Neuroimmune Toxicity Phenotypes of Immune Checkpoint Inhibitors: Real-World Characterization of Myositis, Myocarditis, Myasthenia Gravis and Their Overlap From FAERS
Nazan Demir, Buğra Han Esen, Bahadır Köylü, İlteriş Cevat Kıkılı, Fatih Kemik, Didem Tunalı, Deniz Tural, Şahin Laçin, Şeyda Gündüz, Fatih SelçukbiricikIntroductıon:
Immune Checkpoint Inhibitors (ICIs) can cause rare but potentially fatal immune-related Adverse Events (irAEs) involving myocarditis, myositis, and Myasthenia Gravis (MG), toxicities with direct neuromuscular and cardiac pharmacological consequences. The burden and outcomes of overlap phenotypes in real-world reports remain incompletely characterized.
Methods:
We analyzed FAERS (January 2015-September 2025) cancer reports listing at least one ICI as a suspect drug. MedDRA preferred terms identified were ir-myocarditis, ir-myositis, and ir-MG; reports were classified as isolated or overlap (≥ 2 concurrent phenotypes, including Triple M Overlap Syndrome -TMOS). We summarized serious outcomes and time-to-onset.
Results:
Among 187,347 ICI-associated reports, we identified 3,127 ir-myocarditis, 2,130 ir-myositis, and 1,331 ir-MG cases; 5,142 contained at least one irAE, and 1,151 (22.38%) were overlap. Mortality was highest in ir-myocarditis+ir-MG (43.11%) and TMOS (40.00%); TMOS had frequent life-threatening outcomes (47.46%). Median onset was shorter for overlap (20-22 days) than isolated phenotypes (28-31 days). The anti-PD-1 plus anti-LAG-3 combination had the highest reporting odds of all three irAEs and overlap syndrome.
Discussion:
In these spontaneous reports, ICI-associated neuromuscular and cardiac overlap was characterised by early onset and high reported mortality. The frequent co-reporting and the poor outcomes recorded in TMOS are compatible with shared immunopathological mechanisms across striated muscle and the neuromuscular junction, although this hypothesis cannot be tested in FAERS.
Conclusion:
Overlap neuromuscular-cardiac irAEs in FAERS were associated with substantial early mortality and typically occurred within the first 1-2 treatment cycles. Early, low-threshold multidisciplinary evaluation may improve timely recognition. The nivolumab-relatlimab signal warrants dedicated neuromuscular monitoring in patients receiving LAG-3/PD-1 co-blockade.