Immune checkpoint inhibitor-associated myasthenia gravis, myositis, and myocarditis overlap syndrome

Abstract 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

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Immune Checkpoint Inhibitor-Induced Polymyositis and Myasthenia Gravis with Fatal Outcome

Case Reports in Oncology ◽

10.1159/000510740 ◽

2020 ◽

Vol 13 (3) ◽

pp. 1252-1257

Author(s):

Daniel Giglio ◽

Henrik Berntsson ◽

Åsa Fred ◽

Lars Ny

Keyword(s):

Myasthenia Gravis ◽

Immune Checkpoint ◽

Immune Checkpoint Inhibitor ◽

Checkpoint Inhibitor ◽

Fatal Outcome ◽

Hepatocellular Cancer ◽

Serum Levels ◽

Intravenous Immunoglobulins ◽

Microscopical Examination ◽

Inflammatory Infiltration

We here report on a 74-year-old man diagnosed with a pT3cN0 <i>BRAF</i>-mutated and mismatch repair-deficient adenocarcinoma in the colon ascendens and 3 liver metastases. After hemicolectomy, the patient received treatment with the PD-1 inhibitor pembrolizumab. Three weeks later (on day 22), laboratory tests showed leukocytosis and an increase in transaminases; immune checkpoint inhibitor (ICI)-induced hepatitis was suspected and prednisolone therapy was initiated. On day 29, the patient was acutely hospitalized due to dyspnea, somnolence and walking difficulties. Dysarthria, hoarseness, muscle pain and weakness had developed and the dose of prednisolone was increased. Serum levels of lactate dehydrogenase, creatine kinase and myoglobin were increased and ICI-induced myositis was suspected. Antibodies against acetylcholine receptor and titin were present, indicating myasthenia gravis. Eventually, bulbar myopathy developed, including dysarthria and dysphagia, and the patient could no longer attain saturation without oxygen. The patient was transferred to the intensive care unit, intubated and given methylprednisolone, intravenous immunoglobulins and infliximab. The patient developed carbon dioxide retention and died on day 39. Microscopical examination of the intercostal musculature, diaphragm, cervical musculature and tongue showed inflammatory infiltration and fibrosis consistent with a pronounced myositis. In the liver, microscopical examination did not show metastases from colorectal cancer but instead a hepatocellular cancer. The cause of death was determined as respiratory insufficiency due to polymyositis. In conclusion, ICIs may induce myositis combined with neurological immune-related adverse events. In patients developing muscle weakness and pain under ICI therapy, myositis should be suspected.

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