Expert Review of Clinical Pharmacology

JAK inhibition in the treatment of alopecia areata – a promising new dawn?

Fathima Ferial Ismail & Rodney Sinclair

To cite this article: Fathima Ferial Ismail & Rodney Sinclair (2019): JAK inhibition in the treatment of alopecia areata – a promising new dawn?, Expert Review of Clinical Pharmacology

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EXPERT REVIEW OF CLINICAL PHARMACOLOGY
REVIEW
JAK inhibition in the treatment of alopecia areata – a promising new dawn?
Fathima Ferial Ismail a and Rodney Sinclaira,baSinclair Dermatology, Melbourne, Australia; bDepartment of Medicine, University of Melbourne, Melbourne, Australia

ARTICLE HISTORY
Received 9 November 2019
Accepted 6 December 2019
KEYWORDS
Alopecia areata; Janus kinase inhibitors; tofacitinib; ruxolitinib; baricitinib; CTP- 543; PF-06651600; PF-06700841

1. Introduction

AA is an immune-mediated disorder which produces non- scarring hair loss. It classically presents with asymptomatic, well-defined circular patches of hair loss which may be single or multiple [1]. Patchy scalp alopecia can progress to total scalp hair loss (alopecia totalis, AT) or total body hair loss (alopecia universalis, AU) [1].
AA can be classified as acute or chronic. Forty percent of patients develop a solitary patch of AA that regrows sponta- neously within 6 months [2]. Twenty-seven percent develop additional patches, however still achieve complete and persis- tent remission at 12 months [2]. Chronic AA is defined as AA that continues beyond 12 months [2]. These patients develop additional areas of alopecia and have persistent hair loss. In patients with chronic AA, 30% develop AT and 15% develop AU [2]. In patients with AT or AU, 17% achieve complete hair regrowth [3].
The lifetime incidence of AA has been reported to be 0.7–4% and is similar in both genders [4,5]. The majority of patients with AA are relatively young, with up to 66% being younger than 30 years [6]. People with AA have an increased overall risk of other autoimmune diseases [6].
AA can occur in children and has been reported in infants as young as 1 month of age [7]. In children under the age of 16 years, the mean age of diagnosis is approximately 11 years of age [8]. Earlier age of onset of AA, particularly before the age of 6 years, is associated with poorer prognosis and increased likelihood of refractory disease [8,9]. Positive family

history has been reported in 8.4% to 51.6% of children with AA [7,8,10,11].
Other possible indicators of poor prognosis include disease duration of more than 1 year, multiple discrete patches of hair loss, extensive hair loss affecting >50% of the scalp, ophiasis pattern of alopecia, associated nail disease, Trisomy 21, atopy and a positive family history of AA or other autoimmune disorders [9].
There is an increased lifetime prevalence of psychiatric disorders, particularly depression and generalized anxiety dis- order, in people with AA [12]. This may be linked to the impact that AA can have on health-related quality of life [13,14]. The Dermatology Life Quality Index (DLQI) scores are similar in people with AA to other chronic relapsing skin diseases such as atopic dermatitis and psoriasis [13].
The aims of treatment of AA are to arrest disease progres- sion and reverse hair loss. Treatment options include conser- vative management, topical therapy (with corticosteroids, minoxidil and immunotherapy), intralesional corticosteroids and systemic therapies including corticosteroids and steroid- sparing agents [9].
An Australian expert consensus statement outlined a treatment algorithm for AA, including the indications for and choice of systemic treatment [9]. Patients with a solitary active patch of AA or a solitary stable patch of AA which is impacting their mood or social function should be treated with topical high-potency corticosteroids in children and intra- lesional corticosteroid injections in adults [9]. All patients with
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multiple patches of AA or ophiasis alopecia should be treated with topical or intralesional corticosteroids and if no signifi- cant response is observed after 6 months, topical immu- notherapy or systemic therapy should be considered [9]. Rapid progressive hair loss, or AT/AU, are indications for sys- temic therapy [9].
2. Methods
Electronic searches were performed using Medline Ovid, PubMed, Embase, Cochrane Library and Evidence-Based Medicine Reviews from their dates of inception to September 2019. Search terms included ‘alopecia areata’, ‘JAK inhibitor’, ‘Janus kinase Inhibitor’, ‘ruxolitinib’, ‘tofacitinib’ and ‘baricitinib’ as key words.
3. Pathophysiology of alopecia areata
The hair follicle is a site of relative immune privilege [15,16]. Immune privilege enables antigens in the hair follicle to evade immune surveillance and escape immune attack through sev- eral mechanisms [16]. Abnormalities in hair follicle immune privilege are inherent in people susceptible to autoimmune diseases including AA [16,17]. In AA, inflammatory cells attack anagen hair follicles. Anagen hair bulbs that are in the process of active pigment production are attacked preferentially, but all anagen follicles are susceptible [16]. Although AA may present as localized patches, the biochemical features of AA may extend significantly beyond the areas that are clinically affected [17,18].
AA susceptibility is inherited as a polygenic trait [19,20]. Murine models have furthered our understanding of the mechanisms involved in AA pathogenesis. Carroll et al. [21]

induced AA in normal-haired C3H/HeJ mice by transfer of skin grafts from mice with spontaneous AA. They found that upre- gulation and downregulation of 42 genes during the onset of mouse AA was consistent with an inflammatory cell-mediated disease pathogenesis involving antigen presentation, co- stimulation and a Th1 lymphocyte response [21]. Although their data suggested an autoimmune etiology for both human and mouse AA, a primary disease activating target was not found [21].
Xing et al. [22] demonstrated that cytotoxic CD8+ NKG2D+ T-cells play an integral role in the development of AA. This subset of T-cells infiltrate the epithelial layers of the hair follicle in mice with AA causing an interferon-γ (IFN-γ) response and upregulation of several γ-chain cytokines known to promote the activation and survival of CD8+ NKG2D+ T-cells [22]. Antibody- mediated blockade of IFN-γ, IL-2 or IL-15Rβ prevented disease development, reducing the accumulation of CD8+ NKG2D+ T-cells in the skin [22]. Administration of systemic inhibitors of JAK tyrosine kinases, downstream effectors of IFN-γ and γ-chain cytokine receptors, eliminated the IFN signature and prevented development of AA [22].
Petukhova et al. [23] performed a genome-wide association study which identified associations between AA and several genes controlling the activation and proliferation of regulatory T-cells, cytotoxic T-lymphocyte-associated antigen 4 (CTLA4), interleukin (IL)-2/IL-21, IL-2 receptor A (IL-2RA) and the human leukocyte antigen (HLA) region in AA. There was also a strong association with ULBP (cytomegalovirus UL16-binding protein) [23]. The expression of ULBP in lesional scalp samples was markedly upregulated during active disease [23].
Li et al. [18] analyzed skin biopsies of patients with AA and healthy controls using polymerase chain reaction (PCR). They found that active AA bulbs displayed increased expression of multiple chemokines and chemokine receptors compared with normal hair follicles [18]. In regrown AA bulbs, the transcription pattern remained abnormal, implying that despite recovery of hair growth, these changes persisted in hair follicles previously affected by AA [18]. The ITGAE gene which encodes for CD103, a marker for resident memory T cells, was persistently over- expressed in areas of hair regrowth, although absent in biopsies taken during a first episode of AA, suggesting that these mem- ory T cells develop and lodge in AA bulbs [18].
The role of environmental factors in triggering disease remains speculative [20]. Zhang et al. [24] used a murine model to demonstrate a marked increase in hypothalamic- pituitary-adrenal (HPA) tone and activity in mice with AA. Controlled clinical studies in humans have not found any correlation between stress hormone levels and AA [24].

4. Janus kinase inhibitors
The JAK family is a group of four intracellular enzymes: JAK1, JAK2, JAK3 and TYK2 [25]. JAKs have an important role in host defense, immune responses and hematopoiesis [26]. JAKs phosphorylate sites on a variety of inflammatory cytokine receptors which then act on downstream targets via the signal transducer and activator transcription (STAT) pathway [27]. The JAK-STAT pathway has effects on IFN-γ, IL-2 receptor common γ-chain interleukins (IL-2, IL-4, IL-7, IL-19, IL-15 andIL-21), IL-5, IL-12, IL-13, IL-23, tumor necrosis factor (TNF)-α, IL-1 and IL-17 [28]. Overexpression of these cytokines is implicated in the pathogenesis of many inflammatory and immune-mediated diseases, although not all may be required for the development of AA [29,30].

Pharmacologic inhibition of the JAK enzyme family has been used to treat immune-mediated diseases. Much of our knowledge of JAK inhibitors stems from rheumatology, hema- tology and oncology, and various myeloproliferative diseases are associated with increased JAK activity [25,27]. Murine models have demonstrated that systemic administration of JAK inhibitors may prevent the development of AA by mod- ulating IFN-γ gene expression signatures [22].
Ruxolitinib is a JAK1/JAK2 inhibitor that is approved by the United States Food and Drug Administration (FDA) for the treat- ment of myelofibrosis, polycythemia vera and refractory graft- versus-host disease [31–33]. Tofacitinib targets JAK1/JAK2/JAK3 and to a lesser extent TYK2 [25]. It is approved by the FDA for use in moderate-to-severely active refractory rheumatoid arthri- tis, refractory psoriatic arthritis and moderate-to-severely active ulcerative colitis [33,34]. Baricitinib is a JAK1/JAK2 inhibitor which is approved by the FDA for use in moderate-to-severely active refractory rheumatoid arthritis [33,35].
JAK inhibitors are being evaluated for the treatment of a number of other conditions including atopic dermatitis, vitiligo, cutaneous T-cell lymphoma, systemic lupus erythema- tosus (SLE), renal transplantation, refractory leukemia and solid malignancies [27,28].

5. Adverse effects of JAK inhibitors
JAK inhibitors are associated with an increased risk of a limited number of infections. The most common infections that occur are nasopharyngitis and upper respiratory tract infections [27,36–38]. Urinary tract infections, pneumonia, bronchitis, conjunctivitis, tonsillitis, mononucleosis, bacterial skin infec- tions, herpes zoster, herpes simplex and paronychia have also been reported [27,36,38–40]. Opportunistic infections including tuberculosis, esophageal candidiasis, disseminated or multidermatomal herpes zoster, cytomegalovirus and Pneumocystis jiroveci pneumonia have been reported but are uncommon [27].
The incidence of venous thromboembolic events may be increased in people being treated with higher doses of JAK inhibitors [41,42]. The risk of malignancy associated with JAK inhibitors is comparable to what has been reported with dis- ease-modifying anti-rheumatic drugs (DMARDs) and biologic therapies [43]. The most common malignancies include non- melanoma skin cancer (NMSC), followed by lung cancer, breast cancer, lymphoma and gastric cancer [44]. The risk of malig- nancy is not dose-related except for in the case of NMSC [42,43]. Overall rates and types of malignancies are stable over time with increasing exposure to JAK inhibitors [44].
Smolen et al. [42] evaluated the safety profile of baricitinib in 3492 patients with rheumatoid arthritis. Compared with the placebo group, there were increased rates of infection, deep venous thrombosis (DVT), pulmonary embolism (PE) and laboratory abnormalities (including elevated low-density lipo- protein (LDL), high-density lipoprotein (HDL), creatine phosphokinase (CPK), alanine aminotransferase (ALT) and creatinine) in the baricitinib group [42]. The rate of NMSC was higher for the group treated with 4mg of baricitinib compared with 2mg [42]. There was no difference in the rates of death, malignancies (excluding NMSC), major cardio- vascular events (MACE) or serious infections between the treatment and placebo groups [42].

Other adverse effects which have been reported with JAK inhibitors include gastrointestinal complaints, acneiform erup- tions, weight gain, headaches, fatigue, hyper-seborrhea, ane- mia and neutropenia [28,36–40,45–48]. The use of JAK inhibitors in patients with myelofibrosis is associated with increased rates of aggressive B-cell lymphomas [49].
It is currently recommended that patients who are starting treatment with JAK inhibitors should have a complete blood count, biochemistry profile, fasting lipid panel, hepatitis B (HBV) and C (HCV) serology, human immunodeficiency virus (HIV) testing and tuberculosis screening prior to starting therapy [27,28]. Monitoring investigations are also recom- mended after 1 month of treatment and then every 3 months [28].
6. Oral tofacitinib
6.1. Case series and open label studies
Case series and open label studies have shown that tofacitinib is efficacious in a proportion of adults and adolescents with AA (Table 1). Liu et al. [36] described a case series of 90 patients, most of whom had AT or AU. They were treated with tofacitinib 5–10mg twice daily with or without predni- sone. Twenty percent of patients achieved a complete response with >90% change in Severity of Alopecia Tool (SALT) score from baseline, 38.4% achieved 51–90% change in SALT score, 18.5% achieved 6–50% change in SALT score and 23.1% were non-responders [36]. Patients with AA achieved a greater change in SALT score over 4–18 months of treatment compared with patients with AT or AU [36]. Disease relapse occurred in 12.3% of patients during treat- ment [36]. Subsequent to relapse, hair regrowth was again achieved in 5 patients with tofacitinib monotherapy (5mg twice daily) and 2 with adjuvant therapy [36]. These results suggest that maintenance therapy may be necessary for con- tinued remission of disease.
Kennedy Crispin et al. [38] reported on 66 patients with AA, AT or AU who were treated with tofacitinib 5mg twice daily for 3 months. Thirty-two percent of patients achieved an improve- ment in SALT score of >50% from baseline, 32% had a change in SALT score of 5–50% and 36% were non-responders [38]. Patients with AA and ophiasis subtypes were more responsive than AT and AU [38]. Shorter duration of disease and histolo- gical peribulbar inflammation on pre-treatment scalp biopsies were associated with improvement in SALT score [38]. Twenty patients were followed up 3 months after discontinuation of tofacitinib and all of them experienced hair loss [38].
Serdaroğlu et al. [37] reported on 63 patients with AA, AT or AU who were treated with tofacitinib 5mg twice daily for 12 months. Fifty-two patients had >50% change in SALT score, with 25 of these having a complete response (>90% change in

Table 1. Summary of oral tofacitinib reports in AA, AT and AU.
Author, date Article type N Patient demographics Diagnosis Duration of disease Dose Results*Anzengruber, 2016 [64]CR 1 M 51y AU 2y 5mg BD -Castelo-Soccio, 2017 [52]CS 8 8 adolescents, aged 12–19y AU 1–12y 5mg BD ++
Cheng, 2018 [45]CS 11 3M 8F, aged 21–58y AT, AU 2–11y 5mg daily to 11mg ER BD-,+,++,+++Craiglow, 2014 [53]CR 1 M 25y AU 23y 5mg BD to 15mg daily +++
Craiglow, 2017 [47]CS 13 1M 3F, aged 12–17y AA, AT, AU 1.5–15y 5mg BD to 15mg daily -,+,++,+++Dhayalan, 2016 [67]CS 3 2M 1F, aged 20s-40s AU NR 5mg BD to 15mg daily -/+Erduran, 2017 [54]CR 1 F 23y AU 9y 5mg BD to 15mg daily +++Ferreira, 2016 [55]CR 1 M 38y AU 10y 5mg BD +++Gordon, 2019 [65]CR 1 F 44y AA 5y 5mg BD -Gupta, 2016 [62]CS 2 2M, 42y and NR AU 1–32y 5mg BD ++
Ibrahim, 2017 [51]CS 13 1M 12F, aged 20s–60s AA, AT, AU 5–54y 10–25mg BD-,+,++,+++Jabbari, 2018[39]OL 12 4M 8F, aged 18-52y AA, AT, AU 3–34y 5–10mg BD -,+,++,+++Jabbari, 2016 [59]OL 1 F 40y AA 5y 5mg BD +++Kennedy Crispin, 2016 [38]OL 66 31M 35F, aged 19–65y AA, AT, AU 0.5–43y 5mg BD -,+,++,+++Kim, 2017 [56]CR 1 F 28y AU 8y 5mg BD +++Liu, 2017 [36]CS 90 40M 50F, aged 18–70y AA, AT, AU 2–54y 5–10mg BD ± prednisone -,+,++,+++Morris, 2018 [57]CR 1 M 22y AU 5y 5mg BD +++Mrowietz, 2017 [58]CR 1 F 20y AU 2y 10–15mg daily +++Park, 2017 [50]CS 32 16M 16F, aged 18–54y AA, AT, AU 1–35y 5–20mg BD -,+,++,+++Patel, 2018 [46]CS 2 2M, aged 17–40y AU 4–16y 5mg daily to 5mg BD ++,+++Salman, 2017 [66]CR 1 M 25y AU NR 5mg BD -Scheinberg, 2017 [61]CS 4 2M 2F, aged 20–60y AU 2–10y 5mg BD ++,+++Serdaroğlu, 2019 [37]CS 63 33M 30F, aged 18–62y AA, AT, AU 1–40y 7.5–10mg daily -,+,++,+++Shivanna, 2018 [63]OL 6 3M 3F, aged 22–35y AT, AU 0.5–15y 5–10mg BD -,+,+Vu, 2017 [60]CR 1 M 44y AA 4y 5mg daily +*+++ ≥ 90% regrowth, ++ 50–89% regrowth, + 5–49%% regrowth, – <5% regrowth or relapse on discontinuation,-/+ indeterminate NR = not recorded. BD = twice daily. ER = extended release. CR = case report. CS = case series. OL = open-label study.

SALT score) [37]. Among the complete responders, relapse was observed in two patients when the dose was tapered [37]. Park et al. [50] studied 32 patients with AA, AT or AU, most of whom were refractory to previous treatments. Eighteen patients had >50% hair regrowth, 6 patients had 5–50% hair regrowth and 8 had no response [50].
Ibrahim et al. [51] reported on 13 adults with AA, 7 of whom achieved at least 50% hair regrowth with tofacitinib. In an open-label trial of 12 adults with AA, Jabbari et al. [39] described >50% hair regrowth in 8 of 12 patients after an average length of time of 32 weeks. Cheng et al. [45] reported on 10 patients with AT or AU who had a mean improvement in SALT score of 61% over a mean duration of 14.4 months. Five of these patients experienced complete remission [45].
Castelo-Soccio et al. [52] reported on 8 adolescents with AU who all had >50% scalp, eyebrow, eyelash and body hair regrowth after 4–12 months of treatment with tofacitinib. Two of these patients also had improvement in nail dystrophy associated with AA. Craiglow et al. [47] reported on 13 ado- lescents with AA, 10 of whom experienced hair regrowth on tofacitinib treatment with a mean change in SALT score of 61%.
6.2. Case reports and small case series
There have been numerous case reports and small case series describing clinical improvement in AA using oral tofacitinib at doses of 10mg to 15mg per day (Table 1) [46,53–63]. The timeframe from starting oral tofacitinib treatment to experien- cing significant hair regrowth ranged from 6 weeks to 10 months of therapy. Relapse of AA either during treatment or after discontinuation of oral tofacitinib has been described [64,65].

Improvement in concurrent medical conditions has been reported in patients treated with tofacitinib for AA [53,57,58]. Craiglow et al. [53] and Salman et al. [66] reported improve- ment in concurrent plaque psoriasis with tofacitinib. Mrowietz et al. [58] described improvement in psoriatic arthritis but no improvement in plaque psoriasis. Morris et al. [57] reported on a patient with AU and concurrent atopic dermatitis (AD) who had improvement in both conditions with oral tofacitinib treatment. Vu et al. [60] described a patient with AA, AD and vitiligo who had significant improvement in their AA and AD, and marginal improvement in vitiligo, after 6 months of tofa- citinib treatment. Patel et al. [46] described a patient with AU who had concurrent vitiligo which did not improve on tofaci- tinib treatment. Dhayalan et al. [67] described improvement in AA-associated nail dystrophy with tofacitinib.

7. Oral ruxolitinib
Table 2 summarizes reports of oral ruxolitinib in the treatment of AA. In an open-label trial, Mackay-Wiggan et al. [40] studied 12 patients with AA treated with ruxolitinib 20mg twice daily for 3–6 months. Nine of 12 patients had significant hair regrowth with an average of 92% change from baseline [40]. Three months after cessation of ruxolitinib, 3 of 9 responders had significant hair shedding and 6 had minor shedding [40]. One patient had concurrent vitiligo which improved with ruxolitinib treatment [40].
Liu et al. [48] reported on 8 patients with AA, AT or AU who were treated with ruxolitinib 10–25mg twice daily. Six of these patients had previously been treated with oral tofacitinib for at least 4 months. Five of 8 achieved complete or near- complete hair regrowth with a mean improvement in SALT score of 98% [48]. Of these patients, 2 were never treated with tofacitinib and 2 had previously achieved significant scalp hair

Table 2. Summary of oral ruxolitinib reports in AA, AT and AU.
Author, date Article type N Patient demographics Diagnosis Duration of disease Dose Results*
Harris, 2016 [71]CR 1 M 35y AA 19y 20mg BD +
Liu, 2019 [48]CS 8 4M 4F, aged 14–57 AA, AT, AU 0.5–5y 10–25mg BD -,+++
Mackay-Wiggan, 2016 [40]OL 12 5M 7F, mean age 43.7y AA NR 20mg BD -,+++
Pieri, 2015 [68]CR 1 F 38y AU 4y 15mg BD +++Ramot, 2017 [69]
CR 1 M 33y AU 11y 20mg BD ++Vandiver, 2017 [70]CS 2 2F, aged 45–59y AT, AU 14mo-10y 10–30mg daily +++Xing, 2014 [22]OL 3 NR AA NR 20mg BD +++*+++ ≥ 90% regrowth, ++ 50–89% regrowth, + 5–49%% regrowth, – <5% regrowth or relapse on discontinuation,-/+ indeterminateNR = not recorded. BD = twice daily. CR = case report. CS = case series. OL = open-label study.
regrowth with high dose tofacitinib (10mg twice daily) [48]. One patient had not responded to high-dose tofacitinib pre- viously and achieved near-complete remission with ruxolitinib 10mg twice daily [48]. There have been other case reports or small case series demonstrating significant hair growth with ruxolitinib [22,68–70]. Harris et al. [71] reported on a patient with concurrent vitiligo who experienced rapid improvement in vitiligo on ruxolitinib treatment which subsequently relapsed after cessation of the drug.
8. Oral CTP-543 (deuterated ruxolitinib)
A Phase 2 randomized, placebo-controlled, dose-ranging trial reported that the investigational product CTP-543 was effica- cious in treating patients with moderate to severe AA [72]. CTP-543, an oral JAK1/2 inhibitor, is a deuterium-modified form of the JAK1/2 inhibitor ruxolitinib [72]. The primary effi- cacy endpoint of statistically significant differences relative to placebo in the percentage of patients achieving a ≥ 50% rela-
tive change in SALT from baseline at week 24 was met in the 12mg twice daily cohort (58% of participants) and 8mg twice daily cohorts (47% of participants) [72].

9. Oral PF-06651600 and PF-06700841
A Phase 2a randomized double-blind placebo-controlled trial reported that two new oral JAK inhibitors, PF-06651600 and PF-06700841, were efficacious and well-tolerated in patients with AA with ≥50% scalp hair loss [73]. PF-06651600 is an oral JAK3 inhibitor and PF-06700841 is an oral TYK2/JAK1 inhibi-
tor [73].
A total of 142 participants were randomized to receive either once daily PF-06651600, PF-06700841 or placebo. Statistically significant changes in SALT score versus placebo were observed for both drugs at weeks 4 and 6. At week 24, the SALT score change from baseline, compared to placebo,

was 42.1 for the PF-06651600 group and 53.4 for the PF- 06700841 group in participants with an AA episode duration of less than 3.5 years [73]. The week 24 SALT score change from baseline, compared to placebo, was 22.7 for the PF- 06651600 group and 39.1 for the PF-06700841 group in parti- cipants with an AA episode duration of 3.5 years or longer [73].
10. Oral baricitinib
Improvement in AA with oral baricitinib treatment has been described in a case report by Jabbari et al. [74]. A 17-year-old man with Chronic Atypical Neutrophilic Dermatosis with Lipodystrophy and Elevated temperature (CANDLE) syndrome was commenced on oral baricitinib. He also had a 7-year history of AA which had started in patches and progressed to the ophiasis subtype. He experienced complete remission of AA after 9 months of treatment [74].
11. Topical tofacitinib
Reports of topical tofacitinib use in AA have shown some efficacy, although not to the extent of oral tofacitinib. Table 3 summarizes these reports. In a 24-week open-label trial of 10 patients with AA or AU treated with tofacitinib 2% ointment to the scalp, 3 out of 10 patients were considered responders, with a change in SALT score ranging from 18% to 61% [75]. In another study of 16 patients with AU treated with tofacitinib 2% ointment twice daily over a 12-week period, 6 patients had partial hair regrowth in the treated area [76]. Cheng et al. [45] reported on 4 adults with AU treated with tofacitinib 2% cream twice daily for a mean duration of 7 months, with varying efficacy. Craiglow et al. [77] reported on a patient with upper eyelash loss who was treated with topical tofaciti- nib to the upper eyelid and experienced complete upper

Table 3. Summary of topical tofacitinib reports in AA, AT and AU.
Author, date Article type N Patient demographics Diagnosis Duration of disease Dose Results*
Bayart, 2017 [79]CS 5 1M 3F, aged 3-15y AA, AT, AU 1–11y Tofacitinib 1–2% -,++,+++
Bokhari, 2018 [76]PCT 16 10M 6F, aged 25–59y AU NR Tofacitinib 2% -,+
Cheng, 2018 [45]CS 4 3M 1F, aged 28–58y AU 2–10y Tofacitinib 2% -,+++
Craiglow, 2018 [77]CR 1 F late 20s AA 11mo Tofacitinib 2% +++
Liu, 2018 [75]OL 10 6M 4F, aged 19–58y AA, AU 0.2–26y Tofacitinib 2% -,+,++
Putterman, 2018 [78]CS 11 2M 9F, aged 4–16y AA, AT, AU 2–10y Tofacitinib 2% -,+,++,+++*+++ ≥ 90% regrowth, ++ 50–89% regrowth, + 5–49%% regrowth, – <5% regrowth or relapse on discontinuation,-/+ indeterminate
NR = not recorded. CR = case report. CS = case series. OL = open-label study. PCT = placebo-controlled trial.

Table 4. Summary of topical ruxolitinib reports in AA, AT and AU.
Author, date Article type N Patient demographics Diagnosis Duration of disease Dose Results*
Bayart, 2017 [79]CS 2 1M 1F, aged 4–17y AU 1–14y Ruxolitinib 1–2% -/+
Bokhari, 2018 [76]PCT 16 10M 6F, aged 25–59y AU NR Ruxolitinib 1% -,+Craiglow, 2016 [80]CR 1 F late teens AU NR Ruxolitinib 0.6% +
Deeb, 2017 [81]CR 1 F 66y AT 50y Ruxolitinib 0.6% -
Gordon, 2019 [65]CR 1 F 48y AA 20y Ruxolitinib 1.5% –*+++ ≥ 90% regrowth, ++ 50–89% regrowth, + 5–49%% regrowth, – <5% regrowth or relapse on discontinuation,-/+ indeterminateNR = not recorded. CR = case report. CS = case series. PCT = placebo-controlled trial.
eyelash regrowth after 4 months. Ophthalmologic examina- tion after 2 months of therapy showed no abnormalities [77]. Topical tofacitinib has also been used in children and ado- lescents. Putterman et al. [78] reported on 11 children and adolescents aged 4–16 years treated with topical tofacitinib 2%. Three patients had almost complete remission, 5 had 5–50% hair regrowth and 3 had no response [78]. Bayart et al. [79] reported on 5 children and adolescents aged 3–15 years treated with topical tofacitinib 1–2%, with varying efficacy. One patient had no response when applying tofaciti- nib 2% in VeraBase cream to the scalp but had 95% regrowth
with a liposomal base formulation [79].
12. Topical ruxolitinib
Topical ruxolitinib has been used in AA with limited efficacy (Table 4). In a 12-week placebo-controlled trial of 16 patients with AU, 5 patients had partial regrowth in the areas treated with ruxolitinib 1% ointment [76]. Bayart et al. [79] reported on 2 patients with AU who applied ruxolitinib 1–2% to the eye- brow regions. One had 75% eyelash regrowth and the other had no response [79]. Craiglow et al. [80] described a case of a patient with AU who achieved 10% scalp regrowth and normal eyebrows after 12 weeks of treatment with ruxolitinib 0.6%. Deeb et al. [81] described lack of improvement in AA with ruxolitinib 0.6% cream. Gordon et al. [65] described a case of improvement in SALT score by 73% with topical ruxolitinib, with subsequent relapse after discontinuation of the drug.

13. Topical ATI-502
In a Phase 2 randomized, double-blind, vehicle-controlled clin- ical trial assessing the efficacy of ATI-502, an investigational topical JAK 1/3 inhibitor in patients with AA, statistical super- iority was not demonstrated at the primary or secondary endpoints due to high rates of disease resolution in vehicle- treated patients [82].
14. Conclusion
Chronic AA is an unpredictable, relapsing and remitting dis- ease which significantly impacts quality of life and has limited therapeutic options. Although there is a paucity of high- quality evidence to date, inhibition of JAK enzymes has shown promising results in numerous case reports, case series, open-label studies and most recently in two randomized pla- cebo-controlled trials. JAK inhibitors have a favorable safety

profile. The literature suggests that maintenance therapy may be necessary to produce a sustained response. The most sig- nificant barrier to treatment with JAK inhibitors at present is the cost. Clinical trials are currently underway to further assess the efficacy and safety of JAK inhibitors in AA.
15. Expert opinion
AA is an autoimmune hair loss disease with an incidence of 0.7% to 4% and prevalence of approximately 0.2% [4]. It is a chronic, relapsing and remitting disease that affects adults and children, males and females, with no significant ethnic differences. Approximately 60% of patients develop acute AA that presents with one or more circular patches of scalp hair loss that recovers within 6 to 12 months without treatment [2]. Relapses of acute AA can occur after many years. Approximately 40% of patients develop chronic persistent or chronic relapsing and remitting AA that fails to resolve spon- taneously [2]. Among patients with chronic AA approximately 30% will ultimately experience complete loss of scalp hair (AT), or complete loss of scalp and body hair (AU) [2].
AA has a significant psychological impact, with patients experiencing increased rates of depression and anxiety. Suicide has been reported in adolescents who had been recently diagnosed with AA and who had no preceding psy- chological disorders [83]. No therapy for AA has been approved by the US FDA. Treatments currently used include topical, intralesional and oral corticosteroids and a variety of non-steroidal anti-inflammatory, steroid-sparing medications. A recent systematic review of systemic therapy for AA failed to identify a therapy supported by robust evidence-based data [84].
AA is mediated by T-cells. In a murine model, upregulation of IL-15 in hair follicles led to recruitment and activation of natural-killer, gene 2D-expressing CD8 + T-cells, which pro- duce IFN-γ, leading to breakdown of hair follicle immune privilege [22]. Cell signaling via IFN-γ and IL-15 occurs through the JAK/STAT signaling pathway.
The JAK family of enzymes, JAK1, JAK2, JAK3, and TYK2 are cytoplasmic tyrosine kinases that interact with Type 1 and Type 2 cytokine receptors to mediate signal transduction, thereby affecting the activation, proliferation, and function of leukocytes and other cell types. Results from open-label clin- ical trials and case series evaluating the JAK inhibitors tofaci- tinib and ruxolitinib in patients with AA suggest that JAK inhibitors may be effective at reversing hair loss.
After 40 years of minor and generally inconsequential, incremental advances in the treatment of AA, this

identification of JAK/STAT pathway inhibitors as a treatment for AA represents a major breakthrough as a number of these agents are currently FDA-approved and marketed for myelo- proliferative disorders, inflammatory arthritis and are currently under investigation for inflammatory skin diseases including psoriasis, atopic dermatitis and vitiligo.
Phase 3 clinical trials of JAK inhibitors in AA have com- menced and there is now a growing sense of optimism among patients with long-standing, treatment-refractory, disfiguring AA. Further work is still required to determine optimal dose, the requirement for loading doses and the optimal target within the JAK family. Over the next few years this information will gradually become available along with ideal treatment duration and whether maintenance therapy is universally required.

Funding
This paper was not funded.
Declaration of interest
R Sinclair has served as a consultant or paid speaker for, or participated in clinical trials sponsored by, Leo Pharma, Amgen, Novartis, Merck & Co., Celgene, Coherus Biosciences, Janssen, Regeneron, MedImmune, GlaxoSmithKline, Cutanea, Samson Clinical, Boehringer Ingelheim, Pfizer, MSD, Oncobiologics, Roche, Eli Lilly and Bayer. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the Brepocitinib manuscript apart from those disclosed.
Reviewer disclosures
Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

ORCID
Fathima Ferial Ismail
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