856 Tofacitinib is a potential treatment for Blau syndrome by suppressing the induction of NOD2 expression

Blau syndrome is a rare autosomal dominant autoinflammatory granulomatous disease caused by the mutation in NOD2 gene and characterized by the clinical triad of granulomatous dermatitis, arthritis, and uveitis. Since the efficacy of Janus kinase inhibitors (JAKi) has recently been reported for Blau syndrome in addition to idiopathic sarcoidosis, we evaluate the effect of tofacitinib, a pan JAKi, on inflammatory pathways associated with Blau syndrome. First, the downstream pathway under the mutated NOD2 was analyzed using luciferase assay with overexpression of NOD2 mutants into HEK293 cells. Tofacitinib did not suppress the spontaneous increased transcriptional activity of NF-κB by mutant NOD2. In addition, mutant NOD2 was also not involved in the transcription of ISRE and GAS, which are activated by type 1 and type 2 interferon (IFN), respectively. Next, we evaluated the upstream pathway for the induction of NOD2 expression using induced pluripotent stem (iPS) cells differentiated into monocytes from iPS cells established from a Blau syndrome patient with the p.R334W mutation and these cells further transformed back to wild type (WT) NOD2 by CRISPR/Cas9. In this analysis, IFNγ induces NOD2 expression in both WT and cells with mutated NOD2, but production of pro-inflammatory cytokines by an autoinflammatory mechanism was observed only in cells with mutant NOD2. At this time, tofacitinib showed anti-inflammatory effects through suppression of NOD2 expression. In conclusion, JAKi is a potential therapeutic agent for Blau syndrome because it suppresses the autoinflammation seen in Blau syndrome by inhibiting the induction of NOD2 expression.