Polymyositis Patients Research Articles

Genome-wide DNA methylation and mRNA transcription analysis revealed aberrant gene regulation pathways in dermatomyositis and polymyositis patients.

Genome-wide DNA methylation and mRNA transcription analysis revealed aberrant gene regulation pathways in dermatomyositis and polymyositis patients.

Increased risk of pulmonary embolism in patients with dermatomyositis/polymyositis, a retrospective cohort study from Israel

BackgroundDespite the well-established association between chronic inflammatory conditions and pulmonary embolism(PE), previous investigations of the relationship between Dermatomyositis(DM) and Polymyositis(PM) with PE were scarce and have been subject to significant limitations, including small sample sizes and failure to account for potential confounders. ObjectivesTo investigate the correlation between DM/PM and PE, as well as assessing the impact of serologic status, myonecrosis, and inflammation markers on this relationship. MethodsIn this large, nationwide population-based study, we used the Clalit Health Services medical database and extracted all DM/PM patients who were first diagnosed between 1 January 2002 to 31 December 2018 and compared them with age and gender matched controls in a ratio of 1:5. Serological and laboratory values were obtained for each patient. Rates of PE were compared between groups using multivariate models. ResultsThe study included 1557 DM patients with 7633 controls, and 528 PM patients with 2560 controls. Compared with matched controls, the rates of PE were significantly higher in the DM/PM group, PM patients(2.8 % vs 0.5 % in controls, OR = 5.73, p < 0.001), DM patients(1.2 % vs 0.3 % in controls, OR = 3.42, p < 0.001). APLA seropositivity was significantly more prevalent in DM/PM patients compared with their matched controls, PM patients(10.8 % vs 2.7 % in controls, p < 0.001), DM patients(7.9 % vs 1.6 % in controls, p < 0.001). APLA seropositivity had a synergistic effect for PE in the DM/PM(OR = 23.18, p < 0.001). ConclusionsDM and PM are associated with higher rates of PE. Furthermore, patients with DM/PM demonstrate a significantly higher prevalence APLA which act as a potentiator of thrombosis in these patients.

Polymyositis is a rare and favourable outcome subtype of idiopathic inflammatory myopathy in Chinese patients.

To investigate the prevalence and characteristics of typical polymyositis (PM) in Chinese patients with idiopathic inflammatory myopathy (IIM). Patients diagnosed with IIM according to the 2017 EULAR/ACR criteria were included. Serological aspects including myositis-specific antibodies (MSA) and pathological data were re-evaluated. The diagnosis of typical PM was strictly done using the pathological criteria, while excluding other IIM subtypes such as dermatomyositis (DM), immune-mediated necrotising myopathies (IMNM), anti-synthetase syndrome (ASS), and sporadic inclusion body myositis (sIBM), based on their respective diagnostic criteria. A total of 544 IIM patients with muscle biopsy were involved, and 129 of them were diagnosed with initial PM according to the 2017 EULAR/ACR criteria. Only 6 (1.1%, 6/544) patients met the strict definition of typical PM after re-evaluation. Patients with typical PM were MSA-negative (100% vs. 35.7%, p=0.003) and had CD8+ T cells surrounding or invading non-necrotic muscle fibres in muscle biopsies (100% vs. 7.8%, p<0.001) compared to the initially diagnosed PM patients. All typical PM patients achieved clinical remission at the second-year follow-up. Typical PM patients had a favourable prognosis compared to MSA-negative IMNM and unspecific myositis patients. Strictly defined typical PM is a rare clinical subtype in Chinese IIM patients. Typical PM patients with classical pathology were MSA-negative and responded well to treatment and had a favourable prognosis. It is crucial for clinicians to combine clinical, serological, and pathological features to properly distinguish PM from other IIM subtypes.

Pathogenic mechanisms of disease in idiopathic inflammatory myopathies: autoantibodies as clues.

Idiopathic inflammatory myopathies (IIMs) encompass a spectrum of autoimmune diseases characterized by muscle inflammation and systemic involvement. This review aimed to synthesize current evidence on the clinical significance and pathogenic mechanisms underlying autoantibodies associated with IIMs. Autoantibodies targeting aminoacyl-tRNA synthetases (ARS) play a pivotal role in antisynthetase syndrome (ASS), highlighting associations with interstitial lung disease (ILD) and distinctive clinical features. Anti-Mi-2 antibodies in dermatomyositis (DM) are hallmarked by characteristic cutaneous manifestations and favorable prognostic outcomes. Conversely, anti-TIF1 antibodies are correlated with DM and a higher risk of malignancies, implicating CD8+ T cells in its pathogenesis. Anti-MDA5 antibodies signify clinically amyopathic DM (CADM) with severe ILD, linked to dysregulated neutrophil extracellular trap (NET) formation. In immune-mediated necrotizing myopathies (IMNMs), anti-SRP and anti-HMGCR antibodies induce complement-mediated myopathy, typically following statin exposure. Additionally, anti-TRIM72 antibodies emerge as potential diagnostic markers in IIMs. Anti-cN1A autoantibodies are linked to inclusion body myositis (IBM) and play a decisive role in muscle protein degradation. Meanwhile, anti-FHL1 autoantibodies are associated with severe disease manifestations and muscle damage, as established in experimental models. Anti-eIF3 autoantibodies, recently identified in polymyositis (PM) patients, are rarely detected (<1%) and associated with a favorable prognosis. Elucidating these autoantibodies is anticipated to not only assist in early diagnosis and disease stratification but also inform targeted therapeutic interventions, emphasizing the intricate interplay between autoimmunity, cellular dysfunction, and clinical outcomes in IIMs.

KL-6 in adult polymyositis and dermatomyositis patients and its correlation with interstitial lung disease

BackgroundPulmonary involvement is still regarded as a common cause of morbidity in Polymyositis/Dermatomyositis. Interstitial lung disease can result in potentially fatal consequences such as ventilatory failure, secondary pulmonary arterial hypertension, or cor pulmonale. Early diagnosis of interstitial lung disease is hence a top priority in Polymyositis/Dermatomyositis patients. Krebs von den Lungen-6 is a transmembrane mucoprotein that has recently been identified as a promising marker for interstitial lung disease diagnosis and progression. As a result, it is regarded as a powerful predictor of interstitial lung disease severity. Thirty polymyositis/dermatomyocitis patients were enrolled in this study. Thirty age and sex matched healthy individuals were selected as control group. Cutaneous Dermatomyositis Disease Area Severity index(CDASI) was used for evaluation of skin severity, KL6 was measured using Elisa kit, High-resolution computed tomography, pulmonary function tests were made.ResultsSixteen female and 14 male patients had a mean age of 41.64–8.02 and amedian of the disease duration of 4 years. Fifteen patients (50%) had normal readings on High-resolution computed tomography of the chest HRCT chest, while the other half had significant HRCT chest findings. KL-6 concentrations were seen to be higher in Polymyositis/Dermatomyositis patients mainly those with ILD (mean ± SD 38.66 ± 22.98), compared to the control group (Mean ± S 589.04 ± 409) and in patients without ILD (Mean ± SD 86.70 ± 8.99), (p < 0.001). KL-6 serum concentrations were shown to have a significant connection with the HRCT score (r = 0.803, P < 0.001). Forced vital capacity (FVC%) (r = − 0.910, P < 0.001), forced expiratory volume in 1 s (FEV1%) (r = − 0.767, P < 0.001), and FEV1/FVC% (r = − 0.228, P = 0.112) were all inversely related to KL-6 concentrations.ConclusionIndividuals with PM and DM with concomitant ILD have increased KL-6 serum concentrations in comparison to myositis individuals without ILD, denoting its potential role in diagnosis and follow up of PM/DM with ILD. Further studies are needed to discuss the role of KL6 in large sample of the patient's population, and its correlation with other organ affection rather than ILD. Also to clarify the potentiality of adding the KL6 biomarker to the guidelines of treat to target for Rheumatic diseases with lung affection and to see the effect of treatment on KL6 serum level.

Clinical implications and mechanism of complement C1q in polymyositis.

Polymyositis (PM) is the most common autoimmune disease in neurology and among muscle disorders; it is of great significance to thoroughly understand the mechanism of PM to find new diagnosis and treatment methods. This research intends to elucidate the clinical implications and mechanisms of complement C1q in polymyositis (PM). One hundred fifteen PM patients (research group, RG) and 120 healthy subjects (control group, CG) who visited our hospital between March 2017 and March 2020 were selected. Peripheral blood C1q and creatine kinase (CK) levels of both groups were measured, and their correlations with clinical symptoms and prognostic recurrence of PM. Additionally, to further understand the mechanism of action of C1q in PM, we purchased BALB/c mice and grouped them as follows: control group with normal feeding, PM group with PM modeling, intervention group with PM modeling, and intraperitoneal injection of gC1qR monoclonal antibody 60.11, a C1q protein receptor. Inflammatory factors and muscle histopathology were detected in all groups of mice. Finally, rat macrophages (mø) were isolated, and changes in the biological behavior of mø were observed after silencing the expression of gC1qR. Serum C1q and CK were both higher in RG than in CG, with favorable diagnostic effects on PM (P < 0.05). C1q and CK increased in symptomatic anti-ribonuclear protein antibody (RNP)-positive patients but decreased in anti Jo-1 antibody (Jo-1)- and anti-neutrophil cytoplasmic antibody (ANCA)-positive patients (P < 0.05). PM mice were observed with elevated gC1qR, while model mice exhibited severe infiltration of inflammatory cells in muscle tissue, increased pro-IFs, and reduced anti-IFs, and the animals in the intervention group showed improved conditions (P < 0.05). Finally, it was found that CD68, CD86 protein, and invasion capacity of gC1qR-sh-transfected cells decreased, while CD206 and CD163 increased (P < 0.05). C1q is elevated in PM and is strongly linked to the pathological process of PM. Inhibition of gC1qR expression reduced inflammatory infiltration in PM mice.

Prognosis of spontaneous pneumomediastinum occurring in dermatomyositis or polymyositis patients with interstitial lung disease according to antimelanoma differentiation-associated gene 5 antibody status: a retrospective cohort study

ObjectivesSpontaneous pneumomediastinum (SPNM) historically has been considered a poor prognostic factor in dermatomyositis/polymyositis patients complicated with interstitial lung disease (ILD). However, there is a lack of actual data regarding the...

The efficacy and safety of tacrolimus in patients with dermatomyositis/polymyositis: A meta-analysis and systematic review

ObjectiveTo evaluate the efficacy and safety of tacrolimus for dermatomyositis (DM) and polymyositis (PM) treatment. MethodsWe searched the Embase, PubMed, the Cochrane Central Register of Controlled Trials, and China National Knowledge Infrastructure were used as searching tools from inception up to October 2022. Two authors independently selected studies. The available studies were comprehensively reviewed and investigated. ResultsA total of 9 studies, including 350 patients, were analysed. Pooled results showed a higher overall survival rate in tacrolimus therapy group. Creatine kinase (CK) levels and forced vital capacity (FVC) showed significant improvement after tacrolimus therapy. The incidence of adverse events including infection and renal dysfunction showed no significant differences between the tacrolimus therapy group and conventional therapy group. ConclusionThe results of this meta-analysis indicated that GC therapy in combination with tacrolimus therapy could help improving overall survival rate, pulmonary function and had similar safety outcomes compared to conventional therapy in DM and PM patients.

Quantitative assessment of muscle properties in polymyositis and dermatomyositis using high-frequency ultrasound and shear wave elastography

Polymyositis (PM) and dermatomyositis (DM) are two common types of idiopathic inflammatory myopathy and can lead to a poor prognosis and quality of life. We designed this cross-sectional study to investigate the abilities of high-frequency ultrasound (HFUS) and shear wave elastography (SWE) to assess muscle properties in patients with PM and DM and to distinguish healthy muscles from diseased muscles with PM and DM. A total of 60 patients (26 PM cases and 34 DM cases) and 65 matched healthy volunteers were continuously included in the case and control groups, respectively. For the bilateral deltoid, biceps brachii, rectus femoris, and vastus lateralis, the muscle thickness, echo intensity, and longitudinal shear wave velocity (SWV) of all participants were measured using HFUS and SWE. The intra- and interobserver reliability of SWV measurements of patients with PM and DM and the receiver operating characteristic curve for HFUS and SWE for PM and DM were analyzed. Patients with PM and DM had significantly decreased muscle thickness and increased muscle echo intensity compared to healthy controls (P<0.001). The patients' and healthy participants' deltoid, biceps brachii, rectus femoris, and vastus lateralis thickness was 19.75 and 23.00 mm, 20.45 and 22.80 mm, 18.40 and 20.20 mm, and 20.00 and 22.80 mm, respectively. Except for the biceps brachii, the mean SWV in the longitudinal orientation in patients with PM and DM significantly decreased (P<0.01). The mean SWV of the patients' and healthy participants' deltoid, rectus femoris, and vastus lateralis was 2.47 and 2.57 m/s, 1.73 and 1.87 m/s, and 1.57 and 1.77 m/s, respectively. Excellent intra- and interobserver reliability of SWV measurements on the deltoid and rectus femoris of PM and DM patients were found (intraclass correlation coefficient >0.95; P<0.001). The diagnostic performance of echo intensity in lower-extremity proximal muscles for PM and DM was excellent [area under the curve (AUC) >0.9]. The thickness of most muscles displayed moderate diagnostic performance (the AUC ranged from 0.700 to 0.775). The SWV of the vastus lateralis showed a stable performance (AUC =0.741). The combined diagnostic performance of echo intensity and thickness and the combined diagnostic performance of the 3 indicators were relatively high (the AUC ranged from 0.871 to 0.936 and from 0.898 to 0.938, respectively). Muscle thickness and echo intensity showed statistical differences in different disease stages of PM and DM (P'<0.01). HFUS and SWE may serve as imaging biomarkers for the diagnosis of PM and DM by detecting abnormal muscle thinning, enhanced muscle echo intensity, and reduced muscle SWV.

Clinical and Radiological Features of Interstitial Lung Diseases Associated with Polymyositis and Dermatomyositis.

Polymyositis and dermatomyositis are autoimmune idiopathic systemic inflammatory diseases, characterized by various degrees of muscle inflammation and typical cutaneous lesions-the latter found in dermatomyositis. The underlying pathogenesis is characterized by a high level of uncertainty, and recent studies suggest diseases may have different immunopathological mechanisms. In polymyositis, components of the cellular immune system are involved, whereas in dermatomyositis, the pathogenesis is mainly mediated by the humoral immune response. The interstitial lung disease occurs in one-third of polymyositis and dermatomyositis patients associated with worse outcomes, showing an estimated excess mortality rate of around 40%. Lung involvement may also appear, such as a complication of muscle weakness, mainly represented by aspiration pneumonia or respiratory insufficiency. The clinical picture is characterized, in most cases, by progressive dyspnea and non-productive cough. In some cases, hemoptysis and chest pain are found. Onset can be acute, sub-acute, or chronic. Pulmonary involvement could be assessed by High Resolution Computed Tomography (HRCT), which may identify early manifestations of diseases. Moreover, Computed Tomography (CT) appearances can be highly variable depending on the positivity of myositis-specific autoantibodies. The most common pathological patterns include fibrotic and cellular nonspecific interstitial pneumonia or organizing pneumonia; major findings observed on HRCT images are represented by consolidations, ground-glass opacities, and reticulations. Other findings include honeycombing, subpleural bands, and traction bronchiectasis. In patients having Anti-ARS Abs, HRCT features may develop with consolidations, ground glass opacities (GGOs), and reticular opacities in the peripheral portions; nonspecific interstitial pneumonia or nonspecific interstitial pneumonia mixed with organizing pneumonia have been reported as the most frequently encountered patterns. In patients with anti-MDA5 Abs, mixed or unclassifiable patterns are frequently observed at imaging. HRCT is a sensitive method that allows one not only to identify disease, but also to monitor the effectiveness of treatment and detect disease progression and/or complications; however, radiological findings are not specific. Therefore, aim of this pictorial essay is to describe clinical and radiological features of interstitial lung diseases associated with polymyositis and dermatomyositis, emphasizing the concept that gold standard for diagnosis and classification-should be based on a multidisciplinary approach.

S1544 Celiac Disease Is Associated With Idiopathic Inflammatory Myopathies

Introduction: Celiac disease (CD) is a chronic systemic immune-mediated disorder that occurs in genetically predisposed people upon ingestion of gluten. The complications and associations of CD are wide-ranging, with notable associations with other autoimmune diseases. Few studies have described the association of CD with inflammatory myopathies, such as polymyositis (PM), dermatomyositis (DM), and inclusion body myositis (IBM). However, there have been no studies interrogating the association in large cohorts. We investigated these relationships using a large nation-wide patient dataset. Methods: Utilizing IBM Explorys (Cleveland, OH), a database encompassing over 80 million patients in the United States and spanning the last 2 decades, we defined groups of patients identified with 3 idiopathic inflammatory myopathies using SNOMED Clinical Terms. We collected age, gender, and race-based demographics, in addition to comorbidities including hypothyroidism, alcohol use disorder, tobacco use, and CD, and subsequently performed binary logistic regression using IBM SPSS Statistics v26 (Chicago, IL) to determine significant associations. Results: In the database, which contained 80,920,060 patients at the time of querying, there were 143,330 CD patients (0.18%). 18,270 (0.02%) of the total patients met the definition of dermatomyositis, with 160 (0.88%) of these carrying the diagnosis of CD, while there were 8,970 (0.01%) polymyositis patients (of which there were 70 / 0.78% with CD) and 1,520 (0.002%) IBM patients (30 / 2% with CD). Following logistic regression that incorporated demographics and several comorbidities, CD was significantly associated with all inflammatory myopathies: the OR for CD in dermatomyositis was 3.55 (95%CI 3.11 — 4.04, P< 0.001), 3.23 in polymyositis (95%CI 2.89 — 3.60, P< 0.001) and 11.60 in IBM (95%CI 9.02 — 14.92, P< 0.001) (Table). Conclusion: In this very large aggregate of patients across the United States, CD was significantly associated with the idiopathic inflammatory myopathies of polymyositis, dermatomyositis, and IBM after accounting for a number of possible confounders. Clinicians should be aware of this relationship when assessing myalgia in celiac disease patients. Table 1. - Results of the multivariate regression analysis with odds ratios (OR), confidence intervals, and P-values (significant if <0.05) for each inflammatory myopathy Risk Factor OR for PM P-value OR for DM P-value OR for IBM P-value Celiac Disease 3.23 [2.89-3.60] < 0.001 3.55 [3.11-4.04] < 0.001 11.60 [9.02-14.92] < 0.001 Female gender 1.34 [1.31-1.38] < 0.001 1.36 [1.32-1.40] < 0.001 0.47 [0.43-0.52] < 0.001 Age ≥65 2.51 [2.45-2.57] < 0.001 2.26 [2.20-2.33] < 0.001 9.16 [8.20-10.25] < 0.001 White race 1.49 [1.45-1.53] < 0.001 1.71 [1.65-1.76] < 0.001 1.88 [1.69-2.09] < 0.001 Hypothyroidism 3.59 [3.49-3.69] < 0.001 3.33 [3.21-3.45] < 0.001 3.08 [2.76-3.43] < 0.001 Alcohol use 1.64 [1.53-1.76] < 0.001 1.76 [1.61-1.93] < 0.001 3.01 [2.47-3.67] < 0.001 Tobacco use 1.93 [1.86-2.00] < 0.001 1.93 [1.84-2.02] < 0.001 1.45 [1.25-1.68] < 0.001

NLRP3 inflammasome up-regulates major histocompatibility complex class I expression and promotes inflammatory infiltration in polymyositis

ObjectiveThis study was designed to investigate the role of the nucleotide-binding-domain -and leucine-rich repeat -containing (NLR) family, pyrin-domain-containing 3 (NLRP3) inflammasome in the pathogenesis of polymyositis (PM).MethodsImmunochemistry was performed to analyze the NLRP3, caspase-1 and interleukin-1 beta (IL-1β) expression in the muscle tissue of PM patients. Rat model of PM and C2C12 cell were used to investigate the potential role of NLRP3 inflammasome in PM.ResultsThe percentage of CD 68+ macrophages, and the expression levels of NLRP3, caspase-1 and IL-1β in the muscle tissue were elevated in 27 PM patients. LPS/ATP treatment resulted in activation of NLRP3 inflammasome and secretion of IL-1β as well as interferons (IFNs) and monocyte chemotactic protein-1 (MCP-1) in the Raw 264.7 macrophages. Meanwhile, LPS/ATP challenged activation of NLRP3 inflammasome induced overexpression of major histocompatibility complex class I (MHC-I), a key molecular of PM in the co-cultured C2C12 cells. The effect was decreased by treatment of NLRP3 inflammasome inhibitor MCC950 or siRNA of NLRP3 inflammasome. These findings suggested certain levels of IL-1β rather than IFNs up-regulated MHC-I expression in C2C12 cells. IL-1β blockade using neutralizing IL-1β monoclonal antibody or siRNA of IL-1β suppressed MHC-I overexpression. In vivo, NLRP3 inflammasome inhibition by MCC950 reduced the expression of NLRP3, IL-1β and MHC-I in the muscle tissue of PM modal rats. Also, it attenuated the intensity of muscle inflammation as well as the CRP, CK, and LDH levels in the serum.ConclusionNLRP3/caspase-1/IL-1β axis may play an important role in the development of PM. Inhibition of NLRP3 activation may hold promise in the treatment of PM.

Gut microbiota differences between psoriatic arthritis and other undifferentiated arthritis: A pilot study.

Psoriatic arthritis (PSA) is a form of immune-mediated inflammatory arthritis that predominantly begins with enthesitis. Studying the gut microbiota of PSA patients may offer new insights into the pathogenesis of enthesitis, compared to other arthritis. We designed a prospective study to examine gut microbiome of patients with PSA, primarily with enthesitis and dactylitis, and compared the data with other undifferentiated types of arthritis (NO PSA) patients, without enthesitis or dactylitis. We enrolled 9 PSA patients and 10 NO PSA patients in this study. We excluded rheumatoid arthritis, systemic lupus erythematosus, Sjogren syndrome, systemic sclerosis, mixed connective tissue disease, polymyositis, dermatomyositis, ANCA-associated vasculitis, and gouty arthritis patients. The fecal samples were investigated using 16S rRNA amplicon sequencing, followed by bioinformatics and statistical analyses. None of the available objective clinical laboratory data could differentiate PSA group from the NO PSA subgroup. The microbiota result shows that Family: XIII_AD3011 is significantly higher in NO PSA patients' than in PSA patients' stool samples (P = .039). Megasphaera elsdenii in the PSA group was 10,000 times higher than in the NO PSA group.Our results demonstrated high intragroup homogeneous and high intergroup heterogeneous microbiota. The clinical symptoms of either enthesitis or dactylitis are associated with higher presence of specific microbiota in the current study. The PSA and other undifferentiated arthritis could be differentiated with microbiota analysis. In the future, a larger cohort and thorough biochemical study are needed for confirmation.The microbiota is different between PSA and NO PSA patients, and the species could be used as a differential diagnostic tool between these 2 diseases. The clinically available serum markers may not be enough to reflect the details of patients with different patterns of arthritis. Megasphaera elsdenii species could be a link between gut flora and enthesitis and/or dactylitis clinically in PSA. We confirm the fact that the Bifidobacterium longum correlates negatively with eosinophils.

Amelioration of inflammatory myopathies by glucagon‐like peptide‐1 receptor agonist via suppressing muscle fibre necroptosis

BackgroundAs glucocorticoids induce muscle atrophy during the treatment course of polymyositis (PM), novel therapeutic strategy is awaited that suppresses muscle inflammation but retains muscle strength. We recently found that injured muscle fibres in PM undergo FASLG‐mediated necroptosis, a form of regulated cell death accompanied by release of pro‐inflammatory mediators, contributes to accelerate muscle inflammation and muscle weakness. Glucagon‐like peptide‐1 receptor (GLP‐1R) agonists have pleiotropic actions including anti‐inflammatory effects, prevention of muscle atrophy, and inhibition of cell death, in addition to anti‐diabetic effect. We aimed in this study to examine the role of GLP‐1R in PM and the effect of a GLP‐1R agonist on in vivo and in vitro models of PM.MethodsMuscle specimens of PM patients and a murine model of PM, C protein‐induced myositis (CIM), were examined for the expression of GLP‐1R. The effect of PF1801, a GLP‐1R agonist, on CIM was evaluated in monotherapy or in combination with prednisolone (PSL). As an in vitro model of PM, C2C12‐derived myotubes were treated with FASLG to induce necroptosis. The effect of PF1801 on this model was analysed.ResultsGLP‐1R was expressed on the inflamed muscle fibres of PM and CIM. The treatment of CIM with PF1801 in monotherapy (PF) or in combination with PSL (PF + PSL) suppressed CIM‐induced muscle weakness (grip strength, mean ± SD (g); PF 227 ± 6.0 (P < 0.01), PF + PSL 224 ± 8.5 (P < 0.01), Vehicle 162 ± 6.0) and decrease in cross‐sectional area of muscle fibres (mean ± SD (μm2); PF 1896 ± 144 (P < 0.05), PF + PSL 2018 ± 445 (P < 0.01), Vehicle 1349 ± 199) as well as the severity of histological inflammation scores (median, interquartile range; PF 0.0, 0.0–0.5 (P < 0.05), PF + PSL 0.0, 0.0–0.0 (P < 0.01), Vehicle 1.9, 1.3–3.3). PF1801 decreased the levels of inflammatory mediators such as TNFα, IL‐6, and HMGB1 in the serum of CIM. PF1801 inhibited necroptosis of the myotubes in an AMP‐activated protein kinase (AMPK)‐dependent manner. PF1801 activated AMPK and decreased the expression of PGAM5, a mitochondrial protein, which was crucial for necroptosis of the myotubes. PF1801 promoted the degradation of PGAM5 through ubiquitin‐proteasome activity. Furthermore, PF1801 suppressed FASLG‐induced reactive oxygen species (ROS) accumulation in myotubes, also crucial for the execution of necroptosis, thorough up‐regulating the antioxidant molecules including Nfe2l2, Hmox1, Gclm, and Nqo1.ConclusionsGLP‐1R agonist could be a novel therapy for PM that recovers muscle weakness and suppresses muscle inflammation through inhi biting muscle fibre necroptosis.

The Geospatial Distribution of Myositis and Its Phenotypes in the United States and Associations With Roadways: Findings From a National Myositis Patient Registry.

BackgroundLittle is known about the spatial distribution of idiopathic inflammatory myopathies (IIM) in the United States (U.S.), or their geospatial associations.MethodsWe studied a national myositis patient registry, with cases diagnosed in the contiguous U.S. from 1985–2011 and comprised of dermatomyositis (DM, n = 484), polymyositis (PM, n = 358), and inclusion body myositis (IBM, n = 318) patients. To assess the association of myositis prevalence with distance from roads, we employed log-Gaussian Cox process models, offset with population density.ResultsThe U.S. IIM case distribution demonstrated a higher concentration in the Northest. DM, IBM, and cases with lung disease were more common in the East, whereas PM cases were more common in the Southeast. One area in the West and one area in the South had a significant excess in cases of DM relative to PM and of cases with lung disease relative to those without lung disease, respectively. IIM cases tended to cluster, with between-points interactions more intense in the Northeast and less in the South. There was a trend of a higher prevalence of IIM and its major phenotypes among people living within 50 m of a roadway relative to living beyond 200 m. Demographic characteristics, rural-urban commuting area, and female percentage were significantly associated with the prevalence of IIM and with major phenotypes.ConclusionsUsing a large U.S. database to evaluate the spatial distribution of IIM and its phenotypes, this study suggests clustering in some regions of the U.S. and a possible association of proximity to roadways.

A retrospective cohort study in Chinese patients with adult polymyositis and dermatomyositis: risk of comorbidities and subclassification using machine learning.

To identify the risk factors in Chinese patients with adult polymyositis and dermatomyositis for their comorbidities and explore a subclassification system. Clinical records of 397 patients with idiopathic inflammatory myopathies were retrospectively reviewed. Logistic regression was used to identify potential risk factors for interstitial lung disease (ILD), other rheumatic diseases, and malignancy after bivariate analysis. Hierarchical clustering and decisional tree were utilised to identify subgroups and explore a subclassification system. A total of 119 polymyositis and 191 dermatomyositis patients were included. Anti-PM/Scl, anti-Ro52, anti-aminoacyl-tRNA synthetase and anti-MDA5 (adjusted odds ratios (AOR)=4.779, 1.917, 5.092 and 7.714 respectively) antibodies were risks (p<0.05), whereas overlapping malignancy was protective (AOR=0.107; p=0.002) for ILD across polymyositis, dermatomyositis and the total group. In subgroup models, Raynaud's phenomenon, arthralgia and semi-quantitative anti-nuclear antibody (AOR=51.233, 4.261, 3.047 respectively) were risks for other overlapping rheumatic diseases (p<0.05). For overlapping malignancy, male and anti-TIF1γ antibodies (AOR=2.533, 16.949) were risks (p<0.05), whereas disease duration and combination of ILD (AOR=0.954, 0.106) were protective in the total group (p<0.05); while anti-NXP2 antibodies were identified as risk factors (AOR=73.152; p=0.038) in polymyositis. Hierarchical clustering suggested a subclassification with 6 subgroups: malignancy overlapping dermatomyositis, classical dermatomyositis, polymyositis with severe muscle involvement, dermatomyositis with ILD, polymyositis with ILD, and overlapping of myositis with other rheumatic diseases. Accompanying ILD, other rheumatic diseases and malignancy are strongly associated with clinical manifestation and myositis-specific or myositis-associated autoantibodies among Chinese polymyositis and dermatomyositis patients. The subclassification system proposed a more precise phenotype defining toward stratified treatments.

Prognosis and Treatment of Myositis-Associated Severe Interstitial Lung Disease: A Descriptive Study Using a Nationwide Inpatient Database in Japan.

The aim of this study was to determine the prognosis, clinical course, and current management of severe interstitial lung disease (ILD) associated with myositis in Japan. We conducted a retrospective descriptive study using a nationwide database for inpatient care of acute illness in Japan. Among a total of ~66 million inpatient admissions, we identified patients with severe ILD associated with polymyositis (PM) or dermatomyositis (DM) who required mechanical ventilation and methylprednisolone pulse therapy (≥1 gm/day of methylprednisolone) from July 2010 to March 2018. We identified 155 patients with PM and 394 with DM who fulfilled the above criteria. The median age of patients was 65 years; DM patients were significantly younger than PM patients (64 versus 68 years; P < 0.001). The numbers of patients who were treated with calcineurin inhibitors, intravenous cyclophosphamide, and polymyxin B-immobilized fiber column direct hemoperfusion (PMX-DHP) were 403 (73.4%), 318 (57.9%), and 78 (14.2%), respectively. All these treatments were given significantly more frequently to the patients with DM compared with those with PM. The uses of other treatment options were much less frequent. The median periods after hospitalization when methylprednisolone pulse therapy, calcineurin inhibitors, mechanical ventilation, intravenous cyclophosphamide, and PMX-DHP were initiated and in-hospital death occurred among patients with DM were 2, 4, 7, 8, 17, and 36 days, respectively. In-hospital mortality was significantly higher in patients with DM than in those with PM (76.6% versus 56.8%; P < 0.001). The mortality of patients with myositis-associated severe ILD who require mechanical ventilation is extremely high despite aggressive and prompt interventions.

Targeting necroptosis in muscle fibers ameliorates inflammatory myopathies

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

Overview on Diagnosis and Management of Polymyositis

Polymyositis (PM) is an autoimmune disorder; result from abnormal activation of cytotoxic T lymphocytes (CD8 cells) and macrophages against muscular antigens as well as the strong extrafusal muscular expression of major histocompatibility complex class 1 causing damage to the endomysium of the skeletal muscles. Polymyositis develops over the months as compared to inclusion body myositis (IBM), which is a slowly progressive chronic myopathy developing in older individuals over a period of months to years with more severe symptoms. Many patients require treatment for many years. Polymyositis affects the distal musculature of the esophagus in the late stage of disease in up to 70% of the patients leading to the inability to swallow, as well as regurgitation problems that can cause aspiration pneumonia. The principal goals of therapy are to improve strength and improve physical functioning. Many patients require treatment for several years. The 5-year survival rate for treated patients is in the order of 95%. Up to one-third of PM patients may be left with some degree of residual muscle weakness.

Disease burden and treatment sequence of polymyositis and dermatomyositis patients in Japan: a real-world evidence study

Introduction/objectivesSince new consensus on polymyositis (PM) and dermatomyositis (DM) were released in Japan, an updated evidence on treatment landscape and PM/DM burden was essential. This study evaluates treatment burden and overall treatment cost of PM/DM-related inpatient and outpatient visits, treatments, and procedures/patient/year.MethodThis retrospective, observational study analyzed insurance claims from Japan Medical Data Center (JMDC) database. Patients with at least one PM/DM diagnosis/one dispensation of treatment between 1 January 2009 and 31 December 2019 were enrolled. Patient characteristics, treatment patterns and sequence, treatment choices, healthcare resource utilization (HCRU), and related costs were assessed. Chi-square test and linear regression model were used to assess impact of patient characteristics on treatment choice.ResultsPatients (836/4,961) receiving a relevant treatment were analyzed. Heart disease (35%), interstitial lung disease (27%), and diabetes mellitus (26%) were frequently identified as comorbidities. Concomitant dispensation of immunosuppressants and systemic steroids was largely found in first and second line of treatment (LoT) while systemic steroids remained as single dominant treatment across all LoTs. HCRU was very low for inpatient visits (0.68 [1.43]) or rehabilitation (4.74 [14.57]). The mean (SD) number of inpatient visits decreased from first (1.23 [2.32]) to third year (0.11 [0.54]). Total mean (SD) healthcare cost per patients per year was ¥ 3,815,912 (7,412,241), with overall drug dispensation compounding to 80% of total cost.ConclusionsHigh concomitant immunosuppressant and systemic steroid prescriptions in first LoT recommend early optimal treatment to manage PM/DM. Although inpatient costs are low, outpatient dispensation costs increase overall economic burden.Key Points• Japan faces treatment challenges in the prognosis of polymyositis (PM) and dermatomyositis (DM) and thus, we assessed the real-world treatment landscape, practice, patterns, and healthcare resource utilization as an evidence to support healthcare outcome improvement and treatment burden reduction.• Systemic steroids were the dominant preferred choice of treatment, but it increases the overall cost of the treatment due to the resultant comorbidities considering possible side-effects promotion.• Thus, an increased awareness towards the disease management among patients and medical doctors is required for better management goals based on this real-world practice evidence.