ORIGINAL ARTICLE, p 1302
Filaggrin molecules and their metabolites are crucial for skin barrier functions as they organize the keratin filaments and maintain skin hydration. Loss-of-function mutations in the filaggrin gene (FLG) affect about 10% of people of European descent, resulting in lower levels of filaggrin and its metabolites.1,2 Hence, the skin of heterozygous mutation carriers is in many ways fundamentally different from normal skin, showing xerosis, scales, keratosis pilaris and palmar hyperlinearity, the hallmarks of ichthyosis vulgaris. FLG mutation carriers have a higher risk of atopic dermatitis, asthma, rhinitis and food allergies presumably due to increased skin penetration of allergens.3 As filaggrin molecules are metabolized to their constituent amino acids when the relative humidity drops to below 80%,4FLG mutation carriers display reduced synthesis of the osmolytic ‘natural moisturizing factor’ intended to protect the skin from drying. Based on clinical observations, it has therefore become apparent that FLG mutation carriers are prone to develop inflammation mainly on the dorsal aspects of the fingers and hands,5 sites that are exposed to environmental insults, e.g. sun and wind. Also, FLG mutation carriers develop digital fissures (chapping) more often than those who do not carry the mutation.6
Concomitant exposure to irritants and contact allergens is frequent, especially in the work environment, and may cause contact dermatitis (CD). Pertinently, skin inflammation impedes the synthesis of filaggrin, further reducing skin barrier functions in FLG mutation carriers.7 While previous studies have rejected an association between allergic CD and FLG mutations,8 a higher prevalence of nickel sensitization and an earlier onset of allergic nickel CD have been identified in FLG mutation carriers.9–11 This is probably explained by the lower levels of nickel-chelating histidine residues, a main metabolite of filaggrin, resulting in increased skin penetration of nickel ions. While the FLG mutations alone do not constitute a risk factor for contact sensitization to common haptens (apart from nickel), these are strongly associated with contact sensitization in individuals who have had dermatitis (manuscript in preparation). This finding is probably explained by concomitant exposure to allergens and irritants, which insult the skin barrier, recruit immune cells and cause contact sensitization. In support of this interpretation, case–control studies have shown significant associations between FLG mutations and combined irritant and allergic CD, as well chronic irritant CD.12,13
In this issue of the BJD, Landeck et al.,14 report novel and important findings. A 3-year prospective observational study was performed in 459 patients with occupational irritant CD on the hands. The authors show that not only are hand eczema scores higher in individuals with atopy and FLG mutations, but more importantly, that atopy patients with FLG mutations had more sick leave and a threefold increased risk of job loss compared with controls. Because FLG mutations are associated with early onset and persistence of hand eczema,15 it is crucial that healthcare providers offer special information to mutation carriers. They should be guided towards professions without, or with little, irritant and allergen exposure and be instructed to use moisturizers continuously to maintain skin barrier functions. In those who have already developed hand eczema, early, intensive, multidisciplinary intervention should be initiated to limit morbidity.16 This is likely to prevent personal grief, and save the patient and societies from unnecessary healthcare expenses for the benefit of all.