Hair loss is a frequent clinical complaint encountered by dermatologists, and alopecia areata (AA)-induced hair loss is responsible for 0.7 to 3.8% of dermatology clinic visits. Alopecia areata is characterized by chronic yet reversible, non-scarring hair loss. It is postulated to be an autoimmune process that targets the hair follicle, although the pathogenesis is incompletely understood. This article summarizes the epidemiologic and clinical features of AA, outlines our current understanding of its pathogenesis, and reviews therapeutic options for this condition.
Alopecia areata affects patients of all ages and ethnicities with an equal sex distribution. Approximately 0.1-0.2% of the United States population is affected ; there is a lifetime risk of about 1.7%. Roughly 60% of patients present before age 20, and a family history of AA is seen in about 20% of patients.
Alopecia areata can affect any hair-bearing epidermal site, but involves the scalp in approximately 90%. Classic AA lesions are well-demarcated, ovoid patches with no overt epidermal change. Patients typically present with a spontaneous, asymptomatic hair loss in a solitary nummular patch. Alternate presentations include multiple alopecic patches or rapid progression to complete loss of scalp/facial hair (alopecia totalis) or body hair (alopecia universalis). Rarer hair loss variants include reticular, ophiasis, ophiasis inversus, and diffuse thinning over the entire scalp. Associated clinical findings that aid diagnosis include “exclamation mark” hairs, “cadaver” hairs, red lunulae, rows of nail pitting or trachyonychia, and the presence of other autoimmune disorders.
Alopecia areata is considered a polygenic disorder with variable phenotypes in which several major genes dictate susceptibility to disease and numerous minor genes modulate phenotype. The latter may explain the variable disease severity seen in AA: some patients experience one patch of alopecia, and others demonstrate total body hair loss. The genetic component of alopecia areata is supported by several findings: there is a higher incidence of AA in genetically related individuals: up to 28% of patients report at least one affected family member, monozygotic twins have exhibited similar times of onset and patterns of hair loss, and several human leukocyte antigen (HLA) alleles are associated with AA. Finally, genes on chromosome 21 may be implicated in AA susceptibility because there is an association with both Down syndrome and Autoimmune polyendocrinopathy syndrome type 1, two conditions owing to genetic defects on this chromosome.
The 42% - 55% concordance rate in monozygotic twins not only suggests a genetic etiology of AA, but it also implicates environmental influences in the pathogenesis of this condition. While the inheritance of specific alleles may provide innate susceptibility to developing AA, environmental factors likely trigger disease onset and modify the pattern and extent of hair loss, chronicity of disease, and resistance to treatment. Hormonal fluctuation, infection, vaccinations, and diet have all been cited as possible triggers for AA, though additional research is warranted to clarify these associations. The role that psychosocial stressors play on disease onset and relapse is largely uncharacterized. Life stressors may instigate AA onset and modify disease course, yet evidence is circumstantial and clinical studies are inconclusive: some studies found no correlation between the onset of hair loss and stressful life events, whereas others affirmed that stressful life events preceded disease onset and relapse.
The normal hair cycle has four distinct phases: anagen, catagen, telogen and exogen (Figure 1). AA is characterized by abnormal hair cycling: T lymphocytes attack anagen hair follicles, which are subsequently maintained in a dystrophic state. Such dystrophy precludes hair production of appropriate integrity or size, and the shaft can no longer be firmly anchored in the hair canal, resulting in rapid hair shedding. Other perturbations in the hair cycle are seen: the follicle can be prematurely ushered into telogen and then proceed in a shortened cycle in which it is repeatedly arrested in early anagen. In chronic AA, follicles can persist in a prolonged telogen phase without cycling back to the anagen growth phase. Unlike scarring alopecias, the hair follicle stems cells are not destroyed in AA. Rather, the follicles are effectively switched off: they remain arrested in a hibernation-like state and can resume normal growth after a period of months to years.
The pathophysiology of this process is not fully elucidated, but available evidence suggests a T cell-mediated autoimmune process directed at the hair follicle. Normally, the hair follicle creates a milieu of immunologic privilege, ie, it is protected from immune surveillance by autoreactive T cells. Failure of this immune privilege and development of autoantibodies against a hair follicle antigen is theorized in the pathogenesis of AA (Figure 2). However, the antigens responsible for initiating this autoimmune reaction remain unidentified.
Several circumstantial findings support an autoimmune process. First, AA is associated with a personal and family history of other autoimmune diseases, including thyroid autoimmunity and vitiligo among others. Secondly, lymphocytes are implicated in this disease: active AA lesions have perifollicular T lymphocyte infiltrates, subcutaneous injection of lymph node cells from AA-affected mice into normal mice promoted AA development, and monoclonal antibody-mediated T cell depletion in AA-affected mice induced hair regrowth. Thirdly, there is increased expression of proinflammatory markers such as intercellular cell adhesion molecule and endothelial cell selectin in perifollicular blood vessels. Fourthly, peripheral blood concentrations of anagen hair follicle-specific autoantibodies are greater in patients with AA compared to unaffected controls, and patients with AA demonstrate abnormal perifollicular deposits of immunoglobulins and complement. Finally, an autoimmune mechanism is supported by the fact that immunosuppressive agents to promote hair growth.
Alopecia areata diagnosis is often made clinically: non-scarring hair loss associated with exclamation mark and cadaver hairs, trachyonychia or nail pitting, and other autoimmune diseases suggest the diagnosis. In active expanding alopecia patches, a hair pull test may be positive at the periphery. In equivocal cases, skin biopsy is diagnostic. Histologic examination of acute AA reveals a characteristic “bee swarm” lymphocytic infiltrate around dystrophic anagen hair follicles. Chronic AA demonstrates hair follicle miniaturization with minimal inflammation around telogen follicles. Trichotillomania and tinea capitis are the most important differential diagnoses to consider in patients with asymptomatic patches non-scarring alopecia; telogen effluvium must be ruled out when patients present with diffuse AA. Other entities to consider include secondary syphilis and systemic lupus erythematosus.
There are no curative or preventative treatments in AA; therefore the treatment goal is to suppress disease activity. Topical agents, systemic therapy, or a combination of the two are employed for this purpose. While numerous therapeutic agents have been described, the paucity of randomized, controlled clinical trials and the variable definition of response to treatment limit evidence-based assessments of these modalities.
Topical and Intralesional Corticosteroids
Topical and intralesional corticosteroids (ILCSs) are commonly prescribed and are the treatment of choice for AA in children and adults, respectively. While case reports and randomized controlled trials (RCTs) have described the efficacy of several topical corticosteroids including desoximetasone 0.25% cream, betamethasone valerate 0.1% foam, betamethasone dipropionate 0.05% lotion, triamcinolone 0.1% cream and clobetasol propionate 0.05% ointment and foam, no such studies have assessed the value of ILCS administration. Nevertheless, intralesional triamcinolone acetonide is considered first line therapy for adults with less than 50% scalp involvement in combination with topical steroids between injections.
Topical immunotherapy is indicated for patients with chronic severe AA and AT; this method exploits the allergic contact dermatitis that results from cutaneous application of potent contact allergens. Such allergens include dinitrochlorobenzene (DNCB), diphenylcyclopropenone (DPCP) and squaric acid dibutylester (SADBE). The mechanisms of action of these topical sensitizers are poorly understood; they may include enhanced clearance of follicular antigens, induction of perifollicular lymphocyte apoptosis, antigenic competition, and T lymphocyte inhibition via IL-10 release from follicular keratinocytes. Diphenylcyclopropenone is the sensitizer of choice; non-responders should switch to SADBE. Dinitrochlorobenzene is rarely used today because of its mutagenic potential. Hair regrowth in murine models of AA and humans confirm the efficacy of topical immunotherapy; however, response rates varied greatly across studies and relapses were common after discontinuation. The dearth of randomized trials evaluating these methods warrants further investigations.
Topical anthralin has an unknown mechanism of action and is applied as a short contact therapy. It induced hair regrowth in the C3H/HeJ mouse model of AA, but uncontrolled case studies in humans reveal varied results. It is a good alternative option for children, although one case report describes its inferiority to topical steroids.
This agent has several proposed mechanisms of action and has a long history of use in androgenetic alopecia. It has also been employed in AA treatment: it demonstrated dose-dependent hair regrowth when used as monotherapy, but it is chiefly used as an adjuvant to conventional treatments. Recurrence is common after minoxidil is discontinued because this agent does not alter perifollicular lymphoid infiltration.
Other Topical Therapies
Topical tacrolimus is a calcineurin inhibitor that was effective in murine models of AA, but encountered limited success in humans. Topical pimecrolimus, however, induced fewer side effects and was equally effective compared to topical clobetasol propionate 0.05%, although these results were not statistically significant. Topical retinoids including tretinoin 0.05% cream and bexarotene 1% gel also successfully induced hair regrowth. Finally, although topical cyclosporine is ineffective in humans, a topical liposomal formulation of this drug induced hair growth and reduced inflammation when administered in the DEBR rat model of AA.
Systemic therapy is often employed in cases of multifocal or recalcitrant AA, and systemic corticosteroids are widely used in these instances. Oral steroids are effective, but side effects and relapse upon treatment suspension limit their use. Pulse corticosteroid therapy was introduced to increase the therapeutic effect and minimize the toxicity associated with oral steroids. Pulse therapy as well as intramuscular triamcinolone acetonide successfully induced hair regrowth. While many studies have evaluated systemic steroid value, few compare oral, pulse and intramuscular routes of administration.
Cyclosporine suppresses T-cell activation and has a hypertrichotic side effect, implicating a potential therapeutic role for AA. Oral cyclosporine supports hair regrowth in the DEBR rat model of AA, and some advocate its use in alone or combination with systemic corticosteroids. However, response to treatment ranges from 25% to almost 77%, and AA has developed in transplant patients taking high doses of cyclosporine. These inconsistent treatment responses necessitate further investigations of cyclosporine’s therapeutic potential.
Other Systemic Therapies
Several other systemic therapies have been evaluated either systematically or in uncontrolled case reports. Methotrexate can be used in conjunction with other oral therapies: its concomitant use with low dose prednisone induced hair regrowth in 64% of patients with AT or AU. However, recurrence was common after dose reduction or withdrawal. Oral alitretinoin induced remission of steroid-resistant severe AA, but other investigations of systemic retinoid therapy for AA treatment are sparse. Because AA is T-cell mediated, several biologic agents have been evaluated as AA treatments. However, most biologics failed to show improvement in AA: IM alefacept, subcutaneous etanercept and efalizumab were ineffective; and notably, several cases of AA developed during anti-TNF-alpha treatment for other autoimmune diseases. Finally, the response to oral or topical psoralen plus ultraviolet A light (PUVA) phototherapy has ranged from 15% to 70% in uncontrolled trials, and two large retrospective studies revealed that the response rate is no better than the spontaneous remission rate.
By using graded immunosuppressive treatment, Steven R. Cohen, MD, MPH, Chief of Dermatology at Montefiore Medical Center, estimates one-third of his patients with AA totalis and AA universalis experience complete regrowth of hair. This therapeutic approach is illustrated by a case of progressive alopecia totalis in a 12 year-old female with Down syndrome and autoimmune thyroiditis (Figure 1a). Intralesional triamcinolone acetate (10mg/ml), topical minoxidil (RogaineÔ) and topical steroids administered by several other physicians showed no effect. An induction dose of prednisone, 50 mg daily (0.75 mg/kg) was continued for two weeks followed by a slow taper of 5 mg every fifth day. When the dose of prednisone reached 30 mg daily (approximately 5 weeks after the start of therapy) significant scalp hair regrowth was observed (Figure 3b). At this juncture, cyclosporine, modified, 125 mg twice daily was initiated (3.8 mg/kg). Concurrently, prednisone was tapered (by 5 mg every fifth day) until the daily dose reached 20 mg. Further slowing of the prednisone taper was achieved with a step-down technique.* The return of normal scalp and eyebrow hair density was documented during the ensuing two months (Figure 1c and 1d). As the dose of prednisone reached 10 mg daily, cyclosporine was reduced to 100 mg twice daily (2.8 mg/kg). At the time of this report, the patient has been on prednisone, 7.5 mg daily and cyclosporine, 75 mg twice daily (2.1 mg/kg). It is anticipated that a maintenance regimen of prednisone, 5 mg daily and cyclosporine, 100 mg twice daily will be continued up to 12 month before attempting gradual withdrawal all medications. Topical clobetasol proprionate, 0.05%, initially as an ointment and later a solution has been applied to the scalp throughout.
Stepwise taper of prednisone by alternating 17.5 mg one day with 20 mg on the next day for 6 cycles (20/17.5, 20/17.5, 20/17.5, 20/17.5, 20/17.5, 20/17.5), if no increased hair shedding is described, reduce prednisone to 17.5 mg daily for 6 days, then alternate 15 mg one day with 17.5 mg on the next day for 6 cycles. If no increased hair shedding is described, reduce prednisone to 15 mg daily for 6 days, then alternate 12.5 mg one day with 15 mg on the next day for 6 cycles, if no increased hair shedding is described, reduce to 12.5 mg for 6 days, then alternate 10 mg on one day with 12.5 mg on the next, if no increased hair shedding, reduce to 10 mg. If hair shedding increases at any point in the taper, hold at the previous higher dose or return to 20 mg daily.
The natural course of AA is variable and unpredictable. Many patients present acutely and experience spontaneous hair regrowth within a year; others undergo a chronic course with concomitant regrowth and formation of new alopecic sites. The extent of hair loss is an important prognostic factor: patients with AT or AU are less likely to achieve full remission. Other poor prognostic indicators include a long duration of alopecia, a positive family history, presence of other autoimmune diseases, nail involvement, and a young age of onset.
Alopecia areata is an organ-specific autoimmune disease in which symptom onset and disease course are mediated by the interplay of genetic susceptibility and environmental triggers. Despite decades of research efforts to identify causative agents, target antigens and therapeutic interventions, no clear autoantigen or superior therapy have been identified. This necessitates continued research: a deeper understanding of the pathophysiology of this disease will facilitate the development of more targeted therapies.
Although the dermatologist’s primary concern when treating a patient with AA is to initiate hair regrowth, it is imperative to address the emotional consequences of this condition. The psychological impact of skin disease is often underestimated and dismissed as simply a cosmetic problem. And while AA is primarily of cosmetic concern and is not life-threatening, hair loss significantly affects quality of life and greatly affects a patient’s emotional state. Patients with AA often have psychiatric comorbidities which may surface in response to the aesthetic impact of this disease. Therefore, while dermatologists continue to pursue improved treatment strategies, they must also remember that treating the psychological morbidity of hair loss is of great import.
(Please see the May issue of the Journal of Drugs in Dermatology for Figures 1-3 and full reference list, available at http://jddonline.com)
Allison Kutner and Adam Friedman MD FAAD
Albert Einstein College of Medicine and
Division of Dermatology, Department of Medicine, Department of Physiology and Biophysics, Albert Einstein College of Medicine, Bronx, NY