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Currently, standardized magnetic resonance imaging (MRI) scoring systems and protocols for assessment of idiopathic inflammatory myopathies (IIMs) in children and adults are lacking. Therefore, we will perform a scoping review of the literature to collate and evaluate the existing semi-quantitative and quantitative MRI scoring systems and protocols for the assessment and monitoring of skeletal muscle involvement in patients with IIMs. The aim is to compile evidence-based information that will facilitate the future development of a universal standardized MRI scoring system for both research and clinical applications in IIM. A systematic search of electronic databases (PubMed, EMBASE, and Cochrane) will be undertaken to identify relevant articles published between January 2000 and October 2023. Data will be synthesized narratively. This scoping review seeks to comprehensively summarize and evaluate the evidence on the scanning protocols and scoring systems used in the assessment of diagnosis, disease activity, and damage using skeletal muscle MRI in IIMs. The results will allow the development of consensus recommendations for clinical practice and enable the standardization of research methods for the MRI assessment of skeletal muscle changes in patients with IIMs., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

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., Competing Interests: Declaration of Competing Interest H. Benjamin Larman is a consultant for Tscan Therapeutics, which seeks to develop T cell receptor based cellular therapies. Andrew Mammen and Lisa Christopher-Stine are listed as inventors on a patent (JHU C-11077) for a myositis antibody biomarker licensed to Inova Diagnostics. The remaining authors declare no competing interests., (Copyright © 2020 The Authors. Published by Elsevier B.V. All rights reserved.)

Objective: Activation of the type 1 interferon (IFN1) pathway is a prominent feature of dermatomyositis (DM) muscle and may play a role in the pathogenesis of this disease. However, the relevance of the IFN1 pathway in patients with other types of myositis such as the antisynthetase syndrome (AS), immune-mediated necrotizing myopathy (IMNM), and inclusion body myositis (IBM) is largely unknown. Moreover, the activation of the type 2 interferon (IFN2) pathway has not been comprehensively explored in myositis. In this cross-sectional study, our objective was to determine whether IFN1 and IFN2 pathways are differentially activated in different types of myositis by performing RNA sequencing on muscle biopsy samples from 119 patients with DM, IMNM, AS, or IBM and on 20 normal muscle biopsies., Methods: The expression of IFN1- and IFN2-inducible genes was compared between the different groups., Results: The expression of IFN1-inducible genes was high in DM, moderate in AS, and low in IMNM and IBM. In contrast, the expression of IFN2-inducible genes was high in DM, IBM, and AS but low in IMNM. The expression of IFN-inducible genes correlated with the expression of genes associated with inflammation and muscle regeneration. Of note, ISG15 expression levels alone performed as well as composite scores relying on multiple genes to monitor activation of the IFN1 pathway in myositis muscle biopsies., Conclusions: IFN1 and IFN2 pathways are differentially activated in different forms of myositis. This observation may have therapeutic implications because immunosuppressive medications may preferentially target each of these pathways., (© 2019 American Academy of Neurology.)

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., (© 2019 American College of Rheumatology. This article has been contributed to by US Government employees and their work is in the public domain in the USA.)

Objectives: Imaging plays a role in myositis assessment by detecting muscle changes indicative of pathology. This study was conducted to determine the ultrasonographic pattern of muscle involvement in patients with inclusion body myositis (IBM) through an assessment of muscle echointensity., Methods: Sixty-two individuals were consecutively studied, 18 with IBM, 16 with polymyositis or dermatomyositis and 28 normal controls. Standardised scans were completed bilaterally for the deltoids, biceps, flexor digitorum profundus (FDP), flexor carpi ulnaris, rectus femoris, tibialis anterior and gastrocnemius assessing for muscle echointensity changes., Results: Patients with IBM had a markedly increased muscle echointensity when compared with comparator groups for all muscles studied. This was most discriminating at the FDP, gastrocnemius and rectus femoris. Asymmetry between sides and a heterogeneously increased echointensity were also seen., Conclusions: Ultrasonography can aid in the assessment of IBM by displaying an increased echointensity in characteristically involved muscles, particularly when combined with assessments for asymmetry and echotexture.

Objective: To define the clinical features of myositis patients with anti-PM/Scl-75 and/or anti-PM/Scl-100 autoantibodies at disease onset and during the course of disease and compare them to patients with other forms of myositis., Methods: In this longitudinal cohort study, the prevalence and severity of clinical features at disease onset and during follow-up were compared between anti-PM/Scl-positive patients and those with the antisynthetase syndrome (AS), dermatomyositis (DM), and immune-mediated necrotizing myopathy (IMNM)., Results: Forty-one anti-PM/Scl-positive, 132 AS, 178 DM, and 135 IMNM patients were included. Although muscle weakness was a presenting feature in just 37% of anti-PM/Scl-positive patients, 93% eventually developed weakness. Unlike the other groups, anti-PM-Scl-positive patients had more severe weakness in arm abductors than hip flexors. Interstitial lung disease was a presenting feature in just 10% of anti-PM/Scl-positive patients, but occurred in 61% during follow-up; fewer patients with DM (13%, p < 0.001) and IMNM (6%, p < 0.001) and more patients with AS (80%, p < 0.05) developed interstitial lung disease during the course of disease. Mechanic's hands (80%), Raynaud syndrome (78%), sclerodactyly (66%), telangiectasias (66%), esophageal reflux disease (61%), subcutaneous edema (46%), puffy hands (39%), and calcinosis (39%) occurred more frequently in anti-PM/Scl-positive patients than in the other groups. Although 30% of anti-PM/Scl-positive patients met criteria for systemic sclerosis, less than 5% had renal crisis or finger ulcerations. No differences were found between patients with only anti-PM/Scl-100 or only anti-PM/Scl-75 autoantibodies., Conclusions: Unlike patients with DM, AS, or IMNM, anti-PM/Scl-positive patients have weaker arm abductors than hip flexors. Anti-PM/Scl-positive patients also have the most extensive extramuscular features., (© 2018 American Academy of Neurology.)

Objectives: The aims of this study were to define the pattern of muscle involvement in patients with immune-mediated necrotising myopathy (IMNM) relative to those with other inflammatory myopathies and to compare patients with IMNM with different autoantibodies., Methods: All Johns Hopkins Myositis Longitudinal Cohort subjects with a thigh MRI (tMRI) who fulfilled criteria for IMNM, dermatomyositis (DM), polymyositis (PM), inclusion body myositis (IBM) or clinically amyopathic DM (CADM) were included in the study. Muscles were assessed for intramuscular and fascial oedema, atrophy and fatty replacement. Disease subgroups were compared using univariate and multivariate analyses. Patients with IMNM with anti-signal recognition particle (SRP) autoantibodies were compared with those with IMNM with anti-HMG-CoA reductase (HMGCR) autoantibodies., Results: The study included 666 subjects (101 IMNM, 176 PM, 219 DM, 17 CADM and 153 IBM). Compared with DM or PM, IMNM was characterised by a higher proportion of thigh muscles with oedema, atrophy and fatty replacement (p<0.01). Patients with IMNM with anti-SRP had more atrophy (19%, p=0.003) and fatty replacement (18%, p=0.04) than those with anti-HMGCR. In IMNM, muscle abnormalities were especially common in the lateral rotator and gluteal groups. Fascial involvement was most widespread in DM. Fatty replacement of muscle tissue began early during the course of disease in IMNM and the other groups. An optimal combination of tMRI features had only a 55% positive predictive value for diagnosing IMNM., Conclusions: Compared with patients with DM or PM, IMNM is characterised by more widespread muscle involvement. Anti-SRP-positive patients have more severe muscle involvement than anti-HMGCR-positive patients., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.)

Objective: Individual dermatomyositis (DM)-associated autoantibodies are associated with distinct clinical phenotypes. This study was undertaken to explore the association of these autoantibodies with specific muscle biopsy features., Methods: DM subjects with a muscle biopsy reviewed at Johns Hopkins had sera screened for autoantibodies recognizing Mi-2, transcriptional intermediary factor 1-γ (TIF1-γ), NXP2, MDA5, Ro52, PM-Scl, and Jo1. We also included anti-Jo1–positive patients with polymyositis (PM) who had a biopsy read at Johns Hopkins. Analyzed histological features included perifascicular atrophy, perivascular inflammation, mitochondrial dysfunction, primary inflammation, and myofiber necrosis. Duration of disease, biopsy location, and treatment at biopsy were also analyzed., Results: We studied 91 DM and 7 anti-Jo1–positive patients with PM. In univariate analyses, TIF1-γ+ patients had more mitochondrial dysfunction (47% vs 18%; p = 0.05), NXP2+ patients had less primary inflammation (0% vs 28%; p = 0.01), Mi-2+ patients had more primary inflammation (50% vs 19%; p = 0.03), and PM-Scl+ patients had more primary inflammation (67% vs 18%; p = 0.004) than those who were negative for each autoantibody. Although reliability was limited because of small sample numbers, multivariate analysis confirmed that TIF1-γ+ patients had more mitochondrial dysfunction [prevalence ratio (PR) 2.6, 95% CI 1.0–6.5, p = 0.05] and PM-Scl+ patients had more primary inflammation (PR 5.2, 95% CI 2.0–13.4; p = 0.001) independent of disease duration at biopsy, biopsy site, and treatment at biopsy. No differences in muscle biopsy features were noted between anti-Jo1–positive patients diagnosed with DM and PM., Conclusion: The prevalence of different histological features varies according to autoantibody status in DM. Muscle biopsy features are similar in anti-Jo1 patients with and without a rash.

Polymyositis (PM) and dermatomyositis (DM) are the two major forms of inflammatory muscle diseases. They are characterized clinically primarily by proximal muscle weakness. The disease mechanisms that cause muscle damage and dysfunction are not fully understood. However, because of the association with other autoimmune diseases, the presence of autoantibodies, and response to immunosuppressive medication, they are believed to be autoimmune in origin. Recent studies have highlighted the importance of the innate immune system and non-immune mechanisms and described novel adaptive immune-based pathways in the pathogenesis of polymyositis and dermatomyositis. Stimulation of Toll-like receptors (TLRs) by endogenous antigens, e.g., aminoacyl-tRNA synthetase enzyme, may trigger activation of signaling pathways and thereby induces expression of multiple genes involved in the inflammatory response. High-mobility group box-1 (HMGB1) might interact with the same receptors and cause skeletal muscle inflammation. In addition, this protein may be involved in T lymphocyte survival in muscle tissue. A newly described T cell subset, CD28(-) T cells, may have strong myotoxic properties and comprises the predominant muscle-infiltrating T cell phenotype. Future studies should focus more on understanding the relative contribution of each pathway to the pathogenesis of inflammatory myopathies. Given the connections between the pathways, targeting multiple pathways through combination therapies may be beneficial.

Purpose of Review: To examine new developments in sporadic inclusion body myositis (IBM), including updated clinical and prognostic factors, novel autoantibody associations, unique histopathologic findings, proposed new clinical diagnostic criteria, and novel therapeutic agents., Recent Findings: IBM is a slowly progressive disease, leading to wheelchair use, on average, 12-20 years after onset of symptoms; however, it does not appear to interfere with life expectancy. Older age at the onset of first symptoms as well as immunosuppressive therapy are likely associated with more rapid disease progression. Quantitative muscle strength of knee extensor and the IBM functional rating scale seem to be sensitive disease progression markers and may be useful clinical trial outcome measures. Newly proposed diagnostic criteria utilize data-driven approaches with very high sensitivity and specificity. A novel autoantibody, as well as unique proteins seen histopathlogically, may help hone in on diagnosis as well as to deepen our understanding of IBM pathophysiology. Novel treatments, including follistatin and bimagrumab, are directed at potential therapeutic targets., Summary: We have observed an explosion of knowledge in IBM in the recent past, which challenges traditional dogma and ushers in a new era of understanding with potential clinical implications for those who suffer with IBM.

Purpose of Review: Inflammatory myopathy (IIM) classification criteria have been the source of considerable debate. In the three decades since Bohan and Peter published their criteria which have long stood as the gold standard for diagnosis in clinical practice as well as inclusion into clinical trials, more sophisticated understanding of immunopathogenesis, histology, and specific autoantibody associations has broadened our understanding of these diseases. This editorial review examines the diverse approaches between different subspecialists in deriving appropriate IIM classification utilizing this updated knowledge., Recent Findings: Several investigators have proposed improved IIM classification criteria. More recently, larger scale consensus efforts have been undertaken by various expert groups including the European Neuromuscular Centre (ENMC) and The International Myositis Assessment and Clinical Studies Group (IMACS). The intent is to refine the classification criteria utilizing our enhanced understanding which has matured since the original publication of Bohan and Peter's proposal in 1975., Summary: Many diagnostic/classification criteria have been proposed for different forms of IIM over the last three decades. The majority of these have been based on clinical impressions rather than rigorous data analyses or expert consensus and none has been fully tested for sensitivity or specificity using appropriately powered studies that take into account relevant disease confounders. Different sets of criteria proposed and adopted by different specialties hamper the ability to compare clinical studies and assess clinical trials' outcomes. Large, multicentered, multispecialty studies are required to develop improved IIM criteria.

Objective: Myofiber necrosis without prominent inflammation is a nonspecific finding in patients with dystrophies and toxic or immune-mediated myopathies. However, the etiology of a necrotizing myopathy is often obscure, and the question of which patients would benefit from immunosuppression remains unanswered. The aim of this study was to identify novel autoantibodies in patients with necrotizing myopathy., Methods: Muscle biopsy specimens and serum samples were available for 225 patients with myopathy. Antibody specificities were determined by performing immunoprecipitations from (35)S-methionine-labeled HeLa cell lysates. Selected biopsy specimens were stained for membrane attack complex, class I major histocompatibility complex (MHC), and endothelial cell marker CD31., Results: Muscle biopsy specimens from 38 of 225 patients showed predominantly myofiber necrosis. Twelve of these patients had a known autoantibody association with or other etiology for their myopathy. Sixteen of the remaining 26 sera immunoprecipitated 200-kd and 100-kd proteins; this specificity was observed in only 1 of 187 patients without necrotizing myopathy. Patients with the anti-200/100 autoantibody specificity had proximal weakness (100%), high creatine kinase levels (mean maximum 10,333 IU/liter), and an irritable myopathy on electromyography (88%). Sixty-three percent of these patients had been exposed to statins prior to the onset of weakness. All patients responded to immunosuppressive therapy, and many experienced a relapse of weakness when the medication was tapered. Immunohistochemical studies showed membrane attack complex on small blood vessels in 6 of 8 patients and on the surface of non-necrotic myofibers in 4 of 8 patients. Five of 8 patients had abnormal capillary morphology, and 4 of 8 patients expressed class I MHC on the surface of non-necrotic myofibers., Conclusion: An anti-200/100-kd specificity defines a subgroup of patients with necrotizing myopathy who previously were considered to be autoantibody negative. We propose that these patients have an immune-mediated myopathy that is frequently associated with prior statin use and should be treated with immunosuppressive therapy.

Objective: Autoantibodies against the chromatin remodeler Mi-2 are found in a distinct subset of patients with dermatomyositis (DM). Previous quantitative immunoblotting experiments demonstrated that Mi-2 protein levels are up-regulated in DM muscle. This study was undertaken to define the population of cells expressing high levels of Mi-2 in DM muscle and to explore the regulation and functional role of Mi-2 during muscle regeneration., Methods: The expression of Mi-2 was analyzed by immunofluorescence microscopy in human muscle biopsy specimens. In an experimental mouse model, cardiotoxin was used to induce muscle injury and repair, and expression of Mi-2 during muscle regeneration was studied in this model by immunofluorescence and immunoblotting analyses. In addition, a cell culture system of muscle differentiation was utilized to artificially modulate Mi-2 levels during proliferation and differentiation of myoblasts., Results: In human DM muscle tissue, increased Mi-2 expression was found preferentially in the myofibers within fascicles affected by perifascicular atrophy, particularly in the centralized nuclei of small perifascicular muscle fibers expressing markers of regeneration. In injured mouse muscle tissue, Mi-2 levels were dramatically and persistently up-regulated during muscle regeneration in vivo. Premature silencing of Mi-2 with RNA interference in vitro resulted in accelerated myoblast differentiation., Conclusion: Expression of Mi-2 is markedly up-regulated during muscle regeneration in a mouse model of muscle injury and repair. It is also up-regulated in human DM myofibers expressing markers of regeneration. Results of the in vitro studies indicate that this protein may play a role in modulating the kinetics of myoblast differentiation. Our findings thus suggest that high levels of Mi-2 expression in muscle biopsy tissue from patients with DM reflect the presence of incompletely differentiated muscle cells.