A novel investigational agent, which targets the disease process of rheumatoid arthritis through a unique mechanism of action, may provide a new treatment option for patients, according to research published by the Center for Rheumatology in the November 13 issue of The New England Journal of Medicine.

In a phase II dose-ranging study, CTLA4Ig, which could be the first in a new class of agents called selective costimulation modulators, significantly improved signs and symptoms of rheumatoid arthritis compared to placebo, as measured by the American College of Rheumatology (ACR) score. All 339 patients in the six-month study also received methotrexate, a widely used rheumatoid arthritis treatment.

Of those treated with 10 milligrams per kilogram of body weight (mg/kg) of CTLA4Ig, 60 per cent achieved ACR 20 -- at least a 20 per cent improvement in signs and symptoms; 35 per cent of patients who were given placebo achieved the same improvement.

"CTLA4Ig modulates autoimmune T cell function, which helps to stem the cascade of inflammation that leads to joint damage," said the study's lead author, Joel Kremer, MD, director of research at The Center for Rheumatology in Albany, NY, and clinical professor of medicine, Albany Medical College. "CTLA4Ig was shown to relieve signs and symptoms and appears to be a promising new therapy for rheumatoid arthritis."

One per cent of the world's population suffers from rheumatoid arthritis, accounting for more than 9 million physician visits and 250,000 hospitalizations in the United States annually. The condition, which leads to joint swelling, pain, and often disfigurement, is more common in women than in men. Three out of four patients diagnosed with rheumatoid arthritis are women.

Rheumatoid arthritis is an autoimmune disease. The body's T cells, which, when fully activated, trigger the inflammation that leads to rheumatoid arthritis. CTLA4Ig, which is being developed by Bristol-Myers Squibb and is also known as BMS-188667, blocks one of the two signals needed for full T cell activation.

"What we hope to find with CTLA4Ig is that by modulating the activity of autoreactive T cells, which can orchestrate the immune response that then drives the inflammatory consequences of rheumatoid arthritis, we may alter the disease process," said Dr. Kremer. "We have essentially created a new therapeutic target with this approach. These data demonstrate the value of selective costimulation modulation in the treatment of rheumatoid arthritis."

The primary endpoint of the study was the proportion of patients meeting the ACR 20 score, a way of determining improvement in patients by examining multiple measures of disease activity. The researchers also measured the number of patients achieving ACR 50 and ACR 70 -- 50 or 70 per cent improvements in signs and symptoms.

Among patients receiving 10 mg/kg of CTLA4Ig, 60 per cent achieved ACR 20; 36.5 per cent achieved ACR 50 and 16.5 per cent achieved ACR 70. In patients receiving placebo, 35.3 per cent achieved ACR 20; 11.8 per cent achieved ACR 50 and 1.7 per cent achieved ACR 70. All of these data were statistically significant (p0.001).

The patients receiving 10 mg/kg of CTLA4Ig also had clinically meaningful and statistically significant mental and physical improvements in health-related quality of life, according to the researchers. This was determined by using the Medical Outcomes Study 36-Item Short-Form General Health Survey (SF-36), which assesses patient quality of life by studying eight physical and mental function measures.

CTLA4Ig was administered by a 30-minute intravenous infusion. CTLA4Ig or placebo was infused intravenously on days 1, 15, and 30 of the study and monthly thereafter for a total of six months for this analysis.

CTLA4Ig was generally well tolerated. In general, adverse events were reported at a similar or lower rate in the CTLA4Ig groups than in the placebo group. The most frequently reported adverse event was headache, followed in decreasing order by upper respiratory tract infection, musculoskeletal pain, and nausea and vomiting.

Co-authors include Rene Westhovens, MD, Ph.D., Marc Leon, MD, Eduardo Di Giorgio, MD, Rieke Alten, MD, Serge Steinfeld, MD, Ph.D., Anthony Russell, MD, Maxime Dougados, MD, Paul Emery, MD, FRCP, Issac Nuamah, Ph.D., G. Rhys Williams, Sc.D., Jean-Claude Becker, MD, David Hagerty, MD, and Larry Moreland, MD.