Adding to a growing body of evidence indicating that rheumatoid arthritis (RA) patients are at unusually high risk for cardiovascular (CV) death, new research suggests that signs of systemic inflammation in these patients may predict CV mortality, independently of traditional risk factors.1 The new study appearing in the March issue of Arthritis & Rheumatism shows that higher erythrocyte sedimentation rate (ESR) values, as well as chronic vasculitis and lung disease, were independent predictors of CV death, even after controlling for numerous RA comorbidities and risk factors such as coronary heart disease (CHD) and hypertension.
"We have known for some time that RA patients have an increased risk of death compared to age-matched, non-RA controls, and we have also known that this increase in death is cardiovascular in nature," lead study researcher Sherine Gabriel, MD, chair of the department of health sciences research and professor of medicine and epidemiology at the Mayo Clinic in Rochester, Minnesota, tells CIAOMed. "What is somewhat novel here is that markers of systemic inflammation confer a significant risk for cardiovascular death, even after controlling for traditional cardiovascular risk factors." However, Dr. Gabriel added that while the new study provides "more evidence" that the inflammatory burden that characterizes RA may carry added CV risk, "it is still not perfectly direct."
The new study comprised 603 RA patients from a Rochester, Minnesota, cohort with a mean age of 58 years. During a mean follow-up of 15 years, 354 patients died and CV disease was the primary cause of death in 176 patients. Personal history of CHD, smoking, hypertension, low body mass index (BMI), and diabetes mellitus, as well as various RA comorbidities (peripheral vascular disease, cerebrovascular disease, chronic pulmonary disease, dementia, ulcers, malignancies, renal disease, liver disease, and history of alcoholism), were all significant risk factors for cardiovascular death.
When researchers controlled for these variables, they found that the risk of CV death was significantly higher among RA patients with at least 3 recorded ESR values of ≥60 mm/hour (hazard ratio [HR] 2.03), as well as those with RA-associated vasculitis (HR 2.41) and lung disease (HR 2.32).
The study was unable to track use of NSAIDs, notable for their suspected effects on CV health, and DMARDs such as methotrexate. However, anti-inflammatory corticosteroids commonly used to control inflammation were found to increase risk for CV death in RA patients with no history of CHD (HR 1.78), even after controlling for traditional CV risk factors and RA comorbidities. Consistent with another study, however, the data indicate that corticosteroids may actually have a cardioprotective effect in RA patients with a history of CHD.
Is careful control the answer?
More attention to CV risks is clearly indicated for RA patients, Dr. Gabriel emphasizes. "When someone has a serious chronic illness like RA, it tends to consume their health care...they are worried about their joints and function. But patients and doctors need to focus even more on cardiovascular health "just as we do in diabetes."
She notes that "10 to 15 years ago, diabetes was not so tightly controlled, and now we see that [careful control] does result in improved outcomes." She suggests that the same may be true in RA, although "controlling inflammation is more difficult than controlling blood sugar and can have side effects, so it's a more difficult path. We have drugs that control inflammation, but that also increase risk of cardiovascular disease."
Ultimately, Dr. Gabriel says, more information is needed. "If we controlled inflammation more tightly, could we decrease long-term risk? That is the question raised by these data and it's an important question to answer."
Vigilant and aggressive treatment
Mary Chester Wasko, MD, MSc, associate professor of medicine at the University of Pittsburgh in Pennsylvania, echoed this question at the American College of Rheumatology Innovative Therapies in Autoimmune Diseases conference in Washington, DC.
"The remaining issues in my mind are, to what extent the systemic inflammation of underlying RA is driving the accelerated atherosclerotic cardiovascular events seen in these patients? And how are other factors at play, such as the adverse effects of RA medications that increase the burden of traditional risk factors for cardiovascular disease?" Dr. Wasko tells CIAOMed.
As hypertension is a known consequence of both nonsteroidal anti-inflammatory drugs (NSAIDs) and prednisone, rheumatologists must "be vigilant about aggressively treating known cardiovascular risk factors, including hypertension, hyperlipidemia, diabetes, sedentary lifetsyle and smoking," she says. "We must do what we can to minimize risk in a group already known to be at high risk."
Dr. Wasko also points out that as rheumatologists tend to see these patients most frequently, the responsibility falls to them to educate primary care physicians about the increased risk of cardiovascular mortality in RA patients.
Corroborative Data
In other analyses of the same Rochester cohort, researchers reported that RA patients have approximately twice the risk of congestive heart failure (CHF) as their non-arthritic counterparts, but also that they are at higher risk for unrecognized heart disease and much less likely to complain of angina pectoris.2 The authors of these studies also arrive at the conclusion that this heightened risk of CV disease may be attributed to the systemic inflammation that characterizes RA rather than to traditional risk factors.
Ongoing studies aim to identify other biomarkers for increased CV risk, as well as assess the value of early screening tests for cardiac function. Additionally, studies are being undertaken that seek to determine the cause of the increased risk of CHF3 seen in RA patients, Dr. Gabriel reports.
References
- Maradit-Kremers H, Nicola PJ, Crowson CS, et al. Cardiovascular death in rheumatoid arthritis: A population-based study. Arthritis Rheum. 2005;52:722-732.
- Maradit-Kremers H, Crowson CS, Nicola PJ, et al. Increased unrecognized coronary heart disease and sudden deaths in rheumatoid arthritis: a population-based cohort study. Arthritis Rheum. 2005;52:402-411.
- Nicola PJ, Maradit-Kremers H, Roger VL, et al. The risk of congestive heart failure in rheumatoid arthritis: a population-based study over 46 years. Arthritis Rheum. 2005;52:412-420.