title: Efficacy of tacrolimus in rheumatoid arthritis patients who have been treated unsuccessfully with methotrexate: a six-month, double-blind, randomized, dose-ranging study.
abstract: OBJECTIVE
  To assess the efficacy, safety, and optimal dose of tacrolimus monotherapy in patients with rheumatoid arthritis (RA).
  
  
  METHODS
  This phase II, randomized, double-blind, placebo-controlled monotherapy study was set in 12 community sites and 9 university-based sites. Two hundred sixty-eight patients with RA who were resistant to or intolerant of methotrexate (mean dose 15.2 mg/week) and had active disease for at least 6 months (mean tender joint count 28.2, mean erythrocyte sedimentation rate 46.5 mm/hour) were randomized to receive treatment after discontinuation of methotrexate. Those who received at least 1 dose of tacrolimus were analyzed; 141 completed the study. Stable dosages of nonsteroidal antiinflammatory drugs and low-dose prednisone were allowed during treatment. All patients were given 1, 3, or 5 mg of tacrolimus or placebo once daily for 24 weeks. The American College of Rheumatology definition of 20% improvement (ACR20) and the tender and swollen joint counts at the end of treatment were the primary outcomes.
  
  
  RESULTS
  ACR20 response rates demonstrated a clear dose response. The ACR20 response was observed in 15.5% of patients receiving placebo (95% confidence interval [95% CI] 7.1-23.9%), 29% of the 1 mg tacrolimus group (95% CI 18.3-39.7%) (P < 0.058); 34.4% of the 3 mg group (95% CI 22.7-46.0%) (P < 0.013), and 50% of the 5 mg group (95% CI 37.8-62.3%) (P < or = 0.001). The tender joint count improved statistically significantly in all tacrolimus groups. The swollen joint count, physical function, and patient-assessed pain improved statistically significantly in the 3 mg and 5 mg groups. The incidence of creatinine elevation > or =40% above baseline levels increased in a dose-dependent manner. Dropout rates were high (41-59%) and were more common for inefficacy in the placebo patients (71.4%), whereas they were more common for toxicity in the high-dose tacrolimus groups (31-33%). Discontinuation for creatinine elevation occurred in the 3 mg (3.1%) and 5 mg (10.9%) tacrolimus groups.
  
  
  CONCLUSIONS
  Tacrolimus improved disease activity in methotrexate-resistant or -intolerant patients with RA. A dose response was observed when efficacy and toxicity were assessed at different doses. The optimal dose of tacrolimus appears to be >1 mg but < or=3 mg daily.
authors.affiliation: University of California at Los Angeles Medical School, CA 90024, USA. DEFurst@mednet.ucla.edu
authors.forename: Daniel E
authors.initials: DE
authors.lastname: Furst
authors.forename: Kenneth
authors.initials: K
authors.lastname: Saag
authors.forename: M Roy
authors.initials: MR
authors.lastname: Fleischmann
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Sherrer
authors.forename: Joel A
authors.initials: JA
authors.lastname: Block
authors.forename: Thomas
authors.initials: T
authors.lastname: Schnitzer
authors.forename: Joel
authors.initials: J
authors.lastname: Rutstein
authors.forename: Andrew
authors.initials: A
authors.lastname: Baldassare
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Kaine
authors.forename: Leonard
authors.initials: L
authors.lastname: Calabrese
authors.forename: Frederick
authors.initials: F
authors.lastname: Dietz
authors.forename: Marshall
authors.initials: M
authors.lastname: Sack
authors.forename: R Gordon
authors.initials: RG
authors.lastname: Senter
authors.forename: Craig
authors.initials: C
authors.lastname: Wiesenhutter
authors.forename: Michael
authors.initials: M
authors.lastname: Schiff
authors.forename: C Michael
authors.initials: CM
authors.lastname: Stein
authors.forename: Yoichi
authors.initials: Y
authors.lastname: Satoi
authors.forename: Alan
authors.initials: A
authors.lastname: Matsumoto
authors.forename: Jacques
authors.initials: J
authors.lastname: Caldwell
authors.forename: Robert E
authors.initials: RE
authors.lastname: Harris
authors.forename: Larry W
authors.initials: LW
authors.lastname: Moreland
authors.forename: Eric
authors.initials: E
authors.lastname: Hurd
authors.forename: David
authors.initials: D
authors.lastname: Yocum
authors.forename: David A
authors.initials: DA
authors.lastname: Stamler
mesh_terms: D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000627:therapeutic use; D018501:Antirheumatic Agents / Q000627:therapeutic use; D001172:Arthritis, Rheumatoid / Q000188:drug therapy* / Q000503:physiopathology; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004351:Drug Resistance; D004359:Drug Therapy, Combination; D005260:Female; D006304:Health Status; D006764:Hospitals, Community; D006785:Hospitals, University; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D007596:Joints / Q000187:drug effects / Q000503:physiopathology; D008297:Male; D008727:Methotrexate / Q000627:therapeutic use*; D008875:Middle Aged; D011239:Prednisolone / Q000627:therapeutic use; D012720:Severity of Illness Index; D016559:Tacrolimus / Q000008:administration & dosage / Q000627:therapeutic use*; D016896:Treatment Outcome
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D018501:Antirheumatic Agents; D007166:Immunosuppressive Agents; D011239:Prednisolone; D016559:Tacrolimus; D008727:Methotrexate