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Review Article

Alopecia Areata: Pathophysiology, Diagnosis, and Treatment
Falto-Aizpurua, Leyre A.1, Cosme-Blanco Wilfredo2, Wikramanayake, Tongyu Cao1, Gina M. DelCanto3, Jimenez Joaquin J.,*1,3
1Department of Dermatology and Cutaneous Surgery, University of Miami Miller School of Medicine, 1600 NW 10th Avenue, Rosenstiel Medical Science Building, Miami, FL 33136, USA
2Department of Medical Education, Miami Children’s Hospital, 3100 SW 62nd Ave, Miami, FL 33155, USA
3Department of Biochemistry and Molecular Biology, University of Miami Miller School of Medicine, 1011 NW 15th St, Miami, FL 33136, USA

*Corresponding author: Dr. Jimenez Joaquin, University of Miami Miller School of Medicine, 1600 NW 10th Avenue, RMSB, Room 2023A, FL 33136, USA, Tel : 305-243-6586; E-mail : j.jimenez@med.miami.edu

Submitted: 03-30-2015  Accepted: 05-05-2015 Published: 06-16-2015

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Article

 
Abstract

Alopecia areata is a type of non-scarring hair loss resulting from an autoimmune response towards the hair follicle, with genetic and environmental factors playing significant roles. It has a chronic, relapsing course and is a frequent complaint encountered in the dermatologic practice. However, the treatment options currently available have variable efficacy, and none are curative. In order to provide better treatment options, extensive research on the disease pathophysiology is being performed. In this comprehensive review article, we discuss the disease clinical presentation, pathophysiology, relevant animal models and current and potential treatment options for further investigation.

Keywords: Abatacept; Alopecia Areata; Jak Inhibitors; Methotrexate; Phenol; Platelet Rich Plasma; Quercetin, Stat; Statins

Abbreviations:

AA : Alopecia Areata;
FDA : Food and Drug Administration;
IL : Interlekin;
JAK : Janus Kinase;
MHC I : Major Histocompatibility Complex Class I;
PRP : Platelet Rich Plasma;
PTH : Parathyroid Hormone;
PUVA : Psoralen Ultraviolet A;
TNF : Tumor Necrosis Factor

Introduction

Alopecia areata (AA) is a non-cicatricial alopecia resulting from autoimmune attack of the hair follicle. Both genetic and environmental factors contribute to the disease etiology and severity. Disease prevalence ranges from 0.1-0.2% in the United States, with the ratio of male to female susceptibility ranging from 2.6:1 to 1:1.9 according to different reports [1- 3]. It is common for the disease to present between the second and fourth decades [2]. However, males typically have a childhood disease onset, while females more frequently have an adolescent disease onset [3].

Clinical features

The typical presentation of AA is round, smooth patches of hair loss, with “exclamation point” hairs frequently observed in the periphery of the patches. AA can present as alopecia totalis (loss of all scalp hair), alopecia universalis (loss of all hair), or alopecia in an ophiasis pattern (hair loss in a bandlike pattern in the temporal and occipital scalp). Uncommon variants of AA include the reticular variant, which is characterized by recurrent patchy disease with hair loss in one area and spontaneous hair growth in another, and the diffuse variant, in which there is extensive thinning or thinning only affecting the top of the head [1]. Premature hair whitening is rare and may be associated with AA as well as somatic or psychological factors [4]. A recently described variant is acute diffuse and total alopecia (ADTA), which has rapid disease progression but carries a favorable prognosis [2].

Disease prognosis depends on several factors, including the subtype of AA, disease involvement, family history, and age of onset. Greater disease extent, long duration of disease, positive family history, and young age of onset can be associated with poorer prognosis [5]. Initial hair regrowth is hypopigmented, with normal hair color returning with time [2]. The nails can be involved in up to 66% of AA patients, presenting as nail pitting, trachyonychia, onycholysis, brittle nails, koilonychia, and onychomadesis [1,6]. Commonly associated diseases include thyroid disorders, vitiligo, and atopy [7,8].

Differential diagnosis

The differential diagnosis for AA includes tinea capitis, trichotillomania, temporal triangular alopecia, traction alopecia, secondary syphilis, loose anagen syndrome, pressure related alopecia, aplasia cutis, and “burnt-out” cicatricial alopecia [1,9,10]. A greater degree of inflammation and scale is usually observed in tinea capitis. Trichotillomania may present as irregular or oddly shaped patches of hair loss, with broken hairs of different lengths.

Diagnosis

A clinical diagnosis is usually sufficient. The use of trichoscopy (dermoscopy and videotrichograma) may aid in making a diagnosis [9,11]. Exclamation hairs are a classic feature of AA [2,9]. The presence of yellow dots may be a useful indicator, but these can also be seen in androgenetic alopecia [2]. A scalp biopsy should be performed to confirm doubtful presentations.

Pathology

Histopathologic examination will vary according to disease stage [2]. The presence of an increased amount of eosinophils in lesional skin at any stage is debatable [2,12]. In acute stages, there is a peribulbar lymphocytic infiltrate – likened to a “swarm of bees”—around anagen follicles [12]. This infiltrate is composed mainly of CD4+ and CD8+ cells, with the CD4/CD8 ratio being higher in active disease [2]. Affected hair follicles will have surrounding edema, microvesiculation, apoptosis, macrophages and foreign body giant cells. Lymphocytes may also infiltrate the hair matrix and root sheaths. Pigment incontinence, vacuolar damage, and keratinocyte necrosis might be observed. An uncommon but characteristic finding of is the presence of focal matrix cell vacuolization [13]. In the catagen phase, the hair shaft is weakened, causing breakage at the level of the skin surface [2]. When such hair goes into the telogen phase, the frayed thicker hair tip protrudes, resulting in what is observed as an “exclamation mark” hair. Hair shaft narrowing or pencil point hair is a sign of active disease. Residual inflammation surrounding hair follicles might be observed.

In chronic AA, anagen follicles are miniaturized and are at a deeper location than vellus follicles [2]. An intermediate stage between terminal and vellus hairs is characteristic of this phase. An inflammatory infiltrate around hair follicles and papillary dermis might be observed as well as fibrous tracts along the site of previous terminal follicles extending to the subcutis. In the recovery stage, the terminal/vellus ratio is normal, anagen hairs increase, and there is minimal to no inflammation [2] .When compared to a healthy scalp, the number of follicles may be decreased [13].

Pathophysiology

Disease etiology remains unknown, and different theories are debated [14]. However, current evidence suggests AA is an autoimmune reaction towards the hair follicle in which both genetic and environmental factors play an important role in disease development and prognosis.

Genetic factors

There is a strong genetic component in AA development [15]. This is supported by the observation that many patients with AA have a family history of AA [7,8]. Furthermore, both patients and their family members may also have other, associated autoimmune diseases [7,8]. The presence of family history is associated with a poor prognosis, rapid progression of disease, and a more chronic course. A case-control genome wide association study (GWAS) identified numerous single nucleotide polymorphisms (SNP) associated with the disease, implicating genes of both innate and adaptive im
munity [16]. Specifically, the genes involved include those which control proliferation and activation of T regulatory (Treg) cells and HLA regions. Association was also found for regions of certain genes expressed in the hair follicle, the products of which may serve as autoantigens.

Environmental factors

Stress has also been implicated in the development of AA [17]. A case control study evaluated the effect of several psychological factors in AA as well as its effect on the quality of life of patients [18]. From this, it was concluded that major life events, anxiety, and depression disorders are implicated in disease manifestation. Patients with AA reported a greater number of stressful life events than control patients. Furthermore, in a model of C3H/HeJ mice with induced AA, an altered stress response was observed in the central hypothalamic- pituitary-adrenal (HPA) axis of affected mice and linked to cytokine levels in the skin [19]. However, from this study alone, the role of stress in the onset of AA could not be determined. Viral agents, such as Epstein-Barr virus, have also been implicated in disease development [20].

Immune privilege zone

The inflammation observed in AA and other non-cicatricial alopecias does not permanently affect the bulge area of hair follicles [21,22]. It is hypothesized that this area (i.e., the central and proximal hair follicle) is a zone of immune privilege maintained by down-regulation of MHC I and β2- microglobulin molecules, the presence of immunosuppressant molecules such as TGFβ and α-MSH, and diminished antigen-presenting cell activity [23,24]. In AA, however, asof- yet unidentified autoantigens drive the collapse of this zone by augmenting MHC I expression. IFN-γ, substance P, and IL-2 drive infiltration of auto-reactive CD8+ cells, NKG2D+ cells and other inflammatory cells and cytokines into this zone. Interaction between mast cells and CD8+ cells also seems to be increased and abnormal in AA [17,25].This results in significant inflammation towards the hair follicle, affecting the stem cells and the hair cycle.

An altered Th1/Th2 balance has been observed in AA, with an up-regulated Th1 response (IL-2, IL-12, and IFN-γ)[26]. IL-17A has also been demonstrated to be significantly increased in AA [27]. Uncontrolled proliferation of these cells and therefore continuous expression of inflammatory cytokines can lead to autoimmune disorders and chronic inflammation.

Treatment

Spontaneous resolution of AA within one year has been observed in up to 50% of patients [2]. Current treatments aim to control the disease, as there is no cure at present. Their efficacy is mostly based on experience rather than on randomized, sham- controlled trials [28,29]. The treatment of choice depends on disease extent and severity [29]. Individual drug treatments can be used alone or in combination to achieve maximal efficacy. Corticosteroids can be used in topical, intralesional, or systemic forms [1,30-33]. Minoxidil can be used as adjunctive therapy. Patients with extensive disease can be treated with systemic steroids, but relapses are common upon cessation of therapy [32]. Topical immunomodulators are an alternative for patients with generalized disease [29,33,34]. The 308nm excimer laser has been reported to be an efficient treatment for limited patchy AA, and clinical trials are ongoing [35,36]. Other, less efficient methods with serious adverse effects include psoralen with UVA light (PUVA) and systemic immunomodulators [1]. Therefore, their use is only recommended with unresponsive or extensive disease. Antidepressants treatments have been described to show some improvement but not total regrowth of hair [29].

Numerous clinical trials are being performed to test available treatment options for AA, such as the Excimer laser and PUVA. Other trials are testing drugs with AA as a new potential indication, such as abatacept and ruxolitinib, which seem to work by more specifically modulating the immune response towards the hair follicle. Table 1 summarizes some of the ongoing clinical trials for AA.

Investigational treatments

A significant amount of research has been done to better understand the pathophysiology behind AA. Cellular interactions,variation in cellular markers, and the effects of proinflammatory products on the hair follicle are being studied in detail. Various animal models have been established to investigate pathobiology, providing useful tools for drug development and testing. The most commonly used model to study AA is the C3H/HeJ mouse strain, which spontaneously develops the disease. Animal models for AA have been described and are summarized in Table 2 [37-43]. Overall, these models have been useful to investigate and better understand the complex mechanisms involved in this predominantly CD8+ T cell dependent disease, to identify the immune privilege zone of the hair follicle and its collapse in AA, and to assess in vivo responses to different therapies.

Interleukin-2

Treg cells are impaired in AA and other autoimmune diseases [44,45]. Low doses of IL-2 can induce their proliferation, diminishing the immune response towards the hair follicle [46]. A pilot study demonstrated that low dose IL-2 improved AA universalis after 6 months of treatment with minimal adverse effects [44]. Lesional biopsies demonstrated an increase in Treg cells and a decrease in the CD8+ infiltrate. Alternatively, the use of topical diphenycyclopropene can also increase the levels of IL-2 and should be further studied [45]. However, caution is advised as high doses of IL-2 may induce T cell proliferation and NK cell activity precipitating or exacerbating AA [45].

Interleukin 17

Th17 cells, activated by IL-17, have been implicated in AA pathogenesis [47,48]. Additionally, a case-control
 
Table 1: Ongoing clinical trials related to alopecia areata
biomarkers table 5.1
 
Table 2: Research models used in alopecia areata
 
biomarkers table 5.2
 
association study found that IL17R SNPs were associated with either AA development or AA onset [49]. Activation of the IL-17R, which is expressed by all immune cells, leads to the expression of inflammatory cytokines including IL-β, TNF and IL-6 [49]. Therefore, by diminishing the Th17 cell population or inhibiting the effects of IL-17, AA outcome may be improved. This notion was supported by the observation that ADTA, which responds better to treatment and has a better prognosis, showed lower concentration of IL-17 cells [48].

Abatacept

Defects in T cell activation resulting from dysregulation of the CTL4 gene have been implicated in the development of AA [50,51].This gene codes for a co-stimulatory ligand expressed on activated T cells that binds CD80 and CD86 on antigen presenting cells and is required for T cell activation. The immunosuppressive drug abatacept can block this activation signal by selectively binding to CD80 and CD86 on antigen-presenting cells.[52] Therefore, abatacept also decreases the production of inflammatory cytokines. However, because of its immunosuppressive effects, this drug has been associated with an increased risk of infections [50].

JAK inhibitors

It has been demonstrated that IL-15 levels are increased in AA and that blocking its signaling through the JAK/STAT pathway can reduce the inflammation observed in AA. Il-15 promotes the survival of CD8+ T lymphocytes, including selfreactive memory cells, facilitates production of certain immunoglobulins and contributes to NK cell survival [53]. The main signaling pathway of IL-15 and IL-2 involves JAK1/3 and STAT3/5, whereas IFNγ signaling activates JAK1/2 and, consequently, STAT1[53-54]. By blocking the pathways induced by these cytokines, the subsequent inflammatory effects can be reduced, [53] as direct blockage of IL-15R alone could prevent but not reverse AA in mice [54]. Tofacitinib is an FDA-approved JAK3 inhibitor for the treatment of rheumatoid arthritis. It has been observed to inhibit damage to dermal sheath cells induced by IL-15 [54]. In fact, a patient with AA universalis was reported to have complete hair growth after 8 months of treatment with tofacitinib [55].

Ruxolitinib is an FDA-approved JAK 1/2 inhibitor for the treatment of myelofibrosis. This drug was able to inhibit the effects of IFN-γ-induced IL-15 expression and STAT1 activation in dermal sheath cells [54]. Systemic administration of either JAK inhibitor in mice was able to prevent and reverse AA. Topical application also served to reverse AA [54]. Furthermore, near complete hair growth was observed in patients with moderate to severe AA treated for 3-5 months [54].

Despite the encouraging results obtained with JAK inhibitors, these drugs should be used with caution until further research is conducted, given their potential adverse effects and unknown effects on other systems [56]. For example, recent long-term studies with tofacitinib indicated a reversible, dose-dependent increase in serum creatinine [57]. This increase seems to be directly induced by tofacitinib, though the underlying mechanism remains unknown.

Platelet rich plasma (PRP)

PRP consists of a concentrate of growth factors and other bioactive compounds obtained from platelets that may have anti-inflammatory effects in AA. However, treating AA with PRP has shown inconsistent results. In one study, significant hair growth was observed in mice after PRP injections [58]. The authors demonstrated that PRP administration resulted in an increase of β-catenin (inducing anagen), FGF-7 (prolonging the anagen phase), and Bcl-2 (having an anti-apoptotic effect) in treated dermal papilla cells [58]. In another study, the authors demonstrated formation of new hair follicles and accelerated hair formation in grafts performed in nude mice treated with PRP [59] In a randomized trial, PRP significantly increased hair growth in patients with chronic AA compared to triamcinolone [60]. However, another study performed in patients with severe, chronic AA showed a variable response to PRP, and it failed to prevent disease involvement of new affected sites [61]. The authors hypothesized that a positive response might be mediated by TGF-β immunosuppressive actions [61]. Further studies are needed to investigate the efficacy of PRP for treating AA.

Statins

Statins have been found to have immunosuppressive properties, making them potentially useful in the treatment of AA [62]. They are able to alter the Th1/Th2 balance, interfere with the antigen presentation process, suppress IL-17 effects, inhibit mast cell degranulation, and inhibit lymphocyte migration [62]. Statins can inhibit STAT phosphorylation, which normally activates the transcription of several inflammatory cytokines [63-66]. Atorvastatin, for example, can also decrease the expression of MHC II. This leads to a reduction in antigen presentation and therefore reduced T cell activation and disruption of the immune privilege zone [62,67-69].

A case of AA universalis was reported to have hair regrowth 2 months after treatment with simvastatin and ezetimibe [70]. The authors hypothesized that statins shifted the Th1/ Th2 balance in favor of Th2, limiting the production of IFN-γ. However, casualty could not be proven. Later, another two cases of AA totalis reported improvement after receiving the same treatment [71]. It is known that the combination of simvastatin and ezetimibe significantly decreases CRP levels [72]. We have observed prevention of HSP-induced AA development by simvastatin in mice (unpublished data). The untreated group had overall increased numbers of T cells, with CD4+ and CD8+ cells significantly increased.
 
Phenol

Contact irritants have been successfully used to “deviate” the immune attack typically directed against hair follicles in AA—specifically, phenol has been shown to have some efficacy as a contact irritant in AA [73]. A prospective study was performed using 88% phenol topically on AA patches [74]. After 9 weeks of treatment, the texture and pigmentation of hair significantly improved with 78% of patients showing a good to excellent response. Temporary hypopigmentation was noted in 10% of patients.

Quercetin

Quercetin is a bioflavonoid with anti-inflammatory properties that may be helpful in preventing and treating AA. Quercetin inhibits HSP70 and nuclear factor kappa B (NF-kB) [75].When extracellular, HSP70 can induce the production of inflammatory cytokines by means of NF-kB. Mice with AA showed hair regrowth after 8 days of subcutaneous quercetin treatment [75].It was also demonstrated that quercetin was able to prevent AA onset in heat-induced AA. Systemic administration of quercetin prevented and reduced AA onset in treated mice [75].

Valproic acid

It has been observed that valproic acid promotes hair growth in mice through increasing expression of β-catenin [76]. Activation of the Wnt/β-catenin pathway induces the hair follicles to enter anagen. The authors further described the effects of valproic acid on human hair follicles in vitro [77]. Up to date, its effectiveness has only been tested in androgenetic alopecia [78].

Tianeptine

Tianeptine is an anxiolytic and antidepressant (not available in the United States) that was proven to be effective in treating mice with AA-like lesions induced by ultrasonic wave stress [79]. Following treatment, increases in vitamin D receptor expression, hair cycle recovery, and synthesis of collagen and elastic fibers were observed along with mast cell degranulation and apoptosis around the hair follicle. However, tianeptine treatment was not more efficient than already-approved medications for the treatment of hair loss.

Parathyroid hormone (PTH)

The effects of PTH on the hair cycle have been studied with variable results [80]. PTH activates the Wnt signaling pathway in keratinocytes, increasing nuclear β-catenin, which in turn promotes the hair follicles to enter anagen [81]. A group of authors observed hair growth after the first day of treatment with PTH that lasted for 1-2 weeks [81]. Histological examination showed an increase in anagen follicles despite ongoing inflammatory response.

Vitamin D

Vitamin D deficiency has been implicated in autoimmune disorders because of its effects on lymphocytes [82]. It was demonstrated that AA correlated with vitamin D deficiency [82,83]. and its levels negatively correlated with disease severity [83]. Seasonal variations in AA have also been observed; those with chronic or frequently relapsing AA had reduced vitamin D levels, although these reductions were not statistically significant [84].

It was demonstrated that an adequate hair cycle generation required functional vitamin D receptors in keratinocytes, regardless  of vitamin D levels [85]. A different study observed that a decreased expression of vitamin D receptors was associated with suppression of the wnt/β-catenin pathway and consequently suppression of proliferation and differentiation of hair follicles [86]. Overall, these data showed that correcting vitamin D levels in patients with AA might result in a positive outcome.

Vitamin A

Deficiency or excess of vitamin A can result in alopecia by different mechanisms. Vitamin A can promote strong immune responses and therefore affect AA [87-89]. Duncan et al. demonstrated an increased expression of genes involved in the metabolism of retinoids in AA [88]. Therefore, modulation of retinoid metabolism and its role in AA should be further studied.

Microneedling

The use of microneedling has been applied to improve acne scars, facial rejuvenation, and hair growth [90]. It has been hypothesized that this technique stimulates hair growth by stimulating the dermal papillae and stem cells, improving blood flow to hair follicles, and recruiting growth factors induced by the microinjury [91]. In a study of two patients with refractory AA, the combination of microneedling and triamcinolone acetonide led to excellent results with no recurrence at 3 months and no adverse effects, in both patients [91]. In another study, refractory AA was treated with a scalp roller and application of a mixture of triamcinolone acetonide, minoxidil, and a solution rich in growth factors and amino acids [92]. All showed notable improvement, with patchy AA showing the most improvement, followed by AA universalis and AA in ophiasis pattern.

Low-level Laser Therapy (LLLT)

The use of low-level laser therapy in hair loss has been studied mostly in androgenetic alopecia with positive results [93-95]. The LaserComb® device, for example, is cleared by the FDA for the treatment of androgenetic alopecia in men and women. When the LaserComb was used to treat heat-induced AA in C3H/HeJ mice, hair regrowth and an increased number of hair follicles in anagen phase on histology were observed in comparison to controls [96]. However, these results were not reproduced in mice with spontaneous or graft-induced AA [97]. This could be due to the differences of the animal models used (the later has persistent, extensive AA) or the locations of treatment (dorsal versus ventral) [97].
 
Electroacupuncture

It has been reported that acupuncture can improve hair loss and decrease the medication dose used in AA patients [98]. Electroacupuncture to the ST36 Zusanli point has been demonstrated to significantly reduce mast cell degranulation around the hair follicle in mice with AA, improving hair loss [99]. The mechanism of action remains unknown.

Conclusion

AA is a common disease entity with multifactorial and complex etiology that can be very frustrating for patients and their physicians. Here we have summarized recent literature in an attempt to better elucidate the pathophysiology of the disease. Additionally, we discussed current treatment options under investigation that could more specifically target AA, including those undergoing clinical trials. However, many of these drugs are systemic and have potential adverse effects. Therefore, further research is needed to improve local targeting of the disease and develop drug delivery systems in order to treat patients more effectively.

Acknowledgements

We would like to thank the Locks of Love Foundation for their generous support and Ms. Lucia M. Mauro for her extensive research in alopecia.
 
 
 

References

 References

1.Sperling L, Sinclair R, El Shabrawi-Caelen L. Alopecias. In: JL B, JL J, JV S, eds. Dermatology. Vol 1. 3 ed. United States: Elsevier; 2012:1093-1114.

2.Alkhalifah A, Alsantali A, Wang E, McElwee KJ, Shapiro J. Alopecia areata update: part I. Clinical picture, histopathology, and pathogenesis. J Am Acad Dermatol. 2010, 62(2): 177-188.

3.http://www.ncbi.nlm.nih.gov/pubmed/24719059

4.Nahm M, Navarini AA, Kelly EW. Canities subita: a reappraisal of evidence based on 196 case reports published in the medical literature. Int J Trichology. 2013,5(2): 63-68.

5.Madani S, Shapiro J. Alopecia areata update. J Am Acad Dermatol. 2000, 42(4): 549-566.

6.Gandhi V, Baruah MC, Bhattacharaya SN. Nail changes in alopecia areata: incidence and pattern. Indian journal of dermatology, venereology and leprology. Indian J Dermatol Venereol Leprol. 2003, 69(2):114-115.

7.Hordinsky M, Ericson M. Autoimmunity: alopecia areata. The journal of investigative dermatology. Symposium proceedings. The Society for Investigative Dermatology, Inc. [and] European Society for Dermatological Research. 2004, 9(1): 73-78.

8.http://www.ncbi.nlm.nih.gov/pubmed/16259629

9.Mubki T, Rudnicka L, Olszewska M, Shapiro J. Evaluation and diagnosis of the hair loss patient: Part II. Trichoscopic and laboratory evaluations. J Am Acad Dermatol. 2014, 71(3): 431. e1-431 e411.

10.Mubki T, Rudnicka L, Olszewska M, Shapiro J. Evaluation and diagnosis of the hair loss patient: Part I. History and clinical examination. J Am Acad Dermatol. 2014, 71(3): 415.e-415. e415.

11.Miteva M, Tosti A. Hair and scalp dermatoscopy. J Am Acad Dermatol. 2012, 67(5): 1040-1048.

12.Yoon TY, Lee DY, Kim YJ, Lee JY, Kim MK. Diagnostic Usefulness of a Peribulbar Eosinophilic Infiltrate in Alopecia Areata. JAMA dermatology. 2014, 150(9): 952-956.

13.Sperling L. Alopecia areata. In: LC S, ed. An atlas of hair pathology with clinical correlations. 1st ed. New York: Parthenon Publishing. 2003:109-138.

14.McElwee KJ, Gilhar A, Tobin DJ, Ramot Y, Sundberg JP et al. What causes alopecia areata? Experimental dermatology. 2013,22(9): 609-626.

15.Gilhar A, Etzioni A, Paus R. Alopecia areata. The New England journal of medicine. 2012, 366(16): 1515-1525.

16.Petukhova L, Duvic M, Hordinsky M, Norris D, Price V et al. Genome-wide association study in alopecia areata implicates both innate and adaptive immunity. Nature. 2010, 466(7302): 113-117.

17.Paus R, Arck P. Neuroendocrine perspectives in alopecia areata: does stress play a role? J Invest Dermatol. 2009, 129(6):1324-13266.

18.Gulec AT, Tanriverdi N, Duru C, Saray Y, Akcali C. The role of psychological factors in alopecia areata and the impact of the disease on the quality of life. International journal of dermatology. 2004, 43(5): 352-356.

19.Zhang X, Yu M, Yu W, Weinberg J, Shapiro J et al. Development of alopecia areata is associated with higher central and peripheral hypothalamic-pituitary-adrenal tone in the skin graft induced C3H/HeJ mouse model. J Invest Dermatol. 2009,129(6): 1527-1538.

20.Pender MP. CD8+ T-Cell Deficiency, Epstein-Barr Virus Infection, Vitamin D Deficiency, and Steps to Autoimmunity: A Unifying Hypothesis. Autoimmune Dis. 2012, 2012: 189096.

21.Mobini N, Tam S, Kamino H. Possible role of the bulge region in the pathogenesis of inflammatory scarring alopecia: lichen planopilaris as the prototype. Journal of cutaneous pathology. 2005,32(10): 675-679.

22.Whiting DA. Histopathologic features of alopecia areata: a new look. Archives of dermatology. 2003, 139(12): 1555-1559.

23.Paus R, Bertolini M. The role of hair follicle immune privilege collapse in alopecia areata: status and perspectives. The journal of investigative dermatology. Symposium proceedings / the Society for Investigative Dermatology, Inc. [and] European Society for Dermatological Research. 2013, 16(1):S25-S27.

24.Bertolini M, Gilhar A, Paus R. Alopecia areata as a model for T cell-dependent autoimmune diseases. Experimental dermatology. 2012, 21(6): 477-479.

25.Bertolini M, Zilio F, Rossi A, Kleditzch P, Emelianov VE et al. Abnormal interactions between perifollicular mast cells and CD8+ T-cells may contribute to the pathogenesis of alopecia areata. PloS one. 2014,9(5): e94260.

26.Ito T, Tokura Y. The role of cytokines and chemokines in the T cell-mediated autoimmune process in alopecia areata. Experimental dermatology. 2014, 23(11): 787-791.

27.Tembhre MK, Sharma VK. T-helper and regulatory T-cell cytokines in the peripheral blood of patients with active alopecia areata. The British journal of dermatology. 2013, 169(3):543-548.

28.Delamere FM, Sladden MM, Dobbins HM, Leonardi- Bee J. Interventions for alopecia areata. Cochrane Database Syst Rev. 2008,16 (2): CD004413.

29.Hordinsky M, Donati A. Alopecia areata: an evidence- based treatment update. American journal of clinical dermatology. 2014,15(3): 231-246.

30.Tosti A, Iorizzo M, Botta GL, Milani M. Efficacy and safety of a new clobetasol propionate 0.05% foam in alopecia areata: a randomized, double-blind placebo-controlled trial. J Eur Acad Dermatol Venereol. 2006, 20(10):1243-1247.

31.Sardesai VR, Prasad S, Agarwal TD. A study to evaluate the efficacy of various topical treatment modalities for alopecia areata. International journal of trichology. 2012, 4(4): 265-270.

32.Kar BR, Handa S, Dogra S, Kumar B. Placebo-controlled oral pulse prednisolone therapy in alopecia areata. Journal of the American Academy of Dermatology. 2005, 52(2): 287-290.

33.Alkhalifah A, Alsantali A, Wang E, McElwee KJ, Shapiro J. Alopecia areata update: part II. Treatment. Journal of the American Academy of Dermatology. 2010, 62(2): 191- 202.

34.Tosti A, Bardazzi F, Guerra L. Alopecia totalis: is treating nonresponder patients useful? Journal of the American Academy of Dermatology. 1991, 24(3): 455-456.

35.Zakaria W, Passeron T, Ostovari N, Lacour JP, Ortonne JP. 308-nm excimer laser therapy in alopecia areata. Journal of the American Academy of Dermatology. 2004, 51(5): 837-838.

36.Al-Mutairi N. 308-nm excimer laser for the treatment of alopecia areata. Dermatol Surg. 2007, 33(12):1483- 1487.

37.Sun J, Silva KA, McElwee KJ, King LE, Jr., Sundberg JP. The C3H/HeJ mouse and DEBR rat models for alopecia areata: review of preclinical drug screening approaches and results. Experimental dermatology. 2008, 17(10): 793-805.

38.Silva KA, Sundberg JP. Surgical methods for fullthickness skin grafts to induce alopecia areata in C3H/HeJ mice. Comparative medicine. 2013,63(5): 392-397.

39.Wikramanayake TC, Alvarez-Connelly E, Simon J, Mauro LM, Guzman J et al. Heat treatment increases the incidence of alopecia areata in the C3H/HeJ mouse model. Cell stress & chaperones. 2010,15(6): 985-991.

40.Alli R, Nguyen P, Boyd K, Sundberg JP, Geiger TL. A mouse model of clonal CD8+ T lymphocyte-mediated alopecia areata progressing to alopecia universalis. Journal of immunology (Baltimore, Md. : 1950). 2012, 188(1): 477-486.

41.Gu ME, Song XM, Zhu CF, Yin HP, Liu GJ et al. Breeding and preliminarily phenotyping of a congenic mouse model with alopecia areata. Dong wu xue yan jiu = Zoological research / “Dong wu xue yan jiu” bian ji wei yuan hui bian ji. 2014, 35(4): 249-255.

42.Sundberg JP, Berndt A, Silva KA, Kennedy VE, Sundberg BA et al. Alopecia areata: updates from the mouse perspective. The journal of investigative dermatology. Symposium proceedings / the Society for Investigative Dermatology, Inc. [and] European Society for Dermatological Research. 2013,16(1): S23-S24.

43.Gilhar A, Keren A, Paus R. A new humanized mouse model for alopecia areata. The journal of investigative dermatology. Symposium proceedings / the Society for Investigative Dermatology, Inc. [and] European Society for Dermatological Research. 2013,16(1): S37-S38.

44.Castela E, Le Duff F, Butori C, Ticchioni M, Hofman P et al. Effects of low-dose recombinant interleukin 2 to promote T-regulatory cells in alopecia areata. JAMA dermatology. 2014, 150(7): 748-751.

45.Hordinsky M, Kaplan DH. Low-dose interleukin 2 to reverse alopecia areata. JAMA dermatology. 2014,150(7): 696-697.

46.Zorn E, Nelson EA, Mohseni M, Porcheray F, Kim H et al. IL-2 regulates FOXP3 expression in human CD4+CD25+ regulatory T cells through a STAT-dependent mechanism and induces the expansion of these cells in vivo. Blood. 2006,108(5): 1571-1579.

47.Tanemura A, Oiso N, Nakano M, Itoi S, Kawada A et al . Alopecia areata: infiltration of Th17 cells in the dermis, particularly around hair follicles. Dermatology. 2013, 226(4): 333-336.

48.Tojo G, Fujimura T, Kawano M, Ogasawara K, Kambayashi Y et al. Comparison of interleukin-17- producing cells in different clinical types of alopecia areata. Dermatology. 2013,227(1): 78-82.

49.Lew BL, Cho HR, Haw S, Kim HJ, Chung JH et al. Association between IL17A/IL17RA Gene Polymorphisms and Susceptibility to Alopecia Areata in the Korean Population. Annals of dermatology. 2012, 24(1): 61-65.

50.Sundberg JP, McElwee KJ, Carroll JM, King LE, Jr. Hypothesis testing: CTLA4 co-stimulatory pathways critical in the pathogenesis of human and mouse alopecia areata. The Journal of investigative dermatology. 2011, 131(11): 2323- 2324.

51.John KKG, Brockschmidt FF, Redler S, Christine H, Hanneken S et al. Genetic variants in CTLA4 are strongly associated with alopecia areata. The Journal of investigative dermatology. 2011, 131(5): 1169-1172.

52.Moreland L, Bate G, Kirkpatrick P. Abatacept. Nature reviews. Drug discovery. 2006, 5(3): 185-186.

53.Waldmann TA. The biology of IL-15: implications for cancer therapy and the treatment of autoimmune disorders. The journal of investigative dermatology. Symposium proceedings / the Society for Investigative Dermatology, Inc. [and] European Society for Dermatological Research. 2013;16(1): S28-S30.

54.Xing L, Dai Z, Jabbari A, Cerise JE, Higgins CA et al. Alopecia areata is driven by cytotoxic T lymphocytes and is reversed by JAK inhibition. Nature medicine. 2014, 20: 1043-1049.

55.Craiglow BG, King BA. Killing Two Birds with One Stone: Oral Tofacitinib Reverses Alopecia Universalis in a Patient with Plaque Psoriasis. The Journal of investigative dermatology. 2014, 134: 2988-2990.

56.Belluck P. New Drug Helps Some Bald Patients Regrow Hair. New York Times. August 17, 2014, Health.

57.Isaacs JD, Zuckerman A, Krishnaswami S, Nduaka CH, Lan S et al. Changes in serum creatinine in patients with active rheumatoid arthritis treated with tofacitinib: results from clinical trials. Arthritis research & therapy. 2014, 16(4): R158.

58.Li ZJ, Choi HI, Choi DK, Sohn DK, Cheol K et al. Autologous platelet-rich plasma: a potential therapeutic tool for promoting hair growth. Dermatologic surgery : official publication for American Society for Dermatologic Surgery [et al.]. 2012, 38(7 Pt 1): 1040-1046.

59.Miao Y, Sun YB, Sun XJ, Du BJ, Jiang JD et al. Promotional effect of platelet-rich plasma on hair follicle reconstitution in vivo. Dermatologic surgery : official publication for American Society for Dermatologic Surgery [et al.]. 2013, 39(12): 1868-1876.

60.Trink A, Sorbellini E, Bezzola P, Rodella L, Rezzani R et al. A randomized, double-blind, placebo- and activecontrolled, half-head study to evaluate the effects of plateletrich plasma on alopecia areata. The British journal of dermatology. 2013, 169(3): 690-694.

61.d’Ovidio R, Roberto M. Limited Effectiveness of Platelet-Rich-Plasma Treatment on Chronic Severe Alopecia Areata. Hair Ther Transplant. 2014, 2014(4): 116.

62.Egesi A, Sun G, Khachemoune A, Rashid RM. Statins in skin: research and rediscovery, from psoriasis to sclerosis. Journal of drugs in dermatology : JDD. 2010, 9(8): 921-927.

63.Wurster AL, Tanaka T, Grusby MJ. The biology of Stat4 and Stat6. Oncogene. 2000, 19(21): 2577-2584.

64.Benveniste EN, Liu Y, McFarland BC, Qin H. Involvement of the janus kinase/signal transducer and activator of transcription signaling pathway in multiple sclerosis and the animal model of experimental autoimmune encephalomyelitis. Journal of interferon & cytokine research : the official journal of the International Society for Interferon and Cytokine Research. 2014, 34(8): 577-588.

65.Amadi-Obi A, Yu CR, Liu X, Mahdi RM, Clarke GL et al. TH17 cells contribute to uveitis and scleritis and are expanded by IL-2 and inhibited by IL-27/STAT1. Nature medicine. 2007, 13(6):711-718.

66.Tajiri K, Shimojo N, Sakai S, Machino Ohtsuka T, Imanaka Yoshida K et al. Pitavastatin regulates helper T-cell differentiation and ameliorates autoimmune myocarditis in mice. Cardiovascular drugs and therapy / sponsored by the International Society of Cardiovascular Pharmacotherapy. 2013, 27(5): 413-424.

67.Lawman S, Mauri C, Jury EC, Cook HT, Ehrenstein MR. Atorvastatin inhibits autoreactive B cell activation and delays lupus development in New Zealand black/white F1 mice. Journal of immunology (Baltimore, Md. : 1950). 2004, 173(12): 7641-7646.

68.Nickoloff BJ, Griffiths CE. Aberrant intercellular adhesion molecule-1 (ICAM-1) expression by hair-follicle epithelial cells and endothelial leukocyte adhesion molecule-1 (ELAM-1) by vascular cells are important adhesion-molecule alterations in alopecia areata. The Journal of investigative dermatology. 1991, 96(5): 91S-92S.

69.Weitz-Schmidt G, Welzenbach K, Brinkmann V, Kamata T, Kallen J et al. Statins selectively inhibit leukocyte function antigen-1 by binding to a novel regulatory integrin site. Nature medicine. 2001, 7(6): 687-692.

70.Robins DN. Case reports: alopecia universalis: hair growth following initiation of simvastatin and ezetimibe therapy. Journal of drugs in dermatology : JDD. 2007, 6(9): 946-947.

71.Ali A, Martin JMt. Hair growth in patients alopecia areata totalis after treatment with simvastatin and ezetimibe. Journal of drugs in dermatology : JDD. 2010, 9(1): 62- 64.

72.Pearson TA, Denke MA, McBride PE, Battisti WP, Brady WE et al . A community-based, randomized trial of ezetimibe added to statin therapy to attain NCEP ATP III goals for LDL cholesterol in hypercholesterolemic patients: the ezetimibe add-on to statin for effectiveness (EASE) trial. Mayo Clinic proceedings. 2005, 80(5): 587-595.

73.Savant SS, Shenoy S. Chemical peeling with phenol : For the treatment of stable vitiligo and alopecia areata. Indian journal of dermatology, venereology and leprology. 1999, 65(2): 93-98.

74.Chikhalkar S, Jerajani H, Madke B. Evaluation of utility of phenol in alopecia areata. International journal of trichology. 2013, 5(4): 179-184.

75.Wikramanayake TC, Villasante AC, Mauro LM, Perez CI, Schachner LA et al. Prevention and treatment of alopecia areata with quercetin in the C3H/HeJ mouse model. Cell stress & chaperones. 2012, 17(2): 267-274.

76.Lee SH, Yoon J, Shin SH, Zahoor M, Kim HJ et al. Valproic acid induces hair regeneration in murine model and activates alkaline phosphatase activity in human dermal papilla cells. PloS one. 2012, 7(4): e34152.

77.Jo SJ, Choi SJ, Yoon SY, Lee JY, Park PJ et al. Valproic acid promotes human hair growth in in vitro culture model. Journal of dermatological science. 2013, 72(1): 16-24.

78.Jo SJ, Shin H, Park YW, Paik SH , Park WS et al. Topical valproic acid increases the hair count in male patients with androgenetic alopecia: a randomized, comparative, clinical feasibility study using phototrichogram analysis. The Journal of dermatology. 2014, 41(4): 285-291.

79.Kim HM, Lim YY, Kim MY, Son IP, Kim DH et al. Inhibitory effect of tianeptine on catagen induction in alopecia areata-like lesions induced by ultrasonic wave stress in mice. Clinical and experimental dermatology. 2013, 38(7): 758-767.

80.Gensure RC. Parathyroid Hormone-Related Peptide and the Hair Cycle - is it the Agonists or the Antagonists that Cause Hair Growth? Experimental dermatology. 2014, 23(12): 865-867.

81.Katikaneni R, Gulati R, Suh D, Sakon J, Seymour A et al. Therapy for alopecia areata in mice using parathyroid hormone agonists and antagonists, linked to a collagenbinding domain. J Investig Dermatol Symp Proc. 2013, 16(1): S61-S62.

82.Mahamid M, Abu-Elhija O, Samamra M, Mahamid A, Nseir W et al . Association between vitamin D levels and alopecia areata. The Israel Medical Association journal : IMAJ. 2014, 16(6): 367-370.

83.Aksu Cerman A, Sarikaya Solak S, Kivanc Altunay I. Vitamin D deficiency in alopecia areata. The British journal of dermatology. 2014, 170(6):1299-1304.

84.d’Ovidio R, Vessio M, d’Ovidio FD. Reduced level of 25-hydroxyvitamin D in chronic/relapsing Alopecia Areata. Dermato-endocrinology. 2013, 5(2): 271-273.

85.Demay MB. Physiological insights from the vitamin D receptor knockout mouse. Calcified tissue international. 2013, 92(2): 99-105.

86.Lim YY, Kim SY, Kim HM, Li KS, Kim MN et al. Potential relationship between the canonical Wnt signalling pathway and expression of the vitamin D receptor in alopecia. Clinical and experimental dermatology. 2014, 39(3): 368- 375.

87.Holler PD, Cotsarelis G. Retinoids putting the “a” in alopecia. The Journal of investigative dermatology. 2013, 133(2): 285-286.

88.Duncan FJ, Silva KA, Johnson CJ, King BL, Szatkiewicz JP et al. Endogenous retinoids in the pathogenesis of alopecia areata. The Journal of investigative dermatology. 2013, 133(2): 334-343.

89.Everts HB. Endogenous retinoids in the hair follicle and sebaceous gland. Biochimica et biophysica acta. 2012, 1821(1): 222-229.

90.Dhurat R, Sukesh M, Avhad G, Dandale A, Pal A et al . A randomized evaluator blinded study of effect of microneedling in androgenetic alopecia: a pilot study. International journal of trichology. 2013, 5(1): 6-11.

91.Chandrashekar B, Yepuri V, Mysore V. Alopecia areata- successful outcome with microneedling and triamcinolone acetonide. Journal of cutaneous and aesthetic surgery. 2014, 7(1): 63-64.

92.Deepak SH, Shwetha S. Scalp roller therapy in resistant alopecia areata. Journal of cutaneous and aesthetic surgery. 2014, 7(1): 61-62.

93.Avci P, Gupta GK, Clark J, Wikonkal N, Hamblin MR. Low-level laser (light) therapy (LLLT) for treatment of hair loss. Lasers in surgery and medicine. 2014, 46(2):144-151.

94.Leavitt M, Charles G, Heyman E, Michaels D. Hair- Max LaserComb laser phototherapy device in the treatment of male androgenetic alopecia: A randomized, double-blind, sham device-controlled, multicentre trial. Clinical drug investigation. 2009, 29(5): 283-292.

95.Jimenez JJ, Wikramanayake TC, Bergfeld W, Hordinsky M, Hickman JG et al. Efficacy and safety of a low-level laser device in the treatment of male and female pattern hair loss: a multicenter, randomized, sham device-controlled, double-blind study. American journal of clinical dermatology. 2014, 15(2): 115-127.

96.Wikramanayake TC, Rodriguez R, Choudhary S, Mauro LM, Nouri K et al. Effects of the Lexington LaserComb on hair regrowth in the C3H/HeJ mouse model of alopecia areata. Lasers in medical science. 2012, 27(2): 431-436.

97.King LE, Jr., Silva KA, Kennedy VE, Sundberg JP. Lack of response to laser comb in spontaneous and graft-induced alopecia areata in C3H/HeJ mice. The Journal of investigative dermatology. 2014, 134(1): 264-266.

98.Ge S. Treatment of alopecia areata with acupuncture. Journal of traditional Chinese medicine = Chung i tsa chih ying wen pan / sponsored by All-China Association of Traditional Chinese Medicine, Academy of Traditional Chinese Medicine. 1990, 10(3):199-200.

99.Maeda T, Taniguchi M, Matsuzaki S, Shingaki K, Kanazawa S et al . Anti-inflammatory effect of electroacupuncture in the C3H/HeJ mouse model of alopecia areata. Acupuncture in medicine : journal of the British Medical Acupuncture Society. 2013, 31(1): 117-119.

Cite this article: Joaquin J. Alopecia Areata: Pathophysiology, Diagnosis, and Treatment. J J Biomark. 2015, 1(1): 005.

 

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