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Page 7, Table 1, ASN002 row. The cell entry in column 4, "Manufacturer", which previously read: [ABSTRACT FROM AUTHOR]

Treat‐to‐target (T2T) is a pragmatic therapeutic strategy being gradually introduced into dermatology after adoption in several other clinical areas. Atopic dermatitis (AD), one of the most common inflammatory skin diseases, may also benefit from this structured and practical therapeutic approach. We aimed to evaluate existing data regarding the T2T approach in dermatology, with a specific focus on AD, as well as the views of International Eczema Council (IEC) members on the potential application of a T2T approach to AD management. To do so, we systematically searched for peer‐reviewed publications on the T2T approach for any skin disease in the PubMed and Scopus databases up to February 2022 and conducted a survey among IEC members regarding various components to potentially include in a T2T approach in AD. We identified 21 relevant T2T‐related reports in dermatology, of which 14 were related to psoriasis, five to AD, one for juvenile dermatomyositis and one for urticaria. In the IEC member survey, respondents proposed treatable traits (with itch, disease severity and sleep problems getting the highest scores), relevant comorbidities (with asthma being selected most commonly, followed by anxiety and depression in adults), recommended specialists that should define the approach in AD (dermatologists, allergists and primary care physicians were most commonly selected in adults), and applicable assessment tools (both physician‐ and patient‐reported), in both adult and paediatric patients, for potential future utilization of the T2T approach in AD. In conclusion, while the T2T approach may become a useful tool to simplify therapeutic goals and AD management, its foundation in AD is only starting to build. A multidisciplinary approach, including a wide range of stakeholders, including patients, is needed to further define the essential components needed to utilize T2T in AD. [ABSTRACT FROM AUTHOR]

Background: Our knowledge of etiopathogenesis of atopic dermatitis (AD) is largely derived from skin biopsies, which are associated with pain, scarring and infection. In contrast, tape‐stripping is a minimally invasive, nonscarring technique to collect skin samples. Methods: To construct a global AD skin transcriptomic profile comparing tape‐strips to whole‐skin biopsies, we performed RNA‐seq on tape‐strips and biopsies taken from the lesional skin of 20 moderate‐to‐severe AD patients and the skin of 20 controls. Differentially expressed genes (DEGs) were defined by fold‐change (FCH) ≥2.0 and false discovery rate <0.05. Results: We detected 4104 (2513 Up; 1591 Down) and 1273 (546 Up; 727 Down) DEGs in AD versus controls, in tape‐strips and biopsies, respectively. Although both techniques captured dysregulation of key immune genes, tape‐strips showed higher FCHs for innate immunity (IL‐1B, IL‐8), dendritic cell (ITGAX/CD11C, FCER1A), Th2 (IL‐13, CCL17, TNFRSF4/OX40), and Th17 (CCL20, CXCL1) products, while biopsies showed higher upregulation of Th22 associated genes (IL‐22, S100As) and dermal cytokines (IFN‐γ, CCL26). Itch‐related genes (IL‐31, TRPV3) were preferentially captured by tape‐strips. Epidermal barrier abnormalities were detected in both techniques, with terminal differentiation defects (FLG2, PSORS1C2) better represented by tape‐strips and epidermal hyperplasia changes (KRT16, MKI67) better detected by biopsies. Conclusions: Tape‐strips and biopsies capture overlapping but distinct features of the AD molecular signature, suggesting their respective utility for monitoring specific AD‐related immune, itch, and barrier abnormalities in clinical trials and longitudinal studies. [ABSTRACT FROM AUTHOR]

Circulating skin‐homing cutaneous lymphocyte‐associated antigen (CLA)+ T cells constitute a small subset of human memory T cells involved in several aspects of atopic dermatitis: Staphylococcus aureus related mechanisms, the abnormal Th2 immune response, biomarkers, clinical aspects of the patients, pruritus, and the mechanism of action of targeted therapies. Superantigens, IL‐13, IL‐31, pruritus, CCL17 and early effects on dupilumab‐treated patients have in common that they are associated with the CLA+ T cell mechanisms in atopic dermatitis patients. The function of CLA+ T cells corresponds with the role of T cells belonging to the skin‐associated lymphoid tissue and could be a reason why they reflect different mechanisms of atopic dermatitis and many other T cell mediated skin diseases. The goal of this review is to gather all this translational information of atopic dermatitis pathology. [ABSTRACT FROM AUTHOR]

1Images of patient 4 pre-ustekinumab treatment (A) and 31 months after starting ustekinumab treatment (B) In all patients, 3-5 doses of ustekinumab achieved complete or nearly complete SD clearance, except for one patient with particularly severe disease that necessitated 15 doses until full clinical resolution. Seborrheic dermatitis (SD) is an inflammatory skin disease that affects 50 million Americans of all ages, peaking in infancy and early adulthood [[1]]. [Extracted from the article]

Alopecia areata is an autoimmune hair loss disease that is non-scarring and is characterized by chronic inflammation at the hair follicle level. Clinically, patients' presentation varies from patchy, circumscribed scalp involvement to total body and scalp hair loss. Current management is guided by the degree of scalp and body involvement, with topical and intralesional steroid injections as primarily first-line for mild cases and broad immunosuppressants as the mainstay for more severe cases. Until recently, the limited number of blinded, randomized, placebo-controlled clinical trials for this disease had made establishing an evidence-based treatment paradigm challenging. However, growing insights into the pathogenesis of alopecia areata through blood and tissue analysis of human lesions have identified several promising targets for therapy. T-helper (Th) 1/interferon skewing has traditionally been described as the driver of disease; however, recent investigations suggest activation of additional immune mediators, including the Th2 pathway, interleukin (IL)-9, IL-23, and IL-32, as contributors to alopecia areata pathogenesis. The landscape of alopecia areata treatment has the potential to be transformed, as several novel targeted drugs are currently undergoing clinical trials. Given the recent US FDA approval of baricitinib and ritlecitinib, Janus kinase (JAK) inhibitors are a promising drug class for treating severe alopecia areata cases. This article will review the efficacy, safety, and tolerability of current treatments for alopecia areata, and will provide an overview of the emerging therapies that are leading the revolution in the management of this challenging disease. [ABSTRACT FROM AUTHOR]

Chronic hand eczema (CHE) is a common and burdensome inflammatory skin condition seen in up to 10% of the population, more often in high-risk occupational workers. Topical therapeutics comprise the standard of care, but up to 65% of cases do not resolve after treatment, and moderate-to-severe cases are often resistant to topical therapeutics and require systemic options instead. To date, there are no systemic therapeutics approved to treat CHE in the United States, but several drugs are under investigation as potential treatments for CHE. The primary focus of this review is on the novel therapeutics, topical and systemic, that are under investigation in recently completed or currently ongoing trials. This review also briefly outlines the existing treatments utilized for CHE, often with limited success or extensive adverse effects. CHE represents a major challenge for physicians and patients alike, and efforts to improve the minimally invasive diagnostic tools and treatment paradigms are ongoing. In the near future, CHE patients may benefit from new topical and systemic therapeutics that specifically target abnormally expressed immune markers. [ABSTRACT FROM AUTHOR]

The authors would like to correct the images in figures which are in wrong order and require swapping. [ABSTRACT FROM AUTHOR]

Introduction: Atopic dermatitis (AD) is an incurable, inflammatory skin disease characterized by skin barrier disruption and immune dysregulation. Although AD is considered a childhood disease, adult onset is possible, presenting with daily sleep disturbance and functional impairment associated with itch, neuropsychiatric issues (anxiety and depression), and reduced health-related quality of life. Although such aspects of adult AD disease burden have been measured through standardized assessments and based on population-level data, the understanding of the disease experienced at the patient level remains poor. This text-mining study assessed the impact of AD on the lives of adult patients as described from an experiential perspective. Methods: Natural language processing (NLP) was applied to qualitative patient response data from two large-scale international cross-sectional surveys conducted in the USA and countries outside of the USA (non-USA; Canada, France, Germany, Italy, Spain, and the UK). Descriptive analysis was conducted on patient responses to an open-ended question on how they felt about their AD and how the disease affected their life. Character length, word count, and stop word (common words) count were evaluated; centrality analysis identified concepts that were most strongly interlinked. Results: Patients with AD in all countries were most frequently impacted by itch, pain, and embarrassment across all levels of disease severity. Patients with moderate-to-severe AD were more likely than patients with mild AD to describe sleep disturbances, fatigue, and feelings of depression, anxiety, and a lack of hope that were directly associated with AD. Centrality analysis revealed sleep disturbance was strongly linked with itch. Collectively, these concepts revealed that patients with AD are impacted by both physical and emotional burdens that are intricately connected. Conclusions: Qualitative data from NLP, being more patient-centric than data from clinical standardized measures, provide a more comprehensive view of the burden of AD to inform disease management. [ABSTRACT FROM AUTHOR]

Data underlying the findings described in this manuscript may be obtained in accordance with AstraZeneca's data sharing policy described at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure. Lack of effect of benralizumab on signs and symptoms of moderate-to-severe atopic dermatitis: Results from the phase 2 randomized, double-blind, placebo-controlled HILLIER trial Ninety-six patients (including 26 adolescents) and 98 patients (27 adolescents) were randomized into the benralizumab and placebo groups, respectively. [Extracted from the article]

Background: The incidence of adult‐onset atopic dermatitis (AOAD) is increasing. However, the unique characteristics of AOAD compared to pediatric‐onset AD persisting into adulthood (POAD) are underexplored, hampering the development of targeted‐therapeutics for this growing population. We thus assessed the profile of AOAD in skin and blood compared to that of POAD. Methods: We collected skin biopsies and blood from adults with AOAD, POAD, and healthy controls (n = 15 in each group). Skin samples were analyzed by RNA sequencing, qRT‐PCR, and immunohistochemistry, and Olink Proseek multiplex assay was used to identify the serum proteomic profile. Results: Compared to healthy controls, both AOAD and POAD showed cutaneous immune and barrier dysregulations with a shared Th2/Th22 hyperactivation. Overall, POAD showed greater inflammation in lesional skin, with more prominent expression of Th2/Th17/Th22 markers (CCL17/22, S100A8/9, IL‐36A, PI3/Elafin, DEFB4) in POAD compared to AOAD (p‐value <.05). In contrast, higher Th1‐(IFN‐γ, IL‐2, IL‐15, CCL5) upregulation and Th1‐skewing were seen in AOAD. The epidermal barrier was also more compromised in POAD, with greater epidermal hyperplasia and lower expression of markers related to terminal differentiation, lipids, and cell adhesion. In parallel with increased rates of cardiovascular comorbidities, AOAD demonstrated many more significantly dysregulated proteins in serum (n = 148) compared to POAD (n = 86), including pro‐inflammatory and cardiovascular‐risk markers. Th1‐related products showed significant correlations between their skin and blood expressions only in AOAD subjects. Conclusion: Age‐of‐onset delineates two distinct endophenotypes in adult AD potentially suggesting the need for broader (beyond Th2) therapeutic targeting in AOAD. [ABSTRACT FROM AUTHOR]

Lebrikizumab (LEB) is a novel, high-affinity monoclonal anti - body that selectively binds to interleukin (IL)-13. To evaluate the efficacy and safety of LEB monotherapy in patients with moderate-to-severe atopic dermatitis (AD) in two identical phase 3 trials ADvocate1 (ADv1) and ADvocate2 (ADv2). Patients who responded to LEB 250 mg every 2 weeks (LEB Q2W) at the end of the 16-week induction period were re-randomized in a 2 : 2 :1 ratio to receive LEB Q2W, LEB 250 mg every 4 weeks (LEB Q4W) or placebo (LEB withdrawal) for an additional 36 weeks. Response, at week 16, was defined as achieving an IGA (0, 1) with a ≥2-point improvement or EASI75 and no use of rescue medication. Efficacy outcomes reported at week 52 included IGA (0, 1), EASI 75, ≥4-point reduction in Pruritis Numeric Rating Scale (NRS), EASI 90 and DLQI ≥4-point. Safety analysis was conducted on all patients who received ≥1 dose of LEB. Patients maintained IGA (0, 1) in LEB Q2W (ADv1, 75.8%; ADv2, 64.6%), LEB Q4W (ADv1, 74.2%; ADv2, 80.6%) and LEB withdrawal (ADv1, 46.5%; ADv2, 49.8%). Maintenance of EASI75 was, in LEB Q2W (ADv1, 79.2%; ADv2, 77.4%), LEB Q4W (ADv1, 79.2%; ADv2, 84.7%) and LEB withdrawal (ADv1, 61.3%; ADv2, 72.0%). For Pruritus NRS ≥4-point improvement from baseline, patients-maintained improvement in the LEB Q2W (ADv1, 81.2%; ADv2, 90.3%), LEB Q4W (ADv1, 80.4%; ADv2, 88.1%) and LEB withdrawal (ADv1, 65.4%; ADv2, 67.6%). Maintenance of EASI90 was, in LEB Q2W (ADv1, 66.1%; ADv2, 61.5%), LEB Q4W (ADv1, 66.6%; ADv2, 67.4%) and LEB withdrawal (ADv1, 45.5%; ADv2, 36.9%). DLQI ≥4-point improvement from baseline was LEB Q2W (ADv1, 64.0%; ADv2, 59.0%), LEB Q4W (ADv1, 62.7%; ADv2, 73.0%) and LEB withdrawal (ADv1, 57.7%; ADv2, 45.5%). TEAEs were reported by 58.1% (ADv1) and 67.8% (ADv2) LEB-treated patients at week 52. Serious adverse events were reported by 3.3% of ADv1 patients and 2.7% of ADv2 patients. In ADv1 and ADv2, 2.3% and 3.9% of patients reported an adverse event leading to treatment discontinuation, respectively. Both LEB Q2W and LEB Q4W maintained improvement in all reported outcomes for the treatment of moderate-to-severe AD through 52 weeks. The safety profile was consistent with previously published data. [ABSTRACT FROM AUTHOR]

We found differential effects of eosinophil percent on patient survival that varied by race/ethnicity using logistic regressions (Table 1). The role of circulating eosinophils on COVID-19 mortality varies by race/ethnicity Elevated eosinophil percentage was a significant predictor of shorter hospital stay among Asian patients ( I p i < .05), but was not a significant predictor of hospital stay for White, Black, and Hispanic patients (Table S2). For instance, further investigations are needed to clarify the increasing number of biologic agents that target eosinophils, because decreasing eosinophil counts may potentially contribute to increased mortality among severely ill COVID-19 patients. [Extracted from the article]

Recent literature has shown that AA is associated with an increased risk of myocardial infarction (MI).[1] However, the genetic relationship between AA and MI is largely unknown. The high-risk genetic variants for AA were computed by comparing 289 AA patients to 211,139 controls including 16,380,450 single-nucleotide polymorphisms (SNPs) and for MI by comparing 12,801 MI patients and 187,840 controls including 16,280,433 SNPs. [Extracted from the article]

Background: Etrasimod is an oral, selective, sphingosine 1‐phosphate (S1P) receptor1,4,5 modulator in development for immune‐mediated inflammatory disorders. Efficacy and safety of orally administered S1P receptor modulation in atopic dermatitis (AD) have not yet been examined. Objective: To assess the efficacy and safety of etrasimod monotherapy in adults with moderate‐to‐severe AD. Methods: In this phase 2, randomized, double‐blind, placebo‐controlled trial, participants (≥18 years) with moderate‐to‐severe AD defined as baseline validated Investigator's Global Assessment (vIGA‐AD) score ≥ 3, Eczema Area and Severity Index (EASI) score ≥ 16, and body surface area involvement ≥10% were randomized 1:1:1 to once‐daily oral etrasimod 1 mg, 2 mg or placebo for 12 weeks. The primary outcome was percent change in EASI score from baseline at week 12, assessed in the Full Analysis Set (all randomized participants). Key secondary outcomes were achievement of a vIGA‐AD score of 0 or 1 with a ≥2‐point improvement from baseline and EASI‐75 response at Week 12. Safety was assessed during the double‐blind period. Results: One hundred and forty participants were randomized to etrasimod 2 mg (n = 47), 1 mg (n = 47) or placebo (n = 46). At Week 12, percent change in EASI score was −57.2% in the etrasimod 2‐mg group versus −48.4% in the placebo group (p = 0.18). A significantly greater proportion of participants receiving etrasimod 2 mg achieved vIGA‐AD scores of 0 or 1 with a ≥2‐point improvement at Week 12 versus placebo (29.8% vs. 13.0%; p = 0.045); however, EASI‐75 response was not statistically significant versus placebo. Treatment‐emergent adverse events (AEs) occurred in 59.6%, 40.4% and 47.8% of participants receiving etrasimod 2 mg, 1 mg and placebo, respectively. There were no serious AEs or deaths. Conclusions: The primary outcome was not met, although efficacy was observed for etrasimod 2 mg on several clinician‐ and patient‐assessed measures, and both 1‐ and 2‐mg doses were well tolerated, warranting further clinical investigation in AD. [ABSTRACT FROM AUTHOR]

Background: Atopic dermatitis (AD) is a heterogeneous, chronic inflammatory skin disease linked to skin microbiome dysbiosis with reduced bacterial diversity and el)evated relative abundance of Staphylococcus aureus (S. aureus). Objectives: We aimed to characterize the yet incompletely understood association between the skin microbiome and patients' demographic and clinical cofactors in relation to AD severity. Methods: The skin microbiome in 48 adult moderate-to-severe AD patients was investigated using next-generation deep sequencing (16S rRNA gene, V1–V3 re)gion) followed by denoising (DADA2) to obtain amplicon sequence variant (ASV) composition. Results: In lesional skin, AD severity was associated with S. aureus relative abun)dance (rS = 0.53, p<0.001) and slightly better with the microbiome diversity measure Evenness (rS = −0.58, p<0.001), but not with Richness. Multiple regression confirmed the association of AD severity with microbiome diversity, including Shannon (in le)sional skin, p<0.001), Evenness (in non-lesional skin, p = 0.015) or S. aureus relative abundance (p<0.012), and with patient's IgE levels (p<0.001), race (p<0.032), age (p<0.034) and sex (p = 0.012). The lesional model explained 62% of the variation in AD severity, and the non-lesional model 50% of the variation. Conclusions: Our results specify the frequently reported “reduced diversity” of the AD-related skin microbiome to reduced Evenness, which was in turn mainly driven by S. aureus relative abundance, rather than to a reduced microbiome Richness. Finding associations between AD severity, the skin microbiome and patient's cofac)tors is a key aspect in developing new personalized AD treatments, particularly those targeting the AD microbiome. [ABSTRACT FROM AUTHOR]

Background: The mechanisms driving alopecia areata (AA) are still unclear, hindering development of targeted therapeutics. Specific Th2 targeting with dupilumab in AA provides a unique opportunity to dissect its pathogenesis and explore the role of Th2 pathway. Methods: We evaluated changes in scalp biomarkers in AA patients (with and without concomitant atopy) randomized to weekly dupilumab or placebo for 24 weeks, followed by open‐label dupilumab for 24 weeks. Changes in biomarker levels were measured at weeks 12, 24, and 48 and were also correlated with clinical hair regrowth. Results: At week 24, preceding clinical hair regrowth outcomes, only dupilumab‐treated patients presented significant suppression of cellular infiltrates, and multiple Th2‐related, markers (CCL13/MCP‐4, CCL18/PARC, CCL26/eotaxin‐3, CCL24/Eotaxin‐2), coupled with significant upregulation in the hair keratins. Th1‐related suppression was evident later (week 48) when all patients received open‐label dupilumab. Results were more pronounced in atopic AA patients, that showed 48% and 97% improvements in the lesional AA scalp profile at weeks 24 and 48, respectively, while 2% worsening was seen in the placebo arm at week 24. Moreover, placebo‐treated patients presented 54% worsening in hair keratins when compared with baseline at week 24. At week 24, increases in hair keratins showed significant correlations only with decreases in Th2‐related markers. Conclusions: Scalp biomarkers provide evidence of dupilumab efficacy in AA, detected even prior to clinical response, with exclusive correlations between early suppression of Th2 markers and increased hair keratins. These findings strengthen previous reports suggesting a possible role for Th2 cytokines as AA drivers. [ABSTRACT FROM AUTHOR]

Alopecia areata/AA is an autoimmune cause of nonscarring hair loss. The pathogenesis of AA involves many immune axes, including Th1/Th2 pathways. Delgocitinib is a pan-Janus kinase/JAK inhibitor that broadly blocks pro-inflammatory cytokines and has been effective in other inflammatory skin conditions. Recent human studies/reports have shown that use of some systemic JAK inhibitors led to hair regrowth, suggesting this medication class as a potential therapy for AA. However, topical treatment is desirable due to potential systemic side effects. To assess the efficacy and safety of topical delgocitinib in AA, we conducted a double-blind, randomized, vehicle-controlled clinical trial in 31 moderate-to-severe AA patients that were randomized 2:1 to receive delgocitinib ointment 30 mg/g (n = 20) or ointment vehicle (n = 11) for 12 weeks. The primary endpoint was change in severity of Alopecia Tool/SALT score from baseline to week 12. The secondary endpoint included safety profile by reported adverse events. Twenty-three subjects completed the trial, with eight discontinuing mostly due to voluntary withdrawal. Ten patients receiving delgocitinib ointment and three patients receiving vehicle showed SALT score improvements after 12 weeks, but the mean percent SALT improvement at week 12 compared to baseline between the two arms was not significant (p = 0.92). Our study suggests that delgocitinib ointment is not effective in moderate-to-severe AA, likely due to its inability to penetrate sufficiently deeply into the dermis of the scalp, but larger studies are necessary to assess whether a different formulation of topical JAK inhibitors may be suitable to treat mild or more localized forms of AA. [ABSTRACT FROM AUTHOR]

Improved repigmentation of generalized vitiligo in skin types IV–VI has been reported in clinical response to combined therapy with apremilast and narrowband (NB)-UVB; however, tissue responses to combined therapy versus NB-UVB monotherapy have not been elucidated. We compared the change from baseline in cellular and molecular markers in vitiligo skin after combined therapy versus NB-UVB monotherapy. We assessed lesional and nonlesional skin samples from enrolled subjects and evaluated for immune infiltrates, inflammatory, and melanogenesis-related markers which were compared across different treatment groups. Combined therapy resulted in significant reduction of CD8+T cells and CD11c+ dendritic cells, downregulation of PDE4B and Th17-related markers, and upregulation of melanogenesis markers. This study was limited to small sample size, skin types IV–VI, and high dropout rate. Our molecular findings support the clinical analysis that apremilast may potentiate NB-UVB in repigmentation of generalized vitiligo in skin types IV–VI. [ABSTRACT FROM AUTHOR]

Importance: Treatment of congenital ichthyoses primarily focuses on reversing skin scaling and is not pathogenesis based. Recent studies showed Th17 immune skewing, as in psoriasis, across the spectrum of ichthyosis, suggesting that targeting this pathway might broadly reduce disease severity. Objective: To determine whether secukinumab, an IL-17A inhibitor, can improve ichthyosis across several congenital ichthyosis subtypes. Design: Exploratory 16-week double-blind, randomized, placebo-controlled trial comparing secukinumab 300 mg every 4wks to placebo (1:1 randomization) in adults with the four major congenital ichthyosis subtypes (NCT03041038), followed by a 16-week open-label phase to evaluate response of the placebo-first group and a 20-week extension for safety. Significant differences in secukinumab- vs. placebo-treated subjects at Wk16 in the Ichthyosis Area Severity Index (IASI) score and lack of increased mucocutaneous bacterial and/or fungal infections were the co-primary efficacy and safety endpoints, respectively. Setting: Two tertiary referral centers: Northwestern University Feinberg School of Medicine, Chicago, and Mount Sinai Icahn School of Medicine, New York. Participants: Twenty subjects ≥ 18 yo with genotype-confirmed epidermolytic ichthyosis, Netherton syndrome, lamellar ichthyosis, or congenital ichthyosiform erythroderma with at least moderate erythroderma. Results: IL-17A inhibition did not significantly reduce severity or increase mucocutaneous infections among the 18 who completed the 16-week double-blind phase. Five patients with 29–50% clinical improvement at Wk32 requested drug continuation. Th17-related biomarkers were not significantly reduced vs. baseline or placebo-treated levels. Limitations: Small sample size; heterogeneous ichthyosis subsets. Conclusion: IL-17 inhibition with secukinumab is safe, but not efficacious across the spectrum of adult ichthyoses. ClinicalTrials.gov registration number: NCT03041038; first posted on 02/02/2017. [ABSTRACT FROM AUTHOR]

Background: Atopic dermatitis (AD) is a chronic relapsing inflammatory skin disease, and there is increasing evidence that the interleukin (IL)‐36 pathway may play a role in the pathogenesis of AD. Objectives: To evaluate the efficacy and safety of spesolimab, a novel anti‐IL‐36 receptor antibody, in adult patients with moderate‐to‐severe AD. Methods: In this phase IIa study, 51 eligible patients were randomized 2:1 to receive intravenous doses of spesolimab 600 mg or placebo every 4 weeks. The primary endpoint was the percentage change from baseline in Eczema Area and Severity Index (EASI) score at Week 16. Results: The decrease in EASI score from baseline to Week 16 was –37.9% for spesolimab versus –12.3% for placebo (adjusted mean difference −25.6%, p = 0.149). A predefined sensitivity analysis, excluding data from patients who used restricted corticosteroids, resulted in an adjusted mean difference of −48.3% (nominal p = 0.024). Spesolimab was well tolerated, with no clinically relevant safety signals. Conclusions: This is the first study to evaluate the IL‐36 pathway inhibition in AD. Although not statistically significant, numerical improvements were observed in the primary endpoint of change from baseline in the EASI score. Spesolimab had an acceptable safety profile, with no unexcepted safety concerns. [ABSTRACT FROM AUTHOR]

Background: Atopic diseases are characterized by IgE antibody responses that are dependent on cognate CD4 T cell help and T cell‐produced IL‐4 and IL‐13. Current models of IgE cell differentiation point to the role of IgG memory B cells as precursors of pathogenic IgE plasma cells. The goal of this work was to identify intrinsic features of memory B cells that are associated with IgE production in atopic diseases. Methods: Peripheral blood B lymphocytes were collected from individuals with physician diagnosed asthma or atopic dermatitis (AD) and from non‐atopic individuals. These samples were analyzed by spectral flow cytometry, single cell RNA sequencing (scRNAseq), and in vitro activation assays. Results: We identified a novel population of IgG memory B cells characterized by the expression of IL‐4/IL‐13 regulated genes FCER2/CD23, IL4R, IL13RA1, and IGHE, denoting a history of differentiation during type 2 immune responses. CD23+IL4R+IgG+ memory B cells had increased occurrence in individuals with atopic disease. Importantly, the frequency of CD23+IL4R+IgG+ memory B cells correlated with levels of circulating IgE. Consistently, in vitro stimulated B cells from atopic individuals generated more IgE+ cells than B cells from non‐atopic subjects. Conclusions: These findings suggest that CD23+IL4R+ IgG+ memory B cells transcribing IGHE are potential precursors of IgE plasma cells and are linked to pathogenic IgE production. [ABSTRACT FROM AUTHOR]

Atopic dermatitis (AD) is one of the most common, chronic inflammatory skin diseases with a significant physical, emotional and socioeconomic burden. In recent years the understanding of AD pathogenesis has expanded from the Th2‐centred perspective, with the recognition of the involvement of other immune axes. In different AD endotypes, influenced by environment, genetics and race, transcriptomic profiles have identified differing contributions of multiple immune axes such as, Th17, Th22 and Th1. The enriched pathogenic model of AD has catalysed the development of numerous biologic therapies targeting a range of key molecules implicated in disease progression. Currently, dupilumab and tralokinumab, which both target the Th2 pathway, are the only approved biologic therapies for AD in the United States and Europe. New biologic therapies in development, however, target different Th2‐pathway molecules along with cytokines in other immune axes, including Th17 and Th22, offering promise for varied treatments for this heterogeneous disease. As the biologic pipeline advances, the integration into clinical practice and approval of these experimental biologics may provide more effective, tailored therapeutic solutions and illuminate on the pathologic processes of AD across a broader, more diverse patient population. [ABSTRACT FROM AUTHOR]

Overall, this study suggests that Th2-inhibition with dupilumab does not hinder, and may possibly even improve, Th1-specific T cell responses to COVID-19 infection and mRNA vaccination. Fifty-five samples from patients with prior SARS-CoV-2 infection confirmed by positive anti-SARS-CoV-2 Spike IgG (unvaccinated at the time of sample collection), and 125 post-vaccination samples from different subjects were analyzed. Spike antigens were used to provide comparisons between treatment groups as a measure of T cell responses for both post-infection and post-vaccination samples (the vaccine contains only spike antigen of SARS-CoV-2). [Extracted from the article]

Background: Treatment of inflammatory skin diseases, including atopic dermatitis (AD) and psoriasis, is undergoing transformative changes, highlighting the need to develop experimental models of skin inflammation in humans to predict treatment responses. Methods: We topically or intradermally administered four common sensitizers (dust mite (DM), diphencyprone (DPCP), nickel (Ni), and purified protein derivative (PPD)) to the backs of 40 healthy patients and the skin hypersensitivity response was biopsied and evaluated using immunohistochemistry, RNA‐seq, and RT‐PCR. Results: All agents induced strong increases in cellular infiltrates (T‐cells and dendritic cells) as compared to untreated skin (p <.05), with variable T helper polarization. Overall, DPCP induced the strongest immune responses across all pathways, including innate immunity (IL‐1α, IL‐8), Th1 (IFNγ, CXCL10), Th2 (IL‐5, CCL11), and Th17 (CAMP/LL37) products, as well as the highest regulatory tone (FOXP3, IL‐34, IL‐37) (FDR <0.01). Nickel induced Th17 (IL‐17A), Th1 (CXCL10) and Th2 (IL‐4R) immune responses to a lesser extent than DPCP (p <.05). PPD induced predominantly Th1 (IFNγ, CXCL10, STAT1) and Th17 inflammation (IL‐17A) (p <.05). DM induced modulation of Th2 (IL‐13, CCL17, CCL18), Th22 (IL‐22), and Th17/Th22 (S100A7/9/12) pathways (p <.05). Barrier defects that characterize both AD and psoriasis were best modeled by DPCP and Ni, followed by PPD, including downregulation of terminal differentiation (FLG, FLG2, LOR, LCEs), tight junction (CLDN1/CLDN8), and lipid metabolism (FA2H, FABP7)‐related markers. Conclusion: Our data imply that DPCP induced the strongest immune response across all pathways, and barrier defects characteristic of AD and psoriasis. [ABSTRACT FROM AUTHOR]

Atopic dermatitis (AD) is a chronic, inflammatory skin disease characterized by intense itch and eczematous skin lesions that can impact individuals at any age across any area of the body. There is a need for safe treatments for AD that provide rapid itch relief and skin clearance and that are suitable for long-term use. Upadacitinib is a selective, reversible oral Janus kinase 1 (JAK1) inhibitor, which is approved in multiple countries for the treatment of adolescents and adults with moderate-to-severe AD. The current analysis assessed the long-term safety for up to 4 years of upadacitinib 15 and 30 mg in adolescents and adults with moderate-to-severe AD, using integrated data from three ongoing global pivotal phase 3 studies. The Measure Up 1, Measure Up 2, and AD Up studies are ongoing pivotal phase 3, randomized, placebo-controlled, multicenter studies evaluating the safety and efficacy of upadacitinib 15 mg and upadacitinib 30 mg in adolescents and adults with moderate-to-severe AD. Patients were randomized 1 : 1 : 1 to receive oral upadacitinib 15 mg, upadacitinib 30 mg or placebo once daily alone (Measure Up 1 and Measure Up 2) or with concomitant topical corticosteroids (AD Up). At Week 16, patients receiving upadacitinib 15 or 30 mg during the double-blinded period continued their assigned treatment in the blinded extension (BE) period, whereas patients receiving placebo were re-randomized 1 : 1 to receive either upadacitinib 15 or 30 mg in the BE period (upadacitinib treatment for up to 260 weeks). A total of 2693 adults and adolescents (upadacitinib 15 mg, 1340; upadacitinib 30 mg, 1353) who received at least one dose of upadacitinib were included in the integrated analysis. Treatment-emergent adverse events of special interest (AESI) were analysed as exposure-adjusted rates per 100 patient-years (PY) for the entire treatment period to adjust for potentially different durations of follow-up. Upadacitinib was well tolerated by both adults and adolescents. For all patients, rates of AESIs were similar at the 1-year analysis and up to 4-year analysis for upadacitinib (15 mg/30 mg) for: serious infections, 2.3 and 2.2/2.8 and 2.8; opportunistic infections, 1.6 and 1.8/1.9 and 2.4; active tuberculosis, <0.1/<0.1 at both time points; herpes zoster, 3.5 and 3.1/5.2 and 5.8; nonmelanoma skin cancer (NMSC), 0.3 and 0.4/0.4 and 0.3; malignancy excluding NMSC, 0.1 and 0.4/0.5 and 0.3; and adverse events leading to death, 0 and 0/<0.1 and <0.1. Rates of adjudicated major adverse cardiovascular events (MACE) were 0.1 and <0.1/<0.1 and <0.1, and for venous thromboembolic events (VTE) were <0.1 for both doses at the 1-year analysis and up to 4-year analysis. Rates of gastrointestinal perforations were 0 for both doses at both timepoint analyses. Rates of serious infections remain low (<3.0 E/100 PY). Based on the integrated analysis of long-term safety data for up to 4 years, rates of AESIs remained low throughout a longer duration of treatment with upadacitinib 15 or 30 mg among adults and adolescents with moderate-to-severe AD. No new safety risks were observed. Findings of the current safety analysis continue to support a favorable benefit-risk profile of upadacitinib in the treatment of adults and adolescents with moderate-to-severe AD for up to 4 years of treatment. [ABSTRACT FROM AUTHOR]

Summary: Background: Although alopecia areata (AA) greatly impacts patients' quality of life (QoL), there is no adequate validation of AA‐targeted QoL surveys in clinical trials, hindering sufficient representation of patient‐reported outcomes. Objectives: Better understanding of patient‐reported outcomes may guide treatment goals and future clinical trials. Methods: In a recent randomized controlled trial testing dupilumab in AA, patients were administered the Alopecia Areata Quality of Life Index (AA‐QLI) and the Alopecia Areata Symptom Impact Scale (AASIS) surveys, specifically evaluating QoL in patients with AA. An in‐depth analysis was performed to assess the utility of these questionnaires in this patient population, both at baseline and after treatment, and to determine a threshold for improved patient‐reported outcomes. Results: While AASIS correlated with baseline Severity of Alopecia Tool (SALT) scores and with therapeutic response, AA‐QLI showed no correlation with AA severity before or after treatment. Itch strongly correlated with serum IgE levels across both surveys. Using various approaches to estimate a discriminative threshold for decreased impact of AA on QoL (by AASIS) following treatment, a SALT score of 20 points or less post‐treatment was associated with improved patient‐reported outcomes, including both AA‐related symptoms and items within the daily activities/feelings domain such as 'feeling sad' and 'feeling anxious or worry'. Conclusions: AASIS is better than AA‐QLI to assess patient‐reported outcomes. SALT ≤ 20 following treatment should be considered as a threshold for meaningful therapeutic outcome and as a clinical endpoint in future clinical trials for AA. What is already known about this topic?Alopecia areata greatly compromises quality of life, and affected patients have increased prevalences of depression, anxiety and social phobia.Despite the significant negative impact of the disease on patients' wellbeing, validation of targeted questionnaires in alopecia areata is lacking, and a therapeutic response threshold for improved patient‐reported outcomes is unknown. What does this study add?This study investigated the utility of two different alopecia areata‐targeted questionnaires – Alopecia Areata Quality of Life Index and Alopecia Areata Symptom Impact Scale (AASIS) – in a clinical trial setting.AASIS was found to correlate strongly with alopecia areata severity and clinical response. What are the clinical implications of this work?Patients with ≤ 20% scalp hair loss after treatment reported improvement in multiple quality‐of‐life items, suggesting this as a meaningful therapeutic outcome that may guide clinicians and improve the development of future clinical trials. [ABSTRACT FROM AUTHOR]

Background: The ichthyoses are rare genetic keratinizing disorders that share the characteristics of an impaired epidermal barrier and increased risk of microbial infections. Although ichthyotic diseases share a T helper (Th) 17 cell immune signature, including increased expression of antimicrobial peptides, the skin microbiota of ichthyoses is virtually unexplored. Objectives: To analyse the metagenome profile of skin microbiome for major congenital ichthyosis subtypes. Methods: Body site‐matched skin surface samples were collected from the scalp, upper arm and upper buttocks of 16 healthy control participants and 22 adult patients with congenital forms of ichthyosis for whole metagenomics sequencing analysis. Results: Taxonomic profiling showed significant shifts in bacteria and fungi abundance and sporadic viral increases across ichthyosis subtypes. Cutibacterium acnes and Malassezia were significantly reduced across body sites, consistent with skin barrier disruption and depletion of lipids. Microbial richness was reduced, with specific increases in Staphylococcus and Corynebacterium genera, as well as shifts in fungal species, including Malassezia. Malassezia globosa was reduced at all body sites, whereas M. sympodialis was reduced in the ichthyotic upper arm and upper buttocks. Malassezia slooffiae, by contrast, was strikingly increased at all body sites in participants with congenital ichthyosiform erythroderma (CIE) and lamellar ichthyosis (LI). A previously undescribed Trichophyton species was also detected as sporadically colonizing the skin of patients with CIE, LI and epidermolytic ichthyosis subtypes. Conclusions: The ichthyosis skin microbiome is significantly altered from healthy skin with specific changes predominating among ichthyosis subtypes. Skewing towards the Th17 pathway may represent a response to the altered microbial colonization in ichthyosis. What is already known about this topic?The skin microbiome of congenital ichthyoses is largely unexplored.Microbes play an important role in pathogenesis, as infections are common.The relative abundances of staphylococci and corynebacteria is increased in the cutaneous microbiome of patients with Netherton syndrome, but extension of these abundances to all congenital ichthyoses is unexplored. What does this study add?A common skin microbiome signature was observed across congenital ichthyoses.Distinct microbiome features were associated with ichthyosis subtypes.Changes in microbiome may contribute to T helper 17 cell immune polarization. What is the translational message?These data provide the basis for comparison of the microbiome with lipidomic and transcriptomic alterations in these forms of ichthyosis and consideration of correcting the dysbiosis as a therapeutic intervention. [ABSTRACT FROM AUTHOR]

A correction is presented to the article "OX40 in the Pathogenesis of Atopic Dermatitis-A New Therapeutic Target" which appeared in the previous issue of the periodical.

However, the number of patients who provided no report is unspecified, raising the possibility of nonresponse bias, with perhaps thousands more patients failing the regimen and thus not reporting. Reply to "Combined antibiotic, steroid, and moisturizer for atopic dermatitis: A 2-year case series of patient-reported outcomes" Keywords: efficacy; limitations; safety; tolerability; topical EN efficacy limitations safety tolerability topical 736 737 2 07/07/21 20210501 NES 210501 B To the editor, b We eagerly read the study of Rajkumar et al1 This retrospective observational study examined the effectiveness of applying combined mid-potent topical corticosteroids [TCS] and antimicrobial (eg, mupirocin) compounded in a moisturizer base 5-7 times daily and slowly tapering (Aron regimen). [Extracted from the article]

[This corrects the article DOI: 10.2147/TCRM.S292504.]. [ABSTRACT FROM AUTHOR]

Food allergy (FA) is now one of the most common chronic diseases of childhood often lasting throughout life and leading to significant worldwide healthcare burden. The precise mechanisms responsible for the development of this inflammatory condition are largely unknown; however, a multifactorial aetiology involving both environmental and genetic contributions is well accepted. A precise understanding of the pathogenesis of FA is an essential first step to developing comprehensive prevention strategies that could mitigate this epidemic. As it is frequently preceded by atopic dermatitis and can be prevented by early antigen introduction, the development of FA is likely facilitated by the improper initial presentation of antigen to the developing immune system. Primary oral exposure of antigens allowing for presentation via a well‐developed mucosal immune system, rather than through a disrupted skin epidermal barrier, is essential to prevent FA. In this review, we present the data supporting the necessity of (1) an intact epidermal barrier to prevent epicutaneous antigen presentation, (2) the presence of specific commensal bacteria to maintain an intact mucosal immune system and (3) maternal/infant diet diversity, including vitamins and minerals, and appropriately timed allergenic food introduction to prevent FA. [ABSTRACT FROM AUTHOR]

Atopic dermatitis (AD) is a common inflammatory skin disease characterized by wet, oozing, erythematous, pruritic lesions in the acute stage and xerotic, lichenified plaques in the chronic stage. It frequently coexists with asthma and allergic rhinitis, sharing some mechanistic features with these diseases as part of the 'atopic march.' Controversy exists as to whether immune abnormalities, epidermal barrier defects, or both are the primary factors responsible for disease pathogenesis. In AD patients, there is often a coexisting irritant contact dermatitis (ICD) or allergic contact dermatitis (ACD) that is sometimes clinically difficult to distinguish from AD. ACD shares molecular mechanisms with AD, including increased cellular infiltrates and cytokine activation (Gittler et al., 2013). In this issue, Newell et al. (2013) used an experimental contact sensitization model with dinitrochlorobenzene (DNCB) to gain insight into the unique immune phenotype of AD patients. [ABSTRACT FROM AUTHOR]

Tape strips capture atopic dermatitis-related changes in nonlesional skin throughout maturation Abbreviations AD atopic dermatitis FCH fold-change FLG filaggrin IL interleukin qRT-PCR quantitative real-time polymerase chain reaction Th T helper cell type The extensive therapeutic pipeline for atopic dermatitis (AD) has stemmed from our improved understanding of AD pathogenesis. Tape strips were serially collected from lesional and non-lesional AD and normal skin, as described.3 RT-PCR of 74 AD-related markers from tape-stripped AD and normal skin was performed to compare different age-groups using linear regression. [Extracted from the article]

Chronic spontaneous urticaria (CSU) imposes a significant burden on patients, families and healthcare systems. Management is difficult, due to disease heterogeneity and insufficient efficacy of classical drugs such as H1R‐antihistamines. Better understanding of the mechanisms has enabled a stratified approach to the management of CSU, supporting the use of targeted treatment with omalizumab. However, many practical issues including selection of responders, the definition of response, strategies to enhance the responder rate, the duration of treatment and its regimen (in the clinic or home‐based) and its cost‐effectiveness still require further clarification. The EAACI Guidelines on the use of omalizumab in CSU follow the GRADE approach in formulating recommendations for each outcome. In addition, future therapeutic approaches and perspectives as well as research priorities are discussed. [ABSTRACT FROM AUTHOR]

Atopic dermatitis (AD) is a common inflammatory skin disease associated with barrier disfunction and T SB H sb 2/T SB H sb 22 immune polarity.1,2 Patients with AD are often colonized or infected with I Staphylococcus aureus i ( I S. aureus i ).3 Recent large cohort studies and skin microbiome analyses have identified that AD is dominated by I S. aureus i .4 However, the interaction of cytokines and bacteria in AD skin remains unclear. Keywords: atopic dermatitis; dermatology; infections; inflammation; innate immunity; keratinocytes EN atopic dermatitis dermatology infections inflammation innate immunity keratinocytes 3534 3537 4 11/01/21 20211101 NES 211101 ACKNOWLEDGEMENTS KY was supported by Japan Society for the Promotion of Science (JSPS) overseas research fellowships from 2020 to 2022. TH2 cytokines and Staphylococcus aureus cooperatively induce atopic dermatitis-like transcriptomes. [Extracted from the article]

Atopic dermatitis (AD) is a heterogeneous systemic inflammatory skin disease associated with dysregulated immune responses, barrier dysfunction and activated sensory nerves. To characterize circulating inflammatory profiles and underlying systemic disease heterogeneity within AD patients, blood samples from adult patients (N = 123) with moderate‐to‐severe AD in a phase 2 study of baricitinib (JAHG) were analysed. Baseline levels of 131 markers were evaluated using high‐throughput and ultrasensitive proteomic platforms, patient clusters were generated based on these peripheral markers. We implemented a novel cluster reproducibility method to validate cluster outcomes within our study and used publicly available AD biomarker data set (73 markers, N = 58 patients) to validate our findings. Cluster reproducibility analysis demonstrated best consistency for 2 clusters by k‐means, reproducibility of this clustering outcome was validated in an independent patient cohort. These unique JAHG patient subgroups either possessed elevated pro‐inflammatory mediators, notably TNFβ, MCP‐3 and IL‐13, among a variety of immune responses (high inflammatory) or lower levels of inflammatory biomarkers (low inflammatory). The high inflammatory subgroup was associated with greater baseline disease severity, demonstrated by greater EASI, SCORAD Index, Itch NRS and DLQI scores, compared with low inflammatory subgroup. African‐American patients were predominantly associated with the high inflammatory subgroup and increased baseline disease severity. In patients with moderate‐to‐severe AD, heterogeneity was identified by the detection of 2 disease subgroups, differential clustering amongst ethnic groups and elevated pro‐inflammatory mediators extending beyond traditional polarized immune responses. Therapeutic strategies targeting multiple pro‐inflammatory cytokines may be needed to address this heterogeneity. [ABSTRACT FROM AUTHOR]

Background Urticarial patients are usually treated with oral antihistamines and 50% respond well to this treatment; however, the other 50% do not respond to antihistamines and need a more aggressive approach, such as short or prolonged courses of oral corticosteroids or cyclosporine. Potential adverse effects, however, limit this regimen. Objective To determine the efficacy of mycophenolate mofetil, an immunomodulatory drug, in the treatment of patients with severe chronic urticaria. Methods In an open-label, uncontrolled trial, nine patients with documented chronic urticaria who had been treated previously with antihistamines and/or corticosteroids with poor response were enrolled in the trial. After 2 weeks of baseline assessment, patients received 1000 mg twice daily of mycophenolate mofetil for 12 weeks. Improvement was monitored using the urticarial activity score, which is the sum of the wheal number score and itch severity score. Patients also recorded their daily need for other medications to control allergic symptoms. Results There was a significant decrease in the urticarial activity score relative to the baseline assessment at the end of the study period ( P < 0.001). All patients were able to stop prednisone on completion of the study. There was also a decrease in antihistamine dose, but this did not reach statistical significance. Treatment with mycophenolate mofetil was not associated with significant adverse effects. Conclusions Mycophenolate mofetil may be a valuable and safe treatment for patients with chronic urticaria who do not respond to antihistamines and/or corticosteroids, and who require aggressive treatment to control their disease symptoms. Further controlled clinical studies are needed to determine its value. [ABSTRACT FROM AUTHOR]

Kaposi's sarcoma–associated herpesvirus (KSHV) is one of the few viruses proven to be associated with tumorigenesis in humans. Its causal association with all clinical and epidemiological variants of Kaposi's sarcoma (KS) is well established. KSHV is also involved in the pathogenesis of primary effusion lymphoma (PEL) and a subset of multicentric Castleman's disease (MCD). Possible associations of KSHV with other clinical settings have been extensively examined. The findings from several of these studies are contradictory and are yet to be resolved. Concentrated effort over the last decade, since the initial discovery of KSHV, led to the development of several experimental systems that resulted in a better comprehension of the biological characteristics of KSHV and set the stage for the understanding of mechanisms by which diseases are induced by the virus. The development of molecular, histological, and serological tools for KSHV diagnosis allowed researchers to track the transmission and to study the epidemiology of KSHV. These assays have been applied, in particular in ambiguous cases, in order to confirm clinically and pathologically based diagnoses. Here, we review the advances in the clinical, experimental, diagnostic, and epidemiological research of KSHV. [ABSTRACT FROM AUTHOR]

Background: In atopic dermatitis (AD), some studies have shown an association with increased cardiovascular disease in certain populations. However, other investigations found modest or no association. Despite conflicting results, molecular profiling studies in both AD skin and blood have demonstrated upregulation of atherosclerosis and cardiovascular risk‐related markers. However, the underlying mechanisms connecting AD to vascular inflammation/atherosclerosis are unknown. In this study, we aim to determine factors associated with vascular inflammation/atherosclerosis in AD patients. Methods: We used 18‐FDG PET‐CT to characterize vascular inflammation in AD patients and healthy subjects. In parallel, we assessed their skin and blood immune profiles to determine AD‐related immune biomarkers associated with vascular inflammation. We also assessed levels of circulating microparticles, which are known to be associated with increased cardiovascular risk. Results: We found significant correlations between vascular inflammation and Th2‐related products in skin and blood of AD patients as well as atherosclerosis‐related markers that were modulated by dupilumab. Circulating levels of endothelial microparticles were significantly higher in severe AD patients and tended to correlate with vascular inflammation assessed by PET‐CT. Conclusion: Vascular inflammation in AD is associated with enhanced Th2 response and clinical severity, which may explain cardiovascular comorbidities observed in select AD populations. Larger prospective studies are needed to further evaluate vascular inflammation and cardiovascular events and mortality in AD patients. Finally, as dupilumab treatment demonstrated significant modulation of atherosclerosis‐related genes in AD patients compared to placebo, these data suggest that modulation of vascular inflammation with systemic treatment should be explored in patients with AD. [ABSTRACT FROM AUTHOR]

Background: Flow cytometry is a well‐accepted approach for immune profiling; however, its value is restricted by the limited number of markers that can be analyzed simultaneously. Mass cytometry/CyTOF offers broad‐scale immune characterization integrating large number of parameters. While partial blood phenotyping was reported in atopic dermatitis (AD), patients' comprehensive profiling, critical for leveraging new targeted treatments, is not available. IL‐21 may be involved in inflammatory skin diseases but its role in AD is not well established. Methods: We studied T‐cell polarization in the blood of 20 moderate‐to‐severe AD and 15 controls. Using CyTOF and an unsupervised analysis, we measured the frequencies and mean metal intensities of activated polar CD4+/CD8+ T‐cell subsets. Immunohistochemistry, immunofluorescence, and qRT‐PCR were used to analyze skin samples. Results: Examining 24 surface, intracellular markers, and transcription factors, we identified six CD4+ and five CD8+ T‐cell metaclusters. A CD4+ skin‐homing IL‐13+monocytokine and a novel IL‐13+IL‐21+ multicytokine metaclusters were increased in AD vs. controls (p <.01). While IL‐13 signature characterized both clusters, levels were significantly higher in the IL‐21+ group. Both clusters correlated with AD severity (r = 0.49, p =.029). Manual gating corroborated these results and identified additional multicytokine subsets in AD. Immunohistochemistry and immunofluorescence, validated by mRNA expression, displayed significantly increasedIL‐21 counts and colocalization with IL‐13/IL‐4R in AD skin. Conclusion: A multicytokine signature characterizes moderate‐to‐severe AD, possibly explaining partial therapeutic responses to one cytokine targeting, particularly in severe patients. Prominent IL‐21 signature in blood and skin hints for a potential pathogenic role of IL‐21 in AD. [ABSTRACT FROM AUTHOR]

Background: Alopecia areata (AA) is characterized by immune dysregulation in both scalp and blood, but a large‐scale approach establishing biomarkers of AA incorporating both scalp tissue and serum compartments is lacking. We aimed to characterize the transcriptomic signature of AA lesional and nonlesional scalp compared to healthy scalp and determine its relationship with the blood proteome in the same individuals, with comparative correlations to clinical AA disease severity. Methods: We evaluated lesional and nonlesional scalp tissues and serum from patients with moderate‐to‐severe AA (n = 18) and healthy individuals (n = 8). We assessed 33,118 genes in AA scalp tissue using RNAseq transcriptomic evaluation and 340 inflammatory proteins in serum using OLINK high‐throughput proteomics. Univariate and multivariate approaches were used to correlate disease biomarkers with Severity of Alopecia Tool (SALT). Results: A total of 608 inflammatory genes were differentially expressed in lesional AA scalp (fold change/FCH>1.5, false discovery rate/FDR<0.05) including Th1 (IFNG/IL12B/CXCL11), Th2 (IL13/CCL18), and T‐cell activation‐related (ICOS) products. Th1/Th2‐related markers were significantly correlated with AA clinical severity in lesional/nonlesional tissue, while keratins (KRT35/KRT83/KRT81) were significantly downregulated in lesional compared to healthy scalp (p <.05). Expression of cardiovascular/atherosclerosis‐related markers (MMP9/CCL2/IL1RL1/IL33R/ST2/AGER) in lesional scalp correlated with their corresponding serum expression (p <.05). AA scalp demonstrated significantly greater biomarker dysregulation compared to blood. An integrated multivariate approach combining scalp and serum biomarkers improved correlations with disease severity/SALT. Conclusion: This study contributes a unique understanding of the phenotype of moderate‐to‐severe AA with an integrated scalp and serum biomarker model suggesting the systemic nature of the disease, advocating for the need for immune‐based systemic treatment. [ABSTRACT FROM AUTHOR]

Background: Pivotal phase III studies demonstrated that abrocitinib, an oral, once-daily, JAK1-selective inhibitor, is effective treatment for moderate-to-severe atopic dermatitis (AD) as monotherapy and in combination with topical therapy. Objective: The aim of this study was to evaluate the long-term safety of abrocitinib 200 mg and 100 mg in an integrated analysis of a phase IIb study, four phase III studies, and one long-term extension study. Methods: Two cohorts were analyzed: a placebo-controlled cohort from 12- to 16-week studies and an all-abrocitinib cohort including patients who received one or more abrocitinib doses. Adverse events (AEs) of interest and laboratory data are reported. Results: Total exposure in the all-abrocitinib cohort (n = 2856) was 1614 patient-years (PY); exposure was ≥ 24 weeks in 1248 patients and ≥ 48 weeks in 606 (maximum 108 weeks). In the placebo-controlled cohort (n = 1540), dose-related AEs (200 mg, 100 mg, placebo) were nausea (14.6%, 6.1%, 2.0%), headache (7.8%, 5.9%, 3.5%), and acne (4.7%, 1.6%, 0%). Platelet count was reduced transiently in a dose-dependent manner; 2/2718 patients (200-mg group) had confirmed platelet counts of < 50 × 103/mm3 at week 4. Incidence rates (IRs) were 2.33/100PY and 2.65/100 PY for serious infection, 4.34/100PY and 2.04/100PY for herpes zoster, and 11.83/100PY and 8.73/100PY for herpes simplex in the 200-mg and 100-mg groups, respectively. IRs for nonmelanoma skin cancer, other malignancies, and major adverse cardiovascular events were < 0.5/100PY for both doses. Five venous thromboembolism events occurred (IR 0.30/100PY), all in the 200-mg group. There were three deaths due to gastric carcinoma (diagnosed at day 43), sudden death, and COVID-19. Conclusion: Abrocitinib, with proper patient and dose selection, has a manageable tolerability and longer-term safety profile appropriate for long-term use in patients with moderate-to-severe AD. Trial Registries: ClinicalTrials.gov: NCT02780167, NCT03349060, NCT03575871, NCT03720470, NCT03627767, NCT03422822. [ABSTRACT FROM AUTHOR]

Non‐invasive reflectance confocal microscopy (RCM) and optical coherence tomography (OCT) have been extended to the dermo‐cosmetic field, for skin pathophysiology understanding and therapeutics monitoring. However, standardized methodology and parameters to interpret structures and changes in these settings are still lacking. Present study aimed to propose a validated standard methodology and a list of defined parameters for objective non‐pathological skin assessments in the cosmetically sensitive cheekbone area of the face. OCT and RCM quantitative, semi‐quantitative and qualitative features were considered for assessments. Validation process included 50 sets of images divided into two age groups. Inter‐rater reliability was explored to assess the influence of the proposed methodology. Quantitative OCT parameters of "epidermal thickness," "density and attenuation coefficients" and "vascular density" were considered and calculated. Severity scales were developed for semi‐quantitative OCT features of "disruption of collagen" and "vascular asset," while extent scales were produced for semi‐quantitative RCM "irregular honeycomb," "mottled pigmentation" and "polycyclic papillary contours." Qualitative assessment was obtained for RCM type of collagen, and comparison between age groups was performed for all features considered. Severity visual scales assistance proved excellent inter‐rater agreement across all semi‐quantitative and qualitative domains. The assistance of shareable software systems allows for objective OCT quantitative parameters measurement. The use of standard reference scales, within a defined assessment methodology, offers high inter‐rater reliability and thus reproducibility for semi‐quantitative and qualitative OCT and RCM parameters. Taken together, our results may represent a starting point for a standardized application of RCM and OCT in dermo‐cosmetic research and practice. [ABSTRACT FROM AUTHOR]

Atopic dermatitis imposes a significant burden on patients, families and healthcare systems. Management is difficult, due to disease heterogeneity, co‐morbidities, complexity in care pathways and differences between national or regional healthcare systems. Better understanding of the mechanisms has enabled a stratified approach to the management of atopic dermatitis, supporting the use of targeted treatments with biologicals. However, there are still many issues that require further clarification. These include the definition of response, strategies to enhance the responder rate, the duration of treatment and its regimen (in the clinic or home‐based), its cost‐effectiveness and long‐term safety. The EAACI Guidelines on the use of dupilumab in atopic dermatitis follow the GRADE approach in formulating recommendations for each outcome and age group. In addition, future approaches and research priorities are discussed. [ABSTRACT FROM AUTHOR]

SARS-CoV-2 receptor ACE2 protein expression in serum is significantly associated with age A trend toward significantly greater ACE2 expression was observed in healthy African American adults versus healthy European American adults, as well as in European American AD infants/toddlers versus both Asian and African American AD infants/toddlers ( I P i < .1; Figure S1C). [Extracted from the article]