RESUMO
OBJECTIVE: To evaluate the efficacy and safety of tacrolimus as monotherapy in controlling the signs and symptoms of patients with rheumatoid arthritis (RA). METHODS: This was a 6-month, phase III, double-blind, multicenter study. Patients with active RA who had discontinued all disease-modifying antirheumatic drugs (DMARDs) for an appropriate washout period (at least 1 month) and who, after the washout period, had a stable joint count (at least 10 tender/painful joints and 7 swollen joints) were stratified according to DMARD intolerance or DMARD resistance, and randomized to receive a single daily oral dose of placebo, tacrolimus 2 mg, or tacrolimus 3 mg. RESULTS: A total of 464 patients received at least 1 dose of study drug. Baseline characteristics were similar among the 3 treatment groups. American College of Rheumatology 20% improvement (ACR20) success (defined as completion of 6 months of treatment and an ACR20 response at the month 6 visit) for the placebo, tacrolimus 2 mg, and tacrolimus 3 mg groups was 10.2%, 18.8% (P < 0.05 versus placebo), and 26.8% (P < 0.0005 versus placebo), respectively. At the end of treatment, the ACR20 and ACR50 response rates in the 3-mg group were 32.0% (P < 0.005 versus placebo) and 11.8% (P < 0.05 versus placebo), respectively. DMARD-intolerant patients had better ACR response rates than did DMARD-resistant patients. Although serum creatinine levels increased by >/=40% from baseline at some time during the trial in 20% and 29% of patients receiving tacrolimus 2 mg/day and 3 mg/day, respectively, the serum creatinine level remained within the normal range throughout the trial in approximately 90% of patients. CONCLUSION: Tacrolimus, at dosages of both 2 mg/day and 3 mg/day, is efficacious and safe as monotherapy for patients with active RA, but treatment with the 3-mg dose of tacrolimus resulted in generally better ACR response rates.
Assuntos
Artrite Reumatoide/tratamento farmacológico , Imunossupressores/administração & dosagem , Tacrolimo/administração & dosagem , Administração Oral , Método Duplo-Cego , Resistência a Medicamentos , Feminino , Humanos , Imunossupressores/efeitos adversos , Masculino , Pessoa de Meia-Idade , Tacrolimo/efeitos adversos , Resultado do TratamentoRESUMO
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.