Atopic dermatitis (AD) is characterised by a skin barrier defect, type 2 immune-mediated inflammation, and microbial dysbiosis [1]. Three-dimensional human skin equivalents (3DSE) effectively mimic human skin by providing a stratified barrier grown on a dermis-like matrix. These models enable mechanistic AD studies; however, few have incorporated bacteria or immune cells, both of which are essential to fully recapitulate AD features. In this study, we refined AD-like 3DSEs by integrating Staphylococcus aureus (S. aureus) and immune cells to more accurately simulate AD pathology. 3DSEs were generated following established protocols [2]. An AD-like environment was created by stimulation with IL-4 and IL-13 or Th2-polarised CD4+ T cells, and S. aureus was applied topically. Biopsies from the 3DSEs were taken for histological assessment, bacterial DNA and human RNA isolation, and the basolateral media were collected for multiplex ELISA. Additional information about study methods and findings is available in the following repository: https://zenodo.org/records/14773303. IL-4 and IL-13 were used to stimulate simple 3D skin models of AD. These models showed a reduced expression of filaggrin, involucrin and loricrin compared to unstimulated models (Figure 1A). Cytokine stimulation further induced spongiosis, indicating a profound effect of IL-4/IL-13 on skin barrier integrity (Figure 1B). The inflammatory milieu in the basolateral media of IL-4/IL-13 models was marked by an overall increase in levels of pro-inflammatory cytokines (Figure 1D). The colonisation of skin with S. aureus presents an important factor in AD pathology, as 90% of atopic dermatitis patients, but only 5% of healthy individuals, show S. aureus skin colonisation [3]. Whether the changes in skin morphology are a cause or consequence of increased growth of S. aureus on skin is widely discussed. In clinical settings, dupilumab, a systemic treatment targeting IL4Rα, not only ameliorates AD symptoms but can also reduce pro-inflammatory cytokine levels and has been shown to be associated with reduced S. aureus skin colonisation [4]. Our addition of S. aureus on our simple 3DSEs aimed to mimic the in vivo-observed increase in S. aureus load. However, cytokine treatment did not increase S. aureus load; neither did dupilumab reduce bacterial growth (Figure 1C). Although inducing defects in skin barrier integrity, IL-4/IL-13-stimulated 3DSEs failed to mimic the effects observed in vivo regarding systemic therapy and microbial dysbiosis. Thus, in the current 3DSEs, the in vivo effects cannot be fully mimicked. In recent years, 3D skin models became more advanced by the integration of immune cells [5]. However, these models did not consider the analysis of skin microbial imbalances. We integrated in vitro Th2-polarised CD4+ T cells into our 3D skin equivalents to more accurately replicate the in vivo conditions of AD. For control comparisons, non-polarised CD4+ T cells from healthy donors (pan T cells) were used. The indirect incorporation of Th2-polarised CD4+ T cells into the basolateral media led to decreased expression of filaggrin and involucrin in the skin models, with minor effects on loricrin expression and the development of spongiosis (Figure 1A,B). Although skin barrier defects were less severe in these T cell models, an increased S. aureus load compared to respective control skin models was observed as opposed to cytokine-treated models (Figure 1C). Treatment with dupilumab effectively reduced the increased S. aureus growth in models including Th2-polarised cells. Our results indicate that immunocompetent 3D skin equivalents seem to be essential to recapitulate the increased S. aureus growth observed in AD lesional skin, suggesting that the Th2 milieu is crucial for the induction of S. aureus growth in 3D skin models. Th2 or pan T cell integration both generated a cytokine-rich environment compared to simple models, which was even more enriched when skins were exposed to S. aureus. We observed elevated levels of IL-4, IL-13, IL-1α, IL-1β, IFN-γ, IL-16, IL-22, IL-17A and MDC (Figure 1D). Whether these cytokines were expressed by T cells or skin resident cells like keratinocytes or fibroblasts is not known. The observed induction of IL-1α and IL-1β by S. aureus in our models is consistent with previous studies [6], suggesting this pathway might play an important role in S. aureus-mediated skin barrier impairment. Brauweiler et al. showed that S. aureus-derived lipoteichoic acid reduces filaggrin and involucrin expression and that this reduction is mediated via an IL-1-mediated pathway [7]. Most of the identified pro-inflammatory proteins appear to be a consequence of the increased S. aureus load, as they were further increased after the addition of S. aureus. For instance, IL-17A and IL-22 induce AMP production, which should protect against S. aureus colonisation [8]. Innate immunity markers such as IL-1β are secreted by keratinocytes to promote defence by inducing AMP production [9]. IL-22, detectable in AD lesional skin, induces AMP production but also causes downregulation of epidermal differentiation complex genes, resulting in enhanced S. aureus colonisation [8]. Thus, colonisation by S. aureus may induce the skins defence mechanisms, but unknown factors exist by which S. aureus can continue to propagate. Our results represent a major step forward in the development of complex skin models, including microbial and immunological parameters, with the potential for further enhancement by incorporation of different members of the skin microbiome and other immune players. For future studies, it is crucial to carefully consider the research question to select the appropriate 3D skin model. IL-13 + IL-4 treated 3D skin equivalents seem to be better suited for assessing changes in epidermal organisation and skin barrier impairment, while 3D skin models incorporating Th2 cells are more appropriate for evaluating changes in S. aureus load. Conceptualization: I.S., M.F., H.E. Data curation: I.S., M.F., M.M. Formal analysis: I.S., M.F., H.E. Funding acquisition: S.W. Investigation: I.S., M.F., M.M. Methodology: I.S., M.F., H.E., J.H., M.M. Project administration: S.W., H.E. Resources: S.W., H.E., J.H. Supervision: H.E., J.H., E.R. Validation: I.S., M.F., H.E. Visualisation: J.N.H., M.F. Writing – original draft: I.S., M.F. Writing – review and editing: H.E., S.W., J.H., J.N.H., E.R., M.M. All authors have read and agreed to the final version. Open Access funding enabled and organized by Projekt DEAL. S. Weidinger has received institutional research grants from Sanofi Deutschland GmbH, LEO Pharma, and Pfizer and performed consultancies and/or lectures for AbbVie, Almirall, Boehringer, Eli Lilly, Galderma, Kymab, Leo Pharma, Regeneron, Sanofi-Genzyme, and Novartis. H. Emmert and J. Harder have received institutional research grants from LEO Pharma. The rest of the authors declare that they have no conflicts of interest. The data that support the findings of this study are available from the corresponding author upon reasonable request.

Altered plasma N-glycosylation is increasingly recognized as a contributor to metabolic dysregulation. This study aimed to investigate the role of plasma N-glycans in glucose metabolism and the progression from normoglycemia to prediabetes and type 2 diabetes (T2D). We analyzed longitudinal data from 473 participants in the Cooperative Health Research in the Region of Augsburg (KORA) cohort over 7 years. N-glycan profiles were measured using hydrophilic interaction ultrahigh-performance liquid chromatography with fluorescence detection (HILIC-UHPLC-FLR). Glycan associations with incident prediabetes/T2D and related traits, such as body mass index (BMI), fasting glucose, homeostasis model assessment of insulin resistance (HOMA-IR) were evaluated using longitudinal models based on N-glycan measurements obtained at F4 and FF4. Classification performance at FF4 was assessed using machine learning models interpreted with SHapley Additive exPlanation (SHAP) values. Mendelian randomization (MR) and glycan quantitative trait loci (glycan-QTL) analyses were conducted to explore causality and genetic determinants. During follow-up, 231 individuals progressed to prediabetes/T2D, while 242 remained normoglycemic. Nineteen glycans were associated with diabetes progression in the basic model; 12 remained significant after full adjustment. Glycans such as GP18 and GP32 were also linked to metabolic traits. A glycan-clinical model achieved high classification accuracy (AUC = 0.895). MR supported causal roles for GP18, GP19, and S1. Glycan-QTL analysis revealed SNPs and genes (FUT8, ST3GAL4) are associated with key glycans. Plasma N-glycans are diagnostic of early glycemic deterioration and supported by genetic and causal evidence, highlighting their potential as biomarkers for diabetes risk stratification.

BACKGROUND:Eczema herpeticum (EH) is a potentially life-threatening disseminated skin infection caused by herpes simplex virus (HSV) in a subset of patients with atopic dermatitis (AD). The occurrence of EH in a subset of patients with AD and its frequent recurrence imply the importance of genetic factors in its pathogenesis. OBJECTIVE:We sought to identify novel genetic risk factors for EH and to study their impact on HSV-1 infection. METHODS:Using whole-exome sequencing we identified a heterozygous single nucleotide polymorphism (SNP) in the COL23A1 gene (encoding collagen type XXIII alpha 1 chain or COL23A1) that was associated with EH and validated it by PCR in a larger cohort. We studied the effect of upregulated COL23A1 expression on HSV-1 infection in primary keratinocytes and HaCaT cells and performed bulk RNA sequencing to address the underlying mechanism. RESULTS:Primary keratinocytes derived from patients with EH carrying this heterozygous SNP rs2973744 had elevated COL23A1 mRNA and protein levels as well as an increased susceptibility to HSV-1. Increasing the COL23A1 levels experimentally enhanced HSV-1 infection in human keratinocytes. COL23A1 overexpression elevated syndecan-1 and nectin-1 levels on the cell surface, which are HSV-1 attachment and entry factors, respectively, and downregulated genes involved in antiviral responses, such as IL1R1, IL32, TLR4, IRF1, S100A9, C3, and CFH. CONCLUSIONS:The SNP rs2973744 enhances COL23A1 expression in keratinocytes derived from patients with AD and a history of EH. Upregulation of COL23A1 promotes HSV-1 infection presumably by upregulating the HSV-1 attachment and entry factors syndecan-1 and nectin-1 on the cell surface and attenuating antiviral responses of keratinocytes.

Abstract Background: A subgroup of atopic dermatitis (AD) patients is prone to develop severe, disseminated cutaneous infection with herpes simplex virus (HSV), known as eczema herpeticum (EH). The occurrence of EH in a subset of AD patients and its frequent recurrence implies the importance of genetic factors in its pathogenesis. Objective: We aimed to identify novel genetic risk factors for EH and study their impact on HSV-1 infection. Methods: We performed whole exome sequencing on nine AD patients with (ADEH+) and without (ADEH-) a history of EH in comparison to healthy controls. We validated the finding of a variant of COL23A1 gene (encoding Collagen type XXIII alpha 1 chain) in ADEH in a larger cohort of 117 ADEH+, 117 ADEH- patients and 118 healthy controls by PCR. We studied the expression of COL23A1 in keratinocytes from ADEH+ and ADEH- patients, and the upregulated COL23A1 expression in primary keratinocytes and in the cell line HaCaT to study its role in HSV-1 infection. Results: We identified a single nucleotide polymorphism (SNP), rs2973744 in COL23A1, as a risk factor for EH observed in 5% of ADEH+ patients, 1.6% of healthy donors and 0% of ADEH- patients. Primary human keratinocytes from an ADEH+ patient with SNP rs2973744 expressed higher COL23A1 levels and were more susceptible to HSV-1 than keratinocytes from ADEH- patients. In functional assays we showed that HSV-1 gene expression and cell-to-cell spread was more efficient in keratinocytes with increased expression of COL23A1. Moreover, COL23A1 overexpression in HaCaT cells resulted in transcriptional downregulation of several genes that are involved in an effective immune response (IL1R1, IL32, TLR4, CFH, C3, S100A9, IRF1, and ADAM23) and a notable upregulation of TNC and SPINK5 that are associated with AD. Conclusion: Upregulation of COL23A1 promotes HSV-1 infection presumably by attenuating antiviral responses of keratinocytes. Among other markers, the COL23A1 SNP rs2973744 could be included in the screening of AD patients to identify patients at risk of EH, thus allowing early initiation of therapy. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This study was funded by Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) under Germanys Excellence Strategy-EXC 2155 RESIST- project number 390874280. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The ethics committee of Hannover Medical School (No. 8733\_BO\_S_2019) approved this study and all study participants provided written informed consent. DNA samples from AD patients with and without a history of EH were derived from the GENEVA cohort, Biobank of the University Hospital Schleswig-Holstein (UKSH), Kiel, Germany. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data produced in the present study are available upon reasonable request to the authors.

BACKGROUND:Atopic dermatitis (AD) is the most common paediatric inflammatory skin disease. There are currently no robust biomarkers that could reliably predict its manifestation, and on the molecular level, it is less well characterized than adult AD. OBJECTIVES:This study aimed to extend previous findings and provide evidence for distinct changes of the epidermal proteome and microbiome preceding the onset of AD as well as characterizing early AD. METHODS:We longitudinally analysed epidermal biomarker levels and microbial profiles in a cohort of 50 neonates at high risk for AD, who had participated in a randomized controlled trial on early emollient use for AD prevention. RESULTS:About 26% of the infants developed AD until month 24 with an average age of 10 month at disease onset. In children with later AD, IL-1Ra, TNFβ, IL-8, IL-18, IL-22, CCL2, TARC, TSLP and VEGFa showed increased levels prior to disease manifestation with levels of IL-1Ra, TNFβ and VEGFa already increased shortly after birth. Further, children with later AD displayed a delayed maturation and differentially composed skin microbiome prior to AD onset. At manifestation, levels of multiple Th2, Th17/22 and Th1-associated biomarkers as well as innate immunity markers were elevated, and abundances of commensal Streptococcus species were reduced in favour of Staphylococcus epidermidis. CONCLUSIONS:Our results indicate that elevations of proinflammatory stratum corneum biomarkers and alterations of the skin microbiome precede paediatric AD and characterize the disease at onset.

BACKGROUND:The antimicrobial ribonuclease RNase 7 is abundantly expressed in the epidermis of lesional skin of atopic dermatitis (AD). Host RNase inhibitor (RI) binds to RNase 7 and blocks its ribonuclease activity. This study aimed to evaluate the impact of RNase 7-RI interactions on AD. METHODS:Cultured human primary keratinocytes, with siRNA-mediated downregulation of RNase 7 and RI, were stimulated with the synthetic RNA polyinosinic-polycytidylic acid (poly I:C). Induction of proinflammatory mediators was analyzed by real-time PCR and ELISA. RI expression in AD non-lesional and lesional skin biopsies and healthy controls was analyzed by real-time PCR and immunostaining. RI protein release in vivo on the AD skin surface was determined by western blot. Antimicrobial and ribonuclease assays were used to investigate the functional role of RI. RESULTS:RNase 7 inhibited the RNA-induced expression of proinflammatory mediators in keratinocytes. Accordingly, downregulation of RNase 7 in keratinocytes enhanced RNA-mediated induction of proinflammatory mediators, whereas downregulation of RI had the opposite effect. RI was released by damaged keratinocytes and epidermis. In vivo expression and release of RI on the skin surface were enhanced in lesional AD skin. Rinsing solution from the surface of lesional AD skin blocked the ribonuclease activity of RNase 7. The anti-Staphylococcus aureus activity of RNase 7 was abrogated by RI. CONCLUSIONS:Our data suggest a novel role of RI as a trigger factor of inflammation in AD by blocking the ribonuclease and antimicrobial activity of RNase 7, thereby enhancing RNA-mediated inflammation and S. aureus growth.

BACKGROUND:Interleukin (IL)-13 is a key driver of inflammation and barrier dysfunction in atopic dermatitis (AD). While there is robust evidence that tralokinumab - a monoclonal antibody that neutralizes IL-13 - reduces inflammation and clinical disease activity, less is known about its effects on barrier function. OBJECTIVES:To characterize the effects of tralokinumab treatment on skin barrier function. METHODS:Transepidermal water loss (TEWL), stratum corneum hydration (SCH), natural moisturizing factor content, histopathological characteristics, biomarker expression and microbiome composition were evaluated in lesional, nonlesional and sodium lauryl sulfate-irritated skin of 16 patients with AD over the course of 16 weeks of tralokinumab treatment. RESULTS:All clinical severity scores decreased significantly over time. At week 16, mean TEWL in target lesions decreased by 33% (P = 0.01) and SCH increased by 58% (P = 0.004), along with a histological reduction in spongiosis (P = 0.003), keratin 16 expression and epidermal thickness (P = 0.001). In parallel, there was a significant decrease in several barrier dysfunction-associated and proinflammatory proteins such as fibronectin (P = 0.006), CCL17/TARC (P = 0.03) and IL-8 (P = 0.01), with significant changes seen as early as week 8. Total bacterial load and Staphylococcus aureus abundance were significantly reduced from week 2. CONCLUSIONS:Tralokinumab treatment improved skin physiology, epidermal pathology and dysbiosis, further highlighting the pleiotropic role of IL-13 in AD pathogenesis.

To the editor, Atopic dermatitis (AD) is a complex disease involving epidermal barrier dysfunction and immunological abnormalities.1 The communication between keratinocytes and T cells as major drivers of immune dysfunction has been studied extensively.2 Still, there is data available underlining some contribution of dermal fibroblasts to AD pathogenesis.3 This study therefore aimed to investigate the pathological effects of keratinocyte- and fibroblast-derived factors on 3D skin models focusing on epidermal organization and barrier marker expression. Primary keratinocytes and fibroblasts were cultured and stimulated with AD-relevant cytokines (IL-22, IL-4, IL-13, TNFα) for 24 h. Cells were washed and serum-free keratinocyte differentiation medium (SKDM) was added for 1 h. Supernatant was collected and used for further analyses. Multiplex ELISA (Luminex) was performed to determine protein levels in cell supernatants. For the construction of three-dimensional (3D) skin models, a well-established protocol was used.4 Stimulation of 3D skin models with cytokines (IL-4, IL-13) or cell supernatants was performed for 48 h. The monoclonal interleukin-4 receptor antagonist dupilumab (dpl) was additionally added for 48 h. Two punch biopsies were taken from each 3D skin and embedded in paraffin for histological analyses and used for RNA isolation and following qPCR.5 Detailed methods and additional results are available at https://zenodo.org/records/10036562. We first performed multiplex ELISA to identify soluble factors secreted by fibroblasts and keratinocytes. Analysis revealed that both keratinocyte and fibroblast secretion was increased following cytokine stimulation. For both cell types increased secretion of innate and adaptive immunity markers as well as T cell attracting cytokines and chemokines was observed after stimulation, however, secretion by keratinocytes was higher as compared to fibroblasts. To study the effects of keratinocyte- and fibroblast-derived factors on skin physiology and barrier properties, 3D skin models were constructed and stimulated with either IL-4, IL-13 creating AD-skin models or with supernatants obtained from unstimulated (Sup-Ctrl) or stimulated (Sup-AD) fibroblasts or keratinocytes. Decreased gene expression of the structural proteins filaggrin, involucrin and loricrin in IL-4 and IL-13 treated skin was observed, confirming the induction of an AD-like epidermis phenotype (Figure 1A–C). Treatment with keratinocyte Sup-AD but not Sup-Ctrl caused significantly reduced gene expression of all targeted proteins when compared to control skin. When comparing the effects of K-Sup-AD on gene expression to those of K-Sup-Ctrl, no significant differences could be observed for filaggrin and loricrin expression levels. This might be explained by the high cytokine levels present in keratinocyte Sup-Ctrl. Treatment with fibroblast supernatants resulted in minor changes in gene expression with significantly decreased expression of loricrin when treated with fibroblast Sup-AD. We performed additional H&E histological analysis of 3D skin models and checked for AD-characteristic spongiosis. AD-model skins revealed significantly higher levels of spongiosis compared to control skin (Figure 1D). Skin sections obtained from 3D skin manipulated with supernatants from keratinocytes showed comparable but non-significant changes. Treatment of 3D skin with fibroblast supernatants did not lead to spongiosis development. Taken together, our data underline the contribution of keratinocyte-derived cytokines to skin barrier dysfunction in human skin models. Keratinocytes that were pre-exposed to external stimuli secreted pro-inflammatory factors which caused pathological changes in 3D skin models mimicking AD skin with regard to their histology and structural protein expression. The amounts of pro-inflammatory mediators secreted by fibroblasts seemed to be not sufficient to lead to significant changes in skin models indicating that keratinocyte signalling is key to skin barrier regulation. It is known that IL-4 and IL-13 influence gene expression of involucrin, loricrin and filaggrin,6 but our data suggests that additional keratinocyte-derived cytokines could promote skin barrier disruption in AD. We further assessed whether the observed pathological changes in 3D skin models treated with cell supernatants were primarily caused by IL-4 and IL-13 signalling. 3D skin models were incubated with Sup-AD from keratinocytes or with IL-4 and IL-13 and were additionally treated with dpl in order to block IL-4/IL-13 receptor signalling. Results demonstrated that blockade of IL-4Rα led to a rescue of filaggrin, involucrin and loricrin expression in AD-skin models (Figure 1A–C). Likewise, spongiosis was significantly reduced (Figure 1D). Less pronounced effects were observed when dpl was added to skin models treated with keratinocytes Sup-AD, where spongiosis was significantly improved but only loricrin expression recovered (Figure 1C,D). Our data showed that skin barrier dysfunction in 3D skin models treated with keratinocyte Sup-AD can in part be reverted by blocking IL-4Rα signalling. However, additional factors present in keratinocyte supernatant that do not signal via IL-4Rα seem to contribute to impaired expression of barrier genes comparable to effects of IL-4 and IL-13 signalling. Michaelidou et al. have previously shown that IL-1 family cytokines downregulate loricrin and pro-filaggrin expression in human explants in vivo7 which supports our findings. IL-1 family cytokines are involved in the innate immune response8 and can possibly amplify the inflammatory state in the skin resulting in the observed skin barrier deficiency. The relatively low secretion of IL-1 cytokines by fibroblasts could be a reason for their relatively small effects on 3D skin model physiology. Thus, our findings indicate the important role of the variety of keratinocyte-derived pro-inflammatory signalling in disrupting the skin barrier both in a Th2-dependent and independent matter. Targeting of IL-1 family cytokine signalling with for example recombinant IL-1Ra (anakinra) would be of interest to further characterize the role of keratinocytes and IL-1 family cytokine signalling in AD. Hila Emmert and Melina Fonfara designed the experiments. Melina Fonfara and Carina Brodersen conducted the experiments. Melina Fonfara and Carina Brodersen analysed the data, and Melina Fonfara, Hila Emmert and Ina Suhrkamp interpreted the data. Melina Fonfara and Hila Emmert drafted the article and Hila Emmert, Elke Rodriguez, Ina Suhrkamp and Stephan Weidinger revised it critically. All authors read and approved the final version. Open Access funding enabled and organized by Projekt DEAL. No funders available. S. Weidinger has received institutional research grants from Sanofi Deutschland GmbH, LEO Pharma, and Pfizer and performed consultancies and/or lectures for AbbVie, Almirall, Boehringer, Eli Lilly, Galderma, Kymab, Leo Pharma, Regeneron, Sanofi-Genzyme, and Novartis. H. Emmert has received institutional research grants from LEO Pharma. The rest of the authors declare that they have no conflicts of interest. The data that support the findings of this study are available from the corresponding author upon reasonable request.

BACKGROUND:Atopic dermatitis (AD) patients display an altered skin microbiome which may not only be an indicator but also a driver of inflammation. We aimed to investigate associations among AD patients' skin microbiome, clinical data, and response to systemic therapy in patients of the TREATgermany registry.METHODS:Skin swabs of 157 patients were profiled with 16S rRNA gene amplicon sequencing before and after 3 months of treatment with dupilumab or cyclosporine. For comparison, 16s microbiome data from 258 population-based healthy controls were used. Disease severity was assessed using established instruments such as the Eczema Area and Severity Index (EASI).RESULTS:We confirmed the previously shown correlation of Staphylococcus aureus abundance and bacterial alpha diversity with AD severity as measured by EASI. Therapy with Dupilumab shifted the bacterial community toward the pattern seen in healthy controls. The relative abundance of Staphylococci and in particular S. aureus significantly decreased on both lesional and non-lesional skin, whereas the abundance of Staphylococcus hominis increased. These changes were largely independent from the degree of clinical improvement and were not observed for cyclosporine.CONCLUSIONS:Systemic treatment with dupilumab but not cyclosporine tends to restore a healthy skin microbiome largely independent of the clinical response indicating potential effects of IL-4RA blockade on the microbiome.

Somatic mutations are hypothesized to play a role in many non-neoplastic diseases. We performed whole-exome sequencing of 1,182 microbiopsies dissected from lesional and nonlesional epidermis from 111 patients with psoriasis to search for evidence that somatic mutations in keratinocytes may influence the disease process. Lesional skin remained highly polyclonal, showing no evidence of large-scale spread of clones carrying potentially pathogenic mutations. The mutation rate of keratinocytes was similarly only modestly affected by the disease. We found evidence of positive selection in previously reported driver genes NOTCH1 , NOTCH2 , TP53 , FAT1 and PPM1D and also identified mutations in four genes ( GXYLT1 , CHEK2 , ZFP36L2 and EEF1A1 ) that we hypothesize are selected for in squamous epithelium irrespective of disease status. Finally, we describe a mutational signature of psoralens—a class of chemicals previously found in some sunscreens and which are used as part of PUVA (psoralens and ultraviolet-A) photochemotherapy treatment for psoriasis.

Atopic dermatitis (AD) is a common inflammatory skin condition and prior genome-wide association studies (GWAS) have identified 71 associated loci. In the current study we conducted the largest AD GWAS to date (discovery N = 1,086,394, replication N = 3,604,027), combining previously reported cohorts with additional available data. We identified 81 loci (29 novel) in the European-only analysis (which all replicated in a separate European analysis) and 10 additional loci in the multi-ancestry analysis (3 novel). Eight variants from the multi-ancestry analysis replicated in at least one of the populations tested (European, Latino or African), while two may be specific to individuals of Japanese ancestry. AD loci showed enrichment for DNAse I hypersensitivity and eQTL associations in blood. At each locus we prioritised candidate genes by integrating multi-omic data. The implicated genes are predominantly in immune pathways of relevance to atopic inflammation and some offer drug repurposing opportunities.

Several small studies have indicated that daily emollient use from birth might delay, suppress or prevent atopic dermatitis (AD). Two larger trials did not confirm this; however, a recent smaller study indicated a protective effect if daily emollient use is used in the first 2 months of life. Further research is needed to evaluate the effect of emollient use on development of AD. The current study randomly assigned 50 newborns who were at high risk of developing AD (1:1) to receive general infant skin-care advice (control group), or skin-care advice plus emollient with advice to apply emollient at least once daily until 1 year of age (intervention group). Repeated skin examinations, skin physiology measurements and skin microbiome profiling were performed. Of the children in the intervention and control groups, 28% and 24%, respectively, developed AD (adjusted Relative Risk (RR) 1.19, p = 0.65, adjusted risk difference 0.05). Skin pH decreased and transepidermal water loss and stratum corneum hydration increased over time in both groups with no significant differences. In the intervention group skin microbiome alpha diversity increased earlier, and the abundance of Streptococcus and Staphylococcus species were significantly reduced at month 1. Daily early emollient use in children with high risk of AD was safe, but it did not significantly reduce the risk of developing AD or impact skin physiology development.