Atopic dermatitis is believed to affect up to 20-30% of school-age children in some national populations. The disease has significant social implications, such as causing lost time from school, and can severely affect quality of life, with pruritus leading to sleep deprivation in both children and their parents. For many clinicians, atopic dermatitis is a difficult-to-treat condition, with limited treatment options that have only a minor impact on the symptoms and which do not address the underlying pathophysiology.
There is optimism that this can change, according to Lawrence Eichenfield, MD, who points to intriguing research looking at whether early life treatment of epidermal barrier disruption may shut down the development of atopic dermatitis.
William Ju, MD: Atopic dermatitis has historically been a frustrating disease for clinicians and patients. Do you see that changing in the near future?
Lawrence Eichenfield, MD: This is an exciting time in the field of atopic dermatitis, as there are a host of topical and systemic agents in the pipeline that offer great hope for the millions of patients suffering from this skin condition. In particular, we have learned a lot about the pathogenesis of atopic dermatitis and the intrinsic genetically mediated skin barrier dysfunction, which is associated with filaggrin mutations, and, ultimately, xerotic skin in early life that is manifested by decreased hydration levels and increased transepidermal water loss. In turn, this “leakier skin” may create a set-up for cutaneous sensitization. There have also been tremendous advances in the immunology of eczema using a variety of techniques to show how important Th2 driven inflammation is in the development of eczema and in the clinical manifestations of eczematous dermatitis.
Dr. Ju: What are the research implications of the multifactorial nature of atopic dermatitis?
Dr. Eichenfield: It means there are parallel tracks of research currently looking at how we can both attenuate the genetic component to serve as a preventive strategy and reduce the disease burden in active disease to improve treatment. Alan Irvine and colleagues showed that transepidermal water loss may be detectable in neonates as soon as the first few days after birth, with higher rates of transepidermal water loss positively correlated with the risk of developing atopic dermatitis. Eric Simpson and Hywel Williams and colleagues continued that line of research in studies looking at whether early emollient therapy could prevent the development of atopic dermatitis in at-risk infants. In a preliminary study they have identified both feasibility for neonates to receive regular emollient therapy and some demonstration of a positive treatment effect, with lower rates of atopic dermatitis in the treatment group.
Dr. Ju: If I understand the hypothesis, in those born susceptible to atopic dermatitis and showing high transepidermal water loss, early repair of the barrier could prevent or stop the development of atopic dermatitis?
Dr. Eichenfield: We do not have the answer to that at the moment, but that is certainly one of the most intriguing lines of research in atopic dermatitis at the moment. That could potentially have tremendous impact on the numbers of people who develop atopic dermatitis throughout the world.
Dr. Ju: What are the highlights of the research in the immunologic mediation of eczema?
Dr. Eichenfield: The agent that is furthest along in clinical study is the topical boron-based PDE4 inhibitor crisaborole (Anacor), which has completed the Phase 3 studies. PDE4 is upregulated in inflammatory cells in atopic dermatitis, and it is hoped that inhibition will attenuate or ameliorate the inflammatory cascade. In one year studies, the side effect profile appears to be very good with minimal rates of significant adverse events are seen in the studies. There is also some very elegant work going on in established atopic dermatitis in identifying important inflammatory mediators in inflamed skin that could be relevant therapeutic targets for topical agents. For example, IL-4 receptor alpha subuit-blockade by dupilumab (Rengeron & Sanofi) may inhibit cytokines that are highly important in atopic dermatitis inflammation.
Dr. Ju: Moving an agent from bench to beside is an unpredictable process, but from where we sit today, do you see atopic dermatitis treatment being significantly different in the next 5 or say 10 years compared to now?
Dr. Eichenfield: Yes, I really do. Currently, misperceptions about topical corticosteroids and safety concerns with topical calcineurin inhibitors lead to a lot of under treated disease. So one thing that could change dramatically in the near future is an effort to use current agents more appropriately. However, potentially making a larger impact is that the treatment model is changing to one in which controlling the disease and minimizing its impact on the individual is emphasized. The new agents coming down the pike, both topical and systemic, are being developed to control the disease so there is not even low-grade inflammation on the skin. They should give us a better chance of achieving minimal rashes, minimal itch, minimal sleep disturbance, and, thus, minimal impact of eczema over the lifetime of the individual.
One of the exciting things being looked at is whether biologic agents, or small molecule agents, can be used in younger children to turn off the disease process. The FDA recently ruled that because of the profound clinical impact of atopic dermatitis, that it is appropriate to test systemic agents in younger patients that influence the immunologic pathways that impact the course of atopic dermatitis. That removed a significant regulatory hurdle for industry and moved the promise of potential cure—or at least a prevention strategy—closer to viability.
This series made possible with support from