Methotrexate in combination with other DMARDs is not superior to methotrexate alone for remission induction with moderate-to-high-dose glucocorticoid bridging in early rheumatoid arthritis after 16 weeks of treatment: the CareRA trial

Ann Rheum Dis. 2015 Jan;74(1):27-34. doi: 10.1136/annrheumdis-2014-205489. Epub 2014 Oct 30.


Objectives: To compare the efficacy and safety of intensive combination strategies with glucocorticoids (GCs) in the first 16 weeks (W) of early rheumatoid arthritis (eRA) treatment, focusing on high-risk patients, in the Care in early RA trial.

Methods: 400 disease-modifying antirheumatic drugs (DMARD)-naive patients with eRA were recruited and stratified into high risk or low risk according to classical prognostic markers. High-risk patients (n=290) were randomised to 1/3 treatment strategies: combination therapy for early rheumatoid arthritis (COBRA) Classic (methotrexate (MTX)+ sulfasalazine+60 mg prednisone tapered to 7.5 mg daily from W7), COBRA Slim (MTX+30 mg prednisone tapered to 5 mg from W6) and COBRA Avant-Garde (MTX+leflunomide+30 mg prednisone tapered to 5 mg from W6). Treatment modifications to target low-disease activity were mandatory from W8, if desirable and feasible according to the rheumatologist. The primary outcome was remission (28 joint disease activity score calculated with C-reactive protein <2.6) at W16 (intention-to-treat analysis). Secondary endpoints were good European League Against Rheumatism response, clinically meaningful health assessment questionnaire (HAQ) response and HAQ equal to zero. Adverse events (AEs) were registered.

Results: Data from 98 Classic, 98 Slim and 94 Avant-Garde patients were analysed. At W16, remission was reached in 70.4% Classic, 73.6% Slim and 68.1% Avant-Garde patients (p=0.713). Likewise, no significant differences were shown in other secondary endpoints. However, therapy-related AEs were reported in 61.2% of Classic, in 46.9% of Slim and in 69.1% of Avant-Garde patients (p=0.006).

Conclusions: For high-risk eRA, MTX associated with a moderate step-down dose of GCs was as effective in inducing remission at W16 as DMARD combination therapies with moderate or high step-down GC doses and it showed a more favourable short-term safety profile.

Eudract number: 2008-007225-39.

Keywords: Corticosteroids; DMARDs (synthetic); Early Rheumatoid Arthritis; Methotrexate; Outcomes research.

Publication types

  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Antirheumatic Agents / therapeutic use*
  • Arthritis, Rheumatoid / diagnosis
  • Arthritis, Rheumatoid / drug therapy*
  • Drug Therapy, Combination / methods
  • Early Medical Intervention
  • Female
  • Glucocorticoids / therapeutic use*
  • Humans
  • Induction Chemotherapy / methods
  • Isoxazoles / therapeutic use*
  • Leflunomide
  • Male
  • Methotrexate / therapeutic use*
  • Middle Aged
  • Prednisone / therapeutic use*
  • Risk Assessment
  • Severity of Illness Index
  • Sulfasalazine / therapeutic use*
  • Treatment Outcome


  • Antirheumatic Agents
  • Glucocorticoids
  • Isoxazoles
  • Sulfasalazine
  • Leflunomide
  • Prednisone
  • Methotrexate

Associated data

  • EudraCT/2008-007225-39