A Randomized Controlled Trial Evaluating the Effect of Adalimumab Upon Pre-Clinical Biomarkers of Cardiovascular Disease in ACPA-Positive Rheumatoid Arthritis

ObjectivesRheumatoid arthritis (RA) is associated with elevated risk of cardiovascular (CV) events that has been attributed to inflammation although this is not well supported by randomised controlled trial (RCT) data. This RCT evaluated the effect of adalimumab upon endothelial function and arterial stiffness in ACPA-positive RA. MethodsSixty subjects with active ACPA-positive RA stratified as Early (<12 months n=30) or Established (>12 months n=30) were enrolled and randomised 1:1 within each group to receive 40 mg adalimumab or placebo. They were assessed by DAS28-CRP, Reactive Hyperaemic Index (RHI) and Carotid-Femoral Pulse Wave Velocity (CF-PWV) twice prior to treatment and then at 1, 4, 12 and 24 weeks with one final open-label at 36 weeks. Secondary analysis evaluated the effects of disease duration, Shared Epitope (SE) and smoking status. ResultsThere were significant treatment effects upon DAS28-CRP at weeks 1, 4 and 12 in Early RA with transient effects upon RHI at week 1 in Established RA and CF-PWV in Early RA at week 4. Area-under-the-curve analysis found positive treatment effects in subjects expressing one SE (DAS28-CRP p 0.031, CF-PWV p 0.034) and in non-smokers (DAS28-CRP p 0.096, CF-PWV p 0.033). ConclusionsThis RCT appeared to show positive treatment effects upon CV risk. However, the effect of adalimumab upon RHI may be type 1 statistical error and the effect upon CF-PWV more likely represents physiologic pain-driven mechanisms rather than structural effects. This study highlights the challenges, the limitations, strengths of and opportunities for CV biomarker research in this complex field.