Biological drugs targeting the immune response in the therapy of psoriasis

Abstract

Chronic plaque psoriasis affects more than 2% of world population, has a chronic recurrent behavior, gives a heavy burden to the patients' quality of life, and hence remains a huge medical and social problem. The clinical results of conventional therapies of psoriasis are not satisfactory. According to the current knowledge of the molecular and cellular basis of psoriasis, it is defined as an immune-mediated chronic inflammatory and hyperproliferative skin disease. A new generation of biological drugs, targeting molecules and cells involved into perturbed pro-inflammatory immune response in the psoriatic skin and joints, has been recently designed and applied clinically. These biological agents are bioengineered proteins such as chimeric and humanized antibodies and fusion proteins. In particular, they comprise the antitumor necrosis factor-alpha agents etanercept, infliximab, and adalimumab, with clinical efficacy in both moderate-severe psoriasis and psoriatic arthritis, and the anti-CD11a efalizumab with selective therapeutic action exclusively in the skin. Here, we overview recent findings on the molecular pathways relevant to the inflammatory response in psoriasis and present our clinical experience with the drugs currently employed in the dermatologic manifestations, namely etanercept, infliximab, and efalizumab. The growing body of clinical data on the efficacy and safety of antipsoriasis biological drugs is reviewed as well. Particular focus is given to long-term safety concerns and feasibility of combined therapeutic protocols to ameliorate clinical results.

Keywords: efalizumab; etanercept; immune-mediated inflammation; infliximab; psoriasis.

Figure 1

TNF-α-driven inflammatory cascade in the skin. Among the pre-formed mediators released by mast cells (A), TNF-α boosts the pro-inflammatory activation of resident cell populations which include endothelial cells (B). In their turn, endothelial cells respond to TNF-α with up-regulated expression of surface adhesion molecules, which facilitate the adhesion and migration of leukocytes to peripheral tissues, and a new wave of leukocyte-derived cytokine release (C). Eventually, skin keratinocytes amplify the inflammatory response at the local level, with massive release of cytokines, chemokines, and growth factors (D). Abbreviations: TNF-α, tumor necrosis factor-α.

Figure 2

Strategies for targeted biological therapy of psoriasis. These include existing and potential biological drugs for the therapy of psoriasis, such as anti-TNF-α (A) or anti-LFA-1 (B) antibodies, inhibitors of CD2 expression on the surface of activated pathogenic T cells (C), or cytokines to balance the Th1-skewed immune response (D), these last presently under investigation. Abbreviations: APC, antigen-presenting cell; LFA-1, lymphocyte function-associated antigen-1; TNF-α, tumor necrosis factor-α.