Janus Kinase and Tyrosine Kinase Inhibitors in Dermatology

A Review of Their Utilization, Safety Profile and Future Applications

Mojahed M.K. Shalabi, BS; Benjamin Garcia, BS; Kendall Coleman, BS; Alfredo Siller Jr., MD; Austinn Miller, MD; Stephen K. Tyring, MD, PhD

Disclosures

Skin Therapy Letter. 2022;27(1):4-9. 

In This Article

Applications in Dermatology

JAK inhibitors have shown significant clinical efficacy in patients with psoriasis and psoriatic arthritis.[1] Currently, the FDA-approved JAK inhibitors in dermatology are oral tofacitinib and upadacitinib for the treatment of psoriatic arthritis[1,2] and topical ruxolitinib for mild to moderate atopic dermatitis. However, the use of first and second generation JAK inhibitors in other dermatological diseases such as alopecia areata, atopic dermatitis, dermatomyositis, vitiligo, and systemic lupus erythematosus is being heavily investigated in numerous clinical trials (Table 1).[13]

Alopecia Areata (AA)

AA is a chronic, autoimmune non-scarring hair loss disorder that involves the destruction of hair follicles by autoreactive CD8 T cells.[3] It classically presents as smooth, circular hair loss patches with no erythema, pain, pruritus, or inflammation. JAK-STAT dependent cytokines IFN-γ and IL-15 contribute to signaling cascades through JAK1 and JAK3.[3] They lead to the proliferation of autoreactive T cells that are active in AA.

Systemic and topical administration of JAK inhibitors have shown to be beneficial in patients with AA. In 2014, a case report was published featuring a patient with diagnosed alopecia universalis and psoriasis. While using tofacitinib to treat psoriasis, the patient experienced complete regrowth of body and scalp hair, as well as eyelashes and eyebrows.[4] Since then, several other case reports and studies have been published illustrating the successful treatment of AA using JAK inhibitors (primarily tofacitinib, ruxolitinib, and baricitinib).[5–8,10] However, relapse of hair loss has been reported in the literature after drug discontinuation.[9] In a recent phase II trial, ritlecitinib and brepocitinib were found to be well tolerated and led to clinically meaningful improvements in hair growth. Approximately 25% and 34% of patients treated with ritlecitinib and brepocitinib, respectively, saw near-complete regrowth.[16] Topical JAK inhibitors for the treatment of localized AA could be proven useful, but more studies are needed for validation. In the case of topical tofacitinib, one pilot study of patients treated with 2% tofacitinib twice daily revealed a poor response with only 3 responders.17Another study describes almost complete regrowth of hair with topical 2% tofacitinib every 12 hours for 7 months.[17] Topical ruxolitinib has also shown various responses in AA, with one study showcasing regrowth at 28 weeks in 5 patients in the area treated. In adolescent patients, topical ruxolitinib 0.6% applied twice daily showed complete growth of the eyebrows observed at 3 months, while there was only 10% regrowth of the scalp.[17] Currently, positive results from numerous early phase clinical trials have increased interest in this area. Further investigation is needed to determine optimal dosing of JAK inhibitors in AA and whether maintenance therapy is required.

Psoriasis and Psoriatic Arthritis

Psoriasis has been the most studied dermatological disease in relation to JAK inhibitors. JAK-STAT dependent cytokines are implicated in the pathogenesis of psoriasis, with IL-12 and IL-23 being fundamental mediators.[11] Several phase III randomized controlled clinical trials have shown significant reduction, up to 75%, in the Psoriasis Area and Severity Index (PASI 75) when patients were treated with tofacitinib at both 5 mg and 10 mg twice daily doses, with improvement seen in a dose dependent manner.[12] Improvements from the treatment were sustained up to 52 weeks and side effects appeared to be similar in both dosing regimens. Furthermore, a phase III non-inferiority trial determined that tofacitinib at 10 mg twice daily was non-inferior to etanercept 50 mg twice weekly.[14] Nevertheless, the FDA did not approve tofacitinib for psoriasis, likely attributable to the need for more safety data on the 10 mg dose.

Several other JAK inhibitors have demonstrated promising results. A phase IIb clinical trial of baricitinib showed more patients achieved PASI 75 when compared to placebo in the treatment of moderate-to-severe plaque psoriasis.18 Deucravacitinib, a novel, selective TYK2 inhibitor has demonstrated to be more advantageous in the treatment of moderate-to-severe plaque psoriasis when compared to placebo and apremilast in a phase III clinical trial.[19] Patients achieved PASI 75 after 16 weeks of treatment, with the overall safety of the drug being consistent with previous results.[19]

As opposed to systemic therapy, medications administered topically generally have more favorable safety profiles given less systemic absorption. Topical formulations of ruxolitinib and tofacitinib have been tested in phase II clinical trials for psoriasis.[20] Side effects in both these trials were mild and there were no signs of systemic symptoms in any of the patients. Treatment with topical ruxolitinib twice daily showed improvement in psoriasis lesion size compared with placebo.[21] Improvement in psoriasis was also noted in patients treated with topical tofacitinib. Discontinuation of the topical drugs led to worsening of psoriasis.[20]

Tofacitinib was FDA-approved in December 2017 for the treatment of patients with psoriatic arthritis who have had little to no improvement in their symptoms using methotrexate or other disease-modifying antirheumatic drugs.[13] The decision was based on the results of two phase III clinical trials that showed statistically significant improvements in American College of Rheumatology 20 (ACR 20) response at 3 months when patients were treated with tofacitinib 5 mg and 10 mg twice daily.[13] In a recent 24-week, phase III trial, oral upadacitinib was assigned to patients with psoriatic arthritis at a dose of 30 mg or 15 mg once daily, while other patients received either placebo or subcutaneous adalimumab 40 mg every other week. Results showed that the ACR 20 response rate was significantly higher for patients receiving the two doses of upadacitinib versus placebo. Furthermore, only the 30 mg dose of upadacitinib was shown to be superior to adalimumab.[22]

Atopic Dermatitis

Atopic dermatitis (AD) is one of the most common, chronic and pruritic inflammatory skin diseases. The pathogenesis of this disease is fueled by functional impairment of the epidermal barrier and abnormal immune activation. IL-4 is one of the main culprits in AD known to play a pivotal role in signaling through the JAK-STAT pathway.[1,14]

Oral tofacitinib was reported to be efficacious in 6 patients with moderate-to-severe refractory AD. Tofacitinib 5 mg twice daily or daily for 14 weeks led to a decrease in the average Severity Scoring of Atopic Dermatitis (SCORAD) index by approximately 55%.[23] Moreover, the study reported significant reduction in pruritus scores as well. A recently published, randomized, double-blinded, placebo-controlled phase III clinical trial showed that the treatment of moderate-to-severe AD with oral abrocitinib resulted in greater reductions in signs and symptoms of the disease, as well as greater itch response when compared to dupilumab and placebo.[24] Abrocitinib's pending FDA approval has been delayed for an unspecified amount of time as data analysis continues.[25] In multiple phase III clinical trials, upadacitinib has been shown to improve skin and itch symptoms in adolescent and adult patients with moderate-tosevere AD.[26,27]

Topical JAK-STAT treatments such as tofacitinib, ruxolitinib and delgocitinib have also shown promise in the treatment of AD, with topical delgocitinib being approved in Japan under the trade name Corectim® and topical ruxolitinib (Opzelura™) receiving FDA approval for mild to moderate AD.[28] Topical tofacitinib 2% every 12 hours in 69 patients with mild to moderate AD for 4 weeks led to an 81.7% reduction in Eczema Area and Severity Index score after 4 weeks.[28] Topical ruxolitinib was also found to have a therapeutic benefit for patients by week 4 with each variant of ruxolitinib regimen; the drug rapidly improved pruritus and was well tolerated.[28] Phase I and phase II studies of delgocitinib proved the therapeutic efficiency of the medication with respect to severity and pruritus, with pruritus improving 1 day after initiating treatment.[28]

Evidence for clinical efficacy of JAK inhibitors in the treatment of AD has been shown in several other phase II and III clinical trials, forging a possible future when these drugs may become mainstay therapy for the disease.[29–32]

Dermatomyositis

Dermatomyositis is an autoimmune myopathy that is characterized by symmetric proximal muscle weakness and rash. Pathogenesis of the disease is mediated by CD4 lymphocytes and complement activation. There have been several reported cases demonstrating the efficacy of JAK inhibitors in treatmentrefractory dermatomyositis.[33–36] A case series of three patients treated with tofacitinib reported that they had improved significantly in their Cutaneous Dermatomyositis Disease Area and Severity Index (CDASI) activity score.[35]

Additionally, one case reported a patient with myelofibrosis and concomitant refractory dermatomyositis who improved significantly while on ruxolitinib.[33] Nonetheless, it is unknown whether the improvement of the patient's dermatomyositis was an indirect effect of treating myelofibrosis or a direct effect of ruxolitinib-mediated JAK inhibition. Furthermore, another case report of a patient with dermatomyositis experienced significant improvement in her cutaneous disease, arthritis, and muscle strength while being treated with tofacitinib.[36]

Vitiligo

Vitiligo is an autoimmune condition characterized by absence of pigmentation due to loss of melanocytes. While the exact etiology of the disease is unknown, evidence from literature has shown that the destruction of melanocytes is mediated by CD8 T cells.[1,37] As with AA, IFN-γ plays a vital role in the pathogenesis of vitiligo, thus making this disease susceptible to treatment with JAK inhibitors.[1] For example, a patient with generalized vitiligo showed near complete repigmentation of areas in the hands, forearms, and face over 5 months while on tofacitinib.[38] However, discontinuation of the drug led to depigmentation in affected areas.[38]

An additional case report of a patient with both AA and vitiligo experienced hair regrowth and repigmentation while being treated with ruxolitinib.[39] As is the case with the previous patient mentioned, depigmentation occurred with discontinuation of the drug. Currently, topical ruxolitinib is in a phase 3 clinical trial to evaluate its efficacy and safety in treatment of vitiligo.[40] Clinical trials are vital for clarifying the role of JAK inhibitors in the treatment of vitiligo.

Other Dermatologic Conditions

There is evidence from the literature suggesting that JAK inhibitors are efficacious in the treatment of refractory dermatologic cases or rare diseases with no effective therapies – chronic mucocutaneous candidiasis, cutaneous sarcoidosis, mastocytosis, polyarteritis nodosa, hypereosinophilic syndrome, and chronic actinic dermatitis. Data from case reports and case series hints at potential broader use for JAK inhibitors in the field of dermatology.[1–2,41]

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