Evidence For Differential Acquired Drug Resistance to Anti-TNF Agents in Rheumatoid Arthritis

Axel Finckh ^1*, Julia F. Simard ², Cem Gabay ¹ and Pierre-Andre Guerne ¹

¹ Div. of Rheumatology / University Hospital of Geneva, Switzerland
² Department of Epidemiology / Harvard School of Public Health, United States

^* To whom correspondence should be addressed. E-mail: axel.finckh{at}hcuge.ch.

Accepted 27 November 2005

Abstract

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

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

Results: A total of 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 (HR: 1.73 [99% CI: 1.19 - 2.51]) compared to the two other agents. Infliximab also demonstrated significant dose-escalation over time, with an average dose increase of +12% (99% CI: 8% - 16%) after one year, and +18% (99% CI: 11% - 25%). No significant differences in the discontinuation rates were observed between the three anti-TNF-agents (ANOVA, p = 0.67). The evolution of disease activity over time indicated a lower therapeutic response to infliximab (DAS28, p < 0.001) compared to etanercept, after 6 months of treatment.

Conclusions: In this population, infliximab was associated with a higher risk of requiring intensification of DMARD co-therapy compared to 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 six months of treatment, suggestive of acquired drug resistance.

Keywords: anti-TNF agents, antirheumatic therapy, drug resistance, rheumatoid arthritis

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