Association between antibodies to carbamylated proteins and subclinical atherosclerosis in rheumatoid arthritis patients

Abstract

BackgroundRheumatoid arthritis (RA) patients carry a high risk of cardiovascular morbidity and mortality. The excess of cardiovascular disease cannot be entirely explained by traditional risk factors and the immune system contributes to the development of atherosclerosis. Moreover, post-translational modifications such as citrullination and carbamylation have been linked to inflammation and atherosclerosis. Anti-carbamylated proteins antibodies (anti-CarP) are a new subset of autoantibodies identified in RA patients. This study aimed to investigate a possible association between anti-CarP and subclinical atherosclerosis in RA patients.MethodsWe enrolled RA patients and normal healthy controls (NHS) without known cardiovascular risk factors or heart disease. Cardiovascular risk was assessed using the Modified Systemic Coronary Risk Evaluation (mSCORE). Anti-CarP were investigated by a solid phase “home-made” ELISA. Anti-citrullinated protein antibodies (ACPA) and Rheumatoid Factor (RF) were investigated by ELISA assays. Subclinical atherosclerosis was evaluated by brachial artery Flow-Mediated Dilatation (FMD) and Carotid Intima-Media Thickness (c-IMT) while arterial stiffness by Ankle-Brachial Index (ABI) and Cardio-Ankle Vascular Index (CAVI).ResultsWe enrolled 50 RA patients (34 F and 16 M, mean age 58.4 ± 13.1 years, mean disease duration 127 ± 96.7 months) and 30 age and sex matched NHS. According to the mSCORE, 58% of patients had a low risk, 32% a moderate and 8% a high risk for cardiovascular disease. FMD was significantly lower in RA patients than in NHS (5.6 ± 3.2 vs 10.7 ± 8.1%; p < 0.004) and CAVIs significantly higher in a RA patients compared to NHS (left CAVI 8.9 ± 1.7 vs 8.1 ± 1.5; p < 0.04 for and right CAVI 8.8 ± 1.6 vs 8.0 ± 1.4; p < 0.04 for the). ABI and c-IMT did not differ between the two populations. The multivariate regression analysis showed a significant association of anti-CarP antibodies with FMD, left and right CAVI and both c-IMT (r = 1.6 and p = 0.05; r = 1.7 and p = 0.04; r = 2.9 and p = 0.05; r = 1.5 and p = 0.03; r = 1.1 and p = 0.03 respectively).ConclusionsThis study confirms that RA patients, without evidence of cardiovascular disease or traditional risk factors, have an impaired endothelial function. Moreover, we found an association with anti-CarP antibodies suggesting a possible contribution of these autoantibodies to endothelial dysfunction, the earliest stage of atherosclerosis. Besides ultrasound assessment, anti-CarP should be assessed in RA patients and considered an additional cardiovascular risk factor.

Guidelines for biomarkers in autoimmune rheumatic diseases - evidence based analysis

“…Similarly, Brink et al reported a more severe radiographic damage in 42.2% of RA patients positive for such antibodies over 2 years [46]. Anti-CarP antibodies have been also correlated with subclinical atherosclerosis and mortality in RA patients [47,48]. In the study by Spinelli et al, the association between anti-CarP antibodies and measures of endothelial dysfunction, used as markers of subclinical atherosclerosis, was described in 50 RA patients [47].…”

“…To date, efforts should be pointed out to harmonize and standardize biomarkers detection in order to allow comparison and generalization of results either at a research level, and in the everyday clinical setting. observational studies were retrieved and included in the review [44][45][46][47][48].…”

“…Anti-CarP antibodies have been also correlated with subclinical atherosclerosis and mortality in RA patients [47,48]. In the study by Spinelli et al, the association between anti-CarP antibodies and measures of endothelial dysfunction, used as markers of subclinical atherosclerosis, was described in 50 RA patients [47]. proteins associated with RA disease activity [49,50].…”

Increased cardiovascular risk in rheumatoid arthritis: mechanisms and implications

“…These antibodies were recently identified in rheumatoid arthritis patients and were associated with subclinical cardiovascular disease 6263. In addition, carbamylation has been shown to be pro-atherogenic in other disease states 64.…”

Clinical and etiological meaning of anti-carbamylated protein antibodies in rheumatoid arthritis

“…Anti-CarP Ab is a risk factor for future joint destruction independent of ACPA [1,[33][34][35][36][37]. A previous study reported that the anti-carbamylated albumin antibody was associated with a history of cardiovascular disease (CVD) [15] and anti-CarP Ab was associated with multiple indices of arteriosclerosis [38]. The intensity of treatment and screening plans for CVD may be modulated in accordance with the antibody profile.…”