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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
[+] Article and Author 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@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.


Ann Intern Med. 2002;137(9):726-733. doi:10.7326/0003-4819-137-9-200211050-00007
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This study is one of the first to show that the combination of two metabolic agents, methotrexate and leflunomide, is associated with statistically significant and clinically meaningful improvements in patients with active rheumatoid arthritis when compared with the combination of placebo and methotrexate. Patients in the leflunomide group were more likely than those in the placebo group to experience elevated levels of liver aminotransferase enzymes. However, values normalized in all patients in the leflunomide group, in most cases with no adjustment of leflunomide dose (58.5%) or with one dose decrease (29.3%).

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Figures

Grahic Jump Location
Figure 1.
Patient eligibility, randomization, assignment, and discontinuation.

*Includes one patient in each group who had a fatal adverse event (intracranial aneurysm in the leflunomide and methotrexate group, lymphoma and multiorgan failure in the placebo and methotrexate group).

†Include no wish to continue in study, poor adherence to treatment, protocol violation, and moving away from the study area.

Grahic Jump Location
Grahic Jump Location
Figure 2.
Patients who achieved 20% improvement in American College of Rheumatology rheumatoid arthritis criteria (ACR20).

Those who withdrew early from the study for any reason were automatically considered nonresponders for all visits after withdrawal. Those who did not have sufficient data to allow determination of ACR20 response at a particular visit were considered nonresponders for that visit. The solid line indicates patients receiving leflunomide and methotrexate; the dotted line indicates patients receiving placebo and methotrexate.

Grahic Jump Location

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Summary for Patients

Combination Therapy for Rheumatoid Arthritis

The summary below is from the full report titled “Concomitant Leflunomide Therapy in Patients with Active Rheumatoid Arthritis despite Stable Doses of Methotrexate. A Randomized, Double-Blind, Placebo-Controlled Trial.” It is in the 5 November 2002 issue of Annals of Internal Medicine (volume 137, pages 726-733). The authors are JM Kremer, MC Genovese, GW Cannon, JR Caldwell, JJ Cush, DE Furst, ME Luggen, E Keystone, MH Weisman, WM Bensen, JL Kaine, EM Ruderman, P Coleman, DL Curtis, EJ Kopp, SM Kantor, J Waltuck, HB Lindsley, JA Markenson, V Strand, B Crawford, I Fernando, K Simpson, and JM Bathon.

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