Objective: To assess the safety of tacrolimus used in combination with oral methotrexate (MTX) to control the signs and symptoms of rheumatoid arthritis (RA) in patients whose disease remains active despite treatment with MTX.
Methods: This was a multicenter open-label study conducted at 13 US sites. Eighty patients who at baseline had active RA (mean tender/painful joint count 29.4, mean swollen joint count 17.4, mean erythrocyte sedimentation rate 25.1 mm/hour) despite treatment for >/=1 month with a stable, maximally tolerated dosage of oral MTX (</=20 mg/week, median dosage 15 mg/week, range 5-20 mg/week) were enrolled and received 3 mg/day tacrolimus as a single oral dose once per day for 6 months while continuing to receive MTX at the existing stable dosage. All other disease-modifying antirheumatic drugs were discontinued; stable dosage of nonsteroidal antiinflammatory drugs and oral corticosteroids (</=10 mg/day prednisone or its equivalent) were allowed. All 80 patients received at least one dose of the study drug and were included in the primary safety and efficacy analyses. Seventy-five patients had at least one postbaseline efficacy assessment, and 63 patients (78.8%) completed the study. The primary clinical response criterion was the American College of Rheumatology definition of 20% improvement (ACR20) at the end of treatment.
Results: Seven patients (12.5%) withdrew from the study because of adverse events possibly or probably related to treatment with tacrolimus, and 4 (5.0%) withdrew due to lack of efficacy. One serious adverse event (pancreatitis) was possibly related to tacrolimus treatment. The mean (+/-SD) creatinine (Cr) level increased from 0.74 +/- 0.16 mg/dl at baseline to 0.81 +/- 0.22 mg/dl (P < 0.001) at the end of treatment. Twenty-three patients (28.8%) had a >/=30% maximum increase in the Cr level from baseline during the study, with the Cr level in 3 patients (3.8%) exceeding the range considered normal for their age and sex. The maximum Cr level during the study was 1.8 mg/dl. The ACR20 clinical response rate at the end of treatment was 52.5% (95% confidence interval 41.6-63.4%).
Conclusion: In patients whose active RA persists despite treatment with MTX, tacrolimus in combination with MTX is safe and well-tolerated and provides clinical benefit.