Abstract

Rheumatoid factor (RF), an autoantibody classically directed against the Fc portion of IgG, is most widely 
recognized for its diagnostic and prognostic roles in rheumatoid arthritis. Increasing evidence, however, implicates 
RF in broader systemic processes that extend beyond joint disease, notably in the modulation of oxidative stress 
and redox homeostasis. This review synthesizes mechanistic and clinical data linking RF to systemic redox 
imbalance. We discuss how RF-containing immune complexes amplify reactive oxygen and nitrogen species 
production through Fc receptor engagement, complement activation, and cellular signaling in phagocytes and 
endothelial cells. We examine the contribution of RF to chronic inflammation, mitochondrial dysfunction, and the 
formation of advanced oxidation products and advanced glycation end-products, all of which feed into a 
self-perpetuating cycle of oxidative damage and immune activation. Clinical associations between RF positivity 
and heightened markers of oxidative stress, increased cardiovascular morbidity, and worsened metabolic control in 
disorders such as diabetes are summarized. Potential biomarker roles for RF in stratifying oxidative burden and 
therapeutic implications, including targeted anti-inflammatory treatments, antioxidant strategies, and modulation 
of Fc receptor pathways, are considered. Finally, we identify gaps in existing research, recommending longitudinal 
cohort studies, mechanistic cellular models, and trials combining immune-modulatory and redox-targeted 
therapies to clarify causality and therapeutic potential. Recognizing RF as an active participant in systemic redox 
imbalance reframes an old serologic marker as a potential mechanistic contributor to multisystem disease and a 
candidate target for integrated immunometabolic interventions.