IFNγ causes mitochondrial dysfunction and oxidative stress in myositis.

Idiopathic inflammatory myopathies (IIMs) are severe autoimmune diseases with poorly understood pathogenesis and unmet medical needs. Here, we examine the role of interferon γ (IFNγ) using NOD female mice deficient in the inducible T cell co-stimulator (Icos), which have previously been shown to develop spontaneous IFNγ-driven myositis mimicking human disease. Using muscle proteomic and spatial transcriptomic analyses we reveal profound myofiber metabolic dysregulation in these mice. In addition, we report muscle mitochondrial abnormalities and oxidative stress in diseased mice. Supporting a pathogenic role for oxidative stress, treatment with a reactive oxygen species (ROS) buffer compound alleviated myositis, preserved muscle mitochondrial ultrastructure and respiration, and reduced inflammation. Mitochondrial anomalies and oxidative stress were diminished following anti-IFNγ treatment. Further transcriptomic analysis in IIMs patients and human myoblast in vitro studies supported the link between IFNγ and mitochondrial dysfunction observed in mice. These results suggest that mitochondrial dysfunction, ROS and inflammation are interconnected in a self-maintenance loop, opening perspectives for mitochondria therapy and/or ROS targeting drugs in myositis.

Characterised intron retention profiles in muscle tissue of idiopathic inflammatory myopathy subtypes.

OBJECTIVES: Idiopathic inflammatory myopathies (IIMs) are a group of heterogeneous autoimmune diseases. Intron retention (IR) serves as an important post-transcriptional and translational regulatory mechanism. This study aims to identify changes in IR profiles in IIM subtypes, investigating their influence on proteins and their correlations with clinical features. METHODS: RNA sequencing and liquid chromatography-tandem mass spectrometry were performed on muscle tissues obtained from 174 patients with IIM and 19 controls, following QC procedures. GTFtools and iREAD software were used for IR identification. An analysis of differentially expressed IRs (DEIs), exons and proteins was carried out using edgeR or DEP. Functional analysis was performed with clusterProfiler, and SPIRON was used to assess splicing factors. RESULTS: A total of 6783 IRs located in 3111 unique genes were identified in all IIM subtypes compared with controls. IIM subtype-specific DEIs were associated with the pathogenesis of respective IIM subtypes. Splicing factors YBX1 and HSPA2 exhibited the most changes in dermatomyositis and immune-mediated necrotising myopathy. Increased IR was associated with reduced protein expression. Some of the IIM-specific DEIs were correlated with clinical parameters (skin rash, MMT-8 scores and muscle enzymes) and muscle histopathological features (myofiber necrosis, regeneration and inflammation). IRs in IFIH1 and TRIM21 were strongly correlated with anti-MDA5+ antibody, while IRs in SRP14 were associated with anti-SRP+ antibody. CONCLUSION: This study revealed distinct IRs and specific splicing factors associated with IIM subtypes, which might be contributing to the pathogenesis of IIM. We also emphasised the potential impact of IR on protein expression in IIM muscles.

Causality Assessment Between Idiopathic Inflammatory Myopathies and Lung Cancer: A Bidirectional 2-Sample Mendelian Randomization.

BACKGROUND: Although observational studies have revealed associations between idiopathic inflammatory myopathies (IIMs) and lung cancer (LC), they have not established a causal relationship between these 2 conditions. METHODS: We used a 2-sample Mendelian randomization approach to examine the bidirectional causal associations between IIMs and LC, using single-nucleotide polymorphisms selected from high-quality genome-wide association studies in the FinnGen database. Sensitivity analyses were conducted to assess potential heterogeneity and pleiotropy impacts on the Mendelian randomization results. RESULTS: Our analysis demonstrated a positive causal effect of genetically increased IIM risk on LC (odds ratio, 1.114; 95% confidence interval, 1.057-1.173; p = 5.63 × 10 -5 ), particularly on the lung squamous cell carcinoma subtype (odds ratio, 1.168, 95% confidence interval, 1.049-1.300, p = 0.00451), but not on lung adenocarcinoma or small cell lung cancer. No causal effect of LC on IIMs was identified. Sensitivity analyses indicated that horizontal pleiotropy was unlikely to influence causality, and leave-one-out analysis confirmed that the observed associations were not driven by a single-nucleotide polymorphism. CONCLUSION: Our findings offer compelling evidence of a positive causal relationship between IIMs and LC, particularly with regard to lung squamous cell carcinoma, in the European population. Conversely, there is no evidence of LC causing IIMs. We recommend that LC diagnosis consider the specific characteristics of IIMs.

Novel endotypes of antisynthetase syndrome identified independent of anti-aminoacyl transfer RNA synthetase antibody specificity that improve prognostic stratification.

OBJECTIVES: To systemically analyse the heterogeneity in the clinical manifestations and prognoses of patients with antisynthetase syndrome (ASS) and evaluate the transcriptional signatures related to different clinical phenotypes. METHODS: A total of 701 patients with ASS were retrospectively enrolled. The clinical presentation and prognosis were assessed in association with four anti-aminoacyl transfer RNA synthetase (ARS) antibodies: anti-Jo1, anti-PL7, anti-PL12 and anti-EJ. Unsupervised machine learning was performed for patient clustering independent of anti-ARS antibodies. Transcriptome sequencing was conducted in clustered ASS patients and healthy controls. RESULTS: Patients with four different anti-ARS antibody subtypes demonstrated no significant differences in the incidence of rapidly progressive interstitial lung disease (RP-ILD) or prognoses. Unsupervised machine learning, independent of anti-ARS specificity, identified three endotypes with distinct clinical features and outcomes. Endotype 1 (RP-ILD cluster, 23.7%) was characterised by a high incidence of RP-ILD and a high mortality rate. Endotype 2 (dermatomyositis (DM)-like cluster, 14.5%) corresponded to patients with DM-like skin and muscle symptoms with an intermediate prognosis. Endotype 3 (arthritis cluster, 61.8%) was characterised by arthritis and mechanic's hands, with a good prognosis. Transcriptome sequencing revealed that the different endotypes had distinct gene signatures and biological processes. CONCLUSIONS: Anti-ARS antibodies were not significant in stratifying ASS patients into subgroups with greater homogeneity in RP-ILD and prognoses. Novel ASS endotypes were identified independent of anti-ARS specificity and differed in clinical outcomes and transcriptional signatures, providing new insights into the pathogenesis of ASS.

K2P2.1 is a regulator of inflammatory cell responses in idiopathic inflammatory myopathies.

K2P2.1 (TREK1), a two-pore domain potassium channel, has emerged as regulator of leukocyte transmigration into the central nervous system. In the context of skeletal muscle, immune cell infiltration constitutes the pathogenic hallmark of idiopathic inflammatory myopathies (IIMs). However, the underlying mechanisms remain to be elucidated. In this study, we investigated the role of K2P2.1 in the autoimmune response of IIMs. We detected K2P2.1 expression in primary skeletal muscle and endothelial cells of murine and human origin. We observed an increased pro-inflammatory cell response, adhesion and transmigration by pharmacological blockade or genetic deletion of K2P2.1 in vitro and in in vivo myositis mouse models. Of note, our findings were not restricted to endothelial cells as skeletal muscle cells with impaired K2P2.1 function also demonstrated a strong pro-inflammatory response. Conversely, these features were abrogated by activation of K2P2.1 and improved the disease course of a myositis mouse model. In humans, K2P2.1 expression was diminished in IIM patients compared to non-diseased controls arguing for the translatability of our findings. In summary, K2P2.1 may regulate the inflammatory response of skeletal muscle. Further research is required to understand whether K2P2.1 could serve as novel therapeutic target.

Comprehensive transcriptomic analysis and machine learning reveal unique gene expression profiles in patients with immune-mediated necrotizing myopathy.

BACKGROUND: Immune-mediated necrotizing myopathy (IMNM) is an autoimmune myopathy characterized by severe proximal weakness and muscle fiber necrosis, yet its pathogenesis remains unclear. So far, there are few bioinformatics studies on underlying pathogenic genes and infiltrating immune cell profiles of IMNM. Therefore, we aimed to characterize differentially expressed genes (DEGs) and infiltrating cells in IMNM muscle biopsy specimens, which may be useful for elucidating the pathogenesis of IMNM. METHODS: Three datasets (GSE39454, GSE48280 and GSE128470) of gene expression profiling related to IMNM were obtained from the Gene Expression Omnibus database. Data were normalized, and DEG analysis was performed using the limma package. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses of DEGs were performed using clusterProfiler. The CIBERSORT algorithm was performed to identify infiltrating cells. Machine learning algorithm and gene set enrichment analysis (GSEA) were performed to find distinctive gene signatures and the underlying signaling pathways of IMNM. RESULTS: DEG analysis identified upregulated and downregulated in IMNM muscle compared to the gene expression levels of other groups. GO and KEGG analysis showed that the pathogenesis of IMNM was notable for the under-representation of pathways that were important in dermatomyositis and inclusion body myositis. Three immune cells (M2 macrophages, resting dendritic cells and resting natural killer cells) with differential infiltration and five key genes (NDUFAF7, POLR2J, CD99, ARF5 and SKAP2) in patients with IMNM were identified through the CIBERSORT and machine learning algorithm. The GSEA results revealed that the key genes were remarkably enriched in diverse immunological and muscle metabolism-related pathways. CONCLUSIONS: We comprehensively explored immunological landscape of IMNM, which is indicative for the research of IMNM pathogenesis.

Unprecedented coexistence of autoinflammatory myositis and chronic thrombosis with heterozygotic M694V mutation: An atypical presentation of familial Mediterranean fever.

Familial Mediterranean Fever (FMF) is a hereditary autoinflammatory disorder predominantly characterised by periodic fever, abdominal pain, and joint manifestations. It can exhibit various atypical presentations. However, cases of FMF concurrently presenting with chronic thrombosis and myositis have not been previously reported. A 41-year-old male presented with alternating severe bilateral leg pain, stiffness, and localised swellings without fever or abdominal symptoms. His history included inflammatory joint pain treated with prednisolone. Physical examination revealed leg pain, limited ankle joint movement, and tender swellings in thighs, forearms, and feet. Collateral abdominal veins were also observed. Unresponsive to prednisolone and colchicine, the patient underwent MRI, revealing muscle inflammation in both legs and thighs and chronic thrombosis in the infrarenal inferior vena cava. Genetic testing confirmed the heterozygotic M694V mutation, diagnosing an atypical FMF. This case uniquely showcases coexisting myositis and chronic thrombosis in FMF. Myalgia is common in FMF, with M694V mutation associated with severe muscular symptoms. The lack of fever and myositis findings differentiate our case from protracted febrile myalgia syndrome. FMF's chronic inflammatory state is known to influence thrombosis risk, and our findings align with this association. Chronic thromboembolism and myositis together signify an unusual clinical presentation of FMF. This case highlights the potential for FMF to present with complex manifestations beyond the conventional symptoms. Myositis and vascular involvement should prompt consideration of FMF diagnosis when combined with patient history, clinical features, and laboratory results. These rare associations underscore the need for further research to enhance understanding of FMF's diverse clinical spectrum.

Identification of Unique microRNA Profiles in Different Types of Idiopathic Inflammatory Myopathy.

Dermatomyositis (DM), antisynthetase syndrome (AS), immune-mediated necrotizing myopathy (IMNM), and inclusion body myositis (IBM) are four major types of idiopathic inflammatory myopathy (IIM). Muscle biopsies from each type of IIM have unique transcriptomic profiles. MicroRNAs (miRNAs) target messenger RNAs (mRNAs), thereby regulating their expression and modulating transcriptomic profiles. In this study, 18 DM, 12 IMNM, 6 AS, 6 IBM, and 6 histologically normal muscle biopsies underwent miRNA profiling using the NanoString nCounter system. Eleven miRNAs were exclusively differentially expressed in DM compared to controls, seven miRNAs were only differentially expressed in AS, and nine miRNAs were specifically upregulated in IBM. No differentially expressed miRNAs were identified in IMNM. We also analyzed miRNA-mRNA associations to identify putative targets of differentially expressed miRNAs. In DM and AS, these were predominantly related to inflammation and cell cycle progression. Moreover, our analysis showed an association between miR-30a-3p, miR-30e-3p, and miR-199b-5p downregulation in DM and the upregulation of target genes induced by type I interferon. In conclusion, we show that muscle biopsies from DM, AS, and IBM patients have unique miRNA signatures and that these miRNAs might play a role in regulating the expression of genes known to be involved in IIM pathogenesis.

Idiopathic inflammatory myopathy and non-coding RNA.

Idiopathic inflammatory myopathies (IIMs) are common autoimmune diseases that affect skeletal muscle quality and function. The lack of an early diagnosis and treatment can lead to irreversible muscle damage. Non-coding RNAs (ncRNAs) play an important role in inflammatory transfer, muscle regeneration, differentiation, and regulation of specific antibody levels and pain in IIMs. ncRNAs can be detected in blood and hair; therefore, ncRNAs detection has great potential for diagnosing, preventing, and treating IIMs in conjunction with other methods. However, the specific roles and mechanisms underlying the regulation of IIMs and their subtypes remain unclear. Here, we review the mechanisms by which micro RNAs and long non-coding RNA-messenger RNA networks regulate IIMs to provide a basis for ncRNAs use as diagnostic tools and therapeutic targets for IIMs.

Distinct HLA associations with autoantibody-defined subgroups in idiopathic inflammatory myopathies.

BACKGROUND: In patients with idiopathic inflammatory myopathies (IIM), autoantibodies are associated with specific clinical phenotypes suggesting a pathogenic role of adaptive immunity. We explored if autoantibody profiles are associated with specific HLA genetic variants and clinical manifestations in IIM. METHODS: We included 1348 IIM patients and determined the occurrence of 14 myositis-specific or -associated autoantibodies. We used unsupervised cluster analysis to identify autoantibody-defined subgroups and logistic regression to estimate associations with clinical manifestations, HLA-DRB1, HLA-DQA1, HLA-DQB1 alleles, and amino acids imputed from genetic information of HLA class II and I molecules. FINDINGS: We identified eight subgroups with the following dominant autoantibodies: anti-Ro52, -U1RNP, -PM/Scl, -Mi2, -Jo1, -Jo1/Ro52, -TIF1γ or negative for all analysed autoantibodies. Associations with HLA-DRB1∗11, HLA-DRB1∗15, HLA-DQA1∗03, and HLA-DQB1∗03 were present in the anti-U1RNP-dominated subgroup. HLA-DRB1∗03, HLA-DQA1∗05, and HLA-DQB1∗02 alleles were overrepresented in the anti-PM/Scl and anti-Jo1/Ro52-dominated subgroups. HLA-DRB1∗16, HLA-DRB1∗07 alleles were most frequent in anti-Mi2 and HLA-DRB1∗01 and HLA-DRB1∗07 alleles in the anti-TIF1γ subgroup. The HLA-DRB1∗13, HLA-DQA1∗01 and HLA-DQB1∗06 alleles were overrepresented in the negative subgroup. Significant signals from variations in class I molecules were detected in the subgroups dominated by anti-Mi2, anti-Jo1/Ro52, anti-TIF1γ, and the negative subgroup. INTERPRETATION: Distinct HLA class II and I associations were observed for almost all autoantibody-defined subgroups. The associations support autoantibody profiles use for classifying IIM which would likely reflect underlying pathogenic mechanisms better than classifications based on clinical symptoms and/or histopathological features. FUNDING: See a detailed list of funding bodies in the Acknowledgements section at the end of the manuscript.

Deciphering the crosstalk of immune dysregulation between COVID-19 and idiopathic inflammatory myopathy.

Background: The coronavirus disease (COVID-19) pandemic is a serious threat to public health worldwide. Growing evidence reveals that there are certain links between COVID-19 and autoimmune diseases; in particular, COVID-19 and idiopathic inflammatory myopathies (IIM) have been observed to be clinically comorbid. Hence, this study aimed to elucidate the molecular mechanisms of COVID-19 and IIM from a genomic perspective. Methods: We obtained transcriptome data of patients with COVID-19 and IIM separately from the GEO database and identified common differentially expressed genes (DEGs) by intersection. We then performed functional enrichment, PPI, machine learning, gene expression regulatory network, and immune infiltration analyses of co-expressed genes. Results: A total of 91 common genes were identified between COVID-19 and IIM. Functional enrichment analysis revealed that these genes were mainly involved in immune dysregulation, response to external stimuli, and MAPK signaling pathways. The MCODE algorithm recognized two densely linked clusters in the common genes, which were related to inflammatory factors and interferon signaling. Subsequently, three key genes (CDKN1A, IFI27, and STAB1) were screened using machine learning to predict the occurrence of COVID-19 related IIM. These key genes exhibited excellent diagnostic performance in both training and validation cohorts. Moreover, we created TF-gene and miRNA-gene networks to reveal the regulation of key genes. Finally, we estimated the relationship between key genes and immune cell infiltration, of which IFI27 was positively associated with M1 macrophages. Conclusion: Our work revealed common molecular mechanisms, core genes, potential targets, and therapeutic approaches for COVID-19 and IIM from a genomic perspective. This provides new ideas for the diagnosis and treatment of COVID-19 related IIM in the future.

Molecular signature of neutrophil extracellular trap mediating disease module in idiopathic inflammatory myopathy.

The rarity and heterogeneity of idiopathic inflammatory myopathy (IIM) pose challenges for researching IIM in affected individuals. We analyzed integrated transcriptomic datasets obtained using muscle tissues from patients with five distinct IIM subtypes to investigate the shared and distinctive cellular and molecular characteristics. A transcriptomic dataset of muscle tissues from normal controls (n = 105) and patients with dermatomyositis (n = 89), polymyositis (n = 33), inclusion body myositis (n = 121), immune-mediated necrotizing myositis (n = 75), and anti-synthetase syndrome (n = 18) was used for differential gene-expression analysis, functional-enrichment analysis, gene set-enrichment analysis, disease-module identification, and kernel-based diffusion scoring. Damage-associated molecular pattern-associated pathways and neutrophil-mediated immunity were significantly enriched across different IIM subtypes, although their activities varied. Interferons-signaling pathways were differentially activated across all five IIM subtypes. In particular, neutrophil extracellular trap (NET) formation was significantly activated and correlated with Fcγ R-mediated signaling pathways. NET formation-associated genes were key for establishing disease modules, and FCGRs, C1QA, and SERPINE1 markedly perturbed the disease modules. Integrated transcriptomic analysis of muscle tissues identified NETs as key components of neutrophil-mediated immunity involved in the pathogenesis of IIM subtypes and, thus, has therapeutically targetable value.

Familial Co-Aggregation of Idiopathic Inflammatory Myopathies and Cancer: A Swedish Population-Based Study.

OBJECTIVE: To examine if idiopathic inflammatory myopathies (IIMs) share familial susceptibility with cancer, we estimated the familial co-aggregation of these diseases. METHODS: This Swedish population-based family study with data from national registers included 8,460 first-degree relatives of patients with IIM and 41,127 relatives of matched individuals without IIM. We modeled the adjusted odds ratios (ORs) of familial co-aggregation of IIM and cancer using conditional logistic regressions and adjusted for sex and birth year of index individuals and their first-degree relatives. We examined the associations for cancer overall and stratified by several factors of interest. We also performed exploratory analyses for specific cancer types. RESULTS: We observed no statistically significant familial associations between IIM and cancer overall. However, there was a familial association in male relative pairs of patients with dermatomyositis (adjusted OR for familial association 1.39 [95% confidence interval (95% CI) 1.15-1.68]). The association remained statistically significant after controlling for multiple testing. Moreover, this finding was consistent between kinships. Familial co-aggregation of IIM and cancer diagnosed before 50 years of age was only observed in offspring. In exploratory analyses, only the familial associations for myeloid malignancies (adjusted OR 2.27 [95% CI 1.43-3.60]) and liver cancer (adjusted OR 2.01 [95% CI 1.21-3.33]) in male relative pairs remained significant after controlling for multiple testing. CONCLUSION: We found little evidence of shared familial susceptibility as a major pathologic mechanism contributing to the co-occurrence of IIM and cancer overall. There could be subsets of patients and cancer types for which familial factors including genetics and shared environments are of more importance, but these findings need replication.

Transcriptomic profiling reveals distinct subsets of immune checkpoint inhibitor induced myositis.

OBJECTIVES: Inflammatory myopathy or myositis is a heterogeneous family of immune-mediated diseases including dermatomyositis (DM), antisynthetase syndrome (AS), immune-mediated necrotising myopathy (IMNM) and inclusion body myositis (IBM). Immune checkpoint inhibitors (ICIs) can also cause myositis (ICI-myositis). This study was designed to define gene expression patterns in muscle biopsies from patients with ICI-myositis. METHODS: Bulk RNA sequencing was performed on 200 muscle biopsies (35 ICI-myositis, 44 DM, 18 AS, 54 IMNM, 16 IBM and 33 normal muscle biopsies) and single nuclei RNA sequencing was performed on 22 muscle biopsies (seven ICI-myositis, four DM, three AS, six IMNM and two IBM). RESULTS: Unsupervised clustering defined three distinct transcriptomic subsets of ICI-myositis: ICI-DM, ICI-MYO1 and ICI-MYO2. ICI-DM included patients with DM and anti-TIF1γ autoantibodies who, like DM patients, overexpressed type 1 interferon-inducible genes. ICI-MYO1 patients had highly inflammatory muscle biopsies and included all patients that developed coexisting myocarditis. ICI-MYO2 was composed of patients with predominant necrotising pathology and low levels of muscle inflammation. The type 2 interferon pathway was activated both in ICI-DM and ICI-MYO1. Unlike the other types of myositis, all three subsets of ICI-myositis patients overexpressed genes involved in the IL6 pathway. CONCLUSIONS: We identified three distinct types of ICI-myositis based on transcriptomic analyses. The IL6 pathway was overexpressed in all groups, the type I interferon pathway activation was specific for ICI-DM, the type 2 IFN pathway was overexpressed in both ICI-DM and ICI-MYO1 and only ICI-MYO1 patients developed myocarditis.

Identification of Novel Associations and Localization of Signals in Idiopathic Inflammatory Myopathies Using Genome-Wide Imputation.

OBJECTIVE: The idiopathic inflammatory myopathies (IIMs) are heterogeneous diseases thought to be initiated by immune activation in genetically predisposed individuals. We imputed variants from the ImmunoChip array using a large reference panel to fine-map associations and identify novel associations in IIM. METHODS: We analyzed 2,565 Caucasian IIM patient samples collected through the Myositis Genetics Consortium (MYOGEN) and 10,260 ethnically matched control samples. We imputed 1,648,116 variants from the ImmunoChip array using the Haplotype Reference Consortium panel and conducted association analysis on IIM and clinical and serologic subgroups. RESULTS: The HLA locus was consistently the most significantly associated region. Four non-HLA regions reached genome-wide significance, SDK2 and LINC00924 (both novel) and STAT4 in the whole IIM cohort, with evidence of independent variants in STAT4, and NAB1 in the polymyositis (PM) subgroup. We also found suggestive evidence of association with loci previously associated with other autoimmune rheumatic diseases (TEC and LTBR). We identified more significant associations than those previously reported in IIM for STAT4 and DGKQ in the total cohort, for NAB1 and FAM167A-BLK loci in PM, and for CCR5 in inclusion body myositis. We found enrichment of variants among DNase I hypersensitivity sites and histone marks associated with active transcription within blood cells. CONCLUSION: We found novel and strong associations in IIM and PM and localized signals to single genes and immune cell types.

Juvenile dermatomyositis associated with autoantibodies to small ubiquitin-like modifier activating enzyme: a report of 4 cases from North India and a review of literature.

BACKGROUND: Juvenile dermatomyositis (JDM) is the commonest inflammatory myositis in children. The clinical phenotype is often characterized by the presence of myositis-specific antibodies (MSA). Antibodies to small ubiquitin-like modifier activating enzyme (SAE) are amongst the rarest MSA reported in children. MATERIALS AND METHODS: A review of medical records of all patients diagnosed to have JDM during the period January 1992-April 2022 in our institute was done. Case records of children with JDM who had significant positivity for anti-SAE antibody by myositis immunoblot were analysed in detail. RESULTS: Of the 140 children with JDM, MSA immunoblot was carried out in 53 patients-4 (7.5%) amongst these had significant positivity for anti-SAE antibodies. Median age of onset of symptoms was 5.5 years (range: 5-11 years). Clinical features at presentation included fever, photosensitivity, heliotrope rash, and Gottron papules. Clinically significant proximal muscle weakness was noted in 3/4 patients; 1 had no discernible weakness but had radiological evidence of myositis. None of the 4 patients had evidence of interstitial lung disease or calcinosis. All patients were treated with intravenous pulse methylprednisolone: subcutaneous weekly methotrexate and hydroxychloroquine. One patient received mycophenolate mofetil because of a relapse of muscle disease, while none received cyclophosphamide or biologics. Median follow-up duration was 21.5 months (range: 6-39 months). CONCLUSION: Anti-SAE antibodies were found in 4/53 (7.5%) of North Indian children with JDM. All 4 patients had predominant cutaneous manifestations followed by muscle disease. Response to treatment was brisk and sustained. None had developed calcinosis in the follow-up. KEY MESSAGES: 1. We report high prevalence of anti-SAE antibody positivity (7.5%) in North Indian cohort of JDM. 2. Cutaneous disease precedes muscle weakness in children with anti-SAE positive JDM. 3. No evidence of interstitial lung disease/calcinosis was seen in these children.