The potential benefit of statins in the treatment of lupus

Statins were originally developed for the treatment of hypercholesterolemia. The value in 2004 of the world market for anti-cholesterol drugs was worth over $25 billion, making this drug class the most successful therapeutic area in the world. Statins dominate the market taking over 90% of the market, worth an estimated $22 billion. Statins not only dominate the anti-cholesterol market but also the world market for any drug class. Major changes in drug indications for the statins may extend market revenues even further. The statin, Lipitor (Atorvastatin) is the best selling drug in the world and recent studies have suggested that this therapeutic agent may have immunomodulatory properties in lupus (for a full evaluation of lupus and other autoimmune diseases including emerging therapeutics click here). This chronic disease afflicts up to 1.5 million people in the US alone causing chronic inflammation and atherosclerosis. No new drugs have been approved for the treatment of lupus for over 30 years; the immunomodulatory and anti-atherogenic properties of atorvastatin may redress this situation

Lupus is a chronic inflammatory disease that can affect various parts of the body, especially the skin, joints, blood, and kidneys. For most people, lupus is a mild disease affecting only a few organs. For others, it may cause serious and even life-threatening problems. More than 16,000 Americans develop lupus each year. It is estimated that 500,000 to 1.5 million Americans have been diagnosed with lupus. Current treatments focus on the use of steroids and/or NSAIDs.

The search for new treatments of autoimmune diseases has rapidly gained momentum over recent years. In particular biological drugs have received considerable attention and indeed the sale of such agents for the treatment of autoimmune diseases such as multiple sclerosis, rheumatoid arthritis, inflammatory bowel disease, and psoriasis reached nearly $7 billion in 2003 (for a detailed evaluation of autoimmune disorders, their markets and R&D activity click here). The first biologic for the treatment of asthma was approved in 2003 and competition is increasing amongst biotech companies poised to market what will be the first new lupus drug in over thirty years. Recent research has also demonstrated that a major non-biological class of drugs, the statins, may also be able to revolutionize the treatment of autoimmune disease.

Statins were originally developed for the treatment of hypercholesterolemia. The value in 2004 of the world market for anti-cholesterol drugs was worth over $25 billion, making this drug class the most successful therapeutic area in the world. Statins dominate the market taking over 90% of the market, worth an estimated $22 billion. Statins not only dominate the anti-cholesterol market but also the world market for any drug class. Major changes in drug indications for the statins may extend market revenues even further. The statin, Lipitor (Atorvastatin) is the best selling drug in the world (see our feature "The Cardiovascular Report").

There is growing evidence that statins have effects that extend past their lipid lowering activity. Evidence suggests that statins may slow the progression of Alzheimer's disease although the results of ongoing clinical trials are awaited. Likewise, statins may also have anti-inflammatory activity. This is of considerable interest in the treatment of cardiovascular disease. High lipid levels represent a major risk for the development of atherosclerotic plaques and cardiovascular morbidity and hence statins may be able to launch a two pronged attack; lowering lipid levels and also blocking the inflammatory component of atherosclerosis (see our recent feature "Reducing inflammation as an emerging target for cardiovascular disease"). However the anti-inflammatory potential of the statins encompass a wide range of other inflammatory and autoimmune diseases.

Recent research data demonstrated that statins inhibit the induction of the major histocompatibility (MHC) class II expression by interferon-gamma, leading to repression of MHC II-mediated T-cell activation. This early evidence of anti-inflammatory activity suggested that statins may play an immunomodulatory role in Th1-driven autoimmune disease. More recently statins have been reported to inhibit the expression of specific cell surface receptors on leukocytes preventing their adhesion to vessel walls and the expression of several proinflammatory cytokines. Thus statins may be able to limit leukocyte trafficking into the sites of inflammation in autoimmune diseases. The statins have already been shown to limit disease in experimental models of arthritis and multiple sclerosis. More recently Lawman et al have investigated the effects of atorvastatin in mice with existing lupus-like disease characterized by production of IgG anti-dsDNA Abs and progressive glomerulonephritis.

In their December J Immunol paper Lawman et al report that the administration of atorvastatin to mice with elevated IgG anti-DNA Ab reduced antibody levels while total IgG levels were not affected. Atorvastatin also retarded the progression of lupus nephritis, as shown by significantly less proteinuria; lower serum urea levels; and improved histological appearance. This disease amelioration was mirrored by reduced splenic B lymphocyte MHC-II expression which is critical to the activation and expansion of autoreactive T cells as well as autoantibody production in experimental lupus-like disease. This study suggests that the effects of atorvastatin are due to a direct effect on the antigen presenting B lymphocytes.

In a study published in 2003 Abud-Mendoza et al reported that simvastatin induced a rapid and significant reduction in proteinuria levels in three systemic lupus erythematosus patients. The recent study by Lawman et al confirms the therapeutic activity of statin treatment in an experimental model of lupus and also reports improvement in renal histology. The study also provides valuable mechanistic insight, in particular specific effects on the immune system. Finally it should be noted that hyperlipidemia-induced atherosclerosis is an important cause of morbidity and mortality in patients with systemic lupus erythematosus; consequently, the effect of giving patients a statin may yield a 2-fold benefit, with reductions in their lupus disease activity and in the incidence of atheroma. With a proof of concept in place it is hoped that companies involved in the development of statins will now sponsor clinical trials to evaluate the efficacy of their agents in the treatment of lupus. Positive data would not only expand the long-restricted arsenal of weapons available for the treatment of lupus but they would also drive the expansion of the statin market.

Entry date Sunday, January 23, 2005

Adapted from Lawman et al, J Immunol. 2004 Dec 15;173(12):7641-6