Getting to the heart of CV outcomes in rheumatic disease
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CV events cause substantial morbidity and mortality among patients with rheumatologic diseases. Moreover, a robust body of data chronicles these associations.
It is generally understood that the pathogenesis of CVD in rheumatology is multifactorial and results from the interplay between inflammation, metabolic disease, patient factors such as weight and smoking status, therapeutics and other disease-related issues. But a general understanding and a true ability to parse those myriad influences effectively are two completely different animals.
“These diseases, including psoriasis/psoriatic arthritis, systemic lupus erythematosus (SLE) and rheumatoid arthritis, many times exhibit higher rates of traditional cardiovascular risk such as hypertension, hyperlipidemia and metabolic syndrome. These traditional cardiovascular risk factors can synergistically increase risk in these inflammatory populations,” Michael S. Garshick, MD, director of the Cardio-Rheumatology Clinic, part of the Center for the Prevention of Cardiovascular Disease at NYU Grossman School of Medicine, said in an interview.
The good news is that there is increasing awareness that rheumatology patients are at elevated risk for CV events. However, risk stratification tools used for the general population — including the Framingham and Reynolds risk scores — have proved suboptimal in rheumatology patient populations.
Given these factors, two byproducts would seem reasonable: One is that there should be a broad set of recommendations to follow in managing CV outcomes in patients with rheumatologic diseases; the second is that there should be a clear-cut understanding of how rheumatologic diseases, and the treatments for those diseases, contribute to or mitigate CVD risk.
But neither of those things is the case.
“We do not have a comprehensive, data-driven guideline,” Jon Giles, MD, MPH, associate professor of medicine in the division of rheumatology at the Columbia University Vagelos College of Physicians and Surgeons, told Cardiology Today. “The European League Against Rheumatism has published two guidelines on cardiovascular disease management in rheumatic disease patients, but the level of evidence for most of the recommendations was relatively low, and some of the recommendations have been shown not to improve prediction.”
Garshick said, however, “The American College of Cardiology/American Heart Association now recommends the Pooled Cohort Equation with the incorporation of certain risk enhancers, such as psoriasis/psoriatic arthritis (PsA), SLE, rheumatoid arthritis (RA), high- sensitivity C-reactive protein and even coronary artery calcium score to reclassify cardiovascular risk and encourage the earlier initiation of prevention medications such as statin therapy.”
Thus, clinicians are encouraged to be vigilant in risk factor modification, to work across specialties to keep their patients healthy and to do their best to make sense of a robust, but imperfect, body of data.
Disease-specific associations
“Almost all rheumatic diseases have been associated with higher cardiovascular disease risk,” Giles said. “The best studied are RA and lupus, but there is a growing body of literature on psoriasis, PsA and the other spondyloarthropathies. Cardiovascular events are also higher in many of the vasculitides.”
Historical data have estimated that outcomes like MI and ischemic stroke may be 50% higher in patients with RA compared with the general population, but more recent findings show an improved but still complicated picture.
In a study published in Annals of the Rheumatic Diseases, researchers reported on secular trends in incident ACS risk in RA vs. controls over 5 decades. The results demonstrated reduction, for the first time, in such risk in patients with RA diagnosis in the present decade.
“Indeed, a 40% risk reduction was observed, reflecting improved treatment algorithms and successful awareness campaigns,” George Karpouzas, MD, FACR, investigator at The Lundquist Institute, professor of medicine at the David Geffen School of Medicine at UCLA and chief of the division of rheumatology at Harbor-UCLA Medical Center, said in an interview. “Nevertheless, RA patients still incurred a 40% higher acute coronary syndrome risk, which was restricted to those who were seropositive and had at least moderate disease activity at diagnosis.”
Beyond risk for ACS, Karpouzas said more recent data demonstrate that clinicians treating patients with RA should be aware of a range of other outcomes, including MI, ischemic stroke, HF and venous thromboembolism, all of which are much higher in patients with RA compared with controls.
Regarding lupus, “patients with SLE have a five- to sixfold increased risk of developing cardiovascular disease compared to the general population, with higher risk in young patients,” Karpouzas said.
Ted R. Mikuls, MD, MSPH, Umbach Professor of Rheumatology and vice chair of research at the University of Nebraska Medical Center, said CV events in lupus, in particular, can “put people on their heels,” for one key reason: “You are dealing with young women who you would not normally anticipate having a high-risk cardiovascular disease.”
Regarding spondyloarthritis, a meta-analysis published in Annals of the Rheumatic Diseases showed that MI (RR = 1.38; 95% CI, 1.18-1.61) and stroke (RR = 2.04; 95% CI, 1.11-3.78) were elevated in patients with spondyloarthropathy compared with the general population.
Complicated relationships
Understanding that the diseases may contribute to CV risk is important, but it is only the first part of the equation. The next is understanding which treatments may also contribute to risk, and the extent of that contribution. Unfortunately, there is frequently conflicting evidence.
Results of a 2019 study published in Arthritis Care & Research demonstrated a 30% increased risk for stroke or MI and a 30% increased risk for death in patients with RA taking glucocorticoids.
“The main offender, without question, are corticosteroids,” Giles said. “They have been shown in multiple studies to be associated with atherosclerosis and cardiovascular disease events in proportion to the dose and time of exposure.”
To that point, Karpouzas and colleagues recently published a prospective study of patients with RA with baseline and long-term follow-up coronary atherosclerosis assessments in Arthritis & Rheumatology. Results showed that each additional gram of cumulative prednisone dose used independently was associated with a 6% higher number of coronary segments with plaque, 6% greater stenotic plaque severity and 10% higher CAC score at follow-up.
“Despite the fact that physicians generally prescribe glucocorticoids to patients with higher disease activity, our observations highlight the true deleterious effect of glucocorticoids on the vascular wall, rather than confounding by indication,” Karpouzas said.
But Rekha Mankad, MD, cardiologist and echocardiographer in the department of cardiovascular medicine at Mayo Clinic in Rochester, Minnesota, said there is another side of the glucocorticoid coin.
“Steroid use is not uncommon in rheumatology because of its potent anti-inflammatory effect,” she said. “So, in one way, they are beneficial because of their reduction in inflammation, which we believe is a strong driver of heart disease in these patients.”
Mankad said long-term steroid use is “fraught” with complications that increase CV risk.
“These risks include more potential for weight gain, elevations in blood pressure and salt retention with a potential for lipid abnormalities,” she said.
Another class of drugs with a long history of associations with CVD is NSAIDs.
Mankad described the historic use of NSAIDs as “liberal” among rheumatology patients in the past, noting that this class of drugs has been implicated in increased CVD, but with an important qualification.
“The risk is greater in persons who already have heart disease,” she said.
There may be good news on the horizon, however, according to Mankad.
“Now that there are so many other agents that can be used with these conditions, overall use of NSAIDs has gone down, especially high doses being used chronically,” she said.
Deeper into the armamentarium
The prevailing wisdom is that conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) such as methotrexate and possibly hydroxycholoroquine are beneficial for heart disease largely due to their anti-inflammatory effects. However, data clearly outlining these associations remain elusive.
In the randomized, double-blind, placebo-controlled CIRT trial published in The New England Journal of Medicine,Paul M. Ridker, MD, MPH, Eugene Braunwald Professor of Medicine at Harvard Medical School and the director of the Center for Cardiovascular Disease Prevention at Brigham and Women’s Hospital, and colleagues found low-dose methotrexate did not reduce CV events or levels of interleukin (IL)-1-beta, IL-6, or CRP in patients with a history of MI or multivessel CAD who also had type 2 diabetes or the metabolic syndrome.
“The protective effect, if indeed it is true, seems to be unique to people with underlying inflammation as is seen in RA,” Mikuls said.
Garshick said there are many reasons why CIRT may not have succeeded, and one is that the population was not selected for inflammatory risk.
As for hydroxychloroquine, in a study published in Annals of the Rheumatic Diseases, the drug showed signs it may benefit the metabolic profile and to a lesser extent CV events in patients with RA.
“This suggests its usefulness combined with other csDMARDs,” Karpouzas said.
Increased use of biologic and biosimilar therapies may push csDMARD use to the sidelines. There seems to be cautious optimism surrounding biologic therapies, according to Garshick.
“Meta-analyses have looked at the cardiovascular risk of biologics in the psoriasis/PsA population and they appear safe overall,” he said.
He noted a nonrandomized study published in September in Circulation: Cardiovascular Imaging found that biologic therapy reduced lipid-rich necrotic core, a high-risk coronary plaque feature, in patients with psoriasis.
However, he said, despite there being a correlation between psoriasis severity and vascular inflammation, randomized trials, including one published in Circulation: Cardiovascular Imaging in 2018, have not shown that biologic therapy reduces vascular arterial inflammation in patients with psoriasis.
In a meta-analysis of 26 randomized controlled trials of patients with RA treated with janus kinase (JAK) inhibitors published in Annals of the Rheumatic Diseases, there was no significant change in risk for CV events. However, thromboembolic event risk was elevated among patients treated with both tofacitinib (Xeljanz, Pfizer) and baricitinib (Olumiant, Eli Lilly).
“There has been some concern about the relationship between thromboembolism and high-dose JAK inhibitors in the RA population,” Garshick said.
Mankad also said, “There has also been an implication of biologics resulting in higher cholesterol values.”
Stratifying risk
With many questions surrounding disease-specific associations and therapeutics, clinicians would likely benefit from a risk stratification tool to help guide the way in managing this patient population. But this, too, has proved elusive.
Garshick said comparison studies have shown that traditional scores like Framingham and Reynolds underestimate CV risk in rheumatic conditions ranging from RA to the psoriatic diseases and SLE.
“Even though inflammatory conditions exhibit higher traditional cardiovascular risk factors, which are recognized in traditional cardiovascular risk scores, there is still an independent association between these inflammatory diseases and cardiovascular disease,” he said. “Moreover, in the development and validation of these cardiovascular risk prediction models, inflammatory diagnoses were not accounted for.”
The Reynolds risk score incorporates hsCRP into the equation. Garshick said this should theoretically make it more useful than Framingham for rheumatology patients, but it has not yet been validated in that population.
With these concerns in mind, the medical community has responded to these inaccuracies with a variety of modifications, according to Garshick, who cited the changes to the ACC/AHA guidelines now identifying various rheumatic and inflammatory conditions as risk enhancers for CVD.
However, Mankad said, “Although we call these conditions risk enhancers, we really do not know how much of an enhancer it is in each individual patient.”
EULAR recommends multiplying risk predication models by 1.5 to upgrade CV risk in RA. “But this is still probably inaccurate,” Garshick said. “Joint American Academy of Dermatology-National Psoriasis Foundation guidelines suggest something similar for many psoriasis/PsA patients.”
Garshick said the QRISK2 score for RA and the QRISK3 score, which incorporates SLE and steroid use, can also estimate CV risk.
“Unfortunately, given the heterogeneity of inflammatory diseases, exposure and treatment, it is difficult to capture the impact of varying amounts of underlying inflammation on the degree of atherosclerosis and even impact on thrombosis,” he said. “This is also compounded as we are still trying to grasp mechanistic explanations of what is driving cardiovascular risk in these populations.”
One reason that traditional risk scores fail to be effective is that the relationships between traditional CVD risk factors and atherosclerotic burden are skewed, particularly in RA and lupus, Giles said.
“RA patients have lower LDL cholesterol, on average, than people without RA, and some of them have very low LDL cholesterol, despite having more atherosclerosis burden,” he said. “It is this group of RA patients that has been shown to have a very high rate of cardiovascular events. This was named the lipid paradox.”
Giles and colleagues published a paper showing that these patients had much more coronary atherosclerosis than could be expected from this level of LDL.
“Why this is the case is still unknown, but it probably involves the way that circulating lipids change in the setting of autoimmunity and inflammation that make them less predictive,” he said.
Garshick said researchers have found a link between circulating PCSK9 levels and atherosclerosis in patients with psoriasis, and they have also determined patients with PsA have elevated levels of oxidized-modified lipids.
Fortunately, in the COLCOT and LoDoCo2 trials, the gout drug colchicine showed promise for reducing CV events compared with placebo in patients with residual CVD risk, including inflammatory risk, despite LDL control after treatment with optimal medical therapy. But the extent of benefit in specific rheumatological diseases is not yet known.
In the clinic
M. Elaine Husni, MD, MPH, vice chair of the department of rheumatic and immunologic diseases and director of the Arthritis Center at the Cleveland Clinic, said the level of evidence for these guidelines is problematic. “Of course, I would like to see more prospective, placebo- controlled studies following patients recently diagnosed with a rheumatologic disease to determine when and how they experience cardiovascular outcomes,” she said.
The problem is ethical, according to Husni. “You can’t withhold treatment or treat a patient with placebo in this situation,” she said.
Until a set of guidelines based on randomized controlled trial data emerges, sticking to the basics is the best way to keep patients’ hearts healthy, Husni said.
“Treating to target and lowering systemic inflammation is the first and most important step toward mediating cardiovascular disease risk,” she said.
Garshick said for this purpose, aspirin and statins appear to work particularly well in patients with rheumatic diseases.
There must be further recognition that other parts of the heart, and not just the arteries, can be affected by chronic inflammation, according to Mankad.
“Studies to better identify which of these patients may be at risk for heart failure in the future is important,” she said.
Cross-specialty collaboration is also key between cardiologists and rheumatologists. Husni said hearing messages about diet and exercise from as many health care providers as possible is critical to mitigating CVD.
“We need to work on understanding the mechanism of how low-grade, systemic inflammation can lead to heart disease,” she said. – by Rob Volansky
- For more information:
- Michael S. Garshick, MD, can be reached at michael.garshick@nyulangone.org.
- Jon T. Giles, MD, MPH, can be reached at jtg2122@columbia.edu.
- M. Elaine Husni, MD, can be reached at husnie@ccf.org.
- George A. Karpouzas, MD, FACR, can be reached at gkarpouzas@lundquist.org.
- Rekha Mankad, MD, can be reached at newsbureau@mayo.edu.
- Ted R. Mikuls, MD, MSPH, can be reached at tmikuls@unmc.edu.
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