• Joel Kremer, Zhan-Guo Li, Stephen Hall, Roy Fleischmann, Mark Genovese, Emilio Martin-Mola, John D Isaacs, David Gruben, Gene Wallenstein, Sriram Krishnaswami, Samuel H Zwillich, Tamas Koncz, Richard Riese, and John Bradley.
• Ann. Intern. Med. 2013 Aug 20;159(4):253-61.

BackgroundMany patients with rheumatoid arthritis (RA) do not achieve adequate and safe responses with disease-modifying antirheumatic drugs (DMARDs). Tofacitinib is a novel, oral, Janus kinase inhibitor that treats RA.ObjectiveTo evaluate the efficacy and safety of tofacitinib in combination with nonbiologic DMARDs.Design1-year, double-blind, randomized trial (ClinicalTrials.gov: NCT00856544).Setting114 centers in 19 countries.Patients792 patients with active RA despite nonbiologic DMARD therapy.InterventionPatients were randomly assigned 4:4:1:1 to oral tofacitinib, 5 mg or 10 mg twice daily, or placebo advanced to tofacitinib, 5 mg or 10 mg twice daily.MeasurementsPrimary end points were 20% improvement in American College of Rheumatology (ACR20) criteria; Disease Activity Score for 28-joint counts based on the erythrocyte sedimentation rate (DAS28-4[ESR]) of less than 2.6; DAS28-4(ESR)-defined remission, change in Health Assessment Questionnaire Disability Index (HAQ-DI) score, and safety assessments.ResultsMean treatment differences for ACR20 response rates (month 6) for the 5-mg and 10-mg tofacitinib groups compared with the combined placebo groups were 21.2% (95% CI, 12.2% to 30.3%; P < 0.001) and 25.8% (CI, 16.8% to 34.8%; P < 0.001), respectively. The HAQ-DI scores (month 3) and DAS28-4(ESR) less than 2.6 response rates (month 6) were also superior in the tofacitinib groups versus placebo. The incidence rates of serious adverse events for patients receiving 5-mg tofacitinib, 10-mg tofacitinib, or placebo were 6.9, 7.3, or 10.9 events per 100 patient-years of exposure, respectively. In the tofacitinib groups, 2 cases of tuberculosis, 2 cases of other opportunistic infections, 3 cardiovascular events, and 4 deaths occurred. Neutrophil counts decreased, hemoglobin and low- and high-density lipoprotein cholesterol levels increased, and serum creatinine levels had small increases in the tofacitinib groups.LimitationsPlacebo groups were smaller and of shorter duration. Patients received primarily methotrexate. The ability to assess drug combinations other than tofacitinib plus methotrexate was limited.ConclusionTofacitinib improved disease control in patients with active RA despite treatment with nonbiologic DMARDs, primarily methotrexate.Primary Funding SourcePfizer.

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