Clinical significance of serum RAGE levels in anti-CCP-negative rheumatoid arthritis.

Abstract

Background: Receptor for advanced glycation end products (RAGE) is involved in inflammatory and autoimmune diseases. It plays a significant role in the pathogenesis of rheumatoid arthritis (RA). However, its clinical significance and association with RA disease activity, particularly in anti-cyclic citrullinated peptide (anti-CCP)-negative patients, remain unclear.

Objective: This study aimed to evaluate the association between serum RAGE levels and RA disease activity, clinical features, and serological markers, to evaluate its clinical significance in RA.

Methods: A total of 180 RA patients fulfilling the ACR/EULAR classification criteria and 30 healthy controls (HC) were included. Serum RAGE levels were measured and analyzed in relation to disease activity, serological markers, and clinical manifestations. RA patients were stratified based on Disease Activity Score in 28 joints (DAS28) and anti-CCP status. Receiver operating characteristic (ROC) curve analysis was conducted to determine the disease activity marker potential of RAGE.

Results: Serum RAGE levels were significantly lower in RA patients compared to HC (P < 0.001). RAGE levels were negatively correlated with disease activity markers, including DAS28, erythrocyte sedimentation rate (ESR), and C-reactive protein (CRP). It was also negatively correlated with autoantibodies, including rheumatoid factor (RF), anti-CCP antibodies, and immunoglobulin G (IgG). RA patients with higher RAGE levels had lower disease activity and decreased inflammatory markers level. ROC analysis identified an optimal cutoff value of 2037 pg/mL for distinguishing RA from HC (AUC = 0.783, sensitivity = 75.0%, specificity = 80.0%). RAGE exhibits a stronger association with inflammatory markers in RA patients with low disease activity. Notably, anti-CCP-negative RA patients had significantly higher serum RAGE levels compared to anti-CCP-positive patients (P < 0.001). In anti-CCP-negative RA, RAGE levels were highest in the low disease activity group. ROC analysis revealed that RAGE (AUC = 0.774) had superior diagnostic performance in identifying low disease activity compared to CRP (AUC = 0.705) and ESR (AUC = 0.699).

Conclusion: Serum RAGE is inversely associated with RA disease activity and may be useful for evaluating disease severity. Its diagnostic value is particularly significant in anti-CCP-negative RA, where it outperforms traditional markers in predicting low disease activity. Key Points • Serum RAGE levels are lower in RA patients and negatively correlate with disease activity. • Higher RAGE levels are associated with lower inflammatory markers and reduced autoantibody titers. • Anti-CCP-negative RA patients exhibit significantly higher RAGE levels than anti-CCP-positive patients. • RAGE demonstrates superior diagnostic performance over CRP and ESR in identifying low disease activity in anti-CCP-negative RA.