EARLY IMMUNE SYSTEM CHANGES IN AT-RISK INDIVIDUALS PRIOR TO RHEUMATOID ARTHRITIS SYMPTOM ONSET: A SYSTEMATIC REVIEW

Abstract

Background: Rheumatoid arthritis (RA) develops through a prolonged preclinical phase characterized by progressive immune dysregulation before the onset of clinically apparent arthritis. Increasing evidence suggests that autoantibodies, cytokine abnormalities, cellular immune alterations, environmental exposures, and subclinical inflammation emerge years before diagnosis. Understanding these early immune changes may facilitate earlier prediction and preventive intervention in at-risk individuals. Objective: To systematically review the evidence regarding early immune system alterations associated with progression to rheumatoid arthritis in at-risk individuals prior to symptom onset or clinical arthritis development. Methods: A systematic review was conducted according to PRISMA 2020 guidelines. Electronic searches were performed in PubMed, Scopus, Web of Science, Embase, and Google Scholar for studies published between 2010 and 2025. Eligible studies included prospective cohort studies, observational studies, and nested case–control studies evaluating immunological, serological, imaging, genetic, or environmental predictors of RA development in at-risk populations. Ten studies met the inclusion criteria. Results: Consistent evidence demonstrated that anti-citrullinated protein antibodies (ACPAs), rheumatoid factor (RF), and high anti-CCP titers strongly predicted progression to inflammatory arthritis and RA. Subclinical ultrasonographic abnormalities, including synovitis and power Doppler signals, were associated with future arthritis development. Altered lymphocyte subsets, elevated inflammatory cytokines such as IL-6, Epstein–Barr virus reactivation markers, anti-carbamylated protein antibodies, and environmental factors including smoking and dietary sodium intake also contributed to increased RA risk. Predictive models integrating serological, imaging, and clinical factors showed improved risk stratification accuracy. Conclusion: Early immune dysregulation precedes the onset of rheumatoid arthritis by several years and involves complex interactions between autoimmunity, inflammation, genetic susceptibility, and environmental exposures. Identification of high-risk individuals through integrated predictive approaches may enable earlier intervention and support future RA prevention strategies.