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JAK Inhibitors for the Treatment of Pediatric Alopecia Areata

      Alopecia areata is a common autoimmune condition that disproportionately affects children and can significantly hinder quality of life. Few safe and effective therapies are available for the treatment of severely affected pediatric patients. JAK inhibitors have been recently established as an effective and well-tolerated therapy in adults, but there are limited data regarding the use of JAK inhibitors to treat alopecia areata in children. Here, we review the available literature regarding the use of JAK inhibitors in children in dermatology and across other medical disciplines.

      Abbreviations:

      AA (alopecia areata), AT (alopecia totalis), AU (alopecia universalis), JAK-STAT (JAK-signal transducer and activator of transcription)

      Introduction

      Alopecia areata (AA) is a common autoimmune condition characterized by nonscarring hair loss. Severity of presentation ranges from small, well-circumscribed patches of alopecia to complete loss of hair on the scalp (alopecia totalis, AT) or the body (alopecia universalis, AU). The prevalence of AA in the United States is 0.1–0.2% (
      • Safavi K.
      Prevalence of alopecia areata in the first National Health and Nutrition Examination Survey.
      ) with 5% of patients progressing to AT or AU (
      • Safavi K.H.
      • Muller S.A.
      • Suman V.J.
      • Moshell A.N.
      • Melton 3rd, L.J.
      Incidence of alopecia areata in Olmsted County, Minnesota, 1975 through 1989.
      ).
      Although not an exclusively pediatric condition (
      • 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.
      ), AA disproportionately affects a younger subset of patients (
      • Kyriakis K.P.
      • Paltatzidou K.
      • Kosma E.
      • Sofouri E.
      • Tadros A.
      • Rachioti E.
      Alopecia areata prevalence by gender and age.
      ,
      • Muller S.A.
      • Winkelmann R.K.
      Alopecia areata. An evaluation of 736 patients.
      ) with studies reporting 31–48% of patients developing the condition before the age of 20 years (
      • Shellow W.V.
      • Edwards J.E.
      • Koo J.Y.
      Profile of alopecia areata: a questionnaire analysis of patient and family.
      ,
      • Tan E.
      • Tay Y.K.
      • Goh C.L.
      • Chin Giam Y.
      The pattern and profile of alopecia areata in Singapore--a study of 219 Asians.
      ). Of note, pediatric-onset AA tends to be more severe and carries a worse prognosis than adult-onset disease (
      • De Waard-van der Spek F.B.
      • Oranje A.P.
      • De Raeymaecker D.M.
      • Peereboom-Wynia J.D.
      Juvenile versus maturity-onset alopecia areata--a comparative retrospective clinical study.
      ,
      • Xiao F.L.
      • Yang S.
      • Liu J.B.
      • He P.P.
      • Yang J.
      • Cui Y.
      • et al.
      The epidemiology of childhood alopecia areata in China: a study of 226 patients.
      ). Early age of onset and concomitant atopy are both strong negative prognostic factors (
      • Goh C.
      • Finkel M.
      • Christos P.J.
      • Sinha A.A.
      Profile of 513 patients with alopecia areata: associations of disease subtypes with atopy, autoimmune disease and positive family history.
      ,
      • Muller S.A.
      • Winkelmann R.K.
      Alopecia areata. An evaluation of 736 patients.
      ). Survey studies, although inherently biased toward severe phenotypes, suggest that up to half of pediatric patients presenting with localized AA could progress to AT or AU (
      • Goh C.
      • Finkel M.
      • Christos P.J.
      • Sinha A.A.
      Profile of 513 patients with alopecia areata: associations of disease subtypes with atopy, autoimmune disease and positive family history.
      ,
      • Tosti A.
      • Bellavista S.
      • Iorizzo M.
      Alopecia areata: a long term follow-up study of 191 patients.
      ). AA can severely affect mental health and quality of life in pediatric patients. Children with AA have higher rates of psychiatric disorders, and an AA diagnosis in a child is correlated with a reduction in health-related quality of life for both the child, driven by feeling of self-consciousness, and for caregivers, driven by emotional distress and financial burden (
      • Bilgiç Ö.
      • Bilgiç A.
      • Bahalı K.
      • Bahali A.G.
      • Gürkan A.
      • Yılmaz S.
      Psychiatric symptomatology and health-related quality of life in children and adolescents with alopecia areata.
      ,
      • Liu L.Y.
      • King B.A.
      • Craiglow B.G.
      Alopecia areata is associated with impaired health-related quality of life: a survey of affected adults and children and their families.
      ,
      • Putterman E.
      • Patel D.P.
      • Andrade G.
      • Harfmann K.L.
      • Hogeling M.
      • Cheng C.E.
      • et al.
      Severity of disease and quality of life in parents of children with alopecia areata, totalis, and universalis: a prospective, cross-sectional study.
      ).
      Despite the prevalence of AA in children and the negative impact on the quality of life for patients and families affected, there is a relative paucity of literature focusing on therapy for AA in pediatric patients. Common therapies include topical, subcutaneous or systemic corticosteroids, topical minoxidil, topical contact-sensitizing agents, and rarely, nonsteroidal systemic immunosuppressants such as methotrexate (reviewed in
      • Peloquin L.
      • Castelo-Soccio L.
      Alopecia areata: an update on treatment options for children.
      ). Although a subset of patients will respond favorably to these regimens (response rates in studies focused on children ranged from 13% to 64%), patients with severe disease often have limited benefit and rate of relapse in responders is high, ranging from 70% to 100% at 1 to 2 years after treatment (
      • Peloquin L.
      • Castelo-Soccio L.
      Alopecia areata: an update on treatment options for children.
      ). In younger children, treatment is hindered by poor tolerance of painful procedures or irritating topical formulations. The use of systemic immunosuppressants, particularly systemic steroids, is further limited by side effects and concern regarding the long-term consequences of these regimens on developing children. Given these challenges of treating AA in children, some practitioners prefer to focus care on education, counseling, and psychological support for affected children and their families rather than resolution of disease.
      In the last few years, the JAK-signal transducer and activator of transcription (JAK-STAT) pathway has been implicated in the pathogenesis of a number of inflammatory dermatoses, sparking interest in investigating inhibitors of the JAK receptor family (JAK1, JAK2, JAK3, and tyrosine kinase 2) in the treatment of dermatological conditions.
      Various first-generation JAK inhibitors, which include ruxolitinib (JAK1/2 inhibitor), tofacitinib (JAK1/3 >2 inhibitor) and baricitinib (JAK1/2 inhibitor), have been found to be highly efficacious and well tolerated in patients with psoriasis, atopic dermatitis, vitiligo, and AA among others (reviewed in
      • Damsky W.
      • King B.A.
      JAK inhibitors in dermatology: the promise of a new drug class.
      ). Studies of AA mouse models revealed the importance of JAK-STAT signaling for development of autoreactive cluster of differentiation 8 (CD8+) T-cell targeting of the hair follicle and confirmed that JAK inhibitors promoted hair regrowth in affected animals (
      • 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.
      ). The first patient with AA treated with tofacitinib was reported in 2014 (
      • Craiglow B.G.
      • King B.A.
      Killing two birds with one stone: oral tofacitinib reverses alopecia universalis in a patient with plaque psoriasis.
      ), and since then, a number of case series (
      • Ibrahim O.
      • Bayart C.B.
      • Hogan S.
      • Piliang M.
      • Bergfeld W.F.
      Treatment of alopecia areata with tofacitinib.
      ,
      • Liu L.Y.
      • King B.A.
      Response to tofacitinib therapy of eyebrows and eyelashes in alopecia areata.
      ,
      • 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.
      ,
      • Park H.S.
      • Kim M.W.
      • Lee J.S.
      • Yoon H.S.
      • Huh C.H.
      • Kwon O.
      • et al.
      Oral tofacitinib monotherapy in Korean patients with refractory moderate-to-severe alopecia areata: a case series.
      ) and a few small clinical trials (
      • Almutairi N.
      • Nour T.M.
      • Hussain N.H.
      Janus kinase inhibitors for the treatment of severe alopecia areata: an open-label comparative study.
      ,
      • 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.
      ,
      • 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.
      ) have demonstrated hair regrowth in adult patients with moderate to severe AA treated with JAK inhibitors. Responses were muted in patients with long-standing disease and relapse often occurred upon cessation of therapy. Topical formulations of JAK inhibitors, while less effective for severe presentations (
      • Bokhari L.
      • Sinclair R.
      Treatment of alopecia universalis with topical Janus kinase inhibitors - a double blind, placebo, and active controlled pilot study.
      ,
      • Craiglow B.G.
      • Tavares D.
      • King B.A.
      Topical ruxolitinib for the treatment of alopecia universalis.
      ,
      • Phan K.
      • Sebaratnam D.F.
      JAK inhibitors for alopecia areata: a systematic review and meta-analysis.
      ) have been found to be a useful adjunct therapy for patients with limited disease or distinct areas of desired regrowth (e.g., eyebrows and eyelashes [
      • Craiglow B.G.
      Topical tofacitinib solution for the treatment of alopecia areata affecting eyelashes.
      ]).
      The safety of long-term JAK inhibitor use has been a major focus of investigation as the utility of this drug class has been established in dermatology. Use of tofacitinib and ruxolitinib is associated with increased rates of infection (most commonly urinary tract infection and varicella zoster virus reactivation), lipid abnormalities, and rarely cytopenias and treatment-associated malignancies (reviewed in
      • Damsky W.
      • King B.A.
      JAK inhibitors in dermatology: the promise of a new drug class.
      ). Although associated with serious adverse events in the setting of treatment of hematological malignancy (cytopenias) or transplant immunosuppression (malignancy), at the lower doses required for efficacy in inflammatory dermatoses, JAK inhibitors have been well tolerated. A recent meta-analysis of 313 patients treated with JAK inhibitors for AA reported overall low complication rates associated with treatment (
      • Phan K.
      • Sebaratnam D.F.
      JAK inhibitors for alopecia areata: a systematic review and meta-analysis.
      ). The most common adverse events were mild infections (24.6%), lipid abnormalities (11.8%), transaminitis (1.6%), and leukopenia (1.0%). No malignancies or tuberculosis reactivation events were observed. Several clinical trials exploring the use of JAK inhibitors for AA are currently underway to more systematically assess safety in larger patient cohorts.
      In contrast, there is substantially less data describing the use of JAK inhibitors in children (Table 1). We reviewed the available literature regarding JAK inhibitors in the pediatric population, both for the treatment of AA as well as other conditions. A search was performed in PubMed using combinations of the following search terms: “ruxolitinib,” “baricitinib,” “tofacitinib,” “JAK inhibitor,” “janus kinase inhibitor,” “child,” “adolescent,” “children,” “pediatric” along the MeSh terms: “child” and “adolescent,” producing a list of 170 publications. These were then screened to remove duplicates, retaining only those studies that described the direct treatment of a child (<18 years) with a JAK inhibitor, were in English, and were in full publication form (i.e., not simply an abstract with limited supporting information).
      Table 1JAK Inhibitor Use in Pediatric Alopecia Areata
      PublicationDrugRouteDosePatients (n)Age (y)ResponseReported Side Effects
      • Dai Y.X.
      • Chen C.C.
      Tofacitinib therapy for children with severe alopecia areata.
      TofacitinibOral2.5 mg QD; 2.5, 5 mg alt QD34–550–90% regrowthMild: diarrhea, URI
      • Liu L.Y.
      • King B.A.
      Ruxolitinib for the treatment of severe alopecia areata.
      RuxolitinibOral10 mg BID11491% change in SALTMild: URI, weight gain, acne, drop in WBC
      Side effects listed for all patients in study but only one was an adolescent. Specific side effects experienced by this patient were not listed.
      • Brown L.
      • Skopit S.
      An excellent response to tofacitinib in a pediatric alopecia patient: a case report and review.
      TofacitinibOral5 mg BID148100% change in SALTTreatment limiting HA
      • Craiglow B.G.
      • King B.A.
      Tofacitinib for the treatment of alopecia areata in preadolescent children.
      TofacitinibOral5 mg BID8–100–100% regrowthNone
      • Patel N.U.
      • Oussedik E.
      • Grammenos A.
      • Pichardo-Geisinger R.
      A case report highlighting the effective treatment of alopecia universalis with tofacitinib in an adolescent and adult patient.
      TofacitinibOral5 mg BID11785% change in SALTWeight gain
      • Castelo-Soccio L.
      Experience with oral tofacitinib in 8 adolescent patients with alopecia universalis.
      TofacitinibOral5 mg BID612–1652–79% change in SALTNone
      • Craiglow B.G.
      • Liu L.Y.
      • King B.A.
      Tofacitinib for the treatment of alopecia areata and variants in adolescents.
      TofacitinibOral5 mg BID; 5, 10 mg alt BID1312–171–100% change in SALTMild: HA, URI, transaminitis
      • Putterman E.
      • Castelo-Soccio L.
      Topical 2% tofacitinib for children with alopecia areata, alopecia totalis, and alopecia universalis.
      TofacitinibTopical2%114–1632.3% average change in SALTApplication site irritation
      • Bayart C.B.
      • DeNiro K.L.
      • Brichta L.
      • Craiglow B.G.
      • Sidbury R.
      Topical Janus kinase inhibitors for the treatment of pediatric alopecia areata.
      Tofacitinib, ruxolitinibTopical1%, 2%61–164 of 6 patients; 20–95% regrowthMild laboratory abnormalities
      • Craiglow B.G.
      • Tavares D.
      • King B.A.
      Topical ruxolitinib for the treatment of alopecia universalis.
      RuxolitinibTopical0.60%1Late teens100% growth eyebrows; 10% scalpMild drop in WBC
      Abbreviations: alt, alternating; BID, twice daily; HA, headache; QD, daily; SALT, Severity of Alopecia Tool; URI, upper respiratory infection; WBC, white blood cell count.
      1 Side effects listed for all patients in study but only one was an adolescent. Specific side effects experienced by this patient were not listed.

      Results

      Only a handful of case series and reports have investigated the safety and efficacy of JAK inhibitors for AA in children and adolescents. In two case series of patients aged 12–17 years with AA treated with tofacitinib, 9 of 13 (
      • Craiglow B.G.
      • Liu L.Y.
      • King B.A.
      Tofacitinib for the treatment of alopecia areata and variants in adolescents.
      ) and 6 of 6 treated patients (
      • Castelo-Soccio L.
      Experience with oral tofacitinib in 8 adolescent patients with alopecia universalis.
      ) experienced clinically significant hair regrowth. Both studies dosed tofacitinib at standard levels of 5 mg twice daily, although one patient required an increased dose of 5 mg in the morning and 10 mg in the evening to achieve optimal regrowth after relapse (
      • Craiglow B.G.
      • Liu L.Y.
      • King B.A.
      Tofacitinib for the treatment of alopecia areata and variants in adolescents.
      ). A small case series also investigated the use of tofacitinib in preadolescent children and included four patients with AT or AU aged 8 to 10 years dosed at 5 mg twice daily (
      • Craiglow B.G.
      • King B.A.
      Tofacitinib for the treatment of alopecia areata in preadolescent children.
      ). Two patients experienced complete regrowth at 3 and 6 months, respectively, and a third demonstrated 62% regrowth at 6 months of treatment. Most recently, a small report investigated the use of tofacitinib in three younger children aged 4 to 5 years with AT or AU (
      • Dai Y.X.
      • Chen C.C.
      Tofacitinib therapy for children with severe alopecia areata.
      ). Drug dosing was initiated at 2.5 mg daily. At this dose, two patients experienced clinically significant regrowth with >90% improvement after 12 months. The third patient required a dose increase to 2.5 mg 4 days per week and 5 mg 3 days per week at 6 months, ultimately achieving full regrowth of eyebrows and eyelashes and 50% regrowth of scalp hair at 21 months. Several individual cases of children treated with JAK inhibitors for AA have also been reported with similar results (Table 1). Taken as a whole, these studies demonstrated success rates for systemic JAK inhibitors in children comparable with those found in adults, with a number of dramatic responses and a smaller subset of poor responders. Side effects were minimal and included mild infections, diarrhea, and transient laboratory abnormalities. Although suggestive of JAK inhibitors being a well-tolerated treatment of AA in children, these small case series must be followed with randomized controlled trials to reach definitive conclusions.
      Given the concern regarding long term consequences of JAK inhibitors in developing children, a few studies have focused on the use of topical JAK inhibitors for AA in the pediatric population. A series of six patients aged 3–17 years treated with application of 2% tofacitinib or 1–2% ruxolitinib found variable responses (20–95% improvement) in 4 of 6 patients (
      • Bayart C.B.
      • DeNiro K.L.
      • Brichta L.
      • Craiglow B.G.
      • Sidbury R.
      Topical Janus kinase inhibitors for the treatment of pediatric alopecia areata.
      ). One patient who did not respond to 2% tofacitinib in a nonliposomal base experienced complete regrowth when switched to a liposomal vehicle, demonstrating the importance of the vehicle composition in drug penetration. Another series of 11 pediatric patients ranging from 4 to 11 years treated with 2% tofacitinib experienced an average of 32.3% change in Severity of Alopecia Tool score (
      • Putterman E.
      • Castelo-Soccio L.
      Topical 2% tofacitinib for children with alopecia areata, alopecia totalis, and alopecia universalis.
      ). However, only 3 of 11 patients in this trial were deemed to have cosmetically acceptable growth. A final case report of a single patient in her late teens exhibited near full regrowth of eyebrows after 12 weeks of treatment with 0.6% ruxolitinib cream but only 10% regrowth of scalp hair (
      • Craiglow B.G.
      • Tavares D.
      • King B.A.
      Topical ruxolitinib for the treatment of alopecia universalis.
      ). Of note, in all three studies investigating topical JAK inhibitors in children, minimal adverse effects were noted, consisting of mild laboratory abnormalities and application site irritation. Overall, topical JAK inhibitors in children appear to be best employed in the treatment of localized disease with limited utility in the treatment of more extensive AA, as is the case for adult patients.
      JAK inhibitors have been investigated more extensively in pediatric patients in other medical disciplines, particularly rheumatology and oncology (Table 2). Although mostly consisting of small case reports and case series, there are three larger studies: a phase 1 trial of ruxolitinib in children with refractory solid tumors and hematological malignancies (
      • Loh M.L.
      • Tasian S.K.
      • Rabin K.R.
      • Brown P.
      • Magoon D.
      • Reid J.M.
      • et al.
      A phase 1 dosing study of ruxolitinib in children with relapsed or refractory solid tumors, leukemias, or myeloproliferative neoplasms: a Children's Oncology Group phase 1 consortium study (ADVL1011).
      ), a phase 1 trial of tofacitinib in children with juvenile idiopathic arthritis (
      • Ruperto N.
      • Brunner H.I.
      • Zuber Z.
      • Tzaribachev N.
      • Kingsbury D.J.
      • Foeldvari I.
      • et al.
      Pharmacokinetic and safety profile of tofacitinib in children with polyarticular course juvenile idiopathic arthritis: results of a phase 1, open-label, multicenter study.
      ), and a compassionate use protocol using baricitinib in patients with the rare Mendelian interferonopathies (
      • Kim H.
      • Brooks K.M.
      • Tang C.C.
      • Wakim P.
      • Blake M.
      • Brooks S.R.
      • et al.
      Pharmacokinetics, pharmacodynamics, and proposed dosing of the oral JAK1 and JAK2 inhibitor baricitinib in pediatric and young adult CANDLE and SAVI patients.
      ,
      • Sanchez G.A.M.
      • Reinhardt A.
      • Ramsey S.
      • Wittkowski H.
      • Hashkes P.J.
      • Berkun Y.
      • et al.
      JAK1/2 inhibition with baricitinib in the treatment of autoinflammatory interferonopathies.
      ). These larger studies provide important insight into the pharmacokinetics of JAK inhibitors in children, which can be vastly different than in adult patients. In patients under 40 kg baricitinib had a significantly shorter half-life than found in adults, necessitating 3–4 times daily dosing for optimal effect. Drug levels varied by renal function and weight, and given these complexities, the authors provided an extensive dosing table for baricitinib initial dosing and two dose escalations, organized by weight and glomerular filtration rate (
      • Kim H.
      • Brooks K.M.
      • Tang C.C.
      • Wakim P.
      • Blake M.
      • Brooks S.R.
      • et al.
      Pharmacokinetics, pharmacodynamics, and proposed dosing of the oral JAK1 and JAK2 inhibitor baricitinib in pediatric and young adult CANDLE and SAVI patients.
      ). Analysis of tofacitinib in patients with juvenile idiopathic arthritis also observed a similarly shorter half-life in children as well as a faster clearance rate than expected, requiring higher dosage than that suggested by adult pharmacokinetic studies (
      • Ruperto N.
      • Brunner H.I.
      • Zuber Z.
      • Tzaribachev N.
      • Kingsbury D.J.
      • Foeldvari I.
      • et al.
      Pharmacokinetic and safety profile of tofacitinib in children with polyarticular course juvenile idiopathic arthritis: results of a phase 1, open-label, multicenter study.
      ). In contrast, in children with relapsed malignancies treated with escalating doses of ruxolitinib determined by surface area (15, 21, 29, 39, 50 mg/m2/dose), pharmacokinetics were comparable with that in adults. Toxicities were comparable across all doses tested, and the highest dose (50 mg/m2) was recommended for future trials in patients with cancer (
      • Loh M.L.
      • Tasian S.K.
      • Rabin K.R.
      • Brown P.
      • Magoon D.
      • Reid J.M.
      • et al.
      A phase 1 dosing study of ruxolitinib in children with relapsed or refractory solid tumors, leukemias, or myeloproliferative neoplasms: a Children's Oncology Group phase 1 consortium study (ADVL1011).
      ).
      Table 2JAK Inhibitor Use in Nondermatological Pediatric Disciplines
      DisciplineConditionPublicationDrugDosePatients (n)Age (y)Notable Adverse Events
      Oncology
      GVHD
      • Bauters T.
      • Bordon V.
      • Laureys G.
      • Dhooge C.
      Combined use of ruxolitinib and sirolimus: increased monitoring of triglycerides required.
      RuxolitinibUnspecified110Hypertriglyceridemia with sirolimus
      • González Vicent M.
      • Molina B.
      • González de Pablo J.
      • Castillo A.
      • Díaz M.Á.
      Ruxolitinib treatment for steroid refractory acute and chronic graft vs host disease in children: clinical and immunological results.
      RuxolitinibInfants: 2.5 mg QD; Children: <25 kg–2.5 mg BID; ≥25 kg–5 mg BID; Adolescents: 10 mg BID220.4–18Grade 3 liver toxicity, unrelated to drug; Viral, fungal, bacterial infections; Mild thrombocytopenia
      • Schoettler M.
      • Duncan C.
      • Lehmann L.
      • Furutani E.
      • Subramaniam M.
      • Margossian S.
      Ruxolitinib is an effective steroid sparing agent in children with steroid refractory/dependent bronchiolitis obliterans syndrome after allogenic hematopoietic cell transplantation.
      Ruxolitinib5 mg–10 mg BID; 1 patient 2.5 mg TIW57–21Grade 3 fungal infection while also on corticosteroid
      • Khandelwal P.
      • Teusink-Cross A.
      • Davies S.M.
      • Nelson A.S.
      • Dandoy C.E.
      • El-Bietar J.
      • et al.
      Ruxolitinib as salvage therapy in steroid-refractory acute graft-versus-host disease in pediatric hematopoietic stem cell transplant patients.
      Ruxolitinib<25 kg: 2.5 mg BID; ≥25 kg: 5 mg BID111–16Grade 3–4 elevated transaminases; Grade 3–4 neutropenia, grade 4 thrombocytopenia; infections: EBV, adenovirus, BK, bacterial, fungal
      ALL
      • Ding Y.Y.
      • Stern J.W.
      • Jubelirer T.F.
      • Wertheim G.B.
      • Lin F.
      • Chang F.
      • et al.
      Clinical efficacy of ruxolitinib and chemotherapy in a child with Philadelphia chromosome-like acute lymphoblastic leukemia with GOLGA5-JAK2 fusion and induction failure.
      Ruxolitinib40 mg/m2/dose twice daily110Grade 4 transaminitis, transient; No further cytopenia or toxicities beyond typical chemotherapy
      • Mayfield J.R.
      • Czuchlewski D.R.
      • Gale J.M.
      • Matlawska-Wasowska K.
      • Vasef M.A.
      • Nickl C.
      • et al.
      Integration of ruxolitinib into dose-intensified therapy targeted against a novel JAK2 F694L mutation in B-precursor acute lymphoblastic leukemia.
      Ruxolitinib40 mg/m2/d split twice daily117Persistent thrombocytopenia and neutropenia
      CML
      • Freedman J.L.
      • Desai A.V.
      • Bailey L.C.
      • Aplenc R.
      • Burnworth B.
      • Zehentner B.K.
      • et al.
      Atypical chronic myeloid leukemia in two pediatric patients.
      Ruxolitinib50 mg/m2/d111
      Lymphoma
      • Hanna D.M.T.
      • Fellowes A.
      • Vedururu R.
      • Mechinaud F.
      • Hansford J.R.
      A unique case of refractory primary mediastinal B-cell lymphoma with JAK3 mutation and the role for targeted therapy.
      Tofacitinib15 mg BID114
      PV
      • Coskun M.E.
      • Height S.
      • Dhawan A.
      • Hadzic N.
      Ruxolitinib treatment in an infant with JAK2+ polycythaemia vera-associated Budd-Chiari syndrome.
      Ruxolitinib5 mg BID titrated up to 25 mg BID12None
      Various cancers
      • Loh M.L.
      • Tasian S.K.
      • Rabin K.R.
      • Brown P.
      • Magoon D.
      • Reid J.M.
      • et al.
      A phase 1 dosing study of ruxolitinib in children with relapsed or refractory solid tumors, leukemias, or myeloproliferative neoplasms: a Children's Oncology Group phase 1 consortium study (ADVL1011).
      Ruxolitinib15, 21, 29, 39, 50 mg/m2/dose, BID491–221 grade 5 multiorgan failure at 21 mg/m2/dose; 2 grade 4 neutropenia events at 29 and 39 mg/m2/dose; 1 grade 4 CK elevation at 50 mg/m2/dose
      Rheumatology
      CMC
      • Bloomfield M.
      • Kanderová V.
      • Paračková Z.
      • Vrabcová P.
      • Svatoň M.
      • Froňková E.
      • et al.
      Utility of ruxolitinib in a child with chronic mucocutaneous candidiasis caused by a novel STAT1 gain-of-function mutation.
      Ruxolitinib10 mg BID (20 mg/m2/d)
      Dose was later decreased by 50% owing to drug interactions.
      112URI
      Interferonopathy
      • Kim H.
      • Brooks K.M.
      • Tang C.C.
      • Wakim P.
      • Blake M.
      • Brooks S.R.
      • et al.
      Pharmacokinetics, pharmacodynamics, and proposed dosing of the oral JAK1 and JAK2 inhibitor baricitinib in pediatric and young adult CANDLE and SAVI patients.
      These works analyze the same cohort of patients.
      Baricitinib0.1–17 mg/d (0.01–0.82 mg/kg/d); PK analysis to establish dosing181–24Kidney disease secondary to BK infection; Viral infections: URI, VZV, BK viruria, and viremia; Osteonecrosis
      • Saldanha R.G.
      • Balka K.R.
      • Davidson S.
      • Wainstein B.K.
      • Wong M.
      • Macintosh R.
      • et al.
      A mutation outside the dimerization domain causing atypical STING-associated vasculopathy with onset in infancy.
      Ruxolitinib5 mg daily13Partial response leading to nasal septal destruction
      • Sanchez G.A.M.
      • Reinhardt A.
      • Ramsey S.
      • Wittkowski H.
      • Hashkes P.J.
      • Berkun Y.
      • et al.
      JAK1/2 inhibition with baricitinib in the treatment of autoinflammatory interferonopathies.
      These works analyze the same cohort of patients.
      Baricitinib0.1–17 mg/d (0.01–0.82 mg/kg/d)181–24Kidney disease secondary to BK infection; Viral infections: URI, VZV, BK viruria, and viremia; Osteonecrosis
      • Frémond M.L.
      • Rodero M.P.
      • Jeremiah N.
      • Belot A.
      • Jeziorski E.
      • Duffy D.
      • et al.
      Efficacy of the Janus kinase 1/2 inhibitor ruxolitinib in the treatment of vasculopathy associated with TMEM173-activating mutations in 3 children.
      RuxolitinibNot specified35–12Papillary edema
      JIA
      • Ruperto N.
      • Brunner H.I.
      • Zuber Z.
      • Tzaribachev N.
      • Kingsbury D.J.
      • Foeldvari I.
      • et al.
      Pharmacokinetic and safety profile of tofacitinib in children with polyarticular course juvenile idiopathic arthritis: results of a phase 1, open-label, multicenter study.
      Tofacitinib2–5 mg BID262–18Fatigue
      Juvenile DM
      • Papadopoulou C.
      • Hong Y.
      • Omoyinmi E.
      • Brogan P.A.
      • Eleftheriou D.
      Janus kinase 1/2 inhibition with baricitinib in the treatment of juvenile dermatomyositis.
      Baricitinib6 mg BID111None
      • Aeschlimann F.A.
      • Frémond M.L.
      • Duffy D.
      • Rice G.I.
      • Charuel J.L.
      • Bondet V.
      • et al.
      A child with severe juvenile dermatomyositis treated with ruxolitinib.
      Ruxolitinib10 mg BID (0.5 mg/kg/d)113None
      Abbreviations: ALL, acute lymphocytic leukemia; BID, twice daily; CK, creatine kinase; CMC, chronic mucocutaneous candidiasis; CML, chronic myeloid leukemia; DM, dermatomyositis; GVHD, graft-versus-host disease; JIA, juvenile idiopathic arthritis; PK, pharmacokinetic; PV, polycythemia vera; QD, daily; SALT, Severity of Alopecia Tool; TIW, three times weekly; URI, upper respiratory infection; VZV, varicella zoster virus.
      1 Dose was later decreased by 50% owing to drug interactions.
      2 These works analyze the same cohort of patients.
      These studies also give insight into safety of this drug class in larger cohorts of children. As in adults, these drugs are well tolerated, with most adverse events resulting from increased susceptibility to mild infection, particularly viral infections, including Epstein Barr virus, BK virus, adenovirus, and varicella zoster virus, among others (Table 1). However, there were a few serious complications including instances of severe fungal infections and cytopenias, particularly when used to treat children with malignancy or graft-versus-host disease. As with adult safety data surrounding JAK inhibitor use in oncology, the direct relationship of these adverse events to JAK inhibitors is complicated by concomitant use of chemotherapeutic agents and other immunosuppressants, underlying bone marrow dysfunction, overall poor health of the patients treated, and substantially higher doses used to treat malignancy (for instance, up to 50 mg/m2/d of ruxolitinib, equivalent to a dose of 70 mg/d in the average 10-year-old boy). In comparison, in the phase 1 study testing tofacitinib in children with juvenile idiopathic arthritis, a considerably healthier cohort of patients, only one mild adverse event (fatigue) was considered to be treatment related (
      • Ruperto N.
      • Brunner H.I.
      • Zuber Z.
      • Tzaribachev N.
      • Kingsbury D.J.
      • Foeldvari I.
      • et al.
      Pharmacokinetic and safety profile of tofacitinib in children with polyarticular course juvenile idiopathic arthritis: results of a phase 1, open-label, multicenter study.
      ).

      Conclusion

      Although children develop AA at higher rates and with greater severity than adults, significantly affecting quality of life, few effective, tolerable, and safe treatment options are available to treat severe presentations of this disease in the pediatric population. JAK inhibitors have been identified as a largely safe and highly effective therapy for moderate to severe AA in adults, and a few small studies have suggested that similar results are to be expected in children. Phase 1 studies of JAK inhibitors for the treatment of malignancy and inflammatory conditions in children have supported the potential safety of these medications and have provided dosing guidance. Randomized controlled trials in children with AA are ultimately needed to fully establish the efficacy and safety of this drug class for this patient population.

      ORCIDs

      Conflict of Interest

      CEH has no conflicts of interest. BGC has served on advisory boards and received honoraria from and/or is a consultant to Aclaris, Arena Pharmaceuticals, Leo Pharma, Pfizer, Regeneron, and Sanofi-Genzyme. Her spouse is an investigator for Concert Pharmaceuticals Inc, Eli Lilly and Company, and Pfizer and is a consultant to, has served on advisory boards for, and/or received honoraria from Concert Pharmaceuticals Inc, Dermavant Sciences, Aclaris, Eli Lilly and Company, Pfizer, Regeneron, and Sanofi-Genzyme.

      Acknowledgments

      This article is published as part of a supplement sponsored by the National Alopecia Areata Foundation .
      Funding for the Summit and publication of this supplement was provided by the National Alopecia Areata Foundation. This Summit was supported (in part) by the National Institute Of Arthritis And Musculoskeletal And Skin Diseases under Award Number R13AR074890. The opinions or views expressed in this professional supplement are those of the authors and do not necessarily reflect the official views, opinions or recommendations of the National Institutes of Health or the National Alopecia Areata Foundation.

      Author Contributions

      Conceptualization: BGC; Data Curation: BGC; Formal Analysis: BGC, CEH; Funding Acquisition: BGC, CEH; Investigation: BGC, CEH; Methodology: BGC; Project Administration: BGC; CEH; Resources: BGC, CEH; Software: BGC, CEH; Supervision: BGC; Validation: BGC, CEH; Visualization: BGC, CEH; Writing - Original Draft Preparation: CEH; Writing - Review and Editing: BGC, CEH

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