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ATLANTA - New data presented this week at the American College of Rheumatology Annual Scientific Meeting in Atlanta show that systemic inflammation and rheumatoid arthritis disease activity may contribute to the progression of atherosclerosis in people with RA. The data also show that this progression may be modified favorably by TNF inhibitors and detrimentally by glucocorticoids.

"These data suggest that by limiting inflammation in RA patients, you can potentially limit the rapidity of accumulation of—at least—carotid atherosclerosis, which is what our study looked at," says Jon T. Giles, MD, MPH; assistant professor of medicine in the Division of Rheumatology at Johns Hopkins and lead investigator in the study. "And because carotid atherosclerosis tends to be correlated with coronary atherosclerosis, then potentially you would have fewer cardiovascular events like myocardial infarction and stroke in RA patients. These links with subclinical atherosclerosis make intuitive sense, but they haven't [previously] been shown in prospective studies."

Rheumatoid arthritis is a chronic disease that causes pain, stiffness, swelling, and limitation in the motion and function of multiple joints. Though joints are the principal body parts affected by RA, inflammation can develop in other organs as well. An estimated 1.3 million Americans have RA, and the disease typically affects women twice as often as men.

Coronary and extra-coronary atherosclerosis—the buildup of plaque in the artery walls—are increased in people with RA, when compared to people without the disease. However, few studies have explored predictors of change in atherosclerosis in RA patients. In a study funded in part by the ACR Research and Education Foundation, researchers recently addressed this by following 158 people with RA who were already enrolled in a study of cardiovascular disease in RA.

They focused on monitoring intima-medial thickness - the thickness of artery walls that is used in diagnosing atherosclerosis. Participants underwent an ultrasound of their common and internal carotid arteries (arteries that provide blood to the head and neck) at the first and third study visits, which were an average of 3.2 years apart. Through this, researchers found that the thickness of the common carotid artery walls increased over time in 82 percent of the participants and the thickness in the internal carotid artery walls increased in 70 percent of the participants.

When the researchers adjusted their data to consider demographics, cardiovascular risk factors, and the thickness of the carotid artery walls at the beginning of the study, they found that those participants who used anti-TNF treatment at the beginning of the study had a 37 percent lower rate of progression of the thickness of the common carotid artery walls than those who did not use anti-TNF treatment. They also noted that the adjusted average yearly change in the thickness of the common carotid artery walls was significantly higher for patients earlier in their RA when compared to those who had the disease longer.

When looking at thickness in the internal carotid artery walls, prednisone exposure was the only RA feature researchers associated with progression of atherosclerosis after adjusting the data to consider demographics, cardiovascular risk factors and thickness of the internal carotid artery walls at the beginning of the study. And, this rate was significantly lower in participants who were prescribed statins at the beginning of the study.

"There seem to be some medications used in RA that can either be protective or can promote atherosclerosis," Dr. Giles says. "Prednisone may be more associated with progression of atherosclerosis in some vascular beds, but medications like TNF inhibitors and statins that are taken to lower cholesterol may limit atherosclerosis in these patients."

Finally, researchers noted that those participants with a higher than average number of swollen joints and a higher than average c-reactive protein were independently and significantly associated with incidence of plaque.

The next step for researchers is to conduct interventional studies that randomize patients to receive one medication or another and determine the direct cause-and-effect relationship between the medications and the progression of atherosclerosis, either in coronary artery circulation or the carotid artery circulation.

"Those studies are in the planning stages," Dr. Giles says. "They are big studies and hard to organize, but they're really required to determine what the role of the medications are in terms of protection."

The American College of Rheumatology is an international professional medical society that represents more than 8,000 rheumatologists and rheumatology health professionals around the world. Its mission is to advance rheumatology. The ACR/ARHP Annual Scientific Meeting is the premier meeting in rheumatology. For more information about the meeting, visit Follow the meeting on twitter by using the official hashtag: #ACR2010.


Editor's Notes: Jon T. Giles, MD, MPH will present this research during the ACR Annual Scientific Meeting at the Georgia World Congress Center at 4:30 PM on Wednesday, November 10 in Room A 314. Dr. Giles will be available for media questions and briefing at 8:30 AM on Monday, November 8 in the on-site press conference room, B 212.

Learn more about living well with rheumatic disease as well as rheumatologists and the role they play in health care. Also, discover how the ACR Research and Education Foundation's Within Our Reach: Finding a Cure for Rheumatoid Arthritis campaign is accelerating RA research.

Presentation Number: 2162

Longitudinal Predictors of Progression of Subclinical Carotid Atherosclerosis in Rheumatoid Arthritis

Jon T Giles, MD
(Rheumatology, Johns Hopkins University, Baltimore, MD)

Wendy Post
(Johns Hopkins University, Baltimore, MD)

Roger S Blumenthal
(Johns Hopkins University, Baltimore, MD)

Joseph Polak
(Tufts-New England Medical Center, Boston MA)

Michelle A Petri
(Johns Hopkins University, Baltimore, MD)

Allan C Gelber, MD
(Johns Hopkins University, Baltimore, MD)

Moyses Szklo
(Johns Hopkins University, Baltimore, MD)

Joan M Bathon, MD
(Div of Rheumatology, Johns Hopkins University, Baltimore, MD)

Background: Coronary and extra-coronary atherosclerosis are increased in rheumatoid arthritis (RA) relative to controls; however, few longitudinal studies have explored predictors of change in atherosclerosis in RA patients.

Methods: Men and women with RA enrolled in ESCAPE RA, a cohort study of subclinical cardiovascular (CV) disease in RA, underwent bilateral B-mode ultrasonography of the common (CCA) and internal (ICA) carotid arteries at the first and third study visits, separated by an average of 3.2±0.3 years. Multivariate linear or Poisson regression, as appropriate to the outcome, were used to explore the associations of baseline and cumulative demographic, lifestyle, and RA disease and treatment characteristics with the average yearly change in maximal intima-medial thickness (IMT) of the CCA and ICA, and incident or progressive carotid plaque (defined as newly identified plaque or progression in plaque stenosis). Baseline scans were reanalyzed concurrent with follow-up scans, to control for interpretive drift.

Results: A total of 158 RA patients [36% male; mean baseline age=59±8 years; median baseline RA duration=8.5 years; median baseline DAS28=3.6] underwent carotid scanning at both time points. CCA-IMT increased over time in 82% of patients (median yearly increase=16 µm; p<0.001) and="" ica-imt="" increased="" in="" 70%="" of="" patients="" (median="" yearly="" increase="25" âµm;=""><0.001). after="" adjusting="" for="" demographics,="" cv="" risk="" factors,="" and="" baseline="" imt,="" baseline="" tnf="" inhibitor="" use="" was="" associated="" with="" a="" 37%="" lower="" rate="" of="" cca-imt="" progression="" vs.="" non-users="" (14="" vs.="" 22="" âµm/year;="" p="0.026:" figure,="" panel="" a).="" the="" adjusted="" average="" yearly="" change="" in="" cca-imt="" was="" significantly="" higher="" for="" patients="" with="" earlier="" ra="" compared="" with="" those="" with="" longer="" duration="" disease="" (figure,="" panel="">

Figure:Adjusted Yearly Rate of Change in CCA-IMT According to (A)Baseline TNF Inhibitor Use and (B) RA Duration

For ICA-IMT, cumulative prednisone exposure was the only RA feature associated with progression [1.2 µm per year per gram increase in cumulative dose (95% CI 0.1, 2.4)] after adjustment. This rate was significantly lower in patients prescribed statins at baseline. Any plaque was identified in 104 patients (68%), with 13 of these (12%) demonstrating new or progressive plaque during follow-up. After demographic and CV risk factor adjustment, higher average swollen joint count (SJC) and higher average CRP were significantly and independently associated with incident or progressive plaque. Cumulative CRP and SJC were both more strongly associated with plaque progression than cross-sectional levels obtained at the time of scanning. Other RA disease and treatment characteristics were not associated with plaque progression.

Conclusions: These prospective data provide evidence for systemic inflammation and RA disease activity as a contributor to progression of atherosclerosis in RA patients. Further, they suggest that atherosclerosis progression in RA may be modified favorably by TNF inhibitors and detrimentally by glucocorticoids.

Disclosure: Jon Giles: Nothing to disclose; Wendy Post: Nothing to disclose; Roger Blumenthal: Nothing to disclose; Joseph Polak: Nothing to disclose; Michelle Petri: Nothing to disclose; Allan Gelber: Nothing to disclose; Moyses Szklo: Nothing to disclose; Joan Bathon: Nothing to disclose.

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