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Extended report
Survival, comorbidities and joint damage 11 years after the COBRA combination therapy trial in early rheumatoid arthritis
  1. Lilian H D van Tuyl1,
  2. Maarten Boers1,
  3. Willem F Lems1,
  4. Robert B Landewé2,
  5. Huub Han3,
  6. S van der Linden2,
  7. Mart van de Laar4,
  8. Rene Westhovens5,
  9. J Christiaan van Denderen6,
  10. Marie-Louise Westedt7,
  11. André J Peeters8,
  12. Piet Jacobs9,
  13. Tom W J Huizinga10,
  14. Hans van de Brink11,
  15. Ben A C Dijkmans1,
  16. Alexandre E Voskuyl1
  1. 1VU University Medical Center, Amsterdam, The Netherlands
  2. 2University Medical Center, Maastricht, The Netherlands
  3. 3Medical Center Rijnmond Zuid, Rotterdam, The Netherlands
  4. 4Medisch Spectrum Twente and University Twente, Enschede, The Netherlands
  5. 5University Hospitals, KU, Leuven, Belgium
  6. 6Jan van Breemen Institute, Amsterdam, The Netherlands
  7. 7Bronovo Hospital, Den Haag, The Netherlands
  8. 8Reinier de Graaf Hospital, Delft, The Netherlands
  9. 9Sint Laurentius Hospital, Roermond, The Netherlands
  10. 10Leiden University Medical Center, Leiden, The Netherlands
  11. 11Medical Center Alkmaar, Alkmaar, The Netherlands
  1. Correspondence to Lilian HD van Tuyl, VU University Medical Center, Department of Rheumatology, ZH-3A-56, De Boelelaan 1117, 1081 HV Amsterdam, The Netherlands; L.vantuyl{at}


Background COBRA (for ‘COmbinatie therapie Bij Rheumatoide Artritis’) combination therapy is effective for the treatment of rheumatoid arthritis (RA), but long-term safety is unknown. This study evaluates survival, comorbidities and joint damage in the original COBRA trial cohort.

Methods In the COBRA trial, 155 patients with early RA were treated with sulfasalazine (SSZ) monotherapy (SSZ group) or a combination of step-down prednisolone, methotrexate (MTX) and SSZ (COBRA group). The current 11-year follow-up study of the COBRA trial invited all original patients and performed protocollised scrutiny of clinical records, questionnaires, physical examination, laboratory and imaging tests.

Results In all, 152 out of 155 patients yielded at least partial data. After a mean of 11 years follow-up, 18 (12%) patients had died, 6 COBRA patients and 12 SSZ patients, HR 0.57 (95% CI 0.21 to 1.52). Treatment for hypertension was significantly more prevalent in the COBRA group (p=0.02) with similar trends for diabetes and cataract. Conversely, hypercholesterolaemia, cancer and infection showed a trend in favour of COBRA. Other comorbidities such as cardiovascular disease and fractures appeared in similar frequency. Radiographic findings suggest as a minimum sustained benefit for COBRA therapy, that is, difference in joint damage but similar subsequent progression rates after 5 years. Imputation to compensate for selective dropout suggests increasing benefit for COBRA, that is, difference in yearly progression rates similar to that seen in the first 5 years of follow-up.

Conclusions After 11 years, initial COBRA combination therapy resulted in numerically lower mortality and similar prevalence of comorbidity compared with initial SSZ monotherapy. In addition, lower progression of joint damage suggests long-term disease modification.

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  • Funding This study was partly financed by the Dutch Arthritis Association.

  • Competing interests None.

  • Ethics approval This study was conducted with the approval of the VU University Medical Center.

  • Provenance and peer review Not commissioned; externally peer reviewed.