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Potential benefits

TNF antagonists are proving effective in trials but there are concerns over side effects. Psoriatic arthritis is the concurrence of psoriasis and polyarthritis symptoms that cause joint inflammation and stiffness.

BenefitsPsoriatic arthritis (PA) is the concurrence of psoriasis and polyarthritis symptoms that cause joint inflammation and stiffness.

PA can be a potentially disabling disease if left untreated and, according to Gottlieb and Antoni 2004, there is an unmet need for better therapeutic options as current PA therapies treat associated symptoms but do not prevent the progression of joint damage.

Treatment for the condition normally involves the use of nonsteroidal anti-inflammatories (NSAIDs) for joint disease and topical therapies for the skin. However, tumour necrosis factor (TNF) receptor antagonists have shown significant efficacy and benefits for PA sufferers in recent clinical trials. TNF antagonists pinpoint immunological targets and alter the pathogenic mechanisms to reduce disease progression.

Enbrel
Enbrel (etanercept), a TNF antagonist developed by Amgen and marketed by Wyeth, was launched as a treatment of PA in the US in 2002. Results from a single-centre trial of 60 patients with severe PA found that after 3 months 87 per cent of Enbrel recipients achieved Psoriatic Arthritis Response Criteria (PsARC) (improvements in tender or swollen joints by at least 30 per cent and physician or global improvement by at least 1 point), compared with 23 per cent of placebo recipients.

In addition, there were improvements in median Psoriasis Area and Severity Index (PASI) scores of 46.2 per cent compared with 8.7 per cent in the placebo group.

Enbrel was found to produce durable improvements in PA symptoms that were maintained throughout a 24 week double-blind phase III study.

In this study a significantly greater proportion of Enbrel recipients achieved American College of Rheumatology (ACR) response criteria of at least 20 per cent (ACR20), compared with placebo recipients.

Humira
Abbot Laboratories' TNF antagonist, Humira (adalimumab), has also proved to be effective for patients with PA. In the Adalimumab Effectiveness in Psoriatic Arthritis (ADEPT) trial 313 PA sufferers with at least 3 swollen and tender joints were randomised to receive subcutaneous injections of Humira 40mg, or placebo, on alternate weeks.

At 12 weeks, PsARC was achieved in 71 per cent of Humira-treated patients compared with 30 per cent of placebo.

At 24 weeks, there were improvements in skin and joint symptoms, PASI scores, improved Health Assessment Questionnaire Disability ratings and higher ACR response rates were seen compared with placebo.

A second study of Humira in patients with moderate-to-severe chronic plaque psoriasis and PA also found that it significantly improved Physician Global Assessment (PGA) rates, and the long-term efficacy was proved in the extension study where PGA rates and PASI response rates at 24 weeks were similar to those noted at 12 weeks.

Humira is generally well tolerated; the most common adverse events reported tended to be headache and injection site reactions. Abbot Laboratories is currently waiting for Humira to be approved as an indication for PA in the US and EU.

Remicade
Centocor's Remicade (infliximab) is another TNF antagonist that is waiting to be approved for PA treatment. Favourable results were demonstrated in the Infliximab Multinational Psoriatic Arthritic Controlled Trial (IMPACT). Some 102 patients with active PA, who failed therapy with at least 1 disease modifying antirheumatic drug (DMARD), were randomised to receive an intravenous infusion of Remicade 5 mg/kg or placebo.

In the Remicade group, ACR20, ACR50 and ACR70 response rates were achieved in 69, 49 and 29 per cent of patients, respectively. Only 8 per cent of placebo recipients achieved ACR20.

The benefits of Remicade were evident as early as two weeks in the larger IMPACT 2 trial, and ACR20 and a PsARC response was achieved in 59 and 78 per cent of recipients, respectively, compared with 11 and 18 per cent of placebo recipients.

Potential problems
TNF antagonists have been associated with rare incidences of adverse events. According to Mease and Antoni 2005, TNF antagonists may potentially suppress immunological activity by inhibiting certain immunological processes in order to modify overactive immune responses.

This increases the risk of new infections, exacerbation of existing infections, auto-immune diseases, allergic reactions and cancer. Keane 2004 recommends that all patients undergo tuberculosis (TB) testing prior to initiating TNF antagonist therapy due to the increased risk of opportunistic infections, such as TB.

According to Mease and Antoni 2005, clinical studies have shown that infection rates are similar compared with placebo, but the occurrence of an infection is more problematic for TNF antagonist recipients.

In addition, the safety profile of TNF antagonists in patients with PA has been found to be comparable to that observed in patients with rheumatoid arthritis.

Pipeline is written by Helen Commander, Adis International, using information derived from Adis Clincial Trials Insight and R&D Insight. For more information on Adis services contact Camille Scot-Smith on 020 7981 0733

2nd September 2008

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