Introduction/Aims: Heterozygous CGG repeat expansions in low-density lipoprotein receptor-related protein 12 (LRP12) have recently been identified as a cause of oculopharyngodistal myopathy (OPDM), and the disease is designated as OPDM type 1 (OPDM1). In contrast to broadening of our knowledge on the genetic background of OPDM, what we know of the clinical phenotype of genetically confirmed OPDM1 remains limited.Methods: This investigation was a single-center case series study of OPDM consisting of ten patients from seven families. Repeat-primed polymerase chain reaction and Southern blot analyses were performed to confirm the CGG repeat expansions in LRP12. Clinical findings were retrospectively reviewed.Results: Seven patients from five families were identified as having CGG repeat expansions in LRP12. We found a high prevalence of axial muscle involvement, such as neck muscle weakness (6/7) and fatty infiltration in the rectus abdominis muscle, as revealed by computed tomography (5/5). We identified patients with very subtle oculopharyngeal symptoms, mimicking isolated distal myopathy. Muscle specimens

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...

ObjectiveTo provide evidence that idiopathic inflammatory myopathy (IM) with myasthenia gravis (MG) frequently shows thymoma association and polymyositis (PM) pathology and shares clinicopathologic characteristics with IM induced by immune checkpoint inhibitors (ICIs).MethodsWe analyzed the clinicopathologic features of 10 patients with idiopathic IM and MG identified in 970 consecutive patients with biopsy-proven IM.ResultsSeven patients (70%) had thymoma. IM and MG were diagnosed with more than 5-year time difference in 6 thymomatous patients and within 1 year in 1 thymomatous and 3 nonthymomatous patients. Seven thymomatous patients showed rhabdomyolysis-like features with respiratory failure (4/7), dropped head (3/7), cardiac involvement (2/7), and positive anti–acetylcholine receptor (anti-AChR) and anti-titin antibodies (7/7 and 4/6, respectively) but rarely showed ocular symptoms (2/7) or decremental repetitive nerve stimulation (RNS) responses (1/7) at IM diagnosis. Three nonthymomatous patients showed acute cardiorespiratory failure with rhabdomyolysis-like features (1/3), positive anti-AChR and anti-titin antibodies (3/2 and 2/2, respectively), and fluctuating weakness of the skeletal muscle without ocular symptoms (3/3). Muscle pathology showed a PM pathology with infiltration of CD8-positive CD45RA-negative T-lymphocytes (9/9), scattered endomysial programmed cell death 1 (PD-1)–positive cells (9/9), and overexpression of programmed cell death ligand 1 (PD-L1) on the sarcolemma of muscle fibers around the infiltrating PD-1–positive cells (7/9).ConclusionRhabdomyolysis-like features, positive anti-AChR antibody without decremental RNS responses, and PD-L1 overexpression are possible characteristics shared by ICI-induced IM. Frequent thymoma association in patients with idiopathic IM and MG may suggest thymoma-related immunopathogenic mechanisms, including dysregulation of the immune checkpoint pathway.