Jak inhibitor; Possibility and mechanism as a new disease modifying anti-rheumatic drug

Treatment of rheumatoid arthritis (RA) has developed dramatically by the appearance of biologics. However the development of a new anti-rheumatic drug is necessary because of its issue on route of administration and expense. Recently, inhibitors targeting tyrosine kinase known as Janus kinase (Jak) has shown prominent effect on RA. Jak family is comprised by Jakl, Jak2, Jak3 and Tyk2 which is necessary for signal transduction for inflammatory cytokines. INCB18424 targeting Jak1/2 and CP690,550 targeting Jak3 has been developed and is now on phase II clinical study for RA. Results from those clinical studies have proven that these inhibitors can be effective as biologics with few side effects. However, it has been reported that inhibitors are less specific than it has been expect and that non-specificity can be important for its effect. Therefore, we think that the mechanism of inhibitors cannot be explained by its inhibition of a single kinase. Herein, we describe IL-10 overproduction by Jak3 and Stat6 deficient dendritic cell. We speculate that this is one possible mechanism of action for CP690,550 although as for its non-specificity we need further investigation to predict not only its effect but also its side effect in a long term administration.