Our data demonstrate that a substantial proportion of RA patients thought to have suppressed disease nonetheless have CRP levels that are associated with high (>3 mg/L) and very high (>10 mg/L) risk of cardiovascular events in the general population. Our findings should be viewed in the context of currently recommended therapeutic targets in RA. For example, the American College of Rheumatology (ACR) recommends a therapeutic goal of remission or mild disease activity by CDAI or DAS28 
. In our study, 47% to 83% of those with mild activity by these measures had CRP levels>3 mg/L, and 16% to 19% had CRP levels>10 mg/L. In its guidance on the use of TNF inhibitors for RA, the United Kingdom's National Institute for Health and Clinical Excellence accepts moderate disease activity and requires severe activity by DAS28 for the introduction of TNF inhibitors 
. We observed that 70% to 73% of our patients with moderate disease activity by DAS28 criteria had CRP levels>3 mg/L and that 26% to 33% of these had CRP levels>10 mg/L.
The basis for the high prevalence of elevated CRP levels in RA patients with mild to moderate disease activity is not certain but likely is multifactorial. First, the clinical joint exam lacks sensitivity to detect subtle synovitis and may underestimate the extent of active rheumatoid disease. Indeed, magnetic resonance imaging can detect inflammation in rheumatoid joints clinically thought to be free of synovitis 
. Second, chronic inflammation at extraarticular sites (e.g., gingivitis) might stimulate CRP production. None of our patients had clinically apparent infections at the time of analysis, and CRP levels in our patients with mild disease activity are stable over time (unpublished observations), arguing against an intercurrent event as a source of elevated CRP. Third, the low prevalence of smoking in the SFGH RA cohort (12.5%) excludes an important contribution of smoking to CRP levels in our study. Finally, adipose tissue, particularly visceral fat, is a source of CRP production and can make contributions to the serum CRP levels of RA patients independent of their disease activity 
Several studies suggest that treatment of RA with methotrexate or TNF inhibitors may reduce cardiovascular events and mortality due to CVD 
, but the improvement may only occur in those who have a response to therapy 
The great majority of patients with moderate disease activity or better in our study were on methotrexate or other synthetic disease-modifying anti-rheumatic drugs. Among the patients receiving TNF inhibitors in our study, the median CRP level (6.0 mg/L) and the prevalence of CRP>3 mg/L (76%) or>10 mg/L (27% ) did not differ significantly from those of patients not using TNF inhibitors, but the patients receiving these agents appeared to have more severe disease (data not shown).
While therapies may reduce some of the overall cardiovascular risk of a population of RA patients, there are limited data on the extent of residual cardiovascular risk in individual treated RA patients. For example, it remains to be seen whether treating RA patients to levels of mild disease activity or remission, as assessed by the best available clinical metrics, normalizes cardiovascular risk relative to that of the general population. However, our finding that a majority of patients who achieve these ACR-recommended targets nonetheless have elevated CRP levels suggests that excess cardiovascular risk persists. Consistent with this possibility, endothelial dysfunction was reported in a study of young to middle aged patients with RA who were in remission or had mild disease activity by DAS28-ESR and who were free from other cardiovascular risk factors. In that study, endothelial dysfunction correlated with average CRP levels and disease duration 
Our study has several limitations. First, it is cross-sectional. However, studies demonstrating CRP to be an independent predictor of cardiovascular risk, including those involving RA patients, often used a single, baseline measurement of CRP 
. Second, we examine a biomarker for cardiovascular risk (CRP) rather than cardiovascular outcomes. Levels of cardiovascular risk have not been assigned to specific values of CRP in RA, as has been done in the general population. However, the available evidence, although limited in scope, does not support the notion of differential cardiovascular risk for a given level of CRP between the general population and patients with RA. For example, in a 10 year observational study of newly diagnosed RA, patients whose baseline CRP levels were≥5 mg/L had a hazard ratio of death from CVD of 14.7 (95% CI 2.0–109.2) relative to those with baseline CRP levels<4 mg/L 
. Moreover, RA patients with even modestly elevated CRP levels (>1.92 mg/L) are more insulin-resistant than those with lower CRP levels 
. Inflammation-induced insulin resistance contributes to the deleterious effects of inflammation on the cardiovascular system 
Our study indicates that systemic inflammation, as reflected in an elevated CRP, persists in a sizable number of RA patients with minimal or no clinically detectable joint disease and thus may confer increased cardiovascular risk upon these patients. Future studies should examine the relation of subclinical joint inflammation detected by sensitive imaging techniques to markers of cardiovascular risk. If this risk predicted here is confirmed by future studies, then recognition of these at-risk RA patients may have important implications for therapy. One option might be to base treatment decisions on disease assessment scores more heavily weighted towards markers of inflammation or to treat subclinical joint inflammation. Given the efficacy, toxicity, and expense of current RA therapies, however, an alternative strategy might be to aggressively modify traditional cardiovascular risk factors in those with persistent systemic inflammation. Even in the absence of elevated low density lipoprotein, the use of statins might reduce cardiovascular risk in RA patients with elevated CRP. Of note in this regard, the recently published JUPITER trial of apparently healthy individuals without hyperlipidemia but with CRP≥2 mg/L demonstrated that statin therapy significantly reduced major cardiovascular events, with a hazard reduction of 0.56 (p<0.00001) 
. With respect to RA, our results point to the need to define the extent to which the persistent systemic inflammation places individual RA patients at risk for CVD and to determine the cardiovascular benefits of more aggressive RA therapy, of risk modification, and of the use of statins.