Yozgat State Hospital, Dermatology Clinic, Turkey 2. Ankara Dışkapı Training and Research Hospital, Dermatology Clinic, Turkey

Transcription

1 Chapter 05 Alopecia Areata: What is New in Epidemiology, Etiopathogenesis, Clinical Aspects and Prognosis Gökçen Çelik 1 * and Müzeyyen Gönül 2 1 Yozgat State Hospital, Dermatology Clinic, Turkey 2 Ankara Dışkapı Training and Research Hospital, Dermatology Clinic, Turkey * Corresponding Author: Gökçen Çelik, Yozgat State Hospital, Dermatology Clinic, Yozgat, Turkey, Tel: ; celikgokcen@gmail. com First Published April 23, 2018 Copyright: 2018 Gökçen Çelik and Müzeyyen Gönül. This article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source. 2

2 Abstract Alopecia areata is an autoimmune and inflammatory disorder of hair follicle, which is characterized by non-scarring alopecia. It affects nearly 2% of the general population and occurs in all ethnic groups, ages, and both sexes. Loss of immune privilege of the hair follicle is thought to be an important factor but the exact underlying pathogenesis of this complex polygenic, immune- mediated disease has yet to be elucidated. It usually occurs as one or more round, well-defined hairless patches on the scalp, but diffuse or total hair loss may affect any hair bearing site in severe forms. In the histopathological evaluation, lymphocytic infiltration in and around the bulb or the lower part of the anagen hair follicle and increased number of the catagen and telogen follicles are the main characteristics. The clinical course of the disease varies from self-limited to recurrent episodes over many years. Other autoimmune diseases are associated with alopecia areata, especially thyroid diseases and vitiligo. Introduction Alopecia areata (AA) is a chronic and often psychosocially disabling hair loss problem [1-2]. It is the second-most frequent non-scarring alopecia, after androgenetic alopecia [3]. The Greek term Alopekia was first used by Hippocrates around 400 BC from which the Latin term Alopecia comes. It is thought to be used to refer mange (scabies) which occurs in both humans and other mammals. More than four centruies after Hippocrates, Celsus described the disease we know as AA in a medical encyclopedia titled De Medicina. He mentioned two forms of the disease. The first, known as Alopecia, was complete baldness of individuals of all ages. The second form was named Ophiasis (which means snake) and corresponded to a pediatric form which begins at the hinder part of the head. The name Alopecia Areata was first used by a French physician in 18th century. Untill the outset of the 20th century, AA was claimed to be caused by various microorganisms, emotional physical stress or endocrine dys- 3

3 function [4-5]. Inflammation of the hair follicles in AA mediated by leukocytes was described and after that, autoimmunity in the pathogenesis of AA has been recognized as an underlying cause since the late 1950s [3,6]. Most patients present with sudden, patchy loss on the scalp which may reverse completely or become chronic [7]. There are subgroups of AA including those patients with the complete loss of terminal scalp hair (alopecia totalis) and those patients with total absence of terminal scalp and body hair (alopecia universalis) [8]. Patients usually experience unpredictable remissions and recurrences of varying severity [9]. Epidemiology Depending on geographic area of the world AA-affected individuals account for 0,7-3,8 % of new dermatology outpatient attendances [10-12]. Several epidemiologic studies documented that approximately 2% of the general population (men, women and children) suffer from AA at some point during their lifetime [13-14]. Safevi et al. provided evidence that the incidence of AA was 20.2 per 100,000 person-years [15] and the prevalence of AA was approximately 0.1% in USA [16]. Although the onset of the disease ranges from less than 1 year to the late seventies about 85.5% of the patients had their first episode before the age of 40 [11,17]. AA sufferers experience their first onset of AA by age 20 years in 40.2% of patients and it has been stated that the earlier the age of onset, the more severe the extent of AA [12,18-19]. The mean age of onset has been reported as between ages 5 and 10 years in children [20]. There is generally no sex predilection [13,15] and it is not clear whether sex affects the extent of disease [20]. Most studies report no significant difference in the age of onset or mean duration of AA between two genders [21-22]. Positive family history has been reported to be between 0% and 8.6% [14]. Etiology and Pathogenesis AA is thought to be a tissue-specific disease of hair follicle with genetic predisposition and autoimmune pathogenesis triggered by 4

4 environmental factors [8,23]. T-cell-mediated attack targeting unidentified antigens on anagen hair follicle is suggested to result in AA development in genetically susceptible individuals [23-24]. The etiology of AA remains unknown, but a variety of triggering factors have been proposed including emotional or physical stress [25], infectious agents [26-27], vaccinations [28-29], drugs [30] and diet [31]. Environmental factors (such as exposure to proinflammatory agents and possibly stress and diet) may modify susceptibility to development of AA [32]. AA has a complex genetic basis underlying the heterogeneity seen in AA [33]. It is suggested that inheritance of AA follows the polygenetic additive model [34]. The concordance rate among identical twins is roughly 55% [35]. A positive family history of AA has been reported ranging from 8.6% to 42% of families in different countries [18] [36]. Genetic studies on AA have primarily concentrated on Human Leucocyte Antigen (HLA) class II (HLA-D region), because these genes may enhance the follicular immune attack through varying the capacity of antigen presentation [37]. Consistent associations have been observed between AA and class II haplotypes DR4, DR5, DR6, DR7, DQ3, especially allele DQB1*03 (DQ3) has been strongly associated with a general susceptibility for AA. Patients with more severe forms of the disease (alopecia totalis and alopecia universalis) were found to express increased frequency of HLA alleles DQB1*0301 (DQ7), DRB1*0401 (DR4) and DRB1*1104 (DR11) [9,24,38]. In 2010, a genome-wide association study (GWAS) in AA has revealed eight genetic loci contributing to AA such as the HLA region, the UL16-binding protein gene cluster, cytotoxic T-lymphocyte antigen 4 (CTLA4), interleukins, and several genes that control the differentiation and maintenance of regulatory T cells [39]. ULBP6/ ULBP3 gene locus on chromosome 6q, contains the genes encoding the NK cell receptor D ligands NKG2DL3 (encoded by ULBP3) and retinoic acid early transcript 1L protein (encoded by RAET1L; also known as ULBP6), which are implicated in AA specifically suggesting a key role in pathogenesis [40-41]. CD8+NKG2D+T cells are the major effectors of AA, which have dependency on Interleukin (IL)

5 signaling for their survival. The downstream effectors of this pathway are mediated by Janus Kinase (JAK) [42]. Gene expression profiling studies have revealed predominant signatures of the Interferon gamma pathway and related cytokines which are mediated by JAKs as their downstream effectors too [42-43]. Major histocompatibility complex (MHC) class I polypeptide-related sequence A (MICA, a key NKG2D agonist) polymorphisms have also been identified in association with AA [44]. Several genes on chromosome 21 and IL-1 cluster genes have been implicated in the pathogenesis of AA. Other gene association studies have identified specific polymorphisms in the genes encoding MX1, AIRE and NOTCH4 [23-24]. The hair follicle in the anagen phase has immune privilege [45], accomplished through multiple mechanisms including down regulation of MHC class I and II molecules, decreased frequency of Langerhans cells, expression of immunosuppressive cytokines (α-melanocyte-stimulating hormone, transforming growth factor -β, insulin-like growth factor-1) and low expression of danger signals (ULBP6/3) [40,46-47]. Hair follicles also actively suppress natural killer (NK) cells by macrophage migration inhibitory factor, released from hair follicle epithelium [48]. Immune privilege seems to be essential for protecting the follicles from the skin immune system damage and so maintaining hair cycling [49]. The breakdown of the immune privilege of the hair follicle has been thought to play a crucial part in the pathogenesis of AA [50]. The initiating events are not fully understood, but physical/emotional stress, infections, and hormones have been suggested to play a role [51]. Interferon (IFN)-γ secretion is triggered by infection, bacterial superantigens, psycho-emotional stressors, skin microtrauma, or other damage to hair follicles and upregulates MHC class I expression in hair follicles [46] [47]. After MHC molecules are expressed under the influence of IFN-γ, immune privilege collapses [52]. Because, it has been suggested that the MHC molecules could be important for the presentation of an antigen which is responsible for AA, as for other autoimmune diseases [53]. Although AA do not yet have any 6

6 autoantigen that is clearly associated with the pathogenesis; several autoantigens related with melanogenesis in melanocytes are believed to be immunogenic and, can result in loss of immune privilege in conjunction with other facilitating factors [6,40,54]. Follicular keratinocyte or dermal papilla antigens are other possible candidates [55-56]. The perifollicular infiltrate in AA mainly forms around anagen follicles in those stages of the hair cycle during which pigment is produced [51]. In early lesions the affected anagen follicle is mitotically active, producing a normal inner root sheath; but the hair shaft cortex is incompletely keratinized [57]. Aberrant MHC class I and II expression has been shown to occur in the pre-cortical region where the inflammatory cell infiltrates are localized [6]. These changes suggest that the matrix epithelium that is undergoing early cortical differentiation seems to be the primary target of an immune attack [3,6]. The affected hair follicles are forced to return to telogen phase, in which cortical differentiation does not occur. Although the follicles re-enter the anagen phase normally, they fail to develop beyond anagen III/IV, the point where cortical differentiation begins [58-59]. This leads to disruption and shortening of the normal hair-follicle cycle, resulting in dystrophic anagen follicles and/or increased frequency of telogen state follicles [51]. Less severely affected follicles remain in anagen phases and produce dystrophic hair shafts, till eventually progress to telogen [3]. The matrix cells exhibit vacuolar degeneration in affected anagen follicles. Inflammation-induced dystrophy of the follicle, leads to production of abnormal hair shafts. Increased fragility and defective anchoring of the hair within the follicle explain the formation of the exclamation point hair shaft which is a key characteristic of AA [3,60]. However inflammation can keep follicles in prolonged telogen state in chronic cases, the hair follicle retains its capacity to regenerate and continue cycling [51,60]. Autoantibodies targeting hair follicle proteins such as trichohyalin and certain keratins have been detected in affected humans and experimental mouse models [61-62]. But they are not specific for any antigen and target multiple structures in anagen hair follicles, thus the role of autoantibodies is still unclear [63]. It was shown that the transfer of patient s serum to mice grafted with 7

7 human scalp leaded to deposition of immunoglobulin on follicular structures, but did not induce hair loss [64]. It is suggested that failure of isolating hair follicle antigens (appearing thorughout remodelling of hair follicle) from the immune system by microenviromental regulations; might lead to sensitization of circulating T cells to keratinocyte and/or melanocyte peptides, which might precipitate AA [40]. CD8+ T cells react to autoantigens in the hair follicles, because of the MHC class I molecules strongly expressed in AA lesions [65]. CD8+ T cells are considered to act as the effector cells, whereas CD4+ T cells play a classic helper role in AA onset [66]. Current research strongly implicates CD4+ and CD8+ T lymphocytes but not B cells in the pathogenetic autoimmune etiology of AA. T lymphocytes cultivated from affected scalp have been shown to transfer AA to nonaffected scalp in a severe combined immunodeficiency mouse model [67]. Cytotoxic CD8+NKG2D+ T cells are found within prominent infiltrates around hair follicles from patients with AA; and are both necessary and sufficient for the induction of AA in mouse models of disease [42,48]. NKG2D and NKG2C (activating receptors) carrying CD56+ NK cells were higher in peripheral blood cells of patients with AA than in healthy controls [48]. Genome-wide association studies (GWAS) implicated polymorphisms in the ULBP gene cluster (encoding activating ligands of the NK cell receptor NKG2D) in AA pathogenesis [68]. Subsequently, cytotoxic CD8+ T cells, that possibly attracted to this region by the expression of the NK group 2D (NKG2D) ligand, accumulate in and around the hair bulb and thus a characteristic peribulbar and intrafollicular inflammatory infiltrate consisting of activated CD4+ and CD8+ T lymphocytes occurs. [49,51,65]. By grafting normal human scalp skin onto severe-combined immunodeficient mice, and injections of peripheral blood mononuclear cells from an healthy donor, enriched for NKG2D+ cells and activated by phytohemagglutinin/il-2, into transplanted mice; one can precipitate hair follicle immune privilege collapse and autoimmune type hair loss similar to AA [69]. 8

8 Clinical Findings A sudden-onset patchy loss of terminal hair in well-demarcated, localized areas is the most common manifestation of AA. Typical lesions of AA are characterized by isolated or numerous round-oval, hairless patches with no evidence of scarring [7,8,70] (Figure1). In alopecic areas, the scalp appears slightly depressed due to absence of the supportive effect of the hair shafts [60]. The patches are generally asymptomatic, but tingling, itching, or dysesthesia may be present before the onset of hair loss in rare cases [71]. The affected follicles undergo conversion from anagen to telogen, clinically seen as localized shedding [8]. Exclamation point hairs in which the distal segment of the hair shaft is broader than its proximal end; often localized at the periphery of alopecic patches as a characteristic marker of the AA. These distrophic hairs may be seen during active phases of the disease [3]. Scalp involvement is the most common clinical presentation (90%) and usually the first manifestation [11,16,72]. Any and all hair-bearing sites including eyebrow, eyelash, beard and axilla can be affected [73] (Figure 2). AA is classified as AA circumscripta, AA totalis and AA universalis by extend of the hair shedding. The complete denudation of hair from the scalp is called as alopecia totalis (Figure3). When all scalp and body hairs (including eyebrows, eyelashes, ear, axillary and pubic hairs) are lost, the disease is called alopecia universalis (Figure 4). AA presents in different patterns: patchy (circumscribed patches ), reticular, ophiasis type, sisiapho type, diffuse or perinevoid type [74]. Patchy AA is the most common pattern that may multiply, expand and coalesce into extensive AA [7,24] (Figure 5). Reticular AA represents cooccurrence of multiple patches in active,stable or regrowing stages [9]. Ophiasis is a special clinical pattern of AA with poor prognosis which occurs as band-like hair loss extending along the posterior occipital and temporal scalp margins [7,75] (Figure 6). The opposite of ophiasis variant is called sisiapho, where hairs are lost centrally and spared at the margins of the scalp [76]. Diffuse AA (AA incognita) is characterized by acute 9

9 diffuse shedding of telogen hairs in the absence of typical patches. This form has an acute onset and causes diffuse and severe hair thinning in a few months [77]. It usually does not affect all hairs [74]. An unusual presentation is perinevoid AA that is located around a nevus [78]. A recently described variant of AA is characterized by rapidly progressive diffuse/ total alopecia, histopatological finding of remarkable eosinophilic infiltration and favorable prognosis [79]. The extent of hair loss and the course of disease vary for each individual, in addition to this, different forms of AA may evolve into one another during the disease course [24,60]. AA has a waxing and waning nature but the progress of an initial patch is unpredictable [3]. While new hair growth is present in one region of the scalp, recurrences in different locations may occur [9]. Regrowing hairs may be fine and non-pigmented initially; but return to normal pigmented ones generally [8]. AA may cause nail changes in about 20% of patients [12]. Nail problems occur more frequently in those with severe AA [80]. Children with severe, chronic disease were found to be more prone to have nail lesions [81]. Nail changes seen in AA consist of diffuse fine pitting (the most common) (Figure7), trachyonychia, Beau s line, onychorrhexis, thinning or thickening, onychomadesis, koilonychias, punctuate or transverse leukonychia, and red spotted lunula [8,82]. Onychodystrophy is the less common problem [51]. Nail abnormalities generally occur concurrently with hair loss, but may precede or follow the onset of hair disease [33]. 10

10 Figure 1: An isolated round hairless patch with no evidence of scarring on scalp. 11

11 Figure 2: Eyebrows and eyelashes are affected by alopecia areata. 12

12 Figure 3: Alopecia totalis. 13

13 Figure 4: Alopecia universalis. Figure 5: Patchy alopecia areata on beard. 14

14 Figure 6: Ophiasis pattern alopecia areata. Figure 7: Nail pitting associated with alopecia areata. 15

15 Diagnostic Approches AA is usually diagnosed based on clinical evaluation, particularly when it presents in its classical form with circumscribed hairless patches or large alopecic areas exhibiting preserved follicular ostia [51,77]. Personal history for other autoimmune disorders and family history for AA should be obtained. There is no diagnostic laboratory test indicated for the diagnosis of AA. Thyroid-function tests and tests for thyroid antibodies may be helpful because abnormal results provide supportive information based on the association between AA and thyroid autoimmunity [74]. A positive hair pull test (6 hairs or more /60) with telogen or dystrophic anagen hairs conducted at the periphery of the lesion suggests active disease [8]. Determining nail changes may help clinician during the diagnosis process [74]. Normally trichogram is not necessary [51]. Dermoscopy Although the diagnosis of AA is usually made on clinical grounds, dermoscopy can further validate the diagnosis. The main dermoscopic features of AA include yellow dots, black dots, exclamation point hairs, broken hairs, and short vellus hairs [3]. Yellow dots within the follicular ostium of both empty and hair-bearing follicles are often found in AA but they are not specific (Figure8). The yellow dots histopatologically correspond to keratotic plugs within the dilated follicular ostia of nanogen and miniaturized hair follicles [77,83]. Exclamation mark hair represents short trichorrhexis- like broken hair, which has a broader distal and a tapered proximal segment (Figure 9). Comedo-like cadaver hairs are seen as black dots and may also be present in black-haired individuals [74,84]. In a typical case of AA, dermoscopy helps to evaluate disease activity by detecting dystrophic hairs, exclamation point hairs and cadaverized hair. In study conducted by Inui et al. yellow dots and short vellus hairs were found to be the most sensitive markers, as black dots, tapering hairs, and broken hairs were found to be the most specific markers. Groups of vellus hair are 16

16 thinner and shorter (10 mm) shafts with little pigmentation which can be seen in initial regrowth. A negative correlation of vellus hairs with the disease activity or severity of AA have been demonstrated. Black dots, tapering hairs, and broken hairs indicate strong disease activity, but short vellus hairs are characteristic of remitting disease [84]. Digital videodermatoscopy has also been employed for dealing with hair disorders in many clinics which might help the clinician to identify the right site for biopsy or avoid unnecessary biopsies. Reflectance confocal microscopy is an another tool that may be employed for non-invasive diagnosis of AA, in some cases, even the immune infiltrate can be visualized [77]. Figure 8: Yellow dots, black dots, exclamation point hairs, broken hairs, and short vellus hairs. 17

17 Figure 9: Exclamation mark hair which has a broader distal and a tapered proximal segment. Histopathology Histopatological examination should be performed only if history and examination are not conclusive and the clinical diagnosis is in doubt. A skin biopsy has a key role in making a diagnose of diffuse AA and to differentiate it from telogen effluvium (TE) and androgenetic alopecia (AGA) [85]. In the histopatologic assessment of a scalp biopsy from the margins of expanding lesions of AA, peribulbar lymphocytic infiltration is usually considered to be the principal finding in establishing the diagnosis [86]. The inflammatory cells composed of CD4+ and CD8+ T lymphocytes are especially seen around terminal hair follicles, the bulbs of which are located in the subcutaneous tissue [8,87]. Biopsies from established bald patches show a normal number of miniaturized hair follicle that have telogen or anagen morphology. The histopathologic characteristics of AA depend on the stage of the current episode [60]. 18

18 The early stage of AA is characterized by an increased number of the catagen and telogen follicles, a dense or moderate infiltrate around the anagen hair bulb ( swarm of bees ) comprising lymphocytes and Langerhans cells and eosinophils in the stellae [60,88]. The hair matrix exhibits vacuolar damage and necrosis depending on lymphocyte infiltration. Dermal papillae is effected from this inflammation so, degeneration of hair bulb epithelium around the dermal papilla and pigmentary incontinence concentrated in follicular dermal papillae can be seen [88-90]. This can result in anagen arrest that describes hair growth termination for a short time, and weakening of the hair shaft. Follicular lymphocytic infiltration induces progression to catagen and telogen phases. After the first telogen, affected follicle rapidly returns to anagen and the cycle repeats itself. Trichomalacia (short, incompletely keratined hairs that are susceptible to trauma) and miniaturization are the results of these repeated cycles. In the subacute stage, an increasingly large number of catagen hairs are present, and the inflammatory infiltrate may persist in or around follicular stelae [8,60,88,90]. The late stage of the disease is characterized by numerous miniaturized hair follicles, so there is a reversal of the terminal-vellus ratio. Telogen and nanogen (intermediate stage between vellus and terminal anagen) follicles are present. Inflammation may be absent in longstanding AA, if present, is more likely to be in the papillary dermis around miniaturized hair bulbs. Numerous stellae accompanied by an inflammatory cell infiltrate and melanin pigment are other findings [8,60,91]. Recovery stage, miniaturized hairs grow back into terminal hairs. Terminal to vellus ratio reaches the normal. The percentage of anagen hairs will increase, with little or no inflammation [60]. If there is a prolonged recovery period or a chronic disease, inflammatory infiltrates cannot be seen as a common finding [58]. According to classification of histopathological features of AA by Uno and Orecchia; microfollicles, hair disruption, follicular degeneration, and perifollicular inflammation are associated with disease severity whereas; large follicles and proliferation of perifollicular fibrous tis- 19

19 sue are the criteria for mild disease [47] Although the lymphocytic infiltrate targets lower, transient part of growing follicles and epithelial stem cells are protected in the higher, permanent, bulge region, some authors recently reported that T cells could infiltrate the bulge region [47]. For an accurate histopathological diagnosis of AA, it is important to review both transverse and horizontal sections. While horizontally sectioned specimens provide accurate follicular counts; transverse sections let us to evaluate lower or reticular dermis to capture the terminal hair bulbs and upper or papillary dermis to capture the miniaturized, vellus like hairs [3,60]. Differential Diagnosis Tinea capitis and trichotillomania presenting with solitary areas of non- scarring hair loss involving the scalp can be misdiagnosed as AA [9]. Tinea capitis that usually presents with scaling and signs of inflammation can be ruled out by potassium hydroxide examination or fungal culture [32]. Trichotillomania may cause confusion but the incomplete nature of the hair loss, bizarrely shaped lesions and continuous growing of the broken hairs instead of shedding are distinguishing features [32,92]. Congenital triangular alopecia which typically affects the frontotemporal region and loose anagen hair syndrome are other non-scarring forms of alopecia especially in children [74,93]. Universal hair loss associated with a strong family history suggests the diagnosis of congenital atrichia [94]. If there is a doubt regarding the presence of cicatricial alopecias such as morphea or pseudopelade of Brocq, histopathological examination differentiates AA easily [74]. Clinically, the differential diagnosis is usually between TE and AGA [7]. In TE, the hair loss is generalized, and hair pull test shows pure telogen hairs. But in AA, pattern is usually patchy and the hairs that are shed are either telogen or dystrophic anagen. In AGA, shedding is not prominent and pull test is usually negative. But typical pattern of balding is remarkable [83]. Sisiapho (ophiasis inversus) may mimic AGA [74]. Diffuse AA is a diagnostic challange 20

20 so a 4-mm punch biopsy may be necessary to distinguish diffuse AA from female AGA or TE. In AA incognito, clinical history is negative for possible triggers of TE [77]. A highly positive pull test and the additional presence of patches are supporting clues. Dermoscopy is used to determine the presence of dystrophic hairs [74,85]. A microscopic evaluation of the hairs shed can easily rule out TE and female AGA by revealing dystrophic anagen hairs or pencil point hairs among telogen hairs [95]. AA incognita should be suspected when anagen/ telogen ratio is reduced and/or high percentages of miniaturized dystrophic hairs are present even in the absence of a peribulbar lymphocytic infiltrate. In the papillary dermis, miniaturized hairs surrounded by subtle lymphocytic infiltrate suggests AA [77]. In chronic TE terminal:vellus (T:V) ratio do not change (normal 7:1) but telogen count may increase (more than 6%). Hair shaft variation is not usual. Usually, inflammatory infiltration is not found. Fibrous tracts are rarely seen [83] [96]. In AGA, miniaturization of hairs is present. But lymphoid infiltration at the level of infundibulum and pigment incontinence within fibrous tracts are absent [7]. Anagen effluvium which is seen following administration of cancer chemotherapeutic agents, may mimic diffuse AA with diffuse shedding of dystrophic hairs [92]. Alopecia neoplastica, mostly associated with breast cancer, may resemble AA [97]. Systemic lupus erythematosus and syphilis may also rarely mimic AA so antinuclear antibody or syphilis serology can be performed on the basis of clinical suspicion [3]. Related Diseases AA is related with several diseases, most of which are autoimmune or related with atopy [98]. Thyroid disorders, vitiligo and atopy are found to be the main associated diseases with AA patients [99]. An increased incidence of diabetes mellitus [100], systemic lupus erythematosus [101], and celiac disease [102] may also occur in patients with AA. Some reports have shown an incidence of 8% 28% of AA patients with thyroid disease [103]. Children with AA also have an increased family history of autoimmunity, especially thyroid disease 21

21 [104]. Moreover, AA is more frequent in patients with Down s syndrome and sickle cell anemia [74]. Prognosis The course of the disease is unpredictable but generally AA takes a chronic but mild course with episodic patches. One usually experience several episodes of hair loss and hair regrowth during lifetime [7,105]. In up to 50% of patients with patchy AA, hair will regrow entirely with- in 1 year spontaneously. Severe chronic form of the condition is developed in 7% to 10% of affected individuals. The frequency of full recovery is less than 10% among alopecia totalis and universalis [74]. Well known poor prognostic signs are atopy, the presence of other immune diseases, family history of AA, young age at onset, nail dystrophy, extensive hair loss, and ophiasis [106]. Histologic findings of scarring, indicates a poor response to therapy [107]. While the best indication for prognosis is the extent of the disase at onset, childhood onset AA and ophiasis promises a less favorable prognosis [3]. Conclusion Alopecia areata is a chronic dermatological disorder in which a considerable amount of people are suffering from it. Details of hair follicule immunity and autoantigens of hair follicle are still waiting to be elucidated, thus more genetic and preclinical studies are needed to increase our understanding of the immunopathogenesis of alopecia areata. References 1. Gupta MA, Gupta AK. Depression and suicidal ideation in dermatology patients with acne, alopecia areata, atopic dermatitis and psoriasis. Br J Dermatol. 1998; 139: McDonagh AJ, Messenger AG. Alopecia areata. Clin Dermatol. 2001: 19:

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