Inflammatory myopathy associated with immune checkpoint inhibitors

Abstract

Immune check point inhibitors have shown remarkable benefit in the treatment of a range of cancer types. As cancer treatment with these drugs has become more common, the safety management of immune–related adverse events (irAEs) due to cancer immunotherapy has become more important. Myositis is one of the representative neuromuscular irAEs. A variety of studies have demonstrated that myositis as an irAE is often accompanied by ocular muscle symptoms, which physicians have often termed “myasthenia-like” or “pseudo-myasthenic” symptoms. Physicians often recognize the unique clinical manifestations of irAE myositis and may hesitate to diagnose these patients as pre–existing myositis alone. To comprehensively characterize the inflammatory myopathy associated with programmed cell death 1 inhibitors (PD–1 myopathy), we studied 19 Japanese patients with PD–1 myopathy. PD–1 myopathy occurred 29 days on average after the first administration of PD–1 inhibitor. The initial manifestation of muscle weakness was ptosis in 10 patients. 15 patients had ptosis, 13 diplopia, 8 facial muscle weakness, 10 bulbar symptoms, 13 limb weakness, 14 neck weakness, 4 cardiac involvement, 6 respiratory involvement and 16 myalgia. Ocular, facial, cardiac and respiratory muscle involvement and myalgia were frequently observed. Serum creatine kinase was increased to 5,247 IU/L on average. Autoantibodies related to inflammatory myopathy were negative, while anti–striational antibodies were found in 13 (68%) patients. HLA–C*12:02 alleles were more frequently detected than healthy controls. Muscle pathology was characterized by multifocal necrotic myofibers with endomysial inflammation and expression of MHC class I. There are guidelines for the treatment of neuromuscular irAEs. For all but the minimum symptoms, therapy with PD–1 inhibitors should be withheld. Immunosuppressive therapy with corticosteroids was generally effective for muscle weakness. PD–1 inhibitor induced myositis and myasthenia gravis may share the same pathophysiology, suggesting an emerging clinical entity. Based on our clinical, histological and immunological findings, PD–1 myopathy is a discrete subset of inflammatory myopathy.