The Comparative Effectiveness and Tolerability of Sphingosine-1-Phosphate Receptor Modulators in Patients With Multiple Sclerosis: A Network Meta-Analysis of Randomized Controlled Trials.

Background: Sphingosine-1-phosphate receptor modulators (S1PRM) are used to treat relapsing multiple sclerosis (MS). Each drug has a different S1PR-subtype selectivity. They target the G-protein coupled S1P receptors and exert significant immunomodulatory effects, such as preventing the formation of new CNS lesions and the reactivation of pre-existing lesions.

Objective: This study aims to explore the efficacy and safety of S1PRM in treating MS.

Methods: A systematic literature search of PubMed, Embase, and Cochrane databases was conducted in August 2024. Randomized Controlled Trials that evaluated the efficacy of S1PRM in patients with MS were included. Changes in Annualized Relapse Rate and incidence of adverse effects were chosen as primary outcomes. Standardized mean differences (SMD) and odds ratio (OR) were calculated. Confidence interval was kept at 95%. Individual interventions were compared using the Surface Under Cumulative Ranking Curve (SUCRA). The risk of bias was assessed by the Cochrane risk-of-bias tool for randomized trials (RoB 2).

Results: The search query resulted in a total of 1750 studies. After screening, 17 studies were included in the final analysis, with a population of 16,006. Fingolimod (1.25 mg) was significantly associated with a decreased ARR (SMD = -0.4422, 95% CI = [-0.5450 to -0.3394], p-value < 0.0001, SUCRA = 92.65%). Whereas, ozanimod (1 mg) was associated with the lowest number of new Gadolinium-enhanced lesions (SMD = -0.6516, 95% CI = [-0.8944 to -0.4087], p-value < 0.0001, SUCRA = 86.38%). Siponimod (1.25 mg) was associated with the least number of adverse events (OR = 0.4606, 95% CI = [0.1893 to 1.1205], p = 0.0874, SUCRA = 93.20%). Almost all of the studies had a low risk of bias.

Conclusion: Fingolimod (1.25 mg) and ozanimod (1 mg) had the best efficacy, and siponimod (1.25 mg and 0.25 mg) had the best safety profile among the S1PRM. Further longitudinal studies should be conducted to assess the long-term effects of these drugs on patient-reported outcomes.