Aetiology of atopic dermatitis

Atopic dermatitis is a complex, multifactorial disease with a host of genetic and environmental factors contributing to its development.

Genetic and environmental factors affecting the development of atopic dermatitis.

Figure 5: Genetic and environmental factors affecting the development of atopic dermatitis (Nutten, 2015).

Genetic susceptibility

A family history of atopic disease strongly correlates with atopic dermatitis with around 70% of patients with atopic dermatitis having family members with atopic disease. In fact, the risk of atopic dermatitis increases by 2- to 3-fold when one parent has a history of atopic disease and by 3- to 5-fold when it is both parents (Avena-Wood, 2017). 

Subsequent genetic analyses have identified several chromosomal regions linked to the development of atopic dermatitis. These include genes on chromosome regions 1q21 and 5q31 to 5q33 (Avena-Wood, 2017). In addition, more than 100 published articles have identified over 80 genes with a possible association with atopic dermatitis (McPherson, 2016).

Filaggrin

Filaggrin is a major structural protein of the stratum corneum and plays a crucial role in skin barrier integrity (Kaufman et al., 2018). The FLG gene, which encodes the filaggrin protein, is located on chromosome 1q21.3 and several loss-of-function mutations have been identified (Nutten, 2015). Patients with atopic dermatitis carrying a FLG loss-of-function mutation exhibit an earlier onset of disease, more severe disease, a higher rate of eczema herpeticum, and a greater incidence of other atopic diseases versus those with wildtype FLG (Kaufman et al., 2018).

Approximately 10% of white Europeans are heterozygous carriers of a FLG loss-of-function mutation, however, this increases to about 50% of European atopic dermatitis patients (Nutten, 2015; Avena-Wood, 2017). However, this falls to 27% of Asian patients and is rare in African patients with no association at all observed in an Ethiopian study (Kaufman et al., 2018). These studies suggest that while FLG mutations are associated with the development of atopic dermatitis, the fact that they are absent in many patients and that immune-mediated skin inflammation is similar between patients with and without FLG mutations, other genes are also likely to play a role (Kaufman et al., 2018).

Interleukins

Several interleukins have been identified as potentially playing a role in the pathophysiology of atopic dermatitis. The chromosome region 5q31 to 5q33 has been linked to atopic dermatitis development and within this region are the genes for IL-4, IL-5, IL-12, IL-13 and granulocyte-macrophage colony stimulating factor (GM-CSF). These cytokines can influence atopic dermatitis by upregulating IgE production and reducing the expression of proteins involved in skin barrier function, including filaggrin (Avena-Wood, 2017; Kim & Leung, 2018).

Skin flora

The skin of patients with atopic dermatitis is frequently colonised by Staphylococcus aureus, which can exacerbate or aggravate skin lesions (Cardona et al., 2006). The cause of this may be reduced production of antimicrobial peptides that form part of the innate immune system and are typically found on the skin. These have been seen to be reduced in patients with atopic dermatitis and may be the reason that they are more susceptible to infection (Ong et al., 2002).  Interestingly, a recent study showed that the skin of African American patients with atopic dermatitis was typically colonised by different strains of S. aureus than European American or Mexican American patients (who were shown to have similar strains on their skin). This may go on to influence the presentation and infection types seen in different patient populations (Merriman et al., 2016). 

Environmental factors

A range of environmental factors have been identified that affect the risk of developing atopic dermatitis. Some of these, such as climate variations, can be seen through the differing prevalence rates reported between countries and geographic regions. These environmental factors can influence skin barrier function while microbial exposure may influence immune sensitisation (Nutten, 2015). The below table outlines several environmental risk factors that potentially influence atopic dermatitis development although some of the data remains inconclusive.

Table 1: Selected environmental risk- and protective-factors for atopic dermatitis (Eichenfield et al., 2014; Simpson et al., 2014; Nutten, 2015; Glatz et al., 2018).

Selected environmental risk- and protective-factors for atopic dermatitis (Eichenfield et al., 2014; Simpson et al., 2014; Nutten, 2015; Glatz et al., 2018).