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

Introduction
The Janus kinase and signal transducer and activator of transcription (JAK-STAT) pathway is utilized by cytokines including interleukins, interferons (IFNs), and other molecules to transmit signals from the cell membrane to the nucleus. Upon engagement of extracellular ligands, intracellular JAK proteins, which associate with type I/II cytokine receptors, become activated and phosphorylate STAT proteins which dimerize and then translocate to the nucleus to directly regulate gene expression1,2 (Figure 1). The JAK family of kinases includes JAK1, JAK2, JAK3, and TYK2. Individual JAKs selectively associate with different receptors, but as there are only four JAKs, each member is used by multiple different receptors. The same is true of STATs, of which there are seven family members (STAT1, STAT2, STAT3, STAT4, STAT5a, STAT5b, and STAT6)1,2.
Many inflammatory cytokines and other signaling molecules rely on JAK-STAT signaling, which is indispensable for immune and hematopoietic function. For example, loss-of-function mutations in JAK3 cause severe combined immunodeficiency syndrome (SCID)3,4. Gain-of-function mutations in JAKs act as oncogenes in lymphoproliferative disorders and hematologic malignancies, including cutaneous T cell lymphoma5–7. STAT genes are also essential for proper immune function and loss-of-function mutations in these proteins can be associated with immunodeficiency syndromes, including Job’s syndrome in the case of STAT38. Certain JAK-STAT polymorphisms are associated with an increased risk of developing autoimmune diseases1. In sporadic autoimmune and autoinflammatory conditions, a variety of disease causing cytokines rely on JAK-STAT signaling in order to elicit their pathogenic effect1,2. Together these observations have led to the development of JAK inhibitors for the treatment of human disease9.
The first generation of JAK inhibitors includes tofacitinib, ruxolitinib, baricitinib, and oclacitinib (Table I). Ruxolitinib is FDA approved to treat myelodysplastic disorders. Baricitinib is not yet FDA approved, but is in clinical trials for rheumatoid arthritis (RA) (Phase 3)10, psoriasis (Phase 2)11, and atopic dermatitis (Phase 2, NCT02576938). The first FDA-approved JAK inhibitor for treatment of an autoimmune disease was tofacitinib, although it was initially studied as an anti-rejection agent in organ transplantation12. Oclacitinib has no FDA-approved indication in humans and is used for treatment of atopic dermatitis (AD) in dogs13,14. Second generation JAK inhibitors are in development and will be discussed further below.
In the past 3 years it has become clear that in addition to psoriasis there are other inflammatory dermatologic conditions for which JAK inhibitors might be useful. Many dermatologically relevant cytokines rely on the JAK-STAT pathway and include: IFN-α/β, IFN-γ, IL-2 receptor common γ-chain interleukins (IL-2, IL-4, IL-7, IL-9, IL-15, and IL-21), and IL-5, IL-6, IL-12, IL-13, and IL-23 (Table II). Although other cytokines such as TNF-α, IL-1, and IL-17 do not signal via the JAK-STAT pathway, in some instances JAK inhibitors can indirectly suppress these cytokines (i.e. IL-17) by inhibition of other STAT-dependent cytokines (i.e. IL-23) that act upstream1,15,16.
To date, JAK inhibitors have shown efficacy in the treatment of dermatologic conditions such as AD, alopecia areata (AA), psoriasis, and vitiligo, among others. Both new oral JAK inhibitors and topical JAK inhibitors are being developed and studied in these and other dermatologic conditions. Smaller case series and case reports suggest efficacy in dermatomyositis, chronic actinic dermatitis, erythema multiforme, hypereosinophilic syndrome, cutaneous graft-versus-host disease, and lupus, among others. Preclinical data suggests that the usefulness of JAK inhibitors may be even broader than these early clinical studies suggest.

Atopic dermatitis
The pathogenesis of AD is complex, but is in part the result of increased Th2 immunity driven by JAK-STAT signaling downstream of cytokines such as IL-4, IL-5, and IL-1317. In experimental models, tofacitinib and oclacitinib inhibit IL-4 and IL-13 dependent Th2 differentiation14,15,18. In a mouse model of AD, a topical JAK inhibitor, JTE-053, resulted in decreased IL-4 and IL-13 signaling and improved skin barrier19.
The efficacy of oral tofacitinib was recently reported in 6 consecutive patients with moderate-to-severe AD that had failed all common treatments, including systemic agents20. Tofacitinib 5mg daily or twice daily led to a 66.6% reduction in the Severity Scoring of AD Index (SCORAD) and a 69.9% reduction in pruritus and sleep loss scores20. While this study lacked a control group, the improvement achieved by 6 patients who had failed common therapies was suggestive of a positive benefit of tofacitinib.
A recently published randomized, double-blind, placebo-controlled phase 2a trial showed that treatment of 69 adults with mild-to-moderate AD with tofacitinib 2% ointment resulted in an 81.7% reduction in the Eczema Area and Severity Index (EASI) score at 4 weeks, relative to a decrease of 29.9% in the placebo group21. Additional clinical trials evaluating both oral and topical JAK inhibitors for AD are underway (NCT02001181, NCT02576938, NCT02780167) and will help to define the efficacy of JAK inhibitors in AD.

Alopecia areata
The pathogenesis of AA involves hair follicle attack by autoreactive CD8 T cells22. In AA, JAK-STAT dependent cytokines including IFN-γ and IL-15 drive proliferation and activation of autoreactive T cells22, 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 regrowth23.
In 2014, a patient with both alopecia universalis (AU) and psoriasis was treated with tofacitinib, and complete regrowth of scalp and body hair as well as eyelashes and eyebrows occurred within 8 months24. Since then, 2 open-label clinical trials have been published in addition to case series of adolescent and adult patients and case reports (Table II). In one trial, tofacitinib 5mg twice daily was given to 66 patients with severe AA, alopecia totalis (AT), or AU. After the 3-month treatment period, nearly two-thirds of patients showed some hair regrowth and 32% of patients achieved a >50% improvement in their Severity of Alopecia Tool (SALT) score25. In the second study, treatment of 12 patients with moderate-to-severe AA with ruxolitinib 20mg twice daily for 3–6 months resulted in a marked treatment response in 9 patients, with an average of 92% hair regrowth26. Hair loss appears to recur with treatment discontinuation25,26.
Recently, 2 retrospective studies showed successful treatment of severe AA, AT, and AU over a period up to 18 months using tofacitinib. In 65 adults with either AT/AU with duration of current episode ≤ 10 years or severe AA, 77% of patients achieved some hair regrowth, with 58% achieving >50% improvement and 20% achieving >90% improvement in SALT score. Hair regrowth was attenuated in patients with AT/AU with duration >10 years27. In a series of adolescents (12–17 years old) with severe AA, AT, and AU treatment with tofacitinib resulted in a 93% median change in SALT score from baseline after an average of 6.5 months of treatment28. Although these studies lacked a control group, because there is a low likelihood of spontaneous improvement in patients with long-standing and severe disease, the results are very promising.
In 3 patients with AU and nail dystrophy, tofacitinib 5mg twice daily for 5–6 months resulted in remission of nail dystrophy29. The use of oral JAK inhibitors in AA remains an active area of clinical investigation.
As in AD, topical JAK inhibitors are under investigation in AA. In one report, a patient treated with compounded ruxolitinib 0.6% cream applied twice daily for 12 weeks to the eyebrows and scalp led to complete eyebrow regrowth and partial scalp hair regrowth30. Clinical trials with topical ruxolitinib (INCB018424) and topical tofacitinib are presently underway in AA (NCT02553330, NCT02812342).

Psoriasis
JAK-STAT-dependent cytokines IL-12 and IL-23 are fundamental mediators of psoriasis31,32. 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-1715,31. To date, in dermatology, psoriasis has been the most heavily studied indication for JAK inhibitors. JAK inhibitor use in psoriasis has recently been more extensively reviewed32, but will be briefly reviewed here.
The efficacy of tofacitinib in moderate-to-severe plaque psoriasis was shown in phase 3 randomized controlled trials33,34. In one of the studies, the PASI 75 response to tofacitinib at 12 weeks was 39.5% and 63.6% in the 5mg twice daily and 10mg twice daily groups, respectively34. Tofacitinib at 10mg twice daily dosing was determined to be non-inferior to etanercept therapy (50mg subcutaneously twice weekly)34. Rates of adverse events appeared to be similar in both the 5mg and 10mg dosing regimens33,34. Comparable results were present in the other trial33. The FDA has yet to approve tofacitinib for this indication.
Baricitinib, still in clinical trials and not yet FDA approved for any condition, was recently reported to be efficacious in moderate-to-severe plaque psoriasis in a phase 2b trial11. In this 12 week dose ranging study, patients treated with 8mg and 10mg once daily achieved PASI 75 responses of 43% and 54% respectively11.
The use of topical JAK inhibitors has been explored in psoriasis. Ruxolitinib (INCB018424) 1.0% and 1.5% creams applied twice daily led to reduction in psoriasis lesion size over 4 weeks35. Improvement in psoriasis was also observed with tofacitinib 2% ointment; however, the degree of improvement relative to controls was modest and not always statistically significant36,37.

Vitiligo
Vitiligo is mediated by targeted destruction of melanocytes by CD8 T cells, with IFN-γ playing a central role in disease pathogenesis38,39. IFN-γ signaling utilizes the JAK-STAT pathway, and therefore vitiligo may 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 months40; however, depigmentation recurred after discontinuing tofacitinib. In another report, a patient who had both vitiligo and AA was treated with ruxolitinib 20mg twice daily and over 20 weeks experienced significant facial repigmentation; depigmentation recurred after discontinuing ruxolitinib41.
A pilot study involving 12 patients with vitiligo is underway investigating the efficacy of ruxolitinib 1.5% cream applied twice daily (NCT02809976). Larger controlled studies will be important for elucidating the role of JAK inhibitors in the treatment of vitiligo.

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 RA and psoriasis42–45, and data for ruxolitinib are from clinical trials in myelofibrosis and polycythemia vera46–48.
The risk of infection and overall mortality in patients treated with tofacitinib is not significantly different from that observed with other targeted immunosuppressive therapies42–44. With ruxolitinib, the most common infection was urinary tract infection46,48. With both tofacitinib and ruxolitinib, there is increased risk of varicella zoster virus reactivation46,48,49, usually limited to localized disease. Impaired response to vaccination has been reported with tofacitinib and is theoretically a risk with ruxolitnib, too. Therefore, when possible, immunizations should be performed prior to initiating therapy with JAK inhibitors1,50.
Increases in total cholesterol, LDL cholesterol, and HDL cholesterol have been reported with tofacitinib and ruxolitinib therapy, but are typically mild1,45,51,52. Patients treated with JAK inhibitors do not appear to have an increased risk of major adverse cardiac events or stroke42,45,53,54.
Cytopenias are another potential adverse effect of JAK inhibitors, primarily JAK2 inhibition, because signaling via JAK2 is utilized by erythropoietin, thrombopoietin, and G-CSF1. Accordingly, cytopenias are more commonly encountered with ruxolitinib than tofacitinib due to its greater inhibition of JAK2. In the treatment of bone marrow disorders with ruxolitinib, thrombocytopenia, in particular, can be dose limiting55, but in a study of 12 patients with AA treated with ruxolitinib 20mg twice daily for up to six months, neither this nor other cytopenias were observed26. It may be that patients with healthy bone marrows are less vulnerable to the cytopenias observed with JAK2 inhibition.
A concern with JAK inhibitors is a theoretical increased risk of malignancy, because immunosuppression could dampen anti-tumor immune surveillance. Initial studies of tofacitinib in renal transplantation showed that ~1% of patients treated with tofacitinib developed post-transplant lymphoproliferative disorder56–58. However, in these studies patients were treated with higher doses of tofacitinib (10–30mg twice daily) and in combination with other immunosuppressive agents, i.e. IL-2R anatagonists, mycophenolate mofetil, and corticosteroids. An increased risk of lymphoproliferative disorders and other cancers has not been apparent when tofacitinib is used to treat inflammatory disorders such as RA and psoriasis42,45,59,60; longer term studies, however, will more definitively answer this question. In patients with myelofibrosis and polycythemia vera treated with ruxolitinib, no increased risk of developing a second malignancy has been shown61,62.

Use of JAK inhibitors
The FDA approved dose for tofacitinib in RA is 5mg twice daily. A new extended release formulation (11mg once daily) is also available. In psoriasis clinical trials, tofacitinib 10mg twice daily was more efficacious than 5mg twice daily and adverse events did not seem to be different with the higher dose33,34. Based on the current literature, for treating inflammatory disorders of the skin, 5mg twice daily is often sufficient, but 10mg twice daily is sometimes required. Dose reduction is required with severe renal impairment, moderate hepatic impairment, or with the use of medications such as fluconazole and ketoconazole, which inhibit CYP3A4 and CYP2C9.
The FDA approved dose of ruxolitinib for myelofibrosis and polycythemia vera ranges from 5mg to 25mg twice daily. 20mg twice daily was used in the open-label clinical trial in AA26. As with tofacitinib, dose adjustment is required in the setting of concomitant CYP3A4 and CYP2C9 inhibitors, as well as with hepatic and renal impairment.
Prior to treatment with tofacitinib or ruxolitinib, serologic screening is recommended and includes complete blood count (CBC), creatinine and hepatic function panel (LFTs), and fasting lipid panel together with hepatitis B, hepatitis C, and tuberculosis testing. We also suggest screening for HIV. Subsequently, monitoring CBC, creatinine, LFTs, and fasting lipid panel after 1 month of treatment and then every 3 months thereafter is recommended. Tuberculosis screening should be performed annually.

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 may be a viable strategy to treat multiple other dermatoses including: allergic contact dermatitis63,64, inferface dermatoses including lichen planus65–67, B cell mediated disorders68, pyoderma gangrenosum67, chronic cutaneous lupus67, and eosinophil related disorders69,70. 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).
Presently at least 25 separate clinical trials are underway to evaluate the use of JAK inhibitors in a variety of autoimmune and inflammatory diseases1. A new generation of JAK inhibitors, including both pan-JAK inhibitors (JAK1, JAK2, JAK3, and TYK2) and selective JAK inhibitors (i.e. JAK1 only or JAK3 only), are being developed2,71–78. The advent of JAK inhibitors in dermatology has been met with significant excitement. This class of medications has the potential to significantly advance the treatment of inflammatory dermatoses.