LONDON - Evaluation of a new treatment for rheumatoid arthritis has proved so promising that researchers are planning further trials to test the therapy in people newly diagnosed with the disease.

A trial has shown that the new therapy, which includes a monoclonal antibody called infliximab, can arrest joint damage in people with severe rheumatoid arthritis that no longer is responding to conventional drugs.

Ravinder Maini, Director of the Kennedy Institute of Rheumatology in London, told BioWorld International: "The results of this trial tell us that this treatment is not only controlling the signs and symptoms of the disease, but also controlling joint damage. This degree of arrest of joint damage has not been seen with any previous therapy. If this finding holds true for early arthritis - and there is no reason why it should not - then the benefits would be significant, because we would be able to prevent not only the symptoms but also the joint damage, the disability and the need for surgery associated with this disease."

Rheumatoid arthritis is a chronic disease affecting between 0.5 and 1 percent of the world's population. People of all ages are susceptible to it, and it is more common in females than in males. The cost in terms of human suffering and health care resources is enormous. The disease causes inflammation and destruction of the joints.

Drug therapy for rheumatoid arthritis has improved dramatically in recent years with the discovery that methotrexate, a drug originally developed for cancer, also has anti-inflammatory properties. It is now the gold standard for treating rheumatoid arthritis but it also can have toxic side effects and a limited period of efficacy.

Researchers have therefore been studying the inflammatory processes that take place in affected joints, to try to design rational therapies for this disease. Studies carried out at the Kennedy Institute, which is part of Imperial College School of Medicine at Charing Cross Hospital in London, during the late 1980s showed that tumor necrosis factor-alpha (TNF-a) plays an important role in driving the inflammatory response in rheumatoid arthritis. Maini said, "We found that TNF-alpha is overproduced in the rheumatoid joint, along with many other potentially pro-inflammatory mediators. We also showed, by looking at tissues from patients, that if you neutralized the activity of TNF-alpha, you could have a profound effect on the other inflammatory mediators."

By the early 1990s, the first trials of infliximab, or Remicade, a chimeric anti-TNF-alpha monoclonal antibody made by Centocor Inc., of Malvern, Pa., had begun. After encouraging early findings, a large-scale trial was set up by the ATTRACT study group, and the results of this trial were reported in The Lancet earlier this month, in a paper titled "Infliximab (chimeric anti-tumour necrosis factor alpha monoclonal antibody) versus placebo in rheumatoid arthritis patients receiving concomitant methotrexate: a randomised phase III trial."

Study participants decided that the group of patients who could derive most potential benefit from infliximab were those who were no longer responding to methotrexate or who were experiencing side effects to such an extent that they could no longer continue with it at the dose required to relieve their symptoms. This group probably accounts for about 25 percent of patients with rheumatoid arthritis.

An earlier Phase II study had already shown that there appeared to be greater clinical benefit from a combination of methotrexate and infliximab.

A total of 428 patients were randomized in a double-blind trial to receive either placebo injection plus methotrexate or an injected dose of 3 milligrams per kilogram of body weight of infliximab plus methotrexate, or a dose of 10 mg/kg of infliximab plus methotrexate. The latter two groups were randomized to receive infliximab either every four weeks or every eight weeks, so that there were five groups of patients in all.

The Lancet paper summarizes the findings for the first six months of the trial. Maini said, "We found that all four doses of infliximab with methotrexate were giving equivalent efficacy, and that this efficacy was highly impressive compared with the placebo group, with significant suppression of signs and symptoms of rheumatoid arthritis in up to about 60 percent of patients."

Infliximab is expensive, and the trial has shown that the dose of 3 mg/kg every eight weeks appears to be as effective, after six months of treatment, as the higher dose.

The safety profile of infliximab also is encouraging, Maini said, adding: "Serious adverse events and serious infections, which are always a concern with these biological therapies, did not occur at an increased frequency compared with the control group."

The FDA in the U.S. has granted infliximab a license for the treatment of rheumatoid arthritis. (It already is licensed there and in the European Union for the treatment of Crohn's disease, an inflammatory bowel disease.)

Additional data have also been released, documenting the radiological changes to joints in patients taking infliximab plus methotrexate or placebo plus methotrexate for one year. Maini said, "We found that there was a virtual suppression of joint damage in patients in the treatment groups. The question now is whether it is just as efficacious or even more so in early rheumatoid arthritis, and that trial will be done next."

Following the unblinding of the radiological results at one year, the trial's steering committee, advised by an independent safety committee, decided it would be unethical to continue the placebo arm of the trial, given that patients taking placebo were continuing to suffer joint damage. Comparison of the different doses of infliximab will continue up to the two-year point, to find out if there are any differences in efficacy between the doses.

Scientifically, the findings of the ATTRACT study are also very important, Maini said. "It will allow companies to work on TNF-alpha as a target and, obviously, if you could take a pill instead of having injections that would be a much better prospect for most patients."