Mitochondrial dysfunction and role of harakiri in the pathogenesis of myositis.

The etiology of myositis is unknown. Although attempts to identify viruses in myositis skeletal muscle have failed, several studies have identified the presence of a viral signature in myositis patients. Here we postulate that in individuals with susceptible genetic backgrounds, viral infection alters the epigenome to activate the pathological pathways leading to disease onset. To identify epigenetic changes, methylation profiling of Coxsackie B infected human myotubes and muscle biopsies from polymyositis (PM) and dermatomyositis (DM) patients were compared to changes in global transcript expression induced by in vitro Coxsackie B infection. Gene and protein expression analysis and live cell imaging were performed to examine the mechanisms. Analysis of methylation and gene expression changes identified that a mitochondria-localized activator of apoptosis - harakiri (HRK) - is upregulated in myositis skeletal muscle cells. Muscle cells with higher HRK expression have reduced mitochondrial potential and poor ability to repair from injury as compared to controls. In cells from myositis patient toll-like receptor 7 (TLR7) activates and sustains high HRK expression. Forced over expression of HRK in healthy muscle cells is sufficient to compromise their membrane repair ability. Endurance exercise that is associated with improved muscle and mitochondrial function in PM and DM patients decreased TLR7 and HRK expression identifying these as therapeutic targets. Increased HRK and TLR7 expression causes mitochondrial damage leading to poor myofiber repair, myofiber death and muscle weakness in myositis patients and exercise induced reduction of HRK and TLR7 expression in patients is associated with disease amelioration. © 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Hepatitis C virus infection in inclusion body myositis: A case-control study.

OBJECTIVE: To clarify whether there is any association between inclusion body myositis (IBM) and hepatitis C virus (HCV) infection. METHODS: We assessed the prevalence of HCV infection in 114 patients with IBM whose muscle biopsies were analyzed pathologically for diagnostic purpose from 2002 to 2012 and in 44 age-matched patients with polymyositis diagnosed in the same period as a control by administering a questionnaire survey to the physicians in charge. We also compared clinicopathologic features including the duration from onset to development of representative symptoms of IBM and the extent of representative pathologic changes between patients with IBM with and without HCV infection. RESULTS: A significantly higher number of patients with IBM (28%) had anti-HCV antibodies as compared with patients with polymyositis (4.5%; odds ratio 8.2, 95% confidence interval 1.9-36) and the general Japanese population in their 60s (3.4%). Furthermore, between patients with IBM with and without HCV infection, we did not find any significant difference in the clinicopathologic features, indicating that the 2 groups have essentially the same disease regardless of HCV infection. CONCLUSION: Our results provide the statistical evidence for an association between IBM and HCV infection, suggesting a possible pathomechanistic link between the 2 conditions.

Polymyositis as a paraneoplastic syndrome in cytotoxic molecule-positive and Epstein-Barr virus-associated peripheral T-cell lymphoma, not otherwise specified.

We encountered a rare case of cytotoxic molecule-positive and Epstein-Barr virus (EBV)-associated peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS), which was clinically preceded by polymyositis. A 50-year-old woman with a 4-year history of steroid-refractory polymyositis developed ulcerative skin swelling on her left arm. A diagnosis of cytotoxic molecule (TIA-1)-positive and EBV-associated PTCL-NOS was made on the basis of immunohistochemical and molecular examinations of the biopsied brachial muscle. Combination chemotherapies were ineffective, with a fatal outcome. Reassessment of the biopsy specimens of the muscle taken at the age of 46 years showed that the PTCL was already present, indicating that the polymyositis was likely a paraneoplastic manifestation.

Epstein-Barr virus (EBV) associated lymphoepithelioma-like thymic carcinoma associated with paraneoplastic syndrome of polymyositis: a rare tumor with rare association.

Thymic carcinomas are rare neoplasms representing less than 1% of all thymic malignancies arising from thymic epithelium. Lymphoepithelioma-like thymic carcinoma is a high grade neoplasm with aggressive features and frequent metastasis. Association of lymphoepithelioma-like thymic carcinomas with Epstein-Barr virus was observed in several previously reported case reports. Paraneoplastic syndromes have been reported with lymphoepithelioma-like thymic carcinoma. We report a case of rare association of paraneoplastic syndrome of polymyositis with lymphoepithelioma-like thymic carcinoma. The case highlights generalized increase in fluoro-deoxy-glucose uptake in the skeletal muscles indicating biopsy proven polymyositis-a paraneoplastic syndrome.

T cell infiltrates in the muscles of patients with dermatomyositis and polymyositis are dominated by CD28null T cells.

Dermatomyositis and polymyositis are disabling rheumatic diseases characterized by an appreciable number of T cells infiltrating muscle tissue. The precise phenotype, function and specificity of these cells remain elusive. In this study, we aimed to characterize T cells in muscle tissue and circulation and to investigate their association to clinical phenotype. Twenty-four patients with dermatomyositis and 42 with polymyositis were screened for frequency of CD4+CD28(null) and CD8+CD28(null) T cells in peripheral blood by flow cytometry. Presence of these cells in inflamed muscle tissue from 13 of these patients was analyzed by three-color immunofluorescence microscopy. Effector functions, proliferation and Ag specificity were analyzed by flow cytometry after in vitro stimulation. The clinical relevance of CD28(null) T cells was analyzed by multiple regression analyses including six separate and combined disease variables. We demonstrate that muscle-infiltrating T cells are predominantly CD4+CD28(null) and CD8+CD28(null) T cells in patients with dermatomyositis and polymyositis. Muscle-infiltrating CD28(null) T cells were found already at time of diagnosis. Disease activity correlated with the frequency of CD8+ T cells in the inflamed muscles of polymyositis patients. Circulating CD4+CD28(null) and CD8+CD28(null) T cells were significantly more frequent in human CMV (HCMV) seropositive individuals, responded to HCMV Ag stimulation, and correlated with disease duration. These cells also display a proinflammatory cytokine profile, contain perforin and lack the costimulatory molecule CD28. Our observations imply that CD28(null) T cells represent clinically important effector cells in dermatomyositis and polymyositis, and that HCMV might play a role in propagating disease in a subset of patients.

Steroid-responsive subacute polymyositis in an adult following respiratory syncytial virus infection.

The role of viral infections in the aetiopathogenesis of polymyositis remains speculative. We report a case of profound subacute polymyositis with incipient ventilatory failure following serologically confirmed infection by respiratory syncytial virus (RSV), with a dramatic and sustained response to pulse corticosteroid therapy. We suggest a possible autoimmune mechanism to account for this sequence of events.

Skeletal muscle involvement in human immunodeficiency virus (HIV)-infected patients in the era of highly active antiretroviral therapy (HAART).

Skeletal muscle involvement can occur at all stages of human immunodeficiency virus (HIV) infection, and may represent the first manifestation of the disease. Myopathies in HIV-infected patients are classified as follows: (1) HIV-associated myopathies and related conditions, including HIV polymyositis, inclusion-body myositis, nemaline myopathy, diffuse infiltrative lymphocytosis syndrome (DILS), HIV-wasting syndrome, vasculitic processes, myasthenic syndromes, and chronic fatigue; (2) muscle complications of antiretroviral therapy, including zidovudine and toxic mitochondrial myopathies related to other nucleoside-analogue reverse-transcriptase inhibitors (NRTIs), HIV-associated lipodystrophy syndrome, and immune restoration syndrome related to highly active antiretroviral therapy (HAART); (3) opportunistic infections and tumor infiltrations of skeletal muscle; and (4) rhabdomyolysis. Introduction of HAART has dramatically modified the natural history of HIV disease by controlling viral replication, but, in turn, lengthening of the survival of HIV-infected individuals has been associated with an increasing prevalence of iatrogenic conditions.

Hepatitis B virus replication in damaged endothelial tissues of patients with extrahepatic disease.

Hepatitis B virus (HBV) infection may be complicated by extrahepatic manifestations such as polyarteritis nodosa (PAN), glomerulonephritis, polymyositis, and dermatitis, but the etiology of these processes is not yet clear. HBV replication has been demonstrated in a variety of extrahepatic tissues and cell types, but the possible pathogenetic role of extrahepatic HBV replication has not been fully explored in patients with extrahepatic manifestations of HBV infection. In this case series, immunohistochemistry and in situ hybridization studies were performed on extrahepatic tissues from one HBsAg-positive patient with PAN and another HBsAg-positive patient with polymyositis, using HBsAg-seronegative control subjects with the same vasculitic disorders as controls. Tissue samples from the two study patients had detectable HBV RNA, replicative intermediates of HBV DNA, as well as HBsAg and HBcAg localized to vascular endothelium. In contrast, HBsAg-negative control patients had no tissue reactivity. Our results suggest that patients with HBV-related extrahepatic disease have evidence of viral replication in damaged extrahepatic endothelial tissues. While further studies would be required to support a hypothesis of causality, these findings suggest a role for both immune complex deposition and viral replication within diseased endothelial tissue in the pathogenesis of these poorly understood extrahepatic disorders.

Generalized myositis mimicking polymyositis associated with chronic active Epstein-Barr virus infection.

BACKGROUND: Chronic generalized myositis has not so far been reported as a complication of chronic active Epstein-Barr virus infection (CAEBV). We encountered three patients with chronic generalized myositis mimicking polymyositis associated with CAEBV. METHODS: To clarify the pathological character of this myositis, we investigated the distribution, clonality, and the immunophenotype of EBV-infected cells and lymphocytes infiltrating in muscles. RESULTS: Clinically, two patients showed symmetrical proximal weakness and muscle atrophy as the initial and main symptom. Although the condition resembled polymyositis, they had also lingual and/or orbital myositis. The other patient showed generalized myositis at the late phase of CAEBV. In all of them, immunotherapy was ineffective and prognosis was poor. Intramuscular infiltrating lymphocytes in our patients were mainly CD45RO+, CD3+, CD4-, CD8-, TCR betaF1-, TCR deltaTCS1-, CD56-, CD79a-, CD21-, HLA-DR+, ZEBRA -, LMP1-, and EBER+ T cells. Oligoclonal expansion of EBV-infected T cells was shown in the muscles. However, there were no malignant lymphocytes. CONCLUSIONS: This new form of myositis must be distinguished from polymyositis and the other conventional forms of myositis. Careful investigation of hidden CAEBV is recommended when patients present with steroid non-responsive chronic progressive generalized myositis, in particular, with lingual or orbital involvement.

Human immunodeficiency virus-associated polymyositis: a longitudinal study of outcome.

OBJECTIVE: To determine the clinical course and optimum treatment of human immunodeficiency virus (HIV)-associated myositis. METHODS: Sixty-four patients attending a county outpatient HIV/acquired immunodeficiency syndrome facility were referred for the presence of elevated creatine kinase (CK) levels or muscle weakness. Patients underwent neurologic and rheumatologic evaluation, electromyography, and muscle biopsy after exclusion for recreational drug or alcohol use, metabolic/endocrine disorders, zidovudine therapy, and other infections. RESULTS: Thirteen patients (20%) had biopsy-proven myositis. The median duration of HIV infection prior to diagnosis of myositis was 4.3 years (range 0-11 years). Six patients had concomitant diffuse infiltrative lymphocytosis syndrome. There was no correlation of severity of weakness, stage of HIV infection, or retroviral treatment with the CK level at diagnosis. Eight patients received prednisone (60 mg/day) with 5 attaining complete resolution of myositis. The remaining 3 patients received immunosuppressive therapy (azathioprine or methotrexate and intravenous immunoglobulin) and had normalization of strength and CK. Four patients had spontaneous resolution of their myositis without treatment. CONCLUSION: HIV-associated myositis occurs at any stage of HIV infection, has a relatively good prognosis, responds well to immunosuppressive therapy, and has little evidence of adverse outcome on the HIV infection.

CD4-CD8- T-cell polymyositis in a patient with chronic active Epstein-Barr virus infection.

We describe a 17-year-old woman with chronic active Epstein-Barr virus infection (CAEBV), who developed EBV+CD4-CD8- T-cell polymyositis. At 14 years of age, CAEBV was diagnosed with fever, cytopenia, liver dysfunction, and hepatosplenomegaly. Despite the transient remission of interferon-alpha therapy, migratory lesions emerged in back and extremities. MRI indicated polymyositis. Biopsy specimens revealed intramuscular infiltration of CD3+, CD4-, CD8-, CD56-, and EBV-encoded RNA 1+ cells. Circulating CD4-CD8-Vdelta2/Vgamma9 cells increased. gammadeltaT-cells contained 20-200 times higher EBV-DNA (2 x 10(4) copies/microgDNA) than alphabetaT-cells or NK-cells. The ominous polymyositis might denote the musculotropic invasion of EBV+gammadeltaT-cell lymphoproliferative disease as a consequence of CAEBV.

Molecular analysis of T cell clonotypes in muscle-infiltrating lymphocytes from patients with human T lymphotropic virus type 1 polymyositis.

Epidemiological studies have shown that a correlation may exist between human T cell lymphotropic virus type 1 (HTLV-1) infection and a form of polymyositis (PM). To characterize muscle-infiltrating lymphocytes (MILs) from patients with HTLV-1 PM, we examined the T cell receptor (TCR) beta-chain variable region repertoire and clonotype of MILs and peripheral blood mononuclear cells (PBMC) from 3 patients, using TCR complementarity-determining region 3 (CDR3) length spectratyping and DNA sequencing. Immunohistochemical studies showed that MILs from patients with HTLV-1 PM contain both CD4(+) and CD8(+) T cells. Although some clonotypes observed in PBMC were also found in MILs in all patients examined, MILs consisted predominantly of locally expanded clones. One clonotype in MILs was derived from human leukocyte antigen (HLA)-A*02/Tax11-19 tetramer-positive cells, the CDR3 motif of which contains amino acid residues for HLA-A*02/Tax peptide-TCR interaction. We conclude that certain T cell clones proliferate in the muscle lesions of HTLV-1 PM and may contribute to the pathogenesis of the disease.

[Polymyositis associated with HIV immunodeficiency: clinical case and literature review]. / Polymyosite associée à l'immunodéficience VIH: cas clinique et revue de la littérature.

A 33 year old female, suffering from HIV infection, presents with diffuse myalgia, generalized muscle weakness and painless dysphagia. An extensive work-up allows to diagnose an HIV-related polymyositis; while well-known, this entity is however rarely observed. Technetium-99m MDP skeletal scintigraphy shows multiple extra-osseous accumulations of the tracer: these observations, as well as the differential diagnoses of muscular involvement during HIV infection, are discussed.

Multinodular polymyositis in a patient with human immunodeficiency and hepatitis C virus coinfection.

We report a patient who developed multiple inflammatory muscle masses and generalized polymyositis in the setting of combined human immunodeficiency virus (HIV) and hepatitis C virus (HCV) infection. Magnetic resonance imaging (MRI) of muscles showed patchy edema which was particularly intense within the nodular masses. Polymerase chain reaction (PCR) showed no evidence of either virus within muscle. This report reviews earlier literature on muscle nodules associated with myositis and discusses the differential diagnosis of muscle masses in HIV infection.

Inflammatory myopathy on HTLV-I infection: case report.

We describe a 41 years old woman who 17 years ago presented hypotonia and proximal muscular weakness in the upper and lower limbs. On neurological examination, the biceps, triceps and Achilles reflexes were absent; the brachioradialis reflexes were decreased and the patellar reflexes were normal. There was bilateral Babinski sign. The remainder of the neurological examination was unremarkable. In the investigation a myopathic pattern was found in the electromyography. The nerve-conduction study was normal; a ELISA method for HTLV-I antibodies was positive in the blood and in the cerebral spinal fluid. The muscle biopsy showed inflammatory myopathy, compatible with polymyositis. This paper focuses the polymyositis in the beginning of an HTLV-I infection case.

Inflammatory myopathy on HTLV-I infection: case report

We describe a 41 years old woman who 17 years ago presented hypotonia and proximal muscular weakness in the upper and lower limbs. On neurological examination, the biceps, triceps and Achilles reflexes were absent; the brachioradialis reflexes were decreased and the patellar reflexes were normal. There was bilateral Babinski sign. The remainder of the neurological examination was unremarkable. In the investigation a myopathic pattern was found in the electromyography. The nerve-conduction study was normal; a ELISA method for HTLV-I antibodies was positive in the blood and in the cerebral spinal fluid. The muscle biopsy showed inflammatory myopathy, compatible with polymyositis. This paper focuses the polymyositis in the beginning of an HTLV-I infection case

[Polymyositis and HTLV-I infection: case report]. / Polimiosite associada a infecção por HTLV-I: relato de caso.

We report the case of a 57 years-old woman presenting polymyositis associated to HTLV-I infection without clinical signs of involvement of the central and peripheral nervous system. Pathophysiologic aspects of muscular involvement in HTLV-I infection are discussed.