Oxidative Stress and Cardiovascular Comorbidity in Patients With Rheumatoid Arthritis

Background and Current State of Knowledge Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease affecting approximately 1% of the global population and has a complex pathogenesis. It is characterised by synovial inflammation and cartilage destruction caused by marked cytokine release in the synovium by activated T cells and macrophages, together with an amplified B-cell response responsible for the production of autoantibodies such as rheumatoid factor and anti-citrullinated protein antibodies. Synovial fibroblasts also produce metalloproteinases that destroy cartilage and activate osteoclasts, thereby promoting bone resorption. Neutrophils are another key cell type; upon cytokine activation, they can increase joint destruction and amplify the inflammatory response through the synthesis of additional pro-inflammatory cytokines and chemokines.

These processes induce oxidative stress through the release of reactive oxygen species (ROS), including lipid peroxidation. Ferroptosis, a non-apoptotic form of cell death induced by lipid peroxidation, has recently been proposed as a key pathogenic mechanism in RA; modulation of this pathway may represent a therapeutic target.

ROS production and lipid peroxidation contribute to RA pathogenesis through multiple pathways. ROS released into synovial fluid disrupt the redox balance, counteract antioxidant defences, and may promote accelerated atherosclerosis in RA. They damage extracellular and intracellular matrix components, leading to chondrocyte injury. ROS can also oxidise low-density lipoproteins (LDL), increasing adhesion molecules, chemokines, and advanced glycation end products and thereby amplifying inflammation. Tumour necrosis factor alpha may further induce ROS generation and perpetuate oxidative stress, leading to hydroperoxides that fragment to form truncated phospholipids. These compounds may disrupt mitochondria and increase cytotoxicity through caspase activation. In addition to hydroperoxides, lipid peroxides and several aldehydes are generated, including malondialdehyde (MDA).

MDA is a terminal product of polyunsaturated fatty-acid peroxidation in cell membranes. It is considered a biomarker of oxidative stress and is used to assess ROS-related membrane lipid damage. MDA can be measured non-invasively in serum using the method described by Kikugawa et al. SOD catalyses the dismutation of superoxide into oxygen and hydrogen peroxide and is therefore an important antioxidant defence in oxygen-exposed cells. Similarly, GPX catalyses the oxidation of glutathione to glutathione disulphide using hydrogen peroxide; selenium is a cofactor. GPX protects the body endogenously against the damaging effects of hydroperoxides.

Several studies have reported higher MDA levels in patients with RA than in controls and have related increased MDA concentrations to altered sodium/potassium pump activity, a marker of membrane injury. The identification of lipid-peroxidation-mediated cell death and the role of MDA as a terminal lipid-peroxidation product further justify investigation of this biomarker. However, published series have included relatively few patients and have not assessed the relationship of MDA, SOD, and GPX with cardiovascular disease in RA.