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Study Identifies Six Biomarkers for Cardiovascular Disease Risk Among Rheumatoid Arthritis Patients

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NEW YORK – Six biomarkers found in the blood appear to improve the prediction of risk for cardiovascular disease (CVD) among people with rheumatoid arthritis (RA).

These biomarkers could help better assess cardiovascular risk in a population where CVD is the leading cause of death. Traditional risk models, which rely on factors like age, cholesterol levels, and smoking status, tend to underestimate CVD risk in people with RA, a common form of autoimmune inflammatory arthritis that is known to increase CVD risk.

"Accurate risk scores are really helpful for considering who should get preventive therapy and who should get more intensive diagnostics," Daniel Solomon, professor of medicine at Harvard Medical School, said. "Currently, the general population risk scores don't work so well in RA patients."

Although some studies have shown that these estimates improve with the inclusion of additional clinical factors, Solomon said that most investigators believe that more biomarkers are needed to improve the accuracy of these risk scores among RA patients. In a study published last month in the Journal of the American Heart Association, he and his colleagues sought to expand this pool of biomarkers.

In that paper, they used data from the Treatments Against RA and Effect on FDG PET/CT (TARGET) trial, which was designed to compare the effects of two different treatment strategies on fluorodeoxyglucose positron emission tomography-computed tomography (FDG PET/CT) scans, a sensitive means of detecting arterial inflammation, among 109 participants with active RA.

For the biomarker analysis, Solomon and his colleagues also measured the concentrations of 24 candidate biomarkers known to be associated with RA and systemic inflammation, including cytokines, lipids, and leptins, at baseline and then six months later, and compared them to the imaging results of patients' arteries, which can reflect risk of cardiovascular events.

While numerous other studies have sought biomarkers of CVD among the RA patient population, Solomon said the TARGET study differentiated itself by evaluating a broad range of potential markers with relevant known associations.

"Most studies have looked at [one to three] biomarkers at a time or a huge panel," Solomon said. "We looked at 24 candidate biomarkers that all had prior literature supporting their relationship to RA and CVD."

The team found that six of these biomarkers –– serum amyloid A, C‐reactive protein, soluble tumor necrosis factor receptor 1, adiponectin, YKL‐40, and osteoprotegerin –– did, in fact, associate with higher CVD risk, as measured by changes in arterial inflammation. Further, adding these biomarkers to clinical variables from the pooled cohort equation, a standard tool for estimating a person's 10-year CVD risk, improved the researchers' ability to predict increases in arterial inflammation, as compared to standard clinical indices like the Framingham Risk Score.

"This is a good first step in the discovery process to identify biomarkers that might be useful in improving prediction of cardiovascular events in patients with rheumatoid arthritis," Cynthia Crowson, professor of biostatistics and medicine at the Mayo Clinic, said via email.

Crowson added that while some of the biomarkers identified by Solomon and his team were not surprising, as they have a known association with CVD, their usefulness in predicting long-term risk of CVD still remains an open question.

"It would be helpful to predict events that will happen further in the future, as this gives more time for interventions that could prevent those events from happening," she said. "So more research regarding how far [into] the future these biomarkers can predict future cardiovascular events is needed."

Solomon said that his group is now further assessing the predictive performance of these biomarkers in a larger study.

"We have a current study trying to replicate these results in a different cohort of patients with RA," he said.

In particular, he and his team are in the midst of testing their biomarkers in a cohort of approximately 1,500 RA patients from the Brigham and Women's Rheumatoid Arthritis Sequential Study (BRASS), which has been running since 2003 and whose participants have provided annual biosamples available for study.

"We have just finished confirming cardiovascular events and are now moving on to the measurement of biomarkers," Solomon said.

Beyond testing the associations between the six biomarkers and arterial inflammation, this larger study will also allow researchers to get an idea of whether the biomarkers can actually help predict future cardiac events such as heart attack or stroke.

Crowson also noted that while the use of clinical trial data strengthened Solomon's findings, the fact that all patients in that study had active RA might limit their generalizability.

Solomon said that although he does not currently have plans to study populations without RA, "this may be a good idea in the future."

While RA biomarker tests are commercially available and often incorporate some of the biomarkers identified in the current study, relatively few are specific for the risk of CVD. Labcorp, for example, acquired the Vectra with CV Risk assay from Myriad Genetics in 2021. That assay comprises 12 analytes, four of which are included in the Harvard team's panel: TNFR-1, YKL-40, CRP, and serum amyloid A.

Solomon said his team has not yet filed any patents related to this new biomarker panel but said that if it proves to work in downstream studies, he and his colleagues might consider developing a commercial test.

Crowson noted that while much remains to be done in terms of finding reliable biomarkers of CVD for people living with RA, "this study is a good first step in biomarker discovery."