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Journal of Investigative Dermatology Home

JAK Inhibitors for Treatment of Alopecia Areata

Open ArchivePublished:July 26, 2018DOI:https://doi.org/10.1016/j.jid.2018.05.027
      The advancement of genetic and preclinical studies has uncovered the mechanisms involved in the pathogenesis of alopecia areata (AA). The development of targeted therapies using small molecules blocking specific pathways for the treatment of AA is underway. By repurposing Food and Drug Administration–approved small molecule JAK inhibitors as treatments for AA, it has been demonstrated that JAK inhibitors can effectively reverse hair loss in patients with moderate to severe AA. In this review, we summarize and discuss the current preclinical and clinical studies on JAK inhibitors, as well as the prospects of using JAK inhibitors for the treatment of AA.

      Abbreviation:

      AA (alopecia areata)

      Introduction

      Alopecia areata (AA) is a form of non-scarring hair loss that is mediated by inflammatory mechanisms. With a prevalence of about 1.7–2.1%, AA is one of the most common autoimmune diseases in the US (
      • Strazzulla L.C.
      • Wang E.H.C.
      • Avila L.
      • Lo Sicco K.
      • Brinster N.
      • Christiano A.M.
      • et al.
      Alopecia areata: disease characteristics, clinical evaluation, and new perspectives on pathogenesis.
      ). The development of AA is indiscriminate between the sexes and among ethnicities, with initial onset often occurring before age 30 years. AA typically begins as small, well-defined patches of hair loss on the scalp or beard that may spontaneously remit without intervention, however, AA relapses in about 30% of cases. Discrete AA patches can grow larger and coalesce to form more extensive hair loss that covers the entire scalp (alopecia totalis) or the entire body (alopecia universalis) (
      • Strazzulla L.C.
      • Wang E.H.C.
      • Avila L.
      • Lo Sicco K.
      • Brinster N.
      • Christiano A.M.
      • et al.
      Alopecia areata: disease characteristics, clinical evaluation, and new perspectives on pathogenesis.
      ). Spontaneous remission is rarely observed in patients with alopecia totalis or alopecia universalis. Currently, there are no treatments for AA that offer durable responses or permanent reversal of hair loss.
      Identification of lymphocytic infiltrates in AA lesions gave rise to the hypothesis that there is an autoimmune attack on hair follicles, which is likely a consequence of loss of immune privilege mediated by immune T cells (
      • Paus R.
      • Bulfone-Paus S.
      • Bertolini M.
      Hair follicle immune privilege revisited: the key to alopecia areata management.
      ). Currently, the primary therapeutic approaches in treating AA include non-specific broad immunosuppressant medications given systemically or locally to dampen immune cell attack, or contact sensitizers to redirect autoimmune attack, however, broad non-specific immunosuppression can lead to adverse events. Specifically, topical and intralesional corticosteroids are associated with undesirable side effects, such as local skin atrophy, telangiectasias, and striae, while systemic corticosteroid side effects include acne, adrenal suppression, weight gain, insomnia, and glucose intolerance. Due to the non-specific nature of this treatment, efficacy of immunosuppression and contact sensitization is highly variable from patient to patient. Many of the broad T-cell antagonist medications, immunosuppressants, and biologic drugs did not achieve desirable hair regrowth in AA, potentially because they were not directed at key drivers of disease etiology (
      • Strazzulla L.C.
      • Wang E.H.C.
      • Avila L.
      • Lo Sicco K.
      • Brinster N.
      • Christiano A.M.
      • et al.
      Alopecia areata: an appraisal of new treatment approaches and overview of current therapies.
      ).
      Our recent genetic studies on AA revealed genetic similarities between AA and other autoimmune diseases, such as rheumatoid arthritis and type 1 diabetes (
      • Betz R.C.
      • Petukhova L.
      • Ripke S.
      • Huang H.
      • Menelaou A.
      • Redler S.
      • et al.
      Genome-wide meta-analysis in alopecia areata resolves HLA associations and reveals two new susceptibility loci.
      ,
      • Petukhova L.
      • Duvic M.
      • Hordinsky M.
      • Norris D.
      • Price V.
      • Shimomura Y.
      • et al.
      Genome-wide association study in alopecia areata implicates both innate and adaptive immunity.
      ). AA has been associated with other dermatologic and autoimmune diseases, such vitiligo, atopic dermatitis, allergic rhinitis, and autoimmune thyroid disease (
      • Chu S.Y.
      • Chen Y.J.
      • Tseng W.C.
      • Lin M.W.
      • Chen T.J.
      • Hwang C.Y.
      • et al.
      Comorbidity profiles among patients with alopecia areata: the importance of onset age, a nationwide population-based study.
      ,
      • Drucker A.M.
      • Thompson J.M.
      • Li W.Q.
      • Cho E.
      • Li T.
      • Guttman-Yassky E.
      • et al.
      Incident alopecia areata and vitiligo in adult women with atopic dermatitis: Nurses' Health Study 2.
      ,
      • Lee N.R.
      • Kim B.K.
      • Yoon N.Y.
      • Lee S.Y.
      • Ahn S.Y.
      • Lee W.S.
      Differences in comorbidity profiles between early-onset and late-onset alopecia areata patients: a retrospective study of 871 Korean patients.
      ). Genome-wide association studies in AA also revealed risk alleles in AA patients that identified previously unreported genes and pathways as potential biomarkers or therapeutic targets, such as ULBP3 (a “danger” signal and ligand of NKG2D) and CD8+ expressing NKG2D T cells IL15, IFNγ, and JAK-STAT signaling pathways, among others (
      • Betz R.C.
      • Petukhova L.
      • Ripke S.
      • Huang H.
      • Menelaou A.
      • Redler S.
      • et al.
      Genome-wide meta-analysis in alopecia areata resolves HLA associations and reveals two new susceptibility loci.
      ,
      • Moftah N.H.
      • El-Barbary R.A.
      • Rashed L.
      • Said M.
      ULBP3: a marker for alopecia areata incognita.
      ,
      • Petukhova L.
      • Duvic M.
      • Hordinsky M.
      • Norris D.
      • Price V.
      • Shimomura Y.
      • et al.
      Genome-wide association study in alopecia areata implicates both innate and adaptive immunity.
      ,
      • Xing L.
      • Dai Z.
      • Jabbari A.
      • Cerise J.E.
      • Higgins C.A.
      • Gong W.
      • et al.
      Alopecia areata is driven by cytotoxic T lymphocytes and is reversed by JAK inhibition.
      ). With the recent advancements in genetic techniques and immunological assays, and the development of robust mouse models of AA, such as the C3H/HeJ strain for preclinical research (
      • Gilhar A.
      • Schrum A.G.
      • Etzioni A.
      • Waldmann H.
      • Paus R.
      Alopecia areata: animal models illuminate autoimmune pathogenesis and novel immunotherapeutic strategies.
      ), significant breakthroughs in understanding the mechanism of AA have been made.
      The JAK-STAT signaling pathway in the initiation and progression of AA emerged as a major driver of disease pathogenesis, which provided a strong rationale for the clinical investigation of small molecule JAK inhibitors. Some of these medications have already been Food and Drug Administration–approved for the treatment of other diseases, such as rheumatoid arthritis (tofacitinib, a pan-JAK inhibitor) and myelofibrosis (ruxolitinib, a JAK1/2 inhibitor) (
      • O'Shea J.J.
      • Plenge R.
      JAK and STAT signaling molecules in immunoregulation and immune-mediated disease.
      ). For this review, we will focus on the rationale and evidence of using JAK inhibitors as a treatment for AA and discuss ongoing clinical research and future prospects for JAK inhibitors.

       JAK-STAT signaling

      The JAK-STAT pathway is an intracellular signaling pathway upon which many different proinflammatory signaling pathways converge (
      • Damsky W.
      • King B.A.
      JAK inhibitors in dermatology: the promise of a new drug class.
      ). JAKs are intracellular cytoplasmic tyrosine kinases that signal in pairs and transduce cytokine signaling from membrane receptors via STAT factors to the nucleus (
      • Vanhoutte F.
      • Mazur M.
      • Voloshyn O.
      • Stanislavchuk M.
      • Van der Aa A.
      • Namour F.
      • et al.
      Efficacy, safety, pharmacokinetics, and pharmacodynamics of filgotinib, a selective JAK-1 inhibitor, after short-term treatment of rheumatoid arthritis: results of two randomized phase IIa trials.
      ). Cytokines are critical for immunoregulation, but also play a major role in the immunopathogenesis of autoimmune disease (
      • Schwartz D.M.
      • Bonelli M.
      • Gadina M.
      • O'Shea J.J.
      Type I/II cytokines, JAKs, and new strategies for treating autoimmune diseases.
      ). The JAK-STAT pathway is utilized by cytokines, including ILs, IFNs, and other molecules, such as growth factors and hormones, to transmit signals from the cell membrane to the signaling (
      • Damsky W.
      • King B.A.
      JAK inhibitors in dermatology: the promise of a new drug class.
      ,
      • Paus R.
      • Bulfone-Paus S.
      • Bertolini M.
      Hair follicle immune privilege revisited: the key to alopecia areata management.
      ). Upon engagement of extracellular ligands, intracellular JAK proteins become activated and phosphorylate STAT proteins, which dimerize and then translocate into the nucleus to directly regulate gene expression (
      • Damsky W.
      • King B.A.
      JAK inhibitors in dermatology: the promise of a new drug class.
      ,
      • O'Shea J.J.
      • Schwartz D.M.
      • Villarino A.V.
      • Gadina M.
      • McInnes I.B.
      • Laurence A.
      The JAK-STAT pathway: impact on human disease and therapeutic intervention.
      ,
      • Schwartz D.M.
      • Bonelli M.
      • Gadina M.
      • O'Shea J.J.
      Type I/II cytokines, JAKs, and new strategies for treating autoimmune diseases.
      ). For example, an IFNγ receptor interacts with JAK1 and JAK2, upon the binding of IFNγ, the JAKs phosphorylate STAT1 and STAT2, which subsequently translocate into the nucleus and activate downstream gene expression (
      • Erduran F.
      • Adisen E.
      • Aksakal A.B.
      Excellent response to tofacitinib treatment in a patient with alopecia universalis.
      ).
      There are four known JAKs, including JAK1, JAK2, JAK3, and TYK2. JAK1 commonly mediates signals for a range of inflammatory diseases, whereas JAK2 mediates signaling for a range of cytokines mainly in the context hematopoiesis. JAK3 activity is restricted to the lymphoid lineage (
      • Vanhoutte F.
      • Mazur M.
      • Voloshyn O.
      • Stanislavchuk M.
      • Van der Aa A.
      • Namour F.
      • et al.
      Efficacy, safety, pharmacokinetics, and pharmacodynamics of filgotinib, a selective JAK-1 inhibitor, after short-term treatment of rheumatoid arthritis: results of two randomized phase IIa trials.
      ), and loss of function mutations in JAK3 cause severe combined immunodeficiency syndrome. In contrast, gain of function mutations in JAKs can act as oncogenes in a variety of lymphoproliferative disorders and hematologic malignancies (
      • Damsky W.
      • King B.A.
      JAK inhibitors in dermatology: the promise of a new drug class.
      ). Different combinations of JAKs form a dimer on different cytokine receptors with one of the seven members of STATs (STAT1–4, STAT5a, STAT5b, or STAT6), facilitating downstream effects of cytokine receptors upon ligand binding.

       JAK inhibitors are a class of immunomodulatory drugs

      Two JAK inhibitors are approved by the Food and Drug Administration for use in the US (ruxolitinib, tofacitinib), and one is approved for veterinary use (oclacitinib). These JAK inhibitors each target multiple JAKs with different levels of specificity (
      • O'Shea J.J.
      • Kontzias A.
      • Yamaoka K.
      • Tanaka Y.
      • Laurence A.
      Janus kinase inhibitors in autoimmune diseases.
      ). Ruxolitinib was Food and Drug Administration–approved for the treatment of myelodysplastic disorders and is selective for JAK1/2 (
      • Damsky W.
      • King B.A.
      JAK inhibitors in dermatology: the promise of a new drug class.
      ). Tofacitinib was a Food and Drug Administration–approved JAK inhibitor for the treatment of rheumatoid arthritis, and inhibits JAK1, JAK2, and JAK3, but most potently inhibits JAK3 (
      • Vanhoutte F.
      • Mazur M.
      • Voloshyn O.
      • Stanislavchuk M.
      • Van der Aa A.
      • Namour F.
      • et al.
      Efficacy, safety, pharmacokinetics, and pharmacodynamics of filgotinib, a selective JAK-1 inhibitor, after short-term treatment of rheumatoid arthritis: results of two randomized phase IIa trials.
      ). Baricitinib is in clinical trials for rheumatoid arthritis, psoriasis, and atopic dermatitis, and is selective for JAK1/2 (
      • O'Shea J.J.
      • Schwartz D.M.
      • Villarino A.V.
      • Gadina M.
      • McInnes I.B.
      • Laurence A.
      The JAK-STAT pathway: impact on human disease and therapeutic intervention.
      ). Oclacitinib is a pan-JAK inhibitor and is used for atopic dermatitis treatment in dogs (
      • O'Shea J.J.
      • Schwartz D.M.
      • Villarino A.V.
      • Gadina M.
      • McInnes I.B.
      • Laurence A.
      The JAK-STAT pathway: impact on human disease and therapeutic intervention.
      ).

       Repurposing of JAK inhibitors in AA and preclinical assessment

      We and others demonstrated that IFNγ and IL15 signaling play a crucial role in AA development and disease maintenance, in both humans and the C3H/HeJ mouse model of AA (
      • Divito S.J.
      • Kupper T.S.
      Inhibiting Janus kinases to treat alopecia areata.
      ,
      • Xing L.
      • Dai Z.
      • Jabbari A.
      • Cerise J.E.
      • Higgins C.A.
      • Gong W.
      • et al.
      Alopecia areata is driven by cytotoxic T lymphocytes and is reversed by JAK inhibition.
      ). IFNγ primarily signal through JAK1/2 and IL15 mostly through JAK1/3, providing the rationale to use JAK inhibitors to specifically block the inflammatory response resulting from the activation of these receptors (
      • O'Shea J.J.
      • Plenge R.
      JAK and STAT signaling molecules in immunoregulation and immune-mediated disease.
      ,
      • O'Shea J.J.
      • Schwartz D.M.
      • Villarino A.V.
      • Gadina M.
      • McInnes I.B.
      • Laurence A.
      The JAK-STAT pathway: impact on human disease and therapeutic intervention.
      ,
      • Xing L.
      • Dai Z.
      • Jabbari A.
      • Cerise J.E.
      • Higgins C.A.
      • Gong W.
      • et al.
      Alopecia areata is driven by cytotoxic T lymphocytes and is reversed by JAK inhibition.
      ).
      Our preclinical assessments using ruxolitinib and tofacitinib as a systemic treatment in the C3H/HeJ mouse model of AA showed therapeutic promise because both drugs prevented the induction of AA via skin grafting method (
      • Xing L.
      • Dai Z.
      • Jabbari A.
      • Cerise J.E.
      • Higgins C.A.
      • Gong W.
      • et al.
      Alopecia areata is driven by cytotoxic T lymphocytes and is reversed by JAK inhibition.
      ). We also investigated topical JAK inhibitor treatment daily on mice with longstanding AA, and showed localized hair regrowth in as little as 4 weeks. The skin of treated mice showed a marked decrease of CD4, CD8, major histocompatibility class I and II, as well as a decreased number of CD8+/NKG2D+ cells (
      • Xing L.
      • Dai Z.
      • Jabbari A.
      • Cerise J.E.
      • Higgins C.A.
      • Gong W.
      • et al.
      Alopecia areata is driven by cytotoxic T lymphocytes and is reversed by JAK inhibition.
      ). In a separate study, we used daily topical treatment with 0.5% baricitinib and showed significant hair regrowth in 6 weeks and reduction of inflammatory infiltrates in C3H/HeJ mice (
      • Jabbari A.
      • Dai Z.
      • Xing L.
      • Cerise J.E.
      • Ramot Y.
      • Berkun Y.
      • et al.
      Reversal of alopecia areata following treatment with the JAK1/2 inhibitor baricitinib.
      ). There are now multiple JAK-specific inhibitors being investigated in human clinical trials using both topical and oral formulations (Table 1).
      Table 1Current status of clinical trials of treatment of alopecia areata with JAK inhibitors listed on ClinicalTrials.gov
      Trial ListingIdentifierMoleculeRecruitingLocationStudy TypeAA typeStart Date
      A Study of ATI-50002 Topical Solution for the Treatment of Alopecia AreataNCT03354637Topical JAK inhibitorYesMulticenterPhase 2; RCT with placebo; 120 subjectsModerate to severe (SALT 30–95%)28 November 2017
      Safety and Pharmacokinetic Study of ATI-50002 in Subjects with Alopecia Universalis (AU) and Alopecia Totalis (AT)NCT03315689Topical JAK inhibitorYesMulticenterPhase 2; RCT with placebo; 12 subjectsModerate to severe (AT/AU)20 October 2017
      Study to Evaluate the Safety and Efficacy of CTP-543 in Adult Patients with Moderate to Severe Alopecia AreataNCT03137381Oral JAK inhibitorYesMulticenterPhase 2; RCT with placebo; 90 subjectsModerate to severe2 May 2017
      Study to Evaluate the Efficacy and Safety Profile of PF-06651600 and PF-06700841 in Subjects with Alopecia AreataNCT02974868Oral JAK inhibitorActive, not recruitingMulticenterPhase 2; RCT with placebo; 143 subjectsModerate to severe29 November 2016
      Topical Tofacitinib for the Treatment of Alopecia Areata and its VariantsNCT02812342Oral tofacitinibActive, not recruitingYale UniversityPhase 2; open-label; 10 subjectsModerate to severe (>50% SALT to AT/AU)24 June 2016
      Study to Evaluate the Efficacy of Tofacitinib in Moderate to Severe Alopecia Areata, Totalis and UniversalisNCT02299297Oral tofacitinibActive, not recruitingColumbia UniversityPhase 2; open-label; 15 subjectsModerate to severe (AT/AU)24 November 2014
      LEO 124249 Ointment in the Treatment of Alopecia AreataNCT02561585Topical JAK inhibitorCompletedIcahn/Mount Sinai and North Western UniversityPhase 2; RCT with placebo; 31 subjectsModerate to severe (SALT >30%, AT/AU)28 September 2015
      Tofacitinib for the Treatment of Alopecia Areata and its VariantsNCT02312882Oral tofacitinibCompletedStanford UniversityPhase 2; open-label; 40 subjectsModerate to severe (>50% SALT to AT/AU)9 December 2014
      Tofacitinib for the Treatment of Alopecia Areata and VariantsNCT02197455Oral tofacitinibCompletedYale UniversityPhase 2; open-label; 30 subjectsModerate to severe (>50% SALT to AT/AU)22 July 22 2014
      Pilot Study to Evaluate the Efficacy of Ruxolitinib in Alopecia AreataNCT01950780Oral ruxolitinibCompletedColumbia UniversityPhase 2; open-label; 12 subjectsModerate to severe (SALT 30–95%)25 September 2013
      A Study with INCB018424 Phosphate Cream Applied Topically to Subjects with Alopecia Areata (AA)NCT02553330Topical ruxolitinibTerminatedMulticenterPhase 2; RCT with placebo; 90 subjectsPartial or complete AA17 September 2015
      Abbreviations: RCT, randomized controlled trial; SALT, Severity of Alopecia Tool.

       Treatment of AA in humans using JAK inhibitors

      There have been many clinical studies of JAK inhibitor efficacy in treating AA, most of which used oral medications and a few studies using topical formulations (Table 2) (
      • Kennedy Crispin M.
      • Ko J.M.
      • Craiglow B.G.
      • Li S.
      • Shankar G.
      • Urban J.R.
      • et al.
      Safety and efficacy of the JAK inhibitor tofacitinib citrate in patients with alopecia areata.
      ,
      • Mackay-Wiggan J.
      • Jabbari A.
      • Nguyen N.
      • Cerise J.E.
      • Clark C.
      • Ulerio G.
      • et al.
      Oral ruxolitinib induces hair regrowth in patients with moderate-to-severe alopecia areata.
      ,
      • Wang E.C.E.
      • Dai Z.
      • Christiano A.M.
      Novel therapies for alopecia areata: the era of rational drug development.
      ). The oral formulations had dramatic outcomes with hair regrowth in about 67–75% of patients in several studies (
      • Kennedy Crispin M.
      • Ko J.M.
      • Craiglow B.G.
      • Li S.
      • Shankar G.
      • Urban J.R.
      • et al.
      Safety and efficacy of the JAK inhibitor tofacitinib citrate in patients with alopecia areata.
      ,
      • Mackay-Wiggan J.
      • Jabbari A.
      • Nguyen N.
      • Cerise J.E.
      • Clark C.
      • Ulerio G.
      • et al.
      Oral ruxolitinib induces hair regrowth in patients with moderate-to-severe alopecia areata.
      ). Oral formulations are generally very easy to take for patients, leading to increased compliance and hair regrowth. Tofacitinib can be taken once or twice a day in either 5-mg or 11-mg dosing. However, it is difficult to achieve high concentrations of JAK inhibitor through oral dosing. In some of the most difficult to treat cases, topical formulation may provide opportunities for higher local concentrations to target the disease-causing lymphocytic infiltrate.
      Table 2Case reports of JAK inhibitors as a treatment for alopecia areata
      First Author, YearType of StudyTreatmentNumber of PatientsResponse RateLength of Treatment
      • Jabbari A.
      • Sansaricq F.
      • Cerise J.
      • Chen J.C.
      • Bitterman A.
      • Ulerio G.
      • et al.
      An open-label pilot study to evaluate the efficacy of tofacitinib in moderate to severe patch-type alopecia areata, totalis, and universalis.
      Open-label, single-armTofacitinib, 5 mg b.i.d. then t.i.d.1291%11–64 wk
      • Kennedy Crispin M.
      • Ko J.M.
      • Craiglow B.G.
      • Li S.
      • Shankar G.
      • Urban J.R.
      • et al.
      Safety and efficacy of the JAK inhibitor tofacitinib citrate in patients with alopecia areata.
      Open-label, single-armTofacitinib, 5 mg b.i.d.6632% of patients had at least 50% regrowth3 mo
      • Mackay-Wiggan J.
      • Jabbari A.
      • Nguyen N.
      • Cerise J.E.
      • Clark C.
      • Ulerio G.
      • et al.
      Oral ruxolitinib induces hair regrowth in patients with moderate-to-severe alopecia areata.
      Open-label, single-armRuxolitinib, 20 mg b.i.d.1275% of patients had at least 50% regrowth3–6 mo
      • Liu L.Y.
      • Craiglow B.G.
      • Dai F.
      • King B.A.
      Tofacitinib for the treatment of severe alopecia areata and variants: a study of 90 patients.
      RetrospectiveTofacitinib, 5 mg b.i.d.9077% of patients had at least 50% regrowth 20% complete responseMedian, 12 mo (4–18 mo)
      • Ibrahim O.
      • Bayart C.B.
      • Hogan S.
      • Piliang M.
      • Bergfeld W.F.
      Treatment of alopecia areata with tofacitinib.
      RetrospectiveTofacitinib, 5 mg b.i.d.1353.8% of patients had at least 50% regrowthMean, 4.2 mo (1–9 mo)
      • Craiglow B.G.
      • Liu L.Y.
      • King B.A.
      Tofacitinib for the treatment of alopecia areata and variants in adolescents.
      RetrospectiveTofacitinib, 5 mg b.i.d.13 (adolescents)76.9% of patients had response with median 100% regrowth (20–100%)Median, 5 mo (2–16 mo)
      • Xing L.
      • Dai Z.
      • Jabbari A.
      • Cerise J.E.
      • Higgins C.A.
      • Gong W.
      • et al.
      Alopecia areata is driven by cytotoxic T lymphocytes and is reversed by JAK inhibition.
      Case reportRuxolitinib, 20 mg b.i.d.3Complete regrowth3–5 mo
      • Craiglow B.G.
      • King B.A.
      Killing two birds with one stone: oral tofacitinib reverses alopecia universalis in a patient with plaque psoriasis.
      Case reportTofacitinib, 10 mg am, 5 mg o.n.1 (AU)Complete regrowth8 mo
      • Higgins E.
      • Al Shehri T.
      • McAleer M.A.
      • Conlon N.
      • Feighery C.
      • Lilic D.
      • et al.
      Use of ruxolitinib to successfully treat chronic mucocutaneous candidiasis caused by gain-of-function signal transducer and activator of transcription 1 (STAT1) mutation.
      Case reportRuxolitinib, 20 mg b.i.d. for CMC1Complete regrowth at 3 mo6 mo
      • Jabbari A.
      • Dai Z.
      • Xing L.
      • Cerise J.E.
      • Ramot Y.
      • Berkun Y.
      • et al.
      Reversal of alopecia areata following treatment with the JAK1/2 inhibitor baricitinib.
      Case reportBaricitinib, 7 mg am, 4 mg o.n. for CANDLE1Complete regrowth9 mo
      • Pieri L.
      • Guglielmelli P.
      • Vannucchi A.M.
      Ruxolitinib-induced reversal of alopecia universalis in a patient with essential thrombocythemia.
      Case reportRuxolitinib, 20 mg b.i.d. for ET1 (AU)Complete regrowth10 mo
      • Gupta A.K.
      • Carviel J.L.
      • Abramovits W.
      Efficacy of tofacitinib in treatment of alopecia universalis in two patients.
      Case reportTofacitinib, 5 mg b.i.d.2 (AU)Complete regrowth in both patients8 mo
      • Harris J.E.
      • Rashighi M.
      • Nguyen N.
      • Jabbari A.
      • Ulerio G.
      • Clynes R.
      • et al.
      Rapid skin repigmentation on oral ruxolitinib in a patient with coexistent vitiligo and alopecia areata (AA).
      Case reportRuxolitinib, 20 mg b.i.d.185% regrowth, maintained 12 wk after cessation6 mo
      • Dhayalan A.
      • King B.A.
      Tofacitinib citrate for the treatment of nail dystrophy associated with alopecia universalis.
      Case reportTofacitinib, 5 mg b.i.d.3Improvement in nail dystrophy, 2 of 3 experienced hair regrowth5–6 mo
      • Scheinberg M.
      • Ferreira S.B.
      Reversal of alopecia universalis by tofacitinib: a case report.
      Case reportTofacitinib, 5 mg b.i.d.2 (AU)Partial regrowth9 mo
      • Ferreira S.B.
      • Scheinberg M.
      • Steiner D.
      • Steiner T.
      • Bedin G.L.
      • Ferreira R.B.
      Remarkable improvement of nail changes in alopecia areata universalis with 10 months of treatment with tofacitinib: a case report.
      Case reportTofacitinib, 5 mg b.i.d.1 (AU)Complete regrowth and improvement in nail changes10 mo
      • Anzengruber F.
      • Maul J.T.
      • Kamarachev J.
      • Trueb R.M.
      • French L.E.
      • Navarini A.A.
      Transient efficacy of tofacitinib in alopecia areata universalis.
      Case reportTofacitinib, 5 mg b.i.d. with MTX 15 mg/wk1 (AU)Transient regrowth, relapsed6 mo
      • Vandiver A.
      • Girardi N.
      • Alhariri J.
      • Garza L.A.
      Two cases of alopecia areata treated with ruxolitinib: a discussion of ideal dosing and laboratory monitoring.
      Case reportRuxolitinib up to 30 mg/d2 (AA, AT)Complete regrowth13–14 mo
      • Mrowietz U.
      • Gerdes S.
      • Glaser R.
      • Schroder O.
      Successful treatment of refractory alopecia areata universalis and psoriatic arthritis, but not of plaque psoriasis with tofacitinib in a young woman.
      Case reportTofacitinib, 10 mg o.d. for PsA1 (AU)Complete regrowth9 mo
      • Erduran F.
      • Adisen E.
      • Aksakal A.B.
      Excellent response to tofacitinib treatment in a patient with alopecia universalis.
      Case reportTofacitinib, 10 mg am, 5 mg o.n.1 (AU)Complete regrowth6 mo
      • Bayart C.B.
      • DeNiro K.L.
      • Brichta L.
      • Craiglow B.G.
      • Sidbury R.
      Topical Janus kinase inhibitors for the treatment of pediatric alopecia areata.
      Case reportTofacitinib (2% topical)

      Ruxolitinib (1% and 2% topical)
      6 (adolescents)3 of 6 partial regrowth, 1 complete regrowth3–12 mo
      Abbreviations: AA, alopecia areata; AT, alopecia totalis; AU; alopecia universalis; b.i.d., twice a day; CANDLE, chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature; CMC, chronic mucocutaneous candidiasis; ET, essential thrombocythemia; MTX, methotrexate, o.d., once daily; o.n., once a night; PsA, psoriatic arthritis; t.i.d., three times a day.
      There are several case studies that demonstrated improvement of AA in patients who received JAK inhibitors for other diseases, such as psoriasis, CANDLE (chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature) syndrome, vitiligo, essential thrombocytopenia, and mucocutaneous candidiasis (
      • Craiglow B.G.
      • King B.A.
      Killing two birds with one stone: oral tofacitinib reverses alopecia universalis in a patient with plaque psoriasis.
      ,
      • Harris J.E.
      • Rashighi M.
      • Nguyen N.
      • Jabbari A.
      • Ulerio G.
      • Clynes R.
      • et al.
      Rapid skin repigmentation on oral ruxolitinib in a patient with coexistent vitiligo and alopecia areata (AA).
      ,
      • Higgins E.
      • Al Shehri T.
      • McAleer M.A.
      • Conlon N.
      • Feighery C.
      • Lilic D.
      • et al.
      Use of ruxolitinib to successfully treat chronic mucocutaneous candidiasis caused by gain-of-function signal transducer and activator of transcription 1 (STAT1) mutation.
      ,
      • Jabbari A.
      • Dai Z.
      • Xing L.
      • Cerise J.E.
      • Ramot Y.
      • Berkun Y.
      • et al.
      Reversal of alopecia areata following treatment with the JAK1/2 inhibitor baricitinib.
      ,
      • Pieri L.
      • Guglielmelli P.
      • Vannucchi A.M.
      Ruxolitinib-induced reversal of alopecia universalis in a patient with essential thrombocythemia.
      ). While detailed mechanistic studies were not performed in these case studies, a common theme here is the involvement of autoimmune/autoinflammatory disorders or gain-of-function mutation in the JAK-STAT signaling pathway.

       Topical JAK inhibitors

      While oral JAK inhibitors demonstrated high efficacy in humans with moderate to severe AA, systemic treatments may yield unwanted long-term side effects. Topical application of JAK inhibitors may be a desirable treatment option for AA because it will localize the effect of JAK inhibition to the site of application. Topical JAK inhibitors reversed AA in C3H/HeJ mice with well-established AA within 4 weeks (
      • Xing L.
      • Dai Z.
      • Jabbari A.
      • Cerise J.E.
      • Higgins C.A.
      • Gong W.
      • et al.
      Alopecia areata is driven by cytotoxic T lymphocytes and is reversed by JAK inhibition.
      ). We have tested multiple formulations of topical JAK inhibitors in the C3H/HeJ mouse model and found efficacy, however, topical JAK inhibitors for human trials will need to be formulated differently to compensate for the thickness of human skin, as murine skin is thinner and easier to penetrate. Currently, there are no topical formulations of JAK inhibitors that yield satisfactory results.
      • Bayart C.B.
      • DeNiro K.L.
      • Brichta L.
      • Craiglow B.G.
      • Sidbury R.
      Topical Janus kinase inhibitors for the treatment of pediatric alopecia areata.
      reported in a small retrospective study of six pediatric patients that four showed regrowth after topical application with different combinations of tofacitinib and ruxolitinib. There were no serious adverse effects observed in these patients, however, due to the scale of the study and the lack of a uniformed treatment regimen, the efficacy of the topical formulations used cannot be confirmed yet. If the efficacy can be confirmed in a larger clinical trial with appropriate design, topical JAK inhibitors may be preferable for children with AA because of the potential advantages in the safety profile with long-term use. There have been two phase 2 randomized controlled trials initiated by Incyte Corporation (NCT02553330, terminated) and LEO Pharma (NCT02561585, completed no published results). No results from these trials were published so the efficacy cannot be determined. Currently, trials initiated by Aclaris Therapeutics are recruiting (NCT03354637 and NCT03315689), therefore, the efficacy of topical JAK inhibitors remains undetermined.
      In clinical practice, AA frequently recurs after a patient stops taking oral JAK inhibitors. Some patients require higher oral doses of JAK inhibitors to achieve initial full regrowth, up to 5 mg tofacitinib three times a day. Once regrowth has been achieved, maintenance doses could potentially be titrated down to maintain hair growth or transitioned to a topical regiment. However, to maintain regrowth after use of JAK inhibitors, patients will likely need to continue the medication indefinitely to maintain full regrowth. Ideally, a transition to a topical formulation in patients that have achieved full hair regrowth would be more sustainable.

       Considerations for using JAK inhibitors

      Using topical formulation would mitigate side effects of oral JAK inhibitors, such as increased risk of some cancers and infection. Interferons and natural killer cells are important in tumor surveillance and blockade of their action by JAK inhibition increases the risk of cancer development. The rate of lymphoma or lymphoproliferative disorders with tofacitinib in rheumatoid arthritis was 0.07 per 100 patient years (
      • O'Shea J.J.
      • Kontzias A.
      • Yamaoka K.
      • Tanaka Y.
      • Laurence A.
      Janus kinase inhibitors in autoimmune diseases.
      ).
      The most common adverse events while taking tofacitinib are bacterial, mycobacterial, fungal, and viral infections, increases in serum creatinine, thrombocytopenia, hypercholesterolemia, and neutropenia. Three patients were reported to have pulmonary tuberculosis after tofacitinib, including those who had previous negative tuberculosis screening. Increased frequency of non-disseminated herpes zoster has been reported. The half life is short and if infections occur the drug can be stopped and the immunomodulatory effect is transient. Also at doses exceeding the recommended dosage of 5 mg twice daily, tofacitinib was also associated with anemia (
      • Vanhoutte F.
      • Mazur M.
      • Voloshyn O.
      • Stanislavchuk M.
      • Van der Aa A.
      • Namour F.
      • et al.
      Efficacy, safety, pharmacokinetics, and pharmacodynamics of filgotinib, a selective JAK-1 inhibitor, after short-term treatment of rheumatoid arthritis: results of two randomized phase IIa trials.
      ). The potential side effects of prolonged treatment of JAK inhibitors have not been evaluated.

       Promise of JAK inhibitors in dermatology

      Research efforts into small molecule JAK inhibitors currently focused on targeting the JAK/STAT pathways essential in AA. Also, with more specific targeting, medication side effects and off-target downstream effects will be limited. With further research into the specific target pathways, information on ways to improve durability of treatment will emerge. Furthermore, the cost of JAK inhibitor medications is a barrier to treatment for many patients because JAK inhibitors are used in off-label indications for the treatment of AA.
      JAK inhibitors can also be delivered orally, making them easier for patient administration and compliance. JAK inhibitors are also effective because they can simultaneously target multiple pathogenic pathways identified in AA, such as type I and type II IFN receptor pathways (
      • Freyschmidt-Paul P.
      • McElwee K.J.
      • Hoffmann R.
      • Sundberg J.P.
      • Vitacolonna M.
      • Kissling S.
      • et al.
      Interferon-gamma-deficient mice are resistant to the development of alopecia areata.
      ,
      • Ghoreishi M.
      • Martinka M.
      • Dutz J.P.
      Type 1 interferon signature in the scalp lesions of alopecia areata.
      ,
      • Xing L.
      • Dai Z.
      • Jabbari A.
      • Cerise J.E.
      • Higgins C.A.
      • Gong W.
      • et al.
      Alopecia areata is driven by cytotoxic T lymphocytes and is reversed by JAK inhibition.
      ). Small molecule inhibitors can also be formulated topically, which will decrease the systemic effect and potential adverse reactions that can be associated with oral JAK inhibitor treatment.
      JAK inhibitors may hold promise in treating other inflammatory skin conditions, such as vitiligo, psoriasis, scarring alopecias, or atopic dermatitis, by blocking JAK/STAT-mediated inflammatory signaling. Delivery vehicle and individual JAK/STAT pathway targeting will be important in these applications, which also hold promise for the future treatment of a wide range of inflammatory skin conditions.

      Conflict of Interest

      AMC is a recipient of the research grant from Pfizer and Sanofi. She is also a consultant for Aclaris Therapeutics and Dermira. AMC is a shareholder of Aclaris Therapeutics.
      EHCW, BNS, and CIT state no conflicts of interest.

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