Abstract
Background In clinical trials, the two anti-IL-5 monoclonal antibodies (mAbs, mepolizumab and reslizumab) that are approved to treat severe eosinophilic asthma, reduce exacerbations by approximately 50–60%.
Objective To observe response to anti-IL-5 mAbs in real-life clinical setting, and to evaluate predictors of sub-optimal response.
Methods In four Canadian academic centres, pre-defined clinical end-points in 250 carefully characterised moderate-to-severe asthmatics were collected prospectively to assess response to the two anti-IL-5 mAbs. Sub-optimal responses was determined based on failure to reduce maintenance corticosteroid (MCS) or asthma symptoms scores (ACQ) or exacerbations, in addition to persistence of sputum/blood eosinophils. Worsening in suboptimal responders were assessed based on reduced lung function by 25% or any increase in MCS/ACQ. A representative sub-set of 39 patients were evaluated for inflammatory mediators, autoantibodies and complement activation in sputum (by ELISA) and for immune-complex deposition by immunostaining formalin-fixed paraffin-embedded sputum plugs.
Results Sub-optimal responses were observed in 42.8% (107/250) patients treated with either mepolizumab/reslizumab. Daily prednisone requirement, sinus disease, and late-onset asthma diagnoses were the strongest predictors of sub-optimal response. Asthma worsened in 13% (34/250) of these patients. Majority (79%) of them were prednisone-dependent. Presence of sputum anti-eosinophil peroxidase immunoglobulin (Ig)G was a predictor of sub-optimal response to an anti-IL-5 mAb. An increase in sputum C3c (marker of complement activation) and deposition of C1q-bound/IL-5-bound IgG were observed in the sputa of those patients who worsened on therapy, suggesting an underlying autoimmune-mediated pathology.
Conclusion A significant number of patients who meet currently approved indications for anti-IL5 mAbs show sub-optimal response to them in real-life clinical practice. Monitoring blood eosinophil count is not helpful to identify these patients. The concern of worsening of symptoms associated with immune-complex mediated complement-activation in a small proportion of these patients highlights the relevance of recognising airway autoimmune phenomena and this requires further evaluation.
Footnotes
This manuscript has recently been accepted for publication in the European Respiratory Journal. It is published here in its accepted form prior to copyediting and typesetting by our production team. After these production processes are complete and the authors have approved the resulting proofs, the article will move to the latest issue of the ERJ online. Please open or download the PDF to view this article.
Conflict of interest: Dr. Mukherjee has nothing to disclose.
Conflict of interest: Dr. Forero has nothing to disclose.
Conflict of interest: Dr. Tran has nothing to disclose.
Conflict of interest: ME Boulay has nothing to disclose.
Conflict of interest: Dr. Bertrand has nothing to disclose.
Conflict of interest: Dr. Bhalla has nothing to disclose.
Conflict of interest: Mr. Cherukat has nothing to disclose.
Conflict of interest: Dr. Al-Hayyan has nothing to disclose.
Conflict of interest: Dr. AYOUB has nothing to disclose.
Conflict of interest: Mr. REVILL has nothing to disclose.
Conflict of interest: Dr. Javkar has nothing to disclose.
Conflict of interest: Dr. Radford has nothing to disclose.
Conflict of interest: Melanie Kjarsgaard has nothing to disclose.
Conflict of interest: Ms. Huang has nothing to disclose.
Conflict of interest: Dr. Dvorkin-Gheva has nothing to disclose.
Conflict of interest: Dr. Ask reports grants from Canadian Pulmonary Fibrosis Foundation, grants from Ontario Thoracic Society, grants and personal fees from Boehringer Ingelheim, grants from Synairgen, grants from GSK, grants from Indalo, grants from Unity, grants from Avalyn, grants from Canadian Institutes of Health Research, grants from Synairgen, outside the submitted work.
Conflict of interest: Dr. Olivenstein has nothing to disclose.
Conflict of interest: Dr. Dendukuri has nothing to disclose.
Conflict of interest: Dr. Lemiere reports grants and personal fees from AstraZeneca, personal fees from GlaxoSmithkline, personal fees from Sanofi, personal fees from Novartis, grants and personal fees from TEVA Innovation, outside the submitted work.
Conflict of interest: Dr. Boulet has nothing to disclose.
Conflict of interest: Dr. Martin has nothing to disclose.
Conflict of interest: Dr. Nair reports grants and personal fees from AZ, grants from Novartis, grants and personal fees from Teva, grants from Sanofi, grants and personal fees from Roche, personal fees from Novartis, personal fees from Merck, personal fees from Equillium, outside the submitted work.
This is a PDF-only article. Please click on the PDF link above to read it.
- Received January 20, 2020.
- Accepted May 8, 2020.
- Copyright ©ERS 2020
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