Efficacy and safety of disease-modifying oral drugs in treatment of relapsing-remitting multiple sclerosis: systematic review and network meta-analysis

Background: Relapsing-Remitting Multiple Sclerosis (RRMS) is a chronic inflammatory demyelinating disease affecting the central nervous system, characterized by complex pathogenesis and increasing annual incidence rates. Although current clinical interventions for RRMS are diverse, there remains a relative scarcity of direct comparative studies on the efficacy and safety profiles among different oral disease-modifying drugs, resulting in insufficient comprehensive evidence. Objective: This study aims to apply network meta-analysis techniques to systematically evaluate the relative efficacy and safety of different disease-modifying oral drugs in the treatment of RRMS, clarify their differences, and provide high-quality evidence-based medical support for optimal clinical treatment decision-making. Methods: The systematic search was conducted in PubMed, Embase, Web of Science, and The Cochrane Register of Clinical Trials databases, covering the period from database inception to July 31, 2025. Randomized controlled trials were included, with study populations consisting of adult patients with relapsing-remitting multiple sclerosis, interventions involving disease-modifying oral medications, and comparators being placebo or other treatments. The primary data sources were phase II/III clinical trials, with non-standard treatment regimens serving as crucial observational approaches and thus analyzed as independent nodes for comparison. Primary outcome measures included Annualized relapse rate and Adverse events leading to discontinuation, while secondary outcomes comprised Adverse events, Serious adverse events, active T1 lesions, and active T2 lesions. A random-effects model was employed for network meta-analysis, with dichotomous and continuous variables analyzed using odds ratios (OR) and mean differences (MD) along with their respective 95% confidence intervals (CI) as effect measures to compare various interventions. Treatment rankings were performed using the surface under the cumulative ranking curve (SUCRA) probability method. Results: A total of 15 RCTs involving 14,869 participants were included. The NMA results demonstrated that Siponimod, Ponesimod, Laquinimod, Fingolimod, Cladribine, and Dimethyl Fumarate were all superior to placebo in reducing annualized relapse rates in patients with multiple sclerosis, with Siponimod (2 mg; SUCRA = 86.9%) and Laquinimod 0.3 mg (SUCRA = 10.1%) being the best and worst treatments, respectively. Regarding adverse events leading to study discontinuation, the optimal and least favorable interventions were Fingolimod (0.25 mg; SUCRA = 83.1%) and Siponimod (10 mg; SUCRA = 3.1%), respectively. Conclusions: This NMA demonstrated that Siponimod (2mg) is the most efficacious therapeutic intervention; FIN (0.25 mg) exhibited relative safety advantages in terms of DAE, though this dosage constitutes an exploratory regimen and should not serve as the basis for routine clinical medication. However, these findings still require further validation in subsequent studies. Systematic Review Registration: https://www.crd.york.ac.uk/prospero/, identifier CRD420250654500.