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Review of the role of Janus kinase inhibitors in dermatology

Seyffert, Jennifer L.a; Kramer, Owen N.b

Journal of the Egyptian Women's Dermatologic Society: May 2017 - Volume 14 - Issue 2 - p 73–75
doi: 10.1097/01.EWX.0000508179.74890.d3
Review article
Free

Janus kinase (JAK) inhibition suppresses inflammation and immune cell activation in T-cell-mediated disorders by interrupting intracellular signaling. Because of these properties, JAK inhibitors are being investigated as possible therapeutic agents. The available scientific literature has been reviewed in an effort to evaluate the profile of JAK inhibitors and their role as investigational compounds in the treatment of various dermatologic conditions with a particular focus on the treatment of alopecia areata, vitiligo, psoriasis, atopic dermatitis, and cutaneous dermatomyositis.

aSky Ridge Medical Center, Lone Tree, Colorado

bUniversity of Illinois at Chicago College of Medicine, Chicago, Illinois, USA

Correspondence to Jennifer L. Seyffert, 10099 RidgeGate Parkway, Lone Tree, CO 80124, USA Tel: +1 847 987 4977; fax: +1 720 476 3369; e-mail: jseyffert@westernu.edu

Received July 3, 2016

Accepted October 6, 2016

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Introduction to protein kinases and Janus kinase family

Protein kinases are a large family of proteins involved in cell signaling through phosphorylation. Kinases are a potential drug target, as greater than four hundred human diseases have been linked with aberrant kinase activity 1. A particular family of kinases known as the Janus kinase (JAK) family are intracellular second messengers, which transmit extracellular cytokine signals to stimulate the signal transducer and activator of transcription (STAT) pathway. Numerous cytokines have been found to activate JAKs, and because of this property are considered as activators of the STAT pathway 2. JAK1, JAK2, JAK3, and TYK2 are the four members of the JAK family 3. JAK1 binds with γ-chain cytokines, granulocyte colony-stimulating factor, and interferons. JAK2 is associated with hematopoietic growth factor receptors 4. JAK3 binds to the type I cytokine receptor family. Notably, these cytokines participate in lymphocyte activation and proliferation; therefore, inhibition of these cytokine signaling pathways may result in alteration of the immune response 4–6. JAK inhibition suppressed inflammation and immune cell activation in T-cell-mediated disorders by interrupting intracellular signaling. As a result of these properties, JAKs are being investigated as they represent possible valuable therapeutic agents in conditions such as alopecia areata (AA), psoriasis, vitiligo, atopic dermatitis (AD), and dermatomyositis.

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Alopecia areata

AA is a prevalent chronic immune-mediated condition, which presents with nonscarring hair loss due to inflammation of anagen hair follicles. The presentation of hair loss can range from small round patches on the scalp to variants such as alopecia totalis and alopecia universalis (AU), which correspond to total loss of hair on the scalp or loss of all hair on the body, respectively. The hair loss in AA can resolve spontaneously; however, a small but substantial portion of cases may evolve to severe chronic hair loss 7. To date, the Food and Drug Administration has not approved any treatments for AA, despite it being the most common cause of inflammation-induced hair loss. Off-label treatments that have been studied include corticosteroids (topical and systemic), minoxidil, anthralin, biologics (efalizumab and alefacept), calcineurin inhibitors, sensitizers (diphenylcyclopropenone and dinitrochlorobenzene), and prostaglandin analogs 8.

The immune pathways required for autoreactive T-cell activation in AA are not clearly defined, and there have been numerous theories for the mechanism of autoimmunity. It is proposed that the interferon produced by CD8+NKG2D+ T-cells stimulates the collapse of immune privilege in the hair follicle. JAK signaling pathways that support interferon production by CD8+NKG2D+ lymphocytes and interleukin-15 production by follicular epithelial cells perform an important role in the continuation of this process 9. Thus, the theoretical inhibition of JAK/STAT signaling may play a role in preventing this process from occurring and has actually been demonstrated to promote hair regrowth by stimulating the activation and proliferation of hair follicle stem cells 10.

In support of this theory, marked improvement in AA has been reported in three patients during treatment with various JAK inhibitors, including oral tofacitinib 11, oral baricitnib 12, and topical ruxolitinib 13. The first patient treated with oral tofacitinib suffered from AU and, after 8 months of therapy, had full regrowth of hair at all body sites, except for the arms and legs where the patient historically had sparse hair before onset of AU 11. Further evidence for the use of tofacitinib has been demonstrated recently in a case series of two patients suffering from AU who were prescribed tofacitinib citrate at a dose of 5 mg twice daily and experienced significant improvements in hair growth after only months of treatment in the absence of any significant adverse effects 14. Although further studies are warranted, other case reports have demonstrated the effectiveness of tofacitinib in the treatment of AA 15,16. Furthermore, topical formulations of both tofacitinib and ruxolitinib have been demonstrated to be effective in reversing the murine model of AA 9. Moreover, there is a report of three cases of remission of nail dystrophy, a relatively prevalent finding in certain populations with AA 17, after 5–6 months of treatment with tofacitinib citrate 18.

Although uncommon, serious side effects have been reported in patients taking oral JAK inhibitors. It would be particularly useful to explore the use of topical formulations for these disorders, given the potential for serious adverse effects from oral JAK inhibitors. Additional studies will be needed to confirm efficacy, further explore the safety and tolerability, and determine optimal concentrations of topical agents. Topical JAK inhibitors present an exciting new treatment opportunity in AA with a more favorable safety profile.

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Vitiligo

Vitiligo is a common autoimmune disorder that has limited and inadequate treatment options. There is a suggested common pathogenesis for AA and vitiligo, as these conditions share common genetic risk factors and are seen within families and individual patients 19. Because of these commonalities, it can be theorized that a medication that is effective in treating AA 11 may also be successful in treating vitiligo. Depigmentation in vitiligo is mediated by interferon-γ-induced expression of C-X-C motif chemokine 10 (CXCL10) in keratinocytes 20. Depigmentation has been reversed with antibody neutralization of interferon-γ or CXCL10 21. It has been postulated that, as interferon-γ signal transduction occurs through JAK1 and 2 22, the use of the tofacitinib, a JAK1 and 3 inhibitor, can lead to blockade of interferon-γ signaling and downstream CXCL10 expression, ultimately leading to the return of pigmentation.

Continued research of tofacitinib for efficacy and safety profiles in the treatment of patients with vitiligo will be important, particularly in those with long-standing symptoms. Investigation of the efficacy of a topical formulation for the treatment of localized vitiligo would be useful, as serious adverse effects, although uncommon, have been reported in patients taking tofacitinib.

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Psoriasis

Multiple key mediators in psoriasis pathogenesis signal through the JAK/STAT pathway, prompting investigation of JAK proteins as potential therapeutic targets for psoriasis treatment 23. Tofacitinib is being investigated for use in psoriasis and was shown to be effective for plaque psoriasis in phase III randomized controlled trials when compared with placebo and with etanercept 24–26. A 10 mg twice-daily dose of tofacitinib was shown to be noninferior to etanercept 50 mg subcutaneously twice weekly 26.

Another phase III trial investigated outcomes following tofacitinib withdrawal with outcomes of continuation in patients. After initial treatment of 24-week duration with tofacitinib 5 and 10 mg twice daily, 33.5 and 55.2% achieved both psoriasis area severity index 75 and physician global assessment responses, respectively. Continuous treatment maintained a response when compared with placebo recipients following tofacitinib withdrawal. 60% of those patients who relapsed recaptured a response with tofacitinib 27. Oral tofacitinib at a dose of 10 mg twice daily demonstrated the best response rate in this study as well.

The safety and efficacy of topical solution tofacitinib have been investigated in two randomized studies in patients with chronic plaque psoriasis 28,29. A phase IIa study investigating two ointments containing tofacitinib versus vehicle met its primary endpoint of efficacy for one of the tofacitinib-containing ointments 28. Another study, an intrasubject, left–right, controlled study, enrolled patients who were assigned randomized 2, 0.2, or 0.02% tofacitinib or vehicle solution once or twice daily 29. For 4 weeks, patients treated one plaque with a randomized topical tofacitinib and applied vehicle to a contralateral plaque. The primary efficacy endpoint was not different from baseline for any treatment group. Solution misapplication or cross-contamination was suggested, as skin biopsy detected tofacitinib in both tofacitinib-treated and vehicle-treated plaques of some patients. Lack of efficacy in this trial was hypothesized to be due to the intrasubject study design with unsupervised applications 29.

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Atopic dermatitis

In a recent study, tofacitinib citrate was administered to six patients with moderate-to-severe refractory AD with a history of standard treatment failure 30. Their response to therapy was assessed using AD index scoring. Improvement in the condition was seen in all patients, as demonstrated by a decrease in body surface area involvement of dermatitis, decreased erythema, decreased edema/papulation, decreased lichenification, and decreased excoriation. The AD index decreased by 66.6% after 8–29 weeks of treatment. During this limited series, no adverse events were observed. This presents an interesting alternative for those with AD refractory to conventional therapies.

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Refractory cutaneous dermatomyositis

Dermatomyosis is a rare autoimmune condition with distinct cutaneous manifestations. There are few alternative treatments when available agents such as hydroxychloroquine, methotrexate, mycophenolate mofetil, and intravenous immunoglobulin fail. Studies suggest that tofacitinib suppresses interferon signaling 31, a pathway that has been found to be abnormally upregulated in dermatomyositis 32. In one series, three patients with refractory dermatomyositis observed clinical response after treatment with oral tofacitinib 33. Improvement from moderate-to-severe to mild disease was seen in two patients, both of whom used tofacitinib as a monotherapy. The third patient experienced a lesser, yet clinically significant, response. The greatest degree of improvement was seen in the patient receiving higher doses of tofacitinib, suggesting that its effect may be dose dependent as seen in other conditions such as psoriasis. No adverse events occurred in this limited series.

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Conclusion

Current studies do not demonstrate substantial advantages of tofacitinib in terms of efficacy and safety over existing treatments for psoriasis. Considering the abundant antipsoriatic drugs recently approved or being developed, it seems more advantageous to investigate the use of tofacitinib for other indications such as promoting hair growth in AA, repigmentation in vitiligo, and treatment of AD as well as dermatomyositis. Both AA and vitiligo are common diseases that require more efficacious treatment options than those that currently exist. Further trials with selective JAK inhibitors are required to identify key pathogenic pathways and determine the efficacy and safety in these conditions.

Advances in basic science can help target therapies and guide treatment decisions. As the pathological mechanisms of different diseases are evaluated, existing medications can be repurposed and/or new medications can be developed for these diseases, which historically have limited, if any, treatment options. JAK inhibitors are the subject of intensive research, as they represent possible therapeutic targets in a number of dermatologic conditions with unmet medical needs. Topical JAK inhibitors present an exciting new treatment opportunity with a more favorable safety profile.

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Acknowledgements

Author contributions: Dr Jennifer Seyffert: drafting of the manuscript; Owen N. Kramer: critical revision of the manuscript for important intellectual content.

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Conflicts of interest

There are no conflicts of interest.

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Keywords:

alopecia; atopic dermatitis; Janus kinase inhibitor; psoriasis; refractory cutaneous dermatomyositis; ruxolitinib; tofacitinib; vitiligo

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