Systemic Inflammatory Proteomic Biomarkers in Atopic Dermatitis: Exploring Potential Indicators for Disease Severity.

BACKGROUND: Atopic dermatitis (AD) is a chronic inflammatory cutaneous disorder, that emerges from intricate interplays among genetic predisposition, immune dysregulation, environmental factors, and compromised skin barrier. Understanding the inflammatory pathway in AD is important due to its fundamental role in the pathogenesis of AD. This study aimed to explore the diverse spectrum of proteins linked to the inflammation of AD and the relationship between systemic biomarkers and clinical severity in AD. METHODS: We examined the blood samples from 48 patients with AD and 48 healthy controls (HCs) using the Proximity Extension Assay (Olink). Differentially expressed proteins (DEPs) were identified and Pearson correlation analysis was conducted to determine systemic proteomic biomarkers associated with severity of AD. RESULTS: A total of 29 DEPs were significantly up-regulated and 2 DEPs were significantly down-regulated in AD compared with the HC. The MCP-4, IL-18, MCP-3, TNFRSF9, and IL-17C were the top 5 highest DEPs associated with the severity of AD. CONCLUSION: Our study sheds light on the intricate network of inflammatory proteins in AD and their potential implications for disease severity. Our results indicate that these systemic inflammatory proteins could be valuable for assessing AD severity and enhancing our understanding of the disease's complexity and its potential management strategies.

Exploring novel drug targets for atopic dermatitis through plasma proteome with genome.

Atopic dermatitis (AD) is a chronic inflammatory disease with a complex and heterogeneous clinical presentation, leading to treatment limitations. Therefore, there is an urgent demand for new therapeutic drug targets. This study utilized Summary-data-based Mendelian randomization (SMR) to identify potential drug targets for AD. Summary statistics for 2,940 human plasma proteins were obtained from the UK Biobank, while AD statistics came from the Early Genetics and Epidemiology of Life Processes consortium and the FinnGen consortium. Furthermore, subsequent colocalization analyses confirmed the causal roles of candidate proteins. Moreover, Phenome-Wide Association Studies (PheWAS), protein-protein interaction (PPI), enrichment analysis, and single cell-type expression analysis provided additional insights. Additionally, drug prediction, druggability prediction, and molecular docking informed the discovery of novel drug targets. SMR analysis showed that eight plasma proteins were causally associated with AD: PVALB and TST were associated with a reduced risk of AD, while CA14, ECM1, IL22, IL6R, IL18R1, and MMP12 were associated with an increased risk of AD. Colocalization analysis confirmed significant associations for TST, IL22, and CA14. PheWAS further revealed that candidate drug targets were mainly linked to other allergic diseases. The corresponding protein-coding genes are predominantly expressed in melanocytes, T cells, and macrophages in skin tissue. Importantly, these proteins were identified to be involved in cytokine-cytokine receptor interaction, Th17 cell differentiation, and the JAK-STAT signaling pathway. All of these proteins are druggable, and six of them show great potential as drug targets. In conclusion, this study identified eight plasma proteins causally associated with AD and provided new insights into the etiology and potential drug targets for AD.

Antibody immune responses and causal relationships in four immune skin diseases: Evidence from Mendelian randomization and Bayesian Weighting (Antibody Responses in Skin Diseases: MR & Bayesian).

BACKGROUND: Recent studies increasingly suggest that microbial infections and the immune responses they elicit play significant roles in the pathogenesis of chronic inflammatory skin diseases. This study uses Mendelian randomization (MR) and Bayesian weighted Mendelian randomization (BWMR) to explore the causal relationships between immune antibody responses and four common skin diseases: psoriasis, atopic dermatitis (AD), rosacea, and vitiligo. METHODS: We utilized summary statistics from genome-wide association studies (GWAS) for antibody responses to 13 infectious pathogens and four skin diseases. Single nucleotide polymorphisms (SNPs) were selected as instrumental variables (IVs) to assess causal relationships using multiple MR methods, including inverse variance weighted (IVW), MR Egger, and weighted median. BWMR was also employed to confirm findings and address potential pleiotropy. RESULTS: The IVW analysis identified significant associations between specific antibody responses and the skin diseases studied. Key findings include protective associations of anti-Epstein-Barr virus (EBV) IgG seropositivity and Helicobacter pylori UREA antibody levels with psoriasis and AD. anti-chlamydia trachomatis IgG seropositivity, anti-polyomavirus 2 IgG seropositivity, and varicella zoster virus glycoprotein E and I antibody levels were negatively associated with rosacea, while EBV Elevated levels of the early antigen (EA-D) antibody levels and HHV-6 IE1B antibody levels were positively associated with rosacea. H. pylori Catalase antibody levels were protectively associated with vitiligo, whereas anti-herpes simplex virus 2 (HSV-2) IgG seropositivity was positively associated with vitiligo. The BWMR analysis confirmed these associations. CONCLUSION: This study underscores the significant role of H. pylori and other pathogens in these skin diseases, suggesting both protective and exacerbating effects depending on the specific condition. Understanding these pathogen-immune interactions can lead to the development of more effective, personalized treatments and preventative strategies, ultimately improving patient outcomes and quality of life.

Exploring causal correlations between circulating cytokines and atopic dermatitis: a bidirectional two-sample Mendelian randomization study.

Objectives: Numerous observational studies have reported associations between circulating cytokines and atopic dermatitis (AD); however, the causal relationships between them remain unclear. To explore the causal correlations and direction of causal effects between AD and levels of 91 circulating cytokines. Methods: Two-sample Mendelian randomization (MR) analyses were conducted to examine the causal relationships between 91 circulating cytokines and AD using summary statistics from genome-wide association studies (GWAS). Reverse MR analyses were performed to investigate reverse causation. Pleiotropy and heterogeneity tests were conducted to assess the robustness of the findings. Additional transcriptome database and clinical peripheral blood mononuclear cells (PBMCs) samples were utilized to validate the results of MR analyses. Results: Levels of interleukin (IL)-13, IL-18 Receptor 1, Tumor necrosis factor ligand superfamily member 14 (TNFSF14), TNF-related activation-induced cytokine (TRANCE), C-X-C motif chemokine (CXCL)11, IL-33, TNF-beta and CD5 were suggestively associated with the risk of AD (odds ratio, OR: 1.202, 95% CI: 1.018-1.422, p = 0.030; OR: 1.029, 95% CI: 1.029-1.157, p = 0.004; OR: 1.159, 95% CI: 1.018-1.320, p = 0.026; OR: 1.111, 95% CI: 1.016-1.214, p = 0.020; OR: 0.878, 95% CI: 0.783-0.984, p = 0.025; OR: 0.809, 95% CI: 0.661-0.991, p = 0.041; OR: 0.945, 95% CI: 0.896-0.997, p = 0.038; OR: 0.764, 95% CI: 0.652-0.895, p = 8.26e-04). In addition, levels of cytokines including Axin-1, CXCL5, CXCL10, Oncostatin-M (OSM), Sulfotransferase 1A1 (SULT1A1) and TNFSF14 were suggested to be consequences of AD (Beta: -0.080, p = 0.016; Beta: -0.062, p = 0.036; Beta: -0.066, p = 0.049; Beta: -0.073, p = 0.013; Beta: -0.089, p = 0.008; Beta: -0.079, p = 0.031). IL-13, IL-18R1, TNFSF14, and TRANCE were upregulated in both lesional skin biopsies and PBMCs from AD patients. Conclusion: The study indicates that several cytokines, including IL-13, IL-18R1, TNFSF14, TRANCE, CXCL11, IL-33, TNF-beta, and CD5, are upstream of AD development, whereas a few circulating cytokines are potentially downstream in the development of AD.

Correlation of Maternal Vitamin D Status in Early Pregnancy and Vitamin D Supplementation during Pregnancy with Atopic Dermatitis in Infants: A Prospective Birth Cohort Study.

OBJECTIVE: This study aimed to investigate the association of maternal first-trimester vitamin D levels and vitamin D supplementation during pregnancy with infant atopic dermatitis (AD) and to determine the effect of variables such as mode of conception on the association. METHODS: This study was based on the Shanghai sub-cohort of the International Birth Cohort of China. A total of 4051 woman-infant pairs with singleton pregnancies were recruited. Vitamin D deficiency and insufficiency were defined as serum 25-hydroxyvitamin D concentrations of 25 and 50 nmol/L, respectively. AD in infants was assessed during the first six months using a standardized questionnaire based on the British Working Party criteria. Modified Poisson regression estimated the association between maternal vitamin D status and infant AD. RESULTS: The risk of AD in infants was higher in women with deficient 25-hydroxyvitamin D levels in the first trimester (RR: 1.77, 95% CI: 1.41-2.23). This increased risk was seen in naturally conceived pregnancies, but not in those conceived using assisted reproductive technology (ART). The incidence of AD decreased in infants of mothers who took multi-vitamin (RR: 0.79, 95% CI: 0.67-1.98) and vitamin D supplements (RR: 0.51, 95% CI: 0.37-0.71) compared to those whose mothers did not take any supplements. Maternal vitamin D deficiency had varying effects on AD risk based on passive smoking exposure and breastfeeding patterns. CONCLUSIONS: Our findings highlight the importance of monitoring and supplementing vitamin D during pregnancy, especially in specific maternal populations, to reduce the risk of AD in offspring.

MicroRNA-155 is a potential predictive tool for atopic dermatitis severity in children: A preliminary study.

Atopic dermatitis (AD) is one of the most prevalent chronic inflammatory dermatological disorders in childhood. Assessment of AD severity is the initial step in designing the proper therapeutic plan. Moreover, it is imperative for evaluation of disease improvement during and following therapy. This study was designed to assess the prognostic role of miRNA-155 (miR-155) in the prediction of AD severity as the primary outcome. While the secondary outcome was to correlate the serum miR-155 expression levels with the scoring atopic dermatitis (SCORAD) severity index. This case-control study included 24 children with AD and 24 apparently healthy children as a control group. AD children were stratified according to the SCORAD severity index. Approximately 58% of children had mild AD, 25% moderate AD, and about 17% severe AD. Children with AD had statistically significantly higher miR-155 expression levels in comparison to the control children, (p < 0.001). Children with severe AD had statistically significantly higher miR-155 expression levels compared to mild AD children (p=0.001). The receiver operating characteristic curve analysis for miR-155 demonstrated that miR-155 can differentiate between children with mild AD and those with moderate-to-severe AD, with an area under the curve of 0.879, and an excellent discrimination power. A statistically strong significant positive correlation existed between miR-155 levels and SCORAD severity index (rs= 0.666, p < 0.001). In conclusion, MiR-155 could be considered as a non-invasive biomarker of AD severity in children. It is a promising prognostic tool in the prediction of AD severity.

Genetic support for the causal association between 91 circulating inflammatory proteins and atopic dermatitis: A two-sample Mendelian randomization trial.

BACKGROUND: Atopic dermatitis (AD) is a refractory disease that occurs in clinical practice. One of the most common inflammatory skin diseases, its occurrence and development are related to inflammation. Nevertheless, the precise nature of the relationship between circulating inflammatory proteins and AD remains uncertain. METHODS: A two-sample MR analysis was performed to determine the causal relationship between the expression of 91 circulating inflammatory proteins and AD by using genome-wide association study (GWAS) summary statistics data from the FinnGen consortia. The robustness of the MR results was assessed by means of sensitivity analysis. RESULTS: The causal relationship between the expression of nine specific circulating inflammatory proteins and AD was corroborated by the inverse variance weighted (IVW) method. The findings indicated that three circulating inflammatory proteins, namely, interleukin-18 receptor 1 [OR (CI) = 1.08 (1.05-1.11); p = 0.000001)], interleukin-8 [OR (CI) = 1.07 (1.00-1.14); p = 0.036244)], and tumor necrosis factor ligand superfamily member 14 [OR (CI) = 1.05 (1.00-1.10); p = 0.036842)], were positively correlated with AD. Additionally, six circulating inflammatory proteins were negatively correlated with AD: the T-cell surface glycoprotein CD5 [OR (CI) = 0.89 (0.84-0.95); p = 0.000191)], macrophage colony-stimulating factor 1 [OR (CI) = 0.93 (0.88-0.99); p = 0.031422)], fractalkine [OR (CI) = 0.91 (0.85-0.97); p = 0.003067)], interleukin-24 [OR (CI) = 0.91 (0.83-0.99); p = 0.031673)], signaling lymphocytic activation molecule [OR(CI) = 0.94 (0.89-1.00); p = 0.039818)], and urokinase-type plasminogen activator [OR(CI) = 0.95 (0.90-1.00); p = 0.037037)]. CONCLUSION: This study confirms the potential causal relationship between circulating inflammatory proteins and AD and provides guidance for the clinical diagnosis and treatment of AD.

Serum Concentration of IL-5 Receptor (IL-5R) and Associations with Disease Severity in Patients with Chronic Spontaneous Urticaria (CSU) and Atopic Dermatitis (AD).

The immunological pathogenesis of atopic dermatitis (AD) and chronic spontaneous urticaria (CSU) has not been fully elucidated yet. The aim of our research was to assess the serum concentration of interleukin-5 receptor (IL-5R) in relation to the disease activity and pruritus intensity in adult patients with AD and CSU. This pilot study included 45 participants (15 patients with AD, 15 patients with CSU, and 15 healthy controls). Blood samples were taken to examine the serum levels of IL-5R using the enzyme-linked immunosorbent assay (ELISA) test. The Scoring Atopic Dermatitis (SCORAD) index, the Urticaria Activity Score (UAS7), and the Visual Analogue Scale (VAS) were used to assess the disease activity and the pruritus intensity, respectively. Obtained results revealed that the IL-5R concentration was significantly higher in patients with CSU than in patients with AD and in the controls (p = 0.038). There was a positive correlation between the IL-5R level and the SCORAD index in patients with AD (r = -0.9, p = 0.047), which was not found for the CSU activity by UAS7 and with the pruritus severity by VAS in both examined groups of patients. Our findings underscore higher serum levels of IL-5R among CSU and AD patients, which may highlight its functional role in the pathogenesis of these diseases. In contrast, IL-5R might not be fully useful in reflecting the severity of symptoms. Although our results are promising, this study should be conducted on a larger cohort of patients.

Risk factors of bloodstream infection in erythroderma from atopic dermatitis, psoriasis, and drug reactions: a retrospective observational cohort study.

Background: Atopic dermatitis (AD), psoriasis, and drug reactions associated with erythroderma are frequently complicated by infections. However, bloodstream infection (BSI) have received less research attention. Objectives: This study aimed to investigate the clinical characteristics and risk factors associated with BSI in patients with erythroderma. Methods: A retrospective analysis was conducted on 141 erythroderma cases. Eleven cases were identified as having BSI. Clinical records of both BSI and non-BSI groups were reviewed and compared. Results: BSI was diagnosed in 7.80% (11/141) of erythroderma cases, with a breakdown of 7.14% in AD, 2.00% in psoriasis, and 17.14% in drug reactions. Notably, all positive skin cultures (7/7) showed bacterial isolates concordant with blood cultures. Univariate logistic regression analysis revealed several significant associations with BSI, including temperature (≤36.0 or ≥38.5 °C; odds ratio (OR) = 28.06; p < 0.001), chilling (OR = 22.10; p < 0.001), kidney disease (OR = 14.64; p < 0.001), etiology of drug reactions (OR = 4.18; p = 0.03), albumin (ALB) (OR = 0.86; p < 0.01), C-reaction protein (CRP) (OR = 1.01; p = 0.02), interleukin 6 (IL-6) (OR = 1.02; p = 0.02), and procalcitonin (PCT) (OR = 1.07; p = 0.03). Receiver operating characteristic (ROC) curves demonstrated significant associations with ALB (p < 0.001; the area under curve (AUC) = 0.80), PCT (p = 0.009; AUC = 0.74), and CRP (p = 0.02; AUC = 0.71). Conclusions: Increased awareness of BSI risk is essential in erythroderma management. Patients with specific risk factors, such as abnormal body temperature (≤36.0 or ≥38.5 °C), chilling sensations, kidney disease, a history of drug reactions, elevated CRP (≥32 mg/L), elevated PCT (≥1.00 ng/ml), and low albumin (≤31.0 g/L), require close monitoring for BSI development.

Metabolomic and lipidomic fingerprints in inflammatory skin diseases - Systemic illumination of atopic dermatitis, hidradenitis suppurativa and plaque psoriasis.

Auto-inflammatory skin diseases place considerable symptomatic and emotional burden on the affected and put pressure on healthcare expenditures. Although most apparent symptoms manifest on the skin, the systemic inflammation merits a deeper analysis beyond the surface. We set out to identify systemic commonalities, as well as differences in the metabolome and lipidome when comparing between diseases and healthy controls. Lipidomic and metabolomic LC-MS profiling was applied, using plasma samples collected from patients suffering from atopic dermatitis, plaque-type psoriasis or hidradenitis suppurativa or healthy controls. Plasma profiles revealed a notable shift in the non-enzymatic anti-oxidant defense in all three inflammatory disorders, placing cysteine metabolism at the center of potential dysregulation. Lipid network enrichment additionally indicated the disease-specific provision of lipid mediators associated with key roles in inflammation signaling. These findings will help to disentangle the systemic components of autoimmune dermatological diseases, paving the way to individualized therapy and improved prognosis.

Tissue gene expression profiles and communication networks inform candidate blood biomarker identification in psoriasis and atopic dermatitis.

Overlapping clinical and pathomechanistic features can complicate the diagnosis and treatment of inflammatory skin diseases, including psoriasis and atopic dermatitis (AD). Spatial transcriptomics allows the identification of disease- and cell-specific molecular signatures that may advance biomarker development and future treatments. This study identified transcriptional signatures in keratinocytes and sub-basal CD4+ and CD8+ T lymphocytes from patients with psoriasis and AD. In silico prediction of ligand:receptor interactions delivered key signalling pathways (interferon, effector T cells, stroma cell and matrix biology, neuronal development, etc.). Targeted validation of selected transcripts, including CCL22, RELB, and JUND, in peripheral blood T cells suggests the chosen approach as a promising tool also in other inflammatory diseases. Psoriasis and AD are characterized by transcriptional dysregulation in T cells and keratinocytes that may be targeted therapeutically. Spatial transcriptomics is a valuable tool in the search for molecular signatures that can be used as biomarkers and/or therapeutic targets.

The causal relationship and potential mediators between plasma lipids and atopic dermatitis: a bidirectional two-sample, two-step mendelian randomization.

BACKGROUND: Observational studies have indicated that the plasma lipid profiles of patients with atopic dermatitis show significant differences compared to healthy individuals. However, the causal relationship between these differences remains unclear due to the inherent limitations of observational studies. Our objective was to explore the causal effects between 179 plasma lipid species and atopic dermatitis, and to investigate whether circulating inflammatory proteins serve as mediators in this causal pathway. METHODS: We utilized public genome-wide association studies data to perform a bidirectional two-sample, two-step mendelian randomization study. The inverse variance-weighted method was adopted as the primary analysis technique. MR-Egger and the weighted median were used as supplementary analysis methods. MR-PRESSO, Cochran's Q test, and MR-Egger intercept test were applied for sensitivity analyses to ensure the robustness of our findings. RESULTS: The Mendelian randomization analysis revealed that levels of Phosphatidylcholine (PC) (18:1_20:4) (OR: 0.950, 95% CI: 0.929-0.972, p = 6.65 × 10- 6), Phosphatidylethanolamine (O-18:1_20:4) (OR: 0.938, 95% CI: 0.906-0.971, p = 2.79 × 10- 4), Triacylglycerol (TAG) (56:6) (OR: 0.937, 95% CI: 0.906-0.969, p = 1.48 × 10- 4) and TAG (56:8) (OR: 0.918, 95% CI: 0.876-0.961, p = 2.72 × 10- 4) were inversely correlated with the risk of atopic dermatitis. Conversely, PC (18:1_20:2) (OR: 1.053, 95% CI: 1.028-1.079, p = 2.11 × 10- 5) and PC (O-18:1_20:3) (OR: 1.086, 95% CI: 1.039-1.135, p = 2.47 × 10- 4) were positively correlated with the risk of atopic dermatitis. The results of the reverse directional Mendelian randomization analysis indicated that atopic dermatitis exerted no significant causal influence on 179 plasma lipid species. The level of circulating IL-18R1 was identified as a mediator for the increased risk of atopic dermatitis associated with higher levels of PC (18:1_20:2), accounting for a mediation proportion of 9.07%. CONCLUSION: Our research suggests that plasma lipids can affect circulating inflammatory proteins and may serve as one of the pathogenic factors for atopic dermatitis. Targeting plasma lipid levels as a treatment for atopic dermatitis presents a potentially novel approach.

Characteristics of gut microbiota and serum metabolism in patients with atopic dermatitis.

BACKGROUND: Atopic dermatitis (AD) is a chronic inflammatory skin disease that affects 15%-30% of children and 10% of adults globally, with its incidence being influenced by genetic, environmental, and various other factors. While the immune plays a crucial role in the development, the composition of gut microbiota and serum metabolites also contribute to its pathogenesis. SUBJECT: Study the characteristics of gut microbiota and serum metabolites in patients with atopic dermatitis METHOD: In this study, we collected stool and serum samples from 28 AD patients and 23 healthy individuals (NC) for metagenomic sequencing of gut microbiota and non-targeted metabolomic sequencing of serum. RESULT: Our results revealed a lower diversity of gut microbiota in the AD group compared to the NC group. The predominant Phylum in AD patients were Bacteroidetes, Pseudomonas, and Verrucomicrobia, with the most dominant bacterial genus being Faecalibacterium. At the species level, Prevotella copri and Faecalibacterium prausnitzii were found to be the most abundant bacteria. Significant differences in serum metabolite profiles were observed between NC and AD patients, with noticeable variations in metabolite expression levels. The majority of metabolites in the serum of AD patients exhibited low expression, while a few showed high expression levels. Notably, metabolites such as Cholesterol glucuronide, Styrene, Lutein, Betaine, Phosphorylcholine, Taurine, and Creatinine displayed the most pronounced alterations. CONCLUSION: These findings contribute to a further understanding of the complexities underlying this disease.

Proteomic alterations in patients with atopic dermatitis.

INTRODUCTION: Atopic Dermatitis (AD) is the most common inflammatory skin disease with a complex and multifactorial pathogenesis. The use of proteomics in understanding AD has yielded the discovery of novel biomarkers and may further expand therapeutic options. AREAS COVERED: This review summarizes the most recent proteomic studies and the methodologies used in AD. It describes novel biomarkers that may monitor disease course and therapeutic response. The review also highlights skin and blood biomarkers characterizing different AD phenotypes and differentiates AD from other inflammatory skin disorders. A literature search was conducted by querying Scopus, Google Scholar, Pubmed/Medline, and Clinicaltrials.gov up to June 2023. EXPERT OPINION: The integration of proteomics into research efforts in atopic dermatitis has broadened our understanding of the molecular profile of AD through the discovery of new biomarkers. In addition, proteomics may contribute to the development of targeted treatments ultimately improving personalized medicine. An increasing number of studies are utilizing proteomics to explore this heterogeneous disease.

Hematological Markers in Children and Adults with Atopic Dermatitis: A Retrospective Cohort Study.

INTRODUCTION: Atopic dermatitis (AD) is a common chronic skin disease with an inflammatory pathophysiology that includes the activation of the innate and adaptive immune systems. We aimed to investigate the neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), eosinophil-to-lymphocyte ratio (ELR), and eosinophil-to-neutrophil ratio (ENR) in AD patients, according to age and disease severity. METHODS: This is a retrospective, population-based cohort study conducted between the years 2005 and 2020, comparing hematological markers of AD patients and sex-age-ethnicity-matched controls. AD patients were further divided by age and disease severity (mild, moderate-to-severe AD). We created a decision tree to predict moderate-severe AD. RESULTS: A total of 13,928 patients with AD were included in this study: 6,828 adults and 7,100 children, with 13,548 controls. NLR, PLR, and ELR were lower in children compared to adults (p values <0.001). NLR, PLR, ELR, and ENR were increased in moderate-severe AD patients compared to mild AD patients (p values <0.001). PLR, ELR, and ENR were increased in AD patients versus controls (p values <0.001), with an additional increase in the NLR of moderate-to-severe AD patients. Patients with an ELR <0.21, a PLR >161, and ENR ≤0.016 should be considered high risk for developing severe AD, as well as patients with an ELR >0.21 and age at diagnosis <30 or age >30 years and mean platelet volume ≤9. CONCLUSION: Hematological ratios were significantly higher in moderate-to-severe AD patients, compared to mild AD patients. Hematological markers were lower in children with AD compared to adults, except for ENR, likely reflecting age-related changes in blood count parameters. These markers can assist in the management and follow-up of AD patients.

Screening mitochondria-related biomarkers in skin and plasma of atopic dermatitis patients by bioinformatics analysis and machine learning.

Background: There is a significant imbalance of mitochondrial activity and oxidative stress (OS) status in patients with atopic dermatitis (AD). This study aims to screen skin and peripheral mitochondria-related biomarkers, providing insights into the underlying mechanisms of mitochondrial dysfunction in AD. Methods: Public data were obtained from MitoCarta 3.0 and GEO database. We screened mitochondria-related differentially expressed genes (MitoDEGs) using R language and then performed GO and KEGG pathway analysis on MitoDEGs. PPI and machine learning algorithms were also used to select hub MitoDEGs. Meanwhile, the expression of hub MitoDEGs in clinical samples were verified. Using ROC curve analysis, the diagnostic performance of risk model constructed from these hub MitoDEGs was evaluated in the training and validation sets. Further computer-aided algorithm analyses included gene set enrichment analysis (GSEA), immune infiltration and mitochondrial metabolism, centered on these hub MitoDEGs. We also used real-time PCR and Spearman method to evaluate the relationship between plasma circulating cell-free mitochondrial DNA (ccf-mtDNA) levels and disease severity in AD patients. Results: MitoDEGs in AD were significantly enriched in pathways involved in mitochondrial respiration, mitochondrial metabolism, and mitochondrial membrane transport. Four hub genes (BAX, IDH3A, MRPS6, and GPT2) were selected to take part in the creation of a novel mitochondrial-based risk model for AD prediction. The risk score demonstrated excellent diagnostic performance in both the training cohort (AUC = 1.000) and the validation cohort (AUC = 0.810). Four hub MitoDEGs were also clearly associated with the innate immune cells' infiltration and the molecular modifications of mitochondrial hypermetabolism in AD. We further discovered that AD patients had considerably greater plasma ccf-mtDNA levels than controls (U = 92.0, p< 0.001). Besides, there was a significant relationship between the up-regulation of plasma mtDNA and the severity of AD symptoms. Conclusions: The study highlights BAX, IDH3A, MRPS6 and GPT2 as crucial MitoDEGs and demonstrates their efficiency in identifying AD. Moderate to severe AD is associated with increased markers of mitochondrial damage and cellular stress (ccf=mtDNA). Our study provides data support for the variation in mitochondria-related functional characteristics of AD patients.

Minipuberty period of children with atopic dermatitis compared to healthy children.

Background/aim: Atopic dermatitis (AD) is an inflammatory, pruritic, noncontagious, chronic relapsing skin disease. Skin barrier abnormalities, excessive T helper 2 activity, and immune dysregulation are held responsible. Androgens have a negative effect on the integrity of the epidermal skin barrier, while estrogen has a positive effect. We aimed to investigate whether hormones make a difference between healthy children and children with AD during minipuberty. Materials and methods: A total of 96 infants (postnatal 4-13 weeks), 48 diagnosed with AD and 48 controls, were included. Each group consisted of 23 girls (47.9%) and 25 boys (52.1%). Anthropometric examinations and hormone measurements were compared. Results: The two groups, having similar age, sex, body mass index, and weight-for-length standard deviation scores, were compared. Serum free thyroxine (FT4) levels were found to be lower and insulin-like growth factor binding protein-3 (IGFBP3) levels were found to be higher in children with AD (p < 0.001 and p = 0.038, respectively). In girls with AD, estradiol, FT4, and insulin-like growth factor-1 (IGF-1) levels were found to be lower, but thyroid-stimulating hormone (TSH) levels were found to be higher (p = 0.023, p < 0.001, p = 0.038, and p = 0.034, respectively). In boys with AD, the FT4 level was found to be lower (p = 0.023). Serum FT4 and TSH levels were within normal reference ranges in all comparisons. Conclusion: Especially in girls with AD, decreased estradiol and IGF-1 levels were observed compared to the controls during minipuberty. In the logistic regression model, decreased levels of serum estradiol, dehydroepiandrosterone sulfate, FT4, and IGF-1, and increased levels of IGFBP3 were associated with an increased likelihood of exhibiting atopic dermatitis.

PDE4D and miR-203 are promising biomarkers for canine atopic dermatitis.

BACKGROUND: Canine atopic dermatitis (CAD) is a common genetically predisposed, inflammatory, and pruritic skin disorder that affects dogs globally. To date, there are no specific biomarkers available to diagnose CAD, and the current diagnosis is based on a combination of criteria including patient history, clinical signs, and exclusion of other relevant differential diagnoses. METHODS AND RESULTS: We examined the gene expression of phosphodiesterase 4D (PDE4D) in peripheral blood mononuclear cells (PBMCs), as well as miR-203 and miR-483 in plasma, in three groups: healthy dogs, CAD dogs, and other inflammatory pruritic skin diseases (OIPSD) such as pemphigus foliaceus, scabies, cutaneous lymphoma, and dermatophytosis. Our results showed that PDE4D gene expression in the CAD group is statistically higher compared to those in the healthy and OIPSD groups, suggesting PDE4D may be a specific marker for CAD. Nevertheless, no correlation was found between PDE4D gene expression levels and the lesion severity gauged by CAD severity index-4 (CADESI-4). We also showed that miR-203 is a generic marker for clinical dermatitis and differentiates both CAD and OIPSD inflammatory conditions from healthy controls. CONCLUSIONS: We show that PDE4D is a potential marker to differentiate CAD from non-atopic healthy and OIPSD while miR-203 may be a potential marker for general dermatologic inflammation. Future study of PDE4D and miR-203 on a larger scale is warranted.

Real-world effectiveness and safety of abrocitinib in 12 Japanese patients with atopic dermatitis and transcriptome analysis with peripheral blood.

Atopic dermatitis (AD) is a common chronic inflammatory skin disease characterized by recurrent, pruritic, and localized eczema. Various types of new drugs have been recently investigated for treating AD. The efficacy and safety of abrocitinib in treating AD has been reported in clinical trials, but the real-world data from Japan has not been reported. Herein, we analyzed 12 Japanese patients with AD treated with 100 mg of abrocitinib using our real-world data. We also performed transcriptome analysis with peripheral blood to investigate the effects of abrocitinib on cytokine expressions and inflammatory pathways in AD from three patients. This study included patients with moderate to severe AD treated with abrocitinib at Gunma University Hospital, Japan. All patients were systemic treatment-naïve. All patients received a 100-mg dose of abrocitinib daily, and used strong or very strong topical steroids and moisturizers. The Eczema Area and Severity Index (EASI) response analysis revealed that after 4 weeks, 25% (three of 12) of the cases reached a 75% reduction in the EASI score (EASI-75) and a 90% reduction in the EASI score (EASI-90). After 12 weeks, 83.3.% (10 of 12), 41.6% (five of 12), and 16.7% (two of 12) of the patients reached EASI-50, a 75% reduction in the EASI score (EASI-75), and EASI-90. Peak Pruritus Numerical Rating Scale was achieved in nine patients (75%) at week 12. The most frequent adverse reaction was acne (six cases [50%]). Gene Ontology pathway analysis using Differentially expressed genes from RNA sequencing analysis revealed attenuation of defense responses to biotic stimulus, virus, and cytokines. Th2 cytokine expression was not suppressed, but several chemokines, especially CXCL1, were suppressed by abrocitinib treatment. Our results indicate abrocitinib as a fast-acting and highly antipruritic agent that is effective for moderate skin eruptions.