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 ≤ 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.