{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,12]],"date-time":"2026-06-12T11:56:03Z","timestamp":1781265363810,"version":"3.54.1"},"reference-count":29,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2026,6,12]],"date-time":"2026-06-12T00:00:00Z","timestamp":1781222400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Brain Sciences"],"abstract":"<jats:p>Background: Multiple sclerosis (MS), an autoimmune disease, involves peripheral immune activation followed by CNS inflammation in a compartmentalized manner. Although high-efficacy disease-modifying therapies (HE-DMTs) have been effective in suppressing relapses in MS patients, they fail to effectively target chronic microglial activation and smoldering lesions in MS patients. Bruton\u2019s tyrosine kinase inhibitors (BTKis), which are orally active and capable of crossing the blood\u2013brain barrier, have been found to be effective in modulating B cells and CNS-resident myeloid cells. Objective: The objective was to assess the efficacy and safety of Bruton\u2019s tyrosine kinase inhibitors in patients with relapsing, secondary, and primary progressive MS. Methods: We performed a systematic review and meta-analysis according to the Cochrane and PRISMA guidelines (PROSPERO registration number: 1323474). We included randomized controlled trials (RCTs) that assessed fenebrutinib, evobrutinib, or tolebrutinib in adult MS patient populations. The main outcome measures were annualized relapse rate, MRI lesion activity, disability progression (EDSS), and hepatotoxicity. The quality of the included trials was assessed for bias by the RoB2 tool. Results: Six RCTs with 3616 participants were included. BTK inhibitors significantly reduced ARR compared with control therapy (pooled RR 0.24; 95% CI 0.15\u20130.39). MRI activity was reduced (mean difference \u22121.45 new\/enlarging T2 lesions; 95% CI \u22122.08 to \u22120.82). Disability progression was unchanged in short-term relapsing MS trials. Serious hepatotoxicity was reported in 11.0% of BTKi-treated patients compared with 13.7% of control patients (pooled RR 0.80; 95% CI 0.66\u20130.96). However, increased transaminase elevations were reported in placebo-controlled trials, which indicates that hepatotoxicity remains a clinically relevant safety concern for the class. Conclusions: BTK inhibitors reduce inflammatory disease activity in relapsing MS and have emerging efficacy in progressive MS phenotypes; however, continued monitoring for hepatotoxicity is warranted. Optimization of CNS penetrance and pharmacologic selectivity may influence long-term clinical positioning.<\/jats:p>","DOI":"10.3390\/brainsci16060634","type":"journal-article","created":{"date-parts":[[2026,6,12]],"date-time":"2026-06-12T09:49:51Z","timestamp":1781257791000},"page":"634","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Emerging Role of BTK Inhibitors in Multiple Sclerosis: From Immunobiology to Clinical Translation"],"prefix":"10.3390","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0009-0007-3266-3166","authenticated-orcid":false,"given":"Aashray","family":"Raj","sequence":"first","affiliation":[{"name":"Government Medical College, Bhavnagar, Gujarat 364001, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-7293-8574","authenticated-orcid":false,"given":"Vansh","family":"Patel","sequence":"additional","affiliation":[{"name":"B.J. Medical College, Ahmedabad 380016, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6762-8930","authenticated-orcid":false,"given":"Mehak","family":"Dang","sequence":"additional","affiliation":[{"name":"JSS Medical College, Mysore 570015, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aken","family":"Kayastha","sequence":"additional","affiliation":[{"name":"Kathmandu Model College, Kathmandu 44600, Nepal"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yusuf","family":"Kagzi","sequence":"additional","affiliation":[{"name":"College of Medicine, University of Illinois, Peoria, IL 61605, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-6983-3969","authenticated-orcid":false,"given":"Praveen Nandha Kumar","family":"Pitchan Velammal","sequence":"additional","affiliation":[{"name":"Tirunelveli Medical College, Tirunelveli 627011, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nidhi","family":"Agrawal","sequence":"additional","affiliation":[{"name":"MGM Medical College, Indore 452001, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kushagra","family":"Sharma","sequence":"additional","affiliation":[{"name":"MGM Medical College, Indore 452001, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicholas","family":"Hansen","sequence":"additional","affiliation":[{"name":"Department of Biostatistics, University of Michigan, Ann Arbor, MI 48109, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6955-2917","authenticated-orcid":false,"given":"Sijin","family":"Wen","sequence":"additional","affiliation":[{"name":"Department of Biostatistics, West Virginia Clinical Transitional Sciences, Morgantown, WV 26506, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shruti","family":"Jaiswal","sequence":"additional","affiliation":[{"name":"Department of Neuro-Oncology, MD Anderson Cancer Center, Houston, TX 77030, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shitiz","family":"Sriwastava","sequence":"additional","affiliation":[{"name":"Department of Neurology, Jackson T. Stephens Spine and Neurosciences Institute, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,6,12]]},"reference":[{"key":"ref_1","first-page":"1356","article-title":"Multiple sclerosis and other demyelinating diseases","volume":"108","author":"Mount","year":"1973","journal-title":"Can. Med. Assoc. J."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"647","DOI":"10.1038\/nrneurol.2012.168","article-title":"Progressive multiple sclerosis: Pathology and pathogenesis","volume":"8","author":"Lassmann","year":"2012","journal-title":"Nat. Rev. Neurol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1055\/s-2007-1019124","article-title":"The immunology of multiple sclerosis","volume":"28","year":"2008","journal-title":"Semin. Neurol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"266","DOI":"10.1016\/j.it.2023.02.002","article-title":"Multiple sclerosis: Role of meningeal lymphoid aggregates in progression independent of relapse activity","volume":"44","author":"Ransohoff","year":"2023","journal-title":"Trends Immunol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1622","DOI":"10.1016\/S0140-6736(18)30481-1","article-title":"Multiple sclerosis","volume":"391","author":"Thompson","year":"2018","journal-title":"Lancet"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"305","DOI":"10.1038\/s41582-023-00801-6","article-title":"Inflammation in multiple sclerosis: Consequences for remyelination and disease progression","volume":"19","author":"Klotz","year":"2023","journal-title":"Nat. Rev. Neurol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"e13240","DOI":"10.1111\/bpa.13240","article-title":"The relation between BTK expression and iron accumulation of myeloid cells in multiple sclerosis","volume":"34","author":"Steinmaurer","year":"2024","journal-title":"Brain Pathol."},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Lin, D.Y., and Andreotti, A.H. (2023). Structure of BTK kinase domain with the second-generation inhibitors acalabrutinib and tirabrutinib. PLoS ONE, 18.","DOI":"10.1371\/journal.pone.0290872"},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Weber, A.N.R., Bittner, Z., Liu, X., Dang, T.-M., Radsak, M.P., and Brunner, C. (2017). Bruton\u2019s Tyrosine Kinase: An Emerging Key Player in Innate Immunity. Front. Immunol., 8.","DOI":"10.3389\/fimmu.2017.01454"},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Garc\u00eda-Merino, A. (2021). Bruton\u2019s Tyrosine Kinase Inhibitors: A New Generation of Promising Agents for Multiple Sclerosis Therapy. Cells, 10.","DOI":"10.3390\/cells10102560"},{"key":"ref_11","first-page":"67","article-title":"BTK Signaling in B Cell Differentiation and Autoimmunity","volume":"393","author":"Corneth","year":"2015","journal-title":"Curr. Topics Microbiol. Immunol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1019","DOI":"10.1007\/s40263-022-00951-z","article-title":"Bruton\u2019s Tyrosine Kinase Inhibitors in Multiple Sclerosis: Pioneering the Path Towards Treatment of Progression?","volume":"36","author":"Geladaris","year":"2022","journal-title":"CNS Drugs"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"5601","DOI":"10.1038\/s41598-022-09528-8","article-title":"TIRAP-mediated activation of p38 MAPK in inflammatory signaling","volume":"12","author":"Rajpoot","year":"2022","journal-title":"Sci. Rep."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"e06074","DOI":"10.7554\/eLife.06074","article-title":"Autoinhibition of Bruton\u2019s tyrosine kinase (Btk) and activation by soluble inositol hexakisphosphate","volume":"4","author":"Wang","year":"2015","journal-title":"eLife"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"729","DOI":"10.1016\/S1474-4422(21)00237-4","article-title":"Safety and efficacy of tolebrutinib, an oral brain-penetrant BTK inhibitor, in relapsing multiple sclerosis: A phase 2b, randomised, double-blind, placebo-controlled trial","volume":"20","author":"Reich","year":"2021","journal-title":"Lancet Neurol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"2406","DOI":"10.1056\/NEJMoa1901981","article-title":"Placebo-Controlled Trial of an Oral BTK Inhibitor in Multiple Sclerosis","volume":"380","author":"Montalban","year":"2019","journal-title":"N. Engl. J. Med."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1893","DOI":"10.1056\/NEJMoa2415985","article-title":"Tolebrutinib versus Teriflunomide in Relapsing Multiple Sclerosis","volume":"392","author":"Oh","year":"2025","journal-title":"N. Engl. J. Med."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1119","DOI":"10.1016\/S1474-4422(24)00328-4","article-title":"Safety and efficacy of evobrutinib in relapsing multiple sclerosis (evolutionRMS1 and evolutionRMS2): Two multicentre, randomised, double-blind, active-controlled, phase 3 trials","volume":"23","author":"Montalban","year":"2024","journal-title":"Lancet Neurol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1883","DOI":"10.1056\/NEJMoa2415988","article-title":"Tolebrutinib in Nonrelapsing Secondary Progressive Multiple Sclerosis","volume":"392","author":"Fox","year":"2025","journal-title":"N. Engl. J. Med."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"656","DOI":"10.1016\/S1474-4422(25)00174-7","article-title":"Safety and efficacy of fenebrutinib in relapsing multiple sclerosis (FENopta): A multicentre, double-blind, randomised, placebo-controlled, phase 2 trial and open-label extension study","volume":"24","author":"Dufek","year":"2025","journal-title":"Lancet Neurol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"285","DOI":"10.1007\/s40265-024-02011-w","article-title":"Drugs Targeting CD20 in Multiple Sclerosis: Pharmacology, Efficacy, Safety, and Tolerability","volume":"84","author":"Carlson","year":"2024","journal-title":"Drugs"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"17562864211066751","DOI":"10.1177\/17562864211066751","article-title":"Smouldering multiple sclerosis: The \u2018real MS\u2019","volume":"15","author":"Giovannoni","year":"2022","journal-title":"Ther. Adv. Neurol. Disord."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"e200510","DOI":"10.1212\/NXI.0000000000200510","article-title":"Bruton Tyrosine Kinase Inhibition Limits Multiple Sclerosis Disease\u2013Driving Inflammation While Promoting Regulatory B Cells","volume":"13","author":"Dybowski","year":"2026","journal-title":"Neurol.-Neuroimmunol. Neuroinflamm."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"e208058","DOI":"10.1212\/WNL.0000000000208058","article-title":"Effect of Evobrutinib on Slowly Expanding Lesion Volume in Relapsing Multiple Sclerosis: A Post Hoc Analysis of a Phase 2 Trial","volume":"102","author":"Arnold","year":"2024","journal-title":"Neurology"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"75","DOI":"10.1007\/s00401-024-02730-0","article-title":"BTK inhibition limits microglia-perpetuated CNS inflammation and promotes myelin repair","volume":"147","author":"Geladaris","year":"2024","journal-title":"Acta Neuropathol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"263","DOI":"10.1007\/s40268-024-00468-4","article-title":"Comparative CNS Pharmacology of the Bruton\u2019s Tyrosine Kinase (BTK) Inhibitor Tolebrutinib Versus Other BTK Inhibitor Candidates for Treating Multiple Sclerosis","volume":"24","author":"Turner","year":"2024","journal-title":"Drugs R&D"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"721","DOI":"10.1007\/s11910-022-01229-z","article-title":"Bruton\u2019s Tyrosine Kinase Inhibition in Multiple Sclerosis","volume":"22","author":"Schneider","year":"2022","journal-title":"Curr. Neurol. Neurosci. Rep."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"e213558","DOI":"10.1212\/WNL.0000000000213558","article-title":"Composite Confirmed Disability Worsening\/Progression Is a Useful Clinical Endpoint for Multiple Sclerosis Clinical Trials","volume":"104","author":"Kappos","year":"2025","journal-title":"Neurology"},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Moher, D., Liberati, A., Tetzlaff, J., and Altman, D.G. (2009). Preferred Reporting Items for Systematic Reviews and Meta-Analyses: The PRISMA Statement. PLoS Med., 6.","DOI":"10.1371\/journal.pmed.1000097"}],"container-title":["Brain Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2076-3425\/16\/6\/634\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,6,12]],"date-time":"2026-06-12T10:59:32Z","timestamp":1781261972000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2076-3425\/16\/6\/634"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,6,12]]},"references-count":29,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2026,6]]}},"alternative-id":["brainsci16060634"],"URL":"https:\/\/doi.org\/10.3390\/brainsci16060634","relation":{},"ISSN":["2076-3425"],"issn-type":[{"value":"2076-3425","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,6,12]]}}}