Alopecia areata update

CONTINUING

MEDICAL EDUCATION

Alopecia areata update Shabnam Madani, MD,* and Jerry Shapiro, MD, FRCPC Vancouver, British Columbia Alopecia areata (AA) is a nonscarring hair loss condition. Among the many factors under investigation in the pathogenesis of AA, the main areas of concentration have been genetic constitution as well as nonspecific immune and organ-specific autoimmune reactions. Treatment with intralesional corticosteroid injections for localized patchy AA and topical immunotherapy for extensive AA have proven successful in the majority of patients, although all treatments are palliative and do not change the prognosis of the disease. (J Am Acad Dermatol 2000;42:549-66.)

Learning objective: At the conclusion of this learning activity, participants should be familiar with the latest information on etiology, clinical features, diagnosis, histopathology, and state-of-the-art treatment of alopecia areata.

A

lopecia areata (AA) is an unpredictable, usually patchy, nonscarring hair loss condition. Any hair-bearing surface may be affected. AA is hypothesized to be an organ-specific autoimmune disease mediated by T lymphocytes directed to hair follicles. Although genetic predisposition and environmental factors may trigger the initiation of the disease, the exact cause is still unknown. There have been significant advances in our understanding and treatment of this condition over the past decade. Much of the most recent research and future directions in AA originate from 3 research workshops cosponsored by the National Alopecia Areata Foundation and the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) in 1990, 1994, and 1998. At these meetings, numerous subspecialties, including immunologists, molecular biologists, biochemists, dermatologists, pathologists, and geneticists, discussed AA in an open forum. The proceedings of these meetings have been published in the Journal of Investigative Dermatology.1,2 This article will review the latest

From the Division of Dermatology, University of British Columbia. Reprint requests: Jerry Shapiro, MD, FRCPC, 835 W 10th Ave, Vancouver, British Columbia V5Z 4E8. E-mail: [email protected]. *Dr Madani was Hair Fellow, University of British Columbia Hair Research and Treatment Center during the work for this article. Copyright © 2000 by the American Academy of Dermatology, Inc. 0190-9622/2000/$12.00 + 0 16/2/103909 doi:10.1067/mjd.2000.103909

information on etiology, clinical features, and stateof-the-art treatment for AA.

ETIOLOGY The pathogenesis of AA is still unknown. Among the many factors that have been under investigation in the pathogenesis of AA, genetic constitution as well as nonspecific immune and organ-specific autoimmune reactions have been the main areas of concentration. There are other proposed origins reported, including infectious agents, cytokines, emotional stress, intrinsically abnormal melanocytes or keratinocytes, and neurologic factors. The main areas of concentration in the pathogenesis of AA are summarized in Fig 1. Genetic factors Genetic factors have an important role in the origin of AA. There is a high frequency of a family history of AA in affected persons, ranging from 10% up to 42% of cases (Fig 2).3,4 There is a significantly higher incidence of a family history in patients with early onset of AA. Familial incidence of AA has been reported to be 37% in patients who had their first patch by 30 years of age and 7.1% with the first patch after 30 years of age.5 In addition, there have been reports of AA in twins, with concordance rate of up to 55% in identical twins.6,7 Several closely linked genes such as the human leukocyte antigen (HLA) genetic system are located on the short arm of chromosome 6, forming the major histocompatibility complex (MHC).8,9 Each gene in the HLA genetic system has many variant 549

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Fig 1. Pathogenesis of AA. T lymphocytes mediate the perifollicular immunologic milieu by triggering a cascade of events via cytokine production. Antigen presentation of the responsible epitope helps drive the condition. The exact epitope may be in the follicular kertinocyte, melanocyte, or dermal papilla. Neuropeptides, as well as increased antibody production to follicular components, may also play a significant role. Ab, Antibodies; CK, cytokines; FK, follicular keratinocyte; LG, Langerhans cell; ▲, antigen-presenting cells; M, melanocyte; N, nerve endings; NP, neuropeptides; P, plasma cell; TL, T lymphocytes.

forms (alleles) that differ from one another in the sequence of their nucleotide bases. The HLA complex has been investigated in patients with AA because of the association of many autoimmune diseases with increased frequencies of HLA antigens.8,10 Association with both HLA class I (HLA-A, -B, -C) and class II (HLA-DR, -DQ, -DP) have been studied in AA. The earlier studies identified the association of AA with several class I antigens such as HLA-A9, -B7, and -B8,10 -B12,11 -B18,12 -B13, B27,13 but none of these studies have been confirmed. In the past few years, there has been an increased consistency in evidence revealing associations between AA and HLA class II antigens. The studies revealed a significant association of broad antigens HLA-DR4, -DR5 (antigenic subtypes -DR4 and -DR11, respectively) and -DQ3 (antigen subtypes DQ7 and DQ8) in patients with AA,5,14-21 with HLA-DR5 being linked to the early-onset form of AA and more extensive hair loss.14,15 There is a significant increase in alleles HLA-DQB1*0301 (DQ7), HLA-DQB1*03 (DQ3), and HLA-DRB1*1104 (DR11) in patients with AA.5,20,22 The broad HLADQB1*03 (DQ3) appears to be a susceptibility HLA

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marker for all forms of AA. The HLA alleles DRB1*0401 (DR4) and HLA-DQB1*0301 (DQ7) are markers for more severe long-standing alopecia totalis/universalis.5,20-23 The hypothesis of the polygenic nature of AA has also been reported. There is up to an 8.8% increased frequency of AA in patients with Down syndrome, which suggests involvement of a gene located on chromosome 21 in determining susceptibility to AA.24,25 Furthermore, a polymorphism in the interleukin 1 (IL-1) receptor antagonist gene may be associated with the severity of AA.26 Several studies have confirmed the association between AA and the atopic state,3,4 with more severe AA correlating with atopy. In conclusion, many studies reveal the possibility that AA is a polygenic disease, with certain genes correlated with susceptibility and others with severity. Most likely, there is an interaction between genetic and environmental factors that trigger the disease. Immunologic factors There are reported associations between AA and classic autoimmune disorders; the main associations are with thyroid diseases and vitiligo. Several reports reveal an incidence of 8% to 11.8% in the frequency of thyroid disease in patients with AA compared with only 2% of the normal population.3,4 This evidence has been further confirmed by documentation of an increased prevalence of antithyroid antibodies27,28 and thyroid microsomal antibodies28 in patients with AA. AA has been shown to have a significant association with vitiligo; patients with AA have a 4-fold greater incidence of vitiligo.3,29,30 Other studies have revealed an increased prevalence of gastric parietal cell antibodies27 as well as antinuclear and anti– smooth muscle antibodies31 in sera of patients with AA. There are also reported associations of AA with pernicious anemia,27,30 diabetes,27 lupus erythematosus,32 myasthenia gravis,33 rheumatoid arthritis, polymyalgia rheumatica, ulcerative colitis,4 lichen planus,34 and Candida endocrinopathy syndrome.35 Humoral immunity. Past studies with direct immunofluorescence have failed to show particular antibodies to epidermal cells or hair follicles in AA.36 Studies of passive transfer of serum from AA patients to nude mice failed to inhibit hair growth in grafted transplants of human scalp skin.37 However, Tobin et al38 reported detection of antibodies to pigmented hair follicles by Western blotting in the sera of 100% of the AA patients examined as compared with only 44% of normal controls. In another study by Tobin et al39 that used indirect immunofluorescence and

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Fig 2. Familial AA in mother and son.

compared AA patients with controls, high levels of autoantibodies to multiple structures of anagen hair follicles in AA patients were reported. The antibody response to hair follicles in patients with AA has been found to be heterogeneous because different patients develop different patterns of antibodies to different hair follicle structures. The most common target structures were the outer root sheath, followed by the matrix, inner root sheath, and hair shaft.39 Cell-mediated immunity Studies of cell-mediated immunity in AA have given conflicting results. Circulating total numbers of T lymphocytes have been reported as reduced40,41 or normal.42 Friedmann43 suggested that the number of circulating T cells are reduced in AA and the level of this reduction is related to disease severity. In addition, he suggested that the impairment of helper T-cell function and the change in suppressor T-cell numbers may also reflect changes in disease activity. A slight increase in helper T cells (CD4) and decrease in number of suppressor T cells (CD8) resulting in an increase in the ratio of helper to suppressor cells is correlated with the amount of hair loss.41 Successful treatment of AA with immunomodulatory agents such as oral cyclosporine44 and systemic steroids45 also supports the immune-mediated pathogenesis in AA.

Recently, Gilhar and associates46 reported that AA can be induced in human scalp explants from AA patients transplanted on severe combined immunodeficiency (SCID) mice by transfer of autologous T lymphocytes isolated from involved scalp. In this study, the T lymphocytes that had been cultured with hair follicle homogenate along with antigenpresenting cells were capable of inducing the changes of AA. These changes include hair loss, perifollicular T-cell infiltration, as well as HLA-DR and intercellular adhesion molecule–1 expression of follicular epithelium. T cells that had not been cultured with follicular homogenate were not able to induce AA. The necessity of the follicular homogenate to induce AA suggests that T cells recognize a follicular autoantigen. Furthermore, AA induction was followed by injection with CD8+ cells cultured with follicular homogenate but not the cultured CD4+ cells. This study also suggests that AA is mediated by T cells, particularly CD8+ cells. Shared hereditary susceptibility, increased frequency of organ-specific antibodies, antibodies to pigmented hair follicles, high levels of autoantibodies to multiple structures of anagen hair follicles in AA patients, an increase in the ratio of helper to suppressor cells, and induction of AA on SCID mice by transfer of T lymphocytes cultured with follicular homogenates are evidence supporting the hypothesis that AA is an organ-specific autoimmune disease.

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Fig 3. Alopecic patch of AA with preserved nonpigmented hairs.

The hair follicle has a distinct immune system47 that differs from its surrounding skin.48 The cellular components of the hair follicle immune system are composed of intrafollicular T lymphocytes and Langerhans cells, located exclusively in the distal outer root sheath, and perifollicular mast cells and macrophages.49-51 There is also a unique expression of follicular MHC class Ia/Ib, and ICAM-1.49-51 Human hair follicles may even serve as a Langerhans cell reservoir.52 The epithelium of the proximal anagen hair follicle is immune privileged since the inner root sheath and hair matrix do not express MHC class I molecules.47,53,54 This immune privilege may collapse in AA.55,56 A recent theory for AA proposed by Paus57 involves the upregulation of MHC antigens and/or downregulation of locally produced immunosuppressants (melanocyte-stimulating hormone, adrenocorticotropin, and transforming growth factor), allowing the immune system to recognize the immune-privileged hair follicle antigens leading to onset of AA.

follicle morphology similar to those in AA.58 T helper cells also produce cytokines and they are divided into two subgroups depending on the pattern of cytokine production. Type 1 T helper (TH1) cells produce interferon gamma (IFN-γ) and IL-2. Type 2 T helper (TH2) cells produce IL-4 and IL-5.59,60 An aberrant expression of cytokines of the TH1 type and IL-1β have been detected in affected areas of the scalp in patients with AA.61 Infection A report has been published regarding the possibility of cytomegalovirus (CMV) infection found within the patches of scalp AA. This initial report showed a convincing positive association with CMV,62 but this has not been confirmed because other investigators7,63-65 have reported negative findings. The whole concept of molecular mimicry of the hair follicle with a virus is intriguing, but the evidence for a viral origin of AA at this time is not conclusive.

Cytokines It appears that cytokines have a significant pathogenic role in AA. Cytokines are immunomodulators mediating inflammation and regulating cell proliferation. Cytokines derived from epidermal keratinocytes, IL-1α and IL-1β and tumor necrosis factor alfa (TNF-α) are potent inhibitors of hair follicle growth and in vitro produce changes in hair

Emotional stress Several studies suggest that stress may be a precipitating factor in some cases of AA. Acute psychotrauma before the onset of AA,66 higher number of stressful events in the 6 months of preceding hair loss,67 higher prevalence of diagnosed psychiatric disorders,68 and psychologic factors and family situations69 in patients with AA have been report-

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Fig 4. Animal models of AA: C3H/HeJ mouse and DEBR rat.

ed. In contrast, there are reports revealing that emotional stress does not play a significant role in pathogenesis of AA.70 Intrinsically abnormal melanocytes or keratinocytes Morphological analysis of follicles in active AA lesions have revealed regressive changes in the hair bulbs of anagen hair follicles.71,72 Abnormal melanogenesis and melanocytes are common findings. This evidence together with the presence of antibodies to pigmented hairs of AA38 may explain some of the associated pigmentary anomalies seen clinically in acute AA and the preferred effect of AA on pigmented hairs (Fig 3). In addition, degeneration of precortical keratinocytes has been shown in follicles of active AA lesions.71 Abnormal melanosomes in clinically normal regions, together with degenerative changes including vacuolation in the outer root sheath of all hair follicles from nonbalding lesions of AA,73 correspond well with the hypothesis of a subclinical condition of the disease in clinically normal areas of AA. Neurologic factors It has been suggested that local changes in the peripheral nervous system at the level of the dermal papilla or bulge region may play a role in the evolution of AA because the peripheral nervous system can deliver neuropeptides that modulate a

range of inflammatory and proliferative processes.74 This theory has been supported with the study by Hordinsky et al,75,76 revealing a decrease in calcitonin gene-related peptide (CGRP) and substance P (SP) expression in the scalp of patients with AA. The neuropeptide CGRP has a potent antiinflammatory action,77 and neuropeptide SP is capable of inducing hair growth in the mouse.78 In addition, application of capsaicin, which causes neurogenic inflammation and releases SP, to the entire scalp of two AA patients revealed an enhanced presence of SP in AA perifollicular nerves and induced vellus hair growth.79

ANIMAL MODELS In the past our understanding of the pathogenesis of AA was slow to progress because of the lack of animal models for this disease. Recently, investigations of AA have been facilitated by the use of animal models with either spontaneous or induced AA. Animal models with spontaneous AA include the C3H/HeJ mouse, 80 Dundee experimental bald rat (DEBR) 81 (Fig 4), and Smyth chickens.82 AA can be induced in normal C3H/HeJ mice using full-thickness skin grafts donated from affected C3H/HeJ mice.83 Animal models with AAlike hair loss are significantly useful in investigations regarding pathogenesis, disease behavior, efficacy, and side effects of available or future treatments.

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Fig 5. Peribulbar lymphocytic infiltrate (“swarm of bees”) with no scarring in AA. (Courtesy of M. Trotter, MD, Vancouver, BC. From Shapiro J, Madani S. Int J Dermatol 1999; 38(Suppl 1):1924.)

PATHOLOGY In early active AA, the hair cycle is abnormal with hair follicles entering the telogen or late catagen stage prematurely in the involved areas.84 Hair loss is seen as both intact and fractured hairs. The fractured hairs are telogen hairs and develop because of the damage involving both their cortex and medulla, resulting in distal fractures.85 These hairs are described as “exclamation-mark” hairs because the distal segment is broader than the proximal end. Four distinct stages can be noted in the histopathology of AA: acute hair loss, persistent alopecia, partial telogen to anagen conversion, and recovery.86 A peribulbar lymphocytic infiltrate (“swarm of bees”) with no scarring is characteristic of the diagnosis of all 4 stages of AA (Fig 5). The inflammatory cellular infiltrate is composed chiefly of activated T lymphocytes together with macrophages and Langerhans cells.87,88 In addition, miniaturization of hairs with numerous fibrous tracts along with pigment incontinence within these fibrous tracts is appreciable. During the acute phase of hair loss, matrix cell and matrical melanocyte failure with a formation of dysplastic hair shafts is noted. After complete matrix failure, the involved follicle enters the end-stage telogen. A decreased anagen-to-telogen ratio, resulting in marked increase in telogen and catagen hairs, can be observed in horizontal sections

of scalp biopsy specimens.89,90 In patients with longstanding alopecia, the involved hair follicles arrest in the end-stage telogen phase. In these cases, peribulbar infiltration along with an increase in Langerhans cell numbers,91 a decrease in follicular density, and follicular miniaturization may be present. In patients with complete recovery, normal hair follicles with little or no peribulbar lymphocytic infiltration and no decrease in hair density are noted. Eosinophils are also detectable in all stages of AA, within both the peribulbar infiltrate and fibrous tracts. Although clinical correlation is necessary, this feature is helpful in diagnosis of AA in some biopsy specimens without peribulbar lymphocytic infiltrate.92 Electron microscopic examination of microdissected hair follicles from scalps affected by AA demonstrated ultrastructural abnormalities in the dermal papillae of both lesional and clinically normal hair follicles.93 This shows that even with patchy involvement, AA is not a localized process. Immunohistochemical evaluation of AA specimens reveals a prominent expression of ICAM-1 in the dermal papilla and keratinocytes of the matrix and outer root sheath.94 AA should be differentiated histopathologically from androgenetic alopecia, telogen effluvium, trichotillomania, and syphilitic alopecia. In androgenetic alopecia, miniaturization of hairs is present

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Fig 6. Characteristic patch of AA with “exclamation-mark” hairs. (Courtesy of H. Lui, MD, Vancouver, BC.) (From Shapiro J, Madani S. Int J Dermatol 1999;38(Suppl 1):19-24.)

Fig 7. Ophiasis affecting the periphery of the scalp.

with lack of lymphoid infiltration at the level of infundibulum and a lack of pigment incontinence within fibrous tracts. In telogen effluvium, a normal number of hair follicles with no miniaturization of follicles and a slight decrease in the anagen/telogen

ratio may be noted. Trichotillomania is characterized by empty anagen follicles, multiple catagen hairs, trichomalacia, and pigment casts in the follicular infundibulum. Syphilitic alopecia is very difficult to distinguish histopathologically from AA. The

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Fig 8. Ophiasis inversus sparing the periphery of the scalp. (From Shapiro J, Madani S. Int J Dermatol 1999;38(Suppl 1):19-24.)

presence of plasma cells along with no or few peribulbar eosinophils and abundant lymphocytes in the isthmus or peribulbar area are features of syphilitic alopecia, whereas the presence of peribulbar eosinophils strongly suggests AA.95

CLINICAL FEATURES AA occurs all over the world. It accounts for about 2% of new dermatology outpatient attendances in the United Kingdom and the United States.96 The prevalence of AA in the United States, as reported by the First National Health and Nutrition Examination Survey conducted from 1971 through 1974, was 0.1% to 0.2% of the population.97 The lifetime risk has been estimated at 1.7%.98 AA affects men and women equally.3 Patients are frequently quite young. Sixty percent of patients present with their first patch before 20 years of age.99,100 AA can manifest with several different clinical features. Patients usually report abrupt hair loss and marked hair shedding. Frequently, patients will present to the physician with one or several bags of hair. The characteristic lesion of AA (Fig 6) is commonly a round or oval, totally bald, smooth patch involving the scalp or any hair-bearing area on the body. The patch may have a mild peachy hue. A frequent feature of an AA patch is “exclamation-mark” hairs that may be present at its margin. “Exclamation-mark” hairs are broken, short hairs that taper proximally. The pull test may be positive

at the margins of the patch, indicating very active disease. Although hair loss is usually asymptomatic in most cases, some patients describe paresthesias with mild to moderate pruritus, tenderness, burning sensation, or pain before the appearance of the patches. The clinical presentation of AA is subcategorized according to pattern or extent of the hair loss. If categorized according to pattern, the following forms are seen: patchy AA, round or oval patches of hair loss (most common); reticular AA, reticulated pattern of patchy hair loss; ophiasis bandlike AA (Fig 7), hair loss in the parietal temporo-occipital scalp; ophiasis inversus (sisapho) (Fig 8), a rare bandlike pattern of hair loss in the frontal parietotemporal scalp (the exact opposite of ophiasis)100,101; and diffuse AA, a diffuse decrease in hair density over the entire scalp. If categorized to extent of involvement, the following forms may be seen: alopecia areata, partial loss of scalp hair; alopecia totalis, 100% loss of scalp hair; and alopecia universalis (Fig 9), 100% loss of hair on the scalp and body. Most patients present with the limited patchy type that is easily camouflaged. The initial regrowth in AA is frequently white followed by repigmentation. Both regrowth in one site and extension of the alopecia on another site may be seen at the same time in the same patient. Nail dystrophy may be associated with AA. The reported incidence of onychodystrophy in AA

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Fig 9. Alopecia universalis affecting 100% of hairs.

Fig 10. Red spotted lunula and proximal trachyonychia in AA with nail involvement.

ranges from 10% to 66%,102 depending on how diligently it is looked for. Changes may be seen in one nail, several, or all of the nails. The dystrophy may precede, coincide with, or occur after resolution of the AA. Pitting with an irregular pattern or in organized transverse or longitudinal rows, trachyonychia (longitudinal striations resulting in sandpaper appearance), Beau’s lines (grooves through the nail matching that of the lunula margin), onychor-

rhexis (superficial splitting of the nail extending to the free edge), thinning or thickening (pseudomycotic), onychomadesis (onycholysis with nail loss), koilonychia (concave dorsal nail plate), punctate or transverse leukonychia, and red spotted lunula (Fig 10) may be associated with AA.103

PROGNOSIS The only predictable thing about the progress of

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Fig 11. Intralesional corticosteroid injections into the alopecic patches. (From Shapiro J, Madani S. Int J Dermatol 1999;38(Suppl 1):19-24.)

the AA is that it is unpredictable. Patients usually present with several episodes of hair loss and hair regrowth during their lifetime. The recovery from hair loss may be complete, partial, or none. In the majority of patients, hair will regrow entirely within 1 year without treatment. However, 7% to 10% can eventually develop the severe chronic form of the condition. Indicators of a poor prognosis are atopy, the presence of other immune diseases, family history of AA, young age at onset, nail dystrophy, extensive hair loss, and ophiasis.69,104

DIFFERENTIAL DIAGNOSIS Clinically, the differential diagnosis is usually between telogen effluvium, androgenetic alopecia (AGA), or trichotillomania. In telogen effluvium, hair loss is generalized over the entire scalp, whereas in AA it is usually patchy. Hairs that are shed are either telogen or dystrophic anagen in AA and are purely telogen in telogen effluvium. Patients with AGA usually demonstrate the typical predictable pattern of balding, and shedding is not prominent. The pull test is usually negative in AGA. In trichotillomania, patches of alopecia with twisted and broken hairs are noticed. A 4-mm punch biopsy may be necessary to make a definitive diagnosis in some cases.105 Diffuse AA can be especially difficult to diagnose.

TREATMENT At present, all treatments are palliative, only

controlling the problem; they certainly do not cure the condition. All local treatments may help the treated areas, but do not prevent further spread of the condition. In addition, any mode of treatment may need to be used for long periods because of the chronic nature of AA. The new AA investigational assessment guidelines are helpful in establishing criteria for selecting and assessing patients for clinical studies of AA, facilitating collaboration, comparing data, and measuring extent of scalp involvement.106 At the present time, topical, intralesional, and systemic steroids; topical and systemic immunotherapy; anthralin; minoxidil; and photochemotherapy are available for treatment of AA. All treatment plans for patients depend on two major factors: extent of scalp involvement and age of the patient. Intralesional corticosteroids Intralesional injections of corticosteroids are the first-line therapy for adult patients with less than 50% of scalp involvement.107 Immunosuppression is the main mechanism of action of the corticosteroids. A concentration of 5 mg/mL with a maximum total of 3 mL of triamcinolone acetonide can be used on the scalp in one visit. A weaker concentration of 2.5 mg/mL is used for the beard area and eyebrows. Triamcinolone acetonide is administered with a 0.5-inch long 30-gauge needle as multiple intradermal injections of 0.1 mL per site, approximately 1 cm apart (Fig 11). Initial regrowth

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is often seen in 4 to 8 weeks. Treatments are repeated every 4 to 6 weeks. The main side effect is minimal transient atrophy. This can be prevented by avoiding injections that are too great in volume per injected site, too frequent, or too superficial (intraepidermal). Children younger than 10 years are not usually treated with intralesional steroids because of pain localized at injection sites. After 6 months of treatment, if no response, intralesional corticosteroids should be discontinued because these patients may lack adequate corticosteroid receptors in the scalp.108 Topical therapy Corticosteroids. Topical corticosteroids have been reported to have some effect in the treatment of AA,109,110 but overall topical corticosteroids used as monotherapy are probably ineffective.111 Minoxidil. Minoxidil is a biologic response modifier that enhances hair growth. Minoxidil stimulates follicular DNA synthesis, has a direct effect on the proliferation and differentiation of follicular keratinocytes in vitro, and regulates hair physiology independently of blood flow influences.112,113 Its mode of action in AA is unknown, but it does not have an immunomodulatory effect.114 Cosmetically acceptable hair regrowth in patients with AA using topical minoxidil solution has been shown to be approximately 20% to 45% in patients with 20% to 99% scalp involvement.111,115-117 More successful results are seen in less severe cases of the disease. This treatment should not be expected to be effective in patients with alopecia totalis/universalis.112,116,118 At the University of British Columbia only the extrastrength topical minoxidil 5% solution is used. It must be applied twice daily. Initial hair regrowth is usually seen after 12 weeks. The efficacy of minoxidil solution can be enhanced with anthralin119 or betamethasone dipropionate.120 In combination with topical minoxidil, anthralin is applied 2 hours after the second minoxidil application. Bethamethasone dipropionate cream is applied twice daily, 30 minutes after each use of minoxidil. Although combination therapy has been found to be more effective than monotherapy, this therapy is not effective in patients with alopecia totalis/universalis. Side effects of minoxidil are rare. These include local irritation, allergic contact dermatitis, and facial hair growth, which tends to diminish with continued treatment.118 Systemic absorption is minimal.118,121 Anthralin. Anthralin is used in treatment of AA in concentrations of 0.25% to 1.0%. It may have a nonspecific immunomodulating effect eliciting hair

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regrowth.122,123 Clinical irritation is not necessary for efficacy, and short-contact therapy is effective. Cosmetically acceptable regrowth has been reported to vary from 20% to 25%.122-124 Anthralin 0.5% to 1% cream may be applied overnight123 or as short-contact therapy initially for 30 minutes and gradually to 1 hour with anthralin 1% cream.122 When therapy is effective, new hair growth is usually seen within 3 months. It may take 24 or more weeks for a cosmetically acceptable response. Anthralin is a good choice for children. Side effects of anthralin are irritation, scaling, folliculitis, and regional lymphadenopathy. Patients are cautioned to avoid getting anthralin into the eyes, protect treated skin against sun exposure, and be aware of staining of the treated skin and clothes. Topical immunotherapy. Topical immunotherapy is the most effective and accepted therapeutic modality in the treatment of chronic severe AA.125-127 The mechanism of action of topical immunotherapy is unclear. The immunomodulating effect of the topical sensitizers is supported by a decrease in the peribulbar CD4+/CD8+ lymphocyte ratio,128 a shift in the position of the T lymphocytes away from perifollicular areas to the interfollicular area129 and dermis.130 The earliest theory suggested that the immunogen may attract a new population of T cells into the treated area of the scalp, which could eliminate the antigenic stimulus present in AA.131 Another theory later proposed the concept of antigenic competition.132 This theory presumes that the generation of T-suppressor cells into the area may exert a nonspecific inhibitory effect on the autoimmune reaction to the hair-associated antigen and thus allow hair to regrow. Immunogens may interfere with the initial or continued production of proinflammatory cytokines by the follicular keratinocytes.133 Three contact sensitizers have been used in AA: dinitrochlorobenzene (DNCB), squaric acid dibutyl ester (SADBE), and diphenylcyclopropenone (DPCP). Because of the mutagenic effects of DNCB134,135 on the Ames test, the use of this chemical is less used. Several reports regarding use of SADBE in treatment of AA have revealed good results in 29% to 87% of the patients.136-141 SADBE107 is an ideal immunogen in that it is a strong topical sensitizer, is not found in the natural environment, does not cross-react with other chemicals, and is not mutagenic.142 However, SADBE is not as stable in acetone as DPCP.143,144 Efficacy of DPCP in treatment of AA has varied from study to study. A wide range of response rates, from 4% to 85%,146-153 is reported. The success rate in achieving a cosmetically acceptable result at the

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Fig 12. Initial DPCP application on one half of the scalp.

University of British Columbia Hair Clinic is approximately 60% in those patients with 25% to 99% scalp involvement. However, over the long term approximately one third of responders with cosmetically acceptable results eventually stop responding to the immunogen. Initial responses are usually seen after 12 weeks of therapy, with cosmetically acceptable results after 24 weeks. If there is no response by 24 weeks, DPCP topical immunotherapy is discontinued.125 Significant prognostic factors that have been reported to influence an adverse outcome are duration of AA before treatment, extent of AA, age at onset, a family history of AA, presence of nail changes, and association with atopic eczema.136,146,148,149,151,153,154 DPCP is applied125 with a wooden applicator stick tip with a generous amount of cotton (Fig 12). At the first treatment, a 2% solution in acetone is applied to a 4 × 4-cm area on one side of the scalp. After 1 week, if a severe eczematous response is not observed, a 0.001% solution is applied to the same half of the scalp. If the initial reaction is severe, treatment is delayed to the following week. The aim is to maintain a low-grade tolerable erythema, scaling, and pruritus on the treated side for 24 to 36 hours after application. Each week, DPCP is applied on the same side of the scalp. The concentration of DPCP is titrated according to the severity of the reaction to the previous week’s treatment. Concentrations vary from 0.0001%, 0.001%, 0.01%, 0.025%, 0.05%, 0.1%, 0.25%, 0.5%,

1.0% to 2%. Each time, the DPCP is left on the scalp for 48 hours and then washed off. The patient must protect the scalp from the light because DPCP is degraded when exposed to light.155 Once hair growth is established on one side, the other side is treated. In the presence of full regrowth, less frequent treatments are possible. A few responders regrow most of the scalp hair except for a few small areas that are refractory to the immunogen. These resistant areas are treated with intralesional triamcinolone acetonide, 5 to 10 mg/mL once per month. Side effects of DPCP include eczematous reactions with or without blistering, possible extension of the contact dermatitis to other body areas, itching, edema of scalp or face, lymphadenopathy in the cervical and postauricular areas, and postinflammatory hyperpigmentation or hypopigmentation.125,156 Extreme caution should be exercised in the treatment of patients with darker skin. Contact urticaria,157 vitiligo,158 and erythema multiforme159 have also been reported. Patients should be thoroughly informed about the medication, treatment, expectations, and side effects. DPCP should be administered in a university or hospital setting with ethics review board approval. Informed consent is obtained from each patient and patients should not be given DPCP for self-application. DPCP is contraindicated in pregnancy, although teratogenicity has not been demonstrated.

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Image available in print version only

Fig 13. Treatment plan for alopecia areata. (From Shapiro J, Price V, Lui H. Dermatol Ther 1998;16:353. Reprinted with permission.)

Systemic therapy Photochemotherapy (PUVA). The mechanism of action of PUVA on AA is believed to be a photoimmunologic action.160,161 It may affect T-cell function and antigen presentation and possibly inhibit local immunologic attack against the hair follicle by depleting Langerhans cells. The psoralen is administered either topically or orally and is followed in 1 or 2 hours with UVA. Treatments are administered two to three times a week with gradual increase in UVA dosage. Several studies showed that there is no difference between oral versus topical psoralen and local versus wholebody UVA irradiation.162,163 Burns are more likely to occur with topical therapy, but ocular toxicity is avoided.164 The major problem with PUVA therapy is the high relapse rate, which occurs frequently after the treatment is tapered.161,164 Today’s concern about PUVA and its promotion of all types of skin cancer, including melanoma,165 together with the need for long-term therapy in AA, make PUVA therapy less than satisfactory. Systemic corticosteroids. At the University of British Columbia Hair Clinic systemic corticosteroids are rarely used in the treatment of AA. They are frequently effective, but their use is limited because of their side-effect profile, high relapse rate after reduction of the dose, and the fact that steroids may be

necessary for long periods and do not change the ultimate prognosis. For active disease affecting more than 50% of the scalp in healthy young adults,112,166 one treatment regimen is to use 40 to 60 mg of prednisone per day and taper by 5 mg per week.112 Pulse therapy with intravenous methylprednisolone (250 mg) twice daily for 3 successive days for rapidly progressing extensive multifocal AA was found to be effective in controlling the active phase of hair loss.167 Cyclosporine. Systemic cyclosporine has been shown to be of benefit in AA.168,169 As with systemic corticosteroids, because of their side effect profile, high recurrence rate after discontinuation of the treatment, long treatment periods, and inability to change the ultimate prognosis of the disease, this treatment is simply not practical in AA.

TREATMENT PLAN The University of California, San Francisco– University of British Columbia Alopecia Areata Treatment Protocol is presented in algorithmic form in Fig 13. Patients are divided into those younger than 10 years and those 10 years of age or older. For patients older than 10, patients are then subdivided into those with less than 50% scalp hair loss and those with more than 50% scalp hair loss.

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For those with less than 50% scalp hair loss, the following options are offered. First, we offer the patient no treatment because in many of these patients their hair will regrow without treatment. However, most of our patients are well motivated and want treatment. First-line therapy for scalp AA is intralesional corticosteroid injections into the alopecic patches. If there is no response after 3 to 4 months, we add minoxidil 5% solution twice daily and a superpotent corticosteroid cream such as clobetasol propionate applied 30 minutes after the minoxidil in addition to the monthly injections. If there is no benefit, another option is short-contact anthralin therapy with anthralin 1.0% cream applied for up to 1 hour daily combined with topical minoxidil 5% solution applied twice daily. For those patients with more than 50% scalp involvement, our first line is topical immunotherapy with DPCP. If there is no response by 24 weeks, topical immunotherapy is discontinued. Other options that can be offered to the patient are systemic PUVA, minoxidil 5% solution, short-contact anthralin, and superpotent topical steroids. A scalp prosthesis should be available to all patients with more than 50% scalp involvement. It should be emphasized to the patient that a prosthesis does not imply permanent hair loss, but having one on hand is comforting for episodes of extensive hair loss. Dermatography of eyebrows is a technique that can be recommended for AA patients with prolonged eyebrow loss.170 For children younger than 10 years, treatment options include minoxidil 5% solution with or without topical midpotent corticosteroids or short-contact anthralin therapy. It is important to address the psychologic impact of the condition. It is imperative that the physician spend sufficient time with the patient, just as one would with a patient who has recently been diagnosed as having diabetes. The National Alopecia Areata Foundation (710 C St, Suite 11, San Rafael, CA 94901-3853) offers patients and physicians information including brochures, bimonthly newsletters, research updates, sources for scalp prostheses, children pen pals, videos for children to take to school, and information about support groups, which are present in many large cities in the United States and Canada. REFERENCES 1. Proceedings of the First International Research Workshop on Alopecia Areata. J Invest Dermatol 1991;96(Suppl):67S-98S. 2. Proceedings of the second international research workshop on alopecia areata. J Invest Dermatol 1995;104(Suppl):2S-45S. 3. Muller SA, Winkelmann RK. Alopecia areata: an evaluation of 736 patients. Arch Dermatol 1963;88:290-97.

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4. Shellow WV, Edwards JE, Koo JY. Profile of alopecia areata: a questionnaire analysis of patient and family. Int J Dermatol 1992;31:186-9. 5. Colombe BW, Price VH, Khoury EL. HLA class II antigen associations help to define two types of alopecia areata. J Am Acad Dermatol 1995;33:757-64. 6. Scerri L, Pace JL. Identical twins with identical alopecia areata. J Am Acad Dermatol 1992;27:766-7. 7. Jackow C, Puffer N, Hordinsky M, et al. Alopecia areata and cytomegalovirus infection in twins: genes versus environment? J Am Acad Dermatol 1998;38:418-25. 8. So A. Genetics, polymorphism and regulation of expression of HLA region genes. In: Lechler R, editor. HLA and disease. San Diego (CA): Academic Press; 1994. p. 1. 9. Price VH, Colombe BW. Heritable factors distinguish two types of alopecia areata. Dermatol Clin 1996;14:679-89. 10. Kuntz BM, Selzle D, Braun-Falco O, et al. HLA antigens in alopecia areata. Arch Dermatol 1977;113:1717. 11. Kianto U, Reunala T, Karvonen J. HLA-B12 in alopecia areata. Arch Dermatol 1977;113:1716. 12. Hacham-Zadeh S, Brautbar C, Cohen CA, et al. HLA and alopecia areata in Jerusalem. Tissue Antigens 1981;18:71-4. 13. Averbakh EV, Pospelov LE. HLA antigens in patients with alopecia areata. Vestn Dermatol Venereol 1986;1:24-6. 14. Frentz G, Thomsen K, Jakobsen BK, et al. HLA-DR4 in alopecia areata [letter]. J Am Acad Dermatol 1986;14:129-30. 15. Mikesell JF, Bergfeld WL, Braun WE. HLA-DR antigens in alopecia areata: preliminary report. Cleve Clin Q 1986;53:189-91. 16. Orecchia G, Belvedere MC, Martinetti M. Human leukocyte antigen region involvement in the genetic predisposition to alopecia areata. Dermatologica 1987;175:10-4. 17. Zhang L, Weetman AP, Friedman PS. HLA associations with alopecia areata. Tissue Antigens 1991;38:89-91. 18. Duvic M, Hordinsky MK, Fiedler VC. HLA-D locus associations in alopecia areata Drw52a may confer disease resistance. Arch Dermatol 1991;127:64-8. 19. Morling N, Frenz G, Fugger L, et al. DNA polymorphism of HLA class II genes in alopecia areata. Dis Markers 1991;9:35-42. 20. Welsh EA, Clark HH, Zane S, et al. Human leukocyte antigenDQB01*03 alleles are significantly associated with alopecia areata. J Invest Dermatol 1994;103:758-63. 21. Duvic M,Welsh EA, Jackow C, et al. Analysis of HLA-D locus alleles in alopecia areata patients and families. Arch Dermatol 1995;104(Suppl):5S-6S. 22. Colombe BW, Price VH, Khoury EL, et al. Class II alleles in longstanding alopecia totalis/alopecia universalis and long-standing patchy alopecia areata differentiate these two clinical groups. J Invest Dermatol 1995;104(Suppl):4S-6S. 23. Colombe BW, Lou CD, Price VH. Genetic basis of alopecia areata: HLA in longstanding disease (oral presentation). Third International Research Workshop on Alopecia Areata. Washington, DC, Nov 5, 1998. 24. Carter DM, Jegasothy BV. Alopecia areata and Down syndrome. Arch Dermatol 1976;112:1397-9. 25. Du Vivier A, Munro DD. Alopecia areata, autoimmunity, and Down’s syndrome. Br Med J 1975;1:191-2. 26. Tarlow JK, Clay FE, Cork MJ. Severity of alopecia areata is associated with a polymorphism in the interleukin-1 receptor antagonist gene. J Invest Dermatol 1994;103:387-90. 27. Friedmann PS. Alopecia areata and auto-immunity. Br J Dermatol 1981;105:153-7. 28. Bergfeld WF, Tam RC, Remzi BK. Alopecia areata and thyroid

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disease. Presented as a poster at the Third International Research Workshop on Alopecia Areata, Washington, DC, Nov 5, 1998. 29. Hordinsky M. Alopecia areata and atopy. Presented at the 53rd Annual Meeting of the American Academy of Dermatology, New Orleans, Feb 4-9 1995. 30. Wang SJ, Shohat T, Vadheim C, et al. Increased risk for type I (insulin-dependent) diabetes in relatives of patients with alopecia areata. Am J Med Genet 1994;51:234-9. 31. Hordinsky MK, Hallgren H, Nelson D, et al. Familial alopecia areata. Arch Dermatol 1984;120:464-8. 32. Werth VP, White WL, Sanchez MR, et al. Incidence of alopecia areata in lupus erythematosus. Arch Dermatol 1992;128:36871. 33. Kubota A, Komiyama A, Hasegawa O. Myasthenia gravis and alopecia areata. Neurology 1997;48:774-5. 34. Brenner W, Diem E, Gschnait F. Coincidence of vitiligo, alopecia, onychodystrophy, locolised scleroderma and lichen planus. Dermatologica 1979;159:356-60. 35. Boni R,Trueb RM, Wuthrich B. Alopecia areata in a patient with candidiasis-endocrinopathy syndrome. Dermatology 1995; 191:68-71. 36. Muller HK, Rook AJ, Kubba R. Immunohistology and autoantibody studies in alopecia areata. Br J Dermatol 1980;102:60915. 37. Gilhar A, Pillar T, Assay B, et al. Failure of passive transfer of serum from patients with alopecia areata and alopecia universalis to inhibit hair growth in transplants of human scalp skin grafted on to nude mice. Br J Dermatol 1992;126:166-71. 38. Tobin DJ, Orentreich N, Fenton DA, et al. Antibodies to hair follicles in alopecia areata. J Invest Dermatol 1994;102:721-4. 39. Tobin DJ, Hann S, Song M, et al. Hair follicle structures targeted by antibodies in patients with alopecia areata. Arch Dermatol 1997;133:57-61. 40. Friedmann PS. Decreased lymphocyte reactivity and autoimmunity in alopecia areata. Br J Dermatol 1981;105:145-52. 41. Majewski BBJ, Koh MS, Taylor DR, et al. Increased ratio of helper-to-suppressor T-cells in alopecia areata. Br J Dermatol 1984;110:171-5. 42. Hordinsky MK, Hallgren H, Nelson D. Suppressor cell number and function in alopecia areata. Arch Dermatol 1984;120:18895. 43. Friedmann PS. Clinical and immunologic associations of alopecia areata. Semin Dermatol 1985;4:9-15. 44. Gupta AK, Ellis CN, Cooper KD, et al. Oral cyclosporine for the treatment of alopecia areata. J Am Acad Dermatol 1990;22: 242-50. 45. Olsen EA, Carson SC,Turney EA. Systemic steroids with or without 2% topical minoxidil in the treatment of alopecia areata. Arch Dermatol 1992;128:1467-73. 46. Gilhar A, Ullmann Y, Berkutzki T, et al. Autoimmune hair loss (alopecia areata) transferred by T-lymphocytes to human scalp explants on SCID mice. J Clin Invest 1998;101:62-7. 47. Paus R. Immunology of the hair follicle. In: Bos JD, editor. The skin immune system. Boca Raton (FL): CRC Press; 1997. p. 37798. 48. Bos JD, editor. The skin immune system. Boca Raton (FL): CRC Press; 1997. 49. Paus R, Hofmann U, Eichmuller S, et al. Distribution and changing density of gamma-delta T cells in murine skin during the induced hair cycle. Br J Dermatol 1994;130:281-9. 50. Paus R, Foitzik K, Welker P, et al. Transforming growth factor-

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ta be triggered by emotional stress? Acta Derm Venereol (Stockh) 1992;72:279-80. 71. Tobin SJ. Morphological analysis of hair follicles in alopecia areata. Microsc Res Tech 1997;38:443-51. 72. Tobin DJ, Fenton DA, Kendall MD. Ultrastructural observations on the hair bulb melanocytes and melanosomes in acute alopecia areata. J Invest Dermatol 1990;94:803-7. 73. Nutbrown M, MacDonald-Hull SP, Cunliffe WJ, et al. Abnormalities in the ultrastructure of melanocytes and the outer root sheath of clinically normal hair follicles from alopecia areata scalps. J Invest Dermatol 1995;104(Suppl):12S-13S. 74. Hsoi J, Murphy GF, Egan CL, et al. Regulation of Langerhans cell function by nerves containing calcitonin gene-related peptide. Nature 1993;363:159-63. 75. Hordinsky M, Lorimer S, Worel S. Innervation and vasculature of the normal human and alopecia areata hair follicle: an immunohistochemical and laser scanning confocal microscope study. In: Proceedings of the First Tricontinental Meeting of Hair Research Societies, Brussels, Belgium, 1995. 76. Hordinsky M, Kennedy W, Wendelschafer-Crabb G, et al. Structure and function of cutaneous nerves in alopecia areata. J Invest Dermatol 1995;104(Suppl):28S-29S. 77. Raud J, Lundeberg T, Brodda-Jansen G, et al. Potent antiinflammatory action of calcitonin gene-related peptide. Biochem Biophys Res Commun 1991;180:1429-35. 78. Paus R, Heinzelmann T, Schultz K-D, et al. Hair growth induction by substance P. Lab Invest 1994;71:134-40. 79. Ericson M, Binstock K, Guanche A, et al. Differential expression of substance P in perifollicular scalp blood vessels and nerves after topical therapy with capsaicin 0.075% (Zostrix HP) in controls and patients with extensive alopecia areata. J Invest Dermatol 1999;112:653. 80. Sundberg JP, Cordy WR, King LE. Alopecia areata in aging C3H/HeJ mice. J Invest Dermatol 1994;102:847-56. 81. Michie HJ, Jahoda CAB, Oliver RF, et al. The DEBR rat: an animal model of human alopecia areata. Br J Dermatol 1991;125:94-100. 82. Smyth JR. Alopecia areata and universalis in the Smyth chicken model for spontaneous autoimmune vitiligo. Presented at the Third International Research Workshop on Alopecia Areata. Washington, DC, Nov 5, 1998. 83. McElwee KJ, Boggess D, King Jr LE, et al. Experimental induction of alopecia areata-like hair loss in C3H/HeJ mice using full-thickness skin grafts. J Invest Dermatol 1998;111:797-803. 84. Messenger AG, Slatter DN, Bleehen SS. Alopecia areata: alterations in the hair growth cycle and correlation with the follicular pathology. Br J Dermatol 1986;114:337-47. 85. Peereboom-Wynia JDR, Koerten HK, Van Joost TH, et al. Scanning electron microscopy comparing exclamation mark hairs in alopecia areata with normal hair fibers, mechanically broken by traction. Clin Exp Dermatol 1989;14:47-50. 86. Headington JT. The histopathology of alopecia areata [abstract]. J Invest Dermatol 1991;96(Suppl):69S. 87. Perret C, Wiesner-Menzel L, Happle R. Immunohistochemical analysis of T-cell subsets in the peribulbar and intrabulbar infiltrates of alopecia areata. Acta Derm Venereol (Stockh) 1984;64:26-30. 88. Wiesner-Menzel L, Happle R. Intrabulbar and peribulbar accumulation of dendritic OKT 6-positive cells in alopecia areata. Arch Dermatol Res 1984;276:333-4. 89. Whiting DA, Howsden FL, editors. Alopecia areata: Color atlas of differential diagnosis of hair loss. Cedar Grove (NJ): Canfield Publishing; 1996. p. 32-7.

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90. Whiting DA. Histopathology of alopecia areata in horizontal sections of scalp biopsies. J Invest Dermatol 1995;104(Suppl): 26S-7S. 91. Kohchiyama A, Hatamochi A, Ueki H. Increased number of OKT6-positive dendritic cells in the hair follicles of patients with alopecia areata. Dermatologica 1985;171:327-31. 92. Elston DM, McCollough MLM, Bergfeld WF, et al. Eosinophils in fibrous tracts and near hair bulbs: a helpful diagnostic feature of alopecia areata. J Am Acad Dermatol 1997;37:101-6. 93. Nutbrown M, Hull SPM, Baker TG, et al. Ultrastructural abnormalities in the dermal papillae of both lesional and clinically normal follicles from alopecia areata scalps. Br J Dermatol 1996;135:204-10. 94. McDonagh AJG, Snowden JA, Stierle C. HLA and ICAM-1 expression in alopecia areata in vivo and in vitro: the role of cytokines. Br J Dermatol 1993;129:250-6. 95. Lee JY, Hsu ML. Alopecia syphilitica, a simulator of alopecia areata: histopathology and differential diagnosis. J Cutan Pathol 1991;18:87-92. 96. Dawber RPR, de Berker D, Wojnarowska F. Disorders of hair. In: Champion RH, Burton JL, Burns DA, editors. Rook/Wilkinson/ Ebling Textbook of dermatology. Boston: Blackwell Science; 1998. p. 2869-973. 97. Safavi K. Prevalence of alopecia areata in the First National Health and Nutrition Examination Survey [letter]. Arch Dermatol 1992;128:702. 98. Safavi KHH, Muller SA, Suman VJ, et al. Incidence of alopecia areata in Olmsted County, Minnesota, 1975 through 1989. Mayo Clin Proc 1995;70:628-33. 99. Price V. Alopecia areata: clinical aspects. J Invest Dermatol 1991;96(Suppl):68S. 100. Camacho F. Alopecia areata: clinical features. Dermatopathology. In: Camacho F, Montagna W, editors.Trichology: diseases of the pilosebaceus follicle. Madrid: Aula Medica Group; 1997. p. 417-40. 101. Muralidhar S, Sharma VK, Kaur S. Ophiasis inversus: a rare pattern of alopecia areata [letter]. Pediatr Dermatol 1998;15:326-7. 102. Orecchia G, Douville H, Marelli MA. Nail changes and alopecia areata. Ital Gen Rev Dermatol 1988;25:179-84. 103. Berker DAR, Baran R, Dawber RPR, editors. Handbook of diseases of the nails and their management. Oxford: Blackwell Science Ltd; 1995. p. 76-7. 104. Mitchell A, Krull E. Alopecia areata: pathogenesis and treatment. J Am Acad Dermatol 1984;11:763-75. 105. Madani S, Shapiro J.The scalp biopsy: making it more efficient. Dermatol Surg 1999;25:537-8. 106. Olsen E, Hordinsky M, McDonald-Hull S, et al. Alopecia areata investigational assessment guidelines. J Am Acad Dermatol 1999;40:242-6. 107. Shapiro J. Alopecia areata: update on therapy. Dermatol Clin 1993;11:35-46. 108. Sawaya ME, Hordinsky MK. Glucocorticoid regulation of hair growth in alopecia areata. J Invest Dermatol 1995;194(Suppl 5):30S. 109. Montes L. Topical halcinonide in alopecia areata and alopecia totalis. J Cutan Pathol 1977;4:47-50. 110. Gill K, Baxter D. Alopecia totalis: treatment with fluocinolone acetonide. Arch Dermatol 1963;87:384. 111. Shapiro J, Price V. Hair regrowth: therapeutic agents. Dermatol Clin 1998;16:341-56. 112. Price V, Khoury E. Progress in dermatology. Bull Dermatol Found 1991;25:1.

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