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.
STATINS AND AUTOIMMUNE NECROTIZING MYOPATHY
At the Johns Hopkins Myositis Center, a group of patients was identified who had necrotizing myopathy on biopsy but no known underlying condition or associated autoantibodies. In an attempt to establish an autoimmune basis for their disease, the sera from 26 patients were screened for novel antibodies.9 Sera from 16 of the patients immunoprecipitated a pair of proteins (sizes 100 kd and 200 kd), indicating these patients had an antibody to these proteins. This finding was highly specific for necrotizing myopathy when compared with controls, ie, other patients with myositis. Patients who had this finding displayed proximal muscle weakness, elevated muscle enzyme levels, and myopathic findings on electromyography; 63% had been exposed to statins before the onset of weakness, and when only patients over age 50 were included, the number rose to 83%.
This association of statins with necrotizing myopathy had been previously noted by two other groups. Needham et al10 described eight patients who, while on statins, developed myopathy that continued to worsen despite cessation of the drugs. An analysis of their muscle pathology revealed myofiber necrosis with little inflammatory infiltrate, as well as widespread up-regulation of expression of major histocompatibility complex class 1. These patients required immunosuppressive treatment (prednisone and methotrexate) to control their disease.
Grable-Esposito et al11 corroborated this finding by identifying 25 additional patients who developed a similar necrotizing myopathy while on statins.11 They also noted a significantly higher frequency of statin use in patients with necrotizing myopathy than in age-matched controls with polymyositis or inclusion-body myositis.
The researchers at the Johns Hopkins Myositis Center noted the similarity between these two patient groups and their own group of patients with necrotizing myopathy. Thus, a follow-up study was done to identify the 100-kg and 200-kd autoantigens observed in their earlier study. Exposure to a statin was found to up-regulate the expression of the two molecules.12 HMGCR was hypothesized as being the 100-kd antigen, because of its 97-kd molecular weight, and also because statin treatment had already been shown to up-regulate the expression of HMGCR.13 The researchers concluded that HMGCR was indeed the 100-kd antigen, with no distinctive antibodies recognizing the 200-kd protein. Although the 200-kd protein was once postulated to be a dimer of the 100-kd protein, its identity remains unknown.
The anti-HMGCR antibody was then screened for in a cohort of 750 myositis patients. The 16 patients previously found to have anti-200/100 were all positive for anti-HMGCR antibody. An additional 45 patients from the cohort (6%) were anti-HMGCR-positive by enzyme-linked immunosorbent assay, and all had necrotizing myopathy. Patients with other types of myopathy, including inflammatory myopathy, do not possess this antibody.12
The HMGCR antibody was quite specific for immune-mediated necrotizing myopathy, and this suggested that statins were capable of triggering an immune-mediated myopathy that is then perpetuated even if the drug is discontinued. As it was also demonstrated that statins increase the expression of HMGCR in muscle as well as in regenerating cells, the process may be sustained through persistently increased HMGCR expression associated with muscle repair.12
The C allele of the SLCO1B1 gene, which has been associated with statin-associated myopathy, was not increased in this population of patients positive for anti-HMGCR. Follow-up studies of the prevalence of anti-HMGCR in statin users in the Atherosclerosis Risk in Communities (ARIC) cohort, including those with self-limited statin myotoxicity, have also shown the absence of this antibody.14 This shows that anti-HMGCR is not found in the majority of statin-exposed patients and is highly specific for autoimmune myopathy. This also suggests that statin-associated autoimmune myopathy represents a pathologic process that is distinct from self-limited statin intolerance.
HOW THE CONDITION PRESENTS
Immune-mediated statin myopathy presents similarly to other idiopathic inflammatory myopathies such as polymyositis (Table 1). Symptoms often develop in a subacute to chronic course and can occur at any time with statin treatment. In one study,10 the average duration of statin use before the onset of weakness was 3 years (range 2 months to 10 years). In some patients whose statin had been stopped because of abnormal creatine kinase levels, weakness developed later, at a range of 0.5 to 20 months. Even low doses of statins (such as 10 mg of simvastatin) have been found to trigger this condition.10
Patients uniformly develop symmetric proximal arm and leg weakness, and distal weakness can also occur.11 Other features have included dysphagia, arthralgias, myalgias, and Raynaud phenomenon.9 Men and women are represented in roughly equal numbers.
The muscle enzymes are strikingly elevated in this disease, with a mean creatine kinase value of 10,333 IU/L at initial presentation.9 Although the creatine kinase level may be very elevated, patients often do not present with weakness until a certain threshold value is reached, in contrast with patients with anti-signal recognition particle necrotizing myopathy, who can present with profound weakness at a lower level. Hence, by the time patients are clinically symptomatic, the process may have been going on for some time. Despite the seemingly massive leak in muscle enzymes, the patients do not develop rhabdomyolysis. Inflammatory markers need not be elevated, and an association with other antibodies such as antinuclear antibody is not often seen.
Magnetic resonance imaging of the thigh has shown muscle edema in all patients.9 In decreasing order of frequency, other findings are atrophy, fatty replacement, and fascial edema.
Electromyography of involved muscle has shown irritable myopathy in most patients (88%) and nonirritable myopathy in a few.
Muscle biopsy studies have shown prominent necrotic and regenerating fibers without significant inflammatory infiltrate.11 There is also myophagocytosis of necrotic fibers and diffuse or focal up-regulation of major histocompatability complex class I expression.10
