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Arthritis & Rheumatology (Hoboken, N.J.) Nov 2023Transcript and protein expression were interrogated to examine gene locus and pathway regulation in the peripheral blood of active adult dermatomyositis (DM) and...
OBJECTIVE
Transcript and protein expression were interrogated to examine gene locus and pathway regulation in the peripheral blood of active adult dermatomyositis (DM) and juvenile DM patients receiving immunosuppressive therapies.
METHODS
Expression data from 14 DM and 12 juvenile DM patients were compared to matched healthy controls. Regulatory effects at the transcript and protein level were analyzed by multi-enrichment analysis for assessment of affected pathways within DM and juvenile DM.
RESULTS
Expression of 1,124 gene loci were significantly altered at the transcript or protein levels across DM or juvenile DM, with 70 genes shared. A subset of interferon-stimulated genes was elevated, including CXCL10, ISG15, OAS1, CLEC4A, and STAT1. Innate immune markers specific to neutrophil granules and neutrophil extracellular traps were up-regulated in both DM and juvenile DM, including BPI, CTSG, ELANE, LTF, MPO, and MMP8. Pathway analysis revealed up-regulation of PI3K/AKT, ERK, and p38 MAPK signaling, whose central components were broadly up-regulated in DM, while peripheral upstream and downstream components were differentially regulated in both DM and juvenile DM. Up-regulated components shared by DM and juvenile DM included cytokine:receptor pairs LGALS9:HAVCR2, LTF/NAMPT/S100A8/HSPA1A:TLR4, CSF2:CSF2RA, EPO:EPOR, FGF2/FGF8:FGFR, several Bcl-2 components, and numerous glycolytic enzymes. Pathways unique to DM included sirtuin signaling, aryl hydrocarbon receptor signaling, protein ubiquitination, and granzyme B signaling.
CONCLUSION
The combination of proteomics and transcript expression by multi-enrichment analysis broadened the identification of up- and down-regulated pathways among active DM and juvenile DM patients. These pathways, particularly those which feed into PI3K/AKT and MAPK signaling and neutrophil degranulation, may be potential therapeutic targets.
Topics: Humans; Adult; Dermatomyositis; Transcriptome; Proteomics; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt
PubMed: 37229703
DOI: 10.1002/art.42615 -
Ugeskrift For Laeger Aug 2023
Topics: Humans; Dermatomyositis; Eye Diseases; Angioedema; Edema
PubMed: 37615155
DOI: No ID Found -
MedRxiv : the Preprint Server For... Jan 2024Myositis is a heterogeneous family of autoimmune muscle diseases. As myositis autoantibodies recognize intracellular proteins, their role in disease pathogenesis has...
OBJECTIVES
Myositis is a heterogeneous family of autoimmune muscle diseases. As myositis autoantibodies recognize intracellular proteins, their role in disease pathogenesis has been unclear. This study aimed to determine whether myositis autoantibodies reach their autoantigen targets within muscle cells and disrupt the normal function of these proteins.
METHODS
Confocal immunofluorescence microscopy was used to localize antibodies and other proteins of interest in myositis muscle biopsies. Bulk RNA sequencing was used to study the transcriptomic profiles of 668 samples from patients with myositis, disease controls, and healthy controls. Antibodies from myositis patients were introduced into cultured myoblasts by electroporation and the transcriptomic profiles of the treated myoblasts were studied by bulk RNA sequencing.
RESULTS
In patients with myositis autoantibodies, antibodies accumulated inside myofibers in the same subcellular compartment as the autoantigen. Each autoantibody was associated with effects consistent with dysfunction of its autoantigen, such as the derepression of genes normally repressed by Mi2/NuRD in patients with anti-Mi2 autoantibodies, the accumulation of RNAs degraded by the nuclear RNA exosome complex in patients with anti-PM/Scl autoantibodies targeting this complex, and the accumulation of lipids within myofibers of anti-HMGCR-positive patients. Internalization of patient immunoglobulin into cultured myoblasts recapitulated the transcriptomic phenotypes observed in human disease, including the derepression of Mi2/NuRD-regulated genes in anti-Mi2-positive dermatomyositis and the increased expression of genes normally degraded by the nuclear RNA exosome complex in anti-PM/Scl-positive myositis.
CONCLUSIONS
In myositis, autoantibodies are internalized into muscle fibers, disrupt the biological function of their autoantigen, and mediate the pathophysiology of the disease.
PubMed: 38313303
DOI: 10.1101/2024.01.15.24301339 -
Frontiers in Pediatrics 2023Type I interferonopathies are a broad category of conditions associated with increased type I interferon gene expression and include monogenic autoinflammatory diseases... (Review)
Review
Type I interferonopathies are a broad category of conditions associated with increased type I interferon gene expression and include monogenic autoinflammatory diseases and non-Mendelian autoimmune diseases such as dermatomyositis and systemic lupus erythematosus. While a wide range of clinical presentations among type I interferonopathies exists, these conditions often share several clinical manifestations and implications for treatment. Presenting symptoms may mimic non-Mendelian autoimmune diseases, including vasculitis and systemic lupus erythematosus, leading to delayed or missed diagnosis. This review aims to raise awareness about the varied presentations of monogenic interferonopathies to provide early recognition and appropriate treatment to prevent irreversible damage and improve quality of life and outcomes in this unique patient population.
PubMed: 37622085
DOI: 10.3389/fped.2023.1169638 -
The Journal of Dermatological Treatment Dec 2024Dermatomyositis, systemic and cutaneous lupus erythematosus have a significantly higher prevalence in women than men, emphasizing the relevance of exploring the... (Review)
Review
INTRODUCTION
Dermatomyositis, systemic and cutaneous lupus erythematosus have a significantly higher prevalence in women than men, emphasizing the relevance of exploring the relationship between sex hormones and autoimmune skin diseases. This review analyzes the interplay between sex hormones and these two skin diseases.
MATERIALS AND METHODS
We performed an extensive literature search using the PubMed database from July to August 2023. Search terms included 'contraceptives', 'pregnancy', 'hormone replacement', 'tamoxifen', and 'aromatase inhibitors'.
RESULTS AND DISCUSSION
This comprehensive literature review shows that there remains considerable debate regarding the use of hormonal contraceptives and hormonal replacement therapy in individuals with autoimmune skin conditions. Nonetheless, it is well established that their use is contraindicated in patients with antiphospholipid syndrome or when antiphospholipid antibodies are positive. Individuals experiencing disease flares and uncontrolled symptoms should also avoid these interventions. Pregnancy planning should be timed to coincide with well-managed disease states to minimize obstetric and neonatal complications. Hormonal breast cancer treatment requires close skin monitoring.
CONCLUSION
Pregnancy, menopause, contraceptive use, hormone replacement therapy, and breast cancer treatment drugs result in substantial shifts in hormone levels. Additionally, hormone levels are altered by aromatase inhibitors and anti-estrogen medications. These fluctuations can modulate mechanisms influencing autoimmune skin abnormalities.
Topics: Pregnancy; Male; Infant, Newborn; Humans; Female; Hormones; Autoimmune Diseases; Gonadal Steroid Hormones; Menopause; Breast Neoplasms; Lupus Erythematosus, Systemic
PubMed: 38317519
DOI: 10.1080/09546634.2024.2312241 -
Scientific Reports Oct 2023Dermatomyositis and polymyositis are rare, idiopathic inflammatory myopathies. Interstitial lung disease is one of the most common and potentially severe extra-muscular...
Dermatomyositis and polymyositis are rare, idiopathic inflammatory myopathies. Interstitial lung disease is one of the most common and potentially severe extra-muscular manifestations of dermatomyositis and polymyositis and is strongly linked to poor prognosis and early mortality. We aimed to characterise the demographic and clinical characteristics, incidence, and treatment of interstitial lung disease in patients with dermatomyositis or polymyositis. We conducted a retrospective cohort study using the Japan Medical Data Center healthcare claims database. Patients in the database with dermatomyositis (International Classification of Disease version 10 M33.0, M33.1, M33.9) or polymyositis (M33.2) from 01-Jan-2011 until 31-Dec-2019 were identified and followed-up for interstitial lung disease (J84.x) until death, dis-enrolment, or study end (31 December 2020). Cumulative risk curves compared interstitial lung disease risk in dermatomyositis versus polymyositis. Risk factors were evaluated by Cox proportional hazard models. There were 886 patients with dermatomyositis and 745 patients with polymyositis included in the cohort analysis. Mean (standard deviation) age at dermatomyositis/polymyositis diagnosis was 46.0 (16.0)/49.7 (13.3) years and 300 (34%)/104 (14%) developed interstitial lung disease during follow-up. The incidence rate of interstitial lung disease per 100 person-years was 18.42 (95% CI 16.42-20.59) for dermatomyositis and 5.39 (95% CI 4.43-6.50) for polymyositis. In the analysis adjusted for sex, age, and comorbidity score, the risk of interstitial lung disease was significantly higher in patients with dermatomyositis than with polymyositis (hazard ratio 2.72, 95% CI 2.18-3.41). The rate diverged markedly between the groups in the first year after diagnosis. Risk factors for interstitial lung disease were older age in dermatomyositis, female sex and rheumatoid arthritis in polymyositis. Glucocorticoids with/without tacrolimus were the most common newly prescribed drugs after the interstitial lung disease diagnosis. In conclusion, the risk of developing interstitial lung disease was significantly higher in patients with dermatomyositis than with polymyositis, and risk factors were different in the 2 patient groups.
Topics: Humans; Female; Dermatomyositis; Retrospective Studies; Japan; Polymyositis; Lung Diseases, Interstitial; Cohort Studies; Prognosis
PubMed: 37821555
DOI: 10.1038/s41598-023-44092-9 -
The Journal of Dermatology Mar 2024Dermatomyositis (DM) is a systemic autoimmune disease with variable clinical presentations, including inflammation in the skin, muscle, lungs, and/or joints. Current... (Review)
Review
Dermatomyositis (DM) is a systemic autoimmune disease with variable clinical presentations, including inflammation in the skin, muscle, lungs, and/or joints. Current therapeutic strategies in DM typically include broad immunosuppression; however, the currently used modalities are not universally effective and are associated with various side effects, including risk of infection. There is currently a highly unmet need for more effective and well-tolerated therapies. Recent years have witnessed increased interest in pharmaceutical development of new therapeutic strategies for DM. This review aims to summarize the landscape of therapies that are currently being tested or planned in patients with DM. These therapies have a wide variety of immunological targets, including T cells, B cells, inflammatory signaling pathways, type I interferons, autoantibodies, and other targets.
PubMed: 38433369
DOI: 10.1111/1346-8138.17170 -
Rheumatology (Oxford, England) Dec 2023Among specific autoantibodies in DM, the anti-small ubiquitin-like modifier activating enzyme (SAE) antibody is rare. We aim to describe the clinical characteristics,... (Review)
Review
OBJECTIVE
Among specific autoantibodies in DM, the anti-small ubiquitin-like modifier activating enzyme (SAE) antibody is rare. We aim to describe the clinical characteristics, cancer prevalence, and muscle pathology of anti-SAE-positive DM.
METHODS
Patients with a diagnosis of DM and sera positive for the anti-SAE antibody were recruited from 19 centres in this retrospective observational study. The available muscular biopsies were reviewed. We conducted a comparison with anti-SAE-negative DM and a review of the literature.
RESULTS
Of the patients in the study (n = 49), 84% were women. Skin involvement was typical in 96% of patients, with 10% having calcinosis, 18% ulceration and 12% necrosis; 35% presented with a widespread skin rash. Muscular disease affected 84% of patients, with mild weakness [Medical Research Council (MRC) scale 4 (3, 5)], although 39% of patients had dysphagia. Muscular biopsies showed typical DM lesions. Interstitial lung disease was found in 21% of patients, mainly with organizing pneumonia pattern, and 26% of patients showed dyspnoea. Cancer-associated myositis was diagnosed in 16% of patients and was responsible for the majority of deaths, its prevalence being five times that of the general population. IVIG therapy was administered to 51% of the patients during the course of the disease. Comparison with anti-SAE-negative DM (n = 85) showed less and milder muscle weakness (P = 0.02 and P = 0.006, respectively), lower creatinine kinase levels (P < 0.0001) and less dyspnoea (P = 0.003).
CONCLUSION
Anti-SAE positive DM is a rare subgroup associated with typical skin features but a potentially diffuse rash, a mild myopathy. Interstitial lung disease defines an organizing pneumonia pattern. Cancer associated DM prevalence is five times that of the general population.
TRIAL REGISTRATION
ClinicalTrials.gov, http://clinicaltrials.gov, NCT04637672.
Topics: Humans; Female; Male; Autoantibodies; Dermatomyositis; Myositis; Exanthema; Neoplasms; Ubiquitin-Activating Enzymes; Lung Diseases, Interstitial; Dyspnea; Observational Studies as Topic
PubMed: 37010495
DOI: 10.1093/rheumatology/kead154 -
Briefings in Bioinformatics Nov 2023Idiopathic inflammatory myopathies (IIMs) are a heterogeneous group of muscle disorders including adult and juvenile dermatomyositis, polymyositis, immune-mediated... (Review)
Review
Idiopathic inflammatory myopathies (IIMs) are a heterogeneous group of muscle disorders including adult and juvenile dermatomyositis, polymyositis, immune-mediated necrotising myopathy and sporadic inclusion body myositis, all of which present with variable symptoms and disease progression. The identification of effective biomarkers for IIMs has been challenging due to the heterogeneity between IIMs and within IIM subgroups, but recent advances in machine learning (ML) techniques have shown promises in identifying novel biomarkers. This paper reviews recent studies on potential biomarkers for IIM and evaluates their clinical utility. We also explore how data analytic tools and ML algorithms have been used to identify biomarkers, highlighting their potential to advance our understanding and diagnosis of IIM and improve patient outcomes. Overall, ML techniques have great potential to revolutionize biomarker discovery in IIMs and lead to more effective diagnosis and treatment.
Topics: Adult; Humans; Myositis; Dermatomyositis; Autoimmune Diseases; Biomarkers; Disease Progression
PubMed: 38243695
DOI: 10.1093/bib/bbad514 -
Annals of the Rheumatic Diseases Jun 2024With improved understanding of disease pathogenesis and availability of outcome measures, there has been a remarkable increase in the number of therapeutic clinical...
With improved understanding of disease pathogenesis and availability of outcome measures, there has been a remarkable increase in the number of therapeutic clinical trials in idiopathic inflammatory myopathies (myositis) over the last three years reaching as many as five trials per site. These trials share similar design and inclusion/exclusion criteria resulting in a competitive clinical trial landscape in myositis. While these are exciting times for the myositis field, we have a number of concerns about the design and conduct of the myositis trials. These include competitive landscape, lengthy placebo arms, underrepresentation of minority groups among participants, use of patient reported outcome measures with limited/no data on validity in myositis, antiquated disease classification criteria, and unclear performance of the ACR/EULAR Myositis Response Criteria in skin-predominant patients despite inclusion of these patients in trials. In this viewpoint, we further discuss these concerns and offer potential solutions such as including patient perspectives in the trial design and adoption of innovative frameworks.
Topics: Humans; Clinical Trials as Topic; Myositis; Patient Reported Outcome Measures; Research Design
PubMed: 38216318
DOI: 10.1136/ard-2023-224652