Scientific Retreats 2012

April 23, 2012

Session Topic: Atopic Dermatitis

Introduction

Atopic dermatitis (AD) is a common, chronic inflammatory skin disorder that substantially impairs quality of life due to pruritis. AD patients are also predisposed to allergic hypersensitivity responses, including asthma (referred to as “atopic march”). There is a high incidence of AD in children (10-20% of population) that diminishes in adulthood (1-3% of the population). AD is difficult to control and requires systemic and topical treatments, for example oral and topical steroids, cyclosporine A, and ultraviolet B (UVB) phototherapy, which are often quite ineffective for the treatment of moderate to severe disease. As a result, there is a large unmet need for effective treatment of AD.

Considerable progress has been made in the last few years in elucidating the pathophysiology of AD. Recent findings support a complex model of AD that includes epidermal barrier impairment combined with a defective antimicrobial immune defense, and a hyperactive allergic immune response that is triggered by environmental and endogenous factors. Multiple genetic studies have revealed a strong association between loss-of-function mutations in the skin barrier gene filaggrin (FLG) and AD. Defects in the function or expression of other epidermal barrier genes are also involved in AD. For example, single nucleotide polymorphisms have been linked to decreased expression of the genes hornerin and claudin-1 that encode proteins expressed in the epidermal cornified envelope and skin barrier tight junction, respectively. Modifications in genes involved in the innate and adaptive immune systems that regulate antigen presentation, cell-mediated and humoral responses, signaling, chemotaxis, and differentiation are also associated with AD. Immunobiologic studies reveal that allergens activate immune effector cells, antigen-presenting cells, and keratinocytes. House dust mites are among the most common allergens that induce expression of interleukin 1β (IL-1β? and IL-18 in keratinocytes. In addition, these allergens activate the inflammasome, which is a key part of the innate immune system. Allergen-specific immunoglobulin E antibody titers are elevated in the serum of patients with AD. However, it is unclear whether these antibodies impact relevant pathogenic pathways.

AD is linked to activation of different T cell subsets. T helper 2 (Th2) cells and their cytokines IL-4, IL-13 and IL-31, and Th22 cells expressing IL-22 are associated with disease severity. Another key soluble factor expressed in the epidermis of lesional AD is thymic stromal lymphopoetin (TSLP), which is known to regulate dendritic cell (DC)-induced differentiation of Th2 cells. Myeloid DCs are intimately involved in AD pathophysiology; they modulate allergen uptake, release pro-inflammatory cytokines, and mediate the activation of T cell subsets.

AD is associated with eczema herpeticum (EH), a disseminated herpes simplex virus skin infection. Patients with EH exhibit attenuated induction of the antimicrobial peptides human β-defensin 2, 3 and cathelicidin under inflammatory conditions.

In summary, although we have learned much about the pathophysiology of AD, this knowledge has not been translated into new FDA-approved drugs for the treatment of severe AD.

Purpose of the Session (Goals)

To discuss emerging targets and new therapeutic avenues in AD, and explore potential proof of concept AD clinical trials.

Key Questions

  • • What translational research opportunities have emerged from recent studies on the biology of AD?
  • What are the main factors that contribute to severe AD?
  • Are there new therapeutic targets that should be pursued?
  • Do we have appropriate animal models to validate these targets and test drug candidates?
  • Is there an adequate translational platform (e.g., assays for monitoring biomarker expression) for proof of concept studies in humans?
  • Why don’t most current clinical interventional studies lead to viable drug candidates? Can we improve this record?
  • What are the opportunities for partnerships and leveraging research support and resources?

References

Novak N, Leung DY. Advances in atopic dermatitis. Curr Opin Immunol. 2011 Dec;23(6):778-83. Epub 2011 Oct 19.

Boguniewicz M, Leung DY. Atopic dermatitis: a disease of altered skin barrier and immune dysregulation. Immunol Rev. 2011 Jul;242(1):233-46.