Skin transcriptomics are associated with lung function impairment and distinct cell types in systemic sclerosis-related lung disease

<bold>Introduction:</bold> Systemic sclerosis (SSc) is a connective tissue disease characterized by dysregulated immunity, microvascular damage and progressive fibrosis. SSc-related interstitial lung disease (SSc-ILD) is the leading cause of disease specific mortality and better biomarkers are needed to predict development and progression. In preliminary studies, we identified a cutaneous signature associated with skin and lung severity. In this study, we sought to identify cell-specific enrichment of this severe signature. <bold>Methods:</bold> Three publicly available datasets were identified. The first contained gene expression data from the skin of patients with SSc. The second contained single cell RNA sequencing (scRNAseq) data from lung tissue of patients with SSc-ILD and controls. The third contained scRNAseq data from the skin of patients with diffuse SSc (dSSc) and controls. Seurat was used for scRNAseq analysis. <bold>Results:</bold> In the lung, deconvolution of the severe cutaneous signature showed increased expression in myofibroblasts and CD16+ monocytes while decreased expression was seen in lung epithelial cells. In the skin, the signature showed increased expression in fibroblasts and CD14+ monocytes and decreased expression in epidermal cells and melanocytes. <bold>Conclusion:</bold> Skin transcriptomics of SSc-ILD patients identified a distinct signature associated with disease severity that demonstrated increased expression in distinct structural and immune cells in skin and lung. This non-invasive signature may identify patients at risk of lung disease, novel cell types involved in disease pathogenesis and additional therapeutic targets.