Transforming Treatment of Alopecia Areata

Alopecia areata (AA) is an autoimmune condition that affects about 2% of the population and is the second most common cause of hair loss after androgenetic alopecia.^1-2 Given how severely AA can alter one’s appearance, it is unfortunate that the disease is often minimized or even dismissed with “It’s just hair.” People living with AA, their friends and family members, and the dermatologists who care for them know that this is far from the case. The condition is often devastating, and studies have confirmed an association between AA and a negative impact on quality of life.³ Patients diagnosed with AA also have higher rates of depression and anxiety.⁴ 

There are no FDA-approved medications for AA, and treatment can frequently be challenging. Traditional therapeutic options include topical, intralesional and systemic corticosteroids, topical immunotherapy, and systemic immunomodulatory medications, such as methotrexate. While mild patchy disease often improves with topicals and/or intralesional triamcinolone, more severe AA is far less likely to respond to traditional treatments. Fortunately, progress in the scientific understanding of AA has paved the way for new, promising therapies, namely, Janus kinase (JAK) inhibitors. 

AA Pathogenesis 

Using a mouse model of AA, researchers have been able to characterize some of the primary events in disease pathogenesis. In particular, NKG2D-expressing CD8+ T cells localize to the bulb of the hair follicle and secrete interferon-γ (IFN-γ). IFN-γ, in turn, binds its receptor on the follicular epithelial cell, leading to upregulation and secretion of IL-15 from the follicular epithelial cell, further enhancing the production of IFN-γ and thereby creating a positive feedback loop that targets the hair follicle for attack (Figure 1).⁵ 

JAK Inhibitors 

JAK inhibitors are small molecules that variably target the JAK family of enzymes, of which there are 4 members: JAK1, JAK2, JAK3 and tyrosine kinase 2 (TYK2). Some JAK inhibitors are more selective, eg, JAK1 or JAK3 specific inhibitor, while others have broader activity, eg, JAK1/3 inhibitor. There are many JAK inhibitors in development for use in dermatology and other disciplines. Currently, there are 3 FDA-approved JAK inhibitors: tofacitinib (Xeljanz), which targets JAK 1/3 and is approved for the treatment of rheumatoid arthritis (RA), psoriatic arthritis, and ulcerative colitis; ruxolitinib (Jakafi), which targets JAK 1/2 and is approved for polycythemia vera and myelofibrosis; and baricitinib (Olumiant), which targets JAK 1/2 and is approved for RA. 

JAK Inhibitors Are Targeted Therapy for AA 

The cytokines that are implicated in the pathogenesis of AA (IFN-γ and IL-15) signal directly through the JAK-signal transducer and activator of transcription (JAK-STAT) pathway, which is the mechanism for signal transduction from the cell membrane to the nucleus. Therefore, JAK inhibitors disrupt signaling by IFN-γ and IL-15, which in the case of AA interrupts the positive feedback loop that targets the hair follicle for attack, permitting hair to grow. 

Oral JAK Inhibitors for AA 

Since the first patient with AA successfully treated with tofacitinib in June 2014, there have been open-label clinical trials as well as a multitude of case reports and retrospective series describing successful treatment of AA with tofacitinib and ruxolitinib.^6-12 These studies reported scalp hair regrowth ranging from 50% to 100% over 3 to 12 months in treatment responders, with doses of tofacitinib typically in the range of 5 mg to 10 mg twice daily and ruxolitinib 10 mg to 20 mg twice daily. It is important to note that not all patients responded to treatment. In the larger studies, 50% to 75% of participants experienced >50% scalp hair regrowth and 20% to 66% of participants experienced near-complete or complete regrowth.^7-12 

Long duration of current episode of severe AA (eg, >10 years) may be a predictor of poor response to treatment, suggesting that it may be prudent to initiate treatment as soon as possible for patients experiencing complete or near-complete scalp hair loss for 7-10 years.^7,10,12 Tofacitinib and ruxolitinib were reportedly well tolerated in the above-mentioned studies. It should not be surprising that in these studies disease relapse occurred in cases where treatment was discontinued; after all, AA is a chronic disease. It is important to note that for patients with involvement of scalp, eyebrows, and eyelashes, response to one of these sites does not predict response to another.13 Finally, a few retrospective studies have also evaluated the use of tofacitinib for AA in the pediatric population, and there seems to be at least similar efficacy in children as in adults.^14-16Figure 2 shows complete hair regrowth in a patient treated with tofacitinib, a common result in our clinics. 

Recently, interim phase 2a results from 2 ongoing clinical trials have been reported, providing the first data from randomized, double-blind, placebo-controlled studies of JAK inhibitors for moderate to severe AA. Pfizer’s PF-06651600, a JAK3 inhibitor, and PF-06700841, a TYK2/JAK1 inhibitor, both showed improvement after 24 weeks of treatment as measured by the Severity of Alopecia Tool (SALT) score (change from baseline of 33.6% and 49.5% for JAK3 and TYK2/JAK1, respectively).¹⁷ Concert Pharmaceuticals’ CTP-543, a deuterated form of ruxolitinib, also met its primary efficacy endpoint for participants taking 8 mg twice daily, with 47% of participants experiencing ≥50% reduction in SALT score over 24 weeks.¹⁸ There were no major safety concerns reported in either study. There are several clinical trials currently underway (see Table). 

Topical JAK Inhibitors for AA 

Because hair resides in skin, it is not surprising that there has been some exploration of the use of topical JAK inhibitors for the treatment of AA. Topical therapy may reduce the possibility of systemic adverse effects, not to mention permit the facile treatment of small areas of involvement with AA such as mild scalp disease or eyebrows. Currently, there are no commercially available topical JAK inhibitors and most of the published data is limited to experience with compounded preparations. 

The results of studies investigating the use of topical administration of JAK inhibitors for the treatment of AA have not been particularly promising. In an open-label, pilot study of 10 participants treated with tofacitinib 2% ointment, only 1 patient experienced substantial scalp hair regrowth and 2 participants experienced mild regrowth, with a mean improvement in SALT score of 35% among the 3 patients.⁸ A recently published prospective, placebo-controlled study of 16 participants with alopecia universalis demonstrated partial hair regrowth in 6 participants treated with tofacitinib 2% ointment and 5 patients with ruxolitinib 1% ointment after 7 months. Better efficacy was observed with clobetasol 0.05% ointment, which was used as an active comparator and yielded partial response in 10 participants.¹⁹ Similarly mixed results have been reported in case reports and series of treatment of AA with topical tofacitinib and ruxolitinib.^20,21 A randomized, double-blind, placebo-controlled trial of ruxolitinib 1.5% cream was halted after 1 year, and the results of this and another completed open-label study of a different topical JAK inhibitor are not yet known.^{22, 23} 

Considering the available data and lack of commercially available topical JAK inhibitors, the use of compounded JAK inhibitors for AA is not recommended except for the treatment of limited areas of involvement such as the eyebrow regions or small patches on the scalp. It stands to reason that if treatment of AA with topical JAK inhibitors is possible, then a vehicle/formulation optimized for hair follicle delivery will be important. We await the results of an ongoing clinical trial of an investigational topical JAK inhibitor—NCT03759340.²⁴ 

Safety of JAK Inhibitors 

Regarding safety, the immunomodulatory effects of JAK inhibition must be considered. Like tumor necrosis factor-a inhibitors such as adalimumab (Humira), tofacitinib and baricitinib carry a black box warning for severe infection and malignancy. This labeling emerged from clinical trials of tofacitinib and baricitinib for the treatment of moderate to severe RA, in which a majority of patients were taking concomitant methotrexate, and some were also taking prednisone. Long-term studies of tofacitinib and baricitinib for the treatment of RA, however, do not show an increase in malignancy rates relative to what is expected for patients with moderate to severe RA²⁵ and placebo, respectively.26 It appears that JAK inhibitors have risks similar to those of most biologics, but it will be important to learn about the safety profiles associated with different JAK inhibitors in AA and other dermatologic conditions as large clinical trials are completed. 

Conclusion 

Reliably effective therapy for patients with severe AA has historically been elusive, but a relatively new class of medicines, JAK inhibitors, is leading to a paradigm shift in treatment. Only 4 years after the first patient was successfully treated for AA with a JAK inhibitor, positive results from large clinical trials suggest that in the next few years there will be FDA-approved treatments for this historically refractory disease. Hopefully, this will end the era of “just hair” and, in its place, there will be hope, understanding, and further evolution of effective treatments. 

Dr Craiglow is with the Dermatology Physicians of Connecticut in Fairfield, CT, and with the department of dermatology at Yale School of Medicine in New Haven, CT. 

Dr King is with the department of dermatology at Yale School of Medicine in New Haven, CT. 

References 

1. Mirzoyev SA, Schrum AG, Davis MD, Torgerson RR. Lifetime incidence risk of alopecia areata estimated at 2.1% by Rochester Epidemiology Project, 1990-2009. J Invest Dermatol. 2014;134(4):1141-1142. doi:10.1038/jid.2013.464 

2. Severi G, Sinclair R, Hopper JL, et al. Androgenetic alopecia in men aged 40-69 years: Prevalence and risk factors. Br J Dermatol. 2003;149(6):1207-1213. 

3. Liu LY, King BA, Craiglow BG. Health-related quality of life (HRQoL) among patients with alopecia areata (AA): A systematic review. J Am Acad Dermatol. 2016;75(4):806-12.e3. doi:10.1016/j.jaad.2016.04.035 

4. Aghaei S, Saki N, Daneshmand E, Kardeh B. Prevalence of psychological disorders in patients with alopecia areata in comparison with normal subjects. ISRN Dermatol. 2014;2014:304370. doi:10.1155/2014/304370 

5. 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):1043-1039. doi:10.1038/nm.364 

6. Craiglow BG, King BA. Killing two birds with one stone: Oral tofacitinib reverses alopecia universalis in a patient with plaque psoriasis. J Invest Dermatol. 2014;134(12):2988-2990. doi:10.1038/jid.2014.260 

7. Kennedy Crispin M, Ko JM, Craiglow BG, et al. Safety and efficacy of the JAK inhibitor tofacitinib citrate in patients with alopecia areata. JCI Insight. 2016;1(15):e89776. doi:10.1172/jci.insight.89776 

8. Jabbari A, Sansaricq F, Cerise J, et al. An open-label pilot study to evaluate the efficacy of tofacitinib in moderate to severe patch-type alopecia areata, totalis, and universalis. J Invest Dermatol. 2018;138(7):1539-1545. doi:10.1016/j. jid.2018.01.032 

9. Mackay-Wiggan J, Jabbari A, Nguyen N, et al. Oral ruxolitinib induces hair regrowth in patients with moderate-to-severe alopecia areata. JCI Insight. 2016;1(15):e89790. doi:10.1172/jci.insight.89790