JAK3 as an Emerging Target for Topical Treatment of Inflammatory Skin Diseases

Abstract

The recent interest and elucidation of the JAK/STAT signaling pathway created new targets for the treatment of inflammatory skin diseases (ISDs). JAK inhibitors in oral and topical formulations have shown beneficial results in psoriasis and alopecia areata. Patients suffering from other ISDs might also benefit from JAK inhibition. Given the development of specific JAK inhibitors, the expression patterns of JAKs in different ISDs needs to be clarified. We aimed to analyze the expression of JAK/STAT family members in a set of prevalent ISDs: psoriasis, lichen planus (LP), cutaneous lupus erythematosus (CLE), atopic dermatitis (AD), pyoderma gangrenosum (PG) and alopecia areata (AA) versus healthy controls for (p)JAK1, (p)JAK2, (p)JAK3, (p)TYK2, pSTAT1, pSTAT2 and pSTAT3. The epidermis carried in all ISDs, except for CLE, a strong JAK3 signature. The dermal infiltrate showed a more diverse expression pattern. JAK1, JAK2 and JAK3 were significantly overexpressed in PG and AD suggesting the need for pan-JAK inhibitors. In contrast, psoriasis and LP showed only JAK1 and JAK3 upregulation, while AA and CLE were characterized by a single dermal JAK signal (pJAK3 and pJAK1, respectively). This indicates that the latter diseases may benefit from more targeted JAK inhibitors. Our in vitro keratinocyte psoriasis model displayed reversal of the psoriatic JAK profile following tofacitinib treatment. This direct interaction with keratinocytes may decrease the need for deep skin penetration of topical JAK inhibitors in order to exert its effects on dermal immune cells. In conclusion, these results point to the important contribution of the JAK/STAT pathway in several ISDs. Considering the epidermal JAK3 expression levels, great interest should go to the investigation of topical JAK3 inhibitors as therapeutic option of ISDs.

Treatment of alopecia universalis with topical Janus kinase inhibitors – a double blind, placebo, and active controlled pilot study

“…It may be beneficial to study the effect of topical JAK inhibitors with separate placebo and treatment groups in order to investigate the individual effect of each medication. Additionally, the depigmented regrowth we observed has been previously documented elsewhere in AA patients …”

“…Tofacitinib in a dose of 5 mg twice daily orally has been shown in phase II clinical trials to be effective in the treatment of psoriasis and atopic dermatitis . Tofacitinib 2% ointment applied twice daily and ruxolitinib 1% ointment applied twice daily have both been examined in phase I clinical trials in the treatment of psoriasis, and tofacitinib intraocular eye drops have been trialed for the treatment of iritis.…”

Efficacy and safety of topical JTE-052, a Janus kinase inhibitor, in Japanese adult patients with moderate-to-severe atopic dermatitis: a phase II, multicentre, randomized, vehicle-controlled clinical study

“…JTE‐052 has been shown to inhibit all the types of JAK enzymes (JAK1, JAK2, JAK3 and tyrosine kinase 2) . In AD, JAK1, JAK2 and JAK3 are overexpressed, and various JAK‐related cytokines such as IL‐4, IL‐5, IL‐13, IL‐31 and TSLP play important roles in the pathophysiology of AD . Additionally, the efficacy of JAK inhibitors seen in patients with AD may be attributed to the improving effect on skin barrier dysfunction, as well as the anti‐inflammatory effect, given the involvement of IL‐4 and IL‐13 in keratinocyte differentiation, and the promoting effect of JTE‐052 on the production of keratinocyte proteins such as filaggrin …”

JAK inhibitors in dermatology: The promise of a new drug class

“…Preclinical data suggests that JAK inhibition may be a viable strategy to treat multiple other dermatoses including: allergic contact dermatitis 63,64 , inferface dermatoses including lichen planus 65–67 , B cell mediated disorders 68 , pyoderma gangrenosum 67 , chronic cutaneous lupus 67 , and eosinophil related disorders 69,70 . There is a compassionate use protocol for JAK1/2 inhibition in rare autoinflammatory syndromes including SAVI (STING associated vasculopathy with onset in infancy), CANDLE (chronic atypical neutrophilic dermatoses with lipodystrophy and elevated temperature) syndrome, and juvenile dermatomyositis (NCT01724580).…”