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Biologics for pityriasis rubra pilaris treatment: A review of the literature
Accepted Manuscript Biologics for pityriasis rubra pilaris treatment: a review of the literature Monica Napolitano, MD, PhD, Damiano Abeni, MD, MPH, Biagio Didona, MD PII:
S0190-9622(18)30490-0
DOI:
10.1016/j.jaad.2018.03.036
Reference:
YMJD 12425
To appear in:
Journal of the American Academy of Dermatology
Received Date: 6 February 2018 Revised Date:
21 March 2018
Accepted Date: 25 March 2018
Please cite this article as: Napolitano M, Abeni D, Didona B, Biologics for pityriasis rubra pilaris treatment: a review of the literature, Journal of the American Academy of Dermatology (2018), doi: 10.1016/j.jaad.2018.03.036. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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ACCEPTED MANUSCRIPT
Biologics for pityriasis rubra pilaris treatment: a review of the
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literature
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Monica Napolitano, MD, PhDa, Damiano Abeni, MD, MPHa, and Biagio Didona, MDb
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Rome, Italy
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Correspondence to: Monica Napolitano, MD, PhD, Clinical Epidemiology Unit, Istituto Dermopatico
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dell’Immacolata, IRCCS, Via Monti di Creta 104, 00167, Rome, Italy. Tel +39 06 6646 4305, Fax: +39 06 6646
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4456
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E-mail: [email protected]
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Clinical Epidemiology Unita, and Rare Disease Unit, I Dermatology Divisionb, Istituto Dermopatico
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dell’Immacolata, IRCCS, Via Monti di Creta 104, 00167, Rome, Italy.
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Word count:
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Abstract:200
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Capsule summary:50
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Text:2240
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Fig:1
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Supplemental Tables:2
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Number of references:76
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No reprints requested
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Funding sources: RC 2017-1.2-CRI Rare, Ministry of Health, Italy
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The authors have no conflict of interest to declare
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ACCEPTED MANUSCRIPT ABSTRACT
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Pityriasis rubra pilaris (PRP) is a rare inflammatory papulosquamous skin disease, often refractory to
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conventional therapies. The off-label use of biologics, such as anti-TNF, -IL-12/IL-23, -IL-17 agents, has been
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proven successful, in the last two decades, in PRP treatment.
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Our aim was to analyse the literature for the use of biologics in PRP treatment. We conducted a review by
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“Pubmed” and “clinicaltrial.gov” searches. 68 articles met our selection criteria and were herein discussed. Out
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of 86 PRP patients, the vast majority of which treated with anti-TNF, -IL-12/IL-23, and -IL-17 biologics, either
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alone or in combination therapy, a marked-to-complete response (50-78%), a partial response (11-25%) or
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no/poor response (11-25%) was observed.
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This review has several limitations including small sample sizes, with no shared study design criteria, and the
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fact that -in some instances- PRP may spontaneously resolve. Further, the presence of concomitant therapy
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and/or the lack of detailed data on previous treatments, makes it difficult to strictly define a therapeutic role per
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se of specific biologics in PRP.
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This review shows that biologics may be regarded as a tool for PRP treatment alone or in combination therapy
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although clinical trials are needed to better assess their efficacy and safety.
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ACCEPTED MANUSCRIPT INTRODUCTION
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Pityriasis rubra pilaris (PRP) is a rare, chronic inflammatory skin disease with papulosquamous lesions on a
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diffuse erythematous background, involving trunk, scalp and limbs, with islands of sparing. It is a keratinization
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disorder that often presents with palmoplantar keratoderma and nail dystrophy. PRP is classified in six clinical
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types, i.e. Type I, classical adult and most common form; Type II, an atypical adult entity; Type III, IV and V,
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represent classical, circumscribed and atypical juvenile forms; and Type VI, associated to HIV infection.
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PRP is predominantly an acquired disease, but familial cases have been described, such as autosomal
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dominant forms with caspase recruitment domain (CARD) 14 gain-of function mutations4,5,8-10 with associated
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NFkB activation in the skin.
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The etiology of PRP is unknown, although there have been hypothesized roles for vitamin A deficiency,
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dysregulated immune response to superantigens, tumor necrosis factor (TNF), and IL-12/23 axeses.4,11-15
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Triggers reported include a variety of comorbidities.4,11 Hystologically, PRP can show a “checkerboard pattern”
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of both vertical and horizontal orthokeratosis and parakerathosis, in addition to hypergranulosis. PRP can be
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self-limiting and, especially in Type I cases, may spontaneously heal in 2-3 years.4
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Conventional treatments for PRP include retinoids, phototherapy, emollients, corticosteroids, cyclosporin A
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(CsA), and methotrexate (MTX).4,6-7,14
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Over the last two decades, biologic agents have been widely used in dermatologic diseases such as psoriasis,
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and off-label, in several dermatologic diseases including PRP.4,14-19
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As PRP is a rare disease (incidence between 1:5000 and 1:50.000 per year),4 all available data on the use of
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biologics in its treatment are limited to published case reports and case series; in most instances, such
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patients have shown a successful and prompt clearance of skin lesions.
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We present a review of all biologics that have been reported in PRP treatment including anti-TNF agents, such
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as infliximab, etanercept, and adalimumab, 4,14,18-19 ustekinumab,4, 14,20-21 and secukinumab. 4,14,22-24
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ACCEPTED MANUSCRIPT METHODS
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A review of the literature was conducted by multiple PubMed searches using the key words “pityriasis rubra
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pilaris”; with publication date limits from 01/01/1999 to 01/30/2018. Retrieved references were critically
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appraised by two dermatologists, i.e. M.N and B.D. The inclusion criteria were original articles, reports, letters
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and review articles, English language-only, reporting the treatment of PRP patients with biologics, such as
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monoclonal antibodies and recombinant fusion proteins, alone or in combination therapy with conventional
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drugs. Articles judged irrelevant on the basis of title, abstract and/or text, were excluded from the review. In
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addition, few reviews on relevant topics, such as pityriasis rubra pilaris, TNF inhibitors, and IL-12/23/17
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pathways, were included in the review. Moreover, a search of the website Clinicaltrials.gov was performed up
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to 01/30/2018.
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ACCEPTED MANUSCRIPT RESULTS
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A total of 327 articles were retrieved by multiple PubMed searches conducted until 01/30/2018 using the
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“pityriasis rubra pilaris” keywords. A total of 68 articles were eligible for review, following the criteria described
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above. We excluded 2 articles, as not fully relevant, and a single article,25 due to unavailability of full-length
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text, for further reviewing. A total of 55 case reports/case series, 3 case reports and reviews, and 7 review
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articles, were selected (Fig. 1). We herein reviewed the effects of biologics on a total of 86 type I-V PRP
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patients. Diagnosis of PRP was, in most cases, based on both clinical features and histological analysis. With
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the exception of 5 out of 86 patients, in which biologics were used as a first-line therapy, such molecules were
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utilized in patients refractory to conventional therapies (Supplemental Tables I-II). The dose of biologics used
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for PRP treatment mostly follows the FDA-approved guidelines for other dermatologic diseases such as
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psoriasis (Supplemental Tables I-II). Please note that a single patient may be listed independently, in both the
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text and Supplemental Tables, if treated with more that one biologic agent.
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Effect of anti-TNF agents
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Infliximab
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The present review allowed to assess that, among the anti-TNF biologic agents, infliximab was the most
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commonly used, at the prevalent dose of of 5 mg/kg for few to several weeks (Supplemental Table I). A total of
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37 patients (25 type I, 1 type II, 2 type III, 1 Type IV and 8 unknown type PRP) were treated with infliximab, as
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either refractory to other therapies (33 patients) or as first line therapy (4 patients).19,24,26-46 Their mean age,
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unspecified for 1 patient, was 54.1 years. Men were 18, women 14, gender unspecified for 5 patients.
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Concomitant treatments, present in about 60% of cases, were mainly represented by oral acitretin,
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metothrexate (MTX), and topical and/or systemic corticosteroids (Supplemental Table I). The observed clinical
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response, in few to several weeks, was marked (MR>75% clearing) to complete (CR>95% clearing) in 25
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patients (68%), partial (PR= 50-75% clearing) in 6 patients (16%), and none/poor in 6 patients (16%). Relapse
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of skin lesions was observed in two patients, the first, in which the reintroduction of acitretin restored a CR35
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ACCEPTED MANUSCRIPT and the second who suffered a partial relapse at 3 months while treated with concomitant therapy
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(Supplemental Table I). 41
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Side effects/newly diagnosed disease, occurred in 6/36 patients, and were represented by transitory edema,
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weight increase, new-onset vitiligo, rash/dyspnea/tachicardia, renal insufficiency/skin infections. A small cell
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lymphocytic leukemia was diagnosed 4 weeks after the beginning of infliximab treatment, in a patient
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previously treated for months with MTX, CsA and prednisone (Supplemental Table I). 44
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Etanercept
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Treatment with etanercept was used in a total of 22 patients (11 type I, 2 type II, 1 type III, 1 type IV, 2 type V,
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5 unknown type PRP), all refractory to previous therapies.19-20,35,40-42,47-54 The mean age was 43 years; 11
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patients were male and 11 females. Concomitant treatments, mainly acitretin and MTX, were present in about
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50% of cases. A MR/CR was obtained in 16 patients (72.8%), a PR in 3 patients (13.6%) and none/poor in 3
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patients (13.6%). Four patients showed relapse of skin lesions. One patient relapsed from a CR following
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discontinuation of etanercept, and then reached a PR/CR after its reintroduction;49 another one relapsed from
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a CR at week 16 of treatment;35 a patient relapsed from a CR, 1 month after etanercept cessation,51 and a
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patient relapsed from PR, at week 16 of treatment (Supplemental Table I). 20 Side effect of arthritis aggravation
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occurred in 1 patient out of 21.
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Adalimumab
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A total of 20 patients were treated with adalimumab (9 type I, 2 type II, 1 type IV and 8 unspecified-type PRP)
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as they were all refractory to other therapies.11,19,20,40,42,52,55-64 Adalimumab was administered subcutaneously,
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in most cases, at the dose of 80 mg at week 0 and then 40 mg twice-monthly for several weeks to a few
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months (Supplemental Table I). Concomitant treatments, mainly acitretin, MTX, were administered in 7 cases.
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Mean age was 52 years, and there were 11 males and 9 females. The clinical response to adalimumab, in a
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few weeks, was MR/CR in 10 patients (50%), a PR in 5 patients (25%), and none/poor in 5 patients
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(25%).Three patients showed a relapse: the first after 2 months since PR;59 the second 3 months after
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showed a relapse at week 14, following a CR, after discontinuing phototherapy and steroids11 (Supplemental
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Table I). Side effects/newly diagnosed diseases occurred in three patients, and were gastrointestinal side
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effects/elevation of liver enzymes, follicular non-Hodgkin (NH) lymphoma, and toxic shock syndrome
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(Supplemental Table I).
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Effect of anti IL-12/IL-23, and IL17A agents
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Ustekinumab
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Among the anti IL-12/IL-23, and IL17A agents,13 ustekinumab was the most commonly used. In particular, 12
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studies assessed the efficacy of ustekinumab for the treatment of a total of 18 patients, mean age 49 years,
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with 11 males and 7 females (Supplemental Table II). 12 type I, 1 type II, 1 type IV, 3 patients with familiar,
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and 1 patient with unspecified PRP.9-10,12,20-21,43,65-69 All patients, but one, were refractory to previous therapies.
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Ustekinumab was administered, in most cases, at the dose of 45 mg at weeks 0, 4, and then quarterly for a
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total of several weeks/months. In 16/18 patients ustekinumab was administered alone, and in 2 cases, along
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with acitretin (Supplemental Table II). The clinical response to ustekinumab was MR/CR in 14 patients (78%),
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PR in 2 patient (11%) and none in 2 patients (11%). Interestingly, no side effects were reported. Relapse of
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disease, among the responders, was observed in one patient10 who, after achieving a CR in 12-24 weeks,
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returned to baseline condition at week 30. The eventual dose increase from 45 to 90 mg ustekinumab yielded
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a PR. Further, in another treated patient, a mild relapse of papular lesions of the legs was reported during the
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follow up period.21
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Secukinumab
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Three patients of 67, 33, and 58 yrs old (M, F, M, respectively), unresponsive to previous therapies,22-24 were
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reported being treated with secukinumab 300 mg/week for 5 weeks then monthly22-23 or 300 mg/month24 and,
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in two patients,23-24 also with concomitantly therapy (Supplemental Table II). A CR was observed, in two
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a side effect in one patient.23
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Other biologics
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Efalizumab, that inhibits the CD11a subunit of LFA-1 on T lymphocytes,70 a drug withdrawn from the market in
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2009, was reported in two patients with PRP: one PR71 and one exacerbation of symptoms.70
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Alefacept is a fusion protein of the CD2-binding portion of LFA-3 linked to the IgG Fc. Two PRP patients
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received i.m. Alefacept injections, 15 mg/week for 12 weeks, with no clinical response.42
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Clinical trials on the use of biologics in PRP
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A clinicaltrials.gov search, conducted up to 01/30/2018, using the terms “pityriasis rubra pilaris”; and “pityriasis
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rubra pilaris” AND “biologics”, retrieved: 1) a pilot study of Alefacept for PRP treatment, sponsored by the
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Icahn School of Medicine at Mount Sinai, NY; ended in 2009, that failed to enroll patients, and 2) a “single arm,
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open-label exploratory clinical trial on secukinumab for the treatment of adult onset PRP”, not yet recruiting,
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and sponsored by the Mayo Clinic. To the best of our knowledge, no published peer-reviewed data from
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clinical trials with biologics for PRP are yet available.
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ACCEPTED MANUSCRIPT DISCUSSION
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This review analysed all available published data on the off-label use of biologics in the treatment of PRP.
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From the present searches, the biologics used predominantly consisted of anti-TNF-, anti IL-12/23-, and anti-
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17A- agents, in keeping with previous articles and reviews.4,14,19,32,42,70-71
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Interestingly, treatment of PRP with biologics has given successful results in the majority of cases. From the
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reviewed data, infliximab is the most used biologic agent in PRP treatment, with a high percentage of MR/CR,
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adalimumab yielded the lowest percentage of MR/CR among biologics, and ustekinumab was the most
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commonly administered biologic agent in the absence of concomitant therapy, nothwithstanding a high
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percentage of MR/CR.
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In a few studies, distinct biologic agents have been used sequentially, in the same patients, and evoked either
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no clinical response at all, or only efficacy with a specific biologic agent (Supplemental Tables I-II). Further,
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treatment with infliximab evoked a PR but the occurrence of side effects prompted the authors to switch to
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etanercept with a CR;41 infliximab yielded a CR that was maintained when it was switched, for practical
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reasons, to adalimumab;40 the PR to adalimumab was maintained switching to infliximab;42 a PR to infliximab,
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but with the development of side effects, prompted the switch to ustekinumab with a MR/CR.43
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Although most of the conventional drugs used for the treatment of PRP may show important side effects,
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biologics have intrinsic risks due to immune modulation / suppression activity. In particular it has been reported
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an increased risk of serious infections, and of developing several malignancies including lymphomas.16-17,72-73.
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In this review, 2 out of 86 patients treated with biologics were diagnosed with small cell lymphocytic leukemia
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or follicular NH lymphoma, weeks or months, respectively, following treatment with anti-TNF inhibitors. Such
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tumors could either be sporadic or favoured by previous/concomitant therapy with immune suppressants
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and/or by biologic agents. Noteworthy, cases of paraneoplastic PRP have been reported, although very rarely,
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in association with solid or hematologic malignancies.74
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ACCEPTED MANUSCRIPT Few cases of PRP-like skin lesions induced by biologic agents have been described. A patient with
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Takayasu’s arteritis developed PRP-like skin lesions, following infliximab treatment, part of combination
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therapy, that disappeared after infliximab discontinuation.75 Efalizumab induced an exacerbation of PRP-like
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skin lesions.70 Bevacizumab, a mAb against VEGF, not used for PRP treatment, also has been reported to
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induce a PRP-like eruption.76
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The present review has several limitations mostly due to the fact that the total number of PRP patients treated
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with biologics is quite small i.e. a total of 86. The source of the vast majority of the scientific collected data is
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represented by single case reports, with the exception of rare case series. Diagnosis was based, in most
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cases, upon both clinical and histologic criteria. Also other limitations include the lack of well-defined
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enrollment criteria in the case series. Some data, such as PRP type, length of study, follow-up period, disease
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duration prior to therapy with biologics, side effects and a detailed therapeutic scheme of treatment were
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variably detailed amongst the reports reviewed. Washout period, between previous treatments, was also not
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clearly presented in most reports reviewed. It is difficult to meaningfully assess the effect of single biologic
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agents, per se, in the clinical response of PRP patients as the vast majority of cases had concomitant therapy
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or short duration of therapy with a particular biologic agent.
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Overall the results obtained by several groups in treating PRP with biologics are encouraging, although
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randomised controlled clinical trials are needed for a better assessment of their therapeutic efficacy and safety
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in PRP.
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38) Adnot-Desanlis L, Antonicelli F, Tabary T, et al. Effectiveness of infliximab in pityriasis rubra pilaris is associated with pro-inflammatory cytokine inhibition. Dermatology. 2013;226:41-6. 39) Mattox AR, Chappell JA, Hurley MY. New-onset vitiligo during long-term, stable infliximab treatment of pityriasis rubra pilaris. J Drugs Dermatol. 2013;12:217-9. 40) Vujic I, Richter L, Bartsch K, et al. Pityriasis rubra pilaris types 1 and 2: different responses to
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treatment with TNF-alpha antagonists. Eur J Dermatol. 2013;23:895-6.
41) López-Ferrer A, Dalmau J, Fernández-Figueras MT, et al. Pityriasis rubra pilaris triggered by
285
photodynamic therapy with response to tumor necrosis factor α-blocking agents and acitretin. Cutis.
286
2014;93:E6-7.
SC
284
42) Eastham AB, Femia AN, Qureshi A, et al. Treatment options for pityriasis rubra pilaris including
288
biologic agents: a retrospective analysis from an academic medical center. JAMA Dermatol.
289
2014;150:92-4.
292 293 294 295
ustekinumab and acitretin combination therapy. J Dermatol. 2015;42:830-1.
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291
43) Byekova Y, Sami N. Successful response of refractory type I adult-onset pityriasis rubra pilaris with
44) Krase IZ, Cavanaugh K, Curiel-Lewandrowski C.Treatment of Refractory Pityriasis Rubra Pilaris With Novel Phosphodiesterase 4 (PDE4) Inhibitor Apremilast. JAMA Dermatol. 2016;152:348-50. 45) Karadag AS, Kavala M, Ozlu E, et al. Erythrodermic pityriasis rubra pilaris: Dramatic response to
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infliximab therapy. Indian J Dermatol Venereol Leprol. 2016;82:112. 46) Paganelli A, Ciardo S, Odorici G, et al. Efficacy of ustekinumab after failure of infliximab CT-P13 in a
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HLA-Cw6-positive patient affected by pityriasis rubra pilaris: monitoring with reflectance confocal
298
microscopy (RCM) and optical coherence tomography (OCT). J Eur Acad Dermatol Venereol.
299
2017;31:e249-e251.
300 301 302 303
AC C
296
47) Davis KF, Wu JJ, Murase JE, et al. Clinical improvement of pityriasis rubra pilaris with combination etanercept and acitretin therapy. Arch Dermatol. 2007;143:1597-9. 48) Seckin D, Tula E, Ergun T. Successful use of etanercept in type I pityriasis rubra pilaris. Br J Dermatol. 2008;158:642-4.
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rheumatoid arthritis. Acta Derm Venereol. 2012;92:399-400.
RI PT
309
51) Kim JH, Park MC, Kim SC. Etanercept-induced clinical remission of type II pityriasis rubra pilaris with
52) Chiu HY, Tsai TF. Pityriasis rubra pilaris with polyarthritis treated with adalimumab. J Am Acad Dermatol. 2013;68:187-8.
SC
308
Ther. 2011;24:285-6.
53) Kim BR, Chae JB, Park JT, et al. Clinical remission of pityriasis rubra pilaris with adalimumab in an adolescent patient. J Dermatol. 2015;42:1122-3.
M AN U
307
50) Guedes R, Leite L. Therapeutic hotline. Treatment of pityriasis rubra pilaris with etanercept. Dermatol
54) Lora V, De Felice C, Cota C, et al. A case of juvenile pityriasis rubra pilaris type III successfully treated with etanercept. Dermatol Ther. 2017 Nov 28. doi: 10.1111/dth.12577. 55) Walling HW, Swick BL. Pityriasis rubra pilaris responding rapidly to adalimumab. Arch Dermatol. 2009;145:99-101.
TE D
306
Am Acad Dermatol. 2008;59:S113-4.
56) 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:e155-6. 57) Schreml S, Zeller V, Babilas P, et al. Pityriasis rubra pilaris successfully treated with adalimumab. Clin
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49) Cox V, Lesesky EB, Garcia BD, et al. Treatment of juvenile pityriasis rubra pilaris with etanercept. J
Exp Dermatol. 2010;35:792-3.
58) Zhang YH, Zhou Y, Ball N, et al.Type I pityriasis rubra pilaris: upregulation of tumor necrosis factor
AC C
304
alpha and response to adalimumab therapy. J Cutan Med Surg. 2010;14:185-8. 59) Schmitt L, Inhoff O, Dippel E. Oral alitretinoin for the treatment of recalcitrant pityriasis rubra pilaris. Case Rep Dermatol. 2011;3:85-8. 60) Wassef C, Lombardi A, Rao BK. Adalimumab for the treatment of pityriasis rubra pilaris: a case report. Cutis. 2012;90:244-7. 61) Bravo EA , Carrion L, Paucar SM, et al. Successful treatment of pityriasis rubra pilaris with adalimumab- case report. Dermatol Online J. 2014;20:22374.
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RI PT
335
64) Nic Dhonncha E, Fadalla K, Moriarty B, et al. High grade follicular lymphoma in a patient receiving adalimumab and methotrexate for pityriasis rubra pilaris. J Dermatolog Treat. 2017;28:764-765. 65) Wohlrab J, Kreft B. Treatment of pityriasis rubra pilaris with ustekinumab. Br J Dermatol. 2010;163:655-6.
SC
334
manifestation. J Dermatol. 2017;44:478-479.
66) Ruiz Villaverde R, Sánchez Cano D. Successful treatment of type 1 pityriasis rubra pilaris with ustekinumab therapy. Eur J Dermatol. 2010;20:630-1.
M AN U
333
63) Kitayama N, Nakamizo S, Kaku Y, et al. Case of pityriasis rubra pilaris with annular pattern as an early
67) Di Stefani A, Galluzzo M, Talamonti M, et al. Long-term ustekinumab treatment for refractory type I pityriasis rubra pilaris. J Dermatol Case Rep. 2013;7:5-9
68) Chowdhary M, Davila U, Cohen DJ. Ustekinumab as an alternative treatment option for chronic pityriasis rubra pilaris. Case Rep Dermatol. 2015;7:46-50.
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332
cases from Lebanon. Int J Dermatol. 2014;53:434-9.
69) Di Lernia V, Ficarelli E, Zanelli M. Ineffectiveness of tumor necrosis factor-α blockers and ustekinumab in a case of type IV pityriasis rubra pilaris. Indian Dermatol Online J. 2015;6:207-9 70) Klein A, Szeimies RM, Landthaler M, et al. Exacerbation of pityriasis rubra pilaris under efalizumab
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62) Marrouche N, Kurban M, Kibbi AG, Abbas O. Pityriasis rubra pilaris: clinicopathological study of 32
therapy. Dermatology. 2007;215:72-5. 71) Gómez M, Ruelas ME, Welsh O, et al. Clinical improvement of pityriasis rubra pilaris with efalizumab
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in a pediatric patient. J Drugs Dermatol. 2007;6:337-9. 72) Kopylov U, Afif W. Risk of infections with biological agents. Gastroenterol Clin North Am. 2014;43:50924. 73) Hawryluk EB, Linskey KR, Duncan LM, et al. Broad range of adverse cutaneous eruptions in patients on TNF-alpha antagonists. J Cutan Pathol. 2012;39:481-92. 74) Bar-Ilan E, Gat A, Sprecher E, et al. Paraneoplastic pityriasis rubra pilaris: case report and literature review. Clin Exp Dermatol. 2017;42:54-57.
17
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75) Salman A, Sonmez Y, Sahin H, et al. Infliximab-induced cutaneous eruption resembling pityriasis rubra pilaris in a patient with Takayasu's arteritis. Dermatol Ther. 2017;30: e12443. 76) Brown S, Fletcher JW, Fiala KH. Bevacizumab-induced pityriasis rubra pilaris-like eruption. Proc (Bayl Univ Med Cent). 2016;29:335-6.
AC C
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TE D
M AN U
SC
RI PT
360
18
ACCEPTED MANUSCRIPT FIGURE LEGENDS
362
Fig. 1
363
Flow diagram of search selection
AC C
EP
TE D
M AN U
SC
RI PT
361
AC C
EP
TE D
M AN U
SC
RI PT
ACCEPTED MANUSCRIPT
ACCEPTED MANUSCRIPT Table I Summary of studies on anti-TNF agents for PRP treatment
Side effects /NDD
antibiotics whirpool ther. topical steroids
MR in 3 days2wks
none
topical steroids
topical steroids whirpool therapy
MR in 2 wk
none
topical steroids UVB, acitretin etretinate
topical steroids whirpool therapy UVB, a.histamines
MR in 1 wk
none
acitretin +/- CsA corticosteroids a.histamines whirpool baths
acitretin 25 mg twice daily then 25 mg 3 times/wk
6 mo
acitretin, emollients topical tacrolimus antihistamines
acitretin 50 mg/day
PR in >2 wks
9 wks
none
acitretin 25 mg twice/day
none
77/M
infliximab inf. 5mg/kg at mo 0, 1
none
65/M
infliximab inf. 5mg/kg at mo 0, 1
74/F
infliximab inf. 5mg/kg at mo 0, 1
I
77/M
infliximab inf. 5mg/kg at wk 0, 4, 8, 14, 22
I
53/M
infliximab inf. 5mg/kg at wk 0, 2
56/M
infliximab inf. 5mg/kg at wk 0, 2, 6, 14
Previous treatments
Concomitant treatments
SC
2 mo
>6 mo
MR to CR in 2-22 wk
none
acitretin 50 mg/day till wk 2
MR in 6-30 wk
none
retinoids MTX, CsA emollients antihistamines
none
MR at wk 2 CR in 10 mo residual PP keratod.
none
none
emollients
I
59/F
infliximab inf. 5mg/kg at wk 0, 2, 6, 14, 22, 30
8 mo
corticosteroids salicilic acid a.histamine, MTX fumaric acid mycophenolate m.
MTX 10 mg/wk at wk 6-22 topical salicilic a. betamethasone
Ruiz-Genao et al. 2007
I
63/F
infliximab inf. 5mg/kg at wk 0, 2, 6, 14, 22, 30
7 mo
topical steroids CsA acitretin
Ruzzetti et al. 2008
III
33/F
infliximab inf. 5mg/kg at wk 0, 2, 6, and every 8 wks
25 yrs
Muller et al. 2008
I
32/M
infliximab inf. 5mg/kg at wk 0, 2, 6, 12
2 wks
AC C
Follow-up period
MR at >2wk till 8 mo
Manoharan et al. 2006
EP
Lu et al. 2006
Disease duration prior to therapy
RI PT
Biological agent
Drosou et al. 2003
Liao et al. 2005
Clinical response
Age/sex
M AN U
PRP Type
TE D
Study
4 mo
2 yr
UVB, Ultraviolet B; PUVA, Psoralen-ultraviolet A; CsA, Cyclosporin A; MTX, Methotrexate; GC, glucocorticoids; CR, complete response; MR, marked response; PR, partial response NDD, Newly Diagnosed Disease
MR/CR at wk 1-14
Continued
ACCEPTED MANUSCRIPT Table I Cont’d
Age/sex
Biological agent
Disease duration prior to therapy
Barth et al. 2009
I
65/F
infliximab 5mg/kg X 3
Gemmeke et al. 2010
I
41/M
infliximab inf. 5mg/kg at wk 0, 2, 6
Garcovich et al. 2010
I
30/F
8 wks
I
63/M
infliximab inf. 5mg/kg at wk 0, 2, 6, and every 8 wks (tot 17 wks) infliximab inf. 5mg/kg at wk 0, 2, 6, and every 8 wks (tot 6 wks)
I
50/M
infliximab inf. 5mg/kg at wk 0, 2, 6, and every 8 wks (tot 24 wks)
4 wks
Dessinioti et al. 2011
III
27/F
infliximab inf. 5mg/kg at wk 0, 2, 6 and every 8-7 wks up to 2.5 yrs
14 yrs
Zirbs et al. 2011
I
56/M
infliximab inf. 5mg/kg at wk 0, 2, 6, 14, 22, 30 and every 12 wks
Adnot-Desanlis et al. 2013
I
29/
infliximab inf. 5mg/kg at wk 0, 2, 6, and every 6 wks
I
39/
I
57/
I
51/
Vujic et al. 2013
I
II
topical/systemic c.steroids, MTX
MTX 15-30 mg i.v./wk
topical and systemic c.steroids systemic c.steroids
c.steroids up to 2 wk emollients none
systemic c.steroids MTX
systemic c.steroids
M AN U
4 wks
>6 mo
Concomitant treatments
Follow-up period 1 yr
Clinical response
Side effects /NDD
MR at wk 2 CR at 1 yr PR at wk 2
transitory leg edema at wk 2
1 yr
MR at wk 2
none
none
1 yr
MR at wk 2
none
acitretin 0.2 mg/kg/day at wk 20-24
1 yr
MR at wk 4 relapse at wk 20 CR at wk 24
none
PR to CR
weight increase
acitretin isotretinoin+/NB-UVB isoniazid 300 mg/day (TB Elispot +)
2 wks
none
none
1 yr
CR at wk 6
none
infliximab inf. 5mg/kg at wk 0, 2, 6, and every 6 wks
4 wks
acitretin
none
1 yr
CR at wk 36
none
infliximab inf. 5mg/kg at wk 0, 2, 6, and every 6 wks
87 wks
acitretin CsA
none
1 yr
CR at wk 66
none
infliximab inf. 5mg/kg at wk 0, 2, 6, and every 6 wks
9 wks
acitretin
none
1 yr
CR at wk 42
none
acitretin topical steroids
none
MR-CR
MTX 20 mg/wk+ acitretin 25 mg/day
none
EP
TE D
acitretin topical steroids salicilic acid emollients
AC C
Mattox et al. 2013
2 wks
Previous treatments
RI PT
PRP Type
SC
Study
60/M
infliximab inf. 5-10 mg/kg every 5-6 wks for 27 mo
66/F
infliximab inf. 5 mg/kg at wk 0, 2, 6, and every 8 wks up to 16 wk
4 mo
topical, oral, i.v. corticosteroids NB-UVB, CsA adalimumab
66/F
infliximab inf. 5 mg/kg at wk 0, 2, 6
17 yrs
oral steroids, retinoids, a.histam
PR at wk 6 CR at wk 30
new-onset vitiligo at wk 27
MR/CR at wk 2-6
Continued
ACCEPTED MANUSCRIPT Table I Cont’d
Study
PRP Type
Petrof et al. 2013
Age/sex
Biological agent
Disease duration prior to therapy
Previous Concomitant treatments treatments
Lopez-Ferrer et al. 2014
Clinical response
MTX 10 mg/wk from wk 22
PR at 14 to 52 wks
photodynamic therapy, CsA topical steroids
acitretin 25 mg/day from wk 4
PR in 2 mo partial relapse at mo 3
infliximab inf. 5 mg/kg
I
Follow-up period
infliximab inf. 5 mg/kg at wk 0, 4 up to 2 mo
I
56/F
infliximab inf. 5-7 mg/kg at wk 0, 2, 6, and every 8 wks
12 mo
CsA adalimumab + CsA
MTX 12.5 mg/wk+ acitretin 25 mg/day
PR in 6 wks
I
56/M
infliximab inf. 5 mg/kg at wk 0, 2, 6, and every 8 wks
3 yr
prednisone acitretin+MTX
1) acitretin 50 mg/day 2) MTX 15 mg/wk
PR in 2 wk MR in 2 wk
I
66/F
infliximab inf. 5 mg/kg at wk 0, 2, 6, and every 8 wks
2 wk
I
50/M
infliximab inf. 5-7 mg/kg at wk 0, 2, 6, and every 8 wks
I
84/M
infliximab inf. 5 mg/kg at wk 0, 2, 6, and every 8 wks
Di Lernia et al. 2015
IV
29/F
infliximab inf. 5mg/kg at wk 0, 2, 8
Byekova et al. 2015
I
75/M
infliximab inf. 5 mg/kg at wk 0, 2, 6 and every 8 wk
Krase et al. 2016
70/M
infliximab inf. 5 mg/kg at wk 0
Karadag et al. 2016
31/F
infliximab inf. 5 mg/kg at wk 0, 2, 6, and every 8 wk up to 1 yr
Paganelli et al. 2017
I
78/F
infliximab CT-P13 inf. 5 mg/kg at wk 0, 2, 6 and every 8 wk
Davenport et al. 2017
I
58/M
infliximab 5 mg/kg at wk 0, 2, 6, 14
SC
M AN U
acitretin
acitretin+ prednisone
acitretin 50mg/day
3 yr
MR/CR in 2 wk
8 mo
acitretin+ prednisone
acitretin 50 mg/day
17 mo
MR/CR in 4 wk
CsA, MTX adalimumab etanercept
none
10 mo
none
«systemic therapies»
8 mo
acitretin, MTX prednisone, CsA
4 yrs
systemic retinoids none PUVA, NB-UVB retinoids+NB-UVB MTX topical and oral retinoids,none NB-UVB, PUVA, CsA, MTX topical GC, acitretin MTX, NB-UVB
CsA, prednisone
acitretin 25-50 mg/day
treat. discontinued for rash, dyspnea, bradicardia at mo 2
MR in 12 wk
MTX 20 mg/wk
4 yr
TE D
EP
AC C
Brooke Eastham et al. 2014
RI PT
62/M
Side effects /NDD
2 yr
minimal response then discontinued at wk 14
renal insuff. skin infections from wk 14
PR, discontinued
small cell lymphocytic leukemia at wk 4
MR/CR in 2 wks
none
none
Continued
ACCEPTED MANUSCRIPT Table I Cont’d
Age/sex
O’Kane et al. 2010
+psoriatic arthritis
Schreml et al. 2010
Disease duration prior to therapy 2 wks
Previous Concomitant treatments treatments topical and systemic steroids
adalimumab s.c. 80 mg at wk 0, 40 mg at wk 1, and every second wk, for 32 wks
24/M
adalimumab s.c. 80 mg at wk 0 then 40 mg every 2 wks
MTX
MTX 7.5 mg/wk
<4 mo
CR at wk 4
72/M
adalimumab s.c. 80 mg at wk 0 then 40 mg every 2 wks, for a total of 12 injections
acitretin topical and systemic steroids PUVA, MTX
none
1 mo
CR at wk 4
2 yrs
topical steroids calcipotriol, UVB isotretinoin isotretinoin+ topical steroids
3 yrs
steroids, MTX bath PUVA acitretin, CsA
24/F
adalimumab s.c. 80 mg at wk 0 then 40 mg every 2 wks, for 4 mo
Schmitt et al. 2011
I
74/F
adalimumab s.c. 40mg every 2 wk up to 2 mo
Ivanova et al. 2012
I
37/F
adalimumab s.c. 80 mg at wk 0, 40 mg at wk 1 and every 2 wks, up to 8 mo
Wassef et al. 2012
I
62/M
adalimumab s.c. 40 mg every 2 wks up to 3 mo
2 yrs
topical steroids MTX, vit D UVB, PUVA
adalimumab s.c. 40mg every 2 wks, for 2 mo then new cycle at mo 3
8-9 mo
acitretin etanercept
AC C
EP
TE D
I
+polyarthritis
none
Clinical response
72/M
Zhang et al. 2010
Chiu et al. 2013
Follow-up period
RI PT
Walling et al. 2009
Biological agent
SC
PRP Type
M AN U
Study
24/F
topical steroids NB-UVB
Side effects /NDD
MR/CR at wk 8-32
none
none
PR at 4 wks CR at mo 4
PR in 2 mo then relapse
topical steroids NB-UVB
none
2 mo
gastrointestinal side effects elevation of liver enzymes
CR at wk 4 relapse at wk 14 (after discontinuing NB-UVB and steroids) CR at 16 wk after their reintroduction). CR in 3 mo
acitretin 25 mg every second day
PR at wk 2 relapse at mo 3 after discontinuation PR after reintroduction
Continued
ACCEPTED MANUSCRIPT Table I Cont’d
Age/sex
Biological agent
I
66/F
adalimumab s.c. 80 mg, then 40 mg bimonthly for 8 wk
4 mo
topical, oral, i.v. corticosteroids NB-UVB, CsA
II
66/F
adalimumab s.c. 40 mg bimonthly for 24 mo
17 yr
oral steroids, retinoids a.histamines infliximab (CR)
none
I
56/F
adalimumab s.c. 50 mg/wk
CsA
CsA 100 mg twice/day
PR at 6 wk
51/M
adalimumab s.c. 80 mg at wk 0 then 40 mg every other wk for 7 mo
none
MR/CR at 4 wk
66/M
adalimumab
17/M
adalimumab s.c. 80 mg, then 40 mg every other wk, then every 3 wk for 9 mo
29/F
adalimumab s.c. 80 mg, then 40 mg at wk 1, then every 2 wk for 16 wks
Kitayama et al. 2017
59/M
adalimumab s.c. 80 mg/2 wk
Dhonncha et al. 2017
52/M
adalimumab s.c. 80 mg at wk 0 then 40 mg/wk for 3 mo, every other wk up to 18 mo
Marrouche et al. 2014
II
Kim et al. 2015
Di Lernia et al. 2015
Maloney et al. 2017
IV
2 wks
Follow-up period
none
oral c.steroids antihistamines acitretin emollients
>2 yr
No relapse of infliximabinduced CR
oral c.steroids phototherapy acitretin, CsA etanercept
none
CR at 4 wk
CsA, MTX
none
none
1 mo
c.steroids, UVB retinoids topical Vit D3
MTX 6 mg/w
PR
7 wks
acitretin
1)
PR at 3 mo
2)
acitretin 40 mg/day MTX 15 mg/wk
56/M
adalimumab s.c. 40 mg x 5 for 8 wks
prednisone acitretin
acitretin 10 mg/day
I
66/F
adalimumab s.c. 40 mg every other wk for 12 wks
acitretin
none
none
I
68/M
adalimumab s.c. 40 mg every other wks for 12 wks
acitretin MTX, CsA apremilast
none
none
I
Side effects /NDD
poor/none
topical steroids MTX
13 yrs
Clinical response none
RI PT
SC
Bravo et al. 2014
Previous Concomitant treatments treatments
M AN U
Brooke Eastham et al. 2014
TE D
Vujic et al. 2013
Disease duration prior to therapy
EP
PRP Type
AC C
Study
2 yr
follicular NH lymphoma at mo 18
MR/CR in 1-8 wk toxic shock syndrome at wk 12
Continued
ACCEPTED MANUSCRIPT
Table I Cont’d
Study
PRP Type
Age/sex
Biological agent
Disease duration prior to therapy
Previous treatments
Concomitant treatments
Follow-up period
Clinical response
Side effects /NDD
etanercept s.c. 50 mg twice a wk for 7 mo then 50 mg every other wk
12-15 mo
topical c.steroids calcipotriene acitretin, UVB, CsA, prednisone
acitretin 25 mg/day
MR/CR in 7 mo
Seckin et al. 2008
37/M
etanercept s.c. 50 mg twice a wk for 3 mo then 25 mg twice a wk for other 3 mo
8 mo
NB-UVB CsA acitretin emollients a.ihistamines
none
PR to CR in 3-6 mo
none
Cox et al. 2008
16/F
etanercept s.c. 50 mg twice a wk for 4 mo then tapered and discontinued. Remission for 6 mo. Upon relapse, 50 mg twice a wk for 2 mo and then 50 mg/w.
4 yrs
PR to CR in 4-8 mo relapse after 6 mo PR to CR in 2 mo
none
I
59/M
etanercept s.c. 50 mg/wk for 16 wks
CR in 4 wk relapse at wk 16
none
I
56/M
etanercept s.c. 50 mg/wk for 12 wks
I
59/M
II
I
Kim et al. 2012
II RA
Chiu et al. 2013
+poly arthritis
SC
M AN U
acitretin 0.2 mg/kg/day
12 wks
retinoids
acitretin 0.2 mg/kg/day
12 mo
CR in 8 wk
none
etanercept s.c. 50 mg/wk for 12 wks
24 wks
CsA retinoids
acitretin 0.2 mg/kg/day
12 mo
CR in 7 wk
none
40/M
etanercept s.c. 50 mg/wk for 48 wks
10 yrs
CsA retinoids PUVA
acitretin 0.2 mg/kg/day
12 mo relapse after 8 wk
CR in 12 wk
none
30/F
etanercept s.c. 25 mg twice a wk for 9 mo
1 mo
oral isotretinoin topical c.steroids
58/F
etanercept s.c. 25 mg twice a wk for 9 mo
5 yrs
oral acitretin topical c.steroids sulfasalazine MTX
MTX 12.5 mg/wk
MR/CR in 2 mo recurrence at mo 1 after etan. cessation
24/F
etanercept s.c. 50 mg twice/wk for 9 wk
6 mo
acitretin
acitretin 25 mg every second day
mild improvement
TE D
oral c.steroids CsA, retinoids
EP
Guedes et al. 2011
topical c.steroids topical retinoids calcipotriene
8 wks
AC C
Garcovich et al. 2010
I
RI PT
55/M
Davis et al. 2007
PR in 2 mo CR in 5 mo
arthritis aggravation
Continued
ACCEPTED MANUSCRIPT
Table I Cont’d
Lopez-Ferrer et al. 2014
Di Lernia et al. 2015
Lora et al. 2017
Follow-up period
Clinical response
66/F
etanercept s.c. 50 mg twice weekly for 10 mo, then weekly for a total of 13 mo
topical, oral, i.v. corticosteroids NB-UVB, CsA adalim.,infliximab
MTX 20 mg/wk+ acitretin 25 mg/day
PR/CR in 13 mo
62/M
etanercept s.c. 50 mg/wk (after partial relapse at 1 mo following infliximab discontinuation)
photodynamic therapy, CsA topical steroids infliximab
acitretin 25 mg/day
CR
acitretin+ UVA1
UVA1
MR in > 8 wk
acitretin+NB-UVB MTX+acitretin+bath PUVA, Alefacept
MTX 22.5 mg/wk
PR in > 8 wk
acitretin+PUVA MTX+prednisone
MTX 20 mg/wk+ prednisone 10-60 (then 7.5 mg)/day
MR in > 8 wk
topicals
none
MR in > 1 wk
CsA, MTX adalimumab
none
none
13 yrs
oral c.steroids phototherapy acitretin, CsA
none
none
3 yrs
MTX, CsA acitretin
none
Side effects /NDD
I
56/M (at onset)
etanercept s.c. 50 mg twice/wk for > 8 wk
I
58/F (at onset)
etanercept s.c. 50 mg twice a wk for > 8 wks then weekly
I
33/F (at onset)
etanercept s.c. 50 mg twice a wk for > 8 wks then weekly
V
1/F (at onset)
etanercept s.c. 37 mg/wk for 9 mo
IV
29/F
etanercept s.c. 50 mg/wk for 12 wks
17/M
etanercept 50 mg/wk for 3 mo
I
83/F
etanercept s.c. 50 mg twice a wk for 52 wk
V
4/M
etanercept s.c. 50-75 mg/wk for 7 mo
8 yrs
acitretin MTX, CsA
none
PR in 8wk/7 mo
I
65/F
etanercept s.c. 50 mg/wk for 16 wks
2 yrs
acitretin MTX
none
PR at 8 wk then baseline at 16 wk
III
13/M
etanercept s.c. 50 mg/wk for 8 wk then every 10 days for 1 mo
3 mo
MTX CsA acitretin
none
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Kim et al. 2015 Maloney et al. 2017
Concomitant Previous treatments treatments
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Disease duration prior to therapy
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Biological agent
12 yrs
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Age/sex
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PRP Type
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Study
10 mo
6 mo
MR in <52 wk
CR in 8 wk
none
ACCEPTED MANUSCRIPT
Table II Summary of studies on anti IL-12/23 or anti-17 agents for PRP treatment
Biological agent
Disease duration prior to therapy
I
28/M
ustekinumab 45 mg at wk 0, 4, and every 12 wks
Ruiz Villaverde et al. 2010
I
45/M
ustekinumab 45 mg at wk 0, 4 and quarterly for a total of 6 mo
Di Stefani et al. 2013
I
31/M
ustekinumab 45 mg at wk 0, 4, and quartely
familial PRP
57/M
ustekinumab 90 mg every 8 wk
Chowdary et al. 2015
I
52/F
ustekinumab 90 mg at wk 0, 4 and quarterly
Byekova et al. 2015
I
75/M
ustekinumab 45 mg at wk 0, 4 and quarterly up to 36 mo
Di Lernia et al. 2015
IV
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Eytan et al. 2014
29/F
16 wks
>13 yrs
8 yrs
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ustekinumab 45 at wk 0, 4 and 16
Previous treatments
10 mo
Concomitant treatments
Follow-up period
Clinical response
Side effects /NDD
acitretin bath PUVA
none
none
none
CR at 16 wk
none
acitretin CsA, MTX MTX+ folic acid
none
CR at 16 till 64 wk
none
topical GC retinoids, MTX etanercept adalimumab efalizumab
none
PR at 8 wk CR at 8-36 wk
none
acitretin emollients NB-UVB MTX topical/oral GC minocycline
none
PR/CR at >8 wks
infliximab
acitretin 25 mg/day from wk 20 for >12 wk
PR in 20 wk CR in 32 wks
CsA, MTX adalimumab etanercept Infliximab PUVA therapy
none
none
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Age/sex
SC
PRP Type
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Study
CR at 4-16 wks
none
UVB, Ultraviolet B; PUVA, Psoralen-ultraviolet A; CsA, Cyclosporin A; MTX, Methotrexate; GC, glucocorticoids; CR, complete response; MR, marked response; PR, partial response NDD, Newly Diagnosed Disease Continued
ACCEPTED MANUSCRIPT
Table II Cont’d
PRP Type
Feldmeyer et al. 2017
Age/sex
Biological agent
Disease duration prior to therapy
Previous Concomitant treatments treatments
Follow-up period
Clinical response
Side effects /NDD
40s/M
ustekinumab 45 mg at wk 0, 4 and quarterly for 6 mo
topical treatments
none
topical/oral GC phototherapy CsA, MTX infliximab CT-P13
none
CR in 4-34 wk
none
CR in 12-24 wk baseline at wk 30 PR >30 wk
CR in 1 mo
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Study
I HLA-Cw6+
78/F
ustekinumab 45 mg at wk 0, 4 and quarterly
Lwin et al. 2017
familiar PRP HLA-Cw6-
49/F
ustekinumab 45 mg at wk 0, 4 and quarterly 90 mg from wk 30, quarterly up to 8 mo
20/M
ustekinumab 45 mg at wk 0, 4 and quarterly up to 8 mo
oral retinoids phototherapy topical steroids
none
CR in 12-24 wk
I
67/F
ustekinumab 45 mg X 3 at wk 0, 4
acitretin adalimumab etanercept
none
PR at 4 wks
I
68/M
ustekinumab 45 mg X 3 at wk 0, 8
MTX, CsA acitretin Apremilast adalimumab
none
none
I
52/M
ustekinumab 45 mg at wk 0, 4 and 16
5 mo
CsA
none
15 mo
CR in 4-16 wk
none
I
43/M
ustekinumab 45 mg at wk 0, 4 and 16
4 mo
GC
none
15 mo
CR in 8-16 wk
none
62/F
ustekinumab 45 mg at wk 0, 4 and 16
3 mo
MTX
acitretin 0.2 mg/day at wk 16-22
PR in 4-16 wk
none
58/M
ustekinumab 45 mg at wk 0, 4 and 16
3 mo
MTX
none
13 mo
CR in 6-16 wk
none
28/F
ustekinumab 45 mg at wk 0, 4 and 16
3 mo
GC, acitretin
none
15 mo
CR in 5-16 wk
none
I
I II
oral retinoids phototherapy topical steroids
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Maloney et al. 2017
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Paganelli et al. 2017
3 mo mild relapse legs
Continued
ACCEPTED MANUSCRIPT
Table II Cont’d
PRP Type
Schuster et al. 2016
Age/sex
Biological agent
Disease duration prior to therapy
Previous treatments
Concomitant treatments
Follow-up period
Clinical response
Side effects /NDD
MR in 8 wks6mo
none
oral and esophageal candidosis
67/M
secukinumab s.c. 150 mg/w x 2 for 5 wks, then monthly
>5 mo
acitretin systemic GC topical GC
none
9 yrs
acitretin, MTX prednisone, topical GC, CsA, photochemotherapy, i.v. Igs, infliximab, ustekinumab, prednisone+CsA
prednisone 10 mg plus CsA 5 mg/kg/day
MR in 4 wks
acitretin 25-50 mg/day
PR
II
33/F
secukinumab s.c. 300 mg/wk for 5 wks then monthly
Davenport et al. 2017
I
58/M
secukinumab s.c. 300 mg/mo for 9 mo
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EP
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SC
Gauci et al. 2016
RI PT
Study
topical GC acitretin MTX, NB-UVB infliximab
ACCEPTED MANUSCRIPT 1
CAPSULE SUMMARY
2
•
Biologics are useful treatments for pityriasis rubra pilaris patients refractory to conventional therapies.
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•
This systematic review summarised the studies on the off-label use of biologics in pityriasis rubra
Biologics are promising tools in pityriasis rubra pilaris treatment; nevertheless, clinical trials are
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needed to better assess their efficacy and safety.
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pilaris.
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S0190-9622(18)30490-0
DOI:
10.1016/j.jaad.2018.03.036
Reference:
YMJD 12425
To appear in:
Journal of the American Academy of Dermatology
Received Date: 6 February 2018 Revised Date:
21 March 2018
Accepted Date: 25 March 2018
Please cite this article as: Napolitano M, Abeni D, Didona B, Biologics for pityriasis rubra pilaris treatment: a review of the literature, Journal of the American Academy of Dermatology (2018), doi: 10.1016/j.jaad.2018.03.036. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
1
ACCEPTED MANUSCRIPT
Biologics for pityriasis rubra pilaris treatment: a review of the
2
literature
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Monica Napolitano, MD, PhDa, Damiano Abeni, MD, MPHa, and Biagio Didona, MDb
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Rome, Italy
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Correspondence to: Monica Napolitano, MD, PhD, Clinical Epidemiology Unit, Istituto Dermopatico
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dell’Immacolata, IRCCS, Via Monti di Creta 104, 00167, Rome, Italy. Tel +39 06 6646 4305, Fax: +39 06 6646
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4456
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E-mail: [email protected]
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Clinical Epidemiology Unita, and Rare Disease Unit, I Dermatology Divisionb, Istituto Dermopatico
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dell’Immacolata, IRCCS, Via Monti di Creta 104, 00167, Rome, Italy.
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Word count:
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Abstract:200
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Capsule summary:50
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Text:2240
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Fig:1
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Supplemental Tables:2
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Number of references:76
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No reprints requested
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Funding sources: RC 2017-1.2-CRI Rare, Ministry of Health, Italy
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The authors have no conflict of interest to declare
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ACCEPTED MANUSCRIPT ABSTRACT
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Pityriasis rubra pilaris (PRP) is a rare inflammatory papulosquamous skin disease, often refractory to
24
conventional therapies. The off-label use of biologics, such as anti-TNF, -IL-12/IL-23, -IL-17 agents, has been
25
proven successful, in the last two decades, in PRP treatment.
26
Our aim was to analyse the literature for the use of biologics in PRP treatment. We conducted a review by
27
“Pubmed” and “clinicaltrial.gov” searches. 68 articles met our selection criteria and were herein discussed. Out
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of 86 PRP patients, the vast majority of which treated with anti-TNF, -IL-12/IL-23, and -IL-17 biologics, either
29
alone or in combination therapy, a marked-to-complete response (50-78%), a partial response (11-25%) or
30
no/poor response (11-25%) was observed.
31
This review has several limitations including small sample sizes, with no shared study design criteria, and the
32
fact that -in some instances- PRP may spontaneously resolve. Further, the presence of concomitant therapy
33
and/or the lack of detailed data on previous treatments, makes it difficult to strictly define a therapeutic role per
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se of specific biologics in PRP.
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This review shows that biologics may be regarded as a tool for PRP treatment alone or in combination therapy
36
although clinical trials are needed to better assess their efficacy and safety.
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ACCEPTED MANUSCRIPT INTRODUCTION
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Pityriasis rubra pilaris (PRP) is a rare, chronic inflammatory skin disease with papulosquamous lesions on a
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diffuse erythematous background, involving trunk, scalp and limbs, with islands of sparing. It is a keratinization
41
disorder that often presents with palmoplantar keratoderma and nail dystrophy. PRP is classified in six clinical
42
types, i.e. Type I, classical adult and most common form; Type II, an atypical adult entity; Type III, IV and V,
43
represent classical, circumscribed and atypical juvenile forms; and Type VI, associated to HIV infection.
44
PRP is predominantly an acquired disease, but familial cases have been described, such as autosomal
45
dominant forms with caspase recruitment domain (CARD) 14 gain-of function mutations4,5,8-10 with associated
46
NFkB activation in the skin.
47
The etiology of PRP is unknown, although there have been hypothesized roles for vitamin A deficiency,
48
dysregulated immune response to superantigens, tumor necrosis factor (TNF), and IL-12/23 axeses.4,11-15
49
Triggers reported include a variety of comorbidities.4,11 Hystologically, PRP can show a “checkerboard pattern”
50
of both vertical and horizontal orthokeratosis and parakerathosis, in addition to hypergranulosis. PRP can be
51
self-limiting and, especially in Type I cases, may spontaneously heal in 2-3 years.4
52
Conventional treatments for PRP include retinoids, phototherapy, emollients, corticosteroids, cyclosporin A
53
(CsA), and methotrexate (MTX).4,6-7,14
54
Over the last two decades, biologic agents have been widely used in dermatologic diseases such as psoriasis,
55
and off-label, in several dermatologic diseases including PRP.4,14-19
56
As PRP is a rare disease (incidence between 1:5000 and 1:50.000 per year),4 all available data on the use of
57
biologics in its treatment are limited to published case reports and case series; in most instances, such
58
patients have shown a successful and prompt clearance of skin lesions.
59
We present a review of all biologics that have been reported in PRP treatment including anti-TNF agents, such
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as infliximab, etanercept, and adalimumab, 4,14,18-19 ustekinumab,4, 14,20-21 and secukinumab. 4,14,22-24
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ACCEPTED MANUSCRIPT METHODS
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A review of the literature was conducted by multiple PubMed searches using the key words “pityriasis rubra
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pilaris”; with publication date limits from 01/01/1999 to 01/30/2018. Retrieved references were critically
65
appraised by two dermatologists, i.e. M.N and B.D. The inclusion criteria were original articles, reports, letters
66
and review articles, English language-only, reporting the treatment of PRP patients with biologics, such as
67
monoclonal antibodies and recombinant fusion proteins, alone or in combination therapy with conventional
68
drugs. Articles judged irrelevant on the basis of title, abstract and/or text, were excluded from the review. In
69
addition, few reviews on relevant topics, such as pityriasis rubra pilaris, TNF inhibitors, and IL-12/23/17
70
pathways, were included in the review. Moreover, a search of the website Clinicaltrials.gov was performed up
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to 01/30/2018.
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ACCEPTED MANUSCRIPT RESULTS
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A total of 327 articles were retrieved by multiple PubMed searches conducted until 01/30/2018 using the
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“pityriasis rubra pilaris” keywords. A total of 68 articles were eligible for review, following the criteria described
76
above. We excluded 2 articles, as not fully relevant, and a single article,25 due to unavailability of full-length
77
text, for further reviewing. A total of 55 case reports/case series, 3 case reports and reviews, and 7 review
78
articles, were selected (Fig. 1). We herein reviewed the effects of biologics on a total of 86 type I-V PRP
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patients. Diagnosis of PRP was, in most cases, based on both clinical features and histological analysis. With
80
the exception of 5 out of 86 patients, in which biologics were used as a first-line therapy, such molecules were
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utilized in patients refractory to conventional therapies (Supplemental Tables I-II). The dose of biologics used
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for PRP treatment mostly follows the FDA-approved guidelines for other dermatologic diseases such as
83
psoriasis (Supplemental Tables I-II). Please note that a single patient may be listed independently, in both the
84
text and Supplemental Tables, if treated with more that one biologic agent.
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Effect of anti-TNF agents
86
Infliximab
87
The present review allowed to assess that, among the anti-TNF biologic agents, infliximab was the most
88
commonly used, at the prevalent dose of of 5 mg/kg for few to several weeks (Supplemental Table I). A total of
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37 patients (25 type I, 1 type II, 2 type III, 1 Type IV and 8 unknown type PRP) were treated with infliximab, as
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either refractory to other therapies (33 patients) or as first line therapy (4 patients).19,24,26-46 Their mean age,
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unspecified for 1 patient, was 54.1 years. Men were 18, women 14, gender unspecified for 5 patients.
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Concomitant treatments, present in about 60% of cases, were mainly represented by oral acitretin,
93
metothrexate (MTX), and topical and/or systemic corticosteroids (Supplemental Table I). The observed clinical
94
response, in few to several weeks, was marked (MR>75% clearing) to complete (CR>95% clearing) in 25
95
patients (68%), partial (PR= 50-75% clearing) in 6 patients (16%), and none/poor in 6 patients (16%). Relapse
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of skin lesions was observed in two patients, the first, in which the reintroduction of acitretin restored a CR35
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ACCEPTED MANUSCRIPT and the second who suffered a partial relapse at 3 months while treated with concomitant therapy
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(Supplemental Table I). 41
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Side effects/newly diagnosed disease, occurred in 6/36 patients, and were represented by transitory edema,
100
weight increase, new-onset vitiligo, rash/dyspnea/tachicardia, renal insufficiency/skin infections. A small cell
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lymphocytic leukemia was diagnosed 4 weeks after the beginning of infliximab treatment, in a patient
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previously treated for months with MTX, CsA and prednisone (Supplemental Table I). 44
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Etanercept
104
Treatment with etanercept was used in a total of 22 patients (11 type I, 2 type II, 1 type III, 1 type IV, 2 type V,
105
5 unknown type PRP), all refractory to previous therapies.19-20,35,40-42,47-54 The mean age was 43 years; 11
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patients were male and 11 females. Concomitant treatments, mainly acitretin and MTX, were present in about
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50% of cases. A MR/CR was obtained in 16 patients (72.8%), a PR in 3 patients (13.6%) and none/poor in 3
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patients (13.6%). Four patients showed relapse of skin lesions. One patient relapsed from a CR following
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discontinuation of etanercept, and then reached a PR/CR after its reintroduction;49 another one relapsed from
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a CR at week 16 of treatment;35 a patient relapsed from a CR, 1 month after etanercept cessation,51 and a
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patient relapsed from PR, at week 16 of treatment (Supplemental Table I). 20 Side effect of arthritis aggravation
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occurred in 1 patient out of 21.
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Adalimumab
114
A total of 20 patients were treated with adalimumab (9 type I, 2 type II, 1 type IV and 8 unspecified-type PRP)
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as they were all refractory to other therapies.11,19,20,40,42,52,55-64 Adalimumab was administered subcutaneously,
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in most cases, at the dose of 80 mg at week 0 and then 40 mg twice-monthly for several weeks to a few
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months (Supplemental Table I). Concomitant treatments, mainly acitretin, MTX, were administered in 7 cases.
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Mean age was 52 years, and there were 11 males and 9 females. The clinical response to adalimumab, in a
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few weeks, was MR/CR in 10 patients (50%), a PR in 5 patients (25%), and none/poor in 5 patients
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(25%).Three patients showed a relapse: the first after 2 months since PR;59 the second 3 months after
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ACCEPTED MANUSCRIPT adalimumab discontinuation, followed by recovery of a PR upon drug reintroduction,52 and a third patient
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showed a relapse at week 14, following a CR, after discontinuing phototherapy and steroids11 (Supplemental
123
Table I). Side effects/newly diagnosed diseases occurred in three patients, and were gastrointestinal side
124
effects/elevation of liver enzymes, follicular non-Hodgkin (NH) lymphoma, and toxic shock syndrome
125
(Supplemental Table I).
126
Effect of anti IL-12/IL-23, and IL17A agents
127
Ustekinumab
128
Among the anti IL-12/IL-23, and IL17A agents,13 ustekinumab was the most commonly used. In particular, 12
129
studies assessed the efficacy of ustekinumab for the treatment of a total of 18 patients, mean age 49 years,
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with 11 males and 7 females (Supplemental Table II). 12 type I, 1 type II, 1 type IV, 3 patients with familiar,
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and 1 patient with unspecified PRP.9-10,12,20-21,43,65-69 All patients, but one, were refractory to previous therapies.
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Ustekinumab was administered, in most cases, at the dose of 45 mg at weeks 0, 4, and then quarterly for a
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total of several weeks/months. In 16/18 patients ustekinumab was administered alone, and in 2 cases, along
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with acitretin (Supplemental Table II). The clinical response to ustekinumab was MR/CR in 14 patients (78%),
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PR in 2 patient (11%) and none in 2 patients (11%). Interestingly, no side effects were reported. Relapse of
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disease, among the responders, was observed in one patient10 who, after achieving a CR in 12-24 weeks,
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returned to baseline condition at week 30. The eventual dose increase from 45 to 90 mg ustekinumab yielded
138
a PR. Further, in another treated patient, a mild relapse of papular lesions of the legs was reported during the
139
follow up period.21
140
Secukinumab
141
Three patients of 67, 33, and 58 yrs old (M, F, M, respectively), unresponsive to previous therapies,22-24 were
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reported being treated with secukinumab 300 mg/week for 5 weeks then monthly22-23 or 300 mg/month24 and,
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in two patients,23-24 also with concomitantly therapy (Supplemental Table II). A CR was observed, in two
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ACCEPTED MANUSCRIPT patients, within few weeks22-23 and a PR in one patient, in few weeks to months.24 Candidiasis was reported as
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a side effect in one patient.23
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Other biologics
147
Efalizumab, that inhibits the CD11a subunit of LFA-1 on T lymphocytes,70 a drug withdrawn from the market in
148
2009, was reported in two patients with PRP: one PR71 and one exacerbation of symptoms.70
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Alefacept is a fusion protein of the CD2-binding portion of LFA-3 linked to the IgG Fc. Two PRP patients
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received i.m. Alefacept injections, 15 mg/week for 12 weeks, with no clinical response.42
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Clinical trials on the use of biologics in PRP
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A clinicaltrials.gov search, conducted up to 01/30/2018, using the terms “pityriasis rubra pilaris”; and “pityriasis
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rubra pilaris” AND “biologics”, retrieved: 1) a pilot study of Alefacept for PRP treatment, sponsored by the
155
Icahn School of Medicine at Mount Sinai, NY; ended in 2009, that failed to enroll patients, and 2) a “single arm,
156
open-label exploratory clinical trial on secukinumab for the treatment of adult onset PRP”, not yet recruiting,
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and sponsored by the Mayo Clinic. To the best of our knowledge, no published peer-reviewed data from
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clinical trials with biologics for PRP are yet available.
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ACCEPTED MANUSCRIPT DISCUSSION
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This review analysed all available published data on the off-label use of biologics in the treatment of PRP.
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From the present searches, the biologics used predominantly consisted of anti-TNF-, anti IL-12/23-, and anti-
163
17A- agents, in keeping with previous articles and reviews.4,14,19,32,42,70-71
164
Interestingly, treatment of PRP with biologics has given successful results in the majority of cases. From the
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reviewed data, infliximab is the most used biologic agent in PRP treatment, with a high percentage of MR/CR,
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adalimumab yielded the lowest percentage of MR/CR among biologics, and ustekinumab was the most
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commonly administered biologic agent in the absence of concomitant therapy, nothwithstanding a high
168
percentage of MR/CR.
169
In a few studies, distinct biologic agents have been used sequentially, in the same patients, and evoked either
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no clinical response at all, or only efficacy with a specific biologic agent (Supplemental Tables I-II). Further,
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treatment with infliximab evoked a PR but the occurrence of side effects prompted the authors to switch to
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etanercept with a CR;41 infliximab yielded a CR that was maintained when it was switched, for practical
173
reasons, to adalimumab;40 the PR to adalimumab was maintained switching to infliximab;42 a PR to infliximab,
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but with the development of side effects, prompted the switch to ustekinumab with a MR/CR.43
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Although most of the conventional drugs used for the treatment of PRP may show important side effects,
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biologics have intrinsic risks due to immune modulation / suppression activity. In particular it has been reported
177
an increased risk of serious infections, and of developing several malignancies including lymphomas.16-17,72-73.
178
In this review, 2 out of 86 patients treated with biologics were diagnosed with small cell lymphocytic leukemia
179
or follicular NH lymphoma, weeks or months, respectively, following treatment with anti-TNF inhibitors. Such
180
tumors could either be sporadic or favoured by previous/concomitant therapy with immune suppressants
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and/or by biologic agents. Noteworthy, cases of paraneoplastic PRP have been reported, although very rarely,
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in association with solid or hematologic malignancies.74
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ACCEPTED MANUSCRIPT Few cases of PRP-like skin lesions induced by biologic agents have been described. A patient with
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Takayasu’s arteritis developed PRP-like skin lesions, following infliximab treatment, part of combination
185
therapy, that disappeared after infliximab discontinuation.75 Efalizumab induced an exacerbation of PRP-like
186
skin lesions.70 Bevacizumab, a mAb against VEGF, not used for PRP treatment, also has been reported to
187
induce a PRP-like eruption.76
188
The present review has several limitations mostly due to the fact that the total number of PRP patients treated
189
with biologics is quite small i.e. a total of 86. The source of the vast majority of the scientific collected data is
190
represented by single case reports, with the exception of rare case series. Diagnosis was based, in most
191
cases, upon both clinical and histologic criteria. Also other limitations include the lack of well-defined
192
enrollment criteria in the case series. Some data, such as PRP type, length of study, follow-up period, disease
193
duration prior to therapy with biologics, side effects and a detailed therapeutic scheme of treatment were
194
variably detailed amongst the reports reviewed. Washout period, between previous treatments, was also not
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clearly presented in most reports reviewed. It is difficult to meaningfully assess the effect of single biologic
196
agents, per se, in the clinical response of PRP patients as the vast majority of cases had concomitant therapy
197
or short duration of therapy with a particular biologic agent.
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Overall the results obtained by several groups in treating PRP with biologics are encouraging, although
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randomised controlled clinical trials are needed for a better assessment of their therapeutic efficacy and safety
200
in PRP.
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REFERENCES
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1) Griffiths WA. Pityriasis rubra pilaris. Clin Exp Dermatol. 1980;5:105-12.
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38) Adnot-Desanlis L, Antonicelli F, Tabary T, et al. Effectiveness of infliximab in pityriasis rubra pilaris is associated with pro-inflammatory cytokine inhibition. Dermatology. 2013;226:41-6. 39) Mattox AR, Chappell JA, Hurley MY. New-onset vitiligo during long-term, stable infliximab treatment of pityriasis rubra pilaris. J Drugs Dermatol. 2013;12:217-9. 40) Vujic I, Richter L, Bartsch K, et al. Pityriasis rubra pilaris types 1 and 2: different responses to
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rheumatoid arthritis. Acta Derm Venereol. 2012;92:399-400.
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64) Nic Dhonncha E, Fadalla K, Moriarty B, et al. High grade follicular lymphoma in a patient receiving adalimumab and methotrexate for pityriasis rubra pilaris. J Dermatolog Treat. 2017;28:764-765. 65) Wohlrab J, Kreft B. Treatment of pityriasis rubra pilaris with ustekinumab. Br J Dermatol. 2010;163:655-6.
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in a pediatric patient. J Drugs Dermatol. 2007;6:337-9. 72) Kopylov U, Afif W. Risk of infections with biological agents. Gastroenterol Clin North Am. 2014;43:50924. 73) Hawryluk EB, Linskey KR, Duncan LM, et al. Broad range of adverse cutaneous eruptions in patients on TNF-alpha antagonists. J Cutan Pathol. 2012;39:481-92. 74) Bar-Ilan E, Gat A, Sprecher E, et al. Paraneoplastic pityriasis rubra pilaris: case report and literature review. Clin Exp Dermatol. 2017;42:54-57.
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75) Salman A, Sonmez Y, Sahin H, et al. Infliximab-induced cutaneous eruption resembling pityriasis rubra pilaris in a patient with Takayasu's arteritis. Dermatol Ther. 2017;30: e12443. 76) Brown S, Fletcher JW, Fiala KH. Bevacizumab-induced pityriasis rubra pilaris-like eruption. Proc (Bayl Univ Med Cent). 2016;29:335-6.
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Fig. 1
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Flow diagram of search selection
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ACCEPTED MANUSCRIPT Table I Summary of studies on anti-TNF agents for PRP treatment
Side effects /NDD
antibiotics whirpool ther. topical steroids
MR in 3 days2wks
none
topical steroids
topical steroids whirpool therapy
MR in 2 wk
none
topical steroids UVB, acitretin etretinate
topical steroids whirpool therapy UVB, a.histamines
MR in 1 wk
none
acitretin +/- CsA corticosteroids a.histamines whirpool baths
acitretin 25 mg twice daily then 25 mg 3 times/wk
6 mo
acitretin, emollients topical tacrolimus antihistamines
acitretin 50 mg/day
PR in >2 wks
9 wks
none
acitretin 25 mg twice/day
none
77/M
infliximab inf. 5mg/kg at mo 0, 1
none
65/M
infliximab inf. 5mg/kg at mo 0, 1
74/F
infliximab inf. 5mg/kg at mo 0, 1
I
77/M
infliximab inf. 5mg/kg at wk 0, 4, 8, 14, 22
I
53/M
infliximab inf. 5mg/kg at wk 0, 2
56/M
infliximab inf. 5mg/kg at wk 0, 2, 6, 14
Previous treatments
Concomitant treatments
SC
2 mo
>6 mo
MR to CR in 2-22 wk
none
acitretin 50 mg/day till wk 2
MR in 6-30 wk
none
retinoids MTX, CsA emollients antihistamines
none
MR at wk 2 CR in 10 mo residual PP keratod.
none
none
emollients
I
59/F
infliximab inf. 5mg/kg at wk 0, 2, 6, 14, 22, 30
8 mo
corticosteroids salicilic acid a.histamine, MTX fumaric acid mycophenolate m.
MTX 10 mg/wk at wk 6-22 topical salicilic a. betamethasone
Ruiz-Genao et al. 2007
I
63/F
infliximab inf. 5mg/kg at wk 0, 2, 6, 14, 22, 30
7 mo
topical steroids CsA acitretin
Ruzzetti et al. 2008
III
33/F
infliximab inf. 5mg/kg at wk 0, 2, 6, and every 8 wks
25 yrs
Muller et al. 2008
I
32/M
infliximab inf. 5mg/kg at wk 0, 2, 6, 12
2 wks
AC C
Follow-up period
MR at >2wk till 8 mo
Manoharan et al. 2006
EP
Lu et al. 2006
Disease duration prior to therapy
RI PT
Biological agent
Drosou et al. 2003
Liao et al. 2005
Clinical response
Age/sex
M AN U
PRP Type
TE D
Study
4 mo
2 yr
UVB, Ultraviolet B; PUVA, Psoralen-ultraviolet A; CsA, Cyclosporin A; MTX, Methotrexate; GC, glucocorticoids; CR, complete response; MR, marked response; PR, partial response NDD, Newly Diagnosed Disease
MR/CR at wk 1-14
Continued
ACCEPTED MANUSCRIPT Table I Cont’d
Age/sex
Biological agent
Disease duration prior to therapy
Barth et al. 2009
I
65/F
infliximab 5mg/kg X 3
Gemmeke et al. 2010
I
41/M
infliximab inf. 5mg/kg at wk 0, 2, 6
Garcovich et al. 2010
I
30/F
8 wks
I
63/M
infliximab inf. 5mg/kg at wk 0, 2, 6, and every 8 wks (tot 17 wks) infliximab inf. 5mg/kg at wk 0, 2, 6, and every 8 wks (tot 6 wks)
I
50/M
infliximab inf. 5mg/kg at wk 0, 2, 6, and every 8 wks (tot 24 wks)
4 wks
Dessinioti et al. 2011
III
27/F
infliximab inf. 5mg/kg at wk 0, 2, 6 and every 8-7 wks up to 2.5 yrs
14 yrs
Zirbs et al. 2011
I
56/M
infliximab inf. 5mg/kg at wk 0, 2, 6, 14, 22, 30 and every 12 wks
Adnot-Desanlis et al. 2013
I
29/
infliximab inf. 5mg/kg at wk 0, 2, 6, and every 6 wks
I
39/
I
57/
I
51/
Vujic et al. 2013
I
II
topical/systemic c.steroids, MTX
MTX 15-30 mg i.v./wk
topical and systemic c.steroids systemic c.steroids
c.steroids up to 2 wk emollients none
systemic c.steroids MTX
systemic c.steroids
M AN U
4 wks
>6 mo
Concomitant treatments
Follow-up period 1 yr
Clinical response
Side effects /NDD
MR at wk 2 CR at 1 yr PR at wk 2
transitory leg edema at wk 2
1 yr
MR at wk 2
none
none
1 yr
MR at wk 2
none
acitretin 0.2 mg/kg/day at wk 20-24
1 yr
MR at wk 4 relapse at wk 20 CR at wk 24
none
PR to CR
weight increase
acitretin isotretinoin+/NB-UVB isoniazid 300 mg/day (TB Elispot +)
2 wks
none
none
1 yr
CR at wk 6
none
infliximab inf. 5mg/kg at wk 0, 2, 6, and every 6 wks
4 wks
acitretin
none
1 yr
CR at wk 36
none
infliximab inf. 5mg/kg at wk 0, 2, 6, and every 6 wks
87 wks
acitretin CsA
none
1 yr
CR at wk 66
none
infliximab inf. 5mg/kg at wk 0, 2, 6, and every 6 wks
9 wks
acitretin
none
1 yr
CR at wk 42
none
acitretin topical steroids
none
MR-CR
MTX 20 mg/wk+ acitretin 25 mg/day
none
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acitretin topical steroids salicilic acid emollients
AC C
Mattox et al. 2013
2 wks
Previous treatments
RI PT
PRP Type
SC
Study
60/M
infliximab inf. 5-10 mg/kg every 5-6 wks for 27 mo
66/F
infliximab inf. 5 mg/kg at wk 0, 2, 6, and every 8 wks up to 16 wk
4 mo
topical, oral, i.v. corticosteroids NB-UVB, CsA adalimumab
66/F
infliximab inf. 5 mg/kg at wk 0, 2, 6
17 yrs
oral steroids, retinoids, a.histam
PR at wk 6 CR at wk 30
new-onset vitiligo at wk 27
MR/CR at wk 2-6
Continued
ACCEPTED MANUSCRIPT Table I Cont’d
Study
PRP Type
Petrof et al. 2013
Age/sex
Biological agent
Disease duration prior to therapy
Previous Concomitant treatments treatments
Lopez-Ferrer et al. 2014
Clinical response
MTX 10 mg/wk from wk 22
PR at 14 to 52 wks
photodynamic therapy, CsA topical steroids
acitretin 25 mg/day from wk 4
PR in 2 mo partial relapse at mo 3
infliximab inf. 5 mg/kg
I
Follow-up period
infliximab inf. 5 mg/kg at wk 0, 4 up to 2 mo
I
56/F
infliximab inf. 5-7 mg/kg at wk 0, 2, 6, and every 8 wks
12 mo
CsA adalimumab + CsA
MTX 12.5 mg/wk+ acitretin 25 mg/day
PR in 6 wks
I
56/M
infliximab inf. 5 mg/kg at wk 0, 2, 6, and every 8 wks
3 yr
prednisone acitretin+MTX
1) acitretin 50 mg/day 2) MTX 15 mg/wk
PR in 2 wk MR in 2 wk
I
66/F
infliximab inf. 5 mg/kg at wk 0, 2, 6, and every 8 wks
2 wk
I
50/M
infliximab inf. 5-7 mg/kg at wk 0, 2, 6, and every 8 wks
I
84/M
infliximab inf. 5 mg/kg at wk 0, 2, 6, and every 8 wks
Di Lernia et al. 2015
IV
29/F
infliximab inf. 5mg/kg at wk 0, 2, 8
Byekova et al. 2015
I
75/M
infliximab inf. 5 mg/kg at wk 0, 2, 6 and every 8 wk
Krase et al. 2016
70/M
infliximab inf. 5 mg/kg at wk 0
Karadag et al. 2016
31/F
infliximab inf. 5 mg/kg at wk 0, 2, 6, and every 8 wk up to 1 yr
Paganelli et al. 2017
I
78/F
infliximab CT-P13 inf. 5 mg/kg at wk 0, 2, 6 and every 8 wk
Davenport et al. 2017
I
58/M
infliximab 5 mg/kg at wk 0, 2, 6, 14
SC
M AN U
acitretin
acitretin+ prednisone
acitretin 50mg/day
3 yr
MR/CR in 2 wk
8 mo
acitretin+ prednisone
acitretin 50 mg/day
17 mo
MR/CR in 4 wk
CsA, MTX adalimumab etanercept
none
10 mo
none
«systemic therapies»
8 mo
acitretin, MTX prednisone, CsA
4 yrs
systemic retinoids none PUVA, NB-UVB retinoids+NB-UVB MTX topical and oral retinoids,none NB-UVB, PUVA, CsA, MTX topical GC, acitretin MTX, NB-UVB
CsA, prednisone
acitretin 25-50 mg/day
treat. discontinued for rash, dyspnea, bradicardia at mo 2
MR in 12 wk
MTX 20 mg/wk
4 yr
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EP
AC C
Brooke Eastham et al. 2014
RI PT
62/M
Side effects /NDD
2 yr
minimal response then discontinued at wk 14
renal insuff. skin infections from wk 14
PR, discontinued
small cell lymphocytic leukemia at wk 4
MR/CR in 2 wks
none
none
Continued
ACCEPTED MANUSCRIPT Table I Cont’d
Age/sex
O’Kane et al. 2010
+psoriatic arthritis
Schreml et al. 2010
Disease duration prior to therapy 2 wks
Previous Concomitant treatments treatments topical and systemic steroids
adalimumab s.c. 80 mg at wk 0, 40 mg at wk 1, and every second wk, for 32 wks
24/M
adalimumab s.c. 80 mg at wk 0 then 40 mg every 2 wks
MTX
MTX 7.5 mg/wk
<4 mo
CR at wk 4
72/M
adalimumab s.c. 80 mg at wk 0 then 40 mg every 2 wks, for a total of 12 injections
acitretin topical and systemic steroids PUVA, MTX
none
1 mo
CR at wk 4
2 yrs
topical steroids calcipotriol, UVB isotretinoin isotretinoin+ topical steroids
3 yrs
steroids, MTX bath PUVA acitretin, CsA
24/F
adalimumab s.c. 80 mg at wk 0 then 40 mg every 2 wks, for 4 mo
Schmitt et al. 2011
I
74/F
adalimumab s.c. 40mg every 2 wk up to 2 mo
Ivanova et al. 2012
I
37/F
adalimumab s.c. 80 mg at wk 0, 40 mg at wk 1 and every 2 wks, up to 8 mo
Wassef et al. 2012
I
62/M
adalimumab s.c. 40 mg every 2 wks up to 3 mo
2 yrs
topical steroids MTX, vit D UVB, PUVA
adalimumab s.c. 40mg every 2 wks, for 2 mo then new cycle at mo 3
8-9 mo
acitretin etanercept
AC C
EP
TE D
I
+polyarthritis
none
Clinical response
72/M
Zhang et al. 2010
Chiu et al. 2013
Follow-up period
RI PT
Walling et al. 2009
Biological agent
SC
PRP Type
M AN U
Study
24/F
topical steroids NB-UVB
Side effects /NDD
MR/CR at wk 8-32
none
none
PR at 4 wks CR at mo 4
PR in 2 mo then relapse
topical steroids NB-UVB
none
2 mo
gastrointestinal side effects elevation of liver enzymes
CR at wk 4 relapse at wk 14 (after discontinuing NB-UVB and steroids) CR at 16 wk after their reintroduction). CR in 3 mo
acitretin 25 mg every second day
PR at wk 2 relapse at mo 3 after discontinuation PR after reintroduction
Continued
ACCEPTED MANUSCRIPT Table I Cont’d
Age/sex
Biological agent
I
66/F
adalimumab s.c. 80 mg, then 40 mg bimonthly for 8 wk
4 mo
topical, oral, i.v. corticosteroids NB-UVB, CsA
II
66/F
adalimumab s.c. 40 mg bimonthly for 24 mo
17 yr
oral steroids, retinoids a.histamines infliximab (CR)
none
I
56/F
adalimumab s.c. 50 mg/wk
CsA
CsA 100 mg twice/day
PR at 6 wk
51/M
adalimumab s.c. 80 mg at wk 0 then 40 mg every other wk for 7 mo
none
MR/CR at 4 wk
66/M
adalimumab
17/M
adalimumab s.c. 80 mg, then 40 mg every other wk, then every 3 wk for 9 mo
29/F
adalimumab s.c. 80 mg, then 40 mg at wk 1, then every 2 wk for 16 wks
Kitayama et al. 2017
59/M
adalimumab s.c. 80 mg/2 wk
Dhonncha et al. 2017
52/M
adalimumab s.c. 80 mg at wk 0 then 40 mg/wk for 3 mo, every other wk up to 18 mo
Marrouche et al. 2014
II
Kim et al. 2015
Di Lernia et al. 2015
Maloney et al. 2017
IV
2 wks
Follow-up period
none
oral c.steroids antihistamines acitretin emollients
>2 yr
No relapse of infliximabinduced CR
oral c.steroids phototherapy acitretin, CsA etanercept
none
CR at 4 wk
CsA, MTX
none
none
1 mo
c.steroids, UVB retinoids topical Vit D3
MTX 6 mg/w
PR
7 wks
acitretin
1)
PR at 3 mo
2)
acitretin 40 mg/day MTX 15 mg/wk
56/M
adalimumab s.c. 40 mg x 5 for 8 wks
prednisone acitretin
acitretin 10 mg/day
I
66/F
adalimumab s.c. 40 mg every other wk for 12 wks
acitretin
none
none
I
68/M
adalimumab s.c. 40 mg every other wks for 12 wks
acitretin MTX, CsA apremilast
none
none
I
Side effects /NDD
poor/none
topical steroids MTX
13 yrs
Clinical response none
RI PT
SC
Bravo et al. 2014
Previous Concomitant treatments treatments
M AN U
Brooke Eastham et al. 2014
TE D
Vujic et al. 2013
Disease duration prior to therapy
EP
PRP Type
AC C
Study
2 yr
follicular NH lymphoma at mo 18
MR/CR in 1-8 wk toxic shock syndrome at wk 12
Continued
ACCEPTED MANUSCRIPT
Table I Cont’d
Study
PRP Type
Age/sex
Biological agent
Disease duration prior to therapy
Previous treatments
Concomitant treatments
Follow-up period
Clinical response
Side effects /NDD
etanercept s.c. 50 mg twice a wk for 7 mo then 50 mg every other wk
12-15 mo
topical c.steroids calcipotriene acitretin, UVB, CsA, prednisone
acitretin 25 mg/day
MR/CR in 7 mo
Seckin et al. 2008
37/M
etanercept s.c. 50 mg twice a wk for 3 mo then 25 mg twice a wk for other 3 mo
8 mo
NB-UVB CsA acitretin emollients a.ihistamines
none
PR to CR in 3-6 mo
none
Cox et al. 2008
16/F
etanercept s.c. 50 mg twice a wk for 4 mo then tapered and discontinued. Remission for 6 mo. Upon relapse, 50 mg twice a wk for 2 mo and then 50 mg/w.
4 yrs
PR to CR in 4-8 mo relapse after 6 mo PR to CR in 2 mo
none
I
59/M
etanercept s.c. 50 mg/wk for 16 wks
CR in 4 wk relapse at wk 16
none
I
56/M
etanercept s.c. 50 mg/wk for 12 wks
I
59/M
II
I
Kim et al. 2012
II RA
Chiu et al. 2013
+poly arthritis
SC
M AN U
acitretin 0.2 mg/kg/day
12 wks
retinoids
acitretin 0.2 mg/kg/day
12 mo
CR in 8 wk
none
etanercept s.c. 50 mg/wk for 12 wks
24 wks
CsA retinoids
acitretin 0.2 mg/kg/day
12 mo
CR in 7 wk
none
40/M
etanercept s.c. 50 mg/wk for 48 wks
10 yrs
CsA retinoids PUVA
acitretin 0.2 mg/kg/day
12 mo relapse after 8 wk
CR in 12 wk
none
30/F
etanercept s.c. 25 mg twice a wk for 9 mo
1 mo
oral isotretinoin topical c.steroids
58/F
etanercept s.c. 25 mg twice a wk for 9 mo
5 yrs
oral acitretin topical c.steroids sulfasalazine MTX
MTX 12.5 mg/wk
MR/CR in 2 mo recurrence at mo 1 after etan. cessation
24/F
etanercept s.c. 50 mg twice/wk for 9 wk
6 mo
acitretin
acitretin 25 mg every second day
mild improvement
TE D
oral c.steroids CsA, retinoids
EP
Guedes et al. 2011
topical c.steroids topical retinoids calcipotriene
8 wks
AC C
Garcovich et al. 2010
I
RI PT
55/M
Davis et al. 2007
PR in 2 mo CR in 5 mo
arthritis aggravation
Continued
ACCEPTED MANUSCRIPT
Table I Cont’d
Lopez-Ferrer et al. 2014
Di Lernia et al. 2015
Lora et al. 2017
Follow-up period
Clinical response
66/F
etanercept s.c. 50 mg twice weekly for 10 mo, then weekly for a total of 13 mo
topical, oral, i.v. corticosteroids NB-UVB, CsA adalim.,infliximab
MTX 20 mg/wk+ acitretin 25 mg/day
PR/CR in 13 mo
62/M
etanercept s.c. 50 mg/wk (after partial relapse at 1 mo following infliximab discontinuation)
photodynamic therapy, CsA topical steroids infliximab
acitretin 25 mg/day
CR
acitretin+ UVA1
UVA1
MR in > 8 wk
acitretin+NB-UVB MTX+acitretin+bath PUVA, Alefacept
MTX 22.5 mg/wk
PR in > 8 wk
acitretin+PUVA MTX+prednisone
MTX 20 mg/wk+ prednisone 10-60 (then 7.5 mg)/day
MR in > 8 wk
topicals
none
MR in > 1 wk
CsA, MTX adalimumab
none
none
13 yrs
oral c.steroids phototherapy acitretin, CsA
none
none
3 yrs
MTX, CsA acitretin
none
Side effects /NDD
I
56/M (at onset)
etanercept s.c. 50 mg twice/wk for > 8 wk
I
58/F (at onset)
etanercept s.c. 50 mg twice a wk for > 8 wks then weekly
I
33/F (at onset)
etanercept s.c. 50 mg twice a wk for > 8 wks then weekly
V
1/F (at onset)
etanercept s.c. 37 mg/wk for 9 mo
IV
29/F
etanercept s.c. 50 mg/wk for 12 wks
17/M
etanercept 50 mg/wk for 3 mo
I
83/F
etanercept s.c. 50 mg twice a wk for 52 wk
V
4/M
etanercept s.c. 50-75 mg/wk for 7 mo
8 yrs
acitretin MTX, CsA
none
PR in 8wk/7 mo
I
65/F
etanercept s.c. 50 mg/wk for 16 wks
2 yrs
acitretin MTX
none
PR at 8 wk then baseline at 16 wk
III
13/M
etanercept s.c. 50 mg/wk for 8 wk then every 10 days for 1 mo
3 mo
MTX CsA acitretin
none
AC C
Kim et al. 2015 Maloney et al. 2017
Concomitant Previous treatments treatments
M AN U
Brooke Eastham et al. 2014
Disease duration prior to therapy
RI PT
I
Biological agent
12 yrs
TE D
Vujic et al. 2013
Age/sex
SC
PRP Type
EP
Study
10 mo
6 mo
MR in <52 wk
CR in 8 wk
none
ACCEPTED MANUSCRIPT
Table II Summary of studies on anti IL-12/23 or anti-17 agents for PRP treatment
Biological agent
Disease duration prior to therapy
I
28/M
ustekinumab 45 mg at wk 0, 4, and every 12 wks
Ruiz Villaverde et al. 2010
I
45/M
ustekinumab 45 mg at wk 0, 4 and quarterly for a total of 6 mo
Di Stefani et al. 2013
I
31/M
ustekinumab 45 mg at wk 0, 4, and quartely
familial PRP
57/M
ustekinumab 90 mg every 8 wk
Chowdary et al. 2015
I
52/F
ustekinumab 90 mg at wk 0, 4 and quarterly
Byekova et al. 2015
I
75/M
ustekinumab 45 mg at wk 0, 4 and quarterly up to 36 mo
Di Lernia et al. 2015
IV
EP
AC C
Eytan et al. 2014
29/F
16 wks
>13 yrs
8 yrs
TE D
Wohlrab et al 2010
ustekinumab 45 at wk 0, 4 and 16
Previous treatments
10 mo
Concomitant treatments
Follow-up period
Clinical response
Side effects /NDD
acitretin bath PUVA
none
none
none
CR at 16 wk
none
acitretin CsA, MTX MTX+ folic acid
none
CR at 16 till 64 wk
none
topical GC retinoids, MTX etanercept adalimumab efalizumab
none
PR at 8 wk CR at 8-36 wk
none
acitretin emollients NB-UVB MTX topical/oral GC minocycline
none
PR/CR at >8 wks
infliximab
acitretin 25 mg/day from wk 20 for >12 wk
PR in 20 wk CR in 32 wks
CsA, MTX adalimumab etanercept Infliximab PUVA therapy
none
none
RI PT
Age/sex
SC
PRP Type
M AN U
Study
CR at 4-16 wks
none
UVB, Ultraviolet B; PUVA, Psoralen-ultraviolet A; CsA, Cyclosporin A; MTX, Methotrexate; GC, glucocorticoids; CR, complete response; MR, marked response; PR, partial response NDD, Newly Diagnosed Disease Continued
ACCEPTED MANUSCRIPT
Table II Cont’d
PRP Type
Feldmeyer et al. 2017
Age/sex
Biological agent
Disease duration prior to therapy
Previous Concomitant treatments treatments
Follow-up period
Clinical response
Side effects /NDD
40s/M
ustekinumab 45 mg at wk 0, 4 and quarterly for 6 mo
topical treatments
none
topical/oral GC phototherapy CsA, MTX infliximab CT-P13
none
CR in 4-34 wk
none
CR in 12-24 wk baseline at wk 30 PR >30 wk
CR in 1 mo
RI PT
Study
I HLA-Cw6+
78/F
ustekinumab 45 mg at wk 0, 4 and quarterly
Lwin et al. 2017
familiar PRP HLA-Cw6-
49/F
ustekinumab 45 mg at wk 0, 4 and quarterly 90 mg from wk 30, quarterly up to 8 mo
20/M
ustekinumab 45 mg at wk 0, 4 and quarterly up to 8 mo
oral retinoids phototherapy topical steroids
none
CR in 12-24 wk
I
67/F
ustekinumab 45 mg X 3 at wk 0, 4
acitretin adalimumab etanercept
none
PR at 4 wks
I
68/M
ustekinumab 45 mg X 3 at wk 0, 8
MTX, CsA acitretin Apremilast adalimumab
none
none
I
52/M
ustekinumab 45 mg at wk 0, 4 and 16
5 mo
CsA
none
15 mo
CR in 4-16 wk
none
I
43/M
ustekinumab 45 mg at wk 0, 4 and 16
4 mo
GC
none
15 mo
CR in 8-16 wk
none
62/F
ustekinumab 45 mg at wk 0, 4 and 16
3 mo
MTX
acitretin 0.2 mg/day at wk 16-22
PR in 4-16 wk
none
58/M
ustekinumab 45 mg at wk 0, 4 and 16
3 mo
MTX
none
13 mo
CR in 6-16 wk
none
28/F
ustekinumab 45 mg at wk 0, 4 and 16
3 mo
GC, acitretin
none
15 mo
CR in 5-16 wk
none
I
I II
oral retinoids phototherapy topical steroids
M AN U
TE D
EP
Napolitano et al. 2018
AC C
Maloney et al. 2017
SC
Paganelli et al. 2017
3 mo mild relapse legs
Continued
ACCEPTED MANUSCRIPT
Table II Cont’d
PRP Type
Schuster et al. 2016
Age/sex
Biological agent
Disease duration prior to therapy
Previous treatments
Concomitant treatments
Follow-up period
Clinical response
Side effects /NDD
MR in 8 wks6mo
none
oral and esophageal candidosis
67/M
secukinumab s.c. 150 mg/w x 2 for 5 wks, then monthly
>5 mo
acitretin systemic GC topical GC
none
9 yrs
acitretin, MTX prednisone, topical GC, CsA, photochemotherapy, i.v. Igs, infliximab, ustekinumab, prednisone+CsA
prednisone 10 mg plus CsA 5 mg/kg/day
MR in 4 wks
acitretin 25-50 mg/day
PR
II
33/F
secukinumab s.c. 300 mg/wk for 5 wks then monthly
Davenport et al. 2017
I
58/M
secukinumab s.c. 300 mg/mo for 9 mo
AC C
EP
TE D
M AN U
SC
Gauci et al. 2016
RI PT
Study
topical GC acitretin MTX, NB-UVB infliximab
ACCEPTED MANUSCRIPT 1
CAPSULE SUMMARY
2
•
Biologics are useful treatments for pityriasis rubra pilaris patients refractory to conventional therapies.
3
•
This systematic review summarised the studies on the off-label use of biologics in pityriasis rubra
Biologics are promising tools in pityriasis rubra pilaris treatment; nevertheless, clinical trials are
TE D
M AN U
SC
needed to better assess their efficacy and safety.
EP
6
•
AC C
5
RI PT
pilaris.
4