Patients with Early RA Exhibit Elevated Autoantibody Titers
Patients with Early RA Exhibit Elevated Autoantibody Titers
Rheumatoid arthritis is a chronic inflammatory disease, associated with an excess of cardiovascular morbidity and mortality due to accelerated atherosclerosis. Oxidized low-density lipoprotein (oxLDL), the antibodies against oxLDL and the lipoprotein-associated phospholipase A2 (Lp-PLA2) may play important roles in inflammation and atherosclerosis. We investigated the plasma levels of oxLDL and Lp-PLA2 activity as well as the autoantibody titers against mildly oxLDL in patients with early rheumatoid arthritis (ERA). The long-term effects of immunointervention on these parameters in patients with active disease were also determined. Fifty-eight ERA patients who met the American College of Rheumatology criteria were included in the study. Patients were treated with methotrexate and prednisone. Sixty-three apparently healthy volunteers also participated in the study and served as controls. Three different types of mildly oxLDL were prepared at the end of the lag, propagation and decomposition phases of oxidation. The serum autoantibody titers of the IgG type against all types of oxLDL were determined by an ELISA method. The plasma levels of oxLDL and the Lp-PLA2 activity were determined by an ELISA method and by the trichloroacetic acid precipitation procedure, respectively. At baseline, ERA patients exhibited elevated autoantibody titers against all types of mildly oxLDL as well as low activity of the total plasma Lp-PLA2 and the Lp-PLA2 associated with the high-density lipoprotein, compared with controls. Multivariate regression analysis showed that the elevated autoantibody titers towards oxLDL at the end of the decomposition phase of oxidation and the low plasma Lp-PLA2 activity are independently associated with ERA. After immunointervention autoantibody titers against all types of oxLDL were decreased in parallel to the increase in high-density lipoprotein-cholesterol and high-density lipoprotein-Lp-PLA2 activity. We conclude that elevated autoantibody titers against oxLDL at the end of the decomposition phase of oxidation and low plasma Lp-PLA2 activity are feature characteristics of patients with ERA, suggesting an important role of these parameters in the pathophysiology of ERA as well as in the accelerated atherosclerosis observed in these patients.
Rheumatoid arthritis is a chronic inflammatory condition of unknown etiology affecting primarily the synovium, leading to joint damage and bone destruction. Rheumatoid arthritis causes significant morbidity as a result of synovial inflammation, joint destruction and associated disability. Several investigators have reported an excess of cardiovascular morbidity and mortality among rheumatoid arthritis patients. In active rheumatoid arthritis, the majority of cardiovascular deaths result from accelerated atherosclerosis.
Oxidative modification of low-density lipoprotein (LDL) is an important event in the development and progression of atherosclerosis. Oxidized low-density lipoprotein (oxLDL) is present in atherosclerotic lesions of humans and animal models, and promotes atherosclerosis by several mechanisms. oxLDL has been detected in patients with systemic lupus erythematosus and the antiphospholipid syndrome and also in the synovium and synovial fluids of rheumatoid arthritis patients.
During LDL oxidation both the lipids and apolipoprotein B-100 (Apo B) undergo a variety of chemical changes via radical-mediated reactions as well as modifications by chemically active products formed on oxLDL particles. An important biochemical change that takes place during LDL oxidation is the hydrolysis of its content in oxidized phospholipids and the production of lysophosphatidylcholine. This reaction is catalyzed by the lipoprotein-associated phospholipase A2 (Lp-PLA2), also known as platelet-activating factor acetylhydrolase. Lp-PLA2 exhibits a Ca-independent phospholipase A2 activity and preferentially hydrolyses biologically active phospholipids containing short acyl groups at the sn-2 position, such as platelet-activating factor and oxidized phospholipids; this enzyme therefore plays important roles in inflammatory reactions and atherosclerosis. In human plasma Lp-PLA2 is associated mainly with LDL, whereas a small proportion of circulating enzyme activity is also associated with high-density lipoprotein (HDL). Data from large Caucasian population studies have demonstrated an independent association between plasma Lp-PLA2 (which represents mainly the LDL-associated Lp-PLA2) and the risk of future cardiovascular events. In contrast to the total plasma enzyme, several lines of evidence suggest that HDL-associated Lp-PLA2 activity (HDL-Lp-PLA2), although at low levels in plasma, may contribute to the antiatherogenic effects of this lipoprotein.
oxLDL is immunogenic and some of its constituents (oxidized phospholipids, aldehydes and lysophosphatidylcholine) play important roles in the oxLDL antigenicity, participating in the formation of several different epitopes. These epitopes are recognized by specific autoantibodies, which are present in serum of healthy individuals as well as in various pathologic conditions. We recently showed, using various types of mildly oxLDL as antigens, that the extent of LDL oxidation and the levels of LDL-associated Lp-PLA2 activity significantly influence the antibody titers against oxLDL in patients with stable angina. Furthermore, we recently showed that the LDL-associated Lp-PLA2 plays an important role in modulating the immune responses against various types of mildly oxLDL observed after an acute coronary syndrome without persistent elevation of the ST segment.
The aim of the present study was to investigate the plasma levels of oxLDL and Lp-PLA2 activity as well as the autoantibody titers against various types of mildly oxidized LDL in patients with early rheumatoid arthritis (ERA). The long-term effects of immunointervention on these parameters in patients with active disease were also determined.
Abstract and Introduction
Abstract
Rheumatoid arthritis is a chronic inflammatory disease, associated with an excess of cardiovascular morbidity and mortality due to accelerated atherosclerosis. Oxidized low-density lipoprotein (oxLDL), the antibodies against oxLDL and the lipoprotein-associated phospholipase A2 (Lp-PLA2) may play important roles in inflammation and atherosclerosis. We investigated the plasma levels of oxLDL and Lp-PLA2 activity as well as the autoantibody titers against mildly oxLDL in patients with early rheumatoid arthritis (ERA). The long-term effects of immunointervention on these parameters in patients with active disease were also determined. Fifty-eight ERA patients who met the American College of Rheumatology criteria were included in the study. Patients were treated with methotrexate and prednisone. Sixty-three apparently healthy volunteers also participated in the study and served as controls. Three different types of mildly oxLDL were prepared at the end of the lag, propagation and decomposition phases of oxidation. The serum autoantibody titers of the IgG type against all types of oxLDL were determined by an ELISA method. The plasma levels of oxLDL and the Lp-PLA2 activity were determined by an ELISA method and by the trichloroacetic acid precipitation procedure, respectively. At baseline, ERA patients exhibited elevated autoantibody titers against all types of mildly oxLDL as well as low activity of the total plasma Lp-PLA2 and the Lp-PLA2 associated with the high-density lipoprotein, compared with controls. Multivariate regression analysis showed that the elevated autoantibody titers towards oxLDL at the end of the decomposition phase of oxidation and the low plasma Lp-PLA2 activity are independently associated with ERA. After immunointervention autoantibody titers against all types of oxLDL were decreased in parallel to the increase in high-density lipoprotein-cholesterol and high-density lipoprotein-Lp-PLA2 activity. We conclude that elevated autoantibody titers against oxLDL at the end of the decomposition phase of oxidation and low plasma Lp-PLA2 activity are feature characteristics of patients with ERA, suggesting an important role of these parameters in the pathophysiology of ERA as well as in the accelerated atherosclerosis observed in these patients.
Introduction
Rheumatoid arthritis is a chronic inflammatory condition of unknown etiology affecting primarily the synovium, leading to joint damage and bone destruction. Rheumatoid arthritis causes significant morbidity as a result of synovial inflammation, joint destruction and associated disability. Several investigators have reported an excess of cardiovascular morbidity and mortality among rheumatoid arthritis patients. In active rheumatoid arthritis, the majority of cardiovascular deaths result from accelerated atherosclerosis.
Oxidative modification of low-density lipoprotein (LDL) is an important event in the development and progression of atherosclerosis. Oxidized low-density lipoprotein (oxLDL) is present in atherosclerotic lesions of humans and animal models, and promotes atherosclerosis by several mechanisms. oxLDL has been detected in patients with systemic lupus erythematosus and the antiphospholipid syndrome and also in the synovium and synovial fluids of rheumatoid arthritis patients.
During LDL oxidation both the lipids and apolipoprotein B-100 (Apo B) undergo a variety of chemical changes via radical-mediated reactions as well as modifications by chemically active products formed on oxLDL particles. An important biochemical change that takes place during LDL oxidation is the hydrolysis of its content in oxidized phospholipids and the production of lysophosphatidylcholine. This reaction is catalyzed by the lipoprotein-associated phospholipase A2 (Lp-PLA2), also known as platelet-activating factor acetylhydrolase. Lp-PLA2 exhibits a Ca-independent phospholipase A2 activity and preferentially hydrolyses biologically active phospholipids containing short acyl groups at the sn-2 position, such as platelet-activating factor and oxidized phospholipids; this enzyme therefore plays important roles in inflammatory reactions and atherosclerosis. In human plasma Lp-PLA2 is associated mainly with LDL, whereas a small proportion of circulating enzyme activity is also associated with high-density lipoprotein (HDL). Data from large Caucasian population studies have demonstrated an independent association between plasma Lp-PLA2 (which represents mainly the LDL-associated Lp-PLA2) and the risk of future cardiovascular events. In contrast to the total plasma enzyme, several lines of evidence suggest that HDL-associated Lp-PLA2 activity (HDL-Lp-PLA2), although at low levels in plasma, may contribute to the antiatherogenic effects of this lipoprotein.
oxLDL is immunogenic and some of its constituents (oxidized phospholipids, aldehydes and lysophosphatidylcholine) play important roles in the oxLDL antigenicity, participating in the formation of several different epitopes. These epitopes are recognized by specific autoantibodies, which are present in serum of healthy individuals as well as in various pathologic conditions. We recently showed, using various types of mildly oxLDL as antigens, that the extent of LDL oxidation and the levels of LDL-associated Lp-PLA2 activity significantly influence the antibody titers against oxLDL in patients with stable angina. Furthermore, we recently showed that the LDL-associated Lp-PLA2 plays an important role in modulating the immune responses against various types of mildly oxLDL observed after an acute coronary syndrome without persistent elevation of the ST segment.
The aim of the present study was to investigate the plasma levels of oxLDL and Lp-PLA2 activity as well as the autoantibody titers against various types of mildly oxidized LDL in patients with early rheumatoid arthritis (ERA). The long-term effects of immunointervention on these parameters in patients with active disease were also determined.
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