Materiały źródłowe

• #1 Dermatomyositis – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK558917/

  Dermatomyositis is a rare acquired immune-mediated muscle disease characterized by muscle weakness and skin rash. It is classified as one of the idiopathic inflammatory myopathies (IIM). […] Although the cause of dermatomyositis is unknown, several genetic, immunologic, and environmental factors are implicated in this condition. […] Although autoantibodies are detected in patients with dermatomyositis, it is unclear whether they play a role in pathogenesis. […] Dermatomyositis is thought to be the result of a humoral mediated attack directed against the muscle capillaries and the endothelium of arterioles. The initiating event is the activation of completer factor-3 (C3), which forms C3b and C4b. This is followed by the formation of the neoantigen C3bNEO and the C5b-C9 membrane attack complex (MAC). The membrane attack complex deposits on vascular walls and causes inflammation. Hypoxic injury to the muscle fibers ensues, leading to atrophy of muscle fibers, particularly the fibers at the periphery that are the most remote and away from the vascular supply. Over time, the capillary density reduces, and muscle fibers start to undergo necrosis and degeneration.

• #1 Dermatomyositis: Practice Essentials, Background, Pathophysiology

  https://emedicine.medscape.com/article/332783-overview

  Dermatomyositis is considered to be the result of a humoral attack against the muscle capillaries and small arterioles (endothelium of the endomysial blood vessels). Since 1966, there has been evidence supporting an ongoing microangiopathy. […] Like other idiopathic inflammatory myopathies, dermatomyositis is characterized by the presence of autoantibodies that are conventionally divided into myositis-specific autoantibodies (MSAs) and myositis-associated autoantibodies (MAAs). Individual patients rarely generate more than one MSA simultaneously. MSAs found in dermatomyositis include antiMi-2, anti-MDA5, antiTIF1, anti-NXP2, and anti-SAE. […] The disease starts when putative antibodies or other factors activate C3, forming C3b and C4b fragments that lead to formation of C3bNEO and membrane attack complex (MAC), which are deposited in the endomysial vasculature. Complement C5b-9 MAC is deposited and is needed in preparing the cell for destruction in antibody-mediated disease. B cells and CD4 (helper) cells are also present in abundance in the inflammatory reaction associated with the blood vessels.

• #1 Azthena logo with the word Azthena

  https://www.news-medical.net/news/20210408/Researchers-identify-mechanism-by-which-dermatomyositis-may-develop-in-humans.aspx

  Dermatomyositis is an idiopathic inflammatory myopathy that has been regarded as an autoimmunity-based disorder, although its pathogenesis remains unclear. […] In this study, we investigated the role of a specific autoantibody present in the sera of patients with dermatomyositis, the anti-TIF1 antibody, in the pathogenesis of the disease. […] In normal mice, injection of TIF1 resulted in the production of TIF1-specific T cells and anti-TIF1 autoantibodies, thereby inducing myositis. […] Importantly, the disease severity was significantly reduced when TIF1 was injected into mice that lacked the ability to present antigens to CD8+ T cells. […] This suggests that autoreactive CD8+ T cells against TIF1 contribute to the pathogenesis of dermatomyositis, while autoantibodies against TIF1 are simply non-pathogenic clinical diagnostic markers. […] our results show that autoreactive T cell-mediated autoimmunity to TIF1 may play a causal role in dermatomyositis.

• #1

  https://link.springer.com/article/10.1007/s40272-024-00658-2

  Vasculopathy is thought to be an important part of disease pathogenesis based on vascular abnormalities noted on pathology as well as nailfold and gingival capillary changes observed on physical examination. […] Interferon (IFN) and interferon-related gene and protein expression have been consistently shown to be increased in key tissues (blood, muscle, and skin) from patients with JDM. […] Increased IFN-regulated gene and interferon-regulated protein expression has been found consistently in blood by multiple studies, also correlating with disease activity. […] Interestingly, when IFN alpha is added to skeletal muscle cells in-vitro, this also increases mitochondrial reactive oxygen species (ROS). […] Thus, IFN is tied to multiple biomarker or mechanism in JDM/DM including mitochondrial dysfunction, neutrophils/NETs, and vascular changes.

• #1 Pathophysiological Mechanisms and Treatment of Dermatomyositis and Immune Mediated Necrotizing Myopathies: A Focused Review

  https://www.mdpi.com/1422-0067/23/8/4301

  The exact pathophysiological mechanisms causing IIM remain unknown. In general, and similarly to most other auto-immune disorders, an exogenous trigger (e.g., a viral infection) is presumed to be required in combination with a genetic predisposition. […] Immune-mediated disease mechanisms are thought to encompass both adaptive and innate disease mechanisms. […] The pathogenicity of at least some myositis-specific autoantibodies is plausible, as supported by the finding of related auto-antigen overexpression in IIM patients. […] This leads to IFN-1 overexpression in dermatomyositis, which may cause a pro-inflammatory state, MHC-class I overexpression, and non-immune mediated toxicity via mitochondrial damage and endoplasmatic reticulum stress. […] In short, these mechanisms create a positive feedback loop with inflammation, leading to subsequent impaired muscle contraction, muscle protein dyshomeostasis, and disease damage with atrophy and irreversible muscle fiber alterations.

• #1 Juvenile Dermatomyositis: Practice Essentials, Background, Pathophysiology

  https://emedicine.medscape.com/article/1417215-overview

  Research suggests that type I interferon-alpha/beta inducible genes of the innate immune system play a central role in the pathogenesis of dermatomyositis. […] Plasmacytoid dendritic cells are involved in the innate immune system and produce large amounts of interferon-alpha () and beta () in vivo after viral stimulation. They have been found in the muscle, peripheral blood, and epidermis of skin lesions in patients with dermatomyositis. […] Overproduction of interferon alpha/beta proteins may lead to endothelial and myofiber damage. […] In a study that assessed family histories from 304 families of children with JDM, Niewold et al found that 51% of these families reported at least one additional member affected by an autoimmune disease. […] Higher serum interferon-alpha values were found in untreated subjects with JDM who had a family history of SLE, suggesting that interferon-alpha may be a pathogenic factor shared by these autoimmune diseases. […] Juvenile polymyositis is mediated by cytotoxic CD8+ T cells, activated macrophages, and expression of MHC-I.

• #1

  https://www.healio.com/clinical-guidance/dermatomyositis/pathogenesis-overview

  The pathogenesis of Dermatomyositis (DM) is multifactorial, and influenced by genetic, environmental, and immunological factors. Inflammatory mediators may play a role in DM pathogenesis. Type I interferons, which regulate both innate and adaptive immune responses, play a key role in DM pathogenesis. DM is thought to be caused by a humoral mediated attack against the muscle capillaries and the endothelium of arterioles. […] Activation of complement mediators is followed by formation and deposition of the membrane attack complex on vascular walls, leading to inflammation, endothelial cell death and ischemic muscle fiber damage. Increased release of proinflammatory cytokines and chemokines upregulate the expression of adhesion molecules on the endothelial cell membrane, facilitating the migration of activated CD4+ T cells, B cells, and macrophages to the endomysial tissue. Hypoxic injury to the muscle fibers results in atrophy of muscle fibers, particularly those at the periphery furthest from the vascular supply. Over time, the capillary density reduces, and muscle fibers experience necrosis and degeneration.

• #1 Juvenile Dermatomyositis: Practice Essentials, Background, Pathophysiology

  https://emedicine.medscape.com/article/1417215-overview

  The current model of the pathogenesis of JDM involves both humoral and cell-mediated mechanisms that cause vascular and muscle damage. Autoantibodies directed against an unknown endothelial antigen may cause vascular injury, resulting in ischemia and subsequent muscle damage with increased expression of major histocompatibility complex (MHC) class I and II. […] CD4+ T cells, B cells, plasmacytoid dendritic cells (pDCs), and macrophages are arranged in a perivascular and perifascicular distribution, with capillary thrombosis and deposition of membrane attack complex and complement. […] Immune complex deposition mediates vascular injury, resulting in activation of complement and muscle inflammation. […] T cells, as well as B cells, play a dominant role in disease pathogenesis. TH 17 cells are a subset of CD4 cells that have been found with neutrophils in inflammatory infiltrates and are producers of interleukin (IL)17 found in inflamed tissues of JDM patients. IL-17 induces MHC class I and IL-6 (a proinflammatory cytokine) expression in myoblasts in concert with IL-1 (a proinflammatory cytokine).

• #1

  https://link.springer.com/article/10.1007/s40272-024-00658-2

  Inflammatory immune cell infiltrate including T and B cells has been observed in JDM muscle biopsies. […] B cells and genes related to B-cell survival such as BAFF were found to correlate with disease activity in adult IIM and/or JDM. […] Broad gene expression data from JDM muscle identified mitochondrial dysfunction from functional enrichment analysis. […] Mitochondrial dysfunction has also been identified by increased circulating mitochondrial DNA and MT-ND6 (mitochondrial NADH dehydrogenase 6) protein in JDM versus healthy controls. […] As an overview of these features in autoimmune disease, neutrophils are an innate immune cell that function as a first-line cell-mediated defense with killing of microorganisms. […] Increased LDGs was associated with weakness in JDM as well as activity in skin and vasculopathy, while increased NET markers were associated with muscle and lung disease activity.

• #1 Mitochondrial Contribution to Juvenile Dermatomyositis Pathogenesis – ACR Meeting Abstracts

  https://acrabstracts.org/abstract/mitochondrial-contribution-to-juvenile-dermatomyositis-pathogenesis/

  Mitochondrial Contribution to Juvenile Dermatomyositis Pathogenesis […] Of note, mitochondria are immunogenic, promoting development of anti-mitochondrial antibodies (AMAs). […] However, the role of mitochondrial extrusion in children with juvenile dermatomyositis (JDM) has not been addressed. […] The aim of this study was to investigate markers of mitochondrial extrusion, including mtDNA and AMAs, in JDM children to determine their clinical utility. […] Electron microscopy imaging demonstrated profound mitochondrial abnormalities in JDM muscle, including intramitochondrial calcification associated with degenerate muscle fibers and mitochondrial extrusion. […] As determined by Western blot, JDM patients had autoantibodies reacting towards mitochondrial antigens of 60 kDa, similar to what was seen in jSLE.

• #1 Idiopathic Inflammatory Myopathies – Musculoskeletal and Connective Tissue Disorders – MSD Manual Professional Edition

  https://www.msdmanuals.com/professional/musculoskeletal-and-connective-tissue-disorders/systemic-rheumatic-diseases/idiopathic-inflammatory-myopathies

  The cause of idiopathic inflammatory myopathy seems to be an autoimmune reaction to muscle tissue in genetically susceptible people. Familial clustering occurs, and human leukocyte antigen (HLA) subtypes are associated with myositis. For example, the alleles of the 8.1 ancestral haplotype (HLA-DRB1*03-DQA1*05-DQB1*02) increase risk of polymyositis, dermatomyositis, and interstitial lung disease. Possible inciting events include viral infection, certain medications, and underlying cancer. The association of cancer with dermatomyositis and necrotizing myopathies suggests that a tumor may incite myositis as the result of an autoimmune reaction against a common antigen in the muscle and in the tumor. […] Dermatomyositis is characterized by immune complex deposition in the vessels and is considered a complement-mediated vasculopathy. In contrast, polymyositis is characterized by direct T cell-mediated muscle injury, and immune-mediated necrotizing myopathies are characterized by macrophage-predominant infiltrates and myophagocytosis.

• #1 Environmental triggers of dermatomyositis: a narrative review

  https://atm.amegroups.org/article/view/49740/html

  Dermatomyositis (DM) is an autoimmune disease that affects the skin, lungs, and muscle. Although the pathogenesis of DM is not completely understood, several environmental triggers have been linked to DM onset or flare. […] The objective of this article is to critically review the literature on environmental triggers of DM, specifically herbal supplements, drugs, infections, UV radiation, and environmental pollutants. […] While the exact etiology and pathogenesis of DM are yet to be determined, there is general agreement that DM results from an autoimmune attack on affected organs and can be triggered by environmental factors, such as drugs, infections, ultraviolet (UV) exposure, and pollutant exposure in genetically susceptible individuals. […] Overall, there is general agreement that an autoimmune attack of the skin, muscle, and lungs in DM can be triggered by various environmental factors and warrants further investigation.

• #1 Updates in Juvenile Dermatomyositis: Pathogenesis & Patient Care – The Rheumatologist

  https://www.the-rheumatologist.org/article/updates-in-juvenile-dermatomyositis-pathogenesis-patient-care/

  Hanna Kim, MD, MS, assistant clinical investigator, Juvenile Myositis Pathogenesis and Therapeutics Unit, National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), Bethesda, Md., discussed the pathogenesis of, and treatment options for, JDM. […] Environmental ultraviolet (UV) light exposure may have a role in the pathogenesis of JDM. Dr. Kim noted that exposure to higher UV light index levels is associated with greater skin involvement in juvenile myositis. […] When evaluating muscle pathology, it appears vascular changes, hypoxia and a prominent interferon signature may be linked to histologic changes seen on muscle biopsy. Dr. Kim is the lead author of a study that showed peripheral blood interferon-regulated gene expression in JDM overlaps with that seen in monogenic interferonopathies, such as STING-associated vasculopathy with onset in infancy (SAVI), and correlates with disease activity.

• #1 Juvenile dermatomyositis and other idiopathic inflammatory myopathies: Epidemiology, pathogenesis, and clinical manifestations – UpToDate

  https://www.uptodate.com/contents/juvenile-dermatomyositis-and-other-idiopathic-inflammatory-myopathies-epidemiology-pathogenesis-and-clinical-manifestations

  Juvenile dermatomyositis (JDM) is the most common form of the rare idiopathic inflammatory myopathies (IIM; also called autoimmune or immune-mediated myopathies) affecting children. JDM is characterized by symmetric, proximal muscle weakness and distinct rashes including eyelid heliotrope dermatitis and Gottron papules. Pathologically, it is a capillary vasculopathy. […] JDM and other IIM are thought to be autoimmune disorders. JDM is associated with systemic vasculopathy. It is sometimes associated with occlusive arteriopathy and capillary necrosis; these changes eventually lead to capillary loss and tissue ischemia. Although the etiology remains unclear, it has been proposed that JDM and other IIM are caused by an autoimmune reaction in genetically susceptible persons, possibly in response to infection or environmental triggers such as prenatal exposure to tobacco smoke and particulate inhalants. JDM, as with adult dermatomyositis, is probably an „antibody-dependent, complement-mediated disease characterized by capillary injury that results in perifascicular muscle fiber atrophy.”

• #1 Adult-onset dermatomyositis

  https://dermnetnz.org/topics/adult-onset-dermatomyositis

  Dermatomyositis is thought to be caused by a microangiopathy affecting skin and muscle. […] Most patients have disease-associated autoantibodies, suggesting dermatomyositis is an autoimmune condition. […] Anti-transcriptional intermediary factor 1y antibodies (TIF-1y, anti 155/140) are strongly associated with malignancy-related dermatomyositis in the elderly. […] The JAK inhibitor, baricitinib, was studied in a small, 12-patient, open-label trial with clinically significant improvement seen in as early as week 4 of the study. […] The pathogenesis of dermatomyositis.

• #1 Explore the shared molecular mechanism between dermatomyositis and nasopharyngeal cancer by bioinformatic analysis | PLOS One

  https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0296034

  Multiple malignancies are predisposed to DM patients. Chinese studies have found that DM has a high risk of complications caused by nasopharyngeal carcinomas (NPC). In Taiwan, NPC is the most common (22.95%) in DM patients, followed by lung, breast, and ovarian cancers. High-risk factors for DM complicated by NPC include males, age 40 years, severe rash or muscle damage, dysphagia, and muscle weakness. NPC typically occurs 1 year after the diagnosis of DM. There is poor prognosis for dermatomyositis complicating nasopharyngeal carcinoma patients. Stronger drug resistance and more severe radiotherapy complications lead to poor survival in patients. Tumor radiotherapy enhances the anti-tumor immune response of CD8+ T-cells by radiation-induced activation of STING signaling and subsequent type I interferon (IFN-I) production. Excessive type I IFN production leads to skin and muscle damage, thereby exacerbating dermatomyositis symptoms. Various chemotherapeutic agents such as cisplatin or STING agonists induce IFN-I production to exert anti-tumor effects. However, tumor cells may inhibit STING levels and IFN-I production by increasing the expression of tryptophan metabolites or high expression of the aromatic hydrocarbon receptor AhR, enhancing patient resistance.

• #1 Polymyositis and Dermatomyositis: Pathophysiology | Musculoskeletal Key

  https://musculoskeletalkey.com/polymyositis-and-dermatomyositis-pathophysiology/

  In polymyositis and dermatomyositis, a type I interferon gene signature has been observed in the muscle tissue and peripheral blood, and the interferon gene signature in peripheral blood was associated with disease activity. […] Collectively, these observations indicate that the muscle impairment and fiber damage seen in myositis may be mediated not only exclusively by CD8 + cytotoxic T lymphocyte attack but also through nonimmunologic mechanisms such as the ER stress response and hypoxia. […] The mechanisms that cause muscle fiber degeneration or muscle atrophy have not been clarified, and both cytotoxic cell death and an effect of disuse or a negative effect of glucocorticoids have been suggested.

• #1 YKL-40-mediated Inflammatory Pathogenesis Common to Polymyositis / Dermatomyositis – ACR Meeting Abstracts

  https://acrabstracts.org/abstract/ykl-40-mediated-inflammatory-pathogenesis-common-to-polymyositis-dermatomyositis/

  YKL-40 is a chitinase-like protein that is associated with interstitial lung disease in patients with polymyositis (PM)/dermatomyositis (DM) but not with myositis. […] Here, we investigated whether YKL-40 is associated with PM/DM and assessed its role in PM/DM pathogenesis. […] Age-corrected serum YKL-40 values were significantly increased in patients with PM/DM compared to the HC but significantly decreased before and after treatment. […] Immunohistochemical analysis showed infiltration of YKL-40-positive inflammatory cells in the endomysium and perimysium of the muscle sheath. […] CD8+ and CD4+ T cells are believed to play predominant roles in muscle destruction in PM and DM, respectively. However, YKL-40-positive macrophages observed in both diseases suggest that cells other than CD8+ and CD4+ T cells may cause inflammation. This provides new insights to understand pathophysiological mechanisms of atypical myositis.

• #1 Clinical features, pathogenesis and treatment of juvenile and adult dermatomyositis | Nature Reviews Rheumatology

  https://www.nature.com/articles/nrrheum.2011.139

  Juvenile and adult dermatomyositis (DM) have multiple commonalities, yet display differing prevalence of features, outcomes and comorbidities. […] Both diseases have similar features on muscle biopsy and interferon gene signature, although subtle differences can exist in pathogenesis and pathology, such as more capillary loss and a greater degree of C5b9 complement deposition in affected muscle of juvenile patients. […] Adults with DM are more likely to have myositis-specific antibodies, develop interstitial lung disease, have amyopathic disease, and have a marked association with malignancy and other comorbidities. […] Initiatives are underway to improve classification, markers of disease activity and ability to predict outcome of juvenile and adult DM. […] Despite multiple commonalities between the two diseases, differences between adult and juvenile dermatomyositis (DM) do exist. […] Juvenile DM is associated with increased vasculopathy, but children and adolescents with DM have improved long-term prognosis and survival. […] The purpose of this Review is to compare and contrast the unique features between juvenile and adult disease and to outline new initiatives in the field.

• #1 Anti-MDA5 antibody-positive dermatomyositis: pathogenesis and clinical progress | Nature Reviews Rheumatology

  https://www.nature.com/articles/s41584-023-01054-9

  Anti-melanoma differentiation-associated protein 5 (MDA5) antibody-positive dermatomyositis (MDA5-DM) is a subtype of dermatomyositis. […] Although the aetiology of MDA5-DM is unknown, emerging epidemiological evidence of the seasonal and geographical distributions of MDA5-DM implicate viral infection as a potential trigger. […] The pathomechanism of MDA5-DM is complex, with a potential contributing role for T cells, B cells, neutrophils, macrophages and natural killer cells. […] Several biomarkers, including serum levels of anti-MDA5 antibodies and biomarkers related to macrophage activation, have been identified as useful tools for monitoring disease activity and prognosis. […] Therefore, there is an urgent need to explore the key pathogenic mechanisms of MDA5-DM and develop novel therapeutic options for patients.

• #1 Anti-MDA5 antibody-positive dermatomyositis: pathogenesis and clinical progress | Nature Reviews Rheumatology

  https://www.nature.com/articles/s41584-023-01054-9

  Aberrant activation of the type I interferon system may contribute to the pathogenesis of anti-melanoma differentiation-associated gene 5 dermatomyositis. […] MDA5 expression is associated with TGF–induced fibrosis: potential mechanism of interstitial lung disease in anti-MDA5 dermatomyositis. […] Enhanced immune complex formation in the lungs of patients with dermatomyositis. […] Neutrophil dysregulation is pathogenic in idiopathic inflammatory myopathies. […] RNA-containing immune complexes formed by anti-melanoma differentiation associated gene 5 autoantibody are potent inducers of IFN-. […] Autoimmunity against melanoma differentiation-associated protein 5 advances acute lung injury to interstitial lung disease in mice.

• #1

  https://link.springer.com/article/10.1007/s40265-014-0240-6

  Dermatomyositis (DM) is an autoimmune disease mainly affecting muscle and skin. […] Recent studies have highlighted the activation of the innate immune system, including high expression of interferons (IFNs) and IFN-regulated proteins, as an important pathological hallmark of DM. […] Inappropriate activation of the innate immune system with secondary dysregulation of the adaptive immune response is now considered to be a central pathogenetic feature of DM. […] We discuss how the recent advances in the understanding of the pathomechanisms of DM have altered our conception of the mode of action of established drugs such as chloroquine and methotrexate. […] Interferon-alpha/beta-mediated innate immune mechanisms in dermatomyositis. […] A phase 1b clinical trial evaluating sifalimumab, an anti-IFN-alpha monoclonal antibody, shows target neutralisation of a type I IFN signature in blood of dermatomyositis and polymyositis patients.

• #1 Updates in Juvenile Dermatomyositis: Pathogenesis & Patient Care – Page 2 of 4 – The Rheumatologist

  https://www.the-rheumatologist.org/article/updates-in-juvenile-dermatomyositis-pathogenesis-patient-care/2/

  The presence of myositis-specific antibodies can help clinicians screen for and predict specific manifestations of particular myositis phenotypes that may occur over time in patients lives. Examples: […] Antibodies to nuclear matrix protein-2 (NXP2) correlate with calcinosis, contractures and significant skin involvement. […] Antibodies to transcriptional intermediary factor-1 (TIF-1) often predict severe cutaneous involvement, generalized lipodystrophy, photoerythema and psoriasiform lesions. […] Antibodies to melanoma differentiation-associated gene 5 (MDA5) are associated with amyopathic disease, ulcerations of the skin and interstitial lung disease, which can be rapidly progressive. […] Finally, Dr. Kim presented intriguing evidence that Janus kinase inhibitors (jakinibs) may effectively treat JDM by blocking the interferon signaling pathway. […] Scientists continue to learn more about how these autoantibodies shape pathophysiology, diagnosis, disease monitoring, prognosis and optimum treatment.

• #1 Juvenile Dermatomyositis | PM&R KnowledgeNow

  https://now.aapmr.org/dermatomyositis/

  Juvenile dermatomyositis is an autoimmune disorder associated with systemic vasculopathy that can include occlusive arteriopathy and capillary necrosis. These vascular changes lead to tissue ischemia and perifascicular muscle atrophy. Degeneration and necrosis of both type 1 and type 2 muscle fibers are histopathologic features. […] The widespread tissue inflammation that occurs in JDM predominantly affects skeletal muscle and skin, leading to the hallmark features of symmetric proximal muscle weakness and characteristic cutaneous findings. […] Disease outcome is influenced by time from disease onset, time of initiation of treatment, lab values, and pathophysiology. […] There is emerging research into the role of mitochondrial function relating to development of skeletal muscle calcinosis in JDM. Identification of antimitochondrial autoantibodies may highlight patients at risk for developing calcinosis, and allow for earlier targeted treatment of mitochondrial dysfunction, reducing the risk of calcinosis-related complications in those individuals. […] A key unmet need is to develop individualized therapeutic approaches to optimize the early treatment regimen to avoid unnecessary adverse effects from immunosuppressive medications and to allow administration of more aggressive treatment to those with anticipated severe or refractory disease.

• #2 Pathophysiological Mechanisms and Treatment of Dermatomyositis and Immune Mediated Necrotizing Myopathies: A Focused Review

  https://www.mdpi.com/1422-0067/23/8/4301

  Idiopathic inflammatory myopathies (IIM), collectively known as myositis, are a composite group of rare autoimmune diseases affecting mostly skeletal muscle, although other organs or tissues may also be involved. […] Various components of the immune system are known to be important immunopathogenic pathways in IIM, although the exact pathophysiological mechanisms causing the muscle damage remain unknown. […] In recent decades, both adaptive and innate immune mechanisms have been shown to contribute to the pathogenesis of IIM. […] A better understanding of the overlapping and diverging pathophysiological mechanisms of the major subgroups of myositis is needed to optimize individual treatments for adult myositis patients. […] For DM and IMNM, we first describe the phenotype, including findings in muscle biopsies, and subsequently we describe three pathophysiological mechanisms: the humoral immune response including the role of antibodies, derangements of the complement system, and overexpression of the interferon pathway.

• #2 Dermatomyositis: Practice Essentials, Background, Pathophysiology

  https://emedicine.medscape.com/article/332783-overview

  Dermatomyositis is considered to be the result of a humoral attack against the muscle capillaries and small arterioles (endothelium of the endomysial blood vessels). Since 1966, there has been evidence supporting an ongoing microangiopathy. […] Like other idiopathic inflammatory myopathies, dermatomyositis is characterized by the presence of autoantibodies that are conventionally divided into myositis-specific autoantibodies (MSAs) and myositis-associated autoantibodies (MAAs). Individual patients rarely generate more than one MSA simultaneously. MSAs found in dermatomyositis include antiMi-2, anti-MDA5, antiTIF1, anti-NXP2, and anti-SAE. […] The disease starts when putative antibodies or other factors activate C3, forming C3b and C4b fragments that lead to formation of C3bNEO and membrane attack complex (MAC), which are deposited in the endomysial vasculature. Complement C5b-9 MAC is deposited and is needed in preparing the cell for destruction in antibody-mediated disease. B cells and CD4 (helper) cells are also present in abundance in the inflammatory reaction associated with the blood vessels.

• #2 Dermatomyositis: Practice Essentials, Background, Pathophysiology

  https://emedicine.medscape.com/article/332783-overview

  As the disease progresses, the capillaries are destroyed, and the muscles undergo microinfarction. Perifascicular atrophy occurs in the beginning; however, as the disease advances, necrotic and degenerative fibers are present throughout the muscle. […] The pathogenesis of the cutaneous component of dermatomyositis is poorly understood, but is thought to be similar to that of muscle involvement. […] Studies on the pathogenesis of the muscle component have been controversial. Some suggest that the myopathy in dermatomyositis is pathogenetically different from that in polymyositis. The former is probably caused by complement-mediated (terminal attack complex) vascular inflammation, the latter by the direct cytotoxic effect of CD8+ lymphocytes on muscle. However, other cytokine studies suggest that some of the inflammatory processes may be similar. One report has linked tumor necrosis factor (TNF) abnormalities with dermatomyositis.

• #2 Pathophysiological Mechanisms and Treatment of Dermatomyositis and Immune Mediated Necrotizing Myopathies: A Focused Review

  https://www.mdpi.com/1422-0067/23/8/4301

  The exact pathophysiological mechanisms causing IIM remain unknown. In general, and similarly to most other auto-immune disorders, an exogenous trigger (e.g., a viral infection) is presumed to be required in combination with a genetic predisposition. […] Immune-mediated disease mechanisms are thought to encompass both adaptive and innate disease mechanisms. […] The pathogenicity of at least some myositis-specific autoantibodies is plausible, as supported by the finding of related auto-antigen overexpression in IIM patients. […] This leads to IFN-1 overexpression in dermatomyositis, which may cause a pro-inflammatory state, MHC-class I overexpression, and non-immune mediated toxicity via mitochondrial damage and endoplasmatic reticulum stress. […] In short, these mechanisms create a positive feedback loop with inflammation, leading to subsequent impaired muscle contraction, muscle protein dyshomeostasis, and disease damage with atrophy and irreversible muscle fiber alterations.

• #2

  https://journals.lww.com/co-rheumatology/fulltext/2021/09000/updates_on_interferon_in_juvenile_dermatomyositis_.2.aspx

  Transcriptomic and protein-based studies in different tissues and peripheral IFN- assessment have demonstrated the importance of the dysregulated IFN pathway in JDM. […] Studies confirm IFN, particularly type I and II IFN, is an important part of JDM pathogenesis by the level of dysregulation and correlation with disease activity, as well as IFN recapitulating key JDM muscle pathology.

• #2 Mitochondrial Contribution to Juvenile Dermatomyositis Pathogenesis – ACR Meeting Abstracts

  https://acrabstracts.org/abstract/mitochondrial-contribution-to-juvenile-dermatomyositis-pathogenesis/

  Our novel findings of mitochondrial antibodies in JDM, preceding clinical diagnosis of calcinosis, support i) mitochondrial extrusion as a potential therapeutic targetable pathway, and ii) the use of AMAs as prognostic markers, allowing for early, preventive treatment, reducing development of disabling calcinosis in those children.

• #2 Juvenile dermatomyositis: advances in pathogenesis, evaluation, and treatment. – Document – Gale OneFile: Health and Medicine

  https://go.gale.com/ps/i.do?id=GALE%7CA217512191&sid=googleScholar&v=2.1&it=r&linkaccess=abs&issn=11745878&p=HRCA&sw=w

  Juvenile dermatomyositis (JDM) is a rare, presumably autoimmune illness that causes proximal muscle weakness and a variety of typical cutaneous features. […] Genetic factors are likely important in the pathogenesis of JDM. These include several Human Leukocyte Antigen alleles, in particular those associated with the 8.1 ancestral haplotype and the tumor necrosis factor-[alpha] gene 308 polymorphism. Microchimerism, activation of plasmacytoid dendritic cells, and upregulation of type-1 interferon inducible genes also appear to play an important role in the pathogenesis of JDM.

• #2 Juvenile Dermatomyositis | AMBOSS Rotation Prep

  https://resident360.amboss.com/pediatrics/pediatric-rheumatology/juvenile-dermatomyositis/juvenile-dermatomyositis.html

  The etiology of JDM is not completely understood, but it is likely due to a combination of environmental triggers in a genetically susceptible host that leads to immune dysfunction and an inflammatory tissue response. Geographic and seasonal clustering of cases has been described, lending support to environmental contributors. Additionally, preceding respiratory tract or gastrointestinal (GI) infections and ultraviolet (UV) light exposure are potential JDM triggers. Predisposing genetic factors include certain HLA loci (namely HLA-B, DRB1, and DQA1). Both innate and adaptive immunity are implicated in the pathogenesis of JDM, with humoral and cell-mediated pathways causing vascular and muscular damage.

• #2 Environmental triggers of dermatomyositis: a narrative review

  https://atm.amegroups.org/article/view/49740/html

  The mechanism of action that causes DM-like manifestations is poorly understood. However, one possibility is that DM-like cutaneous eruptions arise due to the drugs cytotoxic effects from inhibiting both DNA repair and DNA synthesis. […] The cytokine-shift hypothesis proposes one explanation for why pharmacologically blocking TNF- counter-intuitively leads to DM onset or flare. […] The anti-Mi-2 antibody has been associated with UV exposure and is more common in DM patients living in regions with higher UV exposure. […] UV exposure should be recognized as a prevalent environmental trigger of DM. […] It is well established that increased particulate matter in the air, such as from vehicle and industrial emissions, is associated with increased mortality. […] The factors that can cause disease and DM pathogenesis are still not fully understood. However, herbal supplements and weight loss powders, drugs, infections, UV radiation, and pollution, are several environmental factors associated with DM onset and flares and may contribute to disease manifestation in genetically susceptible individuals.

• #2 Clinical features, pathogenesis and treatment of juvenile and adult dermatomyositis | Nature Reviews Rheumatology

  https://www.nature.com/articles/nrrheum.2011.139

  Juvenile and adult dermatomyositis (DM) have multiple commonalities, yet display differing prevalence of features, outcomes and comorbidities. […] Both diseases have similar features on muscle biopsy and interferon gene signature, although subtle differences can exist in pathogenesis and pathology, such as more capillary loss and a greater degree of C5b9 complement deposition in affected muscle of juvenile patients. […] Adults with DM are more likely to have myositis-specific antibodies, develop interstitial lung disease, have amyopathic disease, and have a marked association with malignancy and other comorbidities. […] Initiatives are underway to improve classification, markers of disease activity and ability to predict outcome of juvenile and adult DM. […] Despite multiple commonalities between the two diseases, differences between adult and juvenile dermatomyositis (DM) do exist. […] Juvenile DM is associated with increased vasculopathy, but children and adolescents with DM have improved long-term prognosis and survival. […] The purpose of this Review is to compare and contrast the unique features between juvenile and adult disease and to outline new initiatives in the field.

• #2 Anti-MDA5 antibody-positive dermatomyositis: pathogenesis and clinical progress | Nature Reviews Rheumatology

  https://www.nature.com/articles/s41584-023-01054-9

  Aberrant activation of the type I interferon system may contribute to the pathogenesis of anti-melanoma differentiation-associated gene 5 dermatomyositis. […] MDA5 expression is associated with TGF–induced fibrosis: potential mechanism of interstitial lung disease in anti-MDA5 dermatomyositis. […] Enhanced immune complex formation in the lungs of patients with dermatomyositis. […] Neutrophil dysregulation is pathogenic in idiopathic inflammatory myopathies. […] RNA-containing immune complexes formed by anti-melanoma differentiation associated gene 5 autoantibody are potent inducers of IFN-. […] Autoimmunity against melanoma differentiation-associated protein 5 advances acute lung injury to interstitial lung disease in mice.

• #2 Adult-onset dermatomyositis

  https://dermnetnz.org/topics/adult-onset-dermatomyositis

  Dermatomyositis is thought to be caused by a microangiopathy affecting skin and muscle. […] Most patients have disease-associated autoantibodies, suggesting dermatomyositis is an autoimmune condition. […] Anti-transcriptional intermediary factor 1y antibodies (TIF-1y, anti 155/140) are strongly associated with malignancy-related dermatomyositis in the elderly. […] The JAK inhibitor, baricitinib, was studied in a small, 12-patient, open-label trial with clinically significant improvement seen in as early as week 4 of the study. […] The pathogenesis of dermatomyositis.

• #2 Faculty Collaboration Database – Recent Advances in Juvenile Dermatomyositis: Moving toward Integration of Myositis-Specific Antibody Clinical Phenotypes, IFN-Driven Pathogenesis, and Targeted Therapies. J Invest Dermatol 2024 Nov 11

  https://fcd.mcw.edu/?search/showPublication/id/2720732

  Juvenile dermatomyositis (JDM), the most common pediatric inflammatory myopathy, is associated with significant morbidity despite therapeutic advances. […] Because translational data solidify the role of type I IFNs in JDM disease pathogenesis, integration of clinical and molecular phenotyping may impact the choice of targeted therapy. […] This paper reviews clinical and molecular phenotyping in JDM and translational insights into immune pathogenesis that have created emerging options for targeted therapy.

• #3 Pathophysiological Mechanisms and Treatment of Dermatomyositis and Immune Mediated Necrotizing Myopathies: A Focused Review

  https://www.mdpi.com/1422-0067/23/8/4301

  The exact pathophysiological mechanisms causing IIM remain unknown. In general, and similarly to most other auto-immune disorders, an exogenous trigger (e.g., a viral infection) is presumed to be required in combination with a genetic predisposition. […] Immune-mediated disease mechanisms are thought to encompass both adaptive and innate disease mechanisms. […] The pathogenicity of at least some myositis-specific autoantibodies is plausible, as supported by the finding of related auto-antigen overexpression in IIM patients. […] This leads to IFN-1 overexpression in dermatomyositis, which may cause a pro-inflammatory state, MHC-class I overexpression, and non-immune mediated toxicity via mitochondrial damage and endoplasmatic reticulum stress. […] In short, these mechanisms create a positive feedback loop with inflammation, leading to subsequent impaired muscle contraction, muscle protein dyshomeostasis, and disease damage with atrophy and irreversible muscle fiber alterations.

• #3

  https://www.healio.com/clinical-guidance/dermatomyositis/pathogenesis-overview

  The pathogenesis of Dermatomyositis (DM) is multifactorial, and influenced by genetic, environmental, and immunological factors. Inflammatory mediators may play a role in DM pathogenesis. Type I interferons, which regulate both innate and adaptive immune responses, play a key role in DM pathogenesis. DM is thought to be caused by a humoral mediated attack against the muscle capillaries and the endothelium of arterioles. […] Activation of complement mediators is followed by formation and deposition of the membrane attack complex on vascular walls, leading to inflammation, endothelial cell death and ischemic muscle fiber damage. Increased release of proinflammatory cytokines and chemokines upregulate the expression of adhesion molecules on the endothelial cell membrane, facilitating the migration of activated CD4+ T cells, B cells, and macrophages to the endomysial tissue. Hypoxic injury to the muscle fibers results in atrophy of muscle fibers, particularly those at the periphery furthest from the vascular supply. Over time, the capillary density reduces, and muscle fibers experience necrosis and degeneration.

• #3 Dermatomyositis – Radiologica

  https://radiologica.org/knowledge-base/dermatomyositis/

  The exact pathogenesis of DM is not well understood, but it is thought to be an autoimmune process triggered by environmental factors in genetically susceptible individuals. The autoimmune reaction is driven by CD4+ T cells and results in complement activation, leading to muscle fibre damage and necrosis. There is also vasculopathic damage specifically targeting the endomysial capillaries leading to ischemia and perifascicular atrophy. […] The hallmarks of DM on histopathology include perivascular and perifascicular inflammation, muscle fibre necrosis, and perifascicular atrophy. A unique feature is the presence of perifascicular atrophy, attributed to ischemia secondary to vascular damage.

• #3 American College of Rheumatology Annual Meeting

  https://www.healio.com/news/rheumatology/20191119/mitochondrial-abnormalities-a-prognostic-marker-for-juvenile-dermatomyositis

  Patients with juvenile dermatomyositis demonstrate obvious mitochondrial abnormalities in the tissue and periphery, supporting the use of anti-mitochondrial antibodies as a prognostic marker, according to data presented at ACR/ARP 2019. […] Of note, mitochondria are immunogenic, promoting development of anti-mitochondrial antibodies. […] However, the role of mitochondrial extrusion in children with juvenile dermatomyositis has not been addressed. […] According to the researchers, electron microscopy imaging demonstrated profound mitochondrial abnormalities in the muscle tissue of patients with juvenile dermatomyositis. […] These findings suggest anti-mitochondrial antibodies may be used as a prognostic marker for calcinosis development in juvenile dermatomyositis. […] Novel mitochondrial biomarkers are associated with calcinosis, suggesting potential novel therapeutic targets in juvenile dermatomyositis.

• #3 Explore the shared molecular mechanism between dermatomyositis and nasopharyngeal cancer by bioinformatic analysis | PLOS One

  https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0296034

  The viral infection often triggers connective tissue diseases like systemic lupus erythematosus (SLE) and dermatomyositis. Coxsackievirus RNA was detected in muscle biopsies of individuals with DM, along with HIV, Hepatitis B, and Influenza A viruses, all associated with DM onset. However, persistent viral infection remains controversial. Coronavirus-19 mimics the symptoms of DM and causes myositis. As DM occurs more frequently in spring, respiratory viral infections may be associated with an increased risk of anti-MDA5-positive DM. Epstein-Barr virus (EBV) infection can trigger a cascade of inflammatory reactions, aggravating autoimmune diseases. In patients with juvenile dermatomyositis, Epstein-Barr nuclear antigen-IgG as well as EBV capsid antigen-IgG were highly positive. EBV proteins can mimic myosin anti-tRNA synthetases, EC-RF4 maps to histamine-tRNA and alanyl-tRNA to BPFL1. Hence, antiviral antibodies may cross-react with tRNA synthetases. Although type I interferon response is predominant in DM, EBVs latent membrane protein 1 (LMP1) can inhibit IFN-stimulating genes (ISGs) expression by blocking interferon regulatory factor 5 (IRF5) and STAT transcription factors. MDA5 triggers IFN-induced antiviral responses, but MDA5 is not able to sense virus infection since the virus inhibits PP1 dephosphorylation.

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