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Ann Rheum Dis 65:746-752 doi:10.1136/ard.2005.045062
  • Extended report

Evidence for differential acquired drug resistance to anti-tumour necrosis factor agents in rheumatoid arthritis

  1. A Finckh1,3,
  2. J F Simard2,
  3. C Gabay3,
  4. P-A Guerne3,
  5. for the SCQM physicians
  1. 1Department of Medicine, Division of Rheumatology, Immunology and Allergy, Section of Clinical Sciences, Brigham and Women’s Hospital, Harvard Medical School, Boston, USA
  2. 2Department of Epidemiology, Harvard School of Public Health, USA
  3. 3Division of Rheumatology, University of Geneva, Switzerland
  1. Correspondence to:
    Dr A Finckh
    Division of Rheumatology, University Hospital of Geneva, Av. Beau-Séjour 26, 1211 Geneva 14, Switzerland; afinckh{at}post.harvard.edu
  • Accepted 27 November 2005
  • Published Online First 8 December 2005

Abstract

Background: Acquired drug resistance or gradual drug failure has been described with most disease modifying antirheumatic drugs (DMARDs) and is also starting to be recognised with anti-tumour necrosis factor (anti-TNF) agents.

Objective: To study acquired drug resistance to anti-TNF agents in rheumatoid arthritis (RA).

Methods: Swiss health authorities requested continuous monitoring of patients receiving biological agents. Intensification of co-therapy with traditional DMARDs, gradual dose escalation, and drug discontinuation rates in all patients receiving infliximab, etanercept, or adalimumab, adjusting for potential confounders, were analysed. Intensification of DMARD co-therapy and time to discontinuation of the three anti-TNF agents were analysed using a proportional hazards models. Dose escalation and evolution of RA disease activity (DAS28) were analysed using a longitudinal regression model.

Results: 1198 patients contributing 1450 patient-years of anti-TNF treatment met the inclusion criteria. The rate of intensification of traditional DMARD co-therapy over time was significantly higher with infliximab (hazards ratio = 1.73 (99% confidence interval (CI) 1.19 to 2.51)) than with the two other agents. Infliximab also showed significant dose escalation over time, with an average dose increase of +12% (99% CI 8% to 16%) after 1 year, and +18% (99% CI 11% to 25%) after 2 years. No significant differences in discontinuation rates were seen between the three anti-TNF agents (ANOVA, p = 0.67). Evolution of disease activity over time indicated a lower therapeutic response to infliximab (DAS28, p<0.001) compared with etanercept, after 6 months’ treatment.

Conclusions: In this population, infliximab was associated with a higher risk of requiring intensification of DMARD co-therapy than the other anti-TNF agents and a significant dose escalation over time. Analysis of RA disease activity indicated a reduced therapeutic response to infliximab after the first 6 months of treatment, suggestive of acquired drug resistance.

Footnotes

  • Published Online First 8 December 2005