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

Abstract

Immune checkpoint inhibitors (ICIs) are increasingly used and are becoming the standard of care in the treatment of various tumor types. Despite the favorable results in terms of oncological outcomes, these treatments have been associated with a variety of immune-related adverse events (irAEs). Neurological irAEs are rare but potentially severe. Neuromuscular disorders represent the most common neurological irAEs following anti-PD-1, anti-PD-L1, and anti-CTLA-4 treatment, and include myositis, myasthenia gravis, and demyelinating polyradiculoneuropathy. Instrumental findings may differ from typical neuromuscular disorders occurring outside ICIs treatment.Despite initial severity, neurological irAEs often respond to immune-modulating therapies. Prompt irAEs diagnosis, ICIs discontinuation, and early treatment with corticosteroids, together with patient education and a multi-disciplinary approach, are important for optimizing clinical outcomes. Intravenous immunoglobulin, plasma exchange, and other immune-modulating treatments should be considered in more severe cases. Consideration of re-challenging with the same immunotherapy drug may be given in some cases, based on clinical picture and initial severity of irAEs. K E Y W O R D SCTLA-4, demyelinating polyradiculoneuropathy, immune checkpoint inhibitor, myasthenia gravis, myositis, nivolumab, PD-1, PD-L1, pembrolizumab, peripheral neuropathy

Neurological immune‐related adverse events associated with immune checkpoint inhibitors: A review of the literature

“…The references of relevant articles were also screened. Because several systematic reviews of irAEs of neuromuscular diseases have recently been published, [11][12][13][14][15][16][17][18] we focused on irAEs affecting the central nervous system (CNS), with all case reports and case series of encephalitis, meningitis, and myelitis with sufficient information for the analysis included in this review.…”

Immune-Driven Pathogenesis of Neurotoxicity after Exposure of Cancer Patients to Immune Checkpoint Inhibitors

“…Data from anti-PD-1 monotherapy studies (3336 patients with nivolumab and 3301 patients with pembrolizumab) are in keeping with a greater incidence of myositis (2.6% for nivolumab and 1.07% for pembrolizumab) than of peripheral neuropathy (0.73% and 0.28%, respectively) [9]. Moreover, ICI combinations are also associated with a greater risk of myopathies than peripheral neuropathy manifestation [9]. Notably, a meta-analysis focusing on the severe toxic effects associated with ICIs found a significantly increased incidence of myositis, when anti-CTLA4 and anti-PD1 or PD-L1 were administered in combination [4].…”

Rituximab for Immune Checkpoint Inhibitor Myasthenia Gravis

“…14 There are a number of irAEs that have been associated with ICI use, including those that produce rare and di cult to diagnose and treat neurological conditions. [2][3][4][5][6][7][8][9][10] For example, multiple cases of MG associated with ICIs have been reported in the literature. 2,5,6 Guidelines for the treatment of ICI associated MG, include the use of pyridostigmine, corticosteroids, IVIG, and plasmapheresis.…”

“…1 However, several neurological immune-related adverse events (irAEs) have been associated with ICI use, including myasthenia gravis (MG) among other rare neurological syndromes. [2][3][4][5][6][7][8][9][10] These syndromes are rare and di cult to diagnose, and a full neurological evaluation should not be delayed. In addition,…”