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

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Robinson, JI, Md Yusof, MY, Davies, V, Wild, D, Morgan, M, Taylor, JC, El-Sherbiny, Y ORCID: https://orcid.org/0000-0003-4791-3475, Morris, DL, Liu, L, Rawstron, AC, Buch, MH, Plant, D, Cordell, HJ, Isaacs, JD, Bruce, IN, Emery, P, Barton, A, Vyse, TJ, Barrett, H, Vital, EM and Morgan, AW, 2022. Comprehensive genetic and functional analyses of Fc gamma receptors influence on response to rituximab therapy for autoimmunity. EBioMedicine, 86: 104343. ISSN 2352-3964

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Official URL: https://doi.org/10.1016/j.ebiom.2022.104343

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.

Item Type:	Journal article
Publication Title:	EBioMedicine
Creators:	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, H., Vital, E.M. and Morgan, A.W.
Publisher:	Elsevier
Date:	December 2022
Volume:	86
ISSN:	2352-3964
Identifiers:	Number Type 10.1016/j.ebiom.2022.104343 DOI 1616277 Other
Divisions:	Schools > School of Science and Technology
Record created by:	Laura Ward
Date Added:	07 Nov 2022 11:13
Last Modified:	17 Jul 2023 13:11
URI:	https://irep.ntu.ac.uk/id/eprint/47340