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.

Physician- and Patient-Reported Severity and Quality of Life Impact of Alopecia Areata: Results from a Real-World Survey in Five European Countries.

INTRODUCTION: Alopecia areata (AA) can negatively affect quality of life (QoL) and is associated with increased prevalence of anxiety and depression (vs people without AA). This study compared physician-assessed and patient self-rated severity of AA in a European sample and described the patient-reported burden of AA stratified by physician-assessed severity. METHODS: Real-world data were collected from the Adelphi Real World AA Disease Specific Programme™, a retrospective point-in-time cross-sectional survey of dermatologists and their adult patients with AA in five European countries (France, Germany, Italy, Spain, UK). Physicians provided clinical data and an AA severity assessment, according to their own definition of 'mild', 'moderate' and 'severe'. Patients were invited to provide their perception of AA severity and completed patient-reported outcome (PRO) questionnaires, including Skindex-16 for AA (Skindex-16 AA), EuroQol-5-dimension questionnaire 5-level (EQ-5D-5L), Hospital Anxiety and Depression Scale and the Work Productivity and Activity Impairment Questionnaire. RESULTS: Data for 2083 patients were collected by 239 physicians; 561 of these patients completed PRO questionnaires. In 78.5% of cases with available data (N = 549), there was alignment between patient and physician-rated AA severity (severity was rated higher by physicians in 15.7% of cases, by patients in 5.8% of cases). Data from all PRO instruments showed an increase in patient-reported burden and work and activity impairment with increasing physician-rated AA severity. For the Skindex-16 AA, the Emotions scale had the worst scores; anxiety/depression was the EQ-5D-5L dimension with the highest percentages of patients reporting any perceived problem. CONCLUSIONS: These data highlight the significant impact that AA can have beyond hair loss, especially for patients with severe AA. There was substantial physician-patient alignment on severity assessment. Higher physician-rated AA severity was associated with higher levels of patient-reported disease burden, including anxiety and depression, and work and activity impairment. These data may help inform appropriate treatment strategies.

Alopecia areata (AA) can negatively affect quality of life and is associated with increased prevalence of anxiety and depression (vs people without AA). This study used surveys of adult patients with AA in Europe and their dermatologists to compare how doctors and patients assess AA severity. We also looked at how patients rate the overall burden and broader effects of AA (not just hair loss) according to whether their doctor classed their AA as 'mild', 'moderate' or 'severe'. Data for 2083 patients were collected by 239 doctors; 561 patients completed questionnaires about their AA and its potential effects on their quality of life, mental health and ability to work or perform other activities. In 78.5% of cases (from 549 patients with both patient and doctor-rated severity), patients and their doctors agreed on the same AA severity category (mild, moderate or severe). However, in 15.7% of cases, doctors rated AA severity as being higher than reported by the patient, and in 5.8% of cases the patient classed their AA as being more severe than reported by the doctor. Data from patient questionnaires showed that the burden associated with AA was higher in patients with more severe AA (as per their doctor's own definition of severity); anxiety/depression was the most commonly reported problem related to quality of life. This study highlights the significant impact that AA can have beyond hair loss, especially for patients with severe AA. Information from this study may help to inform appropriate treatment strategies for people with AA.

A description of alopecia areata in European patients based on real-world survey data: physician-reported characterization of severity and associated treatment utilization.

Alopecia areata (AA), an autoimmune disease -affecting the hair of the scalp, face, and/or body, can entail substantial psychological and physical burden for patients. There is currently no international agreement on how to treat AA and the approach may vary across countries. This study investigated the management of AA in clinical practice. Data from a point-in-time survey conducted in France, Germany, Italy, Spain, and the United Kingdom, between October 2021-June 2022, were analysed for adults with mild, moderate, and severe AA, based on physician assessment. Dermatologists were surveyed about factors used to assess disease severity, physician-reported treatment goals, and treatment patterns for AA, including the use of wigs. In total, 239 dermatologists reported on 2,083 patients. Physicians' severity assessment and treatment goals were predominantly driven by scalp hair loss. Topical and intralesional corticosteroids were the most prescribed treatments for mild and moderate AA. Conventional immunosuppressants, oral Janus kinase inhibitors, and topical immunotherapy use generally increased with AA severity and therapy line. Wig use was greatest for severe AA. The primary reasons for the last treatment change in the moderate and severe groups were worsening of condition, lack of initial efficacy, and loss of response, and for mild group were improvement in condition, lack of initial efficacy, and worsening of condition. Findings were generally similar across countries. This analysis provides insights into the management of AA in five European countries and confirms the need for more effective therapies, especially for patients with severe AA.

Assessment of the Genetic Spectrum of Uncombable Hair Syndrome in a Cohort of 107 Individuals.

Importance: Uncombable hair syndrome (UHS) is a rare hair shaft anomaly that manifests during infancy and is characterized by dry, frizzy, and wiry hair that cannot be combed flat. Only about 100 known cases have been reported so far. Objective: To elucidate the genetic spectrum of UHS. Design, Setting, and Participants: This cohort study includes 107 unrelated index patients with a suspected diagnosis of UHS and family members who were recruited worldwide from January 2013 to December 2021. Participants of all ages, races, and ethnicities were recruited at referral centers or were enrolled on their own initiative following personal contact with the authors. Genetic analyses were conducted in Germany from January 2014 to December 2021. Main Outcomes and Measures: Clinical photographs, Sanger or whole-exome sequencing and array-based genotyping of DNA extracted from blood or saliva samples, and 3-dimensional protein modeling. Descriptive statistics, such as frequency counts, were used to describe the distribution of identified pathogenic variants and genotypes. Results: The genetic characteristics of patients with UHS were established in 80 of 107 (74.8%) index patients (82 [76.6%] female) who carried biallelic pathogenic variants in PADI3, TGM3, or TCHH (ie, genes that encode functionally related hair shaft proteins). Molecular genetic findings from 11 of these 80 individuals were previously published. In 76 (71.0%) individuals, the UHS phenotype were associated with pathogenic variants in PADI3. The 2 most commonly observed PADI3 variants account for 73 (48.0%) and 57 (37.5%) of the 152 variant PADI3 alleles in total, respectively. Two individuals carried pathogenic variants in TGM3, and 2 others carried pathogenic variants in TCHH. Haplotype analyses suggested a founder effect for the 4 most commonly observed pathogenic variants in the PADI3 gene. Conclusions and Relevance: This cohort study extends and gives an overview of the genetic variant spectrum of UHS based on molecular genetic analyses of the largest worldwide collective of affected individuals, to our knowledge. Formerly, a diagnosis of UHS could only be made by physical examination of the patient and confirmed by microscopical examination of the hair shaft. The discovery of pathogenic variants in PADI3, TCHH, and TGM3 may open a new avenue for clinicians and affected individuals by introducing molecular diagnostics for UHS.

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.

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.

Mutations in Three Genes Encoding Proteins Involved in Hair Shaft Formation Cause Uncombable Hair Syndrome.

Uncombable hair syndrome (UHS), also known as "spun glass hair syndrome," "pili trianguli et canaliculi," or "cheveux incoiffables" is a rare anomaly of the hair shaft that occurs in children and improves with age. UHS is characterized by dry, frizzy, spangly, and often fair hair that is resistant to being combed flat. Until now, both simplex and familial UHS-affected case subjects with autosomal-dominant as well as -recessive inheritance have been reported. However, none of these case subjects were linked to a molecular genetic cause. Here, we report the identification of UHS-causative mutations located in the three genes PADI3 (peptidylarginine deiminase 3), TGM3 (transglutaminase 3), and TCHH (trichohyalin) in a total of 11 children. All of these individuals carry homozygous or compound heterozygous mutations in one of these three genes, indicating an autosomal-recessive inheritance pattern in the majority of UHS case subjects. The two enzymes PADI3 and TGM3, responsible for posttranslational protein modifications, and their target structural protein TCHH are all involved in hair shaft formation. Elucidation of the molecular outcomes of the disease-causing mutations by cell culture experiments and tridimensional protein models demonstrated clear differences in the structural organization and activity of mutant and wild-type proteins. Scanning electron microscopy observations revealed morphological alterations in hair coat of Padi3 knockout mice. All together, these findings elucidate the molecular genetic causes of UHS and shed light on its pathophysiology and hair physiology in general.

Frontal Fibrosing Alopecia and Increased Scalp Sweating: Is Neurogenic Inflammation the Common Link?

Frontal fibrosing alopecia (FFA) is an uncommon scarring hair loss disorder that is characterized by a band-like recession of the frontal hair line with eyebrow hair loss. We present a series of patients with FFA and increased sweating predominantly localized to the scalp, and potential explanations for this association are discussed. We hypothesize that the reported increase in sweating seen in our patients may be in part related to the inflammatory process occurring locally within the skin, either inducing a local axonal sweating reflex or through direct modulation of sweat gland secretion by neuropeptides.

Canine olfactory detection of malignant melanoma.

Our patient is a 75-year-old man who presented after his pet dog licked persistently at an asymptomatic lesion behind his right ear. Examination revealed a nodular lesion in the postauricular sulcus. Histology confirmed malignant melanoma, which was subsequently excised. Canine olfactory detection of human malignancy is a well-documented phenomenon. Advanced olfaction is hypothesised to explain canine detection of bladder, breast, colorectal, lung, ovarian, prostate and skin cancers. Further research in this area may facilitate the development of a highly accurate aid to diagnosis for many malignancies, including melanoma.

Hair loss in patients with inflammatory bowel disease.

BACKGROUND: Little is known about the prevalence, causes, and management of hair loss in patients with inflammatory bowel disease (IBD). Despite the fact that there are relatively few case reports describing hair loss in IBD, anecdotally, it is a common clinical problem. Hair loss is associated with both acute and chronic illness, with nutritional deficiencies, and with adverse drug reactions, all of which are relevant to IBD. METHODS: A literature search was performed using PubMed from 1966 to July 2012 to identify all articles describing cases of and/or the cause of hair loss in patients with IBD. RESULTS: There is relatively little data describing the prevalence, cause, or course of hair loss in people with IBD. Because there are many potential reasons for hair loss in people with IBD, identifying the cause is not always possible. Telogen effluvium associated with acute or chronic flares of IBD is probably the commonest cause of disease-related hair loss, although the prevalence of this is unknown. Other causes include drug side effects and nutritional deficiencies. More recently shared genetic risk factors with alopecia areata and IBD have been identified. CONCLUSIONS: The potential causes of hair loss in IBD are protean, although its prevalence is unknown. A practical guide to assessing and managing patients with hair loss in IBD is presented.

Intravenous glomus tumour of the upper arm.

Glomus tumours are rare, benign tumours of the glomus body, most frequently located in the subungual region of digits, palms and soles, but they have been reported throughout the body. Our patient is a 65-year-old man who presented with a 3-year history of a very painful area on his left upper arm. The overlying skin was normal and there was no lesion to palpate, but the symptoms were very striking, warranting further investigation. An exploratory operation identified a prominent vein with a noticeable bulge in the vessel wall. The vein was ligated and excised. On dissection of the vein, a tumour was present within its lumen. Histological examination and immune profile of the tumour confirmed an intravascular glomus tumour. Following surgical excision, symptoms resolved.

Is erythromycin an effective treatment for chronic bullous disease of childhood? A national survey of members of the British Society for Paediatric Dermatology.

Chronic bullous disease of childhood is the commonest acquired blistering disorder of children. Erythromycin has been reported to be beneficial for this condition. A three question survey was e-mailed to all members of the British Society for Paediatric Dermatology to assess the incidence, preferred treatments and experience of oral erythromycin in treating chronic bullous disease of childhood. A second, more detailed questionnaire was sent to members who had used erythromycin. Forty patients were reported to have been treated over the previous 2 years. The preferred treatment was dapsone. Erythromycin alone had been used in five children as first-line oral treatment. In three of these patients the initial improvement was graded as either "good" or "complete resolution." This benefit was only sustained in one child, with the other two relapsing between 4 and 12 weeks. In a further eight children, erythromycin had been used with other oral agents. In five of these children, erythromycin was associated with long-term benefit. These results suggest that erythromycin is unlikely to produce sustained improvement in chronic bullous disease of childhood when used as a sole first-line agent. However, erythromycin can cause an initial improvement, which may be useful whilst awaiting results of diagnostic tests and may confer benefit when used with other systemic treatments.