Robinson, JI orcid.org/0000-0001-5425-7520, Md Yusof, MY orcid.org/0000-0003-3131-9121, Davies, V et al. (20 more authors) (2022) Comprehensive genetic and functional analyses of Fc gamma receptors influence on response to rituximab therapy for autoimmunity. eBioMedicine, 86. 104343. ISSN 2352-3964
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.
Metadata
Item Type: | Article |
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Authors/Creators: |
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Copyright, Publisher and Additional Information: | © 2022 The Authors. Published by Elsevier B.V. This is an open access article under the terms of the Creative Commons Attribution License (CC-BY 4.0), which permits unrestricted use, distribution and reproduction in any medium, provided the original work is properly cited. |
Keywords: | Autoimmune diseases; B-lymphocytes; Genetics; Rheumatoid arthritis; Rituximab; Systemic lupus erythematosus |
Dates: |
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Institution: | The University of Leeds |
Academic Units: | The University of Leeds > Faculty of Medicine and Health (Leeds) > School of Medicine (Leeds) > Leeds Institute of Cardiovascular and Metabolic Medicine (LICAMM) > Discovery & Translational Science Dept (Leeds) The University of Leeds > Faculty of Medicine and Health (Leeds) > School of Medicine (Leeds) > Institute of Rheumatology & Musculoskeletal Medicine (LIRMM) (Leeds) > Clinical Musculoskeletal Medicine (LIRMM) (Leeds) The University of Leeds > Faculty of Medicine and Health (Leeds) > School of Medicine (Leeds) > Institute of Rheumatology & Musculoskeletal Medicine (LIRMM) (Leeds) > Inflammatory Arthritis (Leeds) |
Funding Information: | Funder Grant number NIHR National Inst Health Research DRF-2014-07-155 Wellcome Trust 204825/Z/16/Z NIHR National Inst Health Research SENIOR INVESTIGATOR AWAR Versus Arthritis (formerly ARUK) M0653 Versus Arthritis (formerly ARUK) 17969 NIHR National Inst Health Research CS-2013-13-032 Wellcome Trust 105615/Z/14/Z MRC (Medical Research Council) R116825 MRC (Medical Research Council) MR/M01665X/1 - R118193 NIHR National Inst Health Research NIHR202395 Leeds Teaching Hospitals Charitable Foundation 9R11/8007 Versus Arthritis (formerly ARUK) 19764 |
Depositing User: | Symplectic Publications |
Date Deposited: | 06 Dec 2022 15:28 |
Last Modified: | 25 Jun 2023 23:09 |
Status: | Published |
Publisher: | Elsevier |
Identification Number: | 10.1016/j.ebiom.2022.104343 |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:193664 |