Juvenile dermatomyositis: Latest advances

Wu, Qiong; Wedderburn, Lucy R.; McCann, Liza

doi:10.1016/j.berh.2017.12.003

Cited by 42 publications

(50 citation statements)

References 87 publications

(65 reference statements)

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“…Neutrophils and other phagocytes were involved in clearance of the mineral crystals, as demonstrated by endocytosed crystals. The presence of infiltrating neutrophils is novel in JDM; in prior studies, neutrophils were not identified in diagnostic muscle biopsies from children with JDM . This discrepancy may be explained by the selection of our patients (e.g., those with calcinosis), but it may also relate to the rapid turnover of neutrophils.…”

Section: Discussionmentioning

confidence: 70%

Neutrophil Extracellular Traps in Tissue and Periphery in Juvenile Dermatomyositis

Duvvuri

Pachman

Morgan

et al. 2020

Arthritis & Rheumatology

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Objective. Neutrophils are key immune cells participating in host defense through several mechanisms, including the formation of neutrophil extracellular traps (NETs). This study was undertaken to investigate the role of neutrophils in juvenile dermatomyositis (JDM).Methods. Electron microscopy was used to identify neutrophils in tissue. NETs were also imaged using fluorescence microscopy and quantified using a myeloperoxidase-DNA enzyme-linked immunosorbent assay (ELISA) in plasma obtained from healthy children (n = 20), disease controls (n = 29), JDM patients (n = 66), and JDM patients with history of calcifications (n = 20). Clinical data included disease activity scores and complement C4 levels. Levels of immune complexes (ICs) and calprotectin were analyzed using ELISA.Results. Using electron microscopy, neutrophils were found to infiltrate affected muscle tissue, engulfing deposited calcium crystals. Uptake of the crystals led to neutrophil activation (P < 0.01) and subsequent phosphatidylinositol 3-kinase-and NADPH oxidase-dependent but peptidylarginine deiminase 4-independent formation of NETs, which contained mitochondrial DNA (P < 0.05), as confirmed in vivo (P < 0.001) and in vitro (P < 0.01). Peripheral NET levels were associated with calcinosis (P = 0.01), ICs (P = 0.008), and interleukin-8 levels (P = 0.004). Children with JDM had impaired NET clearance (P = 0.01), associated with autoantibody profiles including melanoma differentiationassociated protein 5 (P = 0.005), and depressed complement C4 levels (r = −0.72, P = 0.002). Furthermore, children with JDM showed evidence of neutrophil activation, with elevated levels of peroxidase activity (P = 0.02) and calprotectin (P < 0.01), which were associated with disease activity (P = 0.007), and dyslipidemia (odds ratio 4.7, P < 0.05).Conclusion. We found novel mechanisms of both calcium crystal-mediated neutrophil activation and cell death in JDM pathophysiology. Targeting this pathway may reduce the frequency and extent of calcinosis, as well as prevent long-term development of comorbidities, including atherosclerosis.

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Section: Discussionmentioning

confidence: 70%

Neutrophil Extracellular Traps in Tissue and Periphery in Juvenile Dermatomyositis

Duvvuri

Pachman

Morgan

et al. 2020

Arthritis & Rheumatology

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“…However, juvenile and adult DM have different clinical presentation (22) and JDM PB express more Th17-type and FOXP3 transcripts (23). JDM and other myopathies are characterized by a type 1 IFN signature (24–26) and interferons may be a potential therapeutic target (27), but their effects on Tregs remain to be investigated.…”

Section: Altered Tregs In Jia and Jdmmentioning

confidence: 99%

“…JIA and JDM can exhibit an unpredictable disease course. While mounting evidence indicates that an early aggressive treatment is best for severe disease (4, 27, 33, 34), the disease course is unpredictable at presentation. Additionally, due to potential short- and long-term side effects children should not be exposed to unnecessary medication.…”

Section: Tregs As a Biomarker?mentioning

confidence: 99%

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Targeting Tregs in Juvenile Idiopathic Arthritis and Juvenile Dermatomyositis—Insights From Other Diseases

Hoeppli

Pesenacker

2019

Front. Immunol.

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Regulatory T cells (Tregs) are believed to be dysfunctional in autoimmunity. Juvenile idiopathic arthritis (JIA) and juvenile dermatomyositis (JDM) result from a loss of normal immune regulation in specific tissues such as joints or muscle and skin, respectively. Here, we discuss recent findings in regard to Treg biology in oligo-/polyarticular JIA and JDM, as well as what we can learn about Treg-related disease mechanism, treatment and biomarkers in JIA/JDM from studies of other diseases. We explore the potential use of Treg immunoregulatory markers and gene signatures as biomarkers for disease course and/or treatment success. Further, we discuss how Tregs are affected by several treatment strategies already employed in the therapy of JIA and JDM and by alternative immunotherapies such as anti-cytokine or co-receptor targeting. Finally, we review recent successes in using Tregs as a treatment target with low-dose IL-2 or cellular immunotherapy. Thus, this mini review will highlight our current understanding and identify open questions in regard to Treg biology, and how recent findings may advance biomarkers and new therapies for JIA and JDM.

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“…Idiopathic Inflammatory Myopathies (IIM) consist of a group of highly heterogenous diseases characterized by a systemic inflammatory process. Muscle weakness and skin involvement are common characteristics but other organs can also be affected ( 1 ). Juvenile Dermatomyositis (JDM) is the commonest childhood IIM seen in ~85% of cases, while polymyositis consists of <5% of the pediatric IIM cases ( 2 ).…”

Section: Introductionmentioning

confidence: 99%

The Vasculopathy of Juvenile Dermatomyositis

Papadopoulou

McCann

2018

Front. Pediatr.

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Juvenile dermatomyositis (JDM) is a rare autoimmune disease mainly characterized by muscle and skin involvement. Vasculopathy is considered central to the pathogenesis of the disease. The exact nature of vasculopathy is not yet understood but it is a complex process with both an inflammatory and a non-inflammatory, occlusive component. Impaired function of JDM vasculature includes immune complex deposition, altered expression of cell adhesion molecules predominantly inducing Th17 cell infiltration, and endothelial cell dysfunction. Development of vasculopathy is associated with the severe extra-muscular manifestations of JDM, such as gastrointestinal and cardiac manifestations, interstitial lung disease, ulcerative skin disease or development of calcinosis, and portends a poor prognosis. Correlation of histopathological findings, autoantibodies, and extensive diagnostic workup represent key elements to the early detection of vasculopathic features and early aggressive treatment. Monitoring of vasculopathy remains challenging due to the lack of non-invasive biomarkers. Current treatment approaches provide variable benefit, but better understanding of the essential pathogenic mechanisms should help lead to improved outcomes. Whilst acknowledging that evidence is limited, this review aims to describe the vasculopathy of JDM in the context of pathophysiology, clinical features, and treatment of disease.

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Juvenile dermatomyositis: Latest advances

Cited by 42 publications

References 87 publications

Neutrophil Extracellular Traps in Tissue and Periphery in Juvenile Dermatomyositis

Neutrophil Extracellular Traps in Tissue and Periphery in Juvenile Dermatomyositis

Targeting Tregs in Juvenile Idiopathic Arthritis and Juvenile Dermatomyositis—Insights From Other Diseases

The Vasculopathy of Juvenile Dermatomyositis

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