Jacek C. Szepietowski

Guidelines for treatment of atopic eczema (atopic dermatitis) Part I.

The existing evidence for treatment of atopic eczema (atopic dermatitis, AE) is evaluated using the national standard Appraisal of Guidelines Research and Evaluation. The consensus process consisted of a nominal group process and a DELPHI procedure. Management of AE must consider the individual symptomatic variability of the disease. Basic therapy is focused on hydrating topical treatment, and avoidance of specific and unspecific provocation factors. Anti‐inflammatory treatment based on topical glucocorticosteroids and topical calcineurin inhibitors (TCI) is used for exacerbation management and more recently for proactive therapy in selected cases. Topical corticosteroids remain the mainstay of therapy, but the TCI tacrolimus and pimecrolimus are preferred in certain locations. Systemic immune‐suppressive treatment is an option for severe refractory cases. Microbial colonization and superinfection may induce disease exacerbation and can justify additional antimicrobial treatment. Adjuvant therapy includes UV irradiation preferably with UVA1 wavelength or UVB 311 nm. Dietary recommendations should be specific and given only in diagnosed individual food allergy. Allergen‐specific immunotherapy to aeroallergens may be useful in selected cases. Stress‐induced exacerbations may make psychosomatic counselling recommendable. ‘Eczema school’ educational programs have been proven to be helpful. Pruritus is targeted with the majority of the recommended therapies, but some patients need additional antipruritic therapies.

Efficacy and safety of dupilumab in adults with moderate-to-severe atopic dermatitis inadequately controlled by topical treatments: a randomised, placebo-controlled, dose-ranging phase 2b trial

BACKGROUND Data from early-stage studies suggested that interleukin (IL)-4 and IL-13 are requisite drivers of atopic dermatitis, evidenced by marked improvement after treatment with dupilumab, a fully-human monoclonal antibody that blocks both pathways. We aimed to assess the efficacy and safety of several dose regimens of dupilumab in adults with moderate-to-severe atopic dermatitis inadequately controlled by topical treatments. METHODS In this randomised, placebo-controlled, double-blind study, we enrolled patients aged 18 years or older who had an Eczema Area and Severity Index (EASI) score of 12 or higher at screening (≥16 at baseline) and inadequate response to topical treatments from 91 study centres, including hospitals, clinics, and academic institutions, in Canada, Czech Republic, Germany, Hungary, Japan, Poland, and the USA. Patients were randomly assigned (1:1:1:1:1:1), stratified by severity (moderate or severe, as assessed by Investigators Global Assessment) and region (Japan vs rest of world) to receive subcutaneous dupilumab: 300 mg once a week, 300 mg every 2 weeks, 200 mg every 2 weeks, 300 mg every 4 weeks, 100 mg every 4 weeks, or placebo once a week for 16 weeks. We used a central randomisation scheme, provided by an interactive voice response system. Drug kits were coded, providing masking to treatment assignment, and allocation was concealed. Patients on treatment every 2 weeks and every 4 weeks received volume-matched placebo every week when dupilumab was not given to ensure double blinding. The primary outcome was efficacy of dupilumab dose regimens based on EASI score least-squares mean percentage change (SE) from baseline to week 16. Analyses included all randomly assigned patients who received one or more doses of study drug. This trial is registered with ClinicalTrials.gov, number NCT01859988. FINDINGS Between May 15, 2013, and Jan 27, 2014, 452 patients were assessed for eligibility, and 380 patients were randomly assigned. 379 patients received one or more doses of study drug (300 mg once a week [n=63], 300 mg every 2 weeks [n=64], 200 mg every 2 weeks [n=61], 300 mg every 4 weeks [n=65], 100 mg every 4 weeks [n=65]; placebo [n=61]). EASI score improvements favoured all dupilumab regimens versus placebo (p<0·0001): 300 mg once a week (-74% [SE 5·16]), 300 mg every 2 weeks (-68% [5·12]), 200 mg every 2 weeks (-65% [5·19]), 300 mg every 4 weeks (-64% [4·94]), 100 mg every 4 weeks (-45% [4·99]); placebo (-18% [5·20]). 258 (81%) of 318 patients given dupilumab and 49 (80%) of 61 patients given placebo reported treatment-emergent adverse events; nasopharyngitis was the most frequent (28% and 26%, respectively). INTERPRETATION Dupilumab improved clinical responses in adults with moderate-to-severe atopic dermatitis in a dose-dependent manner, without significant safety concerns. Our findings show that IL-4 and IL-13 are key drivers of atopic dermatitis. FUNDING Sanofi and Regeneron Pharmaceuticals.

Assessment of pruritus intensity: prospective study on validity and reliability of the visual analogue scale, numerical rating scale and verbal rating scale in 471 patients with chronic pruritus.

The most commonly used tool for self-report of pruritus intensity is the visual analogue scale (VAS). Similar tools are the numerical rating scale (NRS) and verbal rating scale (VRS). In the present study, initiated by the International Forum for the Study of Itch assessing reliability of these tools, 471 randomly selected patients with chronic itch (200 males, 271 females, mean age 58.44 years) recorded their pruritus intensity on VAS (100-mm line), NRS (0-10) and VRS (four-point) scales. Re-test reliability was analysed in a subgroup of 250 patients after one hour. Statistical analysis showed a high reliability and concurrent validity (r>0.8; p<0.01) for all tools. Mean values of all scales showed a high correlation. In conclusion, high reliability and concurrent validity was found for VAS, NRS and VRS. On re-test, higher correlation and less missing values were observed. A training session before starting a clinical trial is recommended.

Visual analogue scale: evaluation of the instrument for the assessment of pruritus.

The aim of this study was to evaluate the visual analogue scale (VAS) as a method of pruritus assessment. A total of 310 subjects with pruritic dermatoses (148 Caucasian subjects and 162 Asian subjects) were recruited. The patients assessed pruritus intensity using the horizontal and vertical VAS, numeric rating scale (NRS) and verbal rating scale (VRS). All scales showed very good reproducibility (intraclass coefficient (ICC) > 0.8). No significant differences were found between the horizontal and vertical VAS (5.3 ± 2.9 vs. 5.3 ± 3.0 points, p = 0.34). Using NRS, patients rated their pruritus significantly higher than with VAS (5.7 ± 2.6 points, p < 0.01). VRS showed the highest correlation with NRS (R = 0.82, p < 0.001), followed by horizontal (R = 0.75, p < 0.001) and vertical VAS (R=0.74, p < 0.001). Based on detailed analysis following VAS categories were proposed: 0 = no pruritus, > 0-< 4 points = mild pruritus, ≥ 4-< 7 points = moderate pruritus, ≥ 7-< 9 points = severe pruritus, and ≥ 9 points = very severe pruritus. In conclusion, the VAS is a valuable method of pruritus measurement.

European Guideline on Chronic Pruritus In cooperation with the European Dermatology Forum (EDF) and the European Academy of Dermatology and Venereology (EADV)

Elke WEISShAAr1, Jacek C. SzEpIEToWSkI2, Ulf DArSoW3, Laurent MISEry4, Joanna WALLENgrEN5, Thomas METTANg6, Uwe gIELEr7, Torello LoTTI8, Julien LAMbErT9, peter MAISEL10, Markus STrEIT11, Malcolm W. grEAVES12, Andrew CArMIChAEL13, Erwin TSChAChLEr14, Johannes rINg3 and Sonja STaNDEr15 1Department of Clinical Social Medicine, Environmental and Occupational Dermatology, Ruprecht-Karls-University Heidelberg, Germany, 2Department of Dermatology, Venereology and Allergology, Wroclaw Medical University, Poland, 3Department of Dermatology and Allergy Biederstein, Technical University Munchen and ZAUM Center for Allergy and Environment, Munich, Germany, 4Department of Dermatology, University Hospital Brest, France, 5Department of Dermatology, Lund University, Sweden, 6German Clinic for Diagnostics, Nephrology, Wiesbaden, 7Department of Psychosomatic Dermatology, Clinic for Psychosomatic Medicine, University of Giessen, Giessen, Germany, 8Department of Dermatology, University of Florence, Italy, 9Department of Dermatology, University of Antwerpen, Belgium, 10Department of General Medicine, University Hospital Muenster, Germany, 11Department of Dermatology, Kantonsspital Aarau, Switzerland, 12Department of Dermatology, St. Thomas Hospital Lambeth, London, 13Department of Dermatology, James Cook University Hospital Middlesbrough, UK, 14Department of Dermatology, Medical University Vienna, Austria and 15Department of Dermatology, Competence Center for Pruritus, University Hospital Muenster, Germany

Patients with Psoriasis Feel Stigmatized

Stigmatization is defined as having a discrediting mark that leads to social discrimination and alienation. The aim of this study was to estimate the level of stigmatization experienced by patients with psoriasis. A total of 102 individuals with psoriasis were recruited and was assessed using the 6-item Stigmatization Scale and the 33-item Feelings of Stigmatization Questionnaire. In addition, quality of life, stress and depression were evaluated. The majority of patients felt that they were stigmatized by psoriasis. The most bothersome aspect was that other people stared at their skin changes. According to the 33-item questionnaire, anticipation of rejection and feelings of guilt and shame were the major aspects of stigmatization, the level of which correlated significantly with pruritus intensity, stress prior to exacerbation, depressive symptoms and quality of life. In order to decrease the stigmatization level in patients with psoriasis, greater effort is needed to raise awareness in contemporary societies that psoriasis is not contagious, but is a disease like many other chronic conditions.

Emollients improve treatment results with topical corticosteroids in childhood atopic dermatitis: a randomized comparative study.

The aim of the study was to investigate whether adding emollients to the standard topical corticosteroid therapy influences the outcome of children with atopic dermatitis. Fifty‐two children aged between 2 and 12 yr were divided randomly in two subgroups consisting of 26 children each. Both groups applied 0.1% methylprednisolone aceponate cream on lesional atopic skin once daily for 2 wk and were observed for another 4 wk after treatment discontinuation. Group B used additionally emollients for the whole study period. Patients were evaluated at days 0 (baseline), 7, 14 (end of therapy), 28 and 42 (follow‐up). Both groups demonstrated significant improvement of disease severity according to EASI (Eczema Area and Severity Index) scale (group A: 6.8 ± 3.59 before and 0.87 ± 1.25 after therapy, p < 0.001; group B: 9.6 ± 8.39 before and 1.11 ± 2.37 after therapy, p < 0.001). Xerosis improved significantly better in group B compared to group A, both clinically (group A: 1.38 ± 0.57 scores before and 1.5 ± 0.58 scores after therapy, p = 0.11; group B: 1.62 ± 0.64 scores before and 0.12 ± 0.33 scores after therapy, p < 0.001), and by corneometry assessment (group A: 41.7 ± 9.1 units before and 51.3 ± 11.3 units after therapy, p < 0.001; group B: 38.9 ± 12.9 units before and 58.2 ± 13.5 units after therapy, p < 0.001). A trend towards faster resolving of pruritus in group B (group A: 5.44 ± 2.6 scores before and 3.22 ± 2.31 scores after therapy, p = 0.001; group B: 5.87 ± 2.79 scores before and 2.24 ± 1.59 scores after therapy, p < 0.001) was also observed. In group B, the improvement was maintained for couple of weeks after treatment discontinuation, while in group A recurrence of the disease was noted (EASI at day 42 in group A vs. group B: 5.29 ± 5.6 vs. 1.25 ± 1.4, p = 0.01). Similar results were also observed for xerosis (p < 0.001) and pruritus (p = 0.002). Concomitant usage of emollients significantly improves xerosis and pruritus during corticosteroid treatment of atopic dermatitis and enables to maintain clinical improvement after therapy discontinuation.

Long-term management of moderate-to-severe atopic dermatitis with dupilumab and concomitant topical corticosteroids (LIBERTY AD CHRONOS): a 1-year, randomised, double-blinded, placebo-controlled, phase 3 trial

BACKGROUND Dupilumab (an anti-interleukin-4-receptor-α monoclonal antibody) blocks signalling of interleukin 4 and interleukin 13, type 2/Th2 cytokines implicated in numerous allergic diseases ranging from asthma to atopic dermatitis. Previous 16-week monotherapy studies showed that dupilumab substantially improved signs and symptoms of moderate-to-severe atopic dermatitis with acceptable safety, validating the crucial role of interleukin 4 and interleukin 13 in atopic dermatitis pathogenesis. We aimed to evaluate the long-term efficacy and safety of dupilumab with medium-potency topical corticosteroids versus placebo with topical corticosteroids in adults with moderate-to-severe atopic dermatitis. METHODS In this 1-year, randomised, double-blinded, placebo-controlled, phase 3 study (LIBERTY AD CHRONOS), adults with moderate-to-severe atopic dermatitis and inadequate response to topical corticosteroids were enrolled at 161 hospitals, clinics, and academic institutions in 14 countries in Europe, Asia-Pacific, and North America. Patients were randomly assigned (3:1:3) to subcutaneous dupilumab 300 mg once weekly (qw), dupilumab 300 mg every 2 weeks (q2w), or placebo via a central interactive voice/web response system, stratified by severity and global region. All three groups were given concomitant topical corticosteroids with or without topical calcineurin inhibitors where inadvisable for topical corticosteroids. Topical corticosteroids could be tapered, stopped, or restarted on the basis of disease activity. Coprimary endpoints were patients (%) achieving Investigators Global Assessment (IGA) 0/1 and 2-point or higher improvement from baseline, and Eczema Area and Severity Index 75% improvement from baseline (EASI-75) at week 16. Week 16 efficacy and week 52 safety analyses included all randomised patients; week 52 efficacy included patients who completed treatment by US regulatory submission cutoff. This study is registered with ClinicalTrials.gov, NCT02260986. FINDINGS Between Oct 3, 2014, and July 31, 2015, 740 patients were enrolled: 319 were randomly assigned to dupilumab qw plus topical corticosteroids, 106 to dupilumab q2w plus topical corticosteroids, and 315 to placebo plus topical corticosteroids. 623 (270, 89, and 264, respectively) were evaluable for week 52 efficacy. At week 16, more patients who received dupilumab plus topical corticosteroids achieved the coprimary endpoints of IGA 0/1 (39% [125 patients] who received dupilumab plus topical corticosteroids qw and 39% [41 patients] who received dupilumab q2w plus topical corticosteroids vs 12% [39 patients] who received placebo plus topical corticosteroids; p<0·0001) and EASI-75 (64% [204] and 69% [73] vs 23% [73]; p<0·0001). Week 52 results were similar. Adverse events were reported in 261 (83%) patients who received dupilumab qw plus topical corticosteroids, 97 (88%) patients who received dupilumab q2w, and 266 (84%) patients who received placebo, and serious adverse events in nine (3%), four (4%), and 16 (5%) patients, respectively. No significant dupilumab-induced laboratory abnormalities were noted. Injection-site reactions and conjunctivitis were more common in patients treated with dupilumab plus topical corticosteroids-treated patients than in patients treated with placebo plus topical corticosteroids. INTERPRETATION Dupilumab added to standard topical corticosteroid treatment for 1 year improved atopic dermatitis signs and symptoms, with acceptable safety. FUNDING Sanofi and Regeneron Pharmaceuticals Inc.

Psoriatic Nails: A Prospective Clinical Study

Background: Psoriasis is a widespread skin disorder in which nail involvement is a common symptom. Many psoriatic patients have nail changes morphologically resembling onychomycosis. Objective: The present study was undertaken (1) to evaluate the frequency of nail involvement in psoriatic patients, (2) to assess the types of nail changes in psoriasis, (3) to find eventual relationships between nail involvement and some clinical parameters, and finally (4) to determine the prevalence of fungal nail infections in psoriatic individuals. Material and Methods: One hundred six patients hospitalized in our department due to exacerbation of psoriasis participated in the study. Each patient underwent dermatologic examination with special attention paid to the nail changes. In any case of abnormalities clinically suspected of fungal infection, further mycological investigations were performed. Results: Nail changes were present in 83 patients (78.3%) with psoriasis. The most common nail abnormality observed on both fingernails and toenails was subungual hyperkeratosis. Hyperkeratosis, onychorrexis, and discoloration of nail plates were observed significantly more often on toenails. Pitting and longitudinal ridges were significantly more frequent on fingernails. Patients with psoriatic nail dystrophy were significantly older than psoriatic patients without nail abnormalities. Nails were involved statistically more often in patients with arthropathic psoriasis. Positive mycological cultures were obtained from 18% of patients with nail changes. The most commonly isolated fungi were molds. Conclusions: Dystrophic nails are frequently found in psoriatic individuals, especially those suffering from arthropathic psoriasis. Subungual hyperkeratosis and pitting are the most typical lesions. It is difficult to assess definitively whether psoriasis is a predisposing factor to the development of fungal infections of the nails. SommaireAntécédents: Le psoriasis est une affection dermique très fréquente dont l’un des symptômes est l’altération de l’ongle. En effet, un grand nombre de personnes atteintes de psoriasis subissent une transformation morphologique de l’ongle ressemblant à l’onychomycose. Objectif: La présente étude vise (1) l’évaluation de la fréquence de l’affection de l’ongle chez les patients atteints de psoriasis; (2) l’évaluation du type de changements de l’ongle en présence de psoriasis; (3) la découverte de liens possibles entre l’affection de l’ongle et certains paramètres cliniques; et finalement (4) l’estimation de la prévalence des infections fongiques de l’ongle chez les personnes présentant un cas de psoriasis. Méthodes et Matériel: Cent six patients hospitalisés dans notre service àla suite d’une exacerbation du psoriasis ont pris part à l’étude. Chaque patient a subi un examen dermatologique avec une attention particulière prêtée aux altérations des ongles. Dans les cas d’anormalités cliniques pouvant être attributées à des infections fongiques, des essais mycologiques ont été effectués. Résultats: Des transformations au niveau des ongles ont été décelées chez 83 patients (78,3%) atteints de psoriasis. L’anomalie la plus fréquente tant sur les ongles des doigts que sur ceux des orteils était une hyperkératose sous-unguéale. L’apparition d’hyperkératose, d’onychorrexie et de décoloration des limbes était considérablement plus élevée sur les ongles des orteils. Par contre, les ongles en dé à coudre et les stries longitudinales prèvalaient sur les ongles des doigts. Les patients présentant une dystrophie unguéale étaient bien plus âgés que les patients qui ne présentaient pas d’anomalies au niveau des ongles. Les altérations unguéales sont statistiquement plus fréquentes chez les patients souffrant d’arthropathies. Des cultures mycologiques positives ont été prélevées chez 18% des patients présentant une altération aux ongles. Le champignon le plus fréquemment isolé était la moisissure. Conclusions: La dystrophie unguéale est fréquente chez les patients atteints de psoriasis, surtout chez ceux qui souffrent d’arthropathies. L’hyperkeratose sous-unguéale et les stries représentent les lésions les plus communes. Il est toutefois difficile de conclure si le psoriasis est un facteur prédisposant aux infections fongiques des ongles.

Phase I, Randomized, Double-Blind, Placebo-Controlled, Multiple Intravenous, Dose-Ascending Study of Sirukumab in Cutaneous or Systemic Lupus Erythematosus

OBJECTIVE We undertook a 2-part, phase I, double-blind, placebo-controlled study to evaluate the safety and pharmacokinetics of multiple intravenous infusions of sirukumab, a human anti-interleukin-6 monoclonal antibody, in patients with cutaneous lupus erythematosus (CLE) or systemic lupus erythematosus (SLE). METHODS In part A, patients with histologically confirmed CLE were randomized to 4 infusions of placebo or 1, 4, or 10 mg/kg sirukumab every 2 weeks. In part B, SLE patients diagnosed according to American College of Rheumatology criteria with a score of 5-12 on the Safety of Estrogens in Lupus Erythematosus National Assessment version of the SLE Disease Activity Index were randomized to 4 infusions of placebo or 10 mg/kg sirukumab every 2 weeks. RESULTS We treated 31 CLE patients (23 with sirukumab, 8 with placebo) and 15 SLE patients (10 with sirukumab, 5 with placebo). Adverse events (AEs) occurred more often with sirukumab than placebo in CLE patients (91% versus 63%) and in SLE patients (90% versus 80%). Sirukumab led to sustained, dose-independent decreases in white blood cell counts, absolute neutrophil counts (neutropenia), and platelet counts (thrombocytopenia) and to minor elevations in total cholesterol levels. The majority of infections were mild respiratory infections. which were reported similarly across CLE cohorts but more often in sirukumab-treated than in placebo-treated SLE patients. Two serious AEs of infection occurred (pneumonia in the 10 mg/kg-treated group and iatrogenic wound infection in the 4 mg/kg-treated group). Sirukumab showed linear pharmacokinetics in CLE patients. Systemic exposure and half-life were comparable between CLE and SLE patients. No patient developed antibodies to sirukumab through 22 weeks. C-reactive protein and serum amyloid A mean concentrations were suppressed with sirukumab from week 1 to week 14. CONCLUSION Treatment with intravenous sirukumab infusions was generally well tolerated in both CLE and SLE patients with mild, stable, active disease. Sirukumab demonstrated linear pharmacokinetics over the dose range studied and comparable systemic exposure and half-life in CLE and SLE patients.