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Extended report
A non-inferiority trial of an attenuated combination strategy (‘COBRA-light’) compared to the original COBRA strategy: clinical results after 26 weeks
  1. Debby den Uyl1,
  2. Marieke ter Wee1,
  3. Maarten Boers1,2,
  4. Pit Kerstens2,3,
  5. Alexandre Voskuyl1,
  6. Mike Nurmohamed1,2,
  7. Hennie Raterman1,
  8. Dirkjan van Schaardenburg1,2,
  9. Nancy van Dillen2,
  10. Ben Dijkmans1,2,
  11. Willem Lems1,2
  1. 1Department of Rheumatology, VU University Medical Center, Amsterdam, The Netherlands
  2. 2Department of Rheumatology, Jan van Breemen Research Institute /Reade, Amsterdam, Noord Holland, The Netherlands
  3. 3Westfriesgasthuis, Hoorn, The Netherlands
  1. Correspondence to Debby den Uyl, Department of Rheumatology, VU University Medical Center, Room 3A52, De Boelelaan 1117, Amsterdam 1081 HV, The Netherlands; d.denuyl{at}


Background Early, intensive treatment of rheumatoid arthritis (RA) with the combination of (initially high dose) prednisolone, methotrexate and sulfasalazine (COBRA therapy) considerably lowers disease activity and suppresses radiological progression, but is infrequently prescribed in daily practice. Attenuating the COBRA regimen might lessen concerns about side effects, but the efficacy of such strategies is unknown.

Objective To compare the ‘COBRA-light’ strategy with only two drugs, comprising a lower dose of prednisolone (starting at 30 mg/day, tapered to 7.5 mg/day in 9 weeks) and methotrexate (escalated to 25 mg/week in 9 weeks) to COBRA therapy (prednisolone 60 mg/day, tapered to 7.5 mg/day in 6 weeks, methotrexate 7.5 mg/week and sulfasalazine 2 g/day).

Method An open, randomised controlled, non-inferiority trial in 164 patients with early active RA, all treated according to a treat to target strategy.

Results At baseline patients had moderately active disease: mean (SD) 44-joint disease activity score (DAS44) 4.13 (0.81) for COBRA and 3.95 (0.9) for COBRA-light. After 6 months, DAS44 significantly decreased in both groups (–2.50 (1.21) for COBRA and –2.18 (1.10) for COBRA-light). The adjusted difference in DAS44 improvement between the groups, 0.21 (95% CI –0.11 to 0.53), was smaller than the predefined clinically relevant difference of 0.5. Minimal disease activity (DAS44 <1.6) was reached in almost half of patients in both groups (49% and 41% in COBRA and COBRA-light, respectively).

Conclusions At 6 months COBRA-light therapy is most likely non-inferior to COBRA therapy.

Clinical Trial Registration Number 55552928.

  • Early Rheumatoid Arthritis
  • Treatment
  • DMARDs (synthetic)
  • Corticosteroids

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