Putting together the psoriasis puzzle: an update on developing targeted therapies

Leanne M Johnson-Huang, Michelle A Lowes, James G Krueger, Leanne M Johnson-Huang, Michelle A Lowes, James G Krueger

Abstract

Psoriasis vulgaris is a chronic, debilitating skin disease that affects millions of people worldwide. There is no mouse model that accurately reproduces all facets of the disease, but the accessibility of skin tissue from patients has facilitated the elucidation of many pathways involved in the pathogenesis of psoriasis and highlighted the importance of the immune system in the disease. The pathophysiological relevance of these findings has been supported by genetic studies that identified polymorphisms in genes associated with NFκB activation, IL-23 signaling and T helper 17 (Th17)-cell adaptive immune responses, and in genes associated with the epidermal barrier. Recently developed biologic agents that selectively target specific components of the immune system are highly effective for treating psoriasis. In particular, emerging therapeutics are focused on targeting the IL-23-Th17-cell axis, and several agents that block IL-17 signaling have shown promising results in early-phase clinical trials. This review discusses lessons learned about the pathogenesis of psoriasis from mouse-and patient-based studies, emphasizing how the outcomes of clinical trials with T-cell-targeted and cytokine-blocking therapies have clarified our understanding of the disease.

Figures

Fig. 1.
Fig. 1.
Clinical and histological features of psoriasis before and after effective treatment. (A) Clinical presentation of psoriasis showing clearly demarcated red plaques with silver scales. After 12 weeks of treatment with the TNFα inhibitor etanercept, there was marked lesion resolution. (B) Comparative hematoxylin and eosin staining of psoriatic lesional skin showed marked epidermal thickening and cellular infiltration compared with non-lesional skin. These features were reversed 12 weeks post-treatment with etanercept. (C) Increased infiltration of CD3+ T cells in lesional skin compared with non-lesional skin; this infiltration decreased with treatment (week 12). (D) Increased CD11c+ DCs in lesional skin were reduced with treatment (week 12). [Images are unpublished, from a study reported in Zaba et al. (Zaba et al., 2007a).]
Fig. 2.
Fig. 2.
Current model of the maintenance phase of psoriasis, showing the targets of approved or emerging psoriasis drugs. Myeloid DCs produce cytokines that induce IFNγ production by Th1 cells and IL-17 production by Th17 cells. IL-23 also induces production of IL-22 by Th17 and possibly Th22 cells. Th cell cytokines IFNγ, IL-17 and TNFα cooperate to induce the production of anti-microbial peptides (AMPs) and chemokines by keratinocytes, thereby enhancing immune-cell recruitment and inflammation in lesions. IL-22 is also involved in promoting epidermal hyperplasia. The IL-20 subfamily cytokines (IL-19, IL-20 and IL-24), which are mainly produced by monocytes, also contribute to epidermal hyperplasia. Drugs that are currently FDA-approved target upstream molecules in this pathway (anti-p40 antibodies and TNF inhibitors), whereas drugs in the pipeline (antibodies targeting IL-17, IL-17R or IL-22) are directed against downstream molecules.

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