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BIOMARKERS FOUND FOR RHEUMATOID ARTHRITIS

Rheumatoid arthritis (RA), the most common autoimmune inflammatory arthritis, is thought to have both genetic and environmental components to its origins. Evidence suggests that it develops in three phases: a period of genetic risk but with no symptoms; a preclinical phase in which RA-related autoantibodies can be detected; and a clinical phase with signs and symptoms of the disease. A new study examined whether women who developed RA would have evidence of immune activation prior to developing symptoms, compared with women who did not develop the disease. The study was published in the March issue of Arthritis & Rheumatism (http://www3.interscience.wiley.com/journal/76509746/home).

Led by Elizabeth Karlson of Brigham and Women’s Hospital and Harvard Medical School, the study involved samples from two large studies involving women: the Women’s Health Study and the Nurses’ Health Study. Researchers analyzed 170 blood samples obtained prior to symptom onset in women who later developed RA and compared them with three controls per case that were randomly chosen and matched for age, menopausal status, hormone use, and day, time and fasting status at the time of collection. They tested for interleukin-6 (IL-6) and tumor necrosis factor α (TNFα), two cytokines (proteins released by the immune system) that are elevated in the serum and joints during active RA. Since TNFα degrades rapidly in stored samples, they used soluble TNF receptor II (sTNFRII) as a surrogate marker for TNFα. They also tested for high-sensitivity C-reactive protein (hsCRP), a biomarker of inflammation.

The results showed that levels of sTNFRII were elevated up to 12 years prior to the development of RA symptoms and were associated with a 2-fold elevation in risk of RA. The authors note that the levels measured during the preclinical period were much lower than those typically seen in patients with active RA, which suggests that few of the women had active joint inflammation at the time the samples were taken. “However, even modest elevations in these biomarkers were predictive in time intervals up to 8 years before the onset of RA symptoms,” they state. Elevated IL-6 levels were also associated with RA, but only less than four years before symptom onset.

Previous studies have detected the presence of preclinical autoantibodies in RA, a finding that has revolutionized thinking about the origins of autoimmune disease. Studies suggest that when a genetically susceptible host is exposed to environmental factors, autoantibody production is triggered; a second event or exposure might trigger the onset of clinical symptoms.  The complex interaction between genes and environmental factors is not yet fully understood, however. “Our findings suggest that during the preclinical phase of autoantibody production, there is immune reactivity, with production of proinflammatory cytokines that are typically seen in symptomatic RA, namely IL-6 and TNF,” the authors state.

The authors suggest that the results of the current study could have implications regarding screening for biomarkers that could be used for RA risk counseling or for targeted interventions to prevent the disease. They note that targeted therapies are being developed to prevent type 1diabetes, another autoimmune disease that is thought to share some genetic risk factors to RA.  They conclude that further studies with repeated blood collections along with assessments of environmental factors prior to RA symptoms may shed light on the pathway by which immune activation progresses to symptomatic RA.

Article:  “Preclinical Biomarkers of Inflammation and Development of Rheumatoid Arthritis in Women From Two Prospective Cohort Studies,” Elizabeth W. Karlson, Lori B. Chibnik, Shelley S. Tworoger, I-Min Lee, Julie E. Buring, Nancy A. Shadick, JoAnn E. Manson, Karen H. Costenbader, Arthritis & Rheumatism, March 2009.