Clemastine fumarate accelerates accumulation of disability in progressive multiple sclerosis by enhancing pyroptosis
Abstract
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 progression slopes compared with the remaining TRAP-MS participants. Quantification of approximately 7,000 proteins in CSF samples collected before and after clemastine treatment showed significant increases in purinergic signaling and pyroptosis. Mechanistic studies showed that clemastine with sublytic doses of extracellular adenosine triphosphate (ATP) activates inflammasome and induces pyroptotic cell death in macrophages. Clemastine with ATP also caused pyroptosis of induced pluripotent stem cell-derived human oligodendrocytes. Antagonist of the purinergic channel P2RX7, which is strongly expressed in oligodendrocytes and myeloid cells, blocked these toxic effects of clemastine. Finally,…
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Evidence Hub reads this as a clinical trial, done in people. Its evidence level is 3 of 5 (Moderate · trial / cohort / secondary analysis). Trials without a large randomized design, cohorts and secondary analyses give moderate evidence.
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