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

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New molecularly targeted therapeutics are changing dermatologic therapy. Janus kinase–signal transducer and activator of transcription (JAK-STAT) is an intracellular signaling pathway upon which many different proinflammatory signaling pathways converge. Numerous inflammatory dermatoses are driven by soluble inflammatory mediators, which rely on JAK-STAT signaling, and inhibition of this pathway using JAK inhibitors might be a useful therapeutic strategy for these diseases. Growing evidence suggests that JAK inhibitors are efficacious in atopic dermatitis, alopecia areata, psoriasis, and vitiligo. Additional evidence suggests that JAK inhibition might be broadly useful in dermatology, with early reports of efficacy in several other conditions. JAK inhibitors can be administered orally or used topically and represent a promising new class of medications. The use of JAK inhibitors in dermatology is reviewed here.

Section snippets

Atopic dermatitis

The pathogenesis of AD is complex but in part involves increased helper T cell type 2 (TH2) immunity driven by JAK-STAT signaling downstream of cytokines, such as IL-4, IL-5, and IL-13.57 In experimental models, tofacitinib and oclacitinib inhibit IL-4 and IL-13–dependent TH2 differentiation.14, 55, 58 In a mouse model of AD, a topical JAK inhibitor, JTE-053, resulted in decreased IL-4 and IL-13 signaling and improved skin barrier function.59

The efficacy of oral tofacitinib was recently

Alopecia areata

The pathogenesis of AA involves hair follicle attack by autoreactive CD8+ T cells.60 In AA, JAK-STAT dependent cytokines, including IFN-γ and IL-15, drive proliferation and activation of autoreactive T cells,60 suggesting that JAK inhibition might be an effective treatment. In a mouse model of AA, both systemic and topical JAK inhibitors (tofacitinib and ruxolitinib) promoted hair regrowth.26

In 2014, a patient with both alopecia universalis (AU) and psoriasis was treated with tofacitinib, and

Psoriasis

JAK-STAT–dependent cytokines IL-12 and IL-23 are fundamental mediators of psoriasis.61, 62 IL-23 stimulates TH17 cells to produce IL-17, another important pathogenic molecule in psoriasis. Although IL-17 does not rely on JAK-STAT signaling, blockade of upstream IL-23 using JAK inhibitors such as tofacitinib indirectly results in a decrease in IL-17.55, 61 To date, in dermatology, psoriasis has been the most heavily studied indication for JAK inhibitors. JAK inhibitor use in psoriasis has

Vitiligo

Vitiligo is mediated by targeted destruction of melanocytes by CD8+ T cells, with IFN-γ playing a central role in disease pathogenesis.63, 64 Because IFN-γ signaling utilizes the JAK-STAT pathway, vitiligo might be susceptible to treatment with JAK inhibitors. For example, treatment of a patient with generalized vitiligo with tofacitinib resulted in near complete repigmentation of affected areas of the face, forearms, and hands over 5 months53; however, depigmentation recurred after

Topical JAK inhibitors

While not commercially available, the use of topical JAK inhibitors has been explored in AD, psoriasis, AA, and vitiligo. Multiple studies are ongoing in this area. The data for topical therapy in each disease are discussed above and summarized in Table II.

Safety data

Safety data for tofacitinib is derived from large clinical trials in rheumatoid arthritis and psoriasis,65, 66, 67, 68 and data for ruxolitinib are from clinical trials in myelofibrosis and polycythemia vera.69, 70, 71

The risk of infection and overall mortality in patients treated with tofacitinib is not significantly different from that observed with other targeted immunosuppressive therapies.65, 66, 67 With ruxolitinib, the most common infection was urinary tract infection.69, 71 With both

Use of JAK inhibitors

The FDA-approved dosage for tofacitinib in rheumatoid arthritis is 5 mg twice daily. A new extended-release formulation (11 mg once daily) is also available. In clinical trials on psoriasis, tofacitinib 10 mg twice daily was more efficacious than 5 mg twice daily and adverse events did not seem to increase with the higher dosage.48, 49 On the basis of the current literature describing treatments for inflammatory skin disorders, 5 mg twice daily is often sufficient but 10 mg twice daily is

Conclusions and future directions

In addition to the conditions already discussed, JAK inhibitors have shown promise in multiple other dermatologic diseases, including dermatomyositis, chronic actinic dermatitis, erythema multiforme, hypereosinophilic syndrome, cutaneous graft-versus-host disease, and lupus, among others (Table II). Preclinical data suggests that JAK inhibition might be a viable strategy to treat multiple other dermatoses, including allergic contact dermatitis86, 87 and interface dermatoses, such as lichen

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    Funding sources: Dr King received funding support from The Ranjini and Ajay Poddar Resource Fund for Dermatologic Diseases Research.

    Conflicts of interest: Dr King has served on advisory boards or is a consultant for Aclaris Therapeutics Inc, Pfizer Inc, Eli Lilly and Company, and Concert Pharmaceuticals Inc. Dr Damsky has no conflicts of interest to declare.

    Reprints not available from the authors.

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