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Observation and research have confirmed that patients with rheumatoid arthritis (RA) are at greater risk of cardiovascular disease than their peers of similar age and gender, and that traditional risk factors and chronic inflammation associated with RA apparently play a significant role in that risk. However, predicting which patients with rheumatoid arthritis are at greater risk of cardiovascular events and understanding the effects of RA therapies on risk are not known, but published and ongoing research efforts are exploring possible answers.
One dilemma is why traditional risk factors, such as lipids, don’t seem to always be predictive of which patients with RA are at greater risk of cardiovascular events. In some trials, certain therapies lower inflammation but also increase total cholesterol and LDL cholesterol, but whether those increases are clinically important is not understood. Additionally, no validated methods exist that can factor inflammation into the cardiovascular risk equation in RA, according to an editorial by Katherine Liao, MD, MPH, and Daniel Solomon, MD, MPH, in the February issue of Arthritis & Rheumatology.1
According to the authors, the analysis indicated that several baseline characteristics were independently associated with a greater risk of cardiovascular events: a history of cardiac disorders, age at baseline, the baseline atherogenic index and baseline RA disease activity as assessed by DAS28.
After 24 weeks of TCZ therapy, those patients who had greater reductions in their disease activity had a statistically significantly lower risk of events. Disease activity was assessed by increases in DAS28, swollen joint count and tender joint count from baseline to Week 24. Those patients who had less robust therapeutic responses to TCZ from baseline to Week 24 were at higher risk of events, the authors said.
An increasingly recognized paradox for physicians treating patients with RA is that cholesterol is inversely related to risk of cardiovascular disease in patients with RA who are not treated.
The baseline and Week 24 levels of the markers of inflammation (i.e., erythrocyte sedimentation rate [ESR] and C-reactive protein changes) were also evaluated. Changes in the IL-6 level and the ESR were not statistically significantly associated with future development of major cardiovascular events over 24 weeks of therapy.
Treatment with TCZ elevated lipid levels among the patients included in the pooled data. Mean lipid levels increased by 16%, LDL cholesterol by 19%, HDL cholesterol by 7% and triglycerides by 26%. Those changes usually occurred in the first few weeks of treatment and then remained stable during long-term therapy. The increases were seen as a normalization of lipids as inflammation decreased.
The lipid changes were of greater magnitude than elevations reported with other anti-inflammatory agents, the researchers said, but those increases were also not statistically significantly associated with future development of cardiovascular events, they concluded.
According to the researchers, a “direct association regarding the long-term effect of TCZ treatment on [cardiovascular disease] cannot be determined, given that the time during placebo treatment was limited in these trials; therefore, no robust comparison of [major adverse cardiovascular events] risk in placebo-treated patients is possible.”
Inflammatory Burden & Risk
Drs. Liao and Solomon, in commenting about the Rao research in their editorial, said that the statistical power of the study to determine that total cholesterol and LDL levels at Week 24 were not associated with an increased risk of CV events was “limited.”
Dr. Solomon
In an interview, Dr. Solomon, professor of medicine at Harvard Medical School and chief of the Section of Clinical Sciences and Division of Pharmacoepidemiology and Pharmacoeconomics at Brigham & Women’s Hospital in Boston, elaborated on that comment. “There are decades of literature telling us that total cholesterol and LDL levels are bad,” he says. “One should not come away from this paper thinking that you shouldn’t have a concern about the cholesterol issue or that with a response to tocilizumab that patients are safe from the cardiovascular standpoint. That’s an overreach.”
Dr. Liao, assistant professor at the Harvard Medical School and a rheumatologist at Brigham & Women’s Hospital, says that Rao and colleagues examined the association between a change in lipids; for example, an increase in LDL between baseline and 24 weeks, with a CV event occurring after 24 weeks. The mean duration of TCZ treatment in the study was 1.8 years.
“The authors had only a mean of approximately 1.3 years to assess whether the changes in lipids for patients on tocilizumab were related to CV risk in any way,” she says. “Even in populations at high risk for CVD, when assessing for a link between lipids and CV risk, you would either need more follow-up time or more people than were in the study.”
According to Dr. Solomon, the authors in the Rao study “examined the change in DAS28 after 24 weeks on TCZ as a potential correlate of cardiovascular risk. In adjusted models, they found that greater reductions in disease activity after starting TCZ were associated with a lower risk of cardiovascular events. It is unclear if this association is specific for TCZ or would hold for other effective RA treatments. A randomized controlled trial comparing the effects on cardiovascular risk for effective RA treatment strategies is a critical need in our field,” he says.
He and Dr. Liao note that an ongoing phase IV trial is looking into these issues. The clinical outcomes study is evaluating the rate of primary major adverse cardiac events, a composite of cardiovascular death, nonfatal myocardial infarction and nonfatal stroke, in patients with moderate to severe RA who are being treated with either TCZ or etanercept. The randomized, open-label, parallel-group, multicenter study is expected to be complete in October 2016.
Other observational studies are also being conducted and are comparing cardiovascular risk in patients receiving tocilizumab as compared with patients being treated with other biologic DMARDs.
Exploring the Paradox
A review article by Ernest Choy, MD, et al published in Rheumatology noted that “high inflammatory burden associated with RA appears to be a key driver of the increased cardiovascular risk.”3 This heightened inflammation accelerates atherosclerosis and exacerbates both established and novel cardiovascular risk factors, they said. An increasingly recognized paradox for physicians treating patients with RA is that cholesterol is inversely related to risk of cardiovascular disease in patients with RA who are not treated.
A study published in 2011 by Myasoedova et al found evidence that patients with lower total cholesterol and LDL levels and lower atherogenic ratios (ratio of total cholesterol to LDL cholesterol) have an increased risk of cardiovascular disease.4 In that population-based RA-incident cohort with 651 patients, ESR was also associated with risk of cardiovascular disease. Results of this research, the authors said, suggest that the “associations of lipid with [cardiovascular disease] in RA may be confounded by inflammation.”
Beyond the need for trials that compare the efficacy of RA treatment strategies for lowering cardiovascular risk, more data are needed about the role of inflammation and lipids on the cardiovascular risk among patients with RA, Drs. Liao and Solomon say.
They say that it’s possible, as reported in the Rao study, that disease activity “will be an important risk factor, while total cholesterol and LDL levels may be suboptimal measures to guide [cardiovascular] risk estimation and preventative interventions, because the levels appear to fluctuate with therapy in an inverse manner.”
Also, advanced lipoprotein testing may improve accuracy of this needed risk assessment, they add. “Closer investigation into the underlying mechanisms by which inflammation increases the risk of [cardiovascular] events in RA represents an important, rapidly evolving area of study that may have implications beyond rheumatology.”
A consortium of U.S. and European investigators are working to develop an RA-specific cardiovascular risk calculator, given that traditional risk algorithms, such as the Framingham Risk Score in the U.S. and the HeartSCORE in Europe, underestimate the risk for RA patients. Called ATTAC-RA (A TransAtlantic Cardiovascular Risk Calculator for Rheumatoid Arthritis), the effort began in February 2013. The group includes 13 rheumatology centers from 10 countries, has combined data from more than 5,500 patients and includes 476 evaluable cardiovascular events. The researchers are hoping to develop a tool that is more discriminating than current ones, a calculator that incorporates the paradoxical relationship of lipids and cardiovascular risk among patients with RA.
Kathy L. Holliman, MEd, is a medical writer based in Beverly, Mass.
References
- Liao KP, Solomon DH. Inflammation, disease-modifying antirheumatic drugs, lipids, and cardiovascular risk in rheumatoid arthritis. Arthritis Rheum. 2015 Feb;67(2):327–329.
- Rao VU, Pavlov A, Klearman M, et al. An evaluation of risk factors for major adverse cardiovascular events during tocilizumab therapy. Arthritis Rheum. 2015 Feb;67(2):372–380.
- Choy E, Ganeshalingam K, Semb AG, et al. Cardiovascular risk in rheumatoid arthritis: Recent advances in the understanding of the pivotal role of inflammation, risk predictors and the impact of treatment. Rheumatology (Oxford). 2014 Dec;53(12):2143–2154.
- Myasoedova E, Crowson CS, Kremers HM, et al. Lipid paradox in rheumatoid arthritis: The impact of serum lipid measures and systemic inflammation on the risk of cardiovascular disease. Ann Rheum Dis. 2011 Mar;70(3):482–487.
