Improving Our Understanding of Atopic Dermatitis Will Require Research Beyond Immunology and Dermatology

This issue of International Journal of Toxicology presents a review article entitled, “Atopic Eczema: Genetic Associations and Potential Links to Developmental Exposures” by Stephen Bauer (Belmont Abbey College; see 187–198). You may well ask what a review article about a common inflammatory skin disease is doing in a journal devoted to general toxicology. Surely, such a paper would be more appropriate for journals devoted to medical, immunological, and dermatological fields, would it not? There are actually excellent recent reviews on this disease in dermatological/medical journals. ^{1 –3} The present article is intended to raise consciousness among professionals in the field of toxicology because the increasing worldwide prevalence of this disease is likely related, at least in part, to both pre- and postnatal exposures to a variety of environmental toxicants, stressors, and allergens. ³ Accordingly, the much needed research to fully characterize and develop solutions to this problem will need to include basic researchers in toxicology as well as scientists working in risk assessment and government regulatory agencies.

Atopic eczema (also known as atopic dermatitis) is a big problem. Intense itch, sleep deprivation, and profound psychosocial impact due to visible lesions exact an enormous toll of suffering not only on the patients but also on their relatives . The increased risk of depression, anxiety, conduct disorder, and autism in severely afflicted children and an increased likelihood of depression in adult sufferers, as well as other comorbidities, make atopic eczema/dermatitis a very significant biomedical concern. The 2010 World Health Organization Global Burden of Disease Study ranked atopic dermatitis first among common skin diseases with respect to disability-adjusted life years and years lived with a disease. ¹ It has a large economic impact too. Cost of illness studies in Australia, Germany, the United Kingdom, the Netherlands, and the United States produced estimates that have ranged from less than US$100 to greater than US$2,000 per patient per year. Other studies have produced estimates of direct costs in the United States alone of nearly US$5 billion (adjusted to 2014 dollars), which does not even include the considerable indirect costs of over the counter remedies and lifestyle changes. ^1,4

For many years, it has been debated whether atopic dermatitis is primarily caused by dysfunction of the immune system or a dysfunction of the skin barrier, and this has led to the so-called “inside-out” and “outside-in” paradigms to explain disease pathogenesis. ⁵ Available evidence from years of published work in skin biology and immunology is compatible with both models, and it is now clear that there is a complex interplay between genetically determined defects in skin barrier function and immune hyperreactivity, which in concert with developmental, environmental, and lifestyle factors, elicit the symptoms of the disease. Indeed, a number of high-quality epidemiology and genome-wide association studies have been conducted and have identified more than 30 susceptibility loci associated with atopic dermatitis risk, and many of these genes encode proteins involved in skin barrier function (notably Filaggrin), as well as innate host defenses and T-cell function. ⁶ However, frustratingly or fascinatingly (depending on your perspective) one’s genetic endowment only explains approximately 20% of the estimated heritability. ¹ This suggests that the majority of the factors that determine risk reside at levels other than genetic, and these would include epigenetic, posttranscriptional/translational modifications, micro RNA, metabanomic, proteomic, lipidomic, lifestyle, behavioral, and dietary factors, as well as environmental exposures. We are only beginning to understand the contribution of these other factors to disease risk.

It is now an exciting time in the atopic dermatitis field with the recent successes of biologic therapies such as dupilumab, and low-molecular-weight topical drugs such as crisaborole. ^{7 –9} However, not all sufferers worldwide will have access to such therapies (for economic and other reasons), and many on the mild end of the severity spectrum may not need such potent systemic interventions as the biologic therapies.

For all of these reasons, there is a clear need to better characterize the factors that contribute to risk if we are to achieve the dream of personalized therapies for atopic dermatitis, which manifests as a very large severity continuum. This journey will no doubt need to involve researchers who are likely to read this and other journals in the field of toxicology.