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Anthony Bewley,1 Ignasi Figueras-Nart,2 Jainzhong Zhang,3 Mariana Guerreiro,4 Nicole Tietz,4 Sami Chtourou,4 Frederick Durand,4 Ulrike Blume-Peytavi5 1Department of Dermatology, The Royal London Hospital & Queen Mary University, London, UK; 2Department of Dermatology, University Hospital de Bellvitge, Barcelona, Spain; 3Department of Dermatology, Peking University People’s Hospital, Beijing, People’s Republic of China; 4Eli Lilly and Company Ltd, Indianapolis, IN, USA; 5Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Dermatology, Venereology and Allergology, Berlin, GermanyCorrespondence: Anthony Bewley, Department of Dermatology, The Royal London Hospital & Queen Mary University, London, UK, Tel +44 020 7767 3200, Email anthony.bewley@nhs.netPurpose: Alopecia areata (AA) is an autoimmune disease characterized by hair loss that has significant psychosocial implications. This study aims to describe the patient-reported burden of severe AA, coping mechanism and information needs using data from the multinational AA Patient Satisfaction and Unmet Need Survey.Patients and Methods: Participants with current or previous ≥ 50% scalp hair loss (n = 747) were recruited from 11 countries and completed a web-based survey that assessed demographics, clinical characteristics, disease burden and psychosocial impact. Data were stratified according to sex, current age, disease duration and current severity of scalp hair loss.Results: The mean (SD) age of participants was 43.8 (7.1) years, 55.3% were women, and 63.5% reported AA symptoms within 6 months of diagnosis. Most participants had black or brown hair (88.4%), reported a disease duration of 2 years or more (75.6%) and had current scalp hair loss of ≥ 50% (87.4%). Severe hair loss also extended to eyebrow (46.9%), eyelash (48.7), beard (61.5%) and body hair (73.2%). Participants commonly reported comorbidities such as anxiety (26.1%), depression (18.1%) and sleep problems (28.1%). The Dermatology Life Quality Index revealed a severe impact on quality of life; 86.2% of participants scored > 10. Mental health/mood was significantly affected; 55.8% of participants reported a substantial impact. Long-term effects included decreased self-esteem (32.9%), poor mental health (28.1%) and challenges in day-to-day activities (27.2%). Information needs were centered around treatment expectations, mental health, and available treatment options. More severe symptoms and a greater daily impact were reported by women and those with a longer disease duration.Conclusion: The study emphasizes the substantial burden, including impaired quality of life and psychological well-being, of severe AA on the lives of surveyed participants. The findings highlight the importance of comprehensive disease management strategies that address both physical and psychosocial aspects of AA.Plain language summary: Alopecia areata (AA) is a disease that results in hair loss and can greatly affect quality of life and well-being. The authors wanted to understand how this condition affects people’s lives and what they need to cope with it. A survey was completed by adults from 11 different countries who had current or past severe AA. The participants were asked about their demographics, their experiences with the condition and how it impacted their daily lives. The results showed that AA has a severe impact on their quality of life, including their mental health and daily activities. Participants also experienced decreased self-esteem and faced challenges in their relationships and daily routines, and many reported feeling anxious, depressed, and having trouble sleeping. Participants found different ways to cope with their condition and expressed a need for realistic expectations about treatment results, information about mental health, and treatment options. The study also found that women and those with a longer duration of AA tended to have more severe symptoms and the impact on their lives was greater. Overall, this study shows that current or previous episodes of severe AA had a significant impact on people’s lives, including their mental health and daily activities. It emphasizes the need for information about the condition and treatment options with realistic expectations. The findings help to better understand the experiences of people with AA and may aid the provision of appropriate support and information.Keywords: burden of disease, quality of life, disease management

Fiorenza Rancan,1 Xiao Guo,1 Keerthana Rajes,2 Polytimi Sidiropoulou,1 Fatemeh Zabihi,2 Luisa Hoffmann,1 Sabrina Hadam,1 Ulrike Blume-Peytavi,1 Eckart Rühl,3 Rainer Haag,2 Annika Vogt1 1Clinical Research Center for Hair and Skin Science, Department of Dermatology and Allergy, Charité–Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany; 2Institute of Chemistry and Biochemistry, Freie Universität Berlin, Berlin, Germany; 3Physical Chemistry, Institute of Chemistry and Biochemistry, Freie Universität Berlin, Berlin, GermanyCorrespondence: Fiorenza RancanClinical Research Center for Hair and Skin Science, Department of Dermatology and Allergy, Charitéplatz 1, Berlin, 10117, GermanyTel +49 30 450 518 347Fax +49 30 450 518 952Email fiorenza.rancan@charite.deIntroduction: Rapamycin (Rapa) is an immunosuppressive macrolide that inhibits the mechanistic target of rapamycin (mTOR) activity. Thanks to its anti-proliferative effects towards different cell types, including keratinocytes and T cells, Rapa shows promise in the treatment of skin diseases characterized by cell hyperproliferation. However, Rapa skin penetration is limited due to its lipophilic nature (log P = 4.3) and high molecular weight (MW = 914 g/mol). In previous studies, new microenvironment-sensitive core multishell (CMS) nanocarriers capable of sensing the redox state of inflamed skin were developed as more efficient and selective vehicles for macrolide delivery to inflamed skin.Methods: In this study, we tested such redox-sensitive CMS nanocarriers using an inflammatory skin model based on human skin explants co-cultured with Jurkat T cells. Serine protease (SP) was applied on skin surface to induce skin barrier impairment and oxidative stress, whereas phytohaemagglutinin (PHA), IL-17A, and IL-22 were used to activate Jurkat cells. Activation markers, such as CD45 and CD69, phosphorylated ribosomal protein S6 (pRP-S6), and IL-2 release were monitored in activated T cells, whereas pro-inflammatory cytokines were measured in skin extracts and culture medium.Results: We found that alteration of skin barrier proteins corneodesmosin (CDSN), occludin (Occl), and zonula occludens-1 (ZO-1) as well as oxidation-induced decrease of free thiol groups occurred upon SP-treatment. All Rapa formulations exerted inhibitory effects on T cells after penetration across ex vivo skin. No effects on skin inflammatory markers were detected. The superiority of the oxidative-sensitive CMS nanocarriers over the other formulations was observed with regard to drug delivery as well as downregulation of IL-2 release.Conclusion: Overall, our results demonstrate that nanocarriers addressing features of diseased skin are promising approaches to improve the topical delivery of macrolide drugs.Keywords: redox-sensitive nanoparticles, sirolimus, psoriasis, stratum corneum barrier, dermatology, drug release

Fiorenza Rancan, Ulrike Blume-Peytavi, Annika VogtClinical Research Center for Hair and Skin Science, Department of Dermatology and Allergy, Charité – Universitätsmedizin Berlin, GermanyAbstract: Biodegradable polymeric materials are ideal carrier systems for biomedical applications. Features like controlled and sustained delivery, improved drug pharmacokinetics, reduced side effects and safe degradation make the use of these materials very attractive in a lot of medical fields, with dermatology included. A number of studies have shown that particle-based formulations can improve the skin penetration of topically applied drugs. However, for a successful translation of these promising results into a clinical application, a more rational approach is needed to take into account the different properties of diseased skin and the fate of these polymeric materials after topical application. In fact, each pathological skin condition poses different challenges and the way diseased skin interacts with polymeric carriers might be markedly different to that of healthy skin. In most inflammatory skin conditions, the skin's barrier is impaired and the local immune system is activated. A better understanding of such mechanisms has the potential to improve the efficacy of carrier-based dermatotherapy. Such knowledge would allow the informed choice of the type of polymeric carrier depending on the skin condition to be treated, the type of drug to be loaded, and the desired release kinetics. Furthermore, a better control of polymer degradation and release properties in accordance with the skin environment would improve the safety and the selectivity of drug release. This review aims at summarizing the current knowledge on how polymeric delivery systems interact with healthy and diseased skin, giving an overview of the challenges that different pathological skin conditions pose to the development of safer and more specific dermatotherapies.Keywords: nanocarriers, nanoparticles, biodegradable polymers, skin penetration, hair follicles

BackgroundTreatment for both facial and truncal acne has not sufficiently been studied.ObjectivesTo evaluate the long-term safety and efficacy of trifarotene in both facial and truncal acne.MethodsIn a multicentre, open-label, 52-week study, patients with moderate facial and truncal acne received trifarotene 50 μg/g cream (trifarotene). Assessments included local tolerability, safety, investigator and physician's global assessments (IGA, PGA) and quality of life (QOL). A validated QOL questionnaire was completed by the patient at Baseline, Week 12, 26 and 52/ET.ResultsOf 453 patients enrolled, 342 (75.5%) completed the study. Trifarotene-related treatment-emergent adverse events (TEAEs) were reported in 12.6% of patients, and none was serious. Most related TEAEs were cutaneous and occurred during the first 3 months. Signs and symptoms of local tolerability were mostly mild or moderate and severe signs, and symptoms were reported for 2.2% to 7.1% of patients for the face and 2.5% to 5.4% for the trunk. Local irritation increased during the first week of treatment on the face and up to Weeks 2 to 4 on the trunk with both decreasing thereafter. At Week 12, IGA and PGA success rates were 26.6% and 38.6%, respectively. Success rates increased to 65.1% and 66.9%, respectively at Week 52. Overall success (both IGA and PGA success in the same patient) was 57.9% at Week 52. At Week 52 visit, 92/171 (53.8%) patients who had completed their assessments had scores from 0 to 1 (i.e. no effect of acne on their QOL) vs. 47/208 (22.6%) patients at Baseline visit.ConclusionIn this 52-week study, trifarotene was safe, well tolerated and effective in moderate facial and truncal acne.