Abstract
BACKGROUND: Rheumatoid arthritis (RA) is a systemic autoimmune inflammatory disease that can affect the cardiovascular and cerebrovascular systems. Elderly RA patients face a significantly elevated risk of cerebrovascular events, the core mechanism of which may be related to chronic inflammation-mediated vascular endothelial dysfunction and impaired cerebral blood flow regulation. Tumor necrosis factor-alpha (TNF-α) is a key pro-inflammatory cytokine in RA, yet whether its inhibitor can improve cerebral hemodynamics remains unclear. This study aims to investigate the effects and underlying mechanisms of TNF-α inhibitor etanercept on cerebral blood flow in elderly RA patients. OBJECTIVE: This study aimed to evaluate the effects of the TNF-α inhibitor Etanercept on cerebral hemodynamics in elderly RA patients and to explore the relationships between changes in inflammatory markers, endothelial function, and cerebral hemodynamics. METHODS: A single-center, prospective, randomized controlled trial was conducted. A total of 159 elderly RA patients in mild disease activity, recruited from the Department of Rheumatology and Immunology at Xi'an No.5 Hospital between November 2023 and November 2024, were enrolled. Baseline data were collected, and patients were randomly assigned to either the experimental group (TNF-α inhibitor + Methotrexate + Celecoxib) or the control group (Methotrexate + Celecoxib). Before treatment and after 6 months of treatment, transcranial Doppler (TCD) was used to assess the mean flow velocity (Vm), pulsatility index (PI), and resistance index (RI) of the middle cerebral artery (MCA). Cerebrovascular reactivity (CVR) was evaluated using the breath-holding index (BHI). Serum inflammatory markers and vascular endothelial function were also assessed at both time points. Adverse drug reactions during the treatment period were recorded. RESULTS: Compared to the control group, the experimental group showed a significant increase in MCA Vm, significant decreases in PI and RI, and a marked improvement in BHI after treatment. Serum levels of erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), rheumatoid factor (RF), anti-cyclic citrullinated peptide antibody (anti-CCP), interleukin-1β (IL-1β), interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), soluble vascular cell adhesion molecule-1 (sVCAM-1), and endothelin-1 (ET-1) were all significantly reduced. Correlation analysis revealed that the improvement in BHI was significantly associated with reductions in TNF-α, sVCAM-1, and ET-1. The incidence of adverse events was 11.96% (11/92) in the experimental group and 10.87% (10/92) in the control group, with no statistically significant difference. CONCLUSION: The TNF-α inhibitor Etanercept significantly improves cerebral hemodynamics and cerebrovascular reserve function in elderly RA patients, potentially by suppressing systemic inflammation and improving vascular endothelial function. TRIAL REGISTRATION: This study was conducted in accordance with the principles of the Declaration of Helsinki and was approved by the Medical Ethics Committee of Xi'an Fifth Hospital (Ethics Approval No.: [2023] Ethics Review 55). The trial was also registered with the Chinese Clinical Trial Registry (Registration No.: ChiCTR2300077337; Date of Registration: 01/11/2023). Prior to participation, written informed consent was obtained from all individuals involved in the research.