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

James I Robinson; Md Yuzaiful Md Yusof; Vinny Davies; Dawn Wild; Michael Morgan; John C Taylor; Yasser El-Sherbiny; David L Morris; Lu Liu; Andy C Rawstron; Maya H Buch; Darren Plant; Heather J Cordell; John D Isaacs; Ian N Bruce; Paul Emery; Anne Barton; Timothy J Vyse; Jennifer H Barrett; Edward M Vital; Ann W Morgan; MATURA Consortia; MASTERPLANS Consortia

doi:10.1016/j.ebiom.2022.104343

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.

Authors

James I Robinson¹, Md Yuzaiful Md Yusof¹, Vinny Davies², Dawn Wild¹, Michael Morgan³, John C Taylor¹, Yasser El-Sherbiny⁴, David L Morris⁵, Lu Liu⁵, Andy C Rawstron⁶, Maya H Buch⁷, Darren Plant⁸, Heather J Cordell⁹, John D Isaacs¹⁰, Ian N Bruce⁸, Paul Emery¹¹, Anne Barton⁸, Timothy J Vyse⁵, Jennifer H Barrett¹, Edward M Vital¹, Ann W Morgan¹²; MATURA Consortia; MASTERPLANS Consortia

Affiliations

¹ School of Medicine, University of Leeds and NIHR Leeds Biomedical Research Centre, Leeds Teaching Hospitals NHS Trust, UK.
² School of Medicine, University of Leeds and NIHR Leeds Biomedical Research Centre, Leeds Teaching Hospitals NHS Trust, UK; School of Mathematics and Statistics, University of Glasgow, UK.
³ School of Medicine, University of Leeds and NIHR Leeds Biomedical Research Centre, Leeds Teaching Hospitals NHS Trust, UK; Cancer Research UK Cambridge Institute, University of Cambridge, UK.
⁴ Department of Biosciences, School of Science and Technology, Nottingham Trent University, UK; Department of Clinical Pathology, Faculty of Medicine, Mansoura University, Mansoura, Egypt.
⁵ Department of Medical and Molecular Genetics, Faculty of Life Sciences and Medicine, King's College London, UK.
⁶ Haematological Malignancy Diagnostic Service, Leeds Teaching Hospitals NHS Trust, UK.
⁷ School of Medicine, University of Leeds and NIHR Leeds Biomedical Research Centre, Leeds Teaching Hospitals NHS Trust, UK; Versus Arthritis Centre for Genetics and Genomics, Division of Musculoskeletal and Dermatological Sciences, School of Biological Sciences, The University of Manchester and NIHR Manchester BRC, Manchester University NHS Foundation Trust, UK.
⁸ Versus Arthritis Centre for Genetics and Genomics, Division of Musculoskeletal and Dermatological Sciences, School of Biological Sciences, The University of Manchester and NIHR Manchester BRC, Manchester University NHS Foundation Trust, UK.
⁹ Population Health Sciences Institute, Newcastle University, UK.
¹⁰ Translational and Clinical Research Institute, Newcastle University and Musculoskeletal Unit, Newcastle upon Tyne Hospitals NHS Foundation Trust, UK.
¹¹ School of Medicine, University of Leeds and NIHR Leeds Biomedical Research Centre, Leeds Teaching Hospitals NHS Trust, UK; NIHR Leeds Medtech and In vitro Diagnostics Co-operative, Leeds Teaching Hospitals NHS Trust, UK.
¹² School of Medicine, University of Leeds and NIHR Leeds Biomedical Research Centre, Leeds Teaching Hospitals NHS Trust, UK; NIHR Leeds Medtech and In vitro Diagnostics Co-operative, Leeds Teaching Hospitals NHS Trust, UK. Electronic address: a.w.morgan@leeds.ac.uk.

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

Abstract

MeSH terms

Substances

Grants and funding