Immune checkpoint inhibitor-related myositis, myocarditis, and myasthenia gravis overlap syndrome: a systematic review and pooled analysis of individual cases.

Background: Immune checkpoint inhibitor (ICI)-related overlap syndrome involving myositis, myocarditis, and myasthenia gravis (3M overlap syndrome) is rare but potentially fatal. Current evidence is derived mainly from case reports and small case series, and individual case-level data on ancillary diagnostic findings, baseline comorbidities, treatment patterns, and short-term outcomes remain limited. Methods: We performed a systematic review of published case reports and case series and a pooled analysis of individual case data on ICI-related 3M overlap syndrome, supplemented by three patients from our center. The primary endpoint was all-cause in-hospital mortality. Univariable and multivariable logistic regression were used to explore factors associated with in-hospital mortality, and exploratory symptom correlation and hierarchical clustering analyses were performed to describe symptom co-occurrence patterns. Results: Ninety-five published reports comprising 133 patients were included, together with 3 additional institutional cases, for a total of 136 patients. The mean age was 69.8 ± 11.2 years, and 96/136 (70.6%) were male. Melanoma was the most common underlying malignancy (40/136, 29.4%). The median time from first ICI exposure to symptom onset was 22.0 days (IQR, 16.0-31.0).In-hospital outcome was ascertainable for all 136 patients; 53 (39.0%) died during hospitalization and 83 (61.0%) survived to discharge or transfer. Most patients received systemic corticosteroids (133/136, 97.8%) and second-line immunomodulatory therapy (119/136, 87.5%). In the pre-specified multivariable analysis (age, fatigue, and complete conduction block), older age (adjusted odds ratio [aOR], 1.11 per year; 95% confidence interval [CI], 1.05-1.17; P < 0.001) and complete conduction block (aOR, 2.84; 95% CI, 1.10-7.34; P = 0.031) remained independently associated with in-hospital mortality, whereas fatigue was no longer statistically significant after adjustment (aOR, 1.85; 95% CI, 0.75-4.56; P = 0.181). Exploratory clustering identified a possible bulbar/axial symptom cluster characterized by dysphagia, dysarthria, and neck muscle weakness. Conclusions: ICI-related 3M overlap syndrome is an early-onset, fulminant immune-related adverse event with substantial in-hospital mortality. Older age and complete conduction block were factors associated with poorer in-hospital outcomes in this exploratory analysis; these findings should be regarded as hypothesis-generating and require validation in prospective registries or multicenter cohorts.