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

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MATURA Consortia, MASTERPLANS Consortia

Original languageEnglish
Article number104343
JournalEBioMedicine
Volume86
DOIs
PublishedDec 2022

Bibliographical note

Funding 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 . Funding Information: 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 ). We thank all the patients who have contributed to this research, clinical staff who supported patient recruitment and laboratory staff who undertook sample processing. 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 . Publisher Copyright: © 2022 The Authors

King's Authors

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.

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