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Extended report
A randomised controlled trial of etanercept and methotrexate to induce remission in early inflammatory arthritis: the EMPIRE trial
  1. J L Nam1,
  2. E Villeneuve1,2,
  3. E M A Hensor1,
  4. R J Wakefield1,
  5. P G Conaghan1,
  6. M J Green3,4,
  7. A Gough4,
  8. M Quinn4,
  9. R Reece1,5,
  10. S R Cox6,
  11. M H Buch1,
  12. D M van der Heijde7,
  13. P Emery1
  1. 1Leeds Institute of Rheumatic and Musculoskeletal Medicine, University of Leeds, and NIHR Leeds Musculoskeletal Biomedical Research Unit, Leeds Teaching Hospitals NHS Trust, Leeds, UK
  2. 2Rheumatology department, Centre Hospitalier de l'Université de Montréal, Hôpital Notre-Dame, Montréal, Canada
  3. 3Rheumatology Department, Harrogate District Foundation Trust, UK
  4. 4The York Hospital, York Hospitals NHS Foundation Trust, UK
  5. 5Department of Rheumatology, Darlington Memorial Hospital, County Durham and Darlington NHS Foundation Trust, UK
  6. 6Flinders Medical Centre, Adelaide, South Australia, Australia
  7. 7Department of Rheumatology, Leiden University Medical Center, Leiden, The Netherlands
  1. Correspondence to Professor P Emery, Leeds Institute of Rheumatic and Musculoskeletal Medicine, University of Leeds, and NIHR Leeds Musculoskeletal Biomedical Research Unit, Leeds Teaching Hospitals NHS Trust, Leeds LS7 4SA, UK; p.emery{at}


Objective To compare the efficacy of etanercept (ETN) and methotrexate (MTX) versus MTX monotherapy for remission induction in patients with early inflammatory arthritis.

Methods In a 78-week multicentre randomised placebo-controlled superiority trial, 110 DMARD-naïve patients with early clinical synovitis (≥1 tender and swollen joint, and within 3 months of diagnosis) and either rheumatoid factor, anticitrullinated protein antibodies or shared epitope positive were randomised 1:1 to receive MTX+ETN or MTX+placebo (PBO) for 52 weeks. Injections (ETN or PBO) were stopped in all patients at week 52. In those with no tender or swollen joints (NTSJ) for >26 weeks, injections were stopped early. If patients had NTSJ >12 weeks after stopping the injections, MTX was weaned. The primary endpoint was NTSJ at week 52.

Results No statistically significant difference was seen for the primary endpoint (NTSJ at week 52 (32.5% vs 28.1% [adjusted OR 1.32 (0.56 to 3.09), p=0.522]) in the MTX+ETN and MTX+PBO groups, respectively). The secondary endpoints did not differ between groups at week 52 or 78. Exploratory analyses showed a higher proportions of patients with DAS28-CRP<2.6 in the MTX+ETN group at week 2 (38.5% vs 9.2%, adjusted OR 8.87 (2.53 to 31.17), p=0.001) and week 12 (65.1% vs 43.8%, adjusted OR 2.49 (1.12 to 5.54), p=0.026).

Conclusions In this group of patients with early inflammatory arthritis, almost a third had no tender, swollen joints after 1 year. MTX+ETN was not superior to MTX monotherapy in achieving this outcome. Clinical responses, however, including DAS28-CRP<2.6, were achieved earlier with MTX+ETN combination therapy.

Trial registration number The EMPIRE trial is registered on the following trial registries: Eudract-2005-005467-29; ISRCTN 55428162 ( The full trial protocol can be obtained from the corresponding author.

  • Anti-TNF
  • DMARDs (biologic)
  • Early Rheumatoid Arthritis
  • Methotrexate

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