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JAK inhibitors in dermatology: The promise of a new drug class

Published:January 28, 2017DOI:https://doi.org/10.1016/j.jaad.2016.12.005
      New molecularly targeted therapeutics are changing dermatologic therapy. Janus kinase–signal transducer and activator of transcription (JAK-STAT) is an intracellular signaling pathway upon which many different proinflammatory signaling pathways converge. Numerous inflammatory dermatoses are driven by soluble inflammatory mediators, which rely on JAK-STAT signaling, and inhibition of this pathway using JAK inhibitors might be a useful therapeutic strategy for these diseases. Growing evidence suggests that JAK inhibitors are efficacious in atopic dermatitis, alopecia areata, psoriasis, and vitiligo. Additional evidence suggests that JAK inhibition might be broadly useful in dermatology, with early reports of efficacy in several other conditions. JAK inhibitors can be administered orally or used topically and represent a promising new class of medications. The use of JAK inhibitors in dermatology is reviewed here.

      Key words

      Abbreviations used:

      AA (alopecia areata), AD (atopic dermatitis), AT (alopecia totalis), AU (alopecia universalis), CANDLE (chronic atypical neutrophilic dermatoses with lipodystrophy and elevated temperature), FDA (Food and Drug Administration), IFN (interferon), IL (interleukin), JAK (Janus kinase), TH2 (helper T cell type 2), SALT (Severity of Alopecia Tool), SAVI (stimulator of interferon genes–associated vasculopathy with onset in infancy), STAT (signal transducer and activator of transcription), Tyk2 (tyrosine kinase 2)
      • Janus kinase–signal transducer and activator of transcription (JAK-STAT) signaling contributes to multiple inflammatory dermatoses.
      • Recent studies of JAK inhibitors suggest that they are efficacious for alopecia areata, atopic dermatitis, psoriasis, and vitiligo, and a large number of clinical trials are currently underway.
      • JAK inhibitors are likely to have broad applicability in dermatology.
      The Janus kinase–signal transducer and activator of transcription (JAK-STAT) pathway is utilized by cytokines including interleukins (ILs), interferons (IFNs), and other molecules to transmit signals from the cell membrane to the nucleus. Upon engagement of extracellular ligands, intracellular JAK proteins, which associate with type I/II cytokine receptors, become activated and phosphorylate STAT proteins, which dimerize and then translocate into the nucleus to directly regulate gene expression
      • Schwartz D.M.
      • Bonelli M.
      • Gadina M.
      • O'Shea J.J.
      Type I/II cytokines, Jaks, and new strategies for treating autoimmune diseases.
      • 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.
      (Fig 1). The JAK family of kinases includes JAK1, JAK2, JAK3, and tyrosine kinase 2 (Tyk2). Individual JAKs selectively associate with different receptors, but because only 4 JAKs exist, each member is used by multiple different receptors. The same is true of STATs, of which there are 7 family members (STAT 1, STAT 2, STAT 3, STAT 4, STAT 5a, STAT 5b, and STAT 6).
      • Schwartz D.M.
      • Bonelli M.
      • Gadina M.
      • O'Shea J.J.
      Type I/II cytokines, Jaks, and new strategies for treating autoimmune diseases.
      • 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.
      Figure thumbnail gr1
      Fig 1Janus kinase–signal transducer and activator of transcription (JAK-STAT) signaling pathway. JAK inhibitors antagonize JAK protein function and prevent activation of the pathway.
      Many inflammatory cytokines and other signaling molecules rely on JAK-STAT signaling, which is indispensable for immune and hematopoietic function. For example, loss-of-function mutations in JAK 3 cause severe combined immunodeficiency syndrome.
      • Macchi P.
      • Villa A.
      • Giliani S.
      • et al.
      Mutations of Jak-3 gene in patients with autosomal severe combined immune deficiency (SCID).
      • Russell S.M.
      • Tayebi N.
      • Nakajima H.
      • et al.
      Mutation of Jak3 in a patient with SCID: essential role of Jak3 in lymphoid development.
      Gain-of-function mutations in JAKs act as oncogenes in lymphoproliferative disorders and hematologic malignancies, including cutaneous T cell lymphoma.
      • Damsky W.E.
      • Choi J.
      Genetics of Cutaneous T cell lymphoma: from bench to bedside.
      • Yamaoka K.
      Janus kinase inhibitors for rheumatoid arthritis.
      • Choi J.
      • Goh G.
      • Walradt T.
      • et al.
      Genomic landscape of cutaneous T cell lymphoma.
      STAT genes are also essential for proper immune function and loss-of-function mutations in these proteins have been associated with immunodeficiency syndromes, including Job syndrome in the case of STAT 3.
      • Holland S.M.
      • DeLeo F.R.
      • Elloumi H.Z.
      • et al.
      STAT3 mutations in the hyper-IgE syndrome.
      Certain JAK-STAT polymorphisms are associated with an increased risk of developing autoimmune diseases.
      • Schwartz D.M.
      • Bonelli M.
      • Gadina M.
      • O'Shea J.J.
      Type I/II cytokines, Jaks, and new strategies for treating autoimmune diseases.
      In sporadic autoimmune and autoinflammatory conditions, a variety of disease-causing cytokines rely on JAK-STAT signaling to elicit their pathogenic effect.
      • Schwartz D.M.
      • Bonelli M.
      • Gadina M.
      • O'Shea J.J.
      Type I/II cytokines, Jaks, and new strategies for treating autoimmune diseases.
      • 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.
      Together these observations have led to the development of JAK inhibitors for the treatment of human disease.
      • Clark J.D.
      • Flanagan M.E.
      • Telliez J.B.
      Discovery and development of Janus kinase (JAK) inhibitors for inflammatory diseases.
      The first generation of JAK inhibitors includes tofacitinib, ruxolitinib, baricitinib, and oclacitinib (Table I). Ruxolitinib is Food and Drug Administration (FDA) approved to treat myelodysplastic disorders. Baricitinib is not yet FDA approved but is in clinical trials for rheumatoid arthritis (RA) (phase 3),
      • Genovese M.C.
      • Kremer J.
      • Zamani O.
      • et al.
      Baricitinib in patients with refractory rheumatoid arthritis.
      psoriasis (phase 2),
      • Papp K.A.
      • Menter M.A.
      • Raman M.
      • et al.
      A randomized phase 2b trial of baricitinib, an oral Janus kinase (JAK) 1/JAK2 inhibitor, in patients with moderate-to-severe psoriasis.
      and atopic dermatitis (phase 2, NCT02576938). The first FDA-approved JAK inhibitor for treatment of an autoimmune disease was tofacitinib, although it was initially studied as an antirejection agent in organ transplantation.
      • Changelian P.S.
      • Flanagan M.E.
      • Ball D.J.
      • et al.
      Prevention of organ allograft rejection by a specific Janus kinase 3 inhibitor.
      Oclacitinib has no FDA-approved indication in humans and is used for treatment of atopic dermatitis (AD) in dogs.
      • Cosgrove S.B.
      • Wren J.A.
      • Cleaver D.M.
      • et al.
      A blinded, randomized, placebo-controlled trial of the efficacy and safety of the Janus kinase inhibitor oclacitinib (Apoquel(R)) in client-owned dogs with atopic dermatitis.
      • Gonzales A.J.
      • Bowman J.W.
      • Fici G.J.
      • Zhang M.
      • Mann D.W.
      • Mitton-Fry M.
      Oclacitinib (APOQUEL((R))) is a novel Janus kinase inhibitor with activity against cytokines involved in allergy.
      Second generation JAK inhibitors are in development and will be discussed further below.
      Table IFirst generation JAK inhibitors
      DrugInhibitsFDA-approved indicationsFDA-approved dosage
      TofacitinibJAK1/3 > 2Rheumatoid arthritis5 mg, twice daily
      11 mg ER, once daily
      RuxolitinibJAK1/2Myelofibrosis5-25 mg, twice daily
      Polycythemia vera5-25 mg, twice daily
      BaricitinibJAK1/2NoneNone
      OclacitinibJAK1Canine atopic dermatitisN/a
      ER, Extended release; FDA, Food and Drug Administration; JAK, Janus kinase; N/a, not applicable.
      In the past 3 years, it has become clear that in addition to psoriasis JAK inhibitors might be useful for other inflammatory dermatologic conditions. Many of the following dermatologically relevant cytokines rely on the JAK-STAT pathway: IFN-α/β; IFN-γ; IL-2 receptor common γ-chain interleukins (IL-2, IL-4, IL-7, IL-9, IL-15, and IL-21); IL-5; IL-6; IL-12; IL-13; and IL-23 (Table II). Although other cytokines such as tumor necrosis factor–α, IL-1, and IL-17 do not signal via the JAK-STAT pathway, in some instances JAK inhibitors can indirectly suppress certain cytokines (ie, IL-17) by inhibition of other STAT-dependent cytokines (ie, IL-23) that act upstream.
      • Schwartz D.M.
      • Bonelli M.
      • Gadina M.
      • O'Shea J.J.
      Type I/II cytokines, Jaks, and new strategies for treating autoimmune diseases.
      • Ghoreschi K.
      • Jesson M.I.
      • Li X.
      • et al.
      Modulation of innate and adaptive immune responses by tofacitinib (CP-690,550).
      • Takatsu K.
      • Nakajima H.
      IL-5 and eosinophilia.
      Table IISummary of JAK-inhibitor use in the treatment of dermatologic conditions
      DiseaseEvidence for oral therapyEvidence for topical therapy
      Alopecia areataOCT-tofacitinib
      • Kennedy Crispin M.
      • Ko J.M.
      • Craiglow B.G.
      • et al.
      Safety and efficacy of the JAK inhibitor tofacitinib citrate in patients with alopecia areata.
      CR-ruxolitinib
      • Craiglow B.G.
      • Tavares D.
      • King B.A.
      Topical ruxolitinib for the treatment of alopecia universalis.
      OCT-ruxolitinib
      • Mackay-Wiggan J.
      • Jabbari A.
      • Nguyen N.
      • et al.
      Oral ruxolitinib induces hair regrowth in patients with moderate-to-severe alopecia areata.
      CS-tofacitinib
      • 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.
      • Craiglow B.G.
      • Liu L.Y.
      • King B.A.
      Tofacitinib for the treatment of alopecia areata in adolescents.
      CR-tofacitinib
      • Craiglow B.G.
      • King B.A.
      Killing two birds with one stone: oral tofacitinib reverses alopecia universalis in a patient with plaque psoriasis.
      • Dhayalan A.
      • King B.A.
      Tofacitinib Citrate for the treatment of nail dystrophy associated with alopecia universalis.
      • Jabbari A.
      • Nguyen N.
      • Cerise J.E.
      • et al.
      Treatment of an alopecia areata patient with tofacitinib results in regrowth of hair and changes in serum and skin biomarkers.
      • Anzengruber F.
      • Maul J.T.
      • Kamarachev J.
      • Trueb R.M.
      • French L.E.
      • Navarini A.A.
      Transient efficacy of tofacitinib in alopecia areata universalis.

      U. Mrowietz, S. Gerdes, R. Glaser, O. Schroder, Successful treatment of refractory alopecia areata universalis and psoriatic arthritis, but not of plaque psoriasis with tofacitinib in a young woman. Acta Derm Venereol. http.//dx.doi.org/10.2340/00015555-2491, published online June 28, 2016.

      • Gupta A.K.
      • Carviel J.L.
      • Abramovits W.
      Efficacy of tofacitinib in treatment of alopecia universalis in two patients.
      CR-ruxolitinib
      • Xing L.
      • Dai Z.
      • Jabbari A.
      • et al.
      Alopecia areata is driven by cytotoxic T lymphocytes and is reversed by JAK inhibition.
      • Harris J.E.
      • Rashighi M.
      • Nguyen N.
      • et al.
      Rapid skin repigmentation on oral ruxolitinib in a patient with coexistent vitiligo and alopecia areata (AA).
      • Pieri L.
      • Guglielmelli P.
      • Vannucchi A.M.
      Ruxolitinib-induced reversal of alopecia universalis in a patient with essential thrombocythemia.
      • Higgins E.
      • Al Shehri T.
      • McAleer M.A.
      • 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.
      CR-baricitinib
      • Jabbari A.
      • Dai Z.
      • Xing L.
      • et al.
      Reversal of alopecia areata following treatment with the JAK1/2 inhibitor baricitinib.
      Atopic dermatitisCS-tofacitinib
      • Levy L.L.
      • Urban J.
      • King B.A.
      Treatment of recalcitrant atopic dermatitis with the oral Janus kinase inhibitor tofacitinib citrate.
      RCT-tofacitinib
      • Bissonnette R.
      • Papp K.A.
      • Poulin Y.
      • et al.
      Topical tofacitinib for atopic dermatitis: a phase IIa randomized trial.
      Chronic actinic dermatitisCR-tofacitinib
      • Vesely M.D.
      • Imaeda S.
      • King B.
      Tofacitinib citrate for the treatment of refractory, severe chronic actinic dermatitis.
      Chronic mucocutaneous candidiasisCR-ruxolitinib
      • Higgins E.
      • Al Shehri T.
      • McAleer M.A.
      • 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.
      • Mossner R.
      • Diering N.
      • Bader O.
      • et al.
      Ruxolitinib induces interleukin 17 and ameliorates chronic mucocutaneous candidiasis caused by STAT1 gain-of-function mutation.
      Cutaneous T-cell lymphomaOther
      • Damsky W.E.
      • Choi J.
      Genetics of Cutaneous T cell lymphoma: from bench to bedside.
      DermatomyositisCR-tofacitinib
      • Kurtzman D.J.
      • Wright N.A.
      • Lin J.
      • et al.
      Tofacitinib citrate for refractory cutaneous dermatomyositis: an alternative treatment.

      J.J. Paik, L. Christopher-Stine, A case of refractory dermatomyositis responsive to tofacitinib, Semin Arthritis Rheum. http://dx.doi.org/10.2340/00015555-2491, published online August 17, 2016.

      CR-ruxolitinib
      • Hornung T.
      • Janzen V.
      • Heidgen F.J.
      • Wolf D.
      • Bieber T.
      • Wenzel J.
      Remission of recalcitrant dermatomyositis treated with ruxolitinib.
      Erythema multiformeCR-tofacitinib
      • Damsky W.
      • King B.A.
      Idiopathic erythema multiforme: evidence of underlying JAK-STAT activation and successful treatment with tofacitinib.
      Graft-versus-host disease (cutaneous)CS-ruxolitinib
      • Zeiser R.
      • Burchert A.
      • Lengerke C.
      • et al.
      Ruxolitinib in corticosteroid-refractory graft-versus-host disease after allogeneic stem cell transplantation: a multicenter survey.
      Hypereosinophilic syndromeCS-tofacitinib

      King B, Lee AI, Choi J. Treatment of hypereosinophilic syndrome with cutaneous involvement with JAK inhibitors tofacitinib and ruxolitinib. J Invest Dermatol. doi: 10.1016/j.jid.2016.10.044. Published online November 22, 2016.

      Lupus erythematosusCR-tofacitinib
      • Yamamoto M.
      • Yokoyama Y.
      • Shimizu Y.
      • et al.
      Tofacitinib can decrease anti-DNA antibody titers in inactive systemic lupus erythematosus complicated by rheumatoid arthritis.

      N. Konig, C. Fiehn, C. Wolf, et al. Familial chilblain lupus due to a gain-of-function mutation in STING. Ann Rheum Dis. http://dx.doi.org/10.1136/annrheumdis-2016-209841, published online August 26, 2016.

      CR-ruxolitinib
      • Wenzel J.
      • van Holt N.
      • Maier J.
      • Vonnahme M.
      • Bieber T.
      • Wolf D.
      JAK1/2 inhibitor ruxolitinib controls a case of chilblain lupus erythematosus.
      Mastocytosis and mast cell diseaseCR-ruxolitinib
      • Yacoub A.
      • Prochaska L.
      Ruxolitinib improves symptoms and quality of life in a patient with systemic mastocytosis.
      STING vasculopathyCR-tofacitinib

      N. Konig, C. Fiehn, C. Wolf, et al. Familial chilblain lupus due to a gain-of-function mutation in STING. Ann Rheum Dis. http://dx.doi.org/10.1136/annrheumdis-2016-209841, published online August 26, 2016.

      CR-ruxolitinib
      • Fremond M.L.
      • Rodero M.P.
      • Jeremiah N.
      • et al.
      Efficacy of the Janus kinase 1/2 inhibitor ruxolitinib in the treatment of vasculopathy associated with TMEM173-activating mutations in 3 children.
      Palmoplantar pustulosisCR-tofacitinib
      • Koga T.
      • Sato T.
      • Umeda M.
      • et al.
      Successful treatment of palmoplantar pustulosis with rheumatoid arthritis, with tofacitinib: impact of this JAK inhibitor on T-cell differentiation.
      Polyarteritis nodosaCR-tofacitinib
      • Rimar D.
      • Alpert A.
      • Starosvetsky E.
      • et al.
      Tofacitinib for polyarteritis nodosa: a tailored therapy.
      PsoriasisRCT-tofacitinib
      • Papp K.A.
      • Menter M.A.
      • Abe M.
      • et al.
      Tofacitinib, an oral Janus kinase inhibitor, for the treatment of chronic plaque psoriasis: results from two randomized, placebo-controlled, phase III trials.
      • Bachelez H.
      • van de Kerkhof P.C.
      • Strohal R.
      • et al.
      Tofacitinib versus etanercept or placebo in moderate-to-severe chronic plaque psoriasis: a phase 3 randomised non-inferiority trial.
      RCT-tofacitinib
      • Ports W.C.
      • Khan S.
      • Lan S.
      • et al.
      A randomized phase 2a efficacy and safety trial of the topical Janus kinase inhibitor tofacitinib in the treatment of chronic plaque psoriasis.
      • Papp K.A.
      • Bissonnette R.
      • Gooderham M.
      • et al.
      Treatment of plaque psoriasis with an ointment formulation of the Janus kinase inhibitor, tofacitinib: a phase 2b randomized clinical trial.
      RCT-baricitinib
      • Papp K.A.
      • Menter M.A.
      • Raman M.
      • et al.
      A randomized phase 2b trial of baricitinib, an oral Janus kinase (JAK) 1/JAK2 inhibitor, in patients with moderate-to-severe psoriasis.
      CS-ruxolitinib
      • Punwani N.
      • Burn T.
      • Scherle P.
      • et al.
      Downmodulation of key inflammatory cell markers with a topical Janus kinase 1/2 inhibitor.
      Others
      Multiple earlier studies not included.
      VitiligoCR-tofacitinib
      • Craiglow B.G.
      • King B.A.
      Tofacitinib citrate for the treatment of vitiligo: a pathogenesis-directed therapy.
      CS-ruxolitinib

      ClinicalTrials.gov. NCT02809976. 2016.

      CR-ruxolitinib
      • Harris J.E.
      • Rashighi M.
      • Nguyen N.
      • et al.
      Rapid skin repigmentation on oral ruxolitinib in a patient with coexistent vitiligo and alopecia areata (AA).
      Other designates in vitro data on human tumor cells.
      CR, Case reports (<5 patients/study); CS, case series (≥5 patients/study); JAK, Janus kinase; OCT, open-label clinical trial; RCT, randomized-controlled trial; STING, stimulator of interferon genes.
      Multiple earlier studies not included.
      To date, JAK inhibitors have shown efficacy in the treatment of dermatologic conditions such as AD, alopecia areata (AA), psoriasis, and vitiligo, among others. Both new, oral JAK inhibitors and topical JAK inhibitors are being developed and studied in these and other dermatologic conditions. Smaller case series and case reports suggest efficacy in dermatomyositis, chronic actinic dermatitis, erythema multiforme, hypereosinophilic syndrome, cutaneous graft-versus-host disease, and lupus, among others.

      Atopic dermatitis

      The pathogenesis of AD is complex but in part involves increased helper T cell type 2 (TH2) immunity driven by JAK-STAT signaling downstream of cytokines, such as IL-4, IL-5, and IL-13.
      • Leung D.Y.
      • Guttman-Yassky E.
      Deciphering the complexities of atopic dermatitis: shifting paradigms in treatment approaches.
      In experimental models, tofacitinib and oclacitinib inhibit IL-4 and IL-13–dependent TH2 differentiation.
      • Gonzales A.J.
      • Bowman J.W.
      • Fici G.J.
      • Zhang M.
      • Mann D.W.
      • Mitton-Fry M.
      Oclacitinib (APOQUEL((R))) is a novel Janus kinase inhibitor with activity against cytokines involved in allergy.
      • Ghoreschi K.
      • Jesson M.I.
      • Li X.
      • et al.
      Modulation of innate and adaptive immune responses by tofacitinib (CP-690,550).
      • Bao L.
      • Zhang H.
      • Chan L.S.
      The involvement of the JAK-STAT signaling pathway in chronic inflammatory skin disease atopic dermatitis.
      In a mouse model of AD, a topical JAK inhibitor, JTE-053, resulted in decreased IL-4 and IL-13 signaling and improved skin barrier function.
      • Amano W.
      • Nakajima S.
      • Kunugi H.
      • et al.
      The Janus kinase inhibitor JTE-052 improves skin barrier function through suppressing signal transducer and activator of transcription 3 signaling.
      The efficacy of oral tofacitinib was recently reported in 6 consecutive patients with moderate-to-severe AD that previously failed all common treatments, including systemic agents.
      • Levy L.L.
      • Urban J.
      • King B.A.
      Treatment of recalcitrant atopic dermatitis with the oral Janus kinase inhibitor tofacitinib citrate.
      Tofacitinib 5 mg daily or twice daily led to a 66.6% reduction in the Severity Scoring of AD Index and a 69.9% reduction in pruritus and sleep loss scores.
      • Levy L.L.
      • Urban J.
      • King B.A.
      Treatment of recalcitrant atopic dermatitis with the oral Janus kinase inhibitor tofacitinib citrate.
      While this study lacked a control group, the improvement achieved by 6 patients who had failed common therapies was suggestive of a positive benefit of tofacitinib.
      A recently published randomized, double-blind, placebo-controlled phase 2a trial showed that treatment of 69 adults with mild-to-moderate AD with tofacitinib 2% ointment resulted in an 81.7% reduction in the Eczema Area and Severity Index score at 4 weeks relative to a decrease of 29.9% in the placebo group.
      • Bissonnette R.
      • Papp K.A.
      • Poulin Y.
      • et al.
      Topical tofacitinib for atopic dermatitis: a phase IIa randomized trial.
      Additional clinical trials evaluating both oral and topical JAK inhibitors for AD are underway (NCT02001181, NCT02576938, NCT02780167) and will help to define the efficacy of JAK inhibitors in AD.

      Alopecia areata

      The pathogenesis of AA involves hair follicle attack by autoreactive CD8+ T cells.
      • Gilhar A.
      • Schrum A.G.
      • Etzioni A.
      • Waldmann H.
      • Paus R.
      Alopecia areata: animal models illuminate autoimmune pathogenesis and novel immunotherapeutic strategies.
      In AA, JAK-STAT dependent cytokines, including IFN-γ and IL-15, drive proliferation and activation of autoreactive T cells,
      • Gilhar A.
      • Schrum A.G.
      • Etzioni A.
      • Waldmann H.
      • Paus R.
      Alopecia areata: animal models illuminate autoimmune pathogenesis and novel immunotherapeutic strategies.
      suggesting that JAK inhibition might be an effective treatment. In a mouse model of AA, both systemic and topical JAK inhibitors (tofacitinib and ruxolitinib) promoted hair regrowth.
      • Xing L.
      • Dai Z.
      • Jabbari A.
      • et al.
      Alopecia areata is driven by cytotoxic T lymphocytes and is reversed by JAK inhibition.
      In 2014, a patient with both alopecia universalis (AU) and psoriasis was treated with tofacitinib, and complete regrowth of scalp and body hair, as well as eyelashes and eyebrows, occurred within 8 months.
      • Craiglow B.G.
      • King B.A.
      Killing two birds with one stone: oral tofacitinib reverses alopecia universalis in a patient with plaque psoriasis.
      Since then, 2 open-label clinical trials and multiple case series of adolescent and adult patients and case reports have been published (Table II). In one trial, tofacitinib 5 mg twice daily was given to 66 patients with severe AA, alopecia totalis (AT), or AU. After the 3-month treatment period, nearly two-thirds of patients showed some hair regrowth and 32% of patients achieved a >50% improvement in their Severity of Alopecia Tool (SALT) score.
      • Kennedy Crispin M.
      • Ko J.M.
      • Craiglow B.G.
      • et al.
      Safety and efficacy of the JAK inhibitor tofacitinib citrate in patients with alopecia areata.
      In the second study, treatment of 12 patients with moderate-to-severe AA with ruxolitinib 20 mg twice daily for 3-6 months resulted in a marked treatment response in 9 patients, with an average of 92% hair regrowth.
      • Mackay-Wiggan J.
      • Jabbari A.
      • Nguyen N.
      • et al.
      Oral ruxolitinib induces hair regrowth in patients with moderate-to-severe alopecia areata.
      Hair loss appears to recur with treatment discontinuation.
      • Kennedy Crispin M.
      • Ko J.M.
      • Craiglow B.G.
      • et al.
      Safety and efficacy of the JAK inhibitor tofacitinib citrate in patients with alopecia areata.
      • Mackay-Wiggan J.
      • Jabbari A.
      • Nguyen N.
      • et al.
      Oral ruxolitinib induces hair regrowth in patients with moderate-to-severe alopecia areata.
      Recently, 2 retrospective studies showed successful treatment of severe AA, AT, and AU over a period up to 18 months using tofacitinib. In 65 adults with either AT or AU with duration of current episode ≤10 years or severe AA, 77% of patients achieved some hair regrowth, with 58% achieving >50% improvement and 20% achieving >90% improvement in SALT score. Hair regrowth was attenuated in patients with AT and AU with duration >10 years.
      • 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.
      In a series of adolescents (12-17 years old) with severe AA, AT, and AU, treatment with tofacitinib resulted in a 93% median change in SALT score from baseline after an average of 6.5 months of treatment.
      • Craiglow B.G.
      • Liu L.Y.
      • King B.A.
      Tofacitinib for the treatment of alopecia areata in adolescents.
      Although this study lacked a control group, spontaneous improvement in patients with long-standing, severe disease is unlikely, so these results are promising.
      In 3 patients with AU and nail dystrophy, tofacitinib 5 mg twice daily for 5-6 months resulted in remission of nail dystrophy.
      • Dhayalan A.
      • King B.A.
      Tofacitinib Citrate for the treatment of nail dystrophy associated with alopecia universalis.
      The use of oral JAK inhibitors in AA remains an active area of clinical investigation.
      As in AD, topical JAK inhibitors are under investigation in AA. In one report, a patient treated with compounded ruxolitinib 0.6% cream applied twice daily for 12 weeks to the eyebrows and scalp led to complete eyebrow regrowth and partial scalp hair regrowth.
      • Craiglow B.G.
      • Tavares D.
      • King B.A.
      Topical ruxolitinib for the treatment of alopecia universalis.
      Clinical trials with topical ruxolitinib (INCB018424) and topical tofacitinib are presently underway in AA (NCT02553330, NCT02812342).

      Psoriasis

      JAK-STAT–dependent cytokines IL-12 and IL-23 are fundamental mediators of psoriasis.
      • Teng M.W.
      • Bowman E.P.
      • McElwee J.J.
      • et al.
      IL-12 and IL-23 cytokines: from discovery to targeted therapies for immune-mediated inflammatory diseases.
      • Di Lernia V.
      • Bardazzi F.
      Profile of tofacitinib citrate and its potential in the treatment of moderate-to-severe chronic plaque psoriasis.
      IL-23 stimulates TH17 cells to produce IL-17, another important pathogenic molecule in psoriasis. Although IL-17 does not rely on JAK-STAT signaling, blockade of upstream IL-23 using JAK inhibitors such as tofacitinib indirectly results in a decrease in IL-17.
      • Ghoreschi K.
      • Jesson M.I.
      • Li X.
      • et al.
      Modulation of innate and adaptive immune responses by tofacitinib (CP-690,550).
      • Teng M.W.
      • Bowman E.P.
      • McElwee J.J.
      • et al.
      IL-12 and IL-23 cytokines: from discovery to targeted therapies for immune-mediated inflammatory diseases.
      To date, in dermatology, psoriasis has been the most heavily studied indication for JAK inhibitors. JAK inhibitor use in psoriasis has recently been extensively reviewed
      • Di Lernia V.
      • Bardazzi F.
      Profile of tofacitinib citrate and its potential in the treatment of moderate-to-severe chronic plaque psoriasis.
      and will be only briefly reviewed here.
      The efficacy of tofacitinib in moderate-to-severe plaque psoriasis was shown in phase 3 randomized controlled trials.
      • Papp K.A.
      • Menter M.A.
      • Abe M.
      • et al.
      Tofacitinib, an oral Janus kinase inhibitor, for the treatment of chronic plaque psoriasis: results from two randomized, placebo-controlled, phase III trials.
      • Bachelez H.
      • van de Kerkhof P.C.
      • Strohal R.
      • et al.
      Tofacitinib versus etanercept or placebo in moderate-to-severe chronic plaque psoriasis: a phase 3 randomised non-inferiority trial.
      In one of the studies, the Psoriasis Area Severity Index 75 response to tofacitinib at 12 weeks was 39.5% and 63.6% in the 5 mg twice daily and 10 mg twice daily groups, respectively.
      • Bachelez H.
      • van de Kerkhof P.C.
      • Strohal R.
      • et al.
      Tofacitinib versus etanercept or placebo in moderate-to-severe chronic plaque psoriasis: a phase 3 randomised non-inferiority trial.
      Tofacitinib at 10 mg twice daily was determined to be noninferior to etanercept therapy (50 mg subcutaneously twice weekly).
      • Bachelez H.
      • van de Kerkhof P.C.
      • Strohal R.
      • et al.
      Tofacitinib versus etanercept or placebo in moderate-to-severe chronic plaque psoriasis: a phase 3 randomised non-inferiority trial.
      Rates of adverse events appeared to be similar with both the 5 mg and 10 mg dosing regimens.
      • Papp K.A.
      • Menter M.A.
      • Abe M.
      • et al.
      Tofacitinib, an oral Janus kinase inhibitor, for the treatment of chronic plaque psoriasis: results from two randomized, placebo-controlled, phase III trials.
      • Bachelez H.
      • van de Kerkhof P.C.
      • Strohal R.
      • et al.
      Tofacitinib versus etanercept or placebo in moderate-to-severe chronic plaque psoriasis: a phase 3 randomised non-inferiority trial.
      Comparable results were present in another trial.
      • Papp K.A.
      • Menter M.A.
      • Abe M.
      • et al.
      Tofacitinib, an oral Janus kinase inhibitor, for the treatment of chronic plaque psoriasis: results from two randomized, placebo-controlled, phase III trials.
      The FDA has yet to approve tofacitinib for this indication.
      Baricitinib, still in clinical trials and not yet FDA approved for any condition, was recently reported to be efficacious in moderate-to-severe plaque psoriasis in a phase 2b trial.
      • Papp K.A.
      • Menter M.A.
      • Raman M.
      • et al.
      A randomized phase 2b trial of baricitinib, an oral Janus kinase (JAK) 1/JAK2 inhibitor, in patients with moderate-to-severe psoriasis.
      In this 12-week dose ranging study, patients treated with 8 mg and 10 mg once daily achieved Psoriasis Area Severity Index 75 responses of 43% and 54%, respectively.
      • Papp K.A.
      • Menter M.A.
      • Raman M.
      • et al.
      A randomized phase 2b trial of baricitinib, an oral Janus kinase (JAK) 1/JAK2 inhibitor, in patients with moderate-to-severe psoriasis.
      The use of topical JAK inhibitors has been explored in psoriasis. Ruxolitinib (INCB018424) 1.0% and 1.5% creams applied twice daily led to reduction in psoriasis lesion size over 4 weeks.
      • Punwani N.
      • Burn T.
      • Scherle P.
      • et al.
      Downmodulation of key inflammatory cell markers with a topical Janus kinase 1/2 inhibitor.
      Improvement in psoriasis was also observed with tofacitinib 2% ointment; however, the degree of improvement relative to controls was modest and not always statistically significant.
      • Ports W.C.
      • Khan S.
      • Lan S.
      • et al.
      A randomized phase 2a efficacy and safety trial of the topical Janus kinase inhibitor tofacitinib in the treatment of chronic plaque psoriasis.
      • Papp K.A.
      • Bissonnette R.
      • Gooderham M.
      • et al.
      Treatment of plaque psoriasis with an ointment formulation of the Janus kinase inhibitor, tofacitinib: a phase 2b randomized clinical trial.

      Vitiligo

      Vitiligo is mediated by targeted destruction of melanocytes by CD8+ T cells, with IFN-γ playing a central role in disease pathogenesis.
      • Harris J.E.
      • Harris T.H.
      • Weninger W.
      • Wherry E.J.
      • Hunter C.A.
      • Turka L.A.
      A mouse model of vitiligo with focused epidermal depigmentation requires IFN-gamma for autoreactive CD8(+) T-cell accumulation in the skin.
      • Rashighi M.
      • Agarwal P.
      • Richmond J.M.
      • et al.
      CXCL10 is critical for the progression and maintenance of depigmentation in a mouse model of vitiligo.
      Because IFN-γ signaling utilizes the JAK-STAT pathway, vitiligo might be susceptible to treatment with JAK inhibitors. For example, treatment of a patient with generalized vitiligo with tofacitinib resulted in near complete repigmentation of affected areas of the face, forearms, and hands over 5 months
      • Craiglow B.G.
      • King B.A.
      Tofacitinib citrate for the treatment of vitiligo: a pathogenesis-directed therapy.
      ; however, depigmentation recurred after discontinuing tofacitinib. In another report, a patient who had both vitiligo and AA was treated with ruxolitinib 20 mg twice daily and over 20 weeks experienced significant facial repigmentation; depigmentation recurred after discontinuing ruxolitinib.
      • Harris J.E.
      • Rashighi M.
      • Nguyen N.
      • et al.
      Rapid skin repigmentation on oral ruxolitinib in a patient with coexistent vitiligo and alopecia areata (AA).
      A pilot study involving 12 patients with vitiligo is underway investigating the efficacy of ruxolitinib 1.5% cream applied twice daily (NCT02809976). Larger controlled studies will be important for elucidating the role of JAK inhibitors in the treatment of vitiligo.

      Topical JAK inhibitors

      While not commercially available, the use of topical JAK inhibitors has been explored in AD, psoriasis, AA, and vitiligo. Multiple studies are ongoing in this area. The data for topical therapy in each disease are discussed above and summarized in Table II.

      Safety data

      Safety data for tofacitinib is derived from large clinical trials in rheumatoid arthritis and psoriasis,
      • Wollenhaupt J.
      • Silverfield J.
      • Lee E.B.
      • et al.
      Safety and efficacy of tofacitinib, an oral Janus kinase inhibitor, for the treatment of rheumatoid arthritis in open-label, longterm extension studies.
      • He Y.
      • Wong A.Y.
      • Chan E.W.
      • et al.
      Efficacy and safety of tofacitinib in the treatment of rheumatoid arthritis: a systematic review and meta-analysis.
      • Cohen S.
      • Radominski S.C.
      • Gomez-Reino J.J.
      • et al.
      Analysis of infections and all-cause mortality in phase II, phase III, and long-term extension studies of tofacitinib in patients with rheumatoid arthritis.
      • Papp K.A.
      • Krueger J.G.
      • Feldman S.R.
      • et al.
      Tofacitinib, an oral Janus kinase inhibitor, for the treatment of chronic plaque psoriasis: long-term efficacy and safety results from 2 randomized phase-III studies and 1 open-label long-term extension study.
      and data for ruxolitinib are from clinical trials in myelofibrosis and polycythemia vera.
      • Verstovsek S.
      • Mesa R.A.
      • Gotlib J.
      • et al.
      Efficacy, safety, and survival with ruxolitinib in patients with myelofibrosis: results of a median 3-year follow-up of COMFORT-I.
      • Arana Yi C.
      • Tam C.S.
      • Verstovsek S.
      Efficacy and safety of ruxolitinib in the treatment of patients with myelofibrosis.
      • O'Sullivan J.M.
      • McLornan D.P.
      • Harrison C.N.
      Safety considerations when treating myelofibrosis.
      The risk of infection and overall mortality in patients treated with tofacitinib is not significantly different from that observed with other targeted immunosuppressive therapies.
      • Wollenhaupt J.
      • Silverfield J.
      • Lee E.B.
      • et al.
      Safety and efficacy of tofacitinib, an oral Janus kinase inhibitor, for the treatment of rheumatoid arthritis in open-label, longterm extension studies.
      • He Y.
      • Wong A.Y.
      • Chan E.W.
      • et al.
      Efficacy and safety of tofacitinib in the treatment of rheumatoid arthritis: a systematic review and meta-analysis.
      • Cohen S.
      • Radominski S.C.
      • Gomez-Reino J.J.
      • et al.
      Analysis of infections and all-cause mortality in phase II, phase III, and long-term extension studies of tofacitinib in patients with rheumatoid arthritis.
      With ruxolitinib, the most common infection was urinary tract infection.
      • Verstovsek S.
      • Mesa R.A.
      • Gotlib J.
      • et al.
      Efficacy, safety, and survival with ruxolitinib in patients with myelofibrosis: results of a median 3-year follow-up of COMFORT-I.
      • O'Sullivan J.M.
      • McLornan D.P.
      • Harrison C.N.
      Safety considerations when treating myelofibrosis.
      With both tofacitinib and ruxolitinib, the risk for varicella zoster virus reactivation increases,
      • Verstovsek S.
      • Mesa R.A.
      • Gotlib J.
      • et al.
      Efficacy, safety, and survival with ruxolitinib in patients with myelofibrosis: results of a median 3-year follow-up of COMFORT-I.
      • O'Sullivan J.M.
      • McLornan D.P.
      • Harrison C.N.
      Safety considerations when treating myelofibrosis.
      • Winthrop K.L.
      • Yamanaka H.
      • Valdez H.
      • et al.
      Herpes zoster and tofacitinib therapy in patients with rheumatoid arthritis.
      but it is usually limited to localized disease. Impaired response to vaccination has been reported with tofacitinib and is theoretically a risk with ruxolitnib, too. Therefore, when possible, immunizations should be performed prior to initiating therapy with JAK inhibitors.
      • Schwartz D.M.
      • Bonelli M.
      • Gadina M.
      • O'Shea J.J.
      Type I/II cytokines, Jaks, and new strategies for treating autoimmune diseases.
      • Winthrop K.L.
      • Silverfield J.
      • Racewicz A.
      • et al.
      The effect of tofacitinib on pneumococcal and influenza vaccine responses in rheumatoid arthritis.
      Increases in total cholesterol, low-density lipoprotein, and high-density lipoprotein have been reported with tofacitinib and ruxolitinib therapy but are typically mild.
      • Schwartz D.M.
      • Bonelli M.
      • Gadina M.
      • O'Shea J.J.
      Type I/II cytokines, Jaks, and new strategies for treating autoimmune diseases.
      • Papp K.A.
      • Krueger J.G.
      • Feldman S.R.
      • et al.
      Tofacitinib, an oral Janus kinase inhibitor, for the treatment of chronic plaque psoriasis: long-term efficacy and safety results from 2 randomized phase-III studies and 1 open-label long-term extension study.
      • Mesa R.A.
      • Verstovsek S.
      • Gupta V.
      • et al.
      Effects of ruxolitinib treatment on metabolic and nutritional parameters in patients with myelofibrosis from COMFORT-I.
      • Souto A.
      • Salgado E.
      • Maneiro J.R.
      • Mera A.
      • Carmona L.
      • Gomez-Reino J.J.
      Lipid profile changes in patients with chronic inflammatory arthritis treated with biologic agents and tofacitinib in randomized clinical trials: a systematic review and meta-analysis.
      Patients treated with JAK inhibitors do not appear to have an increased risk for major adverse cardiac events or stroke.
      • Wollenhaupt J.
      • Silverfield J.
      • Lee E.B.
      • et al.
      Safety and efficacy of tofacitinib, an oral Janus kinase inhibitor, for the treatment of rheumatoid arthritis in open-label, longterm extension studies.
      • Papp K.A.
      • Krueger J.G.
      • Feldman S.R.
      • et al.
      Tofacitinib, an oral Janus kinase inhibitor, for the treatment of chronic plaque psoriasis: long-term efficacy and safety results from 2 randomized phase-III studies and 1 open-label long-term extension study.
      • Wu J.J.
      • Strober B.E.
      • Hansen P.R.
      • et al.
      Effects of tofacitinib on cardiovascular risk factors and cardiovascular outcomes based on phase III and long-term extension data in patients with plaque psoriasis.
      • Charles-Schoeman C.
      • Wicker P.
      • Gonzalez-Gay M.A.
      • et al.
      Cardiovascular safety findings in patients with rheumatoid arthritis treated with tofacitinib, an oral Janus kinase inhibitor.
      Cytopenias are another potential adverse effect of JAK inhibitors, primarily JAK2 inhibitors, because signaling through JAK2 is mediated by erythropoietin, thrombopoietin, and granulocyte colony-stimulating factor.
      • Schwartz D.M.
      • Bonelli M.
      • Gadina M.
      • O'Shea J.J.
      Type I/II cytokines, Jaks, and new strategies for treating autoimmune diseases.
      Accordingly, cytopenias are more commonly encountered with ruxolitinib than tofacitinib due to its greater ability to inhibit JAK2. In the treatment of bone marrow disorders with ruxolitinib, thrombocytopenia, in particular, can lead to reduced patient doses,
      • Galli S.
      • McLornan D.
      • Harrison C.
      Safety evaluation of ruxolitinib for treating myelofibrosis.
      but in a study of 12 patients with AA treated with ruxolitinib 20 mg twice daily for up to 6 months, neither this nor other cytopenias were observed.
      • Mackay-Wiggan J.
      • Jabbari A.
      • Nguyen N.
      • et al.
      Oral ruxolitinib induces hair regrowth in patients with moderate-to-severe alopecia areata.
      One explanation might be that patients with healthy bone marrows are less prone to cytopenias observed during JAK2 inhibition.
      A concern with JAK inhibitors is a theoretical increased risk for malignancy because immunosuppression could dampen antitumor immune surveillance. Initial studies of tofacitinib in renal transplantation showed that ∼1% of patients treated with tofacitinib developed post-transplant lymphoproliferative disorder.
      • Vincenti F.
      • Silva H.T.
      • Busque S.
      • et al.
      Evaluation of the effect of tofacitinib exposure on outcomes in kidney transplant patients.
      • Busque S.
      • Leventhal J.
      • Brennan D.C.
      • et al.
      Calcineurin-inhibitor-free immunosuppression based on the JAK inhibitor CP-690,550: a pilot study in de novo kidney allograft recipients.
      • Vincenti F.
      • Tedesco Silva H.
      • Busque S.
      • et al.
      Randomized phase 2b trial of tofacitinib (CP-690,550) in de novo kidney transplant patients: efficacy, renal function and safety at 1 year.
      However, in these studies patients were treated with high doses of tofacitinib (10-30 mg twice daily) in combination with other immunosuppressive agents (ie, IL-2 receptor anatagonists, mycophenolate mofetil, and corticosteroids). An increased risk of lymphoproliferative disorders and other cancers has not been apparent when tofacitinib is used to treat inflammatory disorders, such as rheumatoid arthritis and psoriasis
      • Wollenhaupt J.
      • Silverfield J.
      • Lee E.B.
      • et al.
      Safety and efficacy of tofacitinib, an oral Janus kinase inhibitor, for the treatment of rheumatoid arthritis in open-label, longterm extension studies.
      • Papp K.A.
      • Krueger J.G.
      • Feldman S.R.
      • et al.
      Tofacitinib, an oral Janus kinase inhibitor, for the treatment of chronic plaque psoriasis: long-term efficacy and safety results from 2 randomized phase-III studies and 1 open-label long-term extension study.
      • Curtis J.R.
      • Lee E.B.
      • Kaplan I.V.
      • et al.
      Tofacitinib, an oral Janus kinase inhibitor: analysis of malignancies across the rheumatoid arthritis clinical development programme.
      • Yamanaka H.
      • Tanaka Y.
      • Takeuchi T.
      • et al.
      Tofacitinib, an oral Janus kinase inhibitor, as monotherapy or with background methotrexate, in Japanese patients with rheumatoid arthritis: an open-label, long-term extension study.
      ; longer term studies, however, will more definitively answer this question. In patients with myelofibrosis and polycythemia vera treated with ruxolitinib, no increased risk for developing a second malignancy has been shown.
      • Al-Ali H.K.
      • Griesshammer M.
      • le Coutre P.
      • et al.
      Safety and efficacy of ruxolitinib in an open-label, multicenter, single-arm phase 3b expanded-access study in patients with myelofibrosis: a snapshot of 1144 patients in the JUMP trial.
      • Verstovsek S.
      • Vannucchi A.M.
      • Griesshammer M.
      • et al.
      Ruxolitinib versus best available therapy in patients with polycythemia vera: 80-week follow-up from the RESPONSE trial.

      Use of JAK inhibitors

      The FDA-approved dosage for tofacitinib in rheumatoid arthritis is 5 mg twice daily. A new extended-release formulation (11 mg once daily) is also available. In clinical trials on psoriasis, tofacitinib 10 mg twice daily was more efficacious than 5 mg twice daily and adverse events did not seem to increase with the higher dosage.
      • Papp K.A.
      • Menter M.A.
      • Abe M.
      • et al.
      Tofacitinib, an oral Janus kinase inhibitor, for the treatment of chronic plaque psoriasis: results from two randomized, placebo-controlled, phase III trials.
      • Bachelez H.
      • van de Kerkhof P.C.
      • Strohal R.
      • et al.
      Tofacitinib versus etanercept or placebo in moderate-to-severe chronic plaque psoriasis: a phase 3 randomised non-inferiority trial.
      On the basis of the current literature describing treatments for inflammatory skin disorders, 5 mg twice daily is often sufficient but 10 mg twice daily is sometimes required. Dose reduction is required with severe renal impairment, with moderate hepatic impairment, or with the use of medications such as fluconazole and ketoconazole, which inhibit CYP3A4 and CYP2C9.
      The FDA-approved dosage of ruxolitinib for myelofibrosis and polycythemia vera ranges from 5 mg to 25 mg twice daily. Twenty milligrams twice daily was used in the open-label clinical trial in AA.
      • Mackay-Wiggan J.
      • Jabbari A.
      • Nguyen N.
      • et al.
      Oral ruxolitinib induces hair regrowth in patients with moderate-to-severe alopecia areata.
      Similar to tofacitinib, dose adjustment with ruxolitinib is required in the setting of concomitant CYP3A4 and CYP2C9 inhibitors, as well as with hepatic and renal impairment.
      Prior to treatment with tofacitinib or ruxolitinib, serologic screening, including complete blood count, creatinine and hepatic function panel, and fasting lipid panel together with hepatitis B, hepatitis C, and tuberculosis testing is recommended. We also suggest screening for HIV. Subsequently, monitoring complete blood count, creatinine and hepatic function panel, and fasting lipid panel 1 month after treatment and then every 3 months thereafter is recommended. Tuberculosis screening should be performed annually.

      Conclusions and future directions

      In addition to the conditions already discussed, JAK inhibitors have shown promise in multiple other dermatologic diseases, including dermatomyositis, chronic actinic dermatitis, erythema multiforme, hypereosinophilic syndrome, cutaneous graft-versus-host disease, and lupus, among others (Table II). Preclinical data suggests that JAK inhibition might be a viable strategy to treat multiple other dermatoses, including allergic contact dermatitis
      • Fujii Y.
      • Sengoku T.
      Effects of the Janus kinase inhibitor CP-690550 (tofacitinib) in a rat model of oxazolone-induced chronic dermatitis.
      • Fridman J.S.
      • Scherle P.A.
      • Collins R.
      • et al.
      Preclinical evaluation of local JAK1 and JAK2 inhibition in cutaneous inflammation.
      and interface dermatoses, such as lichen planus,
      • Okiyama N.
      • Fujimoto M.
      Clinical perspectives and murine models of lichenoid tissue reaction/interface dermatitis.
      • Di Lernia V.
      Targeting the IFN-gamma/CXCL10 pathway in lichen planus.
      • Alves de Medeiros A.K.
      • Speeckaert R.
      • Desmet E.
      • Van Gele M.
      • De Schepper S.
      • Lambert J.
      JAK3 as an emerging target for topical treatment of inflammatory skin diseases.
      B-cell–mediated disorders,
      • Wang S.P.
      • Iwata S.
      • Nakayamada S.
      • Sakata K.
      • Yamaoka K.
      • Tanaka Y.
      Tofacitinib, a JAK inhibitor, inhibits human B cell activation in vitro.
      pyoderma gangrenosum,
      • Alves de Medeiros A.K.
      • Speeckaert R.
      • Desmet E.
      • Van Gele M.
      • De Schepper S.
      • Lambert J.
      JAK3 as an emerging target for topical treatment of inflammatory skin diseases.
      chronic cutaneous lupus,
      • Alves de Medeiros A.K.
      • Speeckaert R.
      • Desmet E.
      • Van Gele M.
      • De Schepper S.
      • Lambert J.
      JAK3 as an emerging target for topical treatment of inflammatory skin diseases.
      and eosinophil related disorders.
      • Kudlacz E.
      • Conklyn M.
      • Andresen C.
      • Whitney-Pickett C.
      • Changelian P.
      The JAK-3 inhibitor CP-690550 is a potent anti-inflammatory agent in a murine model of pulmonary eosinophilia.
      • Walker S.
      • Wang C.
      • Walradt T.
      • et al.
      Identification of a gain-of-function STAT3 mutation (p.Y640F) in lymphocytic variant hypereosinophilic syndrome.
      There is a compassionate use protocol for JAK1 and JAK2 inhibition in rare autoinflammatory syndromes including SAVI (stimulator of interferon genes–associated vasculopathy with onset in infancy), CANDLE (chronic atypical neutrophilic dermatoses with lipodystrophy and elevated temperature) syndrome, and juvenile dermatomyositis (NCT01724580).
      Presently at least 25 separate clinical trials are underway to evaluate the use of JAK inhibitors in a variety of autoimmune and inflammatory diseases.
      • Schwartz D.M.
      • Bonelli M.
      • Gadina M.
      • O'Shea J.J.
      Type I/II cytokines, Jaks, and new strategies for treating autoimmune diseases.
      A new generation of JAK inhibitors, including both pan-JAK inhibitors (JAK1, JAK2, JAK3, and Tyk2) and selective JAK inhibitors (ie, JAK1 only or JAK3 only), are being developed.
      • 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.
      • Jabbari A.
      • Dai Z.
      • Xing L.
      • et al.
      Reversal of alopecia areata following treatment with the JAK1/2 inhibitor baricitinib.
      • Ludbrook V.J.
      • Hicks K.J.
      • Hanrott K.E.
      • et al.
      Investigation of selective JAK1 inhibitor GSK2586184 for the treatment of psoriasis in a randomized placebo-controlled phase IIa study.
      • Bissonnette R.
      • Luchi M.
      • Fidelus-Gort R.
      • et al.
      A randomized, double-blind, placebo-controlled, dose-escalation study of the safety and efficacy of INCB039110, an oral Janus kinase 1 inhibitor, in patients with stable, chronic plaque psoriasis.
      • Farmer L.J.
      • Ledeboer M.W.
      • Hoock T.
      • et al.
      Discovery of VX-509 (decernotinib): a potent and selective Janus kinase 3 inhibitor for the treatment of autoimmune diseases.
      • Cao Y.J.
      • Sawamoto T.
      • Valluri U.
      • et al.
      Pharmacokinetics, pharmacodynamics, and safety of ASP015K (peficitinib), a new Janus kinase inhibitor, in healthy subjects.
      • Takeuchi T.
      • Tanaka Y.
      • Iwasaki M.
      • Ishikura H.
      • Saeki S.
      • Kaneko Y.
      Efficacy and safety of the oral Janus kinase inhibitor peficitinib (ASP015K) monotherapy in patients with moderate to severe rheumatoid arthritis in Japan: a 12-week, randomised, double-blind, placebo-controlled phase IIb study.
      • Works M.G.
      • Yin F.
      • Yin C.C.
      • et al.
      Inhibition of TYK2 and JAK1 ameliorates imiquimod-induced psoriasis-like dermatitis by inhibiting IL-22 and the IL-23/IL-17 axis.
      • Ishizaki M.
      • Muromoto R.
      • Akimoto T.
      • et al.
      Tyk2 is a therapeutic target for psoriasis-like skin inflammation.
      The advent of JAK inhibitors in dermatology has been met with great interest. This class of medications has the potential to substantially advance the treatment of inflammatory dermatoses.

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