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Combination Leflunomide and Methotrexate (MTX) Therapy for Patients with Active Rheumatoid Arthritis Failing MTX Monotherapy: Open-Label Extension of a Randomized, Double-Blind, Placebo Controlled Trial
JOEL KREMER, MARK GENOVESE, GRANT W. CANNON, JACQUES CALDWELL, JOHN CUSH, DANIEL E. FURST, MICHAEL LUGGEN, ED KEYSTONE, JOAN BATHON, ARTHUR KAVANAUGH, ERIC RUDERMAN, PATRICIA COLEMAN, DAVID CURTIS, ELLIOTT KOPP, SETH KANTOR, MICHAEL WEISMAN, JONATHAN WALTUCK, HERBERT B. LINDSLEY, JOSEPH MARKENSON, BRUCE CRAWFORD, INDRA FERNANDO, KAREN SIMPSON, and VIBEKE STRAND
ABSTRACT. Methods. Following a 24 week, randomized, double-blind trial of adding placebo (PLA) or LEF to stable MTX therapy, patients could enter a 24 week extension. Subjects randomized to LEF and MTX continued treatment [(LEF/LEF) + MTX]. Subjects randomized to PLA and MTX switched to LEF (10 mg/day, no loading dose) and MTX [(PLA/LEF) + MTX]. The double-blind regarding initial randomization was maintained. Results. For subjects in the extension phase, American College of Rheumatology 20% (ACR20) responder rates for the (LEF/LEF) + MTX group were maintained from Week 24 (57/96, 59.4%) to Week 48 (53/96, 55.2%). ACR20 responder rates improved in patients switched to LEF from PLA at Week 24 [(PLA/LEF) + MTX] from 25.0% (24/96) at Week 24 to 57.3% (55/96) at Week 48. Patients in the extension who switched from PLA to LEF without a loading dose exhibited a lower incidence of elevated transaminases compared to patients initially randomized to LEF. Diarrhea and nausea were less frequent during the open-label extension in patients who did not receive a LEF loading dose. Conclusion. Response to therapy was maintained to 48 weeks of treatment in patients who continued to receive LEF and MTX during the extension. Importantly, ACR20 response rates after 24 weeks of LEF therapy were similar between patients switched from PLA to LEF without loading dose, and those who received a loading does of LEF (100 mg/day ´ 2 days) at randomization. Fewer adverse events were reported in patients switched to LEF without a loading dose. (J Rheumatol 2004;31:1521-31) Key Indexing Terms:
RHEUMATOID ARTHRITIS
From the Center for Rheumatology, Albany, New York, USA. Supported by Aventis Pharmaceuticals. J. Kremer, MD, Center for Rheumatology, Albany, NY; M. Genovese, MD, Stanford University Medical Center, Stanford, CA; G.W. Cannon, MD, Veterans Affairs Medical Center and University of Utah, Salt Lake City, UT; J. Caldwell, MD, Florida Arthritis and Allergy Institute, Daytona Beach, FL; J. Cush, MD, Presbyterian Hospital, Dallas, TX; D.E. Furst, MD, Virginia Mason Research Center, Seattle, WA; M. Luggen, MD, University of Cincinnati Medical Center, Cincinnati, OH, USA; E. Keystone, MD, University of Toronto, Toronto, Canada; J. Bathon, MD, The Johns Hopkins University School of Medicine, Baltimore, MD; A. Kavanaugh, MD, University of California San Diego School of Medicine, Division of Rheumatology, Allergy, and Immunology, San Diego, CA; E. Ruderman, MD, Northwestern University Feinberg School of Medicine, Chicago, IL; P. Coleman, MD, Good Clinical Practice, East Lansing, MI; D. Curtis, MD, California Pacific Medical Center, San Francisco, CA; E. Kopp, MD, CARE Center, Raleigh, NC; S. Kantor, MD, Ohio State University, Columbus, OH; M. Weisman, MD, Cedars-Sinai Medical Center, UCLA School of Medicine, Los Angeles, CA; J. Waltuck, MD, The Emory Clinic, Atlanta, GA; H.B. Lindsley, MD, Kansas University Medical Center, Kansas City, KA; J. Markenson, MD, for the Study 4001 LEF+MTX Study Group, Hospital for Special Surgery, New York, NY; B. Crawford, MA, MPH, Mapi Values, Boston, MA; I. Fernando, PhD, Quintiles, Inc., Kansas City, KA; K. Simpson, MD, FACP, Aventis Pharmaceuticals, Bridgewater, NJ; V. Strand, MD, Stanford University School of Medicine, Palo Alto, CA, USA. Address reprint requests to Dr. J.M. Kremer, The Center for Rheumatology, LLP 1367 Washington Avenue, Suite 101, Albany, NY 12206. E-mail: jkremer@joint-docs.com Submitted March 20, 2003; revision accepted February 4, 2004. |