Hypercholesterolemia, atherosclerosis and Systemic lupus erythematosus

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Systemic lupus erythematosus (SLE) is a chronic, autoimmune, multisystemic disease with episodes of lupus flares that alternates with disease control. (1) Its clinical expression has a wide variety of presentations that include damage to various organ systems.

A diverse set of genetic, environmental and sex-related factors are involved in the development of the disease. These factors cause disturbances in immune response, including abnormalities in B and T cell function, complement activation, dysregulation of cytokine and chemotaxin synthesis, with the production of autoantibodies and immune complexes. (2)

Atherosclerosis (AS) is a chronic inflammatory condition that affects large and medium blood vessels. (3) The organic lesions resulting from the immunological abnormalities of SLE (especially aseptic cell necrosis) and hypercholesterolemia are factors related to premature atherosclerosis experienced by patients with lupus compared to controls, a result found in several studies. (4,5)

Complications of atherogenic plaques remain the leading cause of death in the general population, (3) with a higher incidence among patients with autoimmune diseases. Although immunomodulatory treatment of SLE itself has contributed to improve survival rates, it has increased the risk of developing cardiovascular disease by five to ten times compared to controls of the same sex and age, (1) a fact related to alterations in the lipid profile as a side effect of the treatment.

SLE is recognized as the prototypical autoimmune disease and at the same way a predisposing factor for AS. An analysis of the molecular and immunological mechanisms causing AS establishes that circulating low-density lipoproteins (LDLs) initiate the atherogenic process after adhesion to endothelial cells in the intimal space of vessels. (3) At the same time, LDLs become immunogenic through enzymatic and non-enzymatic transformations. (1)

The complex process of oxidative modifications of LDLs plays a fundamental role in the development of atheroma plaques. This modified process takes place in the subendothelial space, and in response to the accumulation of oxidized LDLs (LDL-ox) endothelial cells express proinflammatory cytokines, chemotaxins and adhesion molecules that initiate an immune reaction mediated by CD4+ helper T lymphocytes subtype Th1 and B lymphocytes subtype 1 and 2 that produce anti-LDL-ox IgM-type autoantibodies. (2,3,6)

Altered endothelial function in SLE is associated with a circulation increase in apoptotic endothelial cells, which may be related to an immune response against the vascular endothelium itself. The presence of the triad of antiphospholipid antibodies (lupus anticoagulant [LA], anticardiolipin antibodies [aCL] and beta 2-glycoprotein antibodies [ab2GPI]), which averages around 20-30% of cases in SLE, is associated with increased vascular damage and frequent thrombotic events,(2) both of which produce new atheroma plaques.

SLE patients show higher levels of IgM anti-LDL-ox autoantibodies. Higher anti-LDL-ox IgM titers are present in those patients with positive antinuclear antibody (ANAs) patterns. A similar fact was found in those who showed positive anti-neutrophil cytoplasmic antibodies (ANCA) and especially during the active phase of the disease. (6) The immunoprotective role of IgM anti-LDL-ox antibodies has shown that small circulating amounts cause a higher expression of atherosclerosis and, with it, an increased risk for developing ischemic events. (2)

Positive SLEDAI activity index and high levels of anti-double-stranded DNA antibodies (anti-dsDNA) are significantly associated with elevated levels of circulating triacylglycerols and cholesterols. Moreover, a reduction of blood lipid levels by diet and lipid-lowering drugs improves disease symptoms and the immune response mediated by T and B lymphocytes. (7) Sanchez P et al.(8) reported that the use of statins in SLE patients reduced the levels of serum total cholesterol and LDLs with a mean difference of -31.4 mg/dL.

The literature shows a correlation between autoimmune diseases and atherosclerosis, to a certain extent establishing that AS is an autoimmune disease per se. Alterations in the lipid profile in SLE are linked to the treatment and the disease itself. LDLs-ox due to their immunogenic role tends to form atheroma plaques and increase the risk of developing an ischemic event.

New studies are needed to determine the presence or absence of hypercholesterolemia at the time of diagnosis and in subsequent admissions of patients with SLE, as well as an adequate estimate of ischemic risk as a result of atherosclerosis.


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