| アブストラクト | BACKGROUND: Disease reactivation following cessation of sphingosine 1-phosphate receptor modulators (S1PRM) occurs in ~ 10% of multiple sclerosis (MS) patients. The biological factors underlying this phenomenon remain incompletely understood, including the potential contribution of sex-specific differences. METHODS: We performed a systematic review on published literature and adverse event registries (FAERS, EudraVigilance), as of January 2024, focusing exclusively on fingolimod (FTY) withdrawal in individuals with MS. Disease severity after FTY withdrawal was assessed in the experimental autoimmune encephalomyelitis (EAE) mouse model, using untreated EAE mice as controls. S1P receptor expression was analyzed by immunofluorescence in spinal cord tissue from EAE mice and in brain biopsies from MS patients with disease reactivation after FTY withdrawal and MS controls (no prior FTY or S1PRM treatment). RESULTS: Analysis of eight studies (n = 2579) demonstrated an association between female sex and disease reactivation after FTY cessation (odds ratios: 1.09-7.20), corroborated by pharmacovigilance data (FAERS: OR = 2.00, p < 0.0001; EudraVigilance: OR = 2.42, p < 0.0001). Female EAE mice exhibited greater post-FTY treatment disease severity (2.5-fold increase, p < 0.0001) with increased S1PR1 expression on CD3(+)T cells (p < 0.001). Human brain biopsies showed elevated S1PR1 expression on CD3(+)T cells in active demyelinating lesions during disease reactivation compared to inactive demyelinated lesions (p < 0.0001) and controls (p < 0.05). DISCUSSION: Across clinical, experimental, and neuropathological analyses, female sex was associated with more pronounced disease activity following FTY withdrawal. Increased S1PR1 expression in T cells represents a potential cellular correlate of this sex-associated vulnerability and warrants further mechanistic investigation. |
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| ジャーナル名 | Acta neuropathologica communications |
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| Pubmed追加日 | 2026/6/18 |
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| 投稿者 | Massy, Marine; Marti, Stefanie; Kutllovci, Adriane; Frahm, Niklas; Fneish, Firas; Ellenberger, David; Hammer, Helly; Chan, Andrew; Leichtle, Alexander; Luhder, Fred; Metz, Imke; Pistor, Maximilian; Hoepner, Robert |
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| 組織名 | Department of Neurology, Inselspital, Bern University Hospital and University of;Bern, Freiburgstrasse 16, 3010, Bern, Switzerland.;Graduate School for Cellular and Biomedical Sciences, University of Bern, Bern,;Switzerland.;Institute of Neuropathology, University Medical Center Gottingen, Gottingen,;Germany.;German MS Register, MS Forschungs- Und Projektentwicklungs-gGmbH (MS Research and;Project Development gGmbH (MSFP)), Hannover, Germany.;Laboratory Medicine, Cantonal Hospital Baden, Baden, Switzerland.;Center for Artificial Intelligence in Medicine, University of Bern, Bern,;Institute for Neuroimmunology and Multiple Sclerosis Research, University Medical;Center Gottingen, Gottingen, Germany.;Bern, Freiburgstrasse 16, 3010, Bern, Switzerland. robert.hoepner@insel.ch. |
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| Pubmed リンク | https://www.ncbi.nlm.nih.gov/pubmed/42310690/ |
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