The Changes Of Atherogenic Index Of Plasma And Adhesion Molecules In Rheumatoid Arthritis Patients

Background and objective:Rheumatoid arthritis (RA) is a chronic autoimmune disease which is mainly characterized by synovial hyperplasia in peripheral joints and results in progressive destruction of articular structures. The incidence of RA is about 0.5% worldwde and 0.32%～0.36% of Chinese are affected by RA. At least 10% of RA patients are eventually severely disabled. Cardiovascular disease as one of its major causes of mortality has aroused great attention in recent years. It is proved that RA patients have a two to five times increased risk of developing cardiovascular disease and RA decreases their life expectancy by 5 to 10 years.Atherogenic lipid profile in RA patients has been reported in several studies. It is showed that small and dense LDL particles and serum lipid level are increased and the transfer of cholesterol to the liver is also affected in RA which may contribute to the progression of atherosclerosis. The previous studies regarding the changes of lipid profile in RA are controversial. Some studies showed lipoprotein (a) and LDL levels increased dramatically in RA. Lamarche's study aslo suggested that the low density lipoprotein particle size can act as a risk factor for ischemic heart disease. The risk of future IHD events increased by 35% as the diameter of low density lipoprotein particle decreased every 0.65 nm. But it is not examined routinely in the clinical work due to the high expense. In our study, we adopt atherogenic index of plasma (AIP) as index to reflect the risk of atherosclerosis which was used by Dobiasova in 2001.However some traditional risk factors known to promote and accelerate the progression of atherosclerotic lesions are absent in many patients with RA. In such patients, increased chemokines and adhesion molecules may play a key role in the process of atherosclerosis. The increased adhesion molecules and cytokines are not confined in the inflammatory joints and also circulate in the blood and affect the function of endothelial cells. Adhesion molecules are a large family of glycoproteins located on the cell surface or extracellular matrix which may contribute to the progress of atherosclerosis through promoting adhesion between vascular endothelial cells, leukocytes, platelets and accelerating inflammatory reactions and formation of thrombus. Among those, the role of intercellular cell adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1) and E-selectin (E-sel) is especially important and may be detected in serum as soluble adhesion molecules after falling off into the circulation. Nowadays atherosclerosis is regarded as kind of chronic inflammation process and adhesion molecules play an important role in the formation of atheromatous plaque. Many studies have confirmed that sVCAM-1, sICAM-1 and sE-sel can act as the mark of atherosclerosis.RA patients showed increased adhesion molecule expression which plays central roles in mediating synovial hyperplasia in RA. L-selectin expressed on T cells can bind with endothelial cell Glycosylation-dependent Cell Adhesion Molecule 1 (GlyCAM-1) with low affinity. In the tethering and rolling process, cytokines TNFα, IL-1 released by macrophages can induce T cells to express very late antigen (VLA) and leukocyte function-associated antigen (LFA-1) which interact with their ligands VCAM-1 and ICAM-1 on endothelial cells to promote lymphocyte adhesion and extravasation. Chemokines such as IL8 and RANTES produced by activated synoviocytes also promote the lymphocyte migration to sites of inflammation.To evaluate the role of adhesion molecules in the process of atherosclerosis in RA, we investigated the lipid profile, sVCAM-1, sICAM-1 and sE-sel levels in active RA and the influence of DMARD treatment in our study. We also analyzed their relationship with inflammatory mark such as ESR and CRP.Methods:1. Forty active RA patients met the American College of Rheumatology (ACR) criteria were included in the study. These patients had not received prior treatment. Patients suffering from other autoimmune diseases or cardiovascular diseases, hypertension, diabetes mellitus, familiar dyslipidemia, Cushing's syndrome, kidney disease and smokers were excluded from the study. Lipid profiles, ESR, CRP, sVCAM-1, sICAM-1 and sE-sel levels were measured and compared with 40 well-matched healthy controls.2. All patients were treated with DMARD. Twenty five patients were treated with MTX (15mg/week) and the other fifty patients received leflunomide (20mg/d) for 6 months. Lipid profiles, ESR, CRP, sVCAM-1, sICAM-1 and sE-sel levels were measured at baseline and after treatment.Results:1. Active RA compared with healthy controls:1) AIP increased dramatically in active RA patients (0.83±0.31 vs 0.21±0.18, p<0.01).2) Serum sVCAM-1 level,sICAM-1 level and sE-sel level are higher in active RA patients.(815.8±243.7μg/L vs 592.5±113.9μg/L, p<0.01;345.8±113.3μg/L vs 238.6±107.6μg/L, p<0.01;60.3±16.2μg/L vs 54.8±16.7μg/L, p<0.01)3) Serum sVCAM and sICAM level were positively correlated with AIP ( r=0.727 , p<0.01; r=0.501, p<0.01 separately) as well as ESR, CRP in active RA patients, while serum sE-sel level did not show such correlation with ESR or AIP.2. Changes before and after therapy:1) AIP decreased after effective treatment (0.36±0.20 vs 0.83±0.31, p<0.01).2) Serum sVCAM-1 level and sICAM-1 level reduced after treatment (615.2±277.2μg/L vs 815.8±243.7μg/L, p<0.01;235.3±94.2μg/L vs 345.8±113.3μg/L, p<0.01),while sE-s did not show significant changes.3) Both MTX and leflunomide decreased sVCAM-1, sICAM-1 and E-sel levels(MTX:588.94±256.11μg/L vs 815.47±327.57μg/L,P<0.01;211.87±114.64μg/L vs 313.74±144.78μg/L,P<0.01;58.30±13.62μg/L vs 60.14±13.33μg/L P<0.01;leflunomide:631.88±219.28μg/L vs 884.12±170.54μg/L,P<0.01;299.40±78.69μg/L vs 387.04±83.08μg/L,P<0.01;57.88±12.17μg/L vs 60.48±18.02μg/L P<0.01). The changes did not show significant difference in the two treatment groups.Conclusion:Atherogenic index increased in active RA and is correlated with disease activity. Serum sVCAM and sICAM levels show positively correlation with AIP and disease activity which indicates that increased adhesion molecules may play a role in the atherosclerosis in RA. Effective treatment may reduce AIP, serum sVCAM and sICAM levels then may reduce the risk of the atherosclerotic process and cardiovascular events in RA patients. This may provide a new target for the efficient treatment of RA patients.