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A variety of trials, some recent and some a decade old, have highlighted the role of inflammation on cardiovascular disease risk in both patients with and without rheumatoid arthritis, spurring greater interest in alleviating inflammation across a wide range of patients, Jon T. Giles, MD, said at the Winter Rheumatology Symposium sponsored by the American College of Rheumatology.
However, questions remain about the unique contributions of inflammation to CVD risk in RA patients and the effect of RA treatments on that risk, which future studies hope to answer.
Hints of inflammation’s effects in non-RA patients
The JUPITER trial published more than a decade ago, for example, tested the effects of statins in nearly 18,000 older adults without rheumatoid arthritis (RA) who had elevated levels of inflammation, defined as a C-reactive protein (CRP) level of greater than 2 mg/L and low-density lipoprotein (LDL) cholesterol less than 130 mg/dL. Such patients would otherwise be considered low risk and not eligible for statin therapy, said Dr. Giles, a rheumatologist, epidemiologist, and clinical researcher in the division of rheumatology at Columbia University, New York.
A marked decrease in the incidence of cardiovascular disease (CVD) events was seen in those treated with statins, compared with those who received placebo, and all patient subgroups benefited; the number needed to treat to prevent one event was 32 at 5 years (N Engl J Med. 2008;359:2195-207).
The trial was remarkable in that it was stopped early for efficacy, he noted.
“So the question is: Should we be thinking about systemic inflammation as the real target here? And should RA patients who have elevated persistent levels of CRP really be the people that we’re thinking about?” he asked. “Obviously this needs to be tested; we don’t know.”
The more recent CANTOS trial looking at secondary CVD prevention in more than 10,000 non-RA patients with a prior myocardial infarction also highlighted the role of inflammation and provided “some support that decreasing inflammatory cytokines may be important for reducing [CVD] events,” he said (N Engl J Med. 2017;377:1119-31).
Participants were treated with the interleukin-1 inhibitor canakinumab (Ilaris) or placebo, and canakinumab was associated with about a 15% reduction in CVD events, providing “more proof of concept to look at the inflammatory innate immune contribution to CVD risk,” Dr. Giles said.
Treated patients had more infections, but they also had less gout, less arthritis, and less cancer than did those who received placebo, he noted.
Effect of RA treatments on CVD risk
The effects of existing treatments for RA also highlight the importance of inflammation in CVD risk in RA patients, he said, noting that data support a role for immunomodulators for risk reduction.
“There’s a lot of observational epidemiology in this space – mostly for methotrexate and [tumor necrosis factor (TNF)] inhibitors,” he said.
One analysis showed that across 8 cohort studies involving methotrexate, the disease-modifying antirheumatic agent reduced the risk of CVD events by 28%, and that across 16 cohort studies, TNF inhibitors reduced the risk by 30% (Ann Rheum Dis. 2015 Mar;74[3]:480-9).
All of the methotrexate studies showed a reduction, and almost all of the TNF inhibitor trials showed a reduction, Dr. Giles noted.
With respect to other non-TNF biologics, claims data suggest that abatacept (Orencia) is similar to the TNF inhibitor etanercept (Enbrel) with respect to CVD risk, and in a head-to-head, randomized clinical trial of more than 3,000 RA patients presented as a late-breaking abstract at the ACR annual meeting in 2016, Dr. Giles and his colleagues found similar cardiovascular safety between the anti-IL-6 receptor blocker tocilizumab (Actemra) and etanercept.
“I think we’ll know more about this in the near future,” he said.
As for the mechanisms of these agents, early data and animal models suggest that abatacept may play “a special role” in atherosclerosis reduction related to its effects on T cell CTLA-4 over-expression, and methotrexate also seems to have a number of “potential mechanistic benefits” that render it atheroprotective, he said.
The disappointing findings from the recently reported CIRT trial, which showed no benefit of methotrexate for secondary CVD prevention in non-RA patients (N Engl J Med. 2019;380:752-62), has dampened enthusiasm regarding methotrexate’s role here, but it is important to note that patients enrolled in CIRT, unlike those in JUPITER and CANTOS, were not enrolled based on elevated levels of CRP, Dr. Giles said.
Various studies of TNF inhibitors have shown atheroprotective effects through reductions in macrophage-derived inflammatory cytokines, downregulation of adhesion molecules on endothelial cells, improving the function of high-density lipoprotein, stabilizing atherosclerotic plaque remodeling, and reducing procoagulant states.
The TARGET trial
In a recent study of 17 patients with RA, Dr. Giles and his colleagues showed that TNF inhibitor therapy with either adalimumab (Humira) or etanercept significantly reduced aortic inflammation as measured by baseline and 8-week fluorodeoxyglucose (FDG) PET-CT.
“Is this proof that this helps? It’s not proof; there’s no control group, we don’t know that this is not the natural progression of vascular inflammation in these patients,” he said.
However, the findings were suggestive enough to prompt the launch of the TARGET trial, which is now enrolling patients at centers in the United States and Canada, Dr. Giles said.
The TARGET trial is a project involving his team at Columbia University along with researchers from Brigham and Women’s Hospital, Boston. They plan to enroll 200 RA patients without CVD who have an inadequate response to methotrexate. Participants will be randomized to receive an added TNF inhibitor or added triple therapy, and the primary outcome will be changes in inflammation in the aortic and carotid arteries on FDG PET-CT at 6 months versus baseline.
“So stay tuned and hopefully we’ll have some good information about the effect of two different types of treatments for rheumatoid arthritis on vascular inflammation,” Dr. Giles said.
A final question he addressed is whether the RA-CVD risk link is really a problem that has already been solved – one that “we’re just learning about after the fact.”
“The answer is partially yes and partially no,” he said.
The most up-to-date estimate of whether RA patients have a problem with CVD comes from a Swedish population-based study of more than 15,700 RA patients and nearly 70,900 comparators, which was published in 2018 and showed across-the-board declines in CVD rates over time.
RA and non-RA patients experienced an overall 40% reduction in acute coronary syndromes between 1997 and 2014, but the relative difference in event rates between the groups persisted (Ann Rheum Dis. 2017;76:1642-7).
“There is still a gap ... so we haven’t answered this question yet,” he said, adding that “the rates have been reduced, but we want those rates to be equal or maybe even less.
“Why can’t RA patients have less cardiovascular disease if we’re using drugs that are so effective for treating the inflammatory component of atherogenesis?” he asked.
The authors of the study noted that most RA patients in Sweden are in low disease activity by 3-6 months, so they were “a little confounded by why there is no equalization of these rates as of yet,” he said.
“I think we still have more to learn about this problem, and it is still a problem in our patients,” Dr. Giles said.
Dr. Giles is a consultant for Genentech, Lilly, Horizon, Bristol-Myers Squibb, and UCB, and he has received grant support from Pfizer.
A variety of trials, some recent and some a decade old, have highlighted the role of inflammation on cardiovascular disease risk in both patients with and without rheumatoid arthritis, spurring greater interest in alleviating inflammation across a wide range of patients, Jon T. Giles, MD, said at the Winter Rheumatology Symposium sponsored by the American College of Rheumatology.
However, questions remain about the unique contributions of inflammation to CVD risk in RA patients and the effect of RA treatments on that risk, which future studies hope to answer.
Hints of inflammation’s effects in non-RA patients
The JUPITER trial published more than a decade ago, for example, tested the effects of statins in nearly 18,000 older adults without rheumatoid arthritis (RA) who had elevated levels of inflammation, defined as a C-reactive protein (CRP) level of greater than 2 mg/L and low-density lipoprotein (LDL) cholesterol less than 130 mg/dL. Such patients would otherwise be considered low risk and not eligible for statin therapy, said Dr. Giles, a rheumatologist, epidemiologist, and clinical researcher in the division of rheumatology at Columbia University, New York.
A marked decrease in the incidence of cardiovascular disease (CVD) events was seen in those treated with statins, compared with those who received placebo, and all patient subgroups benefited; the number needed to treat to prevent one event was 32 at 5 years (N Engl J Med. 2008;359:2195-207).
The trial was remarkable in that it was stopped early for efficacy, he noted.
“So the question is: Should we be thinking about systemic inflammation as the real target here? And should RA patients who have elevated persistent levels of CRP really be the people that we’re thinking about?” he asked. “Obviously this needs to be tested; we don’t know.”
The more recent CANTOS trial looking at secondary CVD prevention in more than 10,000 non-RA patients with a prior myocardial infarction also highlighted the role of inflammation and provided “some support that decreasing inflammatory cytokines may be important for reducing [CVD] events,” he said (N Engl J Med. 2017;377:1119-31).
Participants were treated with the interleukin-1 inhibitor canakinumab (Ilaris) or placebo, and canakinumab was associated with about a 15% reduction in CVD events, providing “more proof of concept to look at the inflammatory innate immune contribution to CVD risk,” Dr. Giles said.
Treated patients had more infections, but they also had less gout, less arthritis, and less cancer than did those who received placebo, he noted.
Effect of RA treatments on CVD risk
The effects of existing treatments for RA also highlight the importance of inflammation in CVD risk in RA patients, he said, noting that data support a role for immunomodulators for risk reduction.
“There’s a lot of observational epidemiology in this space – mostly for methotrexate and [tumor necrosis factor (TNF)] inhibitors,” he said.
One analysis showed that across 8 cohort studies involving methotrexate, the disease-modifying antirheumatic agent reduced the risk of CVD events by 28%, and that across 16 cohort studies, TNF inhibitors reduced the risk by 30% (Ann Rheum Dis. 2015 Mar;74[3]:480-9).
All of the methotrexate studies showed a reduction, and almost all of the TNF inhibitor trials showed a reduction, Dr. Giles noted.
With respect to other non-TNF biologics, claims data suggest that abatacept (Orencia) is similar to the TNF inhibitor etanercept (Enbrel) with respect to CVD risk, and in a head-to-head, randomized clinical trial of more than 3,000 RA patients presented as a late-breaking abstract at the ACR annual meeting in 2016, Dr. Giles and his colleagues found similar cardiovascular safety between the anti-IL-6 receptor blocker tocilizumab (Actemra) and etanercept.
“I think we’ll know more about this in the near future,” he said.
As for the mechanisms of these agents, early data and animal models suggest that abatacept may play “a special role” in atherosclerosis reduction related to its effects on T cell CTLA-4 over-expression, and methotrexate also seems to have a number of “potential mechanistic benefits” that render it atheroprotective, he said.
The disappointing findings from the recently reported CIRT trial, which showed no benefit of methotrexate for secondary CVD prevention in non-RA patients (N Engl J Med. 2019;380:752-62), has dampened enthusiasm regarding methotrexate’s role here, but it is important to note that patients enrolled in CIRT, unlike those in JUPITER and CANTOS, were not enrolled based on elevated levels of CRP, Dr. Giles said.
Various studies of TNF inhibitors have shown atheroprotective effects through reductions in macrophage-derived inflammatory cytokines, downregulation of adhesion molecules on endothelial cells, improving the function of high-density lipoprotein, stabilizing atherosclerotic plaque remodeling, and reducing procoagulant states.
The TARGET trial
In a recent study of 17 patients with RA, Dr. Giles and his colleagues showed that TNF inhibitor therapy with either adalimumab (Humira) or etanercept significantly reduced aortic inflammation as measured by baseline and 8-week fluorodeoxyglucose (FDG) PET-CT.
“Is this proof that this helps? It’s not proof; there’s no control group, we don’t know that this is not the natural progression of vascular inflammation in these patients,” he said.
However, the findings were suggestive enough to prompt the launch of the TARGET trial, which is now enrolling patients at centers in the United States and Canada, Dr. Giles said.
The TARGET trial is a project involving his team at Columbia University along with researchers from Brigham and Women’s Hospital, Boston. They plan to enroll 200 RA patients without CVD who have an inadequate response to methotrexate. Participants will be randomized to receive an added TNF inhibitor or added triple therapy, and the primary outcome will be changes in inflammation in the aortic and carotid arteries on FDG PET-CT at 6 months versus baseline.
“So stay tuned and hopefully we’ll have some good information about the effect of two different types of treatments for rheumatoid arthritis on vascular inflammation,” Dr. Giles said.
A final question he addressed is whether the RA-CVD risk link is really a problem that has already been solved – one that “we’re just learning about after the fact.”
“The answer is partially yes and partially no,” he said.
The most up-to-date estimate of whether RA patients have a problem with CVD comes from a Swedish population-based study of more than 15,700 RA patients and nearly 70,900 comparators, which was published in 2018 and showed across-the-board declines in CVD rates over time.
RA and non-RA patients experienced an overall 40% reduction in acute coronary syndromes between 1997 and 2014, but the relative difference in event rates between the groups persisted (Ann Rheum Dis. 2017;76:1642-7).
“There is still a gap ... so we haven’t answered this question yet,” he said, adding that “the rates have been reduced, but we want those rates to be equal or maybe even less.
“Why can’t RA patients have less cardiovascular disease if we’re using drugs that are so effective for treating the inflammatory component of atherogenesis?” he asked.
The authors of the study noted that most RA patients in Sweden are in low disease activity by 3-6 months, so they were “a little confounded by why there is no equalization of these rates as of yet,” he said.
“I think we still have more to learn about this problem, and it is still a problem in our patients,” Dr. Giles said.
Dr. Giles is a consultant for Genentech, Lilly, Horizon, Bristol-Myers Squibb, and UCB, and he has received grant support from Pfizer.
A variety of trials, some recent and some a decade old, have highlighted the role of inflammation on cardiovascular disease risk in both patients with and without rheumatoid arthritis, spurring greater interest in alleviating inflammation across a wide range of patients, Jon T. Giles, MD, said at the Winter Rheumatology Symposium sponsored by the American College of Rheumatology.
However, questions remain about the unique contributions of inflammation to CVD risk in RA patients and the effect of RA treatments on that risk, which future studies hope to answer.
Hints of inflammation’s effects in non-RA patients
The JUPITER trial published more than a decade ago, for example, tested the effects of statins in nearly 18,000 older adults without rheumatoid arthritis (RA) who had elevated levels of inflammation, defined as a C-reactive protein (CRP) level of greater than 2 mg/L and low-density lipoprotein (LDL) cholesterol less than 130 mg/dL. Such patients would otherwise be considered low risk and not eligible for statin therapy, said Dr. Giles, a rheumatologist, epidemiologist, and clinical researcher in the division of rheumatology at Columbia University, New York.
A marked decrease in the incidence of cardiovascular disease (CVD) events was seen in those treated with statins, compared with those who received placebo, and all patient subgroups benefited; the number needed to treat to prevent one event was 32 at 5 years (N Engl J Med. 2008;359:2195-207).
The trial was remarkable in that it was stopped early for efficacy, he noted.
“So the question is: Should we be thinking about systemic inflammation as the real target here? And should RA patients who have elevated persistent levels of CRP really be the people that we’re thinking about?” he asked. “Obviously this needs to be tested; we don’t know.”
The more recent CANTOS trial looking at secondary CVD prevention in more than 10,000 non-RA patients with a prior myocardial infarction also highlighted the role of inflammation and provided “some support that decreasing inflammatory cytokines may be important for reducing [CVD] events,” he said (N Engl J Med. 2017;377:1119-31).
Participants were treated with the interleukin-1 inhibitor canakinumab (Ilaris) or placebo, and canakinumab was associated with about a 15% reduction in CVD events, providing “more proof of concept to look at the inflammatory innate immune contribution to CVD risk,” Dr. Giles said.
Treated patients had more infections, but they also had less gout, less arthritis, and less cancer than did those who received placebo, he noted.
Effect of RA treatments on CVD risk
The effects of existing treatments for RA also highlight the importance of inflammation in CVD risk in RA patients, he said, noting that data support a role for immunomodulators for risk reduction.
“There’s a lot of observational epidemiology in this space – mostly for methotrexate and [tumor necrosis factor (TNF)] inhibitors,” he said.
One analysis showed that across 8 cohort studies involving methotrexate, the disease-modifying antirheumatic agent reduced the risk of CVD events by 28%, and that across 16 cohort studies, TNF inhibitors reduced the risk by 30% (Ann Rheum Dis. 2015 Mar;74[3]:480-9).
All of the methotrexate studies showed a reduction, and almost all of the TNF inhibitor trials showed a reduction, Dr. Giles noted.
With respect to other non-TNF biologics, claims data suggest that abatacept (Orencia) is similar to the TNF inhibitor etanercept (Enbrel) with respect to CVD risk, and in a head-to-head, randomized clinical trial of more than 3,000 RA patients presented as a late-breaking abstract at the ACR annual meeting in 2016, Dr. Giles and his colleagues found similar cardiovascular safety between the anti-IL-6 receptor blocker tocilizumab (Actemra) and etanercept.
“I think we’ll know more about this in the near future,” he said.
As for the mechanisms of these agents, early data and animal models suggest that abatacept may play “a special role” in atherosclerosis reduction related to its effects on T cell CTLA-4 over-expression, and methotrexate also seems to have a number of “potential mechanistic benefits” that render it atheroprotective, he said.
The disappointing findings from the recently reported CIRT trial, which showed no benefit of methotrexate for secondary CVD prevention in non-RA patients (N Engl J Med. 2019;380:752-62), has dampened enthusiasm regarding methotrexate’s role here, but it is important to note that patients enrolled in CIRT, unlike those in JUPITER and CANTOS, were not enrolled based on elevated levels of CRP, Dr. Giles said.
Various studies of TNF inhibitors have shown atheroprotective effects through reductions in macrophage-derived inflammatory cytokines, downregulation of adhesion molecules on endothelial cells, improving the function of high-density lipoprotein, stabilizing atherosclerotic plaque remodeling, and reducing procoagulant states.
The TARGET trial
In a recent study of 17 patients with RA, Dr. Giles and his colleagues showed that TNF inhibitor therapy with either adalimumab (Humira) or etanercept significantly reduced aortic inflammation as measured by baseline and 8-week fluorodeoxyglucose (FDG) PET-CT.
“Is this proof that this helps? It’s not proof; there’s no control group, we don’t know that this is not the natural progression of vascular inflammation in these patients,” he said.
However, the findings were suggestive enough to prompt the launch of the TARGET trial, which is now enrolling patients at centers in the United States and Canada, Dr. Giles said.
The TARGET trial is a project involving his team at Columbia University along with researchers from Brigham and Women’s Hospital, Boston. They plan to enroll 200 RA patients without CVD who have an inadequate response to methotrexate. Participants will be randomized to receive an added TNF inhibitor or added triple therapy, and the primary outcome will be changes in inflammation in the aortic and carotid arteries on FDG PET-CT at 6 months versus baseline.
“So stay tuned and hopefully we’ll have some good information about the effect of two different types of treatments for rheumatoid arthritis on vascular inflammation,” Dr. Giles said.
A final question he addressed is whether the RA-CVD risk link is really a problem that has already been solved – one that “we’re just learning about after the fact.”
“The answer is partially yes and partially no,” he said.
The most up-to-date estimate of whether RA patients have a problem with CVD comes from a Swedish population-based study of more than 15,700 RA patients and nearly 70,900 comparators, which was published in 2018 and showed across-the-board declines in CVD rates over time.
RA and non-RA patients experienced an overall 40% reduction in acute coronary syndromes between 1997 and 2014, but the relative difference in event rates between the groups persisted (Ann Rheum Dis. 2017;76:1642-7).
“There is still a gap ... so we haven’t answered this question yet,” he said, adding that “the rates have been reduced, but we want those rates to be equal or maybe even less.
“Why can’t RA patients have less cardiovascular disease if we’re using drugs that are so effective for treating the inflammatory component of atherogenesis?” he asked.
The authors of the study noted that most RA patients in Sweden are in low disease activity by 3-6 months, so they were “a little confounded by why there is no equalization of these rates as of yet,” he said.
“I think we still have more to learn about this problem, and it is still a problem in our patients,” Dr. Giles said.
Dr. Giles is a consultant for Genentech, Lilly, Horizon, Bristol-Myers Squibb, and UCB, and he has received grant support from Pfizer.
EXPERT ANALYSIS FROM THE WINTER RHEUMATOLOGY SYMPOSIUM