Clinical presentations of alopecia areata

Alopecia areata (AA) may can occur on any hair-bearing region. Patients can develop patchy nonscarring hair loss or extensive loss of all body hair. Hair loss may fluctuate. Some patients experience recurrent hair loss followed by hair regrowth, whereas others may only develop a single patch of hair loss, never to see the disease again. Still others experience extensive loss of body hair. The heterogeneity of clinical presentations has led investigators conducting clinical therapeutic trials to typically group patients into three major groups, those with extensive scalp hair loss [alopecia totalis (AT)], extensive body hair loss [alopecia universalis (AU)], or patchy disease (AA). Treatment outcomes have been correlated with disease duration and extent. Recently, guidelines were established for selecting and assessing subjects for both clinical and laboratory studies of AA, thereby facilitating collaboration, comparison of data, and the sharing of patient-derived tissue. For reporting purposes the terms AT and AU, though still used are defined very narrowly. AT is 100% terminal scalp hair loss without any body hair loss and AU is 100% terminal scalp hair and body loss. AT/AU is the term now recommended to define the presence of AT with variable amounts of body hair loss. In this report the term AA will be used broadly to encompass the many presentations of this disease. Development of AA may occur with changes in other ectodermal-derived structures such as fingernails and toenails. Some investigators have also suggested that other ectodermal-derived appendages as sebaceous glands and sweat glands may be affected in patients experiencing AA. Whether or not function of these glands is truly impaired remains to be confirmed. Many patients who develop patchy or extensive AA complain of changes in cutaneous sensation, that is, burning, itching, tingling, with the development of their disease. Similar symptoms may occur with hair regrowth. The potential involvement of the nervous system in AA has led to morphologic investigations of the peripheral nervous system as well as analysis of circulating neuropeptide levels. In this article the clinical presentations of AA are reviewed. The guidelines for conducting treatment studies of AA are presented and observations on changes in cutaneous innervation are introduced. Throughout the text, unless otherwise noted, AA will be used in a general way to denote the spectrum of this disease.     

Dry dermoscopy in clinical treatment of alopecia areata

Although dermoscopy is conventionally utilized with immersion gel for diagnosis of pigmented tumor, we utilized dry dermoscopy, which is dermoscopy without immersion gel, for clinical treatment of alopecia areata (AA). The scalp skin and hair of a 38-year-old Japanese male, and 23-, 22- and 47-year-old Japanese females with AA, whose normal hair color was black, were examined by dry dermoscopy. Exclamation mark hairs, short hairs, fractured hairs and black dots, all characteristic of AA, were detected by dry dermoscopy of the scalp of the 23-year-old female with ophiasis type AA. In the case of the 47-year-old female with round hair loss on the occipital scalp and diffuse hair loss over the fronto-vertical region, dry dermoscopy was useful for diagnosis of AA based on hair characteristic of AA. After she received corticosteroid pulse therapy with 500 mg of i.v. methylprednisolone on 3 successive days, her hair showed apparent regrowth and disappearance of the abnormal hairs characteristic of AA, evidenced by dry dermoscopy 1 month later. In a case of long-lasting AA in the 23-year-old female, we found a follicular plaque-like appearance at the opened hair follicle pores by dry dermoscopy. Histopathologically, the incompletely differentiated remnant hair shaft was packed in the follicular infundibulum. In addition, regrowing vellus hairs, which were difficult to clinically recognize, were detected by dry dermoscopy. Dry dermoscopy is therefore useful for both diagnosis and follow up of AA.     

Prominent follicular mucinosis with diffuse scalp alopecia resembling alopecia areata

A 56‐year‐old Caucasian female presented with a 2‐month history of alopecia. On examination, she had diffuse hair loss of her scalp with some discrete patches of nonscarring alopecia. Histopathology revealed an inflammatory nonscarring alopecia with prominent follicular mucinosis and findings suggestive of alopecia areata. The patient's alopecia completely resolved with oral prednisone. The histopathologic findings and clinical presentation are most consistent with a diagnosis of alopecia areata with follicular mucinosis, although the differential diagnosis is broad. As follicular mucinosis may be associated with both benign and malignant conditions, it is important to be cautious regarding the clinical diagnosis when this reaction pattern is observed histopathologically.     

Use of trichoscopy for the diagnosis of alopecia areata coexisting with primary scarring alopecia in a female hair loss patient

Despite patchy hair loss being typically observed in alopecia areata (AA), similar lesions can be seen in other forms of alopecia and the diagnosis is sometimes challenging. Of note, patchy primary scarring alopecia (SA) needs to be clearly distinguished from AA as SA can leave permanent hair loss. Herein, we report a previously unreported case of AA coexisting with SA successfully diagnosed by detailed trichoscopic investigation. A 42‐year‐old woman visited us with patchy hair loss lesions on the scalp. On physical examination, alopecic lesions sized up to 2 cm in diameter were observed in the right temporal and parietal regions. A gentle hair pull test collected dystrophic anagen hairs from some patches. Trichoscopy detected tapering hairs and black dots. The diagnosis of AA was made. However, some reddish patches were totally hair pull test negative, urging us to further evaluate the remaining lesions. Additional trichoscopic investigation revealed the disappearance of follicular ostia and the presence of a white and milky‐red area and peripilar scales, suggestive of SA. In histology, the clinically AA lesion showed peribulbar cell infiltration, while the potentially SA lesion demonstrated inflammatory cell infiltration around the isthmus and the decrease in hair follicles, some of which were replaced by fibrotic tissue. The final diagnosis of AA coexisting with SA was made. Intralesional corticosteroid injection improved AA but not SA. These findings emphasize the need for thorough trichoscopic examination for accurate diagnoses of rare hair loss conditions.     

Topical and intralesional therapies for alopecia areata

Alopecia areata is a common form of nonscarring alopecia. It affects males and females equally and has no racial predilection. It usually affects the scalp, but any hair-bearing area can be involved. It presents as patchy hair loss, loss of hair on the entire scalp (alopecia totalis), or the whole body (alopecia universalis). The histopathology varies according to the disease stage, but usually a perifollicular lymphocytic infiltrate is seen. The course of the disease and response to treatment are unpredictable. Various therapeutic modalities are used including topical, intralesional, and systemic agents, although none are curative or preventive. This article will review the available topical and intralesional agents that are used in the treatment of alopecia areata and suggest a management approach based on the age of the patient and extent of the disease.     

Histopathology of alopecia areata,acute and chronic: Why is it important to the clinician?

Alopecia areata (AA) is often easy to diagnose but a scalp biopsy for horizontal sectioning is routine in this research clinic. The characteristic histological feature of AA is the peribulbar and intrabulbar mononuclear cell infiltrate, which occurs in the acute stage of the disease but may be absent in biopsies taken at a later stage. AA evolves through acute, subacute, chronic, and recovery phases. Increased numbers of terminal catagen and telogen hairs are found in the acute and perhaps subacute stages with increased numbers of miniaturized, vellus-like hairs in the subacute and chronic stages. Thus, it is important for clinicians and pathologists to recognize the different phases of AA, so that in the absence of the classic findings of a peribulbar lymphocytic infiltrate, a diagnosis of AA can still confidently be made.     

Trichostasis spinulosa of the scalp mimicking Alopecia Areata black dots

Alopecia areata is a common autoimmune disorder that leads to nonscarring hair loss. Black dots, also called comedo-like cadaver hairs, can be found in almost 50% of alopecia areata patients and indicate disease activity. Trichostasis spinulosa is a follicular disorder resulting from the retention of numerous hairs surrounded by a keratinous sheath in dilated follicles. Trichostasis spinulosa is a relatively common but underdiagnosed disorder of hair follicles. Here, we describe a man with alopecia areata of the eyebrows, androgenetic alopecia and trichostasis spinulosa at the vertex and show how dermoscopy can be useful in distinguishing black dots from Trichostasis spinulosa lesions.     

Etiopathogenesis of alopecia areata: Why do our patients get it?

Alopecia areata (AA) is a nonscarring, inflammatory skin disease that results in patchy hair loss. AA is unpredictable in its onset, severity, and duration making it potentially very stressful for affected individuals. Currently, the treatment options for AA are limited and the efficacy of these treatments varies from patient to patient. The exact etiology of AA is unknown. This article provides some insights into the etiopathogenesis of AA and why some people develop it. The current knowledge on the pathogenesis of AA is summarized and some of the recent hypotheses and studies on AA are presented to allow for a fuller understanding of the possible biological mechanisms of AA.     

Hair shaft abnormalities in alopecia areata evaluated by optical coherence tomography

Background/purpose: Optical coherence tomography (OCT) is able to provide highly reproducible measurements of hair shaft thickness, including hair shaft diameter, cross‐sectional surface area and hair shape, similar to histology but in vivo. Variations in the caliber of hair shafts have been described in patchy hair loss like alopecia areata (AA) using electron microscopy. The aim of this study was to evaluate whether OCT is useful for the evaluation of hair shaft abnormalities in AA. Methods: The measurements were performed on patients with AA (n=9), aged 2–66 years. Fifty hairs from the border of an alopecic area and 50 hairs from an unaffected area without hair loss were examined using the OCT technique. The hair parameters were characterized by the cross‐section (CS) and the form factor. The ratio of the maximal and minimal diameters of the hair at a fixed measuring distance from the scalp surface determined the form factor (d_max/d_min). Results: In all cases, the CS of hairs from an AA patch was significantly lower compared with hairs of an unaffected area. However, the form factor did not indicate any disturbances in hair growth. Conclusions: The results demonstrate that structural abnormalities of hair shafts are found in active lesions of AA, but not in clinically unaffected hairs. The OCT technique is a promising method to gain more insight into the pathogenesis of AA in a non‐invasive way.     

Alopecia areata: autoimmune basis of hair loss

Alopecia areata (AA) is a heterogeneous disease characterized by nonscarring hair loss on the scalp or any hair-bearing surface. A wide range of clinical presentations can occur -- from a single patch of hair loss to complete loss of hair on the scalp (alopecia totalis) or the entire body (alopecia universalis). Particularly in severe or chronic cases, AA may cause considerable psychological and emotional distress for affected individuals. The estimated lifetime risk of developing AA is 1.7%. While the precise etiology of this common disorder has not been elucidated, a substantial body of evidence suggests that AA is an organ-specific, autoimmune disease, targeted to hair follicles. However, the antigenic target(s), mechanisms, and consequences of autoimmune attack in AA have yet to be determined. Here, we critically explore the evidence supporting the hypothesis that AA is an autoimmune disease and propose specific pathways by which self-directed immune responses are generated.     

斑秃皮损的皮肤镜影像及其与临床病理的关系

目的 探讨皮肤镜下斑秃皮损的微细改变及其与临床、病理相关性。方法 使用皮肤镜观察62例斑秃患者和44例其他类型脱发患者的皮损,收集患者临床及实验室资料,并对其中15例斑秃患者进行皮损部位组织病理活检,以了解皮肤镜的组织形态学基础。结果 皮肤镜下斑秃影像为黄点征、黑点征、断发、毳毛、新生短发和感叹号样毛发。黄点征发生率最高（83.9%）,而诊断斑秃的特异性指标为感叹号样毛发、黑点和断发,且后三者发生率与斑秃的活动性及轻拉发试验阳性率呈显著正相关关系。甲状腺过氧化物酶抗体升高发生率与轻拉发实验阳性率及断发发生率呈显著正相关。黄点征发生率和病理下毛囊口角栓阳性率之间呈显著正相关关系,新生短发发生率和毛囊周围肥大细胞浸润发生率以及黑点发生率则与生长期与退行期毛囊之间比例减少均呈显著负相关关系。结论 可以用黄点征作为斑秃诊断的初筛指标,而感叹号样毛发、黑点和断发对于确诊斑秃的特异性较高,且提示患者病情仍处于活动期。斑秃患者皮肤镜影像与病理有一定相关性,可用于判断病情并指导治疗。     

The role of the National Alopecia Areata Foundation in the management of alopecia areata

Like a mysterious thief in the night, alopecia areata (AA) suddenly appears without warning—seemingly without rhyme or reason—randomly robbing the hair and subsequently the self-esteem of those affected. Very persuasive scientific evidence now suggests that AA is a T-lymphocyte-mediated autoimmune disease directed against an as yet unidentified hair follicle autoantigen in genetically susceptible individuals. The severity of the clinical phenotypes seen in AA run the gamut from patchy hair loss localized in one or more areas, to total scalp hair loss [alopecia totalis (AT)], to complete body hair loss [alopecia universalis (AU)]. Although not life threatening, AA is most certainly life altering, and its sudden onset, recurrent episodes, and highly unpredictable course have a profound psychological impact on the lives of those with the disease. There are a limited number of therapeutic agents available to treat AA. Responses vary widely and the hard fact remains that any treatment, no matter how successful, does not alter the ultimate course of this capricious and recalcitrant disease. Founded in 1981 to meet the challenges of AA and mollify the deep emotional pain inflicted by this disease, the National Alopecia Areata Foundation (NAAF) now serves as the world center of information and hope for those with AA. The foundation plays a crucial role in the management of AA by encouraging and funding medical research for better treatment and an ultimate cure, by providing support and resources for those with the condition, and by raising public awareness of the disease.     

Immunoreactivity of corticotropin-releasing hormone, adrenocorticotropic hormone and alpha-melanocyte-stimulating hormone in alopecia areata

Psychological factors are believed to play a role in the pathogenesis of alopecia areata (AA), a frequently encountered hair disorder. In our study, statistically significant elevation of psychological stress was felt by AA patients prior hair loss compared with control, which was strongly believed contributory to hair loss (t-test, P < 0.01). The corticotropin-releasing hormone (CRH) and proopiomelanocortin (POMC) mRNA have been identified in the basal layer of the epidermis and pilosebaceous units of the normal scalp. And with the recent discovery of melanocytes and dermal fibroblasts capable of corticosterone production, the presence of a local stress response system resembling the hypothalamic-pituitary-adrenal (HPA) axis has been suggested. The local stress response system is involved in regulation of the normal hair cycle, but its precise role in AA is unknown. The influence of a local HPA axis or rather, CRH-POMC axis in AA was investigated by analysing immunohistochemically the expression levels of CRH and POMC peptides, including the adrenocorticotropic hormone (ACTH) and alpha-melanocyte-stimulating hormone (alpha-MSH), in a number of AA lesions and normal scalp (as control). The epidermis and pilosebaceous units of normal scalp stained weakly with CRH, ACTH and alpha-MSH, whereas those from the affected sites of the AA group showed intense expression of the peptides (chi-square test, P < 0.01). The meaning of this enhanced expression and their role in the pathogenesis of AA should be further evaluated in future.     

Expression of vascular endothelial growth factor, apoptosis inhibitors (survivin and p16) and CCL27 in alopecia areata before and after diphencyprone treatment: an immunohistochemical study

BACKGROUND: Alopecia areata (AA) is a relatively common inflammatory form of nonscarring hair loss of unknown pathogenesis, but possibly of autoimmune origin. Topical immunotherapy, using a potent contact allergen such as diphencyprone (DPC), is currently considered the most effective mode of treatment. However, the way in which DPC operates on hair follicles in AA still remains to be elucidated. Vascular endothelial growth factor (VEGF), essential for angiogenesis and vascular permeability, may be responsible for maintaining proper vasculature around hair follicles, and several studies provide evidence that apoptosis is a central element in the regulation of hair follicle and vascular regression. The cutaneous lymphocyte-associated antigen (CLA) and the skin-associated chemokine CCL27 highlight an important role for epithelial cells in controlling homeostatic lymphocyte trafficking. OBJECTIVES: To determine the expression pattern of VEGF, factor (F)VIII, survivin, p16, CD4, CD8, CLA and CCL27 in alopecic skin before and after treatment with DPC. Methods Immunohistochemical staining methods were applied to skin biopsy specimens obtained from alopecic areas of 14 patients before and after DPC treatment and from five healthy subjects. Sections were incubated with monoclonal antibodies against VEGF, FVIII, survivin, p16, CCL27, CLA, CD4 and CD8, and their immunohistochemical expression was evaluated by light microscopy. RESULTS: The intensity of VEGF staining in alopecic human hair follicles was significantly lower than in healthy scalp tissue. FVIII immunostaining showed a significantly reduced development of the microvasculature in AA in comparison with healthy scalp tissue. After DPC therapy, cells of alopecic hair follicles showed a significant increase of VEGF immunopositivity, and the number of capillary vessels expressing FVIII was markedly increased in comparison with untreated scalp tissue. The increase in microvessels was associated with strong survivin expression in endothelial cells after treatment. All alopecic specimens showed expression of p16 in the hair follicle outer root sheath (ORS), with a significant increase after therapy. After treatment we observed a significantly decreased number of CD4+ cells and an increase of CD8+ cells (CD4/CD8 ratio 0.85) in alopecic skin compared with untreated scalp tissue (CD4/CD8 ratio 3.45). Most of the T lymphocytes found in inflammatory skin lesions expressed CLA antigen and after therapy we observed a significantly higher CLA positivity in hair follicles (50% or more) in comparison with untreated alopecic scalp tissue. Alopecic patients showed a CCL27 immunopositivity significantly lower than in normal scalp tissue. After DPC therapy the labelling intensity for CCL27 showed a significant increase both in the ORS and in the inner root sheath; similarly, in the basal interfollicular keratinocytes we observed a moderate increase in CCL27 expression. CONCLUSIONS: Topical immunotherapy exerts an important role in angiogenesis, upregulating VEGF in human hair follicle keratinocytes and upregulating survivin to preserve endothelial cell viability. Moreover, it considerably alters the peribulbar CD4/CD8 ratio, restoring a condition close to normal scalp skin. Our study could contribute to explaining some aspects of AA pathogenesis that are still unknown and aid understanding of how DPC could act in this complex disease.     

Increased expression of TLR7 and TLR9 in alopecia areata

Alopecia areata (AA) is thought to be an autoimmune process. In other autoimmune diseases, the innate immune system and Toll-like receptors (TLRs) can play a significant role. Expression of TLR7, TLR9 and associated inducible genes was evaluated by quantitative PCR in peripheral blood mononuclear cells (PBMCs) from 10 healthy individuals and 19 AA patients, categorized according to disease duration, activity and hair loss extent. Microdissected scalp biopsies from five patients and four controls were also assessed by quantitative PCR and immunohistology. TLR9 was significantly upregulated 2.37 fold in AA PBMCs. Notably, TLR9 was most significantly upregulated in patients with active AA, as shown by a positive hair pull test, compared to stable AA patients. In hair follicle bulbs from AA patients, IFNG and TLR7 exhibited statistically significant 3.85 and 2.70 fold increases in mRNA, respectively. Immunohistology revealed TLR7 present in lesional follicles, while TLR9 positive cells were primarily observed peri-bulbar to AA affected hair follicles. The increased expression of TLR7 and TLR9 suggest components of the innate immune system may be active in AA pathogenesis.     

The immunology of alopecia areata and potential application to novel therapies

There is strong evidence indicating alopecia areata (AA) is a tissue-specific, autoimmune disease. Hair loss is associated with a perifollicular lymphocytic infiltrate made up primarily of CD4⁺ cells, associated with a CD8⁺ intrafollicular infiltrate. Evidence of immune activation includes expression of human leukocyte antigen (HLA)-DR, HLA-A,B,C, and intercellular adhesion molecule (ICAM)-1 on the follicular epithelium. It is likely that the follicular expression of HLA-DR and ICAM-1 is induced by interferon (IFN)-γ produced by T cells. Antibodies to follicular epithelium are often present, but their significance is not known. Lesional scalp from AA patients grafted onto nude mice regrows hair coincident with a loss of infiltrating lymphocytes from the graft. It is possible to transfer hair loss to human scalp explants on severe combined immunodeficiency (SCID) mice by injection of lesional T cells. Neuropeptides produced by cutaneous nerves may modify immune reactivity and influence disease. In particular, low levels of the calcitonin gene-related peptide (CGRP) may have a role in initiation of the condition by inducing immune hyperresponsiveness and vasoconstriction. Best evidence is that AA is a mediated by a TH1 T-lymphocyte response. Translation of these data into potential new therapies is discussed.     

The histopathology of alopecia areata in vertical and horizontal sections

Alopecia areata (AA) is a relatively common disease affecting 1.7% of Americans by the age of 50 years. The diagnosis is usually made on clinical grounds. In some cases the diagnosis is elusive and biopsies are necessary. In other cases biopsies are useful from a prognostic point of view to determine whether there are enough follicles left for possible future regrowth. In view of the active research being conducted into AA, biopsies provide valuable material for further investigation. The diagnosis of AA is improved by the use of horizontal sections in addition to or instead of vertical sections of scalp biopsies. The histopathologic features favoring the diagnosis of AA include peribulbar and intrabulbar mononuclear infiltrates, degenerative changes in the hair matrix, decreased numbers of terminal anagen follicles, increased numbers of terminal catagen and telogen follicles, an increased number of follicular stelae, an increased number of miniaturized vellus hair follicles, and pigment incontinence of hair bulbs and follicular stelae. Follicular counts with horizontal sections are particularly helpful in making the diagnosis of AA when the biopsy has been taken between acute episodes and the characteristic peribulbar inflammatory infiltrate is absent.     

Elucidation of demographic,clinical and trichoscopic features for early diagnosis of self-healing acute diffuse and total alopecia

The term “acute diffuse and total alopecia” (ADTA) has been often used as a synonym for self-regressing severe alopecia areata (AA). However, ADTA is originally defined as a rapidly-progressive subtype of AA (RP-AA) with short recovery time and favorable prognosis irrespective of interventions. Indeed, a subpopulation of ADTA recovers spontaneously. We focused on this unique subset of AA, which we coined as “self-healing ADTA” (sADTA). Prompt and accurate differentiation of sADTA from other RP-AA is important to avoid unnecessary treatments, which is still challenging due to the lack of predictive diagnostic hallmarks. In this study, 18 sADTA patients were retrospectively analyzed to delineate their demographics and clinical features, including gentle hair pull test and trichoscopic findings, followed by statistical comparison with those of RP-AA. All sADTA cases were female and the average age was 38.1 ± 15.9 years. The progression of hair loss areas peaked at 3.6 ± 1.5 months, and complete hair regrowth was achieved in 7.9 ± 1.7 months. The identified factors supporting the diagnosis of sADTA included being female; the absence of scalp pain and itch; the absence of extra-scalp hair loss; club hair predominance in hair pull test; predominant short vellus hairs; and increase in vacant follicular ostia on trichoscopy. Subsequently, a scoring system for early diagnosis of sADTA was developed by counting the number of six identified factors present in a tested case. When analyzed by the developed system, all sADTA cases, including an additional four cases, had scores of 4 or above, while all RP-AA cases had scores below 3 except one case. Therefore, the system successfully differentiated sADTA from RP-AA (P < 0.01). Despite some technical limitations, the current study suggested that sADTA is a distinctive entity with unique pathophysiology and that early diagnosis before intervention is feasible based on the characteristics.     

Integrative analysis of rare copy number variants and gene expression data in alopecia areata implicates an aetiological role for autophagy

Alopecia areata (AA) is a highly prevalent autoimmune disease that attacks the hair follicle and leads to hair loss that can range from small patches to complete loss of scalp and body hair. Our previous linkage and genome-wide association studies (GWAS) generated strong evidence for aetiological contributions from inherited genetic variants at different population frequencies, including both rare mutations and common polymorphisms. Additionally, we conducted gene expression (GE) studies on scalp biopsies of 96 patients and controls to establish signatures of active disease. In this study, we performed an integrative analysis on these two datasets to test the hypothesis that rare CNVs in patients with AA could be leveraged to identify drivers of disease in our AA GE signatures. We analysed copy number variants (CNVs) in a case-control cohort of 673 patients with AA and 16 311 controls independent of the case-control cohort of 96 research participants used in our GE study. Using an integrative computational analysis, we identified 14 genes whose expression levels were altered by CNVs in a consistent direction of effect, corresponding to gene expression changes in lesional skin of patients. Four of these genes were affected by CNVs in three or more unrelated patients with AA, including ATG4B and SMARCA2, which are involved in autophagy and chromatin remodelling, respectively. Our findings identified new classes of genes with potential contributions to AA pathogenesis.