Mapping atopic dermatitis and anti–IL-22 response signatures to type 2–low severe neutrophilic asthma - 05/01/22
on behalf of the
U-BIOPRED Study Group§
Abstract |
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.
Le texte complet de cet article est disponible en PDF.Key words : Fezakinumab, atopic dermatitis, gene set variation analysis, IL-22, severe asthma
Abbreviations used : AD, ADEPT, DEG, ES, FC, FDR, FZ, HC, LT, MADAD, MMA, PNR, PR, SA, T2, TAC, U-BIOPRED
Plan
| This study was supported by the Biotechnology and Biological Sciences Research Council Studentship (BBSRC-NPIF studentship/BIDS3000032503) to Y.E.B. Unbiased Biomarkers for the Prediction of Respiratory Disease Outcomes (U-BIOPRED) was supported by an Innovative Medicines Initiative Joint Undertaking (no. 115010), resources from the European Union’s Seventh Framework Programme (FP7/2007-2013), and The European Federation of Pharmaceutical Industries and Associations companies’ in-kind contribution (www.imi.europa.eu). We acknowledge the contribution of the whole U-BIOPRED team. S.-E.D. and I.M.A. are supported by the 3TR (Taxonomy, Treatment, Targets and Remission) project funded by the Innovative Medicines Initiative 2 Joint Undertaking (grant agreement no. 831434). |
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| Disclosure of potential conflict of interest: J. H. Riley, S. Bates, and S. Worsley are employees and shareholders of GlaxoSmithKline (GSK). M. Uddin reports he is an employee of AstraZeneca (AZ) and holds shares in the company. R. Knowles reports being a former employee of GSK. M. Singer reports personal fees from Vertex Pharmaceuticals Switzerland, and personal fees from Novartis Pharma Switzerland, outside the submitted work. S. J. Fowler reports personal fees from AZ, Chiesi, GSK, Novartis, and Teva outside the submitted work and grants and personal fees from Boehringer Ingelheim (BI). P. Chanez reports grants and personal fees from Almirall, BI, ALK, GSK, AZ, Novartis, Teva, and Chiesi, outside the submitted work. J. Kolmert reports personal fees from Gesynta Pharma AB outside the submitted work. D. E. Shaw reports speaker fees from Sanofi, AZ, and Novartis and travel fees from AZ and Novartis. K. F. Chung has received honoraria for participating in Advisory Board meetings of GSK, AZ, Roche, Novartis, Merck, BI, and Shionogi regarding treatments for asthma, chronic obstructive pulmonary disease, and chronic cough and has also been renumerated for speaking engagements. A. H. Maitland-van der Zee has received research grants outside the submitted work from GSK, BI, and Vertex, and is the PI of a P4O2 (Precision Medicine for more Oxygen) public-private partnership sponsored by Health Holland involving many private partners that contribute in cash and/or in kind (BI, Breathomix, Fluidda, Ortec Logiqcare, Philips, Quantib-U, Smartfish, SODAQ, Thirona, TopMD, and Novartis), and has served in advisory boards for AZ, GSK, and BI, with money paid to her institution. R. Djukanovic has received fees for lectures at symposia organized by Novartis, AZ, and TEVA, as well as consultation fees for serving as a member of advisory boards for TEVA and Novartis and participating in a scientific discussion about asthma organized by GSK; and is a cofounder and current consultant of and has shares in Synairgen, a University of Southampton spinout company. S.-E. Dahlen reports personal fees from AZ, GSK, Merck & Company, Novartis, Regeneron, Sanofi, and Teva outside the submitted work. E. Guttman-Yassky reports grants from Abbvie, Celgene, Eli Lilly, Janssen, Medimmune/AZ, Novartis, Pfizer, and Regeneron, outside the submitted work; is an employee of Mount Sinai and has received research funds (grants paid to the institution) from Abbvie, Celgene, Eli Lilly, Janssen, Medimmune/AZ, Novartis, Pfizer, Regeneron, Vitae, Glenmark, Galderma, Asana, Innovaderm, Dermira, and UCB; and is also a consultant for Sanofi Aventis, Regeneron, Stiefel/GSK, MedImmune, Celgene, Anacor, AnaptysBio, Dermira, Galderma, Glenmark, Novartis, Pfizer, Vitae, Leo Pharma, Abbvie, Eli Lilly, Kyowa, Mitsubishi Tanabe, Asana Biosciences, and Promius. I. M. Adcock, G. Roberts, and P. J. Sterk received grants from Innovative Medicines Initiative during the conduct of the study. The rest of the authors declare that they have no relevant conflicts of interest. |
Vol 149 - N° 1
P. 89-101 - janvier 2022 Retour au numéro
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