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Diagnostics Microbiology and immunology, Biochemistry and molecular biology

Predictive Protein

The word “arthritis” often conjures up mental images of people in the later stages of life – people who may have limited movement, need assistance with daily living, or claim to forecast the weather by the feelings in their joints. But new research shows that arthritis, even in its non-juvenile forms, may begin affecting the body long before it makes its presence known. A recently characterized marker reveals that predictive and diagnostic factors for rheumatoid arthritis may arise a decade and a half before clinical signs of the condition actually emerge.

Anticitrullinated protein antibodies (ACPAs) are well-known markers for diagnosing rheumatoid arthritis (1), and the cyclic-citrullinated peptide (CCP) assays used to capture them are designed for high sensitivity and specificity. What they don’t do well is distinguish between subsets of ACPA-positive patients, meaning that they don’t allow doctors to examine the mechanisms of a patient’s disease or discern which treatment approaches might be most successful. Although ACPA assays can detect at least 20 different molecules, diagnostic tests for individual citrullinated proteins usually have low sensitivity. But a research team from the Kennedy Institute of Rheumatology at Oxford University have recently identified another peptide, citrullinated tenascin-C (cTNC), for which antibody testing has been shown to identify approximately 50 percent of rheumatoid arthritis cases with 98 percent diagnostic accuracy (2).

Anja Schwenzer, lead author on the study, says, “We knew that the protein tenascin-C could be found at high levels in the inflamed joints of people with rheumatoid arthritis. We decided to see if it could be citrullinated and, if so, whether it was a target for the autoantibodies that attack the body in rheumatoid arthritis.” The authors analyzed blood samples from more than 2,000 arthritis patients from the United States, the United Kingdom, Sweden and southern Europe. “Around half of them have antibodies against cTNC,” says Schwenzer, “including some patients who were not identified by the CCP test.” The study had an even more exciting outcome; one in five people who went on to develop rheumatoid arthritis had antibodies against cTNC well in advance of clinical signs – on average seven years before the disease became evident, and as much as 16 years in advance.

“People testing positive for these kinds of antibodies could be monitored more closely for symptoms of rheumatoid arthritis and could therefore be diagnosed much earlier,” says Schwenzer of the news. “That will allow doctors to start with the right treatment much earlier, making it more effective and also making it much easier to control the disease.” But first, she and her group would like to find out whether testing for these antibodies would help identify patients at risk of developing a more severe form of the disease. They’d also like to know whether certain patient groups – like smokers or those with gum disease – are more likely to exhibit elevated cTNC antibody levels. Factors like these may make cTNC a useful predictor of disease onset and perhaps even help guide doctors to more appropriate treatments for their patients.

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  1. GA Schellekens et al., “Citrulline is an essential constituent of antigenic determinants recognized by rheumatoid arthritis-specific autoantibodies”, J Clin Invest, 101, 273–281 (1998). PMID: 9421490.
  2. A Schwenzer et al., “Identification of an immunodominant peptide from citrullinated tenascin-C as a major target for autoantibodies in rheumatoid arthritis”, Ann Rheum Dis, [Epub ahead of print] (2015). PMID: 26659718.
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