title: Tofacitinib versus methotrexate in rheumatoid arthritis.
abstract: BACKGROUND
  Methotrexate is the most frequently used first-line antirheumatic drug. We report the findings of a phase 3 study of monotherapy with tofacitinib, an oral Janus kinase inhibitor, as compared with methotrexate monotherapy in patients with rheumatoid arthritis who had not previously received methotrexate or therapeutic doses of methotrexate.
  
  
  METHODS
  We randomly assigned 958 patients to receive 5 mg or 10 mg of tofacitinib twice daily or methotrexate at a dose that was incrementally increased to 20 mg per week over 8 weeks; 956 patients received a study drug. The coprimary end points at month 6 were the mean change from baseline in the van der Heijde modified total Sharp score (which ranges from 0 to 448, with higher scores indicating greater structural joint damage) and the proportion of patients with an American College of Rheumatology (ACR) 70 response (≥70% reduction in the number of both tender and swollen joints and ≥70% improvement in three of five other criteria: the patient's assessment of pain, level of disability, C-reactive protein level or erythrocyte sedimentation rate, global assessment of disease by the patient, and global assessment of disease by the physician).
  
  
  RESULTS
  Mean changes in the modified total Sharp score from baseline to month 6 were significantly smaller in the tofacitinib groups than in the methotrexate group, but changes were modest in all three groups (0.2 points in the 5-mg tofacitinib group and <0.1 point in the 10-mg tofacitinib group, as compared with 0.8 points in the methotrexate group [P<0.001 for both comparisons]). Among the patients receiving tofacitinib, 25.5% in the 5-mg group and 37.7% in the 10-mg group had an ACR 70 response at month 6, as compared with 12.0% of patients in the methotrexate group (P<0.001 for both comparisons). Herpes zoster developed in 31 of 770 patients who received tofacitinib (4.0%) and in 2 of 186 patients who received methotrexate (1.1%). Confirmed cases of cancer (including three cases of lymphoma) developed in 5 patients who received tofacitinib and in 1 patient who received methotrexate. Tofacitinib was associated with increases in creatinine levels and in low-density and high-density lipoprotein cholesterol levels.
  
  
  CONCLUSIONS
  In patients who had not previously received methotrexate or therapeutic doses of methotrexate, tofacitinib monotherapy was superior to methotrexate in reducing signs and symptoms of rheumatoid arthritis and inhibiting the progression of structural joint damage. The benefits of tofacitinib need to be considered in the context of the risks of adverse events. (Funded by Pfizer; ORAL Start ClinicalTrials.gov number, NCT01039688.).
authors.affiliation: From Seoul National University College of Medicine, Seoul, South Korea (E.B.L.); Metroplex Clinical Research Center, Dallas (R.F.); Cabrini Health and Monash University, Melbourne, VIC, Australia (S.H.); Pfizer, Groton, CT (B.W., J.D.B., D.G., S.K., G.V.W., C.Z., S.H.Z.); Pfizer, New York (T.K.); and Karolinska Institute, Stockholm (R.F.V.).
authors.forename: Eun Bong
authors.initials: EB
authors.lastname: Lee
authors.forename: Roy
authors.initials: R
authors.lastname: Fleischmann
authors.forename: Stephen
authors.initials: S
authors.lastname: Hall
authors.forename: Bethanie
authors.initials: B
authors.lastname: Wilkinson
authors.forename: John D
authors.initials: JD
authors.lastname: Bradley
authors.forename: David
authors.initials: D
authors.lastname: Gruben
authors.forename: Tamas
authors.initials: T
authors.lastname: Koncz
authors.forename: Sriram
authors.initials: S
authors.lastname: Krishnaswami
authors.forename: Gene V
authors.initials: GV
authors.lastname: Wallenstein
authors.forename: Chuanbo
authors.initials: C
authors.lastname: Zang
authors.forename: Samuel H
authors.initials: SH
authors.lastname: Zwillich
authors.forename: Ronald F
authors.initials: RF
authors.lastname: van Vollenhoven
mesh_terms: D000284:Administration, Oral; D000328:Adult; D018501:Antirheumatic Agents / Q000008:administration & dosage* / Q000009:adverse effects; D001172:Arthritis, Rheumatoid / Q000097:blood / Q000150:complications / Q000188:drug therapy*; D002784:Cholesterol / Q000097:blood; D003404:Creatinine / Q000097:blood; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D005260:Female; D006562:Herpes Zoster / Q000209:etiology; D006801:Humans; D053616:Janus Kinase 3 / Q000037:antagonists & inhibitors; D008297:Male; D008727:Methotrexate / Q000008:administration & dosage* / Q000009:adverse effects; D008875:Middle Aged; D010880:Piperidines / Q000008:administration & dosage* / Q000009:adverse effects; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000009:adverse effects; D011743:Pyrimidines / Q000008:administration & dosage* / Q000009:adverse effects; D011758:Pyrroles / Q000008:administration & dosage* / Q000009:adverse effects
chemical_list: D018501:Antirheumatic Agents; D010880:Piperidines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D011758:Pyrroles; C479163:tofacitinib; D002784:Cholesterol; D003404:Creatinine; D053616:Janus Kinase 3; D008727:Methotrexate