Background/Purpose: The efficacy of etanercept (ETN) in combination with methotrexate (MTX) in the treatment of rheumatoid arthritis (RA) is well established, and long-term trials¹ and observational data have shown continued treatment maintains clinical responses in most patients. However, it is not yet known whether ETN must be continued in order to maintain a state of low disease activity/ remission (LDA/REM), or if the continuation of MTX alone or MTX combined with a lower dose of ETN, might be equally effective. We undertook a clinical trial “DOSERA” to study this question.

Methods: RA patients on ETN 50 mg wkly plus MTX (stable dose 7.5-25 mg/wk) and documented LDA/REM (DAS28≤3.2, ESR method) for ≥11 mths based on retrospective data were included. Additional key inclusion criteria were: age ≥18 y, stable MTX, no prior non-anti-TNF therapy and no prior attempt to discontinue ETN due to stable disease. Patients were followed for 2 months without major changes in therapy to ensure stable LDA/REM, and stratified based on LDA/remission status and randomly assigned 1:1:1 to ETN50 mg/wk (ETN50), ETN 25 mg/wk (ETN25), or placebo (PBO) while continuing MTX. Failure was defined as DAS28≥3.2 and an increase in DAS28≥0.6 or disease progression as determined by investigator or patient. The primary outcome was the proportion of non-failures at 48 wks, for ETN50 vs. PBO. Secondary outcomes included comparisons of non-failure and DAS28 outcomes for all 3 groups, and time to failure. The primary outcome was analyzed using a Generalized Estimating Equation model and expressed as the odds ratio (OR; 95% CI) for achieving non-failure.

Results: 106 patients were screened, 91 enrolled and 73 randomized. The groups were well-balanced at baseline. 70% were female, the average age (SD) was 57 (11) y, disease duration 13.6 (8.8) y (range 2.8-41.5), and 81% had a baseline DAS28≤2.6. After 48 wks, the proportion of non-failures was 52% for ETN50 and 13% for PBO (OR 7.2 (1.7-29.8), p=0.007). For ETN25, the proportion of non-failures was 44% [OR 4.2 (1.0-17.0); p=0.044 vs. PBO; not sign. vs. ETN50].  Median time to failure was 6 wks from randomization in PBO and 48 and 36 weeks for ETN50 and ETN25, respectively. Adverse events were similar between the groups; no unexpected safety signals were noted.

Conclusion: For RA patients with stable LDA/REM on MTX+ETN 50 mg/wk, continued treatment with ETN at 50 mg/wk or 25 mg/wk provides a significantly higher likelihood of maintaining stable disease state over 48 wks than PBO. The relatively low non-failure rates could be due to the patient population and to allowing multiple reasons for indicating failure. Thus, discontinuing ETN while maintaining a stable disease state appears to be possible for only a small minority of patients. In contrast, the positive results with the reduced ETN dosage seen in this trial provide evidence for an “induction-maintenance” strategy being feasible even in established RA.   

References: 1. Moreland L et al. J Rheumatol. Mar 2006;33:854-61