The Alopecia Areata Severity and Morbidity Index (ASAMI) Study: Results From a Global Expert Consensus Exercise on Determinants of Alopecia Areata Severity.

Importance: Current measures of alopecia areata (AA) severity, such as the Severity of Alopecia Tool score, do not adequately capture overall disease impact. Objective: To explore factors associated with AA severity beyond scalp hair loss, and to support the development of the Alopecia Areata Severity and Morbidity Index (ASAMI). Evidence Review: A total of 74 hair and scalp disorder specialists from multiple continents were invited to participate in an eDelphi project consisting of 3 survey rounds. The first 2 sessions took place via a text-based web application following the Delphi study design. The final round took place virtually among participants via video conferencing software on April 30, 2022. Findings: Of all invited experts, 64 completed the first survey round (global representation: Africa [4.7%], Asia [9.4%], Australia [14.1%], Europe [43.8%], North America [23.4%], and South America [4.7%]; health care setting: public [20.3%], private [28.1%], and both [51.6%]). A total of 58 specialists completed the second round, and 42 participated in the final video conference meeting. Overall, consensus was achieved in 96 of 107 questions. Several factors, independent of the Severity of Alopecia Tool score, were identified as potentially worsening AA severity outcomes. These factors included a disease duration of 12 months or more, 3 or more relapses, inadequate response to topical or systemic treatments, rapid disease progression, difficulty in cosmetically concealing hair loss, facial hair involvement (eyebrows, eyelashes, and/or beard), nail involvement, impaired quality of life, and a history of anxiety, depression, or suicidal ideation due to or exacerbated by AA. Consensus was reached that the Alopecia Areata Investigator Global Assessment scale adequately classified the severity of scalp hair loss. Conclusions and Relevance: This eDelphi survey study, with consensus among global experts, identified various determinants of AA severity, encompassing not only scalp hair loss but also other outcomes. These findings are expected to facilitate the development of a multicomponent severity tool that endeavors to competently measure disease impact. The findings are also anticipated to aid in identifying candidates for current and emerging systemic treatments. Future research must incorporate the perspectives of patients and the public to assign weight to the domains recognized in this project as associated with AA severity.

Establishing the financial burden of alopecia areata and its predictors.

Background: Alopecia areata (AA) can have a significant impact on wellbeing. Consequently, individuals with AA often seek treatments or products to promote hair regrowth or camouflage their hair loss that incur a financial cost to the individual. Objectives: The current study aimed to examine the direct financial burden of AA to understand the wider impact of the condition and the factors which influence spending on products and services. Methods: A total of 829 United Kingdom based participants completed an online survey. Demographic and condition-specific data were collected, alongside spending on AA-related products and services. Participants were asked about their use of products and services, the associated costs, how they financed these costs, and their household income to determine what percentage of income they spent on products and services. Results: Participants predominantly identified as female (85.9%), white (92.7%) with a mean age of 42.7 years and a median AA duration of 10.94 years. Female gender, Asian ethnicity, lower income, and worse AA symptoms predicted higher spend from income. Wigs were the most common product used and incurred the greatest cost (median £700). The highest cost for men was private dermatology services (median = £550). On average people spent 3% of their disposable income (prior to housing costs) on AA-related products and services. Conclusions: This study outlines the risk factors associated with higher financial burden from managing AA which require consideration by health providers, commissioners, and policy makers when designing services to support the wellbeing of people living with AA.

Male pattern hair loss: Can developmental origins explain the pattern?

Male pattern hair loss (MPHL), also referred to as male androgenetic alopecia (AGA) is the most common type of non-scarring progressive hair loss, with 80% of men suffering from this condition in their lifetime. In MPHL, the hair line recedes to a specific part of the scalp which cannot be accurately predicted. Hair is lost from the front, vertex, and the crown, yet temporal and occipital follicles remain. The visual effect of hair loss is due to hair follicle miniaturisation, where terminal hair follicles become dimensionally smaller. Miniaturisation is also characterised by a shortening of the growth phase of the hair cycle (anagen), and a prolongation of the dormant phase (kenogen). Together, these changes result in the production of thinner and shorter hair fibres, referred to as miniaturised or vellus hairs. It remains unclear why miniaturisation occurs in this specific pattern, with frontal follicles being susceptible while occipital follicles remain in a terminal state. One main factor we believe to be at play, which will be discussed in this viewpoint, is the developmental origin of the skin and hair follicle dermis on different regions of the scalp.

Chronic Telogen Effluvium: Is it a Distinct Condition? A Systematic Review.

BACKGROUND: Whilst there are several recognised explanations for persistent telogen-phase hair loss, for a proportion of cases, no clear underlying cause can be identified. These cases have been given the diagnostic label chronic telogen effluvium: a poorly characterised condition where there is legitimate uncertainty as to whether it represents a truly distinct disorder. OBJECTIVE: The aim of this review was to evaluate published cases of purported chronic telogen effluvium and how strongly they support its existence as a distinct disorder. METHODS: We systematically reviewed the literature identified from searching Embase, MEDLINE and Web-of-Science. An additional manual search was performed from the reference lists of publications identified. The review followed PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines. The Joanna Briggs Institute's checklists for case reports, case-series, case-control studies and analytical cross-sectional-studies were used to appraise the quality of identified articles. RESULTS: Eighteen studies (comprising five case-series, seven cross-sectional studies, three case-control studies, one case report, one quasi-experimental study and one diagnostic-accuracy study) were included for evaluation, containing 1628 cases. Eleven were rated of good quality. 97.5% of all cases were female. No studies documented that they had excluded all possible causes of telogen hair shedding. Only three studies (encompassing eight cases) featured a prospective follow-up. All eight studies that undertook biopsies reported a normal terminal to vellus hair ratio in the samples analysed. No studies objectively evaluated the influence of hair length or psychological distress/preoccupation on the likelihood of being diagnosed with chronic telogen effluvium. CONCLUSIONS: The lack of a consensual consistent definition for chronic telogen effluvium is a significant limitation. Many cases presently labelled chronic telogen effluvium likely either represent early female pattern hair loss or incipient secondary telogen effluvium owing to an unidentified underlying secondary cause. Where triggering factors have been definitively excluded, hair shedding may represent an alteration in the hair cycle away from normal total asynchronous cycling. Some cases may also represent a preoccupation with normal hair shedding in anxious long-haired individuals.

Alopecia areata and risk of atopic and autoimmune conditions: population-based cohort study.

BACKGROUND: Alopecia areata (AA) has features of both autoimmune and atopic pathogenesis, but information on the risk of people with AA developing autoimmune and atopic conditions is limited. OBJECTIVE: To assess the prevalence and incidence of atopic and autoimmune conditions in people with AA. METHODS: This was a population-based cohort study of 8051 adults with newly diagnosed AA (AA group) and 32 204 adults in the matched control group, using the UK Oxford-Royal College of General Practitioners (RCGP) Research and Surveillance Centre (RSC) network primary care database, 2009-2018 (trial registration number: NCT04239521). Baseline prevalence of common atopic and autoimmune conditions, and risk of new-onset atopic and autoimmune disease, were estimated. RESULTS: Atopic and autoimmune conditions were more prevalent in the AA group than the control group (atopic 37.2% vs. 26.7%, autoimmune 11.5% vs. 7.9%). The AA group were 43% more likely to develop any new-onset atopic condition [adjusted hazard ratio (aHR) 1.43. 95% confidence interval (CI) 1.28-1.61] and 45% more likely to develop any autoimmune condition (aHR 1.45, 95% CI 1.28-1.66) compared with the control group. When examining individual conditions, the AA group were at increased risk of atopic dermatitis (aHR 1.91, 95% CI 1.67-2.19), allergic rhinitis (aHR 1.32, 95% CI 1.14-1.54), autoimmune hypothyroidism (aHR 1.65, 95% CI 1.35-2.02), systemic lupus erythematosus (aHR 4.51, 95% CI 1.88-10.82) and vitiligo (aHR 2.39, 95% CI 1.49-3.82). There was no evidence for a higher incidence of other conditions examined. CONCLUSION: People with AA have an increased burden of atopic and autoimmune comorbidity. This supports previous work suggesting that both T helper cell (Th)1 and Th2 immune responses may be implicated in the pathogenesis of AA.

Alopecia areata and risk of common infections: a population-based cohort study.

BACKGROUND: It is not known whether alopecia areata (AA) is associated with a greater or reduced risk for infection. AIM: We undertook a population-based study exploring associations between AA and common infections. METHODS: We extracted primary care records from the UK Oxford-Royal College of General Practitioners Research and Surveillance Centre database (trial registration: NCT04239521). The incidence of common and viral infection composite outcomes, and individual respiratory, gastrointestinal (GI), skin, urinary tract, genital and herpes infections, were compared in people with AA (AA group, n = 10 391) and a propensity-matched control group (n = 41 564). Adjusted hazard ratios (aHRs), controlling for sociodemographic and clinical covariates, and comorbidities were used to estimate the association between AA and each infection over 5 years. RESULTS: The incidence (per 100 person-years) of common infections was slightly higher in the AA group [14.2, 95% confidence interval (CI) 13.8-14.6] than the control group (11.7, 95% CI 11.5-11.9). In adjusted analysis, positive associations were observed for composite outcomes (common infections aHR 1.13, 95% CI 1.09-1.17; viral infections aHR 1.11, 95% CI 1.07-1.16) and with respiratory tract, GI, skin and herpes simplex infections (aHR range 1.09-1.32). Excluding people in the control group without a recent consultation with their general practitioner showed no association between AA and infection (common infections aHR 1.01, 95% CI 0.98-1.05, viral infections aHR 0.99, 95% CI 0.95-1.03). CONCLUSIONS: The association between AA and common infection may represent a higher propensity of people with AA to engage with healthcare services (and thereby to have infections recorded), rather than a true association between AA and infection. Overall our findings suggest that AA is not associated with a clinically significantly increased or decreased incidence of common infections.

The associated burden of mental health conditions in alopecia areata: a population-based study in UK primary care.

BACKGROUND: Alopecia areata (AA) is a common cause of nonscarring hair loss that can have a profound psychological impact. OBJECTIVES: To assess the co-occurrence of depression and anxiety in adults with AA compared with the general population, and to evaluate the mental health treatment burden and impact on time off work and unemployment. METHODS: In total, 5435 people with newly diagnosed AA in UK primary care were identified from the Oxford Royal College of General Practitioners Research and Surveillance Centre network database, and matched to 21 740 controls. In cases and controls, we compared the prevalence and incidence of depressive episodes, recurrent depressive disorder and anxiety disorder, rates of time off work and unemployment, and, in those with pre-existing mental health conditions, rates of mental health-related prescribing and referral rates. This observational was registered with ClinicalTrials.gov (NCT04239521). RESULTS: Depression and anxiety were more prevalent in people diagnosed with AA than in controls (P < 0·001). People with AA were also more likely to subsequently develop new-onset depression and anxiety: adjusted hazard ratio (aHR) for recurrent depressive disorder 1·38 [95% confidence interval (CI) 1·13-1·69], depressive episodes aHR 1·30 (95% CI 1·04-1·62) and anxiety disorder aHR 1·33 (95% CI 1·09-1·63); to be issued time off work certificates (aHR 1·56, 95% CI 1·43-1·71); and to be recorded as unemployed (aHR 1·82, 95% CI 1·33-2·49). Higher rates of antidepressant prescribing were also seen in people with AA. CONCLUSIONS: People with AA have higher rates of depression and anxiety than those without AA. This impacts deleteriously on mental health treatment burden, time off work and unemployment. Evidence-based mental health treatment programmes are needed for people with AA.

Epidemiology, management and the associated burden of mental health illness, atopic and autoimmune conditions, and common infections in alopecia areata: protocol for an observational study series.

INTRODUCTION: Alopecia areata (AA) is a common cause of immune-mediated non-scarring hair loss. Links between AA and common mental health, autoimmune and atopic conditions, and common infections have previously been described but remain incompletely elucidated and contemporary descriptions of the epidemiology of AA in the UK are lacking. METHODS AND ANALYSIS: Retrospective study series using a large population-based cohort (5.2 million) from the Oxford Royal College of General Practitioners (RCGP) Research and Surveillance Centre (RSC) database, exploring four themes: AA epidemiology, mental health comorbidities, autoimmune/atopic associations and common infections.In the epidemiology theme, we will describe the incidence and point prevalence of AA overall and by age, sex and sociodemographic factors. Healthcare utilisation (primary care visits and secondary care referrals) and treatments for AA will also be assessed. In the mental health theme, we will explore the prevalence and incidence of mental health conditions (anxiety, depressive episodes, recurrent depressive disorder, adjustment disorder, agoraphobia, self-harm and parasuicide) in people with AA compared with matched controls. We will also explore the mental health treatment patterns (medication and psychological interventions), time off work and unemployment rates. Within the autoimmune/atopic associations theme, we will examine the prevalence of atopic (atopic dermatitis, allergic rhinitis, asthma) and autoimmune conditions (Crohn's disease, ulcerative colitis, coeliac disease, type 1 diabetes, Hashimoto's thyroiditis, Graves' disease, rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, systemic lupus erythematosus (SLE), polymyalgia rheumatica, Sjögren's syndrome, psoriasis, vitiligo, multiple sclerosis, pernicious anaemia) in people with AA compared with matched controls. We will also estimate the incidence of new-onset atopic and autoimmune conditions after AA diagnosis. Within the common infections theme, we will examine the incidence of common infections (respiratory tract infection, pneumonia, acute bronchitis, influenza, skin infection, urinary tract infection, genital infections, gastrointestinal infection, herpes simplex, herpes zoster, meningitis, COVID-19) in people with AA compared with matched controls. ETHICS AND DISSEMINATION: The Health Research Authority decision tool classed this a study of usual practice, ethics approval was not required. Study approval was granted by the RCGP RSC Study Approval Committee. Results will be disseminated through peer-reviewed publications. OBSERVATIONAL STUDY REGISTRATION NUMBER: NCT04239521.

Shedding light on therapeutics in alopecia and their relevance to COVID-19.

As of July 9, 2020, there were more than 12 million confirmed cases of coronavirus disease 2019 (COVID-19) across the globe, with more than 550,000 deaths. Many European countries, including Belgium, the United Kingdom, Italy, and Spain, have had the highest numbers of fatalities per capita. This indicates the potential for the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus to overwhelm even the most advanced health care systems despite extreme societal interventions. Since its emergence, SARS-CoV-2 has disseminated across the globe, affecting the structure of global societies, infrastructure, and economies. Patients with alopecia are a diverse group who, for various indications, are prescribed a number of antimicrobials and antiandrogen treatments in addition to immunomodulatory therapies such as hydroxychloroquine, oral corticosteroids, and a range of broad immunosuppressants. These drugs are being scrutinized for their capacity to potentially affect SARS-CoV-2 outcomes. We examine these treatments and highlight the critical role that patient registries will play in generating real-world evidence to assess their impact on COVID-19 outcomes.

A Global eDelphi Exercise to Identify Core Domains and Domain Items for the Development of a Global Registry of Alopecia Areata Disease Severity and Treatment Safety (GRASS).

Importance: A recent expert consensus exercise emphasized the importance of developing a global network of patient registries for alopecia areata to redress the paucity of comparable, real-world data regarding the effectiveness and safety of existing and emerging therapies for alopecia areata. Objective: To generate core domains and domain items for a global network of alopecia areata patient registries. Evidence Review: Sixty-six participants, representing physicians, patient organizations, scientists, the pharmaceutical industry, and pharmacoeconomic experts, participated in a 3-round eDelphi process, culminating in a face-to-face meeting at the World Congress of Dermatology, Milan, Italy, June 14, 2019. Findings: Ninety-two core data items, across 25 domains, achieved consensus agreement. Twenty further noncore items were retained to facilitate data harmonization in centers that wish to record them. Broad representation across multiple stakeholder groups was sought; however, the opinion of physicians was overrepresented. Conclusions and Relevance: This study identifies the domains and domain items required to develop a global network of alopecia areata registries. These domains will facilitate a standardized approach that will enable the recording of a comprehensive, comparable data set required to oversee the introduction of new therapies and harness real-world evidence from existing therapies at a time when the alopecia areata treatment paradigm is being radically and positively disrupted. Reuse of similar, existing frameworks in atopic dermatitis, produced by the Treatment of Atopic Eczema (TREAT) Registry Taskforce, increases the potential to reuse existing resources, creates opportunities for comparison of data across dermatology subspecialty disease areas, and supports the concept of data harmonization.

The Alopecia Areata Consensus of Experts (ACE) study part II: Results of an international expert opinion on diagnosis and laboratory evaluation for alopecia areata.

BACKGROUND: We previously reported the Alopecia Areata Consensus of Experts study, which presented results of an international expert opinion on treatments for alopecia areata. OBJECTIVE: To report the results of the Alopecia Areata Consensus of Experts international expert opinion on diagnosis and laboratory evaluation for alopecia areata. METHODS: Fifty hair experts from 5 continents were invited to participate in a 3-round Delphi process. Consensus threshold was set at greater than or equal to 66%. RESULTS: Of 148 questions, expert consensus was achieved in 82 (55%). Round 1 consensus was achieved in 10 of 148 questions (7%). Round 2 achieved consensus in 47 of 77 questions (61%). The final face-to-face achieved consensus in 25 of 32 questions (78%). Consensus was greatest for laboratory evaluation (12 of 14 questions [86%]), followed by diagnosis (11 of 14 questions [79%]) of alopecia areata. Overall, etiopathogenesis achieved the least category consensus (31 of 68 questions [46%]). LIMITATIONS: The study had low representation from Africa, South America, and Asia. CONCLUSION: There is expert consensus on aspects of epidemiology, etiopathogenesis, clinical features, diagnosis, laboratory evaluation, and prognostic indicators of alopecia areata. The study also highlights areas where future clinical research could be directed to address unresolved hypotheses in alopecia areata patient care.

The Alopecia Areata Consensus of Experts (ACE) study: Results of an international expert opinion on treatments for alopecia areata.

BACKGROUND: A systematic review failed to identify any systemic therapy used in alopecia areata (AA) where use is supported by robust evidence from high-quality randomized controlled trials. OBJECTIVE: To produce an international consensus statement on the use and utility of various treatments for AA. METHODS: Fifty hair experts from 5 continents were invited to participate in a 3-round Delphi process. Agreement of 66% or greater was considered consensus. RESULTS: In the first round, consensus was achieved in 22 of 423 (5%) questions. After a face-to-face meeting in round 3, overall, consensus was achieved for only 130 (33%) treatment-specific questions. There was greater consensus for intralesional treatment of AA (19 [68%]) followed by topical treatment (25 [43%]). Consensus was achieved in 45 (36%) questions pertaining to systemic therapies in AA. The categories with the least consensus were phototherapy and nonprescription therapies. LIMITATIONS: The study included a comprehensive list of systemic treatments for AA but not all treatments used. CONCLUSION: Despite divergent opinions among experts, consensus was achieved on a number of pertinent questions. The concluding statement also highlights areas where expert consensus is lacking and where an international patient registry could enable further research.

Autosomal-dominant hypotrichosis with woolly hair: Novel gene locus on chromosome 4q35.1-q35.2.

Hypotrichosis simplex (HS) with and without woolly hair (WH) comprises a group of rare, monogenic disorders of hair loss. Patients present with a diffuse loss of scalp and/or body hair, which usually begins in early childhood and progresses into adulthood. Some of the patients also show hair that is tightly curled. Approximately 10 genes for autosomal recessive and autosomal dominant forms of HS have been identified in the last decade, among them five genes for the dominant form. We collected blood and buccal samples from 17 individuals of a large British family with HS and WH. After having sequenced all known dominant genes for HS in this family without the identification of any disease causing mutation, we performed a genome-wide scan, using the HumanLinkage-24 BeadChip, followed by a classical linkage analysis; and whole exome-sequencing (WES). Evidence for linkage was found for a region on chromosome 4q35.1-q35.2 with a maximum LOD score of 3.61. WES led to the identification of a mutation in the gene SORBS2, encoding sorbin and SH3 domain containing 2. Unfortunately, we could not find an additional mutation in any other patient/family with HS; and in cell culture, we could not observe any difference between cloned wildtype and mutant SORBS2 using western blotting and immunofluorescence analyses. Therefore, at present, SORBS2 cannot be considered a definite disease gene for this phenotype. However, the locus on chromosome 4q is a robust and novel finding for hypotrichosis with woolly hair. Further fine mapping and sequencing efforts are therefore warranted in order to confirm SORBS2 as a plausible HS disease gene.

Correction: Alopecia areata patients show deficiency of FOXP3+CD39+ T regulatory cells and clonotypic restriction of Treg TCRß-chain, which highlights the immunopathological aspect of the disease.

[This corrects the article DOI: 10.1371/journal.pone.0210308.].

Alopecia areata patients show deficiency of FOXP3+CD39+ T regulatory cells and clonotypic restriction of Treg TCRß-chain, which highlights the immunopathological aspect of the disease.

Alopecia areata (AA) is a hair loss disorder resulting from an autoimmune reaction against hair follicles. T-helper 1 cells are a major contributor to this disorder, but little is known about the role of T-regulatory cells (Tregs) in AA. Here, we analysed the distribution of circulating Treg subsets in twenty AA patients with active hair loss and fifteen healthy subjects by flow cytometry. The Treg suppressor HLA-DR+ subpopulation was significantly reduced in the patients (P<0.001) and there were significantly fewer cells expressing CD39 among the CD4+CD25+Foxp3+ Treg subpopulation in patients (P = 0.001). FOXP3 CD39 Treg cells were also reduced in hair follicles; by 75% in non-lesional skin and 90% in lesional skin, when compared to control healthy skin. To further characterise Treg cells in AA; Tregs (CD4+CD25+FOXP3+) were investigated for their TCRß sequence. PCR products analysed by Next Generation Sequencing techniques, showed that all frequent public clonotypes in AA Tregs were also present in controls at relatively similar frequencies, excepting two public clonotypes: CATSRDEGGLDEKLFF (V15 D1 J1-4) and CASRDGTGPSNYGYTF (V2 D1 J1-2), which were exclusively present in controls. This suggests that these Treg clonotypes may have a protective effect and that they may be an exciting subject for future therapeutic applications.

Genome-wide association study in frontal fibrosing alopecia identifies four susceptibility loci including HLA-B*07:02.

Frontal fibrosing alopecia (FFA) is a recently described inflammatory and scarring type of hair loss affecting almost exclusively women. Despite a dramatic recent increase in incidence the aetiopathogenesis of FFA remains unknown. We undertake genome-wide association studies in females from a UK cohort, comprising 844 cases and 3,760 controls, a Spanish cohort of 172 cases and 385 controls, and perform statistical meta-analysis. We observe genome-wide significant association with FFA at four genomic loci: 2p22.2, 6p21.1, 8q24.22 and 15q2.1. Within the 6p21.1 locus, fine-mapping indicates that the association is driven by the HLA-B*07:02 allele. At 2p22.1, we implicate a putative causal missense variant in CYP1B1, encoding the homonymous xenobiotic- and hormone-processing enzyme. Transcriptomic analysis of affected scalp tissue highlights overrepresentation of transcripts encoding components of innate and adaptive immune response pathways. These findings provide insight into disease pathogenesis and characterise FFA as a genetically predisposed immuno-inflammatory disorder driven by HLA-B*07:02.

Epigallocatechin-3 Gallate Inhibits STAT-1/JAK2/IRF-1/HLA-DR/HLA-B and Reduces CD8 MKG2D Lymphocytes of Alopecia Areata Patients.

BACKGROUND: Alopecia areata (AA) is associated with Interferon- γ (IFN-γ) mediated T-lymphocyte dysfunction and increased circulating Interleukine-17 (IL-17) levels. Epigallocatechin-3-gallate (EGCG) specifically inhibits IFN-γ pathways and unlike Janus Kinase 1 and 2 (JAK1/JAK2) inhibitors (tofacitinib, ruxolitinib), EGCG is safer, more cost-effective, and is a topically active agent. Our objective is to test the mode of action of EGCG in vitro and ex vivo using HaCat, Jurkat cell lines, and peripheral blood mononuclear cells (PBMCs) of AA patients and healthy controls (HCs), respectively. METHODS: distribution of T helper cells (Th1, Th17), and cytotoxic cells (CD8) in PBMCs isolated from 30 AA patients and 30 HCs was investigated by flowcytomterty. In vitro treatment of HaCat and Jurkat cells with 40 µm EGCG for 48 h was performed to measure the level of phosphorylation of signal transducer and activator of transcription protein STAT1, and replicated in ex vivo model using PBMCs of AA patients. RESULTS: Interestingly, 40 µm EGCG is capable of completely inhibiting phosphorylation of STAT1 after 48 h in HaCat and Jurkat cells and ex vivo in PBMCs of AA patients. Based on QPCR data, the action of EGCG on p-STAT1 seems to be mediated via downregulation of the expression of JAK2 but not JAK1 leading to the inhibition of human leukocyte antigens (HLA-DR and HLA-B) expression probably via IRF-1. On the other hand, AA patients have significantly increased levels of Th1, Th17, and CD8 cells and the production of IFN-γ and IL-17 by PBMCs in AA patients was significantly higher compared to HC; p = 0.008 and p = 0.006, respectively. Total numbers of CD8+ cells were not significantly different between treated and untreated samples. However, CD8+ cells with positive Natural killer group 2 member D (NKG2D) transmembrane receptor (CD8+ NKG2D+ subset) was significantly reduced when PBMCs were treated with 20 µm EGCG for 48 h. CONCLUSION: These results suggest that EGCG has a synergistic action that inhibits expression of HLA-DR and HLA-B molecules via the IFN-γ pathway to maintain immune privilege in HF; also it reduces CD8+ NKG2D+ subset.

Whole Genome Sequencing in an Acrodermatitis Enteropathica Family from the Middle East.

We report a family from Tabuk, Saudi Arabia, previously screened for Acrodermatitis Enteropathica (AE), in which two siblings presented with typical features of acral dermatitis and a pustular eruption but differing severity. Affected members of our family carry a rare genetic variant, p.Gly512Trp in the SLC39A4 gene which encodes a zinc transporter; disease is thought to result from zinc deficiency. Similar mutations have been reported previously; however, the variable severity within cases carrying the p.Gly512Trp variant and in AE overall led us to hypothesise that additional genetic modifiers may be contributing to the disease phenotype. Therefore whole genome sequencing was carried out in five family members, for whom material was available to search for additional modifiers of AE; this included one individual with clinically diagnosed AE. We confirmed that the p.Gly512Trp change in SLC39A4 was the only candidate homozygous change which was sufficiently rare (ExAC allele frequency 1.178e-05) and predicted deleterious (CADD score 35) to be attributable as a fully penetrant cause of AE. To identify other genes which may carry relevant genetic variation, we reviewed the relevant literature and databases including Gene Ontology Consortium, GeneMANIA, GeneCards, and MalaCards to identify zinc transporter genes and possible interacting partners. The affected individual carried variants in RECQL4 and GPAA1 genes with ExAC allele frequency <0.01 and CADD score >10. p.Gly512Trp is highly likely to be the pathogenic variant in this family. This variant was previously detected in a Tunisian proband with perfect genotype-phenotype segregation suggestive of pathogenicity. Further research is required in this area due to small sample size, but attention should be given to RECQL4 and GPAA1 to understand their role in the skin disease.