Rheumatoid arthritis (RA) is associated with increased mortality, predominantly due to accelerated atherosclerosis.1 Traditional cardiovascular disease (CVD) risk factors cannot fully account for this increased propensity and it seems that the sustained inflammatory state of RA represents a crucial element for enhanced atherosclerotic risk.1 2 In fact, CVD mortality in RA appears to be predicted by the level of disease activity and severity of joint damage and extra-articular manifestations.2 3 Some immunological markers, such as rheumatoid factor or antinuclear antibodies, are more often encountered in RA with extra-articular manifestations.4 Anti-cyclic citrullinated peptide (anti-CCP) antibodies have been shown to be highly specific for RA and are predictors of disease severity, even stronger than rheumatoid factor.5 They have been also associated with disease extra-articular manifestations,4 but their association with CVD morbidity has never been examined.

To evaluate the effect of anti-CCP on atherosclerotic damage in RA, carotid intima-media thickness (IMT) of 81 consecutive patients with RA without overt CVD was analysed by ultrasound, as described.6 Seventy-five age- and sex-matched healthy subjects with a similar distribution of risk factors (smoking, high body mass index, hypercholesterolaemia, hypertension, diabetes mellitus and CVD family history) formed the control group. Evaluation of anti-CCP was performed in all patients by an enzyme-linked immunosorbent assay (Diastat, Axis-Shield Diagnostics, Dundee, UK). The study was approved by the local ethical committee.

IMT values were higher in the patients than in controls at all artery domains examined (common, bifurcation and internal carotid) (table 1). Patients with RA with detectable circulating anti-CCP had higher IMT at internal carotid arterial wall than patients without evidence of these antibodies. The fact that we found differences only at the internal carotid may be due to a low number of enrolled patients, but it may also be explained by the observation that atherosclerosis primarily involves the upper carotid tract (internal carotid and bifurcation).7

The patients who were anti-CCP positive did not differ from the other patients for age, disease duration, traditional risk factors and treatment (data not shown), but included a higher number of males. This finding agrees with the demonstration that male patients with RA are more likely to be seropositive for, and have higher titres of anti-CCP compared with female patients.8 Although this may represent a confounding factor that might explain the higher internal carotid IMT found in the patients who were anti-CCP positive, a multivariate analysis showed that only age, smoking and anti-CCP, but not sex or other traditional risk factors, were predictors of internal carotid thickening in our series.

The role of age and smoking as predictors of atherosclerosis in RA has been described in several studies.1 2 9 10 However, to our knowledge, this is the first report showing an association between anti-CCP and subclinical atherosclerosis in patients with RA. The finding that smoking may trigger immunity to citrullinated proteins in genetically predisposed subjects with RA 10 may represent a fascinating pathogenic link between smoking, anti-CCP and atherosclerosis acceleration in RA. Further studies with higher number of patients are ongoing to verify the benefit of anti-CCP determination in identifying patients with RA at high risk for CVD.