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Mapping atopic dermatitis and anti–IL-22 response signatures to type 2–low severe neutrophilic asthma
National Heart and Lung Institute, the Imperial College London, London, United Kingdom; NIHR Imperial Biomedical Research Centre, London, United Kingdom; Data Science Institute, Imperial College London, London, United Kingdom.
Laboratory of Inflammatory Skin Diseases, Department of Dermatology, Icahn School of Medicine at Mount Sinai, NY, New York, United States; Department of Biomedical Engineering, The University of Mississippi, Miss, Oxford, United States.
Data Science Institute, Imperial College London, London, United Kingdom.
GSK Respiratory Therapeutic Area Unit, Stevenage, United Kingdom.
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2022 (English)In: Journal of Allergy and Clinical Immunology, ISSN 0091-6749, E-ISSN 1097-6825, Vol. 149, no 1, p. 89-101Article in journal (Refereed) Published
Abstract [en]

Background: Transcriptomic changes in patients who respond clinically to biological therapies may identify responses in other tissues or diseases.

Objective: We sought to determine whether a disease signature identified in atopic dermatitis (AD) is seen in adults with severe asthma and whether a transcriptomic signature for patients with AD who respond clinically to anti–IL-22 (fezakinumab [FZ]) is enriched in severe asthma.

Methods: An AD disease signature was obtained from analysis of differentially expressed genes between AD lesional and nonlesional skin biopsies. Differentially expressed genes from lesional skin from therapeutic superresponders before and after 12 weeks of FZ treatment defined the FZ-response signature. Gene set variation analysis was used to produce enrichment scores of AD and FZ-response signatures in the Unbiased Biomarkers for the Prediction of Respiratory Disease Outcomes asthma cohort.

Results: The AD disease signature (112 upregulated genes) encompassing inflammatory, T-cell, TH2, and TH17/TH22 pathways was enriched in the blood and sputum of patients with asthma with increasing severity. Patients with asthma with sputum neutrophilia and mixed granulocyte phenotypes were the most enriched (P <.05). The FZ-response signature (296 downregulated genes) was enriched in asthmatic blood (P <.05) and particularly in neutrophilic and mixed granulocytic sputum (P <.05). These data were confirmed in sputum of the Airway Disease Endotyping for Personalized Therapeutics cohort. IL-22 mRNA across tissues did not correlate with FZ-response enrichment scores, but this response signature correlated with TH22/IL-22 pathways.

Conclusions: The FZ-response signature in AD identifies severe neutrophilic asthmatic patients as potential responders to FZ therapy. This approach will help identify patients for future asthma clinical trials of drugs used successfully in other chronic diseases.

Place, publisher, year, edition, pages
Elsevier, 2022. Vol. 149, no 1, p. 89-101
Keywords [en]
atopic dermatitis, Fezakinumab, gene set variation analysis, IL-22, severe asthma
National Category
Respiratory Medicine and Allergy
Identifiers
URN: urn:nbn:se:umu:diva-184129DOI: 10.1016/j.jaci.2021.04.010ISI: 000744544500019PubMedID: 33891981Scopus ID: 2-s2.0-85106638113OAI: oai:DiVA.org:umu-184129DiVA, id: diva2:1563386
Funder
Pfizer ABEli Lilly and CompanyEU, FP7, Seventh Framework Programme, 2007-2013Available from: 2021-06-10 Created: 2021-06-10 Last updated: 2022-07-12Bibliographically approved

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Behndig, Annelie F.

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