To compare the safety of BTK inhibitors against Teriflunomide in patients with relapsing forms of Multiple Sclerosis.

BTK inhibitors modulate B‑cells and microglial activity, and offer a distinct alternative to teriflunomide in relapsing multiple sclerosis. However, comparative safety evidence is needed to guide practice. 

We performed a systematic review and meta-analysis following PRISMA guidelines. Suitable studies were identified through a comprehensive search performed across major databases up to September 2025. Data were analyzed using R (version 4.5.1) in RStudio, with the packages netmeta, gemtc, BUGSnet and bnma. Both frequentist and Bayesian methods were employed to indirectly measure the efficacy using random models. 

Mortality was lower with tolebrutinib than teriflunomide (OR 0.50, CI 0.05-5.58), while evobrutinib had similar rates (OR 1.01, CI 0.06-16.14). SUCRA favored evobrutinib (69%), followed by teriflunomide (59%). Overall adverse events were higher with evobrutinib versus teriflunomide (OR 1.41, CI 1.03-1.95), while tolebrutinib had comparable rates as teriflunomide (OR 1.21, CI 0.88-1.66). SUCRA ranked evobrutinib (84%), followed by tolebrutinib (55%). In contrast, alopecia risk was lower with evobrutinib (OR 0.44, CI 0.32-0.59) and tolebrutinib (OR 0.46, CI 0.34-0.62). SUCRA ranked teriflunomide higher (98.8%) for the risk of alopecia. ALT elevation did not increase with evobrutinib (OR 0.80, CI 0.65-1.00) or tolebrutinib (OR 0.73, CI 0.49-1.09). Nasopharyngitis was similar with evobrutinib (OR 0.98, CI 0.68-1.41) and tolebrutinib (OR 1.17, CI 0.49-1.09). 

BTK inhibitors demonstrated less alopecia events and no increased ALT levels as compared to teriflunomide, whereas evobrutinib has more overall adverse events. These results point to targeted monitoring of patients and highlight the need for more.