From joint to artery: association of cathelicidin LL-37 and toll-like receptor 9 with inflammatory markers and atherogenic lipid indices in rheumatoid arthritis

Abstract Background Rheumatoid arthritis (RA) is a chronic systemic autoimmune disease characterized by persistent inflammation. This systemic inflammatory burden significantly accelerates cardiovascular disease (CVD), which remains the primary cause of mortality in RA patients. Standard lipid panels often fail to predict this risk due to the “Lipid Paradox,” where systemic inflammation lowers total cholesterol while shifting its composition toward a high-risk, pro-atherogenic profile. To evaluate the associations of the LL-37/TLR-9 axis and hematological indices with atherogenic lipid profiles and cardiovascular risk markers in patients with rheumatoid arthritis. Methodology This case-control study involved 180 participants (120 RA patients and 60 healthy controls). Demographic, hematological including neutrophil-to-lymphocyte ratio (NLR) and systemic immune-inflammation index (SII ) and inflammatory markers such as high-sensitivity C-reactive protein (hs-CRP), erythrocyte sedimentation rate (ESR), and Disease Activity Score-28 with C-reactive protein (DAS28-CRP) and immunological markers such as anti-cyclic citrullinated peptide (Anti-CCP), human LL-37, and TLR9 were measured. Lipid profiles were analyzed using the atherogenic index of plasma (AIP), Castelli risk indices (CRI-I/II), and the atherogenic coefficient (AC). Diagnostic accuracy was evaluated via receiver operating characteristic (ROC) curve analysis. Results RA patients exhibited significantly higher disease activity (DAS28-CRP: 6.01) and systemic inflammation (hs-CRP, ESR, p < 0.001). While total cholesterol (TC) and triglycerides (TG) showed no significant difference ( p > 0.05), the AIP (0.306 vs. 0.20, p = 0.004) and AC ( p < 0.001) were significantly elevated in patients, indicating a shift toward small dense LDL. This metabolic rearrangement was accompanied by a profound elevation in the innate immune markers LL-37 ( p < 0.0001) and TLR-9 ( p < 0.0001). ROC analysis identified TLR-9 as an outstanding diagnostic biomarker (AUC = 0.953) with a cut-off of 0.119 ng/ml. Conclusion Our findings suggest that the LL-37/TLR-9 axis may function as a potential mechanistic link between systemic autoimmunity and the ‘lipid paradox’ in RA. A high level of LL-37 appears to be associated with TLR-9-mediated alterations in lipid profiles, contributing to a pro-atherogenic environment despite seemingly normal cholesterol levels. Statistical analysis indicates that the AIP and TLR-9 levels may offer valuable insights into cardiovascular risk than traditional lipid panels, which are often suppressed by active inflammation. Therefore, monitoring the SII and the LL-37/TLR-9 pathway could provide a more comprehensive framework for risk stratification in RA patients.