JAK inhibitors: a pathogenesis-directed therapy for alopecia areata

Preliminary data has shown that JAK inhibitors could represent a promising novel way to treat alopecia areata (AA), a non-scarring alopecia, which affects about 1-2% of the population.

Most commonly it presents as round patches of alopecia. “AA is not cosmetic; it is something we have to treat because it is frequently emotionally devastating,” said Prof. Brittany Craiglow (Yale University School of Medicine, USA) [1]. A review including 11 trials with data from 1,986 patients with AA demonstrated that patients have a really low health-related quality of life (HRQoL), which is similar to patients with atopic dermatitis or psoriasis [2]. Before medical therapy is started, HRQoL and psychosocial functioning should be evaluated in every patient.

Up to now, there were no reliably, effective treatments, especially for advanced disease. Topical, intralesional, and systemic corticosteroids were the mainstay of treatment. Research using human clinical samples and a mouse model demonstrated that cytotoxic T lymphocytes mediate AA in part through JAK signalling. IL-15 and IFNγ are key cytokines in the development of AA. As JAK inhibitors block these cytokines, they prevented disease development in a mouse model [3]. The story of the JAK inhibitors broke after a psoriasis patient with concomitant AA was treated with the JAK inhibitor tofacitinib and experienced a complete regrowth of hair [4]. After this experience, the first open-label trial with the JAK inhibitor tofacitinib was performed. In this trial, 32% of patients experienced 50% or greater improvement in the SALT score [5]. Another 32% of patients showed hair growth of 5-50%, and 36% did not respond to treatment. Drug cessation resulted in disease relapse in 8.5 weeks. In this trial, ophiasis AA subtypes were more responsive than alopecia totalis and alopecia universalis subtypes. In another open-label trial with the JAK inhibitor ruxolitinib, which is administered orally, 9 out of 12 patients demonstrated response, with average hair regrowth of 92% [6]. In both trials, there were no serious adverse events.

“Today we know that a long duration (≥10 years) of complete hair loss is a negative predictor for response to treatment,” said Prof. Craiglow. Scalp, eyebrows, and eyelashes show all a similar response, but response of one of these sites does not predict response of another. JAK inhibitors were generally well tolerated, although some patients developed acne or weight gain during therapy.

Topical treatments for limited disease

“When patients stop therapy, they lose their hair again,” said Prof. Craiglow. Another study has shown that adolescents have a good response to tofacitinib [7]. “Of course, we would love to have topical treatments, but studies are not out yet, and we only have a couple of case reports with mixed results,” said Prof. Craiglow. In a pilot study with 10 patients, a 2% tofacitinib ointment led to a mean improvement by 35%. One patient experienced a substantial and two patients partial hair regrowth [8]. There might be some benefit of a vehicle that enhances delivery, e.g. a liposomal base or solution.

According to Prof. Graiglow, topical therapy will be primarily for patients with small hairless areas. “If you want to treat your patient with JAK inhibitors, the potential for adverse events including malignancy and serious infections must be discussed with the patient and their family,” recommended Prof. Craiglow. “Most of the patients need treatment indefinitely, but some can taper dose. Next year, hopefully we will have some approved therapies, as there are many clinical trials underway,” concluded Prof. Craiglow.

1. Craiglow B. Session S016, AAD Annual Meeting, 1-5 March 2019, Washington DC, USA.
2. Liuy LY et al. J Am Acad Dermatol 2016;75:806-12.
3. Xing L et al. Nat Med 2014;20:1043-9.
4. Craiglow BG, King BA. J Invest Dermatol 2014;134:2988-90.
5. Kennedy Crispin M et al. JCI Insight 2016;1:e89776.
6. Mackay-Wiggan J et al. JCI Insight 2016;1:e89790.
7. Liu LY, King BA. J Investig Dermatol Symp Proc 2018;19:S18-20.
8. Liu LY et al. J Am Acad Dermatol 2018;78:403-4.



Posted on 19 April, 201928 March, 2024