Allison Cinats, MD1; and Emma Heck, BComm2; Lynne Robertson, MD, FRCPC, DABD1

1Division of Dermatology, University of Calgary, Calgary, AB, Canada
2Queen’s University School of Medicine, Queen’s University, Kingston, ON, Canada

Conflict of interest:
The authors have no conflicts to disclose.

Abstract
The class of medications known as Janus kinase inhibitors block cytokine-mediated signaling via the Janus kinase-signal transducer and activator of transcription (JAK-STAT) pathway, which plays an important role in immunoregulation and normal cell growth. This class includes the drugs tofacitinib, approved for the treatment of rheumatoid arthritis, and ruxolitinib, approved for the treatment of myelofibrosis and polycythemia rubra vera. The most common adverse events (AEs) reported in patients taking tofacitinib are infections, whereas the most common AEs in patients taking ruxolitinib are anemia and thrombocytopenia. Both first and second generation Janus kinase inhibitors have become promising treatment modalities for dermatologic conditions such as psoriasis, atopic dermatitis, alopecia areata, vitiligo, dermatomyositis, and graft-versus-host disease. Future promising areas of investigation include treatment of cutaneous lupus, cutaneous T-cell lymphoma, melanoma, allergic contact dermatitis, and lichen planus.

Key Words:
Janus kinase inhibitors, JAK inhibitors, JAK-STAT pathway, tofacitinib, ruxolitinib, alopecia areata, atopic dermatitis, dermatomyositis, graft-versus-host disease, psoriasis, vitiligo

The JAK-STAT Pathway

The development and function of various human cells are controlled by a group of secreted factors known as cytokines. One large subgroup of cytokines, which play a critical role in the signaling systems that underlie normal cell growth and immunoregulation, bind to type 1 or 2 cytokine receptors. The cytokines in this group use the Janus kinase-signal transducers and activators of transcription (JAK-STAT) pathway as a mode of signal transduction.1

When a cytokine binds to a type 1 or 2 receptor on the cell membrane, the receptor dimerizes, allowing the associated cytoplasmic JAK protein to autophosphorylate and phosphorylate the receptor chains.2,3 This process induces recruitment of signaling intermediaries including STAT proteins that transduce the signal from the cytokine receptor to the nucleus, leading to DNA transcription and regulation of gene expression.1

There are four different members of the JAK family – JAK1, JAK2, JAK3 and tyrosine kinase 2 (TYK2). Mutations and polymorphisms within this JAK-STAT pathway have been implicated in both autoimmune and malignant processes. For example, mutations of JAK3 and TYK2 are known causes of immunodeficiency, whereas polymorphisms of JAK2 and STAT3 contribute to a range of autoimmune diseases, including inflammatory bowel disease, psoriasis, ankylosing spondylitis and Behcet’s disease.1 Acquired mutations in JAK2 have been noted in more than half of patients with myeloproliferative neoplasms, including polycythemia rubra vera, essential thrombocythemia, and primary myelofibrosis.4

JAK inhibitors, or jakinibs, inhibit the kinase component of JAKs, thereby preventing them from phosphorylating and stopping the transduction of intracellular signaling. First generation jakinibs, which include the drugs tofacitinib and ruxolitinib, inhibit multiple JAKs. Tofacitinib, which is approved as monotherapy or in combination with methotrexate for the treatment of rheumatoid arthritis, inhibits JAK1 and JAK3, and to a lesser extent the other JAK isoforms. Ruxolitinib, which is approved for use in myelofibrosis and polycythemia rubra vera, inhibits JAK1 and JAK2.5 Second generation jakinibs are still under investigation and more selectively target only one JAK isoform, thereby inhibiting a narrower range of cytokines.6 (Table 1)

Drug Generation Target Status Dermatologic Diseases
Tofacitinib 1st generation JAK3, JAK1, JAK2 (to a lesser extent) FDA approved
FDA approval recommended
Phase II
Psoriatic arthritis
Psoriasis
Alopecia areata
Ruxolitinib 1st generation JAK1, JAK2 Phase III
Phase II
Phase II
Phase II
Phase II
Graft-versus-host-disease
Alopecia areata
Vitiligo
Psoriasis
Atopic dermatitis (topical)
Baricitinib 1st generation JAK1, JAK2 Phase II
Phase II
Phase II
Graft-versus-host-disease
Psoriasis
Atopic dermatitis
Oclacitinib 1st generation JAK1 FDA approved Canine allergic dermatitis
Upadacitinib 2nd generation JAK1 Phase II Atopic dermatitis
Itacitinib 2nd generation JAK1, JAK2 Phase II
Phase II
Psoriasis
Pruritus
PF-06651600 2nd generation JAK3 Phase II Alopecia areata
PF-06700841 2nd generation JAK1, TYK2 Phase II
Phase II
Psoriasis
Alopecia areata
BMS-986165 2nd generation TYK2 Phase II Psoriasis
PF-04965842 2nd generation JAK1 Phase II Atopic dermatitis
Table 1: First and second generation jakinibs, their targets, and their highest level of investigation in dermatologic diseases. Adapted from: Schwartz DM, et al.6 Only those jakinibs that are at least in or post phase II trials have been included. Jakinibs previously investigated in phase II trials in which further development has been discontinued have been excluded from this table.

 

Adverse Events

The most extensive safety data for JAK inhibitors has come from studies looking at their use in rheumatoid arthritis and myelofibrosis patients. The most common adverse events (AEs) reported in patients treated with tofacitinib are infections (>50%) and gastrointestinal symptoms (>20%), with nasopharyngitis, upper respiratory tract infections, urinary tract infections, and diarrhea being the most common in these categories.7,8 Serious infections have been reported (incidence ratio [IR] = patients with events/100 patient years: 2.7), with the most common being herpes zoster, pneumonia, urinary tract infections, and cellulitis. These rates are similar to those observed with other targeted immunotherapies. Rare but serious AEs include disseminated herpes zoster (IR 0.3), opportunistic infections (IR 0.3), tuberculosis (IR 0.2), and gastrointestinal perforation (IR 0.1).9 A systematic review of patients treated with tofacitinib compared to placebo found that they are significantly more likely to develop laboratory abnormalities including neutropenia, dyslipidemia, elevated creatinine and liver enzyme abnormalities. However, these changes were found to improve over time or return to baseline spontaneously or with discontinuation of the drug.10

The most common AEs reported in patients with myelofibrosis treated with ruxolitinib include anemia (>98%) and thrombocytopenia (>83%). This is not surprising given ruxolitinib’s inhibition of JAK2, which is essential in mediating signals from erythropoietin and thrombopoietin. Other commonly reported AEs include fatigue, diarrhea, ecchymosis, dizziness, headache, and urinary tract infections.11, 12

Both tofacitinib and ruxolitinib cause immunosuppression, leading to a theoretical increased risk of malignancy. An analysis of malignancies occurring in patients treated with tofacitinib found that standardized incidence ratios (SIR) were within the range expected for patients with moderate to severe rheumatoid arthritis, and that the SIR remained stable over time with increasing tofacitinib exposure.13 Overall, the risk of malignancy associated with JAK inhibitors is unclear, and more long-term studies are required.

Clinical Uses in Dermatology

Psoriasis and Psoriatic Arthritis

Many of the cytokines involved in the pathogenesis of psoriasis operate through the JAK-STAT signaling pathway. Most studies in psoriasis have involved tofacitinib, which inhibits the expression of interleukin (IL)-23 and differentiation of T helper type 1 (Th1) cells. IL-23 is a key cytokine that controls Th17 cells, therefore tofacitinib’s downstream effects include reducing Th17 cell differentiation and its production of IL-17.14 Several phase III randomized controlled trials (RCTs) have shown that significantly more patients achieve a 75% reduction in the Psoriasis Area and Severity Index (PASI 75) while on tofacitinib compared with placebo. These patients also demonstrated a dose-dependent improvement of PASI 75 on tofacitinib 10 mg twice daily as compared with 5 mg twice daily.15,16 A phase III non-inferiority trial revealed that tofacitinib 10 mg twice daily was non-inferior to etanercept 50 mg twice weekly.17 More recently, a post hoc analysis of the patients included in the above RCTs demonstrated significant improvements in Nail Psoriasis Severity Index (NAPSI) scores on tofacitinib 10 mg twice daily.18

Two newer JAK inhibitors, baricitinib and solcitinib, have shown promise in psoriasis. A study of baricitinib demonstrated significantly more patients achieved PASI 75 as compared with placebo.19 A multi-center study found solcitinib 400 mg twice daily to have similar efficacy to both tofacitinib and baricitinib, with 57% of patients achieving PASI 75.20 However, further developments in solcitinib have been discontinued.6

Topical JAK inhibitors for mild-moderate psoriasis have also been investigated. Tofacitinib showed variable results in a phase IIa trial. Differences in efficacy were speculated to be due to variability in moisturizing properties of the formulations tested.21 Ruxolitinib (INCB018424) was studied in a non-blinded and nonvehicle- controlled trial and was found to reduce the mean area and severity of psoriatic lesions.22

In December 2017, tofacitinib was approved by the US FDA for the treatment of adult patients with active psoriatic arthritis who have had an inadequate response or intolerance to methotrexate or other disease-modifying antirheumatic drugs.23 This was based on the results of two phase III trials, which showed that patients on tofacitinib 5 mg and 10 mg twice daily demonstrated statistically significant improvements in American College of Rheumatology 20 (ACR20) response and change from baseline in the Health Assessment Questionnaire-Disability Index (HAQ-DI) at 3 months, as compared to placebo.24,25

Atopic Dermatitis

The pathogenesis of atopic dermatitis is multifactorial, but IL-4 is known to play a pivotal role, signaling through the JAK-STAT pathway via JAK1 and JAK2 to increase the immunity of T helper type 2 cells and enabling further release of various implicated cytokines.26 One small study of tofacitinib in six patients with moderate to severe atopic dermatitis who had failed standard therapy showed promising results. The average Severity Scoring of Atopic Dermatitis (SCORAD) index decreased by 54.8% at 14 weeks of treatment with tofacitinib 5 mg once or twice daily. A significant reduction in pruritus and sleep loss scores was also noted.27 A phase IIa, randomized, double-blind, vehicle-controlled study has been completed using 2% tofacitinib ointment in 69 adult patients with mild to moderate atopic dermatitis. Although the change from baseline in the Eczema Area and Severity Index (EASI) was significantly greater for tofacitinib versus the vehicle after 4 weeks of treatment, further development of this preparation for atopic dermatitis has been discontinued.28

Two new oral agents have recently shown promise in phase II studies. In results presented at the 2017 European Academy of Dermatology and Venereology Congress, PF-04965842 and baricitinib were found to improve clinical and patient-reported outcomes in atopic dermatitis as compared to placebo.29,30

Alopecia Areata

Alopecia areata (AA) is a T cell-mediated autoimmune disease resulting in premature follicular senescence. Interferon-γ (IFN-γ) has been determined to be crucial in the pathogenesis of activating autoreactive T cells, and global transcriptional profiling in AA has identified up-regulation of many interferon-regulated genes and cytokines such as IL-2 and IL-15. Importantly, both IFN-γ and IL-15 signal through JAK1 and JAK3. IL-15 signaling also involves STAT5.31 Systemic ruxolitinib and tofacitinib were shown in a mouse model to stop the IFN-γ gene expression response and subsequent development of AA. Both systemic and topical administration of these drugs have led to reversal of established disease in mice with widespread AA.32

Human studies also demonstrate benefit of jakinibs in AA. A case report published in 2014 featured a patient with concomitant psoriasis and alopecia universalis who experienced complete hair regrowth while on tofacitinib for psoriasis.33 Several other case reports and studies have since been published demonstrating successful treatment of AA, including the associated nail changes.34-36 A retrospective study found that 58% of patients deemed to be potential responders to therapy (meaning those with alopecia totalis or alopecia universalis with duration of disease of 10 years or less, or AA) had greater than 50% change in their Severity of Alopecia Tool (SALT) score while on tofacitinib.37 An open-label trial demonstrated tofacitinib 5 mg twice daily to be efficacious, with 32% of patients reaching 50% or greater improvement in their SALT score. However, with drug discontinuation, relapse occurred within 8.5 weeks.38 A small series of adolescent patients demonstrated hair regrowth in approximately 70% of patients.39

Jakinibs, other than tofacitinib, are also efficacious in AA. A case report from 2015 described a male patient with chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature (CANDLE) syndrome with concomitant AA. He was enrolled in a trial of baricitinib and experienced complete hair regrowth.40 Ruxolitinib demonstrated sustained, nearcomplete regrowth when used in two patients with AA, and a small open-label trial of 12 patients demonstrated that 75% achieved 92% hair regrowth by the end of treatment. As reported with tofacitinib, however, relapse of hair loss occurred after drug discontinuation.41,42

Vitiligo

The pathogenesis of vitiligo remains unclear, although most evidence implicates T-lymphocytes in the destruction of melanocytes. As with AA, IFN-γ likely plays a key role. A case report of a patient with generalized vitiligo treated with tofacitinib 5 mg once daily showed near complete repigmentation after 5 months of treatment.43 An additional case report of a patient with concurrent vitiligo and AA who was treated with ruxolitinib 20 mg twice daily demonstrated both hair regrowth and regained pigment. However, the majority of the pigment that returned during treatment was not sustained after treatment was discontinued.44 More recently, a small open-label trial of topical ruxolitinib 1.5% cream showed significant repigmentation for facial vitiligo, with 76% improvement in Vitiligo Area Scoring Index (VASI) scoring for four patients with facial vitiligo.45

Dermatomyositis

Several case reports have suggested efficacy of jakinibs in refractory dermatomyositis. The first report was of a patient with refractory dermatomyositis on ruxolitinib for concurrent myelofibrosis whose dermatomyositis improved significantly while on ruxolinitib.46 It was unclear, however, if improvement in the dermatomyositis was a direct effect of the JAK inhibitor or an indirect effect through treatment of the malignancy.47 Since then, a case series of three patients treated with tofacitinib found that they had significant improvement in their Cutaneous Dermatomyositis Disease Area and Severity Index (CDASI) activity score.48 An additional case report described a patient with dermatomyositis treated with tofacitinib and experienced improvement of her cutaneous disease, muscle strength, and arthritis.49

A retrospective, multi-center survey was conducted in Europe and the US with 95 patients who had been given ruxolitinib as salvage therapy for corticosteroid-refractory graft-versus-host disease (GVHD). In patients with both acute and chronic corticosteroidrefractory GVHD, a cohort known to have poor outcomes, response rates were greater than 80% on ruxolitinib.50 Another retrospective study in patients with severe sclerodermatous chronic GVHD demonstrated partial improvement of skin softness in the majority of cases. However, fewer patients demonstrated a complete response and the response rate overall was lower than the study mentioned previously.51 A retrospective study involving pediatric patients with steroid-refractory acute GVHD showed an overall response rate of 45% to ruxolitinib.52

Future Directions

Several other case reports and preclinical evidence suggest that JAK inhibitors may be useful in the treatment of other inflammatory, autoimmune, and malignant skin conditions. These include cutaneous lupus, cutaneous T-cell lymphoma, melanoma, allergic contact dermatitis, and lichen planus.53-59

Conclusion

JAK inhibitors show promise in the treatment of a wide variety of dermatologic disorders. Compared with other targeted immunosuppressants, jakinibs have similar safety profiles including the rate of serious infection. Longer term studies are needed to assess malignancy risk. Given the interest in this class of drugs and the numerous trials underway, JAK inhibitors have the potential to become widely used in dermatology.

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