EXTENDED REPORT

¹ Department of Medicine, Division of Rheumatology, Immunology and Allergy, Section of Clinical Sciences, Brigham and Women’s Hospital, Harvard Medical School, Boston, USA
² Department of Epidemiology, Harvard School of Public Health, USA
³ Division of Rheumatology, University of Geneva, Switzerland

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

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.

Abbreviations: ADL, adalimumab; ANOVA, analysis of variance; CI, confidence interval; DAS28, 28 joint count Disease Activity Score; DMARDs, disease modifying antirheumatic drugs; ETN, etanercept; HAQ, Health Assessment Questionnaire; HR, hazard ratio; INF, infliximab; RA, rheumatoid arthritis; RF, rheumatoid factor; SCQM, Swiss Clinical Quality Management; TNF, tumour necrosis factor

Keywords: rheumatoid arthritis; antirheumatic therapy; anti-tumour necrosis factor agents; drug resistance

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