LAUSR

Atopic dermatitis (AD) is among the most common skin diseases that affect children and adults. It has been associated with several other atopic illnesses like asthma, seasonal allergies and food allergies and is often considered to be the first illness on the march to these other allergic illnesses. PreventADALL was a randomized controlled trial of 2397 mother–child pairs designed to evaluate AD therapeutic prevention strategies using oil-emulsified baths and topical cream. The results showed no therapeutic benefit on the incidence of AD (AD incidence 8% for non-intervention vs. 11% for intervention). Filaggrin loss-of-function (LoF) mutations have been associated with the prevalence and severity of AD and are the most prevalent genetic mutations associated with this condition. The FLG gene is responsible for protein coding of profilaggrin, which is ultimately processed to filaggrin and is important for skin barrier function. FLG genetic variation varies by ancestry and can vary within race. In this issue of the BJD, Hoyer et al. used, regardless of treatment assignment, the prospectively collected PreventADALL dataset for a post hoc evaluation of the association of filaggrin LoF with the prevalence of AD, eczema and skin barrier dysfunction. The latter was assessed by transepidermal water loss (TEWL), which can be technically difficult to measure. Children from PreventADALL were genotyped for the most common European filaggrin LoF mutations – R501X, 2282del4 and R2447X – and were evaluated at 3, 6 and 12 months of age for the presence of dry skin, eczema, AD and skin barrier function (TEWL). About 9% of the cohort had filaggrin LoF, and all subsequent analyses compared patients with filaggrin LoF variants to those without. At all three timepoints filaggrin LoF was associated with eczema, and at the latter two timepoints with AD. Higher TEWL was only noted at month 6 among those with filaggrin LoF. What did we learn? Filaggrin LoF variants were known to be relatively uncommon in the general population and more common in those with AD. However, if barrier dysfunction, as measured by TEWL, is the mechanism that drives the causal relationship between filaggrin LoF and AD, then TEWL should have been elevated at all timepoints and preceded the diagnosis of AD in infants. It is possible that TEWL might not be a good measure of the causal pathway of filaggrin insufficiency and AD, but a better measure of AD severity. All filaggrin LoF variants are not clinically the same, so by focusing on only three variants, other important variants might not have been measured. Keratinocyte filaggrin production is also diminished by T helper 2 cytokines that are common to AD, and this might occur later in life. As a result, immune pathways may have a greater effect on TEWL than filaggrin LoF. Filaggrin insufficiency resulting in an impaired barrier function and then AD is likely to occur both genetically via LoF variants and also via immune inhibition, making filaggrin a not so innocent bystander. As noted by Hoyer et al., further study is needed.