Statin-associated autoimmune myopathy

Statin-associated autoimmune myopathy (SAAM) is a very rare but serious form of muscle damage caused by the immune system in people who take statin medications.

The exact cause is unclear. No particular statin has been associated with SAAM more than others. SAAM is diagnosed by a combination of consistent findings on physical examination, the presence of anti HMG-CoA reductase antibodies in a person with myopathy, evidence of muscle breakdown, and muscle biopsy.

Treatment involves stopping the associated statin medication and taking medication to suppress the immune system.

SAAM is a very rare disorder with an estimated prevalence of 2-3 cases in 100,000 treated individuals and appears to be more common in people over the age of 50.

Signs and symptoms

SAAM is characterized by severe symmetric proximal muscle weakness (shoulders, upper arms, thighs), very high blood levels of creatine kinase (CK) from skeletal muscle breakdown, and persistent symptoms and CK elevation despite stopping the offending statin medication. This differs from other forms of statin myopathy that are expected to resolve following withdrawal of the statin. Mild joint pain and rash may be present. In people affected by SAAM, the median duration of statin therapy was 38 months prior to the onset of muscular symptoms. This indicates that SAAM can affect people who have taken a statin for a long period of time even if they had no previous muscular side effects.

Pathogenesis

It is unclear precisely how statins lead to statin-associated autoimmune myopathy. The disorder has been positively associated with HLA-DR11 and the DRB1*11:01 allele. There are likely as of yet other unidentified genetic and environmental risk factors associated with SAAM given the prevalence of the DRB1 allele and the low incidence of autoimmunity in that group. Statins effectively lower cholesterol levels in the blood by inhibiting the HMG-CoA reductase enzyme activity; however, by doing this, they also increase production of the HMG-CoA reductase protein. In genetically susceptible individuals, it is hypothesized that this increase in production of HMG-CoA reductase may lead to abnormal processing of this protein and subsequent generation of antibodies against it resulting in SAAM. Another theory postulates that the configuration of the HMG-CoA reductase protein may change when statin medications bind to it causing the protein to expose certain antigens that the immune system is not tolerant to resulting in the production of antibodies against it.

Diagnosis

Statin exposure followed by the development of necrotizing myopathy is insufficient to make the diagnosis. Alternate causes of myositis and necrotizing myopathy must first be excluded. A muscle biopsy consistent with SAAM will demonstrate muscle cell death with muscle fiber regeneration and typically has few inflammatory cells. Immunohistochemistry testing may demonstrate additional pathologic features of SAAM including the presence of endothelial cell membrane attack complex in non-necrotic muscle fibers and MHC class I expression.

Antibodies against HMG-CoA reductase occur in 94% of affected individuals. These antibodies have been known to also occur in people who have never been exposed to statin medications. These antibodies have not been found in people who take statin medications but have not developed myopathy; thus, the presence of anti-HMGCoA reductase antibodies in a person who has taken a statin and have myopathy strongly supports this diagnosis. CK levels increase to 10-100 times the normal limit (2000-20,000 IU/L) in more than 90% of cases. Electromyography (EMG) demonstrates a myopathic pattern of findings. Swelling of the muscles may be seen on MRI imaging.

Treatment

SAAM is treated by stopping the offending statin medication and taking immunosuppressive medications. In rare cases, affected people have had spontaneous improvement with stopping the implicated statin alone. However, this is typically not sufficient and immunosuppressive medication is needed in most cases.

Corticosteroids are considered first-line treatment. Prednisone dosed at 1 milligram/kilogram of bodyweight daily is generally recommended. Corticosteroid therapy alone may be reasonable in cases of mild muscular weakness, but otherwise the addition of other immunosuppressive medications such as methotrexate, azathioprine, or mycophenolate is typical at the start of treatment. For severe cases unresponsive to this combination after 8-12 weeks, the addition of another medication (triple therapy) such as intravenous immunoglobulin or rituximab is recommended. Intravenous immunoglobulin has been successfully used as first-line treatment in selected individuals (e.g., people with diabetes mellitus who wish to avoid corticosteroid therapy).

Prognosis

People affected by SAAM often regain complete muscle strength with proper treatment. This can occur even with persistently elevated creatine kinase (CK) levels. Conversely, some people with SAAM do not regain full muscle strength despite normalization of their CK levels. It is recommended that immunosuppressive medications be tapered once strength recovers. Relapse remains possible when these medications are tapered and some people do require long-term immunosuppression. If an affected person is inadequately treated for a long period of time, they are more likely to experience permanent muscle damage and weakness due to replacement of some muscle with fatty tissue, which can be seen on MRI.