Biologic therapeutics in the treatment of psoriasis. Part 1: review.

BACKGROUND: Psoriasis is a chronic inflammatory skin disease principally mediated by activated T cells, which release proinflammatory cytokines with reactive epidermal changes in the skin, producing the characteristic lesions of psoriasis. New research into possible treatment options has been inspired by increased understanding of the pathophysiology of psoriasis and advances in immunology and molecular biology permitting the development of targeted, highly active biologic agents. OBJECTIVE: The aim of this article is to review the efficacy and safety of five biologic therapeutics in the treatment of moderate to severe psoriasis and to provide practical guidelines for integration of these agents in the management of psoriasis. METHODS: We searched MEDLINE (1966-2005) for articles containing the key words: alefacept, efalizumab, etanercept, infliximab, and adalimumab and searched recent conference abstracts. RESULTS: Emerging immunotherapeutic agents (fusion proteins, recombinant cytokines, fusion toxins, or antibodies) target T cells or cytokines responsible for plaque formation that is characteristic of psoriasis. Alefacept is the first biologic to be approved in both the United States and Canada. More recently, efalizumab and etanercept and infliximab have been approved in the United States and Canada for plaque-type psoriasis. Adalimumab is currently in phase III clinical trials. CONCLUSION: These novel biologics offer an intriguing and effective treatment option for patients with moderate to severe psoriasis.

Strategies for optimizing treatment with efalizumab in moderate to severe psoriasis.

With the advent of biological therapies for the treatment of plaque psoriasis, guidance on the usage of these new agents has become necessary. One such agent, efalizumab, a humanized recombinant monoclonal IgG(1) antibody developed to target T-cell-mediated inflammation, provides rapid and sustained efficacy for many psoriasis patients. This article explores the pretreatment, initiation, and treatment phases with efalizumab therapy. In the pretreatment phase, physicians need to assess patients' disease state and educate them about the course of efalizumab treatment. Prior to initiation, physicians need to establish stable disease, ensure an adequate transition or washout of any prior psoriasis therapeutics, and obtain baseline platelet counts. After initiating treatment, both physician and patient must participate in disease monitoring. Patients responding favourably may receive continuous treatment. Those who do not respond to the drug or who experience adverse events should be managed appropriately in order to continue therapy or be transitioned onto another agent. A growing body of clinical evidence, as well as experience from clinical investigators, has provided much insight into the management strategies for patients undergoing treatment with efalizumab.

Recommendations for incorporating biologicals into management of moderate to severe plaque psoriasis: individualized patient approaches.

Psoriasis is a T-cell mediated skin disease that affects approximately 2% of the population worldwide. Despite the prevalence of the disease and long-standing efforts to develop strategies to treat it, there is a need for safe and effective therapies to treat psoriasis, particularly the more severe forms. Biological agents such as alefacept, efalizumab, etanercept, and infliximab have been recognized as a class of treatment distinct from other forms of therapy in the treatment algorithm of psoriasis. Recent national and international consensus meetings have developed statements that position biological agents as an important addition to the treatment armamentarium for moderate to severe psoriasis, along with phototherapy and traditional systemic agents. There has been consensus that treatment should be individualized to each patient's needs and circumstances. Biological agents offer the hope of safe, effective, long-term management of moderate to severe psoriasis. As new agents receive approval from Health Canada, the available range of therapeutic options for treating this chronic disease will broaden. A Canadian Psoriasis Expert Panel recently convened in February 2005 to analyze, based on a series of clinical case scenarios, the indications, contraindications, and considerations for and against each of the four biological agents, derived from product labelling, where available, and from the efficacy and safety data from phase 3 and earlier clinical trials, as well as post-marketing reports. The Panel has formulated a set of recommendations for incorporating these biological agents into the current treatment paradigm of moderate to severe plaque psoriasis and has identified the preferred biological agents for each patient based on individual needs and circumstances.

A favourable benefit/risk ratio with efalizumab: a review of the clinical evidence.

Moderate to severe plaque psoriasis has traditionally been treated with agents that have toxicities associated with long-term use. Many patients therefore cannot be treated safely, conveniently or effectively with traditional therapies. Recent phase 3 clinical trials for efalizumab, a biological agent targeted specifically at the T-cell-based pathology of psoriasis, have demonstrated its short- and long-term efficacy and safety for the treatment of psoriasis. This article reviews results from 12-week, six-month, and three-year trials, focusing on the drug's safety, efficacy, and therapeutic response time, as well as the phenomenon of rebound in non-responding patients. Efalizumab emerges as an important addition to the dermatological pharmacopeia for the long-term treatment of psoriasis.

Efalizumab, a reversible T-cell modulator for psoriasis.

The humanized monoclonal antibody (MAb) efalizumab (Raptiva) was developed to meet a longstanding need for specific, safe, and effective anti-psoriatic treatments. Efalizumab, which is directed at the lymphocyte surface protein LFA-1, prevents multiple interactions between T cells and other cell types. Here, we review the inflammatory pathway that drives the development of psoriasis, and we discuss several mechanisms by which efalizumab suppresses skin inflammation in psoriasis. Efalizumab reversibly increases circulating T-cell counts, as T cells--including pathogenic CD8 memory T cells that are prominent in psoriatic lesions-- are specifically restrained from leaving the bloodstream and entering the skin. Within two weeks of the onset of efalizumab treatment, cell surface and intracellular LFA-1 pools are substantially cleared by lysosomal degradation. Residual surface LFA-1 molecules remain saturated with bound efalizumab for some weeks following cessation of treatment. Efalizumab's pharmacodynamic properties are consistent with its profound and reversible beneficial effects on the histopathology of psoriatic skin.

Efalizumab: integrating a new biologic agent into the long-term management of moderate to severe plaque psoriasis.

Efalizumab, one of a new generation of biological agents, has been approved for use in moderate to severe psoriasis in over 35 countries including Canada. It may hold the promise of a new level of safe, long-term disease control for psoriasis patients, who have had few adequate options to date. Dermatologists and other caregivers may require some background regarding the mechanisms of action and the optimal use of this drug before integrating it into their standard repertoire of treatment. The present supplement discusses efalizumab's biological basis and reviews its clinical safety and efficacy. The salient differences amongst the various biologicals, with regard to safety, efficacy and convenience, are also considered. The supplement concludes with a practical guide to initiating and maintaining patients on efalizumab treatment.

Extended efalizumab therapy sustains efficacy without increasing toxicity in patients with moderate to severe chronic plaque psoriasis.

Agents that safely provide long-term control of psoriasis are needed. To determine the safety and efficacy of extended efalizumab therapy, 339 patients with moderate to severe chronic plaque psoriasis received 2 mg/kg subcutaneous (SC) efalizumab weekly for 12 weeks. At Week 12, 290 patients who achieved > or =50% Psoriasis Area and Severity Index (PASI-50) improvement or a static Physician's Global Assessment grading of "mild," "minimal," or "clear" entered maintenance treatment with weekly SC efalizumab. At Week 12, 82%, 41%, and 13% of 339 patients achieved a PASI-50, PASI-75, and PASI-90 response, respectively. At 15 months, 65%, 50%, and 25% of patients achieved a PASI-50, PASI-75, and PASI-90 response, respectively (intent-to-treat, n = 339). The incidence of adverse events did not increase over time, and no new common adverse events were reported. The majority of patients experienced sustained efficacy with no increase in toxicity. This study is planned to continue; patients will receive up to 36 months of continuous efalizumab.