Indian Journal of Drugs in Dermatology

REVIEW ARTICLE
Year
: 2019  |  Volume : 5  |  Issue : 1  |  Page : 6--13

Janus Kinase Inhibitors in Dermatology


Aditya Kumar Bubna 
 Department of Dermatology, IQ City Medical College, Durgapur, West Bengal, India

Correspondence Address:
Dr. Aditya Kumar Bubna
IQ City Medical College, Sovapur, Bijra Road, Jemua, Durgapur - 713 206, West Bengal
India

Abstract

Janus kinase (JAK) inhibitors are a new addition in the armamentarium of drugs in the treatment of autoimmune dermatoses. They have proven to be valuable in treating a variety of inflammatory dermatoses with lesser side effects compared to their biological counterparts. This review throws light on JAK inhibitors and their role in dermatologic diseases.



How to cite this article:
Bubna AK. Janus Kinase Inhibitors in Dermatology.Indian J Drugs Dermatol 2019;5:6-13


How to cite this URL:
Bubna AK. Janus Kinase Inhibitors in Dermatology. Indian J Drugs Dermatol [serial online] 2019 [cited 2019 Aug 18 ];5:6-13
Available from: http://www.ijdd.in/text.asp?2019/5/1/6/263100


Full Text



 Introduction



With the emergence of new molecular targeted therapies, the picture of therapeutic dermatology is gradually evolving. One such molecular target is the Janus kinase-signal transducer and activation of transcription (JAK-STAT) pathway.

A number of inflammatory dermatoses rely on the JAK-STAT pathway for their pathogenesis. Therefore, utilizing JAK inhibitors may prove to be valuable in targeting the pathogenesis of these disorders. A number of JAK inhibitors have been utilized. Broadly, they have been classified into first-generation JAK inhibitors that include tofacitinib, ruxolitinib, baricitinib, and oclacitinib and second-generation JAK inhibitors that comprise decernotinib, peficitinib, filgotinib, fedratinib, momelotinib, and lestaurtinib. Currently, only the first-generation JAK inhibitors are being utilized in the management of dermatological disorders and are lucidly outlined in [Table 1]. The second-generation JAK inhibitors at present are in their developmental stage.{Table 1}

 Mechanism of Action



In atopic dermatitis

It has been proved that JAK-STAT signaling pathway enhances release of interleukin (IL)-4, IL-5 and IL-13, which play an important role in stimulating TH2 differentiation. In experimental models, tofacitinib and oclacitinib have demonstrated an antagonizing effect on the release of the above cytokines, thereby blocking their inflammatory activity.[6],[7],[8]

In alopecia areata

In alopecia areata (AA), JAK-STAT-dependent cytokines along with interferon (IFN) γ and IL-15 activate autoreactive T-cells.[9] JAK inhibition can prevent the release of these inflammatory cytokines, thereby bringing a halt to the pathogenetic process.

In psoriasis

IL-12 and IL-23 are JAK-STAT-dependent cytokines which majorly serve as inflammatory mediators in psoriasis. Further, IL-23 stimulates TH17 cells to produce IL-17, another important pathogenic molecule in psoriasis. Although IL-17 does not directly rely on JAK-STAT signaling pathway, blockade of IL-23 by JAK inhibitors reduces IL-17, and therefore, these drugs have value in psoriasis.[6],[10],[11]

In vitiligo

It has been demonstrated that depigmentation in vitiligo is mediated by IFN γ-induced expression of C-X-C motif chemokine 10 (CXCL 10) in keratinocytes.[12] As IFN γ signal transduction occurs through JAK 1 and 2, blockade of JAK with tofacitinib inhibits IFN γ signaling, thereby downregulating CXCL 10 expression, leading to return in pigmentation.[13]

 Pharmacokinetics



As tofacitinib is the prototype drug for JAK inhibitors, its pharmacokinetics are discussed in this section. Tofacitinib is rapidly absorbed after oral administration with plasma levels peaking after 1 h of oral intake. Tofacitinib has been demonstrated to have a mean terminal plasma half-life of 3.2 h. Metabolism of tofacitinib occurs in the liver by oxidation, N-demethylation, and glucuronidation. Elimination of tofacitinib occurs via both the hepatic (70%) and renal (30%) routes.[14]

 Indications



Food and Drug Administration approved

Rheumatoid arthritis (tofacitinib, baricitinib)Myelofibrosis and polycythemia rubra vera (ruxolitinib).

Off label

All cutaneous indications as mentioned below.

 Contraindications



Absolute

Hypersensitivity to the drug.

Relative

Liver impairmentStage IV kidney diseaseActive infections.

Pregnancy prescribing status

Category “C.”

 Clinical Uses



Atopic dermatitis

Atopic dermatitis (AD) is a chronic inflammatory condition of the skin associated with significant pruritus.[15] It affects around 10%–30% patients in the pediatric age group and around 1%–3% of the adult population.[16] Currently, the mainstay of pharmacologic therapy in AD comprises topical corticosteroids, topical calcineurin inhibitors, and phototherapy, with systemic immunosuppressive drugs such as cyclosporine, methotrexate, mycophenolate mofetil, and azathioprine being added to the therapeutic armamentarium in recalcitrant cases.[17],[18] These therapies, however, are often insufficient for moderate-to-severe disease.[19],[20] Recent advances in the pathogenesis of AD have demonstrated the utility of tofacitinib, both topically and systemically as a new targeted therapeutic modality for AD.

Levy et al.[21] have reported the clinical efficacy of systemic tofacitinib in six patients aged between 18 and 55 years, with moderate-to-severe AD who were resistant to previous therapies with other immunosuppressive drugs as mentioned above. In these patients, tofacitinib was administered at a dose of 5 mg PO twice daily or once daily, along with concomitant use of topical corticosteroids which resulted in 66.6% reduction in the severity scoring of AD index and 69.9% reduction in pruritus and sleep loss. This was observed after 8-29 weeks of treatment. During this limited series, no adverse events were observed.

A recently published study utilizing 2% tofacitinib ointment in 69 adult patients with mild-to-moderate AD resulted in 81.7% diminution of the eczema area and severity index score at 4 weeks relative to a decrease of 29.9% in the placebo group.[22]

In both the above observations, a stable and significant improvement of the disease was witnessed. Further, a favorable adverse effect profile was also documented in both reports. However, larger randomized controlled trials would be required to further establish the safety profile and efficacy of systemic tofacitinib for moderate-to-severe AD.

Alopecia areata

AA is an autoimmune disorder demonstrating patches of nonscarring alopecia that can involve any area of the body.[23] Currently, no particular treatment has been approved by the US Food and Drug Administration (FDA) for the management of AA. Many off-label treatments are available, but the efficacy of most of them is limited, thereby making room for newer alternatives in treating AA. Increasing evidence elucidates avaluable and effective contribution by JAK inhibitors in the treatment of AA and is summarized in [Table 2].{Table 2}

Psoriasis

Psoriasis is a common, chronic, inflammatory disease of multifactorial origin affecting 1%–3% of the world's population. Chronic plaque psoriasis is the most common manifestation of the disease that is clinically characterized by well-defined erythematous and scaly plaques.

Despite there being a number of treatments available for psoriasis, additional therapeutic options with a distinctive targeted effect would certainly be of value in managing the disease.[35] It has also been observed that the overall efficacy of tumor necrosis factor (TNF)-α blockers diminishes over time owing to their potential immunogenicity.[36] Further, the body mass index also affects the long-term survival rate of TNFα antagonists in patients with psoriasis.[37]

Recently, attention has shifted to newer compounds targeting signaling pathways such as JAK inhibitors. These small molecular weight inhibitors are synthetic compounds that are relatively inexpensive and can be administered both topically and systemically.[38] They have been utilized in psoriasis with promising results. The FDA has yet to approve tofacitinib for this indication. Various studies depicting the utility of JAK inhibitors for psoriasis are summarized in [Table 3].{Table 3}

Vitiligo

Vitiligo is an autoimmune disease associated with skin and mucosal depigmentation. Though not a life-threatening disease, vitiligo is associated with profound psychological implications on the patient's quality of life. Available treatment options for vitiligo are limited and often inadequate. Recent studies on the pathogenesis of vitiligo have suggested the possibility of JAK inhibitors as an effective therapy for the same.[12]

Harris et al.[47] have reported significant repigmentation of vitiligo in a patient with both AA and vitiligo with administration of ruxolitinib 20 mg PO twice daily for 24 weeks. However, depigmentation recurred after discontinuation of the drug.

Another case report by Craiglow and King[48] demonstrated the promising effect of tofacitinib in vitiligo vulgaris in a middle-aged woman who had been unresponsive to topical triamcinolone (0.1%), topical tacrolimus (0.1%), and narrow-band ultraviolet B (UVB) phototherapy. Tofacitinib was first initiated at a dose of 5 mg PO on alternate days for 3 weeks, followed by 5 mg/day for 5 months. After the stated duration, patient experienced nearly complete repigmentation over the forehead and hands and only 5% of the total lesions overall remained depigmented. Further, the safety profile of the drug was also favorable.

Also, rapid repigmentation of vitiligo utilizing tofacitinib along with low-dose narrow band UVB has been documented by Kim et al.,[49] thereby demonstrating synergism while combining these treatment modalities.

Dermatomyositis

Studies have suggested the role of tofacitinib in refractory cutaneous dermatomyositis (DM). Tofacitinib acts by suppressing the abnormally upregulated IFN signaling in DM.[50],[51] In one series, three patients with refractory DM observed clinical response after treatment with oral tofacitinib at a dose of 5–10 mg/day. The mean treatment period was 9.6 months. By the end of 4 weeks of treatment, clinical improvement was noticeable with respect to pruritus and muscle strength.[52] Improvement from moderate-to-severe to mild disease was observed in two patients. In both these patients, tofacitinib was employed as monotherapy after failure of previous conventional therapies. The third patient demonstrated a lesser response though the response was clinically significant.

In a case report by Hornung et al.,[53] ruxolitinib was used to treat recalcitrant DM in a 72-year-old patient who also had polycythemia rubra vera and myelofibrosis. Here, ruxolitinib was administered at a dose of 5 mg PO Q12H for 2 months, which was then increased to 15 mg PO Q12H for 12 months, followed by 10 mg twice daily. Therapy with ruxolitinib was associated with improvement of both cutaneous and musculoskeletal symptoms of DM. Further, no adverse effects were reported in this patient.

Lichen planopilaris

Lichen planopilaris (LPP) is an inflammatory cicatricial alopecia of unclear etiology, whose treatment still remains a challenge. Many different treatment modalities have been advocated for LPP with varying success. A recent study has demonstrated upregulation of JAK1 and JAK3 in dermal inflammatory cells of LPP, thereby postulating a role of JAK inhibitors in reducing IFN-mediated inflammation associated with LPP and in this way preventing further destruction of hair follicles.[54]

In a case series of 10 patients of LPP (aged between 33 and 68 years) treated with oral tofacitinib (10–15 mg/day) for 2–9 months, improvement in erythema, scaling, and hair density was witnessed in eight out of 10 patients. Further, symptoms such as pruritus, pain, and burning demonstrated significant reduction. Of these 10 patients, five received tofacitinib monotherapy with the remaining five also receiving intralesional triamcinolone (2 patients), hydroxychloroquine (1 patient), hydroxychloroquine and triamcinolone (1 patient), and intralesional triamcinolone with topical tacrolimus (1 patient). In all patients, treatment with tofacitinib was well tolerated with no adverse effects being reported.[55]

Lupus erythematosus

In a case report by Wenzel et al.,[56] ruxolitinib dosed at 20 mg PO Q12H for 4 months in a 69-year-old patient with chilblain lupus was associated with complete remission of the condition.

 Special Consideration



Use of Janus kinase inhibitors in the pediatric population

In most of the studies pertaining to JAK inhibitors, it has been seen that either adults or adolescents constituted the study population. However, there are a few reports depicting the utility of these drugs in children and have been elaborated in [Table 4]. Though not associated with major adverse responses, the use of systemic JAK inhibitors should be exercised with caution in children. More studies in this age group would further help in delineating the safety profile of JAK inhibitors in the pediatric population.{Table 4}

 Adverse Effects



Risk of urinary tract infection, nasopharyngitis, and upper respiratory tract infectionsVaricella-zoster virus reactivationImpaired response to vaccinationThrombocytopenia, anemiaDiarrhea, fatigue, dizziness, and headacheIncreased risk of malignancies.

 Monitoring Guidelines



Baseline

Complete blood countRenal function testsLiver function testsFasting lipid profileHBsAgAnti-HCVTesting for tuberculosis (to be done at baseline and then once every year)HIV status.

After 1 month

Complete blood countRenal function testsLiver function testsFasting lipid profile.

Once every 3 months

Complete blood countRenal function testsLiver function testsFasting lipid profile.

 Conclusion



In addition to the entities discussed, JAK inhibitors have also shown to be of value in chronic actinic dermatitis, erythema multiforme, cutaneous graft versus host disease, allergic contact dermatitis, melanoma, and cutaneous T-cell lymphoma.[60],[61],[62],[63],[64],[65]

Based on the currently available data, tofacitinib has been found to be comparable with etanercept as a second-line agent for psoriasis. Further, owing to its oral route of administration and better economic profile over biologic drugs, tofacitinib again scores above them.

Moreover, when compared with other immunosuppressive drugs such as methotrexate, cyclosporine, azathioprine, and mycophenolate mofetil, JAK inhibitors have again elucidated superior results. Also, with topical preparations of JAK inhibitors being available, it could prove beneficial in those patients where systemic therapy with the drug is contraindicated or in milder disease phenotypes where topical therapy would suffice in bringing about disease remission, thereby representing a safer alternative for a number of chronic dermatologic diseases. However, more head-to-head comparative studies with respect to these drugs would further help in delineating things better. Overall, JAK inhibitors are a relatively safe group of drugs.

Today, JAK inhibitors are the subject of intensive research as they represent possible therapeutic targets in a number of cutaneous diseases.

Availability

Tofacitinib is marketed as a 5 mg tablet under the brand name XeljanzRuxolitinib is marketed as 5, 15, and 20 mg tablets under the brand name JakaviBaricitinib is marketed as 2 and 4 mg tablets under the brand name OlumiantTofacitinib is available as a 2% ointmentRuxolitinib is available as a 0.6% ointment.

In India, currently, only the oral preparations of the above-mentioned JAK inhibitors are available.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

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