Interleukin-15 is a hair follicle immune privilege guardian.

The autoimmunity-promoting cytokine, Interleukin-15 (IL-15), is often claimed to be a key pathogenic cytokine in alopecia areata (AA). Yet, rhIL-15 promotes human hair follicle (HF) growth ex vivo. We have asked whether the expression of IL-15 and its receptor (IL-15R) isoforms is altered in human AA and how IL-15 impacts on human HF immune privilege (HF-IP) in the presence/absence of interferon-γ (IFNγ), the well-documented key AA-pathogenic cytokine, as well as on hair regrowth after experimental AA induction in vivo. Quantitative immunohistomorphometry showed the number of perifollicular IL-15+ T cells in AA skin biopsies to be significantly increased compared to healthy control skin, while IL-15, IL-15Rα, and IL-15Rγ protein expression within the hair bulb were significantly down-regulated in AA HFs. In organ-cultured human scalp HFs, rhIL-15 significantly reduced hair bulb expression of MICA, the key "danger" signal in AA pathogenesis, and increased production of the HF-IP guardian, α-MSH. Crucially, ex vivo, rhIL-15 prevented IFNγ-induced HF-IP collapse, restored a collapsed HF-IP by IL-15Rα-dependent signaling (as documented by IL-15Rα-silencing), and protected AA-preventive immunoinhibitory iNKT10 cells from IFNγ-induced apoptosis. rhIL-15 even promoted hair regrowth after experimental AA induction in human scalp skin xenotransplants on SCID/beige mice in vivo. Our data introduce IL-15 as a novel, functionally important HF-IP guardian whose signaling is constitutively defective in scalp HFs of AA patients. Our data suggest that selective stimulation of intrafollicular IL-15Rα signaling could become a novel therapeutic approach in AA management, while blocking it pharmacologically may hinder both HF-IP restoration and hair re-growth and may thus make HFs more vulnerable to AA relapse.

Dandruff lesional scalp skin exhibits epidermal T cell infiltration and a weakened hair follicle immune privilege.

OBJECTIVE: Dandruff is characterised by the presence of perivascular leukocytes and mild inflammation; however, the immune microenvironment of dandruff-affected scalp skin and the potential changes to the hair follicle's (HF) physiological immune privilege (HF IP) remain unknown. Here, we characterised the HF immune microenvironment and immune privilege status in dandruff-affected scalp skin. METHODS: We assessed relevant key parameters in healthy versus dandruff-affected human scalp biopsies using quantitative immunohistomorphometry, laser capture microdissection, and RNA sequencing. RESULTS: The number of epidermal CD4+ and CD8+ T cells was increased in lesional dandruff scalp skin, while the number of MHC class II+ /CD1a+ Langerhans cells was decreased in the infundibulum. The number of intrafollicular and perifollicular CD4+ T cells and CD8+ T cells, perifollicular CD68+ macrophages, and tryptase+ mast cells remained unchanged. Interestingly, MHC class Ia and ß2-microglobulin protein expression were significantly increased specifically in the suprabulbar outer root sheath (ORS) compartment of dandruff-associated HFs. RNAseq analysis of laser capture micro-dissected suprabulbar ORS compartment revealed antigen presentation pathway as the top regulated canonical pathway, along with the upregulation of HF-IP genes such as HLA-C, HLA-DP, and TAP1, which are normally down-regulated in healthy HFs. Intrafollicular protein expression of known HF IP guardians (CD200 and α-MSH) and 'danger signals' (MICA and CXCL10) remained unaltered at the IP sites of dandruff lesional HFs compared to non-lesional and healthy HFs. Instead, the expression of macrophage migration inhibiting factor (MIF), another HF IP guardian, was reduced. CONCLUSION: Together, this work shows that dandruff is associated with epidermal T-cell infiltration and a weakened HF IP in the suprabulbar ORS of HFs in dandruff lesional scalp.

OBJECTIF: Les pellicules sont caractérisées par la présence de leucocytes périvasculaires et une légère inflammation. Cependant, le microenvironnement immunitaire de la peau du cuir chevelu affectée par les pellicules et les modifications potentielles du privilège immunitaire physiologique du follicule pileux (PI FP) restent inconnus. Ici, nous avons caractérisé le microenvironnement immunitaire du follicule pileux (FP) et l'état du privilège immunitaire de la peau du cuir chevelu affectée par les pellicules. MÉTHODES: Nous avons évalué les principaux paramètres pertinents dans des biopsies de cuir chevelu humain sain par rapport à ceux touchés par les pellicules, à l'aide d'une immuno-histomorphométrie quantitative, d'une microdissection au laser et d'un séquençage de l'ARN. RÉSULTATS: Le nombre de lymphocytes T CD4+ et CD8+ épidermiques a augmenté dans la peau du cuir chevelu atteinte de pellicules lésionnelles, tandis que le nombre de cellules de Langerhans du CMH de classe II+ /CD1a+ a diminué dans l'infundibulum. Le nombre de lymphocytes T CD4+ et de lymphocytes T CD8+ intrafolliculaires et périfolliculaires, de macrophages CD68+ périfolliculaires et de mastocytes tryptase+ est resté inchangé. Il est intéressant de noter que l'expression des protéines du CMH de classe Ia et de la ß2-microglobuline a augmenté de manière significative dans le compartiment suprabulbaire de la gaine radiculaire externe (GRE) en particulier des FP associés aux pellicules. L'analyse par séquençage ARN du compartiment suprabulbaire de la GRE micro-disséquée au laser a révélé que la voie de présentation de l'antigène était la voie canonique la plus régulée, ainsi que la régulation à la hausse des gènes PI-FP tels que HLA-C, HLA-DP et TAP1, qui sont normalement régulés à la baisse dans les FP sains. L'expression protéique intrafolliculaire des gardiens connus du PI FP (CD200 et α-MSH) et des « signaux de danger ¼ (MICA et CXCL10) est restée inchangée au niveau des sites du PI des FP à pellicules lésionnelles par rapport aux FP sans pellicules lésionnelles et sains. En revanche, l'expression du facteur d'inhibition de la migration des macrophages (MIF), un autre gardien du PI FP, a été réduite. CONCLUSION: L'ensemble de ces travaux montrent que les pellicules sont associées à une infiltration épidermique des lymphocytes T et à un affaiblissement du PI FP dans la GRE suprabulbaire des FP du cuir chevelu atteint de pellicules lésionnelles.

A folliculocentric perspective of dandruff pathogenesis: Could a troublesome condition be caused by changes to a natural secretory mechanism?

Dandruff is a common scalp condition, which frequently causes psychological distress in those affected. Dandruff is considered to be caused by an interplay of several factors. However, the pathogenesis of dandruff remains under-investigated, especially with respect to the contribution of the hair follicle. As the hair follicle exhibits unique immune-modulatory properties, including the creation of an immunoinhibitory, immune-privileged milieu, we propose a novel hypothesis taking into account the role of the hair follicle. We hypothesize that the changes and imbalance of yeast and bacterial species, along with increasing proinflammatory sebum by-products, leads to the activation of immune response and inflammation. Hair follicle keratinocytes may then detect these changes in scalp microbiota resulting in the recruitment of leukocytes to the inflammation site. These changes in the scalp skin immune-microenvironment may impact hair follicle immune privilege status, which opens new avenues into exploring the role of the hair follicle in dandruff pathogenesis. Also see the video abstract here: https://youtu.be/mEZEznCYtNs.

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.

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.

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.

Human epithelial stem cell survival within their niche requires "tonic" cannabinoid receptor 1-signalling-Lessons from the hair follicle.

The endocannabinoid system (ECS) regulates multiple aspects of human epithelial physiology, including inhibition/stimulation of keratinocyte proliferation/apoptosis, respectively. Yet, how the ECS impacts on human adult epithelial stem cell (eSC) functions remains unknown. Scalp hair follicles (HFs) offer a clinically relevant, prototypic model system for studying this directly within the native human stem cell niche. Here, we show in organ-cultured human HFs that, unexpectedly, selective activation of cannabinoid receptor-1 (CB1)-mediated signalling via the MAPK (MEK/Erk 1/2) and Akt pathways significantly increases the number and proliferation of cytokeratin CK15+ or CK19+ human HF bulge eSCs in situ, and enhances CK15 promoter activity in situ. In striking contrast, CB1-stimulation promotes apoptosis in the differentiated progeny of these eSCs (CK6+ HF keratinocytes). Instead, intrafollicular CB1 gene knockdown or CB1 antagonist treatment significantly reduces human HF eSCs numbers and stimulates their apoptosis, while CB1 knockout mice exhibit a reduced bulge eSCs pool in vivo. This identifies "tonic" CB1 signalling as a required survival stimulus for adult human HF eSCs within their niche. This novel concept must be taken into account whenever the human ECS is targeted therapeutically.

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.

Permanent hair loss associated with taxane chemotherapy use in breast cancer: A retrospective survey at two tertiary UK cancer centres.

PURPOSE: Taxane chemotherapy is commonly used in the management of breast cancer. Hair loss (alopecia) is an expected side effect which may have a significant effect on quality of life. Alopecia is normally temporary but permanent chemotherapy-induced alopecia (pCIA) is increasingly recognised especially following docetaxel chemotherapy. However, the prevalence following docetaxel is not well understood and there is no published literature for paclitaxel chemotherapy. The aim of this study is to investigate the prevalence and patterns of pCIA resulting from both docetaxel and paclitaxel chemotherapy at two tertiary UK cancer centres. METHODS: In collaboration between Clatterbridge Cancer Centre and The Christie NHS Foundation Trusts, a retrospective survey was conducted for breast cancer patients who had received taxane chemotherapy in the neoadjuvant and adjuvant settings. Patients who had concluded chemotherapy at least a year previously were contacted by post and invited to participate by completing a questionnaire and returning it to their treatment centre. Data collected included the incidence and pattern of pCIA using the Savin pictorial hair loss scale, and the methods used by patients to manage it. Fisher's exact test was used to compare pCIA between the docetaxel and paclitaxel cohorts. RESULTS: 383 patients responded to the survey (a 63.3% overall response rate). These comprised 245 patients receiving docetaxel and 138 patients treated with paclitaxel. pCIA was reported by 23.3% of patients receiving docetaxel and 10.1% paclitaxel (p < 0.01). Overall 16.7% of patients in both groups reported the ongoing use of products or appliances such as wigs to camouflage their pCIA. In the docetaxel group, pCIA appeared to be more frequent in post-menopausal women than peri- or pre-menopausal women (37.8%, 12.3% and 19.6% respectively [Chi-square test p < 0.01]). Also in the docetaxel group, there appeared to be a trend for more severe scalp alopecia when the patient also received an aromatase inhibitor (AI) or tamoxifen and this difference was most marked in those who had received both an AI and tamoxifen as components of their treatment regime (p = 0.04). The use of scalp cooling was only recorded in the Christie paclitaxel group (n = 12). Of these 12 patients, 83.3% reported no hair loss. While overall rates of permanent eyebrow, eyelash and nostril hair loss were low, this pattern of hair loss appeared more frequent in the paclitaxel than the docetaxel group 4.3% vs. 1.8% (p = 0.29). CONCLUSIONS: Both docetaxel and paclitaxel may cause permanent scalp hair loss, but it is significantly more prevalent with docetaxel compared with paclitaxel. IMPLICATIONS FOR CANCER SURVIVORS: Clinicians should counsel patients regarding the risk of permanent alopecia prior to embarking upon taxane chemotherapy and routinely offer scalp cooling if available. More research is required to understand the pathobiology of this important and previously under recognised long-term side effect to enable more active preventive and management approaches.

Cholesterol homeostasis: Links to hair follicle biology and hair disorders.

Lipids and lipid metabolism are critical factors in hair follicle (HF) biology, and cholesterol has long been suspected of influencing hair growth. Altered cholesterol homeostasis is involved in the pathogenesis of primary cicatricial alopecia, mutations in a cholesterol transporter are associated with congenital hypertrichosis, and dyslipidaemia has been linked to androgenic alopecia. The underlying molecular mechanisms by which cholesterol influences pathways involved in proliferation and differentiation within HF cell populations remain largely unknown. As such, expanding our knowledge of the role for cholesterol in regulating these processes is likely to provide new leads in the development of treatments for disorders of hair growth and cycling. This review describes the current state of knowledge with respect to cholesterol homeostasis in the HF along with known and putative links to hair pathologies.

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.

Lichen planopilaris is characterized by immune privilege collapse of the hair follicle's epithelial stem cell niche.

Lichen planopilaris (LPP) is a chronic inflammatory disease of unknown pathogenesis that leads to permanent hair loss. Whilst destruction of epithelial hair follicle stem cells (eHFSCs) that reside in an immunologically protected niche of the HF epithelium, the bulge, is a likely key event in LPP pathogenesis, this remains to be demonstrated. We have tested the hypotheses that bulge immune privilege (IP) collapse and inflammation-induced eHFSC death are key components in the pathogenesis of LPP. Biopsies of lesional and non-lesional scalp skin from adult LPP patients (n = 42) were analysed by quantitative (immuno)histomorphometry, real-time quantitative polymerase chain reaction (qRT-PCR), laser capture microdissection and microarray analysis, or skin organ culture. At both the protein and transcriptional level, lesional LPP HFs showed evidence for bulge IP collapse (ie increased expression of MHC class I and II, ß2microglobulin; reduced TGFß2 and CD200 expression). This was accompanied by a Th1-biased cytotoxic T cell response (ie increased CD8(+) GranzymeB(+) T cells and CD123(+) plasmacytoid dendritic cells, with increased CXCR3 expression) and increased expression of interferon-inducible chemokines (CXCL9/10/11). Interestingly, lesional LPP eHFSCs showed both increased proliferation and apoptosis in situ. Microarray analysis revealed a loss of eHFSC signatures and increased expression of T cell activation/binding markers in active LPP, while bulge PPARγ transcription was unaltered compared to non-lesional LPP HFs. In organ culture of non-lesional LPP skin, interferon-γ (IFNγ) induced bulge IP collapse. LPP is an excellent model disease for studying and preventing immune destruction of human epithelial stem cells in situ. These novel findings raise the possibility that LPP represents an autoimmune disease in whose pathogenesis IFNγ-induced bulge IP collapse plays an important role. Therapeutically, bulge IP protection/restoration may help to better manage this highly treatment-resistant cicatricial alopecia.

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.

Vibration assisted analgesia during intralesional corticosteroid therapy for alopecia.

Intralesional corticosteroid therapy (ICT) is a recommended management strategy for various inflammatory hair loss disorders. Pain from ICT can limit the use of this treatment, particularly in younger people and those with needle phobia. We present data demonstrating that vibration assisted analgesia, is a safe, effective and easy to use technique, which minimises pain from ICT, allowing its use in a wider cohort of patients.

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.