FCGR3A Polymorphism Controls B-Cell Repopulation Kinetics in People With Multiple Sclerosis Treated With Ocrelizumab

Fc gamma receptor 3A (FCGR3A) V158F polymorphism has been shown to modify the response to anti-CD20 therapy across several autoimmune diseases. Ocrelizumab (OCR), an anti-CD20 agent, suppresses inflammatory activity in multiple sclerosis (MS), yet whether FCGR3A V158F polymorphism affects its efficacy in MS remains unclear. Here, we tested whether this genetic variant influences B-cell repopulation and disease activity in MS participants treated with OCR and assessed genotype-dependent differences in OCR binding to FcγRIIIa-expressing natural killer (NK) cells.

In this observational cohort study, we enrolled people with MS treated with OCR consecutively between May 2022 and August 2025. FCGR3A V158F genotyping was performed by pyrosequencing. The primary outcome was preinfusion CD19⁺ B-cell repopulation, defined as CD19⁺ B cells ≥1%. Secondary outcomes included clinical and MRI inflammatory activity and composite disease activity/disability-worsening measures. In a parallel mechanistic ex vivo substudy, OCR or rituximab (RTX) binding to NK cells was evaluated in genotype-selected donors by flow cytometry. Cycle-based repeated measures were analyzed using mixed-effects logistic regression.

In 101 participants, 500 interinfusion intervals were analyzed. The odds of B-cell repopulation decreased with higher cycle number (odds ratio [OR] per cycle 0.77; 95% CI 0.65-0.91; p = 0.002) and increased with longer infusion intervals (OR per +30 days, 2.02; 95% CI 1.27-3.21; p = 0.0029). FCGR3A F-carrier status significantly modified the effect of interval length (interaction OR, 2.47; 95% CI 1.04-5.89; p = 0.042). Specifically, the odds of B-cell repopulation increased with longer intervals in MS participants carrying the FCGR3A-F allele (OR, 3.67; 95% CI 1.84-7.34; p = 0.00023) but not in FCGR3A-VV individuals (OR, 1.49; 95% CI 0.87-2.54; p = 0.146). FCGR3A genotype was not associated with clinical or MRI activity outcomes. In ex vivo assays, NK cells from FCGR3A-FF donors exhibited significantly lower binding of OCR (p = 4.34 × 10^-4) and RTX (p = 0.00172) as compared with VV donors.

Longer OCR infusion intervals were associated with higher odds of B-cell repopulation. The FCGR3A V158F polymorphism modified this interval-dependent repopulation, possibly by affecting OCR binding to NK cells. Prospective studies are needed to determine whether FCGR3A V158F polymorphism and B-cell repletion kinetics can inform optimized interval-based OCR dosing in MS.