Efficacy of tacrolimus in rheumatoid arthritis patients who have been treated unsuccessfully with methotrexate: A six‐month, double‐blind, randomized, dose‐ranging study

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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 ≤ 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 ≥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 ≤3 mg daily.