Disease process, treatment side effects worsen cardiovascular risk for RA patients

[Guest guest]

Oct 28, 2002

Disease process, treatment side effects worsen cardiovascular risk for RA

patients

New Orleans, LA - Cardiovascular disease kills half of all patients who have

rheumatoid arthritis (RA), and this is partly because the disease processes

act synergistically to increase risk of death, according to Mayo Clinic

researchers. American College of Rheumatology experts advised clinicians to

be much more aggressive about reducing cardiovascular risk factors even in

younger, female patients. Early reports that infliximab and leflunomide each

increase cholesterol and LDL levels added a worrisome new factor to the mix,

but there are signs that cooling the RA inflammatory process might also help

protect against atherosclerosis.

Dr C Kent Kwoh (University of Pittsburgh, PA) said, " Cardiovascular is a

major problem for our patients. Not only should we be doing more to detect

and reduce their cardiovascular risk factors, but we must consider that

there are actually things that we do as rheumatologists that may aggravate

the cardiovascular risk. "

That risk was astonishingly high in population-based studies reported by

American and Swedish researchers. Dr Hilal Maradit Kremers (Mayo Clinic,

Rochester, MN) reported that the relative risk of dying after a myocardial

infarction (MI) is more than twice as high for rheumatoid factor-positive

(RF+) patients compared with either non-RA controls or to RF-negative RA

patients [1]. " There is a synergistic effect of RF+ rheumatoid arthritis and

cardiovascular that produces mortality far in excess of what would be

expected with either disease alone or from a simple additive effect of both

together, " said Kremers. " In patients who have not had an MI, RF+ disease

increases the risk of death by 68%, but in patients who have had an MI, RF+

arthritis is associated with a 140% increase in risk of death. "

These data were drawn from the Rochester Epidemiology Project, a

population-based database covering the residents of Rochester, MN. The data

analysis included all residents over the age of 18 who had RA first

diagnosed between 1955 and 1994, as well as age- and gender-matched non-RA

control subjects. Medical records for both cohorts were followed

longitudinally beginning 10 years before the RA diagnosis and continuing

until death. An electronic database that contains inpatient and outpatient

diagnoses by all local health care providers was used to determine the

occurrence of MI.

Three hundred and forty one (64%) of the 609 RA subjects were RF+, and 80

subjects (13.1%) had a history of MI. After adjusting for age and gender,

Kremers found that the risk of death among those who had an MI was more than

double for the RF+ patients. The relative hazard for death due to MI was 4.8

for non-RA controls and 4.27 for RF- RA patients but 11.46 for RF+ RA

patients. " The impact of these 2 conditions together was more than would be

expected based on the independent effects of each alone, " Kremers said.

Dr Carl Turesson (Malmö University Hospital, Sweden) reported similar data

from a population-based study in Malmö, Sweden [2]. " We were concerned that

the apparently increased cardiovascular mortality among RA patients reported

in previous studies might be due to patient selection, so we did a study of

virtually all of the RA patients in a defined area using data on all

cardiovascular incidents and mortality, " said Turesson.

The investigators found that the RA subjects were significantly more likely

to have a cardiovascular event during the 2-year study period, and these

were mostly increased numbers of first MIs. They suspect that this is partly

a consequence of RA-associated inflammation, since inflammatory mediators

play a central role in initiating atherosclerosis.

" The main predictor of death in RA patients is the presence of

extra-articular manifestations, indicating systemic involvement. One small

study of methotrexate has shown that bringing RA under control reduces

cardiovascular risk, but that needs to be confirmed, " Turesson said.

The Rochester and Malmö studies found increased risk in both males and

females with RA. Dr H (Brigham and Women's Hospital, Boston)

reported that data from 114 342 women in the Nurses' Health Study showed a

2-fold risk of acute MI in women with RA [3]. For women with RA for 10 years

or longer, the relative risk of acute MI was 3.1.

" Longer duration of RA was associated with increased MI risk regardless of

the patient's age, " said. " Factors that might contribute to the

increased risk include underlying systemic inflammation, exposure to

glucocorticoids or disease-modifying antirheumatic drugs (DMARDs), or

reduced use of cardiovascular prevention measures. The subjects with RA were

understandably less physically active and were less likely to use aspirin. "

said that clinical trials of aggressive cardiovascular risk factor

management in RA patients are needed, but that meanwhile, physicians should

work aggressively to reduce RA activity, discuss cardiovascular risk factors

with their RA patients, and make sure that primary care physicians monitor

factors such as hypertension and hyperlipidemia even in young RA patients.

Two studies raised the possibility that some of the tools for bringing RA

under control might actually raise cardiovascular risk, however. Dr M Vis

and colleagues (Vrije Universiteit Medisch Centrum, Amsterdam, the

Netherlands) reported that 68 patients treated with infliximab had increased

total cholesterol and LDL-cholesterol levels [4]. By week 6 of infliximab

treatment, total cholesterol had increased from 5.17 mmol/L to 5.52 mmol/L

(p<0.001), and HDL-cholesterol had increased from 1.47 mmol/L to 1.59 mmol/L

(p<0.001). " Our study suggests that treatment with infliximab induces

significant increased levels of both total cholesterol and HDL cholesterol,

but the atherogenic index did not change significantly during the [6-week]

study period, " Vis said.

Similar effects associated with leflunomide were reported by Dr Aleksander S

Prokopowitsch and colleagues (University of São o, Brazil) [5]. They

followed lipid profiles in 17 RA patients treated with leflunomide. Total

cholesterol and LDL levels rose steadily over the 18-month treatment period,

and by 12 months atherogenic profiles were significantly worse: the

cholesterol/HDL ratio rose from 3.4 to 4.09 (p=0.03), and the LDL/HDL ratio

rose from 2.1 to 2.90 (p=0.02). " Increased levels of cholesterol and LDL

were consistently observed in 88% of patients treated with leflunomide, to a

mean increase at 18 months of 17% for cholesterol and 27% for LDL, "

Prokopowitsch reported. " This provides compelling evidence of a progressive

deleterious effect of leflunomide on RA lipid profile, and a close

monitoring of lipid abnormalities is essential. "

The one bright spot was a report from Dr Forster and colleagues

(University Hospital, Zûrich, Switzerland) that treatment with infliximab

significantly improves endothelium-dependent (flow-mediated) vasodilation in

patients with active RA [6]. Endothelial dysfunction is one of the first

events in the atherosclerotic process. The investigators used

high-resolution ultrasound to measure the diameter of the brachial artery at

rest, during reactive hyperemia, and after nitroglycerine, before and after

12 weeks of infliximab. They found that endothelium-dependent vasodilation

improved from 3.2% to 4.2% after infliximab (p=0.018). " The data suggest

that endothelial dysfunction in RA is mediated by TNF, " Forster said.

Coauthor Dr Oliver Distler said that anything that reduces systemic

inflammation might be expected to reduce the stiffness of affected blood

vessels but that other antirheumatoid drugs have not been examined for these

effects.

[Guest guest]

a,

Thanks for this article. It perhaps explains why my total cholesterol

recently was 232, up from 199 six months ago. I had even been making a

special effort to lower it, too.

In fact, just today I called my endo for a prescription for a

cholesterol-lowering medication.

Now it makes sense.

Sue in NC

on 10/28/02 11:24 PM, a at paula54@... wrote:

> Similar effects associated with leflunomide were reported by Dr Aleksander S

> Prokopowitsch and colleagues (University of São o, Brazil) [5]. They

> followed lipid profiles in 17 RA patients treated with leflunomide. Total

> cholesterol and LDL levels rose steadily over the 18-month treatment period,

> and by 12 months atherogenic profiles were significantly worse: the

> cholesterol/HDL ratio rose from 3.4 to 4.09 (p=0.03), and the LDL/HDL ratio

> rose from 2.1 to 2.90 (p=0.02). " Increased levels of cholesterol and LDL

> were consistently observed in 88% of patients treated with leflunomide, to a

> mean increase at 18 months of 17% for cholesterol and 27% for LDL, "

> Prokopowitsch reported. " This provides compelling evidence of a progressive

> deleterious effect of leflunomide on RA lipid profile, and a close

> monitoring of lipid abnormalities is essential. "