title: Concomitant leflunomide therapy in patients with active rheumatoid arthritis despite stable doses of methotrexate. A randomized, double-blind, placebo-controlled trial.
abstract: 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.
  
  
  METHODS
  24-week, multicenter, randomized, double-blind, placebo-controlled trial.
  
  
  METHODS
  20 centers in the United States and Canada.
  
  
  METHODS
  Patients with persistent rheumatoid arthritis, as defined by American College of Rheumatology (ACR) criteria, despite receiving methotrexate for at least 6 months.
  
  
  METHODS
  Leflunomide or matching placebo added to existing methotrexate therapy.
  
  
  METHODS
  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.
authors.affiliation: The Center for Rheumatology, LLP, 1367 Washington Avenue, Suite 101, Albany, NY 12206, USA. jkremer@joint-docs.com
authors.forename: Joel M
authors.initials: JM
authors.lastname: Kremer
authors.forename: Mark C
authors.initials: MC
authors.lastname: Genovese
authors.forename: Grant W
authors.initials: GW
authors.lastname: Cannon
authors.forename: Jacques R
authors.initials: JR
authors.lastname: Caldwell
authors.forename: John J
authors.initials: JJ
authors.lastname: Cush
authors.forename: Daniel E
authors.initials: DE
authors.lastname: Furst
authors.forename: Michael E
authors.initials: ME
authors.lastname: Luggen
authors.forename: Ed
authors.initials: E
authors.lastname: Keystone
authors.forename: Michael H
authors.initials: MH
authors.lastname: Weisman
authors.forename: William M
authors.initials: WM
authors.lastname: Bensen
authors.forename: Jeffrey L
authors.initials: JL
authors.lastname: Kaine
authors.forename: Eric M
authors.initials: EM
authors.lastname: Ruderman
authors.forename: Patricia
authors.initials: P
authors.lastname: Coleman
authors.forename: David L
authors.initials: DL
authors.lastname: Curtis
authors.forename: Elliot J
authors.initials: EJ
authors.lastname: Kopp
authors.forename: Seth M
authors.initials: SM
authors.lastname: Kantor
authors.forename: Jonathan
authors.initials: J
authors.lastname: Waltuck
authors.forename: Herbert B
authors.initials: HB
authors.lastname: Lindsley
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Markenson
authors.forename: Vibeke
authors.initials: V
authors.lastname: Strand
authors.forename: Bruce
authors.initials: B
authors.lastname: Crawford
authors.forename: Indra
authors.initials: I
authors.lastname: Fernando
authors.forename: Karen
authors.initials: K
authors.lastname: Simpson
authors.forename: Joan M
authors.initials: JM
authors.lastname: Bathon
mesh_terms: D000328:Adult; D000368:Aged; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000009:adverse effects / Q000627:therapeutic use*; D000963:Antimetabolites / Q000009:adverse effects / Q000627:therapeutic use*; D001172:Arthritis, Rheumatoid / Q000188:drug therapy*; D003967:Diarrhea / Q000139:chemically induced; D004185:Disability Evaluation; D004311:Double-Blind Method; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D007555:Isoxazoles / Q000627:therapeutic use*; D000077339:Leflunomide; D008111:Liver Function Tests; D008297:Male; D008727:Methotrexate / Q000009:adverse effects / Q000627:therapeutic use*; D008875:Middle Aged; D010919:Placebos; D011788:Quality of Life; D011795:Surveys and Questionnaires; D016896:Treatment Outcome
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D000963:Antimetabolites; D007555:Isoxazoles; D010919:Placebos; D000077339:Leflunomide; D008727:Methotrexate