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.

Treatment for central centrifugal cicatricial alopecia-Delphi consensus recommendations.

BACKGROUND: There is no established standard of care for treating central centrifugal cicatricial alopecia (CCCA), and treatment approaches vary widely. OBJECTIVE: To develop consensus statements regarding the use of various pharmacological therapies in treating adults with CCCA. METHODS: We invited 27 dermatologists with expertise in hair and scalp disorders to participate in a 3-round modified Delphi study between January and March 2023. Statements met strong consensus if 75% of respondents agreed or disagreed. Statements met moderate consensus if 55% or more but less than 75% agreed or disagreed. RESULTS: In round 1, 5 of 33 (15.2%) statements met strong consensus, followed by 9 of 28 (32.1%) in round 2. After the final round 3 meeting, strong consensus was reached for 20 of 70 (28.6%) overall statements. Two statements achieved moderate consensus. LIMITATIONS: This study included only English-speaking, US-based dermatologists and did not consider nonpharmacological therapies. CONCLUSION: Despite varying opinions among dermatologists, consensus was reached for several statements to help clinicians manage CCCA. We also highlight areas that lack expert consensus with the goal of advancing research and therapeutic options for CCCA.

Local and Sustained Baricitinib Delivery to the Skin through Injectable Hydrogels Containing Reversible Thioimidate Adducts.

Janus kinase (JAK) inhibitors are approved for many dermatologic disorders, but their use is limited by systemic toxicities including serious cardiovascular events and malignancy. To overcome these limitations, injectable hydrogels are engineered for the local and sustained delivery of baricitinib, a representative JAK inhibitor. Hydrogels are formed via disulfide crosslinking of thiolated hyaluronic acid macromers. Dynamic thioimidate bonds are introduced between the thiolated hyaluronic acid and nitrile-containing baricitinib for drug tethering, which is confirmed with 1H and 13C nuclear magnetic resonance (NMR). Release of baricitinib is tunable over six weeks in vitro and active in inhibiting JAK signaling in a cell line containing a luciferase reporter reflecting interferon signaling. For in vivo activity, baricitinib hydrogels or controls are injected intradermally into an imiquimod-induced mouse model of psoriasis. Imiquimod increases epidermal thickness in mice, which is unaffected when treated with baricitinib or hydrogel alone. Treatment with baricitinib hydrogels suppresses the increased epidermal thickness in mice treated with imiquimod, suggesting that the sustained and local release of baricitinib is important for a therapeutic outcome. This study is the first to utilize a thioimidate chemistry to deliver JAK inhibitors to the skin through injectable hydrogels, which has translational potential for treating inflammatory disorders.

Repurposing DPP4 Inhibition to Improve Hair Follicle Activation and Regeneration.

Skin injury and several diseases elicit fibrosis and induce hair follicle (HF) growth arrest and loss. The resulting alopecia and disfiguration represent a severe burden for patients, both physically and psychologically. Reduction of profibrotic factors such as dipeptidyl peptidase 4 (DPP4) might be a strategy to tackle this issue. We show DPP4 overrepresentation in settings with HF growth arrest (telogen), HF loss, and nonregenerative wound areas in mouse skin and human scalp. Topical DPP4 inhibition with Food and Drug Administration/European Medicines Agency-approved sitagliptin on preclinical models of murine HF activation/regeneration results in accelerated anagen progress, whereas treatment of wounds with sitagliptin results in reduced expression of fibrosis markers, increased induction of anagen around wounds, and HF regeneration in the wound center. These effects are associated with higher expression of Wnt target Lef1, known to be required for HF anagen/HF-activation and regeneration. Sitagliptin treatment decreases profibrotic signaling in the skin, induces a differentiation trajectory of HF cells, and activates Wnt targets related to HF activation/growth but not those supporting fibrosis. Taken together, our study shows a role for DPP4 in HF biology and shows how DPP4 inhibition, currently used as oral medication to treat diabetes, could be repurposed into a topical treatment agent to potentially reverse HF loss in alopecia and after injury.

Differential modularity of the mammalian Engrailed 1 enhancer network directs sweat gland development.

Enhancers are context-specific regulators of expression that drive biological complexity and variation through the redeployment of conserved genes. An example of this is the enhancer-mediated control of Engrailed 1 (EN1), a pleiotropic gene whose expression is required for the formation of mammalian eccrine sweat glands. We previously identified the En1 candidate enhancer (ECE) 18 cis-regulatory element that has been highly and repeatedly derived on the human lineage to potentiate ectodermal EN1 and induce our species' uniquely high eccrine gland density. Intriguingly, ECE18 quantitative activity is negligible outside of primates and ECE18 is not required for En1 regulation and eccrine gland formation in mice, raising the possibility that distinct enhancers have evolved to modulate the same trait. Here we report the identification of the ECE20 enhancer and show it has conserved functionality in mouse and human developing skin ectoderm. Unlike ECE18, knock-out of ECE20 in mice reduces ectodermal En1 and eccrine gland number. Notably, we find ECE20, but not ECE18, is also required for En1 expression in the embryonic mouse brain, demonstrating that ECE20 is a pleiotropic En1 enhancer. Finally, that ECE18 deletion does not potentiate the eccrine phenotype of ECE20 knock-out mice supports the secondary incorporation of ECE18 into the regulation of this trait in primates. Our findings reveal that the mammalian En1 regulatory machinery diversified to incorporate both shared and lineage-restricted enhancers to regulate the same phenotype, and also have implications for understanding the forces that shape the robustness and evolvability of developmental traits.

Automating Hair Loss Labels for Universally Scoring Alopecia From Images: Rethinking Alopecia Scores.

Importance: Clinical estimation of hair density has an important role in assessing and tracking the severity and progression of alopecia, yet to the authors' knowledge, no automation currently exists for this process. While some algorithms have been developed to assess alopecia presence on a binary level, their scope has been limited by focusing on a re-creation of the Severity of Alopecia Tool (SALT) score for alopecia areata (AA). Yet hair density loss is common to all alopecia forms, and an evaluation of that loss is used in established scoring systems for androgenetic alopecia (AGA), central centrifugal cicatricial alopecia (CCCA), and many more. Objective: To develop and validate a new model, HairComb, to automatically compute the percentage hair loss from images regardless of alopecia subtype. Design, Setting, and Participants: In this research study to create a new algorithmic quantification system for all hair loss, computational imaging analysis and algorithm design using retrospective image data collection were performed. This was a multicenter study, where images were collected at the Children's Hospital of Philadelphia, University of Pennsylvania (Penn), and via a Penn Dermatology web interface. Images were collected from 2015 to 2021, and they were analyzed from 2019 to 2021. Main Outcomes and Measures: Scoring systems correlation analysis was measured by linear and logarithmic regressions. Algorithm performance was evaluated using image segmentation accuracy, density probability regression error, and average percentage hair loss error for labeled images, and Pearson correlation for manual scores. Results: There were 404 participants aged 2 years and older that were used for designing and validating HairComb. Scoring systems correlation analysis was performed for 250 participants (70.4% female; mean age, 35.3 years): 75 AGA, 66 AA, 50 CCCA, 27 other alopecia diagnoses (frontal fibrosing alopecia, lichen planopilaris, telogen effluvium, etc), and 32 unaffected scalps without alopecia. Scoring systems showed strong correlations with underlying percentage hair loss, with coefficient of determination R2 values of 0.793 and 0.804 with respect to log of percentage hair loss. Using HairComb, 92% accuracy, 5% regression error, 7% hair loss difference, and predicted scores with errors comparable to annotators were achieved. Conclusions and Relevance: In this research study,it is shown that an algorithm quantitating percentage hair loss may be applied to all forms of alopecia. A generalizable automated assessment of hair loss would provide a way to standardize measurements of hair loss across a range of conditions.

Wound-Induced Hair Neogenesis: A Portal to the Development of New Therapies for Hair Loss and Wound Regeneration.

Adult mammals retain the remarkable ability to regenerate hair follicles after wounding. Wound-induced hair neogenesis (WIHN) in many ways recapitulates embryogenesis. The origin of the stem cells that give rise to a nascent hair follicle after wounding and the role of mesenchymal cells and signaling pathways responsible for this regenerative phenomenon are slowly being elucidated. WIHN provides a potential therapeutic window for manipulating cell fate by the introduction of factors during the wound healing process to enhance hair follicle formation.

Wound-Induced Hair Neogenesis Model.

Skin wounds in adult mammals typically heal with a fibrotic scar and fail to restore ectodermal appendages, such as hair follicles or adipose tissue. Intriguingly, new hair follicles regenerate in the center of large full-thickness wounds of mice in a process called wound-induced hair neogenesis (WIHN). WIHN is followed by neogenesis of dermal adipose tissue. Both neogenic events reactivate embryonic-like cellular and molecular programs. The WIHN model provides a platform for studying mammalian regeneration, and findings from this model could instruct future regenerative medicine interventions for treating wounds and alopecia. Since Ito et al. rediscovered WIHN 15 years ago, numerous investigators have worked on the WIHN model using varying wounding protocols and model interpretations. Because a variety of factors, including environmental variables and choice of mouse strains, can affect the outcomes of a WIHN study, the purpose of this article is to provide an overview of the experimental variables that impact WIHN so that experiments between laboratories can be compared in a meaningful manner.

Thymic stromal lymphopoietin induces adipose loss through sebum hypersecretion.

Emerging studies indicate that the immune system can regulate systemic metabolism. Here, we show that thymic stromal lymphopoietin (TSLP) stimulates T cells to induce selective white adipose loss, which protects against obesity, improves glucose metabolism, and mitigates nonalcoholic steatohepatitis. Unexpectedly, adipose loss was not caused by alterations in food intake, absorption, or energy expenditure. Rather, it was induced by the excessive loss of lipids through the skin as sebum. TSLP and T cells regulated sebum release and sebum-associated antimicrobial peptide expression in the steady state. In human skin, TSLP expression correlated directly with sebum-associated gene expression. Thus, we establish a paradigm in which adipose loss can be achieved by means of sebum hypersecretion and uncover a role for adaptive immunity in skin barrier function through sebum secretion.

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.

Activation of TRPA1 nociceptor promotes systemic adult mammalian skin regeneration.

Adult mammalian wounds, with rare exception, heal with fibrotic scars that severely disrupt tissue architecture and function. Regenerative medicine seeks methods to avoid scar formation and restore the original tissue structures. We show in three adult mouse models that pharmacologic activation of the nociceptor TRPA1 on cutaneous sensory neurons reduces scar formation and can also promote tissue regeneration. Local activation of TRPA1 induces tissue regeneration on distant untreated areas of injury, demonstrating a systemic effect. Activated TRPA1 stimulates local production of interleukin-23 (IL-23) by dermal dendritic cells, leading to activation of circulating dermal IL-17-producing γδ T cells. Genetic ablation of TRPA1, IL-23, dermal dendritic cells, or γδ T cells prevents TRPA1-mediated tissue regeneration. These results reveal a cutaneous neuroimmune-regeneration cascade triggered by topical TRPA1 activators that promotes adult mammalian tissue regeneration, presenting a new avenue for research and development of therapies for wounds and scars.

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.

Single-cell analysis reveals fibroblast heterogeneity and myeloid-derived adipocyte progenitors in murine skin wounds.

During wound healing in adult mouse skin, hair follicles and then adipocytes regenerate. Adipocytes regenerate from myofibroblasts, a specialized contractile wound fibroblast. Here we study wound fibroblast diversity using single-cell RNA-sequencing. On analysis, wound fibroblasts group into twelve clusters. Pseudotime and RNA velocity analyses reveal that some clusters likely represent consecutive differentiation states toward a contractile phenotype, while others appear to represent distinct fibroblast lineages. One subset of fibroblasts expresses hematopoietic markers, suggesting their myeloid origin. We validate this finding using single-cell western blot and single-cell RNA-sequencing on genetically labeled myofibroblasts. Using bone marrow transplantation and Cre recombinase-based lineage tracing experiments, we rule out cell fusion events and confirm that hematopoietic lineage cells give rise to a subset of myofibroblasts and rare regenerated adipocytes. In conclusion, our study reveals that wounding induces a high degree of heterogeneity among fibroblasts and recruits highly plastic myeloid cells that contribute to adipocyte regeneration.

A cross-sectional survey and analysis of Dermatology Foundation Career Development Award recipients.

BACKGROUND: The Dermatology Foundation (DF) has a comprehensive career development award (CDA) program. OBJECTIVE: To assess the impact of this program, a cross-sectional survey of recipients receiving support between 1990 and 2012 was performed. METHODS: Award recipients completed a questionnaire concerning their career status and record of research funding. To verify the self-reported funding data, information about each awardee was extracted from the National Institutes of Health Research Portfolio Online Reporting Tools database and used to define funding acquired by CDA recipients. RESULTS: In all, 84% of CDA recipients responded to the survey. A total of 213 awardees (79%) hold full- or part-time positions in academic medicine. Approximately 70% of the award recipients in academic medicine have received federal research funding. The National Institutes of Health Research Portfolio Online Reporting Tools database and other sources indicated that the funding acquired by CDA recipients through 2015 and 2017 amounted to approximately $365.4 million and $451.8 million, respectively. Each dollar of DF CDA funding through 2015 (ie, $36.2 million) was linked to more than $10 in grant support through 2015 and $12 through 2017. LIMITATIONS: This cross-sectional survey was retrospective and (in part) self-reported. CONCLUSIONS: The DF has succeeded in supporting the career development of basic, translational, and clinical investigators and fostered the promotion and retention of these individuals in academic medicine.

Hedgehog stimulates hair follicle neogenesis by creating inductive dermis during murine skin wound healing.

Mammalian wounds typically heal by fibrotic repair without hair follicle (HF) regeneration. Fibrosis and regeneration are currently considered the opposite end of wound healing. This study sought to determine if scar could be remodeled to promote healing with HF regeneration. Here, we identify that activation of the Sonic hedgehog (Shh) pathway reinstalls a regenerative dermal niche, called dermal papilla, which is required and sufficient for HF neogenesis (HFN). Epidermal Shh overexpression or constitutive Smoothened dermal activation results in extensive HFN in wounds that otherwise end in scarring. While long-term Wnt activation is associated with fibrosis, Shh signal activation in Wnt active cells promotes the dermal papilla fate in scarring wounds. These studies demonstrate that mechanisms of scarring and regeneration are not distant from one another and that wound repair can be redirected to promote regeneration following injury by modifying a key dermal signal.