Predictors of steroid-refractory immune checkpoint inhibitor associated myocarditis

Background/Introduction Immune checkpoint inhibitor (ICI)-associated myocarditis has a high mortality rate of approximately 50%. Clinical decompensation often occurs despite first-line treatment with corticosteroids. Factors associated with steroid failure are currently unknown. Purpose To identify predictors of steroid failure in patients with ICI-associated myocarditis. Methods We developed a web-based registry to collect and study 157 cases with clinical manifestations of ICI-associated myocarditis across 16 countries. Steroid failure was defined as patients who were escalated to immunomodulators after ≥1mg/kg daily dose of prednisone or had in-hospital death due to myocarditis despite ≥1mg/kg daily dose of prednisone. Steroid response was defined as all other patients treated with steroids without escalation to immunomodulators and without death due to myocarditis. A multivariate logistic model accounting for age and sex was used to predict association with steroid failure. Results Compared to steroid responsive cases, steroid failure was more likely to result in fulminant myocarditis (56.7% vs 19.6%, OR=5.37 [2.62–10.98] p<0.001) and all-cause in-hospital mortality (49.1% vs 12.9%, OR=6.50 [2.86–14.73] p<0.001) with shorter time from presentation to death (27.5 vs 43.0 days HR: 2.56 [1.45–4.50] p=0.001). When adjusting for age and sex, cases were more likely to be steroid-refractory if they were female (46.7% vs 30.1%, OR=2.77 [1.31–5.85] p=0.007), higher body mass index (27.2 vs 22.0, OR=1.09 [1.01–1.18] p=0.012), had higher intake creatine kinase (2800.5 vs 528.0 U/L, OR=1.48 [1.14–1.90] p=0.003) had higher intake troponin T (1.40 vs 0.25 ng/mL OR=1.63 [1.00–2.64] p=0.049), or had one or more concomitant non-cardiac immune-related adverse event (90.0% vs 74.2%, OR=3.10 [1.14–8.25] p<0.026). The only immune-related adverse events independently associated with steroid failure in myocarditis were myasthenia gravis-like syndrome (26.7% vs 8.2%, OR=3.84 [1.47–10.10] p=0.006) and myositis (45.0% vs 24.7%, OR=2.38 [1.16–4.92] p=0.018). Steroid failure was not significantly associated with cardiovascular or autoimmune history but was associated with a history of thymoma (12.0% vs 2.6%, OR=18.86 [0.10–356.7] p=0.05) Conclusion(s) Features such as female sex, high body mass index, and pre-existing thymoma as well as findings of elevated cardiac biomarkers and other non-cardiac immune-related adverse events – particularly myositis and myasthenia gravis-like syndrome – may represent a steroid-refractory phenotype of ICI-associated myocarditis. These results suggest that a multidisciplinary approach to diagnosing concomitant non-cardiac immune related adverse events is key to risk-stratifying ICI-associated myocarditis. Forrest Plot Funding Acknowledgement Type of funding source: Private hospital(s). Main funding source(s): National Institutes of Health