BOSTON, Massachusetts—Levels of soluble tumor necrosis factor α receptor II (sTNFRII) begin to rise many years before rheumatoid arthritis (RA) becomes symptomatic and might be a useful screening tool to identify people at risk for developing RA,
“Our findings of elevated levels of sTNFRII...among preclinical RA patients with no documented arthritis symptoms supports the hypothesis that RA develops in 3 phases: genetic susceptibility, and preclinical autoimmunity with immune activation followed by clinical symptoms.”—Elizabeth W. Karlson, MD
according to a landmark study in the March issue of Arthritis & Rheumatism.1

A research team led by Elizabeth W. Karlson, MD, of Brigham and Women's Hospital in Boston, Massachusetts, used blood samples from two large prospective women's health studies to determine that:
  • sTNFRII levels are elevated up to 12 years before RA symptoms develop
  • sTNFRII elevation is associated with a 2-fold increase in RA risk
  • elevated interleukin 6 (IL-6) levels are associated with RA, but only less than 4 years before symptom onset.

The sTNFRII 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,” the authors write, “even modest elevations in these biomarkers were predictive in time intervals up to 8 years before the onset of RA symptoms.”

The study involved samples from 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 each case with 3 matched controls. Samples were tested for IL-6, TNFα, and high-sensitivity C-reactive protein (hsCRP). Since TNFα degrades rapidly in stored samples, the researchers used sTNFRII as a surrogate marker for TNFα.

“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,” Dr. Karlson said.

Translating research into practice: RA biomarkers

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 point to the need for further studies with repeated blood collections along with assessments of environmental factors that might be associated with immune activation and progression to symptomatic RA.

“Our findings of elevated levels of sTNFRII (a surrogate soluble receptor used to assess potential TNFα) levels among preclinical RA patients with no documented arthritis symptoms supports the hypothesis that RA develops in 3 phases: genetic susceptibility, and preclinical autoimmunity with immune activation followed by clinical symptoms,” Dr. Karlson concluded.

Reference

1. Karlson EW, Chibnik LN, Tworoger SS, et al. Biomarkers of inflammation and development of rheumatoid arthritis in women from two prospective cohort studies. Arthritis Rheum 2009;60:641-652.