Treatment options for alopecia areata

Abstract

Alopecia areata (AA) is a common dermatosis characterized by a chronic and unpredictable course. Treatment options aim at hair regrowth and control of remissions. The evaluation of the effectiveness of various existing therapeutic methods is confined by the lack of consensus on a grading system for AA, as well as the absence of a treating algorithm depending on the severity of AA. Therapeutic agents used in the treatment of AA include topical and systemic corticosteroids, minoxidil, anthralin, phototherapy and topical immunotherapy. Intralesional corticosteroid injections are widely used as therapy for patchy alopecia exhibiting good efficacy and tolerance by patients. Topical immunotherapy with the use of diphencyprone or squaric acid dibutylester has well-proven efficacy both in localized and extended disease. Other modalities, such as topical calciceurin inhibitors and biologic agents, have been used with limited success.

Keywords::

• alopecia areata
• anthralin
• biologics
• calcineurin inhibitors
• corticosteroids
• diphencyprone
• minoxidil
• squaric acid dibutylester
• treatment

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All other clinicians completing this activity will be issued a certificate of participation. To participate in this journal CME activity: (1) review the learning objectives and author disclosures; (2) study the education content; (3) take the post-test with a 70% minimum passing score and complete the evaluation at http://www.medscape.org/journal/expertderm; (4) view/print certificate.

Release date: September 28, 2011; Expiration date: September 28, 2012

Learning objectives

Upon completion of this activity, participants should be able to:

• • Assess the clinical presentation of alopecia areata

• • Distinguish the most efficient evidence-based treatment for alopecia areata

• • Compare topical treatments for alopecia areata

• • Evaluate systemic treatments for alopecia areata

Financial & competing interests disclosure

EDITOR

Elisa Manzotti,Editorial Director, Future Science Group, London, UK

Disclosure:Elisa Manzotti has disclosed no relevant financial relationships.

CME AUTHOR

Charles P Vega, MD,Associate Professor; Residency Director, Department of Family Medicine, University of California, Irvine, CA, USA

Disclosure:Charles P Vega, MD, has disclosed no relevant financial relationships.

AUTHORS

Stamatis Gregoriou,University of Athens Medical School, Attikon Hospital, Dermatology Department, Athens, Greece

Disclosure:Stamatis Gregoriou has disclosed no relevant financial relationships.

Charalambos Kazakos,University of Athens Medical School, Attikon Hospital, Dermatology Department, Athens, Greece

Disclosure:Charalambos Kazakos has disclosed no relevant financial relationships.

Dimitris Rigopoulos,University of Athens Medical School, Attikon Hospital, Dermatology Department, Athens, Greece

Disclosure:Dimitris Rigopoulos has disclosed no relevant financial relationships.

Alopecia areata (AA) is a relatively common dermatosis of autoimmune pathogenesis, characterized by nonscarring hair loss in an unpredictable course. It affects males and females equally, most commonly of young age and has a serious impact on social life and self-esteem. Consequently, AA represents an intriguing therapeutic challenge for dermatologists.

Alopecia areata usually manifests as a well-demarkated round or oval patch of hair loss that can be isolated or multiple (patchy AA). The skin of the affected area shows no visible signs of alteration and appears normal. The lesion usually expands in a circumferential way and the periphery may contain thick broken-off exclamation point hair easily observed through dermoscopy. Hairs can be easily removed with a light pull in cases of an expanding lesion. A sign of remission is the white short vellus-type hair that may develop in the center of the patch. The scalp is the most common site affected by AA.

Patchy AA can be classified as localized or extensive according to the number and surface of lesional patches. A 25% total hair loss is recognized by some authors as an accepted borderline between those two forms in terms of management and prognosis [1]. Alopecia totalis (AT) occurs when scalp and face hair such as eyebrows, eyelashes and beard are affected, while the term alopecia universalis (AU) refers to cases of entire body hair loss. Ophiasis pattern refers to AA extending along the posterior occipital and temporal regions of the scalp. Nail involvement is present in about 20% of cases in features such as nail pitting, trachyonychia, Beau’s lines, koilonychia, onychomadesis, onychorrhexis and punctuate or transverse leukonychia.

Histopathology of AA is characterized mainly by follicular inflammatory infiltration. In the acute stage of AA the infiltration is predominant around an increased number of catagen and telogen follicles and the peribulbar lymphocytic accumulation has the characteristic pattern of ‘swarms of bees’. In the chronic stage, the main findings are the miniature type of hair follicles, with abnormal hair only reaching the infundibulum. Inflammatory infiltration may be absent in longstanding nonactive AA [2]. Trichoscopy is also useful in distinguishing between active and long standing AA. Characteristic trichoscopic features of AA are black dots, tapering hairs (exclamation mark hairs), broken hairs, yellow dots and short vellus hairs [3].

Clinical classification has a significant impact on prognosis as ophiasis and AT and AU have significantly lower response rates. Patients presenting with active stage of AA benefit more of more aggressive treatment regimens.

Pathophysiology of AA is still under investigation, although an obvious correlation between alteration of immune status of skin, autoimmune diseases and stressful events or psychological disorders exists. Lesional biopsies show a perifollicular lymphocytic infiltration around anagen hair follicles in patients with AA. AA appears to be precipitated predominantly by CD8⁺ lymphocytes, but the disease mechanism is driven by CD4⁺ cells [4]. Philpott et al. showed that IL-1α, IL-1β and TNF-α were potent inhibitors of hair follicle growth in vitro[5]. Hoffmann et al. studied the effect of a panel of cytokines and growth factors on hair growth: IL-2, IL-10 and IFN-γ had no effect in this regard, whereas TGF-β1 partially inhibited hair growth and EGF, TNF-α and IL-1β completely halted it [6].

Although diverse therapeutic options are available nowadays, none of them seem to be satisfactory. AA is difficult to treat owing to its unpredictable chronic inflammatory nature. Randomized double-blind, trials on the treatment of AA are rare. Spontaneous remission, which appears in almost 50% [7] of patients with limited disease and less than 1 year in duration, complicate evaluation of therapeutic results.

Limited evidence-based knowledge harbors controversies in clinical treatment guidelines. Even though remarkable efforts in that direction have been made in the last few years, no general consensus has been achieved [8]. Clinical guidelines are systematically developed statements in order to assist clinician and patient decisions about appropriate healthcare for specific clinical circumstances and should be based on high-quality evidence if available. Solid knowledge about the efficacy of a treatment can be verified by double-blind, placebo-controlled studies in a sufficient number of patients. In the case of AA, there is a variety of references from trial-based reviews to scarce reports and letters, showing that treatment of AA is mainly based on expert and experienced clinical opinion. This article summarizes the vast majority of different treatments available, topical or systemic, based mainly on published trials.

Therapies of AA most commonly include intralesional corticosteroid injections, corticosteroid creams with or without occlusion, systemic corticosteroids, minoxidil, anthralin, topical immunotherapy and phototherapy. There is also a variety of agents that have been used with variable success in small groups of individuals. The choice of treatment always depends on patient’s age (children do not always tolerate side effects or painful and irritating therapies), extent of disease and both the physician’s and the patient’s personal preference.

Topical treatments

Topical corticosteroids

Potent and superpotent topical corticosteroids are widely used for the treatment of AA, even though their clinical efficacy is still controversial. It has been suggested that topical corticosteroids reduce the inflammatory response in AA. Superpotent corticosteroid ointments with occlusive dressing have been documented to produce excellent results even though patient compliance is low. [9] Tosti et al. showed in a double-blind, placebo-controlled trial that clobetasol propionate 0.05% preparation applied twice daily for 24 weeks, to patients with moderate-to-severe AA, resulted in 47% of the patients achieving at least 25% regrowth [10]. In a parallel-group, investigator-blinded trial by Milani et al., 61% of patients with mild-to-moderate AA using betamethasone valerate foam achieved at least 50% regrowth in comparison to 27% in the control group [11]. While having good results in milder forms of AA, topical corticosteroids are ineffective in AT and AU. Folliculitis is the most common side-effect of this kind of treatment. Even though there is increased skepticism about potential systemic absorption of long-term applied topical steroids, recent studies in pediatric populations of patients with atopic dermatitis downplay the risk to affect the hypothalamic–pituitary–adrenal axis for both low potency and ultrapotency steroids [12–14].

Intralesional corticosteroids

Depot corticosteroids injected intralesionally are preferred by many dermatologists in cases of AA involving less than 50% of the scalp [15].

The basic concept of treatment is to maximize the corticosteroid effect on perifollicular inflammation by penetrating the epidermis barrier. Triamcinolone acetonide 5 mg/ml, betamethasone dipropionate/betamethasone sodium phosphate 5+2 mg/ml and betamethasone sodium phosphate/betamethasone acetate 3 + 3 mg/ml are most common modalities used by dermatologists worldwide [7]. Usually, 5–10 mg of triamcinolone acetonide injections on every session within intervals of 4–6 weeks is a common practice with results to be expected within the next 1–2 months. No limitation on the number of sessions that can be performed has been reported. Furthermore, Shapiro et al. suggest combined treatment of intralesional and superpotent topical corticosteroids for a period of months if a 3–4-month triamcinolone monotherapy fails [7]. A study from Saudi Arabia showed that injected triamcinolone acetonide gave better results in individuals with fewer than five patches of <3 cm in diameter [16]. While the method is effective in localized AA, it has less applicability in more generalized types because of the dose of steroid needed and inefficiency in rapidly progressive AA. On the other hand, a recent study suggests that intralesional treatment may also be useful in more extensive forms of AA [15]. Skin atrophy at the site of injection is a well-known adverse event, particularly when triamcinolone is used. An interesting alternative is the use of a mesotherapy multi-injection round plate which has been presented a few years ago [17], in an attempt to make the procedure more patient-friendly. Special care should be given when injecting in the eyebrow area to avoid eye injuries.

Topical immunotherapy

Diphencyprone & squaric acid dibutylester

Diphencyprone (DPCP) represents a hallmark in AA treatment because its introduction produced reasonable aspirations for effective treatment of generalized AA [18,19]. It has been described in the literature since 1972 as a potent contact allergen in both humans and animals. Even though topical immunotherapy with DPCP is considered as one of the most effective treatments of AA, success rates vary in different studies ranging from 4 to 85% [20–23]. The mode of action of DPCP has not been clearly illuminated. The sensitization and subsequent contact dermatitis results in recruitment of a different T-cell subpopulation to the treated area, that has an impact on the putative follicular antigen [24], alters the expression of antifollicle antibodies [25] or the excessive production of proinflammatory cytokines and growth factors [26–28]. DPCP treatment protocol was described by Happle et al.: the patient is sensitized using a 2% acetone solution of DPCP applied to a small area of the scalp (5 × 5 cm) [29]. No statistically significant correlation between patient’s age and sensitization seems to exist [30]. A total of 2 weeks later, a 0.001% solution of DPCP, is applied and this is repeated at weekly intervals. The concentration is increased at each treatment until a mild dermatitis occurs. Once a maximum response is obtained a reduction of treatment frequency is needed and if full hair regrowth is achieved, it can be discontinued. DPCP is a nonmutagenic factor. A few adverse events are noted like eczematous reactions with blistering and spreading of the induced contact eczema, sleep disturbances, severe urticarial reaction or severe dermographism. The inherent eczematous reaction owing to treatment is the most common side effect which may cause patient complaints. A long period of therapy is needed, a fact which will increase the percentage of responders especially in cases of AT and AU. Unfortunately, there is a high relapse rate especially in the more diffuse types of AA. Maintenance therapy is recommended to reduce the risk of relapse, but few patients maintain follow-up visits after obtaining cosmetically adequate response [31,32]. In addition, drawbacks of topical immunotherapy include the fact that this mode of treatment is used mainly for patients with more than 50% scalp involvement, and lesions become more refractory to the application of DPCP following several courses of treatment. If there is no response following 6 months of application, the treatment should be stopped. In many cases, the therapists themselves might be sensitized by the DPCP.

Like diphencyprone, squaric acid dibutylester (SADBE) is a nonmutagenic irritator, but a less stable one. Assessment of efficacy is based on various trials showing a similar treatment response in patients with moderate and serious AA [33]. Sensitization is performed by topical application of 3% SADBE on a hairless patch or on half of the scalp when the patient presents with diffuse alopecia. Progressively denser dilutions are applied at 3-day intervals, in order to identify the minimal concentration able to elicit an inflammatory response. SADBE application is then performed weekly using the appropriate dilution during each session in order to maintain a mild inflammatory effect [34]. SADBE is also proven to be a valid and suitable treatment for children, particularly those who are resistant to conventional therapies [35] but a rather high relapse rate occurs. SABDE has the same side effects as DPCP.

Minoxidil

Minoxidil is an antihypertensive vasodilator also known for its ability to slow or stop hair loss and promote hair regrowth. The mechanism by which minoxidil promotes hair growth is not fully understood, although it has been widely used for almost 40 years as treatment for various types of alopecia. Topical minoxidil potentially shortens telogen phase, causing premature entry of resting hair follicles into anagen phase [36]. The triggering effect of minoxidil has been attributed to the opening of potassium channels by minoxidil sulfate. In vitro effects of minoxidil include stimulation of cell proliferation, inhibition of collagen synthesis, stimulation of vascular endothelial growth factor and prostaglandin synthesis [36]. Although minoxidil is a well-proven treatment for androgenetic alopecia, data for its efficacy in AA still remain vague. Topical minoxidil treatment is relatively nontoxic, easy to use, and free from any local or systemic side effects. An early double-blind study showed that topical minoxidil 1% seems to have cosmetically acceptable results in localized AA, although patients with more severe and extensive disease, have a worse response and those with AU and AT are less likely to respond [37]. Since then, other controlled trials in patients with extensive AA treated with 1 and 3% preparations reported minimal or enduring results [38,39]. Another randomized double-blind minoxidil versus placebo treatment study also indicated that minoxidil has no effect in the reduction of perifollicular T cells which are supposed to play important role in the pathophysiology of AA [40].

Calcineurin inhibitors

Tacrolimus (also known as FK-506) is a macrolide immunosuppressive agent that inhibits calcineurin and thus reduces IL-2 production by T cells. It is used as a topical preparation in the treatment of severe atopic dermatitis and vitiligo. Despite initial encouraging results of topical tacrolimus in experimental bald animal models, no hair regrowth was achieved in AA patients [41].

Pimecrolimus is an ascomycin macrolactam product that exhibits both anti-inflammatory and immunomodulatory qualities. It prevents calcineurin-mediated dephosphorylation of the nuclear factor of activated T cells, which inhibits synthesis of Th1 and Th2 cytokines from T lymphocytes. Although during recent years the experimental use of pimecrolimus in AA in mice and rat models has given promising results, this has not been confirmed in clinical trials in human AA [42].

Anthralin

Anthralin, or dithranol, is a hydroxyanthrone, anthracene derivative, and one of the oldest and most widely used therapeutic agents for the treatment of psoriasis. An experimental study confirms the potential efficacy of topical anthralin in restoring hair growth in C3H/HeJ mice with AA-like hair loss [43]. The proposed mechanism of action is the downregulation of cytokines that promote perifollicular inflammation. There were also some initial reports of efficacy as an irritant factor for some patients with patchy AA, but the lack of control studies makes the assessment difficult. Contrary to this, other investigators have tried to evaluate the agent’s ability to stimulate hair growth [44] and failed to have acceptable results, especially in serious AA. As a result, the effectiveness of the agent is still unclear. The published data indicate that dithranol needs to be applied in sufficient frequency and in a very dense form to produce appropriate irritation, in order to be effective. Perhaps the unwillingness of the patients to comply in such a time-consuming and demanding treatment is the reason for its recorded poor effectiveness in some studies. Staining of hair limits its use in fair-haired individuals and this is another cause of its unpopularity among physicians and patients [45].

Topical cyclosporin

Large studies on cyclosporin A (CsA) as monotherapy for AA are lacking. The basic concept of topical cyclosporin application is to avoid the adverse events of systemic administration while exhibiting effectiveness on the epidermal appendages where pathogenesis of AA takes place. Experimental studies on rats evaluated the efficacy of CsA, in a topically applied formulation, as a potential treatment for AA with encouraging results [46]. Topical CsA therapy in humans has so far met with little success [47,48]. The large size of cyclosporine molecules combined with its complexity, have been suggested as the reason for the failure to develop a successful topical treatment with CsA.

Prostaglandin & prostamide analogues

Latanoprost 0.005% ophthalmic solution is used for controlling the progression of glaucoma or ocular hypertension by reducing intraocular pressure. Bimatoprost 0.03% solution is also used for glaucoma treatment and has recently been approved by the US FDA for hypotrichosis of the eye lashes. Both prostaglandin and prostamide analogues have been shown to interact with prostanoid receptors in the hair follicle resulting in induction of telogen follicles into the anagen phase. They have also been shown to prolong the anagen phase of eyelashes. However, most of the effects regard healthy eyelashes; results in the treatment of eyelash AA are controversial. A 2-year prospective, nonblinded, nonrandomized controlled study by Coronel-Pérez et al. showed that latanoprost may be an effective drug in the treatment of eyelash AA as it produced acceptable responses (total and moderate) in 45% of the patients compared with the control group treated with triamcinolone acetonide intralesional injections [49]. On the other hand, a recent study by Shapiro et al. reported lack of efficacy of latanoprost in the treatment of eyebrow AA [50]. Despite several case reports of eyelash regrowth in patients with AA treated with bimatoprost [51], a randomized investigator-blinded study by Roseborough et al. showed no results in 11 patients after 16 weeks [52].

Imiquimod

Imiquimod is a potent immune response modifier and antiproliferative agent widely used in the treatment of skin cancers, genital warts and actinic keratoses. Early reports have been vague about its efficacy in terms of AA. Hezel et al. reported a response after 4–6 weeks of therapy with imiquimod 5% cream, but also a loss of regrown hair after the end of the 16-week treatment [53]. Other studies showed imiquimod’s poor efficacy in treatment of both patchy AA and AT/AU, since only limited and temporary vellus hair regrowth was achieved [54,55].

Systemic treatments

Systemic corticosteroids

Systemic corticosteroids have enjoyed a fair share of popularity in the treatment of AA because of their immunosupressing properties. It is widely believed that long-term treatment with corticosteroids will produce regrowth of hair in some individuals, mostly those having localized AA rather than AU/AT [56]. Unfortunately, it has been observed that in most patients, continuous treatment is needed to maintain the achieved hair growth. Many papers have been published using oral, intravenous or intramuscular steroids and achieving various results, but there is lack of controlled studies. It is claimed that an oral pulse of 300 mg prednisolone will induce hair regrowth in many cases of widespread AA and overcome the acute crisis [57]. Satisfactory hair regrowth was observed in seven cases out of 18 patients (38.9%) with AA (extensive patchy and totalis/universalis) who were treated with systemic corticosteroids (15–40 mg prednisolone) daily for several months [58]. Unfortunately, hair loss subsequently occurred on discontinuation or tapering of treatment. One of the major problems of daily long-term corticosteroid administration is that it is responsible for serious side effects affecting multiple systems. That is the reason why many investigators have tried to evaluate the efficacy and safety of long-term pulse corticosteroid therapies in AA. The concept of pulse corticosteroid therapy is well proven and regularly used in cases of pemphigus, juvenile rheumatoid arthritis and renal transplants in order to maximize the efficacy and minimize the toxicity of the drug. A cross-sectional study of children suffering with severe AA treated with methylprednisolone bolus administrations showed poor long-term outcomes, despite the initial modification of the disease [59]. Sharma et al. tried to assess the monthly pulse dose of 5 mg/kg prednisolone in children up to 18 years old [60]. Excellent hair growth was achieved in 60% of patients evaluated in 6 months. Side effects of pulsed corticosteroid administration were minimal, such as transient giddiness and epigastric pain, observed in two individuals. Pulsed corticosteroid treatment is recommended by the authors in widespread AA in young patients, including children. A total of 16 adolescents and adults with AA/AT/AU were treated with betamethasone oral minipulse therapy (5 mg given on two consecutive days every week) for a minimum period of 6 months. In total, 74.7% of them showed good or excellent response with insignificant or minimal side effects [61]. A placebo-controlled, double-blind study used weekly pulses of 200 mg prednisolone for 3 months, followed by 3 months of observation on 43 patients with severe AA. Results indicated low rates of hair regrowth (eight out of 23 patients in the corticosteroid treated group), probably owing to the relatively short period of treatment [62].

Photochemotherapy

Treatment of AA with photochemotherapy (PUVA) has been trialed with variable success and has been reported by a number of later studies to be an effective treatment modality for AA. It was initially proposed as a treatment for AA due to the observation of hypertrichosis developed in patients treated for psoriasis. The use of PUVA is based on the concept that it can eradicate the inflammatory cell infiltrate of the mononuclear cells that surround the affected hair follicles. Early retrospective reviews reported low response rate or suggested that the response was no better than the natural course of the disease, although those observations were uncontrolled [63]. On the other hand, later studies showed that PUVA treatment is efficient even for generalized types of AA. A retrospective evaluation of oral and topical 8-methoxypsoralen administered in combination with UVA irradiation in the management of AT and AU, gave encouraging results, although the patient number was small [64]. Patients, who achieved complete hair regrowth in both the AT and AU groups were of satisfactory proportions (53 and 55%, respectively). A rather low relapse rate was explained by the authors as a result of a gradual reduction of treatment frequency. Similar outcomes were also achieved with the combination of phototoxic UV doses and longer intervals between treatments [65]. On the other hand, it is well known that PUVA treatment has certain limitations concerning the patient’s age and the cumulative UVA dose which one can receive in order to achieve an acceptable result.

Cyclosporin

Cyclosporin A is an immunosuppressant drug and a useful therapy in several pathologies where cellular immunity, especially CD4⁺ T lymphocytes, are causatively implicated. One of known side effects of CsA is hypertrichosis. Many investigators have tried to assess CsA efficacy in AA alone or in combination with other agents through uncontrolled studies in small groups of patients with varied results. Gupta et al. reported a 50% success in a small group of severe AA subjects treated with CsA alone [66]. A combined treatment of CsA and corticosteroids in 48 patients resulted in encouraging efficacy. Treatment protocol combined cyclosporine in a dosage of 200 mg twice daily with methylprednisolone, 24 mg twice daily for men, 20 mg twice daily for women and 12 mg twice daily for children. Methylprednisolone was tapered by 4 mg/day every week, and after discontinuing methylprednisolone, cyclosporine was also gradually reduced [67]. A total of 38 patients (88.4%) had significant hair regrowth and nine (23.7%) relapsed during the next 12 months.

Although CsA is used as an alternative treatment for AA, there are cases of adverse AA stimulation in patients under treatment with cyclosporin for various reasons, such as atopic dermatitis or organ transplantation [68]. AA appears to be precipitated predominantly by CD8⁺ lymphocytes [4]. Cyclosporine affects mostly CD4⁺ T cells. This may serve as an explanation that the beneficial effect of cyclosporine is achieved more following combination with corticosteroids or by relatively high dose of cyclosporine.

Photodynamic therapy

Photodynamic therapy (PDT) with aminolevulinic or methyl 5-aminolevulinic acid (MAL) has been tried for the treatment of AA. Unfortunately, the efficacy of PDT is still being debated, and most clinical trials have produced disappointing results, possibly because of limited drug penetration through the epidermis. An older report mentioned hair regrowth after application of topical formulation of hematoporphyrin and UVA irradiation [69]. Various trials attempted to evaluate treatment of MAL PDT in small groups of patients with AA and claimed no efficacy [70,71]. In another pilot study [72], both the efficacy of PDT in treating AA, and the effect of the use of a microneedle roller for the enhancement of the transepidermal drug delivery were investigated with poor results. [71]. A novel approach suggests possible efficacy of an admixture of 5-aminolevulinic acid and iron ion [73].

Biologic agents

The introduction of biologic agents raised hopes for successful control of many immune-mediated diseases, including AA. Since TNF is supposed to be involved in the pathogenesis of AA, anti-TNF-α agents have been investigated for their ability to restrain AA. While alefacept was reported to have some efficacy [74], a double-blind, randomized, placebo-controlled clinical trial including 45 individuals with chronic and severe AA demonstrated no statistically significant improvement in AA after 12 consecutive weeks when compared with placebo-receiving group [75]. In a prospective, open-label pilot study, etanercept, a TNF-α inhibitor, was found ineffective in the treatment of moderate-to-severe AA [76]. Efalizumab, a recombinant humanized monoclonal antibody, was announced to be efficient [77] but the drug was suspended from the market in 2009 owing to risk of progressive multifocal leukoencephalopathy. Furthermore, scarce reports claim adalimumab [78–81], etanercept [82] and infliximab [83,84] induce AA. In conclusion, there is not enough evidence suggesting that T-cell-targeting biologic agents represent a sufficient modality for AA treatment.

Antidepressants

The use of antidepressant agents in treatment of AA is an intriguing approach, yet often underestimated. Many authors have reported the role of negative or stressful events in stimulating the onset of the disease, and also the connection between anxiety, affective disorders and AA. An early study published in 1987 indicated that the use of antidepressant drugs in AA could lead to hair regrowth in subjects with psychiatric comorbidity [85]. Perini et al. documented good efficacy of imipramine, a tricyclic antidepressant, on the regrowth of hair in 13 patients with AA [86]. Another double-blind, randomized, placebo-controlled trial with a selective serotonin reuptake inhibitor, paroxetine, in a small group of patients with AA and psychiatric comorbidity, gave encouraging results in 40% of the paroxetine group [87].

Azathioprine

Azathioprine interferes with the synthesis of purines, required for the synthesis of DNA. It is a prodrug metabolized to 6-mercaptopurine and to 6-thioinosinic acid, which are active metabolites and affect T and B cells. A recent study in a small cohort with moderate-to-severe AA treated with oral azathioprine, presented hair regrowth in a statistically significant rate after a 6-month period. Long-term efficacy and safety of this treatment through controlled studies on larger number of patients should be investigated since azathioprine is a low-cost and well-tolerated drug [88].

Methotrexate

Methotrexate is an antimetabolite and antifolate drug used in treatment of cancer, autoimmune diseases and various dermatological conditions such as severe psoriasis. It acts by stopping the metabolism of folic acid, specifically by competitive inhibition of dihydrofolate reductase, an enzyme that participates in the tetrahydrofolate synthesis. There are reports of treating severe AA with methotrexate alone or in combination with oral pulse prednisolone, resulting in complete hair regrowth in approximaetly half of these patients in both cases. Lasting improvement required maintenance treatment [89,90].

Sulfasalazine

Sulfasalazine is an anti-inflammatory agent that inhibits the release of prostaglandin E2 and IL-2, and decreases inflammatory cell chemotaxis and cytokine and antibody production, it also probably acts on some lymphocyte subsets. It is treatment of choice in ulcerative colitis, Crohn’s disease and rheumatoid arthritis. Various reports indicate that sulfasalazine may be efficient in cases of AA [91,92]. It was also noted that sustainability of hair growth achieved by sulfasalazine was dose-dependent, meaning that a maintenance dose is necessary to preserve the regrown hair and that further reduction or interruption of treatment leads to relapse of hair loss.

Anti-IFN

Skurkovich et al. have administered anti-IFN-γ intramuscularly to patients with AA [93]. Almost half of them showed response in only 3 days after treatment by stabilization of hair loss and partial or full hair growth after a few months. Since best results were obtained in patients with patchy, progressive hair loss (positive hair pull test at periphery of patches), the results according to the authors support early intervention by anti-IFN as most effective. Of course, a double-blind randomized trial is needed to verify the efficacy of this therapy.

Inosiplex

Inosiplex or inosine pranobex is a combination of inosine, acetamidobenzoic acid and dimethylaminoisopropanol, well known and widely used as a potent immunomodulator that augments cell-mediated immunity. Although initially promising in treatment of AA, it was abandoned later owing to limited observed results [94]. However, a recent placebo-controlled study on refractory AA treated with 50 mg/kg/day per orem in five divided doses showed a significant hair-growth response after week 12 [95]. However, more and larger studies are needed to document a successful effect of inosiplex in the treatment of AA.

Nonpharmacologic agents

Excimer laser

The 308-nm excimer laser is a system that offers high doses of long-wave monochromatic UVB radiation. Various studies demonstrated a high rate of treated lesions responding to treatment both in adults and children [96–100]. The side effects usually observed are limited to mild erythema, hyperpigmentation, itching and mild peeling of the skin.

Infrared irradiation

Super Lizer™ is a linear polarized infrared light instrument, which has been used with success in the treatment of arthralgias and neuralgias. A study in a group of 15 subjects with patchy AA irradiated intermittently for an interval of 3 min once every week or every 2 weeks demonstrated significant hair growth in half of them after a few months [99]. The mechanism of action of infrared irradiation is still unknown. It has been proposed that infrared irradiation may stimulate regrowth in hair bulbs directly, or promote regrowth indirectly via increased blood flow. Yamazaki et al. suggested that it could be a useful apparatus for the treatment of mild forms of AA [99]. The procedure is noninvasive and has no serious adverse effects apart from a local irritation and a sense of burning.

Hair transplantation

Hair transplantation has been reported to be successful mainly in cases of chronic eyebrow AA [100,101]. Ideal candidates should not have an active disease, since relapses are common. Topical steroids and/or intralesional steroids could be administered as an adjuvant treatment.

Tattooing

Tattooing can be applied with good cosmetic results to cover the lack of eyebrows in AA. Various tattooing techniques, such as micropigmentation and permanent pigmentation, have been applied, to rebuild patients’ self-confidence and improve their quality of life. Van der Velden et al. have developed a method named ‘dermatography’ by using Japanese tattooing techniques and making them suitable for medical applications with the use of a modified color injector [102].

Unconventional therapies

Garlic gel has been reported to promote hair growth. A double-blinded study showed that the use of garlic gel significantly increased the efficacy of topical betamethasone valerate in AA. [103]. However, it is difficult to assess the true efficacy of such methods.

Hypnosis

Only few studies have investigated the role of psychotherapeutic interventions in patients with AA, even though significant psychological comorbidity often coexists. Hypnosis was used supplementary to other treatments or as monotherapy in 21 individuals with refractory AA [104] and resulted in 12 of them responding after three to eight sessions of hypnotherapy. Total growth occurred in nine of these 12 patients, including four patients with AU and two with ophiasis, however in five of them, a significant relapse occurred during a 5-year period. However, other investigators concluded that hypnosis may improve psychological symptoms of patients with refractory AA but does not imrove AA lesions [105].

AA treatment in children

Alopecia areata in children represents a special theurapeutic challenge. Children are reluctant to undergo painful or irritating treatments. Adolescents are more capable of following intralesional corticosteroid injections or topical DPCP or anthralin application. A recent study showed that ophiasis or severe patchy AA are more common in pediatric patients than adults [106] and this affects prognosis. Topical corticosteroid or minoxidil treatment should be considered as a safe and well-tolerated modality for localized AA in children, but safety data for generalized clinical subtypes are unavailable [2]. Even though there is increased skepticism about potential systemic absorption of long-term applied topical steroids, recent studies in pediatric populations with atopic dermatitis indicate no effect on the hypothalamic–pituitary–adrenal axis for both low-potency and ultrapotency steroids [12–14]. Topical immunotherapy has been reported to facilitate regrowth in up to 84% of children with AA [107]; however, more than 70% relapse during long-term follow-up [108]. A recent study reported more than a 50% response in five out of 13 children with severe AA methotrexate, who received a mean weekly dose of 18.9 mg for a mean duration of 14.2 months [109]. Systemic pulse steroids, usually methylprednisolone, could be administered in a dose of 5 mg/kg, three pulses, with four week intervals [110]. The 308-nm excimer laser has also been reported to produce regrowth in 60% of AA patches in a pediatric population [98].

Expert commentary

The most evidence-based efficient treatment for AA is DPCP. It works both in limited and extensive disease. The main challenge, in our opinions is maintenance of regrown hair. We have seen many patients exhibiting spectacular response that refuse to comply in a maintenance treatment schedule. Even though regrown hair has a tremendous positive impact on patients’ quality-of-life, the repetitive nature of topical immunotherapy application along with the irritation seems to have its toll in the long run. Consequently, recurrences of AA are common. Unfortunately, recurrences are also more recalcitrant to treatment. Additionally, medical literature lacks data on an evidence-based treatment schedule that will establish the ideal maintenance application in order to minimize recurrences. Clinical studies in this direction should be pursued.

Topical potent and superpotent steroids are widely used, despite controversial reports regarding their efficacy. We believe that they are the treatment of choice in children’s patchy alopecia primarily due to excellent patient compliance, compared to other more painful or irritating methods. Intralesional steroids have excellent results in patchy alopecia and should be considered the first-line treatment in such cases in adults. They should be used with extreme caution in children because of their well-documented adverse events. Minoxidil is most commonly used in conjuction with topical or intralesional steroids or anthralin. Patient compliance is usually poor when treating AA with dithranol owing to the poor cosmetic properties of the regimen. Systemic pulse steroid therapy should be used as second-line treatment. Modalities such as CsA and azathioprine could be used in conjuction with systemic steroids in refractory cases. PUVA treatment could be a good alternative for more severe cases but the age of the patient and the cumulative dose that can be received provide certain limitations. In cases of refractory and severe AA, the psychodynamic nature of the disease must not be neglected. We suggest that a thorough psychiatric evaluation must be performed in order to exclude possible psychiatric comorbidities that may affect the efficacy of our intervention. Suggested treatments for the various forms of AA are presented in Table 1.

All new immunomodulating agents introduced for dermatological disorders during recent years have proven to be a forlorn hope for the treatment of AA. Calcineurin inhibitors have been tried in limited studies, with disappointing results. Insights on the role of TNF-α in pathogenesis of AA also raised interest in the use of biologics for the treatment of the disease, albeit with poor success. It seems we must accept that TNF-α is just one component in pathogenesis of AA. Future studies might shed more light on mechanisms of the disease and introduce new agents for the treatment of the disorder.

Five-year view

Our present knowledge on the pathogenesis of AA indicates a multifactorial disorder. Even though the multiple pathogenesis components are probably the cause for single targeted intervention failure, as in the case of TNF-α agents, they also present a wide array of therapeutic possibilities to be developed in the future. Other cytokines involved in the pathogenesis of AA, such as IFN-γ, IL-1, as well as major histocompatibility complex and Fas antigens, peripheral blood mononuclear cells and natural killer cells, macrophage migration inhibitory factor and stress hormones, could be possible targets of new therapeutic agents in the future. Psychological interventions that have been abandoned since the discovery of the autoimmune pathogenesis seem to attract supporters during the last years and may offer supplementary help during both flares and maintenance treatment of the disorder in the future. However, the single most important issue we should take to remedy during the next few years is the lack of consensus on a grading system for AA, as well as lack of a treating algorithm depending on the severity of AA.

Table 1. Suggested first-, second- and third-line treatment in the various forms of alopecia areata.

Form of alopecia areata	First line	Second line	Third line
Adults patchy	Intralesional steroids	Systemic steroids^†	Systemic steroids + CsA or azathioprine^†
Children patchy	Topical steroids	Systemic steroids^†	Methotrexate or 308-nm excimer laser
Adult and children Totallis/universallis	Topical immunotherapy	Systemic steroids^†	Systemic steroids + CsA or azathioprine^†

^†Systemic treatment has better efficacy on acute rather than long-standing alopecia areata.

CsA: Cyclosporin A.

Key issues

• • Alopecia areata (AA) is a chronic disease with an unpredictable course. Pathogenesis is still under investigation, although an autoimmune mechanism has a key role.

• • Lack of universal consensus in AA grading, small numbers of double-blind clinical trials and the considerable rate of spontaneous remissions, as well as simultaneous hair loss and hair growth in different regions of the same scalp in many cases, make evaluation of therapeutic results difficult.

• • Diphencyprone seems to have efficacy both in localized and extensive AA. An evidence-based treatment schedule for maintenance of remissions must be pursued.

• • Pulsed systemic corticosteroid administration can produce good results with minimal side effects in serious cases of AA. Topical or intralesional corticosteroids may be useful in milder forms of AA.

• • Anti-TNF agents seem to be paradoxically insufficient, despite the fact that tumor necrosis factor is supposed to be involved in the pathogenesis of AA.

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Treatment options for alopecia areata

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1. You are seeing a 10-year-old boy whose mother and father are disturbed by the complete loss of a 4-cm patch of hair on their son’s posterior scalp over the last 2 months. The skin over this area is smooth and otherwise normal. You suspect that this patient has alopecia areata (AA). What can you tell the parents about this diagnosis?

• □ A It follows an unpredictable course

• □ B It is rare among boys

• □ C Erythema is usually present at the site of hair loss

• □ D AA is defined by hair involvement without nail involvement

2. Which of the following is the most efficient evidence-based treatment for AA?

• □ A Topical corticosteroids

• □ B Diphenylcyclopropenone (DPCP)

• □ C Tacrolimus

• □ D Topical cyclosporine

3. You decide to initiate topical treatment for AA for this patient. What should you consider regarding these medications?

• □ A The efficacy of topical corticosteroids is superior to that of other topical treatments

• □ B Intralesional corticosteroid therapy may be performed every 4–6 weeks, with results expected in 1–2 months

• □ C Relapse is rare after effective treatment with DPCP

• □ D Only a minimal amount of dithranol should be applied to maintain efficacy without skin irritation

4. The patient does not respond to topical therapy. What should you consider regarding systemic treatment for AA?

• □ A Pulsed corticosteroid treatment can be effective for children with widespread AA

• □ B More recent studies do not support photochemotherapy in the treatment of AA

• □ C Photodynamic therapy appears highly effective for AA

• □ D Etanercept has emerged as an effective therapy for treatment-resistant AA