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Statins for Atherosclerosis — As Good as It Gets?, Editorial
New England Jnl of Medicine
Volume 352:73-75, January 6, 2005, Number 1
Michael R. Ehrenstein, Ph.D., F.R.C.P., Elizabeth C. Jury, Ph.D., and Claudia Mauri, Ph.D.From the Centre for Rheumatology, Department of Medicine, University College, London
If ever there were a perfect marriage of drug with disease it might be between statins and atherosclerosis. At first the relationship was simple: statins inhibited synthesis of the cholesterol that contributed to atheroma, and less cholesterol meant less atheroma. Just as married couples often adapt to each other, so it is with statins and atheroma, or to be more precise, an increased understanding of their relationship has revealed an apparent adaptation. Atherosclerosis is now recognized to have a notable inflammatory component, and in parallel, statins appear to inhibit inflammatory processes directly. Rheumatologists pondering this phenomenon from the outside (and wondering whether they would eventually be asked to treat cardiovascular disease with immunosuppressive drugs) began to recognize distinct but related connections closer to home. Patients with rheumatoid arthritis and systemic lupus erythematosus (SLE) have a significantly increased risk of cardiovascular disease and therefore might benefit from statin therapy. The other side of the coin is the possibility that the antiinflammatory actions of statins can also improve the autoimmune aspect of the disease itself. Indeed, the list of disorders for which statins might prove beneficial is growing and now extends from multiple sclerosis and neurodegenerative disorders to rheumatoid arthritis and SLE.
The action of statins turns out to be more complex and broader than was originally suspected, and recent studies have revealed their multiple immunologic actions. Among the first reports of the immunologic effects of statins was the finding that this class of drug inhibits the increase in cell-surface proteins of major histocompatibility complex class II induced by interferon-{gamma}. Such proteins are central in presenting antigen and activating T cells, and their expression is often increased in inflammation. Increased production of interferon-{gamma} by activated T cells is characteristic of a number of autoimmune diseases in humans, including collagen-induced arthritis, and experimental autoimmune encephalomyelitis, a murine model of multiple sclerosis. Statin therapy proved effective in both these diseases as well as in murine lupus, in which the cytokine dysregulation is more complex but includes increased production of interferon-{gamma}.
In fact, SLE provides an apt illustration of the complex interaction among statins, atheroma, and the autoimmune disease itself. Interferon-{gamma} is now generally accepted as directly promoting atherosclerosis, and therefore, the increased production of interferon-{gamma} associated with active lupus would accelerate the formation of atheroma. Equally, there is now evidence from a murine model of lupus suggesting that elevated plasma cholesterol levels exacerbate SLE. These results suggest that the use of statins could have several benefits for patients with SLE. Statin-induced reductions in cholesterol decrease atherosclerosis but may also ameliorate the disease itself. Moreover, statins mitigate autoimmunity, thereby opening the possibility of diminishing disease activity and, as a direct consequence, lowering the risk of atherosclerosis.
What about cardiovascular disease? The immunomodulatory effects of statins in various autoimmune diseases apply equally well to cardiovascular disease, in which surprisingly similar immune dysregulation is observed. Indeed, the inflammatory component of atherosclerosis, characterized by increased production of interferon-{gamma} by T cells, has led immunologists to suggest that atherosclerosis should be added to the list of organ-specific autoimmune diseases.
Two articles in this issue of the Journal, one by Nissen et al.4 and one by Ridker et al., confirm that reducing the inflammatory component of cardiovascular disease through the use of statin therapy improves the clinical outcome independently of the reduction in serum cholesterol levels. Critical to the conclusions of both articles is the finding that a decrease in C-reactive protein, a marker of inflammation, is only weakly correlated with changes in serum lipid levels. However, from an immunologic perspective, the association between cholesterol levels and immunologic regulation may be closer than previously realized. Cholesterol is a key component of the structure and function of cell membranes. The response of lymphocytes to exogenous signals such as antigen is orchestrated by a number of molecules that cluster in cholesterol-rich areas of the cell membrane known as lipid rafts. Lipid rafts act as platforms, bringing together molecules essential for the activation of immune cells, but also separating such molecules when the conditions for activation are not appropriate. Several strands of evidence suggest that the inhibition of cholesterol synthesis by statins disrupts these lipid rafts and thereby influences the function of lymphocytes.
Could all the immunomodulation by statins be ascribed to their ability to reduce cholesterol levels in the cell membrane? Serum and membrane cholesterol may be differentially affected by statin treatment, and only by assaying both could the full effects of statins be identified. Although the changes in membrane cholesterol levels may be relevant only at sites of lymphocyte activation, as in atheroma or autoimmune diseases, the possibility that lymphocyte function may be generally impaired in the many patients who are taking statins raises a note of caution. However, even in the area of infection, there are suggestions that statin therapy has a favorable effect on sepsis and can reduce the replication of the human immunodeficiency virus.
The notion that the antiinflammatory effects of statins ameliorate cardiovascular disease suggests that it should be possible to create other antiinflammatory agents, perhaps tailored to the specific immunologic abnormalities in atheroma. Determining the mechanisms of action of statins and their relative importance will help to rationalize the design of such therapies.
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