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Mapping atopic dermatitis and anti-IL-22 response signatures to Type 2-low severe neutrophilic asthma

Mapping atopic dermatitis and anti-IL-22 response signatures to Type 2-low severe neutrophilic asthma
Mapping atopic dermatitis and anti-IL-22 response signatures to Type 2-low severe neutrophilic asthma

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, T H2, and T H17/T H22 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 T H22/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.

Fezakinumab, IL-22, atopic dermatitis, gene set variation analysis, severe asthma
0091-6749
89-101
Badi, Yusef Eamon
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Pavel, Ana B
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Pavlidis, Stelios
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Riley, John H
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Bates, Stewart
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Kermani, Nazanin Zounemat
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Knowles, Richard
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Kolmert, Johan
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Wheelock, Craig E
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Worsley, Sally
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Uddin, Mohib
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Alving, Kjell
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Bakke, Per S
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Behndig, Annelie
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Caruso, Massimo
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Chanez, Pascal
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Fleming, Louise J
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Fowler, Stephen J
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Frey, Urs
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Howarth, Peter
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Horváth, Ildikó
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Krug, Norbert
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Montuschi, Paolo
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Roberts, Graham
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Sanak, Marek
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Shaw, Dominick E
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Singer, Florian
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Sterk, Peter J
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Djukanovic, Ratko
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Dahlen, Sven-Eric
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Guo, Yi-Ke
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Chung, Kian Fan
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Guttman-Yassky, Emma
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Adcock, Ian M
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U-BIOPRED Study Group
Badi, Yusef Eamon
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Pavel, Ana B
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Pavlidis, Stelios
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Riley, John H
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Bates, Stewart
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Kermani, Nazanin Zounemat
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Knowles, Richard
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Kolmert, Johan
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Wheelock, Craig E
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Worsley, Sally
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Frey, Urs
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Howarth, Peter
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Horváth, Ildikó
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Roberts, Graham
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Shaw, Dominick E
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Sterk, Peter J
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Djukanovic, Ratko
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Dahlen, Sven-Eric
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Guttman-Yassky, Emma
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Adcock, Ian M
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Roberts, Graham , U-BIOPRED Study Group (2022) Mapping atopic dermatitis and anti-IL-22 response signatures to Type 2-low severe neutrophilic asthma. Journal of Allergy and Clinical Immunology, 149 (1), 89-101. (doi:10.1016/j.jaci.2021.04.010).

Record type: Article

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, T H2, and T H17/T H22 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 T H22/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.

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More information

Accepted/In Press date: 2021
e-pub ahead of print date: 20 April 2021
Published date: January 2022
Additional Information: Funding Information: 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 ). Funding Information: 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). Publisher Copyright: © 2021 American Academy of Allergy, Asthma & Immunology
Keywords: Fezakinumab, IL-22, atopic dermatitis, gene set variation analysis, severe asthma

Identifiers

Local EPrints ID: 448795
URI: http://eprints.soton.ac.uk/id/eprint/448795
ISSN: 0091-6749
PURE UUID: ae6b7b13-394a-4fd4-b981-e1ec9d2a6f87
ORCID for Ratko Djukanovic: ORCID iD orcid.org/0000-0001-6039-5612

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Date deposited: 06 May 2021 16:30
Last modified: 23 Nov 2022 02:32

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Contributors

Author: Yusef Eamon Badi
Author: Ana B Pavel
Author: Stelios Pavlidis
Author: John H Riley
Author: Stewart Bates
Author: Nazanin Zounemat Kermani
Author: Richard Knowles
Author: Johan Kolmert
Author: Craig E Wheelock
Author: Sally Worsley
Author: Mohib Uddin
Author: Kjell Alving
Author: Per S Bakke
Author: Annelie Behndig
Author: Massimo Caruso
Author: Pascal Chanez
Author: Louise J Fleming
Author: Stephen J Fowler
Author: Urs Frey
Author: Peter Howarth
Author: Ildikó Horváth
Author: Norbert Krug
Author: Anke H Maitland-van der Zee
Author: Paolo Montuschi
Author: Graham Roberts
Author: Marek Sanak
Author: Dominick E Shaw
Author: Florian Singer
Author: Peter J Sterk
Author: Sven-Eric Dahlen
Author: Yi-Ke Guo
Author: Kian Fan Chung
Author: Emma Guttman-Yassky
Author: Ian M Adcock
Corporate Author: U-BIOPRED Study Group

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