Effects of Abatacept in Patients with Methotrexate-Resistant Active Rheumatoid Arthritis

A Randomized Trial

20 June 2006 | Volume 144 Issue 12 | Pages 865-876

Background: The selective co-stimulation modulator abatacept demonstrated efficacy for treating rheumatoid arthritis in early clinical studies.

Objective: To evaluate the effects of abatacept in patients with persistent, active rheumatoid arthritis despite methotrexate treatment.

Design: One-year, multicenter, randomized, double-blind, placebo-controlled trial (November 2002 to October 2004).

Setting: 116 centers worldwide.

Patients: 652 patients with active rheumatoid arthritis despite methotrexate treatment.

Intervention: Once-monthly infusion of a fixed dose of abatacept, approximately 10 mg/kg of body weight, or placebo.

Measurements: Co-primary end points were a 20% improvement in American College of Rheumatology (ACR) response criteria (ACR 20) at 6 months, clinically meaningful improvements in physical function, and change from baseline in joint erosion score at 1 year.

Results: Four hundred thirty-three and 219 patients were randomly assigned to abatacept or placebo, respectively, and 385 (89%) and 162 (74%), respectively, completed 1 year of treatment. In a modified intention-to-treat analysis, 6-month ACR 20, ACR 50, and ACR 70 responses were 67.9% for abatacept versus 39.7% for placebo (difference, 28.2 percentage points [95% CI, 19.8 to 36.7 percentage points]), 39.9% for abatacept versus 16.8% for placebo (difference, 23.0 percentage points [CI, 15.0 to 31.1 percentage points]), and 19.8% for abatacept versus 6.5% for placebo (difference, 13.3 percentage points [CI, 7.0 to 19.5 percentage points]), respectively. At 1 year, the responses increased to 73.1% for abatacept versus 39.7% for placebo (difference, 33.4 percentage points [CI, 25.1 to 41.7 percentage points]), 48.3% for abatacept versus 18.2% for placebo (difference, 30.1 percentage points [CI, 21.8 to 38.5 percentage points]), and 28.8% for abatacept versus 6.1% for placebo (difference, 22.7 percentage points [CI, 15.6 to 29.8 percentage points]), respectively (P < 0.001 for all). Physical function significantly improved in 63.7% versus 39.3% of patients (P < 0.001). At 1 year, abatacept statistically significantly slowed the progression of structural joint damage compared with placebo. Abatacept-treated patients had a similar incidence of adverse events (87.3% vs. 84.0%; difference, 3.3 percentage points [CI, –2.5 to 9.1 percentage points]) and a higher incidence of prespecified serious infections (2.5% vs. 0.9%; difference, 1.6 percentage points [CI, –0.3 to 3.6 percentage points]) and infusion reactions (acute, 8.8% vs. 4.1%; difference, 4.7 percentage points [CI, 0.9 to 8.4 percentage points]; peri-infusional, 24.5% vs. 16.9%; difference, 7.6 percentage points [CI, 1.2 to 14.0 percentage points]) compared with placebo recipients.

Limitations: The study involved only 1 group of patients over 1 year.

Conclusions: Abatacept statistically significantly reduced disease activity in patients with rheumatoid arthritis and an inadequate response to methotrexate. Longer treatment in different patient populations is needed to establish its appropriate role in rheumatoid arthritis.

Editors' Notes Context Abatacept, an agent that selectively modulates the co-stimulatory signal required for T-cell activation, may benefit some patients with rheumatoid arthritis. Contribution This 1-year, randomized, double-blind trial compared once-monthly infusions of abatacept with placebo in 652 patients with symptomatic rheumatoid arthritis despite ongoing methotrexate treatment. Compared with placebo recipients, patients who received abatacept more often had improved physical function, more frequently met standard response criteria, and less often had radiographic progression of joint damage. They also had serious infections (2.5% vs. 0.9%) and infusion reactions more often. Implications Adding abatacept can reduce disease activity in patients with rheumatoid arthritis and an inadequate response to methotrexate. —The Editors

 

Author and Article Information

From the Center for Rheumatology, Albany, New York; University of California, San Francisco, and Synarc Inc., San Francisco, California; University of Alabama at Birmingham School of Medicine, Birmingham, Alabama; University of Alberta, Edmonton, Alberta, Canada; Leeds General Infirmary, Leeds, United Kingdom; Hospital Central, San Luis Potosi, Mexico; University of Medical Sciences, Wroclaw, Poland; Bristol-Myers Squibb, Princeton, New Jersey; and University Hospital Leuven, Leuven, Belgium.

ClinicalTrials.gov identifier: NTC00048568.

Grant Support: By Bristol-Myers Squibb.

Potential Financial Conflicts of Interest: Employment: T. Li (Bristol-Myers Squibb), Z. Ge (Bristol-Myers Squibb), J.-C. Becker (Bristol-Myers Squibb); Consultancies: J.M. Kremer (Bristol-Myers Squibb), H.K. Genant (Bristol-Myers Squibb, Amgen, Wyeth, Novartis, Lilly, Roche), L.W. Moreland (Bristol-Myers Squibb), A.S. Russell (Bristol-Myers Squibb), P. Emery (Amgen, Schering-Plough, Centocor, Bristol-Myers Squibb), R. Westhovens (Schering-Plough, Bristol-Myers Squibb); Honoraria: J.M. Kremer (Bristol-Myers Squibb), H.K. Genant (Bristol-Myers Squibb, Amgen, Wyeth, Novartis, Lilly, Roche), L.W. Moreland (Bristol-Myers Squibb), P. Emery (Wyeth, Roche), R. Westhovens (Schering-Plough, Bristol-Myers Squibb); Stock ownership or options (other than mutual funds): T. Li (Bristol-Myers Squibb), Z. Ge (Bristol-Myers Squibb), J.-C. Becker (Bristol-Myers Squibb); Grants received: J.M. Kremer (Bristol-Myers Squibb), H.K. Genant (Bristol-Myers Squibb, Amgen, Wyeth, Novartis, Lilly, Roche), L.W. Moreland (Bristol-Myers Squibb); Patents pending: J.-C. Becker (Bristol-Myers Squibb).

Requests for Single Reprints: Joel M. Kremer, MD, Center for Rheumatology, 1367 Washington Avenue, Suite 1, Albany, NY 12206; e-mail, jkremer{at}joint-docs.com.

Current Author Addresses: Dr. Kremer: Center for Rheumatology, 1367 Washington Avenue, Suite 1, Albany, NY 12206.

Dr. Genant: Radiology Department, University of California, San Francisco, 505 Parnassus Avenue, Box 0628, San Francisco, CA 94143-0628.

Dr. Moreland: 068 Spain Rehabilitation Center, University of Alabama at Birmingham, 1717 6th Avenue South, Birmingham, AL 35294.

Dr. Russell: Medical Department, University of Alberta Hospital, 562 Heritage Medical Research Centre, Edmonton, T6G 2S2 Alberta, Canada.

Dr. Emery: Academic Unit of Musculoskeletal Disease, Chapel Allerton Hospital, Chapeltown Road, Leeds LS7 4SA, United Kingdom.

Dr. Abud-Mendoza: Hospital Central, Av. Carranza 2395, San Luis Potosi, S.L.P. 78240, Mexico.

Dr. Szechinski: Department of Rheumatology, Medical University of Wroclaw, ul. Winiowa 36a, 53-137 Wrocaw, Poland.

Drs. Li and Becker: Bristol-Myers Squibb, PO Box 4000, Princeton, NJ 08543.

Dr. Ge: 13133 Taylor Court, West Windsor, NJ 08550.

Dr. Westhovens: Rheumatology Department, University Hospitals, K.U. Leuven, Herestraat 49, 3000 Leuven, Belgium.

Author Contributions: Conception and design: J.M. Kremer, H.K. Genant, L.W. Moreland, A.S. Russell, P. Emery, T. Li, J.-C. Becker, R. Westhovens.

Analysis and interpretation of the data: J.M. Kremer, H.K. Genant, L.W. Moreland, P. Emery, C. Abud-Mendoza, T. Li, Z. Ge, J.-C. Becker, R. Westhovens.

Drafting of the article: J.M. Kremer, H.K. Genant, L.W. Moreland, A.S. Russell, T. Li, J.-C. Becker, R. Westhovens.

Critical revision of the article for important intellectual content: J.M. Kremer, H.K. Genant, L.W. Moreland, A.S. Russell, P. Emery, C. Abud-Mendoza, J. Szechinski, T. Li, J.-C. Becker, R. Westhovens.

Final approval of the article: J.M. Kremer, L.W. Moreland, A.S. Russell, P. Emery, C. Abud-Mendoza, J. Szechinski, J.-C. Becker, R. Westhovens.

Provision of study materials or patients: J.M. Kremer, A.S. Russell, P. Emery, C. Abud-Mendoza, J. Szechinski, R. Westhovens.

Statistical expertise: Z. Ge, J.-C. Becker.

Obtaining of funding: J.-C. Becker.

Administrative, technical, or logistic support: J.-C. Becker.

Collection and assembly of data: J.M. Kremer, P. Emery, J.-C. Becker.