In this research letter, we introduce the Inflammatory Skin Diseases (ISD) map, a visual and computational representation of a molecular interaction network of molecular mechanisms of atopic dermatitis (AD) and psoriasis (PsO) (https://disease-maps.io/isd/). This knowledge repository can be used as a graphical review, to visualize complex omics data, or as a simulation testbed for research hypotheses. The purpose of the ISD map is to represent key molecular mechanisms of AD and PsO, facilitating information search and data interpretation, and supporting computational analyses.

INTRODUCTION:Using the James Lind Alliance (JLA) methodology, we established a Priority Setting Partnership (PSP) to identify the most important unanswered research questions in childhood food allergy. This approach places those directly affected, those with food allergy, their parents/carers, and healthcare professionals at the centre of the process. METHODS:A multidisciplinary steering group (n = 19 people) oversaw the PSP. Research uncertainties were collected through a UK-wide online survey distributed to children, young people and adults with food allergy, their parents/carers, and healthcare professionals working in food allergy. A focus group was conducted with seven children aged 8-11 years with food allergy to ensure inclusion of their perspectives. Submitted questions were reviewed, combined into summary questions, and checked against existing evidence to confirm that they represented genuine uncertainties. An interim prioritisation survey was used to rank questions, with equal weighting given to each stakeholder group. A final facilitated workshop used a nominal group technique to agree on the top 10 research priorities. RESULTS:In total, 916 respondents submitted 2563 questions. After removing out-of-scope and already answered questions, an interim prioritisation survey was completed by 1087 participants. The final workshop involved 29 participants, including young people (n = 3), young adults (n = 4), parents (n = 7) and multidisciplinary healthcare professionals (n = 15), who agreed on the top 10 questions. These cover prevention, early diagnosis, treatment, causes, eating out, safety in care settings, impact, emergency treatment, and awareness of food allergy. There was strong consensus from the final workshop across all attendees that prevention should be the number one priority. CONCLUSION:Using a rigorous, transparent, and person-centred approach, we have identified the most important research priorities in childhood food allergy. They highlight the depth and breadth of research required to improve the prevention, diagnosis, treatment, and broader impacts of food allergy on children, families, and carers who live with this condition.

Abstract Introduction and aims Hand cleansing is a common hygiene practice to reduce the spread of infectious disease. However, frequent use of surfactant cleansers and ethanol sanitizers, can result in dermatitis. This work aimed to understand how skin exposure to sodium dodecyl sulfate (SDS) and ethanol damages the skin and compromises skin barrier function. Methods Porcine underbelly skin was exposed for 1 h to SDS solutions (0.1–10%), or 85% ethanol, with or without rinsing. Changes in skin wettability was determined from the contact angle of water on the treated skin. Attenuated total reflectance Fourier transform infrared (ATR-FTIR) spectra of the outer layers of skin exposed to deuterated SDS or ethanol were collected by placing the treated skin on an ATR crystal. To collect spectra as a function of skin depth sequential layers of stratum corneum (SC) were removed by tape stripping. Results Contact angle measurements of water on skin demonstrated a dose-dependent decrease after SDS exposure, indicating a more hydrophilic surface; this was partially recovered for lower SDS concentrations by rinsing with water. In contrast, ethanol exposure increased the contact angle of water on skin, indicating the skin surface was more hydrophobic. ATR-FTIR spectra of tape-stripped skin showed a dose-dependent SDS penetration, which was not removed by rinsing. Ethanol also penetrated the SC but to a lesser extent. Conclusions Skin exposure to both SDS and ethanol alter the surface properties (wettability) of stratum corneum, which will affect the spreading and permeation of exogenous materials. Both SDS and ethanol penetrated several microns into the SC. In future work, the porcine model developed in these studies will be extended to assess the accumulative effects of chronic cleansing and methods applied to human explant and organoid models to test genetic effects on barrier resilience.

Declining tissue function and regenerative capacity underlie many chronic diseases. Experimentally establishing the mechanistic basis for such tissue aging presents substantial challenges, given decades-long timescales and multifactorial origins. Epigenetic alterations have been proposed to have a key etiological role, but whether they are correlative or causal remains a key unanswered question, as does their contribution to specific age-related pathologies. Here we describe an epigenetically driven accelerated aging syndrome. We demonstrate that DNMT3A gain-of-function mutations in Heyn-Sproul-Jackson syndrome recapitulate age-related gains in DNA methylation (DNAme), cause multilineage stem cell dysfunction, and phenocopy aspects of aging in humans and mice. We also show that region-specific DNA hypermethylation at lineage-specific genes can explain reduced stem cell output and lineage skewing. Hence, starting from a Mendelian disorder, we implicate DNAme-mediated stem cell dysfunction in the etiology of medically important age-related hematological, bone and metabolic pathologies, which might be targetable by future therapies.

Background:Managing patients with moderate-to-severe atopic eczema (AE) is challenging. Novel systemic immunomodulatory therapies are effective but costly, whereas conventional treatments require more intense safety monitoring. While available randomized trials assess efficacy, they do not reflect real-world practice or cost-effectiveness. The UK-Irish Atopic Eczema Systemic Therapy Register (A-STAR) was established to generate real-world evidence on systemic AE treatments. Objectives:To assess healthcare resource utilization, costs and health-related quality of life (HRQoL) over 1 year in participants in A-STAR, and to evaluate data quality in a pilot analysis. Methods:A-STAR is a multicentre prospective register that recruits paediatric (aged <16 years) and adult (aged ≥16 years) patients with AE who are initiating or switching systemic immunomodulatory therapy. Healthcare utilization [general practitioner (GP) visits, accident and emergency (A&E) department attendance, hospitalizations, specialist consultations and therapy costs] was valued using national average unit costs and tariffs. HRQoL was measured with the EuroQol 5 Dimension (EQ-5D). Results:Of 120 participants (92 adults and 28 children) with a median follow-up to 12 months, adults had higher mean healthcare costs per year than children, including A&E (£120.41 vs. £84.29), GP (£111.15 vs. £78.46) and specialist (£205.17 vs. £121.00) visits. Mean (SD) systemic therapy costs per year were £25 523 (£24 424) in adults and £20 242 (£18 994) in children, averaged across all treatment options. Mean EQ-5D scores improved from baseline to 1 year (from 0.608 to 0.769 in adults and from 0.482 to 0.751 in children). Conclusions:Systemic therapy improved HRQoL but incurred notable costs. A-STAR is well positioned to support future comparative economic evaluations of alternative treatment strategies to inform clinical and reimbursement decisions.

This is a secondary analysis of a multicentre randomized controlled trial of ciclosporin and methotrexate in children and young people (CYP) with severe atopic dermatitis (AD). Longitudinal trough ciclosporin and erythrocyte methotrexate polyglutamate (MTX-PG) concentrations were measured to evaluate their associations with treatment response and adverse events. Both ciclosporin (4 mg kg-1 daily) and methotrexate (0.4 mg kg-1 weekly) led to a significant reduction in disease severity scores over the 36-week treatment period. Higher trough ciclosporin concentrations were associated with lower disease severity scores and may serve as a useful tool for therapeutic drug monitoring of ciclosporin in CYP with AD. However, in contrast to a previously published study, steady-state erythrocyte-MTX-PG concentrations showed no significant association with treatment response. Drug concentrations were comparable between patients with and without drug-related adverse events.

Background:Environmental factors play a role in the pathogenesis of complex traits including atopic eczema (AE) and a greater understanding of gene-environment interactions (G*E) is needed to define pathomechanisms for disease prevention. We analysed data from 16 European studies to test for interaction between the 24 most significant AE-associated loci identified from genome-wide association studies and 18 early-life environmental factors. We tested for replication using a further 10 studies and in vitro modelling to independently assess findings. Results:The discovery analysis showed suggestive evidence for interaction (p<0.05) between 7 environmental factors (antibiotic use, cat ownership, dog ownership, breastfeeding, elder sibling, smoking and washing practices) and at least one established variant for AE, 14 interactions in total (maxN=25,339). In replication analysis (maxN=252,040) dog exposure*rs10214237 (on chromosome 5p13.2 near IL7R) was nominally significant (ORinteraction=0.91 [0.83-0.99] P=0.025), with a risk effect of the T allele observed only in those not exposed to dogs. A similar interaction with rs10214237 was observed for siblings in the discovery analysis (ORinteraction=0.84[0.75-0.94] P=0.003), but replication analysis was under-powered ORinteraction=1.09[0.82-1.46]). Rs10214237 homozygous risk genotype is associated with lower IL-7R expression in human keratinocytes, and dog exposure modelled in vitro showed a differential response according to rs10214237 genotype. Conclusions:Interaction analysis and functional assessment provide evidence that early-life dog exposure may modify the genetic effect of rs10214237 on AE via IL7R, supporting observational epidemiology showing a protective effect for dog ownership. The lack of evidence for other G*E studied here implies that only weak effects are likely to occur.

Psoriasis is a common inflammatory skin disease with heterogeneous presentation. Up to 30

BACKGROUND:Multiple environmental and genetic factors play a role in the pathogenesis of atopic eczema (AE). We aimed to investigate gene-environment interactions (G × E) to improve understanding of the pathophysiology. METHODS:We analysed data from 16 European studies to test for interaction between the 24 most significant AE-associated loci identified from genome-wide association studies and 18 early-life environmental factors. We tested for replication using a further 10 studies and in vitro modeling to independently assess findings. RESULTS:The discovery analysis (including 25,339 individuals) showed suggestive evidence for interaction (p < 0.05) between seven environmental factors (antibiotic use, cat ownership, dog ownership, breastfeeding, elder sibling, smoking and washing practices) and at least one established variant for AE, 14 interactions in total. In the replication analysis (254,532 individuals) dog exposure × rs10214237 (on chromosome 5p13.2 near IL7R) was nominally significant (ORinteraction = 0.91 [0.83-0.99] p = 0.025), with a risk effect of the T allele observed only in those not exposed to dogs. A similar interaction with rs10214237 was observed for siblings in the discovery analysis (ORinteraction = 0.84 [0.75-0.94] p = 0.003), but replication analysis was under-powered (ORinteraction = 1.09 [0.82-1.46]). rs10214237 homozygous risk genotype is associated with lower IL-7R expression in human keratinocytes, and dog exposure modelled in vitro showed a differential response according to rs10214237 genotype. CONCLUSION:Interaction analysis and functional assessment provide preliminary evidence that early-life dog exposure may modify the genetic effect of rs10214237 on AE via IL7R, supporting observational epidemiology showing a protective effect for dog ownership. The lack of evidence for other G × E studied here implies only weak effects are likely to occur.

Inflammatory skin diseases (ISD), including atopic dermatitis (AD) and psoriasis (PsO), emerge from a complex network of inter- and intracellular biochemical interactions under the influence of genetic and environmental factors. The complexity of ISD mechanisms hinders translation of research findings into effective treatments and may explain the low remission rates despite the availability of modern targeted therapies. To model AD- and PsO-associated mechanisms as networks of context-specific molecular interactions, the so-called ISD map, and to check the usefulness of this map as a graphically guided review of AD and PsO mechanisms and as a mechanistic hypothesis-generating platform. The ISD map was built by assembling mechanistically resolved causal interactions obtained from relevant biomedical literature via manual curation. We demonstrate that the ISD map ( https://imi-biomap.elixir-luxembourg.org/ ) serves as an interactive, graphical review of AD and PsO molecular mechanisms and as a mechanistic hypothesis-generating platform. By analysing the map structure itself or the map integrated with genetics and functional genomics data, we could generate the following mechanistic hypotheses: (i) AD poor response to dupilumab is associated with a potential upregulation of IFNG, IL22, TSLP, IL-17A and IL25 signalling pathways in keratinocytes and/or single nucleotide polymorphisms (SNPs) in genes encoding regulators of IFNG expression in Th1 cells and (ii) PsO resistance to cytokine-induced apoptosis is associated with SNPs in IFNG signalling genes regulating SOCS1 in keratinocytes. Finally, the IL4/IL13 pathway in the AD submap of the ISD map was converted into a probabilistic Boolean model to simulate the effects of IFNG in sensory perception of itching after treatment with dupilumab. Our findings suggest that inhibiting both IFNG and IL4R may improve the therapeutic management of itching. The ISD map provides a significant interactive, computationally accessible resource of molecular knowledge on AD and PsO that can be used to graphically review known AD and PsO mechanisms and generate mechanistic hypotheses.

Atopic dermatitis (AD) is the most common inflammatory skin condition and affects people of all ages. New therapies, including the monoclonal antibody therapy dupilumab, offer excellent efficacy. However, in clinical trials, and emphasized in real-world observations, an unexpected increased frequency of ocular adverse effects has become apparent. The effectiveness of dupilumab and the unpredictability of ocular adverse effects mean that clinicians need guidance on counselling patients prior to treatment and on managing them if adverse effects arise. The British Association of Dermatologists (BAD) and Royal College of Ophthalmologists collaborated on this consensus guidance on managing dupilumab-related ocular surface disorders (DROSD). A multidisciplinary group was formed of adult and paediatric dermatologists and ophthalmologists with expertise in DROSD, patient representatives and the BAD Clinical Standards Unit. A literature search was conducted and the results reviewed. All recommendations were reviewed, discussed and voted on. The recommendations pertain to dermatology and ophthalmology management, and apply to people of all ages, unless otherwise stated. Importantly, initiation of dupilumab for AD should not be delayed for most eye disorders except acute new problems (e.g. infections) or potentially severe conditions (e.g. a history of corneal transplant; ophthalmology advice should be sought first). There is insufficient evidence to recommend lubricant drops prophylactically. Dermatologists should assess eye complaints to diagnose DROSD; a severity grading system is provided. DROSD management differs slightly in those aged < 7 years, as ocular complications may affect neuro-ocular development. Therefore, irrespectively of DROSD severity, this population should be referred for ophthalmology advice. In those aged ≥ 7 years, dermatologists should feel confident to trial treatment and reserve ophthalmology advice for severe or nonresponding cases. Discussion about dupilumab withdrawal should be prompted by a significant impact on quality of life, threat to sight, or other complications. Although dupilumab is a highly effective agent for treating AD, the risk of ocular adverse effects should not inhibit clinicians or patients from using it, but clinicians should be aware of them. If a patient develops DROSD, there are clear pathways to assess severity and offer initial management. Where this is ineffective, dermatologists should assess the urgency and seek advice from or initiate referral to ophthalmology. While the evidence reviewed for these guidelines reflects the extensive literature on dupilumab, we believe our advice has relevance for ocular surface disorders in patients with AD treated with tralokinumab and lebrikizumab.

Background: The use of allergy tests to guide dietary exclusions for disease control in children with atopic dermatitis (AD) is controversial. We undertook a consensus exercise on how to interpret skin prick test (SPT) results and dietary history for cow’s milk, hen’s egg, wheat and soya in children <2 years old with AD. Methods: Fourteen clinicians from general practice, paediatrics, paediatric dermatology, paediatric allergy and paediatric dietetics from UK and Ireland took part in an online modified Delphi study. Over three rounds, participants gave their anonymous opinions and received individualised and group feedback. The findings were discussed in an online workshop. Results: Of 14 symptoms, 12 were identified as relevant to immediate and 7 to delayed allergy. Regarding SPTs, there was consensus over which allergens to use for wheat and soya but not cow’s milk or hen’s egg; for all study foods, wheal size was determined as 0-1 mm negative, ≥5mm sensitised , but between 2-4 mm categorisation varied by food. During the final workshop, consensus was reached on dietary advice should be given according to SPT results and dietary history. Conclusion: We attained consensus on how SPTs combined with dietary history for four common food allergens should be interpreted in young children under two years of age with AD. These pragmatic recommendations may support clinician education, consistency of decision-making and future research.

The progress in our understanding of atopic dermatitis (AD) (atopic eczema) in the last 10 years has been remarkable. Nearly half of the scientific papers ever published on AD have been written in the last 10 years. This contribution of knowledge, in parallel with technological and pharmaceutical progress, has transformed our ability to treat some of the most severe forms of AD. Notably, we have seen the advent of biologics such as the anti–IL-4 receptor biologic dupilumab (Simpson et al, 2016), 2 anti–IL-13 agents (tralokinumab [Wollenberg et al, 2021] and lebrikizumab [Silverberg et al, 2023]), and small-molecular Jak inhibitors (the Jak1 inhibitors upadacitinib [Guttman-Yassky et al, 2021] and abrocitinib [Simpson et al, 2020] and the Jak1/Jak2 inhibitor baricitinib [Zhou et al, 2021]).

Many human skin diseases result from the complex interplay of genetic and environmental mechanisms that are largely unknown. GWASs have yielded insight into the genetic aspect of complex disease by highlighting regions of the genome or specific genetic variants associated with disease. Leveraging this information to identify causal genes and cell types will provide insight into fundamental biology, inform diagnostics, and aid drug discovery. However, the etiological mechanisms from genetic variant to disease are still unestablished in most cases. There now exists an unprecedented wealth of data and computational methods for variant interpretation in a functional context. It can be challenging to decide where to start owing to a lack of consensus on the best way to identify causal genetic mechanisms. This article highlights 3 key aspects of genetic variant interpretation: prioritizing causal genes, cell types, and pathways. We provide a practical overview of the main methods and datasets, giving examples from recent atopic dermatitis studies to provide a blueprint for variant interpretation. A collection of resources, including brief description and links to the packages and web tools, is provided for researchers looking to start in silico follow-up genetic analysis of associated genetic variants.