Abstract
In juvenile dermatomyositis (JDM), the most common pediatric inflammatory myopathy, weakness is accompanied by a characteristic rash that often becomes chronic and is associated with vascular damage. We hoped to understand the molecular underpinnings of JDM, particularly when untreated, which would facilitate the identification of novel mechanisms and clinical targets that might disrupt disease progression. We studied the RNA-Seq data from untreated JDM peripheral blood mononuclear cells (PBMCs; n = 11), PBMCs from a subset of the same patients when clinically inactive (n = 8/11), and separate samples of untreated JDM skin and muscle (n = 4 each). All JDM samples were compared to non-inflammatory control tissues. The untreated JDM PBMCs showed a strong signature for type1 interferon response, along with IL-1, IL-10, and NF-κB. Surprisingly, PBMCs from clinically inactive JDM individuals had persistent immune activation that was enriched for IL-1 signaling. JDM skin and muscle both showed evidence for type 1 interferon activation and genes related to antigen presentation and decreased expression of cellular respiration genes. Additionally, we found that PBMC gene expression correlates with disease activity scores (DAS; skin, muscle, and total domains) and with nailfold capillary end row loop number (an indicator of microvascular damage). This included otoferlin, which was significantly increased in untreated JDM PBMCs and correlated with all 3 DAS domains. Overall, these data demonstrate that PBMC transcriptomes are informative of molecular disruptions in JDM and provide transcriptional evidence of chronic inflammation despite clinical quiescence.
Highlights
In juvenile dermatomyositis (JDM), the most common pediatric inflammatory myopathy, weakness is accompanied by a characteristic rash that often becomes chronic and is associated with vascular damage
Cells (PBMCs) to identify pathways disrupted in children with JDM before treatment when compared to healthy pediatric controls and determined if this signature changed once the child became clinically inactive
With the introduction of corticosteroids, the mortality rate has improved to less than 2% in the US and United Kingdom. Despite these treatment advances and improved outcomes, there is still significant morbidity associated with JDM, such as pulmonary compromise[31] and the development of calcinosis, sometimes with superinfection[32]
Summary
In juvenile dermatomyositis (JDM), the most common pediatric inflammatory myopathy, weakness is accompanied by a characteristic rash that often becomes chronic and is associated with vascular damage. We found that PBMC gene expression correlates with disease activity scores (DAS; skin, muscle, and total domains) and with nailfold capillary end row loop number (an indicator of microvascular damage) This included otoferlin, which was significantly increased in untreated JDM PBMCs and correlated with all 3 DAS domains. Disease activity in children with JDM is associated with systemic damage, including microvascular alterations (evaluated by the nail fold capillary end row loop number and shape); the children often develop premature cardiovascular disease later in life[5,6] It is unclear whether the vascular disease in JDM is driven by the child’s genetic background[7] in addition to the duration of untreated disease, overall disease course, and/or the choice of drugs to treat the disease. We compared the PBMCs profiles with those obtained from a smaller set of JDM skin and muscle samples to assess the specificity of tissue-associated transcriptional signatures and whether the more obtained PBMCs contain representative signatures of disease activity
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
