*5.2.1.1 Topical corticosteroids (Cs)*

High-potency (class 3–4) topical Cs applied once daily to the lesion and 1 cm of healthy perilesional skin are the most frequent treatments for limited patches in adult patients who refuse intralesional therapy or in pediatric patients [69, 70]. The relapse rate of topical therapy varies from 37 to 63% [69]. A response evaluation should be performed after 3 months of treatment and discontinued if there has been no response after 6 months [70].

Possible adverse effects are folliculitis, atrophy, stretch marks, telangiectasias, and acneiform eruptions [69]. Medium potency Cs are recommended for use on face and beard areas [70].

**Figure 5.**

*Treatment strategy for alopecia areata. AA: Alopecia areata. Cs: Corticosteroids. JAKi: JAK inhibitors. MTX: Methotrexate. AZA: Azathioprine.*

## *5.2.1.2 Intralesional corticosteroids*

Considered the first-line treatment for adult patients with one or two small patches, preferred in the active phase of AA, when a positive hair pull test and exclamation mark hairs are present [69, 70]. Small volumes (0.1 ml or less) are injected into multiple sites 1 cm apart, and new growth is usually visible within 6 to 8 weeks [69, 70]. Treatment with intralesional Cs should be discontinued if there is no response at 6 months [70].

The most common adverse effect, local atrophy, can be minimized by limiting the volume injected, injecting not too superficially and using triamcinolone hexacetonide (class 2 glucocorticosteroid) [69].

#### *5.2.2 Topical immunotherapy*

Immunotherapy may be a good treatment option in patients with more than 50% of the scalp affected [71]. It is based on inducing a local allergic contact reaction [69]. The mechanism of action of topical immunotherapy is unknown, but it is believed to have an immunomodulatory effect on the inflammatory infiltrate surrounding the hair follicles [71].

Topical immunotherapy can be performed with diphenylcyclopropenone (DPCP), squaric acid dibutyl ester (SADBE), or dinitrochlorobenzene (DNCB) [71]. DPCP is often preferred over SADBE because it is less expensive, safer, and more stable in solution [69]. In the literature, success rates vary from 9 to 87%, but one systemic review described an average of 53.7% [69, 72].

Longer courses of DPCP therapy are required to consider therapeutic failure (6–12 months) [71]. The main side effects are cervical/occipital lymphadenopathy, disseminated eczema or generalized eczema, and hypo/hyperpigmentation [69]. Treatment is not recommended in pregnant women and patients with a history of atopic eczema [69].

#### *5.2.3 Topical minoxidil*

Although a meta-analysis confirmed the efficacy of topical minoxidil 5% in children and adults with patchy AA, topical minoxidil may be insufficient as monotherapy for extensive AA [73]. Controversy exists as to whether the combination of minoxidil with topical Cs is superior to monotherapy with topical Cs [74]. One milliliter of topical minoxidil solution should be applied once or twice daily, with the 5% solution being more effective than the 2% solution [70, 74]. Patients should be aware that therapy should be continued for at least 3 to 4 months to see any effect. Reversible hypertrichosis and allergic contact dermatitis are possible side effects [69].

#### *5.2.4 Ultraviolet light therapy*

An immunomodulatory effect is proposed in the mechanism of action of ultraviolet light-based therapies, which could be useful in AA [75, 76].

#### *5.2.4.1 Ultraviolet B (UVB) laser excimer*

The excimer laser emits monochromatic ultraviolet B (UVB) light at a wavelength of 308 nm. Its mechanism of action in alopecia areata is believed to involve T-cell apoptosis and the generation of mediators, such as IL-4, IL-10, prostaglandin E2, platelet-activating factor, histamine, and cis-urocanic acid with immunomodulatory effect [75, 76]. In some small studies and case reports, excimer laser treatment was associated with improvement in patchy alopecia areata of the scalp [75, 77]. Patients with limb lesions, alopecia totalis (AT), or alopecia universalis (AU) have not responded to treatment [75].

#### *5.2.4.2 Psoralen plus ultraviolet a (PUVA) therapy*

PUVA photochemotherapy involves topical or oral administration of a psoralen, a photosensitizing agent, followed by exposure to ultraviolet A (UVA) light [76]. A metaanalysis of 36 studies evaluating the efficacy of physical therapies in alopecia found that ultraviolet light in the AA group was superior to control, although with a high relapse rate [76]. In general, the efficacy of PUVA as monotherapy in AA is known, but the response is variable and poorly maintained over time [70]. It is not completely clear at what accumulative dose they appear, but the adverse effects reported in PUVA are skin photoaging, actinic keratosis, and non-melanoma skin cancer [76].

#### *5.2.5 Platelet-rich plasma*

Platelet-rich plasma (PRP) is an autologous plasma preparation with concentrated platelets containing various growth factors and cytocines useful for cell proliferation and differentiation and with anti-inflammatory properties [78].

In a randomized, double-blind, placebo-controlled trial, 45 participants with AA of at least 2 years duration were randomly assigned to intralesional injections of PRP, intralesional triamcinolone acetonide or placebo, and PRP was superior to triamcinolone acetonide in inducing hair growth and revealed significantly better dermoscopic results than intralesional triamcinolone [79]. In a randomized controlled study, a total of 90 patients with different types of AA were randomly assigned to three groups: the first group was treated with topical minoxidil 5% twice daily. The second was treated with three sessions of PRP treatment every 4 weeks. The third group received placebo. Significant hair growth was obtained in patchy AA (70%) and AU (30%) after three PRP sessions; however, AT did not respond to PRP [80].

Although PRP is relatively safe and potentially effective, further large-scale studies are needed to evaluate the efficacy of PRP as monotherapy or in association with other therapeutic modalities for AA [78].

#### *5.2.6 Topical anthralin*

Anthralin is a topical irritant agent, applied as a 0.5–1% cream daily on the affected areas for 20–30 minutes, with progressive increases in exposure time until reaching a mild dermatitis. The available evidence of its use is limited; efficacy has been demonstrated in children undergoing other topical treatment (Cs, minoxidil), although the irritation produced may compromise the adherence [81]. A systematic review found that topical anthralin monotherapy achieved a complete response rate of less than 50% (30–35%) in pediatric patients with AA [82]. The use of anthralin could achieve longer-lasting effects than laser therapy or topical immunotherapy, but less efficacy [82].

#### **5.3 Systemic treatment options**

#### *5.3.1 Systemic corticosteroids*

Systemic corticosteroids can be effective in extensive and rapidly progressive AA, often as a temporary measure or as bridge therapy to other therapies, considering that recurrence after discontinuation of therapy and systemic adverse effects in chronic therapy are common [69].

#### *An Updated in the Management of Alopecia Areata DOI: http://dx.doi.org/10.5772/intechopen.111921*

Daily oral therapy with an initial prednisolone dose of 1–0.5 mg/kg and a gradual reduction over 6 to 12 weeks is often used [70]. There is growing interest in the efficacy of intravenous or oral corticosteroid pulses [69, 70], since the toxicity and recurrence rate may be lower than with daily systemic corticosteroids. A systematic review on pulsed corticosteroid therapy included 41 articles, most of them using intravenous corticosteroid pulses, generally a treatment of 1 to 3 days per month. Very few cases of complete response were found, but in responders the risk of relapse was low (17%). Therefore, therapy may be useful in patients with good prognostic factors: multifocal AA, first episode of AA, and new-onset AA (less than 2 years) [83].

An observational study with a prospective cohort of 40 patients evaluated the efficacy and safety of treatment with dexamethasone minipulses in patients with AA, who did not improve with topical therapies. A significant and progressive overall decrease in SALT score was observed during treatment: at 9 months, a SALT-50 response was achieved in 51.8% of patients. Hypothyroidism and early age of onset were identified as factors for lack of response to treatment [84].

A high recurrence rate, following dose reduction or discontinuation, as well as adverse effects (e.g., pituitary–adrenal axis suppression, weight gain, ocular and skeletal changes, and aggravation of hypertension or diabetes) during long-term therapy have restricted the application of systemic corticosteroids as chronic AA therapy [70].

#### *5.3.2 Oral minoxidil*

A systemic review including 10 articles (19,218 patients) showed that oral administration of low-dose minoxidil (0.25 to 5 mg) twice daily improved 18 to 82.4% of patients (including severe and refractory AA) [85]. The dose of oral minoxidil ranged from 0.25 to 5 mg daily and twice daily. The most frequent adverse effects were generally mild and well tolerated (facial hypertrichosis and postural hypotension), which, together with the convenience of oral administration, may improve adherence to treatment with respect to topical minoxidil [85].

#### *5.3.3 Classic immunosuppressants*

Immunosuppressants used for refractory AA include methotrexate, azathioprine, cyclosporine, and sulfasalazine. The use of these drugs requires monitoring of their toxicity by periodic blood analysis, and there is limited evidence of their efficacy [69, 70].

### *5.3.3.1 Methotrexate (MTX)*

A meta-analysis of 16 observational studies evaluated the efficacy of MTX in severe AA in monotherapy or combined with other therapies, as well as its safety and relapse rate [86]. Patients were generally treated with doses between 7.5 and 25 mg per week. MTX induced hair regrowth of more than 50% in 63.2% of patients with AA. Adults appeared to respond better to methotrexate treatment. MTX taken together with corticosteroids was found to be more effective than in monotherapy. Initial hair regrowth with MTX may be evident after approximately 3 months, and 6 to 12 months of therapy may be required for full regrowth. However, recurrence appears common with gradual tapering of MTX. MTX complication rates were acceptable and similar between adult and pediatric cases [87].

#### *5.3.3.2 Azathioprine (AZA)*

Oral AZA may be a therapeutic option for adult patients with severe recalcitrant AA. However, given the frequency of adverse effects, close follow-up with analytical controls is recommended [70]. In a prospective study of 14 adult patients with AU refractory to other treatments, hair regrowth of ≥75% was achieved in six patients with AZA doses of 2.5 mg/kg/day adjusted for thiopurine methyltransferase levels [88]. Responses occurred 4 to 6 months after treatment initiation, and four of the six responders had a maintained response after discontinuing AZA. Adverse effects (diarrhea, hepatitis, pancreatitis, or myelosuppression) occurred in 35.71% of participants [88].

#### *5.3.3.3 Cyclosporine*

Cyclosporine may be a therapeutic option at doses up to 6 mg/kg/day for the treatment of AA totalis, AA universalis, or multifocal AA (sterkens). However, cyclosporine therapy is associated with the potential for serious adverse effects, including hypertension and nephrotoxicity, that make its use unsuitable as maintenance therapy [69, 70, 74]. A randomized, double-blind, placebo-controlled trial of 32 patients with moderate to severe AA evaluated the efficacy of cyclosporine at a dose of 4 mg/kg per day for 3 months. The treatment group achieved a ≥ 50% reduction in SALT score compared to the placebo group, but the difference between the two groups was not statistically significant [89]. In a retrospective study of 25 patients with severe AA treated with cyclosporine at 2.5–6 mg/kg/day for 2–12 months, 10 achieved significant hair growth [90]. A better response was obtained in patients with AA of less than 4 years duration, so the duration of the disease could influence the efficacy of cyclosporine [90].

#### *5.3.3.4 Sulfasalazine*

It is a prodrug activated by bacteria in the colon to sulfapyridine and 5-aminosalicylic acid with immunosuppressive and immunoregulatory properties [69]. In an open-label, uncontrolled clinical trial, 26 patients with recalcitrant or severe AA on treatment with 3 g/day sulfasalazine for 6 months were followed for 3 years. Six patients showed complete regrowth, nine patients showed partial regrowth, and ten patients experienced complete or partial relapse [91]. In a prospective study of 39 patients with refractory AA, the response to 3 g/day sulfasalazine for 6 months was evaluated. Ten patients experienced 60–100% regrowth, and 17 patients experienced no response [92]. Side effects of sulfasalazine may include gastrointestinal distress, headache, fever, rash and, less commonly, hematologic disorders and hepatotoxicity [91–93]. Starting therapy at a low dose may decrease gastrointestinal symptoms [91–93]. Blood count and liver function should be monitored closely during the first 3 months of therapy and every 3 to 6 months thereafter [93].

#### *5.3.4 Biological drugs and new molecules under investigation*

#### *5.3.4.1 Apremilast*

It is a phosphodiesterase 4 (PDE4) inhibitor that reduces the production of proinflammatory cytokines [69, 94]. PDE4 is found to be upregulated in human scalp

#### *An Updated in the Management of Alopecia Areata DOI: http://dx.doi.org/10.5772/intechopen.111921*

lesions of patients with AA [69, 94]. In a double-blind, placebo-controlled study in 30 patients with moderate to severe AA, the efficacy of oral apremilast administered for 24 weeks was evaluated [94]. At 24 weeks, only 1 of 12 apremilast-treated subjects achieved SALT50, and similarly 1 of 8 placebo-treated subjects achieved SALT50. The difference between the mean percentage improvement in SALT score compared to baseline for the two study groups was not statistically significant [94]. Despite having demonstrated efficacy in animal models, results in humans are conflicting, with lack of efficacy of apremilast in some recent studies of severe AA, but also some case reports of positive effects [69, 74, 94].

#### *5.3.4.2 Dupilumab*

It is a human monoclonal antibody that acts as a dual inhibitor of IL-4 and IL-13, used in the treatment of atopic dermatitis [65, 95]. There have been case reports of patients with atopic dermatitis and AA on dupilumab treatment who have experienced improvement of AA [65, 95]. It is proposed that the efficacy observed in these cases is due to the pathophysiological characteristics shared between atopic dermatitis and AA, with an involvement of the Th2 immune pathway in the pathogenesis of AA [65, 95]. On the other hand, dupilumab has also been associated with AA in patients with preexisting AA and those without prior episodes of AA [96]. Theories for this adverse effect include the amplification of the Th1 pathway as a result of dupilumabinduced downregulation of Th2, which calls into question the involvement of the Th2 pathway in AA [95].

A Phase II, randomized, double-blind, placebo-controlled, pilot study (NCT03359356) investigating dupilumab (300 mg) treatment in AA patients without atopic dermatitis is currently underway [97]. The dupilumab-treated arm included 40 patients. At week 48, the dupilumab-treated group experienced improvement of SALT30/SALT50/SALT75 in 32.5, 22.5, and 15% of patients, respectively [97]. Moreover, patients with baseline IgE levels ≥200 IU/mL had even higher response rates, making baseline IgE postulated as a predictor of response to dupilumab in patients with AA [97].

The most common adverse events reported are injection site reactions, conjunctivitis, blepharitis, ocular pruritus, xerophthalmia, and symptomatic reactivations of herpes simplex virus [95].

#### *5.3.4.3 Ustekinumab*

It is a monoclonal antibody that blocks the p40 subunit of IL-12/IL-23 used for treating psoriasis and Crohn's disease [95]. Ustekinumab caused hair regeneration in three patients with moderate to severe AA [98]. Common adverse effects include injection site reactions, headache, and fatigue [95].

#### *5.3.4.4 Abatacept*

It is a selective modulator of T-cell co-stimulation, composed of cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) with an immunoglobulin (Ig)G1 moiety. It is currently approved for the treatment of rheumatoid arthritis and juvenile idiopathic arthritis [95]. An open-label, single-arm phase II clinical trial (NCT02018042) evaluated the efficacy of abatacept (125 mg daily subcutaneously for 24 weeks) in 15 patients with moderate-to-severe patchy-type AA, AA totalis, and AA universalis [99]. Although most patients had a low or moderate response with abatacept, one patient achieved complete scalp hair growth at week 36. Three subjects did not respond to treatment [99]. Common adverse effects reported include headache, dizziness, nasopharyngitis, cough, back pain, and hypertension [95].
