A systematic review of the literature on the treatment of pityriasis rubra pilaris type 1 with TNF-antagonists

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1 DOI: /j x JEADV SHORT REPORT A systematic review of the literature on the treatment of pityriasis rubra pilaris type 1 with TNF-antagonists G. Petrof,* N. Almaani, C.B. Archer, W.A.D. Griffiths, C.H. Smith St John s Institute of Dermatology, Guy s and St Thomas NHS Foundation Trust, London, UK *Correspondence: G. Petrof. gabriela.petrof@kcl.ac.uk Abstract Background Adult pityriasis rubra pilaris (PRP) type 1 is a rare chronic papulosquamous disorder with clinical and histological parallels with psoriasis. Treatment is challenging and recent case reports suggest a potential role for tumour necrosis factor (TNF) antagonists. Objectives Our objective was to systematically review the literature for evidence of efficacy of TNF antagonists in the treatment of adult PRP. Methods We performed a systematic search of the Cochrane library, EMBASE, Pubmed and MEDLINE databases. We defined diagnosis of PRP, classified clinical response and whether this was clearly attributed to TNFantagonists. We also reviewed disease, treatment duration and follow up. Results Sixteen articles were selected for detailed review. From these, 12 articles (13 cases) met our predefined criteria and were included in the systematic review. The authors identified two more cases from their personal archive. A total of 15 evaluable cases were included for analysis. Twelve showed complete response (CR) (80%) to TNF-antagonists with a mean time to maximal response of 5 months. In 10 of the CR cases (83%) this was clearly attributable to TNF antagonist therapy. Conclusion These data indicate that TNF-antagonists may be of value in treating adult type 1 PRP refractory to other systemic agents but selective reporting bias, together with the lack of standard diagnostic criteria and established spontaneous resolution in PRP, prevent any firm recommendations on their place in management. Received: 10 vember 2011; Accepted: 13 January 2012 Conflict of interest Dr Catherine Smith is invited speaker and receives grant research support, not related to this study, from Abbott, Janssen-Cilag, Schering-Plough, Serono, Wyeth and Pfizer. Funding source The authors acknowledge financial support from the Department of Health via the UK National Institute for Health Research (NIHR) Comprehensive Biomedical Research Centre award to Guy s & St Thomas NHS Foundation Trust in partnership with King s College London and King s College Hospital NHS Foundation Trust. Introduction Classical adult pityriasis rubra pilaris (PRP) is a rare chronic papulosquamous disorder characterized by follicular hyperkeratotic papules and followed by widespread orange-red erythema with islands of sparing and palmoplantar keratoderma. Its prevalence is approximately 2.5 per million of population, or 1 case per of the population 1 occurring in all races and with an equal male to female ratio. 2 The aetiology remains unclear. PRP was classified by Griffiths in 1980 based on age and morphology into five clinical entities 3 and later, a 6th HIV-related category was added to this classification (Table 1). 4 The diagnosis remains primarily clinical as the histological features of PRP are largely non-specific. The eruption typically starts on the upper half of the body and spreads caudally usually progressing to with characteristic small islands of sparing. Histopathological features helpful for diagnosis are alternating orthokeratosis and parakeratosis in both vertical and horizontal directions. Other features are hypergranulosis, thick suprapapillary plates, broad rete ridges, narrow dermal papillae and sparse superficial perivascular lymphocytic infiltrate. 5 Treatment is challenging and options vary from topical steroids to a combination of systemic potent agents. In this report we systematically review the published literature on the treatment of PRP with TNF-antagonists to highlight the current practices and evidence for efficacy to enable clinicians to draw parallels for future use of TNF antagonists in the treatment of PRP.

2 e132 Petrof et al. Table 1 The classification of pityriasis rubra pilaris Type menclature Characteristics 1 Classical adult Commonest type (50% of cases). Spreads caudally. The patient is usually erythrodermic with diffuse thickening of the palms and soles. Ectropion often is present. 2 Atypical adult Long duration. Involves a more ichthyosiform pattern in association with hair loss and areas of eczematous changes. 3 Classical juvenile Similar to type 1 but affects children in the first decade. 4 Circumscribed juvenile Review of the literature Materials and methods Affects children, with sharply demarcated areas of follicular hyperkeratosis and erythema on the knees and elbows. Usually does not progress. 5 Atypical juvenile Appears in the first few years of life and is chronic. Characterized by follicular hyperkeratosis, whereas erythema is not prominent feature. The skin on the hands and feet can appear scleroderma-like. 6 HIV-related Symmetrical, pruritic eruption composed of erythematous and desquamating follicular papules. Is associated with lateonset acne conglobata. Identification of articles A systematic electronic literature search in The Cochrane Library, PUBMED, Medline and Embase was performed from January 1999 until October We used pityriasis rubra pilaris (MESH term) to identify all relevant articles. There was no limitation as to article language. The chronological limits were based on the fact that TNF- antagonists were introduced after Definitions We retrieved all cases with definite or likely diagnosis of PRP type 1. A definite diagnosis of adult type PRP meant all three of the following criteria were met: (i) a compatible clinical history; (ii) typical clinical features and or diagnostic histopathology findings; and (iii) clinical photos consistent with PRP. A likely diagnosis met two out of three of these criteria. If less than two criteria were available in the paper the case was regarded as not assessable because of insufficient evidence. In the absence of defined treatment response criteria or objective disease severity tools for PRP, we defined and classified clinical response as follows (i) Complete response (CR) was defined by the use of any of the following terms : dramatic or spectacular improvement, near clearance, almost clear and complete regression supported by photographic evidence showing adequate body surface area; (ii) Partial response (PR) definition was based on the physician s global evaluation of partial clearing or partial response and or photographic evidence showing 50% of skin disease improvement; and (iii) Poor or no response was defined by the use of these terms in the article. Articles which had no sufficient information to classify clinical response were deemed unassessable. The next aspect we reviewed was whether the clinical response could be clearly assigned to the TNF-antagonists or the presence of other confounders played a significant role. If a person has been on immunomodulatory drugs for over 3 months, at a stable dose and disease severity, when a TNF antagonist is introduced, we assign any subsequent response to the TNF antagonist. On the other hand, if systemic therapy (e.g. acitretin, ciclosporin) has been introduced just prior TNF therapy, any subsequent clinical response could not be clearly assigned to the TNF antagonist. Data abstraction We reviewed the abstracts of all 172 citations yielded by the electronic search, excluded 156 articles after title and abstract review. Only cases treated with TNF-antagonists and type 1 PRP were included. From the 16 articles retrieved for full text review (total of 25 cases), 12 papers (13 cases) met the predefined criteria and were included in the systematic review. We also added the authors two cases (total of 15 cases). Four papers, which included 12 cases, were defined as not assessable and excluded (Fig. 1). Disagreements were resolved by discussion between authors. Data was abstracted and tabulated in a two tables created for this systematic review. The first table (Table 2) summarizes the demographics including age, gender, diagnosis (definite or likely), disease duration prior treatment with TNF-antagonists, duration of treatment and follow up. The second table (Table 3) summarizes anti-tnf agent used, concomitant oral immunosuppressant, compartment of improvement (, scaling and or palmoplantar keratoderma) clinical response and if this can be clearly assigned to the TNF-antagonist used. Clinical response was subclassified to primary and maximal. By primary we mean the point of initial skin improvement and by maximal the point of best skin response. Results A total of 15 cases were included in the systematic review. These included five women and 10 men, with a median age of 59 years (30 65) and 56 years (24 79) respectively. Eight of the 15 cases had a definite diagnosis of PRP and seven a likely diagnosis. The mean disease duration for all the cases included in this systematic review was 9 months. Out of the 15 cases,12showedcomplete response (80%), two partial and one no response. From the 12 cases that showed complete response, in 10 of them (83%), this was clearly and solely attributable to TNF antagonist therapy. In

3 Treatment of pityriasis rubra pilaris type 1 with TNF-antagonists e articles identified by literature search in the Cochrane Library, Medline and Embase 156 articles excluded- (not type 1 PRP and not treated with TNF-antagonists) 16 articles (25 cases) reviewed in full text for eligibility 2 additional cases identified from the authors archive 4 articles (12 cases) excluded (did not meet the pre-defined criteria) Figure 1 Flow chart of literature search and identification of relevant articles. 12 articles (15 cases) included in the systematic review Table 2 Table summarising the demographic characteristics including age, gender, diagnosis (definite or likely), disease duration prior treatment with TNF-antagonists, duration of treatment and follow up of the patients included in the review Gender (n) Mean age in years Diagnosis (n) Mean disease duration prior TNF antagonists in months Mean treatment duration with TNF antagonists in months Mean follow up after initiation of treatment with TNF antagonists in months Female (5) 54.6 (30 65, 59) Definite (3) Likely (2) 13.8 (1 54, 8) 7.7 (1.5 9, 8.5) 8.9 (97.5 9, 8.5) Male (10) 55.8 (24 79, 56) Definite (5) Likely (5) 7.2 (0.5 24, 7) 2.8 ( , 2) 8.2 (2 24, 6) All cases (15) 55.4 (24 79, 56) Definite (8) Likely (7) 9.4 (0.5 54, 7) 4.4 ( , 3.5) 8.5 (2 24, 7.5) TNF, tumour necrosis factor. the rest of the patients they have received methotrexate or acitretin for up to 7 months in one case, which may have contributed to improvement. Half of the cases that showed complete response had a definite diagnosis of PRP. Out of all the cases that showed clinical response (PR or CR) the mean time point for primary response was 5 weeks (1 14 weeks). Out of the cases that showed a complete response the mean time point for maximal response was 5 months (4 52 weeks). Collectively Infliximab, 6 13 Etanercept 14,15 and Adalimumab were used individually or in combination with oral immunosuppressants such as methotrexate and acitretin. A combination of one anti-tnf agent with an oral immunosuppressant (acitretin and methotrexate being the commonest) appears to be the treatment of choice in most cases. However, in 40% of cases (six patients) a TNF-antagonist was used as monotherapy with good results. Infliximab is the most commonly used agent, possibly as the experience with its use for other condition such as inflammatory bowel disease and psoriasis has been established over a longer period of time. Infliximab was administered following the psoriasis protocol at week 0, 2, 6 and every 8 weeks thereafter. The standard dose of 5 mg kg was used. severe immediate or long term side effects were reported and treatment was usually well tolerated. Discussion This review attempts to critically assess the reported cases of PRP type 1 treated with TNF-antagonists. It provides some evidence that TNF-antagonists may be of value in treating adult type 1 PRP refractory to immunomodulatory agents. The most evidence exists for infliximab in combination with acitretin, with half of the infliximab receiving cases showing a complete response. However, this may substantially overestimate the benefit of TNF antagonist therapy given the high risk of selective reporting and publication of positive outcomes. It is important to note that all cases were

4 e134 Petrof et al. Table 3 Table summarizing the treatment, response and compartment of improvement Authors Biologic agent Concomitant oral immunosuppressant and when introduced Our case Infliximab MTX (10 mg week) week 22 to today Barth D. Infliximab MTX (15 30 mg week) week 0 6 Eberst E. Infliximab Acitretin (0.3 mg kg) week 28 to 4 Clinical response clearly assigned to TNF blockade? Compartment of improvement Clinical response (weeks) Primary Maximal 14 PR (52) 3 CR (52) 2 CR (4) Guedes R. Etanercept ne t specified 8 CR (20) Liao WC. Infliximab Acitretin (50 mg day, increased to 75 mg day) week 24 to today. Cyclosporine (3 mg kg day) week 8 to 0 Liao WC. Infliximab Acitretin (50 mg day) week 8 to today Lu R. Infliximab Acitretin (50 mg day) week 0 4 Manoharan S. Infliximab MTX (10 mg week) week 6 22 Decreased erythema Decreased erythema 2 CR (30) 2 PR (2) N A response (14) Erythroderma resolved PPK reduced Müller H. Infliximab ne Complete resolution of erythema and follicular hyperkeratosis O Kane D. Adalimumab MTX (15 mg week reduced to 7.5 mg at week 0) week -8 to week 4 Ruiz-Genao D. Infliximab Acitretin (50 mg day) week 20 to 2 Complete resolution of Erythema and scaling subsided Schreml S. Adalimumab ne erythema and scale Seckin D. Etanercept (dose reduced to 25 mg twice weekly after week 12) ne Regression of Walling HW. Adalimumab ne Resolution of erythema Zirbs M. Infliximab ne Erythema and hyperkeratosis faded CR, complete response; MTX, methotrexate; PPK, palmoplantar keratoderma; PR, partial response; TNF, tumour necrosis factor. 2 CR (30) 1 CR (16) 4 CR (4) 6 CR (30) 3 CR (4) 8 CR (12) 6 CR (8) 6 CR (30) severe refractory to other therapies. Out of the evaluable cases only one that showed no response was reported. 9 There are a number of additional factors that also preclude making definite conclusions about the efficacy or otherwise of TNF antagonists in PRP. Firstly, the diagnosis itself can be difficult. In the cases we reviewed only eight had a definite diagnosis, as defined earlier in the Methods section. Specifically only in seven cases was a skin biopsy taken, with most of the earlier reported cases having no histological evidence of PRP. Secondly, we know that 80% of PRP individuals clear within 3 years 2 although a single case of spontaneous resolution after 20 years has been reported. 19 There is therefore the possibility that in some of the cases reported, the resolution of disease may not necessarily be attributable to treatment, but rather represent spontaneous resolution. The cases reported were followed up for short period of time, with only two reporting follow-up over 1 year. Thirdly, the effect of confounders is important. Most cases were treated with oral immunomodulatory agents prior initiation of TNF antagonists and in nine cases (60%) the patients received concomitant oral immunosuppressants.

5 Treatment of pityriasis rubra pilaris type 1 with TNF-antagonists e135 In conclusion, there is some, but potentially highly biased evidence, that TNF antagonist therapy may be of value in type 1 PRP. Prospective clinical data from well-designed clinical studies of adult type PRP are therefore needed to establish accurately the efficacy of TNF antagonists. References 1 Griffiths A. Pityriasis rubra pilaris. Dowling Oration URL (last accessed: 2 January 2012). 2 Griffiths WA. Pityriasis rubra pilaris an historical approach. 2. Clinical features. Clin Exp Dermatol 1976; 1: Griffiths WA. Pityriasis rubra pilaris. Clin Exp Dermatol 1980; 5: Misery I, Faure M, Claidy A et al. Pityriasis rubra pilaris and human immunodeficiency virus infection type 6 pityriasis rubra pilaris? Br J Dermatol 1996; 135: Soeprono FF. Histologic criteria for the diagnosis of pityriasis rubra pilaris. Am J Dermatopathol 1986; 8: Barth D, Harth W, Treudler R et al. Successful treatment of pityriasis rubra pilaris (type 1) under combination of infliximab and methotrexate. J Dtsch Dermatol Ges 2009; 7: Muller H, Gattringer C, Zelger B et al. Infliximab monotherapy as first-line treatment for adult-onset pityriasis rubra pilaris: case report and review of the literature on biologic therapy. J Am Acad Dermatol 2008; 59: S65 S70. 8 Ruiz-Genao DP, Lopez-Estebaranz JL, Naz-Villalba E, Gamo-Villegas R, Calzado-Villarreal L, Pinedo-Moraleda F. Pityriasis rubra pilaris successfully treated with infliximab. Acta Derm Venereol 2007; 87: Lu R, George SJ, Hsu S. Pityriasis rubra pilaris: failure of combination treatment with acitretin and infliximab. Dermatol Online J 2006; 12: Manoharan S, White S, Gumparthy K. Successful treatment of type I adult-onset pityriasis rubra pilaris with infliximab. Australas J Dermatol 2006; 47: Liao WC, Mutasim DF. Infliximab for the treatment of adult-onset pityriasis rubra pilaris. Arch Dermatol 2005; 141: Eberst E., Dandurand M., Stoebner P. et al. Pityriasis rubra pilaire erythrodermique: efficacite de l association acitretine-infliximab. in Annales de Dermatologie et de Vénéréologie 2007; 134: Zirbs M, Kigitsidou E, Seifert F. et al. Successful treatment with infliximab despite positive tuberculosis ELISpot results in a patient with pityriasis rubra pilaris taking prophylactic isoniazid. Clin Exp Dermatol 2011; 36: Seckin D, Tula E, Ergun T. Successful use of etanercept in type I pityriasis rubra pilaris. Br J Dermatol 2008; 158: Guedes R, Leite L. Therapeutic hotline Treatment of pityriasis rubra pilaris with etanercept. Dermatol Ther 2011; 24: Walling HW, Swick BL. Pityriasis rubra pilaris responding rapidly to adalimumab. Arch Dermatol 2009; 145: O Kane D, Devereux CE, Walsh MY. et al. Rapid and sustained remission of pityriasis rubra pilaris with adalimumab treatment. Clin Exp Dermatol 2010; 35: e155 e Schreml S, Zeller V, Babilas P et al. Pityriasis rubra pilaris successfully treated with adalimumab. Clin Exp Dermatol 2010; 7: Abbott RA, Griffiths WA. Pityriasis rubra pilaris type 1 spontaneously resolving after 20 years. Clin Exp Dermatol 2009; 34: