Filaggrin haploinsufficiency is highly penetrant and is associated with increased severity of eczema: further delineation of the skin phenotype in a prospective epidemiological study of 792 school children

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 < 0·0001, Fisher exact test). FLG null mutations were associated with more severe eczema (P = 0·0042) but the mean difference was only 1–2 points in severity score. Three distinct patterns of palmar hyperlinearity were observed and these are reported for the first time. Conclusions Filaggrin haploinsufficiency appears to be highly penetrant when all relevant skin features are included in the analysis. FLG null mutations are associated with more severe eczema, but the effect size is small in a population setting.     

Distinct barrier integrity phenotypes in filaggrin-related atopic eczema following sequential tape stripping and lipid profiling

Background Filaggrin gene (FLG) loss‐of‐function mutations have been shown to represent the strongest so far known genetic risk factor for atopic dermatitis (AD). Whereas the barrier characteristics in FLG mutation carriers under baseline conditions have been investigated, there are only limited data on the permeability barrier function in filaggrin‐AD under compromised conditions. Aim We investigated: (i) stratum corneum (SC) integrity/cohesion; (ii) barrier recovery after controlled mechanical and irritant‐induced barrier abrogation; and (iii) the lipid composition of the non‐lesional and lesional skin of AD patients harbouring the European R501X, 2282del4, 3702delG, R2447X or S3247X FLG variants. Methods Thirty‐seven AD patients (14 FLG mutation carriers and 23 non‐carriers) and 20 healthy controls participated in the study. Stratum corneum integrity/cohesion was assessed by measurement of transepidermal water loss (TEWL) and amount of removed protein following sequential tape stripping. Barrier recovery was monitored by repeated measurements of TEWL and erythema up to 96 h after barrier abrogation. Samples for lipid analysis were obtained from non‐lesional and lesional skin using the cyanoacrylate method. Results Tape stripping revealed distinct genotype‐related impairment of the SC integrity/cohesion. No differences in the rate of barrier recovery among the groups were found. The SC lipid analysis revealed significant differences regarding the percentage amount of cholesterol, ceramide/cholesterol ratio and triglycerides in the uninvolved skin as well as the amounts of free fatty acids, CER[EOH] and triglycerides in the skin lesions of the AD FLG mutation carriers. Conclusions Our results provide evidence for discernible FLG‐related barrier integrity phenotypes in atopic eczema.     

Filaggrin null mutations increase the risk and persistence of hand eczema in subjects with atopic dermatitis: results from a general population study

Summary Background Hand eczema is prevalent in the general population. It remains unclear whether or not filaggrin gene (FLG) null mutations increase the overall risk of hand eczema or only increase the risk of hand eczema in subjects with atopic dermatitis. Objectives To investigate the association between FLG null mutations and hand eczema. Methods A random sample of 3335 adults from the general population in Denmark was patch tested, FLG genotyped for R501X and 2282del4 null mutations and questioned about hand eczema. Results Participants with combined presence of atopic dermatitis and FLG null mutation status had a significantly higher prevalence of hand eczema, an earlier onset of hand eczema and a higher persistence of hand eczema compared with subjects with normal FLG status and absence of atopic dermatitis. Logistic regression analyses revealed positive associations between hand eczema within the past 12 months and FLG null mutation status in participants with a history of atopic dermatitis [odds ratio (OR) 2·98; 95% confidence interval (CI) 1·27–7·01], but not in subjects without atopic dermatitis (OR 0·82; 95% CI 0·41–1·67). Conclusions FLG null mutations were significantly associated with hand eczema (< 12 months) in subjects with atopic dermatitis. Combined atopic dermatitis and filaggrin null mutation status was strongly associated with early onset of hand eczema and hand eczema persistence.     

FLG mutations in ichthyosis vulgaris and atopic eczema: spectrum of mutations and population genetics

Filaggrin is a key protein involved in skin barrier function. Mutations in the gene encoding filaggrin (FLG) have been identified as the cause of ichthyosis vulgaris and have been shown to be major predisposing factors for atopic eczema (AE), initially in European populations. Subsequently, FLG mutations were identified in Japanese, Chinese, Taiwanese and Korean populations. It was demonstrated that FLG mutations are closely associated with AE in the Japanese population. Notably, the same FLG mutations identified in the European population were rarely found in Asians. These results exemplify differences in filaggrin population genetics between Europe and Asia. For mutation screening, background information needs to be obtained on prevalent FLG mutations for each geographical population. It is therefore important to establish the global population genetics maps for FLG mutations. Mutations at any site within FLG, even mutations in C‐terminal imperfect filaggrin repeats, cause significant reductions in amounts of profilaggrin/filaggrin peptide in patient epidermis as the C‐terminal region is essential for proper processing of profilaggrin into filaggrin. Thus, no genotype–phenotype correlation has been observed in patients with FLG mutations. A restoration of the barrier function seems a feasible and promising strategy for treatment and prevention in individuals with filaggrin deficiency.     

Prednisolone vs. ciclosporin for severe adult eczema. An investigator‐initiated double‐blind placebo‐controlled multicentre trial

Background Patients with severe eczema frequently receive systemic glucocorticosteroids. The efficacy of prednisolone and other steroids, however, has never been evaluated appropriately. A meta‐analysis indicated that ciclosporin is the best evaluated systemic treatment for eczema. Objectives To investigate the comparative efficacy of prednisolone and ciclosporin for severe eczema. Methods In an investigator‐initiated double‐blind randomized multicentre trial, adults with severe eczema (objective SCORAD ≥ 40 and Dermatology Life Quality Index ≥ 10) were randomly allocated to receive prednisolone (initial dose 0·5–0·8 mg kg^?1 daily) for 2 weeks followed by placebo for 4 weeks or ciclosporin (2·7–4·0 mg kg^?1 daily) for 6 weeks and followed for another 12 weeks. Concomitant treatment included a moderately potent topical steroid, emollients, and continuation of antihistamines. Primary endpoint was the proportion of patients with stable remission, i.e. ≥ 50% SCORAD improvement under active treatment and no flare (≥ 75% of baseline SCORAD) during follow‐up. Sample size calculation indicated that 66 patients were needed to see clinically relevant differences between groups. Analysis was by intention‐to‐treat (ClinicalTrials.gov Identifier: NCT00445081). Results Because of unexpectedly high numbers of withdrawals due to significant exacerbations of eczema (n = 15/38) an independent data monitoring and safety board proposed early study termination. Thirty‐eight patients were randomized and analysed. Stable remission was achieved in one of 21 patients receiving prednisolone compared with six of 17 patients treated with ciclosporin (P = 0·031). Conclusions Ciclosporin is significantly more efficacious than prednisolone for severe adult eczema. Despite its frequent use in daily practice, prednisolone is not recommended to induce stable remission of eczema.     

Estimating emollient usage in patients with eczema

Background. Atopic eczema (AE) is characterized by reduced skin hydration (SH) and impaired integrity of the skin. Proper emollient usage is an important facet of AE management and patients are encouraged to use emollients liberally. Aim. To evaluate whether the amount of emollient and skin cleanser used correlates with eczema severity, SH or transepidermal water loss (TEWL), and whether liberal usage alters disease severity, SH and TEWL. Methods. We studied SH and TEWL at three common measurement sites on the forearm (antecubital flexure, 20 mm below the antecubital flexure, mid‐forearm) and determined the SCORing Atopic Dermatitis (SCORAD) score, Nottingham Eczema Severity Score (NESS), Children’s Dermatology Life Quality Index (CDLQI) and the amount of emollient and cleanser usage over a 2‐week period in consecutive new patients seen at the paediatric skin clinic of a teaching hospital. Results. In total, 48 subjects and 19 controls were recruited. Patients with AE had significantly higher TEWL and lower SH in the studied sites. Emollient and cleanser usage was significantly higher (P = 0.001 and P = 0.041, respectively) in patients with AE than in controls. The amount of emollient usage was correlated with NESS, SCORAD, CDLQI, TEWL and mid‐forearm SH. No such correlation was found with cleanser usage. Regardless of SCORAD, prescribing 130 g/m²/week of emollient met the requirement of 95.8% of patients, and 73 g/m²/week met that of 85.4%; for the cleanser, prescribing 136 g/m²/week met the requirement of 91.7% of patients. Although skin dryness and SH were improved, there was no significant improvement in SCORAD or TEWL after 2 weeks. In terms of global acceptability of treatment, three‐quarters of patients with AE and controls rated the combination of cream and cleanser as ‘good’ or ‘very good’. Conclusions. Adequate amounts of emollient and bathing cleanser should be prescribed to patients with AE. These amounts can be conveniently estimated based on body surface area instead of the less readily available tools for disease severity, degree of SH or skin integrity. However, liberal usage of emollients and bathing cleanser alone does not seem to alter disease severity or TEWL within 2 weeks, implying that additional treatments are necessary to manage AE.     

Effects of nonpathogenic gram-negative bacterium Vitreoscilla filiformis lysate on atopic dermatitis: a prospective, randomized, double-blind, placebo-controlled clinical study

Background Atopic dermatitis (AD) is associated with elevated IgE levels and Th2 responses. The oral administration of nonpathogenic bacteria such as probiotics may improve the course of atopic diseases. It is believed that nonpathogenic bacteria prevent the development of allergic diseases by modulating intestinal immune responses. However, the effects of oral probiotics on AD could not be reproduced in all studies and the direct immunomodulation of the skin‐associated immune response by nonpathogenic bacteria has not yet been investigated. Objectives We performed a prospective, double‐blind, placebo‐controlled clinical study with a cream containing a 5% lysate of the nonpathogenic bacteria Vitreoscilla filiformis. Patients and methods Seventy‐five volunteers with AD (6–70 years of age) were randomized to receive either V. filiformis cream 5% or vehicle cream daily for 30 days. Efficacy was evaluated by the SCORe of Atopic Dermatitis (SCORAD), transepidermal water loss (TEWL), assessment of microflora, and the patient’s assessment of itch and loss of sleep. Results Compared with placebo, V. filiformis lysate significantly decreased SCORAD levels (P = 0·0044) and pruritus (P = 0·0171). Active cream significantly decreased loss of sleep from day 0 to day 29 (P = 0·0074). Qualitative and quantitative assessment of cutaneous microbial colonization revealed that V. filiformis lysate reduced Staphylococcus aureus colonization of the skin. The skin barrier as determined by TEWL also improved significantly with the cream alone. Conclusions V. filiformis lysate significantly improved AD. This may be in part due to reduction of S. aureus, but seems to relate in most parts to a direct immunomodulatory effect on skin‐associated immune responses.     

Eczema severity in preadolescent children and its relation to sex,filaggrin mutations,asthma, rhinitis,aggravating factors and topical treatment: a report from the BAMSE birth cohort

Background Filaggrin (FLG) mutations are major genetic determinants for eczema, but their role in eczema severity needs further investigation. Children with eczema are at higher risk of having asthma and rhinitis but it is not known if this risk is associated with the severity of eczema. Objectives To investigate eczema severity in relation to sex, FLG mutations, asthma, rhinitis and topical treatment among preadolescent children in a population‐based cohort. Methods Parental questionnaires were used to obtain data on symptoms of eczema, asthma, and rhinitis among 3301 preadolescent children. Eczema severity was evaluated based on sleep disturbance, extent of disease and total time with eczema the previous year. Genotyping was performed in 1854 individuals for three common FLG mutations (R501X, R2447X and 2282del4). Results Eczema was more prevalent among girls (14·5%) than boys (9·4%). FLG mutations were detected in 13·1% of children with mild eczema and 12·5% with moderate‐to‐severe eczema. Of children with moderate‐to‐severe eczema, 45·1% had rhinitis and 22·0% had asthma compared with 32·7% and 13·8% of children with mild eczema, respectively. Children with moderate‐to‐severe eczema used moisturizers and topical glucocorticoids more frequently than children with mild eczema. Boys used moisturizers less frequently than girls. Conclusions More preadolescent girls than boys had eczema. FLG mutations did not influence eczema severity in our population‐based cohort. Prevalence of rhinitis and asthma was associated with eczema severity, with the highest prevalence among boys with moderate‐to‐severe eczema.     

Experiences with the severity scoring of atopic dermatitis in a population of German pre-school children

Severity scoring of atopic dermatitis (SCORAD) was introduced as a standard tool but has not been used in a population-based epidemiological study; the objective of the present study was to determine the practicability of this instrument in this setting. We assessed the distribution of the severity of atopic eczema in the community and investigated differences between east and west Germany. A factor analysis was then carried out to characterize the variables of this scoring system and to analyse possible relationships within them. A multicentre cross-sectional study was carried out in five east German and two west German locations in 1994; pre-school children (5–6 years old) were investigated and cases of atopic eczema identified by a dermatological examination. The SCORAD was used to determine the severity of atopic eczema and the results assessed using analysis of variance and principal component analysis (varimax rotation). In all, 1511 (76·2%) of the children originally contacted participated and 11·3% were diagnosed with atopic eczema at the time of examination. The median severity score was 21·4 (interquartile range 13·5) and there was a tendency to higher scores in west Germany for the mean overall score, the intensity score and the extent. ‘Erythema’ (1·30 vs. 1·06; P= 0·006) and ‘excoriation’ (0·77 vs. 0·36; P= 0·002) were significantly more prominent in children with eczema from west Germany (adjusted for observer). Interobserver variabilities of the SCORAD parameters were calculated, adjusted for location and were in accordance with earlier findings. Principal component analysis identified three independent factors accounting for 54·1% of the total variance. A severity factor, characterized by ‘extent’, ‘lichenification’, ‘excoriation’ and ‘pruritus’, was separated from a factor with an acute eczema-type profile (‘erythema’, ‘oedema’, ‘oozing’) and a factor whose major characteristics were ‘extent’, ‘dryness’, and ‘sleep loss’. We conclude that atopic eczema is frequent in pre-school children. The SCORAD proved to be readily applicable and useful in epidemiological studies, but further validation is needed.     

A randomized controlled trial in children with eczema: nurse practitioner vs. dermatologist

Background We hypothesized that a nurse practitioner would improve the quality of life of a child with eczema more than a dermatologist because of a structured intervention and more consultation time. Objectives To compare the level of care by nurse practitioners with that by dermatologists in children with eczema. Methods New referrals aged ≤ 16 years with a diagnosis of eczema were recruited. In a randomized, parallel‐group study with a follow‐up period of 1 year, 160 participants were randomized either to conventional care from a dermatologist or to care from a nurse practitioner. The primary outcome measure was change in quality of life at 12 months, as assessed by the Infants’ Dermatitis Quality of Life Index (IDQOL) for children aged ≤ 4 years, and by the illustrated version of the Children’s Dermatology Life Quality Index (CDLQI) for children aged 4–16 years. Secondary outcomes were changes in IDQOL and CDLQI at 4 and 8 months, family impact of childhood atopic dermatitis (Dermatitis Family Impact Questionnaire, DFI), eczema severity (objective SCORAD) and patient satisfaction (Client Satisfaction Questionnaire‐8, CSQ‐8) at 4, 8 and 12 months. Results The mean IDQOL in the dermatologist group improved significantly from 11·6 [SD 8·1; 95% confidence interval (CI) 9·0–14·2] at the baseline to 5·6 (SD 3·9; 95% CI 4·3–7·0) at 12 months with a mean change from the baseline of ?6·5 (SD 6·6; 95% CI ?14·2 to ?8·9; P < 0·001). The mean IDQOL in the nurse practitioner group improved significantly from 10·7 (SD 4·9; 95% CI 9·1–12·3) at baseline to 5·7 (SD 5·4; 95% CI 4·0–7·5) at 12 months with a mean change from the baseline of ?4·9 (SD 5·5; 95% CI ?6·8 to ?3·0; P < 0·001). The between‐groups difference was (?)1·7 (95% CI ?4·6 to 1·2; P = 0·26). The mean CDLQI in the dermatologist group improved significantly from 12·1 (SD 6·3; 95% CI 9·9–14·2) at baseline to 5·6 (SD 4·2; 95% CI 4·2–7·1) at 12 months with a mean change from the baseline of ?5·9 (SD 6·0; 95% CI ?8·0 to ?3·9; P < 0·001). The mean CDLQI in the nurse practitioner group improved significantly from 10·0 (SD 4·4; 95% CI 8·5–11·4) at the baseline to 4·9 (SD 3·5; 95% CI 3·7–6·1) at 12 months with a mean change from the baseline of ?5·2 (SD 4·0; 95% CI ?6·6 to ?3·8; P < 0·001). The between‐groups difference was (?)0·7 (95% CI ?3·3 to 1·7; P = 0·55). The between‐groups comparison was not significant for the IDQOL and the CDLQI at baseline or 4, 8 and 12 months. Both treatment groups showed significant improvement in DFI and objective SCORAD at 12 months. The between‐groups comparison was not significant at baseline or 4, 8 and 12 months. Significantly higher satisfaction levels were observed at 4, 8 and 12 months in the nurse practitioner group. Conclusions The level of care provided by a nurse practitioner in terms of the improvement in the eczema severity and the quality of life outcomes was comparable with that provided by a dermatologist. In addition, the parents were more satisfied with the care that was provided by a nurse practitioner.     

DNA methylation of the filaggrin gene adds to the risk of eczema associated with loss‐of‐function variants

Background Loss‐of‐function variants within the filaggrin gene (FLG) are associated with a dysfunctional skin barrier that contributes to the development of eczema. Epigenetic modifications, such as DNA methylation, are genetic regulatory mechanisms that modulate gene expression without changing the DNA sequence. Objectives To investigate whether genetic variants and adjacent differential DNA methylation within the FLG gene synergistically act on the development of eczema. Methods A subsample (n = 245, only females aged 18 years) of the Isle of Wight birth cohort participants (n = 1456) had available information for FLG variants R501X, 2282del4 and S3247X and DNA methylation levels for 10 CpG sites within the FLG gene. Log‐binomial regression was used to estimate the risk ratios (RRs) of eczema associated with FLG variants at different methylation levels. Results The period prevalence of eczema was 15.2% at age 18 years and 9.0% of participants were carriers (heterozygous) of FLG variants. Of the 10 CpG sites spanning the genomic region of FLG, methylation levels of CpG site ‘cg07548383’ showed a significant interaction with FLG sequence variants on the risk for eczema. At 86% methylation level, filaggrin haploinsufficient individuals had a 5.48‐fold increased risk of eczema when compared to those with wild type FLG genotype (P‐value = 0.0008). Conclusions Our novel results indicated that the association between FLG loss‐of‐function variants and eczema is modulated by DNA methylation. Simultaneously assessing the joint effect of genetic and epigenetic factors within the FLG gene further highlights the importance of this genomic region for eczema manifestation.     

Genotype–phenotype associations in filaggrin loss‐of‐function mutation carriers

Background. Loss‐of‐function mutations in the filaggrin gene (FLG) have been reported to be associated with specific phenotypic characteristics such as hyperlinearity and keratosis pilaris. Objectives. To study phenotypic features in patients with occupational irritant contact eczema of the hands in relation to FLG loss‐of‐function mutations. Materials and methods. In a prospective cohort study, genotype was determined for 459 study subjects for four FLG null alleles, and investigated for selected history, clinical and laboratory features. Results. Overall, 68 patients showed a mutation in the FLG alleles R501X, R2447X, S3247X, and/or 2282del4. Flexural eczema, xerosis cutis, pityriasis alba, dirty neck, pulpitis sicca, hyperlinear palms, keratosis pilaris and family history of eczema were positively associated with FLG mutations (p < 0.05). Although we observed a statistically significant correlation with higher serum IgE in FLG mutation carriers, allergic rhinoconjunctivitis and allergic asthma were not over‐represented in this group. Conclusion. This study shows further genotype–phenotype correlations in patients with occupational irritant contact eczema and FLG mutation carrier status. These features may help to identify those with FLG mutations on a specific phenotype basis.     

The natural history of eczema from birth to adult life: a cohort study

Background Eczema is common in infancy; however, there is little evidence about its natural history to adulthood. Objectives To study the natural history of eczema from birth to young adult life with particular reference to its relation to atopy. Methods A birth cohort of children with atopic family histories was followed for 23 years. Clinical examinations were conducted until the age of 7 years, skin‐prick tests and serum total IgE were recorded in infancy and at ages 7 and 23 years, and questionnaires about eczema symptoms were completed at 15 and 23 years. Results Information was obtained on 497 subjects at birth, 482 at 1 year, 440 at 7 years, 363 at 15 years and 304 at 23 years. Eczema usually remitted from age 1 to 7 years but became more persistent from the age of 15 years, especially in those who were atopic. The prevalence of eczema rose in women from age 15 to 23 years but declined in men. Adults with eczema had higher IgE than those without at 3 months (geometric mean 3·0 vs. 1·7 kU L^?1; P = 0·01), 7 years (107·9 vs. 45·2 kU L^?1; P = 0·01) and 23 years (123·4 vs. 42·3 kU L^?1; P = 0·01), and were more likely to have had positive skin‐prick tests at 1 year of age. Current eczema was associated with raised IgE in infancy and adulthood but not in childhood. Conclusions Predisposed infants and children with eczema usually grow out of the disease, but in adolescence it is more likely to persist. Adult eczema is related to atopy from the age of 3 months.     

Usefulness of a global clinical ichthyosis vulgaris scoring system for predicting common FLG null mutations in an adult caucasian population

Background Loss of function FLG alleles were first identified as causative of ichthyosis vulgaris (IV) and were subsequently found to be major predisposing factors for atopic dermatitis (AD) and atopic disorders. Objectives To identify independent factors associated with the clinical IV phenotype in adult caucasian patients with AD and to assess the performance of a global clinical severity score of IV in predicting common FLG null mutations. Patients and methods This was a prospective study conducted from January 2007 to June 2008. Adult patients attending the department of dermatology with a diagnosis of AD with or without IV were eligible to participate. For each patient, five clinical signs of IV were scored from 0 to 3 – diffuse xerosis, hyperlinearity of palms, scales on legs, scalp desquamation and keratosis pilaris – and a global IV clinical severity score was derived (0–15). Age of onset of AD, SCORAD (SCORing of Atopic Dermatitis), family and personal history for other signs of atopy, and total immunoglobulin E were recorded. Genotyping was performed for R501X and 2282del4. Univariate and multivariate analysis for factors associated with AD or AD + IV were conducted. Results In univariate analysis, family history of atopy, global clinical severity scoring and 2282del4 FLG mutation were positively correlated with the AD + IV phenotype. Using multivariate analysis, SCORAD for AD (OR 0·94, P = 0·01) and global clinical severity scoring for AD + IV (OR 2·62, P < 0·0001) were found to be independent factors. Conclusions The 2282del4 FLG mutation was confirmed as a good marker of early‐onset disease. Moreover, our global clinical severity score yielded a good negative predictive value of common caucasian null FLG mutations.     

What causes flares of eczema in children?

Summary Background Although eczema affects 2–20% of children worldwide, there is little direct evidence on the role of environmental factors in disease flares. Objectives We sought to identify which environmental factors might worsen eczema. Methods Sixty children aged 0–15 years with eczema were studied intensively for up to 9 months. Daily electronic diaries and portable data loggers were used to record indoor exposures, and external meteorological data were obtained from a local monitoring centre. The primary outcome was a daily ‘bother’ score. Autoregressive moving average models were used to study the impact of exposures on eczema severity for individuals. Random effects modelling pooled estimated regression coefficients across participants. Results Increased severity was associated with nylon clothing [pooled regression coefficient 0·23, 95% confidence interval (CI) 0·03–0·43], dust (0·53, 0·23–0·83), unfamiliar pets (0·22, 0·10–0·34), sweating (0·24, 0·09–0·39) and shampoo (0·07, 0·01–0·14). The latter was enhanced in cold weather (0·30, 0·04–0·57). Body‐site specificity was observed for nylon clothing, (trunk P =0·02, limbs P = 0·03), wool clothing (trunk P = 0·03, but not limbs P = 0·62) and unfamiliar pets (hands P < 0·001). A combination of any three of seven likely variables was associated with disease worsening (pooled regression coefficient 0·41, 95% CI 0·20–0·63). Conclusions This exploratory study suggests that nylon clothing, dust, unfamiliar pets, sweating and shampoos may play a direct role in worsening eczema in children with eczema. Combinations of exposures acting in concert may also be important. Such knowledge may be useful to families with eczema and could lead to better strategies for preventing flares.     

Wide spectrum of filaggrin-null mutations in atopic dermatitis highlights differences between Singaporean Chinese and European populations

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.     

The association between null mutations in the filaggrin gene and contact sensitization to nickel and other chemicals in the general population

Background It was recently shown that filaggrin gene (FLG) null mutations are positively associated with nickel sensitization. We have hypothesized that histidine‐rich filaggrin proteins in the epidermis chelate nickel ions and prevent their skin penetration and exposure to Langerhans cells. Furthermore, we have proposed that the low degree of genetic predisposition to nickel sensitization found by a Danish twin study was explained by a high prevalence of ear piercing among participants resulting in ‘bypassing’ of the filaggrin proteins. Objectives To investigate the association between FLG null mutations and (nickel) contact sensitization. Methods A random sample of 3335 adults from the general population in Denmark was patch tested and genotyped for R501X and 2282del4 in the FLG gene. Results The combined carrier frequency of FLG null mutations was 8·1%. Nickel, fragrance and contact sensitization to at least one allergen were not associated with FLG null mutations. A crude analysis on women who did not have ear piercings revealed a positive association between FLG null mutations and nickel sensitization [8·3% vs. 2·4%; odds ratio (OR) 3·71, 95% confidence interval (CI) 0·73–18·96] as well as between FLG null mutations and allergic nickel dermatitis (8·3% vs. 1·3%; OR 6·75, 95% CI 1·17–38·91). FLG mutation status and atopic dermatitis were positively associated with neomycin or ethylenediamine sensitization. Conclusions This study suggests that FLG null mutations may be a risk factor for the development of nickel sensitization. However, ear piercing was a much stronger risk factor in our general population and we could therefore identify a positive association only in women without ear piercings. Contact sensitization to specific chemicals is related to treatment exposure.     

Effect of Aqueous Cream BP on human stratum corneum in vivo

Background Aqueous Cream BP is widely prescribed to patients with eczema to relieve skin dryness. The formulation contains sodium lauryl sulphate (SLS), a chemical that is a known skin irritant and a commonly used excipient in personal care and household products. The chronic effects of Aqueous Cream BP application on skin barrier function have not been determined. Objectives To characterize and assess skin barrier function of healthy skin after application of Aqueous Cream BP and to study the physical effects of the formulation on the stratum corneum (SC). Methods The left and right volar forearms of six human volunteers were each separated into treated and control sides. The treated sides of each forearm were subjected to twice daily applications of Aqueous Cream BP for 4 weeks at the end of which concomitant tape stripping and transepidermal water loss (TEWL) measurements were made. The untreated sides of the forearms were not exposed to any products containing SLS during the study period. Results Changes in SC thickness, baseline TEWL and rate of increase in TEWL during tape stripping were observed in skin treated with Aqueous Cream BP. The mean decrease in SC thickness was 1·1 μm (12%) (P = 0·0015) and the mean increase in baseline TEWL was 2·5 g m^?2 h^?1 (20%) (P < 0·0001). Reduced SC thickness and an increase in baseline TEWL, as well as a faster rate of increase in TEWL during tape stripping, were observed in 16 out of 27 treated skin sites. Conclusions The application of Aqueous Cream BP, containing ～1% SLS, reduced the SC thickness of healthy skin and increased its permeability to water loss. These observations call into question the continued use of this emollient on the already compromised barrier of eczematous skin.     

Filaggrin null mutations associate with increased frequencies of allergen‐specific CD4+ T‐helper 2 cells in patients with atopic eczema

Background Filaggrin null mutations associate with atopic eczema and also with asthma when present with eczema. However, while epidermal dysfunction is an important factor in disease pathogenesis, it is unclear how such dysfunction interacts with immune responses to contribute to cutaneous and other inflammatory atopic disease. Objectives To gain a better understanding of the mechanisms underlying such predisposition in order to understand different disease phenotypes and possibly identify potential treatment targets. Methods We studied 33 individuals with atopic eczema and used interleukin‐4 immunospot and human leucocyte antigen class II tetrameric complexes to investigate the peripheral blood allergen‐specific CD4+ T‐cell responses. Results Filaggrin null mutations associated with significantly (P < 0·05) higher frequencies of allergen‐specific CD4+ T‐helper 2 cell responses. Conclusions These data would support a model where barrier dysfunction possibly promotes greater allergen penetration and delivery to drive allergen‐specific CD4+ T cells. This could further contribute to respiratory and cutaneous inflammatory disease.