Updates in Alopecia Areata: Clinical and Epidemiologic Features, Pathogenesis, and Treatments
Alopecia areata (AA) is an autoimmune T lymphocyte mediated disorder. Clinically, patients present with partial or complete hair loss involving the scalp and/or body. Recent studies have further explored the clinical and epidemiologic features in children with AA,1 pathogenesis,2 and novel treatments.2,3
Alopecia Areata in Children
Wohlmuth-Wieser et al1 investigated clinical and epidemiologic features in children and adolescence with AA via a web-based form (completed by 2218 patients) and a clinical examination (completed by 643 patients).
Of the patients that completed the web-based form, the mean age of AA onset was 5.9 + 4.1 years. There was a female predominance (1.5 to 1), however males were more likely to have severe forms. About 14% of patients reported a first-degree relative affected by AA and 74% of patients reported they had no family history of AA. About 45% of patients reported their worst episode resulted in complete hair loss. The most common concomitant diseases were atopic dermatitis (32.7%), asthma (20.7%), hay fever (20.0%), and allergies (14.2%).
Of the 643 patients that had a clinical evaluation, 25 patients had congenital alopecia. The predominant phenotype of patients that completed the clinical visit was alopecia universalis in 43.5%, followed by patchy, persistent AA in 25.4%. The mean duration of the worst episode in these patients was 3.9 + 3.3 years with a mean age at onset of 7.4 + 4.4 years. Of 609 patients that had nail involvement documented, 43.8% had involvement.1
Pathogenesis of Alopecia Areata
The C3H/HeJ mouse develops spontaneous alopecia similar to humans with AA. This mouse model was used to evaluate the contribution of CD8+NKG2D+ T cells in the pathogenesis of AA. CD8+NKG2D+ T cells were isolated from the lymph nodes of C3H/HeJ mice with the alopecic phenotype. The CD8+NKG2D T cells alone, total lymph node cell populations, and lymph node cell populations depleted of the CD8+NKG2D T cells were then transferred to healthy C3H/HeJ mice. The healthy mice that received the CD8+NKG2D T cells alone and the mice that received the total lymph node cell population developed alopecia. The healthy mice that received the lymph node cells depleted of the CD8+NKG2D T cells did not develop alopecia. This indicated that the CD8+NKG2D T cells were necessary for the development of alopecia but other inflammatory cells in the lymph node did not induce disease.2
Efficacy of Janus Kinases Inhibitors
IFN-g plays an important pathologic role in the development of AA. Janus Kinases (JAK) inhibitors block the downstream signal from IFN-g receptors. Ruxolitinib (Jakafi) inhibits JAK 1/2 kinases, a critical factor in IFN-signaling.2 Tofacitinib (Xeljanz) inhibits JAK 3 leading to blocking of pSTAT5 activation and to a lesser extent inhibits JAK 1 and JAK 2.
Xing et al evaluated the efficacy of ruxolitinib and tofacitinib in a mouse model for the treatment of AA.2 Skin grafts from mice with spontaneous AA can be transferred to healthy C3H/HeJ mice who develop AA 95% to 100% of the time. It was previously determined3,4 that IFN-g deficient mice did not develop AA and mice that had exogenous IFN-g administered developed AA, unless administered with IFN-g neutralizing antibodies. To investigate tofacitinib and ruxolitinib in vivo, the drugs were given at the time of grafting. The mice that received either drug at the time of grafting did not develop AA and showed no histological signs of inflammation.
Tofacitinib was then investigated to see if it could reverse establish disease in mice.2 Mice with AA were treated with tofacitinib and demonstrated hair regrowth and decrease in inflammatory markers, including CD8+NKG2D+ T cells. To investigate efficacy of topical administration of ruxolitinib and tofacitinib, they were administered to diseased mice. Complete hair regrowth was observed within 12 weeks of treatment in areas treated, but areas that were not treated remained alopecic.
Lastly, Xing et al investigated the efficacy of ruxolitinib in human subjects with AA. Three patients treated with ruxolitinib 20 mg twice daily developed hair regrowth. Biopsies in these subjects from baseline to 12 weeks of treatment showed a decrease in inflammation.2
Jabbari et el further investigated the treatment of oral JAK inhibitors in human subjects, with an open pilot study of tofacitinib in moderate to severe patch-type AA, alopecia totalis, and alopecia universalis.5 Twelve patients were enrolled. The dose was started at tofacitinib 5mg twice daily for 1 month and increased to 10mg twice daily if the patient had no terminal hair regrowth on the scalp. If patients experienced regrowth, they remained on the effective dose for 6 to 12 months. Severity in Alopecia Tool (SALT) was used to assess alopecia.
Eight of 12 patients experienced > 50% of hair regrowth from baseline, the study’s primary endpoint.5 Of the responders, the primary end point was reached in 32 weeks, ranging from 8 to 64 weeks. Seven of the 8 responders required 10mg twice daily. Secondary endpoints included global improvement of SALT score, time to regrowth, durability of responses, change in quality of life, and differences between patients with patch-type AA versus patients with alopecia totalis or universalis. Eleven of 12 patients experienced improvements on SALT scores, with 56.8% experiencing regrowth, on average, which ranged from 12.1 to 100% regrowth. Responders to treatment showed regrowth in as early as 4 weeks after the effective dose was initiated. All 12 patients showed variable regrowth in body hair.
Seven patients that were responders were followed for 6 months off tofacitinib.5 Six of the 7 demonstrated shedding following stopping the tofacitinib. Dermatology Life Quality Index was used to assess patient’s quality of live. Seven out of the 12 patients enrolled experienced a decreased quality of life, the significance of the decrease was not provided in the study. Regrowth was similar between the different types of AA. Tofacitinib was discontinued in 1 patient due to hypertensive urgency and in another patient due to persistent 1+ blood on urinalysis. There were no major abnormalities in laboratory evaluations, including complete blood count, basic metabolic panel, hepatic function tests, urinalysis with microscopic evaluation, fasting lipid panel, tuberculosis, serum pregnancy test, hepatitis B and C screening panel, and HIV test.5
Based on these recent publications on AA, we are moving towards a greater understanding of AA, including clinical features, pathogenesis, and efficacy of JAK inhibitors for a treatment option.
1. Wohlmuth-Wieser I, Osei JS, Norris D, et al. Childhood alopecia areata – Data from the National Alopecia Areata Registry. Pediatr Dermatol. 2018;35(2):164-9.
2. Xing L, Dai Z, Jabbari A, et al. Alopecia areata is driven by cytotoxic T lymphocytes and is reversed by JAK inhibition. Nat Med. 2014;20(9):1043-9.
3. Freyschmidt-Paul P, McElwee KJ, Hoffmann R, et al. Interferon-gamma-deficient mice are resistant to the development of alopecia areata. Br J Dermatol. 2006;115(3):515-21.
4. Gilhar A, Kam Y, Assy B, Kalish RS. Alopecia areata induced in C3H/HeJ mice by interferon-gamma: evidence for loss of immune privilege. J Invest Dermatol. 2005;124(1):288-9.
5. Jabbari A, Sansaricq F, Cerise J, et al. An open-labeled pilot study to evaluate the efficacy of tofacitinib in moderate to severe patch-type alopecia areata, totalis, and universalis. J Invest Dermatology. 2018;138(7):1539-45.