| アブストラクト | BACKGROUND: Immune checkpoint inhibitors (ICIs) are associated with rare but life-threatening immune-related adverse events. Myocarditis-myositis-myasthenia gravis (MMM) overlap is among the most severe neuromuscular-cardiac toxicity patterns, but population-scale data on disproportionality, reported death outcomes, and time-to-onset (TTO) remain limited. METHODS: We conducted a retrospective pharmacovigilance study using the FDA Adverse Event Reporting System (FAERS) from 2015Q1 to 2025Q4. Strict MMM overlap was defined at the report level by co-reporting of the Preferred Terms "myocarditis," "myositis," and "myasthenia gravis". ICI exposure was restricted to selected PD-1, PD-L1, and CTLA-4 inhibitors recorded as primary or secondary suspect drugs (PS/SS), with a prespecified sensitivity analysis restricted to PS reports only. Disproportionality was assessed primarily using reporting odds ratios (RORs) with Haldane-Anscombe correction for sparse cells; the Information Component (IC) and IC025 were calculated as complementary Bayesian metrics. Drug-level TTO was estimated by linking therapy start dates and event dates within eligible reports. RESULTS: Among 15,187,311 deduplicated FAERS reports, 151 met the strict MMM overlap definition, including 131 ICI-exposed reports. ICI exposure showed a strong disproportionality signal for strict MMM overlap (ROR 397.29, 95% CI 249.44-632.76; IC 5.50, IC025 5.24). Reported death outcomes were observed in 49/131 (37.4%) ICI-exposed MMM overlap reports, including 31/80 (38.8%) in PD-1 reports, 5/16 (31.3%) in PD-L1 reports, and 13/35 (37.1%) in combination ICI reports. Drug-level TTO was available for 53 ICI-exposed reports, with a median of 25 days (IQR 18-38); restricting to TTO </=365 days yielded a similar median of 24 days (IQR 18-37), supporting a predominantly early-onset pattern. Sensitivity analyses restricted to PS were directionally consistent. CONCLUSION: In FAERS, ICI-associated strict MMM overlap showed a strong disproportionality signal and predominantly early reported onset; reported death outcomes were also observed in a substantial proportion of ICI-exposed overlap reports. These findings support heightened clinical vigilance for cardio-neuromuscular overlap toxicity, particularly during the first months after ICI initiation. |
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| 投稿者 | Pacaci, Burak; Yildirim, Bilal; Tunc, Mustafa Alperen; Demirel, Ahmet; Akagunduz, Firat; Kocaaslan, Erkam; Guren, Ali Kaan; Demircan, Nazim Can; Bayoglu, Ibrahim Vedat |
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