There is increasingly strong evidence that patients with rheumatoid arthritis (RA) experience accelerated atherosclerosis. This results in an approximately twofold increase in mortality from myocardial infarction (MI) and stroke compared with the general population.1,2,3,4,5,6
The increased mortality is apparent within the first 8–10 years from symptom onset5,7
and is most marked in patients who are positive for rheumatoid factor. There is also evidence of an increased risk of non‐fatal MI and heart failure.8,9,10
Although RA and atherosclerotic cardiovascular disease (CVD) share risk factors such as smoking and a poor diet, the increased risk of CVD in RA cannot be explained by traditional risk factors alone. Inflammation and treatment may each have a role. RA is now accepted as an independent risk factor for the development of CVD, with the risk being of the same order of magnitude as is seen in diabetes mellitus.11
The inflammatory link is reinforced by the finding by Choi et al12
that patients with RA treated with methotrexate had a 70% reduced cardiovascular mortality compared with those treated with other traditional disease modifying anti‐rheumatic drugs (DMARDs) after adjusting for potential confounders.
Atherosclerosis too is now being viewed as an inflammatory condition.13
In healthy individuals, high‐sensitivity C‐reactive protein (hsCRP) has been shown to predict incident cardiovascular events in both men and women.14
However, the situation in RA is very different: chronic synovial inflammation is driving a systemic inflammatory response with levels of CRP much higher than those in the hsCRP studies. Nevertheless, the relationship between CRP and CVD holds true in inflammatory arthritis and RA. Work from the Norfolk Arthritis Register, a primary care‐based inception cohort of patients with inflammatory polyarthritis, found raised baseline CRP levels to be strongly associated with death from CVD, with a hazard ratio (compared with normal CRP) of 3.9 for men and 4.2 for women.15
In a population‐based incidence cohort of patients with RA from the Mayo Clinic, the erythrocyte sedimentation rate (ESR) was both a baseline and a time‐dependent predictor of cardiovascular death.16
In both studies, the association between inflammatory markers and cardiovascular death persisted after adjustment for traditional cardiovascular risk factors. Although the nature of the relationship between CRP and cardiovascular events is not clear from these epidemiological studies—Is it causal? Is it a surrogate marker?—they do strongly support a role for inflammation in accelerating the progression of CVD.
Such clinical endpoint cohort studies rely upon long periods of prospective follow‐up or accurate retrospective data regarding cumulative inflammatory burden. An alternative approach increasingly used in CVD studies is to measure subclinical atherosclerosis non‐invasively, allowing exploration of the progression of atherosclerosis before the onset of clinically significant events. Increased carotid artery intima media thickness (IMT), an indicator of generalised atherosclerosis, has been documented in patients with RA without a prior history of CVD both with17,18
traditional risk factors. It is of interest that, although there was no relationship between inflammatory markers and carotid IMT (isolated inflammatory markers may not be a good marker of cumulative disease activity),17,19
there was an association between increased IMT and a history of extra‐articular RA.19
One study explored the association between cumulative inflammation and carotid IMT, finding a positive association with cumulative ESR but not CRP.18
Another component of atherosclerosis, in addition to arterial wall thickening, is arterial stiffness. This is increased in patients with RA compared with normal controls.20,21
Again, the link with inflammation is present with a correlation between arterial stiffness and both disease duration and inflammatory markers (CRP, interleukin (IL)6).20
These findings suggest that reducing the burden of inflammation in RA—particularly sustained reduction of the ESR and/or CRP—might be expected to slow the progression of atherosclerosis and so improve the cardiovascular outcome of these patients.