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Jeffrey M Weinberg
Department of Dermatology
St Luke’s-Roosevelt Hospital Center
Beth Israel Medical Center
New York, NY
Dr Weinberg is a member of the Speaker’s Bureau for Amgen and Genentech. There was no industry support for preparation and publication of this article
The implication of an immunological phenomenon in the pathogenesis of psoriasis has led, over the past few years, to research for new treatment options,(1) resulting in biological therapies targeting the activity of the T-lymphocytes and cytokines that are responsible for the inflammatory nature of this disease. Singri et al(2) recently defined four strategies that clarify the mechanism of action for the various biological agents: reduction of pathogenic T-cells; inhibition of T-cell activation; immune deviation (“deviation” of a Th1 immune response toward a greater Th2-type response, through the involvement of Th2-type cytokines); and blocking the activity of inflammatory cytokines.(2) In this review, we present an update on the progress of four new biological agents.
Infliximab (Remicade) is a chimeric (mouse–human) IgG1 monoclonal antibody (MAb) that binds to tumour necrosis factor alpha (TNFalpha) and inhibits the production of other proinflammatory cytokines, reducing cell infiltration and, eventually, keratinocyte proliferation. The drug is currently approved for Crohn’s disease (CD) and rheumatoid arthritis (RA), as an intravenous (IV) infusion.
Gottlieb et al(3) reported results from the first 10 weeks of a phase II trial evaluating the efficacy and tolerability of infliximab in the treatment of psoriasis. In this study, 249 patients were randomised in a 1:2:2 ratio to infusions of placebo, infliximab (3mg/kg) or infliximab (5mg/kg) and treated at weeks 0, 2 and 6. The proportions of patients reaching psoriasis area and severity index (PASI) 75 at week 10 were as follows: 6% for placebo, 72% for infliximab (3mg/kg) and 88% for infliximab (5mg/kg). The therapy was generally well tolerated.
Infliximab has been associated with a number of adverse events.(4) Infusion reactions, reported in 19% of patients in clinical trials, consist of fever or chills or, more rarely, chest pain, hypotension, hyper-tension and dyspnoea. Neutralising antibodies are formed, and patients can develop a serum sickness reaction days after administration of the drug.(4) Infection is an issue of major concern, and there have been multiple reports of reactivation of latent tuberculosis with infliximab.(5–7) One of the major concerns with the use of TNF inhibitors is the potential risk for the development of lymphomas,(8) and additional epidemiological studies should be initiated to evaluate this possible association formally. The induction of antinuclear (ANA) and anti-DNA antibodies is observed in some patients treated with infliximab and etanercept.(9) Induction of true lupus erythematosus by TNF inhibitors has also been observed.(10–14)
Etanercept (Enbrel) is a fully human TNF receptor created from the fusion of two naturally occurring TNF receptors. It binds to TNF with greater affinity than natural receptors, which are monomeric. The binding of etanercept to TNF renders the bound TNF biologically inactive, resulting in reduction in inflammatory activity. Etanercept is administered subcutaneously (SC) by patients at home.
The results of a phase III study evaluating the efficacy and tolerability of etanercept in psoriasis were recently reported.(15) Etanercept was evaluated at doses of 25mg and 50mg SC twice weekly. At the 2mg dose, the percentage of patients achieving PASI 75 was 34% at 12 weeks and 49% at 24 weeks. At the 50mg dose, the percentage of patients achieving PASI 75 was 49% at 12 weeks and 59% at 24 weeks. Therapy with etanercept was generally well tolerated.(15)
Etanercept has been used safely over the past few years. Injection site reactions are the main adverse events noted.(4) There have been infrequent observations of demyelinating disorders such as multiple sclerosis, allergic reactions and aplastic anaemia.(4) Because etanercept has been available for RA for several years, it possesses a good safety profile with regard to the risk of malignancy and infection. Results from 1,272 patients (3,706 patient-years) in North America demonstrate continued apparent safety of etanercept for over five years of therapy in the population studied.(16) Kwon et al,(17) utilising the FDA’s MedWatch programme, documented 47 patients who developed new or worsening heart failure during TNF antagonist therapy. The authors concluded that, in a fraction of patients, TNF antagonists might induce new-onset heart failure or exacerbate existing disease. However, they noted that these spontaneous reports alone are not sufficient to make causal inferences. (17)
Efalizumab (Raptiva) is a humanised MAb against the CD11a molecule. CD11a and CD18 comprise subunits of leukocyte function-associated antigen-1 (LFA-1), a T-cell surface molecule important in T-cell activation, T-cell migration into the skin and cytotoxic T-cell function. Binding of this drug to CD11a on T-cells blocks the interaction between LFA-1 and intercellular adhesion molecule (ICAM)-1, its partner molecule for adhesion. The blockade is reversible and does not deplete T-cells.
Recently, a phase III trial with SC efalizumab showed promising results in the treatment of moderate-to-severe plaque psoriasis.(18) In this multicentre, randomised, placebo-controlled, double-blind study, 597 subjects with psoriasis were assigned to receive efalizumab (1 or 2mg/kg of body weight per week SC) or placebo for 12 weeks. Depending on the response after 12 weeks, subjects received an additional 12 weeks of treatment with efalizumab or placebo. Study treatments were discontinued at week 24, and subjects were followed for an additional 12 weeks. At week 12, there was an improvement of 75% or more in the PASI in 22% of the subjects who had received efalizumab (1mg/kg per week) and 28% of those who had received efalizumab (2mg/kg per week), compared with 5% of the subjects in the placebo group (p<0.001 for both comparisons). Efalizumab-treated subjects had greater improvement than those in the placebo group as early as week 4 (p<0.001). Among the efalizumab-treated subjects who had an improvement of 75% or more at week 12, improvement was maintained through week 24 in 77% of those who continued to receive efalizumab, compared with 20% of those who were switched to placebo (p<0.001 for both comparisons). After discontinuation of efalizumab at week 24, an improvement of 50% or more in the PASI was maintained in approximately 30% of subjects during the 12 weeks of follow-up. Efalizumab was well tolerated, and adverse events were generally mild to moderate.(18)
In terms of safety, there have been no opportunistic infections, no clinical signs of immuno-suppression and no hepatotoxicity or nephrotoxicity associated with the use of efalizumab.(4) In the phase III trial, there was no evidence of T-cell depletion or increased risk of end-organ toxicity, malignancy or infection.(18)
Psoriatic plaques are characterised by infiltration with CD4+, CD45RO+, CD8+ and CD45RO+ memory-effector T-lymphocytes. The recombinant protein alefacept (Amevive) binds to the CD2 molecule on memory-effector T-lymphocytes, inhibiting their activation and reducing the number of these cells. It is a fusion protein composed of leukocyte function-associated antigen type 3 (LFA-3) protein and human IgG1 Fc domains. The drug is administered by intramuscular (IM) or intravenous injection.
An international multicentre trial randomised more than 500 patients to one of three arms: alefacept (15mg IM once a week for 12 weeks), alefacept (10mg IM once a week for 12 weeks) or placebo.(19) Two weeks after the last dose was given, 21% of patients treated with the 15mg dose achieved at least a 75% reduction from baseline in their PASI score, compared with 5% of patients receiving placebo (p<0.001). Krueger and Ellis(20) recently reported that alefacept therapy produces remission for patients with chronic plaque psoriasis. In these patients, responses were sustained for a median time of 10 months, and for up to 18 months. No patient reported disease rebound after cessation of alefacept.(20)
In terms of adverse events, patients treated with alefacept have a reduction in CD45RO+ memory T-cells, which correlates with improvement in psoriasis. The drug has been studied in more than 1,500 patients, with some receiving as many as six courses of treatment. To date, no clinically significant signs of immunosuppression or opportunistic infections have been observed, and no increase in malignancy has been observed.
Biological agents offer successful therapy of psoriasis, with a lack of organ toxicity seen with traditional systemic therapies such as methotrexate and ciclosporin in the patients treated to date. These agents have demonstrated varying efficacies, and each has individual safety concerns. Issues and potential limitations inherent in the use of these agents include the expected high costs of treatment, the lack of long-term follow-up and the selective nature of subjects treated thus far. Long-term monitoring of these agents is necessary to determine the potential risk for increased infection and malignancy.