| アブストラクト | BACKGROUND: Multiple sclerosis (MS) disease-modifying therapies (DMTs) alter host immunity and may produce pathogen-specific susceptibility to neuroinvasive infection. Comparative evidence is limited because events are rare and postmarketing research focuses mainly on progressive multifocal leukoencephalopathy (PML). METHODS: We analyzed deduplicated US FDA Adverse Event Reporting System (FAERS) reports from 2004Q1 to 2025Q4 using a prespecified case-non-case design. Tier A comprised direct high-certainty non-PML neuroinvasive infection terms. Tier B comprised a possible CNS infectious syndrome plus pathogen evidence elsewhere in the report, without CNS confirmation; tier A+B was a lower-certainty expanded endpoint for sensitivity and pathogen composition analyses. We estimated overall reporting (E1), pathogen composition within tier A+B (E2), and same-pathogen CNS localization (E3). Five DMT mechanisms were compared with contemporaneous active DMTs using calendar-year Mantel-Haenszel reporting odds ratios and covariate-adjusted Jeffreys-prior penalized logistic models. RESULTS: Among 492,514 reports, 675 were tier A and 82 additional reports were tier B. Tier A aRORs (95% CIs) were 0.82 (0.63-1.05) for anti-CD20 therapies, 1.77 (1.44-2.16) for S1P modulators, 1.32 (1.06-1.64) for natalizumab, 3.28 (2.24-4.66) for alemtuzumab, and 0.56 (0.21-1.19) for cladribine. Fingolimod accounted for 145 of 152 S1P cases and had an aROR of 2.15 (1.75-2.64). Among four mechanisms eligible for E2, pathogen composition differed (LRT 210.59, 9 df; bootstrap P = 9.99 x 10(-4)): viral reports were enriched with anti-CD20 therapies (OR 4.24, 2.56-7.02) and natalizumab (2.03, 1.26-3.26), fungal reports with S1P modulators (29.09, 15.77-53.64), and bacterial reports with alemtuzumab (4.99, 2.27-11.01). Only natalizumab-HSV/VZV met the adjusted E3 gate and showed CNS enrichment (aROR 2.80, 1.80-4.38; Holm-adjusted P = 5.81 x 10(-6)). CONCLUSIONS: E1 contrasts were interpreted as separate reporting comparisons, not a formal equality test across mechanisms. S1P reporting was largely fingolimod-driven, and natalizumab-HSV/VZV was the only prespecified pair with adjusted same-pathogen CNS enrichment. Findings support targeted vigilance and confirmatory studies but do not estimate incidence or establish causality. |
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