Take action to mitigate CVD risk in RA patients

Emerging understanding of the increased incidence of cardiovascular disease in patients with rheumatoid arthritis is providing greater insight regarding mitigation of risk, according to Jon T. Giles, MD.

The mechanisms of increased cardiovascular disease (CVD) risk in rheumatoid arthritis (RA) are multifactorial; in addition to traditional risk factors for CVD, chronically elevated levels of systemic inflammatory cytokines likely play a major role in atherogenesis and myocardial dysfunction in RA patients, and the interactions between those elevated cytokine levels and traditional risk factors also play a likely role, Dr. Giles, a rheumatologist, epidemiologist, and clinical researcher in the division of rheumatology at Columbia University, New York, said at the Winter Rheumatology Symposium sponsored by the American College of Rheumatology.

In addition, the relationship between traditional fasting lipids and atherosclerosis is different in RA patients from that in non-RA patients, he said, noting that this has important implications for CVD screening and risk management. The phenotype of CVD in RA based on the current literature is also one involving more coronary atherosclerosis in which the atherosclerotic plaques are more inflamed.

“There’s more myocardial dysfunction,” Dr. Giles said, noting that this dysfunction may be partly mediated by more myocardial fibrosis and possibly active subclinical low-grade myocarditis.

It is possible that traditional CVD risk factors such as smoking and hypertension have a greater impact in RA patients, but it’s likely that most of the differences are related to RA-specific factors such as autoimmunity, inflammation, and genetics, as well as some nontraditional CVD risk factors such as stress, anxiety, and depression that may be increased in RA patients, he noted.


With respect to traditional CVD risk factors, a recent study of more than 5,600 RA patients without CVD who were followed for an average of almost 6 years at 13 centers in Europe and the United States showed that 389 experienced CVD events, and the most common CVD risk factors in those patients were smoking – particularly in men – and hypertension.

“But also, RA characteristics played a big role,” he said.

Disease activity was one of the major risk factors for CVD events in RA patients, and the traditional CVD risk factor of hyperlipidemia, and particularly elevated low-density lipoprotein (LDL) levels, had less influence in RA patients than in the general population. In men it was “a negative predictor” of CVD events, he said (Ann Rheum Dis. 2018;77:48-54).

Prior studies have also shown a “strange relationship” between lipids and CVD risk in RA patients. For example, RA patients with very low LDL cholesterol have been shown to have higher CVD event rates – a phenomenon known as the “lipid paradox” – and it may be related to inflammation, but the mechanism is unclear,” he said.

To further assess whether RA patients with abnormally low LDL cholesterol levels without the use of statin therapy had more atherosclerotic burden, Dr. Giles and his colleagues looked at more than 600 RA patients and more than 1,000 non-RA patients (Arthritis Rheumatol. 2015;67[suppl 10]:Abstract 2127). They found that RA patients did, indeed, have a greater atherosclerotic burden, which was “quite shocking,” he said.

The burden rivaled that seen in patients with LDL levels greater than 160 mg/dL, he noted.

“Interestingly, these patients did not have higher levels of inflammatory markers, and they did not have higher disease activity scores. They looked exactly the same as the rest of the RA patients,” he said, noting that investigation into why the LDL levels in these patients are so low is ongoing.

As for how atherogenic lipoproteins allow for atherosclerosis and atherogenesis to occur in the setting of low LDL in RA patients, it turns out it’s not just the amount, but also the characteristics of the lipoproteins, such as the size and oxidization of the LDL, which change in the context of systemic inflammation, he explained.

Further, during an acute-phase reaction, high-density lipoprotein (HDL) composition changes rapidly from antiatherogenic to proinflammatory.

Extensive evidence shows that endothelial function is diminished in RA, and that RA patients have these and other proatherogenic mechanisms, as well as other elements of immunity that are associated with atherogenesis, including aspects of both innate and adaptive immune function, he said.

Given the emerging understanding of CVD risk in RA, mitigation of that risk is an important consideration. In fact, the European League Against Rheumatism updated its CVD management guidelines in 2015/2016, including a statement that rheumatologists are responsible for CVD risk management in RA patients (Ann Rheum Dis. 2017;76:17-28).

The guidelines are intended for all inflammatory arthritis, and the recommendation with the strongest level of evidence relates to optimization of disease activity. Also recommended are:

• CVD screening every 5 years.
• Use of a 1.5 multiplier for risk scores.
• Secondary screening with imaging for select patients.
• Management of traditional risk factors according to local guidelines.
• Minimization of the use of NSAIDs and corticosteroids.
• Emphasis on lifestyle management.

Importantly, research has suggested that screening for hyperlipidemia is substandard in RA, and that standard risk stratification tools underperform in the setting of RA, he said.

“So my approach, and this is not evidence based yet ... comes down to what [a patient’s] apparent risk is. So if an RA patient is high risk based on your apparent risk prediction, then they are likely high risk and maybe even higher than estimated,” Dr. Giles said. These patients need optimization of their traditional risk factors and their inflammatory factors and should therefore receive a high-intensity statin regardless of lipid levels, he said.

That means atorvastatin at a dose of at least 40 mg or rosuvastatin at a dose of at least 20 mg, he said, adding that some studies have suggested that statins work as well in RA patients as in non-RA patients, and that RA patients with CVD risk do better with a statin than without.

He considers patients who have intermediate risk based on the risk calculation to actually be high risk in most cases, and they, too, need maximal optimization of traditional CVD risk factors and inflammatory factors.

“Consider one-time secondary imaging for all of these patients,” he advised, noting that a coronary calcium score from a chest CT scan is a good option that has low radiation, can be quantified, and is increasingly covered by insurance.

A coronary calcium score of 0 on chest CT is highly reassuring, and a score that is greater than what is expected for age, gender, and/or race can help define the intensity of intervention, he said.

For example, if a patient’s score is 300 but should be 50, that patient should be treated as if he or she has coronary artery disease. Patients with high scores in general – particularly those with scores over 300 – should also be maximally managed, he said.

Patients at low risk based on risk calculations usually are low risk, but some can be high risk, so again, maximal optimization of risk factors is recommended.

Secondary imaging can be considered in some of these patients, and while it’s not entirely clear which are at greatest risk, Dr. Giles said he recommends screening those with treatment-resistant active disease, those with high disease severity, and those with abnormally low LDL.

Dr. Giles is a consultant for Genentech, Lilly, Horizon, Bristol-Myers Squibb, and UCB, and he has received grant support from Pfizer.

[email protected]

Emerging understanding of the increased incidence of cardiovascular disease in patients with rheumatoid arthritis is providing greater insight regarding mitigation of risk, according to Jon T. Giles, MD.

The mechanisms of increased cardiovascular disease (CVD) risk in rheumatoid arthritis (RA) are multifactorial; in addition to traditional risk factors for CVD, chronically elevated levels of systemic inflammatory cytokines likely play a major role in atherogenesis and myocardial dysfunction in RA patients, and the interactions between those elevated cytokine levels and traditional risk factors also play a likely role, Dr. Giles, a rheumatologist, epidemiologist, and clinical researcher in the division of rheumatology at Columbia University, New York, said at the Winter Rheumatology Symposium sponsored by the American College of Rheumatology.

In addition, the relationship between traditional fasting lipids and atherosclerosis is different in RA patients from that in non-RA patients, he said, noting that this has important implications for CVD screening and risk management. The phenotype of CVD in RA based on the current literature is also one involving more coronary atherosclerosis in which the atherosclerotic plaques are more inflamed.

“There’s more myocardial dysfunction,” Dr. Giles said, noting that this dysfunction may be partly mediated by more myocardial fibrosis and possibly active subclinical low-grade myocarditis.

It is possible that traditional CVD risk factors such as smoking and hypertension have a greater impact in RA patients, but it’s likely that most of the differences are related to RA-specific factors such as autoimmunity, inflammation, and genetics, as well as some nontraditional CVD risk factors such as stress, anxiety, and depression that may be increased in RA patients, he noted.


With respect to traditional CVD risk factors, a recent study of more than 5,600 RA patients without CVD who were followed for an average of almost 6 years at 13 centers in Europe and the United States showed that 389 experienced CVD events, and the most common CVD risk factors in those patients were smoking – particularly in men – and hypertension.

“But also, RA characteristics played a big role,” he said.

Disease activity was one of the major risk factors for CVD events in RA patients, and the traditional CVD risk factor of hyperlipidemia, and particularly elevated low-density lipoprotein (LDL) levels, had less influence in RA patients than in the general population. In men it was “a negative predictor” of CVD events, he said (Ann Rheum Dis. 2018;77:48-54).

Prior studies have also shown a “strange relationship” between lipids and CVD risk in RA patients. For example, RA patients with very low LDL cholesterol have been shown to have higher CVD event rates – a phenomenon known as the “lipid paradox” – and it may be related to inflammation, but the mechanism is unclear,” he said.

To further assess whether RA patients with abnormally low LDL cholesterol levels without the use of statin therapy had more atherosclerotic burden, Dr. Giles and his colleagues looked at more than 600 RA patients and more than 1,000 non-RA patients (Arthritis Rheumatol. 2015;67[suppl 10]:Abstract 2127). They found that RA patients did, indeed, have a greater atherosclerotic burden, which was “quite shocking,” he said.

The burden rivaled that seen in patients with LDL levels greater than 160 mg/dL, he noted.

“Interestingly, these patients did not have higher levels of inflammatory markers, and they did not have higher disease activity scores. They looked exactly the same as the rest of the RA patients,” he said, noting that investigation into why the LDL levels in these patients are so low is ongoing.

As for how atherogenic lipoproteins allow for atherosclerosis and atherogenesis to occur in the setting of low LDL in RA patients, it turns out it’s not just the amount, but also the characteristics of the lipoproteins, such as the size and oxidization of the LDL, which change in the context of systemic inflammation, he explained.

Further, during an acute-phase reaction, high-density lipoprotein (HDL) composition changes rapidly from antiatherogenic to proinflammatory.

Extensive evidence shows that endothelial function is diminished in RA, and that RA patients have these and other proatherogenic mechanisms, as well as other elements of immunity that are associated with atherogenesis, including aspects of both innate and adaptive immune function, he said.

Given the emerging understanding of CVD risk in RA, mitigation of that risk is an important consideration. In fact, the European League Against Rheumatism updated its CVD management guidelines in 2015/2016, including a statement that rheumatologists are responsible for CVD risk management in RA patients (Ann Rheum Dis. 2017;76:17-28).

The guidelines are intended for all inflammatory arthritis, and the recommendation with the strongest level of evidence relates to optimization of disease activity. Also recommended are:

• CVD screening every 5 years.
• Use of a 1.5 multiplier for risk scores.
• Secondary screening with imaging for select patients.
• Management of traditional risk factors according to local guidelines.
• Minimization of the use of NSAIDs and corticosteroids.
• Emphasis on lifestyle management.

Importantly, research has suggested that screening for hyperlipidemia is substandard in RA, and that standard risk stratification tools underperform in the setting of RA, he said.

“So my approach, and this is not evidence based yet ... comes down to what [a patient’s] apparent risk is. So if an RA patient is high risk based on your apparent risk prediction, then they are likely high risk and maybe even higher than estimated,” Dr. Giles said. These patients need optimization of their traditional risk factors and their inflammatory factors and should therefore receive a high-intensity statin regardless of lipid levels, he said.

That means atorvastatin at a dose of at least 40 mg or rosuvastatin at a dose of at least 20 mg, he said, adding that some studies have suggested that statins work as well in RA patients as in non-RA patients, and that RA patients with CVD risk do better with a statin than without.

He considers patients who have intermediate risk based on the risk calculation to actually be high risk in most cases, and they, too, need maximal optimization of traditional CVD risk factors and inflammatory factors.

“Consider one-time secondary imaging for all of these patients,” he advised, noting that a coronary calcium score from a chest CT scan is a good option that has low radiation, can be quantified, and is increasingly covered by insurance.

A coronary calcium score of 0 on chest CT is highly reassuring, and a score that is greater than what is expected for age, gender, and/or race can help define the intensity of intervention, he said.

For example, if a patient’s score is 300 but should be 50, that patient should be treated as if he or she has coronary artery disease. Patients with high scores in general – particularly those with scores over 300 – should also be maximally managed, he said.

Patients at low risk based on risk calculations usually are low risk, but some can be high risk, so again, maximal optimization of risk factors is recommended.

Secondary imaging can be considered in some of these patients, and while it’s not entirely clear which are at greatest risk, Dr. Giles said he recommends screening those with treatment-resistant active disease, those with high disease severity, and those with abnormally low LDL.

Dr. Giles is a consultant for Genentech, Lilly, Horizon, Bristol-Myers Squibb, and UCB, and he has received grant support from Pfizer.

[email protected]

Emerging understanding of the increased incidence of cardiovascular disease in patients with rheumatoid arthritis is providing greater insight regarding mitigation of risk, according to Jon T. Giles, MD.

The mechanisms of increased cardiovascular disease (CVD) risk in rheumatoid arthritis (RA) are multifactorial; in addition to traditional risk factors for CVD, chronically elevated levels of systemic inflammatory cytokines likely play a major role in atherogenesis and myocardial dysfunction in RA patients, and the interactions between those elevated cytokine levels and traditional risk factors also play a likely role, Dr. Giles, a rheumatologist, epidemiologist, and clinical researcher in the division of rheumatology at Columbia University, New York, said at the Winter Rheumatology Symposium sponsored by the American College of Rheumatology.

In addition, the relationship between traditional fasting lipids and atherosclerosis is different in RA patients from that in non-RA patients, he said, noting that this has important implications for CVD screening and risk management. The phenotype of CVD in RA based on the current literature is also one involving more coronary atherosclerosis in which the atherosclerotic plaques are more inflamed.

“There’s more myocardial dysfunction,” Dr. Giles said, noting that this dysfunction may be partly mediated by more myocardial fibrosis and possibly active subclinical low-grade myocarditis.

It is possible that traditional CVD risk factors such as smoking and hypertension have a greater impact in RA patients, but it’s likely that most of the differences are related to RA-specific factors such as autoimmunity, inflammation, and genetics, as well as some nontraditional CVD risk factors such as stress, anxiety, and depression that may be increased in RA patients, he noted.


With respect to traditional CVD risk factors, a recent study of more than 5,600 RA patients without CVD who were followed for an average of almost 6 years at 13 centers in Europe and the United States showed that 389 experienced CVD events, and the most common CVD risk factors in those patients were smoking – particularly in men – and hypertension.

“But also, RA characteristics played a big role,” he said.

Disease activity was one of the major risk factors for CVD events in RA patients, and the traditional CVD risk factor of hyperlipidemia, and particularly elevated low-density lipoprotein (LDL) levels, had less influence in RA patients than in the general population. In men it was “a negative predictor” of CVD events, he said (Ann Rheum Dis. 2018;77:48-54).

Prior studies have also shown a “strange relationship” between lipids and CVD risk in RA patients. For example, RA patients with very low LDL cholesterol have been shown to have higher CVD event rates – a phenomenon known as the “lipid paradox” – and it may be related to inflammation, but the mechanism is unclear,” he said.

To further assess whether RA patients with abnormally low LDL cholesterol levels without the use of statin therapy had more atherosclerotic burden, Dr. Giles and his colleagues looked at more than 600 RA patients and more than 1,000 non-RA patients (Arthritis Rheumatol. 2015;67[suppl 10]:Abstract 2127). They found that RA patients did, indeed, have a greater atherosclerotic burden, which was “quite shocking,” he said.

The burden rivaled that seen in patients with LDL levels greater than 160 mg/dL, he noted.

“Interestingly, these patients did not have higher levels of inflammatory markers, and they did not have higher disease activity scores. They looked exactly the same as the rest of the RA patients,” he said, noting that investigation into why the LDL levels in these patients are so low is ongoing.

As for how atherogenic lipoproteins allow for atherosclerosis and atherogenesis to occur in the setting of low LDL in RA patients, it turns out it’s not just the amount, but also the characteristics of the lipoproteins, such as the size and oxidization of the LDL, which change in the context of systemic inflammation, he explained.

Further, during an acute-phase reaction, high-density lipoprotein (HDL) composition changes rapidly from antiatherogenic to proinflammatory.

Extensive evidence shows that endothelial function is diminished in RA, and that RA patients have these and other proatherogenic mechanisms, as well as other elements of immunity that are associated with atherogenesis, including aspects of both innate and adaptive immune function, he said.

Given the emerging understanding of CVD risk in RA, mitigation of that risk is an important consideration. In fact, the European League Against Rheumatism updated its CVD management guidelines in 2015/2016, including a statement that rheumatologists are responsible for CVD risk management in RA patients (Ann Rheum Dis. 2017;76:17-28).

The guidelines are intended for all inflammatory arthritis, and the recommendation with the strongest level of evidence relates to optimization of disease activity. Also recommended are:

• CVD screening every 5 years.
• Use of a 1.5 multiplier for risk scores.
• Secondary screening with imaging for select patients.
• Management of traditional risk factors according to local guidelines.
• Minimization of the use of NSAIDs and corticosteroids.
• Emphasis on lifestyle management.

Importantly, research has suggested that screening for hyperlipidemia is substandard in RA, and that standard risk stratification tools underperform in the setting of RA, he said.

“So my approach, and this is not evidence based yet ... comes down to what [a patient’s] apparent risk is. So if an RA patient is high risk based on your apparent risk prediction, then they are likely high risk and maybe even higher than estimated,” Dr. Giles said. These patients need optimization of their traditional risk factors and their inflammatory factors and should therefore receive a high-intensity statin regardless of lipid levels, he said.

That means atorvastatin at a dose of at least 40 mg or rosuvastatin at a dose of at least 20 mg, he said, adding that some studies have suggested that statins work as well in RA patients as in non-RA patients, and that RA patients with CVD risk do better with a statin than without.

He considers patients who have intermediate risk based on the risk calculation to actually be high risk in most cases, and they, too, need maximal optimization of traditional CVD risk factors and inflammatory factors.

“Consider one-time secondary imaging for all of these patients,” he advised, noting that a coronary calcium score from a chest CT scan is a good option that has low radiation, can be quantified, and is increasingly covered by insurance.

A coronary calcium score of 0 on chest CT is highly reassuring, and a score that is greater than what is expected for age, gender, and/or race can help define the intensity of intervention, he said.

For example, if a patient’s score is 300 but should be 50, that patient should be treated as if he or she has coronary artery disease. Patients with high scores in general – particularly those with scores over 300 – should also be maximally managed, he said.

Patients at low risk based on risk calculations usually are low risk, but some can be high risk, so again, maximal optimization of risk factors is recommended.

Secondary imaging can be considered in some of these patients, and while it’s not entirely clear which are at greatest risk, Dr. Giles said he recommends screening those with treatment-resistant active disease, those with high disease severity, and those with abnormally low LDL.

Dr. Giles is a consultant for Genentech, Lilly, Horizon, Bristol-Myers Squibb, and UCB, and he has received grant support from Pfizer.

[email protected]