Prurigo Nodularis an Update on an Important.1

Review Review article article 119

Prurigo nodularis – an update on an important disease Athanasios Tsianakas, Claudia Zeidler, Claudia Riepe and Sonja Sta¨ nder Department of Dermatology, Center for Chronic Pruritus, University Hospital Muenster, Muenster, Germany Correspondence to Sonja Sta¨ nder, MD Department of Dermatology, Center for Chronic Pruritus, University Hospital Muenster, Von-Esmarch-Str. 58, 48149 Muenster, Germany Tel: + 20 122 296 6670; 6670; fax: + 20 342 10352; 10352; e-mail: [email protected] [email protected]

Received 21 January 2016 Accepted 24 April 2016 Journal of the Egyptian Women’s Dermatologic Society 2016, 13:119–124

Prurigo nodularis (PN) is defined as a clinical pattern of mostly symmetrically papules and nodules and belongs to the group of chronic pruritic diseases. Underlying diseases can be skin diseases (e.g. atopic dermatitis or lichen planus), internal medical diseases diseases (e.g. hepatic or renal diseases), and neurological neurological or psychiatric psychiatric diseases. diseases. Recently, Recently, new insights insights into the pathogenesis pathogenesis of PN have revealed an important role of various neuropeptides such as substance P in the maintenance of the itch–scratch cycle of PN. As a consequence, new clinical trials are being conducted to verify a potential potential benefit by blocking these substances. substances. However, However, till today, standard therapy regimens for PN include, apart from the treatment of underlying diseases, topical steroids, antihistamines, phototherapy, anticonvulsants, antidepressants, opioid receptor antagonists, and, finally, immunosuppressants. Keywords:

antihistamines antihistamines,, aprepitant, aprepitant, chronic chronic pruritus, pruritus, prurigo activity score, prurigo nodularis nodularis J Egypt Women Dermatol Soc 13:119–124 Egyptian Women’s Dermatologic Society 1687-1537 & 2016

Introduction Prurigo rurigo nodula nodularis ris (PN) (PN) is a clinic clinical al pattern pattern defined defined by multiple, typically symmetrically distributed papules and nodules that are often erosive and ulcerative. PN belongs to the the spec spectr trum um of chro chroni nicc prur prurit itic ic dise diseas ases es,, and and develo developme pment nt of its itchy lesions lesions is based based on a viciou viciouss itch–scratch itch–scratch cycle. Etiologically Etiologically,, it could be shown that 50% of the patients with PN have a concomitant atopic disease [1]. [1]. Moreover, there are various other dermatologi logica call pote potent ntia iall llyy prur prurit itic ic dise diseas ases es such such as bull bullou ouss pemphigoid and lichen planus that can lead to PN. In addition, there is a variety of internal medical diseases that can be associated with PN (e.g. chronic kidney and liver liver disease diseases, s, tumors, tumors, dia diabet betes es mellit mellitus, us, chroni chronicc iron iron deficiency, and many others), as well as neurological and psychiatric diseases [2 diseases [2]. ]. Therefore, PN can be a result of chroni chronicc prurit pruritus us of div diverse erse origin, origin, and thus thus a thorou thorough gh medica medicall exami examinat nation ion should should alw always ays be carried carried out to reveal any potential underlying disease.

Methods An intensive intensive literature literature research was performed on PN using using diffe differen rentt elect electron ronic ic medi medica call databa database sess such such as Medline and DIMDI. The key words used were ‘prurigo nodulari nodularis’ s’ and ‘prurigo ‘prurigo nodulari nodularis’ s’ in combina combinatio tion n with with ‘epidemiology’ ‘epidemiology’,, ‘pathophysiolo ‘pathophysiology’, gy’, ‘treatment’, ‘treatment’, and ‘therapy’. apy ’. In wha whatt follo follows, ws, we would would like like to highl highlig ight ht the the pathophysiology, the clinical picture, the connection to the underlying diseases, and the treatment options for PN.

Results Epidemiology

There are only a few studies in the literature reporting the freque frequency ncy of PN among among dermato dermatolog logica icall diseas diseases, es, mostly mostly from from Asia Asia [3,4]. [3,4]. In thes these e publ public icat atio ions, ns, PN is 1687-1537

&

2016 Egyptian Women’s Dermatologic Society

reported as to be among the top 20 of the most common dermatological diseases, and its prevalence ranges from 1.82 1.82 to 3.8% 3.8% [3,4]. [3,4]. Most Most often often,, elde elderl rlyy pati patien ents ts are affected, but there are other reports even about affected children [5 children [5]. ]. Women seem to be more often affected than men men (fem (femal ale e : ma male= le= 1.7 1.7 : 1), 1), and and the the age age of onse onsett is about 60 years [2 years [2]. ]. There does not seem to exist a link of PN to genetic factors [6]. [6 ].

Pathogenesis

Historically, for a long time histamine was thought to be the major major itch-i itch-indu nducin cing g mediat mediator or of PN [7]. [7]. However However, high treatment-failure rates of the antihistaminic therapy have led to a deeper insight into the pathogenesis of PN. Histopathol Histopathologic ogically ally,, increased increased numbers numbers of eosinophili eosinophilicc granulocytes, T-cells, and mast cells can be found in the lesions of PN. Based on the infiltration with eosinophilic gran granul ulocy ocyte tes, s, ther there e are are high high amou amount ntss of eosi eosinop nophi hill cation cationic ic protein protein,, eosino eosinophi phil-d l-deriv erived ed neurot neurotoxi oxin, n, and eosino eosinophi phill protei protein n X in PN lesion lesionss [8]. [8]. In addition, it could could be detecte detected d that that the T-cell-cell-deri derived ved cytoki cytokine ne interl interleuk eukin in (IL)-3 (IL)-31 1 is upregu upregulat lated ed in PN lesion lesionss [9]. [9]. This is also known from atopic dermatitis in which IL-31 serum levels even correlate with disease severity [9,10]. [9,10]. Furthermore, IL-31 is known to induce inflammation and pruritus. Most Most rece recent ntly ly,, ther there e is a focu focuss on chan change gess of the the neuroanatomy in PN lesions. Chronic mechanical irritation tion by scrat scratch chin ing g seem seemss to lead lead to prol prolif ifera erati tion on of keratinocy keratinocytes, tes, fibroblasts, fibroblasts, mast cells, cells, collagenous collagenous fibers, fibers, and dermal nerve fibers [8,11 fibers [8,11]. ]. Recently, an immunohistochem tochemica icall study study has been been publi published shed,, in which which it has been shown that there is an increased expression of the nerve growth factor (NGF) in epidermal epidermal keratinocytes keratinocytes with PN [11 PN [11]. ]. But there exist many other neuropeptides such as substance P, calcitonin gene-related peptide, and DOI: 10.1097/01.EWX.0000481472.60356.9e

Copyright r 2016 Egyptian Women’s Dermatologic Society. Unauthorized reproduction of this article is prohibited.

120 Journal of the Egyptian Women’s Dermatologic Society

the receptor of NGF (TrkA p75NGF) that are increased in PN lesions as well [12,13]. Increase of neuropeptides can lead to nerve growth, but also to inflammation and pruritus, which might be the link between the neurohistological findings and the clinical picture. The itch (reason for inflammation and pruritus)–scratch (causes mechanical irritation with the consequence of inflammation and pruritus) cycle keeps the disease permanently going.

dermatological diseases are scabies, stasis dermatitis, allergic contact dermatitis, lichen planus, bullous pemphigoid, dermatitis herpetiformis (Duhring), or even neoplastic diseases such as cutaneous lymphoma or multiple keratoacanthomata. Therefore, a histological examination involving routine histology of the lesion plus direct immunofluorescence of the surrounding skin of the lesion should be carried out to rule out the abovementioned underlying diseases.

Clinical appearance of prurigo nodularis

Systemic diseases

PN is typically characterized by symmetrically distributed erythematous papules, nodules, and plaques that are highly pruritic. Their number can vary from just a few to more than a hundred.

PN is an often described clinical picture of chronic renal failure. In a study with patients suffering from chronic renal failure, more than half of the patients showed PN lesions [17]; in this trial, the duration of kidney disease correlated with the probability to suffer from PN.

PN rarely occurs in circumscribed areas (typically in neuropathic pruritus). In general, PN lesions affect the extensor surfaces of the extremities and the trunk with a typical butterfly sign (that means the lack of lesions at the central back, which can be explained by the patient’s inability to scratch these skin areas). The face is rarely affected. For conducting clinical trials, it is important to have a reliable measurement tool to evaluate the disease activity. For PN, such a tool has not been made available till now. Therefore, it is a welcome sign that just recently a Prurigo Activity Score has been developed and validated [14]. In addition, there are efforts to analyze prurigo activity by a computer-based software that would evaluate PN lesions automatically in an objective way [15]. For a deeper understanding of the different clinical features and pictures of PN during the time the patient is suffering from PN, a publication by Schedel et al . [16] should be referred. In that publication, it is clearly presented how dynamically the lesions behave during the course of the disease. After a nondefined time of chronic pruritus, PN lesions appear as a consequence of chronicrepetitive mechanical irritation (usually by scratching). This first appearance of PN is characterized by small papules that become bigger in size because of scratching and develop into nodules or even plaques. These stages of PN are therefore called papular type (Fig. 1), nodular type (Fig. 2), and plaque type prurigo (Fig. 3). In the course, these nodes can be massively excoriated, ulcerated (stage of ulcerated prurigo), or show crusts resulting in scars after healing. In some patients, no nodules but ulcerations with fibrosated edges of elevated and hyperplastic epidermis form resulting in the clinical picture of the umbilicated ulcerative prurigo. This was (in former times) described as an own entity (Kyrle’s disease). Underlying diseases Dermatological diseases

In up to 50% of PN patients there is an atopic predisposition, often also showing signs of atopic dermatitis [2]. As PN is a specific clinical skin reaction pattern to chronic pruritus, PN can appear in many other dermatological diseases. Sometimes the clinical picture of PN can be so dominant that the originally underlying skin disease can get hidden by it. Examples for underlying

Metabolic diseases such as diabetes mellitus can also lead to PN. The coexistence of chronic renal failure and diabetes mellitus even leads to a more active stage of PN, with umbilicated ulcerations; see Chapter ‘Clinical appearance of PN’ by Tseng et al. [18]. Cholestatic diseases are known to lead to chronic pruritus and in some cases to the clinical picture of PN. However, in cholestatic pruritus, PN is an exception and patients suffer mostly from chronic pruritus on normally looking skin. Examples are primary sclerosing cholangitis, primary biliary cirrhosis, choledocholithiasis, or hepatocellular carcinoma [19]. Among viral hepatitides, hepatitis C is well-known to be often associated with chronic pruritus [20] and can sometimes also lead to PN [21]. Other infectious diseases such as HIV are also well-known to frequently lead to the appearance of PN [22]. Neurological disease

Neurological diseases are sometimes the reason of localized PN. It is caused by irritation or damage of cutaneous and/or extracutaneous nerves. Examples are postherpetic neuralgia or brachioradial pruritus (often in dermatome C6) [23,24]. Psychiatric diseases

The clinical picture of PN can be erased by the so-called skin-picking disorder in which the patients scratch and maltreat their skin despite lack of pruritus [25]. The result is the appearance of PN-like lesions. In addition, anxiety disorders, depressions, and tactile hallucinations can also lead to chronic pruritus and thereby to PN as well [26]. Treatment of prurigo nodularis

PN requires a multimodal itch therapy based on mainly two arms. The first one is the treatment of the potentially underlying disease, which can often lead to an improvement in the itch (e.g. successful treatment of underlying hepatitis C, HIV, renal and hepatic diseases). The second arm is the symptomatic antipruritic therapy, which is induced in parallel to the first arm and, if a causal therapy is not possible or if it does not lead to a sufficient


Prurigo nodularis Tsianakas et al.

Figure 1.

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Figure 3.

Plaque type of prurigo.

Papular type of prurigo.

Figure 2.

0.1% [27] or hydrocortisone 1% cream [28]). On the bottom of the widespread use of topical calcineurin inhibitors (such as pimecrolimus cream and tacrolimus ointment) in atopic dermatitis, these substances are also sometimes used in PN cases not accordingly responding to topical steroids or because of the side effects of steroids. A randomized controlled trial showed that pimecrolimus 1% cream is as effective as hydrocortisone 1% cream in treating PN [28]. In the case of only single PN lesion, an injection with triamcinolone acetonide is also possible [29]. In localized neuropathic PN, such as brachioradial pruritus, the usage of topical capsaicin is an option. It can be either used as a cream in various concentrations (0.025–0.3%) for up to six times daily or as a ready to use patch [30,31].

Systemic symptomatic therapy

Nodular type of prurigo.

therapeutic effect, should be maintained until all PN lesions are healed. For that, we have developed treatment algorithms for PN treatment (Fig. 4). The different treatment levels are explained in what follows. Topical symptomatic treatments

Generally, clinical experience has shown that a basic topical therapy with moisturizing emollients exhibits antipruritic efficacy and is therefore always concomitantly recommended. Topical emollients are most often not completely sufficient, so that in daily practice the firstline topical treatment of PN is the use of topical steroids. However, there are just a few randomized clinical trials underlining its efficacy (e.g. betamethasone valerate

Antihistamines : Despite missing randomized trials for all kinds of systemic therapies and missing approval of systemic therapy for the treatment of PN, treatment with antihistamines is still the number one option of dermatologists for the systemic therapy of PN. Despite a convincing clinical effect of antihistamines, several patients benefit from a therapy with modern antihistamines. It is recommended to use high doses of nonsedative antihistamines (dosage of four times a day) if necessary, in addition to a sedative antihistamine at night [32]. A combination with antileukotriene agents such as montelukast is also possible [33]. A case series with 12 PN patients showed successful treatment with the antihistaminic fexofenadine 240 mg per day in combination with 10 mg of montelukast per day [33]. UV therapy: An alternative for further systemic treatment or addition to antihistamines and topical steroid or capsaicin treatment is the ultraviolet (UV) phototherapy. There are several case series and a single case report about successful treatment regimens with UVB, (bath) PUVA, UVB excimer laser therapy, or UVA [34–36].

However, the only randomized controlled trial is the one that compared bath PUVA with bath PUVA in combination



Figure 4.

• • •

Immunosuppressants such as cyclosporine A or methotrexate Opioid antagonists such as naltrexone or naloxone Intralesional injection of triamcinolone

Level 3

• •

Topical capsaicin (in localized PN) Antidepressants (SSRI, tricyclic, tetracyclic)

Level 2

• •

Topical primecrolimus and tacrolimus Anticonvulsants (such as gabapentin or pregabalin)

Level 1

• • • •

Treatment of underlying disease Topical steroids Non-sedative antihistamines Phototherapy

Level 4

d i s t u B r a b s i a c n c t h e e , r p a s p y y c , h f o i s n o e m c e a s t i s a c r c y o t n r c e o a m t m i e t a n n t t o t r f e s l a e t m e p e n t

Algorithms of treatment of PN. PN, prurigo nodularis; SSRI, selective serotonin reuptake inhibitor.

with UVB 308 nm excimer light in 22 patients [37]. The combination resulted in lower cumulative PUVA doses. Generally, in daily practice UV therapy has many limitations as it is time-consuming and due to its potential carcinogenicity. Therefore, it is only appropriate for a specific target population. Anticonvulsants : After failure of antihistamines and UV therapy, the group of anticonvulsants has been shown to be effective in PN treatment. Well-known from the therapy of chronic pruritus [38], there are several case reports in the field of treatment of PN [39,40]. Our own clinical experience has shown that the antipruritic character of gabapentin seems to be superior to the one of pregabalin (clinical observation).

For the mode of action for both substances, it is postulated that they react as ligands of the a 2–d subunits of calcium channels of peripheral and central nociceptive neurons. Their binding results in calcium influx with the result of inhibition of depolarization of neuronal cells [41]. Antidepressants : Based on the results of the therapy of chronic pruritus, it is well-known that antidepressive agents have antipruritic properties. Both the group of the selective serotonin reuptake inhibitors (e.g. paroxetine and sertraline) [42–44] and the tetracyclic (e.g. mirtazapine) [45,46] and tricyclic antidepressants (e.g. amitryptiline, doxepin) [47,48] have been shown to be efficacious in treating chronic pruritus. In the case of PN as a subgroup of chronic pruritus, a two-arm, proof-ofconcept study comparing the two selective serotonin reuptake inhibitors, paroxetine and fluvoxamine, in 50 PN patients resulted in complete healing of scratch lesions in 14 patients and partial remission in 17 [49]. Opioid receptor antagonists: The m opioid receptor antagonists naloxone (intravenous dosing) or naltrexone (oral administration) has been described to be efficacious in treating PN, with response rates of up to 67.5% [50].

There are some randomized controlled trials reporting the effects on pruritus in different underlying diseases such as cholestatic pruritus [51,52]. However, potential side effects such as dizziness, inability to drive, and nausea have been considered and discussed with the patients prior to the treatment initiation. Immunosuppressive drugs : After failure or contraindication of the above-mentioned drugs, the use of immunosuppressive drugs such as cyclosporine A or methotrexate can be considered in adults. The dose of cyclosporine A is usually 3–5 mg/kg body weight and for methotrexate it is 7.5–20 mg once per week subcutaneously. A combination of cyclosporine A and methotrexate (each in a drastically reduced dosage) with the aim of reducing the side effects of cyclosporine A can be successful. In a case series of 14 patients treated with cyclosporine A, high response rates of greater than 90% have been detected [53]. Strong results have also been reported in a retrospective observation of 13 patients treated with methotrexate [54]. In addition to the case reports of the efficacious use of thalidomide in PN [55], recently two case reports about the use of its successor lenalidomide in treating PN have been reported [56,57].

Other immunosuppressive drugs such as oral tacrolimus have only been reported in single case reports, and thus the evidence of their efficacy is highly limited [58]. The use of systemic steroids as pulse therapy can be considered as an initial therapy in patients with extremely high degree of suffering. However, long-term use is strictly contraindicated due to the known side effects of steroids after continued treatment duration. Future therapies : During the last few years, treatment of PN has come under the focus of the medical community and the pharmaceutical industry, so that several clinical trials on the treatment of PN are currently in progress (DRKS00005594, NCT01963793, NCT02196324). Examples are ongoing trials on neurokinin-1 receptor antagonists aprepitant and serlopitant. As substance P as a major pruritogenic transmitter is the ligand of neurokinin-1


Prurigo nodularis Tsianakas et al.

receptor, these receptor antagonists should have the potential to considerably reduce chronic pruritus in PN. Furthermore, a combination of m-opioid receptor antagonist and k-agonist nalbuphine is currently under observation in a clinical trial on treating PN (NCT02174419, NCT02174432). With respect to the pruritic properties of IL-31 and its increase in PN lesion, a clinical trial of the recently developed IL-4/IL-13 and IL-31 antagonists might be promising as well.

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Summary

The clinical pattern of PN should encourage the treating physicians to find potentially underlying diseases. Successful treatment of these diseases can lead to a rapid improvement in PN. If this approach fails or is not possible, a stepwise scheme has to developed to simplify and categorize a successful treatment of PN, both topically and systemically.

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Acknowledgements The authors thank Emily Burnett for the help in preparation of the manuscript. The work was supported by the Federal Ministry of Education and Research (BMBF; no. 01KG1305)

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Conflicts of interest There are no conflicts of interest.

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Prurigo Nodularis an Update on an Important.1

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