Airway proteomics reveals broad residual anti-inflammatory effects of prednisolone in mepolizumab-treated asthma
- PMID: 39097197
- DOI: 10.1016/j.jaci.2024.07.020
Airway proteomics reveals broad residual anti-inflammatory effects of prednisolone in mepolizumab-treated asthma
Abstract
Background: Mepolizumab is an anti-IL-5 mAb treatment for severe eosinophilic asthma that reduces asthma exacerbations. Residual airway inflammation with mepolizumab therapy may lead to persistent exacerbations. Oral corticosteroids remain the main treatment for these residual exacerbations.
Objective: Our study aimed to explore the corticosteroid responsiveness of airway inflammation after mepolizumab treatment to find potentially treatable inflammatory mechanisms beyond the IL-5 pathway.
Methods: The MAPLE trial was a multicenter, randomized, double-blind, placebo-controlled, crossover study of 2 weeks of high-dose oral prednisolone treatment at stable state in 27 patients treated with mepolizumab for severe eosinophilic asthma. We analyzed paired sputum (n = 16) and plasma (n = 25) samples from the MAPLE trial using high-throughput Olink proteomics. We analyzed additional sputum proteins using ELISA.
Results: In patients receiving mepolizumab, prednisolone significantly downregulated sputum proteins related to type 2 inflammation and chemotaxis including IL-4, IL-5, IL-13, CCL24, CCL26, EDN, CCL17, CCL22, OX40 receptor, FCER2, and the ST2 receptor. Prednisolone also downregulated cell adhesion molecules, prostaglandin synthases, mast cell tryptases, MMP1, MMP12, and neuroimmune mediators. Neutrophilic pathways were upregulated. Type 2 proteins were also downregulated in plasma, combined with IL-12, IFN-γ, and IP-10. IL-10 and amphiregulin were upregulated.
Conclusions: At stable state, prednisolone has broad anti-inflammatory effects on top of mepolizumab. These effects are heterogeneous and may be clinically relevant in residual exacerbations.
Keywords: Asthma; biologics; clinical trial; corticosteroids; inflammation; proteomics.
Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.
Conflict of interest statement
Disclosure statement This study was funded jointly by the Medical Research Council (MRC) UK (MR/M016579/1) and industrial partners within the MRC Refractory Asthma Stratification Programme consortium and by the National Institute for Health Research Oxford Biomedical Research Centre. Proteomic and transcriptome analysis was funded by GSK (ID: 215294). T.S.C.H. is supported by a Wellcome Trust Fellowship (211050/Z/18/z). All authors had full access to the full data in the study and accept responsibility to submit for publication. Disclosure of potential conflict of interest: I. Howell has received a conference travel grant from GSK. F. Yang and S. E. Diver have received speaker fees from AstraZeneca. A. Azim is currently an employee of AstraZeneca. P. J. McDowell has received support to attend educational meetings from Chiesi. J. Busby has received personal fees from NuvoAir and a research grant to his Institute from AstraZeneca, outside the submitted work. C. Borg has received speaker’s fees from AstraZeneca and GSK and advisory board fees from AstraZeneca. L. G. Heaney has received grants from GSK, AstraZeneca, and Roche/Genentech; has given lectures supported by AstraZeneca, Sanofi, Circassia, and GSK; has received travel grants from AstraZeneca and GSK; and has received honoraria for Advisory Board Meetings from Novartis, Roche/Genentech, GSK, Teva, and Celltrion. I. D. Pavord has received speaker’s honoraria for speaking at sponsored meetings from AstraZeneca, Boehringer Ingleheim, Aerocrine, Almirall, Novartis, Teva, Chiesi, Sanofi/Regeneron, Menarini, and GSK; payments for organizing educational events from AstraZeneca, GSK, Sanofi/Regeneron, and Teva; honoraria for attending advisory panels with Genentech, Sanofi/Regeneron, AstraZeneca, Boehringer Ingelheim, GSK, Novartis, Teva, Merck, Circassia, Chiesi, and Knopp; payments to support US Food and Drug Administration approval meetings from GSK; sponsorship to attend international scientific meetings from Boehringer Ingelheim, GSK, AstraZeneca, Teva; and Chiesi; and a grant from Chiesi to support a phase 2 clinical trial in Oxford. I. D. Pavord is co–patent holder of the rights to the Leicester Cough Questionnaire and has received payments for its use in clinical trials from Merck, Bayer, and Insmed. In 2014-5 and 2019-20, I. D. Pavord was an expert witness for a patent dispute involving AstraZeneca and Teva. C. E. Brightling has received grants and consultancy fees from 4D Pharma, Areteia, AstraZeneca, Chiesi, Genentech, GSK, Mologic, Novartis, Regeneron Pharmaceuticals, Roche, and Sanofi. R. Chaudhuri has received lecture fees from GSK, AstraZeneca, Teva, Chiesi, Sanofi, and Novartis; honoraria for Advisory Board Meetings from GSK, AstraZeneca, and Celltrion; sponsorship to attend international scientific meetings from Chiesi, Sanofi, and GSK; and a research grant to her Institute from AstraZeneca for a multicenter study in the United Kingdom. T. S. C. Hinks has received grants from the Wellcome Trust, guardians of the Beit Fellowship, and National Institute for Health Research Oxford Biomedical Research Centre during the conduct of the study, as well as grants from Pfizer Inc and University of Oxford and personal fees from AstraZeneca, TEVA, and PeerVoice outside the submitted work. The rest of the authors declare that they have no relevant conflicts of interest.
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