Idiopathic inflammatory myopathies (IIM), even though sharing common clinical manifestations, are characterized by diversified molecular pathogenetic mechanisms which may account for the partial inefficacy of currently used immunomodulatory drugs. In the last decades, the role of interferon (IFN) in IIM has been extensively elucidated thanks to genomic and proteomic studies which have assessed the molecular signature at the level of affected tissues or in peripheral blood across distinct IIM subtypes. A predominant type I IFN response has been shown in dermatomyositis (DM), being especially enhanced in anti-melanoma differentiation-associated gene 5 (MDA5)+ DM, while a type 2 IFN profile characterizes anti-synthetase syndrome (ASyS) and inclusion body myositis (IBM); conversely, a less robust IFN footprint has been defined for immune-mediated necrotizing myopathy (IMNM). Intracellular IFN signaling is mediated by the janus kinase/signal transducer and activator of transcription (JAK/STAT) through dedicated transmembrane receptors and specific cytoplasmic molecular combinations. These results may have therapeutic implications and led to evaluating the efficacy of new targeted drugs such as the recently introduced janus kinase inhibitors (JAKi), currently approved for the treatment of rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis. In this review we aim to summarize the most significant evidence of IFN role in IIM pathogenesis and to describe the current state of the art about the ongoing clinical trials on IFN-targeting drugs, with particular focus on JAKi.

Purpose of review: This is a comprehensive review of the current knowledge on predominant immune cell phenotypes involved in idiopathic inflammatory myopathies (IIM). Recent findings: Major circulating immune cell subpopulations described in IIM encompass the lymphocyte compartment. An unbalance in T cell subsets seems to consistently affect the peripheral and muscle compartment, with a predominance of CD4+ T and B cells in dermatomyositis, CD8+ T cells in polymyositis/inclusion body myositis (IBM) and novel findings highlighting novel proinflammatory T subsets, that is, CD8+Tbet+ and CD28− T cells across different IIM subsets. On the other hand, an impairment in Treg cells number and function has been described especially across polymyositis/dermatomyositis and IBM. Total T follicular helper (Tfh) cells, increased in immune-mediated necrotizing myopathy, skewed toward Tfh2 and Tfh17 in dermatomyositis, polymyositis, and juvenile dermatomyositis. B cell compartment is more rarely described in IIM, yet an unbalance in this pool is as well likely. Evidence of plasma cells increased in polymyositis, dermatomyositis, IBM, and Bregs decreased in dermatomyositis have been reported. Perturbations in the memory and naïve subsets are common in dermatomyositis/polymyositis and antisynthetase syndrome. Summary: Protean immune cell abnormalities characterize different IIM subsets, reflecting the complexity of these autoimmune conditions. A deeper understanding of B-cell and T-cell immunophenotyping may promote early diagnosis and identification of new potential therapeutic targets.

There is still a need for an efficient method for the isolation of extracellular vesicles (EVs) from human blood that provides a reliable yield with acceptable purity. Blood is a source of circulating EVs, but soluble proteins and lipoproteins hamper their concentration, isolation, and detection. This study aims to investigate the efficiency of EV isolation and characterization methods not defined as “gold standard”. EVs were isolated from human platelet-free plasma (PFP) of patients and healthy donors through size-exclusion chromatography (SEC) combined with ultrafiltration (UF). Then, EVs were characterized using transmission electron microscopy (TEM), imaging flow cytometry (IFC), and nanoparticle tracking analysis (NTA). TEM images showed intact and roundish nanoparticles in pure samples. IFC analysis detected a prevalence of CD63+ EVs compared to CD9+, CD81+, and CD11c+ EVs. NTA confirmed the presence of small EVs with a concentration of ~10¹⁰ EVs/mL that were comparable when stratifying the subjects by baseline demographics; conversely, concentration differed according to the health status across healthy donors and patients affected with autoimmune diseases (130 subjects in total, with 65 healthy donors and 65 idiopathic inflammatory myopathy (IIM) patients). Altogether, our data show that a combined EV isolation method, i.e., SEC followed by UF, is a reliable approach to isolate intact EVs with a significant yield from complex fluids, which might characterize disease conditions early.

Purpose of review: This review summarizes the recent developments about anti-MDA5 antibody positive dermatomyositis with a focus on its pathogenesis, clinical features and treatment options of rapidly progressive interstitial lung disease, its most ominous complication. Recent findings: Anti-MDA5+ dermatomyositis has a heterogeneous clinical spectrum with different patient subsets exhibiting widely different outcomes; severe acute interstitial lung disease is the main factor impacting prognosis. The pathogenetic role of anti-MDA5 antibodies is an active area of investigation. Summary: Anti-MDA5+ dermatomyositis has a wider spectrum of manifestations than previously thought. A high index of suspicion is needed not to miss atypical presentations. In the setting of acute interstitial lung involvement, once a confident diagnosis is made, an aggressive approach with early combined immunosuppression affords the best chances of survival.

Purpose of review: This review encompasses the main novelties regarding nonimmune mechanisms implicated in the pathogenesis of idiopathic inflammatory myopathies (IIM).Recent findings: In recent years, growing data support a role for endoplasmic-reticulum (ER) stress as a propagator of muscular damage, together with the release of interferon type I and reactive oxygen species in hypoxemic muscle fibers. Other studies evaluating the relationship between autophagy and Toll-like receptors (TLRs) in IIM subtypes have shown increased TLR3 and TLR4 expression in fibers of IIM patients and colocalization with LC3, an autophagy marker, submitting autophagy as a likely player in IIM pathogenesis. Most novel evidences concern the potential role of denervation of the neuromuscular junction in IIM, possibly connected to hyperexpression of MHC-I, and trafficking of extracellular vesicles, which may represent a connection between nonimmune and immune-mediated mechanisms of muscle inflammation and damage.Summary: Nonimmune mechanisms contribute to the pathogenesis of IIM, likely cooperating with immune-mediated inflammation. Consistent data were released for ER stress, autophagy, mitochondrial dysfunction and hypoxia; in addition to, neuromuscular denervation and extracellular vesicles have been proposed as thoughtful links between muscle inflammation, damage and atrophy. Further understanding of nonimmune abnormalities and potential reversible pathways is needed to improve the management of IIM.

Background: The usefulness of myositis-specific autoantibodies (MSAs) and myositis-associated autoantibodies (MAAs) for the assessment of idiopathic inflammatory myopathies (IIMs) is acknowledged, but laboratory standardization remains a challenge. We detected MSAs/MAAs by multi-analytic line immunoassay (LIA) and particle-based multi-analyte technology (PMAT) in a multicenter cohort of patients with IIMs. Methods: We tested the sera from 411 patients affected with definite IIM, including 142 polymyositis (PM), 147 dermatomyositis (DM), 19 cancer-associated myositis, and 103 overlap myositis syndrome (OM), and from 269 controls. MSAs/MAAs were determined by 16Ags LIA in all sera, and anti-HMGCR by ELISA in 157/411 IIM sera and 91/269 control sera. The analytical specificity of LIA/HMGCR ELISA was compared with that of PMAT in 89 MSA+ IIM sera. Results: MSAs/MAAs were positive in 307/411 (75%) IIM patients and 65/269 (24%) controls by LIA (Odds Ratio 9.26, 95% CI 6.43–13.13, p < 0.0001). The sensitivity/specificity of individual MSAs/MAAs were: 20%/100% (Jo-1), 3%/99.3% (PL-7), 4%/98.8% (PL-12), 1%/100% (EJ), 0.7%/100% (OJ), 9%/98% (SRP), 5.6%/99.6% (TIF1γ), 4.6%/99.6% (MDA5), 8%/96% (Mi-2), 1.5%/98% (NXP2), 1.7%/100% (SAE1), 4%/92% (Ku), 8.5%/99% (PM/Scl-100), 8%/96% (PM/Scl-75), and 25.5%/79% (Ro52). Anti-HMGCR was found in 8/157 (5%) IIM patients and 0/176 (0%) controls by ELISA (p = 0.007). Concordance between LIA/HMGCR ELISA and PMAT was found in 78/89 (88%) samples. Individual MSAs detected by LIA were associated with IIM subsets: Jo-1 with PM and OM, PL-12 with OM, Mi-2, TIF1γ, and MDA5 with DM, SRP with PM, and PM/Scl-75/100 with OM (p < 0.001 for all). Conclusions: Since MSAs are mostly mutually exclusive, multi-specific antibody profiling seems effective for a targeted clinical-serologic approach to the diagnosis of IIMs.