Treatment Options in Alopecia Areata

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1 Chapter 09 Treatment Options in Alopecia Areata Nilgun Senturk* Department of Dermatology, Ondokuz Mayis University School of Medicine, Turkey * Corresponding Author: Nilgun Senturk, Department of Dermatology, Ondokuz Mayis University School of Medicine, Samsun, Turkey, Tel: ; Fax ; senturk.nilgun@gmail.com First Published April 23, 2018 Copyright: 2018 Nilgun Senturk. This article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source. 2

2 Abstract Different treatment options including topical, intralesional, and systemic agents, as well as devices, are available for the treatment of alopecia areata, but evidence based data is sparse for most of them. Remission rates may be partly attributed to spontaneous remission, which is expected to occur during the course of the disease. Treatment choice in alopecia areata depends on several factors such as severity, extent of the disease, age of the patient, associated diseases, and involvement of life quality. In this chapter, treatment options and practical considerations will be presented. Topical Agents Topical and Intralesional Steroids Topical and intralesional steroids are the treatment of choice for patients with limited alopecia areata located on the eyebrows and scalp and using corticosteroids needs attention for maximizing efficacy while minimizing side effects [1]. Topical Corticosteroids Topical corticosteroids are preferred in the first step for children and adults in which intralesional steroids are not suitable. Although they are less effective than steroid injections they might be effective approximately 50 % of patients [2-4]. A variety of formulations are available including lotions, creams, ointments, foams and sprays. The choice depends on the features of the area to be treated. Usually use of high potency topical corticosteroids are preferred due to higher efficacy. Application under occlusion increases the potency of topical corticosteroids but also side effects. For long term use, topical steroids should be applied as on-and-off use with intervals. Initial signs of improvement can take six to twelwe weeks with high rates of relapse after discontinuation [2,3]. 3

3 Intralesional Corticosteroids Intralesional corticosteroid injections should be performed on both existing and newly forming patches of alopecia. For this purpose, triamcinolone acetonide is commonly used and it is more effective than topical treatment, such as steroids and calcineurin inhibitors [5,6]. The dose per visit is determined by the extent of disease and tolerance of the patient (Table 1). Clinical improvement takes two to six weeks and at the end of six months, if there is no response alternative treatments may be attempted [4,6]. Table 1: Principals of intralesional corticosteroid injection. Before injection dilute Triamcinolone acetonide as follows 2.5 to 5.0 mg/ml is on the face, eyebrow, beard 5 to 10 mg/ml on the scalp Injection depth should be deep dermis or upper subcutis In order to reduce pain; Inject with 30-gauge needle In small volumes Into multiple sites With 1 cm apart Do not exceed 40 mg per session Repeat treatment every 4-6 weeks if necessary Stop treatment if complete regrowing occurs or no response at the end of 6 months It should be kept in mind that, with multiple injections and higher concentrations, side effects may occur. Topical and intralesional corticosteroids have similar side effects such as, local skin atrophy, folliculitis, telangiectasias, hypopigmentation, and hypothalamic pituitary adrenal axis suppression [5,6]. Although intralesional triamcinolone injection has some risks, it is a good first-line option for patients both adults and adolescenst with limited hair loss. It is not appropriate for those with more severe disease and children younger than 10 years of age because of potential fear of pain [7]. 4

4 Topical Immunotherapy Topical immunotherapy with contact sensitizers has been used since 1970 s to treat dermatological conditions in which altered immunological state assumed to play role. For alopecia areata, topical immunotherapy is suitable option for patients with severe or chronic recurrent disease [8]. Several mechanisms of action have been proposed such as inhibition of the pathologic immune response by antigenic competition, the induction of lymphocyte apoptosis, or the modulation of cytokine profiles leading to an increase in T-regulatory lymphocytes in the inflammatory infiltrate [9-13]. Its efficacy has been shown in some uncontrolled studies and found variable response rates. Some conditions may be associated with poor response to topical immunotherapy (Table 2). Generally patients achieving significant hair regrowth range between 40 to 60 percent with 60 percent relapse rates [14-16]. Table 2: Indicators of poor response to topical immunotherapy. Extensive hair loss Alopecia totalis / alopecia universalis History of thyroid disease Younger onset Nail involvement Long-standing disease Combination with antralin may increase the efficacy of topical sensitization [17]. It is expected that 1 2 % of patients could not be sensitized, and for sensitized patients further development of tolerance is also possible. If sensitization occurs, application should be performed at least three to six months to obtain acceptable hair regrowth (Figures 1a and 1b). 5

5 1: A 1: B Figure 1a and 1b: Improvement of scalp alopecia before and 12 months after treatment with SADBE. 6

6 Due to mutagenity in Ames test, dinitrochlorobenzene (DNCB) which is previously used for contact sensitization, is no longer preferred. Currently diphenylcyclopropenone (DPCP) and squaric acid dibutyl ester (SADBE), are used for topical immunotherapy. DPCP is often favored over SADBE because it is less expensive and more stable in solution. Efficacy investigations have shown similar results with both contact sensitizer [17]. None of them is recommended as a first-line treatment for patchy alopecia, and for eyelashes [18,19]. Principals of topical immunotherapy are summarized in Table 3. Table 3: Principals of topical immunotherapy. Avoid self contact with the solution that results in sensitization Always wear protective gloves and mask Refrigeration and protection from light is necessary for DPCP and SADBE For sensitization begin with the application of a 2% solution to 4x4 cm area, on the scalp After 1-2 weeks of sensitization, begin treatment with the application of a 0.001% concentration of the allergen to the affected areas Do not wash for 48 hours Protect treated areas from direct sunlight If severe eczema occurs a week may be passed or concentration may be decreased Repeat treatment weekly with slowly increasing concentrations to a maximum concentration of 2% Mild erythema and eczematous reaction is desired Hair regrowth may occur after 3 months Once maximal hair regrowth is achieved decrease treatment frequency Discontinue treatment if there is no response after six months Eczematous reaction with blistering is a potential side effect of topical immunotherapy. If reaction is severe, contact allergen should be washed off, cold compress and corticosteroid creams should be initiated. Other potential side effects include cervical and occipital lymphadenopathy, pruritus, urticaria, vitiligo, the development of multiple lentigines and dyschromia. Use in pregnancy is not recom- 7

7 mended because of possible mutagenic properties [18]. Concomitant use of oral non-sedative antihistamin, fexofenadine, may prevent the itch induced by DPCP in patients with alopecia areata [20,21]. Patient compliance, accessibility and the cost are major issues of topical immunotherapy. Anthralin Although evidence of its effectiveness is limited, topical anthralin is used in the treatment of alopecia areata as short contact therapy (Table 4) [1]. It is thought to have an immunomodulatory effect resulting in the inhibition of tumor necrosis factor (TNF)-α/β and interferon (IFN)-γ [22,23]. Table 4: Short-contact therapy with anthralin. Apply anthralin 0.5 or 1% cream to the affected areas for 20 to 30 minutes daily Then rinse off with cool to lukewarm water Increase contact time by 10 minutes every two weeks up to one hour or to the time required to induce mild dermatitis Then continue at that exposure time In small studies, improvement between percent of the patients has been reported with side effects such as pruritus, local erythema, and scaling [24,25]. Mild irritation with erythema and scaling is desired but should not be allowed to become severe vesicular reaction. Treatment should be applied for three months before reevaluating for its effectiveness. Due to low risk potential, it is predominantly used in children as an alternative to corticosteroids. Anthralin will stain hair, skin, and clothing, linens, towels, and showers brown. Patients should wash their hands with lukewarm water immediately after application. 8

8 Minoxidil Minoxidil is an antihypertensive vasodilator agent and has stimulating effect on hair growth. Randomized trials of minoxidil have been small, but some [26-28] of them have found evidence of benefit, at least for patients with limited alopecia areata. Minoxidil 5% solution is more effective than the 2% and few patients achieve cosmetically significant regrowth [29]. In contrast to agents which act on inflammation such as corticosteroids and immunomodulatory agents, minoxidil promote hair growth, and is suitable to use in combination with other modalities [30]. Use of topical minoxidil is also suggested to reduce hair loss after tapering corticosteroids [31]. For evaluation of its effectiveness, minoxidil should be tried at least three to six months and if it works, continued application is required for maintenance. Minoxidil is not effective in patients with alopecia totalis and universalis [32]. Topical minoxidil is generally well tolerated but as an adverse event growth of facial hair in women, pruritus or dermatitis may occur [33,34]. Topical Prostaglandin Analogs Bimatoprost is a prostaglandin F2-α (PGF2 α) analog, which induce hypertrichosis, initially used to treat alopecia areata of eyelashes[35]. In case reports and some studies, effectiveness has been shown and patients with 50 % loss get more benefit [36-38]. Mild eye irritation, hyperemia and conjunctivitis are reported side effects [39,40]. Bimatoprost has been used for the scalp alopecia and showed a higher efficacy to topical corticosteroid therapy (50 % versus 22 %). Although side effects were not reported with bimatoprost, relapse and resistance were observed [39]. Similar results were also obtained in a pediatric case study [40]. 9

9 Photochemotherapy Photochemotherapy is a treatment option for alopecia areata. Psoralen plus ultraviolet A (PUVA) can be administered with the topical or oral 8-methoxypsoralen. Several uncontrolled series have suggested efficacy rates of PUVA of 60 to 65 percent, with a high relapse rate [41-44]. After initial hair regrowth, decreasing in efficacy may be expected due to regrown hair inhibiting the UVA light to reach the skin. Photochemotherapy may be suitable in patients with extensive alopecia areata (more than 75 percent of scalp involved), alopecia totalis, or alopecia universalis when topical immunotherapy is contraindicated or unavailable for the patient. Treatment usually takes four to six months. It should be kept in mind that, long-term treatment with PUVA has been associated with an increased risk for cutaneous malignancy. 308 nm Excimer Laser 308 nm excimer laser has been shown to be effective in patchy alopecia areata. Treatment was performed for 3 months about sessions. But it is not suitable for alopecia totalis or universalis. [45-47]. Systemic Therapies Systemic therapies are suitable for severe and recalcitrant alopecia areata. A high relapse rate, limited efficacy data, and the potential adverse effects of these drugs limit their use to refractory cases. Systemic Steroids Systemic glucocorticoid therapy may induce hair growth in alopecia areata [1]. The efficacy of prednisone (40 mg tapered over six weeks) was investigated in a prospective study of children and adults with alopecia areata, in which 13 patients achieved at least 50 percent hair regrowth, after six weeks of treatment [48]. 10

10 For acute and widespread alopecia areata (more than 30% surface area) systemic corticosteroid therapy, either orally or intravenously, is suitable. For the prevention of side effects, pulsed administration has been proposed as prednisolone 300 mg per oral at 4-week intervals, for a minimum of four doses or until cosmetically acceptable hair growth is obtained [49]. Clinical response may become evident approximately 2 to 3 months of therapy. Additionally, short courses of systemic glucocorticoids (40 to 60 mg per day in adults or 1 mg/ kg per day in children tapered over four to six weeks) may be used to stop rapid disease progression in patients with widespread active disease. Although systemic glucocorticoids stimulate hair growth, the adverse effects associated with these agents limit the duration of therapy and recurrence frequently occurs after the discontinuation of treatment. Minoxidil may be used for preventing recurrences after prednisone discontinuation [48]. Other Immunsupressive Agents Sulfasalazine Sulfasalazine is a drug with immunosuppressive and immunomodulatory properties. In uncontrolled studies, successful therapy in approximately 25 percent of patients with alopecia areata have been reported [50-52]. However, relapse rates of up to 45 percent have been reported [51]. Methotrexate As in other lymphocyte-mediated autoimmune diseases, the use of methotrexate (MTX) alone or in combination with low-dose oral corticosteroids for the treatment of extensive alopecia areata has been proposed with an overall success rate of 64% [53]. Best results are achieved with 30 mg weekly subcutaneous MTX in combination with oral prednisone 20 mg daily: re-growth of hair begins within 2 to 4 months of this regimen [54]. 11

11 Cyclosporine Cyclosporine may induce hair regrowth in alopecia areata via inhibition of helper T cell activation [55]. Although hair growth occurs between the second and the fourth week of therapy with the dose of 6 mg/kg/d, significant hair loss, occurred in all patients within 3 months of discontinuation of cyclosporine treatment [55]. For treatment of severe alopecia areata, combination regimens of oral cyclosporine with low-dose corticosteroids have been found to be effective [56]. Nevertheless, long-term toxicities and risks related to immunosuppression limit its use. Azathioprine Effectiveness of azathioprine has been shown in uncontrolled studies in which hair regrowth encountered in some patients with moderate to severe alopecia areata [57,58]. Responses occurred four to six months after the initiation of treatment, and four of the six responders had persistent improvement after the discontinuation. Adverse effects (diarrhea, liver enzyme elevation, pancreatitis, or bone marrow suppression) occurred in 5 of the 14 treated patients, resulting in treatment cessation in four patients. Statins There is increasing evidence that statins (3-hydroxy-3-methylglutaryl co-enzyme A reductase inhibitors) have immunomodulatory activities. [59]. After original report of hair regrowth in a patient with alopecia universalis following initiation of simvastatin and ezetimibe therapy, effectiveness has been shown in several case reports and case series but findings could not be reproduced subsequently [60-64]. For that reason, limited data obtained from case series of a condition where spontaneous remissions may occur, and these results need to be clarified by large placebo-controlled trials. 12

12 Targeted Therapies Biological agents Neither tumor necrosis factor alpha (TNF alpha) inhibitors such as etanercept and infliximab, nor LFA-1 inhibitor efalizumab were effective for the treatment of alopecia areata. [65-67]. TNF-alpha inhibitors rather worsen the course of the disease [68]. Janus Kinase Inhibitors Hair regrowth during tofacitinib treatment (selective Janus kinase 1/3 inhibitor) has been shown in alopecia areata (Figures 2-4) [69-75]. Effect of tofacitinib may result from inhibition of T lymphocyte activation. In a retrospective study with 90 adults with severe alopecia treatment with tofacitinib (5 to 10 mg twice daily) for at least four months suggests benefit [69]. In this study, patients with longer duration of disease (more than 10 years) had lower response rate and no serious adverse effects noted. Tofacitinib therapy is associated with increased risk for infection, including serious infections [74]. The development of malignancy and laboratory abnormalities has also been reported in patients receiving tofacitinib therapy for other diseases [75]. Similar results were also reported for potential role of Janus kinase 1/2 inhibitor ruxolutinib in the treatment of alopecia areata [76]. In a patient with refractory alopecia universalis, treatment with ruxolitinib 0.6% cream (twice daily for 12 weeks) appeared to stimulate almost full eyebrow regrowth and approximately 10 percent regrowth of scalp hair [77]. Further studies are necessary to conclude the efficacy and safety of topical Janus kinase inhibitors for the treatment of alopecia areata. 13

13 2: A 2: B Figure 2a and 2b: Succesful treatment of alopecia totalis with tofacitinib, before and 12 months after therapy. 14

14 3: A 3: B Figure 3a and 3b: Succesful treatment of alopecia totalis with tofacitinib, before and 12 months after therapy. 15

15 Platelet-Rich Plasma (PRP) PRP has gained popularity in several dermatologic conditions and includes several growth factors such as platelet derived growth factor, TGF-beta, fibroblast growth factor, insulin-like growth factors 1 and 2, vascular endothelial growth factor, epidermal growth factor (EGF), IL-8 and keratinocyte growth factor. In a double-blind, placebo controlled study with 45 patients intralesional injections of PRP, intralesional triamcinolone or placebo were applied on one half of the scalp of the patients with randomized design while other half was not treated. Three treatments were given for each patient, with monthly intervals. PRP was found to increase hair regrowth and decrease hair dystrophy, burning or itching sensation compared to intralesional triamcinolone or placebo [78]. Since detailed immunologic pathogenesis of alopecia areata is almost explored, and targeted therapies gained more attention; treatment with PRP with unknown mechanism may only be used as an adjuctive therapy[79]. Special Conditions Eyebrow Alopecia Areata Topical steroids or steroid injections are the mainstay of treatment of eyebrow AA. Generally in this area use of lower concentrations (2.5 mg/ml) is suggested in order to limit the chance of transient atrophy[7]. Eyebrow tattooing is a popular option for those with treatment-resistant eyebrow AA. Eyelash Alopecia Areata There are no established treatments for the local treatment of eyelash disease. Topical prostaglandin analogues have been studied for this purpose [35,37]. False eyelashes are a cosmetic option for these patients. 16

16 Beard Alopecia Areata Alopecia areata of the beard is challenging and topical treatment with steroids can elicit folliculitis. Usually injections of triamcinolone acetonide (5 mg/ml) is suggested for resistant areas[7]. Atrophy remains a main side effect and must be discussed with all patients. Scalp Camouflage Options Individuals with advanced forms of AA may be benefited from a wig or hairpiece. These products can be worn while using all forms of treatment. Scalp camouflaging options with coloured sprays and fibres can be used to camouflage small areas of hair loss. Wigs are generally less usefull in men where shaving the scalp, are often preferred approach [80]. Children with Alopecia Areata Therapeutic options for children are more limited than for adults due to concerns about tolerability and side-effects [80]. Topical therapies are the primary therapeutic modality in this age group, with potent topical glucocorticoids as the first-line treatment [81,82]. Topical minoxidil and topical immunotherapy are additional options for the treatment of children. Anthralin may also be used, but the significant irritation reaction can limit its use in children. Use of oral glucocorticoids for extensive and progressive alopecia areata may induce hair regrowth, but patients often relapse upon the cessation of therapy. The use of long-term systemic glucocorticoids is generally not recommended due to concern for systemic side effects [81]. Studies of PUVA therapy in children with alopecia areata have variable results and is not favored for the use in children due to its association with cutaneous malignancies [82]. The psychological effects of hair loss are often of concern in children, and particularly adolescents, with alopecia areata. Counseling and support services may be indicated. 17

17 Conclusion Since up to 50 percent of patients with limited alopecia areata will experience spontaneous regrowth of hair less than one year s duration, treatment is not necesarry for all patients. For cosmetic reasons, alopecia areata can cause severe emotional distress; and counseling in such patients is needed. For patients who desire treatment, aproach should be tailored according to the age of the patient, extend of disease, associated conditions and the involvement of life quality (Table 5). Table 5: Practical points for the treatment of alopecia areata. Alopecia areata localized to scalp intralesional injections of corticosteroids is the first choice of treatment. In children or adults with limited disease who cannot tolerate intralesional therapy, topical corticosteroids are suggested. If intradermal or topical corticosteroid therapy is not enough, topical 5% minoxidil either alone or in combination with continued corticosteroid therapy is suggested. Patients with extensive disease, or limited disease who do not respond to topical agents can be treated with topical immunotherapy. If topical immunotherapy does not work or contraindicated, photochemotherapy may be tried but long-term photochemotherapy should be avoided. In patients with widespread active disease systemic short courses of glucocorticoid therapy may be utilized to stop disease progression. For potential adverse effects they are not suitable for long-term use. For resistant cases other immunsupressives or targeted therapies may be tried. Patients who do not desire treatment may benefit from cosmetic interventions such as wigs for female and shaving the scalp for male patients. Eyebrow tattooing or false eyelashes can be helpful. 18

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