Background/Purpose: Systemic sclerosis (SSc) is an autoimmune disease that affects multiple organs asynchronously, leading to highly variable fibrotic damage and consequent increased morbidity and mortality. The significant heterogeneity of time, type and severity of organ involvement often challenges the robustness of short proof-of-concept (PoC) clinical studies. In this study, we integrate high-quality published skin omics datasets and new serum proteomics analysis to deconvolute molecular signatures of SSc over time and across clinical subsets.

Methods: We used the “treat” function from the LIMMA package to identify significantly differentially expressed genes (FDR ≤ .05) in affected early and late SSc skin (GSE130955, GSE58095, and GSE181549). These genes were further analyzed using algorithms of 1) overconnectivity, 2) causal reasoning, 3) hidden nodes, 4) interconnectivity, and 5) network propagation to identify key and significant network objectives (adjusted p ≤ .05). To identify the key affected pathways and processes, we conducted enrichment analysis using Gene Ontology and Metabase Pathway Maps and Networks. Olink Explore-1536 panel serum proteomics of patients spanning from VEDOSS (-2yrs from fulfilling Classification criteria) to late disease ( >7years) allowed identification of independent and significant serum biomarkers (p< 0.05, >Log₂1) of disease activity over time.

Results: The skin transcriptomics profiling revealed a unique set of genes (n=739 biomarkers) and network regulators (overconnected nodes with upregulated genes, n=119; causal reasoning, n=339, hidden nodes, n=89; interconnectivity, n=12; network propagation, n=208) in diffuse cutaneous SSc (dcSSc). Pathway analyses revealed significant dysregulation in inflammatory signaling (Jak-STAT, IL6, Chemotaxis, Interferon, and others) and fibroplasia (cell-matrix interaction, ECM remodeling, others) as unique for early dcSSc, whereas angiogenesis, connective tissue degradation, and blood coagulation pathways are dysregulated throughout the disease natural history and clinical subsets. Altogether, the analyses highlighted 6 biological elements as drivers and potentiators of SSc pathobiology. The analysis of the integrated VEDOSS and SSc cohort indicated that serum biomarkers of Type I IFN (STAT5, CCL5, IL10, TLR3) and inflammatory (PAI1, CCL2, IL6, vWF) signaling as well as epithelial damage (PRSS8, SFTPD, WFDC2, SFTPA1) showed continuity between patients at increased risk of progression to disease or to disease major complications over time (progressive skin and lung involvement).

Conclusion: Our comprehensive molecular profiling highlights the significance of skin and serum omics in defining a pathologic disease continuum in SSc, preceding fulfillment of classification criteria and remaining active through disease progression. The perseverance of inflammatory and epithelial damage biomarkers throughout time underlines the currently unmet therapeutic need of SSc and can be utilized to enrich patients with active disease progression and support a robust short PoC clinical study design.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/deconvolution-of-the-molecular-signature-of-very-early-diagnosis-of-systemic-sclerosis-vedoss-and-established-disease-a-biomarker-blueprint-of-scleroderma-disease-continuum/