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Concomitant Leflunomide Therapy in Patients with Active Rheumatoid Arthritis despite Stable Doses of Methotrexate

A Randomized, Double-Blind, Placebo-Controlled Trial

Joel M. Kremer, MD; Mark C. Genovese, MD; Grant W. Cannon, MD; Jacques R. Caldwell, MD; John J. Cush, MD; Daniel E. Furst, MD; Michael E. Luggen, MD; Ed Keystone, MD; Michael H. Weisman, MD; William M. Bensen, MD; Jeffrey L. Kaine, MD; Eric M. Ruderman, MD; Patricia Coleman, MD; David L. Curtis, MD; Elliot J. Kopp, MD; Seth M. Kantor, MD; Jonathan Waltuck, MD; Herbert B. Lindsley, MD; Joseph A. Markenson, MD; Vibeke Strand, MD; Bruce Crawford, MA, MPH; Indra Fernando, PhD; Karen Simpson, MD; and Joan M. Bathon, MD

5 November 2002 | Volume 137 Issue 9 | Pages 726-733

Background: Disease-modifying antirheumatic drugs may confer greater benefits when combined with the antimetabolite methotrexate.

Objective: To evaluate the efficacy and safety of leflunomide versus placebo when added to ongoing, stable-dose methotrexate therapy in patients with persistently active rheumatoid arthritis.

Design: 24-week, multicenter, randomized, double-blind, placebo-controlled trial.

Setting: 20 centers in the United States and Canada.

Patients: Patients with persistent rheumatoid arthritis, as defined by American College of Rheumatology (ACR) criteria, despite receiving methotrexate for at least 6 months.

Intervention: Leflunomide or matching placebo added to existing methotrexate therapy.

Measurements: The primary efficacy variable was the rate of achievement of 20% improvement in ACR criteria (ACR20) at the end of the study. The Health Assessment Questionnaire Disability Index was assessed at each visit, and the Medical Outcomes Study 36-Item Short Form was completed as an end point analysis.

Results: In the leflunomide and placebo groups, 46.2% and 19.5% of patients, respectively, met ACR20 criteria at 24 weeks (P < 0.001). Clinical improvement was demonstrated by statistically significant mean changes in individual components of the ACR20 response criteria. Discontinuation rates were similar in both treatment groups (23.1% in the leflunomide group and 24.8% in the placebo group), as were the overall incidences of adverse events (89.2% vs. 89.5%, respectively). Adverse events were predominantly mild or moderate.

Conclusions: Combination therapy with leflunomide and methotrexate provides statistically significant clinical benefit in patients with active rheumatoid arthritis who are receiving methotrexate therapy. Leflunomide plus methotrexate is generally well tolerated and can be used safely with appropriate liver enzyme and hematologic monitoring.

Editors' Notes Context Several disease-modifying antirheumatic drugs (DMARDs) slow disease progression in patients with rheumatoid arthritis. Many experts prefer methotrexate, although trials do not uniformly show that it is superior to other DMARDs. It is not known whether combining methotrexate with a second DMARD is better than prescribing methotrexate alone. Contribution This 24-week, randomized, double-blind, placebo-controlled trial shows that leflunomide added to ongoing stable-dose methotrexate therapy in patients with persistently active rheumatoid arthritis improves clinical outcomes compared with methotrexate alone. Cautions Some adverse effects, such as diarrhea, were more common with combination therapy. All patients receiving DMARD therapy need close monitoring for toxicities. –The Editors

 

Author and Article Information

From the Center for Rheumatology, Albany, and Hospital for Special Surgery, New York, New York; Stanford University School of Medicine, Stanford, UCLA Center for Health Sciences, Los Angeles, University of California San Diego, La Jolla, and California Pacific Medical Center, San Francisco, California; Veterans Affairs and University of Utah School of Medicine, Salt Lake City, Utah; Radiant Research, Daytona Beach, and Sarasota Arthritis Center, Sarasota, Florida; Presbyterian Hospital of Dallas, Dallas, Texas; University of Cincinnati Medical Center, Cincinnati, and Ohio State University, Columbus, Ohio; University of Toronto, Toronto, and McMaster University, Hamilton, Ontario, Canada; Northwestern University Feinberg School of Medicine, Chicago, Illinois; Good Clinical Practice, East Lansing, Michigan; C.A.R.E. Center, Raleigh, North Carolina; The Emory Clinic, Atlanta, Georgia; Kansas University Medical Center, Kansas City, Kansas; MAPI Values USA, Boston, Massachusetts; Quintiles, Inc., Kansas City, Missouri; Aventis Pharmaceuticals, Bridgewater, New Jersey; and Johns Hopkins University School of Medicine, Baltimore, Maryland.

Grant Support: By Aventis Pharmaceuticals.

Potential Financial Conflicts of Interest:Employment: K. Simpson; Consultancies: J.M. Kremer, M.C. Genovese, G.W. Cannon, J.R. Caldwell, J.J. Cush, E. Keystone, D.E. Furst, M.H. Weisman, W.M. Bensen, E.M. Ruderman, V. Strand, B. Crawford; Honoraria: J.M. Kremer, M.C. Genovese, G.W. Cannon, J.R. Caldwell, J.J. Cush, D.E. Furst, E. Keystone, M.H. Weisman, W.M. Bensen, E.M. Ruderman, S.M. Kantor, V. Strand; Stock ownership or options: K. Simpson; Grants received: J.M. Kremer, M.C. Genovese, G.W. Cannon, J.R. Caldwell, J.J. Cush, D.E. Furst, E. Keystone, M.H. Weisman, W.M. Bensen, E.M. Ruderman, H.B. Lindsley, J.M. Bathon.

Requests for Single Reprints: Joel M. Kremer, MD, The Center for Rheumatology, LLP, 1367 Washington Avenue, Suite 101, Albany, NY 12206; e-mail, jkremer{at}joint-docs.com.

Current Author Addresses: Dr. Kremer: The Center for Rheumatology, LLP, 1367 Washington Avenue, Suite 101, Albany, NY 12206.

Dr. Genovese: University Medical Center, Stanford Health Services, 1000 Welch Road, Suite 203, Palo Alto, CA 94304.

Dr. Cannon: Division of Rheumatology, University of Utah Medical Center, 50 North Medical Drive, Room 4B-200, Salt Lake City, UT 84132.

Dr. Caldwell: Radiant Research, 311 North Clyde Morris Boulevard, No. 520, Daytona Beach, FL 32114.

Dr. Cush: Division of Rheumatology and Clinical Immunology, Presbyterian Hospital of Dallas, 8200 Walnut Hill Lane, Jackson Building, Dallas, TX 75231-4496.

Dr. Furst: Rheumatology Division, UCLA Medical School, 1000 Veteran Avenue, Rehabilitation Center, Room 3259, Los Angeles, CA 98101.

Dr. Luggen: Division of Immunology, University of Cincinnati Medical Center, 231 Bethesda Avenue, Room 7464, Cincinnati, OH 45267-0563.

Dr. Keystone: Mount Sinai Hospital, University of Toronto, Room 1005, 10th Floor, 600 University Avenue, Toronto, Ontario M5G 1X5, Canada.

Dr. Weisman: Division of Rheumatology, Cedars-Sinai Medical Center, 8700 Beverly Boulevard, Suite B-131, Los Angeles, CA 90048.

Dr. Bensen: Charlton Medical Centre, McMaster University, 20325 Charlton Avenue E, Hamilton, Ontario L8N 1Y2, Canada

Dr. Kaine: Sarasota Arthritis Center, 3500 South Tamiami Trail, Sarasota, FL 34239.

Dr. Ruderman: Division of Rheumatology, Northwestern University Feinberg School of Medicine, 675 North St. Clair, Suite 18250, Chicago, IL 60611.

Dr. Coleman: Good Clinical Practice, 1601 East Michigan, Suite A, Lansing, MI 48912.

Dr. Curtis: California Pacific Medical Center, 2100 Webster Street, Suite 112, San Francisco, CA 94115.

Dr. Kopp: C.A.R.E. Center, 1631 Midtown Place, Suite 101, Raleigh, NC 27609.

Dr. Kantor: Department of Immunology, Ohio State University, 480 West 9th Avenue, Columbus, OH 43210.

Dr. Waltuck: Rheumatology, The Emory Clinic, 1365 Clifton Road, Atlanta, GA 30322.

Dr. Lindsley: University of Kansas Medical Center, 3901 Rainbow Boulevard, Kansas City, KS 66160.

Dr. Markenson: Department of Rheumatology, Hospital for Special Surgery, 535 East 70th Street, New York, NY 10021.

Dr. Strand: Division of Immunology, Stanford University School of Medicine, 306 Ramona Road, Portola Valley, CA 94028.

Mr. Crawford: MAPI Values USA, 15 Court Square, Suite 620, Boston, MA 02108.

Dr. Fernando: Quintiles, Inc., Dock 6, 10245 Hickman Mills Drive, Mail Station F4-M3726, Kansas City, MO 64137.

Dr. Simpson: Medical Research, Aventis Pharmaceuticals, 300 Somerset Corporate Boulevard, Mailstop SC3-305, Bridgewater, NJ 08807-2854.

Dr. Bathon: Department of Medicine, Johns Hopkins Bayview Medical Center, Room 3B.24, 5501 Hopkins Bayview Circle, Baltimore, MD 21224.

Author Contributions: Conception and design: J.M. Kremer, M.C. Genovese, G.W. Cannon, J.J. Cush, D.E. Furst, V. Strand, K. Simpson.

Analysis and interpretation of the data: J.M. Kremer, M.C. Genovese, G.W. Cannon, J.R. Caldwell, J.J. Cush, M.H. Weisman, J.L. Kaine, D.L. Curtis, J.A. Markenson, V. Strand, B. Crawford, I. Fernando, J.M. Bathon.

Drafting of the article: J.M. Kremer, M.C. Genovese, G.W. Cannon, J.R. Caldwell, M.H. Weisman, J.L. Kaine, D.L. Curtis, J. Waltuck, J.A. Markenson, V. Strand.

Critical revision of the article for important intellectual content: J.M. Kremer, M.C. Genovese, G.W. Cannon, J.R. Caldwell, J.J. Cush, D.E. Furst, M.E. Luggen, E. Keystone, M.H. Weisman, W.M. Bensen, J.L. Kaine, E.M. Ruderman, D.L. Curtis, S.M. Kantor, H.B. Lindsley, J.A. Markenson, V. Strand, B. Crawford, J.M. Bathon.

Final approval of the article: J.M. Kremer, M.C. Genovese, G.W. Can-non, J.R. Caldwell, J.J. Cush, D.E. Furst, M.E. Luggen, E. Keystone, M.H. Weisman, W.M. Bensen, J.L. Kaine, E.M. Ruderman, D.L. Curtis, E.J. Kopp, S.M. Kantor, J. Waltuck, H.B. Lindsley, J.A. Markenson, J.M. Bathon.

Provision of study materials or patients: J.M. Kremer, M.C. Genovese, G.W. Cannon, J.R. Caldwell, D.E. Furst, M.E. Luggen, E. Keystone, M.H. Weisman, W.M. Bensen, E.M. Ruderman, P. Coleman, D.L. Curtis, S.M. Kantor, H.B. Lindsley, J.A. Markenson.

Statistical expertise: B. Crawford.

Obtaining of funding: K. Simpson.

Collection and assembly of data: J.M. Kremer, G.W. Cannon, D.E. Furst, S.M. Kantor.

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