New era of biologic therapeutics in atopic dermatitis

Abstract

Introduction: Atopic dermatitis (AD) is a common inflammatory skin disease regulated by genetic and environmental factors. Both skin barrier defects and aberrant immune responses are believed to drive cutaneous inflammation in AD. Existing therapies rely largely on allergen avoidance, emollients and topical and systemic immune-suppressants, some with significant toxicity and transient efficacy; no specific targeted therapies are in clinical use today. As our specific understanding of the immune and molecular pathways that cause different subsets of AD increases, a variety of experimental agents, particularly biologic agents that target pathogenic molecules bring the promise of safe and effective therapeutics for long-term use.

Areas covered: This paper discusses the molecular pathways characterizing AD, the contributions of barrier and immune abnormalities to its pathogenesis, and development of new treatments that target key molecules in these pathways. In this review, we will discuss a variety of biologic therapies that are in development or in clinical trials for AD, perhaps revolutionizing treatment of this disease.

Expert opinion: Biologic agents in moderate to severe AD offer promise for controlling a disease that currently lacks good and safe therapeutics posing a large unmet need. Unfortunately, existing treatments for AD aim to decrease cutaneous inflammation, but are not specific for the pathways driving this disease. An increasing understanding of the immune mechanisms underlying AD brings the promise of narrow targeted therapies as has occurred for psoriasis, another inflammatory skin disease, for which specific biologic agents have been demonstrated to both control the disease and prevent occurrence of new skin lesions. Although no biologic is yet approved for AD, these are exciting times for active therapeutic development in AD that might lead to revolutionary therapeutics for this disease.

Fig. 1. The pathogenesis of atopic dermatitis (AD)

The disease has three main phases, including initiation, acute and chronic stages. Defects in the epidermal barrier lead to the penetration of the skin by epicutaneous antigens, which in turn encounter Langerhans and dermal Dendritic cells that activate Th2 cells and IL-4 and IL-13 production. These cytokines result in two major effects: IgE class switching and increased Th2 cell survival. Additionally, these cytokines gradually increase from nonlesional through chronic disease, and have several direct effects on the epidermis. These include increased TSLP production by keratinocytes, inhibition of anti-microbial peptide (AMP) production, and impaired epidermal differentiation. The resulting disrupted epithelial barrier further increases AD-associated infections. In addition, the inflammatory mediators of Th2 T-cells and DCs induce peripheral eosinophils and mast cells. Also of significance is an increase in Th22 cells in AD skin; this subset produces IL-22, which is most significantly increased in chronic AD skin. IL-22 inhibits terminal differentiation and induces epidermal hyperplasia, which is an important characteristic of chronic disease. Thus, the barrier defect in AD most likely results from a combined effect of Th2 and Th22 cytokines. Similarly to T-cells, there is a progressive increase in dendritic cells and langerhans cells from non-lesional through chronic AD. The role of Th17 T-cells and their cytokine, IL-17 in AD is less significant to the pathogenesis of AD compared with psoriasis, and more modest increases in this cytokine were found in acute and chronic AD, as compared to psoriasis. This might explain the decreased production of AMPs in AD patients as compared with psoriasis, secondary to both Th2 cytokine inhibition and relatively lower levels of IL-17. Adapted from: Guttman-Yassky E, Nograles K, Krueger JG. Contrasting pathogenesis of atopic dermatitis and psoriasis--Part II: Immune cell subsets and therapeutic concepts. J Allergy Clin Immunol 2011;127:1420–1432.