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Previous Volume 349:1907-1915 November 13, 2003 Number 20 Next

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ABSTRACT

Background Effective new therapies are needed for rheumatoid arthritis. Current therapies target the products of activated macrophages; however, T cells also have an important role in rheumatoid arthritis. A fusion protein — cytotoxic T-lymphocyte–associated antigen 4–IgG1 (CTLA4Ig) — is the first in a new class of drugs known as costimulation blockers being evaluated for the treatment of rheumatoid arthritis. CTLA4Ig binds to CD80 and CD86 on antigen-presenting cells, blocking the engagement of CD28 on T cells and preventing T-cell activation. A preliminary study showed that CTLA4Ig may be effective for the treatment of rheumatoid arthritis.

Methods We randomly assigned patients with active rheumatoid arthritis despite methotrexate therapy to receive 2 mg of CTLA4Ig per kilogram of body weight (105 patients), 10 mg of CTLA4Ig per kilogram (115 patients), or placebo (119 patients) for six months. All patients also received methotrexate therapy during the study. The clinical response was assessed at six months with use of the criteria of the American College of Rheumatology (ACR), which define the response according to its extent: 20 percent (ACR 20), 50 percent (ACR 50), or 70 percent (ACR 70). Additional end points included measures of the health-related quality of life.

Results Patients treated with 10 mg of CTLA4Ig per kilogram were more likely to have an ACR 20 than were patients who received placebo (60 percent vs. 35 percent, P<0.001). Significantly higher rates of ACR 50 and ACR 70 responses were seen in both CTLA4Ig groups than in the placebo group. The group given 10 mg of CTLA4Ig per kilogram had clinically meaningful and statistically significant improvements in all eight subscales of the Medical Outcomes 36-Item Short-Form General Health Survey. CTLA4Ig was well tolerated, with an overall safety profile similar to that of placebo.

Conclusions In patients with active rheumatoid arthritis who were receiving methotrexate, treatment with CTLA4Ig significantly improved the signs and symptoms of rheumatoid arthritis and the health-related quality of life. CTLA4Ig is a promising new therapy for rheumatoid arthritis.

Source Information

From the Center for Rheumatology, Albany, N.Y. (J.M.K.); the Department of Rheumatology, Universitaire Ziekenhuizen Leuven, Leuven, Belgium (R.W.); Free University of Brussels, Centre Hospitalier Universitaire Ambroise Paré, Mons, Belgium (M.L.); Centro de Enfermedades Reumáticas, Quilmes, Argentina (E.D.G.); the Department of Rheumatology, Schlosspark-Klinik, Berlin, Germany (R.A.); the Department of Rheumatology, Erasme University Hospital, Brussels, Belgium (S.S.); the University of Alberta Hospital, Edmonton, Alta., Canada (A.R.); Rene Descartes University, Hospital Cochin Assistance Publique — Hôpitaux de Paris, Paris (M.D.); the Department of Rheumatology, Leeds General Infirmary, Leeds, United Kingdom (P.E.); Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, N.J. (I.F.N., G.R.W., J.-C.B., D.T.H.); and the Department of Medicine, University of Alabama at Birmingham School of Medicine, Birmingham (L.W.M.).

Address reprint requests to Dr. Kremer at the Center for Rheumatology, 1367 Washington Ave., Suite 1, Albany, NY 12206, or at jkremer{at}joint-docs.com.

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