Author ManuscriptAuthor ManuscriptAuthor ManuscriptAuthor Manuscript

J Am Acad Dermatol. 2022 June ; 86(6): 1318–1334. doi:10.1016/j.jaad.2021.04.077.

Virginia R. Barton, MD#a, Atrin Toussi, MD#a, Smita Awasthi, MDa,b, Maija Kiuru, MD, PhDa,c aDepartment of Dermatology, University of California Davis, Sacramento bDepartment of Pediatrics, University of California Davis, Sacramento cDepartment of Pathology and Laboratory Medicine, University of California Davis, Sacramento. # These authors contributed equally to this work.

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.

This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/). Correspondence to: Maija Kiuru, MD, PhD, Department of Dermatology, University of California, Davis, School of Medicine, 3301 C Street, Suite 1400, Sacramento, CA 95816. [email protected]. IRB approval status: Not applicable. Conflicts of interest None disclosed.

alopecia areata; contact immunotherapy; corticosteroids; JAK inhibitors; pediatric; quality of life

Alopecia areata (AA) is a nonscarring hair loss disorder that affects up to 2% of the global population.1 It is estimated that nearly 80% of patients with limited, patchy AA spontaneously recover.2 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.3 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.

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 RCTor 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).

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 Tables I to III.4–18

Topical therapies Anthralin.—Useof 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).19–22 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.19 The mean time to maximal response was approximately 9 to 15 months.19–22 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.118

Contact immunotherapy. Diphenylcyclo propenone.: 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).23–30 Complete response rates ranged from 0% to 33.3%, similar to the results of a meta-analysis (30.7%).119 Relapses were common, with relapse rates ranging from 12.5% to 58.3%.28,29,30 One case-control study noted the potential of imiquimod to improve DPCP efficacy.23 Side effects included eczematous reactions of the scalp, pruritus, regional LAD, vesiculation, or, rarely, a secondary infection.29 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%.33–35 A meta-analysis including adult and pediatric patients demonstrated slightly better complete response rates with SADBE (38.4%) than with DPCP (30.7%).119 Relapse rates ranged between 62.5% and 100%. Side effects included irritation, itching, LAD, and contact dermatitis.31 There was 1 case of epidermolysis bullosa aquisita that arose during treatment of AA with SADBE and regressed upon discontinuation.32 There was no evidence of systemic absorption through topical application.120

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.36,121

Minoxidil.—Minoxidil’s efficacy is equivocal for adult AA122 and only case reports exist evaluating its use in 9 children (strongest LoE 4). Minoxidil is mostly used as an adjunctive therapy.41,83 Side effects of minoxidil included extensive hypertrichosis.37–40,42 Although excessive topical administration may lead to systemic absorption (manifesting as palpitations, hypotension, etc.), the typical twice daily dose is generally safe.123

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,44 while the remaining 71% showed no response and often experienced disease progression.45–47,124

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 lowpotency topical corticosteroids in a RCT that included 41 pediatric patients.50 They were also superior to topical tacrolimus44 and anthralin22 and were often used as adjunctive therapies.49,51,63,83 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.48 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.125

Prostaglandins.—Topical prostaglandins, including bimatoprost and latanoprost, may improve the regrowth of scalp and eyelash hair (strongest LoE 1–2) in AA,52–56 although statistically significant differences between bimatoprost and vehicle were not found in a RCT examining eyelash hair growth in pediatric AA patients.52 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.52–56,126

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,60–62,68,72 intravenous pulse-dosed corticosteroids,68,70–74,77,79,81,82 oral pulse-dosed corticosteroids,49,60,69,71,75,76,78,80 oral corticosteroid maintenance or tapered therapy,61,62,64–67 and intramuscular corticosteroids.57–59

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.71 Relapse rates ranged between 16.7 and100% for pulse-dosed and 50% and 100% for nonpulse-dosed corticosteroids.59,64 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).127,128

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.83 Reported side effects included abdominal pain and headache.83

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).60,68,72,84–88 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.60,72,85–88 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%).129 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.89 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.90,91 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.130

Ustekinumab.—A report of 3 adults whose AA responded to ustekinumab, a monoclonal antibody used for psoriasis that blocks interleukins 12 and 23,131 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.92,93 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.132

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.133,134 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.94 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.101

Tofacitinib.: Clinical trials are currently evaluating the efficacy of tofacitinib to treat AA in adults.99 Six case series and reports evaluated systemic tofacitinib for the treatment of AA in 28 pediatric patients.95–100 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.100 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.102–104 Side effects included application site irritation102 and 1 case of borderline leukopenia in a patient with baseline low white blood cell count.104

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).105–108 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).110–115,117 All 5 adolescents treated with a psoralen-soaked towel followed by sun exposure demonstrated partial response.116 Narrow-band ultraviolet B therapy was largely ineffective in pediatric patients,109 similar to the results in adults.135 Mild irritation, erythema, pruritus, and scaling were noted as side effects of phototherapy, similar to adult patients with AA.116

AA is an immune-mediated disease causing non-scarring hair loss with significant psychosocial impact.1 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.44,50 These studies provide the highest LoE for treatment with highpotency 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,136 their use in children is limited by pain.137 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 disease71; however, their use is limited by significant side effects.127,128

Other treatment options include contact immunotherapy with DPCP or SADBE, although evidence in children is limited to case series24–30,33–35 (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 agent122 (Table I). Topical calcineurin inhibitors are ineffective.45–47,124

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.133 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.133 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.99,132

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.138

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.

AA alopecia areata AO alopecia ophiasis

1. AT alopecia totalis
2. 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