A case series of alopecia areata in children: impact of personal and family history of stress and autoimmunity

BACKGROUND: The epidemiology of alopecia areata (AA) is well documented in adults but has not been studied adequately in children. OBJECTIVE: To evaluate the clinical and epidemiological profile of AA in children and assess the significance of thyroid screening. METHODS: One hundred and fifty-seven children (83 boys, 74 girls, aged 1-16 years) who visited our clinic with a first episode of AA from 1996 to 2000 were retrospectively studied. One hundred children served as clinical controls. RESULTS: The age of peak incidence of AA was 0-5 years. The youngest child was 1 year old. In the majority of the cases (131/157, 83.4%) the disease was mild or moderate (less than 50% hair loss). In 15 patients (9.5%), AA was preceded by a stressful event. Five patients had a personal history of autoimmune disease (3.2 vs. 5% of the controls, (P = not significant [NS]) while 18 patients had a personal history of atopy (11.4 vs. 18% of the controls, P = NS). Twenty-one patients had a family history of autoimmune disease other than thyroiditis (13.4 vs. 5% of the controls, P = 0.04), while 23 patients had a family history of thyroid disorder (14.6 vs. 3% of the controls, P = 0.006). In eight patients (5%) subclinical hypothyroidism of autoimmune aetiology (Hashimoto's thyroiditis) was revealed at the time of investigation. Six out of the eight patients with Hashimoto's thyroiditis had a family history of thyroid disorder, which was statistically significant when compared to AA patients without thyroiditis (P < 0.001). The severity of AA was associated with early age of onset of the disease (P = 0.02). CONCLUSION: The age of peak incidence of AA in children is 0-5 years. Children with AA have an increased family history of autoimmunity, and, among children with a first episode and short duration of AA (< 6 months), thyroid screening might be restricted in those with a positive family history of thyroid disorder. Thyroid screening should be routinely performed in all children with long-standing AA.     

Understanding the significance of cytokines and chemokines in the pathogenesis of alopecia areata

Alopecia areata has basically been understood as a type 1 inflammatory disease. Activated NKG2D⁺CD8⁺ cells produce the Th1 cytokine interferon-γ, which leads to the disruption of immune tolerance of hair follicles and the exposure of self-antigens. This results in dense inflammatory cell infiltration and apoptosis around hair follicles, inducing hair loss. A well-known complication of alopecia areata is atopic dermatitis, a typical type 2 inflammatory disease. Hair scientists have shied away from confronting and understanding how alopecia areata, a type 1 inflammatory disease, and atopic dermatitis, a type 2 inflammatory disease, can occur together. This review summarizes the research on the cytokine balance in alopecia areata and then focuses on the classification of the cytokine balance in alopecia areata, including the classification of atopic dermatitis into extrinsic and intrinsic types. Dupilumab reportedly showed dual efficacy in a patient with concomitant atopic dermatitis and alopecia areata, supporting our own experience. Elevated Th2 cytokine levels have also been reported in patients with alopecia areata, with increased serum IL-4, IL-5, IL-6 levels, high IgE levels and elevated eosinophil levels. Because local immunotherapy is a treatment that induces Th2-type inflammation, it may worsen the condition of alopecia areata patients with extrinsic atopic dermatitis. It is desirable to select appropriate treatments with consideration of the cytokine balance.     

斑秃合并特应性皮炎免疫学特性及治疗研究进展

目前大多数研究认为斑秃是Th1细胞介导的自身免疫性疾病,特应性皮炎是经典的Th2细胞主导的炎症性疾病。但最近的研究也显示了Th2轴在斑秃发病中的潜在作用,在斑秃患者的头皮和血清中发现Th2相关生物标志物显著升高。此外,GWAS也在斑秃中鉴定出了Th2的易感性位点(IL-4和IL-13)。同时合并FLG突变的患者更容易发展成重度斑秃。度普利尤单抗和JAK抑制剂在合并特应性皮炎的斑秃患者中的治疗效果,进一步阐明了不同细胞因子通路对斑秃表型的影响,有助于未来斑秃靶向治疗的选择。     

The genetic epidemiology of alopecia areata in China

BACKGROUND: Alopecia areata (AA) is hypothesized to be an organ-specific autoimmune disease with genetic predisposition and an environmental trigger. There are few clinical data in Asians. OBJECTIVES: To describe the genetic epidemiological features of AA patients in China and to determine the possible genetic model for AA. METHODS: Data for 1032 patients with AA were obtained by questionnaire in the Institute of Dermatology of Anhui Medical University in China from 2001 to 2003. Complex segregation analysis and heritability analysis were performed using Falconer's method, EPI INFO 6.0 and SAGE-REGTL programs. RESULTS: In total, 1032 AA patients (male/female ratio 1.1 : 1) were enrolled, representing 0.94% of the total number of cases seen in our outpatient clinic during that time. The mean +/- SD age of onset was 28.98 +/- 13.43 years. The difference between the mean age of onset in males and females was not significant. Most patients (82.6%) experienced their first episode of AA within the first four decades of life. A positive family history of AA was obtained in 87 patients (8.4%). The prevalence of AA in first-, second- and third-degree relatives of the proband with AA was 1.6%, 0.19% and 0.03%, respectively. These figures were higher than those in controls. A greater severity and longer duration of AA were seen in the early onset group than in the late-onset group. The early onset group also had more affected first- and second-degree relatives. The heritability of AA in first-, second- and third-degree relatives was 47.16%, 42.53% and 22.29%, respectively. Based on the REGTL results, the best model was a polygenic additive model for AA. CONCLUSIONS: The effect of genetic factors is strong in AA, but environmental factors such as infection and psychological stress may still play an important role. Our findings on the genetics of AA are consistent with a polygenic additive mode of inheritance.     

Prevalence of childhood acne, ephelides, warts, atopic dermatitis, psoriasis, alopecia areata and keloid in Kaohsiung County, Taiwan: a community-based clinical survey

BACKGROUND: Epidemiological study on childhood dermatoses performed by direct inspection of dermatologists is limited. OBJECTIVE: To investigate the prevalence of selective childhood dermatoses in Taiwan. METHODS: In a cross-sectional study carried out in June 2004, 4067 of 7851 children aged between 6 and 11 years living in the Kaohsiung County in south Taiwan were clinically surveyed and examined by two board-certified dermatologists (response rate 52%), regarding the point prevalence of acne, ephelides, warts, atopic dermatitis (AD), psoriasis, alopecia areata (AA) and keloid. RESULTS: Acne vulgaris was found in girls and boys from the age of 6 and 7, respectively, with comedones being the earliest presentation. Ephelides were not infrequently observed in our children (prevalence rate 8.4%, 95% confidence interval, CI 7.9-9.3%). The prevalence of warts on hands was 2.4% (95% CI 1.9-2.9%). The prevalence of AD was 1.7% (95% CI 1.3-2.1%), without gender difference. There were only four cases of AA but no psoriasis was found. Keloid was identified in 13 boys and 10 girls, accounting for 0.6% (95% CI 0.598-0.602%) of the children. CONCLUSION: Acne vulgaris is as common in Taiwan as in Western countries. Ephelides are not uncommon in our population with the main skin types III-IV. A clustered distribution of the wart infection was noted. The low prevalence of AD in Taiwan seems unaltered over the past decade. AA and psoriasis are rare in our series. Most keloids in our children are caused by BCG vaccination.     

Predictive factors of response to pulse methylprednisolone therapy in patients with alopecia areata: A follow‐up study of 105 Japanese patients

Pulse corticosteroid therapy is effective for alopecia areata (AA) in the early stage. The risk and efficacy of this therapy for patients with several backgrounds, however, remains controversial. To explore the predictive factors of the response and risk factors of this therapy, data from 105 AA patients treated with methylprednisolone (500 mg) i.v. for 3 days consecutively in our facility were retrospectively analyzed. Among good responders, longer time from the onset to therapy was correlated with longer time required for hair regrowth (P = 0.037, n = 27). Multivariate models demonstrated that “severity”, “relapse” and longer “duration from the latest onset” were significantly and independently associated with poorer outcome (P < 0.01). “History of atopic dermatitis (AD)” was also associated with poorer outcome, but this correlation could be explained by the effect that duration from the latest onset of AA was longer among participants with AD. We propose that earlier initiation of pulse corticosteroid therapy is preferable for better outcome of AA, particularly among patients with AD. Clinicians should be mindful of the occurrence of mild adverse effects in the elderly patients.     

Dermatoglyphics in patients with eczema, psoriasis and alopecia areata

Background/aims: The study of patterns of fingerprints is important in anthropology and medical genetics, chiefly because of their diagnostic usefulness. In the present work, we studied the frequencies of various types of skin ridges of the first phalanx in patients with eczema, psoriasis and alopecia areata.
Methods: In a double-blind case-control study, we determined the frequencies of fingerprints in 551 patients (240 cases with eczema, 164 cases with psoriasis and 147 cases with alopecia areata) as well as in general population of Hamadan City (control group: 188 males and 529 females). We compared the frequencies between various fingers, hands and sexes in all three case groups as well as between case groups and control group.
Results: The frequencies of various types of fingerprints are presented in some tables. The results showed that frequencies are not statistically different according to types of fingers, hands (left or right) and sexes as well. But they are significantly different in various case groups and between case groups and control group.
Conclusions: We can conclude that frequencies of various patterns of skin ridges differ in eczema, psoriasis and alopecia areata from normal population.     

Altered polyamine profiling in the hair of patients with androgenic alopecia and alopecia areata

Hair follicles are among the most highly proliferative tissues. Polyamines are associated with proliferation, and several polyamines including spermidine and spermine play anti‐inflammatory roles. Androgenic alopecia results from increased dihydrotestosterone metabolism, and alopecia areata is an autoimmune disease. This study aimed to investigate differences in polyamine profiles in hair samples between patients with androgenic alopecia and alopecia areata. Polyamine concentrations were determined through high‐performance liquid chromatography‐mass spectrometry. Hair samples were derivatized with isobutyl chloroformate. Differences in polyamine levels were observed between androgenic alopecia and alopecia areata compared with normal controls. In particular, polyamine levels were higher in alopecia areata patients than in normal controls. Certain polyamines displayed different concentrations between the androgenic alopecia and alopecia areata groups, suggesting that some polyamines, particularly N‐acetyl putrescine (P = 0.007) and N‐acetyl cadaverine (P = 0.0021), are significantly different in androgenic alopecia. Furthermore, spermidine (P = 0.021) was significantly different in alopecia areata. Our findings suggest that non‐invasive quantification of hair polyamines may help distinguish between androgenic alopecia and alopecia areata. Our study provides novel insights into physiological alterations in patients with androgenic alopecia and those with alopecia areata and reveals some differences in polyamine levels in hair loss diseases with two different modes of action.     

Chronological association between alopecia areata and autoimmune thyroid diseases: A systematic review and meta‐analysis

The association between alopecia areata (AA) and autoimmune thyroid diseases (AITD) has been suggested; however, the chronological relationship between AA and AITD remains elusive. A systematic review and meta‐analysis were conducted to assess the association between AA and AITD focusing on the prevalence of thyroid antibodies, thyroid diseases and serological thyroid dysfunctions, respectively. Data collection was performed in October 2018 by searching for articles in two electronic databases: Medline and Embase. Case–control, cohort and cross‐sectional studies were included. Meta‐analysis of studies eligible for quantitative synthesis was performed to estimate pooled odds ratios of thyroid antibodies; thyroid peroxidase antibody (TPO‐Ab) and thyroglobulin antibody (TG‐Ab), diagnosed thyroid diseases and serological thyroid dysfunctions. Four hundred and eighty nine research papers were identified and 17 studies with 262 581 patients and 1 302 655 control subjects were included for quantitative synthesis. AA was significantly associated with both TPO‐Ab and TG‐Ab. In comparison, there was no significant association between AA and diagnosed hypothyroidism or hyperthyroidism and serological hypothyroidism or hyperthyroidism. In conclusion, AA is significantly associated with the existence of thyroid antibodies rather than with clinical or laboratory thyroid abnormality. Lack of long‐term follow‐up data is a limitation of the existing published work. Our findings do not support routine screening of thyroid diseases for asymptomatic AA patients but highlight the potential future risk of AITD particularly in severe and refractory AA.     

Management of alopecia areata: Updates and algorithmic approach

Alopecia areata is a chronic, recurrent and non‐scarring alopecia. The prognoses of patients are very diverse. The larger the area of hair loss, the poorer the treatment response and greater the probability of chronic disease progression. Numerous treatments have been introduced, but curative treatments have yet to be established. The long‐term efficacy of the current treatments is minimal, and the therapeutic response varies widely. Recent clinical trials have attempted to apply therapeutic metrics, such as the Severity of Alopecia Tool, and many have been designed as randomized controlled studies, enabling a more precise evaluation of existing treatments. There have been updates in practice, efficacy or indications of therapeutics that have been previously used. Moreover, the use of novel treatments such as biologics has recently been introduced. Commonly, the most important factor in determining the treatment modality for alopecia areata has been the extent of hair loss. However, if the disease activity is high and likely to progress, combination therapy with adjuvant modalities will be more desirable. This review will discuss the therapeutic effects of existing and newly‐introduced treatments based on their quantity, quality of evidence and expected complications. In addition, an algorithmic approach to management of alopecia areata is proposed according to clinical subtype, severity, onset and activity of the disease.     

Stress in patients with alopecia areata and vitiligo

OBJECTIVE: To study the involvement of stress before the onset/development of alopecia areata and vitiligo. PATIENTS AND METHOD: Forty-five outpatients with alopecia areata and 32 outpatients with vitiligo were enrolled. The design was a case-control study (controls had skin diseases unrelated to stress). Stressful events were evaluated using Holmes and Rahe's social readjustment rating scale. RESULTS: Mean age was around 30 years in both conditions. More than 65% of cases (both alopecia areata and vitiligo) experienced stressful events compared to 22% of controls. The odds ratio was 7.75 for alopecia areata and 6.81 for vitiligo. There was a significant difference in the mean number of stressful events between alopecia areata patients and controls (P = 0.005), and also a significant difference in the number of stressful events between men (P = 0.05) and women (P = 0.001) across these two groups. In the vitiligo group there was a significant difference in the mean number of stressful events between patients and controls only in women (P = 0.02). A potential stressful situation occurred more often in both patient groups. Alopecia areata patients described family problems in 45.6% of patients (especially women), which was statistically significant when compared to controls (P = 0.0004). Personal problems were reported by 35.7% of alopecia areata patients (P = 0.04 compared to controls). Vitiligo patients mentioned personal problems in 47% of cases (one-third were related to exams) and 31% of cases were related to job/financial problems. Again, this was statistically significant when compared to controls (P = 0.0002). CONCLUSIONS: Stress seems to play an important role in the onset and aggravation of both alopecia areata and vitiligo, mostly with one stressful event before disease onset.     

The genetic epidemiology and autoimmune pathogenesis of alopecia areata

Unlit recently, there was only circumstantial evidence to support the autoimmune and genetic etiology of alopecia areata. The advent of HLA stereotyping and linkage analysis has revealed an increase in specific HLA alleles in patients with alopecia areata and controls. Even more current is the detection of autoantibodies to the hair follicle in the sera from humans with alopecia areata and laboratory animal models of the disease. Recent experiments suggest that there may even be specific HLA class II alleles that play a protective role against the development of alopecia areata. Herein, the circumstantial data and the confirmed linkage data to support a genetic/autoimmune interplay theory of alopecia areata are discussed. The temporal advancements of research in the area of the HLA typing are reviewed for the disease.     

Response to ustekinumab in three pediatric patients with alopecia areata

Alopecia areata (AA) is relatively common and can have a significant impact on quality of life, especially in a pediatric population. Currently available treatments are often ineffective or have poor safety profiles. Recent studies have highlighted the importance of the Th1 pathway in the pathogenesis of AA, suggesting ustekinumab as a treatment modality for this disease. We present three pediatric AA patients who demonstrated hair regrowth after initiating ustekinumab.     

综合疗法治疗斑秃35例的临床观察

目的：观察综合疗法治疗斑秃的临床疗效。方法：对35例斑秃患者采用复方甘草酸苷、地塞米松、匹多莫德口服，斑秃患处用梅花针扣刺，并同时外搽曲安奈德注射液综合治疗，共二个疗程，3个月后判断疗效，并与27例曲安奈德局部注射患者进行对照。结果：治疗组3个月后痊愈24例，显效8例，进步3例，无效0例，痊愈率（68．57％），有效率（91．43％）分别与对照组比较（37．03％，66．67％）差异有显著性（P〈0．05）。结论：综合疗法治疗斑秃，可增加斑秃区的血液循环，促进毛发再生，避免停药后再复发及局部头皮萎缩的副作用，疗效显著。     

Claudin-3 is a novel intestinal integrity marker in patients with alopecia areata: Correlation with the disease severity

Background

The development of alopecia areata is suggested to be influenced by intestinal permeability and gut dysbiosis. Claudin-3, an essential component of tight junctions which may act as an indicator of intestinal barrier integrity.

Aims

The study's objective was to evaluate the plasma concentration level of Claudin-3 in alopecia areata patients and its relationship to the severity of the condition.

Patients and Methods

In this case–control study, 50 alopecia areata patients and 30 healthy age and sex controls were involved. An enzyme-linked immunosorbent assay was used to determine the concentration of claudin-3 in the blood.

Results

Patients with alopecia areata had significantly higher plasma claudin-3 concentrations than healthy controls [median (interquartile range), 7.73 ng/ml (4.49–33.7) vs. 6.14 ng/ml (4.45–15.6), p < 0.005]. Positive relations were found between claudin-3 and SALT score (r = 0.675 & p-value < 0.001).

Conclusions

Claudin-3, a gut permeability biomarker, is elevated in alopecia areata and correlates with disease severity.     

Fexofenadine, an H1-receptor antagonist, partially but rapidly inhibits the itch of contact dermatitis induced by diphenylcyclopropenone in patients with alopecia areata

Antihistamines have been used for the treatment of not only allergic diseases such as allergic urticaria and rhinitis, but also of eczematous skin diseases because of their anti-pruritic effects. Moreover, the pruritus associated with eczematous diseases is considered to be induced, in part, by histamine. However, it is unclear whether antihistamines inhibit the itch of eczematous diseases in the absence of topical corticosteroids. In this study, we investigated the anti-pruritic effect of the antihistamine, fexofenadine, on the itch of contact dermatitis that was induced by topical application of diphenylcyclopropenone for the treatment for alopecia areata. Thirteen patients with alopecia areata, who had been treated weekly with topical immunotherapy with diphenylcyclopropenone for 3 months to 2 years, recorded the severity of their itching on a visual analog scale before and 3, 6, 12, 24, 48 and 72 h after application of diphenylcyclopropenone for 4 consecutive weeks. Seven patients took fexofenadine during the first and third weeks, and six patients took fexofenadine during the second and fourth weeks. The severity of itching reached a maximum 6-12 h after the induction of the contact dermatitis in most of the patients. However, fexofenadine partially but rapidly reduced the severity of itching for 72 h during the entire period of treatment in the absence of topical corticosteroids. Our results suggest that fexofenadine can be beneficial in the daily management of patients with itching due to eczematous disease.     

Age dependence of diphenylcyclopropenone sensitization in patients with alopecia areata

Contact sensitization has been an accepted topical immunotherapy in the treatment of alopecia areata (1, 2). Whether the age of patients is a significant factor in the treatment results is a matter of controversy. In our study, we investigated the correlation between age of the patients and diphenylcyclopropen-one contact sensitization in vivo and in vitro (3, 4).