Rheumatoid arthritis (RA) affects from .5%–1% of the population, presents with a 1.3–3-fold increase in mortality compared with that of the general population, and its 40%–50%1–4 mortality rate from cardiovascular origin is a notable factor.

Studies like those of Solomon et al. and Maradit-Kremers et al. have reported the increase in the risk of acute myocardium infarct (RR: 2.07–3.17) and stroke (RR: 1.48) in patients with RA,5,6 comparable to that described in type 2 diabetes mellitus (OR: 2.7–3.11).7,8

Although the traditional risk factors are important in the pathogenesis of atherosclerosis, they do not fully explain the reason for the increase in cardiovascular events (CVE) described in this patient group.9–11 Cardiovascular disease is therefore currently considered to be an extra articular symptom of RA.12–16 Medium to long-term cardiovascular risk (CVR) estimation is therefore necessary,17 as this would enable prevention activities to be prioritised and for the intensity with which these factors must be treated to be defined.18,19

In 2010, EULAR reached a consensus regarding the modified SCORE (SCOREM) CVR assessment scale, which consisted in multiplying by a conversion factor of 1.5 the result obtained with SCORE for those patients with 2 of the following 3 criteria: duration of the disease higher or equal to 10 years, rheumatoid factor (RF) or the determination of anti cyclic citrullinated peptide (ACCP) antibodies and the presence of extra articular symptoms.20 However, it has been observed that this tool and the factors under consideration under diagnose this risk: up to between 12% and 30% of subclinical atherosclerosis have been identified by carotid ultrasound scan and the development of short to medium term CVE in patients classified as low/intermediate risk,21–26 which has resulted in further attention being paid in recent years to other clinical features linked with RA which could be more associated with an increase in the risk of subclinical atherosclerosis. The most outstanding of these are: the level of activity of the disease, the inflammation markers, the level of compromise or articular erosion or the use of corticoids.27–33

The aim of this study was to calculate the role disease activity plays in the development of subclinical atherosclerosis in patients with RA of low cardiovascular risk.

A cross-sectional, observational, analytical study (blind to the ultrasound scan study) was performed for patients with RA (according to ACR 1987 or ACR/EULAR 2010 criteria) at the General University Hospital of Ciudad Real (HGUCR) during the period from June 2013-May 2014.

Patients over18 who agreed to participate in the study and who signed the informed consent form were included. Patients with non-affiliated arthritis or overlap syndromes, recent clinical history or diagnosis of previous CVE, diabetes mellitus or kidney failure (glomerular filtration rate<60ml/min).

A complete analysis was performed which included serological and activity markers (speed of globular sedimentation, reactive C protein, rheumatoid factor and anti CCPs), together with a metabolic study for the evaluation of CVR (baseline blood sugar level, glycosylated haemoglobin, uricaemia, renal, lipid and thyroid profiles). The degree of activity was calculated through the SDAI (number of swollen joints, number of painful joints, overall patient assessment, overall assessment of the physician and CRP levels). Activity records fro the previous year were collected through the SDAI, including those made at the start of the study and an average was obtained with regard to the activity.

The patients with RA were divided into low CVR and high CVR (patients with medium, high or very high risk) according to the SCOREM.

Finally, a carotid ultrasound scan study was performed by a radiologist who was always unaware into which group each patient belonged. An ultrasound scan of the brand Toshiba Aplio XG, model Ssa-790A was used, with a lineal transductor of 7–10MHz, focusing on the measurement of the intima-media thickness (IMT). It was considered pathological if the IMT was >.9mm and with the presence of the atheromatous plaque (AP) (focal thickening >1.5mm), according to standard protocol.34–36

The information obtained was inserted into a Microsoft Excel database. The variables were assessed using frequency measurements and central tendency/dispersion measurements and the strength of the association of the variables were assessed with the odds ratio and its confidence interval at 95%. STATA 12.0 was used for analysis and the calculation of Yates correction was performed with the IBM SPSS 22.0 programme. The study protocol was approved by the Clinical Research Ethics Committee of the University Hospital of Ciudad Real.

During the period from June 2013 to May 2014 of a total of 119 patients with RA (63.87% females; 36.13% males) agreed to take part in the study (see Table 1).

In the population under study there was a high prevalence of the presence of any CVR factor (84.87%) and a 73.1% presence of standard risk factors. Furthermore, 6.72% had presented a CVE when the study began.

With regard to the clinical RA profile, a prevalence of 79.83% positive serological markers (RF or ACCP) was observed, together with disease course above 10 years in 47% of our sample. Furthermore, 66% received appropriate disease control, both globally via the SDAI (remission or low activity) and through the presence of inflammatory activity biological markers. The most common treatment was the use of corticoid therapy at a 5–10mg/day dose of prednisone or equivalent and disease modifying anti-rheumatic drugs (principally methotrexate).

Eleven patients (9.24%) were excluded at the beginning of the study because they presented with known vascular disease (8 previous events, 4 diabetes mellitus and 2 nephropathies), and therefore a total of 108 patients remained upon whom the study analysis and SCOREM calculation was performed (48 low risk and 60 intermediate, high and very high risk) (Fig. 1).

Fig. 1.

Distribution of the 108 patients after initial estimation using the SCORE and SCOREM.

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Following the specific analytical study results (baseline blood sugar level, lipid and thyroid profiles, creatinine, glomerular filtration, glycosylated haemoglobin, uric acid, acute phase reactants, RF, ACCP, etc.) 27 patients were excluded: 18 due to altered glycosylated haemoglobin and 12 due to glomerular filtration <60ml/min (3 patients with both findings), which elevated the prevalence of CVR factors in our total population sample (Fig. 2).

Fig. 2.

Prevalence in percentages of the cardiovascular risk factors in the 119 patients with rheumatoid arthritis.

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Of the remaining 81 patients (46 low risk and 25 intermediate, high and very high risk), 10 patients did not attend the carotid ultrasound scan, and the study analysis was finally performed on a total of 71 patients (41 low risk and 30 intermediate, high and very high risk) (Table 2). General recommendations were given to all patients regarding healthy lifestyles and high/very high-risk patients were administered with treatments depending on their CVR profile, with subsequent follow-up by the primary care physician.

The variables taken into account for estimation of the SCOREM were more prevalent in the high-risk group. The variables in the high risk group with a statistically significant difference (P<.05) were age, gender, HBP, ACCP and activity measured by SDAI.

Average IMT in the low risk group measured by SCOREM was .65mm and .80mm in the high-risk group. The other ultrasound features per risk groups are shown in Fig. 3.

Fig. 3.

Distribution of ultrasound events in the risk groups according to SCOREM.

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Analysis of the correlation between the CVR stratification by SCOREM and the findings from the ultrasound scan related that, according to our results, stratifying as a high risk (intermediate, high and very high) increases the risk of presenting with atheromatous plaque by 3 times, with a P=.037. However, there is a notable existence of 14.63% patients classified as low risk (6/41) who present with subclinical atherosclerosis due to the presence of atheromatous plaque. This represents 35.39% (6/17) of the total AP identified in our study population (Table 3).

Results are similar if calculation of sensitivity, specificity, VPP and VPN are made using the cut off point of the IMT of ≥.9mm (Table 4). However, results vary if we take the percentile p75 of the IMT as reference, in the healthy Spanish population, as the sensitivity of this tool drops to 38.71%, which determines that 46.34% of patients classified as low risk by SCOREM present with a IMP higher than the IMT p75 depending on gender and age. In the light of these factors, the specificity obtained (55%–64.81%) expresses a limitation in the capacity this test has in detecting those who do not have the sought-after condition (true negatives).

Regarding the link with the level of activity and subclinical atherosclerosis, there is a notably strong association, with an OR 4.95 and P=.008, between the presence of atheromatous plaque and the degree of activity of the disease measured globally with clinical and analytical parameters by the SDAI and not just due to the elevation of the acute phase reactants. The presence of disease activity would condition an increase in the risk of presenting a pathological IMT: IMT>.9mm (OR 2.5; CI 95%: .59–10.55; P=.21) or IMT>p75 (OR 2.2; CI 95: .75–6.4; P=.14) with a fairly acceptable confidence interval (Fig. 4).

Fig. 4.

Association between the level of activity by SDAI and the presence of subclinical atherosclerosis.

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The factors relating to the RA which are taken into consideration by EULAR for modification of the SCORE proposal present an association with the increase in the risk of subclinical atherosclerosis, although this is not statistically significant: evolution time >10 years (P=.19), RF (P=.95), ACCP (P=.73) and extra articular symptoms (P=.34).

Although there is an acceptable correlation between the presence of subclinical atherosclerosis using carotid ultrasound and the SCOREM stratification table proposed by EULAR, there is an underestimation of the risk in 14.63% of the population classified as low risk who present with atheromatous plaque. This leads to low sensitivity and specificity as a screening tool. As a result we recommend performing a carotid ultrasound in patients with RA who are not initially classified as high/very high risk according to the available stratification tables. This would enable us to re-stratify those patients initially considered to be low/intermediate risk and thus change our clinical, therapeutic and follow-up approach. Due to all of the above we believe it essential to create a specific tool for patients with RA which would enable the calculation of their real CVR, taking into account factors which are strongly related to CVR.

Since one of the risk factors most highly associated with the present of subclinical atherosclerosis was the level of inflammatory activity, the aim of our treat to target approach would have an impact on pain control, functional improvement and also reduce CVR in our patients.

The authors have no conflict of interests to declare.