Thursday, February 17, 2011

risk factors for statin myopathy; antibodies of





The field of autoantibodies related to immune-mediated inflammatory myopathies has expanded in recent years and there is now a host of antibodies that have relevance to these myopathies. The 1975 Bohan and Peter criteria for the classification of immune-mediated inflammatory myopathies do not reflect many newer insights, and several newer classification schemes exist, but none enjoy uniform acceptance.12 Some controversy remains as to the pathophysiology behind dermatomyositis, but this disease is probably the most consistently defined. Conversely, polymyositis has several varied definitions, and in the Bohan and Peter criteria it was not delineated from inclusion body myopathy (IBM). The antisynthetase syndrome associated with antibodies described in this section does not cleanly sort under either the dermato- or polymyositis labels. The inflammatory myopathies associated with SRP and 200/100 antibodies do not even necessarily have the inflammatory muscle infiltrates that we traditionally associate with inflammatory myopathies. While IBM has prominent inflammatory features, none of the described autoantibodies are linked to IBM, nor is immunomodulatory treatment of any benefit. For these and other reasons, many authorities believe IBM to be more of a myodegenerative disease with secondary inflammation.13 Granulomatous myopathy, HIV-associated myositis, and graft vs host disease are other immune-mediated inflammatory myopathies without associated muscle-directed antibodies.
There are also the overlap syndromes in which another defined autoimmune condition exists and overlaps with a myositis. This can occur in diseases such as systemic sclerosis, rheumatoid arthritis, systemic lupus erythematosus, and Sjögren syndrome. Distinguishing the primary inflammatory myopathies from the overlap syndromes is done by excluding the conditions causing overlap syndromes, but there are also autoantibodies that are almost unique to the immune-mediated inflammatory myopathies referred to as muscle-specific autoantibodies (MSA). Other antibodies are frequently seen in other connective tissue disorders, and these can be referred to as myositis-associated autoantibodies (MAA). All of these antibodies can help establish the diagnosis of myositis when the muscle biopsy is inconclusive, and the MSAs as well as some of the MAAs are listed in table 2.
The most prevalent MSA is the anti-Jo antibody, which is directed against histidyl-tRNA synthetase. Anti-Jo is detected in about 20% of patients with myositis in most populations. Anti-Jo can be detected in both dermatomyositis and polymyositis and is frequently associated with interstitial lung disease and mechanic's hands. This clinical and laboratory constellation is referred to as the antisynthetase syndrome. Interstitial lung disease is a potentially fatal comorbidity that often requires more aggressive immunomodulatory treatment. Histologically, the inflammation is often more perimysial rather than endomysial.14 There are other newer antisynthetase antibodies with similar clinical features including those that recognize threonyl-tRNA synthetase (anti-PL-7), alanyl-tRNA synthetase (anti-PL-12), glycyl-tRNA synthetase (anti-EJ), isoleucyl-tRNA synthetase (anti-OJ), asparaginyl-tRNA synthetase (anti-KS), anti-tyrosyl-tRNA synthetase, and antiphenylalanyl synthetase (anti-Zo). These other antibodies are each present in a few percent of patients, but there is essentially no overlap between them and patients do not express more than one antisynthetase antibody. A different type of antibody is the Anti-Mi-2 autoantibody. This nuclear antibody is directed against a component of the nucleosome-remodeling deacetylase, is seen more often in dermatomyositis, and is infrequent in most populations.
A clinically useful antibody is the SRP antibody. This antibody can often be found when there is myonecrosis, but little or no inflammation is seen on muscle histology. Identifying the antibody can be helpful in establishing that the myopathy is inflammatory and encourages escalating immunosuppression even if initial attempts are unsuccessful. The target of the new anti-155/140 antibody remains unknown, but this antibody is seen in dermatomyositis and is more common in paraneoplastic dermatomyositis compared to idiopathic autoimmune dermatomyositis.15 The not yet commercially available anti-200/100 autoantibody appears to have specificity for the necrotizing statin myositis (discussed earlier).8 In patients with a myopathy of unclear cause and a nondiagnostic biopsy testing, one should consider testing the anti-Jo antibody and a comprehensive panel of the other MSA, either sequentially or simultaneously

Myopathy: Five New Things

  • Risk of statin toxicity increases along with increases in their lipophilicity, cholesterol-lowering potency, and dosage.
  • In immune-mediated statin myopathy, discontinuation does not translate into immediate recovery.
  • MRI and muscle ultrasound in myopathy may provide detailed anatomic information.
  • Autoantibody testing may be helpful in defining myopathies of unclear cause.
  • Enzyme replacement may improve function in Pompe disease.