Pro-inflammatory IL-6, IL-18, TNFα cytokines and endothelial dysfunction in patients with rheumatoid arthritis and antiphospholipid syndrome

Abstract

Rheumatoid arthritis (RA) is an immunoinflammatory (autoimmune) rheumatic disease of unknown etiology, characterized by chronic erosive arthritis and systemic damage to internal organs, leading to early disability. Unlike systemic lupus erythematosus, systemic scleroderma, systemic vasculitis, and many other rheumatic diseases, the systemic manifestations of RA are somewhat ignored or underestimated. Although, they definitely worsen the prognosis and affect management and ttherapy. Antiphospholipid syndrome (APS) is an autoimmune vascular disorder that clinically manifests with recurrent vascular thrombosis of any site and caliber of vessels, as well as obstetric pathology being associated with the production of antiphospholipid antibodies. The basis of vascular pathology in APS is non-inflammatory thrombotic vasculopathy, which affects vessels of any width and location, from capillaries to the aorta. Endothelial dysfunction (ED) makes a significant contribution to the RA pathogenesis. The level of endothelin-1 (ET-1) is one of the most important indexes of endothelial dysfunction (ED) and being an independent factor in predicting the course of the disease. Aggravation of the clinical pattern is accompanied by sufficient increase in its level. Patients with APS exhibit pronounced ED associated with damage to endothelial cells by antiphospholipid antibodies (aPL) and inflammation, which leads to the development of hypercoagulation and thrombosis. The combination of RA and APS may increase the risk of vascular complications. The aim of our study was to compare changes in IL-6, IL-18, TNFα levels as well as ED marker (ET-1) in RA patients with and without APS. 120 RA patients aged 22 to 65 years were examined, with APS documented in 32 cases (26.7%). Under conditions of RA and APS comorbidity, significantly higher levels of pro-inflammatory cytokines are detected when compared with patients suffering from RA alone. There was a direct correlation between the levels of IL-6, IL-18, TNFα, and ET-1 in the both groups. The relationships in RA and APS were as follows: IL-6, r = 0.543 (p 0.01); IL-18, r = 0.663 (p 0.001); TNFα, r = 0.547 (p 0.01). In RA patients without APS: IL-6, r = 0.198 (p 0.05); IL-18, r = 0.224 (p 0.01); TNFα, r = 0.182 (p 0.05). The combined elevated levels of these cytokines in patients with RA and APS forms a vicious circle where systemic inflammation and autoimmune process may mutually exacerbate each other, leading to severe ED, which is among the key factors determining increased cardiovascular risk and rusk of thrombotic complications. Studying the mechanisms of interaction between pro-inflammatory cytokines and endothelial cells in RA patients with APS opens up prospects for development of new strategies aiming at prevention and treatment of cardiovascular complications.