Safety and efficacy of Bruton’s tyrosine kinase inhibitors in multiple sclerosis: A systematic review and network meta-analysis of randomized controlled trials

Background This systematic review and network meta-analysis evaluated the safety and efficacy of Bruton’s tyrosine kinase (BTK) inhibitors in patients with multiple sclerosis (MS). By assessing their impact on disease progression and adverse events, this study aims to provide insights into the therapeutic potential of BTK inhibition for the management of MS. Methods A comprehensive search was conducted in PubMed, Cochrane Central Register of Controlled Trials (CENTRAL), Scopus, and Web of Science databases for articles published until May 5, 2025. Randomized controlled trials (RCTs) comparing BTK inhibitors with placebo or other medications in patients with MS were included. Data extraction and risk-of-bias assessment were performed following the Cochrane guidelines. Traditional and network meta-analyses were performed to compare the efficacy outcomes, including gadolinium-enhancing lesions, annualized relapse rate (ARR), and new or enlarged T2 lesions, along with safety profiles. Results In total, 5 RCTs ( N ​= ​3812) were included in this study. Evobrutinib 45 and 75 mg twice daily (BID) significantly reduced gadolinium-enhancing lesions compared to placebo (mean difference [MD] ​= ​−3.23, 95 ​% confidence interval [CI]: [–5.12, −1.34], P ​= ​0.0008) and had similar efficacy to teriflunomide 14 mg once daily (QD) (MD = –3.41, 95% CI: [–5.30, –1.51], P = 0.0004). Tolebrutinib (60 ​mg QD) reduced new/enlarged T2 lesions (MD = 1.37, 95 ​% CI: [–2.13, −0.60], P ​= ​0.0005) compared to placebo, but other doses lacked significant efficacy. Neither BTK inhibitor showed a significant reduction in ARR. Evobrutinib was associated with elevated alanine aminotransferase (ALT) (>3× upper limit of normal [ULN]: 11.14 %, 127/1140), followed by teriflunomide (10.82 %, 124/1146) and tolebrutinib (3.67 %, 32/871), necessitating liver monitoring. Tolebrutinib had fewer hepatotoxic effects but lacked robust efficacy on key outcomes. Conclusions Evobrutinib shows efficacy in reducing magnetic resonance imaging (MRI) lesions in MS, comparable to teriflunomide, though without significant ARR reduction. Tolebrutinib’s efficacy appears dose-dependent, warranting further investigation. Hepatotoxicity with evobrutinib and teriflunomide highlights the need for careful monitoring. Further large-scale RCTs are needed to confirm clinical benefits, optimal dosing, and neuroprotective potential.