Crisaborole Ointment Improves Quality of Life of Patients with Mild to Moderate Atopic Dermatitis and Their Families.

IntroductionThe impact of crisaborole ointment, a nonsteroidal phosphodiesterase 4 inhibitor for the treatment of mild to moderate atopic dermatitis (AD), on quality of life (QoL) was assessed in two identically designed phase 3 studies (AD-301: NCT02118766; AD-302: NCT02118792, both at http://www.clinicaltrials.gov ).MethodsIn both studies, patients aged ≥ 2 years with mild to moderate AD per the Investigator's Static Global Assessment were randomly assigned 2:1 to receive crisaborole or vehicle twice daily for 28 days. QoL was assessed using the Children's Dermatology Life Quality Index (CDLQI) (2-15 years), the Dermatology Life Quality Index (DLQI) (≥ 16 years), and the Dermatitis Family Impact Questionnaire (DFI) (parents/caregivers/family of patients aged 2-17 years). Established QoL score severity bands provided clinical context.ResultsGreater mean improvement in QoL was observed in crisaborole-treated patients than in vehicle-treated patients at day 29 [mean change from baseline (∆BL), CDLQI: - 4.6 vs. - 3.0; P < 0.001; DLQI: - 5.2 vs. - 3.5; P = 0.015]. At baseline, more than half the patients had a "moderate effect" or higher of AD on QoL. At day 29, there was a trend toward more crisaborole- than vehicle-treated patients having "small effect" to "no effect", The QoL of parents/caregivers/family improved more for crisaborole-treated than for vehicle-treated patients (∆BL, DFI: - 3.7 vs. - 2.7; P = 0.003).ConclusionCrisaborole treatment results in clinically meaningful improvement in QoL for patients and their parents/caregivers/families.Trial registrationAD-301: http://www.clinicaltrials.gov , NCT02118766; AD-302: http://www.clinicaltrials.gov , NCT02118792.FundingAnacor Pharmaceuticals, Inc., a wholly owned subsidiary of Pfizer Inc., New York, NY

Exploring content and psychometric validity of newly developed assessment tools for itch and skin pain in atopic dermatitis.

BackgroundAtopic dermatitis (AD) is a common skin disorder characterized by chronic inflammation, altered skin barrier function, and inflammatory cell skin infiltration that decreases health-related quality of life (HRQoL). The study objective was to understand the patient perspective of AD burden and determine suitable patient-reported outcome (PRO) measures.MethodsThis mixed methods study involved the collection of qualitative and quantitative information from adults (≥ 18 years old) and adolescents (12 - 17 years old) with clinician-confirmed AD regarding their experiences of AD symptoms and its impact on HRQoL. The first part of the study included three stages: in-person concept elicitation (CE) interviews, a 2-week daily electronic diary (eDiary) study, and in-person cognitive debriefing (CD) interviews. An Itch numeric rating scale (NRS) (v1.0) and a Skin Pain NRS (v1.0) evaluation during CD interviews required participants to think about their 'worst' itch and 'worst' skin pain in the past 24 h. Other PRO measures allowed for psychometric testing. The second part of the study involved telephone-depth interviews (TDIs) and qualitative feedback from participants who had not participated in the CD interviews. Qualitative data were thematically analyzed. Psychometric evaluation of NRS measures was performed using eDiary data.ResultsIn the CE interviews, itch and/or itching and skin pain were the most prevalent symptoms consistently discussed by participants. Both NRS measures demonstrated strong psychometric reliability and were applicable across ages with suitable concurrent validity. During the CD interviews, some participants focused their answers on their 'average' itch/itching in the past 24 h, rather than their 'worst' itch. Some participants answered the Skin Pain NRS thinking about general pain or other types of pain, rather than skin pain specifically. Consequently, modifications to both measures addressed these issues and re-tested as paper-and-pen versions in subsequent TDIs. Itch NRS (v2.0) modifications helped participants focus on their worst itching. Most participants preferred Skin Pain NRS v2.0b, which included skin pain descriptors.ConclusionsItching and skin pain are the most important and relevant AD symptoms. The Itch NRS (v2.0) and Skin Pain NRS (v2.0b) appear to be appropriate endpoints for the assessment of itching and skin pain severity for clinical trials with adults and adolescents with AD

IL-4Rα Blockade by Dupilumab Decreases Staphylococcus aureus Colonization and Increases Microbial Diversity in Atopic Dermatitis.

Dupilumab is a fully human antibody to interleukin-4 receptor α that improves the signs and symptoms of moderate to severe atopic dermatitis (AD). To determine the effects of dupilumab on Staphylococcus aureus colonization and microbial diversity on the skin, bacterial DNA was analyzed from swabs collected from lesional and nonlesional skin in a double-blind, placebo-controlled study of 54 patients with moderate to severe AD randomized (1:1) and treated with either dupilumab (200 mg weekly) or placebo for 16 weeks. Microbial diversity and relative abundance of Staphylococcus were assessed by DNA sequencing of 16S ribosomal RNA, and absolute S. aureus abundance was measured by quantitative PCR. Before treatment, lesional skin had lower microbial diversity and higher overall abundance of S. aureus than nonlesional skin. During dupilumab treatment, microbial diversity increased and the abundance of S. aureus decreased. Pronounced changes were seen in nonlesional and lesional skin. Decreased S. aureus abundance during dupilumab treatment correlated with clinical improvement of AD and biomarkers of type 2 immunity. We conclude that clinical improvement of AD that is mediated by interleukin-4 receptor α inhibition and the subsequent suppression of type 2 inflammation is correlated with increased microbial diversity and reduced abundance of S. aureus

Durability of Response to Abrocitinib in Patients with Moderate-to-Severe Atopic Dermatitis After Treatment Discontinuation in a Phase 2b Trial

ntroduction: Multiple clinical trials showed that 12 weeks of abrocitinib monotherapy was safe and effective for the treatment of moderateto-severe atopic dermatitis (AD). The reversibility of pharmacologic activity after abrocitinib discontinuation was not described. Methods: This post hoc analysis used data from a phase 2b study to evaluate maintenance of disease control during a 4-week drug-free follow-up period in patients with moderate-tosevere AD treated with once-daily abrocitinib (200 mg/100 mg) or placebo for 12 weeks. Proportions of patients who achieved and maintained 50% or 75% improvement in Eczema Area and Severity Index (EASI-50/EASI75), an Investigator’s Global Assessment (IGA) score of 0/1, or at least a 4-point improvement in the pruritus numeric rating scale (pruritus NRS4) were determined. Biomarkers of Janus kinase inhibition and AD disease were measured in blood samples. Results: Among week 12 responders to abrocitinib 200 mg, 77.4%, 42.3%, 21.1%, and 42.9% maintained their EASI-50, EASI-75, IGA, and pruritus NRS4 response at week 16; corresponding proportions of week 12 responders maintaining response to abrocitinib 100 mg were 51.9%, 35.0%, 33.3%, and 43.5%, respectively. Four weeks after abrocitinib discontinuation, all AD biomarkers reverted towar

Phase 2B randomized study of nemolizumab in adults with moderate-to-severe atopic dermatitis and severe pruritus

Background: Nemolizumab targets the IL-31 receptor a subunit involved in atopic dermatitis (AD) pathogenesis. Objective: We sought to evaluate a new dosing strategy of nemolizumab in patients with AD. Methods: We performed a 24-week, randomized, double-blind, multicenter study of nemolizumab (10, 30, and 90 mg) subcutaneous injections every 4 weeks versus placebo, with topical corticosteroids in adults with moderate-to-severe AD, severe pruritus, and inadequate control with topical treatment (n 5 226). The Eczema Area and Severity Index (EASI), the peak pruritus (PP) numeric rating scale (NRS), and the Investigator’s Global Assessment (IGA) were assessed. Standard safety assessments were performed. Results: Nemolizumab improved EASI, IGA, and/or NRS-itch scores, with the 30-mg dose being most effective. Nemolizumab (30 mg) reduced EASI scores versus placebo at week 24 (268.8% vs 252.1%, P 5 .016); significant differences were observed by week 8 (P <_ .01). With significant improvement (P 5 .028) as early as week 4, IGA 0/1 rates were higher for 30 mg of nemolizumab versus placebo at week 16 (33.3% vs 12.3%, P 5 .008) but not week 24 because of an increased placebo/topical corticosteroid effect (36.8% vs 21.1%, P 5 .06). PP-NRS scores were improved for 30 mg of nemolizumab versus placebo at week 16 (268.6% vs 234.3%, P <.0001) and week 24 (267.3% vs 235.8%, P <.0001), with a difference by week 1 (P _4-point decrease) were greater for 30 mg of nemolizumab versus placebo at week 16 (P <_ .001) and week 24 (P <_ .01). Nemolizumab was safe and well tolerated. The most common adverse events were nasopharyngitis and upper respiratory tract infection. Conclusions: Nemolizumab resulted in rapid and sustained improvements in cutaneous signs of inflammation and pruritus in patients with AD, with maximal efficacy observed at 30 mg. Nemolizumab had an acceptable safety profile. (J Allergy Clin Immunol 2020;145:173-82.

Efficacy and safety of lebrikizumab in moderate-to-severe atopic dermatitis: results from two phase III, randomized, double-blinded, placebo-controlled trials

Lebrikizumab, a high-affinity IgG-4 monoclonal antibody targeting interleukin (IL)-13, selectively prevents the formation of the IL-13Ra1/IL-4Ra heterodimer receptor signalling complex. Lebrikizumab demonstrated rapid, dose-dependent efficacy and an acceptable safety profile in patients with moderate-to-severe atopic dermatitis (AD) in a phase IIb trial (NCT03443024). Here, we report 16-week efficacy and safety outcomes of lebrikizumab monotherapy in patients with AD from two ongoing 52-week, randomized, double-blinded, placebo-controlled phase III trials – ADvocate1 (NCT04146363) and ADvocate2 (NCT04178967). Eligible patients with moderate-to-severe AD [adults and adolescents (12–17 years of age, weighing ≥40 kg)] were randomized 2: 1 to subcutaneous lebrikizumab 250 mg or placebo every 2 weeks. Efficacy analyses included proportions of patients achieving Investigator’s Global Assessment (IGA) 0/1, Eczema Area and Severity Index (EASI)-75 and Pruritus Numerical Rating Scale (NRS) ≥ 4-point improvement from baseline (P ≥ 4) at week 16. Nonefficacy-related missing data were imputed by multiple imputation. In ADvocate1, proportions of patients treated with lebrikizumab 250 mg (n = 283) and placebo (n = 141) achieving IGA 0/1 at week 16 were 43.0% and 12.8% (P \u3c 0.001); EASI-75 responses were 59.3% and 16.4% (P \u3c 0.001); P ≥ 4 proportions were 46.3% and 12.7% (P \u3c 0.001), respectively. In ADvocate2 (lebrikizumab, n = 281; placebo, n = 146), corresponding proportions for IGA 0/1 were 33.1% and 10.9% (P \u3c 0.001); EASI-75 responses were 50.8% and 18.2% (P \u3c 0.001); P ≥ 4 proportions were 38.3% and 11.3% (P \u3c 0.001), respectively. The percentage of patients reporting ≥1 TEAE was comparable in ADvocate1 (lebrikizumab, 45.4%; placebo, 51.1%) and ADvocate2 (lebrikizumab 53.0%; placebo 66.2%). Data from two ongoing pivotal phase III trials suggest that lebrikizumab 250 mg Q2W provides an efficacious treatment option with an acceptable safety profile for patients with moderate-to-severe AD

Global Skin Disease Morbidity and Mortality: An Update From the Global Burden of Disease Study 2013.

Importance: Disability secondary to skin conditions is substantial worldwide. The Global Burden of Disease Study 2013 includes estimates of global morbidity and mortality due to skin diseases. Objective: To measure the burden of skin diseases worldwide. Data Sources: For nonfatal estimates, data were found by literature search using PubMed and Google Scholar in English and Spanish for years 1980 through 2013 and by accessing administrative data on hospital inpatient and outpatient episodes. Data for fatal estimates were based on vital registration and verbal autopsy data. Study Selection: Skin disease data were extracted from more than 4000 sources including systematic reviews, surveys, population-based disease registries, hospital inpatient data, outpatient data, cohort studies, and autopsy data. Data metrics included incidence, prevalence, remission, duration, severity, deaths, and mortality risk. Data Extraction and Synthesis: Data were extracted by age, time period, case definitions, and other study characteristics. Data points were modeled with Bayesian meta-regression to generate estimates of morbidity and mortality metrics for skin diseases. All estimates were made with 95% uncertainty intervals. Main Outcomes and Measures: Disability-adjusted life years (DALYs), years lived with disability, and years of life lost from 15 skin conditions in 188 countries. Results: Skin conditions contributed 1.79% to the global burden of disease measured in DALYs from 306 diseases and injuries in 2013. Individual skin diseases varied in size from 0.38% of total burden for dermatitis (atopic, contact, and seborrheic dermatitis), 0.29% for acne vulgaris, 0.19% for psoriasis, 0.19% for urticaria, 0.16% for viral skin diseases, 0.15% for fungal skin diseases, 0.07% for scabies, 0.06% for malignant skin melanoma, 0.05% for pyoderma, 0.04% for cellulitis, 0.03% for keratinocyte carcinoma, 0.03% for decubitus ulcer, and 0.01% for alopecia areata. All other skin and subcutaneous diseases composed 0.12% of total DALYs. Conclusions and Relevance: Skin and subcutaneous diseases were the 18th leading cause of global DALYs in Global Burden of Disease 2013. Excluding mortality, skin diseases were the fourth leading cause of disability worldwide

International observational atopic dermatitis cohort to follow natural history and treatment course: TARGET-DERM AD study design and rationale

INTRODUCTION: As new topical and systemic treatments become available for atopic dermatitis (AD), there is a need to understand how treatments are being used in routine clinical practice, their comparative effectiveness and their long-term safety in diverse clinical settings. METHODS AND ANALYSIS: The TARGET-DERM AD cohort is a longitudinal, observational study of patients with AD of all ages, designed to provide practical information on long-term effectiveness and safety unobtainable in traditional registration trials. Patients with physician-diagnosed AD receiving prescription treatment (topical or systemic) will be enrolled at academic and community clinical centres. Up to 3 years of retrospective medical records, 5 years of prospective medical records, and optional biological samples and patient-reported outcomes will be collected. The primary aims include characterisation of AD treatment regimens, evaluation of response to therapy, and description of adverse events. ETHICS AND DISSEMINATION: TARGET-DERM has been approved by a central IRB (Copernicus Group IRB, 5000 Centregreen Way Suite 200, Cary, North Carolina 27513) as well as local and institutional IRBs. No additional Ethics Committee reviews. Results will be reviewed by a publications committee and submitted to peer-reviewed journals. TRIAL REGISTRATION NUMBER: NCT03661866, pre-results

IL-4R alpha blockade by dupilumab decreases Staphylococcus aureus colonization and increases microbial diversity in atopic dermatitis

Dupilumab is a fully human antibody to interleukin-4 receptor alpha that improves the signs and symptoms of moderate to severe atopic dermatitis (AD). To determine the effects of dupilumab on Staphylococcus aureus colonization and microbial diversity on the skin, bacterial DNA was analyzed from swabs collected from lesional and nonlesional skin in a double-blind, placebo-controlled study of 54 patients with moderate to severe AD randomized (1:1) and treated with either dupilumab (200 mg weekly) or placebo for 16 weeks. Microbial diversity and relative abundance of Staphylococcus were assessed by DNA sequencing of 16S ribosomal RNA, and absolute S. aureus abundance was measured by quantitative PCR. Before treatment, lesional skin had lower microbial diversity and higher overall abundance of S. aureus than nonlesional skin. During dupilumab treatment, microbial diversity increased and the abundance of S. aureus decreased. Pronounced changes were seen in nonlesional and lesional skin. Decreased S. aureus abundance during dupilumab treatment correlated with clinical improvement of AD and biomarkers of type 2 immunity. We conclude that clinical improvement of AD that is mediated by interleukin-4 receptor alpha inhibition and the subsequent suppression of type 2 inflammation is correlated with increased microbial diversity and reduced abundance of S. aureus