Treatment of pediatric alopecia areata: A systematic review

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.

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 irritation 102 and 1 case of borderline leukopenia in a patient with baseline low white blood cell count. 104
Phototherapy.-There were 6 reports involving 26 pediatric AA patients treated with psoralen and ultraviolet A therapy (strongest LoE 4). [110][111][112][113][114][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

DISCUSSION
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 disease 71 ; 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 series [24][25][26][27][28][29][30][33][34][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 agent 122 (Table I). Topical calcineurin inhibitors are ineffective. [45][46][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

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.

Acknowledgments
Funding sources: Dr Kiuru's involvement in this article is in part supported by the National Institute of Arthritis and Musculo-skeletal and Skin Diseases of the National Institutes of Health under award number K23AR074530.  (5) (4) Table I.    Table II.      * 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. ‡

Included studies evaluating systemic treatment of alopecia areata in pediatric patients
No response defined as 0% hair regrowth, (n %) = percent of total number of patients.