Published: Oct 28, 2014 | Updated: Oct 29, 2014
Measures of disease activity at baseline and changes in those markers with tocilizumab (Actemra) treatment among patients with rheumatoid arthritis (RA) were independently associated with increased risk for major adverse cardiovascular events, a post-hoc analysis of five clinical trials suggested.
For instance, on a multivariate analysis, a one-unit increase in baseline disease activity score in 28 joints (DAS28) was associated with a 36% increase in risk for a major cardiac event (HR 1.36, 95% CI 1.06-1.75,P=0.0158), according to Vijay U. Rao, MD, PhD, of Indiana Heart Physicians in Indianapolis, and colleagues.
In addition, a one-unit increase in DAS28 score during 6 months of treatment with tocilizumab was associated with a 29% increase in the adjusted risk for future cardiovascular (CV) events (HR 1.29, 95% CI 1.04-1.60,P=0.0191), the researchers reported online in Arthritis and Rheumatology.
Lipids and Risk?
Unlike measures of disease activity, there was no association between changes in lipid parameters during treatment and risk for cardiovascular events, with nonsignificant hazard ratios for the following:
- Total cholesterol: HR 1.03 (95% CI 0.72-1.46, P=0.8804)
- HDL: HR 0.56 (95% CI 0.18-1.76, P=0.03185)
- LDL: HR 1.07 (95% CI 0.70-1.64, P=0.7670)
- Triglycerides: HR 1.14 (95% CI 0.81-1.63, P=0.4524)
- Lipoprotein A: HR 0.99 (95% CI 0.96-1.02, P=0.6300)
The risk for cardiovascular disease among patients with RA has been a major concern in recent years, with studies suggesting that traditional risk factors don't fully explain it and that measures of inflammation such as erythrocyte sedimentation rate (ESR) and comorbidities such as vasculitis may contribute.
But a particular concern specific to tocilizumab has been the observation that treatment with this monoclonal antibody, which inhibits IL-6 pro-inflammatory signaling, has resulted in elevated levels of HDL and LDL cholesterol and triglycerides in clinical trials. Changes in lipids have been reported during treatment with other anti-inflammatory therapies, including tumor necrosis factor inhibitors, but have been more pronounced with tocilizumab.
In an accompanying editorial, Katherine P. Liao, MD, and Daniel H. Solomon, MD, MPH, of Brigham and Women's Hospital in Boston, wrote, "The interleukin-6 receptor pathway, the target of tocilizumab, was implicated as part of the causal pathway for CV disease in a genetic analysis of approximately 51,000 individuals with heart disease and 136,000 controls. The studies suggested that blocking the IL-6R pathway, the mechanism of action for tocilizumab, may reduce CV risk."
Accordingly, Rao and colleagues explained, "Because IL-6 is a key driver of RA inflammation and RA patients have higher rates of CV disease than do persons without RA, we used this population to explore the complex relationships between traditional (lipid) and RA-specific parameters and CV risk."
Their analyses focused on associations between baseline factors reflecting lipids, inflammation, and disease activity and risk of major CV events, and if changes in these factors with treatment influenced this risk.
Baseline Factors and Risk
At baseline, patients who ultimately experienced a major adverse CV event were older than those without any events (61 versus 52 years) and more often had a history of cardiac disorders (24% versus 8.6%). Other factors such as disease duration and use of nonsteroidal anti-inflammatory drugs were similar in patients with and without subsequent CV events.
During a mean follow-up of 3.7 years, there were 50 major adverse CV events, for a rate of 3.4 per 1,000 patient-years. These events were nonfatal myocardial infarction or stroke or death from a CV cause.
Baseline predictors of major CV events on univariate analyses included a history of cardiac disease, older age, use of statins, DAS28, higher tender and swollen joint counts, higher total cholesterol to HDL ratio, and increased apolipoprotein B and apoprotein B to A1 ratios. IL-6 levels were not predictive.
Multivariable analysis of baseline factors associated with increased risk included a history of cardiac disorders, older age, and higher total cholesterol to HDL ratio, along with the higher baseline DAS28.
Changes During Treatment
Multivariable analysis of changes during the first 6 months of tocilizumab treatment determined that only measures of disease activity were significantly associated with risk. As with DAS28, a one-unit change in swollen joint count was associated with an 8% increase in risk (HR 1.08, 95% CI 0.03-1.14, P=0.0008), while a change in tender joint count was associated with a 4% increase (HR 1.04, 95% CI 1-1.09, P=0.0439).
After 6 months of treatment, among patients receiving 4 or 8 mg/kg intravenously once monthly of tocilizumab with or without methotrexate, there were increases of 19%, 16%, and 7% in LDL, total cholesterol, and HDL.
However, no changes in lipid parameters or measures of inflammation were independently associated with risk of CV events in the multivariate analysis, Rao and colleagues reported. Among the inflammatory markers not found to have an association with risk of a major CV event were ESR (HR 1, 95% CI 0.98-1.02,P=0.8567), IL-6R (HR 1, 95% CI 1-1, P=0.7888), and absolute neutrophil count (HR 1.05, 95% CI 0.90-1.24,P=0.5271).
They suggested that the lack of association between markers of inflammation such as ESR and CV risk may reflect "the fact that tocilizumab is a potent modifier of acute phase reactants."
They also noted that a possible explanation for the lack of association between increased lipid levels and CV risk may be that inflammation somehow lowers lipids. Mechanisms by which this phenomenon could occur "include increased peripheral catabolism (e.g., via decreases in catalytically inactive lipoprotein lipase) and upregulation of scavenger receptors leading to increased partitioning to tissues."
"As such, the lipid increases seen with tocilizumab treatment may in part represent a predictable response to the suppression of inflammation," they explained.
Further Clarifications
In their editorial, Liao and Solomon noted that the "lack of signal for cardiovascular events was reassuring."
However, they argued that more investigation is needed to clarify the relationship between lipids, inflammation, and cardiovascular risk in RA. More specific markers such as pro-inflammatory HDL and the efflux capacity of HDL may be more useful than conventional measures such as total and LDL cholesterol, they commented.
"We believe that closer investigation into the underlying mechanisms by which inflammation elevates CV risk in RA and translation of these findings for use in clinical practice is a rapidly evolving important area which may have implications beyond rheumatology," they stated.
Liao and Solomon also noted that further safety data should be available upon completion of a phase IV randomized study comparing patients with moderate-to-severe RA who were treated with tocilizumab and those given etanercept (Enbrel).
Another important source of information will be the collaborative effort known as A Transatlantic Cardiovascular risk Calculator for RA (ATTAC-RA), which aims to identify factors that will be more accurate for calculating risk than traditional tools such as the Framingham score, which greatly underestimates risk.
Limitations of the analysis included its post-hoc exploratory design, the relatively small number of cardiac events, and a lack of information on confounders that can change over time such as hypertension and medication use.
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