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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.

[No abstract]

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.

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.

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 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).

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.

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 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.

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.

TO THE EDITOR Punctate palmoplantar keratoderma (punctate PPK or PPKP) is a rare autosomal dominant disorder of keratinization. Three variants of this disease have been described; PPKP1 (OMIM ♯148600, Buschke–Fischer–Brauer type) is characterized by the progressive development of discrete areas of hyperkeratosis on the palms and soles, followed by more extensive diffuse hyperkeratosis on the pressure-bearing areas of plantar skin. Linkage analyses of families affected by PPKP1 have previously identified a locus within 15q22–q24 (Martinez-Mir et al., 2003; Gao et al., 2005), but two Chinese pedigrees with a PPKP1 phenotype demonstrated linkage on chromosome 8q24.13–q24.21 (Zhang et al., 2004). Recently, nonsense mutations in AAGAB, the gene encoding alpha- and gamma-adaptin-binding protein p34, were reported in three PPKP1 families (Giehl et al., 2012). Simultaneously, we applied whole-exome sequencing and reported heterozygous loss-of-function mutations in AAGAB in 18 PPKP1 kindreds (Pohler et al., 2012). AAGAB is located on chromosome 15q22, within one of the previously reported linkage regions (Martinez-Mir et al., 2003; Pohler et al., 2012). We now report the AAGAB genotype in a further 12 PPKP1 patients from 6 independent kindreds of Scottish, English, and Mexican ancestry. This study was carried out in accordance with the Declaration of Helsinki Principles, and all subjects gave written informed consent.

The epidermis is a relatively hypoxic tissue, despite being continually exposed to air. The role of hypoxia in epidermal differentiation and skin barrier function is incompletely understood. In this issue, Wong et al. show that hypoxia-inducible factors are central to the processes of epidermal differentiation and barrier formation, in particular by promoting the expression of the key skin barrier protein filaggrin.

To the Editor A key event during epidermal differentiation is the proteolytic breakdown of profilaggrin into “free” filaggrin monomers. A recent study has shown that the skin specific retroviral-like aspartic protease (SASPase) plays a key role in profilaggrin-filaggrin processing (Matsui et al., 2011). SASPase cleaves the linker peptide between the individual filaggrin monomers of profilaggrin and on a hairless mouse background, loss of SASPase leads to dry, scaly skin with reduced stratum corneum hydration accompanied by accumulations of profilaggrin-filaggrin intermediates but an absence of filaggrin monomers (Matsui et al., 2011). In this same study several missense mutations in the SASPase gene in atopic eczema patients and controls were identified, some of which were shown to have a detrimental effect on the ability of SASPase to cleave the profilaggrin linker peptide. Given the important role of filaggrin in skin barrier function and maintaining stratum corneum hydration (O’Regan and Irvine, 2010), these results prompted us to question whether aberrant profilaggrin-filaggrin processing due to altered SASPase activity could provide an alternative pathogenic mechanism for atopic eczema or clinically dry skin. To answer this question, the entire coding region of the SASPase gene, ASPRV1, was amplified by PCR in a single fragment and fully sequenced. To maximize our chances of finding mutations that might be associated with atopic eczema or clinically dry skin we sequenced ASPRV1 from three discovery cohorts; 96 paediatric atopic eczema cases from Ireland, 96 atopic eczema cases from the Cape Town region of South Africa (Xhosa people) and 99 cases of clinically dry skin from patients referred to dermatology clinics in Glasgow, Scotland. Atopic eczema in the Irish paediatric cases was diagnosed using the UK Diagnostic criteria (Williams et al., 1994); atopic eczema in the Xhosa people was diagnosed by experienced dermatologists. Clinically dry skin was defined using a previously published scoring system (Sergeant et al., 2009). Demographic and clinical data relating to the discovery cohorts are shown in Table 1. Table 1 Demographic and clinical data relating to eczema and dry skin cases and population controls Sequencing of the ASPRV1 gene in the discovery cohorts identified a total of 5 non-synonymous mutations and 2 synonymous mutations (Table 2). None of the ASPRV1 mutations identified in a previous Japanese study (Matsui et al., 2011) were detected in our discovery cohorts. We then investigated some of these mutations further by screening an additional 259 Irish atopic eczema cases and 167 Scottish dry skin cases (which included the original 93 cases from the discovery cohort) using custom-designed TaqMan® allelic discrimination assays for the mutations V74I, G87R and S333F (Supplementary Table 1). The G87R mutation was identified only in a single case of atopic eczema and the V74I and S333F mutations were not detected in any of these additional cases. In the 167 cases of dry skin, the G87R and S333F mutations were found only in single cases (ie. in the original discovery cohort) and the V74I mutation was not found in any of the cases. We then carried out two independent case-control studies to investigate any association between the T49A mutation and atopic eczema and clinically dry skin (Supplementary Table 2). 442 Irish atopic eczema cases (which included the original 92 cases from the discovery cohort) and 458 Irish population controls were screened using a TaqMan® allelic discrimination assay. There was no association between the T49A mutation and atopic eczema in the Irish study: chi-square p=0.415, odds ratio 0.98 (95% confidence interval 0.81–1.18). Similarly, screening of 167 clinically dry skin cases and 100 Scottish population controls failed to reveal any association between the T49A mutation and dry skin: p=0.479, odds ratio 0.90 (0.63–1.28). Power calculations showed that the eczema case-control study had >80% power to detect an odds ratio of 1.5 or above and the dry skin case-control study study had >70% power to detect an odds ratio of 2.0 (Quanto 1.2.4, University of Southern California, http://hydra.usc.edu/gxe/). Since FLG null mutations are known to have such a strong effect on eczema risk, it is possible that the effect of ASPRV1 mutations may only be apparent in FLG wild-type individuals. Therefore the four most prevalent FLG null mutations (R501X, 2282del4, R2447X and S3247X) were screened in each of the cases and controls using methods described previously (Kezic et al., 2011; Sandilands et al., 2007). The statistical analyses for each study were repeated after excluding individuals carrying FLG null mutations, but there was still no evidence of association between ASPRV1 mutation T49A and eczema or clinically dry skin (Supplementary Table 3). Table 2 dbSNP minor allele frequencies of ASPRV1 polymorphisms identified in the discovery cohorts With the exception of T49A and to a lesser extent L325L, the remaining ASPRV1 mutations that we identified were rare (

The discovery, in 2006, that loss-of-function mutations in the filaggrin ( FLG ) gene are the cause of ichthyosis vulgaris—the most common disorder of keratinization—and also a strong genetic risk factor for atopic eczema, marked a significant breakthrough in the understanding of eczema pathogenesis. Subsequent investigations of the role of FLG -null mutations have identified a series of significant associations with atopic disease phenotypes, including atopic asthma, allergic rhinitis, and peanut allergy. However, many questions remain to be answered in relation to the precise mechanisms by which deficiency of an intracellular protein expressed primarily in the differentiating epidermis may contribute to the development of cutaneous and systemic pathology. This review aims to highlight the key milestones in filaggrin research over the past 25 years, to discuss the mechanistic, clinical, and therapeutic implications, and to consider possible future directions for ongoing investigation.

Summary Background Null mutations in the filaggrin gene (FLG) cause ichthyosis vulgaris (IV) and predispose to atopic dermatitis (AD). Cohort studies in Europe and Japan have reported an FLG mutation carrier frequency of between 14% and 56%, but the prevalent European FLG mutations are rare or absent in Chinese patients with IV and AD. Objectives To investigate further the spectrum of FLG-null mutations in Chinese patients and to compare it with that in other populations. Methods We conducted comprehensive FLG genetic analysis in a discovery cohort of 92 Singaporean Chinese individuals with IV and/or moderate-to-severe AD. All detected FLG mutations were then screened in a cohort of 425 patients with AD and 440 normal controls. Results In total, 22 FLG-null mutations, of which 14 are novel, were identified in this study; the combined null FLG genotype of 17 mutations detected in cases and controls showed strong association with AD [Fisher’s exact test; P = 5·3 × 10−9; odds ratio (OR) 3·3], palmar hyperlinearity (Fisher’s exact test; P = 9·0 × 10−15; OR 5·8), keratosis pilaris (Fisher’s exact test; P = 0·001; OR 4·7) and with increased severity of AD (permutation test; P = 0·0063). Conclusions This study emphasizes the wider genetic landscape of FLG-null mutations in Asia that is slowly emerging.

Multiple genetic as well as environmental factors interact in the pathogenesis of eczema. Increased understanding of genetic predisposition in atopy and eczema has directed interest toward key pathogenic mechanisms including skin barrier dysfunction. This review provides a succinct update on the current state of knowledge regarding eczema genetics. We discuss the relevance of loss-of-function mutations in the filaggrin gene within the context of other candidate gene studies and suggest possible applications for future research. Knowledge of genetic factors in eczema may translate into a clearer understanding of pathogenic mechanisms and hence more focused therapeutic strategies, but this remains at present a distant possibility.

Summary Background Oral propranolol is widely prescribed as first-line treatment for infantile haemangiomas (IHs). Anecdotally, prescribing practice differs widely between centres. Objectives The Propranolol In the Treatment of Complicated Haemangiomas (PITCH) Taskforce was founded to establish patterns of use of propranolol in IHs. Methods Participating centres entered data on all of their patients who had completed treatment with oral propranolol for IHs, using an online data capture tool. Results The study cohort comprised 1097 children from 39 centres in eight European countries. 76·1% were female and 92·8% had a focal IH, with the remainder showing a segmental, multifocal or indeterminate pattern. The main indications for treatment were periocular location (29·3%), risk of cosmetic disfigurement (21·1%) and ulceration and bleeding (20·6%). In total 69·2% of patients were titrated up to a maintenance regimen, which consisted of 2 mg kg−1 per day (85·8%) in the majority of cases. 91·4% of patients had an excellent or good response to treatment. Rebound growth occurred in 14·1% upon stopping, of whom 53·9% were restarted and treatment response was recaptured in 91·6% of cases. While there was no significant difference in the treatment response, comparing a daily maintenance dose of < 2 mg kg−1 vs. 2 mg kg−1 vs. > 2 mg kg−1, the risk of adverse events was significantly higher: odds ratio (OR) 1 vs. adjusted OR 0·70, 95% confidence interval (CI) 0·33–1·50, P = 0·36 vs. OR 2·38, 95% CI 1·04–5·46, P = 0·04, Ptrend < 0·001. Conclusions The PITCH survey summarizes the use of oral propranolol across 39 European centres, in a variety of IH phases, and could be used to inform treatment guidelines and the design of an interventional study.

Summary Background Cutaneous malignancy forms a major part of the dermatologist's workload. Clinical diagnosis is an important factor in facilitating the urgent excision of squamous cell carcinomas (SCC) and malignant melanomas. Objectives To identify the numbers and types of malignant skin tumours managed in an NHS teaching hospital and to assess the diagnostic accuracy. Methods Data were collected on every histologically proven malignant skin lesion over a 6-month period. Results One thousand one hundred and ninety-five malignant skin tumours were identified: 78% were basal cell carcinomas, 14% were SCC, 6% were malignant melanomas and the remaining 2% included Merkel cell tumours, malignant adnexal tumours and lentigo maligna. Eighty-one per cent of the tumours were managed by dermatologists. The correct clinical diagnosis had been made by the secondary care clinician in 84% of cases but an incorrect clinical diagnosis was given in 32% of SCC. Of the 1195 tumours, 916 (77%) had a primary excision and 92% (843 of 916) of these were completely excised. Conclusions The majority of skin malignancies (968 of 1195, 81%) were managed by dermatologists. Where primary excision was attempted, this was complete in 91% (767 of 916) of cases. The correct clinical diagnosis was made in 84% of all tumours, but 32% of SCC were not correctly diagnosed prior to surgery.

Earwax type and axillary odor are genetically determined by rs17822931, a single-nucleotide polymorphism (SNP) located in the ABCC11 gene. The literature has been concerned with the Mendelian trait of earwax, although axillary odor is also Mendelian. Ethnic diversity in rs17822931 exists, with higher frequency of allele A in east Asians. Influence on deodorant usage has not been investigated. In this work, we present a detailed analysis of the rs17822931 effect on deodorant usage in a large (N∼17,000 individuals) population cohort (the Avon Longitudinal Study of Parents and Children (ALSPAC)). We found strong evidence (P=3.7 × 10−20) indicating differential deodorant usage according to the rs17822931 genotype. AA homozygotes were almost 5-fold overrepresented in categories of never using deodorant or using it infrequently. However, 77.8% of white European genotypically nonodorous individuals still used deodorant, and 4.7% genotypically odorous individuals did not. We provide evidence of a behavioral effect associated with rs17822931. This effect has a biological basis that can result in a change in the family's environment if an aerosol deodorant is used. It also indicates potential cost saving to the nonodorous and scope for personalized genetics usage in personal hygiene choices, with consequent reduction of inappropriate chemical exposures for some.

Atopic eczema treatment now and in the future: Targeting the skin barrier and key immune mechanisms in human skin

TO THE EDITOR Acne vulgaris is a very common skin disorder, affecting to some degree 88–94% of Singaporean adolescents (Tan et al., 2007; Yosipovitch et al., 2007). Genetic predisposition is a significant risk factor, as illustrated by familial and twin studies (Bataille et al., 2002; Ghodsi et al., 2009). The clinical features of acne include sebor-rhea, comedone formation, inflammatory pustules, nodules, and cysts, with resultant scarring. Important pathogenic mechanisms in acne include increased sebum production, hyperkeratinization and occlusion of the follicular duct, proliferation of Propionibacterium acnes, and an inflammatory reaction (Purdy and de Berker, 2006). P. acnes produces lipases, which liberate proinflammatory fatty acids from sebum and also triggers a cytokine response. Filaggrin is expressed in terminally differentiating keratinocytes and has a key role in epithelial barrier formation. Immunostaining demonstrates increased filaggrin expression in the sebaceous duct and infundibulum of acne vulgaris skin (Kurokawa et al., 1988), and P. acnes strains increase the expression of filaggrin and other differentiation-specific markers in normal human epidermal keratinocytes in vitro and in the suprabasal layers of human skin explants (Jarrousse et al., 2007). Similarly, inflammatory cytokines resulted in increased filaggrin expression in sebaceous gland explants (Guy and Kealey, 1998). However, it is not known whether differences in filaggrin expression represent a primary or secondary effect in the pathogenesis of acne. Null mutations in the filaggrin gene (FLG) result in reduced filaggrin expression and cause ichthyosis vulgaris (Smith et al., 2006). Such mutations are common in the general population, being carried by ~10% of Europeans and 7.3% of Singaporean Chinese (Sandilands et al., 2007; Chen et al., personal communication). This high carrier rate in different populations suggests a heterozygote advantage, and it has been proposed that a more permeable skin barrier may have been beneficial in evolutionary history (Irvine and McLean, 2006). The co-existence of FLG null mutations with other gene mutations that disrupt epidermal differentiation may increase phenotype severity (Liao et al., 2007; Gruber et al., 2009). It is also possible that heterozygosity for null mutations has other effects on skin physiology. Studying a cohort of 284 European dermatology patients not selected for dry skin (Sergeant et al., 2009) raised the possibility that carriage of one FLG null mutation could provide a protective effect against acne vulgaris. In the Sergeant study, the odds ratio of acne in the carrier group was 0.3 (95% confidence interval 0.1–1.0), but the difference between these individuals and the group without FLG mutations did not reach statistical significance (P = 0.08). In addition, this study relied¼ on a recalled history of acne. We therefore aimed to test the hypothesis that FLG null mutations are protective against the development of acne vulgaris by studying a well-documented group of patients with acne, and comparing with a population control group. A total of 287 Singaporean Chinese patients presenting with acne vulgaris to the National Skin Centre, a major dermatology outpatient facility in Singapore, were recruited: mean age 22 o years (SD 4.8), range 14–50 (27%

Loss-of-function variants within the filaggrin gene (FLG) increase the risk of atopic dermatitis. FLG also demonstrates intragenic copy number variation (CNV), with alleles encoding 10, 11, or 12 filaggrin monomers; hence, CNV may affect the amount of filaggrin expressed in the epidermis. A total of 876 Irish pediatric atopic dermatitis cases were compared with 928 population controls to test the hypothesis that CNV within FLG affects the risk of atopic dermatitis independently of FLG-null mutations. Cases and controls were screened for CNV and common FLG-null mutations. In this population the 11-repeat allele was most prevalent (allele frequency 51.5%); the 10-repeat allele frequency was 33.9% and the 12-repeat allele frequency was 14.6%. Having excluded FLG mutation carriers, the control group had a significantly higher number of repeats than cases (chi(2) P = 0.043), and the odds ratio of disease was reduced by a factor of 0.88 (95% confidence interval 0.78-0.98, P-0.025) for each additional unit of copy number. Breakdown products of filaggrin were quantified in tape-stripped stratum corneum from 31 atopic dermatitis patients and urocanic acid showed a positive correlation with total copy number. CNV within FLG makes a significant, dose-dependent contribution to atopic dermatitis risk, and therefore treatments to increase filaggrin expression may have therapeutic utility

Summary Background Null mutations within the filaggrin gene (FLG) cause ichthyosis vulgaris and are associated with atopic eczema. However, the dermatological features of filaggrin haploinsufficiency have not been clearly defined. Objectives This study investigated the genotype–phenotype association between detailed skin phenotype and FLG genotype data in a population-based cohort of children. Methods Children (n = 792) aged 7–9 years were examined by a dermatologist. Features of ichthyosis vulgaris, atopic eczema and xerosis were recorded and eczema severity graded using the Three Item Severity score. Each child was genotyped for the six most prevalent FLG null mutations (R501X, 2282del4, R2447X, S3247X, 3702delG, 3673delC). Fisher’s exact test was used to compare genotype frequencies in phenotype groups; logistic regression analysis was used to estimate odds ratios and penetrance of the FLG null genotype and a permutation test performed to investigate eczema severity in different genotype groups. Results Ten children in this cohort had ichthyosis vulgaris, of whom five had mild–moderate eczema. The penetrance of FLG null mutations with respect to flexural eczema was 55·6% in individuals with two mutations, 16·3% in individuals with one mutation and 14·2% in wild-type individuals. Summating skin features known to be associated with FLG null mutations (ichthyosis, keratosis pilaris, palmar hyperlinearity and flexural eczema) showed a penetrance of 100% in children with two FLG mutations, 87·8% in children with one FLG mutation and 46·5% in wild-type individuals (P

Background: Pediatric inflammatory bowel disease (IBD) has a high prevalence of coexistent atopy. Filaggrin (FLG) loss-of-function variants (null-alleles) are associated with eczema and asthma in association with eczema. The aim was to assess the contribution of FLG null-alleles to pediatric IBD susceptibility and to coexistent atopy (eczema, asthma, allergic rhinitis, or food allergy). Methods: FLG variants (R501X and 2282del4) were genotyped in 403 children with IBD, 683 parents, and 996 population controls. Results: In all, 11% of IBD patients carried at least 1 FLG null-allele compared to 11% of population controls (P > 0.4). Carriage of 1 or more null-alleles in patients with atopy (present in 52% of IBD patients) differed from IBD patients without atopy (14% versus 6%, P = 0.01; odds ratio [OR] 2.4, 95% confidence interval [CI] 1.2-5.1). The effect of FLG null-alleles was strongest for eczema (19% versus 7%, P = 0.0003; OR 3.3, 95% CI 1.7-6.6) and food allergy (28% versus 8%, P = 0.0001; OR 4.5, 95% CI 2.0-10.0). The presence of more than 1 atopic disease tended to increase the associated OR: eczema + asthma (23% versus 7%, P = 0.001; OR 3.9, 95% CI 1.6-9.1), eczema + asthma + allergic rhinitis (29% versus 7%, P = 0.0006; OR 5.4, 95% CI 1.9-15.4) and eczema + asthma + allergic rhinitis + food allergy (45% versus 6%, P < 10-4; OR 12.2, 95% CI 3.2-46.3). Logistic regression analysis of IBD cases confirmed the association of carriage of an FLG null-allele with atopy (P = 0.01; OR 2.4, 95% CI 1.2-5.1) and co-occurrence of different forms of atopy (P = 0.003; OR 3.5, 95% CI 1.5-8.1). Conclusions: Filaggrin null-alleles have no effect on IBD susceptibility but contribute to coexistent eczema and food allergy. Copyright © 2009 Crohn's & Colitis Foundation of America, Inc.

Blister formation and eccrine sweat gland necrosis have been recognized to occur in states of impaired consciousness and were first reported following barbiturate intoxication. Their etiology is complex and cannot simply be explained by pressure effects. Now that barbiturates are less frequently used, clinicians are likely to be less aware of the phenomenon of coma blister formation; however, newer drugs have also been associated with the occurrence of coma blisters. We describe 2 new associations of coma blisters and anticonvulsants in children. In the first child, blisters recurred on multiple occasions along with obtundation and edema. Our aims are to alert clinicians to the occurrence of coma blisters in children sedated on anticonvulsant medications and to report the new finding of recurrent coma blisters.

The discovery that null mutations in the filaggrin gene (FLG) are associated with atopic eczema represents the single most significant breakthrough in understanding the genetic basis of this complex disorder. The association has been replicated in multiple independent studies during the past 2 years with the use of various methodologies, from populations in Europe, the United States, and Japan. Filaggrin plays a key role in epidermal barrier function, and its association with atopic eczema emphasizes the importance of barrier dysfunction in eczema pathogenesis. This review aims to summarize the current state of knowledge regarding the role of FLG mutations in ichthyosis vulgaris, atopic eczema, and other skin disorders, with an emphasis on potential clinical applications. Further research is needed to clarify the precise role of filaggrin in skin and systemic atopic disease, to pave the way for novel therapeutic interventions.