Skin Transcriptomics Reveal Shared Molecular Mechanisms for Skin and Lung Involvement in Systemic Sclerosis

OBJECTIVE: Systemic sclerosis (SSc) is characterized by dysregulated immunity, microvascular damage, and progressive fibrosis. SSc-related interstitial lung disease (SSc-ILD) is the leading disease-specific cause of death; it is therefore important to identify biomarkers associated with SSc-ILD. We hypothesized that the skin transcriptome would provide mechanistic clues that could further our understanding of lung impairment in SSc-ILD. METHODS: We conducted a multistage analysis of SSc transcriptomes using weighted gene correlation analysis, gene set enrichment analysis, and single-cell RNA sequencing. RESULTS: We identified seven modules correlated with skin and lung function involvement. Unsupervised clustering of these genes classified patients into two groups, one of which showed severe multiorgan involvement characterized by increased skin fibrosis and decreased lung function (P < 0.05). The KRAS pathway was enriched in the severe cluster. Deconvolution of the severe cutaneous signature in SSc skin and lungs showed increased expression in stromal cells and monocytes, whereas the KRAS pathway was enriched in stromal cells only. Profiling KRAS and downstream signaling in lungs from individuals with SSc-ILD demonstrated activation of these pathways (P < 0.05). CONCLUSION: We found a severe cutaneous transcriptomic signature of SSc associated with multiorgan involvement. By deconvoluting the severe cutaneous signature, we have identified pathways enriched in specific cell types, including KRAS in stromal cells and a combination of stromal and immune cells in the severe signature. The severe SSc signature can provide a framework for understanding shared mechanisms in skin and lung fibrosis and may help identify additional molecular pathways.