Prognostic analysis of MDA5-associated clinically amyopathic dermatomyositis with interstitial lung disease.

OBJECTIVE: To investigate the prognostic factors of patients with anti-melanoma differentiation-associated gene 5 (MDA5) positive clinically amyopathic dermatomyositis (CADM) and interstitial lung disease (ILD). METHODS: A retrospective analysis was conducted on clinical data of 125 patients with anti-MDA5 + CADM-ILD collected from 10 branches in eastern China between December 2014 and December 2022. Prognostic factors were analyzed using χ2 test, Log-rank test, COX and logistic regression analysis. RESULTS: In this cohort, 125 anti-MDA5 + CADM-ILD patients exhibited a rapidly progressive interstitial lung disease (RPILD) incidence of 37.6%, and an overall mortality rate of 24.8%. One patient was lost to follow-up. After diagnosis of RPILD, a mortality rate of 53.2% occurred in patients died within 3 months, and that of 5.6% appeared in those who survived for more than 3 months. Multiple factor analysis revealed that C-reactive protein (CRP) ≥ 10 mg/L (p = 0.01) and recombinant human tripartite motif containing 21 (Ro52) (+) (p = 0.003) were associated with a higher risk of RPILD in anti-MDA5 + CADM-ILD patients; CRP ≥ 10 mg/L (p = 0.018) and the presence of RPILD (p = 0.003) were identified as the factors influencing survival time in these patients, while arthritis was the protective factor (p = 0.016). CONCLUSION: Patients with anti-MDA5 + CADM-ILD will have a higher mortality rate, and the initial 3 months after diagnosis of RPILD is considered the risk window for the dismal prognosis. Patients with CRP ≥ 10 mg/L, Ro52 (+) and RPILD may be related to a shorter survival time, while patients complicated with arthritis may present with relatively mild conditions.

Investigating the disparities among drug categories in drug-induced dermatomyositis: A systematic review.

Drug-induced dermatomyositis (DIDM) is a rare and underestimated variant of dermatomyositis (DM) characterized by muscle damage and skin rash and related to certain drug exposure. The spectrum of drugs causing DIDM has evolved over time, originally implicating hydroxyurea, penicillamine, and statins as causative agents. Tumor necrosis factor α inhibitors and immune checkpoint inhibitors have also been associated with such conditions. To bridge the gap between current literature and clinical practice, and therefore guide clinicians, we conducted a comprehensive review of English literature from Pubmed, EMBASE, and MEDLINE. Our analysis included demographic data, clinical features, laboratory findings, therapeutic outcomes, and extant research pertaining to the probable pathogenesis of DIDM induced by various drugs. Furthermore, we categorized the drugs involved in DIDM cases into biologics and traditional agents for subsequent statistical analysis. Over time, there has been a gradual accumulation of reported DIDM cases. A total of 69 published DIDM cases were documented in our study, among which 33 should be attributed to biologics and the remaining 36 to traditional drugs. Interestingly, 41 of all DIDM cases had a previous history of malignancies. Additionally, DIDM cases exhibited similar cutaneous and muscular manifestations to classic DM, with the exception of cases induced by hydroxyurea, which did not entail muscle damage. Positive antinuclear antibodies and anti-TIF1-γ autoantibodies have been predominantly observed in biologics-induced cases, while positive anti-TIF1-γ antibodies were merely reported in the cases that were primarily diagnosed with malignant diseases and exposed to ICIs afterwards. Anti-TIF1-γ antibodies may potentially serve as a red flag in the identification of co-existing malignant diseases in DM patients. We also provided a comprehensive summary and exploration of potential mechanisms lying behind drug-induced dermatomyositis. In conclusion, our review consolidates the current literature on DIDM, highlighting the evolving spectrum of medications and elucidating the differences in clinical manifestations, laboratory findings, and underlying mechanisms.

Soluble CXCL16 is a prognostic biomarker associated with rapidly progressive interstitial lung disease complicated with dermatomyositis.

OBJECTIVES: Rapidly progressive interstitial lung disease (RPILD) in patients with dermatomyositis (DM) significantly impacts prognosis, leading to high mortality rates. Although several indicators have been demonstrated to strongly correlate with the risk of developing RPILD, their clinical utility still needs to be investigated. The objective of this study was to investigate the clinical significance of soluble CXCL16 (sCXCL16) in DM patients complicated with RPILD. METHODS: Serum sCXCL16 was measured by enzyme-linked immunosorbent assay in 96 patients with DM and 55 matching healthy donors. Correlations between sCXCL16 levels and clinical features, laboratory examinations and the predictive value of baseline sCXCL16 level for RPILD were analysed. RESULTS: The serum sCXCL16 levels were significantly higher in patients with DM (n = 96, 3.264 ± 1.516 ng/mL) compared with healthy donors (n = 55, 1.781 ± 0.318 ng/mL), especially in DM complicated with RPILD (n = 31, 4.441 ± 1.706 ng/mL). The sCXCL16 levels were positively correlated with levels of serum ferritin, C reactive protein, erythrocyte sedimentation rate, lactate dehydrogenase, hydroxybutyrate dehydrogenase, and negatively correlated with peripheral lymphocytes percentage, but showed no correlation with levels of anti-melanoma differentiation-associated gene 5 antibody, Krebs von den Lungen-6 or creatine kinase. Multivariable analysis showed that elevated sCXCL16 was an independent prognostic factor for poor prognosis of RPILD in patients with DM. The 2-year survival rate was significantly lower in patients with high sCXCL16 level than in those with low sCXCL16 level. CONCLUSION: A higher serum sCXCL16 level was identified as a predictive biomarker of RPILD in patients with DM, and closely associated with poor prognosis.

Dermatomyositis: nailfold capillaroscopy patterns and a general survey.

INTRODUCTION: Dermatomyositis (DM) is a group of autoimmune idiopathic inflammatory myopathies characterized by typical cutaneous signs and symptoms of muscle involvement. The diseases can be associated with cancer in the paraneoplastic syndrome, calcinosis, interstitial lung disease, other autoimmune connective tissue diseases (in overlap syndrome), and Raynaud's phenomenon. METHODS: Clinical and capillaroscopic data were gathered from 43 patients with DM. The diagnosis was based on the Bohan‒Peter and European League against Rheumatism / American College of Rheumatology (EULAR/ACR) classification criteria. In addition, nailfold capillaroscopy was performed in all patients. RESULTS: In our cohort, eight patients had overlap syndrome, six had paraneoplastic syndrome, eight presented with interstitial lung disease, and nine had calcinosis, two of whom also had a cancerous pathology. Raynaud's phenomenon was reported in 74% of patients. Upon nailfold capillaroscopy, 84% of patients presented giant capillaries, 81% ramified capillaries, and 70% both. The latter, notably giant ramified capillaries, could be considered specific for DM. The detection of prominent subpapillary venous plexuses was associated with pulmonary involvement. In contrast, alterations of the pericapillary spaces were associated with the severity and prognosis of DM. CONCLUSIONS: Our results underline the usefulness of nailfold capillaroscopy in the diagnosis and prognosis of DM. Based on the results and literature data, specific nailfold capillaroscopy features should be included in DM diagnostic criteria.

Novel Mutation in the Moesin (MSN) Gene Leads to Immunodeficiency with Epstein-Barr Virus (EBV) Infection and Dermatomyositis-Like Symptoms.

PURPOSE: Moesin (MSN) deficiency is a recently reported combined immunodeficiency, and few cases have been reported to date. We describe a Chinese patient with a novel mutation causing MSN deficiency and a novel phenotype. METHODS: Clinical and immunological data were collected. Whole-exome sequencing was performed to identify gene mutations. MSN protein expression and T cell proliferation and activation were determined by flow cytometry. Cell migration was confirmed with a Transwell assay. Autoantibody levels were analyzed using antigen microarrays. RESULTS: The patient was a 10-year-old boy who presented with recurrent fever, oral ulcers and dermatomyositis-like symptoms, such as periorbital edema, facial swelling, elevated creatine kinase levels, and abnormal electromyography and muscle biopsy results. Epstein-Barr virus (EBV) DNA was detected in the serum, cells and tissues of this patient. He further developed nasal-type NK/T-cell lymphoma. A novel hemizygous mutation (c.68 A > G, p.N23S) in the MSN gene was found. The immunological phenotype of this patient included persistent decreases in T and B lymphocyte counts but normal immunoglobulin IgG levels. The patient had attenuated MSN protein expression and impaired T-cell proliferation and migration. The proportions of Tfh cells and CD21low B cells in the patient were higher than those in the controls. Moreover, 82 IgG and 102 IgM autoantibodies were more abundant in the patient than in the healthy controls. CONCLUSIONS: The novel mutation N23S is pathogenic and leads to a severe clinical phenotype. EBV infection, tumor, and dermatomyositis-like autoimmune symptoms may be associated with MSN deficiency, further expanding the understanding of the disease.

Amyopathic Dermatomyositis Presenting with Digital Ulcerations: Case Report and Literature Review.

ABSTRACT: Clinically amyopathic dermatomyositis (CADM) is a rare subtype of dermatomyositis that presents with cutaneous features and no muscle involvement. This case report describes a 26-year-old woman with recurrent and multiple digital ulcerations coinciding with the start of winter each year. There was no evidence of myopathy, and antibody testing yielded negative results. A diagnosis of CADM was ultimately made based on clinicopathologic correlation. The patient's ulcers demonstrated excellent response to a combination therapy of hydroxychloroquine and potent topical and systemic steroids. Herein, the authors discuss the pathologic and immunologic characteristics of CADM.

Serum 25-hydroxyvitamin D levels and dermatomyositis: A 2-sample mendelian randomization study.

BACKGROUND: Previous studies have reported low serum 25-hydroxyvitamin D [25(OH)D] levels in dermatomyositis (DM) patients, but the exact causal relationship between them remains elusive. Our aim is to confirm the causal relationship between 25(OH)D and DM risk through a Mendelian randomization study. METHODS: Retrieve genome-wide association study (GWAS) data on 25(OH)D (n = 441 291) and DM (n cases = 201, n controls = 172 834) from the GWAS database (https://gwas.mrcieu.ac.uk/). Select single-nucleotide polymorphisms (SNPs) strongly correlated with 25(OH)D as instrumental variables (IVs). The primary analytical approach involves the use of the inverse-variance weighted method (IVW), supplemented by MR-Egger regression and weighted median methods to enhance the reliability of the results. Heterogeneity and sensitivity analyses were conducted using Cochran's Q and leave-one-out approaches, respectively. RESULTS: The IVW analysis confirmed a positive causal relationship between genetic variation in 25(OH)D levels and DM (OR = 2.36, 95% CI = 1.01-5.52, p = .048). Although not statistically significant (all p > .05), the other methods also suggested a protective effect of 25(OH)D on DM. Based on MR-Egger intercepts and Cochran's Q analysis, the selected SNPs showed no horizontal pleiotropy and heterogeneity. Sensitivity analysis demonstrated the robustness of the results against individual SNPs. CONCLUSION: We provide the first evidence of a causal relationship between 25(OH)D levels and DM. Our findings support the importance of measuring serum 25(OH)D levels and considering vitamin D supplementation in clinical practice for patients with DM.

Identification of common mechanisms and biomarkers for dermatomyositis and atherosclerosis based on bioinformatics analysis.

BACKGROUND: Dermatomyositis (DM) manifests as an autoimmune and inflammatory condition, clinically characterized by subacute progressive proximal muscle weakness, rashes or both along with extramuscular manifestations. Literature indicates that DM shares common risk factors with atherosclerosis (AS), and they often co-occur, yet the etiology and pathogenesis remain to be fully elucidated. This investigation aims to utilize bioinformatics methods to clarify the crucial genes and pathways that influence the pathophysiology of both DM and AS. METHOD: Microarray datasets for DM (GSE128470, GSE1551, GSE143323) and AS (GSE100927, GSE28829, GSE43292) were retrieved from the Gene Expression Omnibus (GEO) database. The weighted gene co-expression network analysis (WGCNA) was used to reveal their co-expressed modules. Differentially expression genes (DEGs) were identified using the "limma" package in R software, and the functions of common DEGs were determined by functional enrichment analysis. A protein-protein interaction (PPI) network was established using the STRING database, with central genes evaluated by the cytoHubba plugin, and validated through external datasets. Immune infiltration analysis of the hub genes was conducted using the CIBERSORT method, along with Gene Set Enrichment Analysis (GSEA). Finally, the NetworkAnalyst platform was employed to examine the transcription factors (TFs) responsible for regulating pivotal crosstalk genes. RESULTS: Utilizing WGCNA analysis, a total of 271 overlapping genes were pinpointed. Subsequent DEG analysis revealed 34 genes that are commonly found in both DM and AS, including 31 upregulated genes and 3 downregulated genes. The Degree Centrality algorithm was applied separately to the WGCNA and DEG collections to select the 15 genes with the highest connectivity, and crossing the two gene sets yielded 3 hub genes (PTPRC, TYROBP, CXCR4). Validation with external datasets showed their diagnostic value for DM and AS. Analysis of immune infiltration indicates that lymphocytes and macrophages are significantly associated with the pathogenesis of DM and AS. Moreover, GSEA analysis suggested that the shared genes are enriched in various receptor interactions and multiple cytokines and receptor signaling pathways. We coupled the 3 hub genes with their respective predicted genes, identifying a potential key TF, CBFB, which interacts with all 3 hub genes. CONCLUSION: This research utilized comprehensive bioinformatics techniques to explore the shared pathogenesis of DM and AS. The three key genes, including PTPRC, TYROBP, and CXCR4, are related to the pathogenesis of DM and AS. The central genes and their correlations with immune cells may serve as potential diagnostic and therapeutic targets.

Anti-melanoma differentiation-associated gene 5 (anti-MDA5) positive dermatomyositis: early detection is crucial.

Anti-melanoma differentiation-associated gene 5-positive (Anti-MDA5) dermatomyositis (DM) is an aggressive phenotype of DM associated with rapidly progressive interstitial lung disease (RP-ILD). It is a rare condition that carries high mortality. Diagnosis and management of patients with anti-MDA5 DM RP-ILD presents several challenges, including uncertainty around treatment algorithms and a lack of evidence to inform practice. This case report of a patient with anti-MDA5 DM RP-ILD highlights these challenges, emphasising the fulminant course of this disease despite aggressive immunosuppression. Further research is required to guide management and to minimise morbidity and mortality, and greater awareness of the condition is required to minimise delays in diagnosis.

A Rare Case of Anti-TIF-1γ Antibody Positive Dermatomyositis in Adulthood.

Dermatomyositis (DM) presents with inflammatory myopathy and distinct skin manifestations, often linked to specific autoantibodies. Anti-transcriptional intermediary factor-1 gamma (TIF-1γ) antibodies (Abs) are typically linked to DM in older patients and malignancy in 15% to 40% of cases. We highlight a case of a 24-year-old female who presented with weakness of proximal muscles, periorbital edema, heliotrope rash, erosions on oral mucosa, and painful scaly rash on the lower extremities. Transcriptional intermediary factor-1 gamma Abs were positive, confirming inflammatory myopathy. Treatment with steroid pulse therapy and immunoglobulin led to improvement. Evaluation for malignancy yielded unremarkable results. This case underscores the importance of recognizing and managing DM with TIF-1γ Ab positive, even in atypical demographics, and highlights the need for comprehensive malignancy evaluation.

Case report: "Fur stole and turtleneck" and "halter-back" signs: an expanded wardrobe for dermatomyositis.

A diagnosis of dermatomyositis requires recognition of distinct patterns of skin disease in combination with, and sometimes without, muscle weakness. Often, a striking contrast between involved and uninvolved areas is observed. Familiar patterns include eyelid and midfacial eruptions, Gottron papules/sign, and upper back (shawl sign), central chest (V/open collar sign), and lateral thigh (holster sign) involvement. More recently, new specific antibody/phenotype-associated patterns have been reported. We describe a case series of two distinct patterns of skin involvement in six adult patients with both classical and amyopathic dermatomyositis. Three had paraneoplastic disease. All had intermediate to richly pigmented skin; five were of Afro-Caribbean and one was of Asian-Caribbean descent. Four were men, and two were women. Ages ranged from 41 to 89 years. All patients had concomitant hallmark signs (facial, hand, and/or trunk signs). Three were amyopathic. The first pattern involved a sharply demarcated, horizontally oriented hyperpigmented patch/thin plaque across the shoulders and upper chest, extending up the anterior neck. The second was the combination of the classical upper back shawl distribution with distinct mid-back sparing and diffuse involvement of the lower back. Named patterns help with the recognition of skin rashes in dermatomyositis. Based on the current lexicon describing items of apparel, we liken the first pattern to a "fur stole and turtleneck" sign and the latter to a "halter-back" or "reflected-shawl" sign. Biopsies revealed hyperkeratosis and interface dermatitis, often with epidermal atrophy, compatible with dermatomyositis. These patterns perhaps represent the coalescence of already well-described signs, photo-exacerbation, koebnerization, mechanical stretch, and other currently unclear factors contributing to patterning in dermatomyositis. Pattern distribution recognition is particularly valuable in individuals with richly pigmented skin who may lack typical violaceous erythema. The distinct demarcation led to the initial misdiagnosis of allergic contact dermatitis or other exogenous dermatitis in most of our patients. Further work involves evaluation of antibody phenotype and internal involvement associations. Limitations include lack of specific antibody panels and longitudinal follow-up data.

Radiomics based on HRCT can predict RP-ILD and mortality in anti-MDA5 + dermatomyositis patients: a multi-center retrospective study.

OBJECTIVES: To assess the effectiveness of HRCT-based radiomics in predicting rapidly progressive interstitial lung disease (RP-ILD) and mortality in anti-MDA5 positive dermatomyositis-related interstitial lung disease (anti-MDA5 + DM-ILD). METHODS: From August 2014 to March 2022, 160 patients from Institution 1 were retrospectively and consecutively enrolled and were randomly divided into the training dataset (n = 119) and internal validation dataset (n = 41), while 29 patients from Institution 2 were retrospectively and consecutively enrolled as external validation dataset. We generated four Risk-scores based on radiomics features extracted from four areas of HRCT. A nomogram was established by integrating the selected clinico-radiologic variables and the Risk-score of the most discriminative radiomics model. The RP-ILD prediction performance of the models was evaluated by using the area under the receiver operating characteristic curves, calibration curves, and decision curves. Survival analysis was conducted with Kaplan-Meier curves, Mantel-Haenszel test, and Cox regression. RESULTS: Over a median follow-up time of 31.6 months (interquartile range: 12.9-49.1 months), 24 patients lost to follow-up and 46 patients lost their lives (27.9%, 46/165). The Risk-score based on bilateral lungs performed best, attaining AUCs of 0.869 and 0.905 in the internal and external validation datasets. The nomogram outperformed clinico-radiologic model and Risk-score with AUCs of 0.882 and 0.916 in the internal and external validation datasets. Patients were classified into low- and high-risk groups with 50:50 based on nomogram. High-risk group patients demonstrated a significantly higher risk of mortality than low-risk group patients in institution 1 (HR = 4.117) and institution 2 cohorts (HR = 7.515). CONCLUSION: For anti-MDA5 + DM-ILD, the nomogram, mainly based on radiomics, can predict RP-ILD and is an independent predictor of mortality.

MDA5-autoimmunity and interstitial pneumonitis contemporaneous with the COVID-19 pandemic (MIP-C).

BACKGROUND: Anti-MDA5 (Melanoma differentiation-associated protein-5) positive dermatomyositis (MDA5+-DM) is characterised by rapidly progressive interstitial lung disease (ILD) and high mortality. MDA5 is an RNA sensor and a key pattern recognition receptor for the SARS-CoV-2 virus. METHODS: This is a retrospective observational study of a surge in MDA5 autoimmunity, as determined using a 15 muscle-specific autoantibodies (MSAs) panel, between Janurary 2018 and December 2022 in Yorkshire, UK. MDA5-positivity was correlated with clinical features and outcome, and regional SARS-CoV-2 positivity and vaccination rates. Gene expression patterns in COVID-19 were compared with autoimmune lung disease and idiopathic pulmonary fibrosis (IPF) to gain clues into the genesis of the observed MDA5+-DM outbreak. FINDINGS: Sixty new anti-MDA5+, but not other MSAs surged between 2020 and 2022, increasing from 0.4% in 2019 to 2.1% (2020), 4.8% (2021) and 1.7% (2022). Few (8/60) had a prior history of confirmed COVID-19, peak rates overlapped with regional SARS-COV-2 community positivity rates in 2021, and 58% (35/60) had received anti-SARS-CoV-2 vaccines. 25/60 cases developed ILD which rapidly progression with death in 8 cases. Among the 35/60 non-ILD cases, 14 had myositis, 17 Raynaud phenomena and 10 had dermatomyositis spectrum rashes. Transcriptomic studies showed strong IFIH1 (gene encoding for MDA5) induction in COVID-19 and autoimmune-ILD, but not IPF, and IFIH1 strongly correlated with an IL-15-centric type-1 interferon response and an activated CD8+ T cell signature that is an immunologic hallmark of progressive ILD in the setting of systemic autoimmune rheumatic diseases. The IFIH1 rs1990760TT variant blunted such response. INTERPRETATION: A distinct pattern of MDA5-autoimmunity cases surged contemporaneously with circulation of the SARS-COV-2 virus during COVID-19. Bioinformatic insights suggest a shared immunopathology with known autoimmune lung disease mechanisms. FUNDING: This work was supported in part by the National Institute for Health Research (NIHR) Leeds Biomedical Research Centre (BRC), and in part by the National Institutes of Health (NIH) grant R01-AI155696 and pilot awards from the UC Office of the President (UCOP)-RGPO (R00RG2628, R00RG2642 and R01RG3780) to P.G. S.S was supported in part by R01-AI141630 (to P.G) and in part through funds from the American Association of Immunologists (AAI) Intersect Fellowship Program for Computational Scientists and Immunologists.

Coordinated immune dysregulation in juvenile dermatomyositis revealed by single-cell genomics.

Juvenile dermatomyositis (JDM) is one of several childhood-onset autoimmune disorders characterized by a type I IFN response and autoantibodies. Treatment options are limited due to an incomplete understanding of how the disease emerges from dysregulated cell states across the immune system. We therefore investigated the blood of patients with JDM at different stages of disease activity using single-cell transcriptomics paired with surface protein expression. By immunophenotyping peripheral blood mononuclear cells, we observed skewing of the B cell compartment toward an immature naive state as a hallmark of JDM at diagnosis. Furthermore, we find that these changes in B cells are paralleled by T cell signatures suggestive of Th2-mediated inflammation that persist despite disease quiescence. We applied network analysis to reveal that hyperactivation of the type I IFN response in all immune populations is coordinated with previously masked cell states including dysfunctional protein processing in CD4+ T cells and regulation of cell death programming in NK cells, CD8+ T cells, and γδ T cells. Together, these findings unveil the coordinated immune dysregulation underpinning JDM and provide insight into strategies for restoring balance in immune function.