Abstract
Background In clinical trials, the two anti-interleukin (IL)-5 monoclonal antibodies (mAbs: mepolizumab and reslizumab) approved to treat severe eosinophilic asthma reduce exacerbations by ∼50–60%.
Objective To observe response to anti-IL-5 mAbs in a real-life clinical setting, and to evaluate predictors of suboptimal response.
Methods In four Canadian academic centres, predefined clinical end-points in 250 carefully characterised moderate-to-severe asthmatic patients were collected prospectively to assess response to the two anti-IL-5 mAbs. Suboptimal response was determined based on failure to reduce maintenance corticosteroid (MCS) or asthma symptoms scores (Asthma Control Questionnaire (ACQ)) or exacerbations, in addition to persistence of sputum/blood eosinophils. Worsening in suboptimal responders was assessed based on reduced lung function by 25% or increase in MCS/ACQ. A representative subset of 39 patients was 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 Suboptimal responses were observed in 42.8% (107 out of 250) patients treated with either mepolizumab or reslizumab. Daily prednisone requirement, sinus disease and late-onset asthma diagnoses were the strongest predictors of suboptimal response. Asthma worsened in 13.6% (34 out of 250) of these patients. The majority (79%) of them were prednisone-dependent. Presence of sputum anti-eosinophil peroxidase immunoglobulin (Ig)G was a predictor of suboptimal 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 suboptimal response to them in real-life clinical practice, particularly if they are on high doses of prednisone. 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.
Abstract
Severe asthmatics with adult-onset asthma, sinus disease and requiring daily prednisone, are at higher risk for responding suboptimally to current doses of anti-IL-5 mAbs, with further risk of worsening on an IgG1 mAb if they have sputum autoantibodies https://bit.ly/2Ahpvsm
Footnotes
This article has supplementary material available from erj.ersjournals.com
Author contributions: P. Nair and M. Mukherjee developed the concept, M. Mukherjee designed all experiments. P. Nair, J.G. Martin, C. Lemiere and L-P. Boulet recruited patients. S. Tran, M-E. Boulay, M. Bertrand, H. Al-Hayyan, J. Cherukat, M. Kjarsgaard and C. Huang collected and tabulated the data. K. Radford and M. Mukherjee performed molecular experiments. T. Javkar performed all immunostaining protocols while K. Ask, S.D. Revill and A. Ayoub did the microscopy and related validation of image analysis. A. Dvorkin-Gheva, N. Dendukuri and D.F. Forero undertook all statistical analysis. M. Mukherjee wrote the first draft. P. Nair, J.G. Martin, K. Ask, C. Lemiere, L-P. Boulet and N. Dendukuri edited and added to the development of the manuscript. All authors have read and agreed to the submitted manuscript. P. Nair and M. Mukherjee take overall guarantee of the manuscript.
Conflict of interest: M. Mukherjee reports grants from Canadian Institutes of Health Research and Canadian Allergy, Asthma, and Immunology Foundation, grants and personal fees from Methapharm Specialty Pharmaceuticals, and personal fees from Astrazeneca, outside the submitted work.
Conflict of interest: D.F. Forero has nothing to disclose.
Conflict of interest: S. Tran has nothing to disclose.
Conflict of interest: M-E. Boulay has nothing to disclose.
Conflict of interest: M. Bertrand has nothing to disclose.
Conflict of interest: A. Bhalla has nothing to disclose.
Conflict of interest: J. Cherukat has nothing to disclose.
Conflict of interest: H. Al-Hayyan has nothing to disclose.
Conflict of interest: A. Ayoub has nothing to disclose.
Conflict of interest: S.D. Revill has nothing to disclose.
Conflict of interest: T. Javkar has nothing to disclose.
Conflict of interest: K. Radford has nothing to disclose.
Conflict of interest: M. Kjarsgaard has nothing to disclose.
Conflict of interest: C. Huang has nothing to disclose.
Conflict of interest: A. Dvorkin-Gheva has nothing to disclose.
Conflict of interest: K. Ask reports grants from Canadian Pulmonary Fibrosis Foundation, Ontario Thoracic Society, Synairgen, GSK, Indalo, Unity, Avalyn, Canadian Institutes of Health Research and Synairgen, grants and personal fees from Boehringer Ingelheim, outside the submitted work.
Conflict of interest: R. Olivenstein has nothing to disclose.
Conflict of interest: N. Dendukuri has nothing to disclose.
Conflict of interest: C. Lemiere reports grants and personal fees for advisory board work from AstraZeneca and TEVA Innovation, personal fees for advisory board work from GlaxoSmithKline, Sanofi and Novartis, outside the submitted work.
Conflict of interest: L-P. Boulet has nothing to disclose.
Conflict of interest: J.G. Martin has nothing to disclose.
Conflict of interest: P. Nair reports grants and personal fees for lectures from AZ and Teva, grants from Novartis and Sanofi, grants and personal fees for consultancy from Roche, personal fees for lectures from Novartis, personal fees advisory board work from Merck and Equillium, outside the submitted work.
Support statement: This study was funded by a research grant awarded to P. Nair by the Canadian Institutes of Health Research. P. Nair is supported by the Frederick E. Hargreave Teva Innovation Chair in Airway Diseases. M. Mukherjee is supported by an investigator award from CIHR and Canadian Allergy, Asthma and Immunology Foundation/AllerGen NCE. Funding information for this article has been deposited with the Crossref Funder Registry.
- Received January 20, 2020.
- Accepted May 8, 2020.
- Copyright ©ERS 2020
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