Spotlight on Research 2011

September 2011

Research Finds Link Between Statin Use and Progressive Muscle Disease

Each year, millions of Americans take statins, drugs collectively known to lower their blood cholesterol levels. While the drugs have proven effective in reducing heart attacks and strokes, for some people these benefits come at a cost: widespread muscle pain that persists as long as the drugs are taken. New NIAMS-supported research has found that for a subset of patients, statins appear to trigger a far more serious muscle condition that persists long after the drugs are stopped.

This discovery, published in the journal Arthritis & Rheumatism by a multidisciplinary team of researchers at The Johns Hopkins University, began in 2010 when they noted that some patients at the university’s Myositis Center had unique antibodies that seemed to be associated with necrotizing myopathy, a progressive muscle wasting disease of unknown cause. Further investigation revealed that as many as three-fourths of these patients had previously used statins, leading the researchers to suspect from prior related research, that the condition might be an autoimmune disease associated with statins. In other words, they suspected statins might have somehow triggered these people’s immune systems to produce antibodies against components of their own bodies.

Following this hunch, the researchers set out to find the cause of the suspected autoimmune response. A series of "smart guesses" led them to 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR), an enzyme in the body involved in the production of cholesterol, says Lisa Christopher-Stine, M.D., co-director of the Johns Hopkins Myositis Center and one of the NIAMS-funded researchers involved in the discovery. In the patients with necrotizing myopathy, the researchers found that autoantibodies (so-called because they react to the body’s own molecules) attack the body’s natural HMGCR. While statins work by inhibiting the body’s natural HMGCR, the body churns out more of the enzyme in an effort to compensate for the reduction caused by the statin. In a small percentage of people, they suspect, this extra HMGCR is the target of the immune system’s attack.

Making the problem worse was an earlier finding in 2005 by Livia Casciola-Rosen, Ph.D., and colleagues at Johns Hopkins that implicates regenerating muscle cells rather than mature muscle cells as the source of ongoing HMGCR supply in people with statin-induced myopathy. This suggests that, once the immune system starts to attack HMGCR and muscle damage begins, the regeneration to replace damaged muscle only fuels the problem — even when statins are stopped — says Dr. Christopher-Stine.

Unlike more common muscle pain from statins, this condition requires the use of corticosteroids and other drugs to suppress the immune system, with the goal of stopping progressive muscle damage, says Dr. Christopher-Stine. But even in these cases, she warns that stopping the statin — and forgoing its benefits to the cardiovascular system — may not be necessary. Treating with a statin and immunosuppressive drugs simultaneously may be preferable in some cases.

Eventually, the researchers believe their work could lead to tests that would enable doctors to identify which statin users have muscle pain that will improve on its own, and which ones require treatment to slow or stop progressive muscle disease. In the meantime, they urge doctors and patients not to avoid statins, which are among the most useful and commonly prescribed drugs. For patients who take statins and experience muscle pain, they recommend that doctors look for signs that could indicate a more severe problem such as difficulty swallowing, reduced grip strength, blood tests showing persistently elevated muscle enzymes and/or muscle pain that persists longer than 12 weeks despite statin cessation.

The mission of the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), a part of the U.S. Department of Health and Human Services' National Institutes of Health, is to support research into the causes, treatment and prevention of arthritis and musculoskeletal and skin diseases; the training of basic and clinical scientists to carry out this research; and the dissemination of information on research progress in these diseases. For more information about NIAMS, call the information clearinghouse at (301) 495-4484 or (877) 22-NIAMS (free call) or visit the NIAMS website at http://www.niams.nih.gov.

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Casciola-Rosen L, Nagaraju K, Plotz P, Wang K, Levine S, Gabrielson E, Corse A, Rosen A. Enhanced autoantigen expression in regenerating muscle cells in idiopathic inflammatory myopathy. J Exp Med. 2005 Feb 21; 201(4):591-601.

Christopher-Stine L, Casciola-Rosen LA, Hong G, Chung T, Corse AM, Mammen AL. A novel autoantibody recognizing 200-kd and 100-kd proteins is associated with an immune-mediated necrotizing myopathy. Arthritis Rheum. 2010 Sep; 62(9):2757-66.

Mammen AL, Chung T, Christopher-Stine L, Rosen P, Rosen A, Doering KR, Casciola-Rosen LA. Autoantibodies against 3-hydroxy-3-methylglutaryl-coenzyme A reductase in patients with statin-associated autoimmune myopathy. Arthritis Rheum. 2011 Mar; 63(3):713-21.