Atopic Dermatitis Patients Research Articles

Keratinocyte-derived small extracellular vesicles supply antigens for CD1a-resticted T cells and promote their type 2 bias in the context of filaggrin insufficiency.

Exosome-enriched small extracellular vesicles (sEVs) are nanosized organelles known to participate in long distance communication between cells, including in the skin. Atopic dermatitis (AD) is a chronic inflammatory skin disease for which filaggrin (FLG) gene mutations are the strongest genetic risk factor. Filaggrin insufficiency affects multiple cellular function, but it is unclear if sEV-mediated cellular communication originating from the affected keratinocytes is also altered, and if this influences peptide and lipid antigen presentation to T cells in the skin. Available mRNA and protein expression datasets from filaggrin-insufficient keratinocytes (shFLG), organotypic models and AD skin were used for gene ontology analysis with FunRich tool. sEVs secreted by shFLG and control shC cells were isolated from conditioned media by differential centrifugation. Mass spectrometry was carried out for lipidomic and proteomic profiling of the cells and sEVs. T cell responses to protein, peptide, CD1a lipid antigens, as well as phospholipase A2-digested or intact sEVs were measured by ELISpot and ELISA. Data analysis revealed extensive remodeling of the sEV compartment in filaggrin insufficient keratinocytes, 3D models and the AD skin. Lipidomic profiles of shFLGsEV showed a reduction in the long chain (LCFAs) and polyunsaturated fatty acids (PUFAs; permissive CD1a ligands) and increased content of the bulky headgroup sphingolipids (non-permissive ligands). This resulted in a reduction of CD1a-mediated interferon-γ T cell responses to the lipids liberated from shFLG-generated sEVs in comparison to those induced by sEVs from control cells, and an increase in interleukin 13 secretion. The altered sEV lipidome reflected a generalized alteration in the cellular lipidome in filaggrin-insufficient cells and the skin of AD patients, resulting from a downregulation of key enzymes implicated in fatty acid elongation and desaturation, i.e., enzymes of the ACSL, ELOVL and FADS family. We determined that sEVs constitute a source of antigens suitable for CD1a-mediated presentation to T cells. Lipids enclosed within the sEVs secreted on the background of filaggrin insufficiency contribute to allergic inflammation by reducing type 1 responses and inducing a type 2 bias from CD1a-restricted T cells, thus likely perpetuating allergic inflammation in the skin.

Associations between interleukin-13, interleukin-4 and their receptor gene polymorphisms and susceptibility to atopic dermatitis in a Chinese Han population.

Background Atopic dermatitis (AD) is a common skin condition that occurs due to a combined effect of immune dysregulation, skin barrier dysfunction, changes in the cutaneous microbiome, and genetic factors. Recent data from both clinical trials and real-world studies indicate that dupilumab, a biological agent that inhibits interleukin 4 receptor-α is an effective drug in the treatment of AD, which further suggests the important role of IL-13 and IL-4 in the pathogenesis of AD. Objectives To assess the association between gene polymorphisms of IL-13, IL-13 receptor, IL-4, and IL-4 receptor and susceptibility to AD. Methods The single nucleotide polymorphisms (SNPs) of the above-mentioned genes were detected by single base extension (SNaPshot) assay. The association between these SNPs and AD risk was analysed using SPSS software. Results Two hundred and seventy-one subjects including 130 patients with AD and 141 healthy controls were enrolled. There were statistical differences between AD patients and controls in genotype distribution at rs2265753, rs6646259, and rs2254672 of the IL-13 receptor gene (P all < 0.001). Subjects with CG at rs2265753, AG at rs6646259 and TG at rs2254672 had increased risks for AD (P all < 0.001), and subjects with GG at rs2265753, rs6646259, and rs2254672 had reduced risks for AD (P all < 0.001). Limitation This was a single-centre and single-race study, with a relatively small sample size. Conclusions Findings from this study show that rs2265753, rs6646259 and rs2254672 of the IL-13 receptor gene are associated with susceptibility to AD.

Optimization and Validation of an FTIR-based, All-in-one System for Viable MDR Bacteria Detection in Combat-related Wound Infection.

The U.S. Military members experiencing combat-related injuries have a higher chance of developing infections by multidrug-resistant (MDR) bacteria at admission to military hospitals. MDR wound infections result in higher amputation rates and greater risks for subsequent or chronic infections that require readmission or extended stay in the hospital. Currently, there is no FDA-clear, deployable early diagnostic system for suitable field use.We are reporting our efforts to improve a previously developed Rapid Label-free Pathogen Identification (RAPID) system to detect viable MDR bacteria in wound infections and perform antibiotic susceptibility testing (AST). Specifically, we added multiplex and automation capability and significantly simplified the sample preparation process. A functional prototype of the improved system was built, and its performance was validated using a variety of lab-prepared spiked samples and real-world samples. To access the baseline performance of the improved RAPID system in detecting bacteria presence, we selected 17 isolates, most of them from blood or wound infections, and prepared mono-strain spiked samples at 104 to 106 cfu/mL concentration. These samples were processed and analyzed by the RAPID system. To demonstrate the AST capability of the system, we selected 6 strains against 6 different antibiotics and compared the results from the system with the ones from the gold standard method.To validate the system's performance with real-world samples, we first investigated its performance on 3 swab samples from epicutaneous methicillin-resistant Staphylococcus aureus-exposed mouse model. The AST results from our system were compared with the ones from the gold standard method. All animal experiments were approved by the Johns Hopkins University Animal Care and Use Committee (Protocol No. MO21M378). Then, we obtained swab samples from 7 atopic dermatitis (AD) patients and compared our AST results with the ones from the gold standard method. The human subject protocol was approved by the Johns Hopkins Medicines Institutional Review Boards (Study No. CR00043438/IRB00307926) and by USAMRDC (Proposal Log Number/Study Number 20000251). High-quality data were obtained from the spiked samples of all 17 strains. A quantitative analysis model built using these data achieved 94% accuracy in predicting the species ID in 8 unknown samples. The AST results on the spiked samples had shown 100% matching with the gold standard method. Our system successfully detects the presence/absence of viable bacteria in all 3 mouse and 7 AD patient swab samples. Our system shows 100% and 85.7% (6 out of 7) accuracy when compared to the oxacillin susceptibility testing results for the mouse and the AD patient swabs, respectively. Our system has achieved excellent performance in detecting viable bacteria presence and in performing AST in a multiplex, automated, and easy-to-operate manner, on both lab-prepared and real samples. Our results have shown a path forward to a rapid (sample-to-answer time ≤3 hours), accurate, sensitive, species-specific, and portable system to detect the presence of MDR combat-related wound infections in the field environment. Our future efforts involve ruggedizing the RAPID system and evaluating performance under relevant environmental conditions.

Investigating Vα7.2+/CD161- T Cell and MAIT Cell Profiles Using Flow Cytometry in Healthy Subjects and Subjects with Atopic Dermatitis.

This study investigates the roles of mucosal-associated invariant T (MAIT) cells and Vα7.2+/CD161- T cells in skin diseases, focusing on atopic dermatitis. MAIT cells, crucial for bridging innate and adaptive immunity, were analyzed alongside Vα7.2+/CD161- T cells in peripheral blood samples from 14 atopic dermatitis patients and 10 healthy controls. Flow cytometry and machine learning algorithms were employed for a comprehensive analysis. The results indicate a significant decrease in MAIT cells and CD69 subsets in atopic dermatitis, coupled with elevated CD38 and polyfunctional MAIT cells producing TNFα and Granzyme B (TNFα+/GzB+). Vα7.2+/CD161- T cells in atopic dermatitis exhibited a decrease in CD8 and IFNγ-producing subsets but an increase in CD38 activated and IL-22-producing subsets. These results highlight the distinctive features of MAIT cells and Vα7.2+/CD161- T cells and their different roles in the pathogenesis of atopic dermatitis and provide insights into their potential roles in immune-mediated skin diseases.

Safety of Tralokinumab for the Treatment of Atopic Dermatitis in Patients with Up to 4.5 Years of Treatment: An Updated Integrated Analysis of Eight Clinical Trials

Introduction: Clinical trials of up to 52 weeks showed that tralokinumab, a monoclonal antibody that specifically neutralizes interleukin-13, was efficacious and well-tolerated as monotherapy and combination with TCS. Here, we evaluate the long-term safety of tralokinumab in an integrated analysis of seven phase 3 parent trials (PTs) (NCT03131648, NCT03160885, NCT03363854, NCT03562377, NCT03526861, NCT03761537, NCT04587453), and the ongoing, up to 5-year extension study (ECZTEND; NCT03587805).&#x0D; Methods: Two datasets were analyzed: placebo-controlled (initial 16-week period of the PTs), and all-tralokinumab combining PTs with ECZTEND including patients from first dose until end of tralokinumab exposure or data cut-off (April 30th, 2022). In the all-tralokinumab dataset, periods on placebo were disregarded. Treatment-emergent adverse events (AEs) were recorded. AEs of special interest (AESIs) were predefined. Proportions of patients with events and incidence rates (IR) per 100 patient-years of exposure (PYE) were calculated. PYE was defined as time until first event or exposure end, whichever came first, and incidence was defined as first event.&#x0D; Results: 2693 patients (≥12 years) received tralokinumab for up to 238.5 weeks (≈4.5 years) with a median exposure time of 76.5 weeks in the all-tralokinumab dataset. Median age at baseline was 33.0 years (min-max; 12-92). 10.4% of patients were 12-17 years. 2307 patients experienced an AE (IR=202.0), most (97.3%) of which were mild-to-moderate. Serious AEs (SAEs) were reported in 226 patients (IR=4.5); SAEs were considered possibly or probably related by the investigator in 50 patients (IR=0.9). No preferred term level SAEs were reported with an IR≥0.1. Discontinuation of treatment due to AEs was low (IR=2.8). AEs leading to drug withdrawal with an IR&gt;0.1 were dermatitis atopic (IR=0.5) and injection site reaction (ISR) (IR=0.2). Frequently reported AEs in the all-tralokinumab dataset were consistent with the placebo-controlled dataset, including nasopharyngitis (IR=18.4), upper respiratory tract infection (IR=6.9), conjunctivitis (IR=5.0), ISR (IR=3.6), conjunctivitis allergic (IR=2.7), and injection site pain (IR=1.5). AESIs, including eye disorders, skin infections requiring systemic treatment, eczema herpeticum, and malignancies, were observed in the all-tralokinumab dataset at rates similar to or lower than the placebo-controlled dataset.&#x0D; Conclusion: Long-term use of tralokinumab, for up to 4.5 years, was well-tolerated, and the pattern of AEs was consistent with the initial placebo-controlled treatment period with no new safety signals identified.

A Checklist to Aid in Identifying Patients with Atopic Dermatitis Who are Candidates for Systemic Therapy

Introduction: The decision to initiate systemic therapy (ST) in patients with atopic dermatitis (AD) is complex, with no criteria that are globally agreed upon. To aid dermatology providers in this decision-making, the “When to Start Systemic Therapy Checklist” was developed. The checklist comprises three components: (A) clinical severity, (B) subjective burden, and (C) lack of treatment response, each with several criteria. Systemic therapy is indicated when at least one criterion in each component is fulfilled. To corroborate the validity of this checklist, we evaluated the agreement between the decision to initiate ST using the checklist, against the reference, CorEvitas AD Registry patients prescribed a ST. Methods: Adults with moderate-to-severe AD from the prospective, longitudinal CorEvitas AD registry were included in this descriptive analysis (July 2020 – August 2023). Patients were included if they were initiating ST at enrollment (ST group) or not initiating ST at enrollment (non-ST group) but had vIGA-AD® ≥3 and Eczema Area Severity Index ≥12. The checklist criteria were compared against registry outcome measures; when a criterion did not match a measure, either a proxy measure was selected or that part of the questionnaire was excluded. Overall percentage agreement (accord between checklist criteria and ST initiation status [reference standard]) with corresponding 95% confidence intervals (CIs) was calculated. Results: In the ST group (n=1488), 97.0% of patients met at least one criterion from section A, 94.1% from section B, and 92.1% for either section A or B. In the non-ST group (n=208), 100% of patients met at least one criterion from section A, 92.3% from section B, and 92.3% from either section A or B. Among patients in the ST group who met at least one criterion each from section A and B, overall percentage agreement was 81.7% (95% CI: 79.8%, 83.5%). Section C, which addresses “lack of treatment response” could not be evaluated due to the absence of relevant data in the registry. Discussion: Nearly all patients initiating ST met at least one criterion from both section A and B of the “When to Start Systemic Therapy Checklist”, demonstrating a strong alignment between the checklist sections A and B and disease burden of AD patients in the registry. Subsequent research is needed to assess section C due to registry limitations. Future analyses should examine why some patients with high disease burden and severity remain untreated with systemics.

Associations between Atopic Dermatitis and Behavior Difficulties in Children.

Background and Objectives: There has been increasing evidence that atopic dermatitis (AD) is associated with behavioral difficulties (BDs). There is currently a lack of evidence of how the severity of the disease determines BDs and what additional factors may contribute to their manifestation. The aim is to determine what kind of BDs occur in children with AD compared to healthy children and to find out what additional factors may contribute to the development of BDs in AD patients. Materials and Methods: This is a cross-sectional, prospective study with the application of a risk assessment instrument for behavior difficulties (Child Behavior Checklist, CBCL 6/18) in pediatric patients with AD and healthy controls (6-17 years) between 1 January 2020 and 31 December 2022. For statistical comparison, mainly Wilcoxon-Mann-Whitney and Student's t-test were used, considering a significance level of 5%. Results: This study included a total of 101 children: 48% with AD, 52% non-AD. The mean age was 10 ± 2.7 years for AD, and10.5 ± 3.1 years for the control patients. AD patients had higher internal behavior scale scores and T-scores (6.6 ± 6.4 vs. 9.6 ± 6.9 and 47.9 ± 9.5 vs. 52.3 ± 10.2, p = 0.01), anxiety/depression scale score and T-score (2.8 ± 2.7 vs. 4.3 ± 3.5 and 47.7 ± 8.4 vs. 52.5 ± 11, p = 0.02), and somatic problems scale score and T-score (2.1 ± 2.3 vs. 3.5 ± 3 and 47.6 ± 8.5 vs. 52.7 ± 10.9, p = 0.005). Patients with severe AD had sleep disturbance and itching scores higher than those with mild-moderate AD (5.4 ± 2.6 vs. 2.4 ± 2.2, p = 0.000 and 6.6 ± 2.4 vs. 4 ± 2.8, p = 0.001). The mean morning serum cortisol concentration was lower in AD patients compared to controls (252.91 ± 304.34 vs. 351.55 ± 126.09 nmol/L, p = 0.047). Conclusions: Children with AD present a higher risk of BDs than healthy controls. Patients with severe AD experience more sleep disturbances and a greater intensity of itching compared to mild-moderate AD. The occurrence of BDs was not related to serum cortisol levels. The cortisol level, severity, age, gender, duration of illness, intensity of pruritus, and sleep disturbance did not affect the development of BDs.

Dupilumab therapy improves gut microbiome dysbiosis and tryptophan metabolism in Chinese patients with atopic dermatitis

BackgroundDupilumab has demonstrate its potential to orchestrate inflammatory skin microenvironment, enhance skin barrier and shift skin microbiome dysbiosis, collectively contributing to clinical improvement in patients with atopic dermatitis (AD). As the second genome of human body, growing evidence suggests that the gut microbiome might relate to the host response to treatments. Little is known about the association between dupilumab treatment and gut microbiome in AD patients. ObjectiveWe aimed to characterize the gut microbiome among Chinese subjects with or without AD and determine the potential effect of dupilumab on the gut microbiome. ResultsThe 16 s rRNA gene sequencing was conducted on 48 healthy controls (HC), 44 AD patients and 27 AD patients who received dupilumab for 16 weeks. Prior to treatment, we identified the changed beta-diversity, increased Firmicutes/Bacteroidetes ratio, decreased Bifidobacterium and expanded Faecalibacterium among the AD patients compared to HC. After 16 weeks of dupilumab treatment, gut microbiome dysbiosis of the AD patients improved with reversed beta-diversity, closer bacterial connections, increased colonization of Bifidobacterium, Ruminococcus gnavus, and Coprococcus, which were negatively correlated with disease severity indicators. This shift was largely independent of the degree of clinical improvement. Bacterial function analysis revealed further metabolic alterations following dupilumab treatment, including up-regulated expression of genes involved in the indole pathway of tryptophan metabolism, corroborated by quantitative UHPLC-MS/MS analysis. ConclusionDupilumab treatment tends to help shift the gut microbial dysbiosis in AD patients to a healthier state, along with improved intestinal tryptophan metabolism, suggesting the gut flora and its metabolites may mediate part of the synergistic therapeutic effects on the host.

The Burden of Pediatric Atopic Dermatitis: Quality of Life of Patients and Their Families.

(1) Background: Atopic dermatitis (AD) is one of the most common inflammatory skin conditions, thus having a significant impact on the quality of life (QoL) of patients and their families. We performed a survey to gather more data to help describe the burden of AD in Lithuania and to help expand the treatment plan to this important aspect of the disease. (2) Methods: A cross-sectional study was conducted involving healthy and AD pediatric patients. The assessment instruments used were the Patient-Oriented Eczema Measure (POEM), QoL, and original questionnaires (the original questionnaire was designed by the authors to determine the demographics, medical history, and treatment methods of the respondents). (3) Results: This study included 302 participants in total: 247 AD patients (51% boys) and 55 non-AD patients (51% boys). The mean age for AD patients was 6.8 ± 4.4. years, and this was 10.5 ± 3.1 years for the control patients. A significant difference was found between the QoL questionnaire scores and the Family Dermatology Life Quality Index (FDLQI) score for the atopic dermatitis group (QoL: 6.3 ± 5.6; FDLQI: 7.1 ± 6.9) and controls (QoL 0.5 ± 1.1; FDLQI 2.1 ± 5.9) (p = 0.000). The mean QoL questionnaire score for severe AD was 14.3 ± 6.2 (very large effect), that for moderate AD was 6.9 ± 4.4 (moderate effect), and that for mild AD was 4.4 ± 4.2 (small effect) (p = 0.000). (4) Conclusions: Our study revealed a moderate effect of AD on dermatology-related QoL in patients and their families. It has been shown that increased disease severity was associated with a greater impairment of QoL in both patients and patient's parents. The burden of AD in children and their parents is considerable and should be taken into account in the management of atopic dermatitis.

Integrated plasma metabolomic and cytokine analysis reveals a distinct immunometabolic signature in atopic dermatitis.

Disease models for atopic dermatitis (AD) have primarily focused on understanding underlying environmental, immunologic, and genetic etiologies. However, the role of metabolic mechanisms in AD remains understudied. To investigate the circulating blood metabolomic and cytokine profile of AD as compared to healthy control patients. This study collected plasma from 20 atopic dermatitis with moderate-to-severe itch (score of ≥5 on the itch Numeric Rating Scale and IGA score ≥3) and 24 healthy control patients. Mass-spectrometry based metabolite data were compared between AD and healthy controls. Unsupervised and supervised machine learning algorithms and univariate analysis analyzed metabolic concentrations. Metabolite enrichment and pathway analyses were performed on metabolites with significant fold change between AD and healthy control patients. To investigate the correlation between metabolites levels and cytokines, Spearman's rank correlation coefficients were calculated between metabolites and cytokines. Patients were recruited from the Johns Hopkins Itch Center and dermatology outpatient clinics in the Johns Hopkins Outpatient Center. The study included 20 atopic dermatitis patients and 24 healthy control patients. Fold changes of metabolites in AD vs healthy control plasma. In patients with AD, amino acids isoleucine, tyrosine, threonine, tryptophan, valine, methionine, and phenylalanine, the amino acid derivatives creatinine, indole-3-acrylic acid, acetyl-L-carnitine, L-carnitine, 2-hydroxycinnamic acid, N-acetylaspartic acid, and the fatty amide oleamide had greater than 2-fold decrease (all P-values<0.0001) compared to healthy controls. Enriched metabolites were involved in branched-chain amino acid (valine, leucine, and isoleucine) degradation, catecholamine biosynthesis, thyroid hormone synthesis, threonine metabolism, and branched and long-chain fatty acid metabolism. Dysregulated metabolites in AD were positively correlated cytokines TARC and MCP-4 and negatively correlated with IL-1a and CCL20. Our study characterized novel dysregulated circulating plasma metabolites and metabolic pathways that may be involved in the pathogenesis of AD. These metabolic pathways serve as potential future biomarkers and therapeutic targets in the treatment of AD.

Dupilumab‐associated ocular surface disease or atopic keratoconjunctivitis not improved by dupilumab? Upadacitinib may clarify the dilemma: A case report

AbstractDupilumab‐associated ocular surface disease is a common clinical sign appearing in patients with atopic dermatitis (AD) just few months after dupilumab treatment start, developing in about 25% of patients. Atopic keratoconjunctivitis (AKC) is a well‐identified clinical entity, defined as a chronic inflammatory disease of eye that affects 25%–40% of patients with AD. Most clinical signs of ocular involvement in AD patients treated with dupilumab overlaps the AKC symptoms and signs. We supposed that Dupilumab‐associated ocular surface disease and AKC represent the same disease but differently called by dermatologists and ophthalmologists. AKC‐like disease may develop during dupilumab therapy as a consequence of alternative cytokines pathway activation (e.g. IL33) secondary to IL‐4/13 pathway block. The novel upadacitinib drug may bypass ILs pathway through Janus Kinases selective inhibition, avoiding positive or negative ILs feedback at the ocular surface level. In this case report, molecular analysis on conjunctival samples showed a lower ocular surface inflammation (lower expression of HLADR) although higher levels of IL4 and IL13 in a patient with AD and AKC during upadacitinib therapy, compared to prior dupilumab treatment. Target therapies in patients suffering from AD may prevent ocular and dermatological comorbidities improving quality of life before quality of skin and vision.

Patient and Caregiver Perspectives on the Relationship Between Atopic Dermatitis Symptoms and Mental Health.

Background: Atopic Dermatitis (AD) patients have increased likelihood of developing depression and anxiety. The patient and caregiver's perceptions of the correlation of mental health (MH) and AD symptoms are not well understood. Objective: To evaluate patient-reported MH symptoms and their correlation with AD disease severity and understand patient-perceived associations of AD with impacts to their MH. Methods: Adult AD patients (18+ years) or caregivers of AD patients (8-17 years) were recruited to complete a survey about MH and their perception of its relationship with AD. Results: Of 1496 respondents, 954 met inclusion criteria and completed the survey. Respondents were primarily adults (83.3%) with moderate AD (31.4%). In total, 26.0% reported MH symptoms >10 days per month, and most adults (65.5%) scored in the borderline/abnormal range on the Hospital Anxiety and Depression Scale. Most (70.6%) respondents perceived their MH was negatively affected by AD in the past 12 months. AD severity impacted the perception of the relationship between AD and MH; respondents were more likely to believe MH was impacted by AD when they/their child had severe AD. Conclusion: Our study highlights patient and caregiver awareness of the detrimental impact of AD on MH. Addressing MH in AD care settings early in the disease journey may be beneficial.

Cracking the code: unveiling the nexus between atopic dermatitis and addictive behavior: a cross-sectional exploration of risk factors

Atopic dermatitis (AD) stands as a prevalent chronic inflammatory skin disorder with a global reach. Beyond its cutaneous manifestations, AD is accompanied by comorbidities and psychological issues, significantly compromising the overall quality of life for individuals who suffer from AD. Previous research has evidenced a heightened prevalence of addictive disorders among dermatological patients when compared to the general population. Considering these findings, this study endeavors to examine the prevalence of addictive disorders among AD patients and, furthermore, to discern potential risk factors associated with this comorbidity. Therefore, a cross-sectional study was conducted involving patients with AD diagnosed by dermatologists within a large university hospital in Munich, South Germany, between January 2016 and December 2019. Patients received an anonymous paper-based questionnaire comprising standardized and reliable assessment tools concerning disease severity, quality of life, sexual dysfunction, well-being, and anxiety disorder as well as screening tools for various addictive disorders (compulsive internet use, drug abuse, pathological alcohol consumption, and smoking). Data were analyzed descriptively, and a multivariate logistic regression model was conducted. A total of 208 patients participated in the study, comprising 38% males and 62% females with a mean age of 44.8 ± standard deviation:17.9 years. Females showed a higher mean POEM (Patient-Oriented Eczema Measure) score compared to males (female 14.6 ± 7.8; male 12.5 ± 7.7), as well as a higher DLQI (Dermatology Life Quality Index) (female 8.5 ± 6; male 6.5 ± 6.5). Positive addictions were found in 14.9% for daily smoking, 15.4% for critical alcohol consumption, 16.8% for compulsive internet use, and 5.8% for drug abuse. Younger patients were more likely to be affected by one or multiple addictions than older patients. Patients with at least one addiction showed significantly impaired well-being and increased severe anxiety symptoms. Given the notable prevalence of addictive disorders among individuals with AD, it could be useful to implement systematic screening for such conditions as part of patient-centered care, especially focusing on young AD patients or those displaying concurrent indications of depression or anxiety.

Effect of weekly vitamin D supplementation on the severity of atopic dermatitis and type 2 immunity biomarkers in children: A randomized controlled trial.

Vitamin D (VD) deficiency is common among patients with atopic dermatitis (AD) and often associated with severity. However, randomized trials of VD supplementation in AD have had equivocal results, and there is little information regarding the effect of VD supplementation on type 2 immunity in AD patients. To investigate the efficacy of VD supplementation to decrease severity of AD and to alter type 2 immunity biomarkers. We performed a randomized, double-blind, placebo-controlled trial. We randomly assigned 101 children with AD to weekly oral vitamin D3 (VD3) or placebo for 6 weeks. The primary outcome was the change in the Severity Scoring of AD (SCORAD). Mean age of subjects was 6.3 ± 4.0 years, and baseline SCORAD was 32 ± 29. At baseline, 57% of children were VD deficient, with no difference between groups. Change in 25(OH)D was significantly greater with VD3 than placebo (+43.4 ± 34.5 nmol/L vs. +2.3 ± 21.2 nmol/L, p < 0.001). SCORAD change at 6 weeks was not different between VD and placebo (-5.3 ± 11.6 vs. -5.5 ± 9.9, p = 0.91). There were no significant between-group differences in change of eosinophil counts, total IgE, Staphylococcal enterotoxin specific IgE, CCL17, CCL22, CCL27, LL-37 or Staphylococcus aureus lesional skin colonization. Vitamin D receptor (VDR) gene single nucleotide polymorphisms FokI, ApaI and TaqI did not modify subjects' response to VD supplementation. Among children with AD, weekly VD supplementation improved VD status but did not modify AD severity or type 2 immunity biomarkers compared to placebo (ClinicalTrials.gov NCT01996423).

Differentially Expressed Genes in Atopic Dermatitis: Bioinformatics analysis of pooled microarray gene expression datasets in Gene Expression Omnibus

Introduction:&#x0D; Atopic dermatitis (AD) is a chronic and refractory inflammatory skin disease characterized by relapsing eczematous and pruritic skin lesions. Understanding the specific gene expression patterns associated with AD is crucial for advancing diagnosis and targeted treatment development. Using bioinformatics methods, candidate genes and biological pathways involved in AD pathogenesis were identified based on gene expression profiles in the Gene Expression Omnibus (GEO) database.&#x0D; Materials and Methods:&#x0D; A comprehensive analysis of four pooled transcriptomic datasets obtained from the Gene Expression Omnibus (GEO) database were conducted. Differential gene expression analysis was performed using the GEO2R. The differentially expressed genes (DEGs) between lesion skin of AD patients and normal skin of individuals were analyzed using the Gene Ontology (GO) term enrichment analysis, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway, and protein-protein interaction (PPI) network to explore the functional roles of these genes.&#x0D; Results:&#x0D; Among the patient-level gene expression datasets, we identified 133 shared DEGs, consisting of 48 upregulated genes and 85 downregulated genes. GO analyses revealed these DEGs to be significantly enriched in biological processes including inflammatory responses, cytokine-mediated signaling pathway. These DEGs were also enriched in the KEGG pathway, including viral protein interaction with cytokine and cytokine receptor, C-type lectin receptor signaling pathway, cytokine-cytokine receptor interaction, JAK-STAT signaling pathway, and Adipocytokine signaling pathway.&#x0D; Conclusion:&#x0D; By comparing with other studies using the same method, we found that in addition to the already confirmed pathways such as inflammatory response, different studies have found changes in different hub genes and metabolic pathways, which prompts us to develop individualized treatments for AD.

State of the Art on the Role of Staphylococcus aureus Extracellular Vesicles in the Pathogenesis of Atopic Dermatitis.

Atopic dermatitis (AD) is a chronic and relapsing inflammatory cutaneous disease. The role of host defense and microbial virulence factors in Staphylococcus aureus skin colonization, infection, and inflammation perpetuation in AD remains an area of current research focus. Extracellular vesicles (EV) mediate cell-to-cell communication by transporting and delivering bioactive molecules, such as nucleic acids, proteins, and enzymes, to recipient cells. Staphylococcus aureus spontaneously secretes extracellular vesicles (SA-derived EVs), which spread throughout the skin layers. Previous research has shown that SA-derived EVs from AD patients can trigger cytokine secretion in keratinocytes, shape the recruitment of neutrophils and monocytes, and induce inflammatory AD-type lesions in mouse models, in addition to their role as exogenous worsening factors for the disease. In this review article, we aim to examine the role of SA-derived EVs in AD physiopathology and its progression, highlighting the recent research in the field and exploring the potential crosstalk between the host and the microbiota.

Associations of demographics, aggravating factors, comorbidities, and treatments with atopic dermatitis severity in China: A national cross-sectional study.

Atopic dermatitis (AD) is a chronic inflammatory skin disorder impacting populations worldwide, although its clinical characteristics and patient demographics remain uncharacterized in China. The aim of this study was to investigate the demographics, comorbidities, aggravating factors, and treatments in AD patients across different age groups in China. This cross-sectional study included Chinese AD patients from 205 hospitals spanning 30 provinces. Patients completed dermatologist-led surveys of general medical history, comorbidities, AD-related aggravating factors, and medications. Two-level mixed-ordered logistic regression was used to evaluate aggravating factors. Overall, 16,838 respondents were included in the final analysis (age 30.9±24.1years). The proportion of severe AD was the highest in patients with AD onset at ≥60 years (26.73%). Allergic rhinitis and hypertension were the most common atopic and metabolism-related non-atopic comorbidities, respectively. AD severity was significantly associated with chronic urticaria, food allergies, and diabetes. Aggravating factors including foods, seasonal changes, and psychological factors were also linked to AD severity. The cross-sectional survey implied that severe AD may be related to the undertreatment of effective systemic or topical interventions. To enhance the management of AD, it is crucial to consider both aggravating factors and the increased utilization of systemic immunotherapy. ClinicalTrials.gov Identifier: NCT05316805, CORNERSTONE.

The burden of atopic dermatitis in Portuguese patients: an observational study

Atopic dermatitis (AD) is a common inflammatory skin condition that significantly affects patients' lives and imposes both economic and non-economic burdens. The precise societal and individual consequences of AD remain incompletely understood. This study aimed to characterize AD in Portuguese patients and assess its personal, familial, and societal implications, including health status and quality of life. The research, conducted from June 2019 to January 2020, involved 204 confirmed AD patients in Portugal, who completed a 70-question questionnaire. Results show that, on average, patients experienced a two-year delay in diagnosis, with two-thirds having allergic comorbidities. Late-onset AD (after age 20) was found to be correlated with worsening symptoms post-diagnosis. Globally, patients reported substantial effects on health, quality of life, and mental well-being. Effects include significant levels of anxiety, frustration and sleep disorders. Severe AD correlated with more suffering and reduced perceived health, indicating a link between disease severity and quality of life. Remarkably, despite questionable effectiveness, 92% of severe AD patients were prescribed antihistamines, while only 19% received biological treatments. In Portugal, delayed AD diagnosis hinders timely treatment, and despite its profound impact and high comorbidity rates, AD patients tend to remain undertreated. Recognizing the personal and societal repercussions is crucial for enhancing care, contributing to improving QoL, social functioning and global well-being.

Genome-wide identification of dysregulated alternative splicing and RNA-binding proteins involved in atopic dermatitis.

Objectives: We explored the role and molecular mechanisms of RNA-binding proteins (RBPs) and their regulated alternative splicing events (RASEs) in the pathogenesis of atopic dermatitis (AD). Methods: We downloaded RNA-seq data (GSE121212) from 10 healthy control skin samples (healthy, Ctrl), 10 non-lesional skin samples with AD damage (non-lesional, NL), and 10 lesional skin samples with AD damage (lesional, LS). We performed the analysis of differentially expressed genes (DEGs), differentially expressed RBPs (DE-RBPs), alternative splicing (AS), functional enrichment, the co-expression of RBPs and RASEs, and quantitative polymerase chain reaction (qPCR). Results: We identified 60 DE-RBP genes by intersecting 2141 RBP genes from existing reports with overall 2697 DEGs. Most of the DE-RBP genes were found to be upregulated in the AD LS group and related to immune and apoptosis pathways. We observed different ASEs and RASEs among the healthy, AD NL, and AD LS groups. In particular, alt3p and alt5p were the main ASEs and RASEs in AD NL and AD LS groups, compared to the healthy group. Furthermore, we constructed co-expression networks of DE-RBPs and RAS, with particular enrichment in biological pathways including cytoskeleton organization, inflammation, and immunity. Subsequently, we selected seven genes that are commonly present in these three pathways to assess their expression levels in the peripheral blood mononuclear cells (PBMCs) from both healthy individuals and AD patients. The results demonstrated the upregulation of four genes (IFI16, S100A9, PKM, and ENO1) in the PBMCs of AD patients, which is highly consistent with DE-RBP genes analysis. Finally, we selected four RAS genes regulated by RBPs that were related to immune pathways and examined their RASEs in PBMCs from both AD patients and healthy controls. The results revealed an increased percentage of RASEs in the DDX60 gene in AD, which is highly consistent with AS analysis. Conclusion: Dysregulated RBPs and their associated RASEs may have a significant regulatory role in the development of AD and could be potential therapeutic targets in the future.

Serum 25-Hydroxyvitamin D Level Might Be a Useful Indicator of Disease Severity in Obese Children With Atopic Dermatitis: A Case-Control Study

Objective: To assess the relationship between the severity of atopic dermatitis (AD) in children of varying weight categories and their serum 25-hydroxyvitamin D [25(OH)D] levels. Methods: The study population comprised 899 patients with AD and 854 age- and sex-matched controls. The Mann-Whitney U test and Kruskal-Wallis H tests were used to assess differences between groups, and Spearman correlation analysis was used to test correlation. Results: The 25(OH)D level in the AD group was M (Q 25, Q 75), 24.0 (19.7, 28.4) ng/mL, which was significantly lower than the control group (26.4 [23.6, 29.9] ng/mL; Z = −3.34, P = 0.001). 25(OH)D levels in children with AD were negatively correlated with body mass index (r = −0.30, P &lt; 0.001), Severity scoring of Atopic Dermatitis (SCORAD; r = −0.14, P &lt; 0.001), total immunoglobulin E (r = −0.13, P &lt; 0.001), and eosinophil (r = −0.08, P = 0.017). There were statistically significant differences in 25(OH)D (H = 18.46, P &lt; 0.001), total immunoglobulin E (H = 9.13, P = 0.010), eosinophil (H = 67.17, P &lt; 0.001), and SCORAD (H = 10.49, P = 0.005) among groups with different body mass index classification. The 25(OH)D levels were 22.3 (17.5, 27.1) ng/mL in the overweight AD group and 22.3 (17.6, 25.7) ng/mL in the obese AD group, which were significantly lower than those in the normal-weight AD group (24.7 [20.4, 25.5] ng/mL; P = 0.003, P = 0.004). 25(OH)D levels were negatively correlated with SCORAD in obese AD patients (r = −0.25, P = 0.010). Conclusion: Vitamin D insufficient or deficient is obvious in children AD patients. The 25(OH)D levels in the overweight/obese AD group are significantly lower than those in the normal-weight AD group. Vitamin D level is negatively correlated with SCORAD in obese children with AD.