Comparative Therapeutic Strategies for Secondary Progressive Multiple Sclerosis: A Systematic Review and Network Meta-Analysis

Introduction: Secondary progressive multiple sclerosis (SPMS) represents a disabling stage of multiple sclerosis (MS) with limited treatment options. The evidence regarding the effectiveness of disease-modifying therapies (DMTs) in SPMS remains uncertain. This study evaluated the comparative efficacy and safety of DMTs in SPMS using a network meta-analysis (NMA). Methods: A systematic search of PubMed, Embase, Web of Science, and Cochrane databases was conducted from January 2000 to May 2025 to identify randomized controlled trials (RCTs) involving adults with SPMS. The outcomes of interest were confirmed disability progression (CDP) and serious adverse events (SAEs). A frequentist random-effects NMA was performed to estimate odds ratios (ORs) and rank treatments using surface under the cumulative ranking (SUCRA) values. Results: Seven RCTs involving 5,872 patients with SPMS were included in the final analysis. Approximately 60% of participants were women, with a mean age ranging from 39.9 to 48.9 years and a baseline Expanded Disability Status Scale (EDSS) score between 3.0 and 6.5. Tolebrutinib (OR 0.66, 95% confidence interval [CI] 0.50–0.87; SUCRA 0.713) and siponimod (OR 0.72, 95% CI 0.57–0.92; SUCRA 0.606) significantly reduced 6-month CDP compared with placebo. At 3 months, interferon beta-1b (OR 0.64, 95% CI 0.43–0.97; SUCRA 0.663), tolebrutinib (OR 0.73, 95% CI 0.56–0.96; SUCRA 0.554), and siponimod (OR 0.76, 95% CI 0.61–0.96; SUCRA 0.497) showed significant benefits. In terms of safety, tolebrutinib was associated with a higher risk of SAEs (OR 1.53, 95% CI 1.04–2.25), whereas the other agents had safety profiles comparable to placebo. Conclusion: This NMA found that tolebrutinib, IFN-β-1b, and siponimod delay disability progression in SPMS, with IFN-β-1b and siponimod remaining the most practical options. The conclusions should be interpreted cautiously given bias risk, moderate evidence certainty, limited safety data, and clinical heterogeneity.