Background/Purpose: Immune checkpoint inhibitor (ICI)-related adverse events (irAE) recently emerged as new diseases in the field of auto-immunity. Among them, ICI-related myotoxicity has the highest fatality rate and is the second most frequent musculosketal irAE. Ir-myositis differs from its idiopathic counterpart by frequent oculomotor and bulbar symptoms as well as respiratory dysfunction. In addition, the presence of acetylcholine receptor antibodies (AchR Abs) in a subset of patients may suggest concurrent neuromuscular junction disorder. A comprehensive understanding of disease pathology underlying overlapping features of ir-myositis and ir-myasthenia gravis (MG) remains elusive, complicating disease stratification and management. Our study aimed to clarify the ir-myositis pathophysiology.

Methods: An observational, monocentric cohort study was conducted. Inclusion criteria were history of malignancy, ICI exposure, pathologically confirmed myositis, available AchR antibody testing and repetitive nerve stimulation, and absence of dermatomyositis skin rash. Post-mortem histopathology of the orbital muscles and diaphragm was examined in one and three patients, respectively.

Results: Twenty-two patients were enrolled. Median age was 71 [IQR 62-79] years; 14 patients (64%) were male. Two patients reported history of autoimmune disease. Lung (n=9/22), skin (n=3/22) and kidney (n=3/22) cancers were the most frequent indications for ICI therapy. Patients received anti-PD1 or anti-PDL1 monotherapy (77%; n=17/22) or combination therapy (23%; anti-LAG-3, n=1/22 and anti-CTLA4, n=4/22). Time to symptom onset was 25 [19-43] days. Clinical manifestations included proximal and axial muscle weakness (86%; n=19/22) and myalgia (63%; n=14/22). CK level was 3467 [1836-7659] U/L.
Additionally, patients frequently displayed diplopia and/or ptosis (45%; n=10/22) and dysphagia (53%; n=12/22). Respiratory failure requiring ventilatory assistance (invasive or non invasive) occured in a third of cases.

AchR Abs were detected at diagnosis in three patients (14%). We examined serum obtained prior to ICI exposure for presence of antibodies and retrieved positive results in all three cases. Electromyography showed a myopathic pattern in 13 patients (57%), whereas decrement on repetitive nerve stimulation was never observed.
Intensive care unit admission was required in 20 cases (91%). At follow-up (87 [36-255] days), mortality was 50%; death was related directly to myotoxicity in three patients (14%).
Post-mortem examination revealed muscle inflammation of both the oculomotor muscles and diaphragm.

Conclusion: Neuromuscular (oculomotor, bulbar and respiratory) signs typically observed in MG are frequent in ir-myositis and AchR Abs pre-exist in 14% of patients. In our cohort, based on electromyographic analysis, no evidence supports that the neuromuscular signs were related to a neuromuscular junction disorder. Necropsy findings may suggest that muscle inflammation underlies both oculomotor and respiratory dysfunction in ir-myositis patients. AchR Abs could be a biomarker of disease, however their pathogenic role is unclear.

« Back to ACR Convergence 2021

ACR Meeting Abstracts - https://acrabstracts.org/abstract/immune-checkpoint-inhibitor-related-myotoxicity-musculoskeletal-and-or-neuromuscular-junction-disorder/