How we identify and treat neuromuscular toxicity induced by immune checkpoint inhibitors

Abstract

Immune-related neuromuscular adverse events are rare, but potentially life-threatening side-effects of immune checkpoint inhibitors (ICIs). They usually arise within the first 3 months after initiation of ICIs. Subacute symptom onset with more rapid progression than in idiopathic autoimmune neuromuscular diseases is typical. Prompt clinical diagnosis and treatment is essential for a favourable outcome. The importance of careful medical history and a well-established clinical diagnosis is emphasised rather than antibody detection or radiologic visualisation. Muscle weakness as a leading symptom can give rise to the suspicion of either neuropathy or myositis-myasthenia complex and differentiation may be complicated by their overlap. It is of utmost importance to recognise immune-related myositis and monitor for myocardial as well as bulbar involvement that may rapidly lead to cardiac or respiratory failure, persisting disability or even a fatal outcome. Symptoms typically improve with ICI discontinuation and early administration of glucocorticoids (prednisolone 1-2 mg/kg/day) in patients markedly affected. Severe and persisting symptoms including myocardial or bulbar affection can require therapy escalation to steroid-sparing agents. In patients with mild symptoms, not influencing functional abilities, careful clinical monitoring while staying on ICI therapy may be sufficient. Re-challenging with ICIs may be considered in selected cases, based on the initial severity of immune-related adverse events (irAEs) and clinical disease course. Depending on the individual irAE characteristics, the decision should be preferably discussed in an interdisciplinary irAE expert team with an experienced neurologist, rheumatologist and/or cardiologist and take the patient's preferences into account. The yet unmet need of systematic data on treatment, follow-up results and options of re-challenge of ICI treatment in neuromuscular toxicity has to be particularly considered in the shared decision-making process.

Keywords: immune checkpoint inhibitors; myasthenia gravis; myositis; neuromuscular toxicity; neuropathy.