Efficacy and safety of Bruton's tyrosine kinase inhibitors compared to Teriflunomide in relapsing multiple sclerosis: A systematic review and meta-analysis

Abstract

Introduction: Traditional disease-modifying therapies (DMTs) reduce relapse frequency in relapsing-remitting multiple sclerosis (MS) but have a limited impact on relapse-independent progression, underscoring the need for novel therapies. Bruton's tyrosine kinase inhibitors (BTKis), with dual immunomodulatory effects and central nervous system penetration, offer a promising alternative for comparison with established agents such as teriflunomide.

Methods: We systematically searched PubMed, Embase, and Cochrane CENTRAL up to June 2025 for randomized controlled trials (RCTs) comparing BTKis with teriflunomide in patients with relapsing MS. The primary outcome was confirmed disability worsening (CDW) at 3 and 6 months. Secondary outcomes included annualized relapse rate (ARR), magnetic resonance imaging (MRI) lesion activity, and adverse events. Random-effects meta-analyses were performed using hazard ratios (HRs), rate ratios, risk ratios, and mean differences, as appropriate.

Results: Four RCTs with 4136 participants were included. ARR was similar between the groups (Rate Ratio: 1.03; 95% CI: 0.90-1.19). BTK inhibitors reduced the risk of 3-month CDW compared with teriflunomide (HR: 0.81; 95% CI: 0.67-0.97) but not 6-month CDW (HR: 0.88; 95% CI: 0.63-1.24). The slight but significant difference in new T1 gadolinium-enhancing lesions favored teriflunomide (MD: 0.20; 95% CI: 0.15-0.25), whereas no difference was found in new or enlarging T2 lesions (MD:0.07; 95% CI:0.85 to 0.71). The incidence of serious adverse events was comparable between the groups (RR: 1.13; 95% CI: 0.92-1.40).

Conclusion: Compared with teriflunomide, BTK inhibitors were associated with a reduced risk of short-term disability progression, whereas no differences were observed in relapse rates, MRI activity, or safety outcomes.

Keywords: Evobrutinib; Meta-analysis; Systematic review; Teriflunomide; Tolebrutinib.