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

EBioMedicine. 2022 Dec:86:104343. doi: 10.1016/j.ebiom.2022.104343. Epub 2022 Nov 11.

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.

Keywords: Autoimmune diseases; B-lymphocytes; Genetics; Rheumatoid arthritis; Rituximab; Systemic lupus erythematosus.

MeSH terms

  • Arthritis, Rheumatoid / drug therapy
  • Arthritis, Rheumatoid / genetics
  • Autoimmunity / drug effects
  • Autoimmunity / genetics
  • DNA Copy Number Variations
  • Genotype
  • Humans
  • Longitudinal Studies
  • Lupus Erythematosus, Systemic* / drug therapy
  • Lupus Erythematosus, Systemic* / genetics
  • Receptors, IgG* / drug effects
  • Receptors, IgG* / genetics
  • Receptors, IgG* / metabolism
  • Rituximab* / pharmacology
  • Rituximab* / therapeutic use

Substances

  • Receptors, IgG
  • Rituximab