosh S, Biswas A. Digital blood flow in systemic lupus erythematosus by photoplethysmography. Ind J Dermatol 2002; 47: 152-5. 53. Satol M, Kuwana M, Ogasawara T, et al. Association of autoantibodies to topoisomerase I and the phosphorylated (IIO) form of RNA polymerase II in Japanese scleroderma patients. J Rheumatol 1996; 23: 637-40. 54. Spencer-Green G, Alter D, Welch HG. Test performance in systemic sclerosis. Anti-centromere and anti-Scl. 70 antibodies. Am J Med 1997; 103: 241-3. 55. Merkel PA, Polisson RP, Chang Y, et al. Prevalence of antineutrophil cytoplasmic antibodies in a large inception cohort of patients with connective tissue disease. Ann Intern Med 1997; 126: 864-7. 56. Ferri C, Valentini G, Cozzi F, et al. Systemic sclerosis: Demographic, clinical and serologic features and survival in 1,012 Italian patients. Medicine (Baltimore) 2002; 81: 137-41. 57. Denton CP. General approach to the treatment of sclerodorma - I and II, www. UpTo Date.com, 2003 May, 11.2 58. Ghosh S. Digital vasculopathy in systemic scleroderma: Management strategy. AMRI Apollo Journal 2002; 2: 15. 59. Seibold JR, Janeneau AH. Treatment of Raynaud’s phenomenon with ketanserin, a selective antagonist of the serotonin 2 (5-HT2) receptor. Arthritis Rheum 1984; 27: 139-40. 60. Bolte MA, Avery D. Case of fluoxetin-induced remission of Raynaud’s phenomenon: a case report. Angiology 1993; 44: 161-2. 61. Black C, Kom J, Mayes M, et al. Prevention of ischemic digital ulcers in systemic sclerosis by endothelin receptor antagonism (abstract) Arthritis Rheum 2002; 46: 341-4. 62. Stratton R, Shiwen X, Martine G, et al. Iloprost suppresses connective tissue growth factor production in fibroblasts and in the skin of scleroderma patients. J Clin Invest 2001; 108: 240-3. 63. Wigley FM, Wise RA, Scibold RJ, et al. Intravenous iloprost infusion in patient with Raynaud’s phenomenon secondary to systemic sclerosis. A multicenter, placebo controlled, double-blind study. Ann Interm Med 1994; 120: 197-9. 64. Vayssaairat M. Preventive effect of an oral prostacyclin analog, beraprost sodium, on digital necrosis in systemic sclerosis. J Rheumatol 1999; 26: 217-9. 65. O’Brion BM, Kumar PA, Mellow CG, et al. Radical microarteriolysis in the treatment of vasospastic disorders of the hand, especially scleoderma. J Hand Surg 1992; 7: 447-9. 66. Steen VD, Conte C, Medsger TA Jr. Case-control study of corticosteroid use prior to scleroderma renal crisis (abstract). Arthritis Rheum 1994; 37: 5360. 67. Denton CP, Abdullah A, Sweny P, et al. Acute renal failure occurring in scleroderma treated with cyclosporine A: A report of three cases. Brit J Rheumatol 1994; 3: 90-2. 68. Pope JE, Bellamy N, Seibold JR, et al. A randomized, controlled trial of methotrexate versus placebo in early diffuse scleroderma. Arthritis Rheum 2001; 44: 1350-3.


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69. Stratlon RJ, Wilson H, Black CM. Pilot study of anti-thymocyte globulin plus mycophenolate mofetil in recent-onset diffuse scleroderma. Rheumatology (Oxford) 2001; 40: 83-5. 70. Casciola-Rosen L, Wigley F, Rosen A. Scleroderma autoantigens are uniquely fragmented by metal-catalyzed oxidation reactions: Implications for pathogenesis. J Exp Med 1997; 185: 70-3. 71. Clements PJ, Furest DE, Worg WK, et al. High-dose versus low-dose D-penicillamine in early diffuse systemic sclerosis. Arthritis Rheum 1999; 1193-6. 72. Freundlich B, Jimenez SA, Steen VD, et al. Treatment of systemic sclerosis with recombinant inteferon-gamma. Arthritis Rheum 1999; 35: 1133-7. 73. Stratton R, Shiwen X, Martini G, et al. Iloprost suppresses connective tissue growth factor production in fibroblasts and in the skin of scleroderma patients. J Clin Invest 2001; 108: 240-4. 74. Seibola JR, Kom JH, Simms R, et al. Recombinant human relaxin in the treatment of scleroderma. A randomized, double-blind, placebo-controlled trial. Ann Intern Med 2000; 132; 870-4. 75. Le SCH, Morales A, Trentham DE. Minocycline in early diffuse scleroderma. Lancet 1998; 352; 1753-7. 76. Ghosh S. Glimpses of scleroderma. 31st National Conference of IADVL, Kolkata Abstracts, 2003; 76. 77. Binks M, Passweg JR, Furst D, et al. Phase I/II trial of autologous stem cell transplantation in systemic sclerosis: procedure related mortality and impact on skin disease. Ann Rheum Dis 2001; 60: 576-9. 78. McSweerey PA, Nash RA, Sulbivan KM, et al. High dose immunosuppressive therapy for severe systemic sclerosis: initial outcomes. Blood 2002; 100: 16013. 79. Farge D, Marolleau JP, Zohar S, et al. Autologous bone marow transplantation in the treatment of refractory systemic sclerosis: early results from a French multicenter phase I-II study. Brit J Haematol 2002; 119: 724-8. 80. Denton CP, Abraham DJ. Transforming growth factor-beta and connective tissue growth factor: Key cytokines in scleroderma pathogenesis. Curr Opin Rheumatol 2001; 13: 504-7. 81. Cunnigham BB, Landello IDR, Langman G, et al. Topical calcipotriene for morphea/linear scleroderma. J Am Acad Dermatol 1998; 39: 211-5. 82. Kerscher M, Volkanandt M, Gruss C, et al. Low-dose UVA phototherapy for treatment of localised scleroderma. J Am Acad Dermtol 1998; 38: 21-6. 83. Seyger MMB, vanden Hoogen FHJ, de Boo T, et al. Low-dose methotrexate in the treatment of widespread morphea. J Am Acad Dermatol 1998; 39: 220-5. 84. Denton CP. Organ-based therapy in scleroderma. www. UpToDate.com. 2002; August: 10.3. 85. Palmieri GM, Sabes JI, Aclion JA, et al. Treatment of calcinosis with diltiazem. Arthritis Rheum 1995; 38: 1645-8.

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8

A.K. Bajaj

Patch Testing: An Overview The earliest account of patch testing is by Staedler who, in 1847, described the blotting paper method to test idiosyncracy.1 In 1889, Collins,2 an ophthalmologist applied patches of atropine to his patients who were getting reactions to instillation of atropine. It was Jadassohn3 (The father of patch testing) who unequivocally established the role of patch testing in dermatitis medicamentosa. By applying chemicals (on pieces of blotting paper) to the skin he was able to reproduce the clinical picture of contact dermatitis from iodoform mercury salts in patients suffering from skin intolerance to those substances. Bloch, Bonnevie and Sulzberger further contributed towards establishment of patch testing as a useful diagnostic tool in dermatology.4 The standardization and importance of patch testing has rightly been highlighted by Sulzberger as one of the most important advances in clinical dermatology during the twentieth century. Patch testing at present is the only scientific method to detect the cause of contact dermatitis. The present standard test methods involve a device and patch test material. The patch test material consists of allergens incorporated in a suitable base in proper concentrations which are known for most of the substances. ALLERGENS There are more than 6 million chemicals in the world’s environment today and approximately 4000 have been reported to have contact sensitizing properties. Selection of chemicals for patch testing is always difficult and demanding but fortunately a small number of substances account for the majority of contact allergies. National and international groups of patch test specialists recommend that allergen series (standard battery) including mixes of allergens be used for routine testing. Such series comprise 20-25 test substance mixes containing 50-60 different allergens. Testing with these detects about 70-80 percent of allergic contact sensitivity.5 Test series for special purposes include those for footwear, cosmetics, fragrances, sunscreens, preservatives, rubber chemicals, plastics, textile dyes etc and also include occupations such as engineering, hair-dressing, bakery work, dentistry etc. The allergens must be stored properly so that they are protected from environmental influences.

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Polypylene syringes kept in a cool dark place (refrigerator) protect the allergens from heat, light, uv-rays, air, humidity and microbial contaminants. Paraphenylenediamine (PPD) should be kept in amber coloured syringe. VEHICLES The antigens/allergens are incorporated in appropriate vehicles and in proper concentration. At present the standard vehicle is petrolatum due to its refined nature and almost negligible sensitizing potential. Paradoxically petrolatum is highly lipophilic and most allergens are hydrophilic. Aqueous solutions and solvents such as ethanol, acetone, methyl ethyl ketone and ethyl ether have been tried and are recommended for some special allergens only because stability of solutions is low and they are difficult to handle, preserve and quantify. TAPES Most modern tapes have adequate tack and keep the patches in close approximation to the skin. They are made from non-woven textile and acrylate adhesive. Allergy is rare but may occur due to uncured acrylate or to formaldehyde and even to additives. Scanpore, Norgesplaster and Micropore are the common non-occlusive tapes used for occluding the patch test material. Old fashioned tapes used to produce frequent allergic reactions and they were commonly due to colophony.6 PATCH TEST UNITS/DEVICES The earlier patches used were pieces of cotton fabric soaked with allergen solutions. Later filter paper discs were used in a similar way and taped to the skin under a water impermeable cover. The Al-test is a development of this method.7 It is an effective and usually non-irritant test unit that consists of aluminium foil covered with polythene with a 10 mm central disc of filter paper adhered by heat. Reactions to the polythene covering on the aluminium foil, spread of strong positive reactions to surrounding areas, use of occlusive tape with resultant reactions and large areas required for patches are some of the disadvantages leading to the disuse of this patch test device. At present the commonly used device is Finn8 chamber which consists of stiff aluminium and has a diameter of 8 mm and depth of 0.5 mm. The particular advantage of this chamber is its tight apposition to the skin thus localizing reaction to the test site and a small area is required for patch testing. Chambers made of plastic with diameters of 10-15 mm

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have also been introduced. However, even with the correct techniques small amounts of test material may diffuse slightly beyond the site of patch test. Occasionally metal salts-like mercury, cobalt and nickel interact with aluminium but this effect can be eliminated by plastic coated Finn chamber. The concept and technique of patch testing has been revolutionized by the pioneering work of Fischer and Maibach who have introduced the TRUE (Thin layer rapid use epicutaneous) Test.9,10 It is an innovative ready to apply test method that uses polyester patches coated with allergens in hydrophilic vehicle. It meets almost all the pre-requisites of an ideal test method due to the least possible time consumed in application of the patches, uniform distribution and release of antigen, less amount of antigen required, minimum irritant reactions, easy storage and stability, whereas the significant drawbacks are the limited number of antigens available and high cost. Several studies have been conducted comparing Finn chambers and TRUE Test methodologies. In a European multicenter study of TRUE Test,11 808 patients were simultaneously tested with 11 different allergens (Panel 12) by both TRUE Test and Finn Chamber method. Left/right application of the respective test varied at random. Most tests were removed after 48 h and evaluated after 72 or 96 h according to generally accepted recommendations. The concordance of positive reactions was 63 percent between TRUE test and the control method; 17 percent of positive reactions occurred only with TRUE test and 20 percent only with Finn Chamber method. Approximately 75 percent of all positive reactions were explained by the patients‘ present or past history. Irritant/ questionable reactions occurred in the same frequency for the two methods and were less than 10 percent of all patches applied. No late reactions were recorded. In a recent study,12 167 patients were patch tested using both the NACDG (North American Contact Dermatitis Group) standard screening tray and TRUE Test. TRUE Test missed 50 percent of relevant reactions to fragrances that were detected by the fragrance-mix applied with Finn Chamber. In contrast the Finn Chamber method missed only 1 of 14 relevant reactions to fragrances. Of positive reactions with balsam of Peru, 88.9 percent were clinically relevant and 55.6 percent of the relevant reactions detected by Finn Chamber were missed by TRUE Test. Similarly TRUE Test missed 4 of 7 relevant reactions to thiuram mix. TRUE Test performed somewhat better than the Finn Chamber methodology in detecting allergic reactions to nickel, neomycin and kathon CG. Of all relevant positive reactions to nickel sulphate, Finn Chamber missed 25 percent while TRUE Test 6.25 percent. Similarly in the case of neomycin


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Finn Chamber missed 3 of 16 and TRUE Test 1 of 14 relevant reactions. TRUE Test did not miss any relevant reaction to kathon CG while Finn Chambers methodology missed 2 out of 7. Neither the TRUE Test nor the Finn Chamber performed optimally in detecting relevant reactions to formaldehyde or carbamates. A number of other studies13-16 have also shown similar results with some variations. In general the concordance has been 63-75 percent and better detection of kathon CG, nickel and neomycin positivity with TRUE Test while Finn Chamber technique was found to be superior for detection of fragrances, thiuram mix and chromates. More false positive reactions with Finn Chambers and more false negative with TRUE Test were observed. Both the methods seem to have their advantages and disadvantages and the search and research are ongoing for improvement and perfection of the patch test technology. TECHNIQUE OF PATCH TESTING A detailed history should be taken to decide the supplemental antigens required over and above the standard battery of allergens. In case of occupational dermatitis the special kits if available and the substances the patient comes into contact should also be added. Patch testing should not be carried out if the patient has active disease and is on large dose of steroids (>20 mg prednisolone) or is applying topical steroids on the back. Routinely the patches are applied on the upper back after cleaning the area with water, spirit or acetone. Avoid the vertebral column and angle of the scapulae. The patient is instructed to avoid exercise, sweating, wetting the area, rubbing and scratching. The patient should not expose the area to sunlight or sunlamps. The patches are normally removed after about 48 h and reading taken after 30-60 min. The test area should be marked with colored or fluorescent ink. The ICDRG (International Contact Dermatitis Research Group) recommendations of evaluating the patch test reactions are as follows + or ? Doubtful reaction (faint erythema only) + Weak (Nonvesicular ) positive reaction ++ Strong (vesicular) positive reaction +++ Extreme (bullous) positive reaction Negative -, IR Irritant reaction, NT Not tested Reading a diagnostic patch test should not cease at day 2 (D2) after application of allergens as numerous allergic reactions need more time to evolve. Consequently a further reading is regarded as mandatory, but it is not universally agreed upon when it should be taken though recommendations vary from D3 to D7.17-19 Todd et al20 performed

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readings on D2, D3 and D4 after application of patch tests in 88 patients. Ninety patch test reactions in 49 patients were interpreted as allergic. A single D2 reading detected 58 allergic reactions with 32 false negatives and 23 false positives. A single D3 reading detected 77 allergic reactions with 13 false negatives and 17 false positives. A single D4 reading detected 85 allergic reactions with 5 false negatives and 9 false positives. The authors concluded that if only a single reading is feasible it is better performed on D4. Analysis of the data of the Information Network of Departments of Dermatology (INDK) also pointed to possible superiority of D4 reading.21 Geier et al22 carried out retrospective analysis of patch test reactions in 3 groups of patients in order to obtain informations on the best day for the second patch test reading after D2 and also on the usefulness of additional readings after D3. In the years 1990 to 1995, patch tests were routinely read at D3 and D4 in 1096 patients, at D3 and D5 in 1243 patients and at D3 and D6 in 1136 patients. In all the 3 groups, significantly more positive reactions diminished than appeared de novo from D3 to the later reading. Reactions to individual allergens showed wide differences in this connection. Neomycin sulphate, cobalt salts and paraphenylenediamine were slow allergens with reactions increasing than diminishing from D3 to the later readings. With fragrance mix and balsam of Peru the opposite pattern occurred. The authors concluded that D3 reading is better than D4, but if a third reading is performed it should be done at D5 to get the maximum information out of patch testing. In a recent retrospective study,23 the usefulness of an additional patch test reading on D6 or D7 was investigated. In 62 out of 760 patients (8.2%), 77 late positive reactions (after D3) were seen. Allergens most involved in producing late positive reactions were nickel sulphate (20 reactions), neomycin sulphate (7), tixocortol - 21 pivalate (5), paratertiary butylphenol formaldehyde resin (5) and kathon CG (5). The authors concluded that it was preferable to have a reading on D2 and D3 but an extra reading on D6 or D7 was very useful as it gave additional information in 8.2 percent of patch tested patients. INTERPRETATION OF PATCH TEST RESULTS Though apparently a simple procedure, patch testing is fraught with various technical pitfalls depending upon the patch test device, the tape used for occlusion, the vehicle employed for incorporation of the antigen and the antigen itself. Clinical experience is the best guide to the interpretation of patch tests. Difficulty arises when allergic and irritant reactions cannot be differentiated on morphological grounds. The two great errors in patch testing are false positive and false negative results.


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False Positive Reactions A false positive reaction is irritant in nature. Its various causes are: a. Use of wrong test substance; i.e. when a substance is irritant in nature or is used in a higher concentration. Contamination of the test substance may also produce false positive reaction. b. Hyperreactive skin; (Excited skin syndrome; angry back; crazy back; status eczematicus); Mitchell24 in 1975 described a phenomenon, which he termed as “angry back”, characterized by the presence of multiple patch tests associated with one or more strongly positive reactions (+++) in patients submitted to a battery of epicutaneous tests which were not completely reproducible when the patients were tested later. In 1981 Maibach25 changed the name to “excited skin syndrome” (ESS) because the phenomenon could occur in any part of the body to which patch tests were applied. Initially active eczematous dermatitis or several strong positive reactions inducing positive responses to neighbouring tests were implicated for ESS.26,27 Some investigators attributed ESS to factors such as long-term eczematous dermatitis28,29 or to the chemical property of some substances. In a recent study30 17 patients with angry back syndrome were identified over a 4-year period (1994-97). Ten patients were classified as multiple reactors and 7 as exacerbations of atopic eczema. A final diagnosis of relevant allergic contact dermatitis was made in 8 of the 10 patients with multiple reactions. Relevant contact allergens were rubber chemicals, plants, metals and preservatives, all of which can be marginal irritants. None of the reactions in the patients with exacerbation of dermatitis were thought to be relevant. In multiple reactors, marginal irritants were also the most common allergens finally identified. In another very recent study31 ESS developed in 39 of the 630 patients tested, corresponding to a frequency of 6.2 percent. Analysis of data found a longer duration of the primary dermatitis in patients in whom ESS developed compared to those who did not. Parabens, fragrance mix and thimerosal had more positive patch test reactions using standard application technique relative to the retest procedure which placed the substances at a greater distance from one another. This observation suggests that, in addition to the factors previously reported to influence the reduction of ESS, the position of the allergens in the testing procedure also should be considered. ESS is a major cause of false positive non-relevant patch test reactions. The incidence of non-reproducibility of positive patch test reactions can be over 40 percent. In cases of ESS, a detailed retake of clinical history, retesting

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after 6-8 weeks with positive patches placed widely apart and usage test may be helpful. c. Artefact: Sometimes a patient seeking compensation may try to simulate a positive reaction by scratching or otherwise irritating the skin. False Negative Reactions A false-negative reaction is one in which the patch test is negative despite the patient being sensitive to the allergen. The various causes of false negative reaction are: a. The substance is small, the concentration of the allergen is low or it is poorly absorbed or insufficiently released. b. Non-occlusion, loosening of the patch and early removal. c. Refractory state, which sometimes occurs immediately after a very severe allergic contact dermatitis. The patient fails to respond to the dilute allergens but reacts when retested several weeks later. A similar diminution of reactivity may occur in patients who are on oral prednisolone in daily doses of more than 20 mg. d. False false-negative reactions: these reactions are observed when patients are tested with TRUE Test methodology. Sherertz et al32 evaluated 318 patients by patch testing simultaneously with Hermal allergens using Finn Chambers and the TRUE Test allergen system. Finn Chamber tests showed reactions in 84 percent of balsam of Peru, 67 percent of fragrance, 76 percent of thiuram and 75 percent of carba mix reactions. TRUE Test was positive in only 29 percent, 50 percent, 46 percent, and 64 percent respectively for the same allergens in this patient population. These results suggested that positive reactions to fragrance, thiuram and carba mix allergens may be missed if only the TRUE Test is used. PATCH TESTING OF UNKNOWN SUBSTANCES For patch testing of unknown substances, the following steps should be taken. • Try to search for safety data on the given substance. • Perform open test with dilutions. • Try to dissolve the substance in water, petrolatum, acetone, methyl ketone, ethanol etc. • In case of leave on products (body lotions, creams, lipsticks etc.), use them as such for patch testing. • In case of wash off products (shaving creams, tooth pastes etc.), use 10 and 100 times dilutions.


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• In case of industrial products, 100 to 1000 dilutions should be used. • In case of positive reactions to unknown substances, do at least 1020 controls to rule out false positive reactions. The ideal control subjects are trauma patients who are confined to bed (in slings/plaster/traction). They can not run away, do not exercise, do not bathe and are not on immunosuppressive drugs. They are also available in large numbers in any hospital. COMPLICATIONS OF PATCH TESTING Patch testing is a fairly safe investigation, but it may occasionally cause some adverse reactions. 1. Severe reaction: Occasionally, very severe reactions to the allergen occur and may lead to exacerbation of the patient’s eczema. 2. Plaster reactions: A mild plaster reaction due to irritation by an occlusive zinc oxide strapping is not uncommon but in a few cases severe eczematous reactions occur and are usually associated with a reaction to colophony. 3. Persistent positive reaction: A patch test reaction normally takes 1 to 2 weeks to disappear. A test reaction may remain for longer than 1 month and persistence up to 8 months has been reported. 4. Anaphylaxis: Though rare, formaldehyde has been suspected as the cause in a few cases of anaphylaxis during patch testing. 5. Active sensitization: This is a well known complication though its exact incidence is not known. When a patch test site becomes positive 10-14 days later, active sensitization may have occurred. Such reactions are common with dinitrochlorobenzene (DNCB), natural primin, cobalt, p-phenylenediamine and Kathon CG. 6. Focal flare: It means activation at the patch site. It could be due to active sensitization or due to activation of the patient’s eczema leading to flare up of a positive patch test reaction, which had completely subsided. 7. Depigmentation, scars and keloids are other rare risks of patch testing. SENSITIVITY, SPECIFICITY, ACCURACY, AND RELEVANCE OF PATCH TEST REACTION Sensitivity is defined as the ability of a test to detect contact allergy whereas specificity means the capability of the test to discriminate between true allergic and non-allergic test reactions. Thus, low sensitivity indicates a risk of false negative test reactions and low specificity the risk of false positivity. Taken together, sensitivity and specificity describe the accuracy of a test.

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The determination of relevance of positive patch test is highly dependent on the clinical judgement of the physician which is acquired by knowledge and experience. A positive reaction may be having past relavance or relevant to the present episode of dermatitis (primary cause or aggravating factor). Unknown relevance usually means an ignorant physician. The accuracy of a doubtful (±) reaction is low; that of weak (+) positive reactions depends some what on the allergen and the patch test methodology and varies from 20-50 percent. The accuracy of strong positive (++) reaction is 80-90 percent and of extreme (+++) positive reactions is 95-100 percent. In cases of questionable but important reactions, retesting with another test technique or intracutaneous testing may help in confirming the results. A complementary history after the test is extremely useful in establishing relevance. PHOTOPATCH TESTING Antigens are applied in duplicate parallel to each other and covered with opaque material. The patches are removed on day 2 and read as usual. One set is then irradiated with UVA (50% of the minimum erythema dose). When an allergic reaction occurs only on the irradiated side and not on the control side, it is recorded as a positive photoallergic patch test. Phototest series have been developed in various countries. It is important to distinguish phototoxic from photoallergic reactions. OTHER TESTS FOR ALLERGIC CONTACT DERMATITIS Patch testing is the common procedure employed for detecting contact hypersensitivity, but it is an artificial procedure and under certain circumstances other tests may be required to reconfirm or detect the role of some allergens. Open Tests The liquid test substance is dropped on an area of the skin measuring about 1 cm in diameter and the solution is allowed to dry. The time for reading and the characteristics of the reaction are the same as with closed patch testing. The reaction is often weaker and may consist of isolated papules only. Open tests are used as a preliminary screening procedure with less familiar substances to reduce the risk of severe reactions.


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Usage Tests When the history suggests contact hypersensitivity and the patch tests are negative, the patient should be asked to use the preparation again. As it reproduces all the factors associated with the original dermatitis (sweating, friction, damaged skin), it is sometimes positive when a conventional patch test is negative. However, it may not always differentiate allergic from non-allergic reactions. This test is useful in suspected cosmetic and clothing dermatitis. Repeated Open Application Test (ROAT) The substances are applied twice daily on at least a 5 cm2 area on the upper arm for 7 days or until positive eczematous reaction develops.33 This test may be used to help determine the relevance of doubtful positive patch-test reactions to preparations in which the suspected allergen is present in a low concentration. Intradermal Tests It is not commonly used, except for investigative purposes, due to numerous technical pitfalls, non-availability of sterile solutions, active sensitization and ethical considerations. It has been proved reliable for nickel and corticosteroids. REFERENCES 1. Staedeler J. Uber die eigen Thumlichen Bestandtheile der Anacardium Fruchte. Ann Chemie Pharmacie 1847;1:87-98. 2. Collins EJ. Atropine irritation. R Lond opthal Hosp Rep 1889;12:164. 3. Jadassohn J. Zur kenntnis der medicamentosen Dermatosen verhandlingen der Deutschen. Dermatologischen Gesellschaft, V Congress, Wien 1895:103129. 4. Sulzeberger MB, Wise F. The contact or patch test in dermatology. Arch Dermatol 1931;23:519-31. 5. Revised European Standard Series. Contact Dermatitis 1988;19:391. 6. Cronin E, Calnan CD. Allergy to hydroabietic alcohol in adhesive tape. Contact Dermatitis 1978; 4:57-9. 7. Fregert S. Manual of contact dermatitis. 2nd ed. Copenhagen. 8. Fischer T, Maibach HI. The Finn chamber patch test technique. Contact Dermatitis 1984;11:137-140. 9. Fischer T, Maibach HI. The thin layer rapid use epicutaneous test (TRUE test) a new patch test method with high accuracy. Br J Dermatol 1985;112:63-8. 10. Fischer T, Maibach HI. Easier patch testing, TRUE test . J Am Acad Dermatol 1989;20:447-53.

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11. Wilkinson JD, Bruynzeel DP, Ducombs G et al. European multicenter study of TRUE Test Panel 2. Contact Dermatitis 1990;22:218-25. 12. Suneja T, Belsito DV. Comparative study of Finn chambers and TRUE test methodologies in detecting the relevant allergens inducing contact dermatitis. J Am Acad Dermatol 2001;45:836-9. 13. Ruhnek Forsbeck M, Fischer T, Meding B, et al. Comparative multi-center study with TRUE test and Finn Chamber Patch Test Methods in eight Swedish Hospitals. Acta Derm Venereol 1988;68:123-8. 14. Lachapelle JM, Bruynzeel DP, Ducomb G, et al. European multicenter study of the TRUE Test. Contact Dermatitis, 1988;19:91-7. 15. Goh CL. Comparative study of TRUE Test and Finn chamber patch test techniques in Singapore. Contact Dermatitis 1992;27:84-9. 16. Vozmediano JMF, Hita JCA. Concordance and discordance between TRUE Test and Finn chamber. Contact Dermatitis 2000;42:182-3. 17. Cronin E. Contact Dermatitis Edinburgh, London, New York: Churchill Livingstone 1980;7-8. 18. Fisher AA. Contact Dermatitis, 3rd edn. Philadelphia: Lea and Febiger 1986;10,394,423. 19. Rietschel RL, Adams RM, Maibach HI, et al. The case for patch test readings beyond D2. J Am Acad Dermatol 1988;18:42-5. 20. Todd DJ, Handley J, Metwali M, et al. Day 4 is better than day 3 for a single patch test reading. Contact Dermatitis 1996;34:402-04. 21. Uter WCJ, Geier J, Schnuch A. Good clinical practice in patch testing; readings beyond day 2 are necessary. A confirmatory analysis. Am J Contact Dermatitis 1996;7:231-7. 22. Geier J, Gefeller O, Weichmann K, Fuchs T. Patch test reactions at D4, D5 and D6. Contact Dermatitis 1999;40:119-26. 23. Jonker MJ, Bruynzeel DP. The outcome of an additinal patch test reading on days 6 or 7. Contact Dermatitis 2000;42:330-5. 24. Mitchell JC. The angry back syndrome. Eczema creates eczema. Contact Dermatitis 1975;1:193-4. 25. Maibach HI. The excited skin syndrome. In: Ring J, Burg G, eds. New Trends in Allergy. New York: NY Springer Verlag, 1981, 208-291. 26. Mitchell JC. Multiple concomitant positive patch test reactions. Contact Dermatitis 1977;3:315-20. 27. Bruynzeel DP, Maibach HI. Excited skin syndrome (Angry Back). Arch Dermatol 1986;122:323-8. 28. Andersen KE, Maibach HI. Cumulative irritancy in the guinea pig from low grade irritant vehicles and the angry back syndrome. Contact Dermatitis 1980;6:130-4. 29. Kligman A, Gollhausen R. The angry back; a new concept or old confusion? Br J Dermatol 1986;115:93-100. 30. Cockayne SE, Gawkrodger DJ. Angry back syndrome is often due to marginal irritants; a study of 17 cases seen over 4 years. Contact Dermatitis 2000; 43: 280-2. 31. Duarte I, Lazzarini R, Bedrikow R. Excited Skin Syndrome; study of 39 patients. Am J Contact Dermatitis 2002;13:59-65. 32. Sherertz EF, Fransway AF, Belsito DV et al. Patch testing discordance alert; False negative findings with rubber additives and fragrances. J Am Acad Dermatol 2001;45:313-4. 33. Hannuksela M, Salo H. The repeated open application test (ROAT). Contact Dermatitis 1986;14:221-7.

Laboratory Diagnosis and Treatment of Common STDs: An Update

9

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Devinder Mohan Thappa

Laboratory Diagnosis and Treatment of Common Sexually Transmitted Diseases: An Update GENITAL ULCER DISEASES Genital ulcer disease is a common presentation of sexually transmitted diseases. In developing countries, chancroid and granuloma inguinale may be more common, but in developed nations, majority of the cases are due either to herpes genitalis, syphilis or chancroid.1 Regardless of locality, more than one venereal diseases may be detectable in 3 to 10 percent of patients with genital ulceration of infectious etiology, in case they are evaluated by traditional tests. The concomitant occurrence of two or more organisms causing genital ulcers may be even more common. This has been demonstrated when such lesions are evaluated by more sensitive means such as polymerase chain reaction (PCR). Therefore, diagnosis of genital ulceration based solely upon morphologic examination is fraught with difficulty and subject to a high degree of inaccuracy.1 Physical examination findings have a low sensitivity and specificity for diagnosing primary syphilis, chancroid and genital herpes, even in areas where these diseases are common and where attending physicians are experienced in the management of genital ulcer disease.2 All patients with genital ulcers should receive appropriate health education and safer sex practices should be discussed. Serological screening for both syphilis and HIV infection should be offered at the time of genital ulcer presentation and again after 3 months at the end of the window period for both diseases. In clinics where diagnostic facilities are available, patients should be appropriately screened for all pathogens causing genital ulceration as well as for other STDs. Laboratory diagnostic tests and treatment options for common STDs have been summarized in Tables 9.1 and 9.2. Primary Syphilis Syphilis is a sexually transmitted disease due to the fastidious spirochete, Treponema pallidum.1 The primary chancre begins at the site of inoculation

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Recent Advances in Dermatology Table 9.1: Laboratory tests in the diagnosis of STDs

S. Clinical entities No. 1. Primary syphilis

2. Chancroid

3. Donovanosis 4. Lymphogranuloma venereum

5. Herpes genitalis

6. Gonorrhea

7. Non-gonococcal urethritis

8. Trichomoniasis

Laboratory tests required Darkfield examination or direct immunofluorescent staining on serous ulcer exudates, serologic tests for syphilis, solid phase enzyme linked immunosorbent assay and PCR evaluations Gram’s stained smear from genital ulcer, culture for H. ducreyi, multiplex polymerase chain reaction. Histological examination may be useful to exclude malignancy in non-healing or atypical ulcers. Identification of intracellular Donovan bodies is the gold standard for the diagnosis of donovanosis. Culture and PCR are rarely used diagnostic tests. Frei skin test not used now a days. The confirmation of diagnosis of LGV now demands serological tests (complement fixation test, microimmunofluorescence test) or the identification/isolation of C. trachomatis (tissue culture, using HeLa-229 or McCoy cell lines) in appropriate clinical samples (bubo fluid or ulcer material). Virus isolation in cell culture has been the mainstay of HSV diagnosis in Western countries. In our set up, Tzanck smear is still the main tool. Immunofluorescence staining of a Tzanck smear increases the sensitivity and specificity of the Tzanck test. Application of polymerase chain reaction (PCR) offers rapid, sensitive and specific identification of HSV. Serological tests may be used to detect antibodies to HSV in blood, however, they are generally indicative of past infection. The diagnosis of gonorrhea is based on microscopic identification of the organisms and culture. A variety of direct methods including DNA hybridization, direct immunofluorescent examination and ELISA are available. Recently, nucleic acid amplification tests (NAATs) have been introduced. Gram’s stained urethral discharge shows more than 5 pus cells per oil emersion field, but no gramnegative intracellular diplococci are seen. Urethral swabs are sent for N. gonorrhoeae, mycoplasma, and anaerobes culture. Chlamydial antigen detection may be done on swab. Usually accomplished via direct microscopic examination of the vaginal or urethral discharge. Culture of Trichomonas vaginalis is currently the gold standard for diagnosis of trichomoniasis. PCR has given variable results. contd....


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Table contd... S. Clinical entities No. 9. Genital chlamydial infection

10. Bacterial vaginosis

11. Anogenital warts

Laboratory tests required Although there is no absolute “gold standard” for chlamydia diagnostic tests, amplification assays have a sensitivity of at least 90 percent compared with 60-70 percent for culture and 60 percent for a antigen assays. Nucleic acid amplification tests (NAAT) for chlamydia, including polymerase chain reaction, ligase chain reaction and transcription mediated amplification assays, are more sensitive and highly specific. The diagnosis is usually made clinically based upon the composite (Amsel) criteria and is based on detecting at least three of four following composite criteria: • Excessive homogeneous uniformly adherent vaginal discharge • Elevated vaginal pH >4.5 • Positive amine test (Whiff test) • Clue cells (20%) Diagnosis of warts in the anogenital region is based on the history of the exposure, clinical appearance, epidemiological proof of the warts in the sexual contact and the histological appearance. The most sensitive method for detection of HPV DNA is PCR.

after an incubation period of 9-90 days (average 3 weeks). Within one week, non-tender, rubbery, often bilateral, regional lymphadenopathy develops. Without treatment, the chancre will resolve in 3-8 weeks. The presence of a rash in conjunction with a genital ulcer does not rule out syphilis, as 18 to 32 percent of patients may develop signs and symptoms of secondary syphilis before chancre resolution. Although the clinical presentation is commonly the same in the HIV infected host, as it is in the otherwise healthy host, unusual features may be seen.3 The primary stage of syphilis may consist of painful primary chancre due to secondary infection, multiple or more extensive chancres in the HIV patient. Instead of healing within 3 to 6 weeks, persistent ulceration may occur. The diagnosis of syphilis is based upon clinical suspicion and detection of the causative organism within the genital ulcer.1 This should be noted that serologic tests for syphilis might not become reactive for up to two weeks after the onset of chancre. A positive serology may reflect a temporarily distant syphilitic infection and therefore may be misleading. Treponema pallidum can be detected in serous ulcer exudates by darkfield

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Recent Advances in Dermatology Table 9.2: Current treatment options in the STDs

S. Clinical entities No. 1. Primary syphilis

2. Chancroid

3. Donovanosis

4. Lymphogranuloma venereum 5. Herpes genitalis

Treatment options with or without associated HIV infection Single intramuscular injection of 2.4 million units of benzathine penicillin. Non-pregnant, penicillin allergic patients may be given a 2 weeks course of either doxycycline 100 mg twice daily, tetracycline 500 mg 4 times daily or erythromycin 500 mg 4 times daily. Some authorities recommend weekly 3 injections of benzathine penicillin in cases having HIV coinfection. Azithromycin 1 g orally in a single dose or ceftriaxone 250 mg intramuscularly (IM) in a single dose or ciprofloxacin 500 mg orally twice a day for 3 days (contraindicated for pregnant and lactating women) or erythromycin base 500 mg orally three times a day for 7 days. Doxycycline 100 mg orally twice a day for at least 3 weeks or trimethoprim-sulfamethoxazole one doublestrength (800 mg/160 mg) tablet orally twice a day for at least 3 weeks. Alternative regimens include ciprofloxacin 750 mg orally twice a day for at least 3 weeks, or erythromycin base 500 mg orally four times a day for at least 3 weeks, or azithromycin 1 g orally once per week for at least 3 weeks. Doxycycline 100 mg orally twice a day for 21 days. Alternative treatment is erythromycin base 500 mg orally four times a day for 21 days. First clinical episode of genital herpes Acyclovir 400 mg orally three times a day for 7–10 days or acyclovir 200 mg orally five times a day for 7–10 days or famciclovir 250 mg orally three times a day for 7–10 days or valacyclovir 1 g orally twice a day for 7–10 days. Recurrent episodes of HSV disease Acyclovir 400 mg orally three times a day for 5 days acyclovir 200 mg orally five times a day for 5 days acyclovir 800 mg orally twice a day for 5 days famciclovir 125 mg orally twice a day for 5 days valacyclovir 500 mg orally twice a day for 3–5 days valacyclovir 1.0 g orally once a day for 5 days.

or or or or or

For suppressive therapy for recurrent genital herpes Acyclovir 400 mg orally twice a day or famciclovir 250 mg orally twice a day or valacyclovir 500 mg orally once a day or valacyclovir 1.0 gram orally once a day. Periodically, once a year discontinuation of suppressive therapy should be discussed. In HIV infected patients, a higher dose of antiherpes drugs for longer duration may be required. contd....


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Table contd... S. Clinical entities No. 6. Gonorrhea

7. Non-gonococcal urethritis

8. Trichomoniasis 9. Genital chlamydial infection 10. Bacterial vaginosis

11. Anogenital warts

Treatment options with or without associated HIV infection Cefixime 400 mg orally in a single dose or ceftriaxone 125 mg IM in a single dose or ciprofloxacin 500 mg orally in a single dose or ofloxacin 400 mg orally in a single dose or levofloxacin 250 mg orally in a single dose plus, if chlamydial infection is not ruled out, azithromycin 1 g orally in a single dose or doxycycline 100 mg orally twice a day for 7 days. Azithromycin 1 gm PO once or doxycycline 100 mg PO BD for 7 days. Alternative regimen includes erythromycin base 500 mg PO QID for 7 days or ofloxacin 300 mg PO BD for 7 days or levofloxacin 500 mg once daily orally for 7 days. Metronidazole 2 gm orally in a single dose or metronidazole 500 mg twice a day for 7 days. A single dose of azithromycin 1 g or doxycycline 100 mg PO BD for 7 days. The precise dosage and duration varies, but metronidazole 400 mg twice a day for 5 days is adequate. Topical treatments with intravaginal clindamycin 2 percent cream or metronidazole 0.75 percent gels are other treatment options. Therapies which can be employed by the patient at home are: podophyllotoxin (0.15% cream or 0.5% solution) and imiquimod (5% cream). Hospital based/office based treatments include podophyllin, electrosurgery, laser, curettage, scissors excision, cryotherapy and trichloroacetic acid cautery.

examination or direct immunofluorescent staining. More recent technological methods, such as solid phase enzyme linked immunosorbent assay and PCR evaluations, have failed to improve diagnostic detection rates of T. pallidum that are at approximately 85 to 92 percent.1 Penicillin has remained the mainstay of therapy for syphilis.1,3 CDC recommended treatment for primary, secondary and early latent syphilis consists of a single intramuscular injection of 2.4 million units of benzathine penicillin. Treatment failures with this regimen may reach as high as 5 to 10 percent. Non-pregnant, penicillin allergic patients may be given a 2 weeks course of either doxycycline 100 mg twice daily, tetracycline 500 mg 4 times daily or erythromycin 500 mg 4 times daily. The management of early syphilis in those who are HIV co-infected remains controversial. Some authorities recommend weekly 3 injections of benzathine penicillin in order to prevent possible progression to

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neurosyphilis.1,3 In HIV infected patients with syphilis, 2 rules of clinical management apply: (1) disseminated infection, particularly with central nervous system involvement should be assumed as neurosyphilis and appropriate therapy for neurosyphilis should be prescribed for any patient coinfected with syphilis and HIV who has the evidence of compromised immune function, regardless of the apparent clinical stage of syphilis observed; (2) close follow-up with repeated clinical, serological and cerebrospinal fluid examinations are necessary, as even the best regimens will sometimes fail in HIV infected patients with significant immunocompromise.3 Chancroid Chancroid is a sexually transmitted infection caused by the Gramnegative bacterium Haemophilus ducreyi.2 The disease manifests as painful genital ulceration that may be accompanied by regional lymphadenitis and bubo formation. The lymphadenopathy is usually unilateral and tends to be more prevalent in men. The diagnosis of chancroid is basically made on clinical grounds, which has an accuracy of 30 to 50 percent.4 On Gram’s stained smear from genital ulcer, various morphological forms of H. ducreyi have been described such as “schools of fish,” “railroad tracks” and “fingerprints” appearance.2 This pattern is due to an unusual tendency of H. ducreyi to agglutinate. The organisms are visualised extracellularly more often than intracellularly and tend to occur in close proximity to polymorphonuclear leucocytes.5 Smears are only diagnostic in 50 percent of cases in the best hands.6 In vitro culture for H. ducreyi currently remains the main tool for the diagnosis of chancroid in the clinical setting and for many years was the “gold standard” for evaluating newer methods of diagnosis.5 The sensitivity of H. ducreyi culture relative to the multiplex polymerase chain reaction (M-PCR) has been shown to be approximately 75 percent in studies that have used genital ulcer-derived swabs. The technique of M-PCR involves the addition of multiple primer pairs to the reaction mixture in order to simultaneously amplify distinct DNA sequences from different targets in the processed lesion material. The research based M-PCR offers a highly sensitive and specific way to detect the three most common etiological agents of genital ulcer disease—namely, HSV, T. pallidum and H. ducreyi.2 Thus, monoclonal antibody based technology has the potential to provide a simple, inexpensive, rapid and sensitive means of detecting H. ducreyi in genital ulcer specimens. So far, serology has limited usefulness in the routine diagnosis of chancroid


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infection, but may be useful in population based epidemiological research as a screening method for past infection.5 Histological examination is not a recommended diagnostic method for chancroid, but may be useful as a means to exclude malignancy in non-healing or atypical ulcers.5 Plasmid mediated antimicrobial resistance of H. ducreyi has been documented for a number of agents, including penicillins, tetracyclines, chloramphenicol, sulfonamides and aminoglycosides.7 Much less is known about chromosomally mediated resistance to antimicrobials in H. ducreyi, but decreased susceptibility has been described for penicillin, ciprofloxacin, ofloxacin, and trimethoprim.2 Center for Disease Control and Prevention (CDC)8 in 2002 recommends therapy in the form of azithromycin 1 g orally in a single dose, or ceftriaxone 250 mg intramuscularly (IM) in a single dose, or ciprofloxacin 500 mg orally twice a day for 3 days (contraindicated for pregnant and lactating women), or erythromycin base 500 mg orally three times a day for 7 days. Patients should be re-examined 3–7 days after initiation of therapy. If treatment is successful, ulcers usually improve symptomatically within 3 days and objectively within 7 days after therapy. Fluctuant buboes should be aspirated in order to provide symptomatic relief for the patient and to avoid the further complication of spontaneous rupture. Incision and drainage of fluctuant buboes, with subsequent packing of the wound, has also been recommended as an effective management strategy for chancroid and avoids the need for frequent bubo re-aspirations.2,9 Donovanosis Donovanosis is a chronic destructive and slowly progressive, mildly contagious disease caused by Calymmatobacterium granulomatis and is characterized by granulomatous ulceration affecting primarily the genitalia.10,11 Overall, the incidence of donovanosis seems to be decreasing.12 The disease tends to affect the poorest and most disadvantaged communities and it is much more difficult to envisage an efficient casefinding and treatment approach that could work in the crowded slums of Indian cities.13 Identification of intracellular Donovan bodies is the gold standard for the diagnosis of donovanosis. 10 The identification of typical intracellular Donovan bodies within large mononuclear cells is done on Giemsa or Leishman’s or Wright’s stained smears obtained directly from tissue or biopsy samples. These characteristic cells are 25–90 μm in

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diameter while the Donovan bodies are 0.5–0.7 by 1–1.5 μm and may or may not be capsulated.12 Specimens from sites just below the surface of the ulcer are more likely to yield positive results than those from superficial tissue. Donovan bodies have also been identified from Papanicolaou smears used in routine cervical cytology screening. Additional methods used in the past that have only limited relevance now include antigen detection, complement fixation, and skin tests. The causative organism, Calymmatobacterium granulomatis, has been cultured for the first time in many years and a polymerase chain reaction using a colorimetric detection system has been developed that could be used by diagnostic laboratories in the future.12 Important new agents introduced in the treatment of donovanosis include azithromycin, ceftriaxone and fluorinated quinolones.13 WHO guidelines recommend azithromycin 1 g, immediately then 500 mg daily but do not state the duration of therapy.14 In Australia, doses of either 1 g of azithromycin weekly for 4–6 weeks or less, if healing is complete, or 500 mg once daily for 1 week only were adequate.12,15 Center for Disease Control and Prevention (CDC)8 in 2002 recommends therapy in the form of doxycycline 100 mg orally twice a day for at least 3 weeks, or trimethoprim-sulfamethoxazole one double-strength (800 mg/160 mg) tablet orally twice a day for at least 3 weeks. Alternative regimens includes ciprofloxacin 750 mg orally twice a day for at least 3 weeks, or erythromycin base 500 mg orally four times a day for at least 3 weeks, or azithromycin 1 g orally once per week for at least 3 weeks. Therapy should be continued for at least 3 weeks or until all lesions have completely healed. Some specialists recommend addition of an aminoglycoside (e.g., gentamicin 1 mg/kg IV every 8 hours) to the above regimens, if improvement is not evident within the first few days of therapy. Epidemiological treatment can be considered in the absence of signs and symptoms in sexual partners of index cases. Lymphogranuloma Venereum (LGV) Lymphogranuloma venereum (LGV) is a rare disease caused by serovars L1, L2 and L3 of the obligate intracellular bacterium Chlamydia trachomatis.16 Whereas serovars A–K are largely confined to mucosal columnar epithelial surfaces of the genital tract and eye, the LGV serovars infect predominantly monocytes and macrophages, pass through the epithelial surface to regional lymph nodes and may cause disseminated infection. The clinical course of LGV can be divided into three stages. The primary stage involves the site of inoculation; the secondary stage the regional lymph nodes and sometimes the anorectum; and late sequelae, affecting the genitals and/or rectum, comprise the tertiary stage.16


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The diagnosis is established after taking careful history and proper clinical examination, looking especially for painful lymphadenopathy (Groove sign of Greenblat).17 In the past, LGV diagnosis was supported by the Frei skin test (The Frei test antigen is no longer available), a test of delayed type hypersensitivity to chlamydial antigens, similar to the tuberculin test.16 When available, histopathological examination of biopsy specimens can support the diagnosis. The confirmation of diagnosis of LGV now demands serological tests or the identification/isolation of C. trachomatis in appropriate clinical samples. Among the serological tests, complement fixation (CF) test used for diagnosis of chlamydial infections is genus specific.16 This test, therefore, does not distinguish between infections with C. trachomatis, C. psittaci, and C. pneumoniae. Since LGV is more invasive, it leads to higher titers of serum antibody than uncomplicated genital infections with C. trachomatis serovars D–K. A titer of >1:256 strongly supports the diagnosis, while a titer of < 1:32 rules it out except in the very early stages of the disease.18 The microimmunofluorescence (MIF) test can distinguish between infections with different chlamydial species, but has not been much used in routine clinical practice, since it requires a fluorescent microscope and a skilled technologist trained in the technique.19 A number of enzyme immunoassays (EIAs) are available, but they do not distinguish between infections with different chlamydial species.20 C. trachomatis can be identified in bubo fluid following aspiration or in ulcer material. In contrast with chancroid, buboes of which contain large amounts of pus, the buboes of LGV may contain only small amounts of thin milky fluid and it may be necessary to inject 2–5 ml of sterile saline to obtain any fluid by aspiration.21 C. trachomatis can be isolated in tissue culture, using HeLa-229 or McCoy cell lines, but this technique is not widely available. Alternatively, C trachomatis can be identified by direct fluorescent microscopy using a commercially available conjugated monoclonal antibody on a smear of bubo or ulcer material. This method is less demanding, but still requires a fluorescent microscope and a skilled technologist.21 Commercially available EIAs, which detect chlamydial antigens (usually lipopolysaccharide, LPS), are widely used to diagnose urethral and cervical infection with C. trachomatis serovars D–K, but have not been evaluated for the diagnosis of LGV. DNA amplification assays—for example, polymerase chain reaction (PCR) or ligase chain reaction (LCR), which detect Chlamydia specific genomic or plasmid DNA, are the most sensitive tests available for the diagnosis of genital C. trachomatis infection but have not been well evaluated for the diagnosis of LGV. 22

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Recommended treatment for both bubonic and anogenital LGV is doxycycline 100 mg orally twice a day for 21 days. Alternative treatment is erythromycin base 500 mg orally four times a day for 21 days.8 Erythromycin should be given to pregnant women, in whom tetracyclines are contraindicated. Large collections of pus in buboes should be aspirated, using a lateral approach through normal skin.16 Late complications such as rectal stricture may be improved by antibiotic treatment, which reduces the inflammatory component, but does not correct damage due to fibrosis. Rectovaginal fistula, bowel obstruction and esthiomene require surgical correction under antibiotic cover. Genital Herpes Simplex Virus (HSV) Infection In India, genital herpes is the commonest infectious cause of genital ulceration in some centers.23-25 Genital herpes can be caused by either herpes simplex virus (HSV) type 1 or herpes simplex virus type 2.26 Most cases of recurrent genital herpes are caused by HSV-2. Infection is predominantly subclinical and individuals with unrecognized infection account for the majority of new transmission episodes to susceptible partners.27 There is a need for better diagnostic methods to identify individuals with minimally symptomatic disease. The diagnosis of herpes genitalis is usually made clinically in typical cases. It is important to realize that the sensitivity of clinical diagnosis is low.28 In view of the fact that herpes may masquerade as a number of genital ulcer diseases, laboratory tests are frequently called upon to resolve the issue. Laboratory tests available for the diagnosis of herpes virus infection include Tzanck smear, histopathology, viral culture and serology. Tzanck smear test is not a sensitive test. Immunofluorescence staining of a Tzanck smear increases the sensitivity and specificity of the Tzanck test, but is not available in most laboratories. Virus isolation in cell culture has been the mainstay of HSV diagnosis in Western countries.29 Although HSV can be isolated from over 90 percent of vesicular or pustular lesions, the isolation rate from ulcerative lesions is only 70 percent and falls to 27 percent at the crusting stage. The characteristic cytopathic effect of HSV generally appears within 24 to 72 hours, but may take up to five days. Virus isolation is therefore, slow and labour intensive, but has the advantage of demonstrating active infection within a clinical lesion and also allows virus typing and antiviral sensitivity testing. Application of polymerase chain reaction (PCR) offers rapid, sensitive and specific identification of HSV, but has hitherto been difficult to


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apply to routine clinical practice because of its technical requirements.27 However, introduction of the LightCycler (Biogene) has rendered PCR feasible on a larger scale and potentially applicable to routine clinical healthcare practice. Real time PCR protocols employ the incorporation of dyes or the binding of probes during each cycle of the PCR so that accumulation of product can be measured while the reaction is proceeding. In direct comparison of PCR with virus culture in patients presenting to a large GUM clinic with clinical features suggestive of genital herpes, PCR increased the overall detection rate of HSV by 24 percent.27 Serological tests may be used to detect antibodies to HSV in blood, however, they are generally indicative of past infection.29 Although the utility of type specific serology for herpes simplex virus in epidemiological studies is undisputed, the use of these tests for diagnostic purposes remains more contentious.26 Possible uses include assessment of asymptomatic sexual partners of patients with genital herpes, diagnosis of genital ulcers where viral culture repeatedly gives negative results, exclusion of herpes in pregnancy and routine testing as part of a screen for sexually transmitted diseases. There are several limitations: the test usually does not give positive results until about six weeks after exposure; a positive test result indicates previous exposure but does not prove that particular clinical signs or symptoms are due to herpes; and the sensitivity and specificity of the tests range from 95 to 99 percent (in populations with a low prevalence, most positive test results will be false positives).26 Both type-specific and nonspecific antibodies to HSV develop during the first several weeks following infection and persist indefinitely.8 Type specific serological tests are better than the tests based one nonspecific antibodies and they are evaluated by either western blot (which tests for a range of type specific antigens) or glycoprotein G (gG) assays.29 Western blot tests are expensive, take 2–5 days to complete the screening and confirmatory steps, and require expert interpretation. Glycoprotein G assays detect antibodies to the type specific proteins gG-1 and gG-2. Very little sequence homology exists between gG-1 and gG-2, allowing differentiation between established infection with HSV-1 and HSV-2 respectively. A number of gG-based tests have been commercially marketed, using a variety of test formats, most often using enzyme immunoassay (EIA) methods.29 Knowledge of the HSV type has important implications for patient management.29 Firstly, the natural history of first episode genital HSV-1 infection is more favourable than that of HSV-2. Secondly, the frequency of subclinical viral shedding following initial genital infection with HSV-1 is consistently lower than for HSV-2; this is likely to be associated with a reduced risk of future sexual transmission.29

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Center for Disease Control and Prevention (CDC)8 in 2002 recommends following treatment for genital herpes: First Clinical Episode of Genital Herpes Acyclovir 400 mg orally three times a day for 7–10 days, or acyclovir 200 mg orally five times a day for 7–10 days, or famciclovir 250 mg orally three times a day for 7–10 days, or valacyclovir 1 g orally twice a day for 7–10 days. Recurrent Eisodes of HSV Disease Acyclovir 400 mg orally three times a day for 5 days, or acyclovir 200 mg orally five times a day for 5 days, or acyclovir 800 mg orally twice a day for 5 days, or famciclovir 125 mg orally twice a day for 5 days, or valacyclovir 500 mg orally twice a day for 3–5 days, or valacyclovir 1.0 g orally once a day for 5 days. For Suppressive Therapy for Recurrent Genital Herpes Acyclovir 400 mg orally twice a day, or famciclovir 250 mg orally twice a day, or valacyclovir 500 mg orally once a day, or valacyclovir 1.0 gram orally once a day. Periodically, once a year discontinuation of suppressive therapy should be discussed. In HIV infected patients, a higher dose of antiherpes drugs for longer duration may be required. Increasing evidence shows that many herpes infections are asymptomatic.26 The rate of viral shedding from the genital tract of asymptomatic and seropositive people is similar to that of those with a history of symptomatic infection (3% and 2.7%, respectively). Consistent use of condoms may help to reduce the risk by covering exposed or susceptible mucous membranes and skin. It has also been suggested that the continuous use of antiherpes drugs may reduce the risk of transmission by decreasing the quantity of asymptomatic viral shedding. Considerable interest has been shown in the development of a vaccine to prevent acquisition of genital herpes, although results from early trials have been conflicting.26 URETHRITIS, CERVICITIS AND/OR VAGINITIS RELATED STDs Gonorrhea Gonorrhea has always taken second place to syphilis.30 In recent years it has been considered as one of those bacterial sexually transmitted diseases (STDs) that persists despite modern antibiotics. The continued


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spread of the disease warns that the safer sex message has not been brought home to those individuals and their sexual partners. There is also some evidence to link both ulcerative and purulent genital infections to HIV acquisition.30 In men, there is urethral discharge and variable dysuria, but in women, one-third will have no symptoms.30 In heterosexuals, one-third of patients will also be infected with concurrent C. trachomatis. Rectal gonorrhea has either no symptoms, or at the most, some minimal discomfort or discharge. Often, it is a sexual partner who complains of catching an infection. Likewise, gonorrhea in the throat usually has no symptoms; diagnosis is commonly made after a throat culture as part of the clinical examination.30 These days, eye infection is rare in adults.30 Very little of disseminated gonococcal infection or gonococcal dermatitis syndrome seems to be reported at present. The possibility always remains of untreated gonorrhea in men leading to epididymo-orchitis, chronic urinary tract pathology and infertility. If left untreated in women, it leads to acute, then chronic, pelvic inflammatory disease and infertility and rarely, gonococcal perihepatitis. Septic arthritis is more common in women than men.30 Resistance to antimicrobials is found all over the world.30 Comparative results for resistance to penicillin were 8.1 percent, the resistance being either plasmid-mediated or chromosomally-mediated whereas resistance to tetracycline was up to 32.5 percent. Additionally, resistance to azithromycin was shown in 0.3 percent of cases. The worldwide resistance trends to the fluoroquinolones are well recognized, first being noted in Southeast Asia. Resistance to ciprofloxacin has been reported in several regions of the world, including India.31 In India, ciprofloxacin is still being used as single-dose treatment for gonorrhea. In the recently published study from India, 35.3 percent and 52.9 percent of Neisseria gonorrhoeae isolates were found to be resistant and less sensitive, respectively, to penicillin; 67.3 percent and 28.2 percent strains were observed to be resistant and less sensitive, respectively, to ciprofloxacin.31 The diagnosis of gonorrhea is based on microscopic identification of the organisms and culture.32 No serologic testing for N. gonorrhoeae is available. A variety of direct methods including DNA hybridization, direct immunofluorescent examination and ELISA are available, but they have not yet replaced culture and direct examination. Recently, nucleic acid amplification tests (NAATs) have been introduced as critical new tools to diagnose and treat C. trachomatis and N. gonorrhoeae infections.33 NAATs can detect both C. trachomatis and N. gonorrhoeae organisms in the same specimen. However, NAATs are usually more

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expensive than previous tests, making test performance from an economic perspective a key consideration.33 For uncomplicated gonococcal infections of the cervix, urethra, and rectum, Center for Disease Control and Prevention (CDC)8 in 2002 recommends cefixime 400 mg orally in a single dose, or ceftriaxone 125 mg IM in a single dose, or ciprofloxacin 500 mg orally in a single dose, or ofloxacin 400 mg orally in a single dose, or levofloxacin 250 mg orally in a single dose, plus, if chlamydial infection is not ruled out, azithromycin 1 g orally in a single dose or doxycycline 100 mg orally twice a day for 7 days. In Europe, the following antibiotics are all recommended as first-line treatment for uncomplicated gonorrhea in adults: ceftriaxone 250 mg IM single dose, ciprofloxacin 500 mg or ofloxacin 400 mg or cefixime 400 mg orally single dose; or spectinomycin 2 g IM single dose.30 Generally penicillin analogs are not recommended as first-line treatment. In Britain, as one-third of the patients have concomitant chlamydial infection, treatment is given with doxycycline 100 mg twice daily for 7 days or azithromycin 1 g orally to be taken after treatment for gonorrhea. There is always the possibility of chlamydial genital infection, syphilis or viral STDs such as human papilloma virus, herpes genitalis and HIV being acquired at the same time.30 Non-gonococcal Urethritis (NGU) NGU is diagnosed if gram-negative intracellular organisms cannot be identified in the discharge on Gram’s stain in a patient with urethral discharge and burning micturition.34 Chlamydia trachomatis is responsible for 30 to 50 percent, Ureaplasma urealyticum for 10 to 40 percent and the rest are due to Trichomonas vaginalis, yeasts, Herpes simplex virus, Adenovirus, Hemophilus sp., Bacteroides etc. In males, urethritis begins with dysuria and mucoid urethral discharge. In contrast to gonococcal urethritis, symptoms are usually mild. Most cases in females are asymptomatic.34 Gram’s stained urethral discharge shows more than 5 pus cells per oil immersion field but no gram-negative intracellular diplococci are seen.34 Urethral swabs are sent for N. gonorrhoeae, mycoplasma, and anaerobes culture. Chlamydial antigen detection may be done on swab. Center for Disease Control and Prevention (CDC) 8 in 2002 recommends therapy in the form of azithromycin 1 gm PO once or doxycycline 100 mg PO BD for 7 days. Alternative regimen includes erythromycin base 500 mg PO QID for 7 days or ofloxacin 300 mg PO BD for 7 days or levofloxacin 500 mg once daily orally for 7 days.


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Patients, who have persistent or recurrent urethritis, should be retreated with the initial regimen, if they did not comply with the treatment regimen or if they were re-exposed to an untreated sex partner.8 Otherwise, a culture of an intraurethral swab specimen and a first-void urine specimen for T. vaginalis should be performed. Some cases of recurrent urethritis following doxycycline treatment may be caused by tetracycline-resistant U. urealyticum.8 Trichomoniasis Trichomoniasis remains an extremely common infection despite the fact that rates of other treatable sexually transmitted diseases are declining.35 Trichomonas vaginalis, a flagellated parasite, is the causative agent of this infection. Symptoms of trichomoniasis in women include vaginal discharge, irritation and pruritus; however, about half of all women infected with T. vaginalis are asymptomatic.36 Signs of infection in women include vaginal discharge, odor and oedema or erythema. In males, the prevalence and spectrum of disease is far less well characterized; the infection appears usually to be asymptomatic. However, it has been suggested as an increasingly important cause of non-gonococcal urethritis (NGU).37 Diagnosis of trichomoniasis in the female is usually accomplished via direct microscopic examination of the vaginal fluid. The sensitivity of this test is only 60 percent.38 Culture of T. vaginalis is currently the gold standard for diagnosis of trichomoniasis.39 Polymerase chain reaction (PCR) techniques thus far have given variable results, especially in women.35, 40 Diagnosis, in general, is much more difficult for males with the best culture results yielded by combining urethral swabs and urine sediment.37 In most cases, trichomoniasis is easily treated with a single dose of metronidazole and because it is an STD, sexual partners should be routinely treated.8 Center for Disease Control and Prevention (CDC) in 2002 recommends metronidazole 2 g orally in a single dose or alternative regimen-metronidazole 500 mg twice a day for 7 days. Resistant cases of trichomoniasis appear to occur sporadically.41 Tinidazole appears to be an attractive alternative to metronidazole. It has a longer half-life than metronidazole and has been effective in some cases of trichomoniasis that were resistant to metronidazole.41 Chlamydia Infection Chlamydia trachomatis is the most commonly diagnosed bacterial sexually transmitted infection in the developed world and a leading cause of

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pelvic inflammatory disease.26 Genital chlamydial infection is responsible for about half of non-gonococcal urethritis (NGU) cases or even more, if highly sensitive methods are used for diagnosis.42 Chlamydial cervicitis may lead to pelvic inflammatory disease, cervical neoplasia and adverse pregnancy outcome. Given the potential for morbidity from ectopic pregnancy and tubal infertility, the case for screening for chlamydia among those most at risk is strong.26 Many diagnostic tests for C. trachomatis have been available over the past decade, ranging from antigen detection by monoclonal or polyclonal antibodies to molecular biologic methods. The clinical bedside diagnostic test “Two glass test of urine”, however, still remains an effective tool for NGU.43 The presence of NGU is also demonstrated by the absence of gram-negative intracellular diplococci, a negative gonococcal culture and the detection of inflammatory cells (at least five polymorphonuclear leukocytes) in the urethral smear or in the urine sediment.44 In case of females, a simple objective criterion for the clinical diagnosis of cervicitis has been developed.42 The cervical infection with the principal recognized infectious causes (C. trachomatis, N. gonorrhoeae and herpes simplex virus) correlates best with the presence of mucopurulent endocervical discharge and the presence of > 10 polymorphonuclear (PMN) leukocytes per 1000 x microscopic field (oil immersion) in Gram’s stained smears. At times, this mucopus is best confirmed by visualization of yellow or green endocervical mucopus on a white swab (positive swab test). Two other common signs of mucopurulent cervicitis are edema and erythema in an area of ectopy and easily induced mucosal bleeding. Other investigators suggest, the use of > 30 PMN leukocytes per 400x microscopic field in Gram’s stained specimens of endocervical mucus as criterion to diagnose cervicitis.42 Although, there is no absolute “gold standard” for chlamydia diagnostic tests, amplification assays have a sensitivity of at least 90 percent compared with 60-70 percent for culture and 60 percent for antigen assays.26 Nucleic acid amplification tests (NAAT) for chlamydia, including polymerase chain reaction, ligase chain reaction and transcription mediated amplification assays are more sensitive and highly specific. The sensitivity of nucleic acid amplification tests on urine samples from males is high and may even be higher than a urethral swab, perhaps because of the limitations on taking an adequate urethral swab sample. In women the sensitivity of urine testing is lower and a vaginal swab is a better alternative.26 Recent restructuring of an older enzyme immunoassay (EIA) to have an amplified signal, using recycling enzymes, has produced a more promising EIA called IDEIA PCE.45 This assay now deserves further critical evaluation of its use. Also during the antigen detection era of


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the 1980s, the commercialization of nucleic acid hybridization (NAH) testing, the PACE 2 assay from GenProbe became available. This test also contributed substantially towards our understanding of the natural history of C. trachomatis infections, but it too, is being threatened with replacement by NAATs.45 A single dose of azithromycin 1 gm has been shown to be effective in treating chlamydia and other causes of non-gonococcal urethritis, but at a much greater cost than a 7 day course of doxycycline.8,26 Single dose treatment may be cost effective because of improved compliance, however, even with poor compliance the cure rate with doxycycline is still high, typically 95 percent. This is consistent with evidence that the effective dose and possibly the duration of doxycycline treatment is less than that recommended.26 Bacterial Vaginosis Bacterial vaginosis (BV) is a clinical syndrome of unknown etiology characterized by an overgrowth of vaginal anerobes and variable degrees of depletion of the normal Lactobacillus spp. population.46 The organisms most commonly associated with BV are Gardnerella vaginalis, Prevotella (often described generically as Bacteroides) spp., Mobiluncus spp. and Mycoplasma hominis.13 Symptomatic women report an offensive, fishy smelling discharge, which is most marked after unprotected intercourse or at the time of menstruation. Approximately 50 percent of women with BV appear to be asymptomatic.13 BV is the commonest cause of vaginal discharge occurring in women attending the gynecological clinics in our country.46 The diagnosis is usually made clinically based upon the composite (Amsel) criteria and is based on detecting at least three of four following composite criteria: • Excessive homogeneous uniformly adherent vaginal discharge • Elevated vaginal pH > 4.5 • Positive amine test (Whiff test) • Clue cells (20%) These criteria arose from the original description of ‘Hemophilus vaginitis’ by Gardner and Dukes in 1955.47 They recognized the typical thin homogeneous discharge, elevated vaginal pH and the fishy smell. Moreover, they described the appearance, on wet mount examination of vaginal fluid, of epithelial cells covered with so many small bacteria that the border was fuzzy. They called them ‘clue cells’, as their presence was a clue to the diagnosis. These criteria remain the mainstay of diagnosis for clinical practice. They are simple to perform in an ‘office’ setting and, apart from the outlay for the microscope, require minimal materials.13

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BV produces many biochemical changes in vaginal fluid. Anerobic bacteria produce trimethylamine and polyamines such as putrescine or cadaverine, which are associated with the fishy smell. There is an increase in the ratio of succinate to lactate.48,49 Many bacterial enzymes are detectable including sialidase50,51 and proline aminopeptidase.52 These can be measured by techniques such as gas chromatography, HPLC or by biochemical assays. Simple assays have been developed for these and some are now becoming commercially available. A proline aminopeptidase test was found to have a sensitivity of 79 percent and specificity of 95 percent.53 The Gram-stained vaginal smear has been compared with the composite criteria in several studies.13 Typical lactobacilli are large grampositive rods, with blunt ends. In contrast, G. vaginalis is usually a gram-negative coccus, although described as a gram-variable coccobacillus. Mobiluncus spp. are also easily recognised as curved rods with pointed ends. Mob. mulieris bacilli are longer than Mob. curtissi. On wet mount, they are highly motile by means of their central flagella. Systems for interpreting gram-stained smears have been used by Spiegel et al,54 Nugent et al55 and Thomason et al.56 Most of these scoring systems show a high sensitivity, >90 percent, but low specificity, 70–90 percent, when compared with Amsel criteria.13 Because BV follows a relapsing remitting course in many women, the value of treating asymptomatic BV has not been established.13 Antibiotics with good anti-anerobic activity should be effective treatment for BV. The standard treatment for BV is a course of oral metronidazole. The precise dosage and duration varies, but 400 mg twice a day for 5 days is adequate. The cure rate immediately after treatment with metronidazole is up to 95 percent, but after 4 weeks this falls to 80 percent in open label studies and to < 70 percent in blinded studies. A meta-analysis concluded that a single 2 g dose of metronidazole is as effective as 5or 7-day regimens.57 Up to 30 percent of women treated for BV will relapse within 1 month of treatment. 13 Topical treatments with intravaginal clindamycin 2 percent cream, or metronidazole 0.75 percent gels are licensed for the treatment of BV. Efficacy is similar to oral metronida-zole.58, 59 BV is associated with second trimester miscarriage and preterm birth.13,46 Several studies have evaluated the value of screening and treating BV to prevent adverse pregnancy outcome. Unfortunately, the results have been variable. Use of intravaginal preparations is attractive to reduce the incidence of side effects and the potential for teratogenicity. Once infection is established in the uterus, intravaginal treatment is unlikely to be sufficient to prevent progression to preterm birth. Thus, topical treatment might work best in the first trimester of


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pregnancy. On current data from trials, women with a history of second trimester loss or idiopathic preterm birth should be screened and treated with metronidazole, if BV is found, early in the second trimester of pregnancy.13,46 OTHER SEXUALLY TRANSMITTED DISEASES Anogenital Warts Condylomata acuminata are benign anogenital warts caused by human papillomavirus (HPV), genotypes 6 and 11 being found in >90 percent of cases.60 Patients with visible warts may be infected simultaneously with oncogenic “high risk” HPVs, such as types 16 and 18, which mostly give rise to subclinical lesions associated with intraepithelial neoplasia (IN) and anogenital cancer. Anogenital warts are disfiguring and can impact sexual lifestyle.60 They cause feelings of anxiety, guilt, anger and loss of self-esteem and create concerns about future fertility and of cancer risk. Physical symptoms may include inflammation, fissuring, itching, bleeding or dyspareunia. Diagnosis of warts in the anogenital region is based on the history of the exposure, clinical appearance, epidemiological proof of the warts in the sexual contact and the histological appearance.61 A fuller inspection of the fossa navicularis in men is performed by “meatoscopy” using a small speculum (spreader) or an otoscope.60 All women with anogenital warts should have a speculum examination to identify the presence of coexisting vaginal and/or cervical warts. Concurrent perineal and perianal warts exist in one-third of patients, so anoscopy is indicated. Following application of 5 percent acetic acid (Acetic acid test), HPV lesions may turn grayish white for a few minutes. As the test has poor specificity, it is only recommended for use in specialist settings where colposcopy is available. Biopsy is unnecessary for newly occurring, multiple, acuminate lesions, but is recommended in atypical cases for differential diagnostic purposes or in any case where the benign nature of a papular or macular lesion is unclear such as conspicuous Bowenoid papulosis, Bowen’s disease and giant condylomas.60 The most sensitive method for detection of HPV DNA is PCR.61 This technique is able to detect latent infection, but has little benefit in routine diagnosis and management of condyloma and is primarily used as a research tool. Gel electrophoresis and restriction endonuclease cleavage are other methods employed in the detection of viral warts. The principal shortcoming of available therapies is that no method necessarily eradicates warts, maintains clearance and eliminates the virus;

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recurrence rates, including new lesions at previously treated or new, remote sites, are often 20–30 percent.60 All therapies are associated with local skin reactions including itching, burning, erosions and pain. Various treatments tried in the management of genital warts are topical podophyllin, podophyllotoxin, cryotherapy, electrosurgery, chemical cautery, carbon dioxide laser, 5-fluorouracil cream, topical imiquimod cream, and intralesional interferon.62 Podophyllin, a crude plant extract with low efficacy, high toxicity, and a serious mutagenicity profile does not comply with the WHO guidelines for plant-derived treatments.63 It has been suggested that this product should be removed from clinical treatment protocols. Therapies which can be employed by the patient at home are: podophyllotoxin (0.15% cream or 0.5% solution) and imiquimod (5% cream). Each course of podophyllotoxin treatment comprises self application twice daily for 3 days, followed by 4–7 rest days.60 Use of 0.5 percent podophyllotoxin solution is convenient for penile warts. However, vulvar and anal warts are more feasibly and efficiently treated with 0.15 percent podophyllotoxin cream when digital self-examination and tactile sensations facilitate the application procedure. Up to 50–65 percent of patients using podophyllotoxin experience transient and acceptable burning, tenderness, erythema, and/or erosions for a few days when the warts necrotise. Imiquimod (a new immune response modifier) cream, supplied in single use sachets, is applied to the warts three times a week at bedtime and the area washed with mild soap and water the next morning. Treatment continues until wart clearance or for a maximum of 16 weeks. Local reactions at the treatment site may occur and a rest period of several days may be taken if required. The most common adverse reaction seen with imiquimod use is erythema, which occurred in 67 percent of patients. Podophyllotoxin is contraindicated during pregnancy and women of childbearing age must use contraception or abstain from penetrative sexual activity during therapy. No studies have been conducted with imiquimod in pregnant women, but the drug has not been found to be teratogenic in animal studies.60 Hospital based/office based treatments include electrosurgery, laser, curettage, scissors excision, cryotherapy and trichloroacetic acid cautery.60 Extensive genital warts with evidence of keratinisation are often refractory to podophyllin, podophyllotoxin and cryotherapy, etc, and are best dealt with surgically or by topical 5-fluorouracil cream. Scissor excision has been mentioned in the treatment of sessile lesions over the shaft of penis, labia majora, and perianal warts.62 However, circumcision for extensive prepucial warts finds no place in the list of treatments for genital warts in men, which was tried successfully in a case in India.62


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Because of several shortcomings including low efficacy and toxicity problems, routine use of interferons, 5-fluorouracil, or podophyllin is not recommended for use in the primary care setting.60 In the specialist setting, 5-fluorouracil is sometimes used against urethral warts and interferons alfa and beta as adjuvant to surgery in problem cases. Immunosuppression, as consequence of HIV infection, and iatrogenically, as a result of transplant grafting, is linked to a significant increase in multicentric and refractory condylomas and of intraepithelial neoplasia, hence, annual cytological screening of HIV positive women is recommended.60 Sexually Acquired Hepatitis There are now numerous reports of hepatitis A virus (HAV) outbreaks among men who have sex with men (MSM).64 Infection correlates with visits to saunas and darkrooms, sex with anonymous partners, group sex, oro-anal and digital-rectal intercourse and number of partners. Hepatitis B virus (HBV) is very efficiently transmitted sexually during heterosexual65 and male homosexual contact.64 Heterosexual transmission occurs in many situations, which includes sex with female sex workers in many resource-poor countries. Transmission of HBV in homosexual men correlates with duration of sexual activity, number of partners, oroanal and genito-anal sexual contact. Several studies have shown sexual transmission of hepatitis D (delta virus) in both heterosexual couples and homosexual men and this route is significant both in endemic areas and in relation to injecting drug users in low prevalence countries. Hepatitis C virus (HCV) can be sexually transmitted (unprotected vaginal sex),65 but at a relatively low rate, probably 0.5–2 percent per year of a relationship or 5 percent of all heterosexual relationships.64 Transmission rates are markedly higher, if the source patient is also HIV positive. There is also evidence for homosexual spread.64 To conclude, in heterosexual relationships, hepatitis B is readily transmitted sexually and hepatitis C and D less so, with little evidence for sexual transmission of hepatitis A. Hepatitis types A–D are all transmissible sexually in male homosexual relationships under certain conditions. In resource-poor countries, sexual transmission is generally only a significant route of transmission for hepatitis B.64 REFERENCES 1. Rosen T, Brown TJ. Genital ulcers—evaluation and treatment. Dermatol Clin 1998; 16:673-85. 2. Lewis DA. Chancroid: clinical manifestations, diagnosis, and management. Sex Transm Inf 2003; 79:68-71.

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3. Thappa DM. Current status of HIV modified syphilis in Indian scenario. Indian J Sex Transm Dis 2002; 23: 5-13. 4. Balchandran C, Pai BS. Chancroid. In: Sharma VK, ed. Sexually Transmitted Diseases and AIDS, 1st edn, New Delhi: Viva Books Private Limited, 2003: 21620. 5. Lewis DA. Diagnostic tests for chancroid. Sexually Transm Inf 2000; 76:137141. 6. Odom RB, James WD, Berger TG. Andrews’ Diseases of the Skin-Clinical Dermatology, 9th edn. Philadelphia: WB Saunders Company 2000:335. 7. Lewis DA. Chancroid: from clinical practice to basic science. AIDS Patient Care STDs 2000; 14:19–36. 8. Center For Disease Control. Sexually transmitted diseases: Treatment guidelines 2002. MMWR Morbidity Mortality Weekly Report 2002; 51 (No. RR-6): 11-50. 9. Ernst AA, Marvez-Valls E, Martin DH. Incision and drainage versus aspiration of fluctuant buboes in the emergency department during an epidemic of chancroid. Sex Transm Dis 1995; 22:217–20. 10. Ganesh R. Donovanosis. In: Sharma VK, ed. Sexually Transmitted Diseases and AIDS, 1st edn, New Delhi: Viva Books Private Limited, 2003:221-25. 11. Rao MV, Thappa DM, Jaishankar TJ, et al. Extragenital donovanosis of the foot. Sex Transm Inf 1998; 74:298-9. 12. O’Farrel N. Donovanosis. Sex Transm Inf 2002; 78:452-7. 13. Birley H, Duerden B, Hart CA, et al. Sexually transmitted diseases: microbiology and management. J Med Microbiol. 2002; 51(10): 793-807. 14. WHO. Guidelines for the management of sexually transmitted infections. 2001;22-35. 15. Bowden FJ, Mein J, Plunkett C, et al. Pilot study of azithromycin in the treatment of genital donovanosis. Genitourin Med 1994; 72:17–9. 16. Mabey D, Peeling RW. Lymphogranuloma venereum. Sex Transm Inf 2002; 78:90-2. 17. Bajaj AK, Sharma R. Lymphogranuloma venereum. In: Sharma VK, ed. Sexually Transmitted Diseases and AIDS, 1st edn, New Delhi: Viva Books Private Limited, 2003: 247-52. 18. Van Dyck E, Meheus AZ, Piot P. Laboratory diagnosis of sexually transmitted diseases. Geneva: World Health Organization, 1999. 19. Wang SP, Grayston JT. Immunologic relationship between genital TRIC, lymphogranuloma venereum and related organisms in a new microtiter indirect immunofluorescence test. Am J Ophthalmol 1970; 70:367–74. 20. Clad A, Freidank HM, Kunze M, et al. Detection of seroconversion and persistence of Chlamydia trachomatis antibodies in five different serological tests. Eur J Clin Microbiol Infect Dis 2000; 19:932–7. 21. Viravan C, Dance DAB, Ariyarit C, et al. A prospective clinical and bacteriologic study of inguinal buboes in Thai men. Clin Infect Dis 1996; 22:233–9. 22. Black CM. Current methods of laboratory diagnosis of Chlamydia trachomatis infections. Clin Micro Rev 1997; 10:160–84. 23. Kumar B, Gupta S, Sahoo B. Epidemiology of genital herpes-current concepts. Indian J Sex Transm Dis 2001; 22:2-4. 24. Thappa DM. History of venereal diseases and venereology in India. Indian J Sex Transm Dis 2002; 23:67-79. 25. Singh S, Jaisankar TJ, Thappa DM. Risk factors for transmission of HIV among STD clinic attendees at Pondicherry. Indian J Sex Transm Dis 2001; 22:27-30.


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26. Gilson RJC, Mindel A. Recent advances—Sexually transmitted infections. BMJ 2001; 322:1160-4. 27. Scoular A, Gillespie G, Carman WF. Polymerase chain reaction for diagnosis of genital herpes in a genitourinary medicine clinic. Sex Transm Inf 2002; 78:21-5. 28. Sundharam JA. Herpes genitalis. In: Sharma VK, ed. Sexually Transmitted Diseases and AIDS, 1st edn, New Delhi: Viva Books Private Limited, 2003:25972. 29. Scoular A. Using the evidence base on genital herpes: optimising the use of diagnostic tests and information provision. Sex Transm Inf 2002; 78:160-5. 30. Waugh M. Update on Gonorrhea. SKINmed 2003; 2(3): 188-9. 31. Bala M, Ray K, Kumari S. Alarming Increase in Ciprofloxacin- and PenicillinResistant Neisseria gonorrhoeae Isolates in New Delhi, India. Sex Transm Dis 2003; 30:523-5. 32. Braun-Falco O, Plewig G, Wolff HH, et al. Dermatology 2nd edn. Berlin: Springer, 2000:251. 33. Johnson RE, Newhall WJ, Papp JR, et al. Screening tests to detect Chlamydia trachomatis and Neisseria gonorrhoeae infections—2002. MMWR Recomm Rep. 2002; 51(RR-15): 1-38. 34. Thappa DM. Essential in Dermatology with MCQ’s. 1st edn, New Delhi: Ahuja Publishing House, 2003:213. 35. Schwebke J R. Update of trichomoniasis. Sex Transm Inf 2002; 78:378-9. 36. Fouts AC, Kraus SJ. Trichomonas vaginalis: re-evaluation of its clinical presentation and laboratory diagnosis. J Infect Dis 1980; 141:137–43. 37. Krieger JN, Verdon M, Siegel N, et al. Natural history of urogenital trichomoniasis in men. Urology 1993; 149:1455-8. 38. Krieger JN, Tam MR, Stevens CE, et al. Diagnosis of trichomoniasis. JAMA 1988; 259:1223–7. 39. Draper D, Parker R, Patterson E, et al. Detection of Trichomonas vaginalis in pregnant women with the In Pouch TV system. J Clin Microbiol 1993; 31: 1016–8. 40. Lawing L, Hedges S, Schwebke J. Detection of trichomonas in vaginal and urine specimens from women by culture and PCR. J Clin Microbiol 2000; 38:3585–8. 41. Lossick JG, Kent HL. Trichomoniasis: trends in diagnosis and management. Am J Obstet Gynecol 1991; 165:1217–22. 42. Sweet RL. The enigmatic cervix. Dermatol Clin 1998; 16:739-45. 43. Majumdar S, Saha GC. Chlamydia infections and Non-gonococcal urethritis. In: Sharma VK, ed. Sexually Transmitted Diseases and AIDS, 1st edn, New Delhi: Viva Books Private Limited, 2003:232-46. 44. Stary A. Urethritis-Diagnosis of non-gonococcal urethritis. Dermatol Clin 1998; 16:723-6. 45. Chernesky MA. Chlamydia trachomatis diagnostics. Sex Transm Inf 2002; 78:232-4. 46. Thappa DM. Bacterial vaginosis. In: Sharma VK, ed. Sexually Transmitted Diseases and AIDS, 1st edn, New Delhi: Viva Books Private Limited, 2003: 253-8. 47. Gardner HL, Dukes CD. Haemophilus vaginalis vaginitis. A newly defined specific infection previously classified ‘‘nonspecific’’ vaginitis. Am J Obstet Gynecol 1955; 69: 962–76.

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48. Stanek R, Gain RE, Glover DD, et al. High performance ion exclusion chromatographic characterization of the vaginal organic acids in women with bacterial vaginosis. Biomed Chromatog 1992; 6: 231–5. 49. Thomason JL, Gelbart SM, James JA, et al. Is analysis of vaginal secretions for volatile organic acids to detect bacterial vaginosis of any diagnostic value? Am J Obstet Gynecol 1988; 159: 1509–11. 50. Cauci S, Monte R, Driussi S, et al. Impairment of the mucosal immune system: IgA and IgM cleavage detected in vaginal washings of a subgroup of patients with bacterial vaginosis. J Infect Dis 1998; 178: 1698–1706. 51. McGregor JA, French JI, Jones W, et al. Association of cervicovaginal infections with increased vaginal fluid phospholipase A2 activity. Am J Obstet Gynecol 1992; 167: 1588–94. 52. Schoonmaker JN, Lunt BD, Lawellin DW, et al. A new proline aminopeptidase assay for diagnosis of bacterial vaginosis. Am J Obstet Gynecol 1991; 165: 737–42. 53. Thomason JL, Gelbart SM, Wilcoski LM, et al. Proline aminopeptidase activity as a rapid diagnostic test to confirm bacterial vaginosis. Obstet Gynecol 1988; 71: 607-11. 54. Spiegel CA, Amsel R, Holmes KK. Diagnosis of bacterial vaginosis by direct gram stain of vaginal fluid. J Clin Microbiol 1983; 18: 170–7. 55. Nugent RP, Krohn MA, Hillier SL. Reliability of diagnosing bacterial vaginosis is improved by a standardized method of gram stain interpretation. J Clin Microbiol 1991; 29: 297–301. 56. Thomason JL, Anderson RJ, Gelbart SM, et al. Simplified gram stain interpretative method for diagnosis of bacterial vaginosis. Am J Obstet Gynecol 1992; 167: 16–9. 57. Lugo-Miro VI, Green M, Mazur L. Comparison of different metronidazole therapeutic regimens for bacterial vaginosis. A meta-analysis. JAMA 1992; 268: 92–5. 58. Sweet RL. New approaches for the treatment of bacterial vaginosis. Am J Obstet Gynecol 1993; 169: 479–82. 59. Hillier SL, Lipinski C, Briselden AM, et al. Efficacy of intravaginal 0.75% metronidazole gel for the treatment of bacterial vaginosis. Obstet Gynecol 1993; 81: 963–7. 60. von Krogh G, Lacey CJN, Gross G, et al. European course on HPV associated pathology: guidelines for primary care physicians for the diagnosis and management of anogenital warts. Sex Transm Inf 2000; 76:162-8. 61. Usman N. Anogenital warts. In: Sharma VK, ed. Sexually Transmitted Diseases and AIDS, 1st edn, New Delhi: Viva Books Private Limited, 2003:273-82. 62. Dogra S, Kumar B. Circumcision in genital warts—let us not forget! (Letter). Sex Transm Inf 2003; 79:265. 63. von Krogh G, Longstaff E. Podophyllin office therapy against condyloma should be abandoned. Sex Transm Inf 2001; 77:409-12. 64. Brook MG. Sexually acquired hepatitis. Sex Transm Inf 2002; 78:235-40. 65. Singh S, Thappa DM, Jaisankar TJ, et al. Sexual co-transmission of HIV, hepatitis B and hepatitis C viruses, Sex Transm Inf 2000; 76:317.

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K.K. Raja Babu, A. Vilas

Narrowband UV-B Phototherapy: A Newer Advance in the Treatment of Vitiligo Phototherapy using psoralens has been a time-tested treatment for vitiligo, perhaps since vedic times. A combination of oral psoralens and UVA (either from an artificial source or from natural sunlight) still remains the mainstay therapy for vitiligo even in modern times. However, adverse effects like nausea and other gastrointestinal discomfort, persistent UVA sensitivity, the potential risk for liver toxicity, cataracts, melanoma and non-melanoma skin cancer, and therapeutic helplessness in treating children young of age limit the utility of systemic PUVA in the treatment of vitiligo.1 Topical PUVA therapy has some advantages over systemic PUVA therapy but inability to employ on wide areas and an increased potential for photo-irritant reactions limit its use as well. A significant advance in the treatment of dermatological disorders in recent years has been the introduction of fluorescent bulbs (Philips model TL-01) with a spectrum of 310- 315 nm and a peak emission at 311 nm. These longer, specific wavelengths of UV-B, labeled as narrowband UVB which are less erythemogenic than the shorter forms of UV-B have been used successfully for the treatment of a number of dermatological diseases. In studies on psoriasis,2-5 narrowband UV-B therapy has been found to be as effective as PUVA without the distinct disadvantages of the latter and was considerably superior to broadband UV-B (290-320 nm) and bath PUVA. Narrowband UV-B therapy was subsequently found to be effective for the treatment of atopic dermatitis in both children and adults,6-8 and in a host of other diseases that include seborrheic dermatitis,9 subcorneal pustular dermatosis,10,11 small plaque parapsoriasis,12 pruritic folliculitis of pregnancy,13 pruritus of polycythemia vera,14 polymorphic light eruption,15,16 erythropoietic protoporphyria,17 and mycosis fungoides.18 The pioneering work of Westerhof and colleagues

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from Netherlands extended its use to the treatment of vitiligo both in adults and children.19,20 WHAT IS NARROWBAND UV-B THERAPY? Narrowband UV-B therapy involves delivery of specific wavelengths of light (311 nm), in gradually increasing doses two or three times a week, to the entire body or to a part of it using specially designed lamps (TL-01, Philips). The letters TL stand for Tube light! in phototherapy chambers. The nominal wattage of each lamp is 100 watts at 1000 milliAmperes. Now many manufacturers have whole body units that have only narrowband UV-B lamps, (e.g. Spectra 311, Daavlin, USA) or a combination of both narrowband UV-B and UV-A lamps, generally 24 of each (e.g. Spectra 311/350, Daavlin, USA). Hand and foot units that are especially suitable to treat these areas are also available but without the gadgetry or the sophistication of the whole body units (Spectra Mini series, Daavlin, USA). Less expensive Indian-made machines are also currently available. METHOD OF USE Narrowband UV-B therapy is most ideally suited for treatment of patients with generalized vitiligo, although localized disease affecting hands or feet can be treated in the Hand and Foot units. The distinct advantage of narrowband UV-B is the ability to treat children below 12 years of age in whom systemic PUVA therapy is generally contraindicated.21 Children of vitiligo old enough to understand and follow instructions can be considered for narrowband UV-B therapy. It is important to have a general treatment protocol before recruiting patients for narrowband UV-B phototherapy. This should include the patient’s name, age, sex, address and occupation, the duration and extent of the disease and previous treatment if any. A checklist should categorically exclude patients with known history of photosensitivity or photosensitive disorders or a history of skin malignancy. Patients who are inadequately motivated or unwilling to commit themselves to complete the course of treatment should also be excluded. So are also patients, like the elderly and the infirm and those who cannot withstand the ‘rigours’ of therapy. Patients with more than 50 percent of body involvement are also not ideal candidates for narrowband UV-B therapy. To be extra cautious a prior ophthalmic examination may be performed and aphakic patients excluded from therapy if they do not have intraocular lenses implanted. Pregnancy and lactation are not contra-


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indications. Explanatory counseling of the therapy and its potential benefits, or the absence of them, is necessary and an informed consent from each patient should be taken. A phototherapy treatment chart should be prepared and should include the name of the patient, a PIN code, the name of the treating doctor, the center, the date of treatment, the type of treatment (whole body or hands/feet), the dose in mJ/cm2 and any concurrent medication (both topical and systemic), the treatment effects, response to treatment and special instructions, if any. The patient should be questioned about post-treatment erythema and the length of its persistence. Generally patients should be free of lesional erythema before the next treatment. Narrowband UV-B therapy is given twice or thrice a week and not on two consecutive days. As vitiligo lesions are totally devoid of pigment, all patients are to be categorized as Fitzpatrick skin type I and no MED determinations are generally needed. Initial dose is normally between 250 to 300 mJ/cm2 and the dose is increased by 10-20 percent at each session of treatment (20% initially and 10% later). A 50-100 mJ increase at every subsequent visit is satisfactory. In the authors’ experience, the optimal dose is one when minimal post-treatment erythema develops in the lesions, and disappears in a few hours (unpublished observations). Patients should be free from post-treatment lesional erythema before they are ready for the next increase in dose. If erythema persists, a dosage adjustment should be made. No guidelines are available with regard to dosage adjustments in vitiligo, and we may have to extrapolate data from our experience of using narrowband UV-B in psoriasis. If mild, barely perceptible, erythema is present, the previous dose is repeated and the next increments are in the order of 10 percent. In the presence of moderate, well-defined and asymptomatic erythema, it will be prudent to postpone one treatment, and to repeat the earlier dose at next visit, and only 10 percent increments are given further on. With severe erythema (painful and persisting for more than 24 hours), treatment should be postponed and a re-evaluation is made. The eyes must be protected with UV blocking goggles during the treatment sessions, but if the patient has lesions on the eyelids, goggles are not worn but the eyes are kept shut. Unlike with PUVA there is no need to protect the eyes post-treatment. All patients should wear thick cotton underwear to protect the genitalia. The patients should be asked to stay in the center of the chamber to get even exposure to all the affected areas. Parts of the body that are lesion-free can be protected with appropriate clothing. A broad-spectrum sunscreen may be prescribed to prevent post-treatment excess tan of the uninvolved sunexposed skin.

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As narrowband UV-B therapy is fairly a new innovation, experience with its use, especially in vitiligo, is limited. The maximum tolerable dose of narrowband UV-B in patients of vitiligo is unknown. However, patients have been treated up to a maximum dose of 5000 mJ/cm2 (Henry W.Lim, personal communication). Cumulative doses exceeding 100 J/cm2 have been used.20 It is also not clear, how long a patient can be treated without a break. Westerhof recommends that a 3-month break should be given after one year of continuous therapy.22 Once substantial response (75% and more) occurs, the frequency of treatments can be reduced until complete clearance of lesions. The need for maintenance treatments has not been studied. RESPONSE TO TREATMENT With appropriate methodology and dose, re-pigmentation generally begins after about 6 weeks of therapy. Some patients may take longer to respond. If there is no response even after 6 months of continuous therapy, it is not prudent to continue with the exercise any more. Newly formed pigment appears perifollicularly and also at the margin of the lesion and is initially darker than the patient’s skin color. Like PUVA, certain anatomical areas respond better and faster than others. Face, neck, arms, legs and trunk respond in that order. Lips, bony points, fingers and toes respond poorly. Localized and generalized vitiligo respond favourably compared to segmental and acrofacial vitiligo.19,20 Lesions of shorter duration respond better than the long-standing ones. SIDE EFFECTS Narrowband UV-B therapy is generally safe. No phototoxic or photoallergic reactions have been reported. The sun exposed skin may show an excessive tan if it is not protected adequately. Itching is rare. Some patients may develop mild dryness of the treated skin and this quickly clears with emollient application. As narrowband UV-B units emanate certain heat, patients are likely to face some discomfort, especially after longer treatment exposures (Unpublished observations). The fewer the TL-01 lamps in a unit, the longer the exposure time required to receive the same amount of fluence. In such a contingency, patients may be advised to take a break in between a treatment session. Air-conditioning phototherapy room also lessens patient discomfort. MECHANISM OF ACTION OF NARROWBAND UV-B The mechanism of usefulness of narrowband UV-B phototherapy in vitiligo is unknown. Expression of endothelin I, IL-1α and tyrosinase in


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human keratinocytes has been shown to increase both in vitro and in vivo after UV-B radiation suggesting their possible role in UV-B induced pigmentation.23 UV light has also been shown to stimulate the production of nerve growth factor by keratinocytes.24 Whether nerve growth factor has the ability to protect melanocytes in the follicular reservoir from immunological destruction or play some role in their proliferation is not known. What role cis-urocanic acid or the morphological and functional alterations in Langerhans cells that follow UV-B radiation play in the development of new pigment formation is also not clear.25-27 CLINICAL STUDIES Westerhof and Nieweboer-Krobotova19 were the first to study the effect of narrowband UV-B on vitiligo in 1997. In a two-arm treatment trial, the investigators compared twice-weekly topical PUVA with twice-weekly narrowband UV-B therapy. They showed that after 4 months of therapy, 67 percent of vitiligo patients undergoing narrowband UV-B therapy showed re-pigmentation compared to 46 percent of vitiligo patients on topical PUVA. Importantly, 8 percent of patients showed more than 75 percent repigmentation only after 3 months of narrowband UV-B therapy. The researchers concluded that narrowband UV-B phototherapy was an effective treatment option for patients with active, extensive and generalized vitiligo and was associated with fewer side effects. In a further study in 2000, Njoo, Bos and Westerhof reported the effects of narrowband UV-B therapy in children (including one Indian girl child) with generalized vitiligo.20 In an open study, 51 children (20 boys, 31 girls, age range 4 to 16 years) with generalized vitiligo were treated with twice-weekly narrowband UV-B radiation for a maximum of 1 year. The treatment resulted in more than 75 percent overall re-pigmentation in 53 percent of patients and in stabilization of the disease in 80 percent. There were very few adverse effects. One meta-analysis study28 comparing different forms of non-surgical therapies for vitiligo had revealed the following success rates for different types of phototherapy in generalized vitiligo: Oral PUVA—51 percent, UV-B— 57 percent and Narrowband UV-B—63 percent. Scherschun and colleagues from the U.S. reported in 2001 their experience with seven patients of vitiligo (4 males and 3 females, age range 19 to 59 years) who received narrowband UV-B, three times a week, over a 12-month period.29 Three patients were of skin types IV and V, four with types II and III. Five of the 7 patients achieved more than 75 percent pigmentation after a mean of 19 treatments. The remaining 2 patients had 50 percent and 40 percent re-pigmentation after 46 and 48 treatments respectively. Those who responded faster and

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better had their disease for a shorter duration of time. Adverse effects were minimal and transient. In a left-right comparative study in a 20-year-old Indian male with vitiligo, a combination of calcipotriol (50 mcg/g) and narrowband UVB was found to be superior to narrowband UV-B given as monotherapy in achieving lesional re-pigmentation.30 NEWER DEVELOPMENTS Narrowband UV-B Micro-phototherapy One of the disconcerting effects of phototherapy or photochemotherapy is the uneven re-pigmentation of the treated areas (although this is minimal with narrowband UV-B therapy). One of the innovations that is claimed to overcome this ‘erratic’ effect is narrowband UV-B microphototherapy that delivers narrowband UV-B directly to the lesions, using different conical hoods, through special phototherapy devices (Bioskin®). Recent studies31,32 have shown that this type of therapy is particularly applicable for the treatment of limited vitiligo (with less than 30 percent skin surface involvement) and segmental vitiligo. 308-nm Excimer Laser Therapy The 308-nm excimer laser is a new and exciting innovation combining the two major achievements in medical photo-technology, viz., the use of a fiber-optic light delivery system and having a 308 nm emission line, and has FDA, U.S.A. approval for treatment of patients with psoriasis. Several recent studies attest to its usefulness in focal, non-responding recalcitrant plaques of psoriasis.33,34 Its use in vitiligo is new and relatively unexplored. Spencer and colleagues from the US.35 undertook a pilot study to see its effects in focal vitiligo. 29 patches of vitiligo from 18 patients were treated with the laser, 3 times a week for a maximum of 12 treatments. At the end of the study period, partial to near complete re-pigmentation was seen in those who completed the treatment protocol. 308-nm excimer laser carries the same advantages as microphototherapy, but because of the small spot size, its use can be limited only to focal examples of vitiligo. In a recent study, Taneja and colleagues from U.S.A. using twice-weekly 308-nm UV-B radiation for a maximum of 60 treatments demonstrated that the excimer laser is an effective option for inducing re-pigmentation in localized, stable, recalcitrant lesions of vitiligo.36


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CONCLUSIONS While PUVA in its various forms has remained and continues to remain the mainstay therapy for vitiligo for many physicians and most patients who do not have access to sophisticated phototherapy units, Narrowband UV-B therapy is indeed a very significant advance to those adults and children of vitiligo who have such access. Our experience with this new technology is limited at this point of time and its long-term safety is unknown. Although the potential for skin carcinogenicity in type V and VI skin even with PUVA therapy is low, dose-response models suggest that long-term narrowband UV-B therapy may carry less risk for skin cancer than PUVA.18 If proved in further trials, narrowband UV-B microphototherapy and the ‘super narrowband’ 308-nm excimer laser therapy may even be greater advances than narrowband UV-B therapy, as the UV radiation can be directly delivered to the lesions. REFERENCES 1. Morison WL, Baughman RD, Day RM, et al. Consensus workshop on the toxic effects of long-term PUVA therapy. Arch Dermatol 1998;134: 595-8. 2. Coven TR, Burack LH, Gilleaudeau R, et al. Narrowband UV-B produces superior clinical and histopathological resolution of moderate-to-severe psoriasis in patients compared with broadband UV-B. Arch Dermatol 1997; 133: 151422. 3. Tanew A, Radakovic-Fijan S, Schemper M, et al. Narrowband UV-B phototherapy vs photochemotherapy in the treatment of chronic plaque-type psoriasis: a paired comparison study. Arch Dermatol 1999: 135: 519-24. 4. Markham T, Rogers S, Collins P. Narrow-band UV-B (TL-01) phototherapy vs. oral 8-methoxypsoralen UV-A for the treatment of chronic plaque psoriasis. Arch Dermatol 2003;139:325-8. 5. Dawe RS, Cameron H, Yule S, et al. A randomized controlled trial of narrowband ultraviolet B vs. bath-psoralen plus ultraviolet A photochemotherapy for psoriasis. Br J Dermatol 2003;148:1194-1204. 6. George SA, Bilsland DJ, Johnson BE, et al. Narrowband (TL-01) UVB airconditioned Phototherapy for chronic severe adult atopic dermatitis. Br J Dermatol 1993; 128: 49-56. 7. Collins P, Ferguson J. Narrowband (TL-01) UVB air-conditioned Phototherapy for atopic eczema in children. Br J Dermatol 1995; 133:653-5. 8. Der-Petrossian M, Seeber A, Honigsmann H, et al. Half-side comparison study on the efficacy of 8-methoxypsoralen bath-PUVA versus narrow-band ultraviolet B phototherapy in patients with severe chronic atopic dermatitis. Br J Dermatol 2000; 142: 39-43. 9. Pirkhammer D, Seeber A, Honigsmann H, et al. Narrow band ultraviolet B (TL-01) Phototherapy is an effective and safe treatment option for patients with severe seborrhoeic dermatitis. Br J Dermatol 2000; 143: 964-8. 10. Cameron H, Dawe RS. Subcorneal pustular dermatosis (Sneddon-Wilkinson disease) treated with narrowband (TL-01) UVB phototherapy. Br J Dermatol 1997; 137: 150-1.

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11. Orton DI, George SA. Subcorneal pustular dermatosis responsive to narrowband (TL-01) UVB Phototherapy. Br J Dermatol 1997; 137: 149-50. 12. Hofer A, Cerroni L, Kerl H,et al. Narrowband (311-nm) UV-B therapy for small plaque parapsoriasis and early stage mycosis fungoides. Arch Dermatol 1999; 135: 1377-80. 13. Reed J, George S. Pruritic follicultits of pregnancy treated with narrowband (TL-01) ultraviolet B Phototherapy. Br J Dermatol 1999; 141: 177-9. 14. Baldo A, Sammarco E, Plaitano R, et al. Narrowband (TL-01) ultraviolet B phototherapy for pruritus in polycythemua vera. Br J Dermatol 2002; 47:97881. 15. Bilsland D, George SA, Gibbs NK, et al. A comparison of narrow band phototherapy (TL-01) and photochemotherapy (PUVA) in the management of polymorphic light eruption. Br J Dermatol 1993; 129: 708-12. 16. Collins P, Ferguson J. Narrow-band UVB (TL-01) Phototherapy: an effective preventative treatment for the photodermatoses. B J Dermatol 1995; 132: 95663. 17. Warren LJ, George S. Erythropoietic protoporphyria treated with narrow-band (TL-01) UVB phototherapy. Australas J Dermatol 1998; 39: 179-82. 18. Clark C, Dawe RS, Evans AT, et al. Narrowband TL-01 phototherapy for patch stage mycosis fungoides. Arch Dermatol 2000;136: 748-52. 19. Westerhof W, Nieweboer-Krobotova L. Treatment of vitiligo with UV-B radiation vs topical psoralen plus UV-A. Arch Dermatol 1997; 133: 1525-8. 20. Njoo MD, Bos JD, Westerhof W. Treatment of generalized vitiligo in children with narrow–band (TL-01) UVB radiation therapy. J Am Acad Dermatol 2000; 42: 245-53. 21. Drake LA, Dinehart SM, Farmer ER, et al. Guidelines of care for vitiligo. J Am Acad Dermatol 1996;35:620-6. 22. Westerhof W. The treatment of vitiligo with UV-B 311 nm: Fine Tuning. CME lecture on pigmentary disorders. 31st National conference of I.A.D.V and L, 30th January to 2nd February 2003, Kolkata, India. 23. Imokawa G, Miyagishi M, Yada Y. Endothelin-I as a new melanogen: Coordianted expression of its gene and the tyrosinase gene in UVB exposed human epidermis. J Invest Dermatol 1995; 105: 32-7. 24. Huang CL, Nordlund JJ, Boisy R. Vitiligo: A manifestation of apoptosis? Am J Clin Dermatol 2002;3:301-8. 25. Moodycliffe AM, Kimber I, Norval M. The effect of ultraviolet B irradiation and urocanic acid isomers on dendritic cell migration. Immunology 1992;77:3949. 26. el-Ghorr AA, Norval M, Lappin MB, et al. The effect of chronic low-dose UVB radiation on Langerhans cells, sunburn cells, urocanic acid isomers, contact hypersensitivity and serum immunoglobulins in mice. Photochem Photobiol 1995: 62: 326-32. 27. Seite S, Zucchi H, Moyal D, et al. Alterations in human epidermal Langerhans cells by ultraviolet radiation: quantitative and morphological study. Br J Dermatol 2003;148:291-9 28. Njoo MD, Spuls PI, Boss MD, et al. Nonsurgical pigmentation therapies in vitiligo: meta-analysis of the literatue. Arch Dermatol 1998;134: 1532-40. 29. Scherschun L, Kim JJ, Lim HW. Narrow-Band ultraviolet B is a useful and well-tolerated treatment for vitiligo. J Am Acad Dermatol 2001; 44: 999-1003. 30. Dogra S, Parsad D. Combination of narrowband UV-B and topical calcipotriol in vitiligo. Arch Dermatol 2003; 139: 393.


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31. Lotti TM, Menchini G, Andreassi L. UV-B radiation microphototherapy: An elective treatment for segmental vitiligo. J Eur Acad Dermatol Venereol 1999; 113: 102-8 32. Menchini G, Tsoureli-Nikita E, Hercogova J. Narrow-band UV-B microphototherapy: a new treatment for vitiligo. J Eur Acad Dermatol Venereol 2003; 17:171-7. 33. Trehan M, Taylor CR. High dose 308-nm excimer laser for the treatment of psorisis. J Am Acad Dermatol 2002; 46: 732-7. 34. Feldman SR, Mellen BG,Housman TS, et al. Efficacy of the 308-nm excimer laser for treatment of psoriasis: Results of a multicenter study. J Am Acad Dermatol 2002;46:900-6. 35. Spencer JM, Nossa R, Ajmeri J. Treatment of vitiligo with the 308-nm excimer laser: A pilot study. J Am Acad Dermatol 2002; 46: 727-31. 36. Taneja A, Trehan M, Taylor CR. 308-nm excimer laser for the treatment of localized vitiligo. Int J Dermatol 2003; 42: 658-62.

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11

Dinesh Hawelia

Newer Drugs in Dermatology: Systemic Within the past few years, a number of new systemic drugs has been showing quite effective and encouraging therapeutic outcome in different skin diseases. In fact, a few of them are gradually elbowing out the existing choices and establishing their indispensability. Interestingly, certain abandoned drugs have taken rebirth to find new indications. Keeping these in mind, the following newer agents have been chosen and discussed. MYCOPHENOLATE MOFETIL It is a morpholinoethyl ester prodrug of the active mycophenolic acid (MPA), a fermentation product of several Penicillium species. It acts as a potent immunosuppressant.1 Mechanism of Action It selectively and non-competitively inhibits the type 2 isoform of inosine monophosphate dehydrogenase (IMPDH) which is an enzyme required for the conversion of IMP (inosine monophosphate) to XMP (xanthine monophosphate), a precursor of guanine nucleotides.2 Thus the de novo synthesis of guanine nucleotides are blocked, which are necessary substrates for the DNA and RNA synthesis. Lymphocytes depend primarily on de novo pathway of purine synthesis whereas other cell types have a salvage pathway of purine synthesis. Type 2 isoform of IMPDH is present in proliferating lymphocytes3 whereas type 1 isoform is present in resting lymphocytes. Capacity of mycophenolate mofetil (MMF) to inhibit IMPDH type 2 isoform is five times greater than that for type 1 isoform.3 MMF is, therefore, cytotoxic to proliferating T and B – lymphocytes.4 MMF also leads to decreased level of immunoglobulins and delayed type hypersensitivity responses.5 Pharmacokinetics6,7 MMF is well absorbed orally and is rapidly converted to active metabolite MPA by plasma esterases. MPA is then further metabolized in the liver

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to MPA glucuronide (MPAG) which is inactive. MPAG cannot penetrate the cell membrane of most tissue types and more than 90 percent of the drug is excreted in the urine as MPAG and 6 percent is eliminated in feces. Bioavailability of MPA is 94 percent after oral intake. Peak MPA level occurs approximately 1 hour post-dose with a secondary peak occurring 6 to 8 hours later due to enterohepatic recirculation of MPAG and its hydrolysis back to MPA in gastrointestinal tract. Indications and Dosage MMF is primarily used, as approved by FDA, for the prophylaxis of organ rejection in patients receiving allogenic renal, hepatic or cardiac transplant in conjunction with cyclosporine and corticosteroids.8,9 MMF 2 gm daily seems to be an effective therapeutic tool for psoriasis and psoriatic arthritis patients,10 particularly those who are intolerant of or unresponsive to other treatment modalities or who are at risk of developing renal toxicity due to cyclosporine.11-16 MMF may be used as monotherapy for pemphigus vulgaris or bullous pemphigoid17,18 and this offers the advantage of lesser side-effects in comparison to combination with steroids or other immunosuppressants. However, it may be used in combination with steroids19 in refractory cases. It is going to be the drug of choice as adjuvant therapy along with corticosteroids in the treatment of pemphigus vulgaris by replacing other immunosuppressants like azathioprine, cyclophosphamide, etc. MMF is found to be quite safe, effective and well tolerated in moderate to severe atopic dermatitis.20,21 MMF seems to be an attractive treatment option for cases of subacute cutaneous lupus erythematosus (SCLE), not responsive to steroids, immunosuppressants or antimalarials.22 There are reports of successful treatment of resistant cases of DLE of palms and soles with MMF.23 Severe recalcitrant pyoderma gangrenosum may be treated with MMF in combination with cyclosporine or autologous keratinocyte transplantation.24,25 Skin and oral lesions of paraneoplastic pemphigus were found to become inactive with oral MMF.26 MMF alone or in combination with IVIG can avoid side-effects of high doses and prolonged duration of steroid therapy in dermatomyositis and can induce long-lasting remission of this disorder.27 MMF should be administered on an empty stomach because food diminishes its absorption. The dose of the drug is as follows: For renal transplant patients—1 gram twice a day; other diseases— 1 to 2 grams per day in divided doses.

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Contraindications Hypersensitivity to any component of the drug is the chief contraindication. It has category C prescribing status in pregnancy. Adverse Effects MMF is usually well tolerated. The most common side effect is gastrointestinal, which is dose related and includes nausea, vomiting, diarrhoea, anorexia, soft stools, abdominal cramps and anal tenderness.28,29 The incidence of these side-effects decrease dramatically after first year of therapy.7 There may be reversible dose-related anemia, neutropenia and decreased platelet count.30-33 The incidence of infections may increase after MMF therapy, particularly, Herpes Zoster. There may be an increased risk of lymphoma or malignancies when MMF is used as a component of immunosuppressive regimen and this risk is probably due to duration and intensity of immunosuppression rather than to the use of any specific agent. No incidence of carcinogenesis was reported in a 13-year study by Epinette 34 for psoriasis. Urgency, frequency, dysuria and sterile pyuria may be observed and these are common, dose and time dependent sideeffects.7 Clinically significant nephrotoxicity has never been reported. Its potential teratogenic status is still unknown. There are reports of headache, tinnitus, insomnia, weakness and fatigue which, however, do not necessitate discontinuation of therapy. Drug Interaction Agents interfering with enterohepatic recycling (e.g. Antibiotics, bile acid sequestrants) reduce the amount of MPA available for reabsorption. Drugs eliminated by renal tubular secretion (e.g. Acylovir, ganciclovir) inhibit the elimination of MPAG by competing for renal tubular secretion. Concomitant administration of oral MMF with ferrous sulfate tablets may lead to decrease in MMF absorption.35 IVERMECTIN Ivermectin is a semi-synthetic derivative of a family of macrocyclic lactones, the avermectins, which are naturally produced in soil by Streptomyces avermitilis. It is a macrocyclic lactone structurally similar to macrolide antibiotics but devoid of antibacterial activity. It was approved by US-FDA in 1996 for the treatment of strongyloidiasis and onchocerciasis. However, off-label uses of this compound are widespread.


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Mechanism of Action Ivermectin binds selectively and with high-affinity to structures of glutamate-gated chloride ion channels, 36,37 which are present in invertebrate nerve and muscle cells. Some suggest that it binds with glycine-gated structures.38 In either case, ivermectin simulates the ligand and increases the permeability of cell membrane to chloride ions by opening the gate and thus, allowing an efflux of chloride ions leading to the release of associated neuro-transmitter, gamma-aminobutyric acid (GABA) which results in hyperpolarisation of nerve and muscle cells causing paralysis and death of the parasite. At higher concentration, ivermectin acts as an antagonist of the GABA neuro-transmitter. In insects, these GABA neurons and receptors are mainly present in peripheral nervous system whereas in mammals, they are located in central nervous system.36,39 Ivermectin does not readily cross blood-brain barrier in humans and this adds to the safety of ivermectin therapy. Many authorities believe that ivermectin primarily interferes with function of gastrointestinal tract of target parasites and thus, these insects starve to death under the influence of the drug.38,40,41 Pharmacokinetics Ivermectin is absorbed from gastrointestinal tract after oral intake and peak plasma level is achieved in 4 hours. It is absorbed well in an empty stomach. It is 93 percent bound to plasma-proteins and has a plasma elimination half-life of about 12 to 16 hours.42 Main metabolism takes place in liver and it is excreted largely as metabolites over a period of 2 weeks, mainly in feces. Indications and Dosage Ivermectin was approved by US-FDA in 1996 for use in strongyloidiasis and onchocerciasis.43-46 Even low doses of ivermectin are quite effective in strongyloidiasis. When compared with albendazole, it is significantly more effective.48-50 Nearly 95 percent of thiabendazole-treated subjects had short-term adverse effects during therapy in contrast to only 18 percent of those treated with ivermectin.51 Ivermectin is also effective for strongyloidiasis in the setting of HIV infection.52 An oral dose of ivermectin 200 micrograms/kg effectively treats all types of scabies in otherwise healthy patients and in many patients with HIV infections.53,54 Most authorities recommend a second dose 5 to 14 days after the first dose because it is probably not ovicidal.55 Two such doses of ivermectin given 1 to 2 weeks apart are equivalent to topical permethrin in efficacy56

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and a single dose of ivermectin appears to be of equal or better efficacy in comparison to topical lindane.57 Ivermectin is better than benzyl benzoate for childhood scabies.58 Optimum dosing for scabies, however, remains somewhat uncertain.59,60 A dose of 200 mcg /kg should be most widely employed; but whether one, two or three such doses should be routinely given is a subject of conjecture. Therapeutic dose for pediculosis capitis is 400 mcg/kg and should be repeated in 7 to 10 days.61 Ivermectin shows excellent efficacy in several types of filariasis62-65 and dose to be given should be 400 mcg/kg repeated twice yearly. Ivermectin is effective against nematodes, especially ascariasis, threadworm, whipworm and pinworm, but has an insignificant effect on hookworms. Trematodes and cestodes have a natural resistance against ivermectin, since they do not use GABA as a peripheral nervous system neuro-transmitter. It does not cross blood-brain barrier and hence, is not effective in neurocysticercosis. A single dose of ivermectin 200 mcg/kg is potentially quite effective in cutaneous larva migrans caused by cat and dog hookworms.66-69 Ivermectin can be considered in a sufficiently extensive case of myiasis, as suggested by its usage in a single case report.70 Contraindications Ivermectin has the following contra-indications: • Known hypersensitivity to the ivermectin group of drugs. • Pregnancy—safety not established (category C prescribing status). • Should be avoided in patients with CNS disorders. • Children less than 15 kg body weight and those below 5 years of age—safety not established yet. Adverse Effects No major side effects attributable to ivermectin have been seen in onchocerciasis control programmes wherein more than 19.5 million doses have been distributed all over the world. Mild and transient side effects may be tachycardia, flushing, nausea, headache, pruritus, rash, arthralgia, dizziness and lymphadenopathy. The Mazotti’s reaction is a unique reaction seen in onchocerciasis patients undergoing treatment. It is characterized by major features like fever, orthostatic hypotension, bronchospasm and neurologic deterioration and by minor features like itching, rash, headache and joint pain. This serious side effect has been linked to a hypersensitivity reaction to dead and dying systemic parasites.


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Interestingly, multi-drug resistance (MDR) gene product functions as a cellular pump which moves some drugs (including ivermectin) outside the cell. Ivermectin is an excellent substrate for MDR gene product. Perhaps MDR, in association with blood-brain barrier, functions as a potent protector of human central nervous system. Thus, nearly all humans seem to be protected from potential toxic effects of the drug. MDR gene product is entirely absent or dysfunctional in susceptible animals.50,71 Young children weighing less than 15 kg or less than two years of age should be given ivermectin cautiously because of a diminished blood-brain barrier and perhaps defective MDR gene product. THALIDOMIDE Thalidomide is a non-polar glutamic acid derivative, alpha-Nphthalimidoglutarimide and acts as an immunomodulatory agent.72 It was introduced in 1950 in Europe, Australia and various African and Asian countries but was not approved by US-FDA for marketing. It was found to be useful as a barbiturate-free sedative with potent antiemetic action,73 and therefore, was being used as an antiemetic and sedative in pregnancy as well. Soon the reports of infantile limb defects (phocomelia)74,75 and internal deformities came into focus and in 1961, this drug was rapidly withdrawn from the world market in view of its high teratogenic potential. In 1965, it was reported to dramatically improve the symptoms of erythema nodosum leprosum (ENL).76 In 1997, it was granted approvable status for the treatment of ENL by US-FDA.77 Since then, it is being used in various conditions as an off-label drug. Mechanism of Action Thalidomide possesses multiple biologic activities probably attributed to its various cleavage products.77 It has hypno-sedative effect comparable to that of barbiturates, though it acts in a different way not determined as yet. By virtue of this sedative property, it is probably useful in actinic prurigo and prurigo nodularis.77 It has potent anti-inflammatory activity, presumably by specific inhibition of tumour necrosis factor-alpha (TNF-alpha).78 It also inhibits IL-12 production.79 IL-12 inhibition leads to inhibition of interferongamma production80 which suppresses immunity mediated by T-helper (Th) cells.81 There is a selective increased production of IL-4 and IL-5 which are B-cell activators.80 Thalidomide decreases neutrophil chemotaxis and phagocytosis82,83 as well as antagonizes actions of inflammatory mediators82 which explains its role in inflammatory diseases.

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Thalidomide also down-modulates selected cell surface adhesion molecules involved in migration of leucocytes.84,85 It down-regulates beta-2 integrin mainly and also beta-1 integrin and alpha-4 integrin on circulating human leucocytes. Thalidomide inhibits angiogenesis86 especially that stimulated by the protein FGF-2 (fibroblast growth factor-2) and IGF-1(insulin-like growth factor type 1). Anti-angiogenesis explains its teratogenic potential as well as its usefulness as an antineoplastic agent. Thalidomide inhibits TNF-alpha production and NFkB, a cytoplasmic protein that enhances HIV transcription. Inhibition of TNF-alpha and NFkB thus leads to inhibition of HIV replication in vivo.73 Pharmacokinetics It is poorly soluble in water72 and is available as an oral formulation only.77 Food does not interfere with its absorption. It is slowly absorbed from gastro-intestinal tract and peak plasma level is attained within 26 hours.87 Due to its lipid solubility, it readily crosses the placental membrane.76 Absolute bio-availability of thalidomide is not yet characterized in humans because of poor water solubility.72 It undergoes non-enzymatic hydrolysis88 in plasma to most of its twelve theoretically possible metabolites89 and does not appear to be metabolized in liver to a large extent.72 Half-life of thalidomide is approximately 5-9 hours following a single dose and is not altered on multiple dosing.72 Its excretion is primarily non-renal, with less than 1 percent of a dose found unchanged in the urine after 24 hours. Indications and Dosage Thalidomide is the drug of choice for ENL82,90 and is FDA-approved for this purpose. Ninety-nine percent of patients of ENL were found to respond to thalidomide in a review of more than 4500 cases.91 Lesions resolve within 24-48 hours91 and other symptoms also respond in a few days. Motor nerve conduction velocity returns to almost normal within 2 weeks.73 The initial regimen is 100 mg four times daily92-94 and after control of the reaction, the dosage is tapered over two weeks to a maintenance level, usually 100 mg daily.95,96 Thalidomide has no action on M.leprae and anti-leprosy chemotherapy should continue throughout the treatment of reactional state of leprosy.97 The drug is not effective in type 1 lepra reaction.97 Thalidomide is quite effective in HIV-associated mucosal ulceration. AIDS wasting associated with tuberculosis and aphthous ulcer respond


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well.98 Thalidomide99 in the dose of 100-300 mg/day controls the symptoms within two weeks and ulcers heal dramatically within 2-4 weeks,99 but relapses commonly occur on discontinuation of therapy. Interestingly, thalidomide treated group showed increased plasma levels of TNFalpha and HIV-RNA.100 Chronic diarrhea of AIDS patients due to microsporidiosis respond to 100 mg daily dose of thalidomide.101 Thalidomide, probably due to its antiangiogenic property, is found to be useful in Kaposi’s sarcoma in a case study.102 Recurrent aphthous stomatitis and Behcet’s disease in immunocompetent patients also respond to thalidomide at a dose of 100-300 mg/day. Ulcers remit within 1-2 weeks but relapse on cessation of therapy.103 In Behcet’s syndrome, oral and genital lesions heal very rapidly, but not the ocular lesions by thalidomide in a dose of 400 mg/day for five days which is then tapered to 200 mg/ day for up to two months.104 Clearly, patients with HIV-associated oral and esophageal ulcer benefit more from thalidomide therapy than immunocompetent patients with aphthous ulcers with or without Behcet’s disease.73 Thalidomide is an effective therapeutic alternative for various cutaneous forms of lupus erythematosus (LE).105-113 Fifty to ninety percent of patients with chronic cutaneous LE (CCLE)105,107 and subacute cutaneous LE (SCLE)105,110 achieve complete or near-complete remission. Both CCLE and SCLE usually respond to 50-200 mg/day of thalidomide within 2-4 weeks and then a maintenance dose of 25-50 mg/day is required for most patients.105,107,108,110 Relapse occurs in 70-75 percent of patients on discontinuing thalidomide, but patients usually respond to a new course of the drug.105 Systemic features of systemic LE (SLE) do not show any response to thalidomide but skin lesions show 90 percent improvement and steroid dosage can be reduced on concomitant thalidomide therapy. Lupus profundus112 showed favourable response to thalidomide. Thalidomide is useful in treating chronic graft vs host disease (CGVHD)114-116 refractory to conventional immunosuppressive/glucocorticoid therapy, when added to the regime, provided the patients can tolerate side-effects. This beneficial effect is more pronounced in children because they tolerate the drug better. However, thalidomide cannot be used for prophylaxis of CGVHD.117 Actinic prurigo118,119 and prurigo nodularis120,121 respond to thalidomide in initial doses of 300-400 mg/day within three months in most instances. Dose can be tapered to 50 mg/day subsequently but symptoms recur if drug is stopped.119 Ninety percent of patients of polymorphous light eruption (PMLE)122 show good to excellent response in an average of two weeks on thalidomide therapy. Thalidomide may be considered

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as a treatment of choice for Langerhans’ cell histiocytosis123-25 because induction of proliferation of Langerhans’ cells can be reversed by thalidomide’s inhibition of TNF-alpha production.126 Anecdotal evidence exists to support a trial of thalidomide in the following conditions: Weber-Christian disease, 127 palmo-plantar pustulosis,128 uremic pruritus,129 post-herpetic neuralgia,130 bullous pemphigoid,131 cicatricial pemphigoid,131 erythema multiforme,132-134 sarcoidosis,135 pyoderma gangrenosum136,137 and Jessner-Kanof disease.138 Contraindications77 Thalidomide is absolutely contraindicated in: • Known sensitivity to thalidomide • Pregnancy • Women of childbearing potential without strict contraception • Men actively engaging in sexual intercourse with women who may become pregnant • Pre-existing peripheral neuropathy. Relative contraindications are: • Significant liver or kidney impairment • Neuritis or other neurological disorder • Congestive cardiac failure • Hypertension • Significant constipation • Hypothyroidism Adverse Effects If thalidomide is taken during pregnancy, it can cause severe birthdefects or death to an unborn baby. The most common defects are phocomelia (deformity with under-development of arms, legs or both) or amelia (absence of limbs). Other defects are aplasia of thumbs, anotia, facial palsy, microphthalmia and ophthalmoplegia.73 Abnormalities of renal, gastrointestinal and urogenital systems also may occur.74,76 Even a single dose of 50 mg, if taken during pregnancy can cause severe birth defects.74,76 Because of this toxicity and in an effort to make the chance of fetal exposure to thalidomide as negligible as possible, thalidomide is approved for marketing only under a special restricted distribution programme approved by FDA. This programme is called the ‘System for thalidomide education and prescribing safety’ (S.T.E.P.S). Under this programme, only prescribers and pharmacists registered with the programme are allowed to prescribe and dispense the product.


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Effective contraception must be used for at least four weeks before initiating thalidomide therapy, during thalidomide therapy, and for four weeks following discontinuation of thalidomide therapy. Two reliable forms of contraception must be used simultaneously. Pregnancy test with a sensitivity of at least 50 miu/ml should be performed within 24 hours prior to beginning therapy in women of child-bearing potential. Once treatment is begun, pregnancy testing should be done weekly during first month, then monthly thereafter. If menstrual cycles are irregular, pregnancy testing should occur every two weeks. Males receiving thalidomide must always use a latex condom during any sexual contact with women of child-bearing potential. Male patients should not be permitted to donate sperms while on thalidomide therapy. Patients should be instructed not to share medication with anyone else. Peripheral neuropathy is a common, potentially severe, side effect of thalidomide that may be irreversible. It usually occurs following chronic use over a period of months, but short-term use may also cause peripheral neuropathy. Patients most commonly present with mild proximal muscle weakness with pain, tingling and numbness in the hands and feet and sensory loss in lower limbs.139 Patients should be regularly counseled and evaluated for signs and symptoms of peripheral neuropathy, monthly for first three months and thereafter every one to six months as indicated. To detect asymptomatic neuropathy, electrophysiologic testing consisting of measurement of sensory nerve action potential (SNAP) amplitudes from at least three nerves as baseline and every six months thereafter, should be considered. A fall of 40 percent or more from baseline should be considered significant.77 Thalidomide should be immediately stopped if signs and symptoms of neuropathy develop. Motor weakness usually improves rapidly after stopping the drug but sensory dysfunction improves slowly, if at all.74 Thalidomide frequently causes drowsiness and sedation. Patients should be asked to avoid situations where drowsiness may be a problem and concomitant medication that may cause sedation should be avoided. Thalidomide may potentiate somnolence caused by alcohol. Orthostatic hypotension and dizziness may occur after thalidomide intake. Therefore, patients should sit upright for a few minutes before standing up from recumbent position. Other less common side effects with potentially severe complications include neutropenia140 and erythroderma.141,142 If absolute neutrophil count is below 750 per cubic mm, thalidomide should not be started. Total and differential count of WBC and platelet count should be measured on initiating thalidomide therapy and monthly thereafter until the dose is stable.

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HIV seropositive patients may show increase in plasma HIV RNA levels after thalidomide therapy, clinical significance of which is not known. Other adverse effects of less consequence include constipation, nausea, increased appetite, xerosis, pruritus, hyperglycemia, bradycardia, decreased libido, brittle finger-nails.74,143 SJS/TEN and seizures have also been reported.72 INFLIXIMAB Infliximab is a chimeric immunoglobulin (IgG1k) monoclonal antibody144 that binds specifically to and inactivates human tumour necrosis factoralpha (TNF-alfa).145 It is composed of human constant and murine variable regions146 and is produced by a recombinant cell line cultured by continuous perfusion.146 Mechanism of Action Infliximab binds to both monomer and trimer forms of soluble TNF-alfa as well as cell-surface transmembrane forms of TNF-alfa.147 It forms stable complexes with them and inhibits binding of TNF-alfa with its receptors.146 TNF-alfa is a key cytokine in innate immune response and in inflamed skin, keratinocytes and inflammatory cells both produce large amounts of TNF-alfa.148 TNF-alfa increases production of pro-inflammatory cytokines such as IL-1, IL-6, IL-8, NF-kappaB.149 It also enhances migration of leucocytes by increasing the permeability of endothelial cells146 and expession of adhesion molecules (e.g. Intercellular adhesion molecule-1, E-selectine, P-selectine) by endothelial cells and leucocytes.149 TNF-alfa promotes apoptosis by binding to TNF-receptor 1.149 Psoriatic lesions are hyperproliferative despite an increase in TNF-alfa. Perhaps NF-kappaB activation seems to inhibit TNF-alfa-induced apoptosis in psoriasis.149 Blockade of this proinflammatory cytokine, TNF-alfa by infliximab may thus be effectively used in treatment of inflammatory conditions e.g. psoriasis, rheumatoid arthritis, Crohn’s disease, etc.148 Pharmacokinetics There is a predictable and linear relationship between the dose given and the peak serum concentration and area under the concentrationtime curve, after a single IV infusion.146 Terminal half-life of infliximab is 8-9.5 days.146


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Indications and Dosage It is FDA-approved for use in combination with methotrexate in moderately to severely active rheumatoid arthritis showing inadequate response to methotrexate.146 It is also approved by FDA for moderate to severely active Crohn’s disease refractory to conventional therapy146,150,151 and also for reduction in number of draining enterocutaneous fistulae in patients with fistulising Crohn’s disease.146 Infliximab IV infusion as a monotherapy152-155 gives rapid, effective and prolonged remission156 in moderate to severe plaque psoriasis without adverse events.144 A single infusion of infliximab at 5-10 mg/ kg was found to clear recalcitrant plaque of psoriasis and erythroderma rapidly and completely for a period of 3-4 months.145 It may be combined with low-dose methotrexate for severe recalcitrant pustular psoriasis157 and psoriatic arthritis.148,158,159 It is speculated that infliximab may actually alter the natural history of skin manifestation of psoriasis.156 TNF-alfa blockade is being studied in treatment of uveitis, graft vs host disease and myelodysplastic syndrome150 to circumvent serious side-effects with cytotoxic agents and immunosuppressants. Other potential indications160,161 seem to be Behcet’s disease, bullous dermatoses, neutrophilic dermatitis, TEN, systemic vasculitis. Contraindications The principal contraindication is known hypersensitivity to any murine proteins or other components of the product. Adverse Effects Acute infusion reaction may occur during the infusion or within 1-2 hours after the infusion and is manifested by fever or chills, pruritus, urticaria or cardio-pulmonary symptoms. Patients who become positive for antibody to infliximab are more likely to develop infusion reaction. After a drug-free interval of 2 years, reactions may occur on readministration, particularly on those who did not have reaction on initial infliximab therapy.146 Dyspnea, urticaria, and headache are most common adverse effects requiring discontinuation of therapy. Serious infections including sepsis have been reported in patients on infliximab. It should not be given to patients with a clinically important active infection and patients should be monitored for signs and symptoms of infection while on infliximab therapy. Cases of histoplasmosis, listeriosis, pneumocystosis and tuberculosis162 have been reported.

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There may be formation of auto-antibodies against infliximab and rarely lupus-like syndrome may develop which requires discontinuation of therapy.146 In patients with pre-existing or recent onset of CNS demyelinating disorder, one should exercise caution in prescribing infliximab.146 It is recommended that live vaccines should not be given concurrently.146 There are insufficient data to determine whether infliximab contributes to development of malignancies. Infliximab has a pregnancy prescribing category B status. Infliximab may increase triglyceride level and decrease HDL-cholesterol level without affecting total cholesterol level.163 Lipid levels should be checked and monitored in patients receiving infliximab therapy, particularly in patients with vascular disease.163 Conclusion Infliximab forms a member of new generation of biologic therapy targeting the activity of T-lymphocytes and cytokines responsible for inflammatory nature of the disease. Other biologic agents of importance include etanercept, efalizumab and alefacept.164 Further studies of optimal dosing, combination with other therapies and long-term benefits and side effects will emerge from future trials.150 BEXAROTENE It is a novel synthetic retinoid analogue (rexinoid) that binds selectively to retinoid x receptors (RXR)165 and is approved by FDA for all stages of cutaneous T-cell lymphoma (CTCL).166 Mechanism of Action Bexarotene is a selective retinoid x receptor (RXR) agonist. It binds and transactivates nuclear RXR which acts as ligand-activated transcription factors.167 Retinoid receptors bind their ligands in form of dimers. Heterodimers can be formed between RXR and triiodothyronin receptors or vitamin D receptors.168 Gene expression is controlled by these ligandactivated transcription factors which lead to modulation of cell growth, differentiation and apoptosis.167 It may exert its antineoplastic effect by regulating tumour suppressor gene such as RAR-B2.169 Pharmacokinetics Bexarotene is well absorbed orally and its bioavailability is increased if taken with fatty meal.170,171 Peak level of the drug is reached after two


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hours of oral intake172 and it is 99 percent bound to plasma proteins.170 However, within 1 month after stopping the drug, it is not detected in serum. It is mainly metabolized in liver by oxidation and chain-shortening. Terminal elimination half-life of bexarotene is 7 to 9 hours.172 It is mainly excreted through hepatobiliary route.172 Indications and Dosage It is FDA approved for selected cases of mycosis fungoides173-176 which is resistant to at least one systemic therapy. Patch and early plaque stage respond the most.170 It can be used as monotherapy or in combination with interferon, PUVA, etc. Bexarotene shows a dose response antitumour activity in CTCL.173 It is recommended that bexarotene should be taken as a single daily oral dose with a meal and initial dose should be 300 mg/sq.m/day which can be increased later according to the response and may be continued indefinitely. It is not necessary to take precautions for short-term exposure with bexarotene treatment.177 Mycosis fungoides pursues an aggressive course when associated with follicular mucinosis. It may undergo large-cell transformation which is associated with poor prognosis and resistance to therapy.178 Bexarotene in combination with local radiation therapy, total-skin electron beam therapy achieved a durable complete remission of CTCL.178 It is found to be quite effective in palliative therapy of lymphomatoid papulosis.179 It is used in all stages of CTCL at a dosage of 300 mg/sq.m/day180 both as a monotherapy and in combination with other agents.181 Bexarotene is effective both for early stage patients with extensive plaques of long duration and for late stage patients with Sézary’s syndrome or large-cell transformation.182,183 Lesional size, duration and scaling of earlier lesions show marked improvement.184 Use of ‘statins’ with bexarotene permit higher dose usage of the latter with high response rate.181 Adverse Effects The common side effects associated with bexarotene therapy include hypertriglyceridemia, hypercholesterolemia, central hypothyroidism, headache and asthenia.167 Bexarotene increases triglyceride and cholesterol levels even in modest doses.167,170 To circumvent the risk of increased TG and pancreatitis, it is recommended that atorvastatin should be co-administered with bexarotene. Gemfibrozil increases bexarotene level which limits their concurrent use.173,185 Instead, fenofibrate may be used.

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Teratogenicity is the most important adverse effect of bexarotene. Adequate contraception should be employed by females at least 1 month before therapy, during therapy and for 1 month after stopping the drug. At least two methods of contraception should be used. Serum or urine pregnancy test should be obtained within one week of expected menstrual cycle and monthly thereafter. Bexarotene should be started on the second or third day of a normal menstrual cycle. Male patients must use condoms during therapy and for one month after stopping the drug.186 High incidence of reversible acute pancreatitis167 (1-3%) has been seen in patients getting bexarotene 300 mg/day. Patients having riskfactors for pancreatitis should avoid bexarotene. Bexarotene has the potential of inducing reversible central hypothyroidism.167 Baseline TFT should be performed before initiating therapy and then regularly monitored. It may cause reversible leucopenia within 4 to 8 weeks after therapy which becomes normal after stopping the drug or reducing the dose. REFERENCES 1. Mitsui A, Suzuki S. Immunosuppressive effect of mycophenolic acid. J Antibiot (Tokyo) 1969; 22:358-63. 2. Allison AC, Eugui EM. Purine metabolism and immunosuppressive effects of mycophenolate mofetil (MMF). Clin Transplant 1996; 10:77–84. 3. Carr SF, Papp E, Wu JC, et al. Characterization of human type 1 and type 2 IMP dehydrogenases. J Biol Chem 1996;268:27286–90. 4. Eugui EM, Mirkovitch A, Allison AC. Lymphocyte-selective anti – proliferative and immunosuppressive effects of mycophenolic acid in mice. Scand J Immunol 1991;33:175. 5. Schiff MH, Goldblum R , Rees MMC. New DMARD. Mycophenolate mofetil (Myco – M) effectively treats rheumatoid arthritis (RA) patients for one year. Arthritis Rheum 1991;34:S89. 6. Hoffman – La Roche Inc. Cellcept (Mycophenolate mofetil) Product Information, 1995. 7. Nousari HC, Grant JA. Immunosuppressive and immunomodulatory drugs. In: Freedberg IM, Eisen AZ, Wolff K eds. Fitzpatrick‘s Dermatology in general medicine. 5th ed. Philadelphia: McGraw Hill,International ed. 1999:2860. 8. European Mycophenolate Mofetil Cooperative Study Group: Placebo-controlled study of mycophenolate mofetil combined with cyclosporine and corticosteroids for prevention of acute rejection. Lancet 1995;345:1321-5. 9. Solinger HW, US Renal transplant Mycophenolate Mofetil Study Group: Mycophenolate mofetil for the prevention of acute rejection in cadaveric renal allograft recipients. Transplantation 1995;60:225-232. 10. Grundmann-Kollmann M, Mooser G, Schraeder P, et al. Treatment of chronic plaque-stage psoriasis and psoriatic arthritis with mycophenolate mofetil. J Am Acad Dermatol 2000; 42: 835-7. 11. Ameen M, Smith HR, Barker JN. Combined mycophenolate mofetil and cyclosporine therapy for severe recalcitrant psoriasis. Clin Exp Dermatol 2001; 26: 480-3.


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155. Oh CJ, Das KM, Gottlieb AB. Treatment with anti-tumour necrosis factor-alpha (TNF-alpha) monoclonal antibody dramatically decreases the clinical activity of psoriasis lesions. J Am Acad Dermatol 2000;42:829-30. 156. Gottlieb AB. Clinical research helps elucidate the role of tumour necrosis factoralpha in the pathogenesis of T1-mediated immune disorders: Use of targeted immunotherapeutics as pathogenic probes. Lupus 2003;12:190-4. 157. Barland C, Kerdel FA. Addition of low-dose methotrexate to infliximab in the treatment of a patient with severe, recalcitrant pustular psoriasis. Arch Dermatol 2003;139:949-50. 158. Wollina U, Konrad H. Treatment of recalcitrant psoriatic arthritis with antitumour necrosis factor-alpha antibody. J Eur Acad Dermatol Venereol 2002;16:127-9. 159. Mease PJ. Cytokine blockers in psoriatic arthritis. Ann Rheum Dis 2001; 60: 37-40. 160. Mahe E, Descamps V. Anti-TNF alpha in dermatology. Ann Dermatol Venereol 2002;129:1374-9. 161. Laduca JR, Gaspari AA. Targeting tumour necrosis factor alpha. New days used to modulate inflammatory diseases. Dermatol Clin 2001;19:617-35. 162. Cauza E, Cauza K, Hanusch-Enserer U, et al. Intravenous anti TNF-alpha antibody therapy leads to elevated triglyceride and reduced HDL-cholesterol levels in patients with rheumatoid and psoriatic arthritis. Wien Klin Wochenschr 2002;114:1004-7. 163. Weinberg JM, Saini R, Tutrone WD. Biologic therapy for psoriasis—the first wave: infliximab, etanercept, efalizumab, and alefacept. J Drugs Dermatol 2002;1:303-10. 164. Maksymowych WP. Novel therapies in the treatment of spondyloarthritis. Expert Investig Drugs 2002;11:937-46. 165. Prints HM, McCormack C, Ryan G, et al. Bexarotene capsules and gel for previously treated patients with cutaneous T-cell lymphoma: Results of the Australian patients treated on phase 2 trials. Australas J Dermatol 2001;42: 91-7. 166. Hurst RE. Bexarotene ligand pharmaceuticals. Curr Opin Investig Drugs 2000;1:514-23. 167. Lowe MN, Plosker GL. Bexarotene. Am J Clin Dermatol 2000;1:245 –50. 168. Zouboulis CC. Retinoids–which dermatological indications will benefit in the near future? Skin Pharmacol Appl Skin Physiol 2001;14:303-15. 169. Camacho LH. Clinical applications of retinoids in Cancer medicine. J Biol Regul Homeost Agents 2003;17:98-114. 170. Bexarotene (Targretin) package insert and product monograph. San Diego, CA.Ligand Pharmaceuticals, 2000. 171. Wiegand UW, Chou RC. Pharmacokinetics of acitretin and etretinate. J Am Acad Dermatol 1998;39;S25–33. 172. Nguyen EH, Wolverton SE. Systemic retinoids. In: Wolverton SE, ed Comprehensive Dermatologic Drug Therapy, Philadelphia, WB Saunders, 2001:269 –310. 173. Rook AH, Junkins-Hopkins JM, McGinnis KS, et al. Cytokines and other biologic agents as immunotherapeutics for cutaneous T-cell lymphoma. Adv Dermatol 2002;18:29-43. 174. Mielke V, Staib G, Sterry W. Systemic treatment for cutaneous lymphomas. Results Cancer Res Recent1995;139:403-8.


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175. Dreno B, Celerier P, Litoux P. Roferon–A in combination with Tigason in cutaneous T-cell lymphomas. Acta Haematol 1993;89:S28–32. 176. French LE, Ramelet AA, Saurat JH. Remission of cutaneous T-cell lymphoma with combined calcitriol and acitretin (letter). Lancet 1994;344:686–7. 177. Smit JV De Jong EM , Van De Kerkhof PC. Effects of oral Bexarotene (Targretin (R) on the minimal erythema dose for broad spectrum UVB light. Skin Pharmacol Appl Skin Physiol. 2003;16:237-41. 178. Apisarnthanarax N, Ha CS, Duvic M. Mycosis fungoides with follicular mucinosis displaying aggressive tumour–stage transformation: Successful treatment using radiation therapy plus oral bexarotene combination therapy. Am J Clin Dermatol 2003;4:429-33. 179. Krathen RA, Ward S, Duvic M. Bexarotene is a new treatment option for lymphomatoid papulosis. Dermatology 2003;206:142-7. 180. Apisarnthanarax N, Talpur R, Duvic M. Treatment of cutaneous T-cell lymphoma: Current status and future directions. Am J Clin Dermatol 2002;3: 193 –215. 181. Talpur R, Ward S, Apisarnthanarax N, et al. Optimizing bexarotene therapy for cutaneous T-cell lymphoma. J Am Acad Dermatol 2002; 47:672-84. 182. Duvic M, Martin AG, Kim Y, et al: Phase 2 and 3 clinical trial of oral bexarotene (Targretin capsules) for the treatment of refractory or persistent early – stage cutaneous T-cell lymphoma. Arch Dermatol. 2001;137:581- 93. 183. Duvic M. Bexarotene and DAB (389) IL–2 (denileukin diftitox, ONTAK) in treatment of cutaneous T-cell lymphomas: Algorithms. Clin Lymphoma. 2000;1Suppl.1:S51–5. 184. Heald P. The treatment of cutaneous T-cell lymphoma with a novel retinoid. Clin Lymphoma 2000;1Suppl.1:S45–9. 185. Vahlquist C, Olsson AG, Lindholm A, et al. Effects of gemfibrozil (Lopid) on hyperlipidaemia in acitretin-treated patients. Results of a double–blind cross– over study. Acta DermVenereol 1995;75:377–380. 186. Chaspoux C, Lehucher–Ceyrac D, Morel P, et al. Acne in the male resistant to isotretinoin and responsibility of androgens: 9 cases, therapeutic implications. Ann Dermatol Venereol 1999;126:17–9.

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12

Susmit Haldar

Newer Drugs in Dermatology: Topical With the turn of the new millennium, a number of new topical therapeutic agents has emerged as promising and effective remedies for treating various skin diseases. Dermatologists are now happy to have a series of new drugs, both topical and systemic, in their armamentarium. A few topical agents—Tacrolimus and pimecrolimus especially in the treatment of atopic dermatitis (AD), Imiquimod as an immune response modifier in warts, Cidofovir in viral skin diseases and Tazarotene as a new topical retinoid especially for psoriasis and acne—deserve mention. These drugs are discussed and reviewed below. TACROLIMUS Topical corticosteroids are till now the pivot in the management of inflammatory skin diseases since 1952.1 In spite of arduous attempts to lessen the side effects of topical corticosteroids without compromising its efficacy, we could hardly achieve this goal.1 Topical tacrolimus is the first of a new class of non-steroidal immunosuppressants which does not cause dermal atrophy, an important advantage over topical corticosteroid.2 Tacrolimus, previously known as FK506, was first discovered in 19842 and its immunosuppresant properties were first described in 1987.1 Tacrolimus is a macrolide produced by a soil fungus Streptomyces tsukubaensis present in the soil of Mount Tsukuba, Japan.3 The new name Tacrolimus is derived from ‘t’ for Tsukuba, its place of discovery; ‘acrol’ for macrolide, its chemical class; and ‘imus’ for its immunosuppressive activity.2,3 Mechanism of Action The mechanism of action of tacrolimus is closely related to that of cyclosporine.2 Calcineurin, a calcium-activated phosphatase is the common target which is blocked by both cyclosporine and tacrolimus.4

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Tacrolimus exerts its biologic effects after binding to macrophilins, a cytosolic protein formerly called FK506-binding proteins (FK–BP).5 This complex of tacrolimus and macrophilin gains the ability to bind to calcineurin and blocks its ability to dephosphorylate cytoplasmic subunit of the nuclear factor of activated T cells (NFATc).2 As the phosphate is not cleaved off the NFATc, its translocation to the nucleus does not take place. Thus, the nuclear subunit of the nuclear factor of activated T cells (NFATn) cannot bind to NFATc in nucleus. Failure of the formation of an essential complex by these two nuclear factors inhibits transcription of numerous cytokines including tumor necrosis factor α (TNF α) and interleukins 2, 3 and 4 (IL-2, IL-3, IL-4) and thus T–cell response.6,7 In a nutshell, tacrolimus inhibits T-cell response by inhibiting calcineurindependent inflammatory cytokine gene transcription. Other than T-lymphocyte, Langerhans’ cells and other inflammatory dendritic cells are also the targets of tacrolimus. The lesional skin of AD, after being treated with tacrolimus, shows downregulation of high-affinity IgE receptor (FcεRI) present on the Langerhans’ cells and inflammatory dendritic epidermal cells.5 The number of inflammatory dendritic epidermal cells also falls below detection level.8 Tacrolimus blocks the function of Langerhans’ cells 100 times more potently than betamethasone valerate when used topically.9 It has also been shown that tacrolimus and cyclosporine suppress the degranulation of mast cells and expression of genes responsible for leukotriene synthesis and multiple cytokines required to activate cellular immunity.2 Tacrolimus may also exert immunomodulatory action by enhancing expression of the gene coding for transforming growth factor B1 (TGFB1), a multifunctional cytokine with potent immunosuppressive activity.10 TGFB1 inhibits IL–2 dependent T and B—cell proliferation and production of TNFα, β and γ. Pharmacology Tacrolimus can penetrate intact human skin better than cyclosporine presumably because of its lower molecular weight (822.05 versus 1202.635).11 It does not accumulate in the skin or any system following repeated applications.12,13 Systemic absorption of tacrolimus appears to be more during active stage of the disease (of AD) and higher in facial lesion than trunk and limbs in an adult.14 Based on blood concentrations, there is no evidence that tacrolimus accumulates systemically on intermittent topical application for up to 1 year.10 Mean or median blood concentrations of tacrolimus were below the limit of quantification in two 12-week randomized vehicle-controlled clinical trials in adults and children respectively.10 One percent of patient using 0.1 percent ointment

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had tacrolimus blood concentration ≥ 5 μg/L while it is 0.5 percent in case of patient using 0.03 percent ointment. No patient in pediatric age has achieved this blood concentration (≥ 5 μg/L). Topical tacrolimus neither shows any alteration of collagen synthesis (even under occlusion) nor produces any skin atrophy in AD as well as normal human volunteers.11 This is a definite advantage over topical corticosteroids in treating inflammatory dermatoses for a long-term basis. Thus, topical tacrolimus has a special role in treating dermatitis of face, neck which are readily vulnerable for atrophy.11 It also takes an upper hand over topical corticosteroid so far as eyelid dermatitis is concerned. Unlike steroids, with their potential of producing glaucoma, tacrolimus appears to be safe with no evidence of increased intraocular tension.2 Topical tacrolimus is almost exclusively metabolized in the liver by the cytochrome P-450 3A4 isoenzyme in contrast to oral tacrolimus which is metabolized in liver and gut.5 Clinical Uses Atopic Dermatitis (AD) Topical tacrolimus has shown significantly greater efficacy in comparison with vehicle in patients with moderate to severe AD both in adult and pediatric age-group.15-21 The severity of AD is contributed by the colonization of superantigen producing Staphylococcus aureus on the lesional skin.22 In fact, persistence of S.aureus on the skin may be responsible for continued T-cell activation, release of pro-inflammatory mediators, corticosteroid resistance and chronic inflammation.23 It has been shown that tacrolimus specifically blocks S.aureus superantigeninduced T-cell proliferation in patients with AD and healthy volunteers compared with dexamethasone.24 Tacrolimus has no direct inhibitory effect on bacteria including S.aureus, thus, decrease in colonization probably reflects improved skin barrier function.22,25 Although topical tacrolimus shows definite superiority in efficacy compared to vehicle, currently there are a few data comparing its efficacy with topical steroids in AD. There are studies where topical tacrolimus is compared with either mid-potent or very weak topical corticosteroids. While comparing with hydrocortisone butyrate (midpotent ), 0.1 percent tacrolimus ointment showed similar efficacy in adults, but not with 0.03 percent.26 Even both hydrocortisone butyrate and 0.1 percent tacrolimus show statistically and clinically better result than 0.03 percent tacrolimus ointment. Similar equivalent efficacy was found between 0.1 percent tacrolimus and betamethasone valerate.27 In children between 2 to


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15 years, both 0.03 percent and 0.1 percent tacrolimus oinment were more effective than 1 percent hydrocortisone acetate.28 Similar findings were shown when 0.1 percent tacrolimus was compared with aclomethasone dipropionate for atopic eczcma of head and neck.27 Other Uses Topical tacrolimus has been found to be ineffective in chronic plaque psoriasis probably because of poor penetration through hyperkeratotic skin.29 However, it is reported to be effective in facial lesions of psoriasis and initial observations in inverse psoriasis appear encouraging.2 Tacrolimus 0.3 percent in carmellose sodium paste is found to be effective in parastomal pyoderma gangrenosum where 4 out of 5 patients were completely cured.30 A few studies have shown the efficacy of topical tacrolimus in mucosal erosive lichen phanus.31-33 Tacrolimus has been found to be as equally effective as mometasone furoate in chronic dyshidrotic eczema of the hands.34 In a series of 18 cases of graft-versushost disease (GVHD), more than 70 percent has rapid alleviation of erythema and pruritus by 0.1 percent tacrolimus ointment although all patients required additional systemic therapy.2 In these patients of GVHD, tacrolimus is not an adequate therapy, but may be a useful agent in rapid controlling of symptoms while slower therapies are initiated. In open trial of chronic actinic dermatitis involving face and neck, 0.1 percent tacrolimus appeared to be effective in facial skin.35 Tacrolimus has been used successfully in ichthyosis linearis circumflexa, recalcitrant leg ulcers associated with rheumatoid arthritis, allergic contact dermatitis and rosacea while no effect in alopecia areata.2 There are a host of other skin diseases like seborrheic dermatitis, dyshidrotic eczema, hand eczema and vitiligo where trial of topical tacrolimus is going on.2 Side Effects Skin burning at the site of application, flu-like symptoms, headache, skin tingling, folliculitis, alcohol intolerance, skin infection, acne, hyperesthesia and cyst are all reported, but among these, burning at the site has been the most frequently observed side effects.2 Interestingly, skin infection incidence is almost similar between vehicle and 0.03 percent tacrolimus oinment, but 0.1 percent tacrolimus shows significantly lower incidence than vehicle (4.7% versus 11%).17 So far as safety is concerned on long-term use of topical tacrolimus, it can be used safely up to 1 year.17-19 Even then, there is a theoretical risk of skin malignancy on long-term use of topical tacrolimus,3 especially an increased risk of photocarcinogenesis which needs to be monitored.22 Although a formal

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guideline for monitoring patients on topical tacrolimus is lacking, blood sugar assay, renal and hepatic function tests and regular blood pressure recordings are recommended.36 Dosage and Administration10 In US, “tacrolimus ointment is indicated for the short-term or intermittent long-term treatment of moderate to severe AD in adults and children aged 2 to 15 years who are unable to use standard therapies because of potential risks, or who are intolerant to or not adequately treated by standard therapies.” It is to be applied twice a day to the affected skin area and clearing of clinical infection at treatment site must be undertaken prior to the treatment with topical tacrolimus. Both 0.03 percent and 0.1 percent ointments are approved for use in adults, but only 0.03 percent for children. The ointment should neither be used in pediatric patients younger than 2 years nor in patients with Netherton’s syndrome and nursing mother. The ointment used with occlusive dressing is also not recommended. Discontinuation of tacrolimus oinment is being suggested in acute infectious mononucleosis or in presence of lymphadenopathy of unknown etiology. Advice is also given to curtail exposure to natural sunlight or UV light during treatment. In Japan, 0.1 percent ointment once or twice a day application for adults with AD is recommended with the amount not more than 5 gm per dose and a gap of 12 hours should be kept between doses. Contraindications in Japan include application on eroded/ulcerated skin, in pregnant and nursing women, in patients with severe renal damage or severe hyperkalemia and also in patients undergoing UV radiation treatment. Treated skin with tacrolimus should be restricted from prolonged sun exposure. PIMECROLIMUS Pimecrolimus, also known as SDZ ASM 981, is one of the semisynthetic derivatives of a parent compound called Ascomycin.3 Ascomycin was originally isolated in early 1960s from the fermentation product of Streptomyces hygroscopicus var. ascomyceticus. 5 Like tacrolimus, pimecrolimus is also a macrolide immunomodulator that produces its clinical effect by inhibition of calcineurin. Mechanism of Action Pimecrolimus, after binding with macrophilin, inhibits calcineurin. As a consequence, the synthesis of inflammatory cytokines is blocked at the level of gene transcription.37 Although this mechanism of action is very much similar to tacrolimus and cyclosporine, pimecrolimus exerts a


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more selective immunomodulatory effect than either of these two drugs.38 It has been shown that pimecrolimus does not inhibit antigen induction in sensitization phase in experimentally induced allergic contact dermatitis in mice, but does inhibit the elicitation phase of immune response on antigenic re-exposure.38 Pimecrolimus selectively suppresses the activation of both type 1 and type 2 helper T cells (Th1 and Th2) and thereby production of cytokines (like IL–2, IFN-γ by Th1 and IL-4, IL-10 by Th2) are downregulated.5,38 This downregulation is of particular importance so far as treatment of AD is concerned. Several of these cytokines have been implicated at the initiation and persistence of AD.38 Apart from the T-lymphocyte as a target, pimecrolimus also inhibits liberation of inflammatory mediators like hexosaminidase, tryptase and histamine from mast cells and also transcription of the late phase cytokine tumor necrosis factor (TNF-α).5,11,39,40 Furthermore, it inhibits, in a dose– dependent manner, the upregulation of co-receptors CD134 and CD137 which are being implicated in the activation and expansion of effector T cells.37 Pharmacology Compared to tacrolimus, pimecrolimus has a higher affinity to the skin and permeates it to a lesser degree.41 Due to this percutaneous resorption, there is a lower risk of systemic exposure. While investigating the magnitude of systemic absorption of topical pimecrolimus 1 percent ointment in patients with moderate to severe AD in both adults and children, a consistently low level of blood concentration of pimecrolimus has been detected regardless of duration of therapy and extent of lesions treated.37 Systemic accumulation is not also observed during the treatment period. Like tacrolimus, pimecrolimus does not produce any skin atrophy or dermal thinning.38,42,43 Immunosuppressive potency, however, appears to be less than cyclosporine and tacrolimus and it does not prevent graft rejection.38 When taken up into circulation, pimecrolimus is metabolized by the liver by the same isoenzyme (cytochrome P-450 3A4) as in case of tacrolimus.37 Clinical Uses Atopic Dermatitis (AD) Although the clinical effects of pimecrolimus closely resemble those of tacrolimus, it differs in therapeutic effectiveness as well as structure-

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related limitations of formulation.5 This explains why the US-approved indication for pimecrolimus is mild to moderate AD than moderate to severe disease.27 While comparing the safety and efficacy of topical pimecrolimus in different concentrations (0.05%, 0.2%, 0.6% and 1%) with vehicle and also with 0.1 percent betamethasone valerate (BMV) cream, pimecrolimus in all concentrations were more effective than vehicle and BMV cream was more effective than pimecrolimus cream.44 One percent cream was found to be the most effective among all pimecrolimus cream. In a shortterm (6 weeks) study among children and adolescents with mild to moderate AD, 1 percent pimecrolimus was significantly more effective than vehicle.38 An interesting finding in the above study is that the application site burning is lower with pimecrolimus than vehicle (10.4% versus 12.5%). This shows a remarkable difference in skin burning between pimecrolimus and tacrolimus which could be an important therapeutic difference.2 Twice daily application of pimecrolimus cream (1%) was significantly more effective than once daily application in adults with mild to moderate AD.37 Pimecrolimus demonstrated a significant therapeutic effect by second day compared to vehicle. Whether the early treatment of AD can prevent disease flare and influence long-term outcome, pimecrolimus has been compared with conventional therapy as a control.45,46 The more effective reduction of the incidence of eczema flare in both infants and children in early stage of these year-long studies is shown by pimecrolimus. No clinically relevant adverse events are detected and pimecrolimus is found to be safe and well tolerated. Other Uses Apart from AD, pimecrolimus under occlusive condition is found to be effective in chronic psoriatic plaques.5 There is a great potential of these nonsteroidal immunomodulators to be effective in different inflammatory skin diseases. Dosage and Administration Pimecrolimus (1%) cream has got approval in the US for short-term and intermittent long-term treatment of mild to moderate AD in nonimmunocompromised patients aged > 2 years who do not respond well to, or may have adverse effects with, conventional treatments.37 This is to be applied twice daily to all affected skin areas as a thin layer and


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rubbed in gently and completely. 37 For short-term treatment, pimecrolimus cream 1 percent has been recommended to apply twice daily to all affected areas until complete disappearance of signs and symptoms take place. A short course of topical corticosteroids may be used to treat flares not adequately controlled by pimecrolimus.47 Dose adjustment is not required in patients with renal or hepatic insufficiency.37 The use of pimecrolimus is not recommended to apply in areas affected by active cutaneous viral infections.47 As a general precaution, patients should curtail UV exposure during treatment with pimecrolimus.47 IMIQUIMOD This novel molecule is the first of a class of compounds designated as an immune response modifier. The majority of the immunomodulatory agents which are now available or in the process of development exert their activity by inhibiting pathways involved in immune activation. Imiquimod differs from them as it activates immune function.48 It is a synthetic, non-nucleoside, heterocyclic (imidazoquinoline) amine.49 Imiquimod enhances both the innate and acquired (adaptive) immune systems.48 Mechanism of Action The exact mechanism of action in humans is unknown. However, it shows indirect antiviral and antitumor effects in animal models through induction of various cytokines, most notably interferon-alpha (IFN-α) and tumor necrosis factor-alpha (TNF-α).49 The various cytokines induced by imiquimod and their putative actions are given in Table 12.1.50 As stated earlier, imiquimod enhances innate immunity by induction of TNF-α, IFN-α, and acquired immune system by stimulation of NK cells, proliferation of B cells and activation and migration of Langerhans’ cells.3 In response to viral infection, IFN-α induces keratinocytes to produce enzymes and other factors to block viral replication. It itself also gets secreted into intercellular spaces where it helps protecting nearby cells from virally infected cells and waits for a specific cell-mediated immune (CMI) response to take over for more efficient viral killing.51 In warts, this specific CMI is difficult to initiate because virus-infected keratinocytes are sitting merrily on the top of a wall of epidermis and no way in touch with the cells of the immune systems patrolling in the dermis below. Imiquimod helps in this context also. It helps to build up a cytotoxic– specific immune response by inducing lymphocytes to produce the potent antiviral agent, IFN-γ.51 Furthermore, IL-12 induced by imiquimod keeps on nurturing generation of cytotoxic T cells.

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Recent Advances in Dermatology Table 12.1: Cytokines induced by Imiquimod50

1. 2. 3. 4. 5. 6.

Cytokines

Designation

Putative function

Interferon α Interferon γ Interleukin 1 Interleukin 5 Interleukin 6 Interleukin 8

IFN-α IFN-γ IL-1 IL-5 IL-6 IL-8

IL-1RA

Antiviral Antiviral Lymphocyte stimulation B-cell growth and activation NK cell activation T lymphocyte, neutrophil attraction B cell activation NK cell activation; IFN-γ production IL–1 inhibition

GM-CSF

Mimics actions of IFN-γ

MIP1 α,β

Macrophage activation

MCP-1

Macrophage attraction

TNF-α

Interferon-like protective effects Stimulates cytokine production Tumor-killing by macrophages

7. Interleukin 10 8. Interleukin 12 9. Interleukin 1 receptor antagonist 10. Granulocyte-macrophage colony-stimulating factor 11. Macrophage inflammatory protein 12. Macrophage chemotactic protein 13. Tumor necrosis factor-α

IL-10 IL-12

NK—Natural Killer. Quoted and adapted from the article by Mark V. Dahl. J Am Acad Dermatol 2002; 47: S205-8.

On oral administration of imiquimod to human and other animals, the serum concentration of an interferon-inducible enzyme (2’-5’)oligoadenylate synthetase is increased.48 This enzyme confers an “antiviral state” and up-regulates NK cell activity in both vivo and vitro.3,49,51 In a recent study on hairless mice, IFN-α level increases about 50 times the baseline in 4 hours when imiquimod 1 percent cream is applied on the skin.52 It results from local transcription as evidenced by increased mRNA level on treated sites. This quick induction of INF-α probably contributes to the protective effect of imiquimod in herpes simplex infection as shown in guinea pigs when it is used within 48 hour of contracting infection.49 Besides stimulation of macrophages and dendritic cells to produce IFN-α, IL-12 and TNF-α by imiquimod, peripheral blood monocytes are also stimulated. It has been shown that the increased production of cytokines by imiquimod is ceased when monocytes are eliminated by cell depletion methods.49 Imiquimod appears to potentiate T helper cell type 1 (Th-1) immune


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response (cell mediated) while simultaneously suppresses T helper cell type 2 (Th-2) immune response (humoral or antibody-mediated immunity).49,51 This knowledge may be employed in treating diseases where imbalances of Th1/Th2 ratio or their cytokine release are having important pathogenic role. AD, as for an example, can have the benefit possible as imiquimod could theoretically help restoring normal immune balance by shifting the immune system back to Th1 side. Finally, it has been shown that imiquimod activates immune cells through toll-like receptors (TLR), especially TLR 7.53 TLRs are a family of receptors for early recognition of different microbial antigens. Ten human TLRs have been identified till now and they respond to lipopolysaccharide of gram-negative bacteria, lipopeptides of gram-positive cell walls as well as bacterial DNA and flagellar antigens.49 Pharmacology Slade et al have reviewed the pharmacokinetics and metabolism of imiquimod.54 The major systemic metabolite is S-26704, a hydroxylation product of imiquimod.48 The highest plasma concentration of S-26704 is approximately 25 times greater than that of imiquimod. The half-life of imiquimod is 14 hours following use through intravenous route. Recovery of less than 1 percent of imiquimod in the urine is noted after a single topical application. These data are from combined animal and human exposure studies.48 Systemic exposure following daily application of imiquimod cream to genital or perianal skin may occur, but is minimal. This is indicated by sporadically present, quantifiably low level in urine.55 Serum does not show quantifiable level of imiquimod or its metabolite. Clinical Uses Anogenital Warts This is the only approved indication for imiquimod by FDA.49 Imiquimod 5 percent cream is approved currently as a patient-applied treatment option for external genital/perianal warts. It is to be applied three times per week for up to 16 weeks.3 The apparent low recurrence rate of warts is perhaps the greatest advantage of imiquimod compared to other therapies.56 This can be well explained by the fact that imiquimod helps to develop a specific immunity against warts even when the application of imiquimod is stopped.51 Clinical experience also supports this. Fifty-six percent of patients who applied 5 percent cream had clearance of genital warts compared to 11

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percent in placebo group.57 Only 6 patients (13%) of imiquimod group had recurrence of at least 1 wart over a 12-week follow up. In another study, the result of complete clearance of warts by 5 percent imiquimod cream is 52 percent compared to 4 percent by vehicle.58 Beutner et al59 also showed that 40 percent of imiquimod treated patients (by 5% cream) had complete clearance compared to 0 percent of the placebo group. The recurrence rate was 19 percent for imiquimod treated patients. Women have shown a better response than men, an interesting finding observed in a few studies.57,60 Clearance rate for men was 40 percent compared to 77 percent in women when 5 percent imiquimod was used three times a week for 16 weeks.57 A similar higher clearance rate in female was also observed in an open-label study in 20 countries across the world.60 Apart from the advantage of lower recurrence rate, other benefits of imiquimod include: 1) superior efficacy than other chemodestructive therapies like podophyllin, trichloroacetic acid and bichloroacetic acid, 2) less tissue damage than other destructive therapies, 3) the ability to self-treat in the privacy of the home, 4) the saving of time, expense and possible embarrassment of multiple visits to the attending doctor and 5) the advantage of immediate attention to the newer warts by the patients themselves rather than having to wait for an office visit.56 In a costeffectiveness study, imiquimod is found to be more effective and less costlier than provider-administered ablative therapies so far as sustained clearance of warts is concerned.61 Imiquimod was successful to clear off all the warts in difficult cases like flat warts on the penile shaft, extensive penile warts, extensive warts on the glans penis, penile and perianal warts where cryotherapy, trichloroacetic acid and podophyllin had failed.62 It has also been reported to be successful in patients in whom conventional therapy failed.63 In a case report extensive condyloma of the inguinal area and thigh (1,770 mm2) which was resistant to cryotherapy, podophyllin, podofilox and CO2 laser cleared with 5 percent imiquimod topically.64 There are disadvantages also. Lack of visualization, particularly in perianal lesions, renders self-treatment by imiquimod difficult, thereby also increasing the risk of local irritation.56 Another disadvantage is the relatively long duration of therapy. A small number of warts may be more efficiently removed by other methods rather than by imiquimod in a relatively shorter time. Although FDA has approved imiquimod use only for patients aged 12 years and older and effective results have been observed in adults, yet successful results are being reported in children and infants suffering


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from external genital warts.65-67 Non-genital Warts Although not approved, imiquimod has been tried in patients with common warts and plantar warts. The important obstacle is heavily keratinized nature of these warts where imiquimod probably cannot penetrate sufficient enough to induce an immune response. Studies have shown that better efficacy and success are obtained when imiquimod application is combined with some other procedure like cryosurgery, occlusion using 40 percent urea gel, or CO2 laser. A case of periungual warts has been treated successfully by using 5 percent imiquimod under occlusion at night following a single session of cryotherapy.68 Complete clearance at 6 weeks has been noted in a patient of plantar wart treated with nightly application of 5 percent imiquimod under occlusion. The combination of imiquimod and CO2 laser was reported to be effective in treatment of verrucae vulgaris in immunocompromised patients.69 Multiple flat warts on face as well as on fingers and dorsum of the hands have also been cleared completely by thrice weekly application of imiquimod.70,71 Other Uses There are reports of efficacy of imiquimod in various other skin disorders like molluscum contagiosum, superficial basal cell carcinoma (BCC), Bowen’s disease, solar keratoses, cervical intraepithelial neoplasia (CIN) and acyclovir unresponsive herpes simplex virus 2 (HSV-2) infection.3 Preliminary studies show 87 to 88 percent success rate in superficial BCC and 76 percent of treatment response in nodular BCC using oncedaily regimen for 6 weeks and 12 weeks respectively.72 A long-term study (3-5 years) is required to endorse these results with excision surgery as comparator. Other conditions where imiquimod has been reported to be successful are alopecia areata, keloid, stucco keratosis.73 Recurrence rate of excised keloids following application of 5 percent imiquimod in post-operative period is found to be lower.74,75 There are also various case reports of patients being treated effectively with imiquimod in porokeratosis of Mibelli, erythroplasia of Queyrat, infantile hemangioma.3 There are also interesting reports where imiquimod alone or in combination with interlesional IL–2 may emerge as a promising topical adjuvant in treating multiple cutaneous metastases of malignant melanoma.76,77 Preliminary report on cutaneous leishmaniasis shows encouraging result (90% cured at a 6-month follow-up) when imiquimod is used along with conventional antimonial therapy.78 This may be a

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significant advance in the treatment of such a vexing disorder. There may be a possibility of reduction of total antimonial doses, duration of therapy and decrease in protozoal resistance to antimonials. Further studies, of course, are required to substantiate these speculations. Side Effects Local skin reactions like erythema, itching, scaling and burning are the most commonly reported adverse effects.3 These are mainly mild to moderate in nature occurring in < 67 percent of patients who have used 5 percent imiquimod cream thrice a week. The incidence of adverse effects increases with increase in frequency of dosing e.g. daily application. Side effects from overdosage, reported rarely, include fever, diarrhoea, fatigue, abdominal pain and muscle pain. 3 A severe application-site reaction like ulceration with accompanying pain and pruritus is observed in one of the patients of BCCs.79 This has happened because the instruction for taking rest periods during increase in application site reaction is not followed. This reinforces the need for proper pretreatment counselling and its strict adherence. The tolerability profile of imiquimod is found to be favourable compared to podophyllotoxin.80 Safety Profile The topical use of imiquimod appears to be safe both in infants and in older children.3 Imiquimod may be used in pregnancy and has been designated as pregnancy category B.56 Imiquimod 5 percent cream neither produces any detectable photosensitizing potential in humans, nor enhances UVR-induced damage to epidermal cells or DNA.81 CIDOFOVIR The antiviral properties of cidofovir is first described by De Clercq et al82 in 1987. Cidofovir, also known as HPMPC (hydroxy–phosphonylmethoxy-propyl cytosine), is emerging as a promising new drug that has pharmacologic activity against a wide range of DNA viruses. It is a nucleotide analog of deoxcytidine monophosphate.83 Recent studies have shown the efficacy of cidofovir in the treatment of recalcitrant and unmanageable cutaneous infections caused by herpes simplex viruses (HSV), pox viruses and human papilloma viruses (HPV).83 Mechanism of Action After being incorporated into the host cell, cidofovir is changed to its active metabolite, cidofovir diphosphate, by two stages of phosphorylation. The diphosphate has the structural similarity to nucleotides


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and acts as a competitive inhibitor and alternate substrate for viral DNA polymerase.83 When it is incorporated in the DNA strand of a growing virus, it acts as a chain terminator and blocks further viral DNA synthesis. The unique difference between cidofovir and acyclovir (ACV) in an otherwise similar mechanism of action lies in the first step of phosphorylation. While ACV depends on viral thymidine kinase (TK) to undergo first stage phosphorylation, cidofovir does not.83 This can well explain how cidofovir remains sensitive to strains of HSV resistant to acyclovir, ganciclovir or foscarnet.84 In addition, cidofovir inhibits viral DNA polymerase more selectively than human DNA polymerase.85 The human DNA polymerase is not capable of excising the incorporated cidofovir diphosphate from viral DNA strand. This fact, in combination with reduction of viral DNA synthesis, may explain the prolonged activity of cidofovir beyond the half-life (17 to 65 hours) of the active metabolite.86 Cidofovir does not demonstrate activity against RNA viruses. Pharmacology There has been report only for the intravenous preparation of cidofovir so far as the pharmacokinetic properties are concerned.87,88 Cidofovir, when administered systemically, shows pharmacokinetic features (i.e. volume of distribution, Cmax) in a dose-independent manner.86 Approximately 90 percent of cidofovir is recovered in the urine within 24 hours after a single intravenous bolus dose.88 Elimination of cidofovir from the systemic circulation depends not only on filtration, but also on active tubular secretion. This has been suggested based on observation of reduced clearance of cidofovir by probenecid.88 Though no human study report is available regarding the bioavailability of topical or intralesional cidofovir, there are several animal studies on topical administration. While investigating the pharmacokinetic properties of cidofovir in African green monkeys through different routes of administration (IV, oral and subcutaneous), the subcutaneous bioavailability of cidofovir was noted to be 9.8 percent to 15.8 percent.87 Investigations on the bioavailability of topical cidofovir in different vehicles on normal and abraded skin in rabbits show marked increase in abraded skin (41%) compared to normal skin (0.2% to 2.1%) in a vehicle containing propylene glycol.89 Systemic exposure to the drug is found to be negligible on those animals treated with topical cidofovir on intact skin. Regarding systemic adverse reaction to topical or intralesional cidofovir, there has been a report of “precardial” complaints, presumably chest pain, in only one patient of severe recurrent laryngeal papillomatosis treated with intralesional cidofovir (2.5 mg/5 ml).90 But no cardiac

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abnormalities were detected in that patient. In a recent report, acute renal failure with features of tubular acidosis was precipitated by topical cidofovir in a patient of bone marrow transplant with chronic renal failure and treatment-resistant condyloma.83 Spontaneous recovery was observed on withdrawal of cidofovir. Cidofovir is embryotoxic both in rats and rabbits at doses that were also toxic to the mother.83,86 Fetal soft tissue and skeletal anomalies have been reported in rabbits treated intravenously at 1.0 mg/kg daily.86 No studies on pregnant women regarding use of cidofovir in any route are available. Thus, the use of cidofovir, even in topical from, should be avoided in infants and pregnant women.83,86 Clinical Uses Cidofovir is approved by FDA for the treatment of cytomegalovirus (CMV) retinitis in patients with AIDS by intravenous administration.83 Topical formulation has been compounded extemporaneously. 86 However, the topical formulation is prohibitively expensive (approximately $50 to $75 per gram of 3% cream).83 The trial reports of topical cidofovir in different clinical conditions have been discussed below. HPV Infections Condyloma accuminata Snoeck et al91 first reported successful treatment with 1 percent cidofovir cream in 3 patients of relapsing anogenital condylomas with AIDS. In one of the patients, no recurrence was observed 1 year later after discontinuation of therapy. The first double-blind, placebo-controlled study on genital HPV infections in immunocompetent patients showed complete response in 47 percent patients in cidofovir group compared to none in placebo.92 Forty-five percent of the patients of placebo group experienced disease progression compared to none in cidofovir group. Similar effective result was also found in HIV-infected patients in a placebo-controlled single blind cross-over study.93 In another trial using cidofovir gel in different strengths in HIV-positive patients with biopsy-proven condyloma, complete and partial responses were observed in 65 percent of patients. Dose-related application-site reaction were seen in 39 percent of patients and no systemic toxicity was noted.94 Verruca vulgaris A report of 2 cases of verruca vulgaris refractory to conventional therapy showed response to treatment with topical cidofovir 3 percent cream.95 The patients were free of lesions for more than 40 weeks and 12 months respectively following treatment. Topical cidofovir has also been reported to be effective in the treatment of verruca in HIV-


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infected individuals. Successful treatment was seen in a case having a large verrucous plaque on right foot where HPV-66 was identified in the lesional skin biopsy sample.96 There was also report of successful treatment of multiple warts in gingival mucosa in a 45-year-old man with AIDS by cidofovir 1 percent cream.83 Bowenoid papulosis Complete resolution has been observed in a histopathologically proved bowenoid papulosis in a homosexual man with AIDS with 3 cycles of 5 days treatment at 15 days interval with 1 percent topical cidofovir. No recurrence was noted for 4 years after treatment.97 Vulvar intraepithelial neoplasia (VIN) Topical cidofovir 1 percent in Beeler base (cetylic alcohol-15 g, white wax-1 g, propylene glycol-10 g, sodium lauryl sulfate-2 g and water-72 g)83 completely eradicated extensive VIN III in a woman with 20 years history of genital warts who refused surgical resection.98 Cidofovir has also shown specific effect on dysplastic epithelium in a study of cervical intraepithelial neoplasia.99 This has been confirmed by histology and PCR for HPV DNA from the post-treatment surgical excision of cervix. Anogenital squamous cell carcinoma in situ HIV-infected individuals are at increased risk for HPV-associated anogenital intrasquamous epithelial neoplasms including squamous cell carcinoma (SCC).83 Anogenital SCC is emerging as a major problem in HIV-infected individuals.100 Topical cidofovir (3%) was reported to be effective in patients of AIDS with anogenital Bowen’s disease (SCC in situ) refractory to cryotherapy and electrotherapy.83 Painful erosions and irritation were common side effects and lesions healed with post-inflammatory hypoor hyperpigmentation. No systemic side effects were noted. Active antiretroviral therapy (HAART) was unlikely to influence this favorable outcome because the patients were already on HAART. The authors conclude that effective treatment with topical cidofovir might represent a definite therapeutic advance in context of multifocal nature of the anogenital SCC in situ where complete surgical excision is difficult. Laryngeal papillomatosis Successful treatment of this condition has been reported by intralesional injection of cidofovir.86 Erythroplasia of queyrat There is a case report of complete clearance of lesion in a patient of this condition caused by HPV16/18 by 1 percent cidofovir applied for consecutive 5 days a week for 2 weeks.101 No recurrence was observed in 22 months of follow-up.

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Molluscum Contagiosum Virus (MCV) Infection MCV infection in immunocompromised patients (e.g. AIDS) produces usually extensive, recalcitrant lesions. The patients suffer from increased morbidity and disfigurement. Thus, recalcitrant MCV represents a therapeutic challenge. Report of 3 cases of HIV-positive adults showed complete clearing of extensive MCV lesions, 2 among them have been treated with intravenous cidofovir for concomitant CMV retinitis.102 The third individual was treated with 3 percent cidofovir in Dermovan83 (a vehicle that contains propylene glycol). Topical cidofovir has also been found effective in clearing MCV lesions in a boy with Wiskott-Aldrich syndrome.103 Recently, Toro et al104 reported efficacy of 3 percent cidofovir in Dermovan in 2 children with AIDS with recalcitrant facial and disseminated MCV lesions. The patients were socially isolated for their facial disfigurement. Their MCV lesions were unresponsive to liquid nitrogen, cantharidin and 0.05 percent tretinoin gel. They had also low CD4 T-cell count, elevated viral loads despite HAART treatment. The major advantage of topical cidofovir, according to the authors, is its nonsurgical method which helps avoiding systemic side effects86 like nephrotoxicity, neutropenia and metabolic acidosis associated with intravenous use. Herpes Simplex Virus (HSV) Infection There are various case reports where cidofovir intravenously and topically are found to be effective in multi-drug resistant HSV infection in immunocompromised patients. Saint-Leger et al105 reported such a patient of AIDS who responded to IV cidofovir for his HSV-II-induced recurrent scrotal ulcerations. The strain of HSV was found to be resistant to acyclovir (ACV-R), valacyclovir and foscarnet. Topical cidofovir 1 percent helped in healing of an ACV-R HSV facial ulcer in a 4-year old boy with AIDS who did not also respond to flurothymidine and foscarnet.106 Snoeck et al107 reported 2 interesting cases of mucocutaneous HSV infection. In the first patient of AIDS with chronic perineal HSV-II ulceration, there were 2 recurrences which responded every time to 3 percent topical cidofovir gel. In the second patient, who was a bone marrow transplant recipient having ACV-R severe oral HSV-1 infection, two courses of topical cidofovir resulted in emergence of an acyclovir– susceptible strain that responded to ACV subsequently. In a doubleblind, placebo-controlled study on AIDS having ACV-R HSV infection, cidofovir topically shows effective result.108 Fifty percent of the patients of cidofovir group demonstrated complete healing or greater than


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50 percent improvement of the infection compared to 0 percent in placebo group. Application site reactions occurred in 25 percent case of cidofovir group. Kaposi’s Sarcoma Cidofovir has been shown to have marked activity against Kaposi’s sarcoma (KS) associated herpes virus (KSHV; HHV-8) in vitro.83 While evaluating the anti-KSHV activity of various antiviral agents in vitro, cidofovir was found to be a potent inhibitor of KSHV than acyclovir, foscarnet and ganciclovir. There is no trial report of use of topical cidofovir in Kaposi’s sarcoma. Smallpox Although officially eradicated from the world in December 1979, smallpox has been identified as a potential weapon in bioterrorism.83 In this regard, the identification of drugs with antiviral activity against the variola virus becomes important. Cidofovir is the most effective antiOrthopoxvirus agent among all the drugs approved by the FDA.83 Future Research An oral form of cidofovir-related drug, hexadecyloxypropyl-cidofovir (HDP-cidofovir), shows promising result in the process of development.109 HDP-cidofovir is 93 percent orally available in mice compared to cidofovir. It is 100 to 1000-fold more active than cidofovir against herpes virus, CMV in vitro and 100 to 200 times more active than cidofovir against pox viruses including smallpox. Conclusion Topical cidofovir 1–3 percent gel or cream has been found to be effective against many DNA viruses. It also shows potential as an antitumor agent by inhibiting angiogenesis, including tumor cell differentiation and apoptosis.101 In HPV infection, its ability to induce apoptosis has been identified in association with accumulation of oncosuppressor protein p53 and pRb and the cyclin-dependent kinase inhibitor p21/ WAF–1.110 Till date, most of the trials of its use are case reports. So, controlled investigations with randomized trials with long-term followup are necessary to verify its usefulness in different already attempted clinical conditions. As stated earlier, the cost of topical cidofovir is very high. We hope that the cost will decrease in future so that we can use more widespread, especially in a country like India.

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TAZAROTENE It is a synthetic retinoid that has a distinct structural difference from the naturally occurring retinoids—all-transretinoic acid (tretinoin) and alltransretinol.111 It is a prodrug of the more water-soluble tazarotenic acid (TA), a receptor-selective acetylenic retinoid.112 TA is the active metabolite of tazarotene. Mechanism of Action TA has a selective binding affinity to nuclear retinoid acid receptors (RAR), but not with nuclear retinoid X receptors (RXR).111 Among the RARs, relatively strong binding is found with RAR-β subtypes, moderate binding with RAR–γ and minimal with RAR-α (RAR-β > RAR-γ > RARα). TA after binding with these RARs, modulates the expression of retinoid responsive genes that regulates cell proliferation, cell differentiation and inflammation.113-116 The abnormal expressions of epidermal growth factor receptor, keratinocyte transglutaminase I (Tgase I) and hyperproliferative keratins K6 and K16 are also down-regulated by tazarotene.117,118 Tazarotene blocks the induction of ornithine decarboxylase activity, as a result of which cell proliferation and hyperplasia are checked.111 It also inhibits cornified as well as cross-linked envelope formation.111 It has been shown that migration inhibitory factor-related protein (MRP-8), a marker of inflammation decreases with tazarotene treatment.116,118 Pharmacology The majority of topical tazarotene remains in the skin.119 The systemic absorption of tazarotene is virtually negligible because of rapid metabolism (less than 20 minutes) to its more hydrophilic metabolite and for limited percutaneous penetration.111,119 Thus, accumulation of the drug in lipophilic tissues of the body is prevented. The percentages of absorption of a dose of topically applied tazarotene within 10 hours in unoccluded psoriatic skin and occluded normal skin are calculated as less than 1 percent and 6 percent respectively.119 Other than TA, tazarotene is metabolized in the skin and plasma to sulfoxides, sulfones and other polar metabolites. The maximal concentration of TA in the blood occurs 9 hours after application of tazarotene. The elimination half-life of tazarotene and its metabolites is found to be approximately 17 to 18 hours.119 The urinary and fecal elimination almost become complete within 2 to 3 days and 7 days respectively.120 This short stay in the body and the limited percutaneous penetration


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result in low plasma levels of tazarotene and TA. It has also been found that TA does not undergo interconversion to any other retinoids which can activate other retinoid receptors.112 All these above facts are important so far as the potential risk for teratogenicity is concerned. Clinical Uses Psoriasis US-FDA has approved tazarotene cream (0.5% and 0.1%) for treatment of plaque psoriasis in 2000.112 Although tazarotene is effective as monotherapy,121,122 it is more commonly used in combination either with phototherapy or topical corticosteroids with view to enhancing efficacy and tolerability.123-126 Tazarotene 0.1 percent gel plus mometasone furoate cream (each used once daily) are found to be more effective than twice daily treatment of either mometasome furoate or calcipotriol ointment.127,128 Apart from increasing the efficacy, combination of both topical tazarotene and corticosteroid has a few more advantages. Skin atrophy from prolonged use of topical corticosteroids can be prevented when tazarotene is combined.123,129 On the other hand, local site irritation (retinoid dermatitis) by tazarotene can also be taken care of by topical corticosteroid. Another additional benefit of combining tazarotene is that there is less chance of rebound flare up of healed psoriatic plaques compared to plaques treated with corticosteroid monotherapy.130 Even combined therapy results in a better maintenance of remission than vehicle.131 Thus, adjunctive use of tazarotene with corticosteroid promotes superior efficacy, faster remission, more prolonged therapeutic benefit after treatment. The duration of remission is also being prolonged.129 The local side effects of both are also symbiotically handled by each other. The stability of both the compounds remains unaffected in the physical presence of each other, although they are being used on either ends of the day in most of the clinical trials.132 Besides the adjunctive use of tazarotene with topical corticosteroids, the enhanced efficacy have been found with combined use of narrowband UVB phototherapy and bath PUVA.3, 133 Acne Vulgaris US-FDA has also approved 0.1 percent tazarotene cream for the treatment of acne vulgaris in October 2001. The efficacy and tolerability of tazarotene 0.1 percent gel has been compared with those of tretinoin 0.025 percent gel and adapalene 0.1 percent gel in acne vulgaris.134 The reduction of

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number of papules, open comedones and pustules are more effectively controlled by tazarotene than tretinoin, but both are equally effective in case of closed comedones. Tazarotene takes only half of the frequency of application compared to adapalene (every other day versus every day) to reduce inflammatory and non-inflammatory lesions effectively. The tolerability of tazarotene gel is comparable clinically with tretinoin and adapalene. There are several other studies where tazarotene 0.1 gel shows better therapeutic efficacy than tretinoin 0.025 percent, tretinoin microsponge 0.1 percent and adapalene.135-137 Combined tazarotene and clindamycin topically have shown significantly greater global improvement than either of these two used as monotherapy.138 Tazarotene plus erythromycin/benzoyl peroxide are found to be more effective than all other regimens in controlling inflammatory acne lesion.138 Keeping the inherent local irritation potential of topical retinoids (also tazarotene) in mind, short contact therapy (30 seconds to 5 minutes) with tazarotene in acne vulgaris has been designed and claimed to be a safe, effective new method of treatment for acne.139 Other Uses Corticosteroid-induced epidermal atrophy can be significantly minimized by tazarotene.140 Reduction of epidermal thickness was found to be only 28 percent in combined use of tazarotene and diflorasone diacetate as compared to 43 percent by steroid alone.123 Tazarotene has also been found to be effective in photo aging.112 The photo damaged facial skin shows positive changes with the treatment of tazarotene cream formulation.141 There are several reports claiming usefulness of topical tazarotene in different dermatological conditions like warty dyskeratoma,142 fingernail psoriasis,143 elastosis perforans serpiginosa,144 Darier’s disease,145,146 confluent and reticulated papillomatosis,147 basal cell carcinoma,148 keratoderma blenorrhagicum149 and juvenile acanthosis nigricans of familial obesity-induced type.150 Safety and Side Effects The FDA has categorized tazarotene as a category X drug which means “it may or can cause fetal harm when administered to a pregnant woman and is contraindicated in women who are or may become pregnant.”119 Contraceptive counseling should be given to a woman of childbearing potential if topical tazarotene is planned for treatment.112 Although absorption is minimal and plasma level of tazarotene and TA are found to be 100 fold less than that of oral isotretinoin,119 it should not be used by pregnant woman.112


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The side effects of topical tazarotene are mainly localized to skin. Erythema, burning or stinging, pruritus in psoriatic patients and dryness, desquamation, erythema and burning in acne patients are reported.119 These are usually mild to moderate in nature and dose related. Clinically significant changes in hematology, blood chemistry, bone radiography and urinalysis have not been found.119 Contact sensitization, phototoxic and photoallergic reactions, mutagenicity have not also been found with topical use of tazarotene. Koebnerization, however, has been seen in cases of psoriasis.111 It is better to avoid simultaneous use of irritating topical products such as abrasive or medicated soaps, products containing high concentration of alcohol, astringents, lime or spices.111 To minimize local irritation, treatment can be started with lower strength, e.g. 0.05 percent cream and then escalated according to tolerance.112 To protect the surrounding skin with vaseline and to apply tazarotene to the affected skin only at night has also been advocated.151 Drug Interaction Additional dryness can occur if tazarotene topically is used with other cutaneous medications or cosmetics having strong drying effect.112 REFERENCES 1. Allen BR. Tacrolimus ointment: Its place in the therapy of atopic dermatitis. J Allergy Clin Immunol 2002;109(3):401-3. 2. Nghiem P, Pearson G, Langley RG. Tacrolimus and pimecrolimus: From clever prokaryotes to inhibiting calcineurin and treating atopic dermatitis. J Am Acad Dermatol 2002;46:228–41. 3. Thappa DM. Recent advances in topical therapy in dermatology. Indian J Dermatol 2003;48:1-11. 4. Lui J, Farmer JD Jr, Lane WS, et al. Calcineurin is a common target of cyclophilin–cyclosporine A and FKBP–FK506 complexes. Cell 1991;66:807-15. 5. Bornhövd E, Burgdorf WHC, Wollenberg A. Macrolactam immunomodulators for topical treatment of inflammatory skin diseases. J Am Acad Dermatol 2001;45:736-43. 6. Rao A. NF–ATp: A transcription factor required for the co-ordinate induction of several cytokine genes. Immunol Today 1994;15:274–81. 7. Schreiber SL, Crabtree GR. The mechanism of action of cyclosporine A and FK506. Immunol Today 1992;13:136–42. 8. Wollenberg A, Sharma S, Von Bubnoff D, et al. Topical Tacrolimus (FK506) leads to profound phenotypic and functional alterations of epidermal antigen– presenting dendritic cells in atopic dermatitis. J Allergy Clin Immunol 2001;107: 519-25. 9. Panhans–Gross A, Novak N, Kraft S, et al. Human epidermal Langerhans’ cells are targets for the immunosuppressive macrolide tacrolimus (FK-506). J Allergy Clin Immunol 2001;107:345–52.

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10. Cheer SM, Plosker G. Tacrolimus Oinment. A review of its Therapeutic Potential as a Topical Therapy in Atopic Dermatitis. Am J Clin Dermatol 2001; 2(6):389 – 406. 11. Lin AN. Topical Immunotherapy. In: Wolverton SE, ed, Comprehensive Dermatologic Drug Therapy. Philadelphia, Pennsylvania: W.B.Saunders, 2001: 607–29. 12. Smith CM. New approaches to topical therapy. Clin Exp Dermatol 2000; 25:567– 74. 13. Cather JC, Abramovits W, Menter A. Cyclosporine and Tacrolimus in Dermatology. Dermatol Clin 2001;19:119-37. 14. Alaiti S, Kang S, Fiedler VC, et al. Tacrolimus (FK506) ointment for atopic dermatitis: A phase I study in adults and children. J Am Acad Dermatol 1998; 38:69–76. 15. Hanifin JM, Ling MR, Langley R, et al. Tacrolimus ointment for treatment of atopic dermatitis in adult patients: Part I, Efficacy. J Am Acad Dermatol 2001; 44:S28–S38. 16. Paller A, Eichenfield LF, Leung DYM, et al. A 12-week study of tacrolimus ointment for the treatment of atopic dermatitis in pediatric patients. J Am Acad Dermatol 2001; 44:S47–S57. 17. Soter NA, Fleischer AB Jr, Webster GF, et al. Tacrolimus ointment for the treatment of atopic dermatitis in adult patients: Part II, Safety. J Am Acad Dermatol 2001;44:S39–S46. 18. Kang S, Lucky AW, Pariser D, et al. Long term safety and efficacy of tacrolimus ointment for the treatment of atopic dermatitis in children. J Am Acad Dermatol 2001;44:S58–S64. 19. Reitamo S, Wollenberg A, Schopf E, et al. Safety and efficacy of 1 year of tacrolimus ointment monotherapy in adults with atopic dermatitis. Arch Dermatol 2000;136:999-1006. 20. Ruzicka T, Bieber T, Schopf E, et al. A short term trial of tacrolimus ointment for atopic deramatitis. N Engl J Med 1997;337:816–21. 21. Boguniewicz M, Fiedler VC, Raimer S, et al. A randomized, vehicle–controlled trial of tacrolimus ointment for treatment of atopic dermatitis in children. Pediatric Tacrolimus Study Group. J Allergy Clin Immunol 1998;102:637– 44. 22. Reitamo S, Remitz A, Kyllonen H, et al. Topical noncorticosteroid immunomodulation in the treatment of atopic dermatitis. Am J Clin Dermatol 2002;3(6):381–8. 23. Meagher L, Wines NY, Cooper AJ. Atopic dermatitis: Review of immunopathogenesis and advances in immunosuppressive therapy. Australas J Dermatol 2002;45:247–54. 24. Hauk PJ, Leung D. Tacrolimus (FK506): New treatment approach in superantigen–associated diseases like atopic dermatitis? J Allergy Clin Immunol 2001;107:391-2. 25. Remitz A, Kyllonen H, Granlund H, et al. Tacrolimus ointment reduces staphylococcal colonization of atopic dermatitis lesions [letter]. J Allergy Clin Immunol 2001;107:196-7. 26. Reitamo S, Rustin M, Ruzicka T, et al. Efficacy and safety of tacrolimus ointment compared with that of hydrocortisone butyrate ointment in adult patients with atopic dermatitis. J Allergy Clin Immunol 2002;109:547–55. 27. Williams H, Thomas K, Smethurst D, et al. Atopic Eczema. In: Williams H, Bigby M, Diepgen T, et al, eds. Evidence–based Dermatology. London: BMJ Publishing Group, 2003:144–218.


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28. Reitamo S, Van Leent EJM, Ho V, et al. Efficacy and safety of tacrolimus ointment compared with hydrocortisone acetate ointment in children with atopic dermatitis. J Allergy Clin Immunol 2002;109:539–46. 29. Zonneveld IM, Rubins A, Jablonska S, et al. Topical tacrolimus is not effective in chronic plaque psoriasis: A pilot study. Arch Dermatol 1998;134:1101-2. 30. Lyon CC, Smith AJ, Beck MK, et al. Parastomal pyoderma gangrenosum: Clinical features and management. J Am Acad Dermatol 2000;42:992-1002. 31. Vente C, Reich K, Rupprecht R, et al. Erosive mucosal lichen planus: Response to topical treatment with tacrolimus. Br J Dermatol 1999;140:338-42. 32. Kaliakatason P, Hodgson TA, Lewsey D, et al. Management of recalcitrant ulcerative oral lichen planus with topical tacrolimus. J Am Acad Dermatol 2002;46:35–41. 33. Rozycki TW, Rogers RS, Pittelkow MR, et al. Topical tacrolimus in the treatment of symptomatic oral lichen planus: A series of 13 patients. J Am Acad Dermatol 2002; 46:27–34. 34. Schnopp C, Remling R, Mohrenschlager M, et al. Topical tacrolimus (FK-506) and mometasone furoate in the treatment of dyshidrotic plamer eczema: A randomized observer blinded trial. J Am Acad Dermatol 2002; 46:73–7. 35. Uetsu N, Okamoto H, Fujii K, et al. Treatment of chronic actinic dermatitis with tacrolimus ointment. J Am Acad Dermatol 2002; 47:881–4. 36. Bhat R, Rammam M. Tacrolimus. In: Hot topics in Dermato-venereology, 30th National Conference of IADVL, 24th–27th January 2002, Cochin, Kerala: 51– 65. 37. Wellington K, Jarvis B. Spot light on topical pimecrolimus in atopic dermatitis. Am J Clin Dermatol 2002;3(6):435–8. 38. Eichenfield LF, Lucky AW, Boguniewicz M, et al. Safety and efficacy of pimecrolimus (ASM 981) cream 1% in the treatment of mild and moderate atopic dermatitis in children and adolescents. J Am Acad Dermatol 2002;46: 495-504. 39. Grassberger M, Baumruker T, Enz A, et al. A novel anti-inflammatory drug, SDZ ASM 981, for the treatment of skin diseases: In vitro pharmacology. Br J Dermatol 1999;141:264–73. 40. Hultsch T, Muller KD, Meingassner JG, et al. Ascomycin macrolatum derivative SDZ ASM 981 inhibits the release of granule–associated mediators and of newly synthesized cytokines in RBL 2H3 mast cells in an immunophilin– dependent manner. Arch Dermatol Res 1998;290:501–7. 41. T Luger. Pemicrolimus: Skin–selective, anti-inflammatory profile supports clinical efficacy and safety. Satellite Symposium (SA0705) in 20th World Congress of Dermatology 2002 [abstract]. Ann Dermatol Venereol 2002;129:IS81–IS141. 42. Meingassner JG, Grassberger M, Fahrngruber H, et al. A novel anti-inflammatory drug, SDZ ASM 981, for the topical and oral treatment of skin disease: In vivo pharmacology. Br J Dermatol 1997;137:568-76. 43. Queille – Roussel C, Paul C, Duteil L, et al. The new topical ascomycin derivative SDZ ASM 981 does not induce skin atrophy when applied to normal skin for 4 weeks: A randomized, double–blind controlled study. Br J Dermatol 2001;144:507-13. 44. Luger T, VanLeent EJM, Graeber M, et al. SDZ ASM 981: An emerging safe and effective treatment for atopic dermatitis. Br J Dermatol 2001;144:788-94. 45. Kapp A, Papp K, Bingham A, et al. Long-term management of atopic dermatitis in infants with topical pimecrolimus, a nonsteroid anti-inflammatory drug. J

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treated with cidofovir. Arch Dermatol 1997;133:987–90. 103. Davies EG, Thrasher A, Lacey K, et al. Topical cidofovir for severe molluscum contagiosum. Lancet 1999;12;353:2042. 104. Toro JR, Wood LV, Turner ML. Topical cidofovir: A novel treatment of recalcitrant molluscum contagiosum in HIV infected children. Arch Dermatol 2000;136:983-5. 105. Saint–Leger E, Fillet AM, Malvy D, et al. Efficacy of cidofovir in a HIV infected patients with acyclovir and foscarnet resistant herpes simplex virus infection. Ann Dermatol Venereol 2001;128:747–9. 106. Lateef F, Donn PC, Kaufmann M, et al. Treatment of acyclovir-resistant foscarnet unresponsive HSV infection with topical cidofovir in a child with AIDS. Arch Dermatol 1998;134:1169–70. 107. Snoeck R, Andrei G, Gerard M, et al. Successful treatment of progressive mucocutaneous infection due to acyclovir–and foscarnet–resistant herpes simplex virus with (S)–I–(3–hydroxy–2–phosphonylmethoxypropyl) cytosine (HPMPC). Clin Infect Dis1994;8:570–8. 108. Lalezari J, Schacker T, Feinberg J, et al. A randomized double-blind, placebo– controlled trial of cidofovir gel for the treatment of acyclovir–unresponsive mucocutaneous herpes simplex virus infection in patients with AIDS. J Infect Dis 1997;176:892–8. 109. Bradbary J. Orally available cidofovir derivative active against smallpox. Lancet 2002;359:1041. 110. Andrei G, Snoeck R, Schols D, et al. Induction of apoptosis by cidofovir in human papillomavirus (HPV)–positive cells. Oncology Research, 2001;12:397– 408. 111. Prystowsky JH. Topical Retinoids. In: Wolverton SE, ed, Comprehensive Dermatologic Drug Therapy. Philadelphia, Pennsylvania: W.B. Saunders, 2001;578–594. 112. Guenther LC. Topical tazarotene therapy for psoriasis, acne vulgaris and photoaging. Skin Therapy Lett 2002;7:1-4. 113. Foster RH, Brogden RN, Benfield P. Tazarotene. Drugs 1998;55:705–711. 114. Duvic M, Nagpal S, Asano AT, et al. Molecular mechanisms of tazarotene action in psoriasis. J Am Acad Dermatol 1997;37:S18–S24. 115. Chandraratna RAS. Tazarotene: The first receptor–selective topical retinoid for the treatment of psoriasis. J Am Acad Dermatol 1997;37:S12–S17. 116. Chandraratna RAS. Tazarotene-first of a new generation of receptor-selective retinoids. Br J Dermatol 1996;135(S49):18–25. 117. Esgleyes–Ribot T, Chandraratna RA, Lew-Kaya DA, et al. Response of psoriasis to a new topical retinoid, AGN 190168. J Am Acad Dermatol 1994;30:581–590. 118. Duvic M, Asano AT, Hager C, et al. The pathogenesis of psoriasis and the mechanism of action of Tazarotene. J Am Acad Dermatol 1998;39:S129-S133. 119. Menter A. Pharmacokinetics and safety of tazarotene. J Am Acad Dermatol 2000;43:S31–S35. 120. Marks R. Pharmacokinetics and safety review of tazarotene. J Am Acad Dermatol 1998;39(Suppl):S134–S138. 121. Weinstein GD, Krueger GG, Lowe NJ, et al. Tazarotene gel, a new retinoid for topical therapy of psoriasis: Vehicle–controlled study of safety, efficacy and duration of therapeutic effect. J Am Acad Dermatol 1997; 37(1):85–92. 122. Weinstein GD, Koo JYM, Krueger GG, et al. Tazarotene cream in the treatment of psoriasis: two multicenter, double–blind, randomized, vehicle–controlled studies of the safety and efficacy of tazarotene creams 0.05% and 0.1% applied

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tazarotene gel 0.1% on steroid induced epidermal atrophy. Int J Dermatol 2001;40:468–71. Kang S, Leyden JJ, Lowe NJ, et al. Tazarotene cream for the treatment of facial photodamage: A multicenter, investigator-masked, randomized, vehiclecontrolled, parallel comparison of 0.01%, 0.025%, 0.05% and 0.1% tazarotene creams with 0.05% tretinoin emollient cream applied once daily for 24 weeks. Arch Dermatol 2001;137(12):1597-1604. Abramovits W, Abdelmalek N. Treatment of warty dyskeratoma with tazarotenic acid. J Am Acad Dermatol 2002;46(2):S4. Scher RK, Stiller M, Zhu YI. Tazarotene 0.1% gel in the treatment of fingernail psoriasis: A double-blind, randomized, vehicle–controlled study. Cutis 2001;68(5):355–8. Outland JD, Brown TS, Callen JP. Tazarotene is an effective therapy for elastosis perforans serpiginosa. Arch Dermatol 2002;138(2):169–71. Micali G, Nasca MR. Tazarotene gel in childhood Darier’s disease. Pediatr Dermatol 1999;16:243–4. Oster– Schmidt C. The treatment of Darier’s disease with topical tazarotene. Br J Dermatol 1999;141:603–4. Bowman PH, Davis LS. Confluent and reticulated papillomatosis: Response to tazarotene. J Am Acad Dermatol 2003;48:S80–S81. Peris K, Fargnoli MC, Chimenti S. Preliminary observations on the use of topical tazarotene to treat basal–cell carcinoma. N Eng J Med 1999;341:1767– 8. Lewis A, Nigro M, Rosen T. Treatment of keratoderma blennorrhagicam with tazarotene gel 0.1%. J Am Acad Dermatol 2000;43:400-2. Weisshaar E, Bonnekoh B, Franke I, et al. Successful symptomatic tazarotene treatment of juvenile acanthosis nigricans of the familial obesity-associated type in insulin resistance. Hautarzt 2001;52(6):499-503. Arndt KA, Bowers KE. Manual of Dermatologic Therapeutics; 6th edn. Philadelphia: Lippincott Williams and Wilkins 2002:176.

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13

Kaushik Nandy

Wound Dressings: Newer Concepts INTRODUCTION: THE MOIST ENVIRONMENT IN WOUND HEALING Central to the efforts at introducing newer dressing materials has been the establishment of the idea that a moist environment enhances wound healing. This has been demonstrated well as by experimental studies as in the clinical setting.1-5 Being able to choose the right dressing material from among the myriad options available is essential for successful and appropriate management of wounds, in the quickest possible time, with the minimum possible effort and expense and at maximum comfort and convenience to the patient. The right choice of dressing materials is, of course, of real relevance in the context of wounds that are going to heal by secondary intention as also of wounds being prepared for surgical intervention. Maintenance of a moist environment affords many benefits to such wounds.6 It prevents desiccation of the wound which would otherwise lead to cell death and eschar formation. It increases breakdown of dead tissue (slough) and the pericapillary fibrin cuff. It enhances the process of angiogenesis essential to wound healing and also helps growth factors to interact with their target cells. It has been experimentally demonstrated that maintenance of a moist environment shortened the inflammatory and proliferative phase of dermal repair in wounds7 which would be expected to shorten the overall period of healing. A moist environment also helps make the wound more comfortable for the patient. It is worth stating here that for practical purposes, use of special dressings as a means of debriding wounds is recommended only when a comparatively small amount of dead tissue is present. Otherwise a surgical debridement is indicated. The idea of the benefits of maintaining a moist environment for enhancement of wound healing has been taken one step further. Experiments have shown that maintenance of a wet (liquid) as opposed to a moist environment produces quite different results.8 The wet wounds (saline) healed the fastest at least partly because they showed accelerated

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wound contraction. However, granulation tissue formation was fastest in the moist wounds. Though wet wounds healed the fastest, moist wounds healed faster than dry wounds. This incidentally illustrates that, at present, though it can be safely stated that a moist environment enhances wound healing, there are limited guidelines as to the exact level of moisture that is appropriate. Steps have been taken towards addressing this issue of how much moisture is appropriate for optimum wound healing.9 There is no clear answer at present. However, it has been shown that a low dressing water vapour transmission rate (WVTR) is a dependable measure of a particular dressing’s ability to retain moisture and provide an environment that supports healing. There are considerable variations between different available dressings of the same broad category in their WVTR. In general probably it is safe to say that the greater the amount of moisture a dressing is able to retain, the more will be its ability to support early wound healing. There is also reason to believe that the greater the extent of moisture retention, lesser the incidence of clinical infection, greater the patient comfort and greater the reduction in scarring. Maceration, which is likely to occur more commonly with the more moisture retaining dressings is not always associated with adverse events. In general it can be stated that occlusive dressings of various types, which help retain moisture and help maintain a moist environment suitable for wound healing, are currently recommended for use.3 PROPERTIES OF AN IDEAL DRESSING MATERIAL It is always worth enumerating the ideal situation in any context in so far as it helps focus attention towards a (unattainable?) goal which one tries to achieve and in the process hopefully produces the best possible outcome at that point of time. Thus, an ideal dressing material10 keeps the wound: • moist without maceration • free of excessive slough, particles or fibres • free of clinical infection • at an optimum temperature and pH value for proper healing • undisturbed by the need for frequent dressing changes It also must be itself non-toxic, comfortable to the patient and reasonable in terms of cost. WHAT TO LOOK FOR WHEN MAKING A CHOICE? Wounds go through various stages during the process of healing. The stage, in which the wound exists, is important in deciding the type of dressing material to use. For clinical purposes these are as follows:

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• removal of dead tissue • vascularisation and granulation • epithelialisation The type of wound will also determine the type of dressings that is most appropriate. In a wound with dry necrotic tissue, which very often is black, rehydration is a high priority. In a more moist wound with necrotic tissue, which tend to be gray or yellow, depending on the amount of exudates, moisture retention and rehydration or fluid absorption is a priority. Dealing with foul odour can also be important. For a wound which has started granulating, generally fluid absorption, protection of the wound during dressing change, i.e. low adherence, possibly odour removal, etc. are priorities. When the wound is epithelialising, again moisture retention and specially low adherence are of importance. BROAD VARIETIES OF DRESSING MATERIALS There is a vast (and one dare say confusing) array of dressing materials available nowadays. It is of help to classify them under broad types so that their properties can be enumerated thus helping to define a clearer role for the various types in wound healing.10 However, even within broad categories there is sometimes a considerable variation in the exact properties of different brands of dressing materials that has to be accounted for.11,12 Nevertheless, discussing them under different classes helps clarify their usefulness. Before discussing the varieties of dressing materials available, it is worth emphasising that irritant chemicals, that are suitable for cleansing skin, are best avoided on raw areas. Physiological saline is quite adequate for the purpose. (One should never put anything in the wound that cannot be comfortably tolerated in the conjunctival sac.2) Alginate Alginate dressings are manufactured from seaweed. They are biodegradable which gives them the advantage that any alginate fibres which may be trapped in the wound can be removed by the body (biodegraded). It is also highly absorbent because it forms a very strongly hydrophilic gel on contact with fluids. The exact gelling properties vary between manufacturers, some partially gel and form a sheet which can be lifted of, others form an amorphous gel which can be washed off with physiological saline. Because of their highly absorbent property, they


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are suitable for moderate to heavily exuding wounds. They are not suitable for dry wounds or eschars. Because they are removed easily, change of dressings is very comfortable for the patient and there is no damage to the delicate forming granulation tissue. They require a secondary covering. They have no reported adverse effects except for one published report of a florid foreign body giant cell reaction to alginate used in a tooth socket.13 Alginate is used with the purpose of achieving better hemostasis but this has not been substantiated by a controlled trial.14 Comparatively shallow wounds such as leg ulcers can be covered with alginate sheets whereas deeper cavity wounds such as pressure sores15 and abscess cavities16 can be effectively filled with alginate ropes. Alginate has been effectively used in footcare.17 Hydrocolloid Dressings Hydrocolloid dressings contain gel-forming agents such as sodium carboxy-methylcellulose and gelatin together with elastomers and adhesives which are applied to a carrier — usually a polyurethane foam or film. The result is an occlusive, conformable, absorbent, self-adhesive, waterproof wafer. They are non-toxic and non-particulate. On contact with wound exudates, the hydrocolloid absorbs moisture and forms a gel. Though initially waterproof, with the progress of the gelling process, these dressings become progressively permeable. This increases their ability to deal with exudates. Because of their comparatively limited fluid handling capacity, they are suitable for use in mild to moderately exuding wounds only, including leg ulcers and pressure sores. Hydrocolloid powder and pastes are used for filling cavities. Hydrocolloid combination dressings with alginate are available to improve their fluid handling ability. Hydrocolloid dressings provide superior occlusion and can be used in dry wounds to soften them by effective moisture retention and have been used for the prevention of spread of MRSA18 by acting as a physical barrier. A clinically very useful property of hydrocolloid dressings is their ability to adhere to wet surfaces. Once applied to a wound, the peripheral area of the dressings, which needs to overlap onto normal skin, remains firmly adherent whereas the central area in actual contact with the exuding wound forms the gel and loses its adhesive property. Thus, at the time of removal the wound surface is not damaged though the peripheral adhering area has to be removed with caution from delicate skin. Change of dressings is usually required every three to five days which makes them more comfortable and reduces need for nursing attention.

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Limitations of hydrocolloid dressings include, as already mentioned, a comparatively limited moisture handling capacity and thus they are unsuitable for use in heavily exuding wounds. Because of their occlusive nature, they should not be used on clinically infected wounds. Wounds can sometimes hypergranulate under hydrocolloid dressings. As earlier mentioned they need to be removed with caution from fragile skin. Though rarely, they have been associated with allergic contact dermatitis.19 Hydrocolloid dressings have been used as an effective dressing in maggot therapy.20 The role of hydrocolloid dressings in diabetic foot ulcers is less clear and they are best used with caution21,22 in this setting. Bacteriological studies have shown that after prolonged dressings also, the bacterial flora tends to remain unchanged under hydrocolloid dressings and there is no correlation with clinical infection.23,24 Hydrogel Dressings These consist predominantly of a polymer or copolymer and up to 95 percent water. Thus, they are very suitable for donating water to dehydrated tissues. They are able to absorb only limited quantities of moisture and are unsuitable for use on exuding wounds where they will cause maceration. They are non-particulate, non-toxic and non-adherent. They are available in two forms, an amorphous cohesive gel which requires a secondary dressing and hydrogel sheets which have a fixed structure. The amorphous form is very suitable for rehydrating dry sloughy wounds and help in autolytic debridement. They can stay on up to three days and can be easily washed off by irrigation with physiological saline. Sheet hydrogels can be used in minor wounds with minimum exudates where they have a marked cooling and soothing effect. They are also suitable for pressure sore prevention because they can absorb significant amounts of friction and shear. They are unsuitable for infected wounds because they have an occlusive effect. Many amorphous hydrogels contain propylene glycol which can cause allergic reactions. Foam Dressings They are made of polyurethane foam. The properties of these products vary from product to product. Some of them are suitable for use in lightly exuding wounds whereas others are suitable for use in heavily exuding wounds. They may be used as secondary dressings. In a situation where there is hypergranulation, it may be beneficial to change from an


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occlusive (say hydrocolloid) dressing to a more permeable dressing such as foam. Vapour Permeable Films and Membranes They permit passage of oxygen and water vapour but not bacteria or water. They may be of use in very lightly exuding wounds to provide a moist environment but very often their effectiveness is lost because the rate of evaporation cannot keep up with the rate of exudation. Thus, they are unsuitable for leg ulcers. Their best use is probably as secondary dressings over alginates and hydrocolloid gels. They are sometimes used for protection of delicate skin from minor damage. Low Adherence Dressings and Wound Contact Materials These are used as contact material for the wound and used under an absorbent layer. Most commonly used are tulle dressings. These are made up of cotton or viscose material impregnated with white or yellow soft paraffin to make them nonadherent, which in reality is partly successful. The paraffin also reduces absorbency of the dressing. In spite of these drawbacks, these are commonly available and are comparatively inexpensive and when properly used do have a clear role in the Indian context. Medicated tulle dressings have come in for criticism. Framycetin gauze dressing is associated with a high incidence of hypersensitivity and absorption leading to toxicity is possible when large amounts are used. The antibacterial efficacy of chlorhexidine gauze dressings has not been established. Odour Absorbent Dressings Dressings are available which incorporate activated charcoal and are useful in reducing foul odour from wounds. Surgical Absorbents They are useful as secondary absorbent material. Direct contact with the wounds must be avoided as they dehydrate the wound, shed fibres into it and tend to adhere, making it painful to remove them and causing injury to the healing surface. It bears mentioning at this point that in many situations other measures are very important towards achieving appropriate wound management. For instance, in venous leg ulcers graduated compression

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dressings are an important part of the managenent. In pressure ulcers, however, good the quality of dressings, they will be of no use if other measures such as relieving of pressure, maintenance of nutrition etc. are not meticulously attended to. As always, the patient must be treated as a whole. CONCLUSION It bears repeating again and again that it can now be regarded as accepted that maintenance of a moist environment provides many advantages in wound healing. Of course, the other requirements of a good dressing material are also of importance. To this end many dressing materials have been made available in the market. It is noteworthy that sometimes use of a comparatively expensive material that expedites wound healing and requires infrequent change may in the end be a better option. Thus, choosing wisely can go a very long way towards appropriate wound management within the financial constraints we work in India. REFERENCES 1. Bishop SM, Walker M, Rogers AA, et al. Importance of moisture balance at wound-dressing interface. J Wound Care; 2003; 12:125-8. 2. Atiyeh BS, Ioannovich J, Al-Amm Caet, et al. Management of Acute and Chronic open wounds: The importance of moist environment in optimal wound healing. Curr Pharm Biotechnol 2002; 3:179–95. 3. Kannon GA, Garrett AB. Moist wound healing with occlusive dressings: A clinical review. Dermatol Surg. 1995; 21:583–90. 4. Capillas PR, Cabre AV, Gil Colome AM, et al. Comparison of the effectiveness and cost of treatment with humid environment as compared to traditional cure. Clinical trial on primary care patients with venous leg ulcers and pressure ulcers. Rev Enferm 2000; 23:17–24. 5. Vogt PM, Andree C, Breuing K, et al. Dry, moist and wet skin wound repair. Ann Plast Surg 1995; 34:493–9. 6. Field FK, Kerateim MD. Overview of wound healing in a moist environment. Am J Surg 1994; 167:S2-6. 7. Dyson M, Young S, Pendle CL, et al. Comparison of the effects of moist and dry conditions on dermal repair. J Invest Dermatol 1988; 91:434–9. 8. Svensjo T, Pomahac B, Yao F, et al. Accelerated wound healing of full-thickness skin wounds in a wet environment. Plast Reconstr Surg; 2000 106:602–12. 9. Bolton LL, Monte K, Pirone LA. Moisture and healing: Beyond the jargon. Ostomy Wound Manage 2000; 46:S51-62. 10. British National Formulary 2003; 46:733. 11. Agren MS. Alginate dressings in the treatment of partial thickness wounds: A comparative experimental study. J Plast Surg 1996; 49:129–134. 12. Thomas S, Loveless P. A comparative study of the properties of twelve hydrocolloid dressings. World Wide Web 1997.


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13. Odell EQ, Oades P, Lombardi T. Symptomatic foreign body reaction to haemostatic alginate. Br J Oral Maxillofac Surg 1994; 32:178–9. 14. Henderson NJ, Craqford PJ, Reeves BC. A randomised trial of calcium alginate swabs to control blood loss in 3-5-year-old chidren. Br Dent J 1998; 184: 187–190. 15. Sayag J, Meaume S, Bohbor S. Healing properties of calcium alginate dressings. J Wound Care 1996; 5:357–362. 16. Dawson C, Armstrong MW, Fulford SC, et al. Use of calcium alginate to pack abscess cavities: A controlled clinical trial. R Coll Surg Edinb 1992; 37:177–9. 17. Fraser R, Gilchrist T. Sorbsan calcium alginate dressings in footcare. Biomaterials 1983; 4:222–4. 18. Thomas S. Hydrocolloids. Journal of wound care 1992; 1:27–30. 19. Sasseville D, Tennstedt D, Lasgapelle JM. Allergic contact dermatitis from hydrocolloid dressings. Am J Contact Dermat 1997; 8:236–8. 20. Sherman RA. A new dressing design for use with maggot therapy. Plast Reconstr Surg 1997; 100:451–6. 21. Apelqvist J, Larsson J, Stenstrom A. Topical treatment of necrotic foot ulcers in diabetic patients: A comparative trial of DuoDerm and MeZinc. Br J Dermatol 1990; 123:787–92. 22. Laing P. Diabetic foot ulcers. Am J Surg 1994; 167:S31-6. 23. Annoni F, Rosina M, Chiurazzi D, The effects of hydrocolloid dressings on bacterial growth and the healing process of leg ulcers. Int Angiol 1989; 8:224– 8. 24. Gilchrist B, Reed C. The bacteriology of chronic venous ulcers treated with occlusive hydrocolloid dressings. Br J Dermatol 1989; 121:337–44.

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14

Belinda Vaz

Computer and Digital Photography: Newer Tools in Dermatological Practice Dermatology is the most visual specialty in medicine and photography has always been an important tool in illustrating and documenting the different manifestations of dermatological diseases. With the advances in technology and the ability to encode photographic images into computer memory instead of onto film, conventional photography is being replaced by digital photography. Over the last decade, digital equipment has become easier to use, more sophisticated, more affordable and hence easier to incorporate into a dermatological practice. The use of digital imaging in dermatology and the advances in communication technology like the Internet, have opened up various avenues like videoconferencing, multimedia mail, teledermatology and image databases that could not have been envisaged even a decade ago. Digital photography can help the dermatologist communicate more effectively with patients, public and peer groups. It is important for the dermatologist to understand the basics of digital photography and its myriad uses in practice and beyond. BASICS OF DIGITAL PHOTOGRAPHY1-3 Charge Couple Device (CCD) The digital camera has a charge couple device (CCD) that makes it different from a conventional camera. This CCD is a silicon chip composed of photosensitive diodes called photosites or pixels that convert light into voltage. A pixel (picture element) is a little square that makes up the image on the computer screen. The CCD captures many of the pixels that are then stored in its memory and later transferred to a computer. The density of light sensitive elements or pixels that a CCD can reproduce determines its resolution.

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Resolution When the number of pixels that capture an image is high, it produces a digital replica of the original subject wherein the human eye cannot see the dots in the image without looking very closely. This means that the quality of a digital image depends upon the number of pixels used to create the image. Greater the resolution of a digital camera, better the image quality. The size of a digital photograph can be specified in two ways i.e., by its dimensions in pixels (e.g., 1800 × 1600 pixels) or by the total number of pixels it contains (e.g. 2.88 million pixels or mega pixels). A study of dermatological images has shown that the minimum resolution needed to recognize the relevant details of a dermatological lesion is 768 × 512.4 A camera with a higher resolution has a greater memory requirement for storing the image. Compression Compression is one way by which the memory required to store the image is reduced by eliminating redundant information from an image. Many cameras store images in a format called JPEG (Joint Photographic Experts Group) setting. This file format compresses images and specifies how much they are compressed. With compression one can store more images which makes it easier to post an image on a Web page or send it as an e-mail. However, it lowers the quality of the image. For the highest quality printed images, TIFF or RAW format should be used. Storage of Images The number of images that one can store in a camera depends upon the capacity of the storage device (expressed in Megabytes), the resolution used for taking pictures and the amount of compression used. Older cameras have fixed and inbuilt storage capacity. Once the capacity is full, one cannot take any more pictures until the older pictures are erased. Most of the newer digital cameras have some form of removable storage media, usually flash memory cards, floppy disk, CDs or small hard disks. With removable storage media once the capacity is full, one can insert another storage device and take more pictures. Memory cards are very popular these days and come in different capacities from 8 MB to 1 GB. Transfer of Images to a Computer Images can be downloaded from a digital camera to a PC using a cable connected with the serial, parallel or USB port. A USB cable is fast and

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efficient. Software that comes with the camera is used to transfer images from the camera to the computer, to convert images into other file formats for use in word documents or graphics, to organize, work with, and share photos by sending as e-mail, or posting to a personal Web site. Cableless transfer of images is possible if the digital camera stores the images directly on a floppy disc or CD or if a laptop PC has a built-in slot for a memory card. If the system does not have a slot for memory cards, the memory cards are inserted into a card reader, which is connected to the PC using a cable. SELECTING A DIGITAL CAMERA There is a wide range of cameras in the market with features for different applications from outdoor photography to fashion photography. The Internet is a useful resource for evaluating the capabilities of different cameras. Most camera manufacturers have their updated home pages on the Internet. Table 14.1 lists some of the features of different digital cameras. Some features that would be useful in selecting a camera for dermatological practice are: 1. Resolution: Cameras with a resolution of 2 Megapixel are generally adequate for photographing skin lesions. A resolution of 3 Megapixel gives better pictures and a much higher resolution is preferred, if the pictures are to be printed. 2. Type of Camera: Point and shoot cameras are like their name and easy to use because the focus and exposure are automatically set. They have fixed lenses, a built-in flash and are cheaper and more compact. The disadvantage is that the user has limited control over the camera. Single lens reflex (SLR) cameras have removable lenses and so high quality lenses can be used for better pictures. The exposure can be controlled manually when required. Manual mode lets one select both the shutter speed and the aperture. For close up photographs of skin lesions where depth of field is important, an aperture preferred mode lets one select the aperture needed and automatically sets the shutter speed to give a good picture. 3. Macro Mode: Macro mode is a lens that lets one get very close to the lesion to be photographed. It is good for photographing small lesions. 4. Flash: Most digital cameras have a built-in flash. A ring flash is a special kind of flash that fits around the lens and throws a circle of light on the subject. It is ideal for shadowless close up photography of skin lesions. 5. Zoom: It is preferable to have cameras with both optical and digital zoom. Optical zoom is similar to what is found in a conventional

3.2 Mega Pixel

Cybershot DSC-P72

Cybershot DSC-P92

Mavica MVC-CD500

Coolpix SQ

Coolpix 5400

Coolpix 3100

DiMAGE Xt

DiMAGE F300

Powershot G5

Powershot S50

Sony

Sony

Sony

Nikon

Nikon

Nikon

Minolta

Minolta

Canon

Canon

5 Mega Pixel

5 Mega Pixel

5 Mega Pixel

3.2 Mega Pixel

3.2 Mega Pixel

5.1 Mega Pixel

3.1 Mega Pixel

5 Mega Pixel

5 Mega Pixel

Resolution

Manufacturer Model

3X Optical zoom, 4.1X Digital zoom

4X Optical zoom, 4X Digital zoom

4X Digital zoom

4X Digital zoom

3X Optical Zoom

4X Optical, zoomNikkor lens

3X Optical, zoom-Nikkor lens

3X Optical, Total 12 X Zoom

3X Optical, Total 12 X Zoom

3X Optical, Total 9.6 X Zoom

Zoom

Compact flash memory card

Compact flash memory card

Flash memory card

Memory card

Memory Cards

Memory Cards

Memory card

Memory cards, Floppy discs, CD-R

Memory Cards

Memory Cards

Storage

Built-in flash

Built-in flash

Auto flash

Auto flash

Built-in flash

Built-in flash

Built-in flash

Built-in flash

AF illuminator, Built-in flash

AF illuminator, Built-in flash

Flash

Table 14.1: Features of commonly available digital cameras

+

+

+

+

+

+

+

+

+

+

USB cable

Macro made Movie

Movie

Automatic and Manual modes

Ultra thin camera 120 gm

Movie, Date imprint, 14 scene mode

Macro shooting up to lem, movie

Macro shooting up to 4 cm, Swivel zoom lens

Movie

Movie, multi point focus

Movie, multi point focus

Other features

Computer and Digital Photography 245

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6.

7. 8.

9.

10.

11.


camera. When the zoom button is pushed, physical lens elements move inside the camera to achieve the desired zoom effect. Digital zoom consists of an ‘electronic brain’ within the camera that takes a look at the object being photographed and digitally zooms in, usually 2 or 3 times closer. The problem with digital zoom is that when this is done, quality is lost, as the images tend to be more ‘pixelated’, than the same image taken with an optical zoom camera. Auto-focus illuminator: Cameras with auto-focus illuminator cast a bright focussed beam of light onto the subject being photographed so that the camera can focus better. This feature is useful for indoor photography especially where the lighting is not very strong. Photomicrography: Digital cameras can be used to take photographs of histopathological sections. For this there are special lens adaptors. Movie mode: Many digital cameras can provide for a few seconds to a few minutes of video imaging. Thus, one can use the camera as a video recorder albeit for a short time only. This feature is useful to dermatosurgeons for documenting some key steps of a surgical procedure. Most cameras have an audio capability as well. So a short commentary can also be added to the movie clip. Quality settings: The number of photographs that can be taken at a time, for a particular storage capacity, depends upon the quality settings on the camera chosen. The quality settings range, includes economy, standard, fine and superfine. When superfine or the best quality image is chosen, fewer photographs can be taken compared with the lowest quality settings. Printing options: Print-outs of digital photographs can be taken on a regular color inkjet or laser or dye sublimation printer. Photoprinters are also available that use a special paper. They are not very good at printing out just text. Some photoprinters can be attached directly to the camera to produce an instant print like a Polaroid camera. Some photoprinters have slots for memory cards and hence one does not need a PC for printing these photographs. Computer compatibility: Different cameras have different specifications with regards to computer compatibity that should be checked before buying the camera.

COMPUTER REQUIREMENTS FOR DIGITAL PHOTOGRAPHY A key advantage of digital photography is, the ability to transmit one’s photographs to a computer. The computer used may be PC or a Macintosh. In a busy dermatological practice, the number of digital photographs that are stored is likely to be considerable and hence it is


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better to overestimate the need for storage when determining the memory of the computer. The system requirements of PC are as follows: • PC with 300 megahertz or higher processor clock speed recommended; 233 Mhz minimum required (single or dual processor system); Intel Pentium/Celeron family, or AMD K6/ Athlon/Duron family • 128 megabytes (MB) of RAM or higher recommended • 9 gigabytes (GB) hard disk • Super VGA (800 x 600) or higher-resolution video adapter and monitor • CD-ROM or DVD drive • Keyboard and Microsoft Mouse or compatible pointing device • USB port Another commonly used operating system for professional digital photography is Macintosh OS 9. The system requirements of the Macintosh are as follows: • G4 800 MHz processor • 256 MB RAM • 9 GB hard disk • 1920-by-1200-pixel resolution monitor • CD-ROM or DVD drive • Firewire port • USB ports ADVANTAGES OF DIGITAL PHOTOGRAPHY 1. Digital cameras are very user friendly and even beginners can take good photographs. 2. One can immediately review one’s images on the camera’s LCD preview screen and reshoot any unsatisfactory images. 3. One can shoot as many images as the storage capacity of the camera permits, and later choose the best. 4. Digital photographs are more economical in the long run as one saves on print roll and developing and printing charges. 5. Photographs are immediately available. One does not have to finish the roll before having it processed. 6. One can improve or alter the images with a photo editing program. One can crop the photograph to emphasize the key aspect. 7. One can post a photograph on the Internet or e-mail the photograph. 8. Photographs can be compactly stored in the computer or on CDROMs. 9. With some cameras one can record sounds and even short videos with the same camera.

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APPLICATIONS OF DIGITAL PHOTOGRAPHY Clinical Practice A computer is an invaluable help in a busy dermatological practice and is used to maintain patient’s records (demographic data, clinical notes, diagnoses, treatment given), generate legible prescriptions, keep a track of patients’ visits and help with billing. A laptop computer has been found to be a useful tool that allows the dermatologist to deal with a number of problems that arise in a hospital setting, e.g., illegible hand writing, lack of complete information about hospitalised patients in the outpatient chart, lack of effective library resources on the hospital floor and lack of readily available patient education material.5 When using computers for the first time, it is important for the dermatologist to overcome the fear of computers that some adults have, develop typing skills and have the support of user-friendly software and a computer literate colleague to deal with initial teething problems. Digital photographs of patients can become a very important part of the patients’ records. They can also be used to provide documentation of a procedure, to generate notes with pre- and post-treatment photodocumentation to the referring doctor or to generate histopathological photodocumentation. A photographic record makes it easy for a dermatologist to be more objective in monitoring certain diseases like vitiligo, Hansen’s disease, hair loss, etc. It is important to take a patient’s consent before taking a clinical photograph.6,7 A computer adds immense value to a practice but it is also important to use a computer without disturbing the doctor-patient interaction. Dermatosurgeons can use the system for documentation of a surgical procedure and pre- and postoperative results. There are systems also available that allow a prospective cosmetic surgical patient to view their image on a computer screen and modify the image so as to give them an idea of the post-surgical outcome.8 Digital Epiluminescence Microscopy A digital camera can also be combined with dermatoscopy or skin surface microscopy. Digital Epiluminescence Microscopy (DELM) is the term used for use of digital images of dermatoscopy, skin surface microscopy and videomicroscopy techniques.9,10 DELM is a non-invasive clinical technique that uses the optical phenomenon of oil immersion to render the epidermis translucent. Digital videomicroscopes use polarizing light instead of a drop of oil or a glass slide.11 DELM opens a new dimension of skin morphology by including the dermoepidermal junction into the


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macroscopic evaluation of a lesion. It provides for a more detailed inspection of the surface of pigmented skin lesions and morphological criteria that are not readily apparent to the naked eye are easily detected by epiluminescence microscopy. Features like colors, specific patterns, intensity of pigmentation, regularity, configuration and other characteristics of the margin and the surface, aid in differentiating between benign and malignant growth patterns.9 The accurate evaluation of a pigmented skin lesion by DELM depends on the dermatologist’s experience and has been shown to be increased by formal training.12,13 The use of DELM in the follow-up study of patients with melanocytic lesions has indicated that DELM could identify patterns of morphologic changes typical for early melanoma and could, therefore, serve as a useful tool to improve the surveillance of patients with multiple atypical nevi.14 Using sophisticated computer-based systems it is possible to quantitatively analyse the DELM pictures of pigmented skin lesions.15 A digital imaging program has been developed for identifying melanomas rapidly and reproducibly by just scanning in an image of the lesion or through multispectral digital dermoscopy. This technology is useful in those with a high risk of melanoma to avoid unnecessary biopsies.16,17 A videomicroscope consists of a combination of videocamera, microscope and lighting, which allow greater magnification than epiluminescence microscopy. Compact videomicroscopes have been developed that permit clinical inspection of the subsurface structure. Videomicroscopy has been used in the evaluation of port wine stains, to determine the depth of the ectatic vessels.18 Confocal scanning laser microscopy is another system that provides high resolution instantaneous images of nuclear, cellular and architectural detail in human skin in vivo. It is capable of identifying distinct patterns and cytologic features of benign and malignant pigmented skin lesions in vivo.19 Research Digital photography can be used to objectively assess the effect of various medications on parameters like hair growth, size and depth of wrinkles, size of ulcers, etc.20,21 They are used with a special camera system (e.g. Canfield Scientific Camera System) that has a chin rest and a forehead rest with a fibreoptic guide light to ensure proper positioning of the head in before and after pictures. This ensures that the pre- and posttreatment photographs are as similar as possible. The digital images are quantitatively analysed to assess the progress of the variable or clinical parameter that is being assessed.

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Education Digital imaging has made it easy for even the technologically challenged dermatologist to take good pictures. It is possible to add text, lines and graphics to the digital pictures, remove photographic artefacts and alter colour brightness and contrast and thus enhance the communication power of digital images. Photographs can be used for clinical presentations, grand rounds and for teaching medical and postgraduate students. Many dermatology textbooks and atlases are available as CD-ROMs containing digital images. Manipulation of digital photographs used in presentations, journals and scientific meetings is possible with the purpose of wilfully deceiving the audience. Hence, a code of ethics is followed by various scientific bodies to cope with such issues. Communication In Dermatology, sharing images and text on the Internet has great potential. The Internet is a link-up of public, private, government and university computer networks that encompass almost all the countries in the world. There are many Internet sites devoted to Dermatology and vast reserves of specialist literature in the form of news, articles, conference proceedings, patient literature, product catalogues and more.22 Web-sites and home pages are electronic spaces via which one can disseminate information. There are entire textbooks and dermatological atlases available online. It is also possible to access journals online for free or for a fee. E-mail is one way by which digital images can be sent over the Net. There are also various interactive discussion groups for dermatologists on the Internet (e.g., rxderm), where one can post one’s difficult cases and have dermatologists from around the world opine, suggest treatment options and share their own experiences. The ability to post a patient’s digital photograph with the history makes this forum even more interesting. Digital images can also be posted to online journals and online grand rounds. Telemedicine Telemedicine is the application of the advances in telecommunication technology to health care delivery. It allows physicians to consult on patients at a distance via an interactive video format. Since dermatology is a visual speciality and consultation involves a quick recognition of a disease pattern and a straightforward clinical decision, it lends itself well to telemedicine and is known as teledermatology. The transmitted digital images are a substitute for a physical examination. 23,24


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Teledermatology can provide specialized dermatological services to remote areas where there are no or few dermatologists. Teledermatology has even been used in sub-Saharan Africa with Swiss dermatologists providing the teleconsultations.25 A teledermatological set up consists of a digital camera and a computer workstation, which is handled by a primary care physician or health care provider in the remote clinical setting. As in a regular faceto-face consultation, a detailed history is taken, the examination performed and digital images are taken. These are then sent via the computer to the appropriate server or computer network and then to the teledermatologist who assesses the case, makes a diagnosis, suggests further investigation, formulates a treatment plan and communicates this back to the health care provider.26 Digital images of histopathological sections and dermatoscopic examination have also been sent to the teledermatologist to enhance diagnostic accuracy.27,28 The teledermatology consultation can be of 2 types: • Live—using real time video-conferencing between participating parties • Store and Forward Systems (SAF)—Digital images of patients and clinical data are stored electronically and accessed later by the teledermatologist. This system is more economical.29 Various studies have found that the diagnostic accuracy and management efficacy of teledermatological consultations are comparable with conventional hospital consultations.30-33 A patient’s acceptance and satisfaction with telemedicine services has been found to be dependent on the patient’s subjective health status.34 Patients with poor quality of life prefer a face-to-face interaction with expert clinicians. The cost of teledermatology consultations, especially where the services are underutilized, appeared to be higher per patient compared with the cost of conventional care.35 However, the teleconsultations were of greater convenience to the patient as they saved on travel time, they did have a long wait to see the specialist, there was quicker resolution of the problem and fewer interim visits. The general practitioners involved with the teledermatology consultations also experienced enhanced job satisfaction. It is likely that if telemedicine equipment were less expensive and travelling distances greater, teledermatology would be a cost-effective alternative to conventional care. The limitations of teledermatology are the technical drawbacks that the teledermatologist may face when making a diagnosis because of poor quality of digital image and the inability to palpate, change the lighting, perform a total skin examination or view the skin from different angles. The teledermatologist also misses the subtle nuances in history,

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patient’s body language and demeanour that are an important part of a face-to-face consultation that can affect the diagnosis and further management. When questioned specifically, many patients reveal that they would prefer a face-to-face consultation.36 Technical breakthroughs have brought about a great deal of improvement and convenience in patient care but at the cost of depersonalisation of the practice of medicine. It is too early to predict whether dermatology patients need just a simple answer to their questions and problems or they need a little more of the human touch. REFERENCES 1. Ratner D, Thomas CO, Bickers D. The uses of digital photography in dermatology. J Am Acad Dermatol 1999; 41: 749-56. 2. Perednia DA. What dermatologists should know about digital imaging. J Am Acad Dermatol 1991; 25: 89-108. 3. Stone JL, Peterson RL, Wolf JE. Digital imaging techniques in dermatology. J Am Acad Dermatol 1990; 5: 913-7. 4. Bittorf A, Fortasch M, Schuler G, Diepgen TL. Resolution requirements for digital images in dermatology. J Am Acad Dermatol 1997; 37: 195-8. 5. Marchese S, Nadenichek TJ, Brodell RT. The laptop computer in dermatology. J Am Acad Dermatol 1997; 37: 284-6. 6. Hood CA, Hope T, Dove P. Videos, photographs and patient consent. BMJ 1998; 316: 1009-11. 7. Nicholl D, Winters G, Davies D. Publishing information about patients. BMJ 1996; 312: 578-79 8. Koch RJ, Chavez A, Dagum P, Newman JP. Advantages and disadvantages of computer imaging in cosmetic surgery. Dermatol Surg 1998; 24: 195-8. 9. Pehamberger H, Steiner A, Wolff K. In vivo epiluminescence microscopy of pigmented skin lesions. I. Pattern analyses of pigmented skin lesions. J Am Acad Dermatol 1987; 17: 571-83. 10. Steiner A, Pehamberger H, Wolff K. In vivo epiluminescence microscopy of pigmented skin lesions. II. Diagnoses of small pigmented skin lesions and early detection of malignant melanoma. J Am Acad Dermatol 1987; 17: 58491. 11. Seldenari S, Pallacom G, Pepe P. Digital videomicroscopy improves diagnostic accuracy for melanoma. J Am Acad Dermatol 1998; 39: 175-81. 12. Binder M, Schwarz M, Steiner A et al. Epiluminescence microscopy of small pigmented skin lesions: Short-term formal training improves the diagnostic performance of dermatologists. J Am Acad Dermatol 1997; 36: 197-202. 13. Binder M, Schwarz M, Winkler A et al. Epiluminescence microscopy: A useful tool for the diagnosis of pigmented skin lesions for formally trained dermatologists. Arch Dermatol 1995; 131: 286-91. 14. Kettler H, Pehamberger H, Wolff K et al. Follow up of melanocytic skin lesions with Digital epiluminescence microscopy; Patterns of modifications observed in early melanoma, atypical nevi, and common nevi. J Am Acad Dermatol 2000; 43: 467-76. 15. Voigt H, Classen R. Computer vision and digital imaging technology in melanoma detection. Semin Oncol 2002; 29: 308-27.


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16. Del Mar CB, Green AC. Aid to diagnosis of melanoma in primary medical care. BMJ 1995; 310: 492-5. 17. Elbaum M, Kopf AW, Rabinovitz HS et al. Automatic differentiation of melanoma from melanocytic nevi with multispectral digital dermoscopy: A feasibility study. J Am Acad Dermatol 2001; 44: 207-18. 18. Eubanks L, McBurney E. Videomicroscopy of port-wine stains: Correlation of location and depth of lesion. J Am Acad Dermatol 2001; 44: 948-51. 19. Langley R, Rajadhyaksha M, Dwyer P at al. Confocal scanning laser microscopy of benign and malignant melanocytic skin lesions in vivo. J Am Acad Dermatol 2001; 45: 365-76. 20. Gibbons RD, Fiedler-Weiss VC, West DO, Lapin G. Quantification of scalp hair: Computer-aided methodology. J Invest Dermatol 1986; 86: 78-82. 21. Grove GL, Grove MJ, Leyden JJ. Optical profilometry: An objective method of quantification of facial wrinkles. J Am Acad Dermatol 1989; 21: 631-7. 22. Huntley, AC, Bittorf A, Taragin M. Configuring for the World Wide Web: Recommendations for dermatologists. J Am Acad Dermatol 1996; 34: 125-136. 23. Kvedar JC, Edwards RA, Menn ER, et al. The substitution of digital images for dermatologic physical examination. Arch Dermatol 1997; 133: 161-7. 24. Norton SA, Burdick AR, Phillips CM, et al. Teledermatology and underserved populations. Arch Dermatol 1997; 133: 197-200. 25. Schmid-Grendelmeier P, Masenga EJ, Haeffner A, Burg G. Teledermatology as a new tool in sub-Saharan Africa: An experience from Tanzania. J Am Acad Dermatol 2000; 42: 833-5. 26. High WA, Houston MS, Calobrisi SD, et al. Assessment of the accuracy of lowcost store-and forward teledermatology consultation. J Am Acad Dermatol 2000; 42: 776-83. 27. Piccolo D, Smolle J, Wolf IH, et al. Face to face diagnosis of pigmented skin tumors: A teledermoscopic study. Arch Dermatol 1999; 135: 1467-71. 28. Piccolo D, Soyer HP, Burgdorf W, et al. Concordance between telepathologic diagnosis and conventional histopathologic diagnosis: A multiobserver storeand-forward study on 20 skin specimens. Arch Dermatol 2002; 138: 53-8. 29. Zelickson BG, Homan L. Teledermatology in the nursing home. Arch Dermatol 1997; 133: 171-4. 30. Gilmour E, Campbell SM, Loane MA, et al. Comparison of teleconsultation and face to face consultations: Preliminary results of a UK multicentre teledermatology study. Br J Dermatol 1998; 139: 81-7. 31. Phillips CM, Burke WA, Shechter A, et al. Reliability of dermatology teleconsultations with the use of teleconferencing technology. J Am Acad Dermatol 1997; 37: 398-402. 32. Lesher JL, Davis LS, Gourdin FW, et al. Telemedicine evaluation of cutaneous diseases: A blinded comparative study. J Am Acad Dermatol 1998; 38: 27-31. 33. Lowitt MH, Kessler II, Kauffman L, et al. Teledermatology and in-person examinations. Arch Dermatol 1998; 134: 471-6. 34. Williams TL, May CR, Esmail A, et al. Patient satisfaction with teledermatology is related to perceived quality of life. BJD 2001; 145: 911-7. 35. Wootton R, Bloomer SE, Corbett R, et al. Multicentre randomised control trial comparing real time teledermatology with conventional outpatient dermatological care: Societal cost-benefit analysis. BMJ 2000; 320: 1252-6. 36. Gibbs S. Losing touch with the healing art: Dermatology and the decline of pastoral doctoring. J Am Acad Dermatol 2000; 43: 875-8.

Index A Acne vulgaris 223 Acrodermatitis enteropathica 82 Actin 12 Acute hemorrhagic edema 43 Acute skin failure 84 Adverse drug reaction 88 sources of information 88, 89 Allergens 136 Anaplastic large cell lymphoma 18 Angiocentric lymphomas 18 Angioedema 62 hereditary 64 Anogenital squamous cell carcinoma 219 Anogenital warts 165, 213 Antibodies 10 Apoptosis 1 apoptosis and skin disorders 3 genes and apoptosis 3 morphology 2 pathomechanisms 2 Atopic dermatitis 206, 209 Autoimmune disorders 6

B B cell lymphomas 19 Bacterial vaginosis 163 Bexarotene 192 adverse effects 193 indications and dosage 193 mechanism of action 192 pharmacokinetics 192 Bowenoid papulosis 219

C Candidiasis 62 Carcinoembryonic antigen 13 Cell markers 9 common markers used in dermatology 10 Cellulitis 57 Chancroid 152 Charge couple device 242 Chlamydia infection 161 Chromogranin 13 Churg-Strauss syndrome 40 Cidofovir 216

clinical uses 218 mechanism of action 216 pharmacology 217 Collodion baby 72 Compression 243 Condyloma accuminata 218 Cryoglobulinemic vasculitis 42 Cutaneous adverse drug reaction 89 anti-retroviral therapy 103 blistering drug eruption linear IgA bullous dermatosis 100 pemphigoid 101 pemphigus 101 pseudo-porphyria 102 drug induced erythema nodosum 100 drug induced lupus erythematosus 102 drug induced pseudolymphoma syndrome 99 drug induced pustular eruption 98 eczematous drug eruption 93 erythema multiforme 94 examthematous/morbillform/maculopapular drug eruption 90 exfoliative dermatitis/erythroderma 91 fixed drug eruption 96 hypersensitivity syndrome reaction 91 lichenoid drug eruption 97 photosensitive drug eruption 93 psoriasiform drug reaction 97 scleromatoid tissue reaction 103 Stevens-Johnson syndrome 94 toxic epiderma necrolysis 94 urticaria, angioedema and serum sickness 92 vasculitis 98 Cutaneous polyarteritis nodosa 43 Cutaneous tuberculosis clinical features 24 diagnosis 27 in immunosuppressed host 26 pathogenesis 27 treatment 28 Cytokeratins 11

D Death domain 2 Dermatitis medicamentosa 65 Desmin 12

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Digital epiluminescence microscopy 248 Digital photography 242 advantages 247 applications 248 clinical practice 248 communication 250 digital epilumiescence microscopy 248 education 250 research 249 telemedicine 250 computer requirements 246 criteria of selecting a digital camera 244 Donovanosis 153 Dressing materials alginate 236 foam 238 hydrocolloid 237 hydrogel 238 low adherence 239 odour absorbent 239 surgical absorbents 239 vapour permeable films and membranes 239 wound contact materials 239 Drug eruptions 65

E Emergency 56 Epidermolysis bullosa 76 dystrophic 77 junctional 77 Epithelial membrane antigen 13 Erythema elevatum diutinum 44 Erythema multiforme 70 Erythroplasia of Queyrat 219

F

Henoch-Schonlein pupura 41 Herpes simplex virus infection 61, 220 Histiocytic disorders 15 Histiocytosis X 81 HMB-45 15 Hodgkin’s lymphoma 19 HPV infections 218

I Ideal dressing material 235 Imiquimod 211 clinical uses 213 mechanism of action 211 pharmacology 213 safety profile 216 side effects 216 Immunofluorescence 10 Immunohistochemistry 10 Immunophenotyping 9 Infliximab 190 adverse effects 191 contraindications 191 indications and dosage 191 mechanism of action 190 pharmacokinetics 190 Intensive skin care units 86 Involucrin 13 Ivermectin 182 adverse effects 184 contraindications 184 indications and dosage 183 mechanisms of action 183 pharmacokinetics 183

K Kaposi’s sarcoma 221 Kawasaki syndrome 66

Flow cytometry 10

L G Generalized exfoliative dermatitis 69 Genital herpes simplex virus infection 156 Genital ulcer diseases 147 Gonorrhea 158 Graft versus host disease 6, 75 acute and chronic 76 Granuloma faciale 44 Granulomatous slack skin 17

H Hemangiomas 80

Laryngeal papillomatosis 219 Leiner’s disease 84 Leucocyte common antigen 16 Leukemia cutis 20 Leukocytoclastic vasculitis 31 classification 37 diagnosis and treatment 46, 47 drugs used 49 laboratory workup 48 disease associated with 39 drugs causing 35 etiological factors 34 etiopathogenesis 32

Index infections associated with 36 overview of syndromes associated with 40 Lichen planus 5 Lichenoid tissue reaction 5 Linear IgA disease 78 Lymphocytoma cutis 17 Lymphogranuloma venereum 154 Lymphomas 16 Lymphomatoid papulosis 18

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tacrolimus 204 tazarotene 222 Non-genital warts 215 Non-gonococcal urethritis 160 Non-Hodgkin’s lymphoma 19

P

Mastocytosis 82 Melanoma 15 Meningococcal disease 73 clinical features 74 Microscopic polyangitis 41 Moist environment in wound healing 234 Molluscum contagiosum virus infection 220 Mononuclear phagocytic cells 13 Mycophenolate mofetil 180 adverse effects 182 contraindications 182 drug interaction 182 indications and dosage 181 mechanism of action 180 pharmacokinetics 180 Mycosis fungoides 18

Pagetoid reticulosis 17 Patch test units/devices 137 Patch testing 136 complications 143 interpretation of results 140 false-negative reactions 142 false-positive reactions 141 technique 139 testing of unknown substances 142 Pediatric dermatological emergencies 57 Pemphigus 79 Photopatch testing 144 Pimecrolimus 208 clinical uses 209 dosage and administration 210 mechanism of action 208 pharmacology 209 Poorly differentiated neoplasm 14 Prekeratins 11 Psoriasis 223 Pustular vasculitis 44

N

R

Narrowband UV-B therapy 172 clinical studies 175 mechanism of action 174 method of use 172 newer developments 308-nm excimer laser therapy 176 narrowband UV-B micro-phototherapy 176 response to treatment 174 side effects 174 Neurofilaments 12 Neutrophilic dermatosis 44 New drugs in dermatology 180, 204 systemic 180 bexarotene 192 infliximab 190 ivermectin 182 mycophenolate mofetil 180 thalidomide 185 topical 204 cidofovir 216 imiquimod 211 pimecrolimus 208

Resolution 243 Ritter-Lyell syndrome 59

M

S S 100 protein 15 Sclerema neonatorum 83 Scleroderma disorders classification 115 drawbacks 117 diagnosis 124 serological tests 125 etiology 121 drugs 123 genetic factors 121 infectious agents 122 microchimerism 123 non-infectious environmental agents 122 management 126 antifibrotic therapy 129 immuno-modulation therapy 128 other therapeutic agents 130

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therapy for cutaneous involvement 131 vascular therapy 127 manifestations 124 pathogenesis 118 immunologic activity 119 increased fibroblast activity and collagen synthesis 120 vascular changes 118 Sensitivity 143 Serum sickness 45 Sexually acquired hepatitis 167 Sexually transmitted disease 147, 165 current treatment options 150 laboratory tests in the diagnosis 148 Smallpox 221 Specificity 143 Spindle cell neoplasms 14 Staphylococcal scalded skin syndrome 59 Storage of images 243 Sunburn cells 3 Synaptophysin 13 Syphilis 147

T T cell lymphomas 17 T cell pseudolymphoma 17 Tacrolimus 204 clincal uses 206 dosage and administration 208 mechanism of action 204 pharmacology 205 side effects 207

Tazarotene 222 clinical uses 223 drug interaction 225 mechanism of action 222 pharmacology 222 safety and side effects 224 Telemedicine 250 Thalidomide 185 adverse effects 188 contraindications 188 indications and dosage 186 mechanism of action 185 pharmacokinetics 186 Toxic epidermal necrolysis 4, 71 Transfer of images to a computer 243 Trichomoniasis 161 Tuberculids 26

U Urticaria 62 Urticarial vasculitis 46

V Vascular neoplasms 16 Vasculitis 31 Vimentin 12 Vulvar intraepithelial neoplasia 219

W Wegener’s granulomatosis 40

Um1pq.recent.advances.in.Dermatology.volume.1

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