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Journal of Allergy and Clinical Immunology

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Mapping atopic dermatitis and anti–IL-22 response signatures to type 2–low severe neutrophilic asthma - 05/01/22

Doi : 10.1016/j.jaci.2021.04.010 
Yusef Eamon Badi, MSc a, b, c, Ana B. Pavel, PhD d, e, ∗, Stelios Pavlidis, PhD c, ‡, John H. Riley, PhD f, Stewart Bates, PhD f, Nazanin Zounemat Kermani, PhD c, Richard Knowles, PhD g, Johan Kolmert, PhD h, i, Craig E. Wheelock, PhD i, Sally Worsley, MSc j, Mohib Uddin, PhD k, Kjell Alving, PhD l, Per S. Bakke, MD m, Annelie Behndig, MD, PhD n, Massimo Caruso, MD o, Pascal Chanez, MD p, Louise J. Fleming, MD a, b, Stephen J. Fowler, MD, PhD q, r, Urs Frey, MD, PhD s, Peter Howarth, MD, PhD t, u, v, Ildikó Horváth, MD, PhD w, Norbert Krug, MD x, Anke H. Maitland-van der Zee, PharmD, PhD y, Paolo Montuschi, MD z, Graham Roberts, MD, PhD t, u, v, Marek Sanak, MD aa, Dominick E. Shaw, MD, PhD bb, Florian Singer, MD, PhD cc, Peter J. Sterk, MD, PhD y, Ratko Djukanovic, MD, PhD t, u, v, Sven-Eric Dahlen, MD, PhD h, Yi-Ke Guo, PhD c, Kian Fan Chung, MD, DSc a, b, Emma Guttman-Yassky, MD, PhD d, Ian M. Adcock, PhD a, b, ⁎
on behalf of the

U-BIOPRED Study Group§

  Members of the U-BIOPRED study group are listed in the Online RepositoryAppendix (available at www.jacionline.org).

a National Heart and Lung Institute, the Imperial College London, London, United Kingdom 
b NIHR Imperial Biomedical Research Centre, London, United Kingdom 
c Data Science Institute, Imperial College London, London, United Kingdom 
d Laboratory of Inflammatory Skin Diseases, Department of Dermatology, Icahn School of Medicine at Mount Sinai, New York, NY 
e Department of Biomedical Engineering, The University of Mississippi, Oxford, Miss 
f GSK Respiratory Therapeutic Area Unit, Stevenage, United Kingdom 
g Knowles Consulting, Stevenage, United Kingdom 
h Centre for Allergy Research, Institute of Environmental Medicine, Karolinska Institute, Stockholm, Sweden 
i Division of Physiological Chemistry 2, Department of Medical Biochemistry and Biophysics, Karolinska Institute, Stockholm, Sweden 
j GSK Value Evidence and Outcomes, Brentford, United Kingdom 
k Respiratory Global Medicines Development, AstraZeneca, Gothenburg, Sweden 
l Department of Women’s and Children’s Health: Paediatric Research, Uppsala University, Uppsala, Sweden 
m Department of Clinical Science, University of Bergen, Bergen, Norway 
n Department of Public Health and Clinical Medicine, Division of Medicine/Respiratory Medicine, Umeå University, Umeå, Sweden 
o Department of Biomedical and Biotechnological Sciences, University of Catania, Catania, Italy 
p Aix-Marseille Universite, Assistance Publique des Hopitaux de Marseille, Clinic des Bronches, Allergies et Sommeil, Marseille, France 
q Division of Infection, Immunity and Respiratory Medicine, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, United Kingdom 
r Manchester Academic Health Science Centre and NIHR Biomedical Research Centre, Manchester University Hospitals NHS Foundation Trust, Manchester, United Kingdom 
s University Children’s Hospital Basel, University of Basel, Basel, Switzerland 
t Clinical and Experimental Sciences and Human Development in Health, University of Southampton Faculty of Medicine, Southampton, United Kingdom 
u NIHR Southampton Biomedical Research Centre, University Hospital Southampton NHS Foundation Trust, Southampton, United Kingdom 
v David Hide Asthma and Allergy Research Centre, St Mary’s Hospital, Newport, Isle of Wight, United Kingdom 
w Department of Public Health, Semmelweis University, Budapest, Hungary 
x Fraunhofer ITEM, Hannover, Germany 
y Department of Respiratory Medicine, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands 
z Pharmacology, Catholic University of the Sacred Heart, Agostino Gemelli University Hospital Foundation, Rome, Italy 
aa Department of Internal Medicine, Jagiellonian University Medical College, Krakow, Poland 
bb University of Nottingham, NIHR Biomedical Research Centre, Nottingham, United Kingdom 
cc Division of Respiratory Medicine, Department of Paediatrics, Inselspital, University of Bern, Bern, Switzerland 

∗Corresponding author: Ian M. Adcock, PhD, National Heart and Lung Institute, Imperial College London, Dovehouse St, London SW3 6LY, UK.National Heart and Lung InstituteImperial College LondonDovehouse StLondonSW3 6LYUK

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.

Il testo completo di questo articolo è disponibile in 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


Mappa


 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).
 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.


© 2021  American Academy of Allergy, Asthma & Immunology. Pubblicato da Elsevier Masson SAS. Tutti i diritti riservati.
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