麻豆传媒

Inhibition of the Janus kinase (JAK) and signal transducer and activator of transcription (STAT) pathway is showing promise for a variety of dermatologic conditions ranging from alopecia areata to vitiligo.

The first JAK inhibitor, tofacitinib (Xeljanz), was approved in 2012 for rheumatoid arthritis, but has not yet been approved for use in dermatology. Nonetheless, understanding of the basic science involved and clinical experience with JAK inhibition in dermatology have been growing, and experts are expressing confidence about the expanding role for these medications in the future, particularly with the development of topical formulations and more specific agents that target single JAKs.

In fact, one oral JAK inhibitor has already made it to market for a dermatologic indication: oclacitinib, approved for treating pruritus in dogs.

"I might go so far as to say that JAK inhibitors are the future of dermatology, and stand to be transformative," said Brett A. King, MD, PhD, medical director of Yale Dermatology-Middlebury in Connecticut.

From Cytokines to JAK

A key insight deriving from research during the past decades is that multiple cytokines play a central role in autoimmune diseases including rheumatoid arthritis, psoriasis, and inflammatory bowel disease, which "spawned the era of biologics," targeting cytokines on the surface of the cell, explained John J. O'Shea, MD, scientific director of the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) Intramural Research Program and chief of NIAMS's Molecular Immunology and Inflammation Branch in Bethesda, Md.

The biologics are clearly very effective, but a substantial number of patients don't respond to them or lose their response, he told 麻豆传媒. "There are very few circumstances where the biologics are a panacea, putting all patients into robust remission for a long period of time. So there's still a substantial unmet need."

Accordingly, the next strategy has been to target signaling pathways within the cell via the many cytokines acting through the JAK-STAT pathway.

"During the '90s, we knew how important cytokines were, but we did not know how they transmitted their signal inside the cell," O'Shea continued. "For cytokines to exert their effects, they bind to a receptor on the surface, which activates Janus kinases within the cell. This transmits a signal in the cell, telling it that something important has happened -- namely, that cytokines are acting on that cell. The metaphor we used was that we were opening the hood of the car and looking underneath, because we didn't understand how the machinery worked. Ultimately, our group cloned one of these molecules [JAK 3], and figured out how a cytokine acting on the outside of a cell would change the behavior of the cell."

Research had determined that kinases are involved in phosphorylation -- "meaning they transfer phosphate from ATP [adenosine triphosphate] to tyrosine residues of their substrates, an important activation event within cells," O'Shea and colleagues wrote in

Cytokines acting through the JAK-STAT pathway include interferons and certain interleukins. "Upon engagement of extracellular ligands, intracellular JAK proteins, which associate with type I/II cytokine receptors, become activated and phosphorylate STAT proteins, which dimerize and then translocate into the nucleus to directly regulate gene expression," King and a co-author explained in .

JAKs and Psoriasis

Among the cytokines involved in psoriasis are JAK-dependent interleukin (IL)-12 and -23, with IL-23 stimulating the production of IL-17, a primary pathogenic factor in the disease. Upstream blocking of IL-23 with tofacitinib has been shown to effectively decrease IL-17 and reduce disease activity in several large clinical trials.

For example, in , two doses of tofacitinib were compared with placebo for 16 weeks in 1,861 patients with moderate-to-severe chronic plaque psoriasis. At week 16 in the first study, physician global assessment of "clear" or "almost clear" responses were seen in 41.9% of those receiving 5 mg twice daily and 59.2% of those given 10 mg twice daily compared with 9% of those given placebo. For a 75% reduction in the Psoriasis Area and Severity Index (PASI75), the rates were 39.9% in the 5 mg group, 59.2% in the 10 mg group, and 6.2% in the placebo group (P<0.001).

In the second study, clear or almost clear responses were seen in 46%, 59.1%, and 10.9% of patients, respectively, while PASI75 responses were seen in 46%, 59.6%, and 11.4% (P<0.001).

In addition, comparing two doses of tofacitinib with subcutaneous etanercept (Enbrel) found that the higher dose (10 mg twice daily) of the oral medication was not inferior to the tumor necrosis factor inhibitor given in dosages of 50 mg twice weekly. Among 1,101 patients with chronic plaque psoriasis, a PASI75 response was seen in 39.5% of those given tofacitinib 5 mg twice daily, 63.6% of those given tofacitinib 10 mg twice daily, 58.8% of the etanercept group, and 5.6% of the placebo group.

On another primary endpoint, a physician's global assessment of clear or almost clear at week 12, responses were seen in 47.1%, 68.2%, 66.3%, and 15% of the patients, respectively.

"For both co-primary endpoints, tofacitinib 10 mg twice daily was non-inferior to etanercept and was superior to placebo, whereas tofacitinib 5 mg twice daily did not meet the non-inferiority criteria versus etanercept but met the superiority criteria versus placebo," the investigators reported.

Tofacitinib also has demonstrated efficacy in psoriatic arthritis. In a presentation at this year's European League Against Rheumatism annual congress, a study that included 422 patients found that 20% improvement was seen at 3 months in 33% of those receiving placebo, 50% of those given tofacitinib 5 mg twice daily, 61% of those receiving tofacitinib 10 mg twice daily, and 52% of those receiving adalimumab (Humira) 40 mg every 2 weeks.

"The efficacy of tofacitinib in psoriatic arthritis appears similar to what is seen with biologics such as adalimumab," said the researcher who reported the results, Philip J. Mease, MD, of the University of Washington in Seattle.

But in 2015, the to expand the indication for tofacitinib to psoriasis. This may have been related to the dose, with only the 5 mg dose having been approved for rheumatoid arthritis and only the higher dose showing efficacy in psoriasis, suggested King.

"This is just speculation, but a concern for the FDA may have been that if the drug was approved for psoriasis, there probably would be more off-label than on-label use because of the medical literature on vitiligo, alopecia areata, and eczema. The FDA has to take that into consideration, especially because one of these medications, Xeljanz, has a black box warning with a stated cancer and infection risk."

Moreover, there are already seven or eight FDA-approved systemic therapies for psoriasis. The real unmet need, according to King, is for other dermatologic disorders. For alopecia areata, there is no single approved therapy, while for vitiligo, the only approved treatment is a de-pigmenting agent and for atopic dermatitis, the first systemic treatment, dupilumab (Dupixent), was approved only this year. "Yet these are conditions that any dermatologist, whether academic or community-based, will see several times a week."

Other Dermatologic Possibilities

Alopecia areata results from attacks on hair follicles by autoreactive T cells, with JAK-STAT dependent cytokines such as interferon gamma and IL-15 activating those T cells, suggesting a possible role for JAK inhibition.

Three years ago, King and his colleagues reported that a patient with alopecia areata plus psoriasis had within 8 months after taking tofacitinib. "That gave way to quite a bit of international media attention and therefore patient interest."

Subsequently, there have been case studies and two open-label clinical trials of JAK inhibition in alopecia. In one, among 66 patients given 5 mg of tofacitinib twice daily, almost two-thirds of patients had some regrowth at 3 months, while in a second, among 12 patients given ruxolitinib (Jakafi), 20 mg twice daily for 3 to 6 months, an average of 92% regrowth was seen in nine patients.

Additional benefits have been seen in atopic dermatitis, which also is driven by JAK-STAT cytokine signaling. In a study that included six patients for whom standard therapy had failed, that 5 mg tofacitinib once or twice daily resulted in a 66% reduction in the severity scoring index.

Recent research has further suggested that there may be common genetic underpinnings between alopecia areata and vitiligo, and King's group also had success in treating a woman with progressive vitiligo in the

In reporting their results, they explained: "Interferon-gamma–induced expression of C-X-C motif chemokine 10 (CXCL10) in keratinocytes is an important mediator of depigmentation in vitiligo. Antibody neutralization of interferon gamma or CXCL10 reverses depigmentation. We propose that because interferon gamma signal transduction occurs through JAK 1/2, the use of the JAK 1/3 inhibitor tofacitinib effectively leads to blockade of interferon gamma signaling and downstream CXCL10 expression, thus giving rise to repigmentation in vitiligo."

Topical Use and Beyond

Another important focus of interest at present is the route of administration, O'Shea pointed out: "I would liken it to steroids in a way. We've had steroids since the 1940s, and there has been a lot of effort over the years to get improved specificity such as through delivery of topical and inhaled steroids. We're moving into that approach now with JAK inhibitors, looking at whether topical compounds have the efficacy of systemic compounds with fewer side effects."

, King's group found that topical ruxolitinib resulted in partial scalp and full eyebrow regrowth in a patient with alopecia universalis.

And in a that included 69 adults with mild-to-moderate atopic dermatitis, those who received topical 2% tofacitinib or vehicle ointment twice daily had a mean percentage change from baseline in the Eczema Area and Severity Index of -81.7% compared with -29.9% in the placebo group (P<0.001). Significant improvements also were seen for pruritus, physician's global assessment, and the body surface area affected.

Efforts also are underway to develop more specific JAK inhibitors that target only one JAK and involve fewer cytokines than the first-generation agents, O'Shea added. "The hope is that they will be as effective but safer."

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