Tofacitinib, a suppressor of NOD2 expression, is a potential treatment for Blau syndrome.

Introduction: Blau syndrome is a rare autosomal dominant autoinflammatory granulomatous disease caused by a mutation in the gene. It is characterized by a clinical trial of granulomatous dermatitis, arthritis, and uveitis. Tofacitinib is a pan Janus kinase (JAK) inhibitor used for treatment of Blau syndrome and idiopathic sarcoidosis. Here, we evaluated its effect on inflammatory pathways associated with Blau syndrome. The effect of tofacitinib on downstream pathways regulated by mutant was analyzed using luciferase assays with overexpression of mutants.

Methods: The effect of tofacitinib on the upstream pathway for the induction of expression and proinflammatory cytokine production was assessed using monocytic cell lines differentiated from Blau syndrome patient-derived induced pluripotent stem cells.

Results: Tofacitinib did not suppress the increased spontaneous transcriptional activity of NF-κB by mutant . In addition, mutant was not involved in the transcription of ISRE and GAS, which are activated by type 1 and type 2 interferons (IFN), respectively. On the other hand, IFNγ induced the expression of , which led to the production of inflammatory cytokines by an autoinflammatory mechanism only in cells with mutant .

Discussion: Tofacitinib suppressed the induction of by IFNγ, thereby inhibiting the production of pro-inflammatory cytokines. Thus, tofacitinib showed anti-inflammatory effects through suppression of expression. The JAK inhibitor tofacitinib is a potential therapeutic agent for Blau syndrome because it suppresses the autoinflammation seen in Blau syndrome by inhibiting the expression of .