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Background: The effectiveness of emollients for preventing atopic dermatitis/eczema is controversial. The Barrier Enhancement for Eczema Prevention trial evaluated the effects of daily emollients during the first year of life on atopic dermatitis and atopic conditions to age 5 years.Methods: 1394 term infants with a family history of atopic disease were randomized (1:1) to daily emollient plus standard skin-care advice (693 emollient group) or standard skin-care advice alone (701 controls). Long-term follow-up at ages 3, 4 and 5 years was via parental questionnaires. Main outcomes were parental report of a clinical diagnosis of atopic dermatitis and food allergy.Results: Parents reported more frequent moisturizer application in the emollient group through to 5 years. A clinical diagnosis of atopic dermatitis between 12 and 60 months was reported for 188/608 (31%) in the emollient group and 178/631 (28%) in the control group (adjusted relative risk 1.10, 95% confidence interval 0.93 to 1.30). Although more parents in the emollient group reported food reactions in the previous year at 3 and 4 years, cumulative incidence of doctor-diagnosed food allergy by 5 years was similar between groups (92/609 [15%] emollients and 87/632 [14%] controls, adjusted relative risk 1.11, 95% confidence interval 0.84 to 1.45). Findings were similar for cumulative incidence of asthma and hay fever.Conclusions: Daily emollient application during the first year of life does not prevent atopic dermatitis, food allergy, asthma or hay fever.

The promoting effect of FLG loss-of-function mutations on the development of atopic dermatitis (AD) signifies the role of filaggrin in the formation of a protective skin barrier; FLG mutations are also linked to asthma, food allergy and allergic rhinitis despite the absence of the protein in the affected tissues (lungs, intestines, and the majority of the nasal mucosa). AD patients suffer from chronic inflammation and recurrent skin infections; inflammation often precedes the appearance of spatially distant allergic manifestations. Here we show that exosome-enriched small extracellular vesicles (sEVs) secreted by filaggrin-knockdown keratinocytes are extensively remodelled as a consequence of the abnormal keratinocyte differentiation process. This alteration modulates the sEV capacity to promote type 1 and type 2 CD1a-dependent T cell responses by direct effects on self-lipid neoantigen generation; both modulating the amount of permissive (stimulatory) and non-permissive (inhibitory) CD1a ligands released from the sEV membranes by phospholipase A2. We found that this aberrant sEV lipid composition reflects a generalised cellular lipid bias with downregulation of multiple enzymes of lipid metabolic pathways, observed both in filaggrin knockdown keratinocytes in vitro, and in the skin of AD patients. Provision of modulatory ligands by sEVs secreted on a filaggrin insufficiency background, impeding both homeostatic autoreactive and protective antimicrobial CD1a-mediated type 1 and enhancing type 2 T cell responses provides basis for reduced tissue integrity and pathogen clearance and perpetuates inflammation in AD skin as well as in distant tissues to which sEVs are transferred by systemic circulation.

Background: few data exist on differences in treatment effectiveness and safety in atopic dermatitis patients of different skin types.Objective: to investigate treatment outcomes of dupilumab, methotrexate, and ciclosporin, and morphological phenotypes in atopic dermatitis patients, stratified by Fitzpatrick skin type.Methods: in an observational prospective cohort study, pooling data from the Dutch TREAT (TREatment of ATopic eczema) NL (treatregister.nl) and UK-Irish A-STAR (Atopic eczema Systemic TherApy Register; astar-register.org) registries, data on morphological phenotypes and treatment outcomes were investigated.Results: a total of 235 patients were included (light skin types [LST]: Fitzpatrick skin type 1-3, n = 156 [Ethnicity, White: 94.2%]; dark skin types [DST]: skin type 4-6, n = 68 [Black African/Afro-Caribbean: 25%, South-Asian: 26.5%, and Hispanics: 0%]). DST were younger (19.5 vs 29.0 years; P < .001), more often had follicular eczema (22.1% vs 2.6%; P < .001), higher baseline Eczema Area and Severity Index (EASI) scores (20.1 vs 14.9; P = .009), less allergic contact dermatitis (30.9% vs 47.4%; P = .03), and less previous phototherapy use (39.7% vs 59.0%; P = .008). When comparing DST and LST corrected for covariates including baseline EASI, DST showed greater mean EASI reduction between baseline and 6 months with only dupilumab (16.7 vs 9.7; adjusted P = .032). No differences were found for adverse events for any treatments (P > .05).Limitations: unblinded, non-randomized.Conclusions: atopic dermatitis differs in several characteristics between LST and DST. Skin type may influence treatment effectiveness of dupilumab.

Fingerprints are complex and individually unique patterns in the skin. Established prenatally, the molecular and cellular mechanisms that guide fingerprint ridge formation and their intricate arrangements are unknown. Here we show that fingerprint ridges are epithelial structures that undergo a truncated hair follicle developmental program and fail to recruit a mesenchymal condensate. Their spatial pattern is established by a Turing reaction-diffusion system, based on signaling between EDAR, WNT, and antagonistic BMP pathways. These signals resolve epithelial growth into bands of focalized proliferation under a precociously differentiated suprabasal layer. Ridge formation occurs as a set of waves spreading from variable initiation sites defined by the local signaling environments and anatomical intricacies of the digit, with the propagation and meeting of these waves determining the type of pattern that forms. Relying on a dynamic patterning system triggered at spatially distinct sites generates the characteristic types and unending variation of human fingerprint patterns.

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BACKGROUND: Palmar hyperlinearity is a feature of ichthyosis vulgaris, the monogenic skin disorder caused by FLG loss-of-function mutations.OBJECTIVE: To investigate how well the presence or absence of hyperlinear palms (HLP) detect FLG genotype in children.METHODS: STARD criteria are used to report this diagnostic accuracy study. Phenotype and genotype data (four most prevalent FLG null mutations) were obtained from a total of 3656 children in three studies: the UK CLOTHES trial (children 1-5 years with moderate-severe atopic eczema); UK BEEP trial (2-year-olds at high risk of developing atopic eczema); UK-Irish eczema case collection (0 to 16-year-olds with atopic eczema). All participants included in analyses of HLP as the index test and FLG genotype as the reference were of white European ancestry.RESULTS: 32% of participants (1159/3656) had FLG null mutation(s) and 37% (1347/3656) had HLP. In 13% (464/3656) HLP was recorded as 'unsure' or not recorded. The sensitivity and specificity of HLP for detecting FLG mutations in each of the studies was: 67% (95% CI 55-78%) and 75% (67-82%) in CLOTHES; 46% (36-55%) and 89% (86-91%) in BEEP; 72% (68-75%) and 60% (57-62%) in the UK-Irish case collection. Positive and negative likelihood ratios were: 2.73 (1.95-3.81) and 0.44 (0.31-0.62) in CLOTHES; 4.02 (2.99-5.40) and 0.61 (0.52-0.73) in BEEP; 1.79 (1.66-1.93) and 0.47 (0.42-0.53) in the UK-Irish collection.DISCUSSION: Trained observers were able to define palmar hyperlinearity in the majority (3191/3656, 87%) of cases. The presence of HLP is not a reliable sign to detect FLG mutations, but the absence of HLP excludes FLG null genotype with a reasonable degree of certainty. Registration This retrospective study was not pre-registered.

Background Atopic dermatitis (AD) is a common, complex, and highly heritable inflammatory skin disease. Genome-wide association studies offer opportunities to identify molecular targets for drug development. A risk locus on chromosome 11q13.5 lies between 2 candidate genes, EMSY and LRRC32 (leucine-rich repeat-containing 32) but the functional mechanisms affecting risk of AD remain unclear. Objectives We sought to apply a combination of genomic and molecular analytic techniques to investigate which genes are responsible for genetic risk at this locus and to define mechanisms contributing to atopic skin disease. Methods We used interrogation of available genomic and chromosome conformation data in keratinocytes, small interfering RNA (siRNA)–mediated knockdown in skin organotypic culture and functional assessment of barrier parameters, mass spectrometric global proteomic analysis and quantitative lipid analysis, electron microscopy of organotypic skin, and immunohistochemistry of human skin samples. Results Genomic data indicate active promoters in the genome-wide association study locus and upstream of EMSY; EMSY, LRRC32, and intergenic variants all appear to be within a single topologically associating domain. siRNA-knockdown of EMSY in organotypic culture leads to enhanced development of barrier function, reflecting increased expression of structural and functional proteins, including filaggrin and filaggrin-2, as well as long-chain ceramides. Conversely, overexpression of EMSY in keratinocytes leads to a reduction in markers of barrier formation. Skin biopsy samples from patients with AD show greater EMSY staining in the nucleus, which is consistent with an increased functional effect of this transcriptional control protein. Conclusion Our findings demonstrate an important role for EMSY in transcriptional regulation and skin barrier formation, supporting EMSY inhibition as a therapeutic approach., Graphical abstract

BackgroundObservational studies have reported an association between allergic disease and mental health, but a causal relationship has not been established.ObjectiveTo use Mendelian Randomization (MR) to investigate a possible causal relationship between atopic disease and mental health phenotypes.MethodsThe observational relationship between allergic disease and mental health was investigated in UK Biobank. The direction of causality was investigated with bidirectional two-sample MR using summary-level data from published genome-wide association studies. A genetic instrument was derived from associated variants for a broad allergic disease phenotype to test for causal relationships with various mental health outcomes. Genetic instruments were also derived for mental health conditions to assess causality in the reverse direction. We also investigated if these relationships were specific to atopic dermatitis (AD), asthma or hay fever.ResultsThe broad allergic disease phenotype was phenotypically associated with most measures of mental health, but we found little evidence of causality in either direction. However, we did find evidence of genetic liability for bipolar disorder causally influencing hay fever risk (OR=0.94 per doubling odds of bipolar disorder risk; 95%CI=0.90-0.99;P-value=0.02), but evidence of a phenotypic association was weak.ConclusionsFew of the phenotypic associations between allergic disease and mental health were replicated. Any causal effects we detected were considerably attenuated compared to the phenotypic association. This suggests that most co-morbidity observed clinically is unlikely to be causal.Clinical ImplicationWe found little evidence that genetic predisposition to allergic diseasecausesmental ill-health, andvice versa, which suggests that intervening to prevent onset of allergic disease is unlikely to directly prevent the onset of mental ill-health.Key MessagesMendelian randomization effect estimates suggest that the phenotypic association between allergic disease and mental health is likely to be inflatedCausal analysis was unable to corroborate the phenotypic associations observed between allergic disease and mental health phenotypesIntervening on an individual’s allergic disease is not likely to directly improve their mental healthCapsule summaryMendelian Randomization suggests that evidence of a causal relationship between allergic disease and mental health phenotypes is weak. It is unlikely that intervening to prevent onset of allergic disease will prevent poor mental health.

Atopic dermatitis (AD) is a common, complex trait, arising from the interplay of multiple genetic and environmental factors. This review provides an overview of developments in the field of AD genetics. AD shows high heritability; strategies to investigate genetic risk include linkage, candidate gene studies, genome-wide association and animal modelling. Loss-of-function mutations in FLG, encoding the skin barrier protein filaggrin, remain the strongest genetic risk factor identified for AD, but variants influencing skin and systemic immune function are also important. AD is at the forefront of genetic research, from large-scale population studies to in vitro models and detailed molecular analyses. An understanding of genetic risk factors has considerably improved knowledge of mechanisms leading to atopic skin inflammation. Together this work has identified avenues for therapeutic intervention, but further research is needed to fully realise the opportunities of personalised medicine for this complex disease, to optimise patient benefit.

BACKGROUND: Skin barrier dysfunction precedes eczema development. We tested whether daily use of emollient in the first year could prevent eczema in high-risk children.METHODS: We did a multicentre, pragmatic, parallel-group, randomised controlled trial in 12 hospitals and four primary care sites across the UK. Families were approached via antenatal or postnatal services for recruitment of term infants (at least 37 weeks' gestation) at high risk of developing eczema (ie, at least one first-degree relative with parent-reported eczema, allergic rhinitis, or asthma, diagnosed by a doctor). Term newborns with a family history of atopic disease were randomly assigned (1:1) to application of emollient daily (either Diprobase cream or DoubleBase gel) for the first year plus standard skin-care advice (emollient group) or standard skin-care advice only (control group). The randomisation schedule was created using computer-generated code (stratified by recruiting centre and number of first-degree relatives with atopic disease) and participants were assigned to groups using an internet-based randomisation system. The primary outcome was eczema at age 2 years (defined by UK working party criteria) with analysis as randomised regardless of adherence to allocation for participants with outcome data collected, and adjusting for stratification variables. This trial is registered with ISRCTN, ISRCTN21528841. Data collection for long-term follow-up is ongoing, but the trial is closed to recruitment.FINDINGS: 1394 newborns were randomly assigned to study groups between Nov 19, 2014, and Nov 18, 2016; 693 were assigned to the emollient group and 701 to the control group. Adherence in the emollient group was 88% (466 of 532) at 3 months, 82% (427 of 519) at 6 months, and 74% (375 of 506) at 12 months in those with complete questionnaire data. At age 2 years, eczema was present in 139 (23%) of 598 infants with outcome data collected in the emollient group and 150 (25%) of 612 infants in the control group (adjusted relative risk 0·95 [95% CI 0·78 to 1·16], p=0·61; adjusted risk difference -1·2% [-5·9 to 3·6]). Other eczema definitions supported the results of the primary analysis. Mean number of skin infections per child in year 1 was 0·23 (SD 0·68) in the emollient group versus 0·15 (0·46) in the control group; adjusted incidence rate ratio 1·55 (95% CI 1·15 to 2·09).INTERPRETATION: We found no evidence that daily emollient during the first year of life prevents eczema in high-risk children and some evidence to suggest an increased risk of skin infections. Our study shows that families with eczema, asthma, or allergic rhinitis should not use daily emollients to try and prevent eczema in their newborn.FUNDING: National Institute for Health Research Health Technology Assessment.

GWASs have revealed multiple loci associated with atopic dermatitis (AD). Some have confirmed pre-existing knowledge, including the role of skin barrier and type 2 inflammation in AD pathogenesis, whereas others have provided newer insights, including evidence of autoimmunity and previously unrecognized genes controlling epidermal differentiation. The majority of risk loci are in intergenic regions for which functional mechanism(s) remain unknown. These loci require detailed molecular studies carried out in cells and tissues of relevance to AD. Genomic findings to date account for ∼30% of AD heritability, therefore, considerable further work is needed to fully understand individual risk.

Summary Background Epidemiological studies indicate that gene–environment interactions play a role in atopic dermatitis (AD). Objectives To review the evidence for gene–environment interactions in AD aetiology, focusing on filaggrin (FLG) loss‐of‐function mutations. Methods A systematic search from inception to September 2018 in Embase, MEDLINE and BIOSIS was performed. Search terms included all synonyms for AD and filaggrin/FLG; any genetic or epidemiological study design using any statistical methods were included. Quality assessment using criteria modified from guidance (ROBINS‐I and Human Genome Epidemiology Network) for nonrandomized and genetic studies was completed, including consideration of power. Heterogeneity of study design and analyses precluded the use of meta‐analysis. Results Of 1817 papers identified, 12 studies fulfilled the inclusion criteria required and performed formal interaction testing. There was some evidence for FLG–environment interactions in six of the studies (P‐value for interaction ≤ 0·05), including early‐life cat ownership, older siblings, water hardness, phthalate exposure, higher urinary phthalate metabolite levels (which all increased AD risk additional to FLG null genotype) and prolonged breastfeeding (which decreased AD risk in the context of FLG null genotype). Major limitations of published studies were the low numbers of individuals (ranging from five to 94) with AD and FLG loss‐of‐function mutations and exposure to specific environmental factors, and variation in exposure definitions. Conclusions Evidence on FLG–environment interactions in AD aetiology is limited. However, many of the studies lacked large enough sample sizes to assess these interactions fully. Further research is needed with larger sample sizes and clearly defined exposure assessment. Linked Comment: Park and Seo. Br J Dermatol 2020; 183:411., What's already known about this topic? Gene–environment interactions are considered important in the aetiology of atopic dermatitis.Loss‐of-function mutations in the gene coding filaggrin (FLG) are the most consistently reported genetic variants for atopic dermatitis.Studies have reported evidence for gene–environment interaction involving FLG and a range of different environmental exposures. What does this study add? There is some evidence for FLG–environment interactions in the aetiology of atopic dermatitis; however, the evidence is limited.Studies lack large enough sample sizes to achieve adequate power in order to assess these interactions fully. Linked Comment: Park and Seo. Br J Dermatol 2020; 183:411. Plain language summary available online

Background: Atopic dermatitis (AD) is a prevalent disease with variable natural history. Longitudinal birth cohort studies provide an opportunity to define subgroups on the basis of disease trajectories, which may represent different genetic and environmental pathomechanisms.Objectives: We sought to investigate the existence of distinct longitudinal phenotypes of AD and test whether these findings are reproducible in 2 independent cohorts.Methods: The presence of AD was examined in 2 birth cohort studies including 9894 children from the United Kingdom (ALSPAC) and 3652 from the Netherlands (PIAMA). AD was defined by parental report of a typical itchy and/or flexural rash. Longitudinal latent class analysis was used to investigate patterns of AD from birth to the age of 11 to 16 years. We investigated associations with known AD risk factors, including FLG null mutations, 23 other established AD-genetic risk variants, and atopic comorbidity.Results: Six latent classes were identified, representing subphenotypes of AD, with remarkable consistency between the 2 cohorts. The most prevalent class was early-onset-early-resolving AD, which was associated with male sex. Two classes of persistent disease were identified (early-onset-persistent and early-onset-late-resolving); these were most strongly associated with the AD-genetic risk score as well as personal and parental history of atopic disease. A yet unrecognized class of mid-onset-resolving AD, not associated with FLG mutations, but strongly associated with asthma, was identified.Conclusions: Six classes based on temporal trajectories of rash were consistently identified in 2 population-based cohorts. The differing risk factor profiles and diverse prognoses demonstrate the potential importance of a stratified medicine approach for AD.

Background:Atopic eczema is an itchy inflammatory disorder characterised by skin barrier dysfunction. Loss-of-function mutations in the gene encoding filaggrin (FLG) are a major risk factor, but the mechanisms by which filaggrin haploinsufficiency leads to atopic inflammation remain incompletely understood. Skin as an organ that can be modelled using primary cellsin vitroprovides the opportunity for selected genetic effects to be investigated in detail.Methods:Primary human keratinocytes and donor-matched primary fibroblasts from healthy individuals were used to create skin organoid models with and without siRNA-mediated knockdown ofFLG. Biological replicate sets of organoids were assessed using histological, functional and biochemical measurements.Results:FLGknockdown leads to subtle changes in histology and ultrastructure including a reduction in thickness of the stratum corneum and smaller, less numerous keratohyalin granules. Immature organoids showed evidence of barrier impairment withFLGknockdown, but the mature organoids showed no difference in transepidermal water loss, water content or dye penetration. There was no difference in epidermal ceramide content. Mass spectrometry proteomic analysis detected >8000 proteins per sample. Gene ontology and pathway analyses identified an increase in transcriptional and translational activity but a reduction in proteins contributing to terminal differentiation, including caspase 14, dermokine, AKT1 and TGF-beta-1. Aspects of innate and adaptive immunity were represented in both the up-regulated and down-regulated protein groups, as was the term ‘axon guidance’. Conclusions:This work provides further evidence for keratinocyte-specific mechanisms contributing to immune and neurological, as well as structural, aspects of skin barrier dysfunction. Individuals with filaggrin deficiency may derive benefit from future therapies targeting keratinocyte-immune crosstalk and neurogenic pruritus.

Background The first International Society of Atopic Dermatitis (ISAD) global meeting dedicated to atopic dermatitis (AD) in Sub‐Saharan Africa (SSA) was held in Geneva, Switzerland in April 2019. A total of 30 participants were present at the meeting, including those from 17 SSA countries, representatives of the World Health Organization (WHO), the International Foundation for Dermatology (IFD) (a committee of the International League of Dermatological Societies, ILDS http://www.ilds.org), the Fondation pour la Dermatite Atopique, as well as specialists in telemedicine, artificial intelligence and therapeutic patient education (TPE). Results AD is one of the most prevalent chronic inflammatory skin diseases in SSA. Besides neglected tropical diseases (NTDs) with a dermatological presentation, AD requires closer attention from the WHO and national Departments of Health. Conclusions A roadmap has been defined with top priorities such as access to essential medicines and devices for AD care, in particular emollients, better education of primary healthcare workers for adequate triage (e.g. better educational materials for skin diseases in pigmented skin generally and AD in particular, especially targeted to Africa), involvement of traditional healers and to a certain extent also patient education, bearing in mind the barriers to effective healthcare faced in SSA countries such as travel distances to health facilities, limited resources and the lack of dermatological expertise. In addition, several initiatives concerning AD research in SSA were discussed and should be implemented in close collaboration with the WHO and assessed at follow‐up meetings, in particular, at the next ISAD meeting in Seoul, South Korea and African Society of Dermatology and Venereology (ASDV) meeting in Nairobi, Kenya, both in 2020.

Atopic dermatitis (AD) is a complex disease that is thought to be triggered by environmental factors in genetically susceptible individuals. Twin studies have estimated the heritability of AD to be approximately 75%, with the null (loss-of-function) mutations of the gene encoding filaggrin (FLG) (chromosome 1q21.3) as the strongest known genetic risk factor. The discovery of the filaggrin gene was important in the emerging model for AD pathogenesis, combining skin barrier function with adaptive and innate immunity. Assisted by the recent development of large-scale high-throughput genomics, more than 30 genetic loci have been linked to AD across different populations. Identification of these loci, together with functional studies, has already provided new insights into disease biology and identified novel drug targets. Further, these susceptibility loci are laying the groundwork for phenome-wide association studies to test their multiple phenotype relationships and application of Mendelian randomization to investigate causal relationships. Despite many known genes, a majority of the genetic risk for AD is yet unexplored. Therefore, studies investigating refined phenotype groups, low-frequency and rare genetic variation, gene-gene and/or gene-environment interactions, epigenetic mechanisms and data from multi-omics technologies are warranted. In this review, we describe genetic discoveries for AD, including results from candidate gene studies, studies of AD-like genetic diseases, genome-wide association studies and genetic sequencing studies. We explain how some of these genetic discoveries have unraveled new mechanistic insights into the pathogenesis of AD and exemplify how personal genetic data could be used for preventive strategies and a tailored treatment regimen (i.e., precision medicine).

Atopic eczema (synonymous with atopic dermatitis) is a common heterogeneous phenotype with a wide spectrum of severity, from mild transient disease to a severe chronic disorder with atopic and non-atopic comorbidities. Eczema is a complex trait, resulting from the interaction of multiple genetic and environmental factors. The skin, as an organ that can be biopsied easily, provides opportunities for detailed molecular genetic analysis. Strategies applied to the investigation of atopic eczema include candidate gene and genome-wide studies, extreme phenotypes, and comparative analysis of inflammatory skin diseases. Genetic studies have identified a central role for skin barrier impairment in eczema predisposition and perpetuation; this has brought about a paradigm shift in understanding atopic disease, but specific molecular targets to improve skin barrier function remain elusive. The role of Th2-mediated immune dysfunction is also central to atopic inflammation, and has proved to be a powerful target for biological therapy in atopic eczema. Advances in understanding eczema pathogenesis have provided opportunities for patient stratification, primary prevention, and therapy development, but there remain considerable challenges in the application of this knowledge to optimize benefit for patients with atopic eczema in the era of personalized medicine. Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Atopic dermatitis (AD) is a prevalent disease worldwide and is associated with systemic comorbidities representing a significant burden on patients, their families, and society. Therapeutic options for AD remain limited, in part because of a lack of well-characterized animal models. There has been increasing interest in developing experimental approaches to study the pathogenesis of human AD in vivo, in vitro, and in silico to better define pathophysiologic mechanisms and identify novel therapeutic targets and biomarkers that predict therapeutic response. This review critically appraises a range of models, including genetic mutations relevant to AD, experimental challenge of human skin in vivo, tissue culture models, integration of “omics” data sets, and development of predictive computational models. Although no one individual model recapitulates the complex AD pathophysiology, our review highlights insights gained into key elements of cutaneous biology, molecular pathways, and therapeutic target identification through each approach. Recent developments in computational analysis, including application of machine learning and a systems approach to data integration and predictive modeling, highlight the applicability of these methods to AD subclassification (endotyping), therapy development, and precision medicine. Such predictive modeling will highlight knowledge gaps, further inform refinement of biological models, and support new experimental and systems approaches to AD. (J Allergy Clin Immunol 2019;143:36–45.)

Transepidermal water loss (TEWL) is the most widely used objective measurement for assessing the barrier function of skin in healthy individuals but also patients with skin diseases that are associated with skin barrier dysfunction, such as atopic dermatitis. TEWL is the quantity of condensed water that diffuses across a fixed area of stratum corneum to the skin surface per unit time. The water evaporating from the skin is measured using a probe that is placed in contact with the skin surface and contains sensors that detect changes in water vapor density. TEWL can be measured using an open-chamber, unventilated-chamber, or condenser-chamber device. It is a sensitive measure that is affected by properties of the surrounding microclimate such as environmental humidity, temperature, and airflow and should be measured under controlled conditions. TEWL varies significantly across different anatomical sites and also depends on sweat gland activity, skin temperature, and corneocyte properties. Here we describe how to optimally use TEWL measurements as a skin research tool in vivo and in vitro.

ObjectivePsoriasis and eczema are common inflammatory skin diseases that have been reported to be associated with obesity. However, causality has not yet been established. We aimed to investigate the possible causal relationship between body mass index (BMI) and psoriasis or eczema.MethodsFollowing a review of published epidemiological evidence of the association between obesity and either psoriasis or eczema, Mendelian Randomization (MR) was used to test for a causal relationship between BMI and these inflammatory skin conditions. We used a genetic instrument comprising 97 single nucleotide polymorphisms (SNPs) associated with BMI. One-sample MR was conducted using individual-level data (401,508 individuals) from the UK Biobank and the Nord-Trøndelag Health Study (HUNT), Norway. Two-sample MR was performed with summary-level data (731,021 individuals) from published BMI, psoriasis and eczema GWAS. The one-sample and two-sample MR estimates were meta-analysed using a fixed effect model. To explore the reverse causal direction, MR analysis with genetic instruments comprising variants from recent genome-wide analyses for psoriasis and eczema were used to test if inflammatory skin disease has a causal effect on BMI.ResultsPublished observational data show an association of greater BMI with both psoriasis and eczema case status. The observational associations were confirmed in UK Biobank and HUNT datasets. MR analyses provide evidence that higher BMI causally increases the odds of psoriasis (by 53% per 5 units higher BMI; OR= 1.09 (1.06 to 1.12) per 1 kg/m2; P=4.67×10-9) and eczema (by 8% per 5 units higher BMI; OR=1.02 (1.00 to 1.03) per 1 kg/m2; P=0.09). When investigating causality in the opposite direction, MR estimates provide little evidence for an effect of either psoriasis or eczema influencing BMI.ConclusionOur study, using genetic variants as instrumental variables for BMI, shows that higher BMI leads to a higher risk of inflammatory skin disease. The causal relationship was stronger for psoriasis than eczema. Therapies and life-style interventions aimed at controlling BMI or targeting the mechanisms linking obesity with skin inflammation may offer an opportunity for the prevention or treatment of these common skin diseases.

Funding: Wellcome Trust [Grant number 104241/z/14/z] (CPH). Scottish Infection Research Network and Chief Scientist Office through the Scottish Healthcare Associated Infection Prevention Institute consortium funding [CSO Reference: SIRN10] (MTGH, KAP, KO). Bioinformatics and Computational Biology analyses were supported by the University of St Andrews Bioinformatics Unit that is funded by a Wellcome Trust ISSF award [grant 097831/Z/11/Z]. Wellcome Trust grant 098051 (JP, MTGH). Biotechnology and Biological Sciences Research Council grant BB/M014088/1 (AEM). Wellcome Trust Senior Research Fellowship in Clinical Science [106865/Z/15/Z] (SJB). Staphylococcus aureus is an opportunistic pathogen and variable component of the human microbiota. In atopic eczema (AE) a characteristic of the disease is colonization by S. aureus, with exacerbations associated with an increased bacterial burden of the organism. Despite this, the origins and genetic diversity of S. aureus colonizing individual patients during AE disease flares is poorly understood. To examine the micro-evolution of S. aureus colonization we have deep-sequenced S. aureus populations from nine children with moderate to severe AE, and 18 non-atopic children asymptomatically carrying S. aureus nasally. Colonization by clonal S. aureus populations was observed in both AE cases and controls, with all but one of the individuals containing colonies belonging to a single sequence type. Phylogenetic analysis revealed that disease flares were associated with the clonal expansion of the S. aureus population, occurring over a period of weeks to months. There was a significant difference in the genetic backgrounds of S. aureus colonizing AE patients versus controls (Fisher’s Exact test, p=0.03). Examination of intra-host genetic heterogeneity of the colonizing S. aureus populations identified evidence of within-host selection in the AE patients, with AE variants being potentially selectively advantageous for intracellular persistence and treatment resistance. Publisher PDF

Background: Translational research is the direct application of basic and applied research to patient care. It is estimated that there are at least 2,000 different skin diseases, thus there are considerable challenges in seeking to undertake research on each of these disorders.Objective: This eDelphi exercise was conducted in order to generate a list of translational dermatology research questions which are regarded as a priority for further investigations.Results: During the first phase of the eDelphi, 228 research questions were generated by an expert panel which included clinical academic dermatologists, clinical dermatologists, non-clinical scientists, dermatology trainees and representatives from patient support groups. Following completion of the second and third phases, 40 questions on inflammatory skin disease, 20 questions on structural skin disorders/genodermatoses, 37 questions on skin cancer and 8 miscellaneous questions were designated as priority translational dermatology research questions (PRQs). In addition to PRQs on a variety of disease areas (including multiple PRQs on psoriasis, eczema, squamous cell carcinoma (SCC) and melanoma), there were a number of cross-cutting themes which identified a need to investigate mechanisms/pathogenesis of disease and the necessity to improve treatments for patients with skin disease. Conclusion: It is predicted that this list of PRQs will help to provide a strategic direction for translational dermatology research in the UK and that addressing this list of questions will ultimately provide clinical benefit for substantial numbers of subjects with skin disorders.

Background Atopic eczema (AE) is a common skin problem that impairs quality of life and is associated with the development of other atopic diseases including asthma, food allergy and allergic rhinitis. AE treatment is a significant cost burden for health care providers. The purpose of the trial is to investigate whether daily application of emollients for the first year of life can prevent AE developing in high-risk infants (first-degree relative with asthma, AE or allergic rhinitis). Methods This is a protocol for a pragmatic, two-arm, randomised controlled, multicentre trial. Up to 1400 term infants at high risk of developing AE will be recruited through the community, primary and secondary care in England. Participating families will be randomised in a 1:1 ratio to receive general infant skin-care advice, or general skin-care advice plus emollients with advice to apply daily to the infant for the first year of life. Families will not be blinded to treatment allocation. The primary outcome will be a blinded assessment of AE at 24 months of age using the UK Working Party Diagnostic Criteria for Atopic Eczema. Secondary outcomes are other definitions of AE, time to AE onset, severity of AE (EASI and POEM), presence of other allergic diseases including food allergy, asthma and hay fever, allergic sensitisation, quality of life, cost-effectiveness and safety of the emollients. Subgroup analyses are planned for the primary outcome according to filaggrin genotype and the number of first-degree relatives with AE and other atopic diseases. Families will be followed up by online and postal questionnaire at 3, 6, 12 and 18 months with a face-to-face visit at 24 months. Long-term follow-up until 60 months will be via annual questionnaires. Discussion This trial will demonstrate whether skin-barrier enhancement through daily emollient for the first year of life can prevent AE from developing in high-risk infants. If effective, this simple and cheap intervention has the potential to result in significant cost savings for health care providers throughout the world by preventing AE and possibly other associated allergic diseases. Trial registration ISRCTN registry; ID: ISRCTN21528841. Registered on 25 July 2014. Electronic supplementary material The online version of this article (doi:10.1186/s13063-017-2031-3) contains supplementary material, which is available to authorized users.

BackgroundAtopic eczema (AE) is a chronic, itchy, inflammatory skin condition that affects the quality of life of children and their families. The role of specialist clothing in the management of AE is poorly understood.ObjectivesTo assess the effectiveness and cost-effectiveness of silk garments for the management of AE in children with moderate to severe disease.DesignParallel-group, observer-blind, randomised controlled trial of 6 months’ duration, followed by a 2-month observational period. A nested qualitative study evaluated the beliefs of trial participants, health-care professionals and health-care commissioners about the use of silk garments for AE.SettingSecondary care and the community in five UK centres.ParticipantsChildren aged 1–15 years with moderate or severe AE.InterventionsParticipants were randomised (1 : 1 using online randomisation) to standard care or standard care plus 100% silk garments made from antimicrobially protected knitted sericin-free silk [DermaSilkTM(AlPreTec Srl, San Donà di Piave, Italy) or DreamSkinTM(DreamSkin Health Ltd, Hatfield, UK)]. Three sets of garments were supplied per participant, to be worn for up to 6 months (day and night). At 6 months the standard care group received the garments to use for the remaining 2-month observational period.Main outcome measuresPrimary outcome – AE severity using the Eczema Area and Severity Index (EASI) assessed at 2, 4 and 6 months, by nurses blinded to treatment allocation. EASI scores were log-transformed for analysis. Secondary outcomes – patient-reported eczema symptoms (Patient Oriented Eczema Measure); global assessment of severity (Investigator Global Assessment); quality of life of the child (Atopic Dermatitis Quality of Life, Child Health Utility – 9 Dimensions), family (Dermatitis Family Impact Questionnaire) and main carer (EuroQoL-5 Dimensions-3 Levels); use of standard eczema treatments (e.g. emollients, topical corticosteroids); and cost-effectiveness. The acceptability and durability of the clothing, and adherence to wearing the garments, were assessed by parental/carer self-report. Safety outcomes – number of skin infections and hospitalisations for AE.ResultsA total of 300 children were randomised (26 November 2013 to 5 May 2015): 42% female, 79% white, mean age 5 years. The primary analysis included 282 out of 300 (94%) children (n = 141 in each group). Garments were worn for at least 50% of the time by 82% of participants. Geometric mean EASI scores at baseline, 2, 4 and 6 months were 8.4, 6.6, 6.0, 5.4 for standard care and 9.2, 6.4, 5.8, 5.4 for silk clothing, respectively. There was no evidence of difference between the groups in EASI score averaged over all follow-up visits adjusted for baseline EASI score, age and centre (ratio of geometric means 0.95, 95% confidence interval 0.85 to 1.07;p = 0.43). This confidence interval is equivalent to a difference of –1.5 to 0.5 in the original EASI scale units. Skin infections occurred in 39 out of 141 (28%) and 36 out of 142 (25%) participants for standard care and silk clothing groups, respectively. The incremental cost per QALY of silk garments for children with moderate to severe eczema was £56,811 from a NHS perspective in the base case. Sensitivity analyses supported the finding that silk garments do not appear to be cost-effective within currently accepted thresholds.LimitationsKnowledge of treatment allocation may have affected behaviour and outcome reporting for some of the patient-reported outcomes.ConclusionsThe addition of silk garments to standard AE care is unlikely to improve AE severity, or to be cost-effective compared with standard care alone, for children with moderate or severe AE. This trial adds to the evidence base to guide clinical decision-making.Future workNon-pharmacological interventions for the management of AE remain a research priority among patients.Trial registrationCurrent Controlled Trials ISRCTN77261365.FundingThis project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full inHealth Technology Assessment; Vol. 21, No. 16. See the NIHR Journals Library website for further project information.

Background The role of clothing in the management of eczema (also called atopic dermatitis or atopic eczema) is poorly understood. This trial evaluated the effectiveness and cost-effectiveness of silk garments (in addition to standard care) for the management of eczema in children with moderate to severe disease. Methods and findings This was a parallel-group, randomised, controlled, observer-blind trial. Children aged 1 to 15 y with moderate to severe eczema were recruited from secondary care and the community at five UK medical centres. Participants were allocated using online randomisation (1:1) to standard care or to standard care plus silk garments, stratified by age and recruiting centre. Silk garments were worn for 6 mo. Primary outcome (eczema severity) was assessed at baseline, 2, 4, and 6 mo, by nurses blinded to treatment allocation, using the Eczema Area and Severity Index (EASI), which was log-transformed for analysis (intention-to-treat analysis). A safety outcome was number of skin infections. Three hundred children were randomised (26 November 2013 to 5 May 2015): 42% girls, 79% white, mean age 5 y. Primary analysis included 282/300 (94%) children (n = 141 in each group). The garments were worn more often at night than in the day (median of 81% of nights [25th to 75th centile 57% to 96%] and 34% of days [25th to 75th centile 10% to 76%]). Geometric mean EASI scores at baseline, 2, 4, and 6 mo were, respectively, 9.2, 6.4, 5.8, and 5.4 for silk clothing and 8.4, 6.6, 6.0, and 5.4 for standard care. There was no evidence of any difference between the groups in EASI score averaged over all follow-up visits adjusted for baseline EASI score, age, and centre: adjusted ratio of geometric means 0.95, 95% CI 0.85 to 1.07, (p = 0.43). This confidence interval is equivalent to a difference of −1.5 to 0.5 in the original EASI units, which is not clinically important. Skin infections occurred in 36/142 (25%) and 39/141 (28%) of children in the silk clothing and standard care groups, respectively. Even if the small observed treatment effect was genuine, the incremental cost per quality-adjusted life year was £56,811 in the base case analysis from a National Health Service perspective, suggesting that silk garments are unlikely to be cost-effective using currently accepted thresholds. The main limitation of the study is that use of an objective primary outcome, whilst minimising detection bias, may have underestimated treatment effects. Conclusions Silk clothing is unlikely to provide additional benefit over standard care in children with moderate to severe eczema. Trial registration Current Controlled Trials ISRCTN77261365, In a randomized controlled trial, Kim Suzanne Thomas and colleagues examine the effectiveness of silk garments vs. standard care for treating eczema in children., Author summary Why was this study done? Prior to this trial, evidence on the use of silk garments for the management of eczema was limited. Three randomised controlled trials (RCTs) had been conducted, but these were small (74 participants in total) and at risk of bias. The existing evidence was insufficient to guide clinical practice on the use of silk clothing in the management of eczema, and no cost-effectiveness analyses had been undertaken. What did the researchers do and find? We conducted a pragmatic, observer-blind RCT that recruited 300 children with moderate to severe eczema and followed them for six months. Participants were randomised to receive standard eczema care plus silk clothing (100% sericin-free silk garments; DermaSilk or DreamSkin) or standard care alone. After six months, there was no evidence of a difference between the groups in eczema severity (Eczema Area and Severity Index score) assessed by research nurses; the 95% confidence interval ranged from 1.5 points favouring silk clothing to 0.5 points favouring standard care, which is not a clinically important difference. Even if the potential small benefit of silk garments was genuine, our analysis suggests that they are unlikely to be cost-effective within currently accepted thresholds, with an incremental cost per quality-adjusted life year of £56,811. What do these findings mean? The CLOTHES Trial is the first large, independent RCT to have evaluated silk garments for the management of eczema. The results of this trial suggest that silk garments are unlikely to provide additional clinical or economic benefits over standard care for children with moderate to severe eczema. These results provide robust evidence for health commissioners and prescribers to make informed clinical decisions.

Contains fulltext : 177111.pdf (Publisher’s version ) (Closed access) BACKGROUND: Although most patients with atopic dermatitis (AD) are effectively managed with topical medication, a significant minority require systemic therapy. Guidelines for decision making about advancement to systemic therapy are lacking. OBJECTIVE: To guide those considering use of systemic therapy in AD and provide a framework for evaluation before making this therapeutic decision with the patient. METHODS: A subgroup of the International Eczema Council determined aspects to consider before prescribing systemic therapy. Topics were assigned to expert reviewers who performed a topic-specific literature review, referred to guidelines when available, and provided interpretation and expert opinion. RESULTS: We recommend a systematic and holistic approach to assess patients with severe signs and symptoms of AD and impact on quality of life before systemic therapy. Steps taken before commencing systemic therapy include considering alternate or concomitant diagnoses, avoiding trigger factors, optimizing topical therapy, ensuring adequate patient/caregiver education, treating coexistent infection, assessing the impact on quality of life, and considering phototherapy. LIMITATIONS: Our work is a consensus statement, not a systematic review. CONCLUSION: The decision to start systemic medication should include assessment of severity and quality of life while considering the individual's general health status, psychologic needs, and personal attitudes toward systemic therapies.

Background Atopic dermatitis (atopic eczema) is a chronic inflammatory skin disease that has reached epidemic proportions in children worldwide and is increasing in prevalence. Because of the significant socioeconomic effect of atopic dermatitis and its effect on the quality of life of children and families, there have been decades of research focused on disease prevention, with limited success. Recent advances in cutaneous biology suggest skin barrier defects might be key initiators of atopic dermatitis and possibly allergic sensitization. Objective Our objective was to test whether skin barrier enhancement from birth represents a feasible strategy for reducing the incidence of atopic dermatitis in high-risk neonates. Methods We performed a randomized controlled trial in the United States and United Kingdom of 124 neonates at high risk for atopic dermatitis. Parents in the intervention arm were instructed to apply full-body emollient therapy at least once per day starting within 3 weeks of birth. Parents in the control arm were asked to use no emollients. The primary feasibility outcome was the percentage of families willing to be randomized. The primary clinical outcome was the cumulative incidence of atopic dermatitis at 6 months, as assessed by a trained investigator. Results Forty-two percent of eligible families agreed to be randomized into the trial. All participating families in the intervention arm found the intervention acceptable. A statistically significant protective effect was found with the use of daily emollient on the cumulative incidence of atopic dermatitis with a relative risk reduction of 50% (relative risk, 0.50; 95% CI, 0.28-0.9; P = .017). There were no emollient-related adverse events and no differences in adverse events between groups. Conclusion The results of this trial demonstrate that emollient therapy from birth represents a feasible, safe, and effective approach for atopic dermatitis prevention. If confirmed in larger trials, emollient therapy from birth would be a simple and low-cost intervention that could reduce the global burden of allergic diseases.

Streszczenie Wprowadzenie Atopowe zapalenie skory (wyprysk atopowy) jest przewleklą zapalną chorobą skory, ktora na calym świecie przybiera rozmiar epidemii wśrod dzieci, z ciągle zwiekszającą sie zachorowalnością. Z uwagi na istotny wplyw atopowego zapalenia skory spoleczno-ekonomiczny i na jakośc zycia chorych dzieci oraz ich rodzin, przez cale dekady prowadzono badania kliniczne skoncentrowane na zapobieganiu chorobie, z ograniczonym skutkiem. Ostatnie postepy wiedzy na temat biologii skory sugerują, ze zaburzenia bariery skornej mogą byc kluczowymi czynnikami inicjującymi atopowe zapalenie skory i byc moze uczulenie na alergeny. Cel Celem badania bylo sprawdzenie, czy wsparcie bariery skornej od urodzenia jest skuteczną strategią zmniejszenia czestości wystepowania atopowego zapalenia skory u noworodkow z wysokim ryzykiem. Metody Przeprowadzono w Stanach Zjednoczonych i Wielkiej Brytanii kontrolowane badanie kliniczne z randomizacją u 124 noworodkow z wysokim ryzykiem atopowego zapalenia skory. Rodzicow dzieci w ramieniu eksperymentalnym poinstruowano o stosowaniu na cale cialo środka zmiekczającego co najmniej raz dziennie, rozpoczynając w ciągu 3 tygodni od urodzenia. Rodzice w ramieniu kontrolnym byli proszeni o niestosowanie środkow zmiekczających. Glownym miernikiem wykonalności badania byl odsetek rodzin wyrazających zgode na randomizacje. Pierwszorzedowym wynikiem klinicznym byla skumulowana czestośc atopowego zapalenia skory po 6 miesiącach, oceniana przez wyszkolonego badacza. Wyniki Ogolem 42% kwalifikujących sie rodzin wyrazilo zgode na randomizacje do badania. Wszystkie rodziny uczestniczące w ramieniu eksperymentalnym uznaly badaną interwencje za akceptowalną. Wykazano statystycznie istotny efekt zapobiegawczy po codziennym stosowaniu środka zmiekczającego w zakresie skumulowanej czestości wystepowania atopowego zapalenia skory, ze zmniejszeniem ryzyka wzglednego o 50% (ryzyko wzgledne 0,50; 95% CI, 0,28–0,9; p = 0,017). Nie odnotowano zadnych dzialan niepoządanych związanych ze stosowaniem środka zmiekczającego, a takze zadnych roznic dotyczących dzialan niepoządanych pomiedzy grupami badanymi. Wnioski Wyniki badania wykazują, ze stosowanie środka zmiekczającego od urodzenia stanowi wykonalną, bezpieczną i skuteczną strategie zapobiegania atopowemu zapaleniu skory. Jeśli zostanie to potwierdzone w wiekszych badaniach, stosowanie środkow zmiekczających od urodzenia staloby sie prostą i niską kosztowo interwencją, pozwalającą na zmniejszenie globalnego rozprzestrzenienia chorob alergicznych.

Background Psoriasis is a common inflammatory skin disease that has been reported to be associated with obesity. We aimed to investigate a possible causal relationship between body mass index (BMI) and psoriasis. Methods and findings Following a review of published epidemiological evidence of the association between obesity and psoriasis, mendelian randomization (MR) was used to test for a causal relationship with BMI. We used a genetic instrument comprising 97 single-nucleotide polymorphisms (SNPs) associated with BMI as a proxy for BMI (expected to be much less confounded than measured BMI). One-sample MR was conducted using individual-level data (396,495 individuals) from the UK Biobank and the Nord-Trøndelag Health Study (HUNT), Norway. Two-sample MR was performed with summary-level data (356,926 individuals) from published BMI and psoriasis genome-wide association studies (GWASs). The one-sample and two-sample MR estimates were meta-analysed using a fixed-effect model. To test for a potential reverse causal effect, MR analysis with genetic instruments comprising variants from recent genome-wide analyses for psoriasis were used to test whether genetic risk for this skin disease has a causal effect on BMI. Published observational data showed an association of higher BMI with psoriasis. A mean difference in BMI of 1.26 kg/m2 (95% CI 1.02–1.51) between psoriasis cases and controls was observed in adults, while a 1.55 kg/m2 mean difference (95% CI 1.13–1.98) was observed in children. The observational association was confirmed in UK Biobank and HUNT data sets. Overall, a 1 kg/m2 increase in BMI was associated with 4% higher odds of psoriasis (meta-analysis odds ratio [OR] = 1.04; 95% CI 1.03–1.04; P = 1.73 × 10−60). MR analyses provided evidence that higher BMI causally increases the odds of psoriasis (by 9% per 1 unit increase in BMI; OR = 1.09 (1.06–1.12) per 1 kg/m2; P = 4.67 × 10−9). In contrast, MR estimates gave little support to a possible causal effect of psoriasis genetic risk on BMI (0.004 kg/m2 change in BMI per doubling odds of psoriasis (−0.003 to 0.011). Limitations of our study include possible misreporting of psoriasis by patients, as well as potential misdiagnosis by clinicians. In addition, there is also limited ethnic variation in the cohorts studied. Conclusions Our study, using genetic variants as instrumental variables for BMI, provides evidence that higher BMI leads to a higher risk of psoriasis. This supports the prioritization of therapies and lifestyle interventions aimed at controlling weight for the prevention or treatment of this common skin disease. Mechanistic studies are required to improve understanding of this relationship., In a mendelian randomization study, Ashley Budu-Aggrey and co-workers study the influence of body mass index on psoriasis., Author summary Why was this study done? Psoriasis is a common inflammatory skin disease that has been reported to be associated with obesity. However, the direction of causality has not been established. Understanding the causal relationship could inform the management or prevention of disease. What did the researchers do and find? A mendelian randomization (MR) approach was used to investigate the causal relationship between higher body mass index (BMI) and psoriasis. Our analysis included data for a total of 753,421 individuals from two of the largest population-based studies available as well as published genome-wide association studies (GWASs). We found evidence that higher BMI causally increases the risk of psoriasis, supporting observational reports in previous literature. Conversely, there was no evidence to support a causal effect of psoriasis genetic risk upon BMI. What do these findings mean? Our findings suggest that obesity contributes to the pathogenesis of psoriasis, and highlight possible mechanistic relationships. If our findings regarding genetically influenced BMI can be extended to elevated BMI that is amenable to modification by diet or behavior, then they could carry health implications. Further work will be required to determine the effect of a short-term intervention aimed at reducing BMI upon psoriasis patients after disease onset, ideally within a clinical trial setting.