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Treatment of pediatric alopecia areata: A systematic review

Open AccessPublished:April 30, 2021DOI:https://doi.org/10.1016/j.jaad.2021.04.077

      Background

      Alopecia areata (AA) is an autoimmune, nonscarring hair loss disorder with slightly greater prevalence in children than adults. Various treatment modalities exist; however, their evidence in pediatric AA patients is lacking.

      Objective

      To evaluate the evidence of current treatment modalities for pediatric AA.

      Methods

      We conducted a systematic review on the PubMed database in October 2019 for all published articles involving patients <18 years old. Articles discussing AA treatment in pediatric patients were included, as were articles discussing both pediatric and adult patients, if data on individual pediatric patients were available.

      Results

      Inclusion criteria were met by 122 total reports discussing 1032 patients. Reports consisted of 2 randomized controlled trials, 4 prospective comparative cohorts, 83 case series, 2 case-control studies, and 31 case reports. Included articles assessed the use of aloe, apremilast, anthralin, anti-interferon gamma antibodies, botulinum toxin, corticosteroids, contact immunotherapies, cryotherapy, hydroxychloroquine, hypnotherapy, imiquimod, Janus kinase inhibitors, laser and light therapy, methotrexate, minoxidil, phototherapy, psychotherapy, prostaglandin analogs, sulfasalazine, topical calcineurin inhibitors, topical nitrogen mustard, and ustekinumab.

      Limitations

      English-only articles with full texts were used. Manuscripts with adult and pediatric data were only incorporated if individual-level data for pediatric patients were provided. No meta-analysis was performed.

      Conclusion

      Topical corticosteroids are the preferred first-line treatment for pediatric AA, as they hold the highest level of evidence, followed by contact immunotherapy. More clinical trials and comparative studies are needed to further guide management of pediatric AA and to promote the potential use of pre-existing, low-cost, and novel therapies, including Janus kinase inhibitors.

      Key words

      Abbreviations used:

      AA (alopecia areata), AO (alopecia ophiasis), AT (alopecia totalis), AU (alopecia universalis), DPCP (diphenylcyclopropenone), LAD (lymphadenopathy), LoE (Levels of Evidence), PRISMA (Preferred Reporting Items for Systematic Review and Meta-Analyses), RCT (randomized controlled trial), SADBE (squaric acid dibutyl ester)
      • Numerous therapies have been used to treat children and adolescents with alopecia areata (AA) with variable efficacy.
      • Topical corticosteroids have the highest level of evidence for the treatment of pediatric AA, followed by contact immunotherapy. More clinical trials and comparative studies are needed to further guide management of pediatric AA.
      Alopecia areata (AA) is a nonscarring hair loss disorder that affects up to 2% of the global population.
      • Lee H.H.
      • Gwillim E.
      • Patel K.R.
      • et al.
      Epidemiology of alopecia areata, ophiasis, totalis, and universalis: a systematic review and meta-analysis.
      It is estimated that nearly 80% of patients with limited, patchy AA spontaneously recover.
      • Ito T.
      Advances in the management of alopecia areata.
      AA is characterized by relapsing and remitting patches of hair loss that may progress to severe subtypes, such as alopecia totalis (AT), alopecia universalis (AU), or alopecia ophiasis (AO), often resulting in significant psychological detriment. The pediatric population is particularly susceptible to the psychosocial consequences of AA, thus, adequate treatment is critical to prevent further morbidity associated with this disease.
      • Christensen T.
      • Yang J.S.
      • Castelo-Soccio L.
      Bullying and quality of life in pediatric alopecia areata.
      Although there are currently no treatments for AA approved by the Food and Drug Administration, there are numerous off-label treatment options for adults with AA. Therapeutic options for children and adolescents are limited. This systematic review sought to evaluate available off-label therapies for the treatment of AA in patients younger than 18 years of age.

      Methods

      A systematic review was conducted according to the Preferred Reporting Items for Systematic Review and Meta-Analyses (PRISMA) guidelines (Supplemental Table I; available via Mendeley at https://doi.org/10.17632/s9rx4myvnn.1). Using the PubMed database, a search for all published peer-reviewed articles was performed using the following search terms: “alopecia” and “areata” or “totalis” or “universalis” or “ophiasis” and “treatment” or “therapy” or “medication” or “drug.”
      These records were screened using defined criteria for eligibility, which consisted of English articles discussing the direct study or report of treatment modalities for AA in humans younger than 18 years of age. References of included reports were examined and additional sources not identified initially were incorporated. Review articles, animal studies, articles evaluating treatments that are no longer manufactured worldwide, including alefacept, and articles with unavailable full text were excluded. Articles that reported on results for both pediatric and adult patients were only included if individual-level data for the pediatric patients were provided.
      The results were then further classified by the Oxford Centre for Evidence-Based Medicine 2011 Levels of Evidence (LoE): level 1 (systematic review of randomized controlled trials [RCTs] or high-quality randomized controlled trial), level 2 (lesser quality RCT or prospective cohort study), level 3 (case-control study, non-randomized controlled cohort or follow-up study), level 4 (case series), or level 5 (expert opinion, mechanism-based reasoning).

      Results

      A total of 707 publications were retrieved, of which 122 reports were included (Fig 1). These reports consisted of 2 RCTs, 4 prospective comparative cohorts, 83 case series, 2 case-control studies, and 31 case reports. Included articles and results are summarized in Table I, Table II, Table III.
      • Liu L.Y.
      • King B.A.
      Lack of efficacy of apremilast in 9 patients with severe alopecia areata.
      • Cho H.R.
      • Lew B.L.
      • Lew H.
      • Sim W.Y.
      Treatment effects of intradermal botulinum toxin type A injection on alopecia areata.
      • Sarifakioglu E.
      • Degim I.T.
      • Gorpelioglu C.
      Determination of the sildenafil effect on alopecia areata in childhood: an open-pilot comparison study.
      • Fessatou S.
      • Kostaki M.
      • Karpathios T.
      Coeliac disease and alopecia areata in childhood.
      • Boonyaleepun S.
      • Boonyaleepun C.
      • Schlactus J.L.
      Effect of IVIG on the hair regrowth in a common variable immune deficiency patient with alopecia universalis.
      • Shibuya A.
      • Shinozawa T.
      • Danya N.
      • Maeda K.
      Successful bone marrow transplant and re-growth of hair in a patient with posthepatic aplastic anemia complicated by alopecia totalis.
      • Rozin A.P.
      • Schapira D.
      • Bergman R.
      Alopecia areata and relapsing polychondritis or mosaic autoimmunity? The first experience of co-trimoxazole treatment.
      • Zawahry M.E.
      • Hegazy M.R.
      • Helal M.
      Use of aloe in treating leg ulcers and dermatoses.
      • Skurkovich S.
      • Korotky N.G.
      • Sharova N.M.
      • Skurkovich B.
      Treatment of alopecia areata with anti-interferon-gamma antibodies.
      • Willemsen R.
      • Vanderlinden J.
      • Deconinck A.
      • Roseeuw D.
      Hypnotherapeutic management of alopecia areata.
      • Letada P.R.
      • Sparling J.D.
      • Norwood C.
      Imiquimod in the treatment of alopecia universalis.
      • Koblenzer CS.
      Psychotherapy for intractable inflammatory dermatoses.
      • Putt S.C.
      • Weinstein L.
      • Dzindolet M.T.
      A case study: massage, relaxation, and reward for treatment of alopecia areata.
      • Teshima H.
      • Sogawa H.
      • Mizobe K.
      • Kuroki N.
      • Nakagawa T.
      Application of psychoimmunotherapy in patients with alopecia universalis.
      • Arrazola J.M.
      • Sendagorta E.
      • Harto A.
      • Ledo A.
      Treatment of alopecia areata with topical nitrogen mustard.
      Figure thumbnail gr1
      Fig 1PRISMA 2009 flow diagram illustrating a total of 707 publications retrieved, of which 122 reports were included. AA, Alopecia areata; PRISMA, Preferred Reporting Items for Systematic Review and Meta-Analyses.
      Table IIncluded studies evaluating topical and miscellaneous treatment of alopecia areata in pediatric patients
      First authorYearTreatmentLoEStudy typeNAAATAUAOCR
      Complete response defined as ≥95% hair regrowth, (n %) = percent of total number of patients.
      PR
      Partial response defined as <95% and >0% hair regrowth, (n %) = percent of total number of patients.
      NR
      No response defined as 0% hair regrowth, (n %) = percent of total number of patients.
      RR
      Relapse rate defined as number of patients who responded to treatment and experienced recurrence of hair loss, (n %) = percent of responsive patients.
      SE
      Anthralin
       Sardana
      • Sardana K.
      • Gupta A.
      • Gautam R.K.
      Recalcitrant alopecia areata responsive to leflunomide and anthralin-potentially undiscovered JAK/STAT inhibitors?.
      2018Anthralin + leflunomide5Case report1---11 (100%)--NAItching, burning
       Wu
      • Wu S.Z.
      • Wang S.
      • Ratnaparkhi R.
      • Bergfeld W.F.
      Treatment of pediatric alopecia areata with anthralin: a retrospective study of 37 patients.
      2018Anthralin4Case series372483212 (32%)15 (40%)5 (14%)16 (64%)Irritation, LAD
       Ozdemir
      • Özdemir M.
      • Balevi A.
      Bilateral half-head comparison of 1% anthralin ointment in children with alopecia areata.
      2017Anthralin4Case series302712-10 (33.3%)11 (36.7%)9 (30%)2 (9.5%)Irritation, itching, LAD, hyperpigmentation, crusting, oozing, bullous eruption
       Torchia
      • Torchia D.
      • Schachner L.A.
      Bilateral treatment for alopecia areata.
      2015Anthralin + TC5Case report11-----1 (100%)NALAD
      Contact Immunotherapy
       Wasylyszyn
      • Wasylyszyn T.
      • Borowska K.
      Possible advantage of imiquimod and diphenylcyclopropenone combined treatment versus diphenylcyclopropenone alone: an observational study of nonresponder patients with alopecia areata.
      2016DPCP + imiquimod vs DPCP3Case-control9135-Both-2/3 (66.7%)

      DPCP only-0/6 (0%)
      Both-1/3 (33.3%)

      DPCP only-2/6 (33.3%)
      Both-0/3 (0%)

      DPCP only-4/6 (66.7%)
      NAScalp eczema, discomfort, LAD
       Luk
      • Luk N.M.
      • Chiu L.S.
      • Lee K.C.
      • et al.
      Efficacy and safety of diphenylcyclopropenone among Chinese patients with steroid resistant and extensive alopecia areata.
      2012DPCP4Case series3-21---3 (100%)NAItching, erythema, bulla, scaling, LAD, hyperpigmentation, urticarial reactions
       Salsberg
      • Salsberg J.M.
      • Donovan J.
      The safety and efficacy of diphencyprone for the treatment of alopecia areata in children.
      2012DPCP4Case series10882--2612 (11%)23 (21%)27 (25%)NAEdema, dermatitis, vesicles, desquamation, urticaria, erosions, LAD
       Singh
      • Singh G.
      • Okade R.
      • Naik C.
      • Dayanand C.D.
      Diphenylcyclopropenone immunotherapy in ophiasis.
      2007DPCP4Case series3---31 (33.3%)2 (66.7%)-NANone
       Sotiriadis
      • Sotiriadis D.
      • Patsatsi A.
      • Lazaridou E.
      • Kastanis A.
      • Vakirlis E.
      • Chrysomallis F.
      Topical immunotherapy with diphenylcyclopropenone in the treatment of chronic extensive alopecia areata.
      2006DPCP4Case series14734-2 (14.3%)8 (57.1%)4 (28.6%)NAEczema, headache, itching, hyperpigmentation
       Schuttelaar
      • Schuttelaar M.L.
      • Hamstra J.J.
      • Plinck E.P.
      • et al.
      Alopecia areata in children: treatment with diphencyprone.
      1996DPCP4Case series251015--8 (32%)4 (16%)13 (52%)7 (58.3%)Eczema, itching, vesicles, headache, LAD
       Hull
      • Hull S.M.
      • Pepall L.
      • Cunliffe W.J.
      Alopecia areata in children: response to treatment with diphencyprone.
      1991DPCP4Case series1248--4 (33.3%)4 (33.3%)4 (33.3%)4 (50%)Eczema with superimposed infection, blistering
       Orecchia
      • Orecchia G.
      • Rabbiosi G.
      Treatment of alopecia areata with diphencyprone.
      1985DPCP4Case series269710-1 (3.8%)13 (50%)12 (46.1%)4 (28.6%)LAD, itching, eczema
       Chen
      • Chen C.A.
      • Carlberg V.
      • Kroshinsky D.
      Angioedema after squaric acid treatment in a 6-year-old girl.
      2017SADBE5Case report11----1 (100%)-NAAngioedema
       Guerra
      • Guerra L.
      • Pacifico V.
      • Calabresi V.
      • et al.
      Childhood epidermolysis bullosa acquisita during squaric acid dibutyl ester immunotherapy for alopecia areata.
      2017SADBE5Case report11----1 (100%)-1 (100%)Epidermolysis bullosa acquisita
       Tosti
      • Tosti A.
      • Guidetti M.S.
      • Bardazzi F.
      • Misciali C.
      Long-term results of topical immunotherapy in children with alopecia totalis or alopecia universalis.
      1996SADBE4Case series33-1023-10 (30.3%)6 (18.2%)17 (51.5%)10 (62.5%)Contact dermatitis, LAD
       Orecchia
      • Orecchia G.
      • Malagoli P.
      Topical immunotherapy in children with alopecia areata.
      1995SADBE4Case series28NANANANA9 (32.1%)6 (21.4%)13 (46.4%)NANone
       Giannetti
      • Giannetti A.
      • Orecchia G.
      Clinical experience on the treatment of alopecia areata with squaric acid dibutyl ester.
      1983SADBE4Case series15NANANANA1 (6.6%)6 (40%)8 (53.3%)NAEczema, LAD, itching
      Cryotherapy
       Jun
      • Jun M.
      • Lee N.R.
      • Lee W.S.
      Efficacy and safety of superficial cryotherapy for alopecia areata: a retrospective, comprehensive review of 353 cases over 22 years.
      2017Cryotherapy4Case series24NANANANA5 (20.8%)15 (62.5%)4 (16.7%)NAPain, pruritus, inflammation, swelling
      Minoxidil
       Rai
      • Rai A.K.
      Minoxidil-induced hypertrichosis in a child with alopecia areata.
      2017Minoxidil5Case report11-----1 (100%)
      Patient(s) discontinued study due to adverse events.
      NAHypertrichosis
       Guerouaz
      • Guerouaz N.
      • Mohamed A.O.
      Minoxidil induced hypertrichosis in children.
      2014Minoxidil5Case report11----1 (100%)
      Patient(s) discontinued study due to adverse events.
      -NAHypertrichosis
       Herskovitz
      • Herskovitz I.
      • Freedman J.
      • Tosti A.
      Minoxidil induced hypertrichosis in a 2 year-old child.
      2013Minoxidil5Case report11----1 (100%)
      Patient(s) discontinued study due to adverse events.
      -NAHypertrichosis
       Georgala
      • Georgala S.
      • Befon A.
      • Maniatopoulou E.
      • Georgala C.
      Topical use of minoxidil in children and systemic side effects.
      2007Minoxidil4Case series321----3 (100%)
      Patient(s) discontinued study due to adverse events.
      NAPalpitations, dizziness, sinus tachycardia
       Lenane
      • Lenane P.
      • Pope E.
      • Krafchik B.
      Congenital alopecia areata.
      Study listed under both Minoxidil and TC sections as it provides data for both treatments in separate patients.
      2005Minoxidil4Case series1-1----1 (100%)NANone
       Baral
      • Baral J.
      Minoxidil and tail-like effect.
      Study listed under multiple sections due to inclusion of multiple treatments.
      1989Minoxidil + TC + ILC5Case report11----1 (100%)
      Patient(s) discontinued study due to adverse events.
      -NAHypertrichosis
       Weiss
      • Weiss VC
      • West DP
      • Mueller CE
      Topical minoxidil in alopecia areata.
      1981Minoxidil4Case series1--1--1 (100%)-NANone
      Topical Calcineurin Inhibitors
       Jung
      • Jung K.E.
      • Gye J.W.
      • Park M.K.
      • Park B.C.
      Comparison of the topical FK506 and clobetasol propionate as first-line therapy in the treatment of early alopecia areata.
      2017Topical tacrolimus vs clobetasol, split-scalp2Prospective comparative cohort33---TC-2/3 (66.7%)

      TT-0/3 (0%)
      TC-1/3 (33.3%)

      TT-2/3 (66.7%)
      TC-0/3 (0%)

      TT-1/3 (33.3%)
      NANone
       Rigopoulos
      • Rigopoulos D.
      • Gregoriou S.
      • Korfitis C.
      • et al.
      Lack of response of alopecia areata to pimecrolimus cream.
      2007Topical pimecrolimus vs placebo, split-scalp2Prospective comparative cohort11-----1 (100%)NABurning
       Price
      • Price V.H.
      • Willey A.
      • Chen B.K.
      Topical tacrolimus in alopecia areata.
      2005Topical tacrolimus4Case series22-----2 (100%)NANone
       Thiers
      • Thiers B.H.
      Topical tacrolimus: treatment failure in a patient with alopecia areata.
      2000Topical tacrolimus5Case report11-----1 (100%)NANA
      Topical and Intralesional Corticosteroids
       Sankararaman
      • Sankararaman S.
      • Bobonich M.
      • Aktay A.N.
      Alopecia areata in an adolescent with inflammatory bowel disease.
      2017ILC5Case report1---1-1 (100%)-1 (100%)None
       Jung
      • Jung K.E.
      • Gye J.W.
      • Park M.K.
      • Park B.C.
      Comparison of the topical FK506 and clobetasol propionate as first-line therapy in the treatment of early alopecia areata.
      2017Clobetasol vs topical tacrolimus, split-scalp2Prospective comparative cohort33---TC-2/3 (66.7%)

      TT-0 (0%)
      TC-1/3 (33.3%)

      TT-2/3 (66.7%)
      TC-0/3 (0%)

      TT-1/3 (33.3%)
      NANone
       Lalosevic
      • Lalosevic J.
      • Gajic-Veljic M.
      • Bonaci-Nikolic B.
      • Nikolic M.
      Combined oral pulse and topical corticosteroid therapy for severe alopecia areata in children: a long-term follow-up study.
      Study listed under multiple sections due to inclusion of multiple treatments.
      2015Oral PDC + clobetasol4Case series6535151526 (40%)17 (26.2%)22 (33.8%)11 (25.6%)Headache (after oral PDC), skin atrophy
       Torchia
      • Torchia D.
      • Schachner L.A.
      Bilateral treatment for alopecia areata.
      2015Triamcinolone + clobetasol vs anthralin, split-scalp5Case report11---TC side-Anthralin sideNANone
       Lenane
      • Lenane P.
      • Macarthur C.
      • Parkin P.C.
      • et al.
      Clobetasol propionate, 0.05%, vs hydrocortisone, 1%, for alopecia areata in children: a randomized clinical trial.
      2014Clobetasol vs hydrocortisone1Randomized controlled trial4141--->50% regrowth<50% regrowthNASkin atrophy
      Clobetasol-17/20 (85%)

      Hydrocortisone-7/21 (33.3%)
      Clobetasol-3/20 (15%)

      Hydrocortisone-14/21 (66.7%)
       Lenane
      • Lenane P.
      • Pope E.
      • Krafchik B.
      Congenital alopecia areata.
      Study listed under both Minoxidil and TC sections as it provides data for both treatments in separate patients.
      2005TC4Case series422--2 (50%)1 (25%)1 (25%)1 (50%)Skin atrophy
       Baral
      • Baral J.
      Minoxidil and tail-like effect.
      Study listed under multiple sections due to inclusion of multiple treatments.
      1989Minoxidil + TC + ILC5Case report11-----1 (100%)
      Patient(s) discontinued study due to adverse events.
      NAHypertrichosis
       Montes
      • Montes L.F.
      Topical halcinonide in alopecia areata and in alopecia totalis.
      1977Halcinonide4Case series211--2 (100%)--NAFolliculitis
      Prostaglandins
       Borchert
      • Borchert M.
      • Bruce S.
      • Wirta D.
      • et al.
      An evaluation of the safety and efficacy of bimatoprost for eyelash growth in pediatric subjects.
      2016Bimatoprost1/2Randomized controlled trial15NANANANA-Bimatoprost- 5/9 (55.6%); Vehicle-1/6 (16.7%)Bimatoprost- 4/9 (44.4%); Vehicle-5/6 (83.3%)NAConjunctival hyperemia, conjunctivitis, eczema, eyelid erythema
       Li
      • Li A.W.
      • Antaya R.J.
      Successful treatment of pediatric alopecia areata of the scalp using topical bimatoprost.
      2016Bimatoprost (scalp)5Case report11---1 (100%)--NANone
       Zaheri
      • Zaheri S.
      • Hughes B.
      Successful use of bimatoprost in the treatment of alopecia of the eyelashes.
      2010Bimatoprost5Case report11---1 (100%)--NANone
       Yadav
      • Yadav S.
      • Dogra S.
      • Kaur I.
      An unusual anatomical colocalization of alopecia areata and vitiligo in a child, and improvement during treatment with topical prostaglandin E2.
      2009Latanoprost5Case report11---1 (100%)--NANone
       Mehta
      • Mehta J.S.
      • Raman J.
      • Gupta N.
      • Thoung D.
      Cutaneous latanoprost in the treatment of alopecia areata.
      2003Latanoprost5Case report11----1 (100%)-NANone
      AA, Alopecia areata; AO, alopecia ophiasis; AT, alopecia totalis; AU, alopecia universalis; CR, complete response; DPCP, diphenylcyclopropenone; ILC, intralesional corticosteroids; LAD, lymphadenopathy; LoE, level of evidence; N, number of pediatric patients; NA, not available; NR, no response; OC, oral corticosteroids; PDC, pulse dose corticosteroids; PR, partial response; PT, psychotherapy; RR, relapse rate; SADBE, squaric acid dibutylester; SE, side effects; TC, topical corticosteroids; TT, topical tacrolimus.
      Complete response defined as ≥95% hair regrowth, (n %) = percent of total number of patients.
      Partial response defined as <95% and >0% hair regrowth, (n %) = percent of total number of patients.
      No response defined as 0% hair regrowth, (n %) = percent of total number of patients.
      § Relapse rate defined as number of patients who responded to treatment and experienced recurrence of hair loss, (n %) = percent of responsive patients.
      Patient(s) discontinued study due to adverse events.
      Study listed under both Minoxidil and TC sections as it provides data for both treatments in separate patients.
      # Study listed under multiple sections due to inclusion of multiple treatments.
      Table IIIncluded studies evaluating systemic treatment of alopecia areata in pediatric patients
      First authorYearTreatmentLoEStudy typeNAAATAUAOCR
      Complete response defined as ≥95% hair regrowth, (n %) = percent of total number of patients.
      PR
      Partial response defined as <95% and >0% hair regrowth, (n %) = percent of total number of patients.
      NR
      No response defined as 0% hair regrowth, (n %) = percent of total number of patients.
      RR
      Relapse rate defined as number of patients who responded to treatment and experienced recurrence of hair loss, (n %) = percent of responsive patients.
      SE
      Intramuscular Corticosteroids
       Seo
      • Seo J.
      • Lee Y.I.
      • Hwang S.
      • Zheng Z.
      • Kim D.Y.
      Intramuscular triamcinolone acetonide: an undervalued option for refractory alopecia areata.
      2017IMC4Case series2-2--1 (50%)1 (50%)-NANone
       Sato-Kawamura
      • Sato-Kawamura M.
      • Aiba S.
      • Tagami H.
      Acute diffuse and total alopecia of the female scalp. A new subtype of diffuse alopecia areata that has a favorable prognosis.
      2002IMC4Case series1-1--1 (100%)--NANone
       Michalowski
      • Michalowski R.
      • Kuczynska L.
      Long-term intramuscular triamcinolon-acetonide therapy in alopecia areata totalis and universalis.
      1978IMC4Case series6-51-2 (33.3%)2 (33.3%)2 (33.3%)4 (100%)Hypertrichosis, diabetes, moon facies, striae, dysmenorrhea, pseudoacanthosis nigricans
      Adverse events reported in both adult and pediatric patients.
      Oral Corticosteroids
       Anuset
      • Anuset D.
      • Perceau G.
      • Bernard P.
      • Reguiai Z.
      Efficacy and safety of methotrexate combined with low- to moderate-dose corticosteroids for severe alopecia areata.
      Study listed under multiple sections due to inclusion of multiple treatments.
      2016OC + MTX4Case series4112-2 (50%)-2 (50%) (1 on MTX only)2 (100%)Transient elevation of transaminases, weight gain, cataracts, pneumocystis pneumonia
      Adverse events reported in both adult and pediatric patients.
       Gensure
      • Gensure R.C.
      Clinical response to combined therapy of cyclosporine and prednisone.
      2013OC + cyclosporine5Case report1-1--1 (100%)--NAConfluent and reticulated papillomatosis
       Kim
      • Kim B.J.
      • Uk min S.
      • Park K.Y.
      • et al.
      Combination therapy of cyclosporine and methylprednisolone on severe alopecia areata.
      2008OC + cyclosporine4Case series954--5 (55.5%)3 (33.3%)1 (11.1%)NAEdema, acne, weight gain, hypertrichosis, GI disturbance, menstrual abnormality
       Camacho
      • Camacho F.M.
      • Garcia-Hernandez M.J.
      Zinc aspartate, biotin, and clobetasol propionate in the treatment of alopecia areata in childhood.
      1999OC vs ZBC2Prospective comparative cohort18612-OC-0/9 (0%)

      ZBC-3/9 (33.3%)
      OC-4/9 (44.4%)

      ZBC-5/9 (55.5%)
      OC-5/9 (55.5%)

      ZBC-1/9 (11.1%)
      NACushingoid features, delayed physical development
       Alabdulkareem
      • Alabdulkareem A.S.
      • Abahussein A.A.
      • Okoro A.
      Severe alopecia areata treated with systemic corticosteroids.
      1998OC4Case series11-83-1 (9%)5 (45.4%)5 (45.4%)5 (83.3%)Acne, striae, moon facies
       Schindler
      • Schindler A.M.
      The boy whose hair came back.
      1987OC5Case report1--1-1 (100%)--0 (0%)Weight gain, Cushingoid features
       Unger
      • Unger W.P.
      • Schemmer R.J.
      Corticosteroids in the treatment of alopecia totalis. Systemic effects.
      1978OC4Case series6141-3 (50%)3 (50%)-3 (50%)Weight gain
       Winter
      • Winter R.J.
      • Kern F.
      • Blizzard R.M.
      Prednisone therapy for alopecia areata. A follow-up report.
      1976OC4Case series12345-5 (41.7%)-7 (58.3%)NAWeight gain, abdominal pain, cataracts, acne, hypertension, seizure, psychological problems, obesity
      Pulse Dose Corticosteroids
       Chong
      • Chong J.H.
      • Taieb A.
      • Morice-Picard F.
      • Dutkiewicz A.S.
      • Léauté-Labrèze C.
      • Boralevi F.
      High-dose pulsed corticosteroid therapy combined with methotrexate for severe alopecia areata of childhood.
      Study listed under multiple sections due to inclusion of multiple treatments.
      2017IV PDC + MTX4Case series14-14-1 (7.1%)5 (35.7%)8 (57.1%)NAAbdominal discomfort
       John-Bassler
      • Jahn-Bassler K.
      • Bauer W.M.
      • Karlhofer F.
      • Vossen M.G.
      • Stingl G.
      Sequential high- and low-dose systemic corticosteroid therapy for severe childhood alopecia areata.
      2017IV PDC4Case series13652-8 (61.5%)-5 (38.5%)3 (37.5%)Weight gain, acne
       Lalosevic
      • Lalosevic J.
      • Gajic-Veljic M.
      • Bonaci-Nikolic B.
      • Nikolic M.
      Combined oral pulse and topical corticosteroid therapy for severe alopecia areata in children: a long-term follow-up study.
      Study listed under multiple sections due to inclusion of multiple treatments.
      2015Oral PDC + TC4Case series6535151526 (40%)17 (26.2%)22 (33.8%)11 (25%)Headache, skin atrophy
       Smith
      • Smith A.
      • Trüeb R.M.
      • Theiler M.
      • Hauser V.
      • Weibel L.
      High relapse rates despite early intervention with intravenous methylprednisolone pulse therapy for severe childhood alopecia areata.
      2015IV PDC4Case series18223112 (11.1%)9 (50%)7 (38.9%)7 (63.6%)Mood changes, metallic taste, acne, allergic reaction
       Friedland
      • Friedland R.
      • Tal R.
      • Lapidoth M.
      • Zvulunov A.
      • Ben Amitai D.
      Pulse corticosteroid therapy for alopecia areata in children: a retrospective study.
      2013IV PDC4Case series24842109 (37.5%); 5/8 AA, 1/4 AT, 0/2, AU, 3/10 AO7 (29.2%); 1/8 AA, 1/4 AT, 1/2, AU, 4/10 AO8 (33.3%); 2/8 AA, 2/4 AT, 1/2, AU, 3/10 AO13 (81.2%); 5/6 AA, 1/2 AT, 1/1, AU, 6/7 AOVerrucae, gastritis, abdominal pain
       Droitcourt
      • Droitcourt C.
      • Milpied B.
      • Ezzedine K.
      • et al.
      Interest of high-dose pulse corticosteroid therapy combined with methotrexate for severe alopecia areata: a retrospective case series.
      Study listed under multiple sections due to inclusion of multiple treatments.
      2012IV PDC + MTX4Case series22---1 (50%)1 (50%)-2 (100%)Nausea, neutropenia
       Sauerbrey
      • Sauerbrey A.
      Successful immunsuppression in childhood alopecia areata.
      2011IV PDC + TT4Case series2-11-2 (100%)--1 (50%)None
       Hubiche
      • Hubiche T.
      • Léauté-Labrèze C.
      • Taïeb A.
      • Boralevi F.
      Poor long term outcome of severe alopecia areata in children treated with high dose pulse corticosteroid therapy.
      2008IV PDC4Case series12-417-10 (83.3%)2 (16.7%)6 (60%)None
       Sethuraman
      • Sethuraman G.
      • Malhotra A.K.
      • Sharma V.K.
      Alopecia universalis in Down syndrome: response to therapy.
      2006Oral PDC + minoxidil5Case report1--1--1 (100%)-NANone
       Bin Saif
      • Bin Saif G.A.
      Oral mega pulse methylprednisolone in alopecia universalis.
      2006Oral PDC5Case report1--1-1 (100%)--1 (100%)Nocturnal enuresis
       Seiter
      • Seiter S.
      • Ugurel S.
      • Tilgen W.
      • Reinhold U.
      High-dose pulse corticosteroid therapy in the treatment of severe alopecia areata.
      2001IV PDC4Case series4211-2 (50%); 2/2 AA, 0/1 AT, 0/1 AU-2 (50%)NAHeadache, fatigue, nausea, palpitations
       Sharma
      • Sharma V.K.
      • Gupta S.
      Twice weekly 5 mg dexamethasone oral pulse in the treatment of extensive alopecia areata.
      1999Oral PDC4Case series4NANANANA4 (100%)--NANA
       Friedli
      • Friedli A.
      • Labarthe M.P.
      • Engelhardt E.
      • Feldmann R.
      • Salomon D.
      • Saurat J.H.
      Pulse methylprednisolone therapy for severe alopecia areata: an open prospective study of 45 patients.
      1998IV PDC4Case series714111 (14.3%); 1/1 AA, 0/4 AT, 0/1 AU, 0/1 AO2 (28.6%); AA 0/1, AT 1/4, AU 0/1, AO 1/14 (57.1%); AA 1/1, 3/4 AT, AU 1/1, AO 0/12 (66.7%); AA 0/1, AT 1/1, 1/1 AOFatigue, headache, palpitations, dyspnea, nausea
       Sharma
      • Sharma V.K.
      • Muralidhar S.
      Treatment of widespread alopecia areata in young patients with monthly oral corticosteroid pulse.
      1998Oral PDC4Case series16133-16 (37.5%)6 (37.5%)3 (18.7%)4 (33.3%)Epigastric burning, headache
       Kiesch
      • Kiesch N.
      • Stene J.J.
      • Goens J.
      • Vanhooteghem O.
      • Song M.
      Pulse steroid therapy for children's severe alopecia areata?.
      1997IV PDC4Case series731-35 (71.4%); AA 3/3, AO 2/3-2 (28.6%); AT 1/1, AO 1/31 (20%)Abdominal pain
       Perriard-Wolfensberger
      • Perriard-Wolfensberger J.
      • Pasche-Koo F.
      • Mainetti C.
      • Labarthe M.P.
      • Salomon D.
      • Saurat J.H.
      Pulse of methylprednisolone in alopecia areata.
      1993IV PDC4Case series11----1 (100%)-NAFlushing
      Hydroxychloroquine
       Yun
      • Yun D.
      • Silverberg N.B.
      • Stein S.L.
      Alopecia areata treated with hydroxychloroquine: a retrospective study of nine pediatric cases.
      2018HCQ +/- TC and/or minoxidil4Case series9612-1 (11.1%)5 (55.5%)3 (33.3%)NAHeadache, abdominal pain, viral gastroenteritis
      Methotrexate
       Mascia
      • Mascia P.
      • Milpied B.
      • Darrigade A.S.
      • et al.
      Azathioprine in combination with methotrexate: a therapeutic alternative in severe and recalcitrant forms of alopecia areata?.
      2019MTX + azathioprine4Case series321---3 (100%)-NAGI distress, lymphopenia
      Adverse events reported in both adult and pediatric patients.
       Chong
      • Chong J.H.
      • Taieb A.
      • Morice-Picard F.
      • Dutkiewicz A.S.
      • Léauté-Labrèze C.
      • Boralevi F.
      High-dose pulsed corticosteroid therapy combined with methotrexate for severe alopecia areata of childhood.
      Study listed under multiple sections due to inclusion of multiple treatments.
      2017MTX + IV PDC4Case series14-14-1 (7.1%)5 (35.7%)8 (57.1%)NAAbdominal discomfort
       Landis
      • Landis ET, Pichardo-Geisinger R.O.
      Methotrexate for the treatment of pediatric alopecia areata.
      2018MTX4Case series11NANANANA4 (36.4%)7 (63.6%)-2 (18.1%)Leg weakness, tooth sensitivity
       Anuset
      • Chong J.H.
      • Taieb A.
      • Morice-Picard F.
      • Dutkiewicz A.S.
      • Léauté-Labrèze C.
      • Boralevi F.
      High-dose pulsed corticosteroid therapy combined with methotrexate for severe alopecia areata of childhood.
      Patient(s) discontinued study due to adverse events.
      2016MTX + OC4Case series4112-2 (50%)-2 (50%) (1 on MTX only)2 (100%)Transient elevation of transaminases, weight gain, cataracts, pneumocystis pneumonia
      Adverse events reported in both adult and pediatric patients.
       Batalla
      • Batalla A.
      • Á Flórez
      • Abalde T.
      • Vázquez-Veiga H.
      Methotrexate in alopecia areata: a report of three cases.
      2016MTX4Case series311-12 (66.7%)1 (33.3%)1 (50%)Elevated hepatic transaminases
       Lucas
      • Lucas P.
      • Bodemer C.
      • Barbarot S.
      • Vabres P.
      • Royer M.
      • Mazereeuw-Hautier J.
      Methotrexate in severe childhood alopecia areata: long-term follow-up.
      2016MTX4Case series13NANANANA-5 (38.5%)8 (61.5%)2 (40%)Recurrent nausea
       Droitcourt
      • Droitcourt C.
      • Milpied B.
      • Ezzedine K.
      • et al.
      Interest of high-dose pulse corticosteroid therapy combined with methotrexate for severe alopecia areata: a retrospective case series.
      Study listed under multiple sections due to inclusion of multiple treatments.
      2012MTX + IV PDC4Case series22---1 (50%)--2 (100%)Nausea, neutropenia
       Royer
      • Royer M.
      • Bodemer C.
      • Vabres P.
      • et al.
      Efficacy and tolerability of methotrexate in severe childhood alopecia areata.
      2011MTX +/- OC4Case series1477--11 (78.6%)3 (21.4%)3 (27.3%)Nausea, herpes zoster
      Sulfasalazine and Mesalazine
       Kiszewski
      • Kiszewski A.E.
      • Bevilaqua M.
      • De Abreu L.B.
      Mesalazine in the treatment of extensive alopecia areata: a new therapeutic option?.
      2018Mesalazine +/- TC, OC, minoxidil4Case series53-115 (100%)--NANone
       Rashidi
      • Rashidi T.
      • Mahd A.A.
      Treatment of persistent alopecia areata with sulfasalazine.
      2008Sulfasalazine4Case series743---7 (100%)-NADizziness, headache, dyspepsia
       Bakar
      • Bakar O.
      • Gurbuz O.
      Is there a role for sulfasalazine in the treatment of alopecia areata?.
      2007Sulfasalazine + OC4Case series33----3 (100%)-NANone
      Ustekinumab
       Aleisa
      • Aleisa A.
      • Lim Y.
      • Gordon S.
      • et al.
      Response to ustekinumab in three pediatric patients with alopecia areata.
      2019Ustekinumab4Case series321--1 (33.3%)2 (66.7%)-NANA
       Ortolan
      • Ortolan L.S.
      • Kim S.R.
      • Crotts S.
      • et al.
      IL-12/IL-23 neutralization is ineffective for alopecia areata in mice and humans.
      2019Ustekinumab4Case series3-3----3 (100%)NANA
      JAK Inhibitors
       Jabbari
      • Jabbari A.
      • Dai Z.
      • Xing L.
      • et al.
      Reversal of alopecia areata following treatment with the JAK1/2 inhibitor baricitinib.
      2015Baricitinib5Case report11---1 (100%)--NANone
       Craiglow
      • Craiglow B.G.
      • King B.A.
      Tofacitinib for the treatment of alopecia areata in preadolescent children.
      2019Tofacitinib4Case series4-13-2 (50%)1 (25%)1 (25%)NANone
       Dai
      • Dai Y.X.
      • Chen C.C.
      Tofacitinib therapy for children with severe alopecia areata.
      2019Tofacitinib4Case series3-21-1 (33.3%)2 (66.7%)-NADiarrhea, URI
       Brown
      • Brown L.
      • Skopit S.
      An excellent response to tofacitinib in a pediatric alopecia patient: a case report and review.
      2018Tofacitinib5Case report1--1-1 (100%)--NAHeadache
       Patel
      • 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.
      2018Tofacitinib4Case series1--1--1 (100%)-NAIncreased appetite, weight gain
       Castelo-Soccio
      • Castelo-Soccio L.
      Experience with oral tofacitinib in 8 adolescent patients with alopecia universalis.
      2017Tofacitinib4Case series6--6--6 (100%)-NANone
       Craiglow
      • Craiglow B.G.
      • Liu L.Y.
      • King B.A.
      Tofacitinib for the treatment of alopecia areata and variants in adolescents.
      2017Tofacitinib4Case series13616-1 (7.7%)8 (69.2%)4 (30.8%)NAHeadache, URI, transient elevation in hepatic transaminases
       Liu
      • Liu L.Y.
      • King B.A.
      Ruxolitinib for the treatment of severe alopecia areata.
      2019Ruxolitinib4Case series1--1-1 (100%)--NAURI, weight gain, acne, easy bruising, fatigue
      Adverse events reported in both adult and pediatric patients.
       Putterman
      • Putterman E.
      • Castelo-Soccio L.
      Topical 2% tofacitinib for children with alopecia areata, alopecia totalis, and alopecia universalis.
      2018Topical tofacitinib4Case series11146-3 (27.3%)5 (45.4%)1 (9%)NAIrritation
       Bayart
      • Bayart C.B.
      • DeNiro K.L.
      • Brichta L.
      • Craiglow B.G.
      • Sidbury R.
      Topical Janus kinase inhibitors for the treatment of pediatric alopecia areata.
      2017Topical tofacitinib or topical ruxolitinib4Case series61231 (16.7%)3 (50%)2 (66.7%)NANone
       Craiglow
      • Craiglow B.G.
      • Tavares D.
      • King B.A.
      Topical ruxolitinib for the treatment of alopecia universalis.
      2016Topical ruxolitinib5Case report1--1--1 (100%)-NAMinor decrease in WBC
      Laser and Light Therapy
       Fenniche
      • Fenniche S.
      • Hammami H.
      • Zaouak A.
      Association of khellin and 308-nm excimer lamp in the treatment of severe alopecia areata in a child.
      2018308 nm excimer lamp + topical khellin5Case report1---11 (100%)--NoneMild transient erythema
       Al-Mutairi
      • Al-Mutairi N.
      308-nm excimer laser for the treatment of alopecia areata in children.
      2009308 nm excimer laser4Case series1192--5 (45.4%)3 (27.3%)3 (27.3%)4 (50%)Mild erythema, peeling
       Al-Mutairi
      • Al-Mutairi N.
      308-nm excimer laser for the treatment of alopecia areata.
      2007308 nm excimer laser4Case series44----1 (25%)3 (75%)NAMild erythema, peeling
       Zakaria
      • Zakaria W.
      • Passeron T.
      • Ostovari N.
      • Lacour J.P.
      • Ortonne J.P.
      308-nm excimer laser therapy in alopecia areata.
      2004308 nm excimer laser4Case series11----1 (100%)-NAMild erythema, hyperpigmentation
      Phototherapy
       Jury
      • Jury C.S.
      • McHenry P.
      • Burden A.D.
      • Lever R.
      • Bilsland D.
      Narrowband ultraviolet B (UVB) phototherapy in children.
      2006NBUVB4Case series6NANANANA-1 (16.7%)5 (83.3%)NAErythema, blistering, anxiety
       Ersoy-Evans
      • Ersoy-Evans S.
      • Altaykan A.
      • Sahin S.
      • Kolemen F.
      Phototherapy in childhood.
      2008PUVA4Case series10343-2 (20%)NAErythema, pruritus, burning
       Yoon
      • Yoon T.Y.
      • Kim Y.G.
      Infant alopecia universalis: role of topical PUVA (psoralen ultraviolet A) radiation.
      2005PUVA + TT5Case report1--1-1 (100%)--NANone
       Mitchell
      • Mitchell A.J.
      • Douglass M.C.
      Topical photochemotherapy for alopecia areata.
      1985PUVA4Case series532---5 (100%)-3 (75%)None
       Claudy
      • Claudy A.L.
      • Gagnaire D.
      PUVA treatment of alopecia areata.
      1983PUVA4Case series7223-3 (42.8%)-4 (57.1%)NAPruritus
       Amer
      • Amer M.A.
      • El Garf A.
      Photochemotherapy and alopecia areata.
      1983PUVA4Case series211----2 (100%)NANone
       Lux-Battistelli
      • Lux-Battistelli C.
      Combination therapy with zinc gluconate and PUVA for alopecia areata totalis: an adjunctive but crucial role of zinc supplementation.
      2015PUVA + zinc4Case series1-1---1 (100%)-1 (100%)Seborrheic dermatitis, acne
       Majumdar
      • Majumdar B.
      • De A.
      • Ghosh S.
      • et al.
      “Turban PUVAsol:” A simple, novel, effective, and safe treatment option for advanced and refractory cases of alopecia areata.
      2018Topical psoralen + natural sunlight4Case series54-1--5 (100%)-NAErythema, irritation, hyperpigmentation, scaling
       Belezos
      • Belezos N.K.
      Local estrogen and ultraviolet irradiation in the treatment of total alopecia (areata).
      1965UV irradiation + topical estrogen4Case series11---1 (100%)--NANone
      AA, Alopecia areata; AO, alopecia ophiasis; AT, alopecia totalis; AU, alopecia universalis; CR, complete response; GI, gastrointestinal; IMC, intramuscular corticosteroids; IV, intravenous; LoE, level of evidence; MTX, methotrexate; N, number of patients; NA, not available; NBUVB, narrow-band ultraviolet B; NR, no response; OC, oral corticosteroids; PDC, pulse dose corticosteroids; PR, partial response; PUVA, psoralen ultraviolet A; RR, relapse rate; SE, side effects; TC, topical corticosteroids; TT, topical tacrolimus; URI, upper respiratory infection; UV, ultraviolet; WBC; white blood cells; ZBC, zinc biotin, and clobetasol.
      Complete response defined as ≥95% hair regrowth, (n %) = percent of total number of patients.
      Partial response defined as <95% and >0% hair regrowth, (n %) = percent of total number of patients.
      No response defined as 0% hair regrowth, (n %) = percent of total number of patients.
      § Relapse rate defined as number of patients who responded to treatment and experienced recurrence of hair loss, (n %) = percent of responsive patients.
      Adverse events reported in both adult and pediatric patients.
      Patient(s) discontinued study due to adverse events.
      # Study listed under multiple sections due to inclusion of multiple treatments.
      Table IIIIncluded studies evaluating miscellaneous treatment of alopecia areata in pediatric patients
      First authorYearTreatmentLoEStudy typeNAAATAUAOCR
      Complete response defined as ≥95% hair regrowth, (n %) = percent of total number of patients.
      PR
      Partial response defined as <95% and >0% hair regrowth, (n %) = percent of total number of patients.
      NR
      No response defined as 0% hair regrowth, (n %) = percent of total number of patients.
      RR
      Relapse rate defined as number of patients who responded to treatment and experienced recurrence of hair loss, (n %) = percent of responsive patients.
      SE
      Liu
      • Liu L.Y.
      • King B.A.
      Lack of efficacy of apremilast in 9 patients with severe alopecia areata.
      2017Apremilast4Case series1--1---1 (100%)NADiarrhea, nausea, headaches, lethargy
      Cho
      • Cho H.R.
      • Lew B.L.
      • Lew H.
      • Sim W.Y.
      Treatment effects of intradermal botulinum toxin type A injection on alopecia areata.
      2010Botulinum Toxin A4Case series3-12---3 (100%)NANone
      Sarifakioglu
      • Sarifakioglu E.
      • Degim I.T.
      • Gorpelioglu C.
      Determination of the sildenafil effect on alopecia areata in childhood: an open-pilot comparison study.
      2006Topical sildenafil4Case series8-----3 (37.5%)5 (62.5%)NANone
      Fessatou
      • Fessatou S.
      • Kostaki M.
      • Karpathios T.
      Coeliac disease and alopecia areata in childhood.
      2003Gluten-free diet4Case series2----1 (50%)1 (50%)-NANone
      Boonyaleepun
      • Boonyaleepun S.
      • Boonyaleepun C.
      • Schlactus J.L.
      Effect of IVIG on the hair regrowth in a common variable immune deficiency patient with alopecia universalis.
      1999IVIG5Case report1--1--1 (100%)-NANone
      Shibuya
      • Shibuya A.
      • Shinozawa T.
      • Danya N.
      • Maeda K.
      Successful bone marrow transplant and re-growth of hair in a patient with posthepatic aplastic anemia complicated by alopecia totalis.
      1990Bone marrow transplant
      Postoperative cyclosporin and short-term methotrexate were also given for graft-versus-host disease prophylaxis.
      5Case report1-1--1 (100%)--NAChronic GVHD skin eruption
      Rozin
      • Rozin A.P.
      • Schapira D.
      • Bergman R.
      Alopecia areata and relapsing polychondritis or mosaic autoimmunity? The first experience of co-trimoxazole treatment.
      2003Cotrimoxazole5Case report11---1 (100%)--1 (100%)None
      Zawahry
      • Zawahry M.E.
      • Hegazy M.R.
      • Helal M.
      Use of aloe in treating leg ulcers and dermatoses.
      1973Aloe4Case series11----1 (100%)-NANone
      Skurkovich
      • Skurkovich S.
      • Korotky N.G.
      • Sharova N.M.
      • Skurkovich B.
      Treatment of alopecia areata with anti-interferon-gamma antibodies.
      2005Anti-IFN gamma antibodies4Case series16115--12 (75%)4 (25%)1 (8.3%)None
      Willemsen
      • Willemsen R.
      • Vanderlinden J.
      • Deconinck A.
      • Roseeuw D.
      Hypnotherapeutic management of alopecia areata.
      2006Hypnosis
      Both patients were simultaneously treated with selective serotonin reuptake inhibitors.
      4Case series2--2-1 (50%)-1 (50%)1 (100%)None
      Letada
      • Letada P.R.
      • Sparling J.D.
      • Norwood C.
      Imiquimod in the treatment of alopecia universalis.
      2007Topical imiquimod5Case report1--1--1 (100%)-1 (100%)None
      Koblenzer
      • Koblenzer CS.
      Psychotherapy for intractable inflammatory dermatoses.
      1995Psychotherapy
      Psychotherapy was supplemented by minoxidil and anthralin.
      5Case report11----1 (100%)-NANone
      Putt
      • Putt S.C.
      • Weinstein L.
      • Dzindolet M.T.
      A case study: massage, relaxation, and reward for treatment of alopecia areata.
      1994Massage, relaxation, and reward5Case report11----1 (100%)-NANone
      Teshima
      • Teshima H.
      • Sogawa H.
      • Mizobe K.
      • Kuroki N.
      • Nakagawa T.
      Application of psychoimmunotherapy in patients with alopecia universalis.
      1991Psychotherapy (PT) + OC and CYA vs OC and CYA3Case-control5--5-PT + OC and CYA - 2/2 (100%); OC and CYA -1/3 (33.3%)PT + OC and CYA - 0/2 (0%); OC and CYA - 2/3 (66.7%)NANone
      Arrazola
      • Arrazola J.M.
      • Sendagorta E.
      • Harto A.
      • Ledo A.
      Treatment of alopecia areata with topical nitrogen mustard.
      1985Topical nitrogen mustard4Case series422---4 (100%)-NAAllergic contact dermatitis
      AA, Alopecia areata; AO, alopecia ophiasis; AT, alopecia totalis; AU, alopecia universalis; CR, complete response; CYA, cyclosporin; DPCP, diphenylcyclopropenone; GVHD, graft-versus-host disease; ILC, intralesional corticosteroids; IFN, interferon; IVIG, intravenous immunoglobulin; LoE, level of evidence; N, number of pediatric patients; NA, not available; NR, no response; OC, oral corticosteroids; PR, partial response; PT, psychotherapy; RR, relapse rate; SE, side effects.
      Complete response defined as ≥95% hair regrowth, (n %) = percent of total number of patients.
      Partial response defined as <95% and >0% hair regrowth, (n %) = percent of total number of patients.
      No response defined as 0% hair regrowth, (n %) = percent of total number of patients.
      § Relapse rate defined as number of patients who responded to treatment and experienced recurrence of hair loss, (n %) = percent of responsive patients.
      Postoperative cyclosporin and short-term methotrexate were also given for graft-versus-host disease prophylaxis.
      Both patients were simultaneously treated with selective serotonin reuptake inhibitors.
      # Psychotherapy was supplemented by minoxidil and anthralin.

       Topical therapies

       Anthralin

      Use of the irritant anthralin to treat AA in pediatric patients was demonstrated in 4 case series or reports, including 69 patients (strongest LoE 4; Table I).
      • Sardana K.
      • Gupta A.
      • Gautam R.K.
      Recalcitrant alopecia areata responsive to leflunomide and anthralin-potentially undiscovered JAK/STAT inhibitors?.
      • Wu S.Z.
      • Wang S.
      • Ratnaparkhi R.
      • Bergfeld W.F.
      Treatment of pediatric alopecia areata with anthralin: a retrospective study of 37 patients.
      • Özdemir M.
      • Balevi A.
      Bilateral half-head comparison of 1% anthralin ointment in children with alopecia areata.
      • Torchia D.
      • Schachner L.A.
      Bilateral treatment for alopecia areata.
      Complete response rates ranged between 32% and 33.3% with relapse rates of 9.5% to 64%. One case reported complete regrowth when combined with leflunomide.
      • Sardana K.
      • Gupta A.
      • Gautam R.K.
      Recalcitrant alopecia areata responsive to leflunomide and anthralin-potentially undiscovered JAK/STAT inhibitors?.
      The mean time to maximal response was approximately 9 to 15 months.
      • Sardana K.
      • Gupta A.
      • Gautam R.K.
      Recalcitrant alopecia areata responsive to leflunomide and anthralin-potentially undiscovered JAK/STAT inhibitors?.
      • Wu S.Z.
      • Wang S.
      • Ratnaparkhi R.
      • Bergfeld W.F.
      Treatment of pediatric alopecia areata with anthralin: a retrospective study of 37 patients.
      • Özdemir M.
      • Balevi A.
      Bilateral half-head comparison of 1% anthralin ointment in children with alopecia areata.
      • Torchia D.
      • Schachner L.A.
      Bilateral treatment for alopecia areata.
      Anthralin caused staining of the skin and regional lymphadenopathy (LAD), which resolved after cessation of treatment. Other side effects were itching, burning, oozing, and bullous eruptions, but systemic side effects were rare.
      • Shapiro J.
      Current treatment of alopecia areata.

       Contact immunotherapy

       Diphenylcyclopropenone

      Treatment of the affected areas with diphenylcyclopropenone (DPCP) includes sensitization prior to initial treatment and escalating dose concentrations. The essentially painless application method makes DPCP an ideal and frequently utilized treatment option for the pediatric population. Eight articles reported DPCP treatment in 200 children with AA (strongest LoE 3).
      • Wasylyszyn T.
      • Borowska K.
      Possible advantage of imiquimod and diphenylcyclopropenone combined treatment versus diphenylcyclopropenone alone: an observational study of nonresponder patients with alopecia areata.
      • Luk N.M.
      • Chiu L.S.
      • Lee K.C.
      • et al.
      Efficacy and safety of diphenylcyclopropenone among Chinese patients with steroid resistant and extensive alopecia areata.
      • Salsberg J.M.
      • Donovan J.
      The safety and efficacy of diphencyprone for the treatment of alopecia areata in children.
      • Singh G.
      • Okade R.
      • Naik C.
      • Dayanand C.D.
      Diphenylcyclopropenone immunotherapy in ophiasis.
      • Sotiriadis D.
      • Patsatsi A.
      • Lazaridou E.
      • Kastanis A.
      • Vakirlis E.
      • Chrysomallis F.
      Topical immunotherapy with diphenylcyclopropenone in the treatment of chronic extensive alopecia areata.
      • Schuttelaar M.L.
      • Hamstra J.J.
      • Plinck E.P.
      • et al.
      Alopecia areata in children: treatment with diphencyprone.
      • Hull S.M.
      • Pepall L.
      • Cunliffe W.J.
      Alopecia areata in children: response to treatment with diphencyprone.
      • Orecchia G.
      • Rabbiosi G.
      Treatment of alopecia areata with diphencyprone.
      Complete response rates ranged from 0% to 33.3%, similar to the results of a meta-analysis (30.7%).
      • Lee S.
      • Kim B.J.
      • Lee Y.B.
      • Lee W.S.
      Hair regrowth outcomes of contact immunotherapy for patients with alopecia areata: a systematic review and meta-analysis.
      Relapses were common, with relapse rates ranging from 12.5% to 58.3%.
      • Schuttelaar M.L.
      • Hamstra J.J.
      • Plinck E.P.
      • et al.
      Alopecia areata in children: treatment with diphencyprone.
      ,
      • Hull S.M.
      • Pepall L.
      • Cunliffe W.J.
      Alopecia areata in children: response to treatment with diphencyprone.
      ,
      • Orecchia G.
      • Rabbiosi G.
      Treatment of alopecia areata with diphencyprone.
      One case-control study noted the potential of imiquimod to improve DPCP efficacy.
      • Wasylyszyn T.
      • Borowska K.
      Possible advantage of imiquimod and diphenylcyclopropenone combined treatment versus diphenylcyclopropenone alone: an observational study of nonresponder patients with alopecia areata.
      Side effects included eczematous reactions of the scalp, pruritus, regional LAD, vesiculation, or, rarely, a secondary infection.
      • Hull S.M.
      • Pepall L.
      • Cunliffe W.J.
      Alopecia areata in children: response to treatment with diphencyprone.
      No systemic side effects except headache were reported.

       Squaric acid dibutyl ester

      The efficacy of squaric acid dibutyl ester (SADBE) was studied in 78 pediatric patients (strongest LoE 4). Complete response rates ranged from 0% to 33.3%.
      • Tosti A.
      • Guidetti M.S.
      • Bardazzi F.
      • Misciali C.
      Long-term results of topical immunotherapy in children with alopecia totalis or alopecia universalis.
      • Orecchia G.
      • Malagoli P.
      Topical immunotherapy in children with alopecia areata.
      • Giannetti A.
      • Orecchia G.
      Clinical experience on the treatment of alopecia areata with squaric acid dibutyl ester.
      A meta-analysis including adult and pediatric patients demonstrated slightly better complete response rates with SADBE (38.4%) than with DPCP (30.7%).
      • Lee S.
      • Kim B.J.
      • Lee Y.B.
      • Lee W.S.
      Hair regrowth outcomes of contact immunotherapy for patients with alopecia areata: a systematic review and meta-analysis.
      Relapse rates ranged between 62.5% and 100%. Side effects included irritation, itching, LAD, and contact dermatitis.
      • Chen C.A.
      • Carlberg V.
      • Kroshinsky D.
      Angioedema after squaric acid treatment in a 6-year-old girl.
      There was 1 case of epidermolysis bullosa aquisita that arose during treatment of AA with SADBE and regressed upon discontinuation.
      • Guerra L.
      • Pacifico V.
      • Calabresi V.
      • et al.
      Childhood epidermolysis bullosa acquisita during squaric acid dibutyl ester immunotherapy for alopecia areata.
      There was no evidence of systemic absorption through topical application.
      • Singh G.
      • Lavanya M.
      Topical immunotherapy in alopecia areata.

       Cryotherapy

      One case series documented the use of cryotherapy in 24 patients <10 years of age and 40 patients between the ages of 10 and 20 (strongest LoE 4). Complete response was seen in 20.8% of patients <10 years of age. Side effects were localized, but included pain, pruritus, inflammation, and swelling.
      • Jun M.
      • Lee N.R.
      • Lee W.S.
      Efficacy and safety of superficial cryotherapy for alopecia areata: a retrospective, comprehensive review of 353 cases over 22 years.
      ,
      • Zawar V.P.
      • Karad G.M.
      Liquid nitrogen cryotherapy in recalcitrant alopecia areata: a study of 11 patients.

       Minoxidil

      Minoxidil's efficacy is equivocal for adult AA
      • Stoehr J.R.
      • Choi J.N.
      • Colavincenzo M.
      • Vanderweil S.
      Off-label use of topical minoxidil in alopecia: a review.
      and only case reports exist evaluating its use in 9 children (strongest LoE 4). Minoxidil is mostly used as an adjunctive therapy.
      • Lenane P.
      • Pope E.
      • Krafchik B.
      Congenital alopecia areata.
      ,
      • Yun D.
      • Silverberg N.B.
      • Stein S.L.
      Alopecia areata treated with hydroxychloroquine: a retrospective study of nine pediatric cases.
      Side effects of minoxidil included extensive hypertrichosis.
      • Rai A.K.
      Minoxidil-induced hypertrichosis in a child with alopecia areata.
      • Guerouaz N.
      • Mohamed A.O.
      Minoxidil induced hypertrichosis in children.
      • Herskovitz I.
      • Freedman J.
      • Tosti A.
      Minoxidil induced hypertrichosis in a 2 year-old child.
      • Georgala S.
      • Befon A.
      • Maniatopoulou E.
      • Georgala C.
      Topical use of minoxidil in children and systemic side effects.
      • Baral J.
      Minoxidil and tail-like effect.
      Although excessive topical administration may lead to systemic absorption (manifesting as palpitations, hypotension, etc.), the typical twice daily dose is generally safe.
      • Suchonwanit P.
      • Thammarucha S.
      • Leerunyakul K.
      Minoxidil and its use in hair disorders: a review.

       Topical calcineurin inhibitors

      The consensus of 4 studies that included 7 pediatric AA patients is that topical calcineurin inhibitors, tacrolimus and pimecrolimus, are not effective for the treatment of AA (strongest LoE 2). Approximately 29% showed only a minimal response,
      • Jung K.E.
      • Gye J.W.
      • Park M.K.
      • Park B.C.
      Comparison of the topical FK506 and clobetasol propionate as first-line therapy in the treatment of early alopecia areata.
      while the remaining 71% showed no response and often experienced disease progression.
      • Rigopoulos D.
      • Gregoriou S.
      • Korfitis C.
      • et al.
      Lack of response of alopecia areata to pimecrolimus cream.
      • Price V.H.
      • Willey A.
      • Chen B.K.
      Topical tacrolimus in alopecia areata.
      • Thiers B.H.
      Topical tacrolimus: treatment failure in a patient with alopecia areata.
      • Price V.H.
      Therapy of alopecia areata: on the cusp and in the future.

       Topical and intralesional corticosteroids

      The use of topical corticosteroids, particularly high-potency topical corticosteroids, is supported by the literature (strongest LoE 1) and is considered a safe and effective first-line treatment option in children with patchy AA. High-potency topical corticosteroids showed a higher efficacy than low-potency topical corticosteroids in a RCT that included 41 pediatric patients.
      • Lenane P.
      • Macarthur C.
      • Parkin P.C.
      • et al.
      Clobetasol propionate, 0.05%, vs hydrocortisone, 1%, for alopecia areata in children: a randomized clinical trial.
      They were also superior to topical tacrolimus
      • Jung K.E.
      • Gye J.W.
      • Park M.K.
      • Park B.C.
      Comparison of the topical FK506 and clobetasol propionate as first-line therapy in the treatment of early alopecia areata.
      and anthralin
      • Torchia D.
      • Schachner L.A.
      Bilateral treatment for alopecia areata.
      and were often used as adjunctive therapies.
      • Mehta J.S.
      • Raman J.
      • Gupta N.
      • Thoung D.
      Cutaneous latanoprost in the treatment of alopecia areata.
      ,
      • Coronel-Pérez I.M.
      • Rodríguez-Rey E.M.
      • Camacho-Martínez F.M.
      Latanoprost in the treatment of eyelash alopecia in alopecia areata universalis.
      ,
      • Perriard-Wolfensberger J.
      • Pasche-Koo F.
      • Mainetti C.
      • Labarthe M.P.
      • Salomon D.
      • Saurat J.H.
      Pulse of methylprednisolone in alopecia areata.
      ,
      • Yun D.
      • Silverberg N.B.
      • Stein S.L.
      Alopecia areata treated with hydroxychloroquine: a retrospective study of nine pediatric cases.
      High-potency topical corticosteroids were generally well tolerated in children. Side effects included skin atrophy, telangiectasias, and folliculitis. Although intralesional corticosteroid (triamcinolone) therapy is effective, these studies are rare in children due to the pain associated with the injections.
      • Sankararaman S.
      • Bobonich M.
      • Aktay A.N.
      Alopecia areata in an adolescent with inflammatory bowel disease.
      Based on data on adult patients, the most common side effects are pain, skin atrophy, and dyspigmentation. Other adverse effects are rare, although anaphylaxis and cataracts and increased intraocular pressure, if used close to the eyes, have been reported.
      • Kumaresan M.
      Intralesional steroids for alopecia areata.

       Prostaglandins

      Topical prostaglandins, including bimatoprost and latanoprost, may improve the regrowth of scalp and eyelash hair (strongest LoE 1-2) in AA,
      • Borchert M.
      • Bruce S.
      • Wirta D.
      • et al.
      An evaluation of the safety and efficacy of bimatoprost for eyelash growth in pediatric subjects.
      • Li A.W.
      • Antaya R.J.
      Successful treatment of pediatric alopecia areata of the scalp using topical bimatoprost.
      • Zaheri S.
      • Hughes B.
      Successful use of bimatoprost in the treatment of alopecia of the eyelashes.
      • Yadav S.
      • Dogra S.
      • Kaur I.
      An unusual anatomical colocalization of alopecia areata and vitiligo in a child, and improvement during treatment with topical prostaglandin E2.
      • Mehta J.S.
      • Raman J.
      • Gupta N.
      • Thoung D.
      Cutaneous latanoprost in the treatment of alopecia areata.
      although statistically significant differences between bimatoprost and vehicle were not found in a RCT examining eyelash hair growth in pediatric AA patients.
      • Borchert M.
      • Bruce S.
      • Wirta D.
      • et al.
      An evaluation of the safety and efficacy of bimatoprost for eyelash growth in pediatric subjects.
      While prostaglandins, specifically latanoprost, can cause irreversible iris and eyelid hyperpigmentation, uveitis, eyelash curling, and conjunctival hyperemia, these side effects were not reported in patients with AA.
      • Borchert M.
      • Bruce S.
      • Wirta D.
      • et al.
      An evaluation of the safety and efficacy of bimatoprost for eyelash growth in pediatric subjects.
      • Li A.W.
      • Antaya R.J.
      Successful treatment of pediatric alopecia areata of the scalp using topical bimatoprost.
      • Zaheri S.
      • Hughes B.
      Successful use of bimatoprost in the treatment of alopecia of the eyelashes.
      • Yadav S.
      • Dogra S.
      • Kaur I.
      An unusual anatomical colocalization of alopecia areata and vitiligo in a child, and improvement during treatment with topical prostaglandin E2.
      • Mehta J.S.
      • Raman J.
      • Gupta N.
      • Thoung D.
      Cutaneous latanoprost in the treatment of alopecia areata.
      • Coronel-Pérez I.M.
      • Rodríguez-Rey E.M.
      • Camacho-Martínez F.M.
      Latanoprost in the treatment of eyelash alopecia in alopecia areata universalis.

       Systemic therapies

       Corticosteroids

      Systemic corticosteroid therapy was the most studied treatment modality for AA in both children and adults, comprising 27 studies, mostly case series, that included 272 pediatric patients (strongest LoE 2; Table II). The studies included combination therapy with an adjunctive systemic drug including methotrexate or cyclosporine,
      • Anuset D.
      • Perceau G.
      • Bernard P.
      • Reguiai Z.
      Efficacy and safety of methotrexate combined with low- to moderate-dose corticosteroids for severe alopecia areata.
      • Gensure R.C.
      Clinical response to combined therapy of cyclosporine and prednisone.
      • Kim B.J.
      • Uk min S.
      • Park K.Y.
      • et al.
      Combination therapy of cyclosporine and methylprednisolone on severe alopecia areata.
      • Chong J.H.
      • Taieb A.
      • Morice-Picard F.
      • Dutkiewicz A.S.
      • Léauté-Labrèze C.
      • Boralevi F.
      High-dose pulsed corticosteroid therapy combined with methotrexate for severe alopecia areata of childhood.
      • Droitcourt C.
      • Milpied B.
      • Ezzedine K.
      • et al.
      Interest of high-dose pulse corticosteroid therapy combined with methotrexate for severe alopecia areata: a retrospective case series.
      intravenous pulse-dosed corticosteroids,
      • Chong J.H.
      • Taieb A.
      • Morice-Picard F.
      • Dutkiewicz A.S.
      • Léauté-Labrèze C.
      • Boralevi F.
      High-dose pulsed corticosteroid therapy combined with methotrexate for severe alopecia areata of childhood.
      ,
      • Smith A.
      • Trüeb R.M.
      • Theiler M.
      • Hauser V.
      • Weibel L.
      High relapse rates despite early intervention with intravenous methylprednisolone pulse therapy for severe childhood alopecia areata.
      • Friedland R.
      • Tal R.
      • Lapidoth M.
      • Zvulunov A.
      • Ben Amitai D.
      Pulse corticosteroid therapy for alopecia areata in children: a retrospective study.
      • Droitcourt C.
      • Milpied B.
      • Ezzedine K.
      • et al.
      Interest of high-dose pulse corticosteroid therapy combined with methotrexate for severe alopecia areata: a retrospective case series.
      • Sauerbrey A.
      Successful immunsuppression in childhood alopecia areata.
      • Hubiche T.
      • Léauté-Labrèze C.
      • Taïeb A.
      • Boralevi F.
      Poor long term outcome of severe alopecia areata in children treated with high dose pulse corticosteroid therapy.
      ,
      • Seiter S.
      • Ugurel S.
      • Tilgen W.
      • Reinhold U.
      High-dose pulse corticosteroid therapy in the treatment of severe alopecia areata.
      ,
      • Friedli A.
      • Labarthe M.P.
      • Engelhardt E.
      • Feldmann R.
      • Salomon D.
      • Saurat J.H.
      Pulse methylprednisolone therapy for severe alopecia areata: an open prospective study of 45 patients.
      ,
      • Kiesch N.
      • Stene J.J.
      • Goens J.
      • Vanhooteghem O.
      • Song M.
      Pulse steroid therapy for children's severe alopecia areata?.
      ,
      • Perriard-Wolfensberger J.
      • Pasche-Koo F.
      • Mainetti C.
      • Labarthe M.P.
      • Salomon D.
      • Saurat J.H.
      Pulse of methylprednisolone in alopecia areata.
      oral pulse-dosed corticosteroids,
      • Lalosevic J.
      • Gajic-Veljic M.
      • Bonaci-Nikolic B.
      • Nikolic M.
      Combined oral pulse and topical corticosteroid therapy for severe alopecia areata in children: a long-term follow-up study.
      ,
      • Anuset D.
      • Perceau G.
      • Bernard P.
      • Reguiai Z.
      Efficacy and safety of methotrexate combined with low- to moderate-dose corticosteroids for severe alopecia areata.
      ,
      • Jahn-Bassler K.
      • Bauer W.M.
      • Karlhofer F.
      • Vossen M.G.
      • Stingl G.
      Sequential high- and low-dose systemic corticosteroid therapy for severe childhood alopecia areata.
      ,
      • Friedland R.
      • Tal R.
      • Lapidoth M.
      • Zvulunov A.
      • Ben Amitai D.
      Pulse corticosteroid therapy for alopecia areata in children: a retrospective study.
      ,
      • Sethuraman G.
      • Malhotra A.K.
      • Sharma V.K.
      Alopecia universalis in Down syndrome: response to therapy.
      • Bin Saif G.A.
      Oral mega pulse methylprednisolone in alopecia universalis.
      • Sharma V.K.
      • Gupta S.
      Twice weekly 5 mg dexamethasone oral pulse in the treatment of extensive alopecia areata.
      • Sharma V.K.
      • Muralidhar S.
      Treatment of widespread alopecia areata in young patients with monthly oral corticosteroid pulse.
      oral corticosteroid maintenance or tapered therapy,
      • Gensure R.C.
      Clinical response to combined therapy of cyclosporine and prednisone.
      ,
      • Kim B.J.
      • Uk min S.
      • Park K.Y.
      • et al.
      Combination therapy of cyclosporine and methylprednisolone on severe alopecia areata.
      ,
      • Alabdulkareem A.S.
      • Abahussein A.A.
      • Okoro A.
      Severe alopecia areata treated with systemic corticosteroids.
      • Schindler A.M.
      The boy whose hair came back.
      • Unger W.P.
      • Schemmer R.J.
      Corticosteroids in the treatment of alopecia totalis. Systemic effects.
      • Winter R.J.
      • Kern F.
      • Blizzard R.M.
      Prednisone therapy for alopecia areata. A follow-up report.
      and intramuscular corticosteroids.
      • Seo J.
      • Lee Y.I.
      • Hwang S.
      • Zheng Z.
      • Kim D.Y.
      Intramuscular triamcinolone acetonide: an undervalued option for refractory alopecia areata.
      • Sato-Kawamura M.
      • Aiba S.
      • Tagami H.
      Acute diffuse and total alopecia of the female scalp. A new subtype of diffuse alopecia areata that has a favorable prognosis.
      • Michalowski R.
      • Kuczynska L.
      Long-term intramuscular triamcinolon-acetonide therapy in alopecia areata totalis and universalis.
      Although doses and frequencies varied among each route of administration, approximately 45% (range 0% to 100%) of patients receiving intravenous or oral pulse-dosed corticosteroids demonstrated a complete response and 34% (range 0% to 55.5%) of patients receiving traditional oral corticosteroid regimens demonstrated a complete response. For pulse-dosed therapy, shorter disease duration, younger age at disease onset, and multifocal disease (as opposed to AT and AU) were found to be associated with a better response.
      • Friedland R.
      • Tal R.
      • Lapidoth M.
      • Zvulunov A.
      • Ben Amitai D.
      Pulse corticosteroid therapy for alopecia areata in children: a retrospective study.
      Relapse rates ranged between 16.7 and100% for pulse-dosed and 50% and 100% for non-pulse-dosed corticosteroids.
      • Michalowski R.
      • Kuczynska L.
      Long-term intramuscular triamcinolon-acetonide therapy in alopecia areata totalis and universalis.
      ,
      • Alabdulkareem A.S.
      • Abahussein A.A.
      • Okoro A.
      Severe alopecia areata treated with systemic corticosteroids.
      Significant side effects were reported, including weight gain, cataracts, infections, hypertension, Cushingoid features, psychiatric disturbances, striae, and acne. Side effects were greater and more frequent for non-pulse-dosed regimens (Table II).
      • Shreberk-Hassidim R.
      • Ramot Y.
      • Gilula Z.
      • Zlotogorski A.
      A systematic review of pulse steroid therapy for alopecia areata.
      ,
      • Efentaki P.
      • Altenburg A.
      • Haerting J.
      • Zouboulis C.C.
      Medium-dose prednisolone pulse therapy in alopecia areata.

       Hydroxychloroquine

      A single case series of 9 pediatric patients examined the use of hydroxychloroquine (strongest LoE 4). When used in conjunction with topical corticosteroids and/or minoxidil, complete response was seen in 11% and partial response in 55% of patients.
      • Yun D.
      • Silverberg N.B.
      • Stein S.L.
      Alopecia areata treated with hydroxychloroquine: a retrospective study of nine pediatric cases.
      Reported side effects included abdominal pain and headache.
      • Yun D.
      • Silverberg N.B.
      • Stein S.L.
      Alopecia areata treated with hydroxychloroquine: a retrospective study of nine pediatric cases.

       Methotrexate

      Eight articles reported studies of methotrexate, either as a solitary agent or in conjunction with oral or intravenous corticosteroids or azathioprine, for the treatment of AA in 42 pediatric patients (strongest LoE 4).
      • Anuset D.
      • Perceau G.
      • Bernard P.
      • Reguiai Z.
      Efficacy and safety of methotrexate combined with low- to moderate-dose corticosteroids for severe alopecia areata.
      • Chong J.H.
      • Taieb A.
      • Morice-Picard F.
      • Dutkiewicz A.S.
      • Léauté-Labrèze C.
      • Boralevi F.
      High-dose pulsed corticosteroid therapy combined with methotrexate for severe alopecia areata of childhood.
      • Droitcourt C.
      • Milpied B.
      • Ezzedine K.
      • et al.
      Interest of high-dose pulse corticosteroid therapy combined with methotrexate for severe alopecia areata: a retrospective case series.
      ,
      • Mascia P.
      • Milpied B.
      • Darrigade A.S.
      • et al.
      Azathioprine in combination with methotrexate: a therapeutic alternative in severe and recalcitrant forms of alopecia areata?.
      • Landis ET, Pichardo-Geisinger R.O.
      Methotrexate for the treatment of pediatric alopecia areata.
      • Batalla A.
      • Á Flórez
      • Abalde T.
      • Vázquez-Veiga H.
      Methotrexate in alopecia areata: a report of three cases.
      • Lucas P.
      • Bodemer C.
      • Barbarot S.
      • Vabres P.
      • Royer M.
      • Mazereeuw-Hautier J.
      Methotrexate in severe childhood alopecia areata: long-term follow-up.
      • Royer M.
      • Bodemer C.
      • Vabres P.
      • et al.
      Efficacy and tolerability of methotrexate in severe childhood alopecia areata.
      Complete response was seen on average in 17.9% (range 0% to 50%; Table II) and partial response in 47.9% (range 0% to 100%) with doses ranging from 2.5 mg to 25 mg per week.
      • Anuset D.
      • Perceau G.
      • Bernard P.
      • Reguiai Z.
      Efficacy and safety of methotrexate combined with low- to moderate-dose corticosteroids for severe alopecia areata.
      ,
      • Droitcourt C.
      • Milpied B.
      • Ezzedine K.
      • et al.
      Interest of high-dose pulse corticosteroid therapy combined with methotrexate for severe alopecia areata: a retrospective case series.
      ,
      • Landis ET, Pichardo-Geisinger R.O.
      Methotrexate for the treatment of pediatric alopecia areata.
      • Batalla A.
      • Á Flórez
      • Abalde T.
      • Vázquez-Veiga H.
      Methotrexate in alopecia areata: a report of three cases.
      • Lucas P.
      • Bodemer C.
      • Barbarot S.
      • Vabres P.
      • Royer M.
      • Mazereeuw-Hautier J.
      Methotrexate in severe childhood alopecia areata: long-term follow-up.
      • Royer M.
      • Bodemer C.
      • Vabres P.
      • et al.
      Efficacy and tolerability of methotrexate in severe childhood alopecia areata.
      A meta-analysis revealed a higher complete response in adult versus pediatric AA patients (44.7% vs 11.6%), although the relapse rate in children was significantly lower than that in adults (31.7% vs 52%).
      • Phan K.
      • Ramachandran V.
      • Sebaratnam D.F.
      Methotrexate for alopecia areata: a systematic review and meta-analysis.
      Reported side effects included nausea, elevations in hepatic transaminases, and hematologic changes (Table II).

       Sulfasalazine and mesalazine

      Limited data exist for the use of sulfasalazine and mesalazine for pediatric AA (strongest LoE 4). Complete response to mesalazine, with or without concurrent oral or topical corticosteroids and minoxidil, was reported in 1 case series of 5 pediatric patients.
      • Kiszewski A.E.
      • Bevilaqua M.
      • De Abreu L.B.
      Mesalazine in the treatment of extensive alopecia areata: a new therapeutic option?.
      Ten adolescent AA patients treated with oral sulfasalazine in 2 studies all demonstrated partial response with a starting dose of 1 g/week, which was escalated to a final dose of 3 g/week.
      • Rashidi T.
      • Mahd A.A.
      Treatment of persistent alopecia areata with sulfasalazine.
      ,
      • Bakar O.
      • Gurbuz O.
      Is there a role for sulfasalazine in the treatment of alopecia areata?.
      Side effects for sulfasalazine included dizziness, headache, and dyspepsia (Table II). This was similar to the side-effect profile in adults, which included gastrointestinal distress, rash, headache, and lab abnormalities.
      • Aghaei S.
      An uncontrolled, open label study of sulfasalazine in severe alopecia areata.

       Ustekinumab

      A report of 3 adults whose AA responded to ustekinumab, a monoclonal antibody used for psoriasis that blocks interleukins 12 and 23,
      • Guttman-Yassky E.
      • Ungar B.
      • Noda S.
      • et al.
      Extensive alopecia areata is reversed by IL-12/IL-23p40 cytokine antagonism.
      prompted the treatment in pediatric AA and AT patients with variable results (strongest LoE was 4). One case series showed a complete or partial response in all 3 patients, while the other study reported no response.
      • Aleisa A.
      • Lim Y.
      • Gordon S.
      • et al.
      Response to ustekinumab in three pediatric patients with alopecia areata.
      ,
      • Ortolan L.S.
      • Kim S.R.
      • Crotts S.
      • et al.
      IL-12/IL-23 neutralization is ineffective for alopecia areata in mice and humans.
      Although injection-site reactions, infections, nausea, and vomiting are known side effects of ustekinumab, none were reported in these 2 studies.

       Janus kinase inhibitors

      Increasing evidence suggests that JAK inhibitors may be effective in the treatment of AA, but data in children are limited (strongest LoE 4). Side effects included infections, diarrhea, hypertension, thrombosis, gastrointestinal perforation, laboratory abnormalities, and hematologic malignancies.
      • Gilhar A.
      • Keren A.
      • Paus R.
      JAK inhibitors and alopecia areata.

       Baricitinib

      Clinical trials have been initiated to evaluate the safety and efficacy of baricitinib for the treatment of AA in adults but not yet in children.,
      • Howell M.D.
      • Kuo F.I.
      • Smith P.A.
      Targeting the Janus kinase family in autoimmune skin diseases.
      Only 1 pediatric case has been reported (strongest LoE 5). A 17-year-old male with a longstanding history of recalcitrant AA initially showed a partial response with baricitinib 7 mg once daily, followed by a complete response when the dose was increased to 11 mg once daily.
      • Jabbari A.
      • Dai Z.
      • Xing L.
      • et al.
      Reversal of alopecia areata following treatment with the JAK1/2 inhibitor baricitinib.
      No relapse was reported.

       Ruxolitinib

      A case series of 8 AA patients treated with ruxolitinib included only 1 pediatric patient, who was treated with ruxolitinib 10 mg twice daily for 10 months and experienced a 91% improvement in the Severity of Alopecia Tool score with no adverse events.
      • Liu L.Y.
      • King B.A.
      Ruxolitinib for the treatment of severe alopecia areata.

       Tofacitinib

      Clinical trials are currently evaluating the efficacy of tofacitinib to treat AA in adults.
      • Castelo-Soccio L.
      Experience with oral tofacitinib in 8 adolescent patients with alopecia universalis.
      Six case series and reports evaluated systemic tofacitinib for the treatment of AA in 28 pediatric patients.
      • Craiglow B.G.
      • King B.A.
      Tofacitinib for the treatment of alopecia areata in preadolescent children.
      • Dai Y.X.
      • Chen C.C.
      Tofacitinib therapy for children with severe alopecia areata.
      • Brown L.
      • Skopit S.
      An excellent response to tofacitinib in a pediatric alopecia patient: a case report and review.
      • 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.
      • Castelo-Soccio L.
      Experience with oral tofacitinib in 8 adolescent patients with alopecia universalis.
      • Craiglow B.G.
      • Liu L.Y.
      • King B.A.
      Tofacitinib for the treatment of alopecia areata and variants in adolescents.
      Of these patients, 82% showed complete or partial response and all nonresponders were patients with AU. Similarly, adults with severe AT or AU present for >10 years were less likely to respond to tofacitinib.
      • Craiglow B.G.
      • Liu L.Y.
      • King B.A.
      Tofacitinib for the treatment of alopecia areata and variants in adolescents.
      Side effects included diarrhea, headaches, upper respiratory infection, increased appetite, weight gain, fatigue, and transient elevation in transaminases.

       Topical tofacitinib and ruxolitinib

      In 3 reports documenting a total of 18 pediatric patients, 13 responded to topical therapy.
      • Putterman E.
      • Castelo-Soccio L.
      Topical 2% tofacitinib for children with alopecia areata, alopecia totalis, and alopecia universalis.
      • Bayart C.B.
      • DeNiro K.L.
      • Brichta L.
      • Craiglow B.G.
      • Sidbury R.
      Topical Janus kinase inhibitors for the treatment of pediatric alopecia areata.
      • Craiglow B.G.
      • Tavares D.
      • King B.A.
      Topical ruxolitinib for the treatment of alopecia universalis.
      Side effects included application site irritation
      • Putterman E.
      • Castelo-Soccio L.
      Topical 2% tofacitinib for children with alopecia areata, alopecia totalis, and alopecia universalis.
      and 1 case of borderline leukopenia in a patient with baseline low white blood cell count.
      • Craiglow B.G.
      • Tavares D.
      • King B.A.
      Topical ruxolitinib for the treatment of alopecia universalis.

       Laser and phototherapy

       Laser therapy

      Seventeen patients received treatment with a 308 nm excimer laser twice weekly with 58.8% response rate (strongest LoE 4).
      • Fenniche S.
      • Hammami H.
      • Zaouak A.
      Association of khellin and 308-nm excimer lamp in the treatment of severe alopecia areata in a child.
      • Al-Mutairi N.
      308-nm excimer laser for the treatment of alopecia areata in children.
      • Al-Mutairi N.
      308-nm excimer laser for the treatment of alopecia areata.
      • Zakaria W.
      • Passeron T.
      • Ostovari N.
      • Lacour J.P.
      • Ortonne J.P.
      308-nm excimer laser therapy in alopecia areata.
      Side effects included mild scalp erythema and desquamation.

       Phototherapy

      There were 6 reports involving 26 pediatric AA patients treated with psoralen and ultraviolet A therapy (strongest LoE 4).
      • Ersoy-Evans S.
      • Altaykan A.
      • Sahin S.
      • Kolemen F.
      Phototherapy in childhood.
      • Yoon T.Y.
      • Kim Y.G.
      Infant alopecia universalis: role of topical PUVA (psoralen ultraviolet A) radiation.
      • Mitchell A.J.
      • Douglass M.C.
      Topical photochemotherapy for alopecia areata.
      • Claudy A.L.
      • Gagnaire D.
      PUVA treatment of alopecia areata.
      • Amer M.A.
      • El Garf A.
      Photochemotherapy and alopecia areata.
      • Lux-Battistelli C.
      Combination therapy with zinc gluconate and PUVA for alopecia areata totalis: an adjunctive but crucial role of zinc supplementation.
      • Belezos N.K.
      Local estrogen and ultraviolet irradiation in the treatment of total alopecia (areata).
      All 5 adolescents treated with a psoralen-soaked towel followed by sun exposure demonstrated partial response.
      • Majumdar B.
      • De A.
      • Ghosh S.
      • et al.
      “Turban PUVAsol:” A simple, novel, effective, and safe treatment option for advanced and refractory cases of alopecia areata.
      Narrow-band ultraviolet B therapy was largely ineffective in pediatric patients,
      • Jury C.S.
      • McHenry P.
      • Burden A.D.
      • Lever R.
      • Bilsland D.
      Narrowband ultraviolet B (UVB) phototherapy in children.
      similar to the results in adults.
      • Mlacker S.
      • Aldahan A.S.
      • Simmons B.J.
      • et al.
      A review on laser and light-based therapies for alopecia areata.
      Mild irritation, erythema, pruritus, and scaling were noted as side effects of phototherapy, similar to adult patients with AA.
      • Majumdar B.
      • De A.
      • Ghosh S.
      • et al.
      “Turban PUVAsol:” A simple, novel, effective, and safe treatment option for advanced and refractory cases of alopecia areata.

      Discussion

      AA is an immune-mediated disease causing nonscarring hair loss with significant psychosocial impact.
      • Lee H.H.
      • Gwillim E.
      • Patel K.R.
      • et al.
      Epidemiology of alopecia areata, ophiasis, totalis, and universalis: a systematic review and meta-analysis.
      While a majority of children with limited AA spontaneously recover, the variability of the disease course and unpredictable response to therapy make AA challenging to treat. Although numerous therapies have been reported, the evidence is mostly weak. As a general guideline, low-risk topical therapies are a reasonable option for limited AA, while higher-risk systemic therapies may be warranted for patients who have extensive AA refractory to other therapies and who experience a significant psychosocial impact.
      A limited number of trials have been conducted in pediatric AA patients, mostly involving topical corticosteroids.
      • Jung K.E.
      • Gye J.W.
      • Park M.K.
      • Park B.C.
      Comparison of the topical FK506 and clobetasol propionate as first-line therapy in the treatment of early alopecia areata.
      ,
      • Lenane P.
      • Macarthur C.
      • Parkin P.C.
      • et al.
      Clobetasol propionate, 0.05%, vs hydrocortisone, 1%, for alopecia areata in children: a randomized clinical trial.
      These studies provide the highest LoE for treatment with high-potency topical corticosteroids and have led to their preference as first-line therapy for pediatric AA. While intralesional corticosteroids are recommended as first-line treatment for patchy AA in adults,
      • Messenger A.G.
      • McKillop J.
      • Farrant P.
      • McDonagh A.J.
      • Sladden M.
      British Association of Dermatologists' guidelines for the management of alopecia areata 2012.
      their use in children is limited by pain.
      • Goldberg L.J.
      • Castelo-Soccio L.A.
      Alopecia: kids are not just little people.
      Systemic steroids also can be efficacious, particularly in patients with a shorter disease duration, those who are at a younger age at disease onset, and those with multifocal disease
      • Friedland R.
      • Tal R.
      • Lapidoth M.
      • Zvulunov A.
      • Ben Amitai D.
      Pulse corticosteroid therapy for alopecia areata in children: a retrospective study.
      ; however, their use is limited by significant side effects.
      • Shreberk-Hassidim R.
      • Ramot Y.
      • Gilula Z.
      • Zlotogorski A.
      A systematic review of pulse steroid therapy for alopecia areata.
      ,
      • Efentaki P.
      • Altenburg A.
      • Haerting J.
      • Zouboulis C.C.
      Medium-dose prednisolone pulse therapy in alopecia areata.
      Other treatment options include contact immunotherapy with DPCP or SADBE, although evidence in children is limited to case series
      • Luk N.M.
      • Chiu L.S.
      • Lee K.C.
      • et al.
      Efficacy and safety of diphenylcyclopropenone among Chinese patients with steroid resistant and extensive alopecia areata.
      • Salsberg J.M.
      • Donovan J.
      The safety and efficacy of diphencyprone for the treatment of alopecia areata in children.
      • Singh G.
      • Okade R.
      • Naik C.
      • Dayanand C.D.
      Diphenylcyclopropenone immunotherapy in ophiasis.
      • Sotiriadis D.
      • Patsatsi A.
      • Lazaridou E.
      • Kastanis A.
      • Vakirlis E.
      • Chrysomallis F.
      Topical immunotherapy with diphenylcyclopropenone in the treatment of chronic extensive alopecia areata.
      • Schuttelaar M.L.
      • Hamstra J.J.
      • Plinck E.P.
      • et al.
      Alopecia areata in children: treatment with diphencyprone.
      • Hull S.M.
      • Pepall L.
      • Cunliffe W.J.
      Alopecia areata in children: response to treatment with diphencyprone.
      • Orecchia G.
      • Rabbiosi G.
      Treatment of alopecia areata with diphencyprone.
      ,
      • Tosti A.
      • Guidetti M.S.
      • Bardazzi F.
      • Misciali C.
      Long-term results of topical immunotherapy in children with alopecia totalis or alopecia universalis.
      • Orecchia G.
      • Malagoli P.
      Topical immunotherapy in children with alopecia areata.
      • Giannetti A.
      • Orecchia G.
      Clinical experience on the treatment of alopecia areata with squaric acid dibutyl ester.
      (Table I). Protocols for the application of SADBE at home have been utilized more recently, increasing its convenience but increasing out-of-pocket cost when purchasing SADBE from compounding pharmacies. With respect to topical adjuvant therapy, minoxidil is commonly used as the “go-to” secondary agent in clinical practice, but our evidence does not support its use as a first-line agent
      • Stoehr J.R.
      • Choi J.N.
      • Colavincenzo M.
      • Vanderweil S.
      Off-label use of topical minoxidil in alopecia: a review.
      (Table I). Topical calcineurin inhibitors are ineffective.
      • Rigopoulos D.
      • Gregoriou S.
      • Korfitis C.
      • et al.
      Lack of response of alopecia areata to pimecrolimus cream.
      • Price V.H.
      • Willey A.
      • Chen B.K.
      Topical tacrolimus in alopecia areata.
      • Thiers B.H.
      Topical tacrolimus: treatment failure in a patient with alopecia areata.
      • Price V.H.
      Therapy of alopecia areata: on the cusp and in the future.
      A better understanding of the molecular pathogenesis of AA has resulted in the development of targeted therapies, including JAK inhibitors. Current clinical trials for adults with AA include treatment with tofacitinib, ruxolitinib, and baricitinib. Furthermore, clinical trials have been initiated recently to evaluate a JAK inhibitor, PF-06651600, for AA treatment in adults and adolescents older than 12 years of age. If pediatric data are able to reflect preliminary adult responses to systemic JAK inhibitors, these currently show promise as potential future therapies, but more trials, including trials with pediatric patients, are needed. While systemic JAK inhibitors may be an effective new therapy, their safety profile as well as cost may significantly limit their use to severe, treatment-refractory cases.
      • Castelo-Soccio L.
      Experience with oral tofacitinib in 8 adolescent patients with alopecia universalis.
      ,
      • Gilhar A.
      • Keren A.
      • Paus R.
      JAK inhibitors and alopecia areata.
      It is also important to counsel patients and families regarding the chronicity of AA and the relapsing and remitting nature of the disease. Because of the lack of an evidence-based treatment algorithm, we recommend counseling patients and their families on the wide range of severity and varied responses to treatment among the different AA subtypes. Specifically, most data on AA are generalized from heterogenous groups of individuals, including patients with AT and AU. Subtype-specific response to treatment is not well-documented; however, it is known that the AT and AU subtypes generally bode more recalcitrant disease and worse outcomes. Clinicians should also highlight the existence and impact of AA comorbidities, particularly co-occurring autoimmune conditions, such as vitiligo, which add to the psychosocial impact of an AA diagnosis and can have long-lasting effects on self-esteem during childhood.
      • Vivar K.L.
      • Kruse L.
      The impact of pediatric skin disease on self-esteem.

      Conclusions

      Pediatric AA has a variable disease course with significant psychosocial impact. Although topical corticosteroids remain the preferred first-line treatment for pediatric AA, RCTs, and prospective comparative studies are needed to help define treatment guidelines. Additionally, a better understanding of prognostic markers in AA would be valuable.

      Conflicts of interest

      None disclosed.

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