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Robinson, J.I., Md Yusof, M.Y., Davies, V., Wild, D., Morgan, M., Taylor, J.C., El-Sherbiny, Y. 
ORCID: 0000-0003-4791-3475, 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.,
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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1616277_El-Sherbiny.pdf - Post-print Download (1MB) | Preview |
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 | ||||||
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| 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 | ||||||
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| 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 |
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