Safety and efficacy of anti-CD20 monoclonal antibodies versus teriflunomide in relapsing multiple sclerosis: a systematic review and meta-analysis.

BACKGROUND: Anti-CD20 monoclonal antibodies are highly effective disease-modifying therapies for relapsing multiple sclerosis (RMS), but their comparative efficacy and safety versus teriflunomide, a dihydroorotate dehydrogenase inhibitor, remain clinically important. Teriflunomide is an oral platform treatment with moderate efficacy and a favorable administration profile, making it a relevant comparator for evaluating the benefit-risk profile of anti-CD20 therapies. OBJECTIVES: To assess the efficacy and safety of anti-CD20 monoclonal antibodies compared with teriflunomide in adults with RMS. METHODS: A systematic search of PubMed, Cochrane Library, Embase, ScienceDirect, and Scopus was conducted from inception to April 30, 2026. Randomized controlled trials (RCTs) and observational studies comparing anti-CD20 therapies with teriflunomide were eligible. Outcomes included annualized relapse rate, gadolinium-enhancing T1 lesions, new or enlarging T2 lesions, brain volume change, adverse events, serious adverse events, and infections. Pooled mean differences, rate ratios or risk ratios with 95% confidence intervals were calculated using Review Manager (RevMan) version 5.4. Sensitivity analysis on the basis of leave-one-out principle was performed. Risk of bias of RCTs was assessed using Cochrane Risk of Bias Tool (ROB 2.0). RESULTS: Six trials, reported in four studies, were included in the systematic review, and five trials were included in the quantitative synthesis. Anti-CD20 therapies significantly reduced annualized relapse rate compared with teriflunomide (rate ratio [RR] = 0.45, 95% CI [0.38, 0.53]; p < 0.00001), gadolinium-enhancing T1 lesions (MD = - 0.41, 95% CI - 0.52 to - 0.30), and new or enlarging T2 lesions (MD = - 3.05, 95% CI - 3.52 to - 2.58). However, no significant difference was observed in brain volume change. Overall adverse events and infections were comparable between groups, but serious adverse events were increased with anti-CD20 therapies (RR = 1.27, 95% CI 1.01 to 1.61). CONCLUSION: Anti-CD20 therapies provide effective control of relapse and MRI disease activity compared with teriflunomide in RMS. However, no clear advantage over teriflunomide was observed in reducing brain volume loss, and findings regarding disability progression were inconsistent. The modestly increased risk of serious adverse events highlight the need of large scale RCTs, individualized treatment decisions, and long-term safety monitoring.