Immune checkpoint inhibitor-associated myopathy: a clinicoseropathologically distinct myopathy

Abstract Immune checkpoint inhibitors have revolutionized the landscape of cancer treatment. Alongside their many advantages, they elicit immune-related adverse events, including myopathy, which potentially result in substantial morbidity if not recognized and treated promptly. Current knowledge of immune checkpoint inhibitor-associated myopathy is limited. We conducted a 5-year retrospective study of patients with immune checkpoint inhibitor-associated myopathy. Clinical features, survival and ancillary test findings were analysed and compared with those of immune-mediated necrotizing myopathy patients without immune checkpoint inhibitor exposure seen during the same time period. We identified 24 patients with immune checkpoint inhibitor-associated myopathy (median age 69 years; range 28–86) and 38 patients with immune-mediated necrotizing myopathy. Ocular involvement occurred in 9/24 patients with immune checkpoint inhibitor exposure, without electrodiagnostic evidence of neuromuscular transmission defect, and in none of the immune-mediated necrotizing myopathy patients (P < 0.001). Myocarditis occurred in eight immune checkpoint inhibitor-associated myopathy patients and in none of the immune-mediated necrotizing myopathy patients (P < 0.001). Median creatine kinase was 686 IU/l in the immune checkpoint inhibitor cohort (seven with normal creatine kinase) compared to 6456 IU/l in immune-mediated necrotizing myopathy cohort (P < 0.001). Lymphopenia was observed in 18 and 7 patients with and without immune checkpoint inhibitor exposure, respectively (P < 0.001). Myopathological findings were similar between patients with and without immune checkpoint inhibitor exposure, consisting of necrotic fibres with no or subtle inflammation. Necrotic fibres however arranged in clusters in 10/11 immune checkpoint inhibitor-associated myopathy patients but in none of the immune checkpoint inhibitor-naïve patients (P < 0.001). Despite the lower creatine kinase levels in immune checkpoint inhibitor-exposed patients, the number of necrotic fibres was similar in both groups. Immune checkpoint inhibitor-associated myopathy patients had a higher frequency of mitochondrial abnormalities and less number of regenerating fibres than immune-mediated necrotizing myopathy patients (P < 0.001). Anti-hydroxy-3-methylglutaryl-CoA reductase or signal recognition particle antibodies were absent in patients with immune checkpoint inhibitor exposure but positive in two-thirds of immune checkpoint inhibitor-naïve patients. Most patients with immune checkpoint inhibitor-associated myopathy responded favourably to immunomodulatory treatments, but four died from myopathy-related complications and one from myocarditis. Intubated patients had significantly shorter survival compared to non-intubated patients (median survival of 22 days; P = 0.004). In summary, immune checkpoint inhibitor-associated myopathy is a distinct, treatable immune-mediated myopathy with common ocular involvement, frequent lymphopenia and necrotizing histopathology, which contrary to immune-mediated necrotizing myopathy, is featured by clusters of necrotic fibres and not accompanied by anti-hydroxy-3-methylglutaryl-CoA reductase or signal recognition particle antibodies. Normal or mildly elevated creatine kinase level does not exclude the diagnosis.