Comparative Efficacy and Safety of Bruton’s Tyrosine Kinase Inhibitors in Relapsing Multiple Sclerosis: An Updated Systematic Review and Network Meta-Analysis of Randomized Controlled Trials

Background: Bruton’s tyrosine kinase inhibitors (BTKis) are emerging oral disease-modifying therapies for relapsing multiple sclerosis (RMS). Their comparative effects on relapse prevention, disability progression and liver-related adverse events remain uncertain. Objective: To compare individual BTKis and eligible controls for efficacy and safety in adults with RMS. Methods: We will systematically search bibliographic databases, trial registries and relevant conference sources for randomized controlled trials (RCTs), regardless of direction or statistical significance of results or publication status. Comparable phase 3 trials will form the primary clinical-efficacy synthesis; qualifying phase 2 trials will be considered in outcome-specific or sensitivity analyses. Annualized relapse rate will be the primary efficacy outcome. Key secondary outcomes will include 3- and 6-month confirmed disability progression/worsening, MRI activity, serious adverse events and hepatotoxicity. Eligible conference-, preprint- or registry-only results with sufficient extractable data will be included and assessed in publication-status sensitivity analyses. Where network connectivity and transitivity permit, random-effects network meta-analyses will estimate treatment effects and treatment rankings. Otherwise, pairwise syntheses or structured narrative summaries will be reported. Risk of bias will be assessed using RoB 2 and certainty of network evidence using CINeMA.