Uses
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Rheumatoid Arthritis in Adults
Tofacitinib citrate is used for the management of moderately to severely active rheumatoid arthritis in adults who have had an inadequate response or intolerance to methotrexate. Tofacitinib can be used alone or in combination with methotrexate or other nonbiologic disease-modifying antirheumatic drugs (DMARDs; examples include hydroxychloroquine, leflunomide, minocycline, and sulfasalazine). Concomitant use of tofacitinib with biologic DMARDs, such as tumor necrosis factor (TNF) blocking agents (e.g., adalimumab, certolizumab pegol, etanercept, golimumab, infliximab), interleukin-1 (IL-1) receptor antagonists (e.g., anakinra), anti-CD20 monoclonal antibodies (e.g., rituximab), selective costimulation modulators (e.g., abatacept), and anti-interleukin-6-receptor monoclonal antibodies (e.g., tocilizumab), is not recommended. Concomitant use of tofacitinib with potent immunosuppressive agents (e.g., azathioprine, cyclosporine) also is not recommended.
Safety and efficacy of tofacitinib have been evaluated in 5 randomized, double-blind, controlled studies of 6-24 months' duration in adults (18 years of age or older) with moderate to severe active rheumatoid arthritis. In these studies, tofacitinib was administered as monotherapy in patients with an inadequate response to at least one biologic or nonbiologic DMARD, in combination with methotrexate in patients with an inadequate response to methotrexate or at least one TNF blocking agent, or in combination with nonbiologic DMARD(s) in patients with an inadequate response to at least one biologic or nonbiologic DMARD. Patients in these studies generally had 6 or more tender joints and 6 or more swollen joints. Those receiving low stable dosages of corticosteroids (equivalent to 10 mg or less of prednisone daily) and/or stable dosages of nonsteroidal anti-inflammatory agents (NSAIAs) generally could continue such agents. In some studies, patients also were allowed to continue stable dosages of antimalarial agents. Tofacitinib was administered orally at a dosage of 5 or 10 mg twice daily. In all 5 studies, patients randomized to receive placebo were subsequently advanced in a blinded manner to a second predetermined treatment of tofacitinib 5 or 10 mg twice daily. Advancement to tofacitinib therapy occurred at 3 months in clinical studies of 6 months' duration. In studies of at least 12 months' duration, treatment was advanced at 3 months in placebo recipients who were nonresponders and at 6 months in all other placebo recipients.
The principal measures of clinical response in studies evaluating the efficacy of tofacitinib were the American College of Rheumatology criteria for improvement (ACR response) in measures of disease activity, changes in the Health Assessment Questionnaire-Disability Index (HAQ-DI, a measure of physical function and disability), and achievement of a Disease Activity Score (DAS28 [ESR]) of less than 2.6 (i.e., DAS-defined remission) at 3 or 6 months. DAS28 (ESR) is a composite index of 4 weighted variables: swollen and tender counts for 28 joints, patient global assessment, and erythrocyte sedimentation rate (ESR). An ACR 20 response is achieved if the patient experiences a 20% or greater improvement in tender and swollen joint count and a 20% or greater improvement in at least 3 of the following criteria: patient pain assessment, patient global assessment, physician global assessment, patient self-assessed disability, or laboratory measures of disease activity (i.e., ESR or C-reactive protein [CRP] level). An ACR 50 or ACR 70 response is defined using the same criteria but with a level of improvement of 50 or 70%, respectively. Structural damage, as measured by changes in the total modified Sharp/van der Heijde score, a composite measure of radiographically assessed structural damage (i.e., joint erosion and joint space narrowing), also was assessed in the 2-year study.
Clinical evaluations of tofacitinib indicate that, in adults with active rheumatoid arthritis despite therapy with methotrexate or other DMARD(s), administration of tofacitinib (alone or in combination with methotrexate or other nonbiologic DMARDs) at a dosage of 5 or 10 mg twice daily results in higher ACR 20, ACR 50, and ACR 70 response rates at 3 and 6 months compared with placebo. In clinical trials, higher ACR 20 response rates compared with placebo were observed within 2 weeks. In clinical trials with a duration of at least 12 months, ACR response rates and HAQ-DI results were consistent at 6 and 12 months in patients receiving tofacitinib. Across the 5 clinical trials, improvements in HAQ-DI scores for tofacitinib versus placebo were similar.
In a 6-month study evaluating tofacitinib as monotherapy, 610 patients who had an inadequate response to prior DMARD therapy (biologic or nonbiologic) received tofacitinib 5 mg twice daily, tofacitinib 10 mg twice daily, or placebo. An ACR 20 response at 3 months was achieved in 59, 65, or 26% of patients receiving tofacitinib 5 mg twice daily, tofacitinib 10 mg twice daily, or placebo, respectively. The ACR 20 response rate following 6 months of therapy with tofacitinib 5 or 10 mg twice daily was 69 or 70%, respectively. Patients receiving tofacitinib experienced greater improvements in physical functioning (as measured by change in HAQ-DI score) from baseline to 3 months, but were not substantially more likely to achieve DAS-defined remission at 3 months, compared with patients receiving placebo.
In a 12-month clinical study evaluating concomitant therapy with tofacitinib and methotrexate, 717 patients with an inadequate response to prior methotrexate therapy were randomized to receive tofacitinib 5 or 10 mg twice daily, adalimumab 40 mg subcutaneously every other week, or placebo, each given in conjunction with a stable dosage of methotrexate. Patients receiving tofacitinib 5 or 10 mg twice daily demonstrated greater improvement from baseline in physical functioning at 3 months compared with patients receiving placebo. The mean difference from placebo in HAQ-DI improvement from baseline was -0.22 or -0.32 in patients receiving tofacitinib 5 or 10 mg twice daily, respectively. At 6 months, an ACR 20 response was achieved in 52, 53, 47, or 28% and DAS-defined remission was achieved in 6, 13, 7, or 1% of patients assigned to receive tofacitinib 5 mg twice daily, tofacitinib 10 mg twice daily, adalimumab, or placebo, respectively; in these analyses, in order to account for patients who switched from placebo to tofacitinib at 3 months, patients who did not respond by 3 months were considered nonresponders even if they responded after 3 months.
In a 24-month clinical study evaluating concomitant therapy with tofacitinib and methotrexate, 797 patients with an inadequate response to prior methotrexate therapy were randomized to receive tofacitinib 5 or 10 mg twice daily or placebo, each given in conjunction with a stable dosage of methotrexate. Patients receiving tofacitinib 10 mg twice daily, but not those receiving tofacitinib 5 mg twice daily, demonstrated greater improvement from baseline in HAQ-DI scores at 3 months compared with patients receiving placebo. An ACR 20 response at 3 months was achieved in 55, 67, or 27% of patients receiving tofacitinib 5 mg twice daily, tofacitinib 10 mg twice daily, or placebo, respectively; at 6 months, ACR 20 response rates were 50, 62, and 25%, respectively. DAS-defined remission at 6 months was reported in 6, 13, or 1% of patients assigned to receive tofacitinib 5 mg twice daily, tofacitinib 10 mg twice daily, or placebo, respectively. In these analyses, patients who did not achieve a response by month 3 were considered nonresponders even if they achieved a response after month 3. Although radiographic findings at 6 and 12 months suggested that tofacitinib slows progression of joint damage, interpretation of the results is complicated because the proportion of study patients with radiographic progression of structural damage during this time period was small, approximately one-half of placebo recipients were considered nonresponders at 3 months and were advanced to a tofacitinib regimen, and missing data created problems with analysis. Further study is needed to fully elucidate the drug's effects on progression of structural damage.
Another 6-month clinical study evaluated concomitant therapy with tofacitinib and methotrexate in 399 patients with an inadequate response to prior therapy with at least one TNF blocking agent; patients were randomized to receive tofacitinib 5 or 10 mg twice daily or placebo, each given in conjunction with a stable dosage of methotrexate. An ACR 20 response at 3 months was achieved in 41, 48, or 24% of patients receiving tofacitinib 5 mg twice daily, tofacitinib 10 mg twice daily, or placebo, respectively. The ACR 20 response rate following 6 months of therapy with tofacitinib 5 or 10 mg twice daily was 51 or 54%, respectively. Patients receiving tofacitinib experienced greater improvements in physical functioning (as measured by change in HAQ-DI score) from baseline to 3 months and were substantially more likely to achieve DAS-defined remission at 3 months compared with patients receiving placebo. DAS-defined remission was reported at 3 months in 7, 9, or 2% of patients receiving tofacitinib 5 mg twice daily, tofacitinib 10 mg twice daily, or placebo, respectively. The DAS-defined remission rate following 6 months of therapy with tofacitinib 5 or 10 mg twice daily was 8 or 15%, respectively.
In a 12-month study in 792 patients with an inadequate response to at least one biologic or nonbiologic DMARD, tofacitinib 5 or 10 mg twice daily or placebo was added to a stable dosage of a nonbiologic DMARD (excluding potent immunosuppressive agents such as azathioprine or cyclosporine). ACR responses and improvements in physical functioning generally were similar to those observed in other clinical studies evaluating tofacitinib for management of rheumatoid arthritis.
The optimal role of tofacitinib in the management of rheumatoid arthritis has not been established. Some clinicians suggest that, until additional data are available, use of tofacitinib should be reserved for patients with rheumatoid arthritis who have had an inadequate response to treatment with other biologic DMARDs. For further information on the treatment of rheumatoid arthritis,