ABSTRACT Atopic dermatitis (AD) is a chronic pruritic skin condition characterized by lesions associated with colonization and infection by Staphylococcus aureus . There is growing evidence that S. aureus contributes to symptoms and persistence of AD through production of cytotoxins, superantigens, and proteases. When AD is treated with the interleukin-4 receptor blocking antibody, dupilumab, S. aureus colonization declines rapidly. Here, we examined the possible involvement of the host lysozyme-mediated innate immune response in helping to control S. aureus burden in AD patients. S. aureus is not killed by lysozyme, but the molecule inhibits S. aureus exotoxin and exoenzyme (exoprotein) production. Reduced S. aureus abundance during dupilumab treatment correlated positively with reduced lysozyme levels. S. aureus colonization and lysozyme levels were not altered in placebo-treated participants until they entered the open-label phase of the study (non-blinded phase) when all participants were treated with dupilumab. During that phase, the S. aureus and lysozyme levels declined. These findings suggest that AD patients may respond to cutaneous S. aureus colonization by upregulating lysozyme production. IMPORTANCE Staphylococcus aureus is increasingly viewed as an important contributor to atopic dermatitis (AD) persistence. The host responds to AD by producing cationic peptides, including lysozyme. Lysozyme cannot kill S. aureus , but the innate defense molecule downregulates exotoxin and exoenzyme production, limiting S. aureus-induced inflammation. Clinical improvement of AD likely requires balancing the inflammatory cascades induced by S. aureus versus host innate immunity.

BACKGROUND:Perinatal phthalate exposure has been suggested as a potential contributor to atopic dermatitis (AD). OBJECTIVE:To investigate whether neonatal urinary phthalate levels predict the development of AD and to explore mechanisms involving immune activation and skin barrier dysfunction. METHODS:Urinary phthalate metabolites collected within 48 hours after birth were analyzed by liquid chromatography-tandem mass spectrometry. AD at 12 months of age was identified based on physician diagnosis and treatment history. Logistic regression analysis was used to evaluate the associations between phthalate levels and AD development. Peripheral blood mononuclear cells, human neonatal epidermal keratinocytes (HEKs), and organotypic skin cultures were exposed to phthalates to assess cytokine and epidermal barrier protein expression and to evaluate transepidermal water loss. RESULTS:Among 61 neonates, 11 (18.0%) developed AD by 12 months of age. Neonatal urinary concentrations of di(2-ethylhexyl) phthalate metabolites were associated with AD development (adjusted odds ratio, 2.03; 95% CI, 1.12-3.68; P = .020). Phthalate exposure increased interleukin-1β expression in peripheral blood mononuclear cells and HEKs (1.54-fold; 95% CI, 1.27-1.81; and 1.23-fold; 95% CI, 1.11-1.36, respectively), tumor necrosis factor-α expression (1.29-fold; 95% CI, 1.16-1.42; and 1.80-fold; 95% CI, 1.22-2.39, respectively), and interleukin-6 expression (1.55-fold; 95% CI, 1.36-1.74; and 1.96-fold; 95% CI, 1.31-2.62, respectively). Phthalate (10 ng/mL) inhibited filaggrin (0.68 ± 0.08; P < .05) and loricrin (0.67 ± 0.07; P < .05) expression in HEKs compared with media alone (1.03 ± 0.06 and 1.05 ± 0.04, respectively) and increased transepidermal water loss in an organotypic skin model (47.73 ± 3.72 vs 33.46 ± 1.56 g/m2h, P < .01). CONCLUSION:Elevated neonatal urinary phthalate metabolites are associated with an increased risk of AD development. Phthalate-induced skin barrier dysfunction may contribute to the development of early-onset AD. CLINICAL TRIAL REGISTRATION:The study was registered in the Clinical Research Information Service, Republic of Korea, which is part of the World Health Organization International Clinical Trials Registry Platform (registration number: KCT0007286).

BACKGROUND:Skin barrier dysfunction and inflammation characterize both lesional and nonlesional skin in moderate-to-severe atopic dermatitis (AD) and are associated with relapses and atopic march progression. OBJECTIVE:To assess the effects of dupilumab treatment on skin barrier function and integrity using noninvasive methods in children aged 6 to 11 years with moderate-to-severe AD compared with matched healthy volunteers. METHODS:Patients received dupilumab for 16 weeks. Transepidermal water loss (TEWL) before (basal) and after skin tape stripping and epidermal thickness (TE), measured by optical coherence tomography, were assessed to week 28. RESULTS:The PEdiatric skin barrier function and LIpidomics STudy in patients with Atopic Dermatitis (PELISTAD) enrolled 23 patients and 18 healthy volunteers. Mean ± SD basal TEWL was significantly higher in AD lesional/nonlesional skin at baseline (55.1 ± 5.5/28.0 ± 3.1 g × m-2 × h-1) than in healthy skin (14.0 ± 1.6) and decreased to 30.3 ± 3.1/22.0 ± 2.6 at week 16 and to 29.7 ± 4.3/18.3 ± 2.1 at week 28; TEWL after 5 of 20 skin tape stripping improved similarly. Baseline mean ± SD TE in lesional/nonlesional skin (251.1 ± 25.8/166.1 ± 15.2 µm) was significantly higher than in healthy skin (118.2 ± 5.1) and decreased to 196.8 ± 18.4/141.9 ± 11.9 at week 16 and to 160.4 ± 12.9/142.7 ± 15.6 at week 28. At weeks 16 and 28, there was no significant difference between TEWL and epidermal thickness in AD lesional and nonlesional skin vs healthy skin. CONCLUSION:Using noninvasive techniques to monitor epithelial function, dupilumab treatment restored skin barrier function in children with AD. Improvements achieved at week 16 were sustained to week 28. TRIAL REGISTRATION:ClinicalTrials.gov Identifier: PELISTAD (NCT04718870).

BACKGROUND:Immune-related cutaneous adverse events (ircAEs) complicate management in many cancer patients receiving checkpoint inhibitor (CPI) immunotherapy. A new approach to early prognosis and ircAE treatment monitoring is needed in order to improve patient adherence to CPI immunotherapy. METHODS:Skin tape strips (STS) and plasma were collected prospectively from 22 oncology patients prior to starting CPI and after 6 weeks of CPI therapy. Patients were then followed for ircAE development for 6 months. Ten patients subsequently developed ircAEs. STS were analyzed for cytokines and lipids, while plasma was analyzed for cytokines. RESULTS:A significant increase in stratum corneum (SC) ceramides with short chain fatty acids was observed in patients who developed ircAEs (p < 0.05 compared to non-ircAE groups). This lipid abnormality was already present in the skin of future ircAE patients before starting CPI immunotherapy, and was further dysregulated on CPI therapy. Following CPI initiation, significant increases in skin (but not plasma) IL-8, IL-18, and IP-10 (CXCL10), IL-12, IFNa, MDC (CCL22), and TARC (CCL17) production were observed in patients who subsequently developed ircAEs (p < 0.05 compared to non-ircAE groups). CONCLUSION:STS analysis of patients developing ircAEs demonstrated SC lipid abnormalities prior to CPI treatment. When studied after 6 weeks of CPI therapy, these SC barrier lipid abnormalities were worsened. In addition, significant increases in proinflammatory cytokine levels were identified in the skin, but not in plasma. These findings point to mechanisms of ircAE development and may allow early identification of patients at risk of developing ircAEs for close monitoring and future prevention of treatment-limiting ircAEs.

Atopic dermatitis (AD) is a highly prevalent, chronic inflammatory skin disease that predominantly begins in early childhood. Increasing evidence supports that pediatric AD is not a single entity, but rather a spectrum of overlapping phenotypes and endotypes, defined by clinical presentation, immune profile, genetics, ethnicity, and comorbid atopic conditions. This review provides a comprehensive synthesis of current knowledge on childhood AD heterogeneity, emphasizing severity, age of onset, allergen sensitization, allergic comorbidities, ethnicity, and disease trajectory. Phenotypic classification - based on clinical severity, lesion distribution, and disease course - offers valuable prognostic insight, particularly in relation to the risk of asthma, allergic rhinitis, food allergy and eosinophilic esophagitis. Endotyping approaches, including transcriptomic, proteomic, lipidomics, metabolomics and cellular analyses, have revealed distinct immune signatures across age and ethnic groups, including Th2-predominant, Th17/Th22-skewed, or mixed inflammatory pathways. Ethnic-specific differences, such as Th17 activation in Asian populations or Th2/Th22 predominance in individuals of African ancestry, further underscore the need for tailored therapeutic strategies. The emergence of multiomics and clustering-based approaches has begun to identify molecular subgroups, although challenges remain in standardizing methods and validating findings across diverse cohorts. Importantly, the identification of biomarkers to predict disease trajectory and treatment response is a critical unmet need. Future research should prioritize longitudinal, multiethnic, and integrative studies to refine endotyping, enable early intervention, and guide precision medicine in pediatric AD. Understanding the dynamic interplay between genetics, immune dysregulation, and environment will be key to unlocking improved outcomes for children affected by this complex disease.

The skin is far from a passive shield; it functions as a dynamic "living barrier" whose structural and immunological integrity is paramount in preventing atopic dermatitis (AD) and the subsequent progression of the atopic march toward food allergy (FA). While prophylactic emollient therapy has emerged as a promising strategy for primary prevention, recent large-scale randomized controlled trials have yielded conflicting results. In this review, we examine the complex interplay between emollient formulations, skin barrier biology, and immune responses in the context of AD and FA prevention. We discuss the functional roles of occlusives, humectants, and barrier-replenishing lipids, highlighting how their composition, ratios, and physicochemical properties determine their effects on barrier integrity. We further evaluate the impact of additional formulation components, including food-derived ingredients, haptens, irritants, and pH, as well as external factors such as product handling and application practices, which may inadvertently promote barrier disruption and transcutaneous sensitization. Collectively, current evidence supports a shift from generalized emollient use toward a precision-based, barrier-directed approach. Optimized formulations that restore physiological lipid composition, combined with early intervention and integration of objective biomarkers, may offer a more effective strategy to prevent AD and the atopic march.

INTRODUCTION:Atopic Dermatitis (AD) is a chronic inflammatory skin disease characterized by complex pathogenesis, variable clinical phenotypes, and broad severity spectrum. We utilized a serum-proteomic approach integrated with machine learning (ML) to identify novel biomarkers that distinguish mild from severe AD. METHODS:Serum from sixty-seven AD adults, stratified by Eczema Area and Severity Index/EASI and Rajka-Langeland/RJL into mild (≤ 7 and ≤ 4, respectively; n = 33) or severe (≥ 20 and ≥ 8, respectively; n = 34), was analyzed with Olink Explore 3072. Differentially expressed proteins (DEPs) were identified using t-tests and False Discovery Rate correction (FDR ≤ 0.05). Tissue enrichment analysis was conducted using HPAStainR. Pearson correlations were performed between DEPs and clinical variables, serum lactate dehydrogenase/LDH and biomarkers for Th-pathways. ML (TMLE/SuperLearner, Boruta, MUVR) was used to identify top severity biomarkers. RESULTS:469 DEPs distinguished severe vs. mild AD. DEPs were significantly enriched for epithelial proteins (e.g., skin, tonsil, and esophagus epithelium). Subsets correlated strongly with LDH (68 DEPs) and/or Th2/Th22 markers (90 DEPs; r ≥ 0.6, FDR ≤ 0.05). Nine serum proteins (CCL17, CCL22, DEFB4A/B, EZR, GPR15L, IL22, PRSS53, SERPINB8, SETMAR) overlapped across three ML analyses as severity discriminating biomarkers (cross-validated AUC = 0.989; 95% CI: 0.974-1.00). CONCLUSIONS:Severe AD exhibits a proteomic footprint enriched in epithelial-associated proteins that correlate with LDH-associated tissue injury and/or Th2/Th22 pathways. In this cross-sectional cohort, ML identified biomarkers that discriminated mild/severe AD groups with high cross-validated accuracy. Longitudinal and external validation studies, including healthy controls, are needed to determine specificity, generalizability, and prognostic utility.

12156 Background: Biologic agents are increasingly used to treat immune-related cutaneous adverse events (ircAEs). However, limited data exist regarding immune checkpoint inhibitor (ICI) rechallenge and ICI efficacy following biologic therapy for ircAE management. Methods: We conducted a retrospective cohort study of patients enrolled under U01AR077511-01 (PIs Leung, Kern, Lacouture) treated with ICIs who developed dermatologist-confirmed grade ≥2 ircAEs. Demographics, ircAE treatments, and dermatologic and oncologic outcomes were collected via chart review and compared using t-tests and chi-square tests. Results: We identified 159 patients who developed grade ≥2 ircAEs, including 80 treated with biologic agents. Mean age was 66.8 years; 40% were female, 79% White, and 78% had stage IV disease. The most common tumor types were kidney (20%), lung (16%), and melanoma (12%). Common ICI regimens included ICI monotherapy (46%), ICI–ICI combination (21%), and ICI+chemotherapy (19%). Pruritus (23%), maculopapular rash (21%), and eczema (19%) were the most common ircAEs. Most patients received topical steroids (88%), while systemic steroids were used sparsely (13%). Biologics were used in ~50% of patients; the most common agents were dupilumab (43%), omalizumab (33%), and ustekinumab (11%). Median biologic duration was 16 weeks, with 25% receiving therapy for >40 weeks. ICI rechallenge occurred in 60% of biologic-treated versus 67% of non-biologic patients (p=0.35). Rechallenge rates were 67% vs 65% for grade 2 (p=0.85) and 44% vs 74% for grade 3 ircAEs (p=0.05) (biologic vs non-biologic, respectively). Antitumor outcomes were similar between biologics and non-biologic groups: 31% vs 28% achieved partial/complete response, 43% had stable disease, and 26% vs 29% had progressive disease, respectively. Conclusions: In this oncodermatology-managed cohort, ircAEs were primarily treated with topical corticosteroids and targeted biologics, with infrequent systemic steroid use. Biologic therapy enabled ICI rechallenge in most patients, and oncologic outcomes were comparable to those not receiving biologics. Overall, these findings support biologics as a steroid-sparing option for moderate-to-severe ircAEs that may allow continued immunotherapy without apparent loss of antitumor efficacy, warranting prospective validation. Clinical characteristics. Variable Overall n=159 No Biologics n=79 Biologics n=80 Age at ICI (mean) 66.8 64.3 69.4 Tumor Types Kidney/Lung/Melanoma (%) 20/16/12 22/17/9 18/15/15 Line of treatment 1L/2L/2+L (%) 52/25/23 49/27/24 54/24/22 ircAEs: Pruritus/MPR/Eczema/Others (%) 23/21/19/37 22/33/17/28 25/9/21/45 ircAE Grade 2/Grade 3 (%) 74/26 76/24 71/29 Dupilumab/Omalizumab/Ustekinumab/Others (%) 33/33/11/23 N/A 33/33/11/23 Systemic Steroids - Yes (%) 13 8 18 ICI Rechallenge - Yes (%) 64 67 60 Response CR-PR/SD/PD (%) 30/43/27 31/43/26 28/43/29

BACKGROUND:Eosinophilic esophagitis (EoE), like atopic dermatitis (AD), is a disease of epithelial barrier dysfunction. The predisposing factors remain under investigation and few commonalities between the skin and the esophagus are known. There are no surrogate markers for EoE risk. OBJECTIVE:We sought to assess for concurrent skin and esophageal dysfunction by evaluating ceramide (CER) levels in the skin of children with EoE. METHODS:We collected up to 21 skin tape strips (STSs) from the volar forearm of non-AD subjects with EoE (n = 21) and non-AD, non-EoE controls (n = 17) and evaluated skin lipid composition by liquid chromatography tandem mass spectrometry. RESULTS:Of the subjects with EoE, 38% were female, 57% had IgE-mediated food allergy, and 57% were in histologic remission at STS collection. The time between endoscopy and STS was 75.7 days (range, 0-467). Compared with controls, the skin of subjects with EoE had significant decreases in CERs with 22-carbon long-chain sphingosine or 22-carbon long-chain phytosphingosine and nonhydroxy fatty acids (P < .05) and in all α-hydroxy fatty acid-containing sphingosine CERs (with 18-, 20-, and 22-carbon long-chain sphingosines) (P < .01). Ultralong-chain fatty acid-containing CERs were particularly reduced in the skin of subjects with EoE. CONCLUSIONS:There are demonstrable differences in long-chain CERs in the skin of children with EoE but without AD as compared with non-AD, non-EoE subjects. These data suggest that skin barrier could be a biomarker for EoE and conceptually suggests that the skin and esophagus may represent a "unified epithelial barrier."

Background:Staphylococcus capitis occasionally causes human infections. We report a case of S. capitis infection associated with inflammatory destructive hip abscess/osteomyelitis. Case Summary:A 63-year-old man with severe hip osteoarthritis and recent left hip replacement presented with 2 months of worsening right hip pain. Radiographic imaging showed right femoral head destruction. The patient had no known hip trauma. His white blood cell count, C-reactive protein, and erythrocyte sedimentation rate were abnormal. Pre-operative aspirate of the hip showed purulent fluid. The examining radiologist believed the changes seen were due to inflammatory arthritis with infection from low-virulence organisms. The patient underwent image-guided biopsies of the synovium and the acetabulum, which showed pure cultures of S. capitis and infiltrating neutrophils. The patient's native hip was removed, and an antibiotic spacer was placed. The patient was treated with intravenous cefazolin (6 weeks), after which he was transitioned to oral cefadroxil. The patient is doing well. The S. capitis was analyzed by nucleotide sequencing and biochemically for secreted virulence factors. The strain contained the polysaccharide intercellular adhesin biofilm operon. The strain was negative for urease, hemolysins, and major superantigens. The organism secreted a neutrophil pro-inflammatory autolysin protease and an analog of the immunodominant antigen B of S. aureus, previously with no known biological function. Conclusion:Our data suggest that the inflammatory lesion in the patient's right hip was due to S. capitis subspecies capitis, and furthermore, it is likely that two secreted proteins (autolysin and an analog of immunodominant antigen B) contributed to the inflammation.

Background Lipids play an essential role in epithelial barrier integrity. Despite increasing evidence of epithelial barrier dysfunction in eosinophilic esophagitis (EoE), the lipid composition of the esophageal epithelium is not characterized and any disruptions in EoE are unknown. Methods Esophageal brushings and biopsies were collected from patients (ages 1-19 years) who underwent clinically indicated esophagogastroduodenoscopy. Participants were classified based on the number of eosinophils per high-power field (eos/HPF) in esophageal biopsies into: an EoE group (> 15 eos/HPF) and a control group (0-1 eos/HPF). Brushing samples were analyzed by targeted lipidomics using liquid chromatography tandem-mass spectrometry. The expression of inflammatory mediators and lipid biosynthesis enzymes was quantified by RT-PCR in esophageal biopsies and in a primary human esophageal epithelial cell line treated with IL-4/IL-13. Results EoE group had a significant increase in non-hydroxy fatty acid sphingosine ceramides (NS-CER) (p < 0.01), and a decrease in non-hydroxy fatty acid phytoceramides (NP-CER) with 18-carbon sphingoid bases, resulting in selectively increased NS-CER/NP-CER ratios as compared to controls in esophageal brushes (Mean +/- SD: 5.0 +/- 1.9 vs. 1.6 +/- 1.2 p < 0.01). EoE biopsies had significantly decreased expression of DEGS1 (p < 0.01) and DEGS2 (p < 0.05) mRNA, enzymes responsible for the biosynthesis of NS-CER and NP-CER. A significant inverse correlation between NS-CER/NP-CER and DEGS2/DEGS1 mRNA ratios (p < 0.01) was observed. Conversely, a positive correlation between the NS-CER/NP-CER ratio and CCL26, IL-5, and IL-13 mRNA expression (p < 0.05) was noted. IL-4/IL-13 significantly dysregulated the expression of DEGS1 and DEGS2 mRNA in a primary esophageal epithelial cell line. Conclusion Distinctive abnormalities in esophageal epithelium sphingolipid composition and production were revealed in EoE. Mechanistic ex vivo data demonstrate dysregulation of lipid biosynthesis enzymes by IL-4/IL-13. The characteristic lipid profile in EoE has significant implications for epithelial barrier dysfunction and may serve as a biomarker of disease activity.

Background: Skin lipids are crucial components of the skin barrier. Individuals with atopic dermatitis (AD or eczema) have a different skin lipid profile from those without. However, whether altered skin lipids precede and predict the subsequent risk of AD remained unclear, especially for different AD phenotypes. Objective: We sought to examine the relationship between skin lipids and subsequent AD and AD phenotypes in infants. Methods: Skin lipids from the forearms of 133 infants with family history of allergic disease were sampled using tape strips at age 6 weeks. Lipids were quantified using liquid chromatography-tandem mass spectrometry. AD by age 1 year was diagnosed using modified UK Working Party Criteria. Allergic sensitization was assessed using skin prick tests. Associations and predictive discrimination were estimated using univariable logistic regression. Potential causation was explored using multivariable logistic regression. Results: Reduced levels of 6 protein-bound v-hydroxyl sphingosine (POS) ceramides with C30 and C32 fatty acids at 6 weeks were associated with increased risk of AD by age 1 year. In univariate models, a number of POS ceramides predicted subsequent AD, such as PO30:0-C20S (area under the curve, 0.65; 95% CI, 0.55-0.75). After confounderswere adjusted, only PO30:0-C20S was associated with AD (adjusted odds ratio, 0.62; 95% CI, 0.39-0.96 per 1-SD increase), and a trend for AD without sensitization (adjusted odds ratio, 0.57; 95% CI, 0.31-1.05) but not ADwithsensitization (adjustedodds ratio, 0.76; 95% CI, 0.39-1.47). Conclusions: Reduced levels of POS ceramides are associated with the development of nonatopic AD, suggesting that these lipids may play a role in the pathogenesis of AD and may be useful predictive biomarkers. Interventions that increase POS ceramides may reduce the incidence of AD.

Researchers have shown significant interest in the early prediction of atopic dermatitis (AD) and food allergy (FA) by analyzing factors such as genetics, skin barrier function, skin lipid profiles, epidermal cytokine profiles, cutaneous microbiome, and environmental influences, including air pollution and temperature. Early intervention is critical for preventing and mitigating the severity and progression of AD and FA. This article explored the pathogenesis of both AD and FA and highlighted the potential of skin tape stripping as a promising noninvasive tool for identifying predictive and follow-up biomarkers in infants predisposed to these conditions.