Cardiovascular Disease in Rheumatoid Arthritis

The heart, symbolically and literally, is a subject of introspection and study for humans throughout history. For patients with rheumatoid arthritis (RA) and their rheumatologists, the heart is a cause of concern because patients with RA have an increased risk of heart disease compared with the general population.¹ In fact, RA patients were found to have a higher mortality rate than expected due to cardiovascular disease (CVD).² This increased risk of CVD is attributed to the chronic inflammation associated with the RA.³ A big question facing rheumatologists is what we can do to improve management of heart disease in RA patients. To do so, we need to answer three important questions:

1. How do we estimate risk of CVD in RA?
2. Which interventions decrease CVD risk?
3. What should be the targets of the interventions?

Although we don’t have definitive answers to these questions, this article will provide an overview of what we know so far.

An Educated Guess

Uncle Henry and Aunt Em didn’t need to see the cyclone to know it was coming and to call for Dorothy and run for cover; all they needed was their intuition about the risk of a cyclone approaching based on the signs in weather preceding its appearance. Years of clinical practice provide us with intuition about the risk of heart disease in our patients. However, in an ideal world, we would have hard evidence to back our treatment decisions.

For some patients, aggressive primary preventive therapy (e.g., a target low-density lipoprotein (LDL) of 100 mg/dL) is an obvious goal, regardless of their formal Framingham Risk Score. I recently met a new patient, a 55-year-old man with seropositive RA for five years who has hypertension, is overweight, and is living a sedentary lifestyle. His family history is notable for his father who died of sudden cardiac death at the age of 57. Pertinent findings include his nonsmoking status, a blood pressure of 125/80 mmHg (on antihypertensive therapy), a total cholesterol of 192 mg/dL, and a high-density lipoprotein (HDL) of 40 mg/dL. Although his fasting LDL was 128 mg/dL, a reasonable level according to national guidelines, I started him on a statin drug after his first visit. In most cases, the choice for treatment is not that obvious. My clinical intuition often tells me that a particular patient is at higher risk, but how much higher?

In the United States, there are two main methods for estimating CV risk, the Framingham Risk Score and the Reynold’s Risk Score.^4,5 The Framingham Risk Score, the most established of the two, incorporates risk factors such as total cholesterol levels and blood pressure to estimate the 10-year risk for a coronary event. The Reynold’s Risk Score also includes traditional risk factors but takes into account inflammation with the addition of high-sensitivity C-reactive protein (hsCRP).

Neither method is believed to accurately estimate the risk of heart disease in RA, but both are good starting points. The Framingham Risk Score likely underestimates risk by approximately 50%, largely because inflammation is not taken into account.⁶ The European League Against Rheumatism published their recommendation on estimating CV risk in RA by multiplying a patient’s Framingham Risk Score by 1.5 if a patient has two or more of the following: disease duration greater than 10 years, rheumatoid factor or anticyclic citrullinated peptide antibody positivity, or the presence of extraarticular manifestations.6 This multiplier was developed as a result of evidence-based expert opinion but has not been validated.

The Reynold’s Risk Score, which does incorporate inflammation as a risk factor, includes hsCRP as a risk factor. One of the main issues with applying the Reynold’s risk score to RA patients is that the population where the risk score was developed had a mean hsCRP of 2.0mg/L. In the Brigham Rheumatoid Arthritis Sequential Study, a prospective cohort of approximately 1,100 treated RA patients, the mean CRP was 9.7mg/L, which is consistent with other established RA cohorts and is well above the range of hsCRP levels for which the Reynold’s Risk Score was calibrated.⁷

Preventing Heart Disease

“All the same,” said the Scarecrow, “I shall ask for brains instead of a heart; for a fool would not know what to do with a heart if he had one.”

Fortunately, we have much guidance about how to prevent heart disease in RA based on the wealth of studies in the general population. The first, and perhaps the hardest, intervention is a change in habit: eating a well-balanced diet, exercising on a regular basis, and maintaining a healthy weight. We all know how well that works. Additionally, prevention can be achieved with treatment intervention of the risk factors for heart disease such as angiotensin-converting enzyme inhibitors, statins, and, in some patients, metformin. We also have targets to aim for based on a patient’s risk profile, such as blood-pressure goals (Joint National Committee VII), LDL levels (Adult Treatment Panel III Guidelines), and hemoglobin A1C.

Inflammation in RA is also a risk factor for which we have effective treatments. Would a target for “inflammation” be beneficial in decreasing CVD risk in RA? Should the target be remission, a low CRP level, or lack of swollen joints? Is targeting specific inflammatory pathways more beneficial for CV risk reduction than another? Pursuing answers to these questions is a topic of active research. A recent genetic study suggests that tocilizumab could potentially target a causal pathway for CVD.⁸ Would this be a better drug to use than a tumor necrosis factor (TNF) inhibitor in RA patients at high risk for CVD, even if the TNF inhibitor controlled their RA? Sometimes it feels as if we have more questions than answers.

I believe an important first step beyond aggressively treating RA is to be cognizant of the status of CV risk factors in our patients and to assess whether they are adequately treated, as per national guidelines. I find that I often see my patients more frequently than their primary care physician (PCP) because of their RA. In a perfect world, patients regularly follow up with their PCPs and these risk factors would be well controlled. In reality, very few people visit their PCPs on a regular basis, and some of my patients do not even have a PCP, despite my strong recommendation to establish care with one. We already routinely check blood pressures in our practice. What I have started doing on a regular basis is screening lipids, since I am often ordering monitoring labs for their disease-modifying antirheumatic drug therapy. As a result, I have started a few patients on statins in conjunction with their PCPs.

Deciding on targets for therapy still requires applying some component of the “art” of medicine. As an example, my 55-year-old patient by Framingham Risk Score and Adult Treatment Panel III guidelines had a recommended LDL goal of 130 mg/dL, but none of the risk factor calculations take into account that he has RA. In our practice, we work closely with a group of cardiologists who provide their expert opinion on patients, some of whom, according to guidelines, would not require more aggressive therapy but, by our estimation, seem to require it. As there are no formal guidelines for RA, we use our expert opinion to guide treatment decisions for each individual patient. I also work with the patient’s PCP (if they have one) to help reinforce lifestyle modifications such as smoking cessation and the treatments already prescribed to treat CV risk factors.

Finally, to obtain a historical perspective on why heart disease has come into the spotlight only in recent years, I walked down two offices and asked Ronald Anderson, MD, associate professor in the division of rheumatology, immunology, and allergy at Brigham and Women’s Hospital and Harvard Medical School in Boston, who trained almost everyone in our division, whether heart disease in RA patients was a major concern in the past. To provide me with a point of reference, he said, “In the 1960s and 1970s, patients with RA were often told that there was nothing that could be done for their disease and they should move to a single-floor house.” He also added that high-dose aspirin was a major component of therapy at that time, and this may have been more effective for CVD than for their RA. We have come a long way in terms of treatment options for RA. Although heart disease will always be present, I am hopeful that, in the next decade, excess risk of death from heart disease in RA will also be something that I can say to my trainees used to be seen “back in the day.”

“I shall take the heart,” returned the Tin Woodman, “for brains do not make one happy, and happiness is the best thing in the world.”

Dr. Liao is an instructor in medicine at Harvard Medical School, Brigham and Women’s Hospital in Boston.

References

1. Solomon DH, Karlson EW, Rimm EB, et al. Cardiovascular morbidity and mortality in women diagnosed with rheumatoid arthritis. Circulation. 2003;107:1303-1307.
2. Gabriel SE, Crowson CS, Kremers HM, et al. Survival in rheumatoid arthritis: a population-based analysis of trends over 40 years. Arthritis Rheum. 2003;48:54-58.
3. Del Rincon I, Williams K, Stern MP, Freeman GL, O’Leary DH, Escalante A. Association between carotid atherosclerosis and markers of inflammation in rheumatoid arthritis patients and healthy subjects. Arthritis Rheum. 2003;48:1833-1840.
4. D’Agostino RB, Sr., Grundy S, Sullivan LM, Wilson P. Validation of the Framingham coronary heart disease prediction scores: Results of a multiple ethnic groups investigation. JAMA. 2001;286:180-187.
5. Ridker PM, Buring JE, Rifai N, Cook NR. Development and validation of improved algorithms for the assessment of global cardiovascular risk in women: The Reynolds Risk Score. JAMA. 2007;297:611-619.
6. Peters MJ, Symmons DP, McCarey D, et al. EULAR evidence-based recommendations for cardiovascular risk management in patients with rheumatoid arthritis and other forms of inflammatory arthritis. Ann Rheum Dis. 2010;69:325-331.
7. Iannaccone CK, Lee YC, Cui J, et al. Using genetic and clinical data to understand response to disease-modifying anti-rheumatic drug therapy: Data from the Brigham and Women’s Hospital Rheumatoid Arthritis Sequential Study. Rheumatology (Oxford). 2011;50:40-46.
8. Hingorani AD, Casas JP. The interleukin-6 receptor as a target for prevention of coronary heart disease: A mendelian randomisation analysis. Lancet. 2012;379:1214-1224.