The oxidative stress index in rheumatoid arthritis: A diagnostic biomarker with paradoxical correlation to disease activity

Abstract

Rheumatoid arthritis (RA) is characterized by chronic inflammation and oxidation; however, traditional biomarkers lack specificity, particularly in seronegative cases. This study aimed to develop and validate a novel composite Oxidative Stress Index (OSI) for diagnosing RA and to investigate its relationship with disease activity. A case-control study was conducted to establish plasma levels of indices of oxidation, such as lipid peroxidation (LPO) and nitric oxide (NO), and antioxidant enzymes that protect against oxidation: superoxide dismutase (SOD), catalase (CAT), and reduced glutathione (GSH), in 85 patients with RA and 85 healthy controls. Biomarker values were normalized to the control median to facilitate the mathematical formulation of the normalized OSI. The OSI-normalized showed an exceptional diagnostic ability with an area under the curve (AUC) of 0.991 (95% CI: 0.974 to 1.000), sensitivity of 95.3%, and specificity of 100% at a fixed threshold above 0.188, surpassing the C-reactive protein-based test with an AUC of 0.951. Logistic regression analysis supported OSI as a strong predictor of RA (odds ratio per standard deviation unit increase = 350,224.9; p < 0.001). Paradoxically, within the RA cohort, the OSI revealed a strong inverse correlation with disease activity (DAS28-ESR, β = -0.474, p < 0.001), explaining 22.5% of the variance. However, subgroup analysis indicated that with the disease progression, there appears to be a compensatory boost in antioxidant mechanisms, explaining the inverse relationship. In conclusion, the normalized OSI was found to be an extremely reliable diagnostic biomarker for RA, especially in seronegative rheumatoid arthritis. However, its inverse association with disease activity limits its utility in monitoring, highlighting the complex and dynamic nature of redox balance in RA pathophysiology.