Circulating serum interleukin-6, serum chitinase-3-like protein-1, and plasma vascular endothelial growth factor are not predictive for remission and radiographic progression in patients with early rheumatoid arthritis: post-hoc explorative and validation studies based on the CIMESTRA and OPERA trials

Objective: To investigate serum interleukin-6 (IL-6), serum chitinase-3-like protein-1 (YKL-40), and plasma vascular endothelial growth factor (VEGF) as measures of disease activity and predictors of clinical remission and radiographic progression in two early rheumatoid arthritis (RA) randomized controlled trials (RCTs).Method: Treatment-naive patients with early RA (<6months' duration) and active disease, participating in two investigator-initiated RCTs, were treated according to a predefined treat-to-target algorithm aiming at inflammatory control, using methotrexate (MTX)+cyclosporine versus MTX+placebo (CIMESTRA study, n=150, 5year follow-up) or MTX+adalimumab versus MTX+placebo (OPERA study, n=180, 2year follow-up). The 28-joint Disease Activity Score (DAS28) and conventional radiography [bilateral hands and feet at baseline, 2years and 5years (only CIMESTRA)] were obtained at baseline and during follow-up. Serum IL-6, serum YKL-40, and plasma VEGF were measured in baseline blood samples and during follow-up. Hypotheses regarding the biomarkers' relation with DAS28 and ability to predict clinical remission (DAS28<2.6) and radiographic progression (change in total Sharp van der Heijde score 2) were generated in CIMESTRA and validated in OPERA, by Spearman's correlation and logistic regression analyses.Results: Baseline IL-6, YKL-40, and VEGF correlated significantly with DAS28 in CIMESTRA (r=0.50, r=0.36, r=0.36, respectively, all p<0.01) and these results were confirmed in OPERA patients (r=0.52, p<0.01; r=0.18, p=0.01; r=0.23, p=0.002, respectively). None of the biomarkers (absolute values or change) was predictive of clinical remission or radiographic progression at 2 or 5years in either study.Conclusion: Serum IL-6, serum YKL-40, and plasma VEGF were significantly correlated with DAS28 at baseline, but did not have consistent predictive value for clinical remission or radiographic progression in two early RA RCTs.