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Leflunomide for the Treatment of Rheumatoid Arthritis: A Systematic Review and Metaanalysis
MANATHIP OSIRI, BEVERLEY SHEA, VIVIAN ROBINSON, MARIA SUAREZ-ALMAZOR, VIBEKE STRAND, PETER TUGWELL, and GEORGE WELLS
ABSTRACT. Objective. To systematically review the evidence from clinical trials on the efficacy and toxicity of leflunomide for the treatment of active rheumatoid arthritis (RA). Methods. We searched Medline, Embase, Current Contents, and the Cochrane Controlled Trial Register for human randomized controlled trials (RCT) and controlled clinical trials up to December 2001. We also hand-searched reference lists and conference proceedings and consulted content experts. Relative benefit (RB), and weighted mean differences or standardized mean differences with their 95% confidence interval (95% CI) were calculated. Results. Six RCT totaling 2044 patients with RA were included in this review. Using specific criteria, all trials were considered of high methodological quality. Leflunomide improved the ACR20 response rate roughly 2 times over placebo both at 6 months (RB = 1.93, 95% CI 1.51, 2.47) and at 12 months (RB = 1.99, 95% CI 1.42, 2.77). Other clinical outcomes of disease activity and function and radiological scores were also significantly better for leflunomide patients than those taking placebo. No significant differences for most of the outcomes were observed between leflunomide and sulfasalazine (SSZ) or methotrexate (MTX). Adverse events were more common in the leflunomide group, but withdrawal rates were fewer than for placebo. Overall, withdrawal rates and adverse events in the leflunomide group were not different from SSZ or MTX. Conclusion. Leflunomide improves all clinical outcomes and delays radiographic progression at 6 and 12 months of RA treatment compared to placebo. Its efficacy and adverse events at 2 years of treatment are comparable to SSZ and MTX. Longterm efficacy and toxicity remain to be established. (J Rheumatol 2003;30:1182-90) Key Indexing Terms:
LEFLUNOMIDE
From the Department of Medicine, Faculty of Medicine, Chulalongkorn University Hospital, Bangkok, Thailand; Institute of Population Health, University of Ottawa, Ottawa, Ontario, Canada; Health Service Research, Baylor College of Medicine – Veteran Affairs Medical Center, Houston, Texas; Department of Medicine, Stanford University, San Francisco, California, USA; and Department of Epidemiology and Community Medicine, University of Ottawa, Ottawa, Ontario, Canada. Supported in part by a grant from The Arthritis Society, Canada (Metro A. Ogryzlo Fellowship). M. Osiri, MD, Assistant Professor, Department of Medicine, Faculty of Medicine, Chulalongkorn University Hospital; B. Shea, MSc, Director of Research Operations, Institute of Population Health, University of Ottawa; V. Robinson, MSc, Research Associate, Institute of Population Health, University of Ottawa; M. Suarez-Almazor, MD, Associate Professor, Health Service Research, Baylor College of Medicine–Veteran Affairs Medical Center; V. Strand, MD, Clinical Professor, Division of Immunology, Stanford University School of Medicine; P. Tugwell, MD, MSc, FRCPC, Professor of Medicine, Director, Global Health, Institute of Population Health, University of Ottawa; G. Wells, PhD, Department of Epidemiology and Community Medicine, University of Ottawa. Address reprint requests to Prof. P. Tugwell, Global Health, Institute of Population Health, University of Ottawa, Ottawa, Ontario K1H 8L6, Canada. E-mail: elacasse@uottawa.ca Reviewed and co-published by the Cochrane Musculoskeletal Group. |