Redefining clinical response in psoriasis: targeting the pathological basis of disease

Journal of Drugs in Dermatology, Jan-Feb, 2004 by Jean-Paul Ortonne

Abstract

Psoriasis is a chronic inflammatory disease of the skin that can have a major effect on patient quality of life. Conventional psoriasis treatments, often identified empirically, fail to meet the clinical needs for a safe and remittive therapy. These unmet needs, together with the rapid advances in understanding the molecular basis of psoriasis, have led to the development of targeted biologic therapies. Using recombinant DNA technology, a new generation of therapeutic agents is being designed to interfere at specific pathogenic steps that involve T-cells or T-cell-mediated immune responses. These targeted therapies promise improved tolerability and safety in the treatment of psoriasis. Furthermore, they will redefine clinical response in psoriasis by providing long-lasting remissions of disease and extended treatment-free periods.

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Introduction

Psoriasis is an inflammatory disease of the skin that affects approximately 2% to 3% of the population worldwide (1). The disease is characterized by the formation of thick and scaly erythematous plaques. In addition to physical discomfort, pain, and pruritus, psoriasis has a significant detrimental effect on the quality of life of affected individuals (2).

Hyperproliferation of keratinocytes and an abnormal epidermal differentiation are the histologic hallmarks of psoriasis. Until recently, these events were widely considered the primary cause of the disease. Rapid advances in understanding the immunologic basis of psoriasis haves led to redefining the disease as being mediated by T-cells (3). Epidermal hyperplasia is now thought to be a process that is secondary to the T-cell-mediated immune response (4).

These advances in the understanding of the molecular basis for psoriasis have led to the ongoing development of drugs that target its immunopathology. Novel therapeutic agents (biologics) have been designed using recombinant DNA technology to mimic or interfere with the actions of naturally occurring proteins (5). These biologics hold promise in improving psoriasis treatment and fulfilling a need currently unmet by existing therapies.

Conventional systemic therapies for psoriasis, including cyclosporine, methotrexate, retinoids, and phototherapy, are limited by two key factors: major organ system toxicities, and lack of the ability to provide disease remission. With the exception of psoralen plus ultraviolet A light (PUVA), these therapies are predominantly suppressive; once treatment is stopped, psoriasis returns and, in some cases, is worse than before treatment (6).

To overcome the limitations of existing therapies for psoriasis, the ideal biologic agent should be able to shift the treatment paradigm from short-term symptom suppression to long-term disease remission that addresses the chronic inflammatory nature of psoriasis. Alefacept (Amevive[R], Biogen, Inc.) is the first and only approved biologic for use in patients with moderate to severe chronic plaque psoriasis. Of the other biologics that are currently being investigated, three are in the fore-front: efalizumab (Raptiva[R], Genentech), etanercept (Enbrel[R], Amgen Inc.), and infliximab (Remicade[R], Centocor). In this review, the key studies that have led to the development of these biologic agents are discussed, as well as the clinical experienced gained thus far from their use in psoriasis treatment.

Immunopathology of Psoriasis

Historically, hyperproliferation of epidermal kerationocytes was thought to be the primary pathogenic mechanism leading to psoriasis (7,8). Consequently, keratinocytes were presumed to be the main target of topical and systemic agents. In the late 1970s, several investigators reported immunohistologic detection of T cells in psoriatic lesions (9-11). The hypothesis that T cells might play a pathogenic role in psoriasis gained further momentum with the serendipitous observation that cyclosporine cleared lesions in patients with psoriasis (12-14). The dramatic result with cyclosporine was proposed to be a direct result of T-cell inhibition, and agents previously used in the treatment of psoriasis were re-examined in light of this hypothesis. Methotrexate, PUVA, and UVB were all found to have an effect on T-cell function (15-17). Further acceptance of an immunologic basis for psoriasis came from reports that psoriasis could be transmitted between patients via bone marrow transplantation (18,19). Due to the lack of any direct evidence, however, the pathogenic role of T cells in psoriasis remained speculative.

Direct evidence for T-cell involvement in psoriasis came from two lines of investigations. First, selective agents were used to specifically target T-cells and inhibit their activity in patients with psoriasis. These included a fusion protein composed of diphtheria toxin and interleukin-2 (DAB389IL-2), which inhibits T-cells by selectively binding to high-affinity IL-2 receptors on activated T-cells, and an anti-CD4 monoclonal antibody. When administered to patients with psoriasis, both agents caused a resolution of lesions (20-22).