LAUSR

OBJECTIVES To date, no immunomodulatory drug has demonstrated its efficacy in primary Sjögren's syndrome (pSS). We sought to analyze potential commonalities between pSS transcriptomic signatures and signatures of various drugs or specific knock-in or knock-down genes. METHODS Gene expression from peripheral blood samples of patients with pSS was compared with that of healthy controls in 2 cohorts and 3 public databases. In each of the 5 datasets, we analyzed the 150 most up- and downregulated genes between pSS patients and controls with regard to the differentially expressed genes resulting from the biological action on 9 cell lines of 2837 drugs, 2160 knock-in and 3799 knock-down genes in the Connectivity Map database. RESULTS We analyzed 1008 peripheral blood transcriptomes from 5 independent studies (868 patients with pSS and 140 healthy controls). Eleven drugs could represent potential candidate drugs, with histone deacetylases and PI3K inhibitors among the most significantly associated. Twelve knock-in genes were associated with a pSS-like profile and 23 knock-down genes were associated with a pSS-revert profile. Most of those genes (28/35, 80%) were interferon-regulated. CONCLUSION This first drug repositioning transcriptomic approach in Sjögren's syndrome confirms the interest of targeting interferons and identifies histone deacetylases and PI3K inhibitors as potential therapeutic targets.