There is now a substantial body of evidence linking rheumatoid arthritis (RA) with cardiovascular disease (CVD) (1–3) and, in particular, with increased death from cardiovascular causes (4–6). We have previously observed that within 8 years of the onset of arthritis symptoms, patients with rheumatoid factor (RF)–positive inflammatory polyarthritis (IP) have increased CVD mortality rates (7). In RF-positive women with IP, all the excess deaths observed could be attributed to cardiovascular causes.
Although there are a number of possible explanations for this link, one key question concerns the role of inflammatory activity. Atherosclerosis is now accepted to be a chronic inflammatory process (8). The concentration of C-reactive protein (CRP), both in the general population and in patients with known CVD, shows a strong association with subsequent events attributable to CVD (9–12). CRP is an acute-phase protein that is produced in the liver in response to an elevation in interleukin-6 levels. There is evidence that CRP has direct effects at the vessel wall that may promote atherosclerosis. These direct effects include stimulating the production of cellular adhesion molecules by vascular endothelial cells (13), facilitating the adhesion and migration of monocytes through the vessel wall, mediating the uptake of low-density lipoprotein cholesterol by macrophages (14), and causing complement activation (15).
Substantial evidence linking CRP concentrations and subsequent CVD risk in the general population now exists (16). Most of the studies that show such a link (17, 18) have utilized high-sensitivity CRP assays, which estimate the value of CRP within what is considered to be the normal range. This might not be relevant to the situation in RA, since most patients with this disease have an elevated CRP level. Thus, it is unclear whether the CRP level will be a useful predictor of subsequent CVD events in patients with chronic inflammatory joint conditions such as IP and RA.
We therefore examined whether the CRP concentration measured early in the IP disease process predicts future death from CVD. We also investigated whether this effect is independent of other markers of disease activity.
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- SUBJECTS AND METHODS
A total of 539 consecutive subjects in the NOAR had a CRP measurement, based on their inclusion in previous analyses of factors predicting disease outcome (24). At the baseline assessment, approximately one-half of the cohort satisfied the ACR criteria for RA. Data, including demographic, clinical information, and RF status, were incomplete for 33 participants. The study was therefore restricted to the remaining 506 patients with complete data.
The baseline demographic and clinical disease characteristics of the study cohort are shown in Table 1. Approximately 1 in 5 participants was taking a cardiovascular drug at study entry, including 37 (7%) who were taking 2 or more cardiovascular drugs. Two-thirds of the participants had ever smoked, and one-fourth of the participants were current smokers at the time of their first assessment. CRP concentrations ≤4 mg/liter were observed in 234 (46.3%) of the cohort. Of those patients with “elevated” CRP concentrations, 146 had levels in the range of 5–15 mg/liter and 126 had levels of 16 mg/liter and above.
Table 1. Baseline demographic and disease characteristics of the 506 subjects in the study cohort*
|Demographic variables|| |
| Sex, no. (%) male||179 (35.4)|
| Age at disease onset, median (IQR) years||55 (42–68)|
| Socioeconomic status, no. (%) manual occupation||238 (47.2)|
| Smoking status, no. (%)|| |
| Never smoked||153 (30.2)|
| Ex-smoker||221 (43.7)|
| Current smoker||132 (26.1)|
| Taking cardiovascular drugs, no. (%)||93 (18.4)|
|Disease variables|| |
| Delay to presentation, median (IQR) months||5.5 (2.9–12.0)|
| Swollen joint count, median (IQR)||7 (2–14)|
| Tender joint count, median (IQR)||9 (3–20)|
| HAQ score, median (IQR)||0.75 (0.25–1.50)|
| RF positive, no. (%)||173 (34.2)|
| CRP concentration, median (IQR) mg/liter||6 (2–15)|
| Nodules, no. (%)||50 (9.8)|
| RA (by ACR criteria), no. (%)||253 (50.0)|
| Taking NSAIDs, no. (%)||356 (70.4)|
Patients were followed up to December 31, 2001, with a median followup period of 10.1 years (interquartile range [IQR] 9.3–10.8). Over this time period, there were 104 deaths (Table 2). The all-cause mortality rate was 21.9 (95% confidence interval [95% CI] 18.1–26.5) per 1,000 person-years of followup. The mortality rate was higher in men than in women. Cardiovascular deaths occurred in 40 patients, with death from ischemic heart disease being reported most frequently (Table 3). The CVD mortality rate was 8.4 (95% CI 6.2–11.5) per 1,000 person-years of followup.
Table 2. Causes of death in the study cohort*
|Cause of death||Men (n = 179)||Women (n = 327)||All subjects (n = 506)|
|All causes||54 (30.2)||50 (15.3)||104 (20.6)|
|Cardiovascular causes||20 (11.2)||20 (6.1)||40 (7.9)|
|Respiratory causes||9 (5.0)||5 (1.5)||14 (2.8)|
|Neoplastic causes||17 (9.5)||14 (4.2)||31 (6.1)|
Table 3. Cardiovascular causes of death*
|Underlying cardiovascular cause of death||ICD-9 codes||ICD-10 codes||No. of subjects|
|Ischemic heart diseases|| || || || || |
| Acute myocardial infarction||410||I21, I22||3||6||9|
| Acute/subacute ischemic heart disease||411||I24||1||1||2|
| Chronic ischemic heart disease||414||I25||5||9||14|
| Total deaths from ischemic heart disease||410–414||I20–I25||9||16||25|
|Other vascular diseases|| || || || || |
| Pulmonary circulation||415–417||I26–I28||2||1||3|
| Other forms of heart disease||420–429||I30–I52||1||0||1|
| Cerebrovascular disease||430–438||I60–I69||5||2||7|
| Disease of arteries, arterioles, and capillaries||440–448||I70–I79||2||1||3|
|Total deaths from cardiovascular diseases||390–459||I00–I99||20||20||40|
In the univariate analysis, an elevated CRP (≥5 mg/liter) was associated with death from all causes, with a hazards ratio [HR] of 2.7 (95% CI 0.9–3.0) in men and 2.7 (95% CI 1.5–5.1) in women, and was strongly associated with death from CVD, with an HR of 3.9 (95% CI 1.2–13.4) in men and 4.22 (95% CI 1.4–12.6) in women. Figure 1 shows survival curves for death from CVD according to the CRP concentration. There was a trend toward an increasing risk of death with an increasing stratum of CRP for all-cause mortality and cardiovascular mortality, both in men and in women (Table 4). The associations were stronger for cardiovascular causes and were similar in both men and women.
Figure 1. Kaplan-Meier survival estimates of death from cardiovascular disease, by baseline concentration of C-reactive protein (CRP).
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Table 4. CRP concentration as a predictor of death, stratified by cause of death*
|CRP concentration||All causes||Cardiovascular causes|
|No. of subjects||Mortality rate||HR (95% CI)||No. of subjects||Mortality rate||HR (95% CI)||Mortality rate||HR (95% CI)||Mortality rate||HR (95% CI)|
|≤4 mg/liter||69||24.9||1.0 (referent)||165||8.5||1.0 (referent)||4.7||1.0 (referent)||2.4||1.0 (referent)|
|5–15 mg/liter||62||32.9||1.5 (0.7–2.9)||84||19.9||1.5 (0.7–3.1)||16.5||3.7 (1.0–13.9)||8.7||2.2 (0.6–7.6)|
|≥16 mg/liter||48||52.5||2.3 (1.0–3.7)||78||27.5||2.0 (1.0–4.0)||21.0||4.0 (1.1–15.2)||12.4||3.0 (0.9–9.8)|
Data stratified by RF status and RA classification, pooled across both sexes and adjusted for age, are shown in Table 5. The results show a substantial association between a raised CRP level and death from cardiovascular causes in subjects who were RF positive, with a virtual absence of an association in subjects who were RF negative, and a suggestion of a strong association between the CRP level and death from CVD in patients who met the ACR classification criteria for RA at baseline (Table 5). There was no evidence of a dose-response effect, with similar levels of risk in subjects with a CRP level of 5–15 mg/liter and those with a level ≥16 mg/liter. We finally tested whether there was any dose-response effect at levels below 5 mg/liter, comparing subjects with CRP levels <3 mg/liter with subjects with levels in the range of 3–5 mg/liter, and no difference was found.
Table 5. CRP concentration as a predictor of death from cardiovascular disease, stratified by baseline RF and RA status*
|CRP concentration||RF positive||RF negative||RA|
|No. of subjects||HR (95% CI)||No. of subjects||HR (95% CI)||No. of subjects||HR (95% CI)|
|≤4 mg/liter||58||1.0 (referent)||176||1.0 (referent)||96||1.0 (referent)|
|5–15 mg/liter||58||8.0 (1.8–36.2)||88||0.9 (0.2–3.8)||79||13.6 (1.7–107.1)|
|≥16 mg/liter||57||6.4 (1.3–30.8)||69||2.2 (0.7–7.0)||78||15.6 (2.0–120.7)|
|Elevated CRP (≥5 mg/liter)||115||7.4 (1.7–32.2)||157||1.5 (0.5–4.5)||157||14.7 (2.0–109.2)|
Multivariate analysis was used to examine whether elevated CRP levels predicted death from CVD, after adjustment for demographic and disease-related potential confounders including age, sex, HAQ score, socioeconomic class, swollen joint counts, smoking status (current and ex-smokers), and RF status. Only RF positivity and CRP levels ≥5 mg/liter were observed to be both independent and strong predictors of death (Table 6). This association between CRP and death from CVD persisted after adjusting for comorbid CVD, as assessed by the use of cardiovascular drugs at baseline (Table 7). All models satisfied the proportional hazards assumption.
Table 6. Multivariate model for the prediction of cardiovascular death*
|Variable||Hazards ratio (95% CI)|
|Age, per decade||2.9 (2.1–4.1)|
|Female sex||0.9 (0.5–1.8)|
|CRP level ≥5 mg/liter||3.3 (1.4–7.6)|
|RF positive||3.0 (1.6–5.8)|
|Swollen joint count, per joint||1.0 (0.9–1.0)|
|Smoking status, ever smoked||2.0 (0.8–5.1)|
|HAQ score, per unit||0.9 (0.6–1.5)|
Table 7. Alternative multivariate model with cardiovascular drug variables*
|Variable||Hazards ratio (95% CI)|
|Age, per decade||2.7 (1.9–4.0)|
|Female sex||0.8 (0.4–1.6)|
|CRP level ≥5 mg/liter||2.6 (1.1–6.3)|
|RF positive||3.0 (1.6–5.9)|
|Swollen joint count, per joint||1.0 (0.9–1.0)|
|Taking 1 cardiovascular drug||1.5 (0.6–3.8)|
|Taking ≥2 cardiovascular drugs||5.7 (2.6–12.5)|
|Smoking status, ever smoked||1.7 (0.7–4.5)|
|HAQ score, per unit||0.8 (0.5–1.2)|
- Top of page
- SUBJECTS AND METHODS
This analysis is the first to show that the baseline level of CRP is a predictor of all-cause mortality, and specifically CVD mortality, in both sexes in the 10-year period following the onset of IP. The major effect seems to be restricted to those who were RF positive or who met the ACR classification criteria for RA at baseline. Interestingly, other measures of disease activity at baseline, for example, tender or swollen joint counts or HAQ score, were not independently predictive of subsequent death from cardiovascular causes after allowing for the effect of the CRP level. This suggests that it is specifically CRP (or something closely associated with it) that is responsible for the link between RA and CVD. These data add to the studies showing that modest elevations in the CRP concentration in apparently healthy adults are associated with subsequent cardiovascular events (18, 25). The finding that a CRP concentration above the normal range is a significant predictor of death from CVD in groups of patients with inflammatory joint disease provides further evidence for the role of inflammation in promoting atherosclerotic disease.
This study had a number of strengths. It was a true prospective enquiry of a large inception cohort followed up for a substantial period of time and with complete followup data on mortality. The clinical and laboratory data collection were also standardized. However, there are some methodologic issues that need to be discussed. This study only measured CRP concentrations at the baseline NOAR assessment. It is possible that some patients would have received treatment of their inflammatory disease that may have modified their CRP concentration prior to this assessment. It is also possible that cumulative CRP concentrations during the period of followup would be even more predictive of subsequent death from CVD. However, despite this, it is of considerable interest that a single CRP measurement early in the inflammatory disease process proved so predictive of death from CVD. There is some evidence that the level of inflammation in RA is determined early in the disease course (26), and so, baseline CRP levels may be predictive of cumulative CRP levels. Baseline CRP levels have also been shown to predict subsequent radiologic progression in RA (27).
Another limitation of this study was that comorbid CVD was not recorded at baseline. The presence of comorbid CVD might have confounded the association between the CRP concentration and death from cardiovascular causes. Prescribed CVD drugs at baseline was used as a proxy measurement of baseline comorbid CVD. While we accept that this method is not ideal, the use of CVD drugs has previously been shown to be predictive of physician-confirmed CVD, with high specificity (95%) but low sensitivity (28). Therefore, it is likely that estimating comorbid CVD using this method will have introduced some misclassification and reduced the accuracy of our results. Patients who were receiving CVD drugs at baseline had higher baseline CRP levels (median 9 mg/liter [IQR 3–21]) than patients who were not receiving CVD drugs (median 5 mg/liter [IQR 2–14]) (P = 0.02). However, when we repeated the multivariate analysis excluding the patients who were taking CVD medications, elevated CRP concentrations were still associated with death from CVD (adjusted HR 2.9 [95% CI 1.0–8.2]). While it is possible that this group will still include a small number of patients with CVD comorbidity, we believe that it is more likely that the magnitude of CRP concentrations reflect the underlying inflammatory joint disease rather than undiagnosed and untreated comorbid CVD.
It has been suggested that traditional risk factors for CVD do not explain the increase in CVD events in RA (2). However, several studies have highlighted the association between CRP concentrations and traditional CVD risk factors (29, 30). In particular, smoking and body mass index (BMI) appear to be strongly and independently associated with CRP concentrations (31, 32). An important limitation of this study was that complete CVD risk factor data, and more importantly BMI, were not recorded at baseline. We did have data available from the simultaneous assessment of both BMI and CRP at 5 years in this cohort. At this time point, there was only a very weak association between these variables (rs = 0.08). Adjusting for current smoking at the baseline assessment did not alter the associations seen. Health-related behaviors do change over time, and it is possible that baseline smoking status does not reflect tobacco exposure during the followup period.
Recent population-based studies have used high-sensitivity assays that measure CRP in the range of 0.1–10 mg/liter (33). Such assays were not used in the current study. However, we were able to detect an association with death from CVD with only modest increases in the CRP concentration as measured using traditional assays. Treating CRP as a continuous variable in the multivariate model revealed that for every 1-mg rise in CRP concentration, we observed a 0.8% rise in the risk of death from CVD. However, as discussed above, stratification of CRP values <5 mg/liter did not reveal any trend in risk.
The subjects recruited for this study came from an inception cohort based on attendance in the primary care setting, and results may not be generalizable to patients with RA who are referred to a hospital. Approximately 50% of our subjects satisfied the ACR criteria for RA at baseline. However, we have previously demonstrated that these criteria are not stable in early disease (34) and, indeed, are probably not appropriate to use in that situation (35). Nonetheless, we found that CRP was a strong predictor of death from CVD within that group of patients meeting criteria for RA at baseline, although with wider confidence limits. More convincing was the association between elevated CRP and death from CVD in the RF-positive group, where a modest increase in CRP was associated with a 7-fold increased risk of death from CVD. A raised CRP was not associated with mortality in the seronegative subgroup. CRP concentrations in the seropositive patients (median CRP 9 mg/liter [IQR 3–22]) were higher than those in the seronegative patients (median CRP 4 mg/liter [IQR 1–13]). These data are consistent with our previous observation that compared with the general population, an increased risk of death from CVD was restricted to seropositive IP patients (7). It is possible that the mortality outcome in these seronegative patients is influenced by their lower inflammatory disease burden.
The diagnosis of death due to CVD was based on the underlying cause of death as recorded on the death certificate. The cause of death is not always known, and in some patients, CVD was recorded elsewhere on the death certificate but not as the underlying cause of death. Thus, the current analysis is restricted to those dying from CVD as opposed to those dying with CVD. It would also have been preferable if we had been able to verify the cause of death by inspection of the relevant medical charts, but the entire medical record was not available to us, particularly for subjects that had died some years prior to this analysis. These inevitable errors, which are typical of studies that rely on death certificates, should only have introduced random misclassification rather than systematic bias, since the extent of such errors is likely to be independent of CRP status.
A total of 33 subjects were excluded from this analysis because of incomplete data. There were 5 CVD deaths in this excluded group, and so, they were at a slightly higher risk of this end point than were patients included in the analysis. When the age-adjusted analyses were repeated, retaining the data for the excluded patients, stronger associations were observed between elevated CRP levels and death from CVD: HR 4.2 (95% CI 1.2–14.2) in men and HR 3.2 (95% CI 1.1–9.3) in women.
It is widely accepted that atherosclerosis is an inflammatory condition, and although initially, it was considered that CRP might just act as a marker of this inflammatory activity, it is possible that it plays a pathogenic role, promoting atherosclerosis. CRP levels in excess of 5 mg/liter have been found to be associated with increased vasoreactivity in patients with both stable and unstable angina (36). It may be that systemic inflammation associated with inflammatory arthritis will potentiate any underlying atherosclerosis and increase the risk of death from CVD.
In conclusion, we have found that an elevated CRP concentration measured early in the disease process is a powerful predictor of death from CVD in patients with IP and RA. The CVD outcomes in these high-risk patients may be improved by targeted interventions to reduce traditional risk factors for CVD and may also be improved by more aggressive suppression of their inflammatory joint disease.