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Clinician-reported outcome measures (ClinROMs) are an important part of disease assessment in daily practice and clinical trials. There is a broad disagreement on the most appropriate ClinROM for a comprehensive assessment of alopecia areata (AA) severity. This paper aims to identify the currently available ClinROMs for AA through a systematic literature search, address their practical strengths and weaknesses, and identify the road ahead for future research. A search was conducted of the published, peer-reviewed literature via PubMed (Medline) and EMBASE (via Ovid) databases. Articles published in English within the last 23 years (post-2000) that objectively measured AA severity were included. We did not select scoring systems that were solely based on patient-reported outcomes (PROs). The literature search identified 1376 articles, of which 27 were chosen for full-text review. Based on our eligibility criteria, fourteen articles were identified, describing sixteen different ClinROMs. Five ClinROMs solely measured scalp hair loss (SALT, SALTâ ¡, ALODEX, pSALT, and AA-IGA). Three trichoscopy-based ClinROMs assessed disease activity (AAPI, AAPS, and Coudability hair score). Six ClinROMs exclusively assessed non-scalp areas (BETA, BELA, ALBAS, ClinRO for Eyelash, Eyebrow, and Nail assessment). Two ClinROMs assessed both the scalp and beyond-scalp areas (AASI and AASc). The practical strengths and weaknesses of each assessment tool were described. Various practical limitations associated with established tools have impeded their universal implementation in routine clinical practice. There is a significant need for a holistic clinical severity scoring system to capture all the key severity identifiers beyond the involvement of the scalp.
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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.
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Alopecia Areata , Humanos , Alopecia/diagnóstico , Alopecia Areata/diagnóstico , Consenso , Morbilidad , Calidad de VidaAsunto(s)
Alopecia Areata , Azetidinas , Humanos , Niño , Alopecia Areata/tratamiento farmacológico , Purinas , Azetidinas/uso terapéuticoRESUMEN
Excitotoxicity, a neuronal death process in neurological disorders such as stroke, is initiated by the overstimulation of ionotropic glutamate receptors. Although dysregulation of proteolytic signaling networks is critical for excitotoxicity, the identity of affected proteins and mechanisms by which they induce neuronal cell death remain unclear. To address this, we used quantitative N-terminomics to identify proteins modified by proteolysis in neurons undergoing excitotoxic cell death. We found that most proteolytically processed proteins in excitotoxic neurons are likely substrates of calpains, including key synaptic regulatory proteins such as CRMP2, doublecortin-like kinase I, Src tyrosine kinase and calmodulin-dependent protein kinase IIß (CaMKIIß). Critically, calpain-catalyzed proteolytic processing of these proteins generates stable truncated fragments with altered activities that potentially contribute to neuronal death by perturbing synaptic organization and function. Blocking calpain-mediated proteolysis of one of these proteins, Src, protected against neuronal loss in a rat model of neurotoxicity. Extrapolation of our N-terminomic results led to the discovery that CaMKIIα, an isoform of CaMKIIß, undergoes differential processing in mouse brains under physiological conditions and during ischemic stroke. In summary, by identifying the neuronal proteins undergoing proteolysis during excitotoxicity, our findings offer new insights into excitotoxic neuronal death mechanisms and reveal potential neuroprotective targets for neurological disorders.
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Muerte Celular , Neuronas , Sinapsis , Animales , Masculino , Ratones , Ratas , Calpaína/metabolismo , Células Cultivadas , Inhibidores de Cisteína Proteinasa/farmacología , Péptidos y Proteínas de Señalización Intercelular/metabolismo , Ratones Endogámicos C57BL , Proteínas del Tejido Nervioso/metabolismo , Neuronas/patología , Neuronas/fisiología , Neuroprotección , Proteoma/análisis , Ratas Wistar , Accidente Cerebrovascular/patología , Sinapsis/patología , Sinapsis/fisiologíaRESUMEN
Alopecia areata (AA) has an impact on health-related quality of life (HRQoL). The Women's Androgenetic Alopecia Quality of Life (WAA-QoL) questionnaire is a reliable, validated HRQoL measure in women with androgenetic alopecia (AGA). There is no equivalent measure for female patients with AA. Data were collected as part of the Global Registry of Alopecia Areata Disease Severity and Treatment Safety (GRASS) Australia. The WAA-QoL, Dermatology Life Quality Index (DLQI) and Skindex-16 for AA, as well as the Severity of Alopecia Tool score, were extracted from GRASS for adult female patients. Cronbach's alpha and factor analysis were employed to determine the internal consistency of the measure, and nonparametric correlation testing assessed the validity of the questionnaire. Overall, 137 individuals completed the questionnaires. There was excellent internal consistency of the WAA-QoL among women with AA (Cronbach's α = 0.98). A moderate and high positive correlation was found between the WAA-QoL and the DLQI and the Skindex-16 for AA, respectively. The WAA-QoL is a reliable and valid assessment of HRQoL among women with AA.
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Alopecia Areata , Adulto , Humanos , Femenino , Calidad de Vida , Reproducibilidad de los Resultados , Encuestas y CuestionariosRESUMEN
Introduction: Precise evaluation of changes in hair count is crucial for monitoring progression of hair loss and the effects of treatment. The focus of this study is the comparison of the various examination and assessment techniques in terms of the precision of hair count change observed in trichoscopy images. Methods: Controlled hair extraction of the same scalp spot was used to simulate hair loss, and the different examination techniques were performed to detect this change. The investigators who performed the counting were blinded. Results: For trichoscopy images, the average error in determining the terminal hair count change (relative to total hair count) was 9 ± 1% for automatic assessment with manual correction and 0.4 ± 0.2% for hair-to-hair matched images. For phototrichogram, the automatic measurement results were found to deviate from truth on average by 12 ± 2%. The manually corrected hair count results were much closer to the truth with average deviation at the level of 7 ± 1%. The hair-to-hair matched results corresponded to approximately 0.6 ± 0.3% average discrepancy. Conclusion: Combination of manually corrected image processing, follicular mapping, and hair-to-hair matching appears to be the most precise way of evaluating the change in hair count over time. These novel techniques should be considered valuable, especially in research and clinical trials.
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Hipertricosis , Minoxidil , Administración Tópica , Alopecia/inducido químicamente , Alopecia/tratamiento farmacológico , Anilidas , Femenino , Humanos , Hipertricosis/inducido químicamente , Hipertricosis/tratamiento farmacológico , Minoxidil/uso terapéutico , Nitrilos , Estudios Retrospectivos , Compuestos de TosiloAsunto(s)
Hipertricosis , Minoxidil , Administración Tópica , Alopecia/inducido químicamente , Alopecia/tratamiento farmacológico , Anilidas , Femenino , Humanos , Hipertricosis/inducido químicamente , Hipertricosis/tratamiento farmacológico , Minoxidil/uso terapéutico , Nitrilos , Estudios Retrospectivos , Compuestos de TosiloRESUMEN
High-quality dermatology patient registries often require considerable time to develop and produce meaningful data. Development time is influenced by registry complexity and regulatory hurdles that vary significantly nationally and institutionally. The rapid emergence of the coronavirus disease 2019 (COVID-19) global pandemic has challenged health services in an unprecedented manner. Mobilization of the dermatology community in response has included rapid development and deployment of multiple, partially harmonized, international patient registries, reinventing established patient registry timelines. Partnership with patient organizations has demonstrated the critical nature of inclusive patient involvement. This global effort has demonstrated the value, capacity, and necessity for the dermatology community to adopt a more cohesive approach to patient registry development and data sharing that can lead to myriad benefits. These include improved utilization of limited resources, increased data interoperability, improved ability to rapidly collect meaningful data, and shortened response times to generate real-world evidence. We call on the global dermatology community to support the development of an international federation of patient registries to consolidate and operationalize the lessons learned during this pandemic. This will provide an enduring means of applying this knowledge to the maintenance and development of sustainable, coherent, and impactful patient registries of benefit now and in the future.
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COVID-19 , Pandemias , Humanos , Sistema de Registros , SARS-CoV-2RESUMEN
Tofacitinib is a JAK1/3 inhibitor used off-label to treat alopecia areata (AA). Oral tofacitinib undergoes extensive hepatic metabolism and has numerous drug interactions and a half-life of 3 hours necessitating twice daily dosing. Sublingual delivery bypasses hepatic first-pass metabolism, which may provide pharmacokinetic benefits and reduce gastrointestinal side effects. We investigate sublingual tofacitinib as a novel form of administration in a cohort of treatment-resistant patients. The objective of this work is to assess the efficacy and pharmacokinetics of sublingual tofacitinib in moderate-to-severe AA patients. An open-label, roll-over pilot clinical trial was conducted. Participants were recruited from a preceding trial. All responders (≥50% reduction in Severity of Alopecia Tool [SALT] score, SALT50) in the preceding trial continued on the same treatment (cyclosporine/placebo), whereas nonresponders rolled over to receive open-label sublingual tofacitinib 5 mg twice daily for 12 weeks. Treatment response as reduction in SALT score after 12 weeks (low: 15-29%, medium: 30-49%, good: 50-75%, and high grade: 75-100%) was measured. Pharmacokinetics was analyzed using liquid chromatography tandem mass spectrometry. Eighteen participants completed the trial. Total treatment response to tofacitinib was 37.5%. SALT50 was achieved in 12.5%. The mean improvement in SALT score was 15.57%. Mean maximum plasma concentration was 43.18 ng/ml occurring after 1 hour. Elimination half-life is estimated to be up to 11 hours. An estimated half-life of up to 11 hours may be achieved with sublingual tofacitinib, which is significantly longer than the oral form and may facilitate daily dosing. Larger clinical trials are required to further characterize its pharmacokinetics and efficacy.
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Alopecia Areata , Alopecia Areata/tratamiento farmacológico , Humanos , Piperidinas , Inhibidores de Proteínas Quinasas , Pirimidinas , Pirroles , Resultado del TratamientoRESUMEN
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.
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Alopecia/tratamiento farmacológico , Tratamiento Farmacológico de COVID-19 , Alopecia/clasificación , Antagonistas de Andrógenos/uso terapéutico , Antibacterianos/uso terapéutico , Antimaláricos/uso terapéutico , Ciclosporina/uso terapéutico , Glucocorticoides/uso terapéutico , Humanos , Hidroxicloroquina/uso terapéutico , Inmunosupresores/uso terapéutico , Inhibidores de las Cinasas Janus/uso terapéutico , Metotrexato/uso terapéutico , Pronóstico , Sistema de Registros , SARS-CoV-2RESUMEN
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.
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Alopecia Areata/epidemiología , Alopecia Areata/terapia , Sistema de Registros , Alopecia Areata/diagnóstico , Consenso , Técnica Delphi , Humanos , Internacionalidad , Índice de Severidad de la Enfermedad , Encuestas y CuestionariosRESUMEN
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.
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Alopecia Areata/diagnóstico , Consenso , Dermatología/normas , Carga Global de Enfermedades , Alopecia Areata/epidemiología , Alopecia Areata/etiología , Alopecia Areata/terapia , Comorbilidad , Técnica Delphi , Dermatología/métodos , Dermoscopía , Folículo Piloso/diagnóstico por imagen , Folículo Piloso/crecimiento & desarrollo , Folículo Piloso/patología , Humanos , Cooperación Internacional , Guías de Práctica Clínica como Asunto , Pronóstico , Factores de Riesgo , Índice de Severidad de la EnfermedadRESUMEN
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.
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Alopecia Areata/terapia , Administración Oral , Administración Tópica , Corticoesteroides/uso terapéutico , Factores de Edad , Alopecia Areata/tratamiento farmacológico , Terapia Combinada , Terapias Complementarias , Técnica Delphi , Fármacos Dermatológicos/uso terapéutico , Testimonio de Experto , Humanos , Inyecciones Intralesiones , Fototerapia , Índice de Severidad de la Enfermedad , Resultado del TratamientoRESUMEN
BACKGROUND: Oral Janus kinase (JAK) inhibitors are currently being investigated in phase II and phase III clinical trials for several inflammatory skin diseases including alopecia areata (AA). Topical JAK inhibitors have been investigated in atopic dermatitis, psoriasis, and AA. While a number of case series using topical JAK inhibitors in AA have been published, to date there have been no randomized controlled clinical trials. METHODS: We conducted a phase I, 28 week prospective, placebo-controlled, double-blind study in patients with alopecia universalis investigating hair regrowth with two topical JAK inhibitors, 2% tofacitinib and 1% ruxolitinib. Topical clobetasol dipropionate 0.005% was the active comparator while vehicle was used as the placebo control. Sixteen patients were recruited for the study. RESULTS: Six patients demonstrated partial hair regrowth in areas treated with 2% tofacitinib ointment applied twice daily. Five patients demonstrated partial hair regrowth in the areas treated with 1% ruxolitinib ointment. Ten patients demonstrated partial hair regrowth in the areas treated with clobetasol dipropionate 0.05% ointment. No regrowth was observed in the placebo treated area. Interestingly, generalized hair regrowth was observed in two patients. One patient had 100% regrowth over his entire scalp and eyebrows by week 24 but relapsed after 12 weeks. A second patient also experienced generalized scalp regrowth and significant eyebrow growth and continued to maintain growth 14 weeks later. CONCLUSION: Our findings suggest that topical JAK inhibitors could be developed as a potential new treatment for AA and alternative to clobetasol dipropionate 0.05% ointment.