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

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

Authors/Creators:

Robinson, JI https://orcid.org/0000-0001-5425-7520
Md Yusof, MY https://orcid.org/0000-0003-3131-9121
Davies, V
Wild, D
Morgan, M
Taylor, JC https://orcid.org/0000-0002-2518-5799
El-Sherbiny, Y
Morris, DL
Liu, L
Rawstron, AC
Buch, MH
Plant, D
Cordell, HJ
Isaacs, JD
Bruce, IN
Emery, P
Barton, A
Vyse, TJ
Barrett, JH
Vital, EM https://orcid.org/0000-0003-1637-4755
Morgan, AW https://orcid.org/0000-0003-1109-624X
MATURA Consortia
MASTERPLANS Consortia

© 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:

Accepted: 18 October 2022
Published (online): 11 November 2022
Published: December 2022

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