biostudies-literatureKocot JDivision of Intramural Research, National Institute of Allergy and Infectious Diseases, NIHe183941https://www.ebi.ac.uk/biostudies/studies/S-EPMC12077908biostudies-literatureUnknown135(10)Multiple sclerosis (MS) is an immune-mediated demyelinating disease of the CNS. Clemastine fumarate, the over-the-counter antihistamine and muscarinic receptor blocker, has remyelinating potential in MS. A clemastine arm was added to an ongoing platform clinical trial, targeting residual activity by precision, biomarker-guided combination therapies of multiple sclerosis (TRAP-MS) (ClinicalTrials.gov NCT03109288), to identify a cerebrospinal fluid (CSF) remyelination signature and to collect safety data on clemastine in patients progressing independently of relapse activity (PIRA). The clemastine arm was stopped per protocol-defined criteria when 3 of 9 patients triggered individual safety stopping criteria. Clemastine-treated patients had significantly higher treatment-induced disability pThe Journal of clinical investigationClemastine fumarate accelerates accumulation of disability in progressive multiple sclerosis by enhancing pyroptosis.PMC12077908Division of Intramural Research,National Institute of AllergyInfectious Diseases,NIHPeterson KAshida SKocot JPirjanian NAGoldbach-Mansky RBielekova BFossati VHolland SMKosa PfalseClemastine fumarate accelerates accumulation of disability in progressive multiple sclerosis by enhancing pyroptosis.Multiple sclerosis (MS) is an immune-mediated demyelinating disease of the CNS. Clemastine fumarate, the over-the-counter antihistamine and muscarinic receptor blocker, has remyelinating potential in MS. A clemastine arm was added to an ongoing platform clinical trial, targeting residual activity by precision, biomarker-guided combination therapies of multiple sclerosis (TRAP-MS) (ClinicalTrials.gov NCT03109288), to identify a cerebrospinal fluid (CSF) remyelination signature and to collect safety data on clemastine in patients progressing independently of relapse activity (PIRA). The clemastine arm was stopped per protocol-defined criteria when 3 of 9 patients triggered individual safety stopping criteria. Clemastine-treated patients had significantly higher treatment-induced disability p2025-01-01T00:00:00Z2025 May2026-06-02T13:09:34.123Z2026-04-18T03:11:21.784ZS-EPMC120779084037164210.1172/JCI183941