Limited response to first-line etanercept in very early RA
medwireNews: First-line etanercept given together with methotrexate does not offer substantial benefits over a methotrexate treat-to-target strategy for patients with very early rheumatoid arthritis (RA), according to findings from the VEDERA study.
The randomized phase 4 pragmatic trial included 120 patients with RA disease duration of 1 year or less and no prior exposure to DMARDs who were randomly assigned to receive first-line treatment with etanercept plus methotrexate (n=60) or a methotrexate treat-to-target protocol (n=60).
Participants in the etanercept group were given the tumor necrosis factor (TNF) inhibitor at a dose of 50 mg/week, together with methylprednisolone 120 mg/week, and a weekly dose of methotrexate 15 mg, increasing to 20 mg at week 4 and 25 mg at week 8. Those in the methotrexate treat-to-target arm received once-weekly depomedrone 120 mg and methotrexate 15 mg, increasing to 25 mg at 2 weeks, with subsequent addition of sulfasalazine and hydroxychloroquine between weeks 8 and 20, and etanercept at week 24, according to disease activity.
As reported in the Annals of the Rheumatic Diseases, the proportion of patients achieving DAS28-ESR remission (≤2.6 points) at week 48 was numerically higher in the etanercept than in the control arm (52 vs 38%), but the difference did not reach statistical significance.
These findings do not support “a heightened difference in remission rate” with first-line etanercept versus methotrexate, as was previously suggested in an exploratory post-hoc analysis of the COMET trial, say the VEDERA (Very early Etanercept and MTX versus MTX with Delayed Etanercept in RA) investigators.
They note that the VEDERA trial “was not designed to demonstrate [a] standard level of superiority” for etanercept–methotrexate, but rather to validate the “much larger effect” of approximately 30 percentage points seen in the post-hoc analysis.
Maya Buch (University of Leeds, UK) and team say that the remission rates observed in their trial are “what we would consider suboptimal rates for the contemporary era,” indicating that “despite incorporating all the recommended [treat-to-target] strategies in a real-life, treatment-naïve, early (≤12 months symptom) RA cohort, a ceiling effect […] exists” with both regimens.
Nevertheless, participants in the etanercept group did experience significant improvements in some secondary outcomes. DAS28-ESR remission rates were significantly higher among patients given the TNF inhibitor versus those in the control arm at the 12-week follow-up (39 vs 17%), and remission was achieved earlier in the etanercept than in the control arm (24 vs 36 weeks). There were no significant differences in patient-reported outcomes nor measures of radiographic progression among the groups, however.
Buch et al say that the precise mechanisms underlining the “generally poorer than expected performance” of first-line etanercept in the VEDERA trial are “unclear,” but suggest that the high proportion of participants with comorbidities may have played a role, with half of the participants having one or more comorbidities and 20% having at least two.
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