Comparison of lesional juvenile myositis and lupus skin reveals overlapping yet unique disease pathophysiology.

OBJECTIVE: Skin inflammation heralds systemic disease in juvenile myositis (JM), yet we lack an understanding of pathogenic mechanisms driving skin inflammation in JM. The goal of this study is to define cutaneous gene expression signatures in JM and identify key genes and pathways that differentiate skin disease in JM from childhood-onset systemic lupus erythematosus (cSLE). METHODS: We utilized formalin-fixed paraffin-embedded (FFPE) skin biopsy samples from 15 JM (9 lesional, 6 non-lesional), 5 cSLE, and 8 control patients to perform transcriptomic analysis and identify significantly differentially expressed genes (DEGs; q-value ≤ 5%) between patient groups. We utilized Ingenuity Pathway Analysis (IPA) to highlight enriched biological pathways and validated DEGs using immunohistochemistry and quantitative real-time PCR. RESULTS: Comparison of lesional JM to control revealed 221 DEGs, with the majority of upregulated genes representing interferon-stimulated genes. CXCL10, CXCL9 and IFI44L represented the top three DEGs (fold-change respectively = 23.2, 13.3, 13.0, q-value < 0.0001). IPA revealed interferon (IFN) signaling as the top canonical pathway. When compared to cSLE, JM lesional skin shared a similar gene expression pattern, with only 28 unique DEGs, including FBLN2, CHKA and SLURP1. Notably, JM patients with NXP2 autoantibodies exhibited the strongest IFN signature and also demonstrated the most extensive MX1 immunostaining, both in keratinocytes and perivascular regions. CONCLUSION: JM lesional skin demonstrates a striking IFN signature similar to that previously reported in muscle and peripheral blood. Further investigation into the association of a higher IFN score with NXP2 autoantibodies may lend insight into disease endotypes and pathogenesis.