Myasthenia gravis, myositis, myocarditis and anti-titin antibodies after Nivolumab/Ipilimumab: response with plasmapheresis

Context: Severe neurological manifestations following use of immune checkpoint inhibitors (ICIs) occur in 0.93% of patients, and together with cardiac toxicity have the higher lethality. Myasthenia gravis (MG) and polymyositis (PM) are rare, and treatment includes discontinuation of the immunotherapy, corticosteroids, and intravenous immunoglobulin (IVIG), with occasional use of plasmapheresis (PLEX). Biomarkers are not consistently reported. We report the case of a patient with MG, PM and myocarditis after ICI, with positive anti-titin antibodies and response to plasmapheresis. Case report: 81-year-old male developed ascending, subacute, progressive tetraparesis, dysphagia, ophthalmoparesis, and respiratory failure 2 weeks after second cycle of nivolumab/ipilimumab for metastatic melanoma. Physical examination showed: globally reduced strength, hypoactive reflexes, bilateral sixth nerve palsy and bilateral semi-ptosis. Prostigmine test was positive and electroneuromyography was compatible with myopathy. Labs revealed CPK 4000 U/L, troponin 9000U/L, autoimmune myositis panel negative, anti-titin antibodies (described in paraneoplastic MG and associated with severity) positive and cardiac MRI without fibrosis. Clinical picture was compatible with MG and PM with cardiac involvement. He received methylprednisolone and six PLEX sessions, with complete recovery. Four months after treatment, he developed cognitive impairment and large B-cell lymphoma (ICI complication). Conclusions: PM and MG may occur after ICI, especially in the first cycles, and anti-titin may be a biomarker of severity in these patients. Although guidelines recommend adding IVIG or PLEX in refractory or severe cases, PLEX may be first choice, especially if multiple ICI are present.

Inflammatory myopathy with myasthenia gravis

ObjectiveTo provide evidence that idiopathic inflammatory myopathy (IM) with myasthenia gravis (MG) frequently shows thymoma association and polymyositis (PM) pathology and shares clinicopathologic characteristics with IM induced by immune checkpoint inhibitors (ICIs).MethodsWe analyzed the clinicopathologic features of 10 patients with idiopathic IM and MG identified in 970 consecutive patients with biopsy-proven IM.ResultsSeven patients (70%) had thymoma. IM and MG were diagnosed with more than 5-year time difference in 6 thymomatous patients and within 1 year in 1 thymomatous and 3 nonthymomatous patients. Seven thymomatous patients showed rhabdomyolysis-like features with respiratory failure (4/7), dropped head (3/7), cardiac involvement (2/7), and positive anti–acetylcholine receptor (anti-AChR) and anti-titin antibodies (7/7 and 4/6, respectively) but rarely showed ocular symptoms (2/7) or decremental repetitive nerve stimulation (RNS) responses (1/7) at IM diagnosis. Three nonthymomatous patients showed acute cardiorespiratory failure with rhabdomyolysis-like features (1/3), positive anti-AChR and anti-titin antibodies (3/2 and 2/2, respectively), and fluctuating weakness of the skeletal muscle without ocular symptoms (3/3). Muscle pathology showed a PM pathology with infiltration of CD8-positive CD45RA-negative T-lymphocytes (9/9), scattered endomysial programmed cell death 1 (PD-1)–positive cells (9/9), and overexpression of programmed cell death ligand 1 (PD-L1) on the sarcolemma of muscle fibers around the infiltrating PD-1–positive cells (7/9).ConclusionRhabdomyolysis-like features, positive anti-AChR antibody without decremental RNS responses, and PD-L1 overexpression are possible characteristics shared by ICI-induced IM. Frequent thymoma association in patients with idiopathic IM and MG may suggest thymoma-related immunopathogenic mechanisms, including dysregulation of the immune checkpoint pathway.