Efficacy of tacrolimus in rheumatoid arthritis patients who have been treated unsuccessfully with methotrexate: a six-month, double-blind, randomized, dose-ranging study.
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.
Furst
Daniel E
DE
University of California at Los Angeles Medical School, CA 90024, USA. DEFurst@mednet.ucla.edu
Saag
Kenneth
K
Fleischmann
M Roy
MR
Sherrer
Yvonne
Y
Block
Joel A
JA
Schnitzer
Thomas
T
Rutstein
Joel
J
Baldassare
Andrew
A
Kaine
Jeffrey
J
Calabrese
Leonard
L
Dietz
Frederick
F
Sack
Marshall
M
Senter
R Gordon
RG
Wiesenhutter
Craig
C
Schiff
Michael
M
Stein
C Michael
CM
Satoi
Yoichi
Y
Matsumoto
Alan
A
Caldwell
Jacques
J
Harris
Robert E
RE
Moreland
Larry W
LW
Hurd
Eric
E
Yocum
David
D
Stamler
David A
DA
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
D000894:Anti-Inflammatory Agents, Non-Steroidal; D018501:Antirheumatic Agents; D007166:Immunosuppressive Agents; D011239:Prednisolone; D016559:Tacrolimus; D008727:Methotrexate