Polymyositis Patients Research Articles

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.

Pro-inflammatory S100A11 is elevated in inflammatory myopathies and reflects disease activity and extramuscular manifestations in myositis

BackgroundS100A11 (calgizzarin), a member of the S100 family, is associated with oncogenesis, inflammation and myocardial damage. Our aim was to analyse S100A11 in idiopathic inflammatory myopathies (IIMs) and its association with disease activity features and cancer development. MethodsS100A11 in muscle was determined by immunohistochemistry in polymyositis (PM), dermatomyositis (DM), myasthenia gravis (MG) and in subjects without autoimmune inflammatory disease (HC). S100A11 in plasma was measured in 110 patients with IIMs (PM, DM, and cancer associated myositis (CAM) patients) and in 42 HC. Disease activity was assessed by myositis disease activity assessment (MYOACT), muscle enzymes and C-reactive protein (CRP) were measured by routine laboratory techniques; autoantibodies by immunoprecipitation or by immunoblot. ResultsWe observed an accumulation of S100A11 in the cytoplasm of regenerating and necrotizing muscle fibres of PM and DM patients. S100A11 was increased in plasma of all myositis patients compared to HC (3.8 (1.5–16.8) vs 2.8 (1.7–11.2) ng/ml, p = 0.011) and in DM and CAM patients compared to HC (4.0 (2.2–14.9) and 4.5 (1.5–9.1) vs 2.8 (1.7–11.2) ng/ml, p < 0.001 and p = 0.022, respectively). In all myositis patients, S100A11 correlated with the levels of lactate dehydrogenase (r = 0.256, p = 0.011), aspartate aminotransferase (AST) (r = 0.312, p = 0.002), CRP (r = 0.254, p = 0.022) and MYOACT (r = 0.245, p = 0.022). S100A11 was associated with MYOACT (r = 0.377, p = 0.030) and pulmonary and cutaneous disease activity in DM patients (r = 0.408, p = 0.017 and r = 0.417, p = 0.01, respectively). S100A11 was related to the levels of AST (r = 0.412, p = 0.027) in PM and to the levels of creatine phosphokinase (r = 0.432, p = 0.028) in CAM patients. ConclusionsWe show for a first time a potential implication of S100A11 in the local inflammatory and tissue remodelling processes in myositis and an association of circulating S100A11 with disease activity and extra muscular manifestations in DM.

Serum-soluble TRAIL: a potential biomarker for disease activity in myositis patients.

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a member of the TNF super-family, which is involved in the regulation of immune response and pathogenesis of autoimmune diseases, including polymyositis (PM) and dermatomyositis (DM). In this study, we examined the level and origin of serum-soluble TRAIL (sTRAIL) in patients with PM and DM and analyzed its association with disease activity and clinical features. 11 PM patients, 33 DM patients, and 20 healthy controls were enrolled in this study. Clinical features were recorded when admitted, and disease activity was evaluated by myositis disease activity assessment visual analogue scale (MYOACT). TRAIL expression in muscle tissues was detected by immunohistochemistry. Serum sTRAIL levels were measured by enzyme-linked immunosorbent assay. The expression of membrane TRAIL (mTRAIL) and its receptors, including DR4 and DR5, on circulating T cells was analyzed by flow cytometry. TRAIL was expressed in infiltrated inflammatory cells in muscle tissues from patients. The serum sTRAIL level was markedly increased in patients and was positively correlated with the disease activity. Serum sTRAIL was decreased after therapy in patients and was specifically higher in patients with dysphagia, but lower in patients with autoantibody Jo-1 positive. The frequency of mTRAIL and its receptors on circulating T cells from patients were significantly elevated than that from healthy controls. The serum sTRAIL could be a biomarker for evaluating the disease activity of PM and DM, and targeting the generation of TRAIL in T cells might be a potential approach in the treatment of PM and DM.

Malignancy in a retrospective cohort of 17 patients with Dermatomyositis or Polymyositis in southern Tunisia.

The prognosis of dermatomyositis (DM)/ polymyositis (PM) in adults is partly related to their association with neoplasia. The aim of our study was to report the epidemiologic, clinical, paraclinical, therapeutic and evolutionary aspects of DM associated with malignancy in patients from Sfax, south eastern of Tunisia. A retrospective cohort study of patients with DM or PM admitted in Dermatology and Internal Medicine Departments of Hedi Chaker University Hospital of Sfax between 1996 and 2015. Cases of DM or PM associated with malignancy were retained. Seventeen cases (13.5%) of DM or PM associated with malignancy were noted. Fourteen patients had DM and 3 patients had PM. The Sex ratio M / F was 0.3 and the mean age at diagnosis was 56.5 years. In DM patients, malignancy preceded the myositis in 64.2% of cases. In PM patients, only one patient was known to have breast cancer and the myositis revealed the cancer for 2 others. Treatment consisted of corticosteroids associated with methotrexate in 4 cases. Outcome was fatal in 5 cases (29.4%), due to the underlying cancer in 3 cases. Swallowing disorders related to DM/PM were responsible for death in 2 cases. There are no specific clinical or biological features in paraneoplastic DM. In our series, breast neoplasm represented the first cancer associated with DM. Cancers of nasopharynx, colon and urinary tract had the second position.

Corneal Involvement of Patients with Polymyositis and Dermatomyositis

ABSTRACTPurpose: To evaluate corneal parameters in patients with polymyositis (PM) and dermatomyositis (DM) and compare them with those of healthy controls.Methods: A total of 43 PM and 32 DM patients and 93 controls were enrolled in this cross-sectional, observational, case-control study. Corneal parameters were evaluated by Pentacam. Objective clinical tests of dry eye disease (DED) were also performed.Results: All pachymetric measurements and corneal volumes (CVs) proved to be significantly lower both in PM and DM patients. The values of DM patients were closer to control values than those of the PM patients. For tear break-up time and Schirmer-I test values significant differences were observed between patients and controls, with values decreased both in PM and DM patients.Conclusions: PM patients rather than DM patients tend to develop thinner and low-volume corneas as compared to controls. Additionally, a high prevalence of DED among both PM and DM patients was also detected.

T-cell transcriptomics from peripheral blood highlights differences between polymyositis and dermatomyositis patients

BackgroundPolymyositis (PM) and dermatomyositis (DM) are two distinct subgroups of idiopathic inflammatory myopathies, a chronic inflammatory disorder clinically characterized by muscle weakness and inflammatory cell infiltrates in muscle tissue. In PM, a major component of inflammatory cell infiltrates is CD8+ T cells, whereas in DM, CD4+ T cells, plasmacytoid dendritic cells, and B cells predominate. In this study, with the aim to differentiate involvement of CD4+ and CD8+ T-cell subpopulations in myositis subgroups, we investigated transcriptomic profiles of T cells from peripheral blood of patients with myositis.MethodsTotal RNA was extracted from CD4+ T cells (PM = 8 and DM = 7) and CD8+ T cells (PM = 4 and DM = 5) that were isolated from peripheral blood mononuclear cells via positive selection using microbeads. Sequencing libraries were generated using the Illumina TruSeq Stranded Total RNA Kit and sequenced on an Illumina HiSeq 2500 platform, yielding about 50 million paired-end reads per sample. Differential gene expression analyses were conducted using DESeq2.ResultsIn CD4+ T cells, only two genes, ANKRD55 and S100B, were expressed significantly higher in patients with PM than in patients with DM (false discovery rate [FDR] < 0.05, model adjusted for age, sex, HLA-DRB1*03 status, and RNA integrity number [RIN]). On the contrary, in CD8+ T cells, 176 genes were differentially expressed in patients with PM compared with patients with DM. Of these, 44 genes were expressed significantly higher in CD8+ T cells from patients with PM, and 132 genes were expressed significantly higher in CD8+ T cells from patients with DM (FDR < 0.05, model adjusted for age, sex, and RIN). Gene Ontology analysis showed that genes differentially expressed in CD8+ T cells are involved in lymphocyte migration and regulation of T-cell differentiation.ConclusionsOur data strongly suggest that CD8+ T cells represent a major divergence between PM and DM patients compared with CD4+ T cells. These alterations in the gene expression in T cells from PM and DM patients might advocate for distinct immune mechanisms in these subphenotypes of myositis.

Current Classification and Management of Inflammatory Myopathies.

Inflammatory disorders of the skeletal muscle include polymyositis (PM), dermatomyositis (DM), (immune mediated) necrotizing myopathy (NM), overlap syndrome with myositis (overlap myositis, OM) including anti-synthetase syndrome (ASS), and inclusion body myositis (IBM). Whereas DM occurs in children and adults, all other forms of myositis mostly develop in middle aged individuals. Apart from a slowly progressive, chronic disease course in IBM, patients with myositis typically present with a subacute onset of weakness of arms and legs, often associated with pain and clearly elevated creatine kinase in the serum. PM, DM and most patients with NM and OM usually respond to immunosuppressive therapy, whereas IBM is largely refractory to treatment. The diagnosis of myositis requires careful and combinatorial assessment of (1) clinical symptoms including pattern of weakness and paraclinical tests such as MRI of the muscle and electromyography (EMG), (2) broad analysis of auto-antibodies associated with myositis, and (3) detailed histopathological work-up of a skeletal muscle biopsy. This review provides a comprehensive overview of the current classification, diagnostic pathway, treatment regimen and pathomechanistic understanding of myositis.

Localization and Expression of Nuclear Factor of Activated T-Cells 5 in Myoblasts Exposed to Pro-inflammatory Cytokines or Hyperosmolar Stress and in Biopsies from Myositis Patients.

Aims: Regeneration in skeletal muscle relies on regulated myoblast migration and differentiation, in which the transcription factor nuclear factor of activated T-cells 5 (NFAT5) participates. Impaired muscle regeneration and chronic inflammation are prevalent in myositis. Little is known about the impact of inflammation on NFAT5 localization and expression in this group of diseases. The goal of this study was to investigate NFAT5 physiology in unaffected myoblasts exposed to cytokine or hyperosmolar stress and in myositis.Methods: NFAT5 intracellular localization and expression were studied in vitro using a cell culture model of myositis. Myoblasts were exposed to DMEM solutions enriched with pro-inflammatory cytokines IFN-γ with IL-1β or hyperosmolar DMEM obtained by NaCl supplementation. NFAT5 localization was visualized using immunohistochemistry (IHC) and Western blotting (WB) in fractionated cell lysates. NFAT5 expression was assessed by WB and RT-qPCR. In vivo localization and expression of NFAT5 were studied in muscle biopsies of patients diagnosed with polymyositis (n = 6), dermatomyositis (n = 10), inclusion body myositis (n = 11) and were compared to NFAT5 localization and expression in non-myopathic controls (n = 13). Muscle biopsies were studied by means of quantitative IHC and WB of total protein extracts.Results: In unaffected myoblasts, hyperosmolar stress ensues in NFAT5 nuclear translocation and increased NFAT5 mRNA and protein expression. In contrast, pro-inflammatory cytokines did not lead to NFAT5 nuclear translocation nor increased expression. Cytokines IL-1β with IFN-γ induced colocalization of NFAT5 with histone deacetylase 6 (HDAC6), involved in cell motility. In muscle biopsies from dermatomyositis and polymyositis patients, NFAT5 colocalized with HDAC6, while in IBM, this was often absent.Conclusions: Our data suggest impaired NFAT5 localization and expression in unaffected myoblasts in response to inflammation. This disturbed myogenic NFAT5 physiology could possibly explain deleterious effects on muscle regeneration in myositis.

Role of the chemokine receptors CXCR3, CXCR4 and CCR7 in the intramuscular recruitment of plasmacytoid dendritic cells in dermatomyositis

To explore the possible mechanism implicated in the recruitment of plasmacytoid dendritic cells (pDCs), we investigated the expression of the chemokine receptors CXCR3, CXCR4, and CCR7 on intramuscular and circulating pDCs from patients with dermatomyositis (DM). Using immunohistochemistry, preferential expression of CXCR3, CXCR4 and CCR7 was identified in the perivascular inflammatory infiltrates within the perimysium in DM muscle. Western-blot analysis showed marked up-regulation of expression of CXCR3, CXCR4 and CCR7 in muscle homogenate from patients with DM compared with that in non-diseased controls. Co-localization of CD303+ pDCs with these chemokine receptors was further examined by double immunofluorescence staining, which showed extensive co-localization of CD303 with CXCR3/CXCR4/CCR7 in DM biopsies. Flow cytometry was then used to investigate the proportion of pDCs among the total PBMCs and the expression of CXCR3, CXCR4 and CCR7 on circulating pDCs. The proportion of CD123+CD303+ pDCs in peripheral blood from DM patients was markedly decreased compared to that from polymyositis (PM) patients and normal controls. Significantly increased expression of CXCR3, but not CXCR4 or CCR7, was further identified on circulating pDCs in DM. Correlation analysis showed that the expression of CXCR3 correlated inversely with the frequency of pDCs in peripheral blood. Our findings indicate that the chemokine receptors, CXCR3, CXCR4 and CCR7 may be involved in the recruitment of pDCs from peripheral blood to muscle tissues in DM via different mechanisms, and in which CXCR3 may play an important role under DM conditions.

Circulating plasma microRNA profiling in patients with polymyositis/dermatomyositis before and after treatment: miRNA may be associated with polymyositis/dermatomyositis

BackgroundMicroRNAs (miRNAs) are involved in the regulation of key biological processes and have been implicated in various diseases, including autoimmune disorders. The pathogenesis of polymyositis (PM) and dermatomyositis (DM) is considered to be mediated by autoimmune reactions. To determine miRNA role in the development and progression of PM and DM, we performed plasma miRNA profiling in PM/DM patients before and after treatment.MethodsTotal RNA was isolated from plasma of 10 patients before and after treatment with prednisolone, or, in case of prednisolone resistance or complications, with the combination of calcineurin inhibitors (cyclosporine or tacrolims) and/or pulse intravenous cyclophosphamide. The expression of miRNAs was determined using miRNA microarray and validated by qRT-PCR.ResultsMore differentially expressed miRNAs were found in plasma of DM patients compared to PM patients before and after treatment, and their profiles were different. Among the differentially expressed plasma miRNA identified by microarray, the levels of hsa-miR-4442 were confirmed by qRT-PCR to be significantly decreased by treatment. In addition, plasma hsa-miR-4442 content in active PM/DM significantly exceeded that in other active autoimmune diseases such as rheumatoid arthritis and systemic lupus erythematosus, as well as in healthy individuals. The level of plasma hsa-miR-4442 was positively correlated with Skeletal Disease Activity in MITAX (Myositis Intention to Treat Activity Index).ConclusionThis is the first report describing plasma miRNA expression profiles in PM/DM patients. The present data suggest that plasma levels of miRNAs may be associated with polymyositis/dermatomyositis and hsa-miR-4442 could be used as a biomarker for PM/DM diagnosis and/or disease activity.

Patients with pure dermatomyositis/polymyositis and anti-PM/Scl autoantibody resembling anti-synthetase syndrome

OBJECTIVE: The anti-PM/Scl autoantibody has been described in patients with scleromyositis. However, there are scant studies evaluating its prevalence and reactivity in dermatomyositis and polymyositis. METHOD: A cross-sectional, single center study evaluating the anti-PM/Scl autoantibody in 85 dermatomyositis and 32 polymyositis patients, without overlapping syndrome, was conducted between 2000 and 2016. Clinical data and complementary examinations were reviewed from electronic medical records with pre-parameterized information. RESULTS: The mean age of dermatomyositis and polymyositis patients was 41.1 and 42.8 years, respectively. The presence of anti-PM/Scl was observed in 5 (5.9%) dermatomyositis and 2 (6.3%) polymyositis patients. Two of these patients also had the anti-Ku antibody. The relevant clinical manifestations of these 7 patients were constitutional symptoms (100% of cases), muscular (100%), pulmonary (85.7%) and joint (71.4%) involvement, mechanic hands (85.7%), Raynaud phenomenon (85.7%) and plantar hyperkeratosis (85.7%). The 7 patients had relapses of disease activity, but at conclusion of the present study, 5 had complete clinical response and 2 complete remission of the disease. CONCLUSION: There is a low frequency of the anti-PM/Scl autoantibody in dermatomyositis and polymyositis patients. In addition, patients with this autoantibody exhibit a similar pattern of manifestations to that of antisynthetase syndrome.

Pregnancy outcomes in adult patients with dermatomyositis and polymyositis.

The idiopathic inflammatory myopathies dermatomyositis (DM) and polymyositis (PM) are autoimmune diseases that can affect females of childbearing potential. We assessed pregnancy outcomes in DM and PM patients compared with the general obstetric population. The Nationwide Inpatient Sample (NIS) (1993-2007) was used to identify delivery-associated hospitalizations in women with DM or PM (DM/PM, n = 853). Controls were from the general obstetric population delivery-associated hospitalizations matched to each case by year of delivery. Pregnancy outcomes included hospital length of stay (LOS), hypertensive disorders (HTN), premature rupture of membranes (PROM), intrauterine growth restriction (IUGR), and cesarean delivery. Multivariate regression analyses were performed using maternal age, race/ethnicity, and diabetes mellitus as covariates. On multivariate analysis, patients with DM/PM had longer LOS compared to controls (p < 0.001). DM/PM was associated with an increased risk of hypertensive disorders compared to controls (OR = 2.90, 95% CI: 2.00-4.22). There were no differences in rates of PROM, IUGR, or cesarean section in patients with DM/PM compared with controls. Independent of a DM/PM diagnosis, African-American race, older age, and diagnosis of diabetes increased the hospital LOS (p < 0.001). African-American race and diabetes increased the risk of hypertensive disorders (OR = 1.38, 95% CI: 1.19-1.60; OR = 2.94, 95% CI: 2.04-4.23, respectively) compared to controls. These data suggest that patients with inflammatory myopathies are at increased risk of hypertensive disorders of pregnancy and longer length of hospitalization. Vigilant monitoring of blood pressure is advisable in pregnant patients with DM or PM.

Serum Interleukin-18 Level is Associated With Disease Activity and Interstitial Lung Disease in Patients With Dermatomyositis.

This study aims to demonstrate the utilization of serum interleukin-18 (IL-18) level as a biomarker for disease activity and organ damage in patients with dermatomyositis (DM) or polymyositis (PM) using the Myositis Disease Activity Assessment Tool. Forty-nine patients (13 males, 36 females) with idiopathic inflammatory myopathies were enrolled in the study. Patients were diagnosed with DM (n=33) or PM (n=16). Twenty age- and sex-matched healthy volunteers (9 males, 11 females) who were determined to be free of autoimmune disease were included as a control group. Disease activity and organ damage were assessed with Myositis Disease Activity Assessment Tool. Serum IL-18 level was measured with enzyme-linked immunosorbent assay and the differences between patient groups were determined. The mean ages of DM or PM patients were 44 and 45, respectively. Interstitial lung disease (ILD) was found in 24 patients (48.98%), including 18 patients with DM (54.55%) and six patients with PM (37.5%). There was no significant difference of disease duration between DM patients (17.5±22.3 months) and PM patients (14.9±28.7 months). Serum IL-18 level in DM (669.2±528.1 pg/mL) was significantly higher than that in the control group (388.3±139.4 pg/mL, p=0.017), but no significant difference was observed between the PM and control group. IL-18 was significantly higher in DM patients with ILD (890.5±618.8 pg/mL) than in patients without ILD (403.8±84.8 pg/mL, p=0.003). It was significantly elevated in patients with severe disease activity (1001.71±694.2 pg/mL) than in those with moderate (485.3±102.2 pg/mL) or mild disease activity (421.0±270.2 pg/mL) (p=0.039). In DM patients, IL-18 was significantly correlated with global disease activity and disease activity in the skin, lung, and heart. Serum IL-18 level was higher in patients with DM and this was associated with disease activity and ILD complication. Thus, it can be used as a valuable serological marker for DM disease activity and ILD complication.

Altered chemokine receptor expression in the peripheral blood lymphocytes in polymyositis and dermatomyositis

ObjectiveTo examine the expression of chemokine receptors in different peripheral blood T-cell subsets in patients with polymyositis (PM) and dermatomyositis (DM). MethodsWe used flow cytometry to measure the frequencies of chemokinereceptors CXCR3 and CCR4 expression in the CD4+ or CD8+ lymphocytes. Enzyme linked immunosorbent assays were also used to measure the concentrations of C-X-C motif chemokine 10 (CXCL10), thymus and activation regulated chemokine (TARC) and macrophage derived chemokine (MDC). ResultsComparing to 20 healthy controls, %CD4+CXCR3+ and %CD8+CXCR3+ T cells significantly decreased in 33DM patients, and %CD8+CXCR3+ cells decreased in 24PM patients, but %CD4+CCR4+ and %CD8+CCR4+ cells did not significantly change in both the PM and DM patients. Accordingly, the Th1/Th2 polarization, analyzed as the balance obtained after dividing %CD4+CXCR3+ cells by %CD4+CCR4+ cells, showed a significant reduction in DM. The serum concentration of CXCR3+ ligand, CXCL10, significantly increased and negatively correlated with circulating %CD4+CXCR3+ cells in DM patients. There was no significant change of TARC and MDC in PM and DM patients. Furthermore, %CD4+CXCR3+ cells decreased more severely in the patients with interstitial lung disease. ConclusionsThe present results indicate that the distributions of circulating CXCR3+ T-cells differ among the PM and DM cases. Our findings suggest a pathogenic difference between PM and DM.

Multiple values of 18F-FDG PET/CT in idiopathic inflammatory myopathy.

This study aimed to investigate the multiple values of 18F-FDG PET/CT in detecting malignant tumors, evaluating myopathy, and determining interstitial lung disease in patients with idiopathic inflammatory myopathy (IIM). We retrospectively analyzed the data of 38 patients who were examined by 18F-FDG PET/CT and eventually diagnosed as IIM. We also collected the data of another 22 cases with negative PET/CT as the control. Pulmonary HRCT images were acquired simultaneously with regular 18F-FDG PET/CT imaging for each patient. Image analysis included the presence of malignant lesions, muscular FDG uptake, and interstitial lung disease and its imaging features. IIM was classified into polymyositis (PM), classic dermatomyositis (CDM), and clinical amyopathic dermatomyositis (CADM). All suspected malignant lesions were confirmed by histopathological examination. Interstitial lung disease was diagnosed by HRCT. Rapidly progressive interstitial lung disease (RP-ILD) was determined according to clinical follow-ups. The significance of 18F-FDG PET/CT in the detection of malignancy, observation of activity of myopathy, and determination of interstitial lung disease in IIM patients was explored based on the final clinical diagnosis. In the 38 patients with IIM, 3 cases were classified as PM, 18 as CDM, and 17 as CADM. PET/CT correctly detected 7 cases (18.4%) of malignant tumors, and all of which were found in CDM and PM patients. The muscular FDG uptake in IIM patients was higher than the control population, and it was higher in patients with myopathy (including PM and CDM) than in patients with CADM. The muscular FDG uptake in IIM patients was correlated with elevated serum creatine kinase level (r=0.332, P=0.042) and impaired muscle strength (r=-0.605, P<0.001). Interstitial lung disease was detected by HRCT in 30 patients (78.9%), and 7 of them were eventually confirmed as RP-ILD, according to the clinical outcome. The FDG uptake in lung lesions of RP-ILD patients was higher than those with chronic interstitial lung diseases, even though no significant difference was found between the CT features of RP-ILD and chronic interstitial lung disease. When SUVmax≥2.4 was employed as the threshold for RP-ILD prediction, the diagnostic efficiency was yield with a sensitivity of 100.0% (7/7), specificity of 87.0% (20/23), and accuracy of 90.0% (27/30), respectively. For IIM patients, 18F-FDG PET/CT has multiple values in identifying malignancies, observing the status of inflammatory myopathy, detecting interstitial lung disease, and predicting the occurrence of RP-ILD. Therefore, it is recommended to use PET/CT in the clinical course of diagnosis and management of IIM.

Effect of endurance exercise on microRNAs in myositis skeletal muscle-A randomized controlled study.

ObjectiveTo identify changes in skeletal muscle microRNA expression after endurance exercise and associate the identified microRNAs with mRNA and protein expression to disease-specific pathways in polymyositis (PM) and dermatomyositis (DM) patients.MethodsFollowing a parallel clinical trial design, patients with probable PM or DM, exercising less than once a week, and on stable medication for at least one month were randomized into two groups at Karolinska University Hospital: a 12-week endurance exercise group (n = 12) or a non-exercised control group (n = 11). Using an Affymetrix microarray, microRNA expression was determined in paired muscle biopsies taken before and after the exercise intervention from 3 patients in each group. Ingenuity pathway analysis with a microRNA target filter was used to identify microRNA transcript targets. These targets were investigated at the mRNA (microarray) and protein (mass spectrometry) levels in patients.ResultsEndurance exercise altered 39 microRNAs. The microRNAs with increased expression were predicted to target transcripts involved in inflammatory processes, metabolism, and muscle atrophy. Further, these target transcripts had an associated decrease in mRNA expression in exercised patients. In particular, a decrease in the NF-κB regulator IKBKB was associated with an increase in its target microRNA (miR-196b). At the protein level, there was an increase in mitochondrial proteins (AK3, HIBADH), which were associated with a decrease in microRNAs that were predicted to regulate their expression.ConclusionImprovement in disease phenotype after exercise is associated with increasing microRNAs that target and downregulate immune processes at the transcript level, as well as decreasing microRNAs that target and upregulate mitochondrial content at the protein level. Therefore, microRNAs may improve disease by decreasing immune responses and increasing mitochondrial biogenesis.Trial registrationClinicalTrials.gov NCT01184625

Clinicopathologic features of myositis patients with CD8-MHC-1 complex pathology.

To determine the clinical features of myositis patients with the histopathologic finding of CD8-positive T cells invading non-necrotic muscle fibers expressing major histocompatibility complex class 1 (CD8-MHC-1 complex), which is shared by polymyositis (PM) and inclusion body myositis (IBM), in relation to the p62 immunostaining pattern of muscle fibers. All 93 myositis patients with CD8-MHC-1 complex who were referred to our hospital from 1993 to 2015 were classified on the basis of the European Neuromuscular Center (ENMC) diagnostic criteria for IBM (Rose, 2013) or PM (Hoogendijk, 2004) and analyzed. The 93 patients included were 17 patients with PM, 70 patients with IBM, and 6 patients who neither met the criteria for PM nor IBM in terms of muscle weakness distribution (unclassifiable group). For these PM, IBM, and unclassifiable patients, their mean ages at diagnosis were 63, 70, and 64 years; autoimmune disease was present in 7 (41%), 13 (19%), and 4 (67%); hepatitis C virus infection was detected in 0%, 13 (20%), and 2 (33%); and p62 was immunopositive in 0%, 66 (94%), and 2 (33%), respectively. Of the treated patients, 11 of 16 PM patients and 4 of 6 p62-immunonegative patients in the unclassifiable group showed responses to immunotherapy, whereas all 44 patients with IBM and 2 p62-immunopositive patients in the unclassifiable group were unresponsive to immunotherapy. CD8-MHC-1 complex is present in patients with PM, IBM, or unclassifiable group. The data may serve as an argument for a trial of immunosuppressive treatment in p62-immunonegative patients with unclassifiable myositis.

Clinical Heterogeneity of Interstitial Lung Disease in Polymyositis and Dermatomyositis Patients With or Without Specific Autoantibodies

BackgroundThe aim of this study was to compare the heterogeneity of interstitial lung disease (ILD) in patients with polymyositis and dermatomyositis (PM/DM) according to serological type. MethodsA total of 182 patients with PM/DM-ILD were observed retrospectively. Antiaminoacyl-tRNA synthetase (ARS) and antimelanoma differentiation-associated gene5 (MDA5) antibodies were screened using immunoblotting approach. The patients with ILD were divided into 3 groups: MDA5 (with anti-MDA5 antibody), ARS (with anti-ARS antibody) and MSN (without anti-MDA5 or anti-ARS antibody) group. Pulmonary features, treatment responses and prognoses were compared among the groups. ResultsA higher percentage of rapidly progressive ILD (RP-ILD) occurrences (55.8% versus 25% versus 16.9%, P < 0.001) was observed in the MDA5 group compared to ARS and MSN groups. The MSN group experienced lower dyspnea (48.2% versus 79% versus 71.4%, P = 0.001) and fever (18.1% versus 39.5% versus 37.5%, P = 0.01) frequencies compared to MDA5 and ARS groups. Response to 6-month treatment among 95 patients showed highest deterioration ratio (70%, P = 0.001) of ILD in the MDA5 group. Additionally, the highest frequency of ILD improvement (60%, P = 0.04) was observed in the ARS group. During the observation period, 24 patients died of respiratory failure. The 5-year survival rates were significantly lower in MDA5 group (50.2%) compared to ARS group (97.7%) or the MSN group (91.4%) (P < 0.001). ConclusionsMDA5-ILD was associated with severe pulmonary manifestations, poor response to treatment and aggravated prognosis. The ARS-ILD group had favorable treatment response and prognosis. MSN-ILD patients had relatively worse treatment response and prognosis compared to the ARS group, even though they expressed milder pulmonary manifestation.

Increased Incidence of Amyotrophic Lateral Sclerosis in Polymyositis: A Nationwide Cohort Study.

Past studies have shown common pathologic characteristics and shared immunologic features between polymyositis (PM) and amyotrophic lateral sclerosis (ALS). To explore the potential relationship between the 2 diseases, we performed a nationwide cohort study. We identified all newly diagnosed patients with PM from Taiwan's Registry of Catastrophic Illness Database between January 1, 1998 and December 31, 2011. Each PM patient was matched to ≤5 control patients from the National Health Insurance Research Database by sex, age, and entry date. Cumulative incidence of ALS was calculated by the Kaplan-Meier method and compared using the log rank test. Cox hazard regression was used to calculate the hazard ratio of ALS. A total of 1,778 PM patients and 8,124 control patients were enrolled. PM patients had a higher cumulative incidence of ALS (P < 0.001). There was a positive correlation in being diagnosed with ALS in patients previously diagnosed with PM when stratified by sex. Consistent trends were conserved across different age strata. The strength of this association remained statistically significant after adjusting for sex, age, and concomitant autoimmune diseases (hazard ratio 25.72 [95% confidence interval 2.95-224.58]; P = 0.003). This study demonstrates that a diagnosis of PM increased the likelihood of a subsequent ALS diagnosis, independent of sex, age, and concomitant autoimmune diseases. Future studies are warranted to clarify the underlying biologic mechanisms and to translate them into clinical therapeutic options.

Autoantibodies to Su/Argonaute 2 in Japanese patients with inflammatory myopathy

BackgroundAnti-Su antibodies are found in 5–20% of cases of various systemic autoimmune rheumatic diseases and in 5–10% of dermatomyositis (DM)/polymyositis (PM) patients. In 2006, the 100kDa Su antigen was identified as argonaute2 (Ago2), and it was found to play a major role in RNA interference. However, immunoprecipitation (IP) remains the main method for detecting anti-Su and the clinical significance of the antibodies is uncertain. MethodsSera from patients with DM/PM (n=224) were screened by an ELISA that uses recombinant biotinylated Ago2 protein. Some serum samples were tested by IP and by indirect immunofluorescence (IIF) analysis. ResultsSeventeen (7.5%, 17/224) sera from DM/PM were positive in ELISA. Of the 33 IP-tested sera (17 ELISA-positive and 16 ELISA-negative with high background), 13 were found to be anti-Ago2/Su-positive in IP and ELISA. Only one IP-positive serum was judged to be ELISA-negative. Among the 13 patients with anti-Su/Ago2, 7 cases also had myositis-specific autoantibodies. Six sera that were positive by both IP and ELISA showed the GW body pattern in IIF. Interestingly, one ELISA-positive serum with an inconclusive result in IP also showed the GW body pattern. ConclusionOur novel ELISA appears to be useful for screening anti-Su/Ago2 antibodies (sensitivity: 93%, specificity: 79%).