Immune checkpoint inhibitors and myocarditis-myositis-myasthenia gravis overlap: a FAERS pharmacovigilance study with time-to-onset characterization.

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.