Infliximab: no major benefit in polymyalgia rheumatica or giant-cell arteritis?

Wednesday 2nd May 2007

Two controlled trials just published investigated whether infliximab might have benefits in polymyalgia rheumatica (PR) or giant-cell arteritis (GCA), but found no significant effect. These two conditions are rheumatic diseases with overlapping clinical features – they are fairly common and generally affect older people. Currently, the cornerstone of therapy is corticosteroid treatment, but this may need to be prolonged and many patients have significant corticosteroid-related adverse effects. Some evidence suggests cytokines may be involved in pathogenesis, and the two studies aimed to determine whether blockade of tumour necrosis factor (TNF) with infliximab had any benefits.

The GCA study compared infliximab with placebo in newly diagnosed patients who were receiving standard corticosteroid therapy (prednisolone or prednisone) to induce remission. Patients received corticosteroid, plus infliximab or placebo IV infusion at zero, two, and six weeks, then every eight weeks thereafter; corticosteroid dose was tapered according to a defined schedule. Planned study duration was 54 weeks and the primary outcomes were number of patients remaining free of relapse and adverse events.

A total of 44 patients were randomised (infliximab n=28, placebo n=16). Interim analysis at 22 weeks found no significant difference between the groups in primary efficacy outcome (remission rates infliximab 43% vs placebo 50%), neither was there any difference in time to relapse. As a result, the study was stopped early. There was no significant difference in adverse events, although infliximab was associated with a higher incidence of infections and infusion-site reactions. The authors conclude that infliximab failed to increase duration of remission or reduce corticosteroid requirements in patients with newly diagnosed GCA. They comment that the study could only have demonstrated a large effect, and a more modest effect would have been missed: a larger trial would be required to detect this, if present. However, a more modest effect might not justify the risk and cost of using this drug. The study also provides no evidence on use for relapsed patients or those not responding to corticosteroids.

The second study looked at the use of infliximab in PR, using a similar design. Patients had newly diagnosed PR and were initially treated with standard doses of corticosteroid to induce remission. Infliximab or placebo was given by IV infusion at weeks zero, two, six, 14 and 22, and the corticosteroid dose tapered according to standard procedures. Planned study duration was 52 weeks, and the primary outcome was the proportion of patients without relapse or recurrence through to week 52.

A total of 51 patients were randomised (infliximab n=23, placebo n=28). There was no significant difference between the groups in the primary outcome at the end of the study (relapse- or recurrence-free – infliximab 30% vs placebo 37%). There were also no significant differences in any secondary endpoints or in adverse events. The authors conclude that infliximab added to a standard corticosteroid regimen does not affect outcomes in patients with newly diagnosed PR. As for the GCA trial, this was too small to demonstrate a modest benefit; again, however, a modest benefit might not justify the risks and costs of using infliximab.

An accompanying editorial discusses the two studies. The author notes that both were small and would thus only demonstrate a large effect reliably. However, he concurs that using an expensive and potentially toxic drug such as infliximab would only be justifiable if the benefit was large. He suggests that the evidence for TNF as a significant pathogenic factor is limited and that other cytokines (eg, interleukin-6) may be more important. Until further research has clarified the role of these, corticosteroids remain a cornerstone of treatment.

Ann Intern Med 2007;146:621-39