Neuromuscular adverse events associated with anti-PD-1 monoclonal antibodies

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.

Immune checkpoint inhibitors‐induced neuromuscular toxicity: From pathogenesis to treatment

“…In a recent systematic review of 86 patients with metastatic melanoma (n = 51) or NSCLC (n = 15) treated with nivolumab or pembrolizumab, whether or not in combination with ipilimumab, 20 patients (23%) were diagnosed with demyelinating polyradiculoneuropathy . Patients commonly present with acute or subacute sensory motor symptoms and cranial nerve involvement with bulbar symptoms and dyspnea. Chronic evolution has been reported rarely eventually following an initial acute presentation .…”

“…Patients commonly present with acute or subacute sensory motor symptoms and cranial nerve involvement with bulbar symptoms and dyspnea. Chronic evolution has been reported rarely eventually following an initial acute presentation . Cerebrospinal fluid (CSF) analysis commonly shows albumino‐cytologic dissociation, possibly associated with mild lymphocytic pleocytosis (10‐15 cells/mm 3 ) .…”

Severe Neurological Toxicity of Immune Checkpoint Inhibitors: Growing Spectrum

“…However, these reports have generally been limited to single malignancies (melanoma) and/or ICI class (anti–PD‐1 antibodies) . Other studies have reported clinical presentation of MG among patients treated with either nivolumab or ipilimumab monotherapy utilizing pharmaceutical company postmarketing surveillance databases . Because irAE‐N may present atypically with overlapping neurological manifestations and cancer, mortality and quality of life outcomes of currently recommended treatments are unknown; comprehensive phenotypic characterization and additional real‐world outcome data with longitudinal follow‐up are needed.…”

Diaphragm involvement in immune checkpoint inhibitor‐related myositis

“…However, multiple factors may contribute to respiratory deterioration, especially severe diaphragm involvement . The latest systematic review of neuromuscular adverse events associated with ICIs revealed that respiratory involvement is frequent (43%), and mortality is high . We describe here a patient with an irAE with persistent damage to the diaphragm muscle that was proven by electrophysiological and ultrasound (US) examination.…”

“…2,3 The latest systematic review of neuromuscular adverse events associated with ICIs revealed that respiratory involvement is frequent (43%), and mortality is high. 4 We describe here a patient with an irAE with persistent damage to the diaphragm muscle that was proven by electrophysiological and ultrasound (US) examination. After treatment with pulsed methylprednisolone injection (1 g for 3 days) and intravenous immunoglobulin (0.4 g/kg for 5 days) with subsequent oral corticosteroids (60 mg daily), the limb muscle weakness recovered but respiratory function did not.…”