Comparative Effectiveness of Rituximab Dosed Every 6 and 12 Months in Relapsing Multiple Sclerosis

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Abstract
Rituximab (RTX) dosed every 6 months is an affordable and highly effective treatment for relapsing multiple sclerosis (RMS). However, higher cumulative doses are associated with greater risks of infections. Whether extending dosing intervals at a low dose (500 mg) increases the risk of return of disease activity, particularly in those with only 1 year of stability or with significant return of B cells, is uncertain. Our objective was to compare whether extending RTX dosing to every 12 months (q12mo) vs continuing every 6 months (q6mo) dosing in patients with RMS increased the risk of return of disease activity. We emulated a target trial comparing the effectiveness of RTX 500 mg q12mo to q6mo starting in year 2 (baseline) among patients with RMS who had active disease at RTX start and no evidence of disease activity (NEDA) during the first year on RTX. Eligible patients were identified from the retrospective cohort of patients with MS treated with RTX between 2008 and 2023 in Kaiser Permanente Southern California. The absence of relapses, MRI disease activity, and disability progression (NEDA-3) were analyzed by intention-to-treat (ITT) and per-protocol (PP) with inverse probability of treatment weighting of receiving q6mo or q12mo dosing. We identified 140 patients (mean age 40.4 years, 73.6% female) who received q12mo dosing and 468 patients (mean age 38.4, 70.9% female) on q6mo dosing after baseline with a median ITT follow-up of 2.6 (interquartile range [IQR] 1.9-3.3) and 3.9 years (IQR 2.4-4.8), respectively. Relapses and/or MRI disease activity (3.5%) and failing NEDA-3 (3.8%) up to 4 years later were uncommon. Extending dosing to q12mo was associated with significant B-cell repopulation (70.5% with ≥80 cells/μL PP, 75.7% ITT) compared with q6mo intervals (23.3% with ≥80 cells/μL PP, 60.2% ITT) but not with an increased risk of failing NEDA-3 up to 4 years after baseline in propensity score-adjusted ITT (hazard ratio [HR] 1.60, 95% CI 0.69-3.68) or PP analyses (HR 1.44, 95% CI 0.45-4.61). Extending low-dose RTX treatment intervals after 1 year of stability to q12mo was highly effective and did not result in an increased risk of disease activity despite high B-cell counts compared with continuing q6mo dosing over 2 or more years of follow-up. This study provides Class IV evidence that in persons with RMS with NEDA-3 in the 12 months following RTX, extending the dosing interval to 12 months did not increase the risk of disease activity compared with continuing q6mo dosing.

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