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Introduction Skin from patients with Very Early Systemic Sclerosis (VEDOSS) shows early histopathological fibrotic changes, including collagen accumulation and perivascular immune infiltration, despite evidence of clinical skin thickening. 1 Epidermal cells, once considered passive bystanders in Systemic Sclerosis (SSc) pathogenesis, are now thought to actively contribute to immune-fibrotic processes, including driving a type I IFN signature.2 The sub-epidermal perivascular region also acts as a key immuno-fibrotic niche and a hotspot for cellular crosstalk.Objectives To identify the early transcriptomic changes evident in very early disease and highlight biomarkers of progression to SSc in key regions of the skin.Material and Methods We employed spatial transcriptomics to map whole genome-wide transcriptome expression in the epidermis and area immediately surrounding CD34-stained vessels in the superficial and deeper dermis, as well as SMAalpha positive regions ( figure 1B). Differentially expressed genes (p<0.05, log2FC>0) were analyzed to identify relevant canonical pathways and biological processes.Results Six skin biopsies from VEDOSS were compared with six from healthy individuals. Cell deconvolution revealed non-keratinocyte populations in the VEDOSS epidermis, notably fibroblasts and melanocytes. The superficial CD34+ region was enriched with diverse fibroblast subsets and endothelial cells, along with immune populations such as T cells and macrophages. VEDOSS-associated changes included loss of secretory papillary fibroblasts, increased lymphatic endothelial cells, and erythrocyte depletion. A greater proportion of mesenchymal fibroblasts were noted in VEDOSS SMAalpha regions. Pathway analysis revealed both overlapping and region-specific signalling in VEDOSS skin compared with healthy controls. In the epidermis, enrichment was observed in Syndecan interactions, IGF and Notch signalling, innate immune activation, and extracellular matrix (ECM) pathways. The superficial CD34+ perivascular region showed activation of Cyclophilin signalling, oxidative phosphorylation, neutrophil degranulation, cellular response to hypoxia, and mitochondrial dysfunction ( figure 1C). The deeper dermis was enriched for pulmonary fibrosis signalling, collagen biosynthesis and degradation, wound healing, integrin interactions, and impaired NRF2-mediated oxidative stress responses. SMAa+ regions were dominated by immune-fibrotic pathways, including IL-6, TNF, B cell and CD27 signalling, and reactive oxygen species production.Conclusions Changes in oxidative stress response and immune activation was observed in all regions of VEDOSS skin. Mitochondrial dysfunction was observed within the dermis. ECM changes were observed within the epidermis and deeper dermis and SMAa+ regions. Together, our data highlight key therapeutic targets for potentially halting progression to SSc.References Ross RL, et al. 2024. doi:10.1093/rheumatology/keae698Bryon J, et al. 2025. doi: 10.1002/art.43029Conclusions Initial therapy was associated with improved survival and reduced PAH progression in SSc-PAH, with consistent effects across haemodynamic thresholds and risk strata. These findings support guideline-recommended early intervention, highlight the importance of high-quality observational data in rare diseases, and underscore the need for RCTs to clarify treatment effects in patients with milder haemodynamic impairment.Abstract OC.14 Figure 1