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Systemic Immunomodulatory Treatments for Patients With Atopic DermatitisA Systematic Review and Network Meta-analysis

Educational Objective
To compare the effectiveness and safety of systemic immunomodulatory treatments for patients with atopic dermatitis.
1 Credit CME
Key Points

Question  What is the relative effectiveness of systemic treatments for patients with atopic dermatitis?

Findings  This network meta-analysis of 39 randomized clinical trials including 6360 patients found that dupilumab and cyclosporine were similarly effective for adult patients with atopic dermatitis for up to 16 weeks of treatment and were more effective than methotrexate and azathioprine.

Meaning  Cyclosporine and dupilumab may have better short-term effectiveness than methotrexate and azathioprine for patients with atopic dermatitis; this analysis will be updated to add evidence as new medications are approved.

Abstract

Importance  Most clinical trials assessing systemic immunomodulatory treatments for patients with atopic dermatitis are placebo-controlled.

Objective  To compare the effectiveness and safety of systemic immunomodulatory treatments for patients with atopic dermatitis in a systematic review and network meta-analysis.

Data Sources  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.

Study Selection  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 Extraction and Synthesis  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.

Main Outcomes and Measures  Prespecified outcomes were change in signs of disease, symptoms, quality of life, itch, withdrawals, and serious adverse events.

Results  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.

Conclusions and Relevance  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.

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Article Information

Accepted for Publication: February 26, 2020.

Published Online: April 22, 2020. doi:10.1001/jamadermatol.2020.0796

Open Access: This is an open access article distributed under the terms of the CC-BY License. © 2020 Drucker AM et al. JAMA Dermatology.

Corresponding Author: Carsten Flohr, PhD, Unit for Population-Based Dermatology Research, St John’s Institute of Dermatology, St Thomas’ Hospital, Westminster Bridge Road, London SE1 7EH, United Kingdom (carsten.flohr@kcl.ac.uk).

Author Contributions: Dr Drucker had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: Drucker, Ellis, Arents, Burton, Spuls, Schmitt, Flohr.

Acquisition, analysis, or interpretation of data: Drucker, Ellis, Bohdanowicz, Mashayekhi, Yiu, Rochwerg, Di Giorgio, Arents, Spuls, Küster, Siegels, Schmitt, Flohr.

Drafting of the manuscript: Drucker, Ellis, Di Giorgio, Flohr.

Critical revision of the manuscript for important intellectual content: Drucker, Ellis, Bohdanowicz, Mashayekhi, Yiu, Rochwerg, Arents, Burton, Spuls, Küster, Siegels, Schmitt, Flohr.

Statistical analysis: Ellis, Rochwerg, Flohr.

Obtained funding: Drucker, Flohr.

Administrative, technical, or material support: Drucker, Mashayekhi, Yiu, Rochwerg, Di Giorgio, Küster, Schmitt, Flohr.

Supervision: Drucker, Spuls, Flohr.

Conflict of Interest Disclosures: Dr Drucker reported serving as an investigator and receiving research funding from Sanofi and Regeneron; serving as a consultant for Sanofi, RTI Health Solutions, Eczema Society of Canada, and Canadian Agency for Drugs and Technology in Health; and receiving honoraria from Prime Inc, Spire Learning, CME Outfitters, Eczema Society of Canada, and the Canadian Dermatology Association; and his institution has received educational grants from Sanofi and AbbVie. Dr Spuls reported being chief investigator of the government-funded TREAT NL registry (www.treatregister.nl) and principal investigator of the Methotrexate Versus Azathioprine in Severe Atopic Dermatitis RCTs; serving as an unpaid consultant for Sanofi and AbbVie; receiving independent research grants from Schering Plough and LeoPharma; and performing clinical trials with many pharmaceutical industries that manufacture drugs used for the treatment of psoriasis and atopic dermatitis for which her department receives financial compensation. Mss Küster and Siegels reported receiving institutional funding for investigator-initiated trials from Novartis, Sanofi, Pfizer, and ALK. Dr Schmitt reported receiving institutional funding for investigator-initiated trials from Novartis, Sanofi, Pfizer, and ALK; receiving fees for consulting from Novartis and Pfizer; and being co–principal investigator of the German national AD registry TREATgermany, which is funded by Sanofi. Dr Flohr reported being chief investigator of the UK National Institute for Health Research–funded TREAT (ISRCTN15837754) and SOFTER (ClinicalTrials.gov: NCT03270566) trials as well as the UK-Irish Atopic Eczema Systemic Therapy Register (A-STAR; ISRCTN11210918) and being a principal investigator in the European Union Horizon 2020–funded BIOMAP Consortium (http://www.biomap-imi.eu/); and his department has received funding from Sanofi-Genzyme for skin microbiome work. No other disclosures were reported.

Funding/Support: This work was supported through a UK National Institute for Health Research (NIHR) Career Development Fellowship held by Dr Flohr (CDF-2014-07-037). Dr Flohr is also supported by the NIHR Biomedical Research Centre based at Guy’s and St Thomas’ NHS Foundation Trust and King’s College London. Knowledge translation components of this work are funded by the Eczema Society of Canada and the Innovation Fund of the Alternate Funding Plan for the Academic Health Sciences Centres of Ontario.

Role of the Funder/Sponsor: The funding sources had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Additional Contributions: Karen Lau, MA, Women’s College Hospital, provided administrative contributions to the study as a salaried research assistant. Zarif Jabbar-Lopez, MBBS, Unit for Population-Based Dermatology, St John’s Institute of Dermatology, Kings College London, assisted with the protocol stage; he was not compensated for his contribution. David Prieto-Merino, PhD, Applied Statistical Methods in Medical Research Group, Universidad Católica de Murcia, and Faculty of Epidemiology and Population Health, London School of Hygiene and Tropical Medicine, provided guidance on the adverse event analyses; he was not compensated for his contributions. We thank LEO Pharma, Dermira, and Emma Guttman-Yassky, MD, PhD, Mt Sinai Hospital, for providing unpublished outcomes data; Dr Guttman-Yassky was not compensated for her contribution. Evelien Roekevisch, MD, Dermatologisch Centrum Utrecht, provided information from a previous systematic review; she was not compensated for her contribution.

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