Background/Purpose: Juvenile dermatomyositis (JDM) and childhood-onset SLE (cSLE) are systemic autoimmune diseases characterized by overlapping yet distinct clinical manifestations and treatment responses. In this study, we evaluate unique signatures in JDM using multi-omic approaches of plasma proteomics and single cell resolution tissue transcriptomics.

Methods: Plasma protein levels were measured using the Olink® Explore 3072 panel in 36 JDM, 18 cSLE and 14 controls (CTL). All JDM and cSLE met EULAR/ACR classification criteria. Differential expression analysis identified differentially regulated proteins (DRPs) (false discovery rate (FDR)< 0.10) in (1) all JDM, (2) all cSLE and (3) treatment naïve (TN) JDM (n=6) relative to CTL. Regulated pathways were assessed using MetaCoreTM (FDR< 0.10). Pearson correlation evaluated association of DRPs with global and organ-specific JDM disease activity measures (p< 0.05). We further evaluated candidate disease activity-associated DRPs by analyzing cell-type specific RNA expression of genes encoding the DRPs in a JDM single-nucleus transcriptomic dataset from muscle (n=6) and single-cell transcriptomic datasets from skin (n=12) and blood (n=5).

Results: We identified 91 DRPs in JDM and 334 in cSLE, of which 29 DRPs overlapped in JDM and cSLE (Fig 1A). 62 DRPs were unique to JDM, representing five biological pathway themes, including skeletal muscle development and contraction, inflammation, apoptosis, metabolism and cell adhesion (Fig 1B). In TN JDM vs. CTL, 962 DRPs were identified, with neutrophil degranulation, IL-10 and death receptor signaling representing top biological pathways. To identify a chronic JDM signature, we analyzed DRPs in non-TN JDM, which resulted in 21 DRPs (Fig 2A,B), including both immune signaling (IL-10, CCL7, CXCL10) and muscle and metabolism-associated (CSRP3, MYBPC1, KLHL41, CALCB, ACHE, SOD2, GOT1). A protein expression score incorporating the 20 overlapping proteins from chronic and TN JDM was higher in JDM versus CTL (p< 0.05) (Fig 2C). Ten of these chronically elevated DRPs correlated with JDM disease activity measures (Fig 3A). Upon evaluation of cell-type specific, single-cell expression of these ten markers, we identified a predominant tissue-based origin, with only CXCL10, SOD2 and GOT1 exhibiting expression in circulating immune cells (Fig 3B). Interestingly, IL-10 displayed specific expression only in skin and muscle tissue macrophages, while CXCL10 exhibited widespread expression, including circulating CD14 and CD16+ monocytes and resident muscle and skin populations (FAPS, ECs, basal keratinocytes, fibroblasts) (Fig 3B).

Conclusion: JDM as compared to cSLE demonstrated increased expression of proteins associated with myogenesis and metabolism. We identified a chronic disease signature in JDM, which included DRPs associated with metabolism (GOT1, SOD2), myogenesis/muscle structure (KHL41, CSRP3, MYBPC1), and immune dysregulation (CXCL10, IL10, CCL7). The majority of chronic DRPs in JDM, including DRPs specific to immune cells, exhibited higher gene expression in tissue, highlighting the need for further tissue-based studies in JDM to identify targeted therapies and biomarkers.

Figure 1. Comparison of plasma proteomic signature in JDM vs. cSLE highlights altered muscle signaling in JDM and shared interferon and innate immune signature with cSLE. A.) Venn Diagram highlighting number of differentially regulated proteins (DRPs) in each JDM (n=36) and cSLE (n=18) relative to CTL (n=14), with heatmap on left demonstrating 62 DRPs unique to JDM vs. CTL comparison and heatmap on right highlighting 29 DRPs in common between each JDM and cSLE relative to CTL. In the heatmaps, each column represents an individual patient sample while each row represents a DRP, with color indicating NPX z-score expression of each protein. B.) Alluvial plot showing biological pathways and associated proteins regulated in JDM.

Fig 2. Identification of 20 common differentially regulated proteins (DRPs) in both treatment naïve (TN) and chronic JDM. A.) Venn diagram displaying number of DRPs in each TN JDM (n=6) and chronic JDM (n=30) relative to CTL (n=14). B.) Heat map demonstrating NPX z-score expression of the 20 common DRPs in each TN and chronic JDM samples. C.) Protein expression score of the 20 common DRPs in TN JDM, chronic JDM and CTL samples. Protein expression score is higher in both TN and chronic JDM compared to CTL.

Fig 3. Ten differentially regulated proteins in chronic JDM also display association with JDM disease activity measures. A.) Pearson correlation of ten DRPs from chronic JDM with JDM disease activity measures for skin (Cutaneous Dermatomyositis Disease Area and Severity Index; CDASI activity score), muscle (Manual Muscle Testing; MMT-8 scores) and global (Physician’s Global Activity Assessment; PGA scores) disease activity (p < 0.05). B.) Dot plots displaying normalized and scaled gene expression (indicated by color) and percent of cells (indicated by size of dot) expressing the ten candidate markers in three additional datasets: single-nuclei RNA-sequencing data from muscle (n=6 JDM), single-cell RNA-sequencing data from skin (n=12 JDM) and treatment naïve peripheral blood mononuclear cells (PBMCs) (n=5 JDM).

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/chronic-jdm-plasma-proteomic-signature-reflects-inflammation-from-immune-and-tissue-resident-muscle-and-skin/