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Over the past few decades, allergic diseases have become more prevalent and impact around 20% of the global population. There is clinical significance of allergic march as it places a burden on the quality of life of children and their families. To assess the current situation of allergy conditions experienced by children attending elementary and junior high schools in Oyama and Tochigi cities, Japan. A letter was sent to parents informing them about an opt-in online survey concerning children's allergies along with a weblink and a QR code. A video explained the survey process and informed parents that their replies could not be retracted. Parents who had watched the explanation video and answered yes to participating were considered to have provided consent for the survey. A total of 2038 valid replies were gathered. Allergic Rhinitis was the most commonly diagnosed allergy, followed by Asthma, Food Allergy, and Atopic Dermatitis. Around 70% of the children were affected by the allergies, of whom half had been affected by multiple allergies. Most children affected by Atopic Dermatitis, Food Allergy or Asthma were affected by other allergies. Atopic Dermatitis and Food Allergy were mostly diagnosed before Asthma and Allergic Rhinitis. Children who are diagnosed with either Atopic Dermatitis or a Food Allergy will likely be affected by other allergies later in life. Allergic march perpetuated an earlier peak diagnosis incident rate for allergic rhinitis. Allergic Rhinitis can occur independently from other allergies compared to Atopic Dermatitis, Food Allergy and Asthma. [ABSTRACT FROM AUTHOR]

Dupilumab effectively treats atopic dermatitis (AD); however, its role in halting the atopic march remains uncertain. To investigate dupilumab's effect on atopic march in pediatric AD patients versus conventional immunomodulators. This retrospective cohort study utilized data from the TriNetX US Collaborative Network (2011-2024). Pediatric AD patients (≤18 years) were categorized into DUPI-cohort (newly prescribed dupilumab) or CONV-cohort (prescribed conventional immunomodulators without dupilumab). After 1:1 propensity-score matching, we analyzed atopic march progression, defined by the incident asthma or allergic rhinitis (AR). Cumulative incidence was plotted using Kaplan-Meier, with risk assessment via Cox regression. The study included 2192 patients in each cohort. The 3-year cumulative incidence of atopic march progression was lower in the DUPI-cohort than the CONV-cohort (20.09% vs 27.22%; P <.001). The DUPI-cohort demonstrated significant risk reduction in atopic march progression (hazard ratio [HR] 0.68, 95% CI 0.55-0.83), individual asthma (HR 0.60, 0.45-0.81), and individual AR (HR 0.69, 0.54-0.88). Younger patients on dupilumab exhibited a greater risk reduction for atopic march progression and individual asthma, contrasting with the opposite age-related pattern for individual AR. Observational study. Among pediatric AD patients, dupilumab was associated with reduced risk of atopic march progression compared with conventional therapies. [ABSTRACT FROM AUTHOR]

Tapinarof cream 1% once daily (QD), a topical aryl hydrocarbon receptor agonist, downregulates pro-inflammatory Th2 cytokines, upregulates skin-barrier components, and reduces oxidative stress. To assess tapinarof efficacy and safety in adults and children down to 2 years of age with atopic dermatitis (AD). Eight hundred and thirteen patients were randomized to tapinarof or vehicle QD in two 8-week phase 3 trials. The primary efficacy endpoint, Validated Investigator Global Assessment for Atopic Dermatitis score of 0 or 1 and ≥2-grade improvement from baseline at Week 8, was met with statistical significance in both trials: 45.4% versus 13.9% and 46.4% versus 18.0% (tapinarof vs vehicle; both P <.0001). Significantly superior Eczema Area and Severity Index 75 (EASI75) responses were also observed with tapinarof versus vehicle at Week 8: 55.8% versus 22.9% and 59.1% versus 21.2% (both P <.0001). Rapid improvements in patient-reported pruritus were also significant with tapinarof versus vehicle. Common adverse events (≥5%) of folliculitis, headache, and nasopharyngitis were mostly mild or moderate, with lower discontinuations due to adverse events in the tapinarof groups than with vehicle. Long-term efficacy was not assessed. Tapinarof demonstrated highly significant efficacy and favorable safety and tolerability in a diverse population of patients with AD down to 2 years of age. [ABSTRACT FROM AUTHOR]

Dermatitis has been reported after initiation of IL-6 receptor (IL-6R) inhibitors (IL-6Ri), while genetic association studies of atopic dermatitis (AD) have implicated IL-6R pathway signaling. However, causality remains unclear. As the indications for IL-6Ri expand, so do the clinical importance of determining whether there is mechanistic evidence linking it to AD. Our aim was to examine the association between IL-6Ri and risk of AD. To genetically mimic IL-6Ri, we selected single-nucleotide polymorphisms within or near the IL6R gene associated with C-reactive protein at genome-wide significance among 343,524 individuals. Genetic data were obtained from 10,788 individuals with AD and 30,047 controls of European ancestry. We used inverse variance–weighted and pleiotropy-robust methods and examined genetic confounding using colocalization. Analyses were replicated by using 13,473 Finnish and 2,385 East Asian individuals with AD. The results from 3 independent analyses were pooled by meta-analysis. Genetically proxied IL-6Ri was associated with increased risk of AD (odds ratio [OR] = 1.78 per 4.4-mg/L reduction in C-reactive protein level [95% CI = 1.28-2.48] [ P = 6.5 × 10–4]). The results were replicated using Finnish outcome data (OR = 2.07 [95% CI = 1.58-2.72] [ P = 1.57 × 10–7]) and Eastern Asian data (OR = 1.68 [95% CI = 1.12-2.54] [ P =.013]). Meta-analysis of 3 independent populations (OR = 1.89 [95% CI = 1.57-2.28] [ P = 2.68 × 10–11]) showed no evidence of heterogeneity (P =.65). We found no statistical evidence for pleiotropy or genetic confounding. This genetic investigation provides consistent evidence (across independent multiancestry populations) that IL-6R signaling is causally implicated in AD susceptibility. Clinicians should remain vigilant for adverse effects resembling AD when using IL-6R inhibitors for immune-mediated inflammatory diseases. [ABSTRACT FROM AUTHOR]

Long-term daily practice data on patient-reported benefits of dupilumab for atopic dermatitis (AD) remains limited. To evaluate patient-reported outcome measures (PROMs) and the safety of dupilumab in patients with moderate-to-severe AD over a follow-up period of up to 5 years. Data were extracted from the prospective, multicenter BioDay registry (October 2017–2022) of patients with moderate-to-severe AD treated with dupilumab in daily practice. In total 1223 patients, 1108 adults and 115 pediatric patients were included. After ≥1 year of treatment, mean Patient-Oriented Eczema Measure (POEM), Dermatology Life Quality Index (DLQI), Numeric rating scale (NRS)-pruritus ranged between 7.8 and 8.7, 3.5 and 4.2, and 2.9 and 3.1 in adults, respectively, whilst these patient-reported outcome measures (PROMs) ranged between 8.9 and 10.9, 4.4 and 6.4, and 3.0 and 3.7 in pediatric patients, respectively. At follow-up, overall work impairment decreased from 40.1% to 16.3% to 13.3% in adults. Furthermore, class I obesity and itch-dominant patients generally had less favorable treatment response. Of all patients, 66.8% reported ≥1 adverse event, with conjunctivitis being the most common (33.7%). The overall percentage of missing values for selected PROMs was 26% in adults and 46% in pediatric patients. In addition to favorable safety, dupilumab has demonstrated sustained effectiveness across various PROMs, underscoring the treatment benefits from patients' perspectives. [ABSTRACT FROM AUTHOR]

Dupilumab, a human monoclonal antibody targeting the interleukin 4 alpha receptor, is used for treatment of moderate to severe atopic dermatitis (AD). Previous studies have reported diagnoses of cutaneous T cell lymphoma (CTCL) after dupilumab use. Investigate the risk of CTCL after dupilumab use in patients with AD. Using the TrinetX database, incidence of cutaneous and lymphoid malignancies including CTCL was compared between a cohort of patients with AD who used dupilumab and a cohort of patients with AD who never used dupilumab. A second analysis excluding prior disease-modifying antirheumatic drug use was performed. Propensity score matching was performed to control for covariates. An increased risk of CTCL was found in the cohort of AD patients who used dupilumab (odds ratio 4.1003, 95% confidence interval 2.055-8.192). The increased risk persisted after exclusion of prior disease-modifying antirheumatic drug use. Risk was not increased for other cutaneous or lymphoid malignancies. Most (27/41) cases of CTCL were diagnosed more than 1 year after dupilumab use. There is potential for misclassification in the database. Severity of AD could not be assessed. Association between dupilumab and CTCL does not prove causality. Dupilumab use is associated with an increased risk of CTCL in patients with AD in this cohort. [ABSTRACT FROM AUTHOR]

Monogenic lesions in pathways critical for effector functions responsible for immune surveillance, protection against autoinflammation, and appropriate responses to allergens and microorganisms underlie the pathophysiology of inborn errors of immunity (IEI). Variants in cytokine production, cytokine signaling, epithelial barrier function, antigen presentation, receptor signaling, and cellular processes and metabolism can drive autoimmunity, immunodeficiency, and/or allergic inflammation. Identification of these variants has improved our understanding of the role that many of these proteins play in skewing toward T H 2-related allergic inflammation. Early-onset or atypical atopic disease, often in conjunction with immunodeficiency and/or autoimmunity, should raise suspicion for an IEI. This becomes a diagnostic dilemma if the initial clinical presentation is solely allergic inflammation, especially when the prevalence of allergic diseases is becoming more common. Genetic sequencing is necessary for IEI diagnosis and is helpful for early recognition and implementation of targeted treatment, if available. Although genetic evaluation is not feasible for all patients with atopy, identifying atopic patients with molecular immune abnormalities may be helpful for diagnostic, therapeutic, and prognostic purposes. In this review, we focus on IEI associated with T H 2-driven allergic manifestations and classify them on the basis of the affected molecular pathways and predominant clinical manifestations. [ABSTRACT FROM AUTHOR]

[Display omitted] The contribution of Staphylococcus aureus to the exacerbation of atopic dermatitis (AD) is widely documented, but its role as a primary trigger of AD skin symptoms remains poorly explored. This study sought to reappraise the main bacterial factors and underlying immune mechanisms by which S aureus triggers AD-like inflammation. This study capitalized on a preclinical model, in which different clinical isolates were applied in the absence of any prior experimental skin injury. The development of S aureus– induced dermatitis depended on the nature of the S aureus strain, its viability, the concentration of the applied bacterial suspension, the production of secreted and nonsecreted factors, as well as the activation of accessory gene regulatory quorum sensing system. In addition, the rising dermatitis, which exhibited the well-documented AD cytokine signature, was significantly inhibited in inflammasome adaptor apoptosis-associated speck-like protein containing a CARD domain– and monocyte/macrophage-deficient animals, but not in T- and B-cell–deficient mice, suggesting a major role for the innate response in the induction of skin inflammation. However, bacterial exposure generated a robust adaptive immune response against S aureus , and an accumulation of S aureus– specific γδ and CD4+ tissue resident memory T cells at the site of previous dermatitis. The latter both contributed to worsen the flares of AD-like dermatitis on new bacteria exposures, but also, protected the mice from persistent bacterial colonization. These data highlight the induction of unique AD-like inflammation, with the generation of proinflammatory but protective tissue resident memory T cells in a context of natural exposure to pathogenic S aureus strains. [ABSTRACT FROM AUTHOR]

Atopic dermatitis (AD), a chronic inflammatory skin disease with T cell activation as a key feature, in which Th2 cell–mediated responses play a pivotal role. Regulatory T cells (Treg) are central immune cells that restrict autoimmunity and inflammation in the body. Patients with immune dysregulation, polyendocrinopathy, or enteropathy X-linked syndrome, an immune disease characterized by a deficiency in Treg, develop skin inflammation and allergic disorders, indicating that Treg play a crucial role in the development of allergic skin inflammation. we investigated the underlying mechanisms by which Treg control cutaneous allergic inflammation. An allergic skin inflammation mouse model was constructed using MC903, and Treg-depleted mouse model was constructed using diphtheria toxin. Neutralization of IFN-γ was constructed using anti-mouse-IFN-γ mouse antibody. Neutrophil infiltration was analyzed by flow cytometry and immunohistochemistry. Neutrophil extracellular traps (NETs), a process called NETosis, were detected using immunofluorescence. In vitro neutrophil stimulation and immunocytochemistry was conducted to demonstrate the effect of IFN-γ on NETosis. The depletion of Foxp3+ Treg led to significantly exacerbated AD-like skin inflammation, including increased recruitment of neutrophils and expression of Th1 cytokine IFN-γ. Neutrophil infiltrating in skin of Treg-depleted mice released more NETs than wild type. Neutralization of IFN-γ abolished neutrophil infiltration and NETosis in Treg-depleted mice. Neutrophils stimulated with IFN-γ were more prone to release NETs in vitro. Finally, Foxp3+ Treg control cutaneous allergic inflammation by regulating IFN-γ-driven neutrophilic infiltration and NETosis. Our results highlight the previously underestimated Treg-IFN-γ-neutrophil inflammatory axis. [Display omitted] ● Depletion of Treg exacerbates MC903-induced allergic skin inflammation. ● Neutrophil infiltration and NETosis were detected in Treg-depleted mice during allergic skin inflammation. ● Neutralization of IFN-γ abolished aggravated inflammation in Treg-depleted mice. ● IFN-γ is sufficient to induce NETosis in vitro. [ABSTRACT FROM AUTHOR]

Lympho-epithelial Kazal-type-related inhibitor (LEKTI) is a serine protease inhibitor consisting of multiple domains. A loss of function mutation is described in Netherton patients that show severe symptoms of atopic lesions and itch. LEKTI domain 6 (LD6) has shown strong serine protease-inhibitory action in in vitro assays and thus it was tested in vitro and in vivo for potential anti-inflammatory action in models of atopic skin disease. Human skin equivalents were treated with LD6 and an inflammatory reaction was challenged by kallikrein-related endopeptidase 5 (KLK5). Furthermore, LD6 was tested on dorsal root ganglia cells stimulated with KLK5, SLIGRL and histamine by calcium imaging. The effect of topically administered LD6 (0.4–0.8%) in lipoderm was compared to a topical formulation of betamethasone-diproprionate (0.1%) in a therapeutic setting on atopic dermatitis-like lesions in NC/Nga mice sensitized to house dust mite antigen. Endpoints were clinical scoring of the mice as well as determination of scratching behaviour. KLK5 induced an upregulation of CXCL-8, CCL20 and IL-6 in skin equivalents. This upregulation was reduced by pre-incubation with LD6. KLK5 as well as histamine induced calcium influx in a population of neurons. LD6 significantly reduced the calcium response to both stimuli. When administered onto lesional skin of NC/Nga mice, both LD6 and betamethasone-dipropionate significantly reduced the inflammatory reaction. The effect on itch behaviour was less pronounced. Topical administration of LD6 might be a new therapeutic option for treatment of lesional atopic skin. • LEKTI domain 6 reduces activation of sensory neurons provoked by proteases. • LEKTI domain 6 reduces activation of sensory neurons provoked by histamine. • LEKTI domain 6 reduces the inflammatory response in skin constructs. • LEKTI domain 6 reduces the inflammatory response in a murine atopic dermatitis model. [ABSTRACT FROM AUTHOR]

[Display omitted] Atopic dermatitis (AD) is the most common chronic inflammatory skin disease in both pediatric and adult populations. The development of AD has been linked to antibiotic usage, which causes perturbation of the microbiome and has been associated with abnormal immune system function. However, imbalances in the gut microbiome itself associated with antibiotic usage have been inconsistently linked to AD. This study aimed to elucidate the timing and specific factors mediating the relationship between systemic (oral or intravenous) antibiotic usage and AD. We used statistical modeling and differential analysis to link CHILD Cohort Study participants' history of antibiotic usage and early-life gut microbiome alterations to AD. Here we report that systemic antibiotics during the first year of life, as compared to later, are associated with AD risk (adjusted odds ratio [aOR] = 1.81; 95% CI: 1.28-2.57; P <.001), with an increased number of antibiotic courses corresponding to a dose response–like increased risk of AD risk (1 course: aOR: 1.67; 95% CI: 1.17-2.38; 2 or more courses: aOR: 2.16; 95% CI: 1.30-3.59). Further, we demonstrate that microbiome alterations associated with both AD and systemic antibiotic usage fully mediate the effect of antibiotic usage on the development of AD (β indirect = 0.072; P <.001). Alterations in the 1-year infant gut microbiome of participants who would later develop AD included increased Tyzzerella nexilis , increased monosaccharide utilization, and parallel decreased Bifidobacterium and Eubacterium spp, and fermentative pathways. These findings indicate that early-life antibiotic usage, especially in the first year of life, modulates key gut microbiome components that may be used as markers to predict and possibly prevent the development of AD. [ABSTRACT FROM AUTHOR]

Atopic dermatitis (AD) is a complex and heterogeneous skin disease for which achieving complete clinical clearance for most patients has proven challenging through single cytokine inhibition. Current studies integrate biomarkers and evaluate their role in AD, aiming to advance our understanding of the diverse molecular profiles implicated. Although traditionally characterized as a T H 2-driven disease, extensive research has recently revealed the involvement of T H 1, T H 17, and T H 22 immune pathways as well as the interplay of pivotal immune molecules, such as OX40, OX40 ligand (OX40L), thymic stromal lymphopoietin, and IL-33. This review explores the mechanistic effects of treatments for AD, focusing on mAbs and Janus kinase inhibitors. It describes how these treatments modulate immune pathways and examines their impact on key inflammatory and barrier biomarkers. [ABSTRACT FROM AUTHOR]

Inflammatory skin diseases such as atopic eczema (atopic dermatitis [AD]) affect children and adults globally. In AD, the skin barrier is impaired on multiple levels. Underlying factors include genetic, chemical, immunologic, and microbial components. Increased skin pH in AD is part of the altered microbial microenvironment that promotes overgrowth of the skin microbiome with Staphylococcus aureus. The secretion of virulence factors, such as toxins and proteases, by S aureus further aggravates the skin barrier deficiency and additionally disrupts the balance of an already skewed immune response. Skin commensal bacteria, however, can inhibit the growth and pathogenicity of S aureus through quorum sensing. Therefore, restoring a healthy skin microbiome could contribute to remission induction in AD. This review discusses direct and indirect approaches to targeting the skin microbiome through modulation of the skin pH; UV treatment; and use of prebiotics, probiotics, and postbiotics. Furthermore, exploratory techniques such as skin microbiome transplantation, ozone therapy, and phage therapy are discussed. Finally, we summarize the latest findings on disease and microbiome modification through targeted immunomodulatory systemic treatments and biologics. We believe that targeting the skin microbiome should be considered a crucial component of successful AD treatment in the future. [ABSTRACT FROM AUTHOR]

The aryl hydrocarbon receptor (AhR) is a ligand-dependent transcription factor that has wide-ranging roles, including regulation of inflammation and homeostasis. AhR is not a cell surface receptor; rather, it exists in a cytoplasmic complex that responds to a wide variety of structurally dissimilar endogenous, microbial, and environmental ligands. The ubiquitous expression of AhR, its ability to be activated by a wide range of ligands, and its capacity to act as a master regulator for gene expression and homeostasis make it a promising new therapeutic target. Clinical trials of tapinarof cream have now validated AhR agonism as a therapeutic approach that can deliver significant efficacy for treating inflammatory skin diseases, including psoriasis and atopic dermatitis. Tapinarof 1% cream is a first-in-class, nonsteroidal, topical, AhR agonist with a pharmacokinetic profile that results in localized exposure at sites of disease, avoiding systemic safety concerns, drug interactions, or off-target effects. Psoriasis and atopic dermatitis both involve epidermal inflammation, cellular immune responses, dysregulation of skin barrier protein expression, and oxidative stress. On the basis of the clinical effectiveness of tapinarof cream for treating inflammatory skin diseases, we review how targeting AhR may offer a significant opportunity in other conditions that share key aspects of pathogenesis, including asthma, inflammatory bowel disease, eosinophilic esophagitis, ophthalmic, and nervous system diseases. [ABSTRACT FROM AUTHOR]

Gestational diabetes mellitus has been linked to inflammation, immune dysregulation in offspring, and changes in the microbiota. It may have long-term implications for the health of children. The aim of this study was to determine if gestational diabetes mellitus increases the risk of allergic diseases in offspring. The data source was the National Health Insurance Research Database (NHIRD) of Taiwan. The pairing of mothers and children was established by connecting the NHIRD with the Taiwan Maternal and Child Health Database. First-time pregnant mothers between 2004 and 2019 were enrolled. The GDM group consisted of 22,741 cases. The control group was selected from individuals without GDM matched by maternal age, neonatal gender, and neonatal birthdate at a ratio of 1–4. The primary endpoint was the incidence of childhood allergic diseases, such as asthma, allergic rhinitis, atopic dermatitis, and urticaria. The secondary endpoint was the risk associated with the development of allergic diseases in offspring, considering the presence or absence of insulin therapy. The development of allergic rhinitis, atopic dermatitis, and urticaria were found to be significantly associated with GDM. However, no significant association was observed between GDM and asthma. GDM control without insulin was associated with an increased risk of developing allergic rhinitis, urticaria, and atopic dermatitis. However, in the group receiving insulin treatment, there was no significant elevation in the risk of any allergic diseases. GDM may elevate the risk of certain atopic diseases in offspring, such as allergic rhinitis, atopic dermatitis, and urticaria. [ABSTRACT FROM AUTHOR]

Atopic dermatitis (AD) is a complex disease characterized by dry, pruritic skin and significant atopic and psychological sequelae. Although AD has always been viewed as multifactorial, early research was dominated by overlapping genetic determinist views of either innate barrier defects leading to inflammation or innate inflammation eroding skin barrier function. Since 1970, however, the incidence of AD in the United States has increased at a pace that far exceeds genetic drift, thus suggesting a modern, environmental etiology. Another implicated factor is Staphylococcus aureus ; however, a highly contagious microorganism is unlikely to be the primary etiology of a noncommunicable disease. Recently, the roles of the skin and gut microbiomes have received greater attention as potentially targetable drivers of AD. Here too, however, dysbiosis on a population scale would require induction by an environmental factor. In this review, we describe the evidence supporting the environmental hypothesis of AD etiology and detail the molecular mechanisms of each of the AD-relevant toxins. We also outline how a pollution-focused paradigm demands earnest engagement with environmental injustice if the field is to meaningfully address racial and geographic disparities. Identifying specific toxins and their mechanisms can also inform in-home and national mitigation strategies. [ABSTRACT FROM AUTHOR]

[Display omitted] Mesenchymal stem cells (MSCs) play important roles in therapeutic applications by regulating immune responses. We investigated the safety and efficacy of allogenic human bone marrow–derived clonal MSCs (hcMSCs) in subjects with moderate to severe atopic dermatitis (AD). The study included a phase 1 open-label trial followed by a phase 2 randomized, double-blind, placebo-controlled trial that involved 72 subjects with moderate to severe AD. In phase 1, intravenous administration of hcMSCs at 2 doses (1 × 106 and 5 × 105 cells/kg) was safe and well tolerated in 20 subjects. Because there was no difference between the 2 dosage groups (P =.9), it was decided to administer low-dose hcMSCs only for phase 2. In phase 2, subjects receiving 3 weekly intravenous infusions of hcMSCs at 5 × 105 cells/kg showed a higher proportion of an Eczema Area and Severity Index (EASI)-50 response at week 12 compared to the placebo group (P =.038). The differences between groups in the Dermatology Life Quality Index and pruritus numeric rating scale scores were not statistically significant. Most adverse events were mild or moderate and resolved by the end of the study period. The hcMSC treatment resulted in a significantly higher rate of EASI-50 at 12 weeks compared to the control group in subjects with moderate to severe AD. The safety profile of hcMSC treatment was acceptable. Further larger-scale studies are necessary to confirm these preliminary findings. [ABSTRACT FROM AUTHOR]

Atopic dermatitis (AD) is an inflammatory skin disease characterized by intense pruritus. AD is harmful to both children and adults, but its pathogenic mechanism has yet to be fully elucidated. The development of mouse models for AD has greatly contributed to its study and treatment. Among these models, the exogenous drug-induced mouse model has shown promising results and significant advantages. Until now, a large amount of AD-related research has utilized exogenous drug-induced mouse models, leading to notable advancements in research. This indicates the crucial significance of applying such models in AD research. These models exhibit diverse characteristics and are highly complex. They involve the use of various strains of mice, diverse types of inducers, and different modeling effects. However, there is currently a lack of comprehensive comparative studies on exogenous drug-induced AD mouse models, which hinders researchers' ability to choose among these models. This paper provides a comprehensive review of the features and mechanisms associated with various exogenous drug-induced mouse models, including the important role of each cytokine in AD development. It aims to assist researchers in quickly understanding models and selecting the most suitable one for further investigation. [Display omitted] • Exogenous-drugs induced mouse models are very helpful in studying the pathogenesis of AD in humans. • Hapten-induced mouse models are cost-effective but time-consuming. • OVA-induced mouse models are widely applicable. • MC903-induced mouse models are ideal for rapid AD modelling. [ABSTRACT FROM AUTHOR]

Although several mouse models of exogenous-agent – induced atopic dermatitis (AD) are currently available, the lack of certainty regarding their similarity with human AD has limited their scientific value. Thus, comprehensive evaluation of the characteristics of mouse models and their similarity with human AD is essential. To compare six different exogenous-agent – induced AD mouse models and find out the optimum models for study. Female BALB/c mice underwent induction of AD-like dermatitis by MC903 alone or in combination with ovalbumin (OVA), dinitrofluorobenzene (DNFB) alone or in combination with OVA, OVA alone, or Staphylococcus aureus. Gross phenotype, total immunoglobulin E (IgE) level, histopathological manifestations, and skin lesion transcriptome were analyzed, and metagenomic sequencing of the gut microbiome was performed. The DNFB plus OVA model showed the highest disease severity, while the OVA model showed the lowest severity. The MC903 and MC903 plus OVA models showed high expression of T-helper (Th)2- and Th17-related genes; the DNFB and DNFB plus OVA models showed upregulation of Th1-, Th2-, and Th17-related genes; while the S. aureus inoculation model showed more enhanced Th1 and Th17 immune responses. In contrast to the other models, the OVA-induced model showed the lowest expression levels of inflammation-related genes, while the MC903 model shared the largest overlap with human AD profiles. The intestinal microbiota of all groups showed significant differences after modeling. Each AD mouse model exhibited different characteristics. The MC903 model was the best to recapitulate most features of human AD among these exogenous-agent – induced AD models. • Each exogenous-agent–induced AD model exhibited different characteristics. • The MC903 model was the best to recapitulate most features of human AD among these exogenous-agent–induced AD models. • The intestinal microbiota of all models showed significant differences after modeling. [ABSTRACT FROM AUTHOR]

Elderly atopic dermatitis (AD) is a subtype of AD defined by age (≥ 60 years). The molecular characteristics of elderly AD remain to be clarified. We sought to characterize the molecular features of skin lesions and peripheral blood mononuclear cells (PBMCs) in patients with AD across different age, focusing on elderly AD. Skin and PBMCs samples were used for RNA sequencing. Analysis of differentially expressed genes and gene set variation analysis were performed. Immunofluorescence staining, quantitative real-time PCR (qRT-PCR), flow cytometry and transwell assay were used for validation. Compared with healthy controls, the skin transcriptome of AD patients showed common signatures of AD, like barrier dysfunction and enhanced Th1/Th2/Th17 immune pathways. In PBMCs, the expression of Th1/Th2 response genes was more remarkable in adult AD, while expression of Th17-related genes was significantly higher in childhood AD. The gene modules associated with natural killer (NK) cells were downregulated in elderly AD. In skin lesions, elderly AD exhibited enrichment of macrophages, fibroblasts and senescence-associated secretory phenotype (SASP) related genes. The correlation among fibroblasts, SASP and innate immune cells were revealed by the co-localization of fibroblasts, macrophages and NK cells in the lesions across different age groups. Fibroblasts under inflammation or senescence could induce stronger chemotaxis of macrophages and NK cells. We identified the molecular phenotypes of skin lesions and PBMCs in elderly AD individuals. Fibroblasts, innate immune cells, and SASP might play important roles in the pathogenesis of elderly AD. • Elderly patients with AD present distinct transcriptomic characteristics. • Senescent fibroblasts may be the main source of SASP. • Senescent fibroblasts induce cascade activation of innate immune cells and are involved in the pathogenesis of elderly AD. [ABSTRACT FROM AUTHOR]

Air pollutants may aggravate atopic dermatitis (AD). However, the association between Air Quality Index (AQI) and incidence of AD remains unknown. To investigate association between AQI and incidence of AD, using the nationwide cohort in the Taiwan National Health Insurance Research Database (NHIRD). We included 21,278,938 participants from the NHIRD not diagnosed with AD before 2008. Long-term average AQI value, obtained from the Taiwan Air Quality Monitoring System Network, before AD diagnosis was calculated and linked for each participant. 199,205 incident cases of AD were identified from 2008 to 2018. Participants were classified into 4 quantiles (Q) by AQI value. With the lowest quantile, Q1, as reference, the AD risk increased significantly in the Q2 group (adjusted hazard ratio [aHR]: 1.29, 95% confidence interval [CI]: 1.04-1.65), Q3 group (aHR: 4.71, 95% CI: 3.78-6.04), and was highest in the Q4 group (aHR: 13.20, 95% CI: 10.86-16.60). As AQI treated as a continuous variable, an increase of 1 unit of AQI value added 7% of AD risk (aHR, 1.07, 95% CI: 1.07-1.08). The NHIRD lacks detailed information on individual subjects. The results demonstrated a significant positive association between AQI and incidence of AD with a clear dose-response relationship. [ABSTRACT FROM AUTHOR]

T reg plays a pivotal role in the suppression of Th2 cell and the maintenance of immune homeostasis. The precise molecular mechanism underlying the disruption of T reg suppression of Th2 cell and the promotion of Th2 type inflammation in allergic diseases remains elusive. This study aims to investigate the molecular mechanism underlying quantitative and functional changes of T reg in AD. The molecular mechanism was investigated using flow cytometry, mRNA sequencing, co-culture experiments, co-immunoprecipitation, chromatin immunoprecipitation, and bisulfite sequencing in vitro or in AD mice model and patients with AD. Increased proportion of T reg was detected in mild and moderate AD. Conversely, characteristic decrease in both the number and CTLA-4 expression of T reg was relevant to serum IL-4 level in severe AD patients, which was verified under a high concentration of IL-4 treatment in vitro. The underlying mechanism is that IL-4/pSTAT6 pathway recruits DNMT1 and HDAC2 to inhibit transcriptional regulation of Foxp3 and CTLA-4 loci. High level of IL-4 impaired the suppression of T reg against Th2 cell differentiation mediated by CTLA-4, and blockade of IL-4Rα signaling in T reg restored T reg number and suppression of Th2 cell in AD model mice and patients with AD. The number of T reg is relevant to stratification of severity and serum IL-4 level in patients with AD. Abnormal high level of IL-4 epigenetically triggers a decrease in both the number and CTLA-4 expression of T reg. The reduced expression of CTLA-4 on T reg induced by IL-4 impairs suppression of Th2 cell differentiation. • The number of T reg is relevant to stratification of severity and serum IL-4 level in patients with AD. • High level of IL-4 epigenetically triggers a decrease in both the number and CTLA-4 expression of T reg in severe AD. • IL-4-induced reduction in both number and CTLA-4 expression of T reg impaired CTLA-4-mediated suppression of Th2 cell. • Blockade of IL-4Rα signaling in T reg restores T reg expression and its suppression of Th2 type inflammation in severe AD. [ABSTRACT FROM AUTHOR]

Certain immune-mediated inflammatory diseases (IMIDs) may increase patients' risk for venous thromboembolisms (VTEs), yet how atopic dermatitis (AD) influences VTE risk remains unclear. Describe VTE incidence in patients with AD compared with other IMIDs and unaffected, AD-matched controls. This retrospective, observational, comparative cohort study used Optum Clinformatics United States claims data (2010-2019) of adults with AD, rheumatoid arthritis (RA), Crohn's disease (CD), ulcerative colitis (UC), psoriasis (PsO), psoriatic arthritis (PsA), or ankylosing spondylitis (AS). Unaffected control patients were matched 1:1 with patients with AD. Of 2,061,222 patients with IMIDs, 1,098,633 had AD. Patients with AD had a higher VTE incidence (95% CI) than did unaffected, AD-matched controls (0.73 [0.72-0.74] versus 0.59 [0.58-0.60] cases/100 person-years). When controlling for baseline VTE risk factors, however, AD was not associated with increased VTE risk (HR 0.96 [0.90-1.02]). VTE risk was lower in patients with AD versus RA, UC, CD, AS, or PsA; VTE risk was similar to patients with PsO. Disease activity and severity were not accounted for. AD did not increase VTE risk when accounting for underlying risk factors. AD was associated with lower VTE risk compared with several rheumatologic and gastrointestinal IMIDs. [ABSTRACT FROM AUTHOR]

[Display omitted] The development of atopic dermatitis (AD) drugs is challenged by many disease phenotypes and trial design options, which are hard to explore experimentally. We aimed to optimize AD trial design using simulations. We constructed a quantitative systems pharmacology model of AD and standard of care (SoC) treatments and generated a phenotypically diverse virtual population whose parameter distribution was derived from known relationships between AD biomarkers and disease severity and calibrated using disease severity evolution under SoC regimens. We applied this workflow to the immunomodulator OM-85, currently being investigated for its potential use in AD, and calibrated the investigational treatment model with the efficacy profile of an existing trial (thereby enriching it with plausible marker levels and dynamics). We assessed the sensitivity of trial outcomes to trial protocol and found that for this particular example the choice of end point is more important than the choice of dosing regimen and patient selection by model-based responder enrichment could increase the expected effect size. A global sensitivity analysis revealed that only a limited subset of baseline biomarkers is needed to predict the drug response of the full virtual population. This AD quantitative systems pharmacology workflow built around knowledge of marker-severity relationships as well as SoC efficacy can be tailored to specific development cases to optimize several trial protocol parameters and biomarker stratification and therefore has promise to become a powerful model-informed AD drug development and personalized medicine tool. [ABSTRACT FROM AUTHOR]

Atopic dermatitis is usually associated with various ocular complications. We report a 21-year-old Chinese male who presented to our ophthalmology clinic with bilateral retinal detachment and cataracts. The patient had a clear medical history of atopic dermatitis, which had been diagnosed eight years earlier and had been treated with loratadine and pimecrolimus. Cataract surgery was performed for both eyes, combined with scleral buckling for the right eye and pars plana vitrectomy for the left eye. During postoperative follow-up, fundus fluorescein angiography showed retinal vasculitis in both eyes and macular edema in the left eye, which coincided with an exacerbation of atopic dermatitis. Macular edema improved after four months of regular dupilumab treatment in the dermatology department. The ocular condition remained stable three years postoperatively. [ABSTRACT FROM AUTHOR]

Mast cells (MCs) are tissue-resident immune cells, well-positioned at the host-environment interface for detecting external antigens and playing a critical role in mobilizing innate and adaptive immune responses. Sensory neurons are afferent neurons innervating most areas of the body but especially in the periphery, where they sense external and internal signals and relay information to the brain. The significance of MC–sensory neuron communication is now increasingly becoming recognized, especially because both cell types are in close physical proximity at the host-environment interface and around major organs of the body and produce specific mediators that can activate each other. In this review, we explore the roles of MC–sensory neuron crosstalk in allergic diseases, shedding light on how activated MCs trigger sensory neurons to initiate signaling in pruritus, shock, and potentially abdominal pain in allergy, and how activated sensory neurons regulate MCs in homeostasis and atopic dermatitis associated with contact hypersensitivity and type 2 inflammation. Throughout the review, we also discuss how these 2 sentinel cell types signal each other, potentially resulting in a positive feedback loop that can sustain inflammation. Unraveling the mysteries of MC–sensory neuron crosstalk is likely to unveil their critical roles in various disease conditions and enable the development of new therapeutic approaches to combat these maladies. [ABSTRACT FROM AUTHOR]

[Display omitted] Atopic dermatitis (AD) is a chronic inflammatory skin disease characterized by dry, pruritic skin. Several studies have described nocturnal increases in itching behavior, suggesting a role for the circadian rhythm in modulating symptom severity. However, the circadian rhythm of metabolites in the skin and serum of patients with AD is yet to be described. We sought to assess circadian patterns of skin and serum metabolism in patients with AD. Twelve patients with moderate to severe AD and 5 healthy volunteers were monitored for 28 hours in a controlled environment. Serum was collected every 2 hours and tape strips every 4 hours from both lesional and nonlesional skin in participants with AD and location-, sex-, and age-matched healthy skin of controls. We then performed an untargeted metabolomics analysis, examining the circadian peaks of metabolism in patients with AD. Distinct metabolic profiles were observed in AD versus control samples. When accounting for time of collection, the greatest differences in serum metabolic pathways were observed in arachidonic acid, steroid biosynthesis, and terpenoid backbone biosynthesis. We identified 42 circadian peaks in AD or control serum and 17 in the skin. Pathway enrichment and serum-skin metabolite correlation varied throughout the day. Differences were most evident in the late morning and immediately after sleep onset. Although limited by a small sample size and observational design, our findings suggest that accounting for sample collection time could improve biomarker detection studies in AD and highlight that metabolic changes may be associated with nocturnal differences in symptom severity. [ABSTRACT FROM AUTHOR]

Atopic dermatitis (AD) is predominantly characterized by intense itching, but concomitant skin pain is experienced by more than 40% of patients. Patients with AD display considerable somatosensory aberrations, including increased nerve sensitivity to itch stimuli (hyperknesis), perception of itch from innocuous stimuli (alloknesis), or perception of pain from innocuous stimuli (allodynia). This review summarizes the current understanding of the similarities and differences in the peripheral mechanisms underlying itch and pain in AD. These distinct yet reciprocal sensations share many similarities in the peripheral nervous system, including common mediators (such as serotonin, endothelin-1, IL-33, and thymic stromal lymphopoietin), receptors (such as members of the G protein–coupled receptor family and Toll-like receptors), and ion channels for signal transduction (such as certain members of the transient receptor potential [TRP] cation channels). Itch-responding neurons are also sensitive to pain stimuli. However, there are distinct differences between itch and pain signaling. For example, specific immune responses are associated with pain (type 1 and/or type 3 cytokines and certain chemokine C-C [CCL2, CCL5] and C-X-C [CXCL] motif ligands) and itch (type 2 cytokines, including IL-31, and periostin). The TRP melastatin channels TRPM2 and TRPM3 have a role in pain but no known role in itch. Activation of μ-opioid receptors is known to alleviate pain but exacerbate itch. Understanding the connection between itch and pain mechanisms may offer new insights into the treatment of chronic pain and itch in AD. [ABSTRACT FROM AUTHOR]

Type 2 inflammation is characterized by overexpression and heightened activity of type 2 cytokines, mediators, and cells that drive neuroimmune activation and sensitization to previously subthreshold stimuli. The consequences of altered neuroimmune activity differ by tissue type and disease; they include skin inflammation, sensitization to pruritogens, and itch amplification in atopic dermatitis and prurigo nodularis; airway inflammation and/or hyperresponsiveness, loss of expiratory volume, airflow obstruction and increased mucus production in asthma; loss of sense of smell in chronic rhinosinusitis with nasal polyps; and dysphagia in eosinophilic esophagitis. We describe the neuroimmune interactions that underlie the various sensory and autonomic pathologies in type 2 inflammatory diseases and present recent advances in targeted treatment approaches to reduce type 2 inflammation and its associated symptoms in these diseases. Further research is needed to better understand the neuroimmune mechanisms that underlie chronic, sustained inflammation and its related sensory pathologies in diseases associated with type 2 inflammation. [ABSTRACT FROM AUTHOR]

Various bacterial species form a microbiome in the skin. In the past, dead Staphylococcus aureus derived from atopic dermatitis (AD) are taken up by keratinocytes; however, whether live S. aureus can be taken up by keratinocytes is unknown. This study aimed to examine whether live AD strains of S. aureus internalize into the keratinocytes and how the internalization changes under conditions in which other bacterial species including S. epidermidis are present. HaCaT cells were cultured with live S. aureus and S. epidermidis (live or heat-treated) or their culture supernatants. After coculture, the change in the amount of S. aureus in the cytoplasm of HaCaT cells was analyzed using, a high-throughput imaging system, Opera Phenix™. Live S. aureus were taken up in the cytoplasm of HaCaT cells. Coculturing live S. aureus with live S. epidermidis or the culture supernatants decreased the abundance of S. aureus in the cytoplasm. The heat-treated culture supernatants of live S. epidermidis or culture supernatants of other S. strains did not decrease the abundance of S. aureus in the cytoplasm. Live S. aureus was internalized into the cytoplasm of HaCaT cells as does heat-treated S. aureus. In addition, the heat-sensitive substances secreted by coculture with S. epidermidis and keratinocytes inhibited the uptake of S. aureus by keratinocytes. • HaCaT cells internalized live AD strains of Staphylococcus (S.) aureus. • The coexistence of S. epidermidis inhibits uptake of S. aureus into HaCaT cells. • Co-culture supernatant with S. epidermidis and HaCaT cells inhibits the uptake. • S. epidermidis alone does not inhibit uptake of S. aureus. • The factors that inhibit the uptake of S. aureus are inactivated by heat treatment. [ABSTRACT FROM AUTHOR]

Atopic dermatitis (AD) is thought to precede the onset of other allergic illness (OAI) in a temporal progression (ie, atopic march), yet the timing and progression has been questioned. It is also unclear how parental allergic illness impacts the development of these illnesses in offspring. (1) Explore risk of incident AD and (2) timing of allergic disease onset in children of mothers with AD compared with mothers without AD from the United Kingdom. We created a birth cohort of mother-child pairs using IQVIA Medical Research Data database and developed Cox proportional models to examine the above associations (hazard ratio, HR [95% confidence interval, CI]). Among 1,224,243 child-mother pairs, mean child (standard deviation) follow-up time was 10.8 (8.3) years and 50.1% were males (N = 600,905). Children were 59% (HR = 1.59 [1.57, 1.60]) more likely to have AD if their mothers had AD compared with no AD with mean age of first AD diagnosis at 3.3 (4.8) years. Most children with any diagnosis of AD present with AD first (91.0%); however, in those with asthma, only 67.8% developed AD first. Children born to mothers with AD are more prone to develop AD and some develop OAI first, suggesting that not all follow the same sequential pathway. • The atopic march describes the temporal association of initial onset of atopic dermatitis at an early age followed by subsequent development of other atopic illness. • We observed that whereas this may be true for some, not all patients with allergic diseases including atopic dermatitis, will follow the same "sequential" march. [ABSTRACT FROM AUTHOR]

Eblasakimab, an interleukin (IL)-13 receptor α1 antagonist, blocks IL-4 and IL-13 signaling through the type 2 receptor. The safety and efficacy of eblasakimab was evaluated in adults with moderate-to-severe atopic dermatitis (AD). In this phase 1b randomized, double-blinded study, 52 patients with moderate-to-severe AD received weekly subcutaneous injections of eblasakimab 200, 400, or 600 mg, or placebo for 8 weeks. Primary outcome was the incidence of treatment-emergent adverse events. Secondary outcomes included percentage change in the Eczema Area and Severity Index from baseline; Eczema Area and Severity Index improvement of at least 50%, 75%, or 90% from baseline; and percentage change in the peak-pruritus numeric rating scale score from baseline. Treatment-emergent adverse events were reported in 47% placebo and 71% eblasakimab patients; most were considered mild or moderate and did not lead to study discontinuation. At week 8 eblasakimab 600 mg showed statistically significant improvement in mean percentage change in Eczema Area and Severity Index versus placebo (–65% vs –27%, P =.014). Other key secondary physician- and patient-reported end points were met. Longer studies are required to confirm eblasakimab safety and efficacy in AD patients. Treatment of adults with moderate-to-severe AD with eblasakimab was well-tolerated and associated with significant clinical improvements versus placebo. [ABSTRACT FROM AUTHOR]

Tissue-resident memory T (T RM) cells serve as a first line of defense in peripheral tissues to protect the organism against foreign pathogens. However, autoreactive T RM cells are increasingly implicated in autoimmunity, as evidenced in chronic autoimmune and inflammatory skin conditions. This highlights the need to characterize their phenotype and understand their role for the purpose of targeting them specifically without affecting local immunity. To date, the investigation of T RM cells in human skin diseases has focused mainly on lesional tissues of patients. Accumulating evidence suggests that self-reactive T RM cells are still present in clinically healed lesions of patients and play a role in disease flares, but T RM cells also populate skin that is apparently normal. This review discusses the ontogeny of T RM cells in the skin as well as recent insights regarding the presence of self-reactive T RM cells in both clinically healed skin and nonlesional skin of patients with autoimmune and inflammatory skin conditions, with a particular focus on psoriasis, atopic dermatitis, and vitiligo. [ABSTRACT FROM AUTHOR]

Tacrolimus (TRL) is used for the treatment of atopic dermatitis (AD) due to its T-cell stimulation effect. However, its significantly poor water solubility, low penetration and cytotoxicity have reduced its topical applications. Herein, tacrolimus loaded nano transfersomes (TRL-NTs) were prepared, followed by their incorporation into chitosan gel to prepare tacrolimus loaded nano transfersomal gel (TRL-NTsG). TEM analysis of the TRL-NTs was performed to check their morphology. DSC, XRD and FTIR analysis of the TRL-NTs were executed after lyophilization. Similarly, rheology, spreadability and deformability of the TRL-NTsG were investigated. In vitro release, ex vivo permeation and in vitro interaction of TRL-NTsG with keratinocytes and fibroblasts as well as their co-cultures were investigated along with their in vitro cell viability analysis. Moreover, in vivo skin deposition, ear thickness, histopathology and IgE level were also determined. Besides, 6 months stability study was also performed. Results demonstrated the uniformly distributed negatively charged nanovesicles with a mean particle size distribution of 163 nm and zeta potential of -27 mV. DSC and XRD exhibited the thermal stability and amorphous form of the drug, respectively. The TRL-NTsG showed excellent deformability, spreadability and rheological behavior. In vitro release studies exhibited an 8-fold better release of TRL from the TRL-NTsG. Similarly, 6-fold better permeation and stability of the TRL-NTsG with keratinocytes and fibroblasts as well as their co-cultures was observed. Furthermore, the ear thickness (0.6 mm) of the TRL-NTsG was found significantly reduced when compared with the untreated (1.7 mm) and TRL conventional gel treated mice (1.3 mm). The H&E staining showed no toxicity of the TRL-NTsG with significantly reduced IgE levels (120 ng/mL). The formulation was found stable for at least 6 months. These results suggested the efficacy of TRL in AD-induced animal models most importantly when incorporated in NTsG. [ABSTRACT FROM AUTHOR]