Autoimmune rheumatologic diseases
Systemic lupus erythematosus (SLE) is a complex autoimmune disease that follows an unpredictable disease course and affects multiple tissues. Despite decades of research and millions of dollars of R&D, therapeutic options for SLE treatment remain inadequate. We present an integrated, multi-cohort analysis of 4,325 gene expression microarray samples from 37 studies that leverages study heterogeneity to identify a highly persistent SLE signature. The SLE signature is significantly elevated in relatives of SLE patients compared to unrelated healthy volunteers, distinguishes SLE from other autoimmune, inflammatory, and infectious diseases, and persists across diverse tissues and cell types, including kidney, synovium, B cells, and T cells. Additionally, the SLE signature is significantly correlated with disease activity (SLEDAI) and clinical measures of inflammation, and decreases in response to treatment. Interestingly, many genes contained in the signature are independent of the type I and II interferon pathways. In particular, we notice a significant enrichment in genes from pathways related to nucleic acid metabolism. We prospectively validate our analysis in an independent cohort of pediatric SLE patients using RT-qPCR. In conclusion, the robust SLE signature has potential to aid clinicians in the diagnosis and monitoring SLE, and implicates novel biological pathways in SLE pathogenesis.