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

Abstract

Objective. To assess the efficacy, safety, and optimal dose of tacrolimus monotherapy in patients with rheumatoid arthritis (RA).Methods. This phase II, randomized, doubleblind, 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

Effect of Additional Administration of Tacrolimus in Patients With Rheumatoid Arthritis Treated With Biologics

“…Tac also suppresses the production of cytokines such as IL -2 and TNFα 11,12) . The usefulness of Tac for RA has been demonstrated in double -blind, placebo -controlled, parallel -group studies and controlled studies compared with other drugs 13,14) . Tac up to 3 mg/daily is approved to be used for the patients with RA in Japan.…”

Inflammatory cytokine levels in paw tissues during development of rat collagen-induced arthritis: Effect of FK506, an inhibitor of T cell activation

“…FK506 exerts its immunosuppressive effects by inhibiting calcineurin phosphatase, an enzyme involved in activation of transcription factor NF-AT, required for the expression of cytokine genes in T cells [19]. FK506 is reported to suppress the onset of CIA in prophylactic treatment [26,29], and is also effective in the treatment of RA [30]. We have shown that FK506 reduces both levels of IL-1b [25,31] and IL-6 [25] in paw tissue during therapeutic treatment of AIA.…”

Comparison of anti-arthritic properties of leflunomide with methotrexate and FK506: Effect on T cell activation-induced inflammatory cytokine production in vitro and rat adjuvant-induced arthritis

“…FK506 is an immunosuppressive agent that specifically inhibits T cell activation via calcineurin inhibition [20,21]. FK506 has been shown to be effective in RA patients failing MTX treatment [22,23]. In the present study, we attempted to characterize anti-arthritic properties of LEF, by comparing with MTX and FK506.…”