Comprehensive genetic and functional analyses of Fc gamma receptors influence on response to rituximab therapy for autoimmunity

Robinson, J. I. et al. (2022) Comprehensive genetic and functional analyses of Fc gamma receptors influence on response to rituximab therapy for autoimmunity. EBioMedicine, 86, 104343. (doi: 10.1016/j.ebiom.2022.104343) (PMID:36371989) (PMCID:PMC9663864)

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Abstract

Background: Rituximab is widely used to treat autoimmunity but clinical response varies. Efficacy is determined by the efficiency of B-cell depletion, which may depend on various Fc gamma receptor (FcγR)-dependent mechanisms. Study of FcγR is challenging due to the complexity of the FCGR genetic locus. We sought to assess the effect of FCGR variants on clinical response, B-cell depletion and NK-cell-mediated killing in rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). Methods: A longitudinal cohort study was conducted in 835 patients [RA = 573; SLE = 262]. Clinical outcome measures were two-component disease activity score in 28-joints (2C-DAS28CRP) for RA and British Isles Lupus Assessment Group (BILAG)-2004 major clinical response (MCR) for SLE at 6 months. B-cells were evaluated by highly-sensitive flow cytometry. Single nucleotide polymorphism and copy number variation for genes encoding five FcγRs were measured using multiplex ligation-dependent probe amplification. Ex vivo studies assessed NK-cell antibody-dependent cellular cytotoxicity (ADCC) and FcγR expression. Findings: In RA, carriage of FCGR3A-158V and increased FCGR3A-158V copies were associated with greater 2C-DAS28CRP response (adjusted for baseline 2C-DAS28CRP). In SLE, MCR was associated with increased FCGR3A-158V, OR 1.64 (95% CI 1.12–2.41) and FCGR2C-ORF OR 1.93 (95% CI 1.09–3.40) copies. 236/413 (57%) patients with B-cell data achieved complete depletion. Homozygosity for FCGR3A-158V and increased FCGR3A-158V copies were associated with complete depletion in combined analyses. FCGR3A genotype was associated with rituximab-induced ADCC, and increased NK-cell FcγRIIIa expression was associated with improved clinical response and depletion in vivo. Furthermore, disease status and concomitant therapies impacted both NK-cell FcγRIIIa expression and ADCC. Interpretation: FcγRIIIa is the major low affinity FcγR associated with rituximab response. Increased copies of the FCGR3A-158V allele (higher affinity for IgG1), influences clinical and biological responses to rituximab in autoimmunity. Enhancing FcγR-effector functions could improve the next generation of CD20-depleting therapies and genotyping may stratify patients for optimal treatment protocols. Funding: Medical Research Council, National Institute for Health and Care Research, Versus Arthritis.

Item Type:Articles
Additional Information:This research was funded/supported by joint funding from the Medical Research Council (MRC) and Versus Arthritis for MATURA (grant codes 36661 and MR/K015346/1). MASTERPLANS was funded by the MRC (grant code MR/M01665X/1). The Leeds Biologics Cohort was part-funded by programme grants from Versus Arthritis (grant codes 18475 and 18387), the National Institute for Health and Care Research (NIHR) Leeds Biomedical Research Centre (BRC) and Diagnostic Evaluation Co-operative and the Ann Wilks Charitable Foundation. The BILAG-BR has received funding support from Lupus UK, and unrestricted grants from Roche and GSK. The functional studies were in part supported through a NIHR/HEFCE Clinical Senior Lectureship to AWM, a Versus Arthritis Foundation Fellowship (grant code 19764) to JIR and Wellcome Trust Institutional Strategic Support Fund to JIR and MYMY (204825/Z/16/Z), NIHR Doctoral Research Fellowship to MYMY (DRF-2014-07-155) and NIHR Clinician Scientist to EMV (CS-2013-13-032). AWM, INB, JDI and PE were supported by NIHR Senior Investigator awards. Work in JDI’s laboratory is supported by the NIHR Newcastle BRC, the Research Into Inflammatory Arthritis Centre Versus Arthritis, and Rheuma Tolerance for Cure (European Union Innovative Medicines Initiative 2, grant number 777357). INB is funded by the NIHR Manchester BRC.
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Davies, Dr Vinny
Authors: Robinson, J. I., Md Yusof, M. Y., Davies, V., Wild, D., Morgan, M., Taylor, J. C., El-Sherbiny, Y., Morris, D. L., Liu, L., Rawstron, A. C., Buch, M. H., Plant, D., Cordell, H. J., Isaacs, J. D., Bruce, I. N., Emery, P., Barton, A., Vyse, T. J., Barrett, J. H., Vital, E. M., and Morgan, A. W.
College/School:College of Science and Engineering > School of Mathematics and Statistics > Statistics
Journal Name:EBioMedicine
Publisher:Elsevier
ISSN:2352-3964
ISSN (Online):2352-3964
Published Online:11 November 2022
Copyright Holders:Copyright © 2022 The Authors
First Published:First published in EBioMedicine 86: 104343
Publisher Policy:Reproduced under a Creative Commons License

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
301069Rheuma Tolerance for CureIain McInnesEuropean Commission (EC)777357III - Immunology