Pragmatic randomised controlled trial of very early etanercept and MTX versus MTX with delayed etanercept in RA: the VEDERA trial

Abstract

ObjectivesWe sought to confirm in very early rheumatoid arthritis (ERA) a much greater superiority (30%) of first-line etanercept+methotrexate (ETN+MTX) over treat-to-target MTX (MTX-TT) than previously reported in ERA (14%); and explore whether ETN following initial MTX secures a comparable response to first-line ETN+MTX.MethodsPragmatic, open-label, randomised controlled trial of treatment-naïve ERA (≤12 months symptom), Disease Activity Score 28 joint (DAS28)-erythrocyte sedimentation rate (ESR) ≥3.2, rheumatoid factor (RF)+/−anticitrullinated peptide antibody (ACPA) positive or ultrasound power Doppler (PD) if RF and ACPA negative. Subjects were randomised 1:1 to ETN+MTX; or MTX-TT, escalated to ETN if week 24 DAS28-ESR ≥2.6 and intramuscular corticosteroid at protocolised time points. Primary endpoint of week 48 DAS28ESR remission with clinical and imaging secondary endpoints.ResultsWe randomised 120 patients, 60 to each arm (71% female, 73% RF/84% ACPA positive, median (IQR) symptom duration 20.3 (13.1, 30.8) weeks; mean (SD) DAS28 5.1 (1.1)). Remission rates with ETN+MTX and MTX-TT, respectively, were 38% vs 33% at week 24; 52% vs 38% at week 48 (ORs 1.6, 95% CI 0.8 to 3.5, p=0.211). Greater, sustained DAS28-ESR remission observed with ETN+MTX versus MTX-TT (42% and 27%, respectively; p=0.035). PD was fully suppressed by week 48 in over 90% in each arm. Planned exploratory analysis revealed OR 2.84, 95% CI 0.8 to 9.6) of achieving remission after 24 weeks of ETN administered first line compared with administered post-MTX.ConclusionsCompared with remission rates typically reported with first-line tumour necrosis factor inhabitor+MTX versus MTX-TT, we did not demonstrate a larger effect in very ERA. Neither strategy conferred remission in the majority of patients although ultrasound confirmed local inflammation suppression. Poorer ETN response following failure of MTX-TT is also suggested.Trial registration numberNCT02433184

Cardiovascular effects of biological versus conventional synthetic disease-modifying antirheumatic drug therapy in treatment-naïve, early rheumatoid arthritis

“…Remission defined response status, aligned with the primary endpoint of the associated VEDERA RCT although holds potential weaknesses. 12 However, we also did not identify an association with cumulative burden of disease activity, nor did change in AD correlate with change in ESR or CRP (data not shown). Previous studies to report on such associations have been contradictory.…”

“…Our study was not designed to assess for the known deleterious effects of corticosteroid 38 and non-steroidal anti-inflammatory drug (NSAID) comedication, however, equivalent corticosteroid usage across both treatment arms ensures balance in any possible interaction. 12 In summary, this is a first RCT-derived longitudinal study in a new onset, treatment-naïve ERA cohort with no history of CVD. This study demonstrated the presence of CV abnormalities at the earliest stage of RA and the ability of RA therapy to improve vascular stiffness.…”

“…The CV radiographer and investigators who performed and analysed the scans, respectively, were blinded to treatment arm, specific treatment allocation and the RA clinical trial data over the entire study duration. Similarly, as previously reported for the parent RCT, 12 RA clinical assessments were undertaken by blinded joint count assessors to inform the RA trial outcomes.…”

“…rheumatoid factor±anticitrullinated protein antibody±abnormal ultrasound power Doppler in any joint) and a maximum of one traditional CVD risk factor. Diabetes mellitus was excluded in all patients.As part of the parent RCT,12 all patients were randomised on a 1:1 basis either to: first-line TNFi, etanercept (ETN) + MTX (15 mg weekly, optimised to 25 mg weekly by week 8); or firstline MTX-TT (MTX monotherapy 15 mg weekly increased to 25 mg weekly at 2 weeks with further protocolised csDMARD escalation if indicated).…”

Good response to methotrexate is associated with a decrease in the gene expression of the drug transporter ABCG2 in patients with rheumatoid arthritis

“…Methotrexate (MTX) is a rst-line therapeutic drug for the treatment of rheumatoid arthritis (RA), it is the anchor drug for disease-modifying anti-rheumatic drugs (DMARDs), and it is used throughout the world for treatment-naïve, active RA patients [1][2][3]. Approximately 30% of early RA patients achieve clinical remission with MTX monotherapy after six months treatment [4,5]. The remaining patients are classi ed as partial responders or non-responders and treatment with additional DMARDs is required according to the "treat to target" strategy [6].…”