Identifying statin-associated autoimmune necrotizing myopathy
ABSTRACTStatins up-regulate expression of 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR), the rate-limiting enzyme in cholesterol synthesis and the major target of autoantibodies in statin-associated immune-mediated necrotizing myopathy. As muscle cells regenerate, they express high levels of HMGCR, which may sustain the immune response even after statin therapy is stopped. Awareness of this entity will help physicians who prescribe statins to take action to limit the associated morbidity.
KEY POINTS
- Most cases of muscle symptoms associated with statin use are a direct effect of the statin on the muscle and resolve after the statin is discontinued.
- In contrast to simple myalgia or myositis, statin-associated autoimmune necrotizing myopathy can persist or even arise de novo after the statin is stopped.
- This condition presents with symmetric proximal arm and leg weakness and striking elevations of muscle enzymes such as creatine kinase.
- Treatment can be challenging and requires immunosuppressive drugs; referral to a specialist is recommended.
- Statin therapy should be discontinued once this condition is suspected. Patients who continue to have elevated muscle enzymes or weakness should undergo further testing with electromyography, magnetic resonance imaging, and muscle biopsy.
PATIENTS WITH ANTI-HMGCR WHO HAVE AND WHO HAVE NEVER TAKEN STATINS
When the anti-HMGCR antibody was tested for in the Johns Hopkins cohort,12 33% of patients with a necrotizing myopathy associated with this antibody had never taken a statin. The two groups were clinically indistinguishable, save for a few aspects. Compared with patients who had taken a statin, those who had never taken a statin were younger (mean age 37 vs 59), had higher levels of creatine kinase (13,392 vs 7,881 IU/L), and had a different race distribution (46.7% vs 86.7% white). Initial HMGCR antibody levels were also noted to correlate with creatine kinase levels and strength in statin-exposed patients but not in those who had never taken a statin.15
We hypothesize that in patients who have never taken a statin, other genetic or environmental factors may be the cause of the increased HMGCR expression, which then triggers the autoimmune response. Until further data are gathered, we should probably treat these patients as we treat those who develop this disease after taking a statin, and avoid giving them statins altogether.
MANAGEMENT OF STATIN-ASSOCIATED AUTOIMMUNE NECROTIZING MYOPATHY
Treatment of statin-associated autoimmune necrotizing myopathy can be challenging and requires immunosuppressive drugs.
Statin therapy should be stopped once this condition is suspected. Patients who continue to have elevated muscle enzymes or weakness should undergo further testing with electromyography, magnetic resonance imaging, and muscle biopsy. Electromyography detects myopathy and shows chronicity, distribution, and degree of severity. Although not necessary for diagnosis, magnetic resonance imaging helps to evaluate the extent of muscle involvement and damage and provides guidance when choosing a site for muscle biopsy. Muscle biopsy is necessary to determine the actual pathology and to exclude mimics such as dystrophy or metabolic myopathies.
When an immune-mediated myopathy is confirmed, prompt referral to a rheumatologist or a neuromuscular specialist is recommended.
Steroids are usually the first-line treatment for this disease. Other immunosuppressives, such as methotrexate, azathioprine, mycophenolate mofetil, and rituximab have been used with varying levels of success. In our experience, intravenous immunoglobulin has been particularly beneficial for refractory cases. With treatment, muscle enzyme levels and weakness improve, but relapses can occur. The ideal choice of immunosuppressive therapy and the duration of therapy are currently under investigation.
Rechallenge with another statin
At this time, the issue of rechallenging the patient with another statin has not been clarified. Given the autoimmune nature of the disease, we would avoid exposing the patient to a known trigger. However, this may be a difficult decision in patients with cardiovascular risk factors who require statins for primary or secondary prevention. We suggest using alternative cholesterol-lowering agents first and using them in combination if needed.
We have had some success in maintaining a handful of patients on a statin while treating them concurrently with immunosuppression. This is not ideal because they are constantly being exposed to the likely trigger for their disease, but it may be unavoidable if statins are deemed absolutely necessary. We have also had a patient with known statin-associated immune-mediated necrotizing myopathy who later became profoundly weak after another physician started her on a newer-generation agent, pitavastatin. This suggests to us that rechallenging patients, even with a different statin, can have deleterious effects.
IMPLICATIONS FOR CLINICAL PRACTICE
The true prevalence of statin-associated autoimmune myopathy in practice is unknown. In the Johns Hopkins Myositis Center cohort of patients with suspected myopathy, anti-HMGCR was found in 6% of the patients and was the second most frequent antibody found after anti-Jo1.12
Given the frequency of muscle-related complaints in patients on statins, we recommend obtaining baseline muscle enzyme measurements before starting statin therapy. As recommended by the National Lipid Association Statin Safety Assessment Task Force, the creatine kinase level should be measured when a patient develops muscular complaints, to help gauge the severity of the disease and to help decide whether to continue therapy.8 Random testing of the creatine kinase level in asymptomatic patients is not recommended.
At present, the diagnosis of statin-associated autoimmune necrotizing myopathy is based on a combination of findings—elevated muscle enzyme levels, muscle weakness, irritable findings on electromyography, and necrotizing myopathy on biopsy in a patient on a statin. The finding of the HMGCR antibody confirms the diagnosis. A test for this antibody is now commercially available in the United States. We suggest testing for the antibody in the following scenarios:
- A persistently elevated or rising creatine kinase, aspartate aminotransferase, alanine aminotransferase, or aldolase level after the statin is stopped; although no fixed creatine kinase level has been determined, a level above 1,000 U/L would be a reasonable cutoff at which to test
- Muscle symptoms (proximal or distal weakness) that persist 12 weeks after statin cessation regardless of the creatine kinase level, especially if the patient has dysphagia
- The finding of muscle irritability on electromyography or diffuse muscle edema on magnetic resonance imaging when testing for other myositis-specific antibodies is negative
- Muscle biopsy showing necrotizing myopathy with little or no inflammation.
In addition, since necrotizing myopathy is known to be associated with malignancy and since necrotizing myopathy is more common in older people, who are also more likely to be taking a statin, an age-appropriate malignancy evaluation is warranted as well.
