Background/Purpose:

The randomized clinical trial “DOSERA” has shown that in patients receiving concomitant methotrexate (MTX) therapy, continuation of etanercept (ETN) at 50 mg wkly is clinically superior to placebo, as is continuation at 25 mg wkly. The aim of this post hoc analysis was to investigate differences in radiographic progression between these treatment groups.

Methods:

RA patients on stable ETN 50 mg/wk plus MTX (stable dose 7.5-25 mg/wk) and documented low disease activity/remission (LDA/REM; DAS28 ≤3.2) 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 mths on ETN 50 mg/wk plus MTX to ensure stable LDA/REM, and stratified based on LDA/REM 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 on ≥1 occasion or disease progression as determined by investigator or patient. In cases of failure, patients received open-label ETN 50 mg/wk. Radiographs of hands and feet were obtained at baseline and at 48 wks and scored double-blindly by two investigators using the van der Heijde modified Sharp method (SHS). Radiographic progression was assessed from week 0 to week 48 on an intent-to-treat basis and independent of whether patients entered open-label ETN50 mg/wk.

Results:

Of 106 patients screened, 91 were enrolled, and 73 randomized. The groups were demographically and clinically well-balanced at baseline, but a higher baseline SHS was seen in the ETN25 group. The average age (SD) was 57 (11) y and disease duration was 13.6 (8.8) y. After 48 wks the % of non-failures was 52% for ETN50, 44% for ETN25, and 13% for PBO (p=0.007 and 0.044 for the two doses vs. PBO, respectively). Sixty-four patients had radiographs at baseline and at 40–48 wk follow-up. SHS (mean±SD) at baseline was 51.0±53.4 and at follow-up was 51.2±53.4. The mean progression in all patients was 0.13 (median 0) and was numerically highest for PBO (0.43) and lower for ETN50 (–0.13), and ETN25 (0.10). The number of patients with progression (SHS change >0) was 9/20 (45%) for PBO, 6/24 (25%) for ETN25, and 2/20 (10%) for ETN50. Radiographic progression was limited to ≤2 points in all but one patient in the PBO group (SHS change 3). Adverse events were similar between the groups; no unexpected safety signals were noted.

Conclusion:

For RA patients with stable LDA/REM on ETN 50 mg/wk + MTX, continued treatment with ETN at 50 mg/wk or 25 mg/wk provides a significantly higher likelihood of non-failure of treatment over 48 wks than PBO. More patients in the PBO group had radiographic progression than those in the ETN50 and ETN25 groups. These radiographic data plus the clinical findings suggest that discontinuing ETN after achieving a stable LDA/REM state may lead to clinical worsening and radiographic damage, and should therefore not be recommended. In addition, the results from the reduced ETN dosage used in this trial provide further evidence that an “induction-maintenance” strategy may be feasible even in some patients with established RA.