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.

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.

The misery of living with atopic eczema (syn. dermatitis, AD) cannot be overstated for it may have a profoundly negative effect on the health-related quality of life (HRQoL) of children and their family unit in many cases. As it is one of the commonest chronic relapsing childhood dermatosis (UK lifetime prevalence 16-20% by 20 years), with increasing worldwide prevalence, this has major social and financial implications for individuals, healthcare providers and society as a whole. This review explores the impact of AD on the lives of children and their family units and the use of some of the recently developed HRQoL measures, which have enabled investigation and categorisation of the physical, psychological and psycho-social effects of childhood eczema across all aspects of life. These effects include symptoms of itching and soreness, which cause sleeplessness in over 60%. Sleep deprivation leads to tiredness, mood changes and impaired psychosocial functioning of the child and family, particularly at school and work. Embarrassment, comments, teasing and bullying frequently cause social isolation and may lead to depression or school avoidance. The child's lifestyle is often limited, particularly in respect to clothing, holidays, staying with friends, owning pets, swimming or the ability to play or do sports. Restriction of normal family life, difficulties with complicated treatment regimes and increased work in caring for a child with eczema lead to parental exhaustion and feelings of hopelessness, guilt, anger and depression. The hidden costs involved in eczema management can be significant and have particular impact on lower income families. The impairment of quality of life caused by childhood eczema has been shown to be greater than or equal to other common childhood diseases such as asthma and diabetes, emphasising the importance of eczema as a major chronic childhood disease. HRQoL measures are proving to be valuable tools for use in the clinical setting, as outcome measures for pharmaceutical studies, for health economics and audit purposes. It is therefore recommended that in future, they should be used in conjunction with objective measures of severity, as part of the assessment process of a child with atopic eczema. Lack of information on eczema and treatments heightens parental anxiety. Education of all individuals involved in the care of children with eczema is fundamental in the management of AD and it is essential to provide simple clear, unambiguous information on treatment and disease management in order to reduce the negative impact on HRQoL.

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.

No abstract