A new proposal for phenotypic classification and outcome assessment of dermatomyositis based on clinical manifestations and serological testing.

BACKGROUND: Dermatomyositis (DM) is an infrequent disease subgroup of idiopathic inflammatory myopathies characterized by distinct skin lesions. However, high heterogeneity makes clinical diagnosis and treatment of DM very challenging. OBJECTIVES: Unsupervised classification in DM patients and analysis of key factors related to clinical outcomes. METHODS: This retrospective study was conducted between 2017 and 2022 at the Department of Rheumatology, Xiangya Hospital, Central South University. 162 DM patients were enrolled for unsupervised hierarchical cluster analysis. In addition, we divided the clinical outcomes of DM patients into four subgroups: withdrawal, stabilization, aggravation, and death, and compared the clinical profiles amongst the subgroups. RESULTS: Out of 162 DM patients, three clusters were defined. Cluster 1 (n = 40) was mainly grouped by patients with prominent muscular involvement and mild Interstitial Lung Disease (ILD). Cluster 2 (n = 72) grouped patients with skin rash, anti-Melanoma Differentiation Associated protein 5 positive (anti-MDA5+), and Rapid Progressive Interstitial Lung Disease (RP-ILD). Cluster 3 (n = 50) grouped patients with the mildest symptoms. The proportion of death increased across the three clusters (cluster 3 < cluster 1 < cluster 2). STUDY LIMITATIONS: The number of cases was limited for the subsequent construction and validation of predictive models. We did not review all skin symptoms or pathological changes in detail. CONCLUSIONS: We reclassified DM into three clusters with different risks for poor outcome based on diverse clinical profiles. Clinical serological testing and cluster analysis are necessary to help clinicians evaluate patients during follow-up and conduct phenotype-based personalized care in DM.

Myxovirus resistance protein A (MxA) expression in myositides: Sarcoplasmic expression is common in both dermatomyositis and lupus myositis.

INTRODUCTION/AIMS: Myxovirus resistance protein A (MxA) is a type I interferon (IFN1) pathway activation marker and MxA sarcoplasmic expression is currently recognized as a highly specific marker for dermatomyositis (DM). However, we have frequently observed endothelial tubuloreticular inclusions (TRI), another surrogate IFN1 activation marker, in a variety of overlap myositides. The aim of this study was to examine MxA expression in those myositides. METHODS: We retrospectively performed MxA immunostaining on a wide range of myositides. RESULTS: MxA sarcoplasmic expression was present in DM (94.4%, 17/18), active lupus myositis (LM, 80%,16/20), inactive LM (36%, 4/11), antisynthetase syndrome (ASyS, 20%, 2/10), systemic sclerosis (13%, 2/15), Sjogren's syndrome (7.7%, 1/13), and human immunodeficiency virus (HIV) myositis (5.6%, 1/18) and was absent in immune-mediated necrotizing myopathy (IMNM, 0/16) and hydroxychloroquine myopathy (0/5). The sensitivity and specificity of MxA sarcoplasmic expression for LM and DM combined compared with all other myositides were 84.6% (95% CI: 69.5-94.1) and 92.1 (95% CI: 83.6-97.0), respectively, and superior to TRIs. MxA capillary expression was nonspecific. Histologically, 35% of LM cases demonstrated a unique panfascicular necrotizing myopathy pattern. The remainder of the LM cases had significant morphological overlap with DM/ASyS (20%), IMNM (20%), or polymyositis (15%). DISCUSSION: MxA sarcoplasmic expression is highly prevalent in LM and DM and is a useful marker in differentiating DM and LM from other myositides. LM can manifest in various pathology patterns that need to be differentiated from DM, IMNM, ASyS, and polymyositis.

Causes and Clinical Presentation of Drug-Induced Dermatomyositis: A Systematic Review.

Importance: While several medications are known to induce dermatomyositis (DM), most existing studies are case reports or small case series from a single institution. There is also limited information on DM induced by immune checkpoint inhibitors, which are increasingly used in oncologic therapy. Objective: To characterize causes and clinical presentation of drug-induced DM based on the current literature. Evidence Review: A systematic review was performed in PubMed according to Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guidelines, from inception to August 22, 2022. Articles meeting preestablished inclusion criteria (written in English and classified as original articles, case reports, literature reviews, and observation letters) were selected and data abstracted. Articles that met the scope of the review were also added from reference lists. When possible, study results were quantitatively combined. Findings: In 134 studies (114 from the literature search and 20 additional studies pulled from reference lists) describing 165 cases, 88 patients (53.3%) were female, and the median (IQR) age was 61 (49-69) years. Among the cases of drug-induced DM, the most common associated medications were hydroxyurea (50 [30.3%]), immune checkpoint inhibitors (27 [16.4%]), statins (22 [13.3%]), penicillamine (10 [6.1%]), and tumor necrosis factor inhibitors (10 [6.1%]). Histopathologic testing, when undertaken, helped establish the diagnosis. There was a median (IQR) of 60 (21-288) days between drug initiation and drug-induced DM onset. History of cancer was reported in 85 cases (51.6%). Conclusions and Relevance: In this systematic review, drug-induced DM was associated with multiple types of medications, including chemotherapies and immunotherapies. It is essential that dermatologists promptly recognize and diagnose drug-induced DM so that they can guide management to minimize interruption of therapy when possible.

Effect of type I interferon on engineered pediatric skeletal muscle: a promising model for juvenile dermatomyositis.

OBJECTIVE: To investigate pathogenic mechanisms underlying JDM, we defined the effect of type I IFN, IFN-α and IFN-ß, on pediatric skeletal muscle function and expression of myositis-related proteins using an in vitro engineered human skeletal muscle model (myobundle). METHODS: Primary myoblasts were isolated from three healthy pediatric donors and used to create myobundles that mimic functioning skeletal muscle in structural architecture and physiologic function. Myobundles were exposed to 0, 5, 10 or 20 ng/ml IFN-α or IFN-ß for 7 days and then functionally tested under electrical stimulation and analyzed immunohistochemically for structural and myositis-related proteins. Additionally, IFN-ß-exposed myobundles were treated with Janus kinase inhibitors (JAKis) tofacitinib and baricitinib. These myobundles were also analyzed for contractile force and immunohistochemistry. RESULTS: IFN-ß, but not IFN-α, was associated with decreased contractile tetanus force and slowed twitch kinetics. These effects were reversed by tofacitinib and baricitinib. Type I IFN paradoxically reduced myobundle fatigue, which did not reverse after JAKi. Additionally, type I IFN correlated with MHC I upregulation, which normalized after JAKi treatment, but expression of myositis-specific autoantigens Mi-2, melanocyte differentiation-associated protein 5 and the endoplasmic reticulum stress marker GRP78 were variable and donor specific after type I IFN exposure. CONCLUSION: IFN-α and IFN-ß have distinct effects on pediatric skeletal muscle and these effects can partially be reversed by JAKi treatment. This is the first study illustrating effective use of a three-dimensional human skeletal muscle model to investigate JDM pathogenesis and test novel therapeutics.

Disease spectrum of myopathies with elevated aldolase and normal creatine kinase.

BACKGROUND AND PURPOSE: Elevation of serum creatine kinase (CK) or hyperCKemia is considered a biological marker of myopathies. However, selective elevation of serum aldolase with normal CK has been reported in a few myopathies, including dermatomyositis, immune-mediated myopathy with perimysial pathology and fasciitis with associated myopathy. The aim was to investigate the disease spectrum of myopathies with isolated aldolase elevation. METHODS: Medical records were reviewed to identify patients >18 years old seen between December 1994 and June 2020 who had pathologically proven myopathies with elevated aldolase and normal CK level. Patients with alternative causes of aldolase elevation were excluded. RESULTS: Thirty-four patients with various types of myopathies were identified. Myopathies were treatable in 27 patients. The three most common etiologies were dermatomyositis (n = 8), overlap myositis (n = 4) and nonspecific myopathy (n = 4). Perimysial pathology comprising inflammation, fragmentation, vasculitis, calcified perimysial vessels or extracellular amyloid deposition was found in 17/34 patients (50%). Eight dermatomyositis patients with selective elevated aldolase were compared to 24 sex- and age-matched patients with dermatomyositis and hyperCKemia. Dermatomyositis patients with normal CK significantly (p < 0.05) had less frequent cutaneous involvement (50.0% vs. 100.0%) and fibrillation potentials (50.0% vs. 90.5%) but higher median erythrocyte sedimentation rate (33.5 vs. 13.5 mm/h) and more common perifascicular mitochondrial pathology (37.5% vs. 4.2%). CONCLUSION: Isolated aldolase elevation can be found in a greater variety of myopathies than initially thought and most were treatable. Dermatomyositis is the most common myopathy with selective elevation of aldolase in our cohort, which features some unique characteristics compared to dermatomyositis with hyperCKemia.

Dermatomyositis presenting with diffuse calcinosis.

We present the case of a woman in her early 50s who initially presented to an orthopedist for nodules located near the posterior knee. Imaging revealed diffuse subcutaneous calcifications and she was subsequently referred to rheumatology. Additional testing included myositis panel, electromyography (EMG) and muscle biopsy which indicated the presence of an inflammatory myopathy. It was determined that this patient had an uncommon presentation of dermatomyositis in which her primary complaint was calcinosis cutis. While rash and muscle weakness are often the symptoms most commonly associated with dermatomyositis, it is essential to have a wide differential for patients presenting with calcium deposition in soft tissues. This is particularly important in patients with certain antibodies, including the NXP-2 antibody, which can be associated with malignancy and should prompt an appropriate malignancy workup.

Single cell RNA sequencing sheds light on infiltrating T cells in idiopathic inflammatory myopathies.

Idiopathic inflammatory myopathies (IIM), also referred to as "myositis," are a group of heterogeneous autoimmune disorders characterised by muscle weakness, atrophy and progressive reduced mobility (Lundberg et al, 2021). IIM represent a significant health burden in adult populations, affecting individuals at a mean age of 50 with an estimated prevalence of 2.9-34 per 100,000 (Dobloug et al, 2015; Svensson et al, 2017). IIM encompass several subtypes including dermatomyositis, immune-mediated necrotising myopathy, inclusion-body myositis, antisynthetase syndrome and polymyositis, which are characterised by specific clinical features, histopathological findings and autoantibody status (Pinal-Fernandez et al, 2020).

The Plasma Cell Infiltrate Populating the Muscle Tissue of Patients with Inclusion Body Myositis Features Distinct B Cell Receptor Repertoire Properties.

Inclusion body myositis (IBM) is an autoimmune and degenerative disorder of skeletal muscle. The B cell infiltrates in IBM muscle tissue are predominantly fully differentiated Ab-secreting plasma cells, with scarce naive or memory B cells. The role of this infiltrate in the disease pathology is not well understood. To better define the humoral response in IBM, we used adaptive immune receptor repertoire sequencing, of human-derived specimens, to generate large BCR repertoire libraries from IBM muscle biopsies and compared them to those generated from dermatomyositis, polymyositis, and circulating CD27+ memory B cells, derived from healthy controls and Ab-secreting cells collected following vaccination. The repertoire properties of the IBM infiltrate included the following: clones that equaled or exceeded the highly clonal vaccine-associated Ab-secreting cell repertoire in size; reduced somatic mutation selection pressure in the CDRs and framework regions; and usage of class-switched IgG and IgA isotypes, with a minor population of IgM-expressing cells. The IBM IgM-expressing population revealed unique features, including an elevated somatic mutation frequency and distinct CDR3 physicochemical properties. These findings demonstrate that some of IBM muscle BCR repertoire characteristics are distinct from dermatomyositis and polymyositis and circulating Ag-experienced subsets, suggesting that it may form through selection by disease-specific Ags.

Linear juvenile dermatomyositis: A segmental manifestation.

A 7-year-old girl presented with proximal muscle weakness and skin lesions. Physical examination revealed violaceous papules on the right forearm in a blaschkoid distribution. Her symptoms and test results were consistent with juvenile dermatomyositis. An unusual superimposed segmental manifestation of this disease is discussed.

Immunoproteasome subunit ß5i promotes perifascicular muscle atrophy in dermatomyositis by upregulating RIG-I.

BACKGROUND: Perifascicular atrophy is a unique pathological hallmark in dermatomyositis (DM)-affected muscles; however, the mechanism underlying this process remains unclear. In this study, we aimed to investigate the potential role of the immunoproteasome subunit ß5i and retinoic acid-inducible gene-I (RIG-I) in DM-associated muscle atrophy. METHODS: The expression of ß5i and RIG-I in the muscles of 16 patients with DM was examined by PCR, western blotting and immunohistochemistry. The associations between ß5i and RIG-I expression levels and muscle disease severity were evaluated. Lentivirus transduction was used to overexpress ß5i in human skeletal muscle myoblasts (HSMMs) and consequent cell functional changes were studied in vitro. RESULTS: ß5i and RIG-I expression in the muscle of patients with DM was significantly increased and closely associated with muscle disease severity. Immunohistochemistry and immunofluorescence analyses showed the marked colocalised expression of ß5i and RIG-I in perifascicular myofibres. ß5i overexpression in HSMMs significantly upregulated RIG-I, the muscle atrophy marker MuRF1, type I IFN-related proteins (MxA and IFNß) and NF-κB pathway-related proteins (pIκBα, pIRF3 and pNF-κBp65). In addition, the viability of HSMMs decreased significantly after ß5i overexpression and was partly recovered by treatment with a ß5i inhibitor (PR957). Moreover, activation of RIG-I by pppRNA upregulated IFNß and MuRF1 and reduced the cell viability of HSMMs. CONCLUSION: The immunoproteasome subunit ß5i promotes perifascicular muscle atrophy in DM via RIG-I upregulation; our findings suggest a pathomechanistic role of ß5i and RIG-I in DM-associated muscle damage, highlighting these components as potential therapeutic targets for the treatment of DM.

New onset MDA-5 positive dermatomyositis and massive perivillous fibrin deposition in third trimester of pregnancy: A case report.

We report a case of a 42-year-old woman (Gravida 1, Para 1) who presented in her third trimester of pregnancy with a photo distributed eruption and arthralgias and was subsequently diagnosed with dermatomyositis. She had an emergency Caesarean section at 34 weeks plus 6 days gestation due to decreased fetal movements and non-reassuring fetal heart rate. Her placenta was sent for histopathology and showed features of massive perivillous fibrin deposition. To our knowledge, this is the first case of MDA-5 positive dermatomyositis in pregnancy with a live delivery.

Potential role of type I interferon/IP-10 axis in the pathogenesis of anti-MDA5 antibody-positive dermatomyositis.

OBJECTIVES: Dermatomyositis (DM) patients with anti-melanoma differentiation-associated protein 5 (MDA5) antibodies are known for poor prognosis. This study was designed to identify humoral factors that are readily detectable in the disease and may reflect its activity and pathophysiology. METHODS: We first quantified the serum level expression of 28 cytokines in the serum of patients with collagen vascular diseases using bead-based multiplex immunoassays. We completed these evaluations at hospital admission and followed up with three DM patients with anti-MDA5 antibodies during hospitalisation. We also performed an immunohistochemical analysis of skin samples obtained from two patients. RESULTS: The serum level of interferon gamma-induced protein 10 (IP-10) was significantly higher in DM patients with anti-MDA5 antibodies than in those without the antibody, decreasing drastically upon treatment. Interestingly, this time course paralleled not that of interferon (IFN)-γ, which was originally reported to be the inducer of IP-10, but that of IFN-α2. Immunohistochemical analysis revealed that most of the IP-10-positive cells were macrophages. Furthermore, monocytes stimulated with type I IFN in vitro produced IP-10 in a dose-dependent manner. CONCLUSIONS: IP-10 is a potentially useful disease activity marker of DM with anti-MDA5 antibodies, correlating more with IFN-α2 then IFN-γ. IP-10 released from macrophages might prompt the infiltration of macrophages themselves. Thus, the type I IFN/IP-10 axis may play a pivotal role in the pathogenesis of this intractable disease.

Proteomics Analysis of Plasma-Derived Exosomes Unveils the Aberrant Complement and Coagulation Cascades in Dermatomyositis/Polymyositis.

Dermatomyositis and polymyositis (DM/PM) are systemic autoimmune diseases characterized by proximal muscle weakness. The underlying pathogenetic mechanism of this disease remains under-researched. Here, using proteomics analysis, a great overlap of differentially expressed plasma exosomal proteins involved in the complement and coagulation cascade pathway, including FGA, FGB, FGG, C1QB, C1QC, and VWF, was identified in DM/PM patients versus healthy controls. Correlation analysis showed that the expression levels of complement-associated proteins (C1QB and C1QC) correlated positively with CRP, ESR, and platelet count. ROC curve analysis demonstrated that complement and coagulation cascade-associated proteins could be strong predictors for DM/PM. In addition, we also identified several other proteins that were differentially expressed in DM and PM. The selected candidate proteins were further validated by parallel reaction monitoring (PRM) and enzyme-linked immunosorbent assay (ELISA). Together, our findings indicate that these exosome-derived proteins might participate in microvascular damage in DM/PM through the activation of the complement and coagulation cascade pathway and function as biomarkers for the clinical diagnosis of DM/PM.

Anti-MDA5 antibody-positive dermatomyositis with mild encephalopathy with reversible splenial lesion: a possible rare association?

Central nervous system (CNS) involvement in dermatomyositis (DM) is seldom observed. However, there are very rare case reports of CNS involvement with juvenile dermatomyositis. Encephalopathy in DM may occur for a number of reasons, such as cerebral vasculitis and hypoperfusion/hypertensive encephalopathy, but mostly as a consequence of immunosuppressant treatment. We report here for the first time the case of a patient with two rare diseases, namely anti-MDA5 antibody-positive dermatomyositis and mild encephalopathy with reversible splenial lesion (MERS).

Linear morphea with overlying lichen sclerosus and calcinosis cutis associated with juvenile dermatomyositis.

Juvenile dermatomyositis (JDM) is associated with many distinguishing features including cutaneous calcinosis, vasculitis, and ulcerated lesions. In this case, we describe an unusual presentation in a 12-year-old girl who had muscle weakness along with linear morphea over the right upper and lower extremities with overlying lichen sclerosus and calcinosis cutis. Of interest, these initial cutaneous manifestations occurred years before onset of myositis.

Myostatin in idiopathic inflammatory myopathies: Serum assessment and disease activity.

AIMS: In idiopathic inflammatory myopathies (IIM), disease activity is difficult to assess, and IIM may induce severe muscle damage, especially in immune-mediated necrotising myopathies (IMNM) and inclusion body myositis (IBM). We hypothesise that myostatin, a negative regulator of muscle mass, could be a new biomarker of disease activity and/or muscle damage. METHODS: Prospective assessment of myostatin protein level in 447 IIM serum samples (dermatomyositis [DM], n = 157; IBM, n = 72; IMNM, n = 125; and antisynthetase syndrome [ASyS], n = 93) and 59 healthy donors (HD) was performed by ELISA. A gene transcript analysis was also carried out on 18 IIM muscle biopsies and six controls to analyse myostatin and myostatin pathway-related gene expression. RESULTS: IIM patients had lower myostatin circulating protein levels and gene expression compared to HD (2379 [1490; 3678] pg/ml vs 4281 [3169; 5787] pg/ml; p < 0.0001 and log2FC = -1.83; p = 0.0005, respectively). Myostatin-related gene expression varied accordingly. Based on the Physician Global Assessment, inactive IIM patients showed higher myostatin levels than active ones. This was the case for all IIM subgroups, except IMNM where low myostatin levels were maintained (2186 [1235; 3815] vs 2349 [1518; 3922] pg/ml; p = 0.4). CONCLUSIONS: Myostatin protein and RNA levels are decreased in all IIM patients, and protein levels correlate with disease activity. Inactive ASyS and DM patients have higher myostatin levels than active patients. Myostatin could be a marker of disease activity in these subgroups. However, IMNM patients do not have significant increase in myostatin levels after disease remission. This may highlight a new pathological disease mechanism in IMNM patients.