Loss-of-function mutations in the gene encoding filaggrin cause ichthyosis vulgaris.

Ichthyosis vulgaris (OMIM 146700) is the most common inherited disorder of keratinization and one of the most frequent single-gene disorders in humans. The most widely cited incidence figure is 1 in 250 based on a survey of 6,051 healthy English schoolchildren. We have identified homozygous or compound heterozygous mutations R501X and 2282del4 in the gene encoding filaggrin (FLG) as the cause of moderate or severe ichthyosis vulgaris in 15 kindreds. In addition, these mutations are semidominant; heterozygotes show a very mild phenotype with incomplete penetrance. The mutations show a combined allele frequency of approximately 4% in populations of European ancestry, explaining the high incidence of ichthyosis vulgaris. Profilaggrin is the major protein of keratohyalin granules in the epidermis. During terminal differentiation, it is cleaved into multiple filaggrin peptides that aggregate keratin filaments. The resultant matrix is cross-linked to form a major component of the cornified cell envelope. We find that loss or reduction of this major structural protein leads to varying degrees of impaired keratinization.

Common loss-of-function variants of the epidermal barrier protein filaggrin are a major predisposing factor for atopic dermatitis.

Atopic disease, including atopic dermatitis (eczema), allergy and asthma, has increased in frequency in recent decades and now affects approximately 20% of the population in the developed world. Twin and family studies have shown that predisposition to atopic disease is highly heritable. Although most genetic studies have focused on immunological mechanisms, a primary epithelial barrier defect has been anticipated. Filaggrin is a key protein that facilitates terminal differentiation of the epidermis and formation of the skin barrier. Here we show that two independent loss-of-function genetic variants (R510X and 2282del4) in the gene encoding filaggrin (FLG) are very strong predisposing factors for atopic dermatitis. These variants are carried by approximately 9% of people of European origin. These variants also show highly significant association with asthma occurring in the context of atopic dermatitis. This work establishes a key role for impaired skin barrier function in the development of atopic disease.

Therapeutic patient education in atopic dermatitis: worldwide experiences.

Therapeutic patient education (TPE) has proven effective in increasing treatment adherence and improving quality of life (QoL) for patients with numerous chronic diseases, especially atopic dermatitis (AD). This study was undertaken to identify worldwide TPE experiences in AD treatment. Experts from 23 hospitals, located in 11 countries, responded to a questionnaire on 10 major items. Patients in TPE programs were mainly children and adolescents with moderate to severe AD or markedly affected QoL. Individual and collective approaches were used. Depending on the center, the number of sessions varied from one to six (corresponding to 2 to 12 hours of education), and 20 to 200 patients were followed each year. Each center's education team comprised multidisciplinary professionals (e.g., doctors, nurses, psychologists). Evaluations were based on clinical assessment, QoL, a satisfaction index, or some combination of the three. When funding was obtained, it came from regional health authorities (France), insurance companies (Germany), donations (United States), or pharmaceutical firms (Japan, Italy). The role of patient associations was always highlighted, but their involvement in the TPE process varied from one country to another. Despite the nonexhaustive approach, our findings demonstrate the increasing interest in TPE for managing individuals with AD. In spite of the cultural and financial differences between countries, there is a consensus among experts to integrate education into the treatment of eczema.

Managing childhood eczema: qualitative study exploring carers' experiences of barriers and facilitators to treatment adherence.

AIM: To explore parents and carers' experiences of barriers and facilitators to treatment adherence in childhood eczema BACKGROUND: Childhood eczema is common and causes significant impact on quality of life for children and their families, particularly due to sleep disturbance and itch. Non-adherence to application of topical treatments is the main cause of treatment failure. DESIGN: Qualitative interview study. METHODS: Qualitative interviews were carried out with 31 carers from 28 families of children with eczema. Participants were recruited through primary care and included if they had a child aged 5 or less with a diagnosis of eczema. Interviews were carried out between December 2010-May 2011. Data were analysed using a constant comparative approach. FINDINGS: Barriers to treatment adherence included carer beliefs around eczema treatment, the time consuming nature of applying topical treatments, and child resistance to treatment. Families employed a range of strategies in an attempt to work around children's resistance to treatment with varying success. Strategies included involving the child in treatment, distracting the child during treatment, or making a game of it, using rewards, applying treatment to a sleeping child or, in a few cases, physically restraining the child. Some carers reduced frequency of applications in an attempt to reduce child resistance. CONCLUSIONS: Regular application of topical treatments to children is an onerous task, particularly in families where child resistance develops. Early recognition and discussion of resistance and better awareness of the strategies to overcome this may help carers to respond positively and avoid establishing habitual confrontation.

Towards global consensus on outcome measures for atopic eczema research: results of the HOME II meeting.

The use of nonstandardized and inadequately validated outcome measures in atopic eczema trials is a major obstacle to practising evidence-based dermatology. The Harmonising Outcome Measures for Eczema (HOME) initiative is an international multiprofessional group dedicated to atopic eczema outcomes research. In June 2011, the HOME initiative conducted a consensus study involving 43 individuals from 10 countries, representing different stakeholders (patients, clinicians, methodologists, pharmaceutical industry) to determine core outcome domains for atopic eczema trials, to define quality criteria for atopic eczema outcome measures and to prioritize topics for atopic eczema outcomes research. Delegates were given evidence-based information, followed by structured group discussion and anonymous consensus voting. Consensus was achieved to include clinical signs, symptoms, long-term control of flares and quality of life into the core set of outcome domains for atopic eczema trials. The HOME initiative strongly recommends including and reporting these core outcome domains as primary or secondary endpoints in all future atopic eczema trials. Measures of these core outcome domains need to be valid, sensitive to change and feasible. Prioritized topics of the HOME initiative are the identification/development of the most appropriate instruments for the four core outcome domains. HOME is open to anyone with an interest in atopic eczema outcomes research.

'You don't know which bits to believe': qualitative study exploring carers' experiences of seeking information on the internet about childhood eczema.

OBJECTIVE: We sought to explore parents and carers' experiences of searching for information about childhood eczema on the internet. DESIGN: A qualitative interview study was carried out among carers of children aged 5 years or less with a recorded diagnosis of eczema. The main focus of the study was to explore carers' beliefs and understandings around eczema and its treatment. As part of this, we explored experiences of formal and informal information seeking about childhood eczema. Transcripts of interviews were analysed thematically. SETTING: Participants were recruited from six general practices in South West England. PARTICIPANTS: Interviews were carried out with 31 parents from 28 families. RESULTS: Experiences of searching for eczema information on the internet varied widely. A few interviewees were able to navigate through the internet and find the specific information they were looking for (for instance about treatments their child had been prescribed), but more found searching for eczema information online to be a bewildering experience. Some could find no information of relevance to them, whereas others found the volume of different information sources overwhelming. Some said that they were unsure how to evaluate online information or that they were wary of commercial interests behind some information sources. Interviewees said that they would welcome more signposting towards high quality information from their healthcare providers. CONCLUSIONS: We found very mixed experiences of seeking eczema information on the internet; but many participants in this study found this to be frustrating and confusing. Healthcare professionals and healthcare systems have a role to play in helping people with long-term health conditions and their carers find reliable online information to support them with self-care.

A randomised, controlled trial of a 4% cutaneous emulsion of sodium cromoglicate in treatment of atopic dermatitis in children.

INTRODUCTION: Atopic dermatitis (AD) is a chronic inflammatory skin disease. Sodium cromoglicate (SCG) is a chromone with anti-inflammatory, anti-itch and anti-allergic activity. This trial is a 12-week comparison (RCT) of a 4% SCG cutaneous emulsion with its vehicle in AD. MATERIALS AND METHODS: 208 children aged 2-12 years participated, 104 in each group. The primary endpoint was change in SCORAD score. Secondary endpoints included SASSAD score, topical steroid usage and global assessments. RESULTS: SCORAD was reduced by 28% (SCG group) and by 19% (vehicle): difference was statistically significant (p = 0.03) after 8 weeks and nearly significant (p = 0.09) after 12. A similar result occurred in SASSAD (p = 0.001 at 8 weeks). In subjects without major protocol deviations (SCG-64, vehicle-63), difference in SCORAD remained significant at 12 weeks (p = 0.04). Weight of topical steroids reduced in both groups: -0.60 ± 1.3 g/day (35%), SCG and -0.05 ± 1.1 g/day vehicle (p = 0.04). Treatment success, defined as investigator global opinion graded very or moderately effective, was significantly more frequent in SCG group (p = 0.025). Application site discomfort reported by 12.5% of subjects in SCG group and 16.5% in vehicle group. CONCLUSIONS: SCG 4% cutaneous emulsion provides an effective, well-tolerated, steroid-sparing treatment for AD in children.

Experiences of carers managing childhood eczema and their views on its treatment: a qualitative study.

BACKGROUND: Childhood eczema causes significant impact on quality of life for some families, yet non-concordance with treatment is common. AIM: To explore parents' and carers' views of childhood eczema and its treatment. DESIGN AND SETTING: Qualitative interview study in primary care in the south of England. METHOD: Carers of children aged ≤5 years with a recorded diagnosis of eczema, who reported that eczema was still a problem, were invited to participate. Thirty-one parents were interviewed from 28 families. RESULTS: Many parents expressed frustration with both medical care and prescribed treatments. They felt their child's suffering was not 'taken seriously', and experienced messages about a 'trial and error' prescribing approach and assurance that their child would 'grow out of it' as a further 'fobbing off', or dismissal. Many carers were ambivalent about eczema treatments, mainly topical corticosteroids but also emollients. Dietary exclusions as a potential cure were of interest to most families, although they perceived healthcare professionals as uninterested in this. Families varied in the extent to which they felt able to manage eczema and the length of time taken to gain control. In some instances, this was linked to not understanding advice or receiving conflicting advice from different healthcare providers. CONCLUSION: Poor concordance with treatments seems unsurprising in the presence of such dissonance between carers' and healthcare providers' agendas. Acknowledging the impact of the condition, greater attention to how key messages are delivered and addressing carers' treatment beliefs are likely to improve engagement with effective self-care.

Emollients, education and quality of life: the RCPCH care pathway for children with eczema.

OBJECTIVES: The Royal College of Paediatrics and Child Health (RCPCH) Science and Research Department was commissioned by the Department of Health to develop national care pathways for children with allergies. The eczema pathway focuses on defining the competences to improve the equity of care received by children with eczema. METHOD: The eczema pathway was developed by a multidisciplinary working group and was based on a comprehensive review of evidence. The pathway was reviewed by a broad group of stakeholders including paediatricians, allergists, dermatologists, specialist nurses, dietician, patients' representatives and approved by the Allergy Care Pathways Project Board and the RCPCH Clinical Standards Committee. It was also reviewed by a wide range of stakeholders. RESULTS: The results are presented in three sections: the evidence review, mapping and the core knowledge document. The various entry points to the ideal pathway of care are defined from self-care through to follow-up. There is considerable emphasis on good skin care and when allergy problems should be dealt with. The pathway algorithm and associated competences can be downloaded from http://www.rcpch.ac.uk/allergy/eczema. CONCLUSIONS: Effective eczema management is holistic and encompasses an assessment of severity and impact on quality of life, treatment of the inflamed epidermal skin barrier, recognition and treatment of infection and assessment and management of environmental and allergy triggers. Patient and family education which seeks to maximise understanding and concordance with treatment is also important in all children with eczema.

Filaggrin mutations are genetic modifying factors exacerbating X-linked ichthyosis.

Mutations inactivating the STS gene cause X-linked ichthyosis (XLI), whereas null mutations in the FLG gene cause ichthyosis vulgaris. Two brothers presented with XLI. One had a typical fine scaling, and the other was much more severely affected. Both patients carried STS missense mutation T165I. Furthermore, the more severely affected patient also carried heterozygous FLG mutation R501X, which was absent from his mildly affected brother. These data suggest that disrupting epidermal differentiation via different pathways can increase phenotypic severity. Owing to the high population frequency of FLG mutations, filaggrin is a possible genetic modifier in other genodermatoses.

Zoonotic poxvirus infections in humans.

PURPOSE OF REVIEW: The 2003 USA monkeypox epidemic caused by imported African rodents, newly emergent poxvirus zoonoses in Brazil and the possible use of variola virus for biological warfare has led to renewed interest in poxviruses and anti-poxviral therapies. Increasing foreign travel and importation of exotic animal species increases the likelihood of poxvirus infections occurring outside their usual geographical range and diagnostic delay has important implications. The present review provides an overview of these rare zoonoses. RECENT FINDINGS: Three genera of Poxviridae are known to cause human zoonoses: orthopoxviruses, parapoxviruses and yatapoxvirus. Most cases are occupational, sporadic and have few cutaneous lesions with low morbidity. The exception is monkeypox, similar to smallpox, with significant morbidity and childhood mortality. Molecular characterization using polymerase chain reaction (PCR) amplification and other methods provides accurate phylogenetic identification and suggests that a cowpox-like virus is the probable ancestor of variola and other zoonotic poxviruses. DNA genomic sequencing of the Brazilian Cantagalo and Araçatuba viruses shows a close relationship to vaccinia virus. Poxviruses have potential in cancer immunotherapy and their ability to evade host-cell immune responses may provide a basis for new antipoxvirus therapies. Other agents, particularly nucleoside phosphonates such as cidofovir, show therapeutic action against poxviruses. SUMMARY: Human zoonotic poxvirus infections are rare but increasingly encountered outside their usual geographical range. The 2003 USA monkeypox outbreak emphasizes the importance of early accurate diagnosis, particularly because increasing numbers of immunosuppressed individuals increases the potential for severe or fatal infections. PCR methodology enables accurate phylogenetic typing and has identified new diseases, but rapid, reliable methods must be made available for clinicians. More research into therapeutic agents for the prevention and treatment of poxvirus infections is required.