Κυριακή, 12 Μαρτίου 2017

JAK INHIBITORS FOR DERMATOLOGIC DISEASES

Janus kinase (JAK) inhibitors are emerging as a potential treatment option for alopecia areata, eczema, and vitiligo.
These drugs "are going to change how we think about what we do," said Brett King, MD, PhD, from Yale University in New Haven, Connecticut, who has been at the forefront of research in this area.
Two JAK inhibitors — small molecules that interrupt cytokine signaling — were approved about 5 years ago by the US Food and Drug Administration for the treatment of rheumatoid arthritis and bone marrow disorders: ruxolitinib (Jakafi, Incyte) and tofacitinib (Xeljanz, Pfizer). However, they have not yet been approved for use in dermatologic conditions.
That will likely happen soon, Dr King told Medscape Medical News. He said he expects a JAK inhibitor to be approved for the treatment of moderate to severe eczema in 2 years and for the treatment of moderate to severe alopecia areata in 2 to 3 years.
"We'll see what we can do in vitiligo in the next year to make the case for large clinical trials," he added.
Tofacitinib and ruxolitinib have had parallel successes, but tofacitinib was the focus of Dr King's presentation here at the American Academy of Dermatology Annual Meeting. This was in part, he explained, because ruxolitinib costs "more than $100,000 per year and tofacitinib is more in the range of biologics."
Evidence supporting the use of tofacitinib for alopecia areata is mounting, he pointed out.
Alopecia Areata
In a recent retrospective study of 90 adults with severe alopecia areata (at least 40% scalp hair loss) who were treated for 4 to 18 months with tofacitinib, 20% had nearly total hair regrowth, 58% had more than 50% regrowth, and 77% had some regrowth (J Am Acad Dermatol2017;76:22-28).
And in a retrospective study of adolescents with severe alopecia who were treated with tofacitinib, the median change in Severity of Alopecia Tool (SALT) score was 93% (mean, 61%) in nine of the 13 study participants after an average of 6.5 months of treatment (J Am Acad Dermatol2017;76:29-32). Tofacitinib was well tolerated, and there were no serious adverse effects, Dr King reported.
Tofacitinib does not improve male pattern baldness, and it is "important to note that not all people respond," he explained. And adverse effects have included acne eruption and weight gain, he added.
Eczema Treatment
Evidence for eczema is also mounting. "I can say that, based on the experience of my patients with moderate to severe atopic dermatitis treated with oral tofacitinib, pruritus responds over hours or days," said Dr King.
A randomized, double-blind, vehicle-controlled study of 69 patients with mild to moderate atopic dermatitis showed that tofacitinib ointment was significantly more effective than the vehicle (82% vs 30%) (Br J Dermatol2016;175:902-911). Improvements in itch were seen by day 2, the study investigators report, and sleep disturbance and itch scores dropped significantly over 4 weeks.
Other clinical trials are currently underway, said Dr King.
JAK inhibitors have also shown effectiveness in vitiligo.
Rapid Repigmentation in Vitiligo
A case study of a woman in her 50s with widespread vitiligo was coauthored by Dr King (JAMA Dermatol2015;151:1110-1112).
Oral tofacitinib 5 mg every other day was initiated. After 3 weeks, the dosage was increased to 5 mg daily. After 2 months, "partial repigmentation of the face and upper extremities was evident," Dr King and his coauthor write. And after 5 months, "repigmentation of the forehead and hands was nearly complete."
"The fairly rapid response and the repigmentation of the hands, which are often resistant to therapy, are noteworthy," the pair writes.
And the case of a patient with vitiligo and alopecia treated with oral ruxolitinib who experienced rapid repigmentation was recently described (J Am Acad Dermatol2016;74:370-371).
Excitement Among Dermatologists
"I'm highly optimistic about JAK inhibitors for inflammatory skin diseases," said Emma Guttman, MD, PhD, from the Icahn School of Medicine at Mount Sinai Medical Center in New York City.
JAK inhibitors will likely have better safety profiles for skin disease than for arthritic disease. "In skin diseases, we will probably not have the toxicity level we had in rheumatoid arthritis because people with skin diseases are usually healthy people," she told Medscape Medical News. However, safety information will need to be gathered over time, she added.
Dr Guttman said she agrees that JAK inhibitors will be approved for eczema first, probably in 3 years, because studies are well establishedbut for alopecia, she puts the timeline closer to 5 to 6 years.
More information is needed about vitiligo, she explained, because "it's not clear how well we can reverse the disease in full."
Among those waiting for results from clinical trials of JAK inhibitors is Lucky Meisenheimer, MD, a dermatologist in private practice in Orlando. These three disorders share an underlying impairment of the immune system and they all tend to be chronic conditions, he told Medscape Medical News.
"It's always exciting when the possibility of new drugs with different mechanisms of action from current mainstay treatments show promise," he added.
Dr King reports relationships with Aclaris Therapeutics, Concert Pharmaceuticals, Eli Lilly and Company, Pfizer, and Regeneron. Dr Guttman reports relationships with AbbVie, Almirall, Anacor Pharmaceuticals, Asana Biosciences, Celgene, Dermira, Eli Lilly and Company, Galderma Research & Development, Glenmark Generics, Janssen Pharmaceuticals, Kyowa Hakko Kirin Pharma, Leo Pharma, Medimmune, Mitsibushi Pharma, Novartis, Pfizer, Regeneron, sanofi-aventis, Sanofi/Regeneron, Stiefel, and Vitae Pharmaceuticals. Dr Meisenheimer has disclosed no relevant financial relationships.
American Academy of Dermatology (AAD) Annual Meeting: Abstract U086. Presented March 6, 2017.

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