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ObjectivesInflammatory 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.MethodsBulk 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).ResultsUnsupervised 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.ConclusionsWe 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.

Background: Immune-mediated necrotising myopathy is an autoimmune myopathy characterised by proximal muscle weakness, high creatine kinase concentrations, and autoantibodies recognising 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) or the signal recognition particle (SRP). No approved therapies exist for people with immune-mediated necrotising myopathy. Previous studies have suggested that complement activation might be pathogenic in immune-mediated necrotising myopathy; therefore, zilucoplan, a complement C5 (C5) inhibitor, could be a potential therapy. We aimed to evaluate the efficacy, safety, and tolerability of zilucoplan in adult participants with anti-HMGCR or anti-SRP autoantibody-positive immune-mediated necrotising myopathy. Methods: IMNM-01 was a phase 2, multicentre, randomised, double-blind, placebo-controlled study done at 15 hospital sites across the USA, the UK, France, and the Netherlands. Participants aged 18?74 years were eligible for inclusion if they had a clinically confirmed diagnosis of immune-mediated necrotising myopathy, positive serology for anti-HMGCR or anti-SRP autoantibodies, clinical evidence of weakness, serum total creatine kinase concentration of more than 1000 U/L at screening, and no change in glucocorticoids or other immunosuppressive therapies for 30 days before baseline or expected during the first 8 weeks of the study. Participants were randomly assigned (1:1) to receive daily subcutaneous zilucoplan (0?3 mg/kg) or placebo for 8 weeks by use of a computerised randomisation algorithm; with optional enrolment in the study open-label extension. Randomisation was stratified by autoantibody status. Participants and study staff were masked to treatment group assignment. Primary efficacy endpoint (in the intent-to-treat population, defined as all participants who were randomly assigned to a treatment group) was percent change from baseline to week 8 in creatine kinase concentrations. Safety analyses were performed on the safety population (participants who received at least one dose of study drug during the main study, irrespective of whether they continued to the extension period?study participants were analysed on the basis of the treatment received). This study is registered with ClinicalTrials.gov, NCT04025632. Findings: Between Nov 7, 2019, and Jan 7, 2021, we randomly assigned 27 participants (13 female and 14 male) to receive zilucoplan (n=12) or placebo (n=15). All 27 participants completed the 8-week main study. At week 8 there were no significant differences between treatment groups in median percent change of creatine kinase concentrations versus baseline (?15?1% [IQR ?31?1 to 3?2] in the zilucoplan group vs ?16?3% [?43?8 to 5?9] in the placebo group; p=0?46) and no clinically relevant improvement over time within the treatment group despite target engagement based on mode of action. There were no unexpected adverse safety or tolerability findings. Treatment-emergent adverse events were reported in nine (75%) of 12 participants in the zilucoplan group, and in 13 (87%) of 15 participants in the placebo group, and serious treatment-emergent adverse events were reported in zero participants in the zilucoplan group and three (20%) participants in the placebo group. The most frequent treatment-emergent adverse events were headache (four [33%] participants in the zilucoplan group and four [27%] participants in the placebo group) and nausea (three [25%] participants in the zilucoplan group and three [20%] participants in the placebo group). Interpretation: C5 inhibition does not appear to be an efficacious treatment modality for people with immune-mediated necrotising myopathy. Rather than being the primary driver for disease activity, complement activation might be secondary to muscle injury. Funding: Ra Pharmaceuticals (now part of UCB Pharma).

ObjectivesIn dermatomyositis (DM), autoantibodies are associated with unique clinical phenotypes. For example, anti-TIF1γ autoantibodies are associated with an increased risk of cancer. The purpose of this study was to discover novel DM autoantibodies.MethodsPhage ImmunoPrecipitation Sequencing using sera from 43 patients with DM suggested that transcription factor Sp4 is a novel autoantigen; this was confirmed by showing that patient sera immunoprecipitated full-length Sp4 protein. Sera from 371 Johns Hopkins patients with myositis (255 with DM, 28 with antisynthetase syndrome, 40 with immune-mediated necrotising myopathy, 29 with inclusion body myositis and 19 with polymyositis), 80 rheumatological disease controls (25 with Sjogren’s syndrome, 25 with systemic lupus erythematosus and 30 with rheumatoid arthritis (RA)) and 200 healthy comparators were screened for anti-SP4 autoantibodies by ELISA. A validation cohort of 46 anti-TIF1γ-positive patient sera from the University of Pittsburgh was also screened for anti-Sp4 autoantibodies.ResultsAnti-Sp4 autoantibodies were present in 27 (10.5%) patients with DM and 1 (3.3%) patient with RA but not in other clinical groups. In patients with DM, 96.3% of anti-Sp4 autoantibodies were detected in those with anti-TIF1γ autoantibodies. Among 26 TIF1γ-positive patients with anti-Sp4 autoantibodies, none (0%) had cancer. In contrast, among 35 TIF1γ-positive patients without anti-Sp4 autoantibodies, 5 (14%, p=0.04) had cancer. In the validation cohort, among 15 TIF1γ-positive patients with anti-Sp4 autoantibodies, 2 (13.3%) had cancer. By comparison, among 31 TIF1γ-positive patients without anti-Sp4 autoantibodies, 21 (67.7%, pConclusionsAnti-Sp4 autoantibodies appear to identify a subgroup of anti-TIF1γ-positive DM patients with lower cancer risk.

Alloreactive and autoimmune responses after allogeneic hematopoietic cell transplantation can occur in nonclassical chronic graft-versus-host disease (chronic GVHD) tissues and organ systems or manifest in atypical ways in classical organs commonly affected by chronic GVHD. The National Institutes of Health (NIH) consensus projects were developed to improve understanding and classification of the clinical features and diagnostic criteria for chronic GVHD. Although still speculative whether atypical manifestations are entirely due to chronic GVHD, these manifestations remain poorly captured by the current NIH consensus project criteria. Examples include chronic GVHD impacting the hematopoietic system as immune mediated cytopenias, endothelial dysfunction, or as atypical features in the musculoskeletal system, central and peripheral nervous system, kidneys, and serous membranes. These purported chronic GVHD features may contribute significantly to patient morbidity and mortality. Most of the atypical chronic GVHD features have received little study, particularly within multi- institutional and prospective studies, limiting our understanding of their frequency, pathogenesis, and relation to chronic GVHD. This NIH consensus project task force report provides an update on what is known and not known about the atypical manifestations of chronic GVHD while outlining a research framework for future studies to be undertaken within the next 3 to 7 years. We also provide provisional diagnostic criteria for each atypical manifestation, along with practical investigation strategies for clinicians managing patients with atypical chronic GVHD features.

Background and ObjectivesSporadic inclusion body myositis (IBM) is the most common acquired myopathy in individuals older than 50 years. The disorder is slowly progressive, and although many therapies have been investigated, response has generally been poor. Clinical heterogeneity may influence treatment responsiveness; however, data regarding heterogeneity in IBM are limited and often conflicting. We aim to identify clinically distinct subgroups within a large IBM cohort and prognostic factors for disease progression.MethodsClinical, histologic, radiologic, and electrophysiologic data were analyzed for all patients with IBM and other forms of myositis enrolled in a longitudinal cohort from The Johns Hopkins Myositis Center from 2003 to 2018. Patients with IBM were included if they met at least one of the following criteria: Griggs possible, European Neuromuscular Centre 2011 probable, or Lloyd-Greenberg data-derived criteria for IBM. Univariate, multivariate, and graphical analyses were used to identify prognostic factors in patients with IBM. Thus, linear and logistic regressions were used to adjust for potential confounding variables. The evolution of creatine kinase and muscle strength was studied using multilevel linear regression models. Nonmodifiable risk factors (sex, race, disease duration, and age at the onset of first symptoms) were used as adjusting covariates for the regression analyses.ResultsAmong the 335 patients meeting the inclusion criteria for IBM, 64% were male with an average age of disease onset of 58.7 years and delay to diagnosis of 5.2 years. Initial misdiagnosis (52%) and immunosuppressant treatment (42%) were common. Less than half (43%) of muscle biopsies demonstrated all 3 pathologic hallmarks: endomysial inflammation, mononuclear cell invasion, and rimmed vacuoles. Black patients had significantly weaker arm abductors, hip flexors, and knee flexors compared with non-Black patients. Female patients had stronger finger flexors and knee extensors compared with their male counterparts. Younger age (DiscussionOur study demonstrates that female and Black patients have distinct clinical phenotypes and trajectories within the overarching IBM clinical phenotype. These subgroups may have different responses to therapies, which may influence the design of future clinical trials in IBM.

Background The objectives of the study were to (1) determine the sensitivity of EULAR/ACR criteria to properly classify myositis-specific autoantibody (MSA) positive myositis patients, (2) describe the phenotype and muscle involvement over time in different MSA-positive patients, and (3) compare MSAs with the EULAR/ACR subgroups to predict clinical phenotypes. Methods The study included 524 MSA-positive myositis patients from the Johns Hopkins Myositis Center. Each patient was classified using the EULAR/ACR classification criteria. Patient phenotypes were summarized using factor analysis of mixed data (FAMD). We compared the ability of MSAs with the EULAR/ACR subgroups to predict the phenotype of patients by applying the Akaike information criterion (AIC) and the Bayesian information criteria (BIC) to the linear regression models. Results Overall, 91% of MSA-positive patients met EULAR/ACR criteria to be classified as myositis. However, 20% of anti-HMGCR and 50% of anti-PL7 patients were incorrectly classified as not myositis. Furthermore, ~10% of anti-SRP and anti-HMGCR patients were misclassified as having inclusion body myositis. FAMD demonstrated that patients within each MSA-defined group had similar phenotypes. Application of both the AIC and BIC to the linear regression models revealed that MSAs better predict myositis phenotypes than the subgroups defined by the EULAR/ACR criteria. Conclusions Although the EULAR/ACR criteria successfully classified 91% of MSA-positive myositis patients, certain MSA-defined subgroups, including those with autoantibodies against HMGCR, SRP, and PL7, are frequently misclassified. In myositis patients with MSAs, autoantibodies outperform the EULAR/ACR-defined subgroups to predict clinical phenotypes. These findings underscore the need to include MSAs in a revised myositis classification scheme.

To define the prevalence and clinical phenotype of anti-cortactin autoantibodies in adult and juvenile myositis.In this longitudinal cohort study, anti-cortactin autoantibody titers were assessed by enzyme-linked immunosorbent assay in 670 adult myositis patients and 343 juvenile myositis patients as well as in 202 adult healthy controls and 90 juvenile healthy controls. The prevalence of anti-cortactin autoantibodies was compared among groups. Clinical features of patients with and those without anti-cortactin autoantibodies were also compared.Anti-cortactin autoantibodies were more common in adult dermatomyositis (DM) patients (15%; P = 0.005), particularly those with coexisting anti-Mi-2 autoantibodies (24%; P = 0.03) or anti-NXP-2 autoantibodies (23%; P = 0.04). In adult myositis, anti-cortactin was associated with DM skin involvement (62% of patients with anti-cortactin versus 38% of patients without anti-cortactin; P = 0.03), dysphagia (36% versus 17%; P = 0.02) and coexisting anti-Ro 52 autoantibodies (47% versus 26%; P = 0.001) or anti-NT5c1a autoantibodies (59% versus 33%; P = 0.001). Moreover, the titers of anti-cortactin antibodies were higher in patients with interstitial lung disease (0.15 versus 0.12 arbitrary units; P = 0.03). The prevalence of anti-cortactin autoantibodies was not different in juvenile myositis patients (2%) or in any juvenile myositis subgroup compared to juvenile healthy controls (4%). Nonetheless, juvenile myositis patients with these autoantibodies had a higher prevalence of "mechanic's hands" (25% versus 7%; P = 0.03), a higher number of hospitalizations (2.9 versus 1.3; P = 0.04), and lower peak creatine kinase values (368 versus 818 IU/liter; P = 0.02) than those without anti-cortactin.The prevalence of anti-cortactin autoantibodies is increased in adult DM patients with coexisting anti-Mi-2 or anti-NXP-2 autoantibodies. In adults, anti-cortactin autoantibodies are associated with dysphagia and interstitial lung disease.

ObjectiveDiagnostic muscle biopsies are routinely immunostained for major histocompatibility complex class I (MHC-I) protein. In this study we analysed the prevalence and patterns of MHC-I immunostaining in biopsies from patients with different types of myopathies and neurogenic disorders.MethodsAll 357 diagnostic muscle biopsies processed at the Johns Hopkins Neuromuscular Pathology Laboratory from August 2013 to January 2017 were immunostained for MHC-I. The prevalence and patterns of MHC-I immunostaining were compared between patients with histologically normal muscle biopsies (n = 31), idiopathic inflammatory myopathies (IIMs; n = 170), non-inflammatory myopathies (n = 60) and neurogenic disorders (n = 96).ResultsMHC-I immunostaining was abnormal in most patients with DM (98%), sporadic IBM (sIBM; 100%), immune-mediated necrotizing myopathy (IMNM; 100%) and polymyositis (77%). In contrast, MHC-I immunostaining was less frequently present in non-inflammatory myopathies (32%) or neurogenic disorders (30%). Overall, abnormal MHC-I immunostaining had a sensitivity of 0.95 and a specificity of 0.82 for diagnosing IIMs. A focal MHC-I staining pattern was associated with IMNM, whereas a global pattern was more prevalent in sIBM and a perifascicular pattern was significantly more common in dermatomyositis. Among 18 DM biopsies without perifascicular atrophy, 50% had a perifascicular MHC-I staining pattern. Sarcoplasmic upregulation staining was more common than sarcolemmal staining across all groups.ConclusionMHC-I immunostaining was useful to distinguish IIMs from non-inflammatory myopathies or neurogenic disorders. Of note, a perifascicular MHC-I staining pattern was present only in those with DM, including half of those without perifascicular atrophy; many of these biopsies may not otherwise have been diagnostic for DM.

ObjectivesInflammatory myopathy or myositis is a heterogeneous family of immune-mediated diseases including dermatomyositis (DM), antisynthetase syndrome (AS), immune-mediated necrotizing myopathy (IMNM), and inclusion body myositis (IBM). Immune checkpoint inhibitors (ICI) can also cause myositis (ICI-myositis). This study was designed to define gene expression patterns in muscle biopsies from patients with ICI-myositis.MethodsBulk 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 (7 ICI-myositis, 4 DM, 3 AS, 6 IMNM, and 2 IBM).ResultsUnsupervised 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 co-existing myocarditis. ICI-MYO2 was composed of patients with predominant necrotizing 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.ConclusionsWe 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 ICIDM and ICI-MYO1, and only ICI-MYO1 patients developed myocarditis.

Objectives To define the clinical features of anti-Ku-positive myositis patients and to determine the reliability of the Euroline assay to detect anti-Ku autoantibodies. Methods Serum samples were screened for anti-Ku autoantibodies by Euroline and positive samples were confirmed by ELISA. The prevalence and severity of clinical features at onset and during follow-up in patients with anti-Ku-positive myositis were compared to those with dermatomyositis, immune-mediated necrotizing myopathy (IMNM), the antisynthetase syndrome (AS), inclusion body myositis (IBM), anti-U1-RNP-positive myositis, and anti-PM/Scl-positive myositis. Results 72 (2.9%) of 2475 samples were anti-Ku positive by Euroline using the manufacturer's recommended cutoff of >15. Just 17 (23.6%) of these were confirmed by ELISA and considered anti-Ku-positive for the analysis. Comparators included 169 IMNM, 168 AS, 387 IBM, 20 anti-U1-RNP-positive, and 47 anti-PM/Scl-positive patients. Muscle weakness was a presenting feature in 38% of anti-Ku-positive patients; 81% developed weakness during follow-up. Anti-Ku-positive patients had increased distal weakness compared to the non-IBM comparators. Interstitial lung disease (ILD) was present in 19% of anti-Ku-positive patients at the first visit and eventually developed in 56% of them. Throughout the course of disease, Gottron's papules and/or heliotrope rashes were less common in anti-Ku-positive patients (19%) compared to those with dermatomyositis (94%) or anti-PM/Scl-positive myositis (89%). Anti-Ku-positive patients never developed calcinosis. Conclusions The phenotype of anti-Ku positive myositis is distinguished by distal weakness, frequent ILD, infrequent rash, and no calcinosis. When used according to the current manufacturer's instructions, the Euroline assay has a high false-positive rate for anti-Ku autoantibodies.

Dermatomyositis (DM) is a systemic autoimmune disease affecting multiple organs, including the skeletal muscle, skin, and lungs. Although DM disease mechanisms are incompletely understood, accumulating evidence suggests that interferons may play a significant role. Consequently, it is of considerable interest that drugs blocking the activity of interferons by inhibiting the Janus Kinase/Signal Transducer and Activator of Transcription (JAK-STAT) pathway have been approved for use in other autoimmune diseases. This manuscript will examine the IFN pathways and their importance in DM, review the existing literature on the use of JAK-STAT inhibitors in patients with adult or juvenile DM, and discuss the potential utility of JAK-STAT inhibitors to treat this disease. Recent reports suggest that muscle and skin involvement in patients with either adult or juvenile DM responds favorably to JAK-STAT inhibitors. Moreover, preliminary data indicates that JAK-STAT inhibitors may be useful to treat clinical manifestations of this disease that are complicated to manage otherwise, such as calcinosis or rapidly progressive interstitial lung disease in DM patients with anti-MDA5 autoantibodies. An increasing number of reports suggest that JAK-STAT inhibitors may be useful to treat the varied manifestations of adult and juvenile DM. However, as most studies were either small or lacked appropriate comparators, further research will be necessary to define the role of these drugs in DM treatment.

Objective The aim of this study was to assess disease activity by different PET/CT measurements in IgG4-related disease (IgG4-RD) flares and their correlation with the IgG4-RD responder index (IgG4-RI). Patients and methods Patients were retrospectively recruited from a single center in Barcelona, Spain. They all had IgG4-RD flares with an 18F-FDG PET/CT examination performed within the 2 first weeks of the flare onset and another one after at least 3 months of treatment between 2012 and 2018. Epidemiologic, clinical, laboratory, and therapeutic data were collected at baseline and at follow-up. Semiquantitative and volumetric measurements from PET/CT explorations were recorded. In addition, a 5-point visual scale was (adapted Deauville score) trialed. The IgG4-RI was used as the criterion standard to assess response before and after treatment. Results Eighteen patients with a total of 23 flares were included. The median time to second PET/CT examination was 7 months. Remission (complete and partial) according to IgG4-RI was observed in 20 flares (87%). All PET/CT measurements (SUVmax and SUVmean, total lesion glycolysis, MTV, and adapted Deauville score) were statistically significantly lower on the follow-up evaluation, except for the size of the lesion. The correlation of all these parameters with the IgG4-RI was positive except for SUVmean and the size of the lesion. Conclusions Semiquantitative, volumetric, and visual parameters in PET/CT scans correlated with response to treatment assessed by IgG4-RI. Volumetric and visual items are less subject to variations and could be used to improve activity scores and treatment strategies.

Cancer-associated myositis (CAM) is defined as when cancer appears within 3 years of myositis onset. Dermatomyositis and seronegative immune-mediated necrotizing myopathy are the phenotypes mostly related to cancer. In general, treatment principles in myositis patients with and without CAM are similar. However, some aspects of myositis management are particular to CAM, including (a) the need for a multidisciplinary approach and a close relationship with the oncologist, (b) the presence of immunosuppressive and antineoplastic drug interactions, and (c) the role of the long-term immunosuppressive therapy as a risk factor for cancer relapse or development of a second neoplasm. In this review, we will also discuss immunotherapy in patients treated with checkpoint inhibitors as a treatment for their cancer.Studies on cancer risk in patients treated with long-term immunosuppressive drugs, in autoimmune diseases such as systemic lupus erythematosus or rheumatoid arthritis, and in solid organ transplant recipients have shed some light on this topic. Immunotherapy, which has been a great advance for the treatment of some types of malignancy, may be also of interest in CAM, given the special relationship between both disorders.Management of CAM is a challenge. In this complex scenario, therapeutic decisions must consider both diseases simultaneously.The online version contains supplementary material available at 10.1007/s40674-022-00197-2.

Immune checkpoint inhibitors (ICIs) have changed the cancer treatment landscape, but severe immune-related adverse events (irAEs) can be life-threatening or fatal and may prohibit patients from receiving further ICI treatment. While the clinical features of irAEs are well documented, molecular signatures, predictive biomarkers, and mechanisms of impending irAEs are largely unknown. In addition, the markers and mechanisms of ICI-induced antitumor immunity often overlap with those for irAEs. It is thus critical to uncover signatures associated specifically with irAEs but not with antitumor immunity. To identify circulating immune cell states associated with irAEs, we applied multimodal single cell analysis (CITE-seq) to simultaneously measure the transcriptome and surface proteins from peripheral blood mononuclear cells (PBMCs) collected before and after treatment with an anti-PD-L1 antibody (avelumab) in patients with thymic cancers (thymic epithelial tumors). All patients had an antitumor response, yet a subset developed muscle autoimmunity (myositis), a potentially life-threatening irAE. Mixed-effect modeling disentangled cell type-specific transcriptional states associated with ICI treatment responses from those of irAEs to identify temporally stable pre-treatment immune set points associated with irAEs only. These pre-treatment baseline signatures of irAE developed post-avelumab irAEs reflect correlated transcriptional states of multiple innate and adaptive immune cell populations, including elevation of metabolic genes downstream of mTOR signaling in T-cell subsets. Together these findings suggest putative pre-treatment biomarkers for irAEs following ICI therapy in thymic cancer patients and raise the prospect of therapeutically dampening autoimmunity while sparing antitumor activity in cancer patients treated with ICIs. Together, pre-treatment biomarkers and interventional therapeutics could help mitigate treatment discontinuation and improve clinical outcomes.

Objectives Several IgG4-related disease (IgG4-RD) phenotypes have been proposed and the first set of classification criteria have been recently created. Our objectives were to assess the phenotype distribution and the performance of the classification criteria in Spanish patients as genetic and geographical differences may exist. Methods We performed a cross-sectional multicentre study (Registro Español de Enfermedad Relacionada con la IgG4, REERIGG4) with nine participating centres from Spain. Patients were recruited from November 2013 to December 2018. The 2019 American College of Rheumatology/European League Against Rheumatism classification criteria (AECC) were used. Results We included 105 patients; 88% had Caucasian ethnicity. On diagnosis, 86% met the international pathology consensus while 92% met the Japanese comprehensive criteria. The phenotype distribution was head and neck 25%, Mikulicz and systemic (MS) 20%, pancreato-hepato-biliary (PHB) 13%, retroperitoneal and aorta (RA) 26%. Sixteen per cent had an undefined phenotype. Seventy-seven per cent of the cases met the AECC. From the 24 patients not meeting the AECC, 33% met exclusion criteria, and 67% did not get a score ≥20 points. Incomplete pathology reports were associated to failure to meet the AECC. Conclusions The PHB phenotype was rare among Spanish IgG4-RD patients. The MS phenotype was less frequent and the RA phenotype was more prevalent than in other, Asian patient series. An undefined phenotype should be considered as some patients do not fall into any of the categories. Three quarters of the cases met the 2019 AECC. Incomplete pathology reports were the leading causes of failure to meet the criteria.

Background and ObjectivesSporadic inclusion body myositis (IBM) is the most common acquired myopathy in individuals over age 50. The disorder is slowly progressive and while many therapies have been investigated, response has generally been poor. Clinical heterogeneity may influence treatment responsiveness; however, data regarding heterogeneity in IBM is limited and often conflicting. We aim to identify clinically distinct subgroups within a large IBM cohort, as well as prognostic factors for disease progression.MethodsClinical, histologic, radiologic, and electrophysiologic data were analyzed for all patients with IBM and other forms of myositis enrolled in a longitudinal cohort from The Johns Hopkins Myositis Center from 2003-2018. Univariate, multivariate, and graphical analyses were used to identify prognostic factors in IBM patients.ResultsAmong the 335 IBM patients meeting inclusion criteria, 64% were male with an average age of disease onset of 58.7 years and a delay to diagnosis of 5.2 years. Initial misdiagnosis (52%) and immunosuppressant treatment (42%) were common. Less than half (43%) of muscle biopsies demonstrated all three pathologic hallmarks: endomysial inflammation, mononuclear cell invasion, and rimmed vacuoles. Black patients had significantly weaker arm abductors, hip flexors, and knee flexors compared to non-Black patients but were less likely to develop dysphagia. Female patients had stronger finger flexors and knee extensors compared to their male counterparts but were more likely to develop dysphagia. A significant number (20%) of patients had an age of onset less than 50 years. This group of younger patients was weaker at their first visit; however, this may be accounted for by a longer disease duration at first visit.DiscussionAlthough IBM has long been considered a disorder predominately of older, White men, female, and non-White patients comprise a significant proportion of the IBM population. Our study demonstrates that female and Black patients have distinct clinical phenotypes within the overarching IBM clinical phenotype.

ObjectivesIn dermatomyositis (DM), different autoantibodies are associated with unique clinical phenotypes. For example, anti-TIF1γ autoantibodies are associated with a substantially increased risk of cancer. The purpose of this study was to discover novel DM autoantibodies.MethodsPhage ImmunoPrecipitation Sequencing using sera from 67 DM patients suggested that transcription factor Sp4 is a novel autoantigen; this was confirmed by showing that patient sera immunoprecipitated full-length Sp4 protein. Sera from 371 Johns Hopkins myositis patients (255 with DM, 28 with antisynthetase syndrome [ASyS], 40 with immune-mediated necrotizing myopathy [IMNM], 29 with inclusion body myositis [IBM], and 19 with polymyositis [PM]), 75 rheumatologic disease controls (25 with Sjogren’s syndrome, 25 with systemic lupus erythematosus, and 25 with rheumatoid arthritis), and 200 healthy comparators were screened for anti-SP4 autoantibodies by an enzyme-linked immune absorption assay. Serum from 23 Spanish TIF1γ-positive DM patients was also screened for anti-Sp4 autoantibodiesResultsAnti-Sp4 autoantibodies were present in 11.4% of DM and 8% of rheumatoid arthritis patients but not in any other clinical group. Among DM patients, 90% of anti-Sp4 autoantibodies were detected in patients with anti-TIF1γ autoantibodies. Among anti-TIF1γ-positive DM patients from Johns Hopkins and Spain, those with coexisting anti-Sp4 autoantibodies had a decreased risk of cancer (0% vs. 31%; p=0.001, Chi-squared test).ConclusionsAnti-Sp4 autoantibodies are enriched in anti-TIF1γ-positive DM patients without cancer, suggesting that the development of an anti-Sp4 immune response may correlate with a relatively low risk of cancer in these patients.KEY MESSAGESWhat is already known about this subject?Dermatomyositis patients with anti-TIF1γ autoantibodies have an increased risk of cancer.What does this study add?Anti-Sp4 autoantibodies are enriched in dermatomyositis patients with anti-TIF1γ autoantibodies.Anti-Sp4 autoantibodies are only found in dermatomyositis patients without cancer.Muscle strength is greater in dermatomyositis patients with anti-Sp4 autoantibodies.Anti-Sp4 autoantibodies are not present in patients with antisynthetase syndrome, immune-mediated necrotizing myopathy, or inclusion body myositis.Autoantibodies against Sp4 are absent in those with systemic lupus erythematosus or Sjogren’s syndrome and present in 8% of those with rheumatoid arthritis.How might this impact on clinical practice?Testing for anti-Sp4 autoantibodies may define a population of anti-TIF1γ-positive dermatomyositis patients without a substantially increased risk of cancer.

ObjectivesMyositis is a heterogeneous family of diseases including dermatomyositis (DM), immune-mediated necrotising myopathy (IMNM), antisynthetase syndrome (AS) and inclusion body myositis (IBM). Myositis-specific autoantibodies define different subtypes of myositis. For example, patients with anti-Mi2 autoantibodies targeting the chromodomain helicase DNA-binding protein 4 (CHD4)/NuRD complex (a transcriptional repressor) have more severe muscle disease than other DM patients. This study aimed to define the transcriptional profile of muscle biopsies from anti-Mi2-positive DM patients.MethodsRNA sequencing was performed on muscle biopsies (n=171) from patients with anti-Mi2-positive DM (n=18), DM without anti-Mi2 autoantibodies (n=32), AS (n=18), IMNM (n=54) and IBM (n=16) as well as 33 normal muscle biopsies. Genes specifically upregulated in anti-Mi2-positive DM were identified. Muscle biopsies were stained for human immunoglobulin and protein products corresponding to genes specifically upregulated in anti-Mi2-positive muscle biopsies.ResultsA set of 135 genes, includingSCRT1andMADCAM1, was specifically overexpressed in anti-Mi2-positive DM muscle. This set was enriched for CHD4/NuRD-regulated genes and included genes that are not otherwise expressed in skeletal muscle. The expression levels of these genes correlated with anti-Mi2 autoantibody titres, markers of disease activity and with the other members of the gene set. In anti-Mi2-positive muscle biopsies, immunoglobulin was localised to the myonuclei, MAdCAM-1 protein was present in the cytoplasm of perifascicular fibres, and SCRT1 protein was localised to myofibre nuclei.ConclusionsBased on these findings, we hypothesise that anti-Mi2 autoantibodies could exert a pathogenic effect by entering damaged myofibres, inhibiting the CHD4/NuRD complex, and subsequently derepressing the unique set of genes defined in this study.

Objective: This study aimed to elucidate the molecular features of inclusion body myositis (IBM). Methods: We performed RNA sequencing analysis of muscle biopsy samples from 67 participants, consisting of 58 myositis patients with the pathological finding of CD8-positive T cells invading non-necrotic muscle fibers expressing major histocompatibility complex class I (43 IBM, 6 polymyositis, and 9 unclassifiable myositis), and 9 controls. Results: Cluster analysis, principal component analysis, and pathway analysis showed that differentially expressed genes and pathways identified in IBM and polymyositis were mostly comparable. However, pathways related to cell adhesion molecules were upregulated in IBM as compared with polymyositis and controls (p¿

Sporadic inclusion body myositis (IBM) is the most common acquired muscle disease in adults over age 50, yet it remains unclear whether the disease is primarily driven by T cell–mediated autoimmunity. IBM muscle biopsies display nuclear clearance and cytoplasmic aggregation of TDP-43 in muscle cells, a pathologic finding observed initially in neurodegenerative diseases, where nuclear loss of TDP-43 in neurons causes aberrant RNA splicing. Here, we show that loss of TDP-43–mediated splicing repression, as determined by inclusion of cryptic exons, occurs in skeletal muscle of subjects with IBM. Of 119 muscle biopsies tested, RT-PCR–mediated detection of cryptic exon inclusion was able to diagnose IBM with 84% sensitivity and 99% specificity. To determine the role of T cells in pathogenesis, we generated a xenograft model by transplanting human IBM muscle into the hindlimb of immunodeficient mice. Xenografts from subjects with IBM displayed robust regeneration of human myofibers and recapitulated both inflammatory and degenerative features of the disease. Myofibers in IBM xenografts showed invasion by human, oligoclonal CD8 + T cells and exhibited MHC-I up-regulation, rimmed vacuoles, mitochondrial pathology, p62-positive inclusions, and nuclear clearance and cytoplasmic aggregation of TDP-43, associated with cryptic exon inclusion. Reduction of human T cells within IBM xenografts by treating mice intraperitoneally with anti-CD3 (OKT3) suppressed MHC-I up-regulation. However, rimmed vacuoles and loss of TDP-43 function persisted. These data suggest that T cell depletion does not alter muscle degenerative pathology in IBM.

BackgroundImmune checkpoint inhibitors (ICIs) have changed the cancer treatment landscape, but immune-related adverse events (irAEs) can affect a wide range of tissues in patients receiving ICIs. Severe irAEs can be life-threatening or fatal and prohibit patients from receiving further ICI treatment. While the clinical features of irAEs are well documented, the pathological mechanisms and predictive biomarkers are largely unknown. In addition, there is a critical need to preserve ICI-induced anti-tumor immunity while controlling for irAEs, which requires deciphering molecular and cellular signatures associated specifically with irAEs beyond those more generally linked to anti-tumor immunity.MethodsTo unbiasedly identify immune cells and states associated with irAEs, we applied CITE-seq to measure transcripts and surface proteins (83 protein markers) from PBMCs collected from patients with thymic epithelial tumors before and after treatment with an anti-PD-L1 antibody (avelumab, NCT01772004, NCT03076554).ResultsSamples from 9 patients were analyzed. No patient had a history of pre-existing paraneoplastic autoimmune disease. Anti-tumor activity was observed in all cases, and 5 patients had clinical and/or biochemical evidence of immune-related muscle inflammation (myositis with or without myocarditis). Multilevel models applied within highly resolved cell clusters revealed transcriptional states associated with ICI response and more uniquely with irAEs. A total of 190,000 cells were included in the analysis after quality control. Most notably, CD45RA+ effector memory CD8 T cells with an mTOR transcriptional signature were highly enriched at baseline and post treatment in patients with irAEs.ConclusionsOur findings suggest the potential therapeutic avenues by using mTOR inhibitors to dampen autoimmune responses while potentially sparing anti-tumor activity, to prevent treatment discontinuation and improve clinical outcomes for cancer patients treated with ICIs.AcknowledgementsThis research was supported in part by the Intramural Research Program of the NCI (the Center for Cancer Research), NIAID and NIAMS, and through a Cooperative Research and Development Agreement between the National Cancer Institute and EMD Serono.Trial RegistrationNCT01772004, NCT03076554Ethics ApprovalThis study is approved by NCI institutional review board.

Myositis comprises a heterogeneous group of skeletal muscle disorders which converge on chronic muscle inflammation and weakness. Our understanding of myositis pathogenesis is limited, and many myositis patients lack effective therapies. Using muscle biopsy transcriptome profiles from 119 myositis patients (spanning major clinical and serological disease subtypes) and 20 normal controls, we generated a co-expression network of 8101 dynamically regulated transcripts. This network organized the myositis transcriptome into a map of gene expression modules representing interrelated biological processes and disease signatures. Universally myositis-upregulated network modules included muscle regeneration, specific cytokine signatures, the acute phase response, and neutrophil degranulation. Universally myositis-suppressed pathways included a specific subset of myofilaments, the mitochondrial envelope, and nuclear isoforms of the anti-apoptotic humanin protein. Myositis subtype-specific modules included type 1 interferon signaling and titin (dermatomyositis), RNA processing (antisynthetase syndrome), and vasculogenesis (inclusion body myositis). Importantly, therapies exist to target influential proteins in many myositis-dysregulated modules, and nearly all modules contained understudied proteins and non-coding RNAs – many of which were extraordinarily dysregulated in myositis and may represent novel therapeutic targets. Finally, we apply our network to patient classification, finding that a deep learning algorithm trained on patient-level network “images” successfully assigned patients to clinical groups and further into molecular subclusters. Altogether, we provide a global resource to probe and contextualize differential gene expression in myositis.

Background and objectives Sporadic inclusion body myositis (sIBM) diagnosis is frequently delayed or confused with another class of disorders, and misdiagnosis is common. Sometimes, we have problems diagnosing an sIBM in the early stages or predicting when a PM is going to become an sIBM. In this sense, we believe that p62 immunostaining could help clinicians. Case report We report the case of a 61-year-old patient with sIBM who six years earlier had been diagnosed with polymyositis (PM). After muscle biopsies analyses, we showed the natural history of sIBM by p62 expression. Results When we looked for p62 aggregates retrospectively we could see small dotted p62 aggregates in the muscle fibres of the first muscle biopsy. Six years later, the patient presented with the typical clinical picture of sIBM, also the muscle biopsy was characteristic, with large p62 aggregates. Conclusions Probably p62 immunostaining could help to distinguish PM patients that are going to become sIBM, but to date there has been no systematic study to clarify p62 utility in myositis.

ObjectiveTo define the clinical phenotype of dermatomyositis (DM) with anti-Mi2 autoantibodies.MethodsIn this longitudinal cohort study, the prevalence and severity of clinical features at disease onset and during follow-up in patients with anti-Mi2–positive DM were compared to patients with anti-Mi2–negative DM, antisynthetase syndrome (AS), and immune-mediated necrotizing myopathy (IMNM). Longitudinal anti-Mi2 autoantibody titers were assessed.ResultsA total of 58 patients with anti-Mi2–positive DM, 143 patients with anti-Mi2–negative DM, 162 patients with AS, and 170 patients with IMNM were included. Among patients with anti-Mi2–positive DM, muscle weakness was present in 60% at disease onset and occurred in 98% during longitudinal follow-up; fewer patients with anti-Mi2–negative DM developed weakness (85%; p = 0.008). Patients with anti-Mi2–positive DM were weaker and had higher creatine kinase (CK) levels than patients with anti-Mi2–negative DM or patients with AS. Muscle biopsies from patients with anti-Mi2–positive DM had prominent necrosis. Anti-Mi2 autoantibody levels correlated with CK levels and strength (p < 0.001). With treatment, most patients with anti-Mi2–positive DM had improved strength and CK levels; among 10 with multiple serum samples collected over 4 or more years, anti-Mi2 autoantibody titers declined in all and normalized in 3, 2 of whom stopped immunosuppressant treatment and never relapsed. Patients with anti-Mi2–positive DM had less calcinosis (9% vs 28%; p = 0.003), interstitial lung disease (5% vs 16%; p = 0.04), and fever (7% vs 21%; p = 0.02) than did patients with anti-Mi2–negative DM.ConclusionsPatients with anti-Mi2–positive DM have more severe muscle disease than patients with anti-Mi2–negative DM or patients with AS. Anti-Mi2 autoantibody levels correlate with disease severity and may normalize in patients who enter remission.

Resume Contexte La maladie associee aux IgG4 (MAG-4) est une maladie auto-immune qui declenche une cascade inflammatoire aboutissant a une fibrose. Les criteres d’evaluation sont limites et les options therapeutiques insuffisamment explorees. Objectifs Evaluer la variation du score d’activite de la MAG-4 (IgG4-RI) dans une cohorte de patients atteints et explorer leurs traitements et resultats. Methodes Nous avons etudie le phenotype clinique, la gravite de la maladie et la reponse au traitement dans une etude longitudinale multicentrique ambispective menee dans 14 hopitaux en Espagne. Tous les patients remplissaient les criteres de diagnostic du consensus international de 2012 sur cette maladie. Resultats Soixante-huit patients ont ete inclus, d’âge moyen 53,4 ans, avec une predominance d’hommes. Les tissus les plus frequemment touches etaient le retroperitoine (33 %), des pseudotumeurs de l’orbite (28 %) et les sinus maxillaires et paranasaux (24 %). Le score IgG4-RI etait plus eleve lorsque plusieurs organes etaient atteints et avant traitement. Il diminuait apres le traitement, ce qui est conforme aux taux eleves de reponse au traitement. La plupart des patients ont ete traites par glucocorticoides (GC), chirurgie, azathioprine (AZA), mycophenolate mofetil (MMF) ou rituximab (RTX). La plupart des episodes d’activite de la MAG-4 ont ete pris en charge avec des GC seuls, des GC et une intervention chirurgicale ou des GC et de l’AZA. Les taux de reponse etaient eleves pour tous les traitements mais les rechutes et les poussees etaient frequentes. Conclusion Le score IgG4-RI, encore en developpement, est un indicateur prometteur dans la MAG-4. Les algorithmes de traitement ne sont pas clairement definis. Les GC et le RTX sont les traitements medicamenteux disponibles soutenus par le plus d’elements probants. Il est possible que les traitements de fond antirhumatismaux jouent un role dans la MAG-4, justifiant de nouvelles etudes prospectives.

Objective Although more than a dozen myositis-specific autoantibodies (MSAs) have been identified, most patients with myositis are positive for a single MSA. The specific overexpression of a given myositis autoantigen in myositis muscle has been proposed as initiating and/or propagating autoimmunity against that particular autoantigen. The present study was undertaken to test this hypothesis. Methods In order to quantify autoantigen RNA expression, RNA sequencing was performed on muscle biopsy samples from control subjects, MSA-positive patients with myositis, regenerating mouse muscles, and cultured human muscle cells. Results Muscle biopsy samples were available from 20 control subjects and 106 patients with autoantibodies recognizing hydroxymethylglutaryl-coenzyme A reductase (n = 40), signal recognition particles (n = 9), Jo-1 (n = 18), nuclear matrix protein 2 (n = 12), Mi-2 (n = 11), transcription intermediary factor 1γ (n = 11), or melanoma differentiation-associated protein 5 (n = 5). The increased expression of a given autoantigen in myositis muscle was not associated with autoantibodies recognizing that autoantigen (all q > 0.05). In biopsy specimens from both myositis muscle and regenerating mouse muscles, autoantigen expression correlated directly with the expression of muscle regeneration markers and correlated inversely with the expression of genes encoding mature muscle proteins. Myositis autoantigens were also expressed at high levels in cultured human muscle cells. Conclusion Most myositis autoantigens are highly expressed during muscle regeneration, which may relate to the propagation of autoimmunity. However, factors other than overexpression of specific autoantigens are likely to govern the development of unique autoantibodies in individual patients with myositis.

Although autologous and allogeneic hematopoietic cell transplantation are used to treat hematologic diseases, they are associated with high morbidity and mortality. The goal of this cross-sectional study was to describe the incidence, characteristics, severity and clinical correlates of neuropathy and muscle cramps, as self-reported by hematopoietic cell transplantation survivors. We included all respondents to a survey conducted July 1, 2020, to June 30, 2021. Surveys were completed online or on-paper according to participants' preferences; they received one reminder if no survey was received 1 month after distribution. Statistics are primarily descriptive comparing subgroups of patients. Of 4641 potentially eligible patients, 1745 responded and are included in the analysis. Participants (615 [35%] autologous, 1130 [65%] allogeneic) were a median age of 64.1 years (interquartile range [IQR] 55.2-70.8) and surveyed at a median of 11 years (IQR 4-21) after their most recent transplantation. Neuropathy symptoms were reported by 65% of autologous recipients, 66% of allogeneic transplant recipients with current chronic graft versus host disease (GVHD), and 45% of allogeneic recipients who never developed chronic GVHD. Muscle cramps were reported by 56% of autologous recipients, and 52% of allogeneic recipients and were rated as "very painful" by nearly half of patients who experienced them. These results suggest that neuropathy symptoms and muscle cramps are much more prevalent among survivors after hematopoietic cell transplantation than previously recognized. Better approaches for prevention and treatment of these bothersome complications are needed.

Objective To assess anti–cytosolic 5′‐nucleotidase 1A (anti–cN‐1A) autoantibodies in children with juvenile dermatomyositis (DM) and healthy controls, using 3 different methods of antibody detection, as well as verification of the results in an independent cohort. Methods Anti–cN‐1A reactivity was assessed in 34 Dutch juvenile DM patients and 20 healthy juvenile controls using the following methods: a commercially available full‐length cN‐1A enzyme‐linked immunosorbent assay (ELISA), a synthetic peptide ELISA, and immunoblotting with a lysate from cN‐1A–expressing HEK 293 cells. Sera from juvenile DM patients with active disease and those with disease in remission were analyzed. An independent British cohort of 110 juvenile DM patients and 43 healthy juvenile controls was assessed using an in‐house full‐length cN‐1A ELISA. Results Anti–cN‐1A reactivity was not present in sera from juvenile DM patients or healthy controls when tested with the commercially available full‐length cN‐1A ELISA or by immunoblotting, in either active disease or disease in remission. Additionally, in the British juvenile DM cohort, anti–cN‐1A reactivity was not detected. Three Dutch juvenile DM patients had weakly positive results for 1 of 3 synthetic cN‐1A peptides measured by ELISA. Conclusion Juvenile DM patients and young healthy individuals did not show anti–cN‐1A reactivity as assessed by different antibody detection techniques.

Purpose of the review Idiopathic inflammatory myopathies are a heterogeneous group of autoimmune disorders. The presence of different autoantibodies allows clinicians to define distinct phenotypes. Antibodies against the melanoma differentiation-associated protein 5 gene, also called anti-MDA5 antibodies, are associated with a characteristic phenotype, the clinically amyopathic dermatomyositis with rapidly progressive interstitial lung disease. This review aims to analyze the different pharmacological options for the treatment of rapidly progressive interstitial lung disease in patients with anti-MDA5 antibodies. Recent findings Evidence-based therapeutic recommendations suggest that the best initial approach to treat these patients is an early combination of immunosuppressive drugs including either glucocorticoids and calcineurin inhibitors or a triple therapy adding intravenous cyclophosphamide. Tofacitinib, a Janus kinase inhibitor, could be useful according to recent reports. High ferritin plasma levels, generalized worsening of pulmonary infiltrates, and ground-glass opacities should be considered predictive factors of a bad outcome. In this scenario, clinicians should consider rescue therapies such as therapeutic plasma exchange, polymyxin-B hemoperfusion, veno-venous extracorporeal membrane oxygenation, or even lung transplantation. Summary Combined immunosuppressive treatment should be considered the first-line therapy for patients with anti-MDA5 rapidly progressive interstitial lung disease. Aggressive rescue therapies may be useful in refractory patients.

Sporadic inclusion body myositis (IBM) is the most common acquired muscle disease in adults over age 50, yet it remains unclear whether the disease is primarily driven by T cell-mediated autoimmunity. IBM muscle biopsies exhibit nuclear clearance and cytoplasmic aggregation of TDP-43 in muscle cells, a pathologic finding observed initially in neurodegenerative disease, and nuclear loss of TDP-43 in neurons causes aberrant RNA splicing. Here, we show that loss of TDP-43 splicing repression, as determined by inclusion of cryptic exons, occurs in skeletal muscle of IBM patients. Out of 119 muscle biopsies tested, RT-PCR-mediated detection of cryptic exon expression is 84% sensitive and 99% specific for diagnosing IBM, indicating utility as a functional and diagnostic biomarker. To determine the role of T cells in pathogenesis, we generated a novel xenograft model by transplanting human IBM muscle into the hindlimb of immunodeficient mice. Xenografts from IBM patients display robust regeneration of human myofibers and recapitulate both inflammatory and degenerative features of the disease. Myofibers in IBM xenografts are invaded by human, oligoclonal CD8+ T cells and exhibit MHC-I upregulation, rimmed vacuoles, mitochondrial pathology, p62-positive inclusions, and nuclear clearance and cytoplasmic aggregation of TDP-43, resulting in expression of cryptic exons. Depletion of human T cells within IBM xenografts by treating mice intraperitoneally with anti-CD3 (OKT3) suppresses MHC-I upregulation, but rimmed vacuoles and loss of TDP-43 function persist. These data suggest that myofiber degeneration occurs independent of T cells, and muscle cell-intrinsic mechanisms, such as loss of TDP-43 splicing repression, drive IBM pathogenesis.One Sentence SummaryDepletion of T cells in a xenograft model of sporadic inclusion body myositis suppresses inflammation but not TDP-43 pathology or muscle degeneration.

Strategies to determine who could be safely discharged home from the Emergency Department (ED) in COVID-19 are needed to decongestion healthcare systems.To describe the outcomes of an ED triage system for non-severe patients with suspected COVID-19 and possible pneumonia based on chest X-ray (CXR) upon admission.Retrospective, single-center study performed in Barcelona (Spain) during the COVID-19 peak in March-April 2020. Patients with COVID-19 symptoms and potential pneumonia, without respiratory insufficiency, with priority class IV-V (Andorran triage model) had a CXR upon admission. This approach tried to optimize resource use and to facilitate discharges. The results after adopting this organizational approach are reported.We included 834 patients, 53% were female. Most patients were white (66%) or Hispanic (27%). CXR showed pneumonia in 523 (62.7%). Compared to those without pneumonia, patients with pneumonia were older (55 vs 46.6 years old) and had a higher Charlson comorbidity index (1.9 vs 1.3). Patients with pneumonia were at a higher risk for a combined outcome of admission and/or death (91 vs 12%). Death rates tended to be numerically higher in the pneumonia group (10 vs 1). Among patients without pneumonia in the initial CXR, 10% reconsulted (40% of them with new pneumonia).CXR identified pneumonia in a significant number of patients. Those without pneumonia were mostly discharged. Mortality among patients with an initially negative CXR was low. CXR triage for pneumonia in non-severe COVID-19 patients in the ED can be an effective strategy to optimize resource use.La pandemia de COVID-19 conlleva una alta ocupación de los servicios de urgencias (SU). Se requieren nuevas estrategias para optimizar la gestión de estos recursos.Describir los resultados de un sistema de triaje en urgencias para pacientes no graves con sospecha de COVID-19 y posible neumonía, basado en la radiografía de tórax (RT).Estudio retrospectivo, unicéntrico realizado en Barcelona (España) entre marzo y abril de 2020. Se realizó una RT al ingreso en SU de pacientes con síntomas de COVID-19 y sospecha de neumonía, sin insuficiencia respiratoria, con una prioridad clase IV-V (sistema andorrano de triaje). Esta medida pretende optimizar los recursos y facilitar las altas. Se reportan los resultados tras adoptar esta estrategia.Se incluyeron 834 pacientes (53% mujeres, 66% caucásicos, 27% hispánicos). La RT mostró neumonía en 523 (62,7%). Comparados con los pacientes sin neumonía, los que sí la padecían eran mayores (55 vs. 46,6 años), con un índice de comorbilidad de Charlson más elevado (1,9 vs. 1,3) y con mayor riesgo de ingreso y/o muerte (91 vs. 12%). La mortalidad fue numéricamente mayor en el grupo con neumonía (10 vs. 1). El 10% de los pacientes sin neumonía en RT consultaron de nuevo al SU (40% con neumonía).La RT identificó neumonía en múltiples pacientes. Los que no tenían neumonía fueron mayoritariamente dados de alta. La mortalidad entre pacientes con RT negativa fue baja. La RT como triaje para neumonía en pacientes con COVID-19 no grave puede ahorrar recursos.

We analyzed the prevalence of anti-mitochondrial autoantibodies (AMA) in adult- and juvenile-onset myositis longitudinal cohorts and investigated phenotypic differences in myositis patients with AMA. We screened sera from myositis patients including 619 adult- and 371 juvenile-onset dermatomyositis (DM, JDM), polymyositis (PM, JPM), inclusion body myositis (IBM), or amyopathic DM patients and from healthy controls, including 164 adults and 92 children, for AMA by ELISA. Clinical characteristics were compared between myositis patients with and without AMA. AMA were present in 5% of adult myositis patients (16 of 216 DM, 10 of 222 PM, 4 of 140 IBM, 1 of 19 amyopathic DM), 1% of juvenile myositis patients (3 of 302 JDM, 1 of 25 JPM), and 1% of both adult and juvenile healthy controls. In patients with adult-onset myositis, AMA were associated with persistent muscle weakness, Raynaud’s phenomenon, dysphagia, and cardiomyopathy. Adult myositis patients with AMA may have more severe or treatment refractory disease, as they more frequently received glucocorticoids and intravenous immunoglobulin. In juvenile myositis, children with AMA often had falling episodes and dysphagia, but no other clinical features or medications were significantly associated with AMA. AMA are present in 5% of adult myositis patients and associated with cardiomyopathy, dysphagia, and other signs of severe disease. The prevalence of AMA is not increased in patients with juvenile myositis compared to age-matched healthy controls. Our data suggest that the presence of AMA in adult myositis patients should prompt screening for cardiac and swallowing involvement. Key Points• Approximately 5% of a large North American cohort of adult myositis patients have anti-mitochondrial autoantibodies.• Adults with anti-mitochondrial autoantibodies often have chronic weakness, Raynaud’s, dysphagia, cardiomyopathy, and more severe disease.• Anti-mitochondrial autoantibodies are rare in juvenile myositis and not associated with a specific clinical phenotype.

We have read with great interest the article of Dr. Hou et al.(1) in which muscle ISG15 expression was shown to be strongly associated with the diagnosis of juvenile dermatomyositis. Moreover, they found that anti-MDA5 juvenile dermatomyositis patients have a higher expression of ISG15 than other subgroups. This confirms previous studies, both in adults and in children, emphasizing the relevance of the interferon pathway in patients with dermatomyositis.(2-6).

Thank you for your constructive comments.1 We agree that transcriptomic data from affected muscle tissue have the potential to improve the diagnosis and treatment of inflammatory myopathies.2 First, transcriptomic data may allow us to identify the most relevant inflammatory pathways in a particular patient and thereby individualise therapy. For example, patients with marked upregulation of interferon-induced genes may benefit most from treatment with Janus kinase inhibitors. Second, transcriptomic analysis requires very little muscle tissue while providing a large amount of biological information. Thus, transcriptomic analysis using needle muscle biopsies may be as diagnostically useful as conventional surgical muscle biopsies. Finally, visual interpretation of muscle biopsies is a complicated task that, even when performed by experts, has relatively poor interrater reliability.3 In contrast, the analysis of transcriptomic data is objective and can be automated. In our study, the presence of interstitial lung disease was almost always present in certain myositis subgroups (anti-MDA54 and anti-Jo15) and almost completely absent in others (anti-Mi2,6 anti-NXP2,7 anti-TIF1g,8 anti-SRP,9 anti-HMGCR,10 IBM11).Thus, the sample size of patients with and without interstitial lung disease within each subgroup was not sufficient …

The chromodomain helicase and DNA binding 4 (CHD4) protein is upregulated in regenerating myofibers. To define the role of CHD4 in muscle differentiation and regeneration, we generated mice with CHD4 ablated in muscle satellite cells (SCs). Embryonic day 18.5 CHD4 KO mice are non-viable, with atrophic intercostal and back muscles and altered expression of muscle contraction genes. Tamoxifen-inducible conditional CHD4 KO in adult mouse SCs diminished myoblast proliferation, induced premature differentiation, and altered expression of muscle contraction genes at the myotube stage. Following cardiotoxin–induced muscle injury, CHD4 KO regenerating myofibers had reduced cross-sectional area. ChIP-Seq analysis revealed that CHD4 binds actin a1, Wnt and b-catenin genes, which are known to play roles in the regulation of myogenesis. Together, our results suggest an important role for CHD4 in the control of embryonic myogenesis, SC differentiation, and the control of muscle fiber size in adult skeletal muscle during regeneration.

Objectives Pneumocystis jirovecii pneumonia (PJP) is associated with significant morbidity and mortality in adult myositis patients; however, there are few studies examining PJP in juvenile myositis [juvenile idiopathic inflammatory myopathy (JIIM)]. The purpose of this study was to determine the risk factors and clinical phenotypes associated with PJP in JIIM. Methods An research electronic data capture (REDCap) questionnaire regarding myositis features, disease course, medications and PJP infection characteristics was completed by treating physicians for 13 JIIM patients who developed PJP (PJP+) from the USA and Canada. Myositis features and medications were compared with 147 JIIM patients without PJP (PJP–) from similar geographic regions who enrolled in National Institutes of Health natural history studies. Results PJP+ patients were more often of Asian ancestry than PJP– patients [odds ratio (OR) 8.7; 95% CI 1.3, 57.9]. Anti- melanoma differentiation associated protein 5 (MDA5) autoantibodies (OR 12.5; 95% CI 3.0, 52.4), digital infarcts (OR 43.8; 95% CI 4.2, 460.2), skin ulcerations (OR 12.0; 95% CI 3.5, 41.2) and interstitial lung disease (OR 10.6; 95% CI 2.1, 53.9) were more frequent in PJP+ patients. Before PJP diagnosis, patients more frequently received pulse steroids, rituximab and more immunosuppressive therapy compared with PJP– patients. Seven PJP+ patients were admitted to the intensive care unit and four patients died due to PJP or its complications. Conclusions PJP is a severe infection in JIIM that can be associated with mortality. Having PJP was associated with more immunosuppressive therapy, anti-MDA5 autoantibodies, Asian race and certain clinical features, including digital infarcts, cutaneous ulcerations and interstitial lung disease. Prophylaxis for PJP should be considered in juvenile myositis patients with these features.

Background Myositis, or idiopathic inflammatory myopathy (IIM), is a group disorders of unknown etiology characterized by the inflammation of skeletal muscle. The role of T cells and their antigenic targets in IIM initiation and progression is poorly understood. T cell receptor (TCR) repertoire sequencing is a powerful approach for characterizing complex T cell responses. However, current TCR sequencing methodologies are complex, expensive, or both, greatly limiting the scale of feasible studies. Methods Here we present Framework Region 3 AmplifiKation sequencing (“FR3AK-seq”), a simplified multiplex PCR-based approach for the ultra-efficient and quantitative analysis of TCR complementarity determining region 3 (CDR3) repertoires. By using minimal primer sets targeting a conserved region immediately upstream of CDR3, undistorted amplicons are analyzed via short read, single-end sequencing. We also introduce the novel algorithm Inferring Sequences via Efficiency Projection and Primer Incorporation (“ISEPPI”) for linking CDR3s to their associated variable genes. Findings We find that FR3AK-seq is sensitive and quantitative, performing comparably to two different industry standards. FR3AK-seq and ISEPPI were used to efficiently and inexpensively characterize the T cell infiltrates of surgical muscle biopsies obtained from 145 patients with IIM and controls. A cluster of closely related TCRs was identified in samples from patients with sporadic inclusion body myositis (IBM). Interpretation The ease and minimal cost of FR3AK-seq removes critical barriers to routine, large-scale TCR CDR3 repertoire analyses, thereby democratizing the quantitative assessment of human TCR repertoires in disease-relevant target tissues. Importantly, discovery of closely related TCRs in muscle from patients with IBM provides evidence for a shared antigen-driven T cell response in this disease of unknown pathogenesis. Funding This work was supported by NIH grant U24AI118633 and a Prostate Cancer Foundation Young Investigator Award.