Mojahed M.K. Shalabi, BS1*; Benjamin Garcia, BS2*; Kendall Coleman, BS3; Alfredo Siller Jr., MD4; Austinn Miller, MD4; Stephen K. Tyring, MD, PhD5

1Texas A&M College of Medicine, Dallas, TX, USA
2University of Texas Medical Branch, Galveston, TX, USA
3University of Texas Health Science Center McGovern Medical School, Houston, TX, USA
4Center for Clinical Studies, Webster, TX, USA
5Department of Dermatology, University of Texas Health Science Center, Houston, TX, USA

Conflict of interest:
None.

Funding resource:
None.

*Co-first authors

Abstract:
Janus kinase inhibitors, also commonly referred to as JAK inhibitors, are a novel drug class that target and block cytokine signaling mediated by the Janus kinase-signal transducer and activator of transcription (JAK-STAT) pathway, thereby regulating immune response and cell growth. Although JAK inhibitors are mainly used for rheumatological conditions such as rheumatoid arthritis, their application in the field of dermatology is actively being investigated. Tofacitinib is US FDA-approved for psoriatic arthritis and showing promise for treating psoriasis. Most recently, regulatory approvals for the US were gained by ruxolitinib as a first-in-class, selective, topical therapy for atopic dermatitis and oral upadacitinib for active psoriatic psoriasis. Additionally, abrocitinib and upadacitinib have demonstrated efficacy in atopic dermatitis and are pending FDA approval for this indication. The therapeutic potential of JAK inhibitors in dermatological conditions such as alopecia areata, psoriasis, atopic dermatitis, vitiligo, and dermatomyositis are showing promising results in clinical trials. Adverse events for JAK inhibitors seem to be similar to that of biologic drugs. Common adverse effects include increased risk of infections and thromboembolic events. Further investigation is needed to not only better understand the safety profile of JAK inhibitors, but also their full utility within the field of dermatology.

Key Words:
Janus kinase inhibitors, JAK inhibitors, JAK-STAT, tyrosine kinase inhibitors, TYK2 inhibitors, dermatology, ruxolitinib, abrocitinib, upadacitinib, tofacitinib, baricitinib

Introduction

Autoimmune and inflammatory diseases are common and on the rise, affecting 3% to 5% of the Western population.1-4 These disorders are thought to evolve from a complex, incompletely understood interplay of host genetics, microbiota, and environmental factors that contribute to dysregulated T-cell and B-cell activity against the host, leading to tissue damage.1 In the realm of dermatology, there have been considerable advances enabling examination of deep molecular processes and immunological pattern analyses that allow us to better understand the pathophysiological mechanisms of autoimmune and inflammatory skin diseases.5-8 Furthermore, skin biopsy analysis has facilitated our ability to characterize the influencing factors such as cytokines, receptors, and signaling molecules in order to develop targeted therapeutic agents.5

Various therapeutics can be used to attenuate the immune response either through direct suppression of T-cell activity or by directly or indirectly blocking cytokines. Glucocorticoids have long been used to suppress an aberrant immune response; however, they have the drawback of eliciting nonspecific immunosuppressive effects. Many cells express steroid receptors and adverse effects of glucocorticoids are common, thus their use in the management of chronic autoimmune or inflammatory diseases should be cautioned given their side effect profile.1 Cytokine activity can likewise be inhibited by biologic therapy. Most recently, inhibitors of signaling proteins have been introduced for the treatment of psoriatic arthritis and rheumatoid arthritis.1 These inhibitors target the Janus kinases (JAKs) family of proteins by modulating the inflammatory process through activation of intracytoplasmic transcription factors called signal transducer and activator of transcription (STAT).5 STATs get activated, dimerize, and translocate into the nucleus where they modulate the expression of various genes.

Inflammation of the skin relies on this interaction between cytokines, as well as immune and tissue cells, to propagate the different distinct inflammatory cascades. Because of these unique mechanisms, JAK-STAT inhibitors are gaining traction in clinical development as new potential therapeutics for various inflammatory dermatological conditions.

Aims and Objectives

The aim of this literature review is to provide updates on the mechanism of JAK inhibitors and assess their efficacy in the treatment of alopecia areata, psoriasis, psoriatic arthritis, atopic dermatitis, dermatomyositis, and vitiligo. A class-wide safety review and future considerations will also be discussed.

Methods

A review of the literature regarding the mechanism of action and efficacy of JAK inhibitors in skin diseases was done by searching the PubMed, Scopus, and EBSCO databases. The following keywords were used to find articles: ‘Janus kinase-inhibitors’, ‘JAK-inhibitors’, ‘JAK-inhibitors pathway’ combined with ‘dermatology’, ‘atopic dermatitis’, ‘alopecia areata’, ‘psoriasis’, ‘dermatomyositis’, ‘vitiligo’, ‘side effects’, and ‘safety’.

JAK-STAT Signaling Pathway

The JAK-STAT pathway is activated by numerous different cytokines, which bind directly to the Janus kinase receptor and initiate transphosphorylation. This ligand-mediated receptor binding brings two JAKs in close proximity, allowing for its autophosphorylation and activation. The activated JAKs subsequently lead to the phosphorylation of the tyrosine residues on the receptor. The phosphorylation of the tyrosine residues on the receptor recruits STATs, inactive latent transcription factors in the cytoplasm. Using their SH2 domain, the STATs bind to the phosphorylated tyrosine residue on the receptor and are phosphorylated by JAKs. This causes the STATs to dissociate from the receptor, dimerize, and travel from the cytosol into the nucleus where they are able to modify gene transcription.9 There are four members within the JAK family of kinases (JAK1, JAK2, JAK3, and tyrosine kinase 2 [TYK2]), and the STAT family has six proteins (STAT1, STAT2, STAT3, STAT5A/B and STAT6).10

One or more members of the JAK and STAT families may be recruited by any specific receptor influencing different aspects of immune cell development and function.11 Various combinations of different types of JAK proteins can be associated with several receptors that have variable effects on specific signaling pathways of the immune system, such as the combination of JAK1 and JAK3 related to cytokine receptors fundamental for the function of lymphocytes or the TYK2/JAK2 combination that is essential for the signaling of interferon (IFN)-a, interleukin (IL)-12, and IL-23 receptors.11 The varied distribution amongst different JAK/STAT proteins across distinct cell types shows how a genetic defect of JAKs or STATs might determine various clinical conditions, such as JAK3 deficiency in severe combined immunodeficiency syndrome.11 Additionally, the modulation or inhibition of the activity of these intracellular pathways represents a potential target in immune mediated diseases such as psoriasis and atopic dermatitis.11,12

The mechanism of action of JAK inhibitors targets the kinase component of JAKs. This prevents the JAK protein from phosphorylating, thus halting the intracellular signaling transduction.1 First generation JAK inhibitors, such as baricitinib, ruxolitinib, and tofacitinib, inhibit many JAKs. For example, tofacitinib, which is FDA-approved for psoriatic arthritis, inhibits JAK1 and JAK3 mainly, with some selectivity towards the JAK2 isoform.13 The rationale behind the nonselective, multi-JAK inhibition is the notion that blocking multiple JAKs may enhance therapeutic efficacy.14 On the other hand, the second generation JAK inhibitors are more selective to particular JAK isoforms to limit adverse effects and possibly maintain treatment efficacy. Deucravacitinib is a second generation JAK inhibitor that specifically targets TYK2.13-15 This drug has shown efficacy in the treatment of systemic lupus erythematosus and is currently in a phase III trial for psoriasis.1 Research into the efficacy of JAK inhibitors continues at a rapid pace as a host of new drug candidates are under development, thus shedding light on their mechanisms in treating rheumatological and dermatological diseases.

Janus Kinase and Tyrosine Kinase Inhibitors in Dermatology: A Review of Their Utilization, Safety Profile and Future Applications - image
Figure 1: The JAK-STAT signaling pathway using IL-4 and IL-2 as an example. The cytokine will attach to the membrane receptor, which causes the phosphorylation of JAK1/JAK3 residues; subsequently, STATs get recruited and are phosphorylated by JAK. This leads to dimerization of STATs, their translocation into the nucleus and finally their effects on the activation of various genes. Created with BioRender.com.

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 arthritis1,2 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

DrugGenerationTargetStatusDermatologic Conditions
Ruxolitinib1stJAK1, JAK2Phase II
Phase III
Phase II
Phase III
FDA-approved		Alopecia areata
Vitiligo (topical)
Psoriasis (topical)
Graft-versus-host disease
Atopic dermatitis (topical)
Tofacitinib1stJAK3, JAK1, JAK2 (with less
selectivity)		Phase I
Phase II
Phase III
Phase IV
FDA-approved		Dermatomyositis
Atopic dermatitis (topical)
Psoriasis
Alopecia areata
Psoriatic arthritis
Baricitinib1stJAK1, JAK2Phase II
Phase II
Phase III
Phase III		Psoriasis
Graft-versus-host disease
Systemic lupus erythematosus
Atopic dermatitis
Oclacitinib1stJAK1FDA-approvedCanine allergic dermatitis
Upadacitinib2ndJAK1Phase III
FDA-approved		Atopic dermatitis
Active psoriatic arthritis
Itacitinib2ndJAK1, JAK2Phase II
Phase II		Psoriasis
Graft-versus-host disease
Filgotinib2ndJAK1Phase II
Phase II		Psoriatic arthritis
Cutaneous lupus erythematosus
Abrocitinib2ndJAK1Phase IIIAtopic dermatitis
INCB547072ndJAK1Phase IIHidradenitis suppurativa
Deucravacitinib2ndTYK2Phase II Phase II Phase IIISystemic lupus erythematosus
Psoriatic arthritis
Psoriasis
Ritlecitinib2ndJAK3Phase II Phase IIIVitiligo
Alopecia areata
Brepocitinib2ndJAK1, TYK2Phase II
Phase II
Phase II
Phase II Phase II Phase II		Vitiligo
Systemic lupus erythematosus
Atopic dermatitis (topical)
Alopecia areata Psoriatic arthritis Psoriasis
Gusacinitib2ndJAK1, JAK2, JAK3, TYK2, SYKPhase IIb Phase IIbChronic hand eczema Atopic dermatitis
Delgocitinib2ndJAK1, JAK2, JAK3, TYK2Phase IIb Phase IIbChronic hand eczema Atopic dermatitis
CTP-5432ndJAK1, JAK2Phase IIIAlopecia areata
Table 1: First and second generation JAK inhibitors, their selectivity, and level of investigation in the treatment of dermatologic conditions. Adapted from Cinats, et al.13 JAK inhibitors in which further investigation has been discontinued were excluded from this table.

 

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

Adverse Effects and Safety Profile

The JAK inhibitors that are approved for autoimmune disease have an associated black box warning for the potential increased incidence of malignancy, serious infections, and thrombosis based on data from oral use in rheumatoid arthritis.1 Tofacitinib and baricitinib have the most data on their safety and side effect profiles. However, the long-term safety of JAK inhibitors is still not completely understood. Current data suggests the safety of JAK inhibitors may be comparable to other biologics, and as investigations of this promising drug class continue, the safety profile should become more clear.1 According to the literature, JAK inhibitors may potentially increase the risk of malignancies, as they could impair the immune system’s surveillance mechanism to vet inconspicuous cells that could eventually become cancers.1 The rate of serious infections in patients treated with JAK inhibitors is comparable to that of other biologic agents such as TNF-a,1,20 though there is an increased risk of herpes zoster with JAK inhibitor usage.1,21 Baricitinib, tofacitinib, ruxolitinib and upadacitinib all include warnings for potential deep vein thrombosis, pulmonary embolism, and arterial thrombosis.1,18 Though these risks appear to be low and dose dependent, additional studies are needed to determine the exact mechanism behind it’s pro-thrombotic effects.1,37 Additional adverse effects include gastrointestinal perforations, hyperlipidemia, as well as impaired drug metabolism due to interaction with the CYP3A4 system.1,42

Discussion

There is an increasing body of evidence that suggests JAK inhibitors may be an effective treatment for various inflammatory skin conditions. However, numerous cytokines and immunomodulating molecules act via the JAK-STAT pathway and blunting its activity may have unintended consequences. Long-term follow up studies are needed to establish treatment guidelines and evaluate the risk-benefit profile of JAK inhibitors. As mentioned before, tofacitinib was found to be non-inferior to etanercept for plaque psoriasis, but more studies are needed to compare the efficacy of JAK inhibitors to biologics currently approved for dermatologic use.43 Lastly, future studies should assess the utility and safety of JAK inhibitors in pregnancy and for the pediatric population.

Conclusion

Many inflammatory cytokines involved in the pathogenesis of skin disorders signal via the JAK-STAT pathway. Thus, this drug class has the potential for broad therapeutic utility within dermatology. Currently, JAK inhibitors are only FDA approved for dermatologic, rheumatologic, and hematologic conditions. Recent studies show the utility of JAK inhibitors in treating atopic dermatitis, psoriasis, psoriatic arthritis, vitiligo, and alopecia areata. However, more robust studies are needed to assess long-term safety and establish treatment guidelines. JAK inhibitors are poised to become important additions to the therapeutic arsenal for a wide range of inflammatory skin conditions.

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