title: Validation of the methotrexate-first strategy in patients with early, poor-prognosis rheumatoid arthritis: results from a two-year randomized, double-blind trial.
abstract: OBJECTIVE
  Methotrexate (MTX) taken as monotherapy is recommended as the initial disease-modifying antirheumatic drug for rheumatoid arthritis (RA). The purpose of this study was to examine outcomes of a blinded trial of initial MTX monotherapy with the option to step-up to combination therapy as compared to immediate combination therapy in patients with early, poor-prognosis RA.
  
  
  METHODS
  In the Treatment of Early Rheumatoid Arthritis (TEAR) trial, 755 participants with early, poor-prognosis RA were randomized to receive MTX monotherapy or combination therapy (MTX plus etanercept or MTX plus sulfasalazine plus hydroxychloroquine). Participants randomized to receive MTX monotherapy stepped-up to combination therapy at 24 weeks if the Disease Activity Score in 28 joints using the erythrocyte sedimentation rate (DAS28-ESR) was ≥3.2.
  
  
  RESULTS
  Attrition at 24 weeks was similar in the MTX monotherapy and combination groups. Of the 370 evaluable participants in the initial MTX group, 28% achieved low levels of disease activity and did not step-up to combination therapy (MTX monotherapy group). The mean ± SD DAS28-ESR in participants continuing to take MTX monotherapy at week 102 was 2.7 ± 1.2, which is similar to that in participants who were randomized to immediate combination therapy (2.9 ± 1.2). Participants who received MTX monotherapy had less radiographic progression at week 102 as compared to those who received immediate combination therapy (mean ± SD change in modified Sharp score 0.2 ± 1.1 versus 1.1 ± 6.4). Participants assigned to initial MTX who required step-up to combination therapy at 24 weeks (72%) demonstrated similar DAS28-ESR values (3.5 ± 1.3 versus 3.2 ± 1.3 at week 48) and radiographic progression (change in modified Sharp score 1.2 ± 4.1 versus 1.1 ± 6.4 at week 102) as those assigned to immediate combination therapy. The results for either of the immediate combination approaches, whether triple therapy or MTX plus etanercept, were similar.
  
  
  CONCLUSIONS
  These results in patients with early, poor prognosis RA validate the strategy of starting with MTX monotherapy. This study is the first to demonstrate in a blinded trial that initial MTX monotherapy with the option to step-up to combination therapy results in similar outcomes to immediate combination therapy. Approximately 30% of patients will not need combination therapy, and the 70% who will need it are clinically and radiographically indistinguishable from those who were randomized to receive immediate combination therapy.
authors.affiliation: University of Nebraska and Omaha VA Medical Center, Omaha, NE 68198-3025, USA. jrodell@unmc.edu
authors.forename: James R
authors.initials: JR
authors.lastname: O'Dell
authors.forename: Jeffrey R
authors.initials: JR
authors.lastname: Curtis
authors.forename: Ted R
authors.initials: TR
authors.lastname: Mikuls
authors.forename: Stacey S
authors.initials: SS
authors.lastname: Cofield
authors.forename: S Louis
authors.initials: SL
authors.lastname: Bridges
authors.forename: Veena K
authors.initials: VK
authors.lastname: Ranganath
authors.forename: Larry W
authors.initials: LW
authors.lastname: Moreland
mesh_terms: D018501:Antirheumatic Agents / Q000627:therapeutic use*; D001172:Arthritis, Rheumatoid / Q000175:diagnosis / Q000188:drug therapy*; D018450:Disease Progression; D004311:Double-Blind Method; D004359:Drug Therapy, Combination; D000068800:Etanercept; D005260:Female; D006304:Health Status; D006801:Humans; D006886:Hydroxychloroquine / Q000627:therapeutic use; D007074:Immunoglobulin G / Q000627:therapeutic use; D007596:Joints / Q000473:pathology / Q000503:physiopathology; D008297:Male; D008727:Methotrexate / Q000627:therapeutic use*; D008875:Middle Aged; D011379:Prognosis; D018124:Receptors, Tumor Necrosis Factor / Q000627:therapeutic use; D012720:Severity of Illness Index; D012460:Sulfasalazine / Q000627:therapeutic use; D013997:Time Factors; D016896:Treatment Outcome
chemical_list: D018501:Antirheumatic Agents; D007074:Immunoglobulin G; D018124:Receptors, Tumor Necrosis Factor; D012460:Sulfasalazine; D006886:Hydroxychloroquine; D000068800:Etanercept; D008727:Methotrexate