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ORLANDO -- Evidence continues to grow supporting the concept that reducing inflammation in patients with rheumatoid arthritis (RA) will not only improve their articular symptoms but also lower their cardiovascular (CV) risk, a researcher said at the annual meeting of the Florida Society of Rheumatology here.

But more answers are still needed to address questions about whether treating that inflammation will influence CV outcomes, according to Daniel H. Solomon, MD, of Harvard Medical School and Brigham and Women's Hospital in Boston.

Almost 2 decades of data have demonstrated that inflammation plays an important role in the development of CV disease, such as that included 15,000 healthy men and showed that those who had high levels of the pro-inflammatory cytokine interleukin (IL)-6 were at increased risk of subsequent myocardial infarction (MI).

"In the general population this has been found over and over again, including in a of 54 studies looking at the relationship of inflammatory C-reactive protein and coronary heart disease and vascular deaths," Solomon said.

"Fast forward to 2017 to the , in which Paul Ridker hypothesized that blocking IL-1 would reduce the risk of cardiovascular disease." In that study, there was a 15% reduction in CV events over 5 years, "which was a relatively small reduction but proof of concept that if you use a drug [canakinumab, Ilaris] that has no impact on traditional risk factors, lipids, blood pressure, or diabetes, you could actually have a reduction in CV risk."

Meanwhile, as the importance of inflammation in the pathogenesis and progression of RA became clearer, the effects of reducing inflammation beyond the joints in RA was coming into focus. As early as 2003, Solomon and his colleagues reported that, in the , the risk of MI was doubled among women with RA. "If these data are confirmed, aggressive coronary heart disease prevention strategies should be tested for persons with rheumatoid arthritis," the team wrote in Circulation.

Another major concern in the growing awareness of CV risk in RA has been the need for accurate risk stratification. "We all grew up with the Framingham risk score, but that underestimates the risk in RA," Solomon pointed out.

To develop a more suitable risk score for RA, therefore, he and his colleagues from the Consortium of Rheumatology Researchers of North America Registry developed a specific to RA. In a study cohort of more than 23,000 patients, RA-specific variables that improved the accuracy of discrimination included a Clinical Disease Activity Index above 10, a Health Assessment Questionnaire disability index higher than 0.5, daily prednisone use, and disease duration of 10 years or more.

"Use of this risk tool meant that 17% more RA patients would have their CV risk correctly classified," he observed.

So for a typical patient -- a 50-year-old woman with 12 months of hand pain and morning stiffness, who has hypertension and is overweight but has no known coronary artery disease -- the question has become should her cardiovascular profile influence the decision of what medications to use, because the risks clearly differ among the various drugs used for RA, according to Solomon.

"The answer is probably yes, but we need more information. Inflammation predicts atherosclerosis, but it's still unclear if treating inflammation in RA reduces CV risk. It likely does, but I'm an evidence-based practitioner and I want to see that trial that shows me that."

A tool to help address that question is (18)F-fluorodeoxyglucose positron emission tomography with computed tomography co-registration , which measures aortic inflammation and can be used to identify correlations with clinical response to treatment. "This is a great marker for vascular inflammation and has a strong association with CV endpoints," he said.

Accordingly, he and his colleagues have begun enrolling patients in a study known as TARGET (Treatments Against RA and Effect on FDG PET/CT), which will involve open-label comparison of tumor necrosis factor inhibitor therapy versus triple therapy (methotrexate, hydroxychloroquine, and sulfasalazine) for 24 weeks. Thus far, 53 patients have been enrolled, with a goal of 200 from 35 sites.

The primary endpoint will be the difference in change in FDG PET/CT between the treatment arms, to clearly determine whether joint inflammation in RA correlates with vascular inflammation.

TARGET's clinical protocol states: "This study seeks to answer the fundamental but as yet unproven hypothesis guiding most CV-related research in RA, that chronically elevated levels of inflammation (either systemic, vascular, or both) in RA patients compared to the general population is the main risk factor predisposing to increased rates of CVD. The most critical unanswered question about CV risk in RA populations is whether anti-inflammatory disease-modifying anti-rheumatic drugs for RA also reduce CVD, which this study will assess using a surrogate measure of CV inflammation."

"Enroll your patients!" Solomon exhorted the audience members.

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