Trends and developments in the pharmacological treatment of psoriasis.

Abstract

In the history of psoriasis pharmacotherapy , the milestone developments have largely occurred by chance. Serendipitous observations in single patients have led to the discovery of such important treatments as methotrexate (1), deltanoids (active form of vitamin D and its analogues) (2), cyclosporin (3) and, most recently, tumour necrosis factor alpha (TNF-a) inhibitors (4). While these observations have been of therapeutic importance, they have also had a major impact on current views on the pathogenesis of this skin disease. From the initial model, where the hyperproliferation of epidermal keratinocytes was considered to be a central event, the current understanding places the immune system at the hub of the pathogenic series of events. Vigorous research and constantly increasing insight into the mechanisms of psoriasis have led to the identi® cation of a number of potential targets for therapeutic intervention. For the ® rst time, the rational, mechanism-based development of new anti-psoriatic therapeutic has become a reality. The purpose of this article is to present a systematic review of emerging drug therapies for psoriasis that, although in the early stage of development today, may enter the clinical practice of tomorrow. The current, established treatments are not mentioned; readers are referred to recently published excellent reviews on this subject (5 ± 8). The compounds included in this review have been selected from a screening of the Medline records; where references are not cited the information has been obtained from IDdb (Investigationa l Drugs Database, Current Drugs Ltd., http://www.iddb3.com/) and PharmaProjects (PJP Publications Ltd.# 2002, http://www.pharmaprojects.co.uk). IMMUNOSUPPRESSIVE AND ANTIINFLAMMATORY DRUGS The autoimmune cutaneous reaction is believed to play a causative role in the development of skin lesions in psoriasis (9). Most of the compounds under current development for psoriasis belong to different classes of immunosuppressives and anti-in ammatory drugs. The central cell in the current pathogenic model is the memory (CD45RO ) T-lymphocyte mediating the type 1 immune response. A type 1 immune response is mediated by TH1 and TC1 lymphocytes secreting a speci® c cytokine pro® le (IFN-g, TNF-a, IL-12). The recently reviewed immunopathogenesis of psoriasis (9, 10) will be mentioned only to the extent necessary for an understanding of the mechanism of action of the drugs included here. The memory T-lymphocytes secrete three major cytokines, IL-2, TNF-a and IFN-g. IL-2 acts at the early stages of T-cell activation and clone expansion, while TNF-a and IFN-g have a twofold role: to drive and stabilize the type I immune reaction (11) and by direct action on keratinocytes to stimulate their growth leading to epidermal hyperproliferation (12). The latter aspect is believed to be an aberrant regenerative response of the epidermal stem cells (12, 13).