{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,31]],"date-time":"2026-10-31T17:47:16Z","timestamp":1793468836454,"version":"4.5.0"},"reference-count":77,"publisher":"SAGE Publications","license":[{"start":{"date-parts":[[2024,1,1]],"date-time":"2024-01-01T00:00:00Z","timestamp":1704067200000},"content-version":"unspecified","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Novartis Pharma AG"}],"content-domain":{"domain":["journals.sagepub.com"],"crossmark-restriction":true},"short-container-title":["Ther Adv Neurol Disord"],"published-print":{"date-parts":[[2024,1]]},"abstract":"<jats:p>Bruton\u2019s tyrosine kinase (BTK) inhibitors are an emerging class of therapeutics in multiple sclerosis (MS). BTK is expressed in B-cells and myeloid cells, key progenitors of which include dendritic cells, microglia and macrophages, integral effectors of MS pathogenesis, along with mast cells, establishing the relevance of BTK inhibitors to diverse autoimmune conditions. First-generation BTK inhibitors are currently utilized in the treatment of B-cell malignancies and show efficacy in B-cell modulation. B-cell depleting therapies have shown success as disease-modifying treatments (DMTs) in MS, highlighting the potential of BTK inhibitors for this indication; however, first-generation BTK inhibitors exhibit a challenging safety profile that is unsuitable for chronic use, as required for MS DMTs. A second generation of highly selective BTK inhibitors has shown efficacy in modulating MS-relevant mechanisms of pathogenesis in preclinical as well as clinical studies. Six of these BTK inhibitors are undergoing clinical development for MS, three of which are also under investigation for chronic spontaneous urticaria (CSU), rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). Phase II trials of selected BTK inhibitors for MS showed reductions in new gadolinium-enhancing lesions on magnetic resonance imaging scans; however, the safety profile is yet to be ascertained in chronic use. Understanding of the safety profile is developing by combining safety insights from the ongoing phase II and III trials of second-generation BTK inhibitors for MS, CSU, RA and SLE. This narrative review investigates the potential of BTK inhibitors as an MS DMT, the improved selectivity of second-generation inhibitors, comparative safety insights established thus far through clinical development programmes and proposed implications in female reproductive health and in long-term administration.<\/jats:p>","DOI":"10.1177\/17562864241233041","type":"journal-article","created":{"date-parts":[[2024,4,17]],"date-time":"2024-04-17T08:48:52Z","timestamp":1713343732000},"update-policy":"https:\/\/doi.org\/10.1177\/sage-journals-update-policy","source":"Crossref","is-referenced-by-count":38,"title":["A review of Bruton\u2019s tyrosine kinase inhibitors in multiple sclerosis"],"prefix":"10.1177","volume":"17","author":[{"given":"Laura","family":"Airas","sequence":"first","affiliation":[{"name":"Division of Clinical Neurosciences, University of Turku, Turku, Finland"},{"name":"Neurocenter, Turku University Hospital, Turku, Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert A.","family":"Bermel","sequence":"additional","affiliation":[{"name":"Mellen Center for MS, Neurological Institute, Cleveland Clinic, Cleveland, OH, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tanuja","family":"Chitnis","sequence":"additional","affiliation":[{"name":"Brigham Multiple Sclerosis Center, Harvard Medical School, Boston, MA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0614-6989","authenticated-orcid":false,"given":"Hans-Peter","family":"Hartung","sequence":"additional","affiliation":[{"name":"Department of Neurology, Medical Faculty, Heinrich-Heine-University, D\u00fcsseldorf, Germany"},{"name":"Brain and Mind Center, University of Sydney, Sydney, NSW, Australia"},{"name":"Department of Neurology, Palack\u00fd University Olomouc, Olomouc, Czech Republic"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jin","family":"Nakahara","sequence":"additional","affiliation":[{"name":"Department of Neurology, Keio University School of Medicine, Tokyo, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0469-6872","authenticated-orcid":false,"given":"Olaf","family":"Stuve","sequence":"additional","affiliation":[{"name":"Department of Neurology, University of Texas Southwestern Medical Center, Dallas, TX, USA"},{"name":"Neurology Section, VA North Texas Health Care System, Dallas, TX, USA"},{"name":"Peter O\u2019Donnell Brain Institute, University of Texas Southwestern Medical Center, Dallas, TX, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mitzi J.","family":"Williams","sequence":"additional","affiliation":[{"name":"Joi Life Wellness MS Center, Atlanta, GA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bernd C.","family":"Kieseier","sequence":"additional","affiliation":[{"name":"Department of Neurology, Medical Faculty, Heinrich-Heine-University, D\u00fcsseldorf, Germany"},{"name":"Novartis Pharma AG, Basel, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4310-3432","authenticated-orcid":false,"given":"Heinz","family":"Wiendl","sequence":"additional","affiliation":[{"name":"Department of Neurology, University Hospital Muenster, Albert-Schweitzer-Campus 1, Building A 1, Muenster 48149, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"179","published-online":{"date-parts":[[2024,4,17]]},"reference":[{"key":"bibr1-17562864241233041","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2021.662223"},{"key":"bibr2-17562864241233041","doi-asserted-by":"publisher","DOI":"10.1007\/s00401-020-02204-z"},{"key":"bibr3-17562864241233041","doi-asserted-by":"publisher","DOI":"10.1177\/2040620714539906"},{"key":"bibr4-17562864241233041","doi-asserted-by":"publisher","DOI":"10.3389\/fcell.2021.630942"},{"key":"bibr5-17562864241233041","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0085834"},{"key":"bibr6-17562864241233041","doi-asserted-by":"publisher","DOI":"10.1186\/s12943-018-0779-z"},{"key":"bibr7-17562864241233041","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.181.1.288"},{"key":"bibr8-17562864241233041","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1400395"},{"key":"bibr9-17562864241233041","doi-asserted-by":"publisher","DOI":"10.1084\/jem.187.8.1235"},{"key":"bibr10-17562864241233041","doi-asserted-by":"publisher","DOI":"10.3233\/BPL-200100"},{"key":"bibr11-17562864241233041","doi-asserted-by":"publisher","DOI":"10.1111\/jth.13651"},{"key":"bibr12-17562864241233041","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2017-07-793786"},{"key":"bibr13-17562864241233041","doi-asserted-by":"publisher","DOI":"10.1038\/nri3871"},{"key":"bibr14-17562864241233041","doi-asserted-by":"publisher","DOI":"10.1038\/s41582-019-0170-8"},{"key":"bibr15-17562864241233041","doi-asserted-by":"publisher","DOI":"10.1177\/1352458517729455"},{"key":"bibr16-17562864241233041","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2018.03116"},{"key":"bibr17-17562864241233041","doi-asserted-by":"publisher","DOI":"10.1080\/14728214.2020.1822817"},{"key":"bibr18-17562864241233041","doi-asserted-by":"publisher","DOI":"10.1002\/ana.25119"},{"key":"bibr19-17562864241233041","volume-title":"Proceedings of the 8th annual meeting of The Lupus Academy","author":"Becker AD"},{"key":"bibr20-17562864241233041","doi-asserted-by":"publisher","DOI":"10.1002\/cpt.1056"},{"key":"bibr21-17562864241233041","doi-asserted-by":"publisher","DOI":"10.1111\/cts.13005"},{"key":"bibr22-17562864241233041","doi-asserted-by":"publisher","DOI":"10.1111\/cts.13162"},{"key":"bibr23-17562864241233041","volume-title":"Proceedings of the annual meeting of the American Association of Cancer Research 2020","author":"Zhang B"},{"key":"bibr24-17562864241233041","doi-asserted-by":"publisher","DOI":"10.1002\/cti2.1295"},{"key":"bibr25-17562864241233041","doi-asserted-by":"publisher","DOI":"10.1186\/s41073-019-0064-8"},{"key":"bibr26-17562864241233041","doi-asserted-by":"publisher","DOI":"10.1007\/s00401-022-02411-w"},{"key":"bibr27-17562864241233041","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awab045"},{"key":"bibr28-17562864241233041","volume-title":"Proceedings of the 38th congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS)","author":"Nuesslein-Hildesheim B"},{"key":"bibr29-17562864241233041","doi-asserted-by":"publisher","DOI":"10.1159\/000078339"},{"key":"bibr30-17562864241233041","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2022.818325"},{"key":"bibr31-17562864241233041","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awh707"},{"key":"bibr32-17562864241233041","doi-asserted-by":"publisher","DOI":"10.1016\/j.jneuroim.2016.05.021"},{"key":"bibr33-17562864241233041","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awx113"},{"key":"bibr34-17562864241233041","doi-asserted-by":"publisher","DOI":"10.3389\/fphar.2019.00286"},{"key":"bibr35-17562864241233041","doi-asserted-by":"publisher","DOI":"10.1177\/17562864211066751"},{"key":"bibr36-17562864241233041","doi-asserted-by":"publisher","DOI":"10.1016\/S1474-4422(21)00237-4"},{"key":"bibr37-17562864241233041","doi-asserted-by":"publisher","DOI":"10.1038\/s41587-020-00790-7"},{"key":"bibr38-17562864241233041","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1901981"},{"key":"bibr39-17562864241233041","unstructured":"Multiple Sclerosis News Today. Orelabrutinib reduces brain lesions in RRMS by 90% in phase 2 trial, https:\/\/multiplesclerosisnewstoday.com\/news-posts\/2023\/03\/29\/orelabrutinib-reduces-rrms-brain-lesions-90-percent-trial-analysis\/ (2023, accessed 26 July 2023)."},{"key":"bibr40-17562864241233041","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejmech.2018.03.062"},{"key":"bibr41-17562864241233041","doi-asserted-by":"publisher","DOI":"10.1186\/s13045-021-01049-7"},{"key":"bibr42-17562864241233041","doi-asserted-by":"publisher","DOI":"10.1021\/acschembio.6b00480"},{"key":"bibr43-17562864241233041","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.93.25.14800"},{"key":"bibr44-17562864241233041","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jmedchem.1c00926"},{"key":"bibr45-17562864241233041","first-page":"118","volume":"26","author":"Scaramozza M","year":"2020","journal-title":"Mult Scler J"},{"key":"bibr46-17562864241233041","volume-title":"in vitro","author":"Pulz P"},{"key":"bibr47-17562864241233041","author":"Johnson A","year":"2020","journal-title":"Proceedings of the 8th joint ACTRIMS\u2013ECTRIMS meeting"},{"key":"bibr48-17562864241233041","doi-asserted-by":"publisher","DOI":"10.1182\/bloodadvances.2018013060"},{"key":"bibr49-17562864241233041","doi-asserted-by":"publisher","DOI":"10.3324\/haematol.2017.164285"},{"key":"bibr50-17562864241233041","doi-asserted-by":"publisher","DOI":"10.1182\/blood.2020008758"},{"key":"bibr51-17562864241233041","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbmt.2019.06.023"},{"key":"bibr52-17562864241233041","unstructured":"Sanofi. Patient enrollment of phase III tolebrutinib trials paused in the U.S. https:\/\/www.sanofi.com\/en\/media-room\/press-releases\/2022\/2022-06-30-05-30-00-2471767 (2022, accessed 1 August 2023)."},{"key":"bibr53-17562864241233041","unstructured":"Nicolas O, Cabanis M, Brun P, et al. Tolebrutinib demonstrates cerebrospinal fluid exposure at bioactive levels in a single-ascending dose study in healthy volunteers. (Poster session presented at ACTRIMS 2023.) In: Proceedings of the 8th annual Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS) Forum, 23\u201325 February 2023, San Diego, CA, USA."},{"key":"bibr54-17562864241233041","doi-asserted-by":"publisher","DOI":"10.1016\/j.msard.2021.103001"},{"key":"bibr55-17562864241233041","volume-title":"Proceedings of the 8th annual Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS) Forum","author":"Blazier AS","year":"2023"},{"key":"bibr56-17562864241233041","volume-title":"Proceedings of the European Academy of Dermatology & Venereology (EADV) 30th congress","author":"Maurer M"},{"key":"bibr57-17562864241233041","doi-asserted-by":"publisher","DOI":"10.1038\/s41591-021-01537-w"},{"key":"bibr58-17562864241233041","volume-title":"Proceedings of the American College of Rheumatology (ACR) convergence 2020","author":"Peterfy C","year":"2020"},{"key":"bibr59-17562864241233041","author":"Oh J","year":"2021","journal-title":"Proceedings of the American Academy of Neurology (AAN) annual meeting"},{"key":"bibr60-17562864241233041","first-page":"733","volume":"78","author":"Morimoto A","year":"2019","journal-title":"Ann Rheum Dis"},{"key":"bibr61-17562864241233041","doi-asserted-by":"publisher","DOI":"10.1002\/art.41275"},{"key":"bibr62-17562864241233041","volume-title":"Proceedings of the 2019 American College of Rheumatology (ACR)\/Association of Rheumatology Professionals (ARP) annual meeting","author":"Cohen S","year":"2019"},{"key":"bibr63-17562864241233041","author":"Wallace DJ","year":"2020","journal-title":"Proceedings of the American College of Rheumatology (ACR) convergence 2020"},{"key":"bibr64-17562864241233041","doi-asserted-by":"publisher","DOI":"10.1002\/art.41811"},{"key":"bibr65-17562864241233041","volume-title":"Proceedings of the 37th congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS)","author":"Montalban X","year":"2021"},{"key":"bibr66-17562864241233041","volume-title":"Proceedings of the 37th congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS)","author":"Arnold D","year":"2021"},{"key":"bibr67-17562864241233041","volume-title":"Proceedings of the 8th joint ACTRIMS-ECTRIMS meeting","author":"Hauser S","year":"2020"},{"key":"bibr68-17562864241233041","doi-asserted-by":"publisher","DOI":"10.1007\/s40265-021-01482-5"},{"key":"bibr69-17562864241233041","doi-asserted-by":"publisher","DOI":"10.1007\/s10637-022-01219-5"},{"key":"bibr70-17562864241233041","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jmedchem.9b01916"},{"key":"bibr71-17562864241233041","unstructured":"Sanofi. Media update: tolebrutinib clinical trial program update, https:\/\/www.sanofi.com\/en\/media-room\/press-releases\/2022\/2022-08-08-17-08-40-2494173 (2022, accessed 1 August 2023)."},{"key":"bibr72-17562864241233041","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaci.2022.08.027"},{"key":"bibr73-17562864241233041","unstructured":"MS International Federation. Atlas of MS. 3rd edition, https:\/\/www.msif.org\/wp-content\/uploads\/2020\/12\/Atlas-3rd-Edition-Epidemiology-report-EN-updated-30-9-20.pdf (2020, accessed 1 August 2023)."},{"key":"bibr74-17562864241233041","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejps.2022.106155"},{"key":"bibr75-17562864241233041","doi-asserted-by":"publisher","DOI":"10.3389\/fneur.2022.851413"},{"key":"bibr76-17562864241233041","doi-asserted-by":"publisher","DOI":"10.1182\/hematology.2020000118"},{"key":"bibr77-17562864241233041","doi-asserted-by":"publisher","DOI":"10.1038\/jhg.2011.61"}],"container-title":["Therapeutic Advances in Neurological Disorders"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/journals.sagepub.com\/doi\/pdf\/10.1177\/17562864241233041","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/journals.sagepub.com\/doi\/full-xml\/10.1177\/17562864241233041","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/journals.sagepub.com\/doi\/pdf\/10.1177\/17562864241233041","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,3,3]],"date-time":"2025-03-03T13:56:12Z","timestamp":1741010172000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.sagepub.com\/doi\/10.1177\/17562864241233041"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,1]]},"references-count":77,"alternative-id":["10.1177\/17562864241233041"],"URL":"https:\/\/doi.org\/10.1177\/17562864241233041","relation":{},"ISSN":["1756-2864","1756-2864"],"issn-type":[{"value":"1756-2864","type":"print"},{"value":"1756-2864","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,1]]},"article-number":"17562864241233041"}}