Muscular disorder related to immune checkpoint inhibitors: forewarned is forearmed

We would like to bring to the attention of the medical community the emergence of a serious acquired muscular disorder arising from immune checkpoint inhibitors (ICIs) that are now widely used in anticancer treatment. This is of particular interest to neurologists and oncologists, as they will have a pivotal role in the management of such cases.

In the past decade, better understanding of cancer immunosurveillance escape mechanisms has led to the identification of new therapeutic targets (eg, programmed cell death protein 1, cytotoxic T lymphocyte antigen 4), and later to the development of new drugs (eg, nivolumab, ipilimumab). This has dramatically improved the prognosis for numerous cancers, and these drugs are now considered as supplementary or alternatives to conventional cancer treatment.¹ Owing to their mechanisms of action, these drugs cause potentially serious autoimmune adverse events (mainly dermatological, gastrointestinal, and endocrine).^2,3 Ipilimumab was the first ICI extensively used, mainly in melanoma, and has been responsible for emergence of atypical neurological complications.⁴ In the past 2 years, nivolumab has been approved for an increasing number of cancers and is currently undergoing clinical trial in neuro-oncology. With this increased use, a limited but increasing number of ICI-related myositis cases have been reported,⁵ some of which were associated with myasthenia gravis, as well as fatal myocarditis.⁶ In addition, 3 cases of ICI-related muscular disorder have been recently diagnosed in the Lyon university hospitals (2 women/1 man, ages 65, 68, and 79 y). All cases had pulmonary adenocarcinoma with lymph node metastasis (stage IIIa–b), and were initially treated by surgery with adjuvant chemotherapy (pemetrexed and carboplatin). After tumor escape, patients received nivolumab monotherapy with partial remission and stable disease for a period of time (6, 14, and 16 mo). No patient had radiotherapy. Muscular symptoms developed after the first, second, and seventeenth injections of nivolumab; the interval between last administration and symptoms was short (7, 16, 15 d). Patients had initially moderate bilateral proximal weakness, rapidly progressing to severe (dysphagia and dyspnea, n = 2/3). Several atypical elements were present: severe myocarditis (28% initial ventricular ejection fraction, n = 1/3), and myastheniform symptoms (ptosis, oculomotor disturbance, and dysphonia, n = 2/3). Blood tests found elevated creatine kinase levels (1300, 2450, and 10000; N < 200 UI/L), positivity of antinuclear auto-antibody as well as anti-Rach auto-antibody (n = 1/2), and negativity for specific myositis auto-antibodies (including anti–transcriptional intermediary factor 1-gamma, the paraneoplastic anti-antibody associated with dermatomyositis) (2/2). Electromyography identified myopathic pattern without decrements on repetitive stimulations (n = 2/2). Morphological investigation found myositis and myocarditis pattern on MRI (n = 2/2; Fig. 1A, B). No metastases were identified by brain MRI. Pathological analysis found inflammatory infiltrates and necrosis in skeletal and cardiac muscles (n = 2/3) inside of which was programmed death ligand 1 (PD-L1) immunohistochemical staining positivity (n = 1/1) (Fig. 1C, D). Diagnosis of ICI-related muscular disorder was established for these 3 cases. Medical management was complex, as there was at the same time immunodeficiency against cancer and an immune overresponse against muscles. Nivolumab was discontinued and oral steroids were introduced (1 mg/kg/d with slow tapering) (n = 3/3), leading to progressive muscular improvement within several months. The patient with myocarditis also benefited from intravenous immunoglobulin (2 g/kg/4 wk). However, the irreversibility of cardiac dysfunction led to death for 1 patient within 6 months. To date, nivolumab has not been re-administered.

Fig. 1.

(A) Cardiac MRI: diffuse myocardic hyperintensity on T2 mapping weighted images (arrows). (B) Lower limbs MRI: axial T2 short tau inversion recovery image shows diffuse hyperintensity in some thigh muscles (arrowheads, vastus lateralis and medialis muscles). (C–E) Histological analysis (scale bars, 50 µm). (C, D) Hematoxylin and eosin–stained sections. (C) Skeletal muscle analysis: focal inflammatory infiltrates in endomysium. (D) Cardiac muscle analysis, inflammatory infiltrates within pericardium and myocardium. (E) PD-L1 immunohistochemical staining positivity within muscular inflammatory infiltrates (PD-L1 [Clone QR1] BIOCYC).

Prevalence of ICI-related muscular disorders is probably underestimated owing to underrecognition of this new adverse reaction and the multifactorial cause of worsening in these fragile patients. Nevertheless, the widespread use of these promising drugs requires neurologists and oncologists to be familiar with them, particularly regarding their potential severity and the necessity to react promptly.³ Along these lines, creatine kinase and cardiac monitoring might be useful tools. Despite electromyography normality, the myastheniform symptoms question neuromuscular junction involvement and highlight the atypical clinical picture of this new acquired neuromuscular disorder.