Do Outcomes Largely Differ in Very Early Rheumatoid Arthritis Treated with First-line Etanercept Plus Methotrexate versus Treat-to-Target Methotrexate?

A study compared superiority outcomes in very early rheumatoid arthritis (RA) treated with first-line etanercept plus methotrexate (ETN+MTX) versus treat-to-target MTX (MTX-TT), and questioned whether delayed ETN treatment after initial MTX was comparable to first-line ETN-MTX.

“Biological disease-modifying antirheumatic drugs (bDMARDs) are established in the treatment of rheumatoid arthritis (RA) but failure of conventional synthetic DMARD (csDMARD), usually methotrexate (MTX), is a minimum hurdle requirement,” the researchers wrote. “Extensive evaluation of first-line csDMARD and bDMARD, mainly tumour necrosis factor inhibitor (TNFi), including pragmatic strategic studies in DMARD-naïve and MTX-naïve cohorts have been contradictory in demonstrating clear benefit of bDMARD. Therefore, bDMARDs are still restricted to MTX-inadequate response (IR), which avoids overtreatment.”

The Very early Etanercept and MTX versus MTX with Delayed Etanercept in RA (VEDERA) study was pragmatic, open-label, randomized controlled trial that assessed a real-life cohort of RA patients. VEDERA eligibility criteria included “no prior DMARD therapy; ≤12 months symptom duration; disease activity score 28 joint (DAS28)-erythrocyte sedimentation rate (ESR) ≥3.2 with clinical evidence of synovitis; positive anticitrullinated peptide antibody (ACPA) and/or rheumatoid factor (RF), or if RF and/or ACPA negative, evidence on hand ultrasound (US) of power Doppler (PD) defined as grade ≥1 in at least one joint.” Patients were randomized 1:1 to receive either ETN+MTX or MTX-TT with ETN at week 24 if DAS28-ESR ≥2.6. The main outcome measure was week 48 DAS28ESR remission; clinical and imaging outcomes were secondary endpoints.

A total of 120 patients were randomized (71% were female), with 60 in each group. Median symptom duration was 20.3 weeks, and mean DAS28 was 5.1. The 24-week remission rate in the ETN+MTX group was 38%, compared to 33% in the MTX-TT group; at week 48, remission rates were 52% and 38%, respectively. ETN+MTX was associated with greater, sustained DAS28-ESR remission (42%) compared to MTX-TT (27%). In both groups, at week 48, PD was completely suppressed in more than 90% of patients.

The study was published in the Annals of the Rheumatic Diseases.

“In summary, the VEDERA study did not demonstrate the larger than standard effect size (of 30%), which was proposed to exist in a previous exploratory subgroup analysis with first-line TNFi-MTX in very ERA. These data also highlight a ceiling effect in achieving remission in a real life, comorbid ERA cohort. The suggestion that expedient addition of ETN to MTX-TT-IR may not be as effective in a proportion as in treatment-naïve patients requires validation and further investigation,” the researchers concluded.