Are drug treatment strategies really effective against alopecia areata?

KEYWORDS:

• Alopecia areata
• guideline
• management
• medical treatment
• pharmacotherapy

1. Introduction

Alopecia areata (AA) is an autoimmune disease of the hair follicle affecting approximately 0.1–0.2% of the general population [1]. Its pathogenesis is associated with loss of follicular immune privilege and T-cell mediated inflammatory response, leading to interruption of the hair growth cycle. AA can present several characteristics, including solitary or multiple well-defined alopecic patches, diffuse or complete scalp hair loss, or body hair loss. Although AA manifests in spontaneous remission, approximately 40% of patients may show recurrence and recalcitrant diseases [2]. The chronic relapsing course of the disease has made AA a difficult-to-treat condition and a significant impact on patients’ quality of life. Currently, there is no treatment for AA approved by the US Food and Drugs Administration. However, several treatment modalities for AA have been introduced with variable outcomes. Although topical and systemic immunomodulators are the mainstay options, there is still a lack of high-quality randomized controlled trials (RCTs) supporting these treatment modalities [2]. Moreover, the complexities of interventional study design in AA, including assessment of alopecia and hair regrowth, study duration, and follow-up of patients, could potentially lead to challenges in evaluating treatment effectiveness. In this article, we critically appraise whether drug treatment strategies are effective against AA.

2. Rationale for the treatment of AA

There is no consensus regarding the standard treatment guideline for AA; however, various strategies have been proposed by several expert groups based on the current evidence [3–8]. Treatment decisions in each algorithm depend on patient age, disease activity, disease severity, and treatment responses. Patients aged under ten years are recommended to use topical treatments such as topical corticosteroids (TC) alone or in combination with topical 5% minoxidil or short-contact anthralin (dithranol), while all treatment forms are applicable in patients aged over ten years. Disease activity is considered the most crucial aspect to identify the prognosis of AA, and patients with severe disease activity should receive aggressive treatment [5]. The indicators associated with high disease activity include positive hair pull test and the presence of trichoscopic features, such as exclamation mark hairs, tapered hairs, angulated hairs, black dots, and broken hairs [5,9]. The Severity Alopecia Tool (SALT) score, which uses the percentage of the affected scalp area, is a universally well-accepted method to determine disease severity. Patients with a SALT score of > 50 or no response to treatment within six months should be administered topical contact immunotherapy or Janus kinase (JAK) inhibitors. Scalp prosthesis may be considered in some recalcitrant cases. Factors that may indicate poor responsiveness to treatment include younger age at onset, extensive hair loss (alopecia totalis and alopecia universalis), longer disease duration, ophiasis subtype, and family history [4]. Treatment strategies for AA are summarized in Tables 1 and 2.

Table 1. Summary of topical and intralesional treatments for alopecia areata

Drug	Recommended dose	Adverse effects
Topical agents
Corticosteroids (mid to high potency)	• Apply twice daily	• Folliculitis, itching, burning, skin atrophy, telangiectasia
Minoxidil 2–5%	• Apply twice daily	• Contact dermatitis
Anthralin 0.5–1%	• Short contact for 10–30 minutes daily	• Irritation, folliculitis, staining of the skin, regional lymphadenopathy
Bimatoprost 0.1–0.3%	• Apply once or twice daily	• Contact dermatitis
Topical contact immunotherapy (DPCP or SADBE)	• Apply once for 24–48 hours weekly	• Eczematous reaction, facial and scalp edema, regional lymphadenopathy
Intralesional agents
Triamcinolone acetinide	• 2.5–10 mg/mL at 4–6-week intervals	• Folliculitis, skin atrophy, telangiectasia

DPCP = diphenylcyclopropenone. SADBE = squaric acid dibutylester.

Table 2. Summary of systemic treatments for alopecia areata

Drug	Recommended dose	Adverse effects
Corticosteroids
Prednisolone	• 0.4–0.6 mg/kg/day • 200 mg once weekly	• Weakness, acneiform eruption, weight gain, gastrointestinal upset, dysmenorrhea, hypothalamic-pituitary-adrenal axis suppression
Betamethasone	• 5 mg for two consecutive days weekly
Dexamethasone	• 0.5 mg/day
Triamcinolone acetonide	• Intramuscular 40 mg once monthly
Methylprednisolone	• Intravenous 500 mg for three consecutive days at four-week intervals
Other systemic agents
Methotrexate	• 15–25 mg/week	• Hepatotoxicity, leukopenia
Cyclosporine	• 3–5 mg/kg/day	• Hypertension, renal dysfunction
Azathioprine	• 2–3 mg/kg/day	• Gastrointestinal upset, leukopenia, thrombocytopenia
Mycophenolate mofetil	• 2 g/day	• Gastrointestinal upset
Sulfasalazine	• 3–4 g/day	• Gastrointestinal upset, dizziness, headache
Dapsone	• 50 mg twice daily	• Hemolysis, methemoglobinemia
Tofacitinib	• 5–10 mg twice daily	• Anemia, neutropenia, headache
Ruxolitinib	• 10–25 mg twice daily	• Anemia, thrombocytopenia
Apremilast	• 30 mg twice daily	• Gastrointestinal upset
Simvastatin/ezetimibe	• 40 mg/10 mg once daily	• Headache, muscle pain, abnormal liver function tests, diarrhea

3. Topical and intralesional treatments for AA

TCs are considered the first-line therapy for patch-type AA. High-potency TCs such as 0.05% clobetasol propionate in different forms or 0.25% desoximetasone cream are usually prescribed in adults with response rates of approximately 47% and 60%, respectively. However, in children, mid-potency TCs are often recommended. The relapse rate of TC was between 37% and 63% after discontinuation [10]. Adjunctive treatment with 5% minoxidil showed a response rate of 81% [11]. Intralesional corticosteroids (IC), mainly triamcinolone acetonide with a concentration between 2.5–10 mg/mL at 4–6-week intervals, are commonly used as monotherapy or combined with TCs in adults. The response rate of IC ranges from 64% to 97% [10]. A recent study using time-to-event analysis reported comparable efficacies among TC monotherapy, IC monotherapy, and combined TC and IC in patch-type AA [10]. Therefore, either TC or IC monotherapy is sufficient for patients with mild severity.

Topical contact immunotherapy, such as diphenylcyclopropenone (DPCP) or squaric acid dibutylester (SADBE), is considered a modality for AA with more than 50% scalp involvement or recalcitrant cases [4,12]. The response rate is about 50–60%; however, the relapse rate is up to 60%. The treatment should be discontinued if there is no response after six months of treatment [4]. DPCP is preferred over SADBE, since the latter is less stable and more expensive than the former. Short contact therapy with 0.5–1% anthralin may be considered in recalcitrant cases since it showed response rates of 75% and 25% in patients with patch-type AA and alopecia totalis, respectively [4]. Other topical treatments for AA reported in the literature include calcineurin inhibitors, vitamin D analogs, prostaglandin analogs, and phosphodiesterase-4 inhibitors [4,13].

4. Systemic treatments for AA

Systemic treatments are considered for patients with severe or recalcitrant AA aged over ten years. Regarding systemic corticosteroids, the dose of prednisolone, an oral corticosteroid (OC), starts at 0.5 mg/kg/day and tapering within 6–12 weeks [4]. Other regimens reported for treating severe AA include pulse oral prednisolone 200 mg once weekly or oral betamethasone 5 mg for two consecutive days weekly for 12 weeks, intramuscular triamcinolone acetonide (imTA) 40 mg once monthly for six months, and intravenous methylprednisolone (ivMP) 500 mg for three consecutive days at four-week intervals for three months [4–8]. The response rate of systemic corticosteroids is about 80%; however, approximately 50% of patients experience recurrence after discontinuation of treatment [4–8]. Due to the longer half-life of imTA and ivMP compared to OCs, both treatments provide a higher risk of potential adverse effects, especially hypothalamic-pituitary-adrenal axis suppression.

Corticosteroid-sparing agents are recommended in patients with AA who require long-term systemic treatment. Methotrexate revealed complete hair regrowth in 63% of patients [4–8]. The dose was started at 5–10 mg once weekly and slightly increased every four to six weeks up to 15–25 mg/week [14]. Cyclosporine is prescribed at 3–5 mg/kg/day, demonstrating a response rate of 55–76%; however, treatment duration should be limited to 6–12 months due to its side effects of renal dysfunction and increased blood pressure [4–8,15]. JAK inhibitors are a novel treatment and reveal promising results for recalcitrant AA. Studies regarding the efficacy of ruxolitinib and tofacitinib for treating AA showed hair regrowth in 75% and 64% of patients, respectively [16]. Other systemic treatments for AA, including azathioprine, sulfasalazine, mycophenolate mofetil, dapsone, simvastatin/ezetimibe, ustekinumab, dupilumab, IL-17A inhibitors, abatacept, and apremilast, have been reported with variable efficacies [4–8,17].

5. Expert opinion

Several methods are available for the treatment of AA, including topical, intralesional, and systemic therapies. However, these treatment modalities show variable outcomes with relatively high recurrent rates, and few of them have been evaluated by RCTs. The aim of treatment is to halt disease progression and promote hair regrowth. Despite recent insights into the pathogenesis of AA directing several ongoing studies regarding new treatment methods, no pharmacotherapy can cure and prevent disease recurrence. The treatment concept of AA should comprise disease severity, quality of life measures, comorbidity profile, and overall long-term safety in a personalized, patient-based approach. An important challenge will be the decision to prescribe the best treatment options for patients who will benefit the most. A shared decision-making approach between the physician and patient is also important. Patients should be informed of the evidence of efficacy and safety, the lack of high-quality RCTs, and rates of spontaneous remission that range from 8% to 68% for severe and limited disease, respectively [2]. Furthermore, the psychosocial impact and compliance of the patient should be evaluated. Quality of life measures could achieve patients’ perspectives of their preferences for disease and treatment outcomes.

Patient age and extent of hair loss are important factors influencing the treatment approach. Physicians should first categorize patients into age under versus over ten-years. Disease severity should be estimated using the SALT score or percentage of the affected scalp area before prescribing therapy. Evaluating disease activity also helps to suggest the strength of the treatment and to evaluate its efficacy. Comorbidity may complicate the treatment decision since medications recommended by several guidelines for AA result in the potential for adverse drug-drug and drug-disease interactions. Topical therapies are preferred for mild and limited AA, while systemic agents are recommended for severe and extensive disease in adults. However, no evidence supports that active treatment alters the natural course of the disease, and prioritization of patient safety is essential. The response to the treatment of AA is unpredictable. Although patients achieve complete hair regrowth, recurrent hair loss may occur. Prevention of relapse by maintenance therapy is also currently not recommended since the interval between occurrences is unpredictable. According to several major treatment guidelines for AA, patients with hair regrowth less than expected after six months of therapy are considered a treatment failure necessitating consideration of other therapeutic methods [3–8]. Prognostic factors may predict inadequate treatment response and help physicians select appropriate modalities that can be used as long-term therapy safely, such as topical contact immunotherapy. Besides, JAK inhibitors may be prescribed since previous studies have demonstrated their positive results for chronic, severe, and recalcitrant AA. The use of corticosteroid-sparing agents is not compulsory, and treatment discontinuation may be considered when risk outweighs potential benefits. Alternatively, scalp prosthesis or scalp micropigmentation may be used for cosmetic purposes.

Due to the refractory course of AA, the disease presents a major challenge to physicians. Several new treatments for AA have been reported to be effective, albeit under-investigated. Among them, JAK inhibitors, both topical and oral forms, are leading clinical trials and represent a breakthrough in the treatment of AA. Furthermore, robust evidence supporting the efficacy and safety of several modalities that have been reported in the literature is lacking. Further studies using double-blind RCTs in a large number of subjects and optimal follow-up time are required to report more accurate findings and to establish effective optimal treatment guidelines for the treatment of AA.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

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Funding

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