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Recently we characterized polymyositis in the Dutch Kooiker dog. The familial occurrence of the disease were suggestive of an inherited cause. Here we report the results of our molecular genetic investigation. A genome-wide association study of 33 cases and 106 controls indicated the involvement of a region on chromosome CFA19 (p = 4.7*10-10). Haplotype analysis indicated that the cases shared a 2.9 Mb region in the homozygous or the heterozygous state. Next Generation Sequencing of genomic DNA implicated a deletion of a 39 kb DNA fragment, located 10 kb upstream of the neighbouring interleukin genes IL21 and IL2. The frequency of the deletion allele was 0.81 in the available cases and 0.25 in a random sample of the Kooiker dog breed. Leukocytes of affected, untreated dogs that were homozygous for the deletion overexpress IL21 and IL2 upon stimulation with mitogens. We suggest that elements located 10-49 kb upstream of the IL21/IL2 locus play an important role in the regulation of the canine genes and that deletion of these elements is a risk factor for polymyositis in Kooiker dogs. Postulating causality, the penetrance of the disease phenotype was estimated at 10-20% for homozygous dogs and 0.5-2% for dogs that were heterozygous for the deletion. Our results suggest that distant variants upstream of IL21 could also be important for human autoimmune diseases that have been found to be associated with the IL21/IL2 chromosome region., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2025 Opmeer et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Objective: We aim to investigate transcriptomic and immunophenotypic features of muscle specimens from patients with idiopathic inflammatory myopathy (IIM)., Methods: Bulk RNA-sequencing was performed on muscle biopsy samples from 16 patients with dermatomyositis (DM) and 9 patients with polymyositis (PM). Seven tested positive for anti-aminoacyl transfer RNA synthetase antibodies in the patients with DM (ARS-DM). We conducted weighted gene coexpression network analysis (WGCNA), differentially expressed gene (DEG) analysis, and gene set variation analysis to assess contributions of specific pathways. Cell proportions in muscle specimens were estimated using a deconvolution approach., Results: WGCNA revealed significant positive correlations between serum creatine kinase (CK) levels and gene modules involved in cellular respiration, phagocytosis, and oxidative phosphorylation (OXPHOS). Significant positive correlations were also observed between CK levels and proportions of CD16-positive and negative monocytes and myeloid dendritic cells. Notably, patients with DM demonstrated enrichment of complement and interferon-α and γ pathway genes compared with those with PM. Furthermore, ARS-DM demonstrated a higher proportion of Th1 cells and DEGs related to OXPHOS. Additionally, serum Krebs von den Lungen-6 levels correlated with gene modules associated with extracellular matrix and the transforming growth factor-β signaling pathway., Conclusion: Our study highlights a significant involvement of monocytes in muscle damage and delineates pathologic differences among IIM subtypes. DM was characterized by complement and interferon-α and γ signaling, whereas ARS-DM was associated with OXPHOS. Distinctive gene expression variations in muscle specimens suggest that different pathologic mechanisms underlie muscle damage in each IIM phenotype., (© 2024 The Author(s). Arthritis & Rheumatology published by Wiley Periodicals LLC on behalf of American College of Rheumatology.)

Aims/Background The association between rheumatic immune diseases and polycystic ovary syndrome (PCOS) remains elusive. The purpose of this study was to investigate the causal relationship between rheumatic immune diseases and the risk of PCOS through a two-sample Mendelian randomization (MR) analysis. Methods In the assessment of exposure variables, we chose systemic lupus erythematosus (SLE), polymyositis (PM), and rheumatoid arthritis (RA) as representative rheumatic immune diseases, while PCOS was designated as the outcome of interest. All data utilized in this investigation were obtained from the Medical Research Council Integrative Epidemiology Unit (MRC-IEU) database. A two-sample MR analysis was conducted using summary statistics for both the exposure and outcome variables, which were gathered from the genome-wide association study (GWAS) datasets. Single nucleotide polymorphisms (SNPs) significantly associated with rheumatic diseases were selected as instrumental variables (IVs) to estimate the causal effects on PCOS. The final results were analyzed using five MR analysis methods, namely MR-Egger, inverse variance weighted (IVW), weighted median (WM), simple mode, and weighted mode. Causal estimation of MR was primarily obtained using the IVW method. Sensitivity analyses were also conducted to evaluate pleiotropy and heterogeneity. Results In this two-sample MR analysis, a total of 1,000,246 participants were included. Among them, there were 647 cases of SLE, 44 cases of PM, 5539 cases of RA, and 797 cases of PCOS. The IVW approach indicated a causal relationship between RA and an increased risk of PCOS (odds ratio [OR] = 1.069, 95% confidence interval [CI] = 1.007-1.134, p = 0.041). The MR-Egger intercept and Cochran's Q test ( p > 0.005) further verified the stability of the MR results. However, no significant correlation was observed between the other two rheumatic immune diseases (PM and SLE) and the risk of developing PCOS (both p > 0.05). Conclusion This study suggests a potential causal association between RA and PCOS, while SLE and PM do not exhibit a causal association with PCOS, enhancing our comprehension of the etiological factors of PCOS and shedding light on prevention strategies for the disease. Additional research is required to elucidate the underlying biological mechanisms by which RA contributes to the progression of PCOS.

Polymyositis is a prominent subgroup of idiopathic inflammatory myopathy, considered to have an autoimmune etiology. However, research exploring the condition between immunocytes and polymyositis remains limited, indicating the need for further investigation to unravel these intricate associations. We employed bidirectional Mendelian randomization (MR) analysis to ascertain causality between 731 immunocytes and polymyositis. We also compared the positive immunocytes with dermatomyositis. Our primary analytical method was inverse variance weighted, supplemented by 4 other MR techniques. Additionally, Cochran Q test was performed to assess heterogeneity, MR-Egger to appraise pleiotropy, and MR-PRESSO to identify and eliminate potential outliers. Furthermore, the leave-one-out test evaluated the impact of each instrumental variable (IV) on the causal effect. The inverse variance weighted results revealed that 10 immunocytes exert a protective effect against polymyositis (P < .05, OR < 1), while 16 immunocytes are connected with an elevated risk of the disease (P < .05, OR > 1). In reverse MR, polymyositis was found to decrease the levels of 2 immune cells (P < .05, OR < 1) and elevate the expression of 5 immune cell phenotypes (P < .05, OR > 1). A complex correlation was found between polymyositis and the immunocyte phenotypes CD8, CD33dim, HLA-DR, CD11b, and CD45. Additionally, it was discovered that 15 types of immune cells share a causal relationship between polymyositis and dermatomyositis. All analyses demonstrated no heterogeneity or horizontal pleiotropy (P > .05). Our study provides compelling evidence regarding the intricate causal relationships between immunocytes and polymyositis. Polymyositis and dermatomyositis share common immunocytes' regulatory mechanisms. CD8, CD33dim, HLA-DR, CD11b, and CD45 may represent potential immune cell markers for polymyositis. These findings hold implications for planning prognosis and therapeutic strategies for polymyositis, offering novel insights for drug development., Competing Interests: The authors have no funding and conflicts of interest to disclose., (Copyright © 2024 the Author(s). Published by Wolters Kluwer Health, Inc.)

Objective: Observational studies have revealed a higher probability of hypothyroidism in patients with dermatomyositis (DM) or polymyositis (PM), but there is no consensus on whether hypothyroidism causally influences DM or PM. In the present study, we assessed the causal association between hypothyroidism and the risk of dermatomyositis or polymyositis using two-sample Mendelian randomization (TSMR)., Methods: The genome-wide association data of hypothyroidism and dermatomyositis/polymyositis were obtained from the IEU Open GWAS project. Then, TSMR was used to determine whether hypothyroidism is causally associated with DM or PM. Single-nucleotide polymorphisms (SNPs) significantly associated with hypothyroidism were identified and used as instrumental variables (IVs), and the causal relationship between hypothyroidism and DM/PM was examined using TSMR. MR pleiotropy and Cochran's Q test were used to confirm the heterogeneity and pleiotropy of identified IVs, then four different models, including the inverse variance weighted model (IVW), MR-Egger, weighted median and weighted model were applied in this MR analysis., Results: Sixty-eight SNPs for DM and 68 SNPs for PM were selected as the IVs (P<5×10 -8 ; linkage disequilibrium R 2 <0.001) to assess the causal association between hypothyroidism and DM/PM selected from GWASs on hypothyroidism. The results revealed a positive causal effect of hypothyroidism on both DM and PM (DM: OR 2.563, 95% CI [1.348, 4.874], P = 0.00156; PM: OR1.709, 95% CI [1.157, 2.525], P =0.007). Moreover, there was no heterogeneity or pleiotropy in the results., Conclusion: In conclusion, the MR analysis results provided strong evidence to indicate that hypothyroidism might be causally associated with DM and PM. These findings may have important implications for the pathogenesis and possible future therapies of DM/PM., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Li, Yang, Ma, Huang, Zhi, Wang and Lu.)

Objective: To investigate the variability in the expression profile of genes associated with polymyositis (PM), explore the potential molecular mechanisms underlying PM, and predict novel targets for intervention., Study Design: Descriptive study. Place and Duration of the Study: Department of Rheumatology, Taizhou Municipal Hospital, Taizhou, China, from August to November 2023., Methodology: Three microarray datasets (GSE3112, GSE39454, and GSE128470) were extracted from the gene expression omnibus (GEO). The analysis of this research involved identifying the differentially expressed genes (DEGs) in PM compared to normal samples. Enrichment analysis, gene-microRNA, gene-transcription factor (TF), and protein-protein interaction (PPI) network studies were conducted to identify hub genes and relevant pathways. Additionally, the drug-gene interaction database (DGIdb) was used to predict therapeutic medications., Results: Eighty-eight DEGs were identified. The enrichment analysis results highlighted the significant involvement of downregulated DEGs in antigen processing and presentation. Based on the PPI networks, seven hub genes with high connectivity degrees were selected including a cluster of differentiation 74 (CD74), human leukocyte antigen (HLA)-DPA1, HLA-B, guanylate-binding protein 1 (GBP1), recombinant 2', 5'-oligoadenylate synthetase 1 (OAS1), HLA-C, and HLA-E., Conclusion: This research screened-out core genes, projected prospective therapeutic medications, discovered DEGs between PM and normal samples, and offered fresh perspectives for additional research into the possible mechanism and therapeutic targets of PM., Key Words: Polymyositis, DEGs, Hub genes, Bioinformatics, Potential therapeutic agents.

Background: Polymyositis (PM) is an acquirable muscle disease with proximal muscle involvement of the extremities as the main manifestation; it is a category of idiopathic inflammatory myopathy. This study aimed to identify the key biomarkers of PM, while elucidating PM-associated immune cell infiltration and immune-related pathways., Methods: The gene microarray data related to PM were downloaded from the Gene Expression Omnibus database. The analyses using Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes, gene set enrichment analysis (GSEA), and protein-protein interaction (PPI) networks were performed on differentially expressed genes (DEGs). The hub genes of PM were identified using weighted gene co-expression network analysis (WGCNA) and least absolute shrinkage and selection operator (LASSO) algorithm, and the diagnostic accuracy of hub markers for PM was assessed using the receiver operating characteristic curve. In addition, the level of infiltration of 28 immune cells in PM and their interrelationship with hub genes were analyzed using single-sample GSEA., Results: A total of 420 DEGs were identified. The biological functions and signaling pathways closely associated with PM were inflammatory and immune processes. A series of four expression modules were obtained by WGCNA analysis, with the turquoise module having the highest correlation with PM; 196 crossover genes were obtained by combining DEGs. Subsequently, six hub genes were finally identified as the potential biomarkers of PM using LASSO algorithm and validation set verification analysis. In the immune cell infiltration analysis, the infiltration of T lymphocytes and subpopulations, dendritic cells, macrophages, and natural killer cells was more significant in the PM., Conclusion: We identified the hub genes closely related to PM using WGCNA combined with LASSO algorithm, which helped clarify the molecular mechanism of PM development and might have great significance for finding new immunotherapeutic targets, and disease prevention and treatment., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Jia, Hao, Lu, Sun, Shao, Su and Huang.)

Objective: This study was designed to investigate the role of the nucleotide-binding-domain -and leucine-rich repeat -containing (NLR) family, pyrin-domain-containing 3 (NLRP3) inflammasome in the pathogenesis of polymyositis (PM)., Methods: Immunochemistry was performed to analyze the NLRP3, caspase-1 and interleukin-1 beta (IL-1β) expression in the muscle tissue of PM patients. Rat model of PM and C2C12 cell were used to investigate the potential role of NLRP3 inflammasome in PM., Results: The percentage of CD 68+ macrophages, and the expression levels of NLRP3, caspase-1 and IL-1β in the muscle tissue were elevated in 27 PM patients. LPS/ATP treatment resulted in activation of NLRP3 inflammasome and secretion of IL-1β as well as interferons (IFNs) and monocyte chemotactic protein-1 (MCP-1) in the Raw 264.7 macrophages. Meanwhile, LPS/ATP challenged activation of NLRP3 inflammasome induced overexpression of major histocompatibility complex class I (MHC-I), a key molecular of PM in the co-cultured C2C12 cells. The effect was decreased by treatment of NLRP3 inflammasome inhibitor MCC950 or siRNA of NLRP3 inflammasome. These findings suggested certain levels of IL-1β rather than IFNs up-regulated MHC-I expression in C2C12 cells. IL-1β blockade using neutralizing IL-1β monoclonal antibody or siRNA of IL-1β suppressed MHC-I overexpression. In vivo, NLRP3 inflammasome inhibition by MCC950 reduced the expression of NLRP3, IL-1β and MHC-I in the muscle tissue of PM modal rats. Also, it attenuated the intensity of muscle inflammation as well as the CRP, CK, and LDH levels in the serum., Conclusion: NLRP3/caspase-1/IL-1β axis may play an important role in the development of PM. Inhibition of NLRP3 activation may hold promise in the treatment of PM., (© 2022. The Author(s).)

Objective: Polymyositis (PM) is a chronic autoimmune connective tissue disease whose pathogenic mechanisms are unclear. This study aimed to identify the main genes and functionally enriched pathways involved in PM using weighted gene coexpression network analysis (WGCNA)., Methods: To identify the candidate genes of PM, microarray datasets GSE128470, GSE3112, GSE39454 and GSE125977 were obtained from the Gene Expression Omnibus database. The gene network of GSE128470 was constructed, and WGCNA was used to divide genes into different modules. Subsequently, Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analyses were applied to the most PM-related modules. The datasets were used to verify the expression profile and diagnostic capabilities of the hub genes. Additionally, gene set enrichment analysis (GSEA) was carried out. Moreover, gene signatures were then used as a search query to explore the connectivity map (CMap)., Results: A weighted gene coexpression network was constructed, and the genes were divided into 66 modules. The enriched functions and candidate pathway modules included interferon-γ, type I interferon, cellular response to interferon-γ, neutrophil activation, neutrophil degranulation, neutrophil-mediated immunity and neutrophil activation involved in the immune response. A total of 22 hub genes were identified. The Mann-Whitney U test was performed on these 22 genes using the three datasets of muscle samples and one dataset of whole blood samples, and two genes significantly differentially expressed in all datasets were obtained: VCAM1 and LY96. Receiver operating characteristic curve analysis determined that VCAM1 and LY96 gene expression can distinguish PM from healthy controls (the area under the curve [AUC] was greater than 0.75). Logistic regression analysis was performed on the combination of LY96 and VCAM1. The accuracy, sensitivity, specificity, and AUC of the combination reached 1.0. GSEA of VCAM1 and LY96 revealed their relation to 'inflammatory response', 'TNF-α signalling via NF-κB', 'complement' and 'myogenesis'. CMap research revealed a few compounds with the potential to counteract the effects of the dysregulated molecular signature in PM., Conclusions: We used WGCNA to observe all aspects of PM, which helped to elucidate the molecular mechanisms of PM onset and progression and provide candidate targets for the diagnosis and treatment of PM. Key Points • Four microarray datasets were analysed in patients with polymyositis and healthy controls, and VCAM1 and LY96 were significant genes in all datasets. • GSEA of VCAM1 and LY96 revealed that they were mainly related to 'inflammatory response', 'TNF-α signalling via NF-κB', 'complement' and 'myogenesis'. • CMap found a few compounds such as dimethyloxalylglycine and HNMPA-(AM)3 with the potential to counteract the effects of the dysregulated molecular signature in PM., (© 2021. International League of Associations for Rheumatology (ILAR).)

Objective: Polymyositis (PM) and dermatomyositis (DM) are heterogeneous disorders. However, the etiology of PM/DM development has not been thoroughly clarified., Methods: Gene expression data of PM/DM were obtained from Gene Expression Omnibus. We used robust rank aggregation (RRA) to identify differentially expressed genes (DEGs). Gene Ontology functional enrichment and pathway analyses were used to investigate potential functions of the DEGs. Weighted gene co-expression network analysis (WGCNA) was used to establish a gene co-expression network. CIBERSORT was utilized to analyze the pattern of immune cell infiltration in PM/DM. Protein-protein interaction (PPI) network, Venn, and association analyses between core genes and muscle injury were performed to identify hub genes. Receiver operating characteristic analyses were executed to investigate the value of hub genes in the diagnosis of PM/DM, and the results were verified using the microarray dataset GSE48280., Results: Five datasets were included. The RRA integrated analysis identified 82 significant DEGs. Functional enrichment analysis revealed that immune function and the interferon signaling pathway were enriched in PM/DM. WGCNA outcomes identified MEblue and MEturquoise as key target modules in PM/DM. Immune cell infiltration analysis revealed greater macrophage infiltration and lower regulatory T-cell infiltration in PM/DM patients than in healthy controls. PPI network, Venn, and association analyses of muscle injury identified five putative hub genes: TRIM22 , IFI6 , IFITM1 , IFI35 , and IRF9 ., Conclusions: Our bioinformatics analysis identified new genetic biomarkers of the pathogenesis of PM/DM. We demonstrated that immune cell infiltration plays a pivotal part in the occurrence of PM/DM.

Oxidative damage-induced mitochondrial dysfunction may activate muscle catabolism and autophagy pathways to initiate muscle weakening in idiopathic inflammatory myopathies (IIMs). In this study, Single nucleotide polymorphisms (SNPs) in the mitochondrial displacement loop (D-loop) and mitochondrial DNA (mtDNA) copy number were assessed and their association with the risk of polymyositis and dermatomyositis (PM/DM) was evaluated. Excessive D-loop SNPs (8.779 ± 1.912 vs. 7.972 ± 1.903, p = 0.004) correlated positively with mtDNA copy number (0.602 ± 0.457 vs. 0.300 ± 0.118, p < 0.001). Compared with that of the controls, the mtDNA of PM/DM patients showed D-loop SNP accumulation. In addition, the distribution frequencies of 16304C (p = 0.047) and 16519C (p = 0.043) were significantly higher in the patients with PM/DM. Subsequent analysis showed that reactive oxygen species (ROS) generation was increased in PM/DM patients compared with that in the controls (18,477.756 ± 13,574.916 vs. 14,484.191 ± 5703.097, p = 0.012). Further analysis showed that the PM/DM risk-related allele 16304C was significantly associated with lower IL-4 levels (p = 0.021), while 16519C had a trend to be associated with higher IL-2 expression (p = 0.064). The allele 16519C was associated with a positive antinuclear antibody (ANA) status in PM/DM patients (p = 0.011). Our findings suggest that mitochondrial D-loop SNPs could be potential biomarkers for PM/DM risk and these SNPs associated with cytokine expression may be involved in the development of PM/DM. Further, mtDNA copy number-mediated mitochondrial dysfunction may precede the onset of PM/DM., (© 2022. The Author(s).)

A 26-year-old Asian woman with persistent muscle weakness was diagnosed with polymyositis based on biopsy findings at another hospital 11 years ago. However, her symptoms fluctuated repeatedly under treatment with prednisone and immunosuppressive agents, and worsened 2 months prior to the current presentation. A second muscle biopsy suggested metabolic myopathy, and genetic testing revealed a novel c.1074C > T variant in the glycogen synthase 1 gene ( GYS1 ), which is implicated in muscle glycogen storage disease type 0. However, no abnormalities in glycogen deposition were found by biopsy; rather, muscle fibers exhibited large intracellular lipid droplets. Furthermore, muscle strength was greatly restored and circulating levels of creatine kinase indicative of muscle degeneration greatly reduced by vitamin B2 treatment. Therefore, the final diagnosis was lipid storage myopathy.

Muscle cell death in polymyositis is induced by CD8 + cytotoxic T lymphocytes. We hypothesized that the injured muscle fibers release pro-inflammatory molecules, which would further accelerate CD8 + cytotoxic T lymphocytes-induced muscle injury, and inhibition of the cell death of muscle fibers could be a novel therapeutic strategy to suppress both muscle injury and inflammation in polymyositis. Here, we show that the pattern of cell death of muscle fibers in polymyositis is FAS ligand-dependent necroptosis, while that of satellite cells and myoblasts is perforin 1/granzyme B-dependent apoptosis, using human muscle biopsy specimens of polymyositis patients and models of polymyositis in vitro and in vivo. Inhibition of necroptosis suppresses not only CD8 + cytotoxic T lymphocytes-induced cell death of myotubes but also the release of inflammatory molecules including HMGB1. Treatment with a necroptosis inhibitor or anti-HMGB1 antibodies ameliorates myositis-induced muscle weakness as well as muscle cell death and inflammation in the muscles. Thus, targeting necroptosis in muscle cells is a promising strategy for treating polymyositis providing an alternative to current therapies directed at leukocytes., (© 2022. The Author(s).)

Background: Macrophage migration and infiltration contribute to the pathogenesis of polymyositis (PM). This study aims to investigate the effect and underlying mechanism of miR-409-3p on macrophage migration in PM., Methods: The GSE143845 database was used to predict the altered expression of microRNAs (miRNAs) in PM. The quantitative real-time PCR (qRT-PCR), western blot and Transwell assay were performed to detect migration of macrophages and expressions of related molecules. A luciferase activity assay was conducted to confirm the binding of miR-409-3p and CXCR4 3'-UTR. Next, a mouse model of experimental autoimmune myositis (EAM) was established. Haematoxylin and eosin (HE) staining, immunohistochemistry (IHC), and enzyme-linked immunosorbent assay (ELISA) were used to measure associated factors., Results: MiR-409-3p was downregulated in PM of GSE143845 database and patients. Differently, the serum creatine kinase (s-CK), TNF-α, and IL-6 in patients with PM were increased. Furthermore, miR-409-3p mimic transfection reduced the migration of macrophages and CXCR4 levels, while miR-409-3p inhibitor exerted the opposite effects. CXCR4 was a target of miR-409-3p, and the effect of CXCR4 on promoting macrophage migration was reversed by miR-409-3p mimic. In vivo , miR-409-3p agomir injection reduced inflammatory cells, macrophages, and TNFα and IL-6 levels in muscles and serum of EAM mouse models., Conclusions: In conclusion, miR-409-3p reduces the migration of macrophages through negatively regulating CXCR4 expression in PM.

Objectives: Myositis is a heterogeneous family of diseases that includes dermatomyositis (DM), antisynthetase syndrome (AS), immune-mediated necrotising myopathy (IMNM), inclusion body myositis (IBM), polymyositis and overlap myositis. Additional subtypes of myositis can be defined by the presence of myositis-specific autoantibodies (MSAs). The purpose of this study was to define unique gene expression profiles in muscle biopsies from patients with MSA-positive DM, AS and IMNM as well as IBM., Methods: RNA-seq was performed on muscle biopsies from 119 myositis patients with IBM or defined MSAs and 20 controls. Machine learning algorithms were trained on transcriptomic data and recursive feature elimination was used to determine which genes were most useful for classifying muscle biopsies into each type and MSA-defined subtype of myositis., Results: The support vector machine learning algorithm classified the muscle biopsies with >90% accuracy. Recursive feature elimination identified genes that are most useful to the machine learning algorithm and that are only overexpressed in one type of myositis. For example, CAMK1G (calcium/calmodulin-dependent protein kinase IG), EGR4 (early growth response protein 4) and CXCL8 (interleukin 8) are highly expressed in AS but not in DM or other types of myositis. Using the same computational approach, we also identified genes that are uniquely overexpressed in different MSA-defined subtypes. These included apolipoprotein A4 (APOA4), which is only expressed in anti-3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR) myopathy, and MADCAM1 (mucosal vascular addressin cell adhesion molecule 1), which is only expressed in anti-Mi2-positive DM., Conclusions: Unique gene expression profiles in muscle biopsies from patients with MSA-defined subtypes of myositis and IBM suggest that different pathological mechanisms underly muscle damage in each of these diseases., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. No commercial re-use. See rights and permissions. Published by BMJ.)

Polymyositis (PM) and dermatomyositis (DM) are both classified as idiopathic inflammatory myopathies. They share a few common characteristics such as inflammation and muscle weakness. Previous studies have indicated that these diseases present aspects of an auto-immune disorder; however, their exact pathogenesis is still unclear. In this study, three gene expression datasets (PM: 7, DM: 50, Control: 13) available in public databases were used to conduct meta-analysis. We then conducted expression quantitative trait loci analysis to detect the variant sites that may contribute to the pathogenesis of PM and DM. Six-hundred differentially expressed genes were identified in the meta-analysis (false discovery rate (FDR) < 0.01), among which 317 genes were up-regulated and 283 were down-regulated in the disease group compared with those in the healthy control group. The up-regulated genes were significantly enriched in interferon-signaling pathways in protein secretion, and/or in unfolded-protein response. We detected 10 single nucleotide polymorphisms (SNPs) which could potentially play key roles in driving the PM and DM. Along with previously reported genes, we identified 4 novel genes and 10 SNP-variant regions which could be used as candidates for potential drug targets or biomarkers for PM and DM.

Polymyositis with mitochondrial pathology (PM-Mito) is a rare form of idiopathic inflammatory myopathy with no definite diagnostic criteria and similarities to both PM and sporadic inclusion body myositis (s-IBM). The aim of this study is to address the dilemma of whether PM-Mito is a subtype of inflammatory myopathy or represents a disease falling into the spectrum of s-IBM. Herein, we report four female patients diagnosed with PM-Mito, highlighting their rather atypical clinical and histopathological characteristics that seem to indicate a diagnosis away from s-IBM. Muscle weakness was rather proximal and symmetrical and lacked the selective pattern observed in s-IBM. Patients had large-scale deletions in mtDNA, reflecting the mitochondrial component in the pathology of the disease. Conclusively, our study adds to the limited data in the literature on whether PM-Mito is a distinct form of myositis or represents a prodromal stage of s-IBM. Although the latter seems to be supported by a substantial body of evidence, there are, however, important differences, such as the different patterns of muscle weakness, and the good response to treatment observed in some patients. Larger-scale studies are certainly needed to clarify pathogenesis and clinical characteristics of PM-Mito patients, especially in therapeutic and prognostic terms.

The aim of our study was to investigate the association between single nucleotide polymorphisms (SNPs) in the BANK1 gene and polymyositis/dermatomyositis (PM/DM) in a Chinese Han population. In total, 363 PM patients, 654 DM patients, and 1280 healthy controls were recruited and genotyped using the Sequenom MassArray system. A significant allele association was observed in rs3733197 among the PM/DM patients (OR 0.81, 95%CI 0.70-0.94, Pc = 1.83 × 10 -2 ). Notably, rs3733197 was associated with DM and PM/DM patients with ILD involvement (Pc = 0.026; Pc = 6.0 × 10 -3 , respectively). However, no statistically significant difference was observed in the allele or genotype frequencies of three SNPs (rs4522865, rs17266594, and rs10516487) among the DM, PM, and PM/DM patients and healthy controls (all Pc > 0.05). This study was the first to demonstrate that a BANK1 gene SNP (rs3733197) could confer genetic predisposition in PM/DM patients and PM/DM patients with ILD in a Chinese Han population.

Background: Inflammatory myopathies are characterized by infiltration of inflammatory cells into muscle. Typically, immune-mediated disorders such as polymyositis, dermatomyositis and inclusion body myositis are diagnosed., Objective: A small family of dogs with early onset muscle weakness and inflammatory muscle biopsies were investigated for an underlying genetic cause., Methods: Following the histopathological diagnosis of inflammatory myopathy, mutational analysis including whole genome sequencing, functional transport studies of the mutated and wild-type proteins, and metabolomic analysis were performed., Results: Whole genome resequencing identified a pathological variant in the SLC25A12 gene, resulting in a leucine to proline substitution at amino acid 349 in the mitochondrial aspartate-glutamate transporter known as the neuron and muscle specific aspartate glutamate carrier 1 (AGC1). Functionally reconstituting recombinant wild-type and mutant AGC1 into liposomes demonstrated a dramatic decrease in AGC1 transport activity and inability to transfer reducing equivalents from the cytosol into mitochondria. Targeted, broad-spectrum metabolomic analysis from affected and control muscles demonstrated a proinflammatory milieu and strong support for oxidative stress., Conclusions: This study provides the first description of a metabolic mechanism in which ablated mitochondrial glutamate transport markedly reduced the import of reducing equivalents into mitochondria and produced a highly oxidizing and proinflammatory muscle environment and an inflammatory myopathy.

Aim: Dermatomyositis (DM) and polymyositis (PM) are refractory systemic autoimmune diseases with unknown pathogenesis. miRNAs is an important epigenetic mechanism to regulate gene expression., Methods: We performed whole miRNAs analysis, transcription analysis and the association between miRNAome and mRNAome., Results: For transcription and miRNAs analysis, there were common and specific mRNAs and miRNAs in the muscles of DM and PM. Among them, the expression levels of miR-196a-5p and CPM were negatively correlated in PM, miR-193b-3p and NECAP2 were negatively correlated in DM and PM. Protein carboxypeptidase M (CPM) plays roles in the degradation of extracellular proteins and in the migration and invasion of cancer cells, and protein NECAP2 plays roles in adaptor protein AP-1-mediated fast recycling from early endosomes. The functions of them in the pathogenesis of DM/PM need further studies., Conclusion: Our study identified and confirmed differentially miRNAs and mRNAs in DM and PM. Our observations have laid the groundwork for further diagnostic and mechanistic studies of DM and PM.

The downregulation of microRNA (miR)-381 has been detected in various diseases. The present study aimed to investigate the effects, and underlying mechanisms of miR-381 on inflammation and macrophage infiltration in polymyositis (PM). A mouse model of experimental autoimmune myositis (EAM) was generated in this study. Hematoxylin and eosin staining was conducted to detect the inflammation of muscle tissues. In addition, ELISA and immunohistochemistry were performed to determine the expression levels of associated factors, and reverse transcription-quantitative polymerase chain reaction and western blotting were used to detect the expression levels of related mRNAs and proteins. A luciferase activity assay was used to confirm the binding of miR-381 and high mobility group box 1 (HMGB1) 3' untranslated region. Transwell assays were also performed to assess the migratory ability of macrophages. The results demonstrated that serum creatine kinase (s-CK), HMGB1 and cluster of differentiation (CD)163 expression in patients with PM were increased compared within healthy controls. Conversely, the expression levels of miR-381 were downregulated in patients with PM. Furthermore, high HMGB1 expression was associated with poor survival rate in patients with PM. In the mouse studies, muscle inflammation and CD163 expression were decreased in the anti-IL-17 and anti-HMGB1 groups, compared with in the EAM model group. The expression levels of s-CK, HMGB1, IL-17 and intercellular adhesion molecule (ICAM)-1 were also downregulated in response to anti-IL-17 and anti-HMGB1. These findings indicated that HMGB1 was closely associated with inflammatory responses. In addition, the present study indicated that transfection of macrophages with miR-381 mimics reduced the migration of inflammatory macrophages, and the expression levels of HMGB1, IL-17 and ICAM-1. Conversely, miR-381 inhibition exerted the opposite effects. The effects of miR-381 inhibitors were reversed by HMGB1 small interfering RNA. In conclusion, miR-381 may reduce inflammation and the infiltration of macrophages; these effects were closely associated with the downregulation of HMGB1.

Background: Polymyositis (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., Methods: Total 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., Results: In 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., Conclusions: Our 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.

This study aims to explore the roles of cysteine-rich protein 61 (Cyr61/CCN1), connective tissue growth factor (CTGF/CCN2) and vascular endothelial growth factor (VEGF) in the vascular process of polymyositis (PM)/dermatomyositis (DM).Real-time quantitative polymerase chain reaction was used to determine the mRNA expression of Cyr61, CTGF, and VEGF in muscle tissues of initially treated PM/DM patients and controls. Enzyme-linked immunosorbent assay (ELISA) was used to determine the serum levels of Cyr61, CTGF, and VEGF of initially treated PM/DM patients before and after treatment. Data were statistically analyzed using statistical software SPSS 17.0.The mRNA expression levels of Cyr61, CTGF, and VEGF in muscle tissues were higher in the PM and DM groups than in the control group (P < .05). Differences in the mRNA expression levels of Cyr61, CTGF, and VEGF in muscle tissues between the PM and DM groups were not statistically significant (P > .05). Before treatment, the serum levels of Cyr61, CTGF, and VEGF were higher in the PM and DM groups than in the control group (P < .05). Furthermore, in the PM and DM groups, the expression levels of Cyr61, CTGF, and VEGF in serum at 6 months after treatment were lower than those before treatment (P < .05).Cyr61, CTGF, and VEGF are involved in the pathogenesis of PM/DM. These may be involved in the pathogenesis mainly by affecting the formation of blood vessels and promoting inflammatory response. This suggests that microvascular lesions play an important role in the immune pathogenesis of inflammatory myopathy PM/DM.

Background: The prevalence of dermatomyositis (DM) versus DM and polymyositis (PM) combined has been shown to be negatively associated with latitude. This observation has been attributed to increasing exposure to ultraviolet (UV) light towards the equator. In this study, we investigated whether differing genetic background in populations could contribute to this distribution of DM., Methods: Case data derived from the MYOGEN (Myositis Genetics Consortium) Immunochip study (n = 1769) were used to model the association of DM prevalence and DM-specific autoantibodies with latitude. Control data (n = 9911) were used to model the relationship of human leucocyte antigen (HLA) associated with DM autoantibodies and DM or PM single-nucleotide polymorphisms (suggestive significance in the Immunochip project, P < 2.25 × 10 - 5 ) in healthy control subjects with latitude. All variables were analysed against latitude using ordered logistic regression, adjusted for sex., Results: The prevalence of DM, as a proportion of DM and PM combined, and the presence of anti-transcription intermediary factor 1 (anti-TIF1-γ) autoantibodies were both significantly negatively associated with latitude (OR 0.96, 95% CI 0.95-0.98, P < 0.001; and OR 0.95, 95% CI 0.92-0.99, P = 0.004, respectively). HLA alleles significantly associated with anti-Mi-2 and anti-TIF1-γ autoantibodies also were strongly negatively associated with latitude (OR 0.97, 95% CI 0.96-0.98, P < 0.001 and OR 0.98, 95% CI 0.97-0.99, P < 0.001, respectively). The frequency of five PM- or DM-associated SNPs showed a significant association with latitude (P < 0.05), and the direction of four of these associations was consistent with the latitude associations of the clinical phenotypes., Conclusions: These results lend some support to the hypothesis that genetic background, in addition to UV exposure, may contribute to the distribution of DM.

Objectives: Idiopathic inflammatory myopathies (IIMs) are a heterogeneous group of rare autoimmune diseases in which both genetic and environmental factors play important roles. To identify genetic factors of IIM including polymyositis, dermatomyositis (DM) and clinically amyopathic DM (CADM), we performed the first genome-wide association study for IIM in an Asian population., Methods: We genotyped and tested 496 819 single nucleotide polymorphism for association using 576 patients with IIM and 6270 control subjects. We also examined the causal mechanism of disease-associated variants by in silico analyses using publicly available data sets as well as by in in vitro analyses using reporter assays and apoptosis assays., Results: We identified a variant in WDFY4 that was significantly associated with CADM (rs7919656; OR=3.87; P=1.5×10 -8 ). This variant had a cis-splicing quantitative trait locus (QTL) effect for a truncated WDFY4 isoform (tr- WDFY4 ), with higher expression in the risk allele. Transexpression QTL analysis of this variant showed a positive correlation with the expression of NF-κB associated genes. Furthermore, we demonstrated that both WDFY4 and tr-WDFY4 interacted with pattern recognition receptors such as TLR3, TLR4, TLR9 and MDA5 and augmented the NF-κB activation by these receptors. WDFY4 isoforms also enhanced MDA5-induced apoptosis to a greater extent in the tr-WDFY4-transfected cells., Conclusions: As CADM is characterised by the appearance of anti-MDA5 autoantibodies and severe lung inflammation, the WDFY4 variant may play a critical role in the pathogenesis of CADM., Competing Interests: Competing interests: None declared., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Aim: Racial differences and genetic overlap have been shown to be responsible for the difference in susceptibility to dermatomyositis (DM)/polymyositis (PM) in a variety of populations. Single nucleotide polymorphisms (SNPs) in the GLI-similar 3 (GLIS3) and tyrosine kinase 2 (TYK2) genes have been associated with various autoimmune diseases. The aim of this study was to investigate whether SNPs in GLIS3 (rs7020673, rs10758593, and rs10814916) and TYK2 (rs280519, rs2304256, rs17000730, and rs280501) were associated with an increase in susceptibility to DM/PM in a Chinese Han population., Materials and Methods: SNPs in GLIS3 and TYK2 were analyzed in a cohort of 1017 patients with DM/PM and 1280 healthy controls using a Sequenom MassArray system. Association analyses were performed using the PLINK v1.07 software., Results: In our study, the GLIS3 polymorphisms rs7020673 and rs10758593 were initially found to be predisposing risk factors for PM and PM with interstitial lung disease (p < 0.05). Both rs7020673 and rs10758593 were associated with PM in both additive and dominant models (p < 0.05); however, these observed associations were not apparent after Bonferroni correction. Other SNPs examined in our study were not associated with susceptibility to DM/PM., Conclusion: GLIS3 and TYK2 polymorphisms are not associated with DM/PM in the Chinese Han population. As associations of SNPs in these genes in patients with DM/PM have been previously reported in other populations, we may conclude that the lack of association in our study may be the result of differences in genetic background. Further studies in other populations are needed to confirm our findings.

We report the case of a 32-year-old woman with severely elevated serum creatine kinase (CK; 80,000 U/l) and progressive proximal pareses. As muscular biopsy showed inflammatory infiltrates, polymyositis was suspected and immunosuppressive treatment was initiated. However, clinical improvement could not be achieved. Gene sequencing of the DYSF-gene showed a previously unreported homozygous mutation. In summary, elevated serum CK and inflammatory infiltrates in the muscle biopsy are not specific for polymyositis, but may also occur in degenerative diseases (muscular dystrophy), such as dysferlinopathy.

Purpose of Review: This article reviews the advances that have been made in our understanding of the genetics of the idiopathic inflammatory myopathies (IIM) in the past 2 years, with a particular focus on polymyositis, dermatomyositis and inclusion body myositis., Recent Findings: Two large human leukocyte antigen (HLA) imputation studies have confirmed a strong association with the 8.1 ancestral haplotype in clinical subgroups of myositis and suggest multiple independent associations on this haplotype. Risk in these genes may be due to specific amino acid positions within the peptide-binding grooves of HLA molecules. A large genetic study in 2566 IIM patients revealed associations such as PTPN22, STAT4, UBE2L3 and BLK, which overlap with risk variants reported in other seropositive autoimmune diseases. There is also evidence of different genetic architectures in clinical subgroups of IIM. Candidate gene studies in the Japanese and Chinese populations have replicated previous IIM associations which suggest common aetiology between ethnicities., Summary: International collaborations have facilitated large genetic studies in IIM that have revealed much about the genetics of this rare complex disease both within the HLA region and genome-wide. Future approaches, such as sequencing and trans-ethnic meta-analyses, will advance our knowledge of IIM genetics.

Objectives: The idiopathic inflammatory myopathies (IIMs) are a heterogeneous group of rare autoimmune diseases characterised by muscle weakness and extramuscular manifestations such as skin rashes and interstitial lung disease. We genotyped 2566 IIM cases of Caucasian descent using the Immunochip; a custom array covering 186 established autoimmune susceptibility loci. The cohort was predominantly comprised of patients with dermatomyositis (DM, n=879), juvenile DM (JDM, n=481), polymyositis (PM, n=931) and inclusion body myositis (n=252) collected from 14 countries through the Myositis Genetics Consortium., Results: The human leucocyte antigen (HLA) and PTPN22 regions reached genome-wide significance (p<5×10(-8)). Nine regions were associated at a significance level of p<2.25×10(-5), including UBE2L3, CD28 and TRAF6, with evidence of independent effects within STAT4. Analysis of clinical subgroups revealed distinct differences between PM, and DM and JDM. PTPN22 was associated at genome-wide significance with PM, but not DM and JDM, suggesting this effect is driven by PM. Additional suggestive associations including IL18R1 and RGS1 in PM and GSDMB in DM were identified. HLA imputation confirmed that alleles HLA-DRB1*03:01 and HLA-B*08:01 of the 8.1 ancestral haplotype (8.1AH) are most strongly associated with IIM, and provides evidence that amino acids within the HLA, such as HLA-DQB1 position 57 in DM, may explain part of the risk in this locus. Associations with alleles outside the 8.1AH reveal differences between PM, DM and JDM., Conclusions: This work represents the largest IIM genetic study to date, reveals new insights into the genetic architecture of these rare diseases and suggests different predominating pathophysiology in different clinical subgroups., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/)

An 80-year-old man, who developed multiple lymph node and skin metastasis of malignant melanoma, received nivolumab monotherapy. Two weeks after the first dose, he experienced anorexia and fatigue, and suffered from progressive, severe dyspnea and muscle weakness. We diagnosed him with myocarditis, myositis, and myasthenic crisis induced by nivolumab. We commenced steroid therapy, immune absorption therapy, plasma exchange therapy, and i.v. immunoglobulin therapy, and succeeded in saving his life. Because his serum level of anti-acetylcholine receptor antibodies in a sample collected before nivolumab treatment were positive and were elevated significantly after nivolumab, we suspected that nivolumab triggered a severe autoimmune response, which progressed subclinical myasthenia gravis to myasthenic crisis. We carried out T cell receptor repertoire analysis using next-generation sequencing technologies and identified infiltration of clonally expanded T cell populations in the skeletal muscle after nivolumab treatment, implying a very strong T cell immune response against muscular cells. To avoid severe immune-related adverse events, the exclusion of patients with subclinical autoimmune disease is very important for treatment with immune checkpoint inhibitors., (© 2016 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

Objective An association has been reported between inflammatory myopathies (IMs), which include polymyositis (PM) and dermatomyositis (DM), and malignancy, and the concept of cancer-associated myositis (CAM) was recently proposed. We herein attempted to determine the features and etiologies of these myopathies. Methods We analyzed the gene expression levels via microarray and real-time quantitative reverse transcription polymerase chain reaction analyses to identify genes that were specifically upregulated or downregulated with suspected inflammatory involvement and verified the microarray data via an immunohistochemical (IHC) analysis in additional cases. Patients We selected 14 patients with the following conditions: PM without malignancy (n=3), DM without malignancy (n=3), CAM (n=3), and Controls (no pathological changes or malignancy; n=5). Results PM was distinct from DM and CAM in a clustering analysis and exhibited the highest numbers of overexpressed genes and specific pathologies in a gene ontology analysis. The IHC analysis confirmed the gene expression results. Conclusion PM is associated with severe inflammatory pathological findings, primarily in the cell-mediated immune system. DM and CAM exhibit similarities in the gene expression and IHC results, which suggest that humoral immunity is the main etiology for both myopathies, indicating the importance of cancer screening in patients with IMs, particularly DM.

Autoimmune muscle diseases (myositis) comprise a group of complex phenotypes influenced by genetic and environmental factors. To identify genetic risk factors in patients of European ancestry, we conducted a genome-wide association study (GWAS) of the major myositis phenotypes in a total of 1710 cases, which included 705 adult dermatomyositis, 473 juvenile dermatomyositis, 532 polymyositis and 202 adult dermatomyositis, juvenile dermatomyositis or polymyositis patients with anti-histidyl-tRNA synthetase (anti-Jo-1) autoantibodies, and compared them with 4724 controls. Single-nucleotide polymorphisms showing strong associations (P<5×10(-8)) in GWAS were identified in the major histocompatibility complex (MHC) region for all myositis phenotypes together, as well as for the four clinical and autoantibody phenotypes studied separately. Imputation and regression analyses found that alleles comprising the human leukocyte antigen (HLA) 8.1 ancestral haplotype (AH8.1) defined essentially all the genetic risk in the phenotypes studied. Although the HLA DRB1*03:01 allele showed slightly stronger associations with adult and juvenile dermatomyositis, and HLA B*08:01 with polymyositis and anti-Jo-1 autoantibody-positive myositis, multiple alleles of AH8.1 were required for the full risk effects. Our findings establish that alleles of the AH8.1 comprise the primary genetic risk factors associated with the major myositis phenotypes in geographically diverse Caucasian populations.

Objectives: Our objective was to better understand the roles of single nucleotide polymorphisms (SNPs) in the CCL21, ERBB3, and TERT genes region in the development of idiopathic inflammatory myopathies (IIMs), we explored the associations between SNPs in the mentioned three genes and IIMs susceptibility in a Chinese Han population., Methods: Chinese polymyositis (PM) patients (n =291), dermatomyositis (DM) patients (n=526) and ethnically-matched healthy controls (n =968) were genotyped for the CCL21 region SNPs (rs951005 and rs2492358), ERBB3 (rs2292239 and rs11171739), and TERT (rs2853676 and rs10069690), by using the Sequenom MassArray system., Results: Our study indicated strong allele and genotype associations between rs951005 (OR: 1.65, 95%CI: 1.18-2.30, Pc=0.015; Pc=0.041, respectively) in CCL21 gene and PM patients. Additionally, rs951005 was associated with interstitial lung disease (ILD) in PM patients (Pc =0.01), and was associated with PM patients in additive model. However, the Chinese Han PM/DM patients and controls had statistically similar frequencies of alleles, genotypes and different genetic models (additive, dominant, and recessive) of ERBB3 and TERT polymorphisms., Conclusions: This was the first study to demonstrate that the CCL21 gene SNP (rs951005) might confer genetic predisposition to PM patients or such patients with ILD in a Chinese Han population.

Idiopathic inflammatory myopathies (IIMs) are autoimmune diseases influenced by genetic background and environmental factors. Recently, FAM167A-BLK gene has been identified as a potential genetic susceptibility locus for dermatomyositis (DM) in patients of European and Japanese populations. Our aim here was to investigate the association between FAM167A-BLK polymorphisms and IIMs risk in Chinese Han. The FAM167A-BLK single nucleotide polymorphisms (SNPs) rs2736340, rs7812879, rs13277113, rs2618479, rs2254546 and rs2248932 were analyzed in polymyositis (PM) patients (n = 310), DM patients (n = 535) and 968 ethnically matched healthy controls, with the Sequenom MassArray system. Our present study demonstrated that strong allele association was observed in overall PM/DM and PM patients for rs2736340 (P c = 6.48 × 10(-3); P c = 0.013, respectively), rs7812879 (P c = 0.017; P c = 0.034, respectively) and rs13277113 (P c = 0.011; P c = 0.047, respectively). These three SNPs were significantly associated with interstitial lung disease (ILD) in overall PM/DM patients (all, P c < 0.05). The frequency of the five haplotypes of the five SNPs (rs2736340, rs7812879, rs13277113, rs2618479 and rs2254546) was also significantly different between overall PM/DM, PM or DM patients and healthy controls. This was the first study to demonstrate that the FAM167A-BLK polymorphisms were associated with Chinese PM/DM patients or these patients with ILD, indicating that PM/DM might share common gene with other autoimmune diseases.

Pompe disease is a rare metabolic myopathy whose diagnosis is sometimes delayed despite being essential for improving clinical outcomes. We aimed to investigate the prevalence of late-onset Pompe disease among patients with a myopathy of unknown etiology, including polymyositis, or with idiopathic rise of creatine kinase (CK) levels, in a department of internal medicine. A cohort study was conducted in 241 subjects: 140 patients with myopathies of unknown origin or increased CK levels, 30 with polymyositis and 71 who constituted the control group of other myopathies. Acid α-glucosidase (GAA) activity was tested in dried blood spots. If a positive result was obtained, GAA activity in isolated lymphocytes and/or genetic testing was performed as a confirmatory diagnosis. Out of the 140 investigated patients, 2 patients with myopathies of unknown origin were confirmed to be positive for Pompe disease. Thus, late-onset Pompe disease should be considered among adult patients with myopathy of unknown origin., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Objective: The Norwegian nationwide MCTD cohort was established to obtain unbiased data on key disease issues, and thereby reappraise the concept of MCTD. In the current study, the aims were to obtain detailed HLA profile data on the large Norwegian MCTD cohort and compare these with the HLA profiles of ethnically matched healthy controls and related CTD controls., Methods: HLA profiles, determined by sequence-based typing of HLA-B* and DRB1*, were compared between four control groups of Norwegian ancestry, SLE (n = 96), SSc (n = 95), PM/DM (n = 84), healthy individuals (n = 282), the complete MCTD cohort (n = 155) and MCTD subsets defined by key clinical parameters., Results: HLA-B*08 [odds ratio (OR) 2.05, P = 1.31 × 10(-4)) and DRB1*04:01 (OR 2.82, P = 3.64 × 10(-8)) were identified as risk alleles for MCTD, while DRB1*04:04, DRB1*13:01 and DRB1*13:02 were protective. Risk alleles for SLE and PM/DM were B*08 and DRB1*03:01. SSc risk was associated with DRB1*08:01. Analyses of MCTD subsets identified B*18 [OR 3.32 (95% CI 1.38, 8.01)] and DRB1*03:01 [OR 1.83 (95% CI 1.03, 3.25)] as independent risk factors for lung fibrosis., Conclusion: Novel HLA alleles associated with MCTD and disease subsets were identified and DRB1*04:01 was confirmed as a major risk allele. Altogether, the data reinforce the notion of MCTD as a disease entity distinct from SLE, SSc and PM/DM., (© The Author 2014. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Background: Single-nucleotide polymorphisms (SNPs) in the TNFAIP3, IFIH1, and IRF5 genes have been associated with several auto-inflammation diseases, while the susceptibility between these genes and idiopathic inflammatory myopathies (IIMs) were not reported. This study aimed to investigate whether TNFAIP3, IFIH1, and IRF5 gene polymorphisms confer susceptibility for the IIMs in Chinese Han population., Methods: A large case-control study of Chinese subjects with polymyositis (PM) (n = 298) and dermatomyositis (DM) (n = 530) was accomplished. 968 healthy and ethnically matched controls were available for comparison. Six SNPs in the TNFAIP3 region (rs2230926 and rs5029939), the IFIH1 gene (rs1990760 and rs3747517) and the IRF5 region (rs4728142 and rs729302) were assessed and genotyped using the Sequenom MassArray iPLEX platform., Results: Our study indicated a strong allele association was observed in PM/DM and PM patients for rs2230926 (OR: 1.61, 95%CI: 1.20-2.16, P(c) = 7.5×10(-3); OR: 1.88, 95%CI: 1.30-2.74, P(c) = 4.0×10(-3), respectively) and rs5029939 (OR: 1.64, 95%CI: 1.21-2.21, P(c) = 6.0×10(-3); OR: 1.88, 95%CI: 1.28-2.76, P(c) = 5.5×10(-3), respectively). And rs2230926 and rs5029939 were significantly associated with interstitial lung disease (ILD) in PM/DM and PM patients (P(c) = 0.04 and P(c) = 0.016; P(c) = 0.02 and P(c) = 0.03, respectively). In addition, rs4728142 allele and genotype had significant association with PM/DM patients (P(c) = 0.026 and P(c) = 0.048, respectively). Further analysis with three logistic regression genetic models revealed statistically significant difference in the genotypic distribution in the PM/DM, PM or DM patients when the additive and dominant models were used., Conclusions: This was the first study to reveal TNFAIP3 and IRF5 polymorphisms were associated with PM/DM patients or these patients with ILD, indicating that TNFAIP3 and IRF5 might be the susceptibility gene for PM/DM patients in Chinese Han population.

Objective: To investigate the role of adhesion molecules in C protein-induced myositis (CIM), a murine model of polymyositis (PM)., Methods: CIM was induced in wild-type mice, L-selectin-deficient (L-selectin(-/-) ) mice, intercellular adhesion molecule 1 (ICAM-1)-deficient (ICAM-1(-/-) ) mice, and mice deficient in both L-selectin and ICAM-1 (L-selectin(-/-) ICAM-1(-/-) mice). Myositis severity, inflammatory cell infiltration, and messenger RNA expression in the inflamed muscles were analyzed. The effect of dendritic polyglycerol sulfate, a synthetic inhibitor that suppresses the function of L-selectin and endothelial P-selectin, was also examined., Results: L-selectin(-/-) mice and L-selectin(-/-) ICAM-1(-/-) mice developed significantly less severe myositis compared to wild-type mice, while ICAM-1 deficiency did not inhibit the development of myositis. L-selectin(-/-) mice that received wild-type T cells developed myositis. Treatment with dendritic polyglycerol sulfate significantly diminished the severity of myositis in wild-type mice compared to treatment with control., Conclusion: These data indicate that L-selectin plays a major role in the development of CIM, whereas ICAM-1 plays a lesser role, if any, in the development of CIM. L-selectin-targeted therapy may be a candidate for the treatment of PM., (Copyright © 2014 by the American College of Rheumatology.)

We investigated the molecular mechanisms involved in the pathogenesis of three inflammatory myopathies, dermatomyositis (DM), polymyositis (PM) and inclusion body myositis (IBM). We performed microarray experiments(†) using microdissected pathological muscle fibres from 15 patients with these disorders and five controls. Differentially expressed candidate genes were validated by immunohistochemistry on muscle biopsies, and the altered pathways were analysed in human myotube cultures. Up-regulation of genes involved in viral and nucleic acid recognition were found in the three myopathies but not in controls. In DM, retinoic acid-inducible gene 1 (RIG-I, DDX58) and the novel antiviral factor DDX60, which promotes RIG-I-mediated signalling, were significantly up-regulated, followed by IFIH1 (MDA5) and TLR3. Immunohistochemistry confirmed over-expression of RIG-I in pathological muscle fibres in 5/5 DM, 0/5 PM and 0/5 IBM patients, and in 0/5 controls. Stimulation of human myotubes with a ligand of RIG-I produced a significant secretion of interferon-β (IFNβ; p < 0.05) and up-regulation of class I MHC, RIG-I and TLR3 (p < 0.05) by IFNβ-dependent and TLR3-independent mechanisms. RIG-I-mediated innate immunity, triggered by a viral or damage signal, plays a significant role in the pathogenesis of DM, but not in that of PM or IBM., (Copyright © 2014 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.)

Background: Polymyositis (PM) and dermatomyositis (DM) are idiopathic inflammatory myopathies. Genetic variability in human leukocyte antigen (HLA) genes plays an important role in the pathogenesis of PM and DM. However, few studies on the subject in Chinese populations have been reported thus far., Methods: We studied the influence of HLA polymorphisms on DM and PM susceptibility by analyzing HLA-DRB1, HLA-DQA1, and HLA-DQB1 alleles in 71 adult DM patients, 20 adult PM patients, and 113 controls in a Han Chinese population., Results: A positive association was found between HLA-DQA1*0104 and DM (p = 0.01; corrected p (pcorr) NS; odds ratio (OR) = 2.58; 95% confidence interval (CI): 1.18-5.64), while an inverse correlation was noted between HLA-DQB1*0303 and myositis patients with interstitial lung inflammation (p = 0.01; pcorr NS; OR = 0.25; 95% CI: 0.07-0.73). A positive relationship was also observed between HLA-DRB1*07 and DM (p = 0.01; pcorr NS; OR = 2.26; 95% CI: 1.12-4.59), while HLA-DRB1*03 seems to be protective against DM (p = 0.01; pcorr NS; OR = 0.26; 95% CI: 0.06-0.81). The lung complication was closely associated with HLA-DRB1*04 (p = 0.01; pcorr NS; OR = 2.82; 95% CI: 1.15-6.76) and HLA-DRB1*12 (p = 0.02; pcorr NS; OR = 2.52; 95% CI: 1.02-6.07). The frequency of HLA-DRB1*07 was significantly higher among myositis patients with dysphagia than among controls (p = 0.01; pcorr NS; OR = 4.78; 95% CI: 1.03-24.42). The putative haplotype DRB1*07-DQA1*01-DQB1*02 was positively correlated with DM (p = 0.03; pcorr NS; OR = 2.90; 95% CI: 1.02-8.93) and the lung complication (p = 0.02; pcorr NS; OR = 3.45; 95% CI: 1.04-11.58)., Conclusions: Our results demonstrate that HLA alleles may be involved in susceptibility to adult DM and PM in the Han Chinese population.

Background: Accumulating evidence has shown that several non-HLA genes are involved in the susceptibility to polymyositis/dermatomyositis. This study aimed to investigate the involvement of C8orf13-BLK, one of the strongest candidate genes for autoimmune diseases, in susceptibility to polymyositis/dermatomyositis in the Japanese population. A possible gene-gene interaction between C8orf13-BLK and STAT4, which we recently showed to be associated with Japanese polymyositis/dermatomyositis, was also analyzed., Methods: A single-nucleotide polymorphism in C8orf13-BLK (dbSNP ID: rs13277113) was investigated in the Japanese population using a TaqMan assay in 283 polymyositis patients, 194 dermatomyositis patients, and 656 control subjects., Results: The C8orf13-BLK rs13277113A allele was associated with overall polymyositis/dermatomyositis (P<0.001, odds ratio [OR] 1.44, 95% confidence interval [CI] 1.19-1.73), as well as polymyositis (P = 0.011, OR 1.32, 95% CI 1.06-1.64) and dermatomyositis (P<0.001, OR 1.64, 95% CI 1.26-2.12). No association was observed between the C8orf13-BLK rs13277113A allele and either interstitial lung disease or anti-Jo-1 antibody positivity. The C8orf13-BLK rs13277113 A and STAT4 rs7574865 T alleles had an additive effect on polymyositis/dermatomyositis susceptibility. The strongest association was observed in dermatomyositis, with an OR of 3.07 (95% CI; 1.57-6.02) for the carriers of four risk alleles at the two SNP sites, namely, rs1327713 and rs7574865., Conclusions: This study established C8orf13-BLK as a new genetic susceptibility factor for polymyositis/dermatomyositis. Both C8orf13-BLK and STAT4 exert additive effects on disease susceptibility. These observations suggested that C8orf13-BLK, in combination with STAT4, plays a pivotal role in creating genetic susceptibility to polymyositis/dermatomyositis in Japanese individuals.

Introduction: We sought to study the intensity and pattern of major histocompatibility complex (MHC) I and II expression in muscle from patients with biopsy-proven idiopathic inflammatory myositis (IIM) including the subgroups, polymyositis (PM), dermatomyositis (DM), and inclusion body myositis (IBM)., Methods: A total of 120 muscle biopsies (61 PM, 14 DM, and 45 IBM) were immunostained for MHC I and II. Staining was graded as follows. 0: no staining, 1+: ≤10% fibers, 2+: 10% to 25%, 3+: 25% to 50%, 4+: 50% to 99%, and 5+ 100%., Results: All IIM biopsies showed MHC I positivity; 93% showed MHC II positivity. The proportion of patients with MHC II score ≥3+ was higher in IBM than DM or PM. In DM, MHC I expression showed a perifascicular pattern. All IBM biopsies were immunopositive for MHC I and II; 30/45 were scored 5+., Discussion: Immunostaining for MHC I and II is a useful adjunctive test in diagnosis and subclassification of IIM.

Aims: Increasing evidences suggest a similarity in the pathophysiological mechanisms of neuronal cell death in amyotrophic lateral sclerosis (ALS) and myofibre degeneration in sporadic inclusion body myositis (sIBM). The aim of this study is to elucidate the involvement of ALS-causing proteins in the pathophysiological mechanisms in sIBM., Methods: Skeletal muscle biopsy specimens of five patients with sIBM, two with oculopharyngeal muscular dystrophy (OPMD), three with polymyositis (PM), three with dermatomyositis (DM), three with neurogenic muscular atrophy, and three healthy control subjects were examined. We analysed the expression and localization of familial ALS-causing proteins, including transactive response DNA binding protein-43 (TDP-43), fused in sarcoma/translocated in liposarcoma (FUS/TLS), Cu/Zn superoxide dismutase (SOD1) and optineurin (OPTN) by immunohistochemistry., Results: TDP-43, OPTN and, to a lesser extent, FUS/TLS were more frequently accumulated in the cytoplasm in patients with sIBM and OPMD than in patients with PM, DM, neurogenic muscular atrophy, or healthy control subjects. SOD1 was accumulated in a small percentage of myofibres in patients with sIBM and OPMD, and to a very small extent in patients with PM and DM. Confocal microscopy imaging showed that TDP-43 proteins more often colocalized with OPTN than with FUS/TLS, p62 and phosphorylated Tau., Conclusions: These findings suggest that OPTN in cooperation with TDP-43 might be involved in the pathophysiological mechanisms of skeletal muscular degeneration in myopathy with rimmed vacuoles. Further investigation into these mechanisms is therefore warranted., (© 2012 The Authors. Neuropathology and Applied Neurobiology © 2012 British Neuropathological Society.)

Familial Mediterranean fever (FMF) is an autosomal recessive disease affecting populations surrounding the Mediterranean area. In this case report, we report a Japanese female patient with polymyositis (PM) who presented with periodic fever. Genetic analysis revealed that she had compound heterozygous mutations in exon 2 of the MEFV gene (L110P/E148Q/R202Q). Treatment with colchicines (1.0 mg/day) successfully eliminated febrile attack and normalized the elevated levels of neutrophil CD64 expression, leading to the diagnosis of FMF. The association of FMF and PM has not previously been reported, so we discuss this rare association.

A breed-specific polymyositis is frequently observed in the Hungarian Vizsla. Beneficial clinical response to immunosuppressive therapies has been demonstrated which points to an immune-mediated aetiology. Canine inflammatory myopathies share clinical and histological similarities with the human immune-mediated myopathies. As MHC class II associations have been reported in the human conditions we investigated whether an MHC class II association was present in the canine myopathy seen in this breed. 212 Hungarian Vizsla pedigree dogs were stratified both on disease status and degree of relatedness to an affected dog. This generated a group of 29 cases and 183 "graded" controls: 93 unaffected dogs with a first degree affected relative, 44 unaffected dogs with a second degree affected relative, and 46 unaffected dogs with no known affected relatives. Eleven DLA class II haplotypes were identified, of which, DLA-DRB1*02001/DQA1*00401/DQB1*01303, was at significantly raised frequency in cases compared to controls (OR = 1.92, p = 0.032). When only control dogs with no family history of the disease were compared to cases, the association was further strengthened (OR = 4.08, p = 0.00011). Additionally, a single copy of the risk haplotype was sufficient to increase disease risk, with the risk substantially increasing for homozygotes. There was a trend of increasing frequency of this haplotype with degree of relatedness, indicating low disease penetrance. These findings support the hypothesis of an immune-mediated aetiology for this canine myopathy and give credibility to potentially using the Hungarian Vizsla as a genetic model for comparative studies with human myositis.

Background: It has been speculated that viral infection might be one of the potential aetiologies for adult-onset clinically amyopathic dermatomyositis (CADM). The molecular pathogenesis remains largely unknown., Objectives: To explore whether dysregulation of the type I interferon (IFN) system is involved in the pathogenesis of CADM., Methods: We studied 16 patients with CADM and compared them with healthy control subjects (n = 20) and patients with classic dermatomyositis (DM, n = 16) and polymyositis (PM, n = 16). Expressions of mRNA for serial toll-like receptor genes (TLR2, TLR3, TLR4, TLR7, TLR8 and TLR9) and type I IFN-regulated genes (IRF7, ISG15 and MxA) in peripheral blood leucocytes (PBL) were detected by real-time polymerase chain reaction analysis. The level of IFN-α in blood was tested by enzyme-linked immunosorbent assay., Results: The mRNA expressions of TLR7, TLR9 and IRF7 were greatly elevated in the PBL from patients with CADM compared with controls. Upregulation of the ISG15 and MxA genes was detected in the PBL from patients with CADM, as well as from patients with classic DM. Among the four study groups, the overproduction of IFN-α in blood was most significant in the CADM group. Especially, IFN-α level was obviously high in the clinical interstitial lung disease (ILD) subgroup of patients with CADM. Positive correlations were found between IFN-α concentration and other unfavourable prognostic factors of CADM-associated ILD., Conclusions: Our data suggest that the dysregulation of the type I IFN system may be implicated in CADM pathogenesis. IFN-α may be a useful biomarker for assessing the disease severity of CADM-associated ILD., (© 2012 The Authors. BJD © 2012 British Association of Dermatologists 2012.)

In polymyositis and inclusion body myositis, muscle fibers are surrounded and invaded by CD8-positive cytotoxic T cells expressing the αβ-T cell receptor (αβ-TCR) for antigen. In a rare variant of myositis, muscle fibers are similarly attacked by CD8-negative T cells expressing the γδ-TCR (γδ-T cell-mediated myositis). We investigated the antigen specificity of a human γδ-TCR previously identified in an autoimmune tissue lesion of γδ-T cell-mediated myositis. We show that this Vγ1.3Vδ2-TCR, termed M88, recognizes various proteins from different species. Several of these proteins belong to the translational apparatus, including some bacterial and human aminoacyl-tRNA synthetases (AA-RS). Specifically, M88 recognizes histidyl-tRNA synthetase, an antigen known to be also targeted by autoantibodies called anti-Jo-1. The M88 target epitope is strictly conformational, independent of post-translational modification, and exposed on the surface of the respective antigenic protein. Extensive mutagenesis of the translation initiation factor-1 from Escherichia coli (EcIF1), which served as a paradigm antigen with known structure, showed that a short α-helical loop around amino acids 39 to 42 of EcIF1 is a major part of the M88 epitope. Mutagenesis of M88 showed that the complementarity determining regions 3 of both γδ-TCR chains contribute to antigen recognition. M88 is the only known example of a molecularly characterized γδ-TCR expressed by autoaggressive T cells in tissue. The observation that AA-RS are targeted by a γδ-T cell and by autoantibodies reveals an unexpected link between T cell and antibody responses in autoimmune myositis.

The objective of this study was to evaluate the relationship between blood mRNA, disease activity and treatment effects in a longitudinal study of patients with dermatomyositis (DM) or polymyositis (PM). In all, 24 patients with DM or PM were followed for up to 6 years (mean of 1.9 years) at 2-7 follow-up visits while receiving standard clinical care. Clinical data and blood samples collected at 80 patient visits were used for the analysis of cytokine-induced gene expression for the signaling pathways of type 1 interferon (IFN), tumor necrosis factor-α, IL-1β, granulocyte-monocyte colony-stimulating factor, IL-10 and IL-13. A type 1 IFN signature score, but not other cytokine signature scores in the blood of patients with DM or PM, correlated highly with disease activity, decreased significantly with immunomodulatory therapies and showed concordant changes with major changes in disease activity. Type 1 IFN signature score in the blood correlates with disease activity in longitudinal follow-up of individual patients with DM or PM. The type 1 IFN-inducible gene transcripts in the blood have potential utility for monitoring disease activity in patients with DM or PM.