Statins significantly reduce the incidence of cardiovascular disease, are generally safe, and have an acceptable side-effect profile. It is now recognized, however, that in very rare cases, an autoimmune myopathy develops in patients treated with statins; this disorder is characterized by muscle weakness, evidence of muscle-cell necrosis on biopsy, and the presence of autoantibodies against 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase. In contrast to most patients who have side effects from statin therapy, those with statin-associated autoimmune myopathy may have progressive weakness that must be controlled with immunosuppressive therapy.
Statins are widely used and lower the risk of death from cardiovascular causes. In a small fraction of patients, an autoimmune myopathy may develop, characterized by the development of autoantibodies to the target enzyme, HMG-CoA reductase. A new Review Article summarizes.
Clinical Pearl
• What are some of the features of statin-associated autoimmune myopathy?
Although the onset of myopathy may occur very soon after the initiation of statin therapy, treatment with any one of the available statins may have no side effects in a given patient for years before causing such symptoms as difficulty rising from a chair, ascending steps, or lifting heavy objects. After weakness is noticed, it usually persists or worsens even if statin therapy is discontinued. In most cases, patients have only mild-to-moderate weakness. Although the myopathy primarily affects skeletal muscles, mild joint pain or rash may also be present. On physical examination, patients with statin-associated autoimmune myopathy usually present with symmetric proximal weakness. The creatine kinase levels are universally and persistently elevated in persons with active disease; in nearly 90% of cases, the level exceeds 2000 IU per liter, which is more than 10 times the upper limit of the normal range of 0 to 150 IU per liter (although it should be noted that normal ranges of creatine kinase levels may vary according to sex and race).
Clinical Pearl
• What are the characteristic histologic findings on muscle biopsy of patients with statin-associated autoimmune myopathy?
Muscle-cell necrosis and regeneration are the most prominent histologic features in muscle-biopsy specimens from patients with statin-associated autoimmune myopathy. Cellular infiltrates, found predominantly in endomysial and perivascular regions, are composed largely of macrophages, which probably play a role in tissue repair. Small numbers of CD4+ and CD8+ lymphocytes, as well as CD123+ plasmacytoid dendritic cells, may also be present. Diffuse or multifocal up-regulation of major histocompatibility complex class I molecules is common. Taken together, these histologic features are consistent with a diagnosis of immune-mediated necrotizing myopathy.
Figure 1. Muscle-Cell Necrosis and Macrophage Infiltration in Statin-Associated Autoimmune Myopathy.
Morning Report Questions
Q: How helpful is the presence of autoantibodies against HMG-CoA reductase in diagnosing statin-associated autoimmune myopathy?
A: Autoantibodies against HMG-CoA reductase, the pharmacologic target of statins, are found predominantly in biopsy specimens from patients with necrotizing myopathy and much less frequently in specimens from patients with other muscle conditions. Moreover, to date, anti–HMG-CoA reductase autoantibodies have not been detected in statin-treated patients who do not have muscle disease or those in whom self-limited statin-related myopathy develops. Thus, in patients who have myopathy after statin exposure, a positive test for anti–HMG-CoA reductase autoantibodies strongly supports the diagnosis of an autoimmune process. In antibody-negative patients, alternative diagnoses should be considered.
Q: How is statin-associated autoimmune myopathy treated?
A: A few patients with statin-triggered autoimmune myopathy and anti–HMG-CoA reductase autoantibodies have had spontaneous improvement of their condition without treatment after the discontinuation of statin therapy. This finding suggests that, in patients with very mild weakness, statin therapy can be stopped and the patients closely observed, with immunosuppressive therapy initiated only if the muscle disease fails to improve or continues to worsen. In most patients, however, treatment with statins should be discontinued and the patients treated with immunosuppressive medications similarly to those with other forms of autoimmune muscle disease. Although no clinical trials of treatment for statin-associated autoimmune myopathy have been conducted, clinical experience suggests that initial therapy should usually include oral prednisone at a dose of 1 mg per kilogram of body weight per day. Unless the patient has only mild weakness, another agent, such as methotrexate, azathioprine, or mycophenolate mofetil, should be included at the outset. In those in whom severe weakness develops or in whom the condition does not respond to the initial combination of medications after 8 to12 weeks, intravenous immune globulin or another agent, such as rituximab, may be added. Triple therapy, usually including intravenous immune globulin, has been used to treat nearly half of all patients with statin-triggered autoimmune myopathy described in the literature.