ARTICLE IN BRIEF
Investigators used a dot blot assay to detect autoantibodies to the protein, cytosolic 5'-nucleotidase 1A, and found it was effective in identifying inclusion body myositis — with a sensitivity of 72 percent, a specificity of 92 percent, and an overall accuracy rate of 85 percent at that level.
NEW ORLEANS — A blood test for sporadic inclusion body myositis (sIBM), using detection of autoantibodies against a newly identified protein, identified the disease in 72 percent of cases and, of those identified, correctly predicted the disease 92 percent of the time, according to a new study, which was presented here at the annual meeting of the American Neurological Association in October.
The findings provide support for a diagnostic test that might be particularly useful for doctors who are not neuromuscular specialists, and might even forego the need for biopsy in some cases, said Steven A. Greenberg, MD, associate professor of neurology at Harvard Medical School, who spent 10 years doing research that led to the identification of the protein at the heart of the new test.
The test is already growing in use by some doctors, Dr. Greenberg said.
Sporadic inclusion body myositis is a rare but debilitating disease in which muscles wither away in a degenerative and inflammatory process. Other treatments, including methotrexate and intravenous immunoglobulin (IVIg), have not proven to be very effective, and many doctors don't even attempt to treat the disease.
“This field could definitely use a blood test for this disease,” he said. “It would be a big help because patients are misdiagnosed commonly. A published series of papers has shown a misdiagnosis rate of about 50 or 60 percent, and a mean time to correct diagnosis of more than five years.”
In the study, a dot blot assay was used to detect autoantibodies to the protein, cytosolic 5'-nucleotidase 1A, or cN1A. Serum samples from 200 people — 47 sIBM patients, 118 with other types of muscle disease, and 35 normal controls — were used to test for the autoantibodies. A reactivity cut-off level of 2.5 arbitrary units was identified as optimal, with a sensitivity of 72 percent, a specificity of 92 percent, and an overall accuracy rate of 85 percent at that level.
Part of the reason IBM is misdiagnosed by non-neuromuscular specialists is that the disease is slow to manifest itself. Those misdiagnoses lead not only to lost time, but also to use of medications that aren't useful or needed, Dr. Greenberg said.
“Most of these patients get misdiagnosed with something else, are often treated for that something else, often with corticosteroids; a few years go by, and the treating physician realizes the treatment's not working and that the diagnosis may be wrong.”
The sensitivity for the test is only 70 percent, he said, but it's the specificity that's more important, particularly for a neuromuscular specialist who has high suspicion that a patient has IBM prior to muscle biopsy — due to a certain pattern of muscle weakness and a certain age group affected. In that setting, the purpose of an sIBM test should be to confirm the clinical suspicion and that, if negative, not to direct doctors away from performing muscle biopsy for suspected IBM. For that reason, the specificity is more important than the sensitivity, Dr. Greenberg said.
He said it “would be nice” to have greater sensitivity but that he is not too concerned about patients missed by the blood test because “they're eventually going to get diagnosed by muscle biopsy.”
A positive IBM blood test might even mean that a biopsy isn't needed, since muscle biopsies correctly identify only about 85 percent of IBM cases, Dr. Greenberg said.
The identification of the cN1A protein as the autoantibody target represents a change in the direction of the autoimmune response in IBM. For years, the focus was on the T-cell pathway, which can be technically difficult to investigate, Dr. Greenberg said.
“It was microarray experiments in muscle that showed me that something was wrong with the dogma of the disease — that there really were B cells producing autoantibodies in muscle itself even though previous studies had said there are no or sparse B cells in IBM muscles,” he said.
Beyond the significance of the blood test, identification of the cN1A protein in sIBM sheds new light on a lingering question: whether there is a link between the autoimmune response and the degeneration involved in the disease.
The answer is yes, Dr. Greenberg said. Examination of tissue using immunohistochemistry shows that the protein cN1A accumulates in areas of muscle degeneration.
“So there is a link between the autoimmunity and the degeneration — but I don't know what that link is,” he said. “How best to approach this scientifically is currently unclear. But conceptually there is muscle degeneration and this protein is being overexpressed in that area, or accumulating in that area, and the immune system is generating a response to that protein.”
Glenn Lopate, MD, associate professor of neurology at Washington University who specializes in neuromuscular disease, said the findings show that the test has real value, but he does not think it should be the final word in diagnosis.
“A test with 70 percent sensitivity, while not optimal, would still be useful, especially given the high specificity,” he said. “Seventy percent sensitivity is a bit low. It suggests that this test alone will not be enough to diagnose all patients with IBM — a muscle biopsy will still be needed.”
He said he and his colleagues are using the test in their lab and they expect it to become more widely used.
“Ultimately, it will only gain widespread use if it becomes clinically available through a dedicated nationwide lab,” he said. “However, I don't see it replacing muscle biopsy and I think muscle biopsy will (and) should be done in all patients with myopathy. I would think of it as akin to other muscle autoantibodies, e.g. Jo-1, SRP, that do not replace muscle biopsy, but help to further define the muscle disease and suggest appropriate treatments.”
Yadollah Harati, MD, professor of neurology and chief of the neuromuscular section at the Baylor College of Medicine, agreed that the test would not necessarily replace a muscle biopsy. “At best, this test will be an additional test,” he said. “The gold standard is still going to be the muscle biopsy.”
He pointed out, however, that in certain cases handled by neuromuscular specialists who see “classic” signs of IBM, the blood test alone might be used, to spare a patient from having the muscle biopsy.
He said he expects use of the test to catch on among non-neurologists.
“I'm sure that rheumatologists are going to use that often now,” he said, “because many patients that we see in the neurology neuromuscular clinic with this kind of problem either have seen a rheumatologist or sometimes they will see the rheumatologist.”
LINK UP FOR MORE INFORMATION:
•. Neurology archive on inclusion body myositis: bit.ly/1gex7tG.
•. Larman HB, Salajegheh M, Nazareno R, et al. Cytosolic 5'-nucleotidase 1A autoimmunity in sporadic inclusion body myositis. Ann Neurol
© 2013 American Academy of Neurology
•. Greenberg SA. Biomarkers of inclusion body myositis. Curr Opin Rheumatol
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