In the past few years, there has been much excitement among physicians and patients regarding the development of new therapeutic modalities for treating psoriasis. Most of the recent research activities have focused on new systemic agents for moderate to severe cases of psoriasis. The hope is that the more targeted “smart bomb” approach to psoriasis therapy with the new biologic agents may lead to development of systemic agents that can be used long term with no major organ toxicity. Here, we’ll review the newest systemic therapies available.n
Efalizumab (Xanelim). Efalizumab is a humanized monoclonal antibody against the CD11a molecule. CD11a and CD18 form the lymphocyte-associated antigen 1 (LFA-1), which plays a critical role in allowing lymphocytes to adhere to other cell types. Binding of efalizumab to CD11a on T-cells blocks the interaction between LFA-1 and ICAM-1, its partner molecule for adhesion. The blockade is reversible and does not deplete T-cells. The inhibition of adhesion prevents psoriasis-inducing T-cells from binding to the blood vessel wall and trafficking into the skin. Inhibition of adhesion to antigen-presenting cells reduces T-cell activation.
Early Phase I and II studies have demonstrated efficacy for the intravenous (IV) application of the drug.1-3 Subsequently, in an open label phase 1C trial, patients received subcutaneous (SC) injections of efalizumab once a week for 8 weeks. Forty-eight percent of patients in the 1.0 mg/kg and 54% in the 2.0 mg/kg group achieved a response of “good or better,” according to the Physicians Global Assessment (PGA).4 The efficacy of efalizumab was similar whether administered subcutaneously or intravenously. Efalizumab was well tolerated with the most frequent side effects being mild-to-moderate, transient flu-like symptoms, in particular after the first one or two injections. No systemic organ toxicity has been noted.
The results of two pivotal Phase III trials with many patients treated with once-a-week SC efalizumab are now under analysis. Preliminary presentations from the studies seem to confirm earlier positive efficacy and safety data.
n Alefacept (Amevive). Alefacept is a novel immunomodulator that targets the T-cells involved in the pathogenesis of psoriasis. It’s a fully human fusion protein, consisting of the first extracellular domain of LFA-3 fused to the hinge, CH2, and CH3 sequences of human IgG1. Alefacept binds CD2 on T-cells and FcgRI and FcgRIII on accessory cells (eg, natural killer cells and macrophages), thereby inhibiting T-cell activation and proliferation and inducing T-cell apoptosis.5,6 Alefacept selectively targets memory-effector (CD45RO+) T-cells because CD2 expression is higher on this T-cell subset compared with the naïve (CD45RA+) T-cell population.7,8 You can administer the drug by intravenous bolus or intramuscular injection.
The results of a randomized, placebo-controlled, double-blind study were recently published.9 Patients (n=229) with chronic plaque psoriasis received placebo or alefacept (0.025, 0.075 or 0.150 mg/kg) once
weekly as a 30-second intravenous bolus for 12 weeks, followed by a 12-week observation phase. The optimal benefit was achieved with the 0.075-mg/kg dose. At this dose, 60% and 33% of patients achieved 50% and 75% PASI improvement, respectively. The onset of action was within 2 weeks of treatment initiation, and further improvement was evident during follow-up. Disease rebound or flare did not occur after the 12-week regimen.
The clinical responses were durable. Among patients who showed marked improvement, the median time before retreatment was 306 days. Dose-related reductions in circulating memory-effector T-cells correlated with clinical efficacy. Side effects were generally mild, and no serious, drug-related adverse events were noted. The incidence of infections was similar in the placebo and alefacept groups and unrelated to dose.
Additional clinical studies provide further evidence of the efficacy and safety of alefacept. In an ongoing, open-label extension trial, multiple courses of alefacept are being evaluated.10 Currently, 170 and 50 patients are able to be evaluated for efficacy after one and two retreatment courses, respectively. Two weeks after dosing in both retreatment courses, mean PASI was reduced from baseline by 50%, with more rapid improvement seen in course 2.
In another study, psoriasis patients treated with alefacept maintained a normal antibody response to a recall antigen (tetanus toxoid) and to a neo-antigen (phiX174), demonstrating alefacept does not broadly suppress the immune system.11 Alefacept reduced the number of infiltrating Th1-type IFNg+CD3+ T-cells in lesional skin, which correlated with PASI improvement,12 and inhibited IFNg production by normal and psoriatic peripheral T-cells.13 Pivotal studies of alefacept for treating chronic plaque psoriasis have recently been completed — results will be published in 2002. This drug has been submitted to the FDA and the EMEA for marketing authorization.
n Etanercept (Enbrel). Etanercept acts by binding tumor necrosis factor (TNF), one of the dominant cytokines or proteins that plays an important role in normal immune function and the cascade of reactions that cause the inflammatory process of rheumatoid arthritis. Etanercept competitively inhibits binding of TNF molecules to the TNF receptor (TNFR) sites. The binding of etanercept to TNF renders the bound TNF biologically inactive, resulting in significant reduction in inflammatory activity. Etanercept is currently approved for rheumatoid arthritis.
In the Phase II psoriasis clinical study (personal communication with Dr. Zitnik), 112 patients with moderate to severe plaque psoriasis were randomized evenly to receive 25 mg of etanercept or placebo twice a week for 6 months. The primary endpoint of the study was the proportion of patients achieving a 75% improvement in PASI score after 12 weeks. Patients treated with etanercept experienced significant improvement compared to those on placebo, with 30% of patients on etanercept achieving PASI 75 compared to 2% of those on placebo.
After 6 months of treatment, about half the patients receiving etanercept achieved an improvement of 75% or better in the PASI score, compared to a 5% improvement for patients on placebo. About 20% of patients receiving etanercept for 6 months improved by 90% or more, and no patients in the placebo group achieved that level of response. Etanercept was well tolerated.
Results from a 12-week, double-blind placebo-controlled study of 60 patients with psoriatic arthritis (PsA) and psoriasis14 showed etanercept was well tolerated and provided significant improvement in the signs and symptoms of PsA as well as the skin lesions of psoriasis.
Additional larger multi-center, double-blind placebo-controlled Phase III clinical study provides further evidence of the efficacy and safety of etanercept.15 Patients (n= 205) with PsA and psoriasis were randomized to receive either etanercept or placebo evenly. Randomization was stratified by concomitant methotrexate use. Patients received 25 mg etanercept or placebo for 24 weeks. Psoriasis activity was measured by improvement in target lesion score, and, in a subset of patients (n=62 for placebo; n=66 for etanercept), by using the PASI. Patients treated with etanercept showed significantly more improvement in target lesions than patients treated with placebo; the median improvement in target lesion at 24 weeks was 47% in patients receiving etanercept, as compared with 0% in placebo controls in this subset of patients.
n Infliximab (Remicade). Infliximab is a chimeric (mouse-human) IgG1 monoclonal antibody designed to bind to TNFa. It’s also designed to inhibit production of other pro-inflammatory cytokines, reducing cell infiltration and eventually keratinocyte proliferation. This agent is already approved for rheumatoid arthritis and Crohn’s disease. Because this agent has been widely used for these other indications, it has reported incidences of extremely rare serious side effects including reactivation of tuberculosis, invasive systemic fungal infection and other opportunistic, life-threatening infections. Remicade patients are at least four times more likely than placebo to get active tuberculosis.16,17
In a published double-blind, randomized 10-week study involving 33 patients with moderate to severe plaque-type psoriasis, conducted at Robert Wood Johnson Medical Center, NJ,18 5 mg/kg IV infusion of remicade resulted in 82% of patients showing at least 75% improvement in PASI. At 10 mg/kg IV infusion, 73% had at least 75% improvement in PASI while placebo group only showed 15% improvement in PASI. The mean response time was 4 weeks for both active treatment groups. Treatment group and placebo group differences were significant at week 2. In this limited pilot study, headache was the only major adverse event noted compared with the placebo group. Two patients in the 5 mg/kg group developed asymptomatic positive anti-nuclear antibody titers. Even though published data are limited, results suggest efficacy comparable to cyclosporin. But, this needs verification by larger, multi-center pivotal studies. Also, the side effect profile needs examination in a larger study to determine if the most serious side effects reported with rheumatoid arthritis patients applied to psoriasis patients.

Tackling The Hurdles
Along with these advances in systemic therapy, we’ve seen progress with new uses of existing topical medications and new data on phototherapy that we’ll discuss in upcoming issues. But, currently, patients with moderate to severe psoriasis have to choose between convenience and toxicity. Phototherapy is systemically safe but inconvenient, while currently available systemic agents are convenient but associated with possible serious, adverse effects.
Before these biologic agents are accessible to patients, there are many hurdles. Even after FDA approval, there are hurdles that need to be overcome:
n Comfort level. You need to be interested in and comfortable using new agents. We need well-targeted, educational approach of adequate duration and impact.
n Financial incentive. You need a monetarily incentive to learn new skills (i.e. teaching patients how to give themselves subcutaneous injections) and to take possible, unknown risks of using new agents.
n Insurance challenges. There must be a way to minimize insurance hassle with regard to reimbursement.
These challenges are worth taking on since the alternative is the possibility of losing the expertise and most up-to-date management skill for treating moderate to severe psoriasis possible to other specialties, such as rheumatology. These new developments are an opportunity and a challenge. n
Dr. Koo is the director of the Psoriasis and Skin Treatment Center and vice chairman of the department of dermatology UCSF Medical Center. Ms. Nguyen is with the Finch University of Health and Sciences/The Chicago Medical School.