title: Tofacitinib in combination with nonbiologic disease-modifying antirheumatic drugs in patients with active rheumatoid arthritis: a randomized trial.
abstract: BACKGROUND
  Many 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.
  
  
  OBJECTIVE
  To evaluate the efficacy and safety of tofacitinib in combination with nonbiologic DMARDs.
  
  
  METHODS
  1-year, double-blind, randomized trial (ClinicalTrials.gov: NCT00856544).
  
  
  METHODS
  114 centers in 19 countries.
  
  
  METHODS
  792 patients with active RA despite nonbiologic DMARD therapy.
  
  
  METHODS
  Patients 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.
  
  
  METHODS
  Primary 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.
  
  
  RESULTS
  Mean 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.
  
  
  CONCLUSIONS
  Placebo groups were smaller and of shorter duration. Patients received primarily methotrexate. The ability to assess drug combinations other than tofacitinib plus methotrexate was limited.
  
  
  CONCLUSIONS
  Tofacitinib improved disease control in patients with active RA despite treatment with nonbiologic DMARDs, primarily methotrexate.
  
  
  BACKGROUND
  Pfizer.
authors.forename: Joel
authors.initials: J
authors.lastname: Kremer
authors.forename: Zhan-Guo
authors.initials: ZG
authors.lastname: Li
authors.forename: Stephen
authors.initials: S
authors.lastname: Hall
authors.forename: Roy
authors.initials: R
authors.lastname: Fleischmann
authors.forename: Mark
authors.initials: M
authors.lastname: Genovese
authors.forename: Emilio
authors.initials: E
authors.lastname: Martin-Mola
authors.forename: John D
authors.initials: JD
authors.lastname: Isaacs
authors.forename: David
authors.initials: D
authors.lastname: Gruben
authors.forename: Gene
authors.initials: G
authors.lastname: Wallenstein
authors.forename: Sriram
authors.initials: S
authors.lastname: Krishnaswami
authors.forename: Samuel H
authors.initials: SH
authors.lastname: Zwillich
authors.forename: Tamas
authors.initials: T
authors.lastname: Koncz
authors.forename: Richard
authors.initials: R
authors.lastname: Riese
authors.forename: John
authors.initials: J
authors.lastname: Bradley
mesh_terms: D000328:Adult; D018501:Antirheumatic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D001172:Arthritis, Rheumatoid / Q000188:drug therapy*; D004311:Double-Blind Method; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D053616:Janus Kinase 3 / Q000037:antagonists & inhibitors*; D008297:Male; D008727:Methotrexate / Q000627:therapeutic use; D008875:Middle Aged; D010880:Piperidines / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D011743:Pyrimidines / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D011758:Pyrroles / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D012074:Remission Induction; D016896:Treatment Outcome
chemical_list: D018501:Antirheumatic Agents; D010880:Piperidines; D011743:Pyrimidines; D011758:Pyrroles; C479163:tofacitinib; D053616:Janus Kinase 3; D008727:Methotrexate