Altered Osteoprotegerin/RANKL Ratio Contributes to Primary Liver Dysfunction and Bone Loss in Rheumatoid Arthritis: Insights into Extra-Articular Manifestations

Background: Rheumatoid arthritis (RA) is an autoimmune disease characterized by sustained systemic inflammation, leading to joint damage and extra-articular manifestations, such as liver dysfunction. Hypothesis: Reduced osteoprotegerin (OPG) and increased receptor activator of nuclear factor-kappa B ligand (RANKL) levels in RA contribute to primary liver dysfunction. Materials and Methods: A total of 284 female RA patients and 78 healthy controls were included. RA patients were categorized into low (LDA), moderate (MDA), and high disease activity (HDA) groups based on disease activity scores (DAS-28). Serum levels of interleukin-18 (IL-18), tumor necrosis factor-alpha (TNF-α), OPG, and RANKL were measured through ELISA. Liver function tests, bone mineral density (BMD), and histological analyses were performed. Results: Serum IL-18, TNF-α, and RANKL levels were significantly elevated, while OPG levels were reduced in RA patients, with the highest alterations observed in the HDA group. The OPG/RANKL ratio was inversely correlated with disease activity, liver enzyme levels, and positively correlated with BMD. Histological analysis revealed synovial inflammation and pannus formation, with increased expression of IL-18, TNF-α, and RANKL. RA patients exhibited abnormal liver function parameters, decreased BMD, and osteopenia/osteoporosis. Conclusion: Sustained inflammation in RA, characterized by altered OPG/RANKL homeostasis, contributes to primary liver dysfunction and bone loss, suggesting a potential therapeutic target for managing extra-articular manifestations.