Assuntos
Adenosina Trifosfatases/genética , Variação Genética/genética , Doenças Arteriais Intracranianas/tratamento farmacológico , Doenças Arteriais Intracranianas/genética , Pirimidinas/efeitos adversos , Ubiquitina-Proteína Ligases/genética , Humanos , Doenças Arteriais Intracranianas/diagnóstico por imagem , Masculino , Pessoa de Meia-Idade , Proteínas Tirosina Quinases/antagonistas & inibidores , Proteínas Tirosina Quinases/metabolismoRESUMO
A 53-year-old man suffering from squamous cell lung cancer presented with bilateral ptosis and bulbar palsy a month after initial treatment with the immune checkpoint inhibitor nivolumab. The symptoms showed worsening from midday, suggesting myasthenia gravis (MG), although anti-AChR antibody was negative. Although no muscle weakness was detected, the CK level was elevated to 5,255â IU/l, and MRI of the thigh revealed inflammation of the bilateral rectus femoris muscle. A muscle biopsy showed signs of necrotizing myopathy with expression of sarcolemmal HLA class I and accumulation of macrophages, CD4, CD8, and CD20-positive lymphocytes. Positivity for anti-titin antibody, one of the anti-striated muscle antibodies, was evident. The patient was diagnosed as having nivolumab-related necrotizing myopathy with myasthenia gravis, an immune-related adverse event (irAE). Treatment with prednisolone rapidly ameliorated the symptoms, and the serum CK level normalized. There have been several reports of nivolumab-related myositis with MG. On the basis of the muscle pathology and antibody data, we were able to clarify that necrotizing myopathy was related to the pathogenesis of this case.
Assuntos
Conectina/imunologia , Doenças Musculares/induzido quimicamente , Miastenia Gravis/induzido quimicamente , Nivolumabe/efeitos adversos , Autoanticorpos/sangue , Biomarcadores/sangue , Carcinoma de Células Escamosas/tratamento farmacológico , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Doenças Musculares/diagnóstico , Doenças Musculares/tratamento farmacológico , Doenças Musculares/patologia , Miastenia Gravis/diagnóstico , Miastenia Gravis/tratamento farmacológico , Necrose , Nivolumabe/uso terapêutico , Prednisolona/administração & dosagem , Músculo Quadríceps/patologia , Resultado do TratamentoRESUMO
OBJECTIVE: To characterize the inflammatory myopathy associated with programmed cell death 1 inhibitors (PD-1 myopathy). METHODS: We studied 19 Japanese patients with PD-1 myopathy (13 men and 6 women, mean age 70 years), who were referred to Keio University. As control groups, we used 68 patients with anti-signal recognition particle antibodies, 51 patients with anti-aminoacyl transfer RNA synthetase antibodies and 460 healthy subjects. RESULTS: In regard to muscle-disease severity, 10 patients showed a mild form of disease and 9 patients showed a severe form. Non-small cell lung cancer was the most common underlying cancer. PD-1 inhibitor consisted of 11 nivolumab and 8 pembrolizumab. 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 involvement and myalgia were more frequently observed than controls. Serum creatine kinase was increased to 5247 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. Immunosuppressive therapy with corticosteroids was generally effective for muscle weakness. CONCLUSIONS: Based on our clinical, histological and immunological findings, PD-1 myopathy is a discrete subset of inflammatory myopathy.
Assuntos
Anticorpos Monoclonais Humanizados/efeitos adversos , Autoanticorpos/imunologia , Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Miosite , Proteínas de Neoplasias/antagonistas & inibidores , Nivolumabe/efeitos adversos , Receptor de Morte Celular Programada 1 , Adulto , Idoso , Idoso de 80 Anos ou mais , Aminoacil-tRNA Sintetases/imunologia , Anticorpos Monoclonais Humanizados/administração & dosagem , Carcinoma Pulmonar de Células não Pequenas/imunologia , Carcinoma Pulmonar de Células não Pequenas/patologia , Feminino , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Miosite/induzido quimicamente , Miosite/imunologia , Miosite/patologia , Proteínas de Neoplasias/imunologia , Nivolumabe/administração & dosagem , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Receptor de Morte Celular Programada 1/imunologiaRESUMO
OBJECTIVE: To clarify the genetic, clinicopathologic, and neuroimaging characteristics of patients with hereditary diffuse leukoencephalopathy with spheroids (HDLS) with the colony stimulating factor 1 receptor (CSF-1R) mutation. METHODS: We performed molecular genetic analysis of CSF-1R in patients with HDLS. Detailed clinical and neuroimaging findings were retrospectively investigated. Five patients were examined neuropathologically. RESULTS: We found 6 different CSF-1R mutations in 7 index patients from unrelated Japanese families. The CSF-1R mutations included 3 novel mutations and 1 known missense mutation at evolutionarily conserved amino acids, and 1 novel splice-site mutation. We identified a novel frameshift mutation. Reverse transcription PCR analysis revealed that the frameshift mutation causes nonsense-mediated mRNA decay by generating a premature stop codon, suggesting that haploinsufficiency of CSF-1R is sufficient to cause HDLS. Western blot analysis revealed that the expression level of CSF-1R in the brain from the patients was lower than from control subjects. The characteristic MRI findings were the involvement of the white matter and thinning of the corpus callosum with signal alteration, and sequential analysis revealed that the white matter lesions and cerebral atrophy relentlessly progressed with disease duration. Spotty calcifications in the white matter were frequently observed by CT. Neuropathologic analysis revealed that microglia in the brains of the patients demonstrated distinct morphology and distribution. CONCLUSIONS: These findings suggest that patients with HDLS, irrespective of mutation type in CSF-1R, show characteristic clinical and neuroimaging features, and that perturbation of CSF-1R signaling by haploinsufficiency may play a role in microglial dysfunction leading to the pathogenesis of HDLS.