Immune Checkpoint Inhibition-Related Myasthenia-Myositis-Myocarditis Responsive to Complement Blockade

Abstract

Objective: Immune checkpoint inhibitors (ICIs) have revolutionized cancer therapy but come with immune-related adverse events (irAEs) that provide a novel challenge for treating physicians. Neuromuscular irAEs, including myositis, myasthenia gravis (MG), and demyelinating polyradiculoneuropathy, lead to significant morbidity and mortality.

Methods: We present a case of severe myasthenia-myositis-myocarditis overlap in a patient receiving ICIs for breast cancer. Clinical findings were recorded.

Results: A 47-year-old woman developed tetraparesis, dysphagia, and muscle pain during ICI treatment. MG with a thymoma had been diagnosed earlier. Neuromuscular overlap irAEs with cardiac affection was confirmed, and ICI treatment was discontinued. Given a lack of clinical response to standard therapies, a muscle biopsy was performed demonstrating complement deposition. Eculizumab treatment led to rapid improvement in muscle strength and cardiac function.

Discussion: Neuromuscular irAEs are associated with a high in-hospital mortality, and specific treatment strategies remain an unmet need. Here, early muscle biopsy enabled targeted therapy after standard approaches failed, thereby highlighting the value of identifying a specific treatment target. To improve therapeutic outcomes, the development of patient-tailored strategies for neuromuscular irAEs requires further studies.

Figure. Clinical Findings and Course of Disease

(A) Timeline of preceding events, in-hospital stay and follow-up. (B) Quantitative myasthenia gravis (QMG) score, creatine kinase (CK), and troponin levels during the course of disease. (C) MRI of the lower thigh demonstrating myositis of the gastrocnemius muscle on both sides 2 weeks after admission (left) and 7 weeks after admission (right). T2 sequences with contrast are shown. (D) Hematoxylin and eosin (H&E) stain (left) demonstrating necrotizing myopathy with scattered necrotic and regenerating fibers and numerous capillaries with thickened vessel walls. Immunohistochemistry staining for CD8 (middle). Sparse CD8 positive cells are seen in the vicinity of damaged muscle fibers. Immunohistochemistry staining for C5b-9 (right) displaying complement deposition on scattered muscle fibers and capillaries (marked by black arrows in inlet). 20× magnification was used for image acquisition. (E) Cardiac MRI 4 weeks after admission demonstrating pericardial effusion (a) and substantial edema (b) as signs of myocarditis. T2 sequences are shown (left) and quantification of water content (right; water is indicated in red, healthy tissue in green). (F) Follow-up cardiac MRI 4 months after discharge demonstrating no myocarditis (c) but pericardial effusion (a) and signs of cancer therapy–related cardiac dysfunction with myocardial fibrosis (d). T2 sequences are shown (left) and quantification of water content (middle; water is indicated in red, healthy tissue in green). Furthermore, T2 late gadolinium enhancement is depicted (right).