Granulomatous myositis induced by anti–PD-1 monoclonal antibodies

Abstract

With the expanding use of immune checkpoint blockers typified by anti-programmed death-1 (PD-1) and anti-cytotoxic T-lymphocyte-associated protein 4 monoclonal antibodies (Abs) for antitumor therapy, the number of patients showing immune-related adverse events (irAEs) is increasing. Skeletal muscle is one of the target tissues of irAEs and several features of myopathy as irAEs have been reported: myasthenia gravis (MG) overlap, cardiac involvement, necrotizing myopathy, and inflammatory myopathy with T-cell and B-cell infiltration. [1][2][3][4] However, the immunopathogenesis of muscle destruction remains unclear. Here, we report 2 cases of granulomatous myositis after anti-PD-1 therapy. Case reportsCase 1 A 79-year-old woman with stage IV lung adenocarcinoma developed nonfatigable mild proximal limb weakness (Medical Research Council [MRC] grade 4) 14 days after the fourth cycle of nivolumab. She presented no skin rash and showed no ocular, bulbar, truncal, or respiratory symptoms. She had well-controlled concurrent breast cancer. Laboratory test results showed an elevated serum creatine kinase (CK) level of 1,638 IU/L. Myositis-specific autoantibodies (MSAs), anti-acetylcholine receptor (AChR) Ab, and anti-titin Ab were negative. Antistriated muscle Abs were not measured. Electrocardiography findings were normal. EMG showed spontaneous activity. Chest CT showed no lesions except the cancers.Biopsy of the biceps brachii muscle showed patchy mononuclear cell infiltrates and granuloma formation in muscle fascicles ( figure 1A). In the granulomas, CD11c + M1 and CD163 + M2 macrophages were abundant (figure e-1, links.lww.com/NXI/A46), and CD11c + M1 macrophages frequently invaded non-necrotic fibers and formed granulomatous collection inside the basal lamina of muscle fibers (figure 1, B-D). CD8 + T cells invading non-necrotic fibers were also observed ( figure 1E). PD-1 + cells were scattered in granulomas (figure 1F), and programmed death-ligand 1 (PD-L1) was upregulated on the non-necrotic fibers around granulomas ( figure 1G). Electron microscopy confirmed the macrophage invasion of non-necrotic fibers (figure e-2, links.lww.com/NXI/A46). Nivolumab was discontinued, and oral prednisolone 50 mg was started. Her symptoms improved dramatically with complete resolution, and prednisolone was tapered off within 3 weeks. During 20 months of follow-up, she showed no neurologic recurrence and received conventional chemotherapy. Case 2A 70-year-old man who received pembrolizumab (anti-PD-1 Ab) and axitinib (tyrosine kinase inhibitor) for treatment of renal cell carcinoma developed left ptosis, diplopia, and weakness with myalgia in his neck and left shoulder (MRC grade 4) without bulbar, respiratory, or cardiac Biopsy of the left deltoid muscle showed mononuclear cell infiltration and giant-cell granulomas ( figure 1H). CD11c + M1 macrophages frequently invaded non-necrotic fibers (figure 1, I and J). Small granulomas replacing muscle fibers always contained both CD11c + M1 and CD163 + M2 macrophages (figure 1, K and L...

Pembrolizumab on pre-existing inclusion body myositis: a case report

“…Wiendl et al firstly reported that PD-L1 was expressed in inflamed skeletal muscle fibers in polymyositis, dermatomyositis, and sIBM [7]. We also found upregulated PD-L1 expression in non-necrotic skeletal muscle fibers in ICI-induced myositis [1]. Furthermore, PD-L1 expression in inflamed cardiac muscle fibers was reported in ICI-induced cardiomyositis [8].…”

“…Furthermore, PD-L1 expression in inflamed cardiac muscle fibers was reported in ICI-induced cardiomyositis [8]. The significance of PD-L1 expression in muscle fibers is not fully understood, but PD-L1 expression in muscles was proposed to be a protective mechanism to inflammation [1,7,8]. Additional studies are needed to elucidate the function of PD-L1 on muscle fibers in inflammation and the effect of ICI therapy on the expression of PD-L1.…”

“…Immune checkpoint inhibitors (ICIs) potentiate T-cell activity and show dramatic efficacy in treating cancers, but they may also induce immune-related adverse events (irAEs) resembling autoimmune diseases [ 1 – 3 ]. Several reports have documented ICI-induced exacerbation of pre-existing autoimmune diseases [ 2 , 4 , 5 ].…”

Inflammatory myopathy with myasthenia gravis

“…Some immune-related adverse events induced by antitumor therapy with ICIs have been recently reported to cause the association of MG with IM. 14,16,17 A recent study of 12 nonthymomatous patients who developed MG after antitumor therapy with nivolumab (an anti–PD-1 monoclonal Ab) reported that 4 patients had IM and 3 patients had myocarditis, including 1 patient with both IM and myocarditis. 15 This study also showed the following clinical features of patients with nivolumab-induced MG: markedly elevated CK levels (10/12, 83%), positive anti-AChR Ab (10/12, 83%), positive edrophonium infusion test (4/7, 57%), and abnormal decremental RNS responses (2/7, 29%).…”

Trouble at the junction: When myopathy and myasthenia overlap

“…Other patients present with a primarily myopathic phenotype. In these patients, muscle biopsy findings range from nonspecific myopathic abnormalities to necrotizing myopathy, granulomatous myopathy, or dermatomyositis . Both oculomotor and bulbar weakness have been identified in ICI‐associated myopathy patients in the absence of a decrement on low‐frequency RNS.…”