Topically Administered Janus-Kinase Inhibitors Tofacitinib and Oclacitinib Display Impressive Antipruritic and Anti-Inflammatory Responses in a Model of Allergic Dermatitis

Abstract

The prevalence of allergic skin disorders has increased rapidly, and development of therapeutic agents to alleviate the symptoms are still needed. In this study, we orally or topically administered the Janus kinase (JAK) inhibitors, tofacitinib and oclacitinib, in a mouse model of dermatitis, and compared the efficacy to reduce the itch and inflammatory response. In vitro effects of JAK inhibitors on bone marrow-derived dendritic cells (BMDCs) were analyzed. For the allergic dermatitis model, female BALB/c mice were sensitized and challenged with toluene-2,4-diisocyanate (TDI). Each JAK inhibitor was orally or topically applied 30 minutes before and 4 hours after TDI challenge. After scratching bouts and ear thickness were measured, cytokines were determined in challenged skin and the cells of the draining lymph node were analyzed by means of flow cytometry. In vitro, both JAK inhibitors significantly inhibited cytokine production, migration, and maturation of BMDCs. Mice treated orally with JAK inhibitors showed a significant decrease in scratching behavior; however, ear thickness was not significantly reduced. In contrast, both scratching behavior and ear thickness in the topical treatment group were significantly reduced compared with the vehicle treatment group. However, cytokine production was differentially regulated by the JAK inhibitors, with some cytokines being significantly decreased and some being significantly increased. In conclusion, oral treatment with JAK inhibitors reduced itch behavior dramatically but had only little effect on the inflammatory response, whereas topical treatment improved both itch and inflammatory response. Although the JAK-inhibitory profile differs between both JAK inhibitors in vitro as well as in vivo, the effects have been comparable.

Immunomodulatory in vitro effects of oclacitinib on canine T‐cell proliferation and cytokine production

“…Investigations of several JAK inhibitors reveal a dose‐dependent decrease in T‐cell cytokine production with a predicted inhibitory potency frequently proposed based on a high concentration of 10 μM . Both oclacitinib at 1 μM concentration and ciclosporin (200 ng/mL) reduced the spontaneous IL‐2, IL‐15 and IFN‐γ secretion from spontaneously growing T cells; however, the treatments did not demonstrate significant changes.…”

Efficacy of tofacitinib in treatment of alopecia universalis in two patients

“…As tofacitinib relies on a small molecule mechanism, the idea of a topical delivery is logistically feasible. A topical version of tofacitinib has previously been investigated for the treatment of plaque psoriasis dry eyes and allergic contact dermatitis …”

Emerging Treatment Options in Atopic Dermatitis: Topical Therapies

“…Several pharmaceutical agents targeting this group of tyrosine kinases (comprising TYK2, JAK1, JAK2, and JAK3) are being evaluated in patients with AD both as systemic and topical therapies. The small size of the JAK inhibitors makes them suitable for topical use, and this is in part substantiated by a recent study demonstrating great antipruritic and anti-inflammatory effects from topically administered tofacitinib and oclacitinib in a mouse model of allergic dermatitis [41]. Tofacitinib Tofacitinib (NCT02001181) is approved for rheumatoid arthritis and has previously been investigated in a range of dermatological conditions like psoriasis, alopecia areata, and systemic lupus erythematosus.…”