title: Therapies for active rheumatoid arthritis after methotrexate failure.
abstract: BACKGROUND
  Few blinded trials have compared conventional therapy consisting of a combination of disease-modifying antirheumatic drugs with biologic agents in patients with rheumatoid arthritis who have active disease despite treatment with methotrexate--a common scenario in the management of rheumatoid arthritis.
  
  
  METHODS
  We conducted a 48-week, double-blind, noninferiority trial in which we randomly assigned 353 participants with rheumatoid arthritis who had active disease despite methotrexate therapy to a triple regimen of disease-modifying antirheumatic drugs (methotrexate, sulfasalazine, and hydroxychloroquine) or etanercept plus methotrexate. Patients who did not have an improvement at 24 weeks according to a prespecified threshold were switched in a blinded fashion to the other therapy. The primary outcome was improvement in the Disease Activity Score for 28-joint counts (DAS28, with scores ranging from 2 to 10 and higher scores indicating more disease activity) at week 48.
  
  
  RESULTS
  Both groups had significant improvement over the course of the first 24 weeks (P=0.001 for the comparison with baseline). A total of 27% of participants in each group required a switch in treatment at 24 weeks. Participants in both groups who switched therapies had improvement after switching (P<0.001), and the response after switching did not differ significantly between the two groups (P=0.08). The change between baseline and 48 weeks in the DAS28 was similar in the two groups (-2.1 with triple therapy and -2.3 with etanercept and methotrexate, P=0.26); triple therapy was noninferior to etanercept and methotrexate, since the 95% upper confidence limit of 0.41 for the difference in change in DAS28 was below the margin for noninferiority of 0.6 (P=0.002). There were no significant between-group differences in secondary outcomes, including radiographic progression, pain, and health-related quality of life, or in major adverse events associated with the medications.
  
  
  CONCLUSIONS
  With respect to clinical benefit, triple therapy, with sulfasalazine and hydroxychloroquine added to methotrexate, was noninferior to etanercept plus methotrexate in patients with rheumatoid arthritis who had active disease despite methotrexate therapy. (Funded by the Cooperative Studies Program, Department of Veterans Affairs Office of Research and Development, and others; CSP 551 RACAT ClinicalTrials.gov number, NCT00405275.)
authors.affiliation: Veterans Affairs (VA) Nebraska-Western Iowa Health Care System and University of Nebraska Medical Center, Omaha, NE 68105, USA. james.o'dell@va.gov
authors.forename: James R
authors.initials: JR
authors.lastname: O'Dell
authors.forename: Ted R
authors.initials: TR
authors.lastname: Mikuls
authors.forename: Thomas H
authors.initials: TH
authors.lastname: Taylor
authors.forename: Vandana
authors.initials: V
authors.lastname: Ahluwalia
authors.forename: Mary
authors.initials: M
authors.lastname: Brophy
authors.forename: Stuart R
authors.initials: SR
authors.lastname: Warren
authors.forename: Robert A
authors.initials: RA
authors.lastname: Lew
authors.forename: Amy C
authors.initials: AC
authors.lastname: Cannella
authors.forename: Gary
authors.initials: G
authors.lastname: Kunkel
authors.forename: Ciaran S
authors.initials: CS
authors.lastname: Phibbs
authors.forename: Aslam H
authors.initials: AH
authors.lastname: Anis
authors.forename: Sarah
authors.initials: S
authors.lastname: Leatherman
authors.forename: Edward
authors.initials: E
authors.lastname: Keystone
mesh_terms: D000368:Aged; D018501:Antirheumatic Agents / Q000009:adverse effects / Q000627:therapeutic use*; D001172:Arthritis, Rheumatoid / Q000188:drug therapy*; D004311:Double-Blind Method; D004359:Drug Therapy, Combination; D000068800:Etanercept; D005260:Female; D006801:Humans; D006886:Hydroxychloroquine / Q000009:adverse effects / Q000627:therapeutic use*; D007074:Immunoglobulin G / Q000009:adverse effects / Q000627:therapeutic use*; D008297:Male; D008727:Methotrexate / Q000009:adverse effects / Q000627:therapeutic use*; D008875:Middle Aged; D018124:Receptors, Tumor Necrosis Factor / Q000627:therapeutic use*; D012720:Severity of Illness Index; D012460:Sulfasalazine / Q000009:adverse effects / Q000627:therapeutic use*; D017211:Treatment Failure
chemical_list: D018501:Antirheumatic Agents; D007074:Immunoglobulin G; D018124:Receptors, Tumor Necrosis Factor; D012460:Sulfasalazine; D006886:Hydroxychloroquine; D000068800:Etanercept; D008727:Methotrexate