Steroid-Sparing Effects of Methotrexate in Systemic Lupus Erythematosus: A Double-Blind, Randomized, Placebo-Controlled Trial PAUL R. FORTIN, 1 MICHAL ABRAHAMOWICZ, 2 DIANE FERLAND, 3 DIANE LACAILLE, 4 C. DOUGLAS SMITH, 5 MICHEL ZUMMER, 6 FOR THE CANADIAN NETWORK FOR IMPROVED OUTCOMES IN SYSTEMIC LUPUS ERYTHEMATOSUS Objective. To assess the potential benefits of methotrexate in patients with systemic lupus erythematosus (SLE). Methods. A 12-month, double-blind, placebo-controlled trial of methotrexate with folic acid was conducted. Intent-to- treat analyses were performed with mixed linear models and   0.04 (96% confidence interval [96% CI]) to account for interim analysis of longitudinal data to assess the treatment effects on lupus disease activity and daily steroid dose across monthly measurements, and to test if the treatment effects depended on selected participant characteristics. Results. Of 215 participants screened, 94 were excluded, 35 declined, and 86 were randomized (methotrexate  41, placebo  45). The groups were balanced for demographic and disease characteristics. Antimalarial use was more frequent in the placebo group, which was adjusted for in multivariable analyses. Sixty participants (27 methotrexate, 33 placebo) completed the study and 26 terminated early. Among participants who had the same baseline prednisone dose, those taking methotrexate received, on average, 1.33 mg/day less prednisone during the trial period (96% CI 0.06, 2.72 mg/day; a 22% reduction of their average-during-trial daily dose) compared with those in the placebo group. For the primary measure of disease activity (revised Systemic Lupus Activity Measure), methotrexate use was also associated with a marginally significant reduction in the mean during-trial score of 0.86 units (96% CI 0.01, 1.71; P  0.039). A significant interaction between treatment and baseline damage was found (P  0.001). Conclusion. Methotrexate conferred a significant advantage in participants with moderately active lupus by lowering daily prednisone dose and slightly decreasing lupus disease activity. As a therapeutic option in moderate SLE, metho- trexate can be considered to be steroid sparing. INTRODUCTION Methotrexate, an antifolate drug that leads to adenosine re- lease and other antiinflammatory and immunosuppressive effects, is the most prescribed drug for rheumatoid arthritis (1). Results of prospective case series (2– 8) and 1 random- ized controlled trial (9) suggest that methotrexate may have disease-remitting and steroid-sparing effects in systemic lu- pus erythematosus (SLE). Our objective was to determine the efficacy and safety of methotrexate with folic acid in moder- ately active SLE in a 12-month, double-blind, randomized, parallel-group, placebo-controlled trial. Our primary hypoth- esis was that methotrexate would decrease disease activity and would have a steroid-sparing effect. The Canadian Network for Improved Outcomes in Sys- temic Lupus Erythematosus is a voluntary group of Cana- dian Lupus Investigators with no other funding than that of the sponsor of the study (The Arthritis Society of Canada) with participation from Faulding Canada, Inc. (now Mayne Pharma [Canada] Inc.) under an Arthritis Society industry peer-review grant. Dr. Fortin holds a Distinguished Senior Research Investigator award from The Arthritis Society. Dr. Abrahamowicz is a James McGill Professor at McGill Uni- versity. Mrs. Ferland received salary support from Lupus Canada. Dr. Lacaille’s salary is supported by a New Inves- tigator award from the Canadian Institute of Health Re- search and The Arthritis Society. 1 Paul R. Fortin, MD, MPH, FRCPC: University Health Network, Toronto Western Hospital, Toronto Western Re- search Institute, Toronto, Ontario, Canada; 2 Michal Abra- hamowicz, PhD: McGill University, Montreal, Quebec, Can- ada; 3 Diane Ferland, RN, BA, BScN: University Health Net- work, Toronto Western Research Institute, Toronto, Ontario, Canada; 4 Diane Lacaille, MD, MHSc, FRCPC: The Arthritis Research Centre of Canada, Vancouver, British Co- lumbia, Canada; 5 C. Douglas Smith, MD, FRCPC: The Arthritis Centre, The Ottawa Hospital, Ottawa, Ontario, Canada; 6 Michel Zummer, MD, FRCPC: Ho ˆ pital Maisonneuve-Rose- mont, Montreal, Quebec, Canada. Address correspondence to Paul R. Fortin, MD, MPH, FRCPC, MP-10-304, 399 Bathurst Street, Toronto, Ontario, Canada M5T 2S8. E-mail: pfortin@uhnresearch.ca. Submitted for publication June 5, 2007; accepted in re- vised form July 31, 2008. Arthritis & Rheumatism (Arthritis Care & Research) Vol. 59, No. 12, December 15, 2008, pp 1796 –1804 DOI 10.1002/art.24068 © 2008, American College of Rheumatology ORIGINAL ARTICLE 1796