Efficacy of tacrolimus in RA patients who have been treated unsuccessfully with MTX: study

[Guest guest]

Arthritis Rheum 2002 Aug;46(8):2020-8

Efficacy of tacrolimus in rheumatoid arthritis patients who have been

treated unsuccessfully with methotrexate: a six-month, double-blind,

randomized, dose-ranging study.

Furst DE, Saag K, Fleischmann MR, Sherrer Y, Block JA, Schnitzer T,

Rutstein J, Baldassare A, Kaine J, Calabrese L, Dietz F, Sack M, Senter

RG, Wiesenhutter C, Schiff M, Stein CM, Satoi Y, Matsumoto A, Caldwell

J, RE, Moreland LW, Hurd E, Yocum D, Stamler DA.

University of California at Los Angeles Medical School, CA 90024, USA.

DEFurst@...

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. CONCLUSION: 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.

PMID: 12209503