Abstract
Neuromuscular adverse events following cancer treatment with anti-programmed cell death protein 1 (PD-1) monoclonal antibodies are relatively rare, yet potentially fatal. We performed a systematic review to characterize the clinical presentation, diagnostic workup, and management of neuromuscular disorders (NMDs) in patients treated with nivolumab or pembrolizumab monotherapy or concurrent with other immunologic agents, such as ipilimumab. Sixty-one publications on 85 patients (mean age 66.9 years [range 34-86]; male/female 2.6:1; 59% metastatic melanoma) were identified from selected indexing databases until June 2018. Forty-eight patients had received nivolumab and 39 pembrolizumab. The mean number of PD-1 inhibitor treatment cycles prior to onset of symptoms was 3.6 (range 1-28). Symptoms included oculomotor (47%), respiratory (43%), bulbar (35%), and proximal weakness (35%), as well as muscle pain (28%). Diagnoses were categorized as myasthenia gravis (27%), neuropathy (23%), myopathy (34%), or a combination of these (16%). After a critical review of the data, however, evidence did not support the stated NMD diagnosis in 13% of cases, while up to 25% of patients had signs of additional NMDs. Cardiac complications occurred in more than 30% of patients diagnosed with myasthenia gravis or myositis. Mortality was high in these patients, despite adequate treatment strategies including corticosteroid, IV immunoglobulins, and plasma exchange. The clinical presentation of NMDs associated with PD-1 inhibitors is often atypical, with considerable overlap between myasthenia gravis and myopathy, and cardiac/respiratory complications are common.
Highlights
Neurological adverse events following cancer treatment with immune checkpoint inhibitor antibodies are relatively rare, yet potentially fatal complications[1,2,3]
In patients treated with an anti-PD-1 monoclonal antibody for disseminated cancer or melanoma, who develop neuromuscular symptoms or who have pre-existing neuromuscular symptoms that become more pronounced following anti-PD-1 monoclonal antibody therapy (P), do neurological examination and laboratory workup, including neurophysiology and antibody titers, (I) sufficiently discriminate between neuropathies and myopathies, including myositis, on one hand (C) and neuromuscular junction failure compatible with myasthenia gravis on the other (O)?
Our aim was to investigate whether patients with neuromuscular symptoms after nivolumab or pembrolizumab treatment could meaningfully be classified into conventional diagnostic groups, i.e. NMJ/myasthenia gravis, myopathy and neuropathy
Summary
Neurological adverse events following cancer treatment with immune checkpoint inhibitor antibodies are relatively rare, yet potentially fatal complications[1,2,3]. Two human IgG4 anti-Programmed cell death protein 1 (PD-1) monoclonal antibodies, were approved for treatment of unresectable melanoma by the US Food and Drug Administration[4] in 2014 and by the European Medicines Agency in 20155,6. Both drugs have since been approved for treatment of other types of cancer, including non-small cell lung cancer. We performed a systematic review to characterize the symptoms, clinical findings and laboratory results of presumed anti-PD-1 monoclonal antibody treatment associated neuromuscular disease, focusing on how to distinguish these adverse events and we provide a case description for illustration (Box 1)
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