Cardiovascular Risks in RA: Current Challenges and Future Directions

There are substantial data linking cardiovascular diseases (CVDs) to heightened mortality among patients with rheumatoid arthritis (RA). In particular, research has identified a relationship between RA and traditional cardiovascular (CV) risk factors, subclinical atherosclerosis, arrhythmias, and coronary calcifications.¹

Despite this knowledge, there are still myriad challenges in assessing the true CV risk in patients with RA. According to research published in Clinical Reviews in Allergy and Immunology,¹ even recommendations set forth by the European League Against Rheumatism,² which encourage physicians to use a 1.5-fold multiplication when assessing CV risk in RA, still underestimate CV risk.

Challenges in Current Algorithms

Detailed in a 2009 study published in the Annals of the Rheumatic Diseases, 18 members of the European League Against Rheumatism Standing Committee for Clinical Affairs developed a set of evidence-based recommendations for management of CV risks in RA, ankylosing spondylitis, and psoriatic arthritis.² Ten recommendations were developed, the strength of which was highest for patients with RA. Although the researchers ultimately concluded that the “clear relationship between disease activity and CVD underlines the importance of tight disease control,” Dr Cutolo and colleagues emphasize that this understanding is not enough.

“Current algorithms for CV risk stratification in RA still remain tailored [to the] general population,” wrote Maurizio Cutolo, MD, Director of Research Laboratories and the Academic Division of Clinical Division of Rheumatology in the Department of Internal Medicine at the University of Genoa in Genoa, Italy, and colleagues.¹ “Regrettably, this leads to a significant underestimation of the actual risk in this particular setting of patients.”

A 2017 study published in Current Rheumatology Reports³ examined guidelines, recommendations, and evidence to synthesize 3 potential strategic approaches to CV risk management in RA: (1) an RA-centric approach to treatment and medication management, (2) a comprehensive assessment of individual risk using calculated risk scores, and (3) management of CV risk factors through a clinic population-based model.

In particular, author Christine M. Bartels, MD, MS, Assistant Professor at the University of Wisconsin School of Medicine and Public Health in Madison, Wisconsin, and colleagues³ highlighted the American College of Cardiology/American Heart Association atherosclerotic CVD risk calculator: However, they noted that “this tool does not take into account RA-specific concerns including disease activity, glucocorticoids, or interactions that raise CVD risk.” Even prediction tools that are RA-specific—for example, the Extended Risk Score-RA and A Transatlantic Cardiovascular Risk Calculator for RA—have been utilized only “with varying success.”³

In an article published in Trends in Cardiovascular Medicine, Katherine P. Liao, MD, MPH, of the Division of Rheumatology, Immunology, and Allergy at Brigham and Women’s Hospital in Boston, Massachusetts, pointed out that CV management in RA is far from an exact science.⁴

“One of the major challenges to understanding CV risk in RA is accurately defining the at-risk population,” Dr Liao wrote.⁴ “The excess CV risk in RA is attributed to inflammation; however, current methods to assess CV risk cannot account for long term exposure to inflammation.” Traditional risk assessment tools, including the Framingham Risk Score and the Reynolds Risk Score, significantly underestimate CV risk in RA.

“Based on the evidence available today, CV management in RA patients remains an art of combining general population-based guidelines with expert opinions,” wrote Dr Liao. She suggests that future research focus on the “interrelationship between inflammation and traditional CV risk factors … and how this relationship may differ from the general population.”⁴

Cost-Effectiveness of Screening

Despite the challenges in current screening methods, Wietske Kievit, PhD, of the Department for Health Evidence at Radboud University Medical Center in Nijmegen, The Netherlands, found that screening for CV risks in RA was cost-effective.⁵

In total, 182 consecutive patients with RA, but without known CVD were screened for CV risk based on age, smoking status, blood pressure, high-density lipoprotein cholesterol, and total cholesterol level. Ten-year risks for myocardial infarction or stroke for each patient were calculated, and yearly probabilities were simulated. In 82% of simulations, screening was dominant, suggesting that screening for CV risks “result[ed] in a cost savings and a [quality-adjusted life year] gain, as compared [with] no screening.”⁵

This study was one of the first to show that screening, and subsequent statin intervention, is cost-effective and cost-saving. This cost-effectiveness may be increased by accurately identifying patients with RA who are high-risk and in need of preventive therapy.⁵

Identifying Possible Screening Targets

Researchers have proposed potential alternative targets that clinicians can screen for when assessing CV risk in RA. Dr Cutolo and colleagues, for example, examined the genetic, metabolic, and inflammatory mechanisms that should be taken into consideration when screening patients for CV risk in RA.¹

There are “several lines of evidence” that “underline the critical role of common susceptibility genes in determining the increased CV risk in [patients with RA],” in particular, the discovery of numerous disease-associated single-nucleotide polymorphisms present in both RA and CVDs. Additionally, at least 2 variants of tumor necrosis factor-a (rs1800629 and 1799964) have been associated with RA and related CV complications, as well as tumor necrosis factor-b, osteoprotegerin, and CD40/CD40 ligand.¹

Dr Cutolo and colleagues also suggested screening for markers of metabolic syndrome, including pro-inflammatory cytokines, adiponectin, leptin, and visfatin.¹ Dyslipidemia is a frequent finding in patients with RA; active RA has been linked with a “lipid paradox” phenomenon, in which these patients see a reduction in both low-density and high-density lipoprotein. However, patients with RA are more likely to have pro-inflammatory high-density lipoprotein, which results in low-density lipoprotein oxidation, foam cell formation, and the accelerated enlargement of atherosclerotic plaques.

Finally, Dr Cutolo and colleagues suggested that the gut microbiome may be a “critical player” in autoimmune disease and CVDs. In particular, the dental and salivary microbiomes may carry increase serum markers of RA. One common feature of both RA and atherosclerotic CVD is the presence of oral bacteria within the gut microbiome. However, experimental models are needed to fully “elucidate whether a specific microbiota composition may have a pathophysiological role in determining CV risk in RA patients.”¹

Dr Liao pointed out that carotid intima media thickness (cIMT) has been explored as a potential way to better identify patients with RA who may be at an elevated risk for CV conditions.⁴ Although one meta-analysis found an increased cIMT in patients with RA compared with control patients and another noted that elevated levels of inflammation are associated with increased cIMT, only 1 study of 47 patients has been published showing the relationship between cIMT and future CV events in this patient population.⁴

Continued Research Is Needed

One thing that the current literature agrees on is that future studies are needed to further clarify the interplay between inflammation, CV risks, and RA.

“The increased CV risk due to RA is determined by several factors, including genetic background, metabolic status, gut microbiome, and systemic inflammation,” wrote Dr Cutolo and colleagues.¹ The researchers noted the importance of a deeper understanding of the pathways that underlie the “pro-atherosclerotic environment which characterizes RA.”¹

“Future directions … include examining the interrelationship between inflammation and traditional CV factors … and how this relationship may differ from the general population,” Dr Liao concluded.⁴ “RA is a human model of inflammation where the levels of inflammation are exaggerated compared to the general population. The higher levels of inflammation serve as a magnifying glass, providing more power to study the pathways and mechanisms of inflammation that impact CVD.”

References

1. Carbone F, Bonaventura A, Liberale L, et al. Atherosclerosis in rheumatoid arthritis: promoters and opponents [published online September 26, 2018]. Clin Rev Allerg Immunol. doi: 10.1007/s12016-018-8714-z

2. Peters MJL, Symmons DPM, 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(2):325-331. doi: 10.1136/ard.2009.113696

3. Chodara AM, Wattiaux A, Bartels CM. Managing cardiovascular disease risk in rheumatoid arthritis: clinical updates and three strategic approaches. Curr Rheumatol Rep. 2017; 19(4):16. doi: 10.1007/s11926-017-0643-y

4. Liao KP. Cardiovascular disease in patients with rheumatoid arthritis. Trends Cardiovasc Med. 2017; 27(2):136-140. doi: 10.1016/j.tcm.2016.07.006

5. Kievit W, Maurits JSF, Arts EE, van Riel PLCM, Fransen J, Popa CD. Cost-effectiveness of cardiovascular screening in patients with rheumatoid arthritis. Arthritis Care Res. 2017; 69(2):175-182. doi: 10.1002/acr.22929