Reimbursement and safety concerns have spurred growing interest in strategies that involve treatment dose reduction or discontinuation once subjects achieve adequate response.

Data from the Randomized, Double-Blind Study Comparing the Safety & Efficacy of Once-Weekly Etanercept 50 mg, Etanercept 25 mg, & Placebo in Combination With Methotrexate in Subjects With Active Rheumatoid Arthritis [PRESERVE; NCT00565409] show that patients with moderately active rheumatoid arthritis (RA) achieve and maintain low disease activity and remission with anti-tumor necrosis factor (anti-TNF) therapy more successfully than those with high RA activity [Keystone E et al. J Rheumatol 2009].

The PRESERVE trial compared the efficacy and safety of continuing etanercept 50 mg once weekly+methotrexate 50 mg (E50/M), reducing etanercept from 50 mg to 25 mg once weekly+methotrexate 25 mg (E25/M), then withdrawing etanercept and giving placebo once weekly +methotrexate (P/M) over 52 weeks after sustained low disease activity had been induced during 9 months of E50/M treatment. The primary outcome of the randomized double-blind trial was Disease Activity Score (DAS28) over 88 weeks.

Participants were 18 to 70 years of age, with a diagnosis of RA who were currently receiving an optimal dose of oral MTX (at least 15 mg/week) but no more than 25 mg/week for the treatment of RA. Potential subjects were required to have RA at the time of screening.

Those with moderately active RA (DAS28>3.2 and ≤5.1) who achieved DAS28 low disease activity (DAS≤3.2, average from Weeks 12 to 36) or remission (DAS28<2.6) on E5O/M at Week 36 of Period 1 entered the double-blind Period 2. A total of 604 subjects were randomized based on DAS28 low disease activity/remission to E50/M (n=202), E25/M (n=202), or P/M (n=200) for 52 weeks. MTX was maintained at the same dose throughout the trial (15 to 25 mg).

In all, 497 subjects completed Period 2. The percent of subjects maintaining DAS28 low disease activity at Week 88 was significantly higher in the E50/M (82.6%) and E25/M (79.1%) groups compared with the P/M group (42.6%; p<0.0001 vs either etanercept group). Significantly more subjects had a DAS28 score <2.6 at Week 88 on E50/M (66.7%) and E25/M (60.2%) compared with P/M (29.4%; p<0.0001 vs either etanercept group).

Significantly more subjects on E50/M and E25/M achieved SDAI low disease activity and remission, ACR 20/50/70 responses, and a normal HAQ score (≤0.5) compared with P/M (Table 1). There was a significant change in the modified total Sharp score (units/y) from baseline between the E50/M (–0.06) and P/M (0.60; p=0.0259) groups, but not between the E25/M (0.05) and P/M (0.60; p=0.0696) groups, or the E50/M and E25/M (p=0.6737) groups. No significant differences in safety were observed. Among subjects, 35 (5.8%) reported serious adverse events, including 2 deaths (0.3%) in the E50/M group due to pulmonary embolism and septicemia during Period 2.

PRESERVE, the first trial in adults with moderately active RA despite MTX treatment, evaluated induction of DAS28 low disease activity, as well as clinical, functional, and radiographic outcomes with etanercept full-dose continuation, reduction, or elimination on a background of MTX. Subjects were significantly more likely to successfully maintain DAS28 low disease activity (and other clinical benefits) over 52 weeks with the two etanercept treatment regimens than with a step down to P/M. Further research is needed on the longer term implications of these 52-week observations.

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The editors would like to thank the many members of the American College of Rheumatology 2011 Annual Meeting presenting faculty who generously gave their time to ensure the accuracy and quality of the articles in this publication.