Systemic Immunomodulatory Treatments for Patients With Atopic Dermatitis

Aaron M Drucker,Michal Bohdanowicz,Phyllis I Spuls,Jochen Schmitt,Denise Küster,Tim Burton,Soudeh Mashayekhi,Zenas Z N Yiu,Doreen Siegels,Sonya Di Giorgio,Carsten Flohr,Bram Rochwerg,Alexandra G Ellis,Bernd W M Arents

doi:10.1001/jamadermatol.2020.0796

Abstract

Most clinical trials assessing systemic immunomodulatory treatments for patients with atopic dermatitis are placebo-controlled. To compare the effectiveness and safety of systemic immunomodulatory treatments for patients with atopic dermatitis in a systematic review and network meta-analysis. The Cochrane Central Register of Controlled Trials, MEDLINE, Embase, Latin American and Caribbean Health Science Information database, Global Resource of Eczema Trials database, and clinical trial registries were searched from inception to October 28, 2019. English-language randomized clinical trials of 8 weeks or more of treatment with systemic immunomodulatory medications for moderate to severe atopic dermatitis were included. Titles, abstracts, and articles were screened in duplicate. Of 10 324 citations, 39 trials were included. Data were extracted in duplicate, and the review adhered to Preferred Reporting Items for Systematic Reviews and Meta-analyses for Network Meta-Analyses guidelines. Random-effects bayesian network meta-analyses were performed and certainty of evidence was assessed using Grading of Recommendations Assessment, Development and Evaluation criteria. Prespecified outcomes were change in signs of disease, symptoms, quality of life, itch, withdrawals, and serious adverse events. A total of 39 trials with 6360 patients examining 20 medications and placebo were included. Most trials were conducted for adults receiving up to 16 weeks of therapy. Dupilumab, 300 mg every 2 weeks, was associated with improvement in the Eczema Area and Severity Index score vs placebo (mean difference, 11.3-point reduction; 95% credible interval [CrI], 9.7-13.1 [high certainty]). Cyclosporine (standardized mean difference, -1.1; 95% CrI, -1.7 to -0.5 [low certainty]) and dupilumab (standardized mean difference, -0.9; 95% CrI, -1.0 to -0.8 [high certainty]) were similarly effective vs placebo in clearing clinical signs of atopic dermatitis and may be superior to methotrexate (standardized mean difference, -0.6; 95% CrI, -1.1 to 0.0 [low certainty]) and azathioprine (standardized mean difference, -0.4; 95% CrI, -0.8 to -0.1 [low certainty]). Several investigational medications for atopic dermatitis are promising, but data to date are limited to small early-phase trials. Safety analyses were limited by low event rates. Dupilumab and cyclosporine may be more effective for up to 16 weeks of treatment than methotrexate and azathioprine for treating adult patients with atopic dermatitis. More studies directly comparing established and novel treatments beyond 16 weeks are needed and will be incorporated into future updates of this review.

Highlights

In analyses of outcomes in adult patients receiving between 8 and 16 weeks of treatment, dupilumab was efficacious based on highcertainty evidence with regards to improving clinical signs, including clinically important differences in Eczema Area and Severity Index (EASI) scores
Dupilumab and the investigational Janus kinase inhibitors upadacitinib and abrocitinib provided clinically meaningful improvement in Patient-Oriented Eczema Measure (POEM) scores and dupilumab and abrocitinib were associated with clinically meaningful improvements in the Dermatology Life Quality Index (DLQI) score compared with placebo
Dupilumab and higher-dose cyclosporine appear to have better effectiveness during the first 4 months of therapy in improving clinical signs, itch, and quality of life relative to methotrexate and azathioprine. These analyses are limited by pooling outcome measures such as peak itch and mean itch, which measure the same domain but in different ways, and their inclusion of trials only up to 16 weeks, which may favor medications with more rapid onset of action. Despite these concerns and low certainty according to GRADE, our stratification of the currently available treatments should be useful to stakeholders including patients, clinicians, guideline developers, and health technology assessors

Summary

Methods

Search Strategy and Selection Criteria We searched the Cochrane Central Register of Controlled Trials, MEDLINE via Ovid (from 1946), Embase via Ovid (from 1974), the Latin American and Caribbean Health Science Information database (from 1982), and the Global Resource of Eczema Trials database. We performed searches of the following trial registers: the ISRCTN (International Standard Randomised Controlled Trial Number) registry, ClinicalTrials.gov, the Australian New Zealand Clinical Trials Registry, the World Health Organization International Clinical Trials Registry Platform, and the EU Clinical Trials Register. The full, updated search strategy can be found at http://eczematherapies.com/ research. We searched for supplemental results on trial registries and contacted study authors and pharmaceutical companies to obtain further data. For logistical reasons and because language restriction has not been shown to consistently bias the results of quantitative syntheses, we included only studies published in English.

Results

Discussion

Conclusion