RAGE Expression and Serum HMGB1 Levels in Rheumatoid Arthritis Patients and their Relations to Disease Activity

Rheumatoid arthritis (RA) is a systemic autoimmune disease characterized by chronic synovial inflammation, which ultimately leads to the destruction of cartilage and bone in the affected joints. Synovial hyperplasia is a hallmark pathology of RA, and fibroblast-like synoviocytes play a critical role in RA pathogenesis by producing pro-inflammatory soluble factors or activating other immune cells. Consistent with the capacity of high-mobility group box 1 (HMGB 1) for immune activation and inducing inflammatory cytokine-like activity and the ability of single HMGB1 injection into rodent joint of inducing long-lasting destructive arthritis, this work was planned to study the serum level of HMGB 1 and the expression of its receptor RAGE in synovial tissues of patients with rheumatoid arthritis and their correlations with some clinical variables and methotrexate (MTX) therapy. Subjects and Methods: Group IA was 15 cases of newly diagnosed RA patients without MTX therapy. Group IB was 33 cases of RA patients with MTX therapy. 28 apparently normal individuals matched for age and sex were taken as a control group (group II). In addition to routine laboratory investigations, serum HMGB 1 was measured by using commercial enzyme-linked immunosorbent assay (ELISA) kit and RAGE expression in synovial tissues was assessed using immunohistochemistry for all subjects. Results: RAGE expression and serum HMGB 1 were significantly higher in RA (group I) when compared with the control group. Also, they were significantly higher in RA patients without MTX therapy compared with those patients with MTX therapy. There were significant positive correlations between serum HMGB 1 and some markers of disease activity (DAS-28, erythrocyte sedimentation rate and C-reactive protein), age of the patients and anti-CCP in group I. On the other hand, no significant correlations could be established between HMGB 1 levels and duration of the disease, gender of patients and rheumatoid factor (p 0.05). Also, no significant correlations could be found between RAGE and the clinical variables (p 0.05). However, there was a significant positive correlation between serum HMGB 1 and RAGE expression in synovial tissues in group I (p 0.01). Conclusion: HMGB 1 level and RAGE expression are increased in RA patients and may play important roles in the pathogenesis of the disease. Blockade of extracellular HMGB1 and RAGE expression may offer a novel therapeutic alternative for the treatment of RA. Further studies correlating HMGB 1 and RAGE with autophagy and apoptosis are recommended.