Anti-citrullinated fibrinogen (anti-cit-fibrinogen) may serve as a potential biomarker for assessing cardiovascular (CV) risk in patients with rheumatoid arthritis (RA).
In examining 10 types of anti-cit-fibrinogens in patients with RA, anti-cit-fibrinogens as a group were associated with coronary artery disease (CAD) outcomes, with the association driven by a subset of autoantibodies in a subgroup that contained seven of the 10 anti-cit-fibrinogens, found researchers from Boston and Bordeaux, France.
Boris P. Hejblum, PhD, of Harvard School of Public Health in Boston, and the University of Bordeaux in France, and colleagues wrote that their study supports preclinical data and suggests that anti-cit-fibrinogens can improve CV risk stratification in RA patients.
“While our study adjusted for traditional CV risk factors, future Phase 4 biomarker development studies investigating the predictive value of these biomarkers in an independent cohort are needed,” they wrote in Arthritis Care & Research.
CV disease is the leading cause of death for patients with RA. Traditional risk factors tend to underestimate CV risk in patients with RA. A specific class of anti-citrullinated proteins antibodies (ACPAs), anti-cit-fibrinogen, have been studied as a potential marker for CV disease in RA, with research to suggest “a mechanistic pathway whereby inflammation promoted cit-fibrinogen in atherosclerotic plaques, and thus the development of anti-cit-fibrinogen may be a useful marker of inflammation, atherosclerotic burden and CV risk in RA,” Hejblum and colleagues wrote. A subsequent study that used a different platform to measure anti-cit-fibrinogen, however, failed to detect an association between carotid intima media thickness and anti-cit-fibrinogen titers.
These previous studies examined surrogate CV outcomes, prompting the authors to examine the association between ACPAs and CAD outcomes in a cohort of 1,006 patients with RA from two large tertiary care hospitals. Plasma samples from patients were measured for anti-cit-fibrinogen. Antibodies directed against 10 epitopes of cit-fibrinogen were measured.
The mean age of the patients was 61.0 years; 79.0% were female, and 72.2% were positive for anti-cyclic citrullinated peptide (CCP).
A principal components analysis (PCA) was performed to assess whether the anti-cit-fibrinogens clustered into groups, and each group was tested for its association with CAD.
From the PCA analysis, three main groups emerged: PC1, PC2, and PC3. PC1 accounted for more than 80% of the anti-cit-fibrinogen antibody variability among all anti-cit-fibrinogen antibodies. PC2 explained an additional 7.7% of variability; and PC3, an additional 3.5% of variability.
As a group, the anti-cit-fibrinogens were associated with a higher risk of CAD, adjusted for age, gender, race, diabetes, hypertension, hyperlipidemia, smoking, and use of non-biologic disease-modifying antirheumatic drugs (DMARDs), biologic DMARDs, and prednisone (P=0.00011). By subgroup, the strongest association was observed in group PC2, which included seven of the 10 anti-cit-fibrinogens examined (P=0.015).
A sensitivity analysis using ICD9 codes showed a similar association between anti-cit-fibrinogen as a group with ischemic heart disease (P=0.00029), as well as between-group PC2 and ischemic heart disease (P=0.004). Using the same covariates for adjustment, no association between anti-CCP positivity and CAD was observed (OR 1.3, 95% CI 0.7-2.3).
A total of 897 RA patients had high-sensitivity C-reactive protein (hsCRP) data recorded. The association between anti-cit fibrinogens and CAD remained significant, adjusting for CV risk factors and hsCRP (P=0.00022 among overall cohort, P=0.0071 for group PC2). This association remained significant after adjusting the model to include hsCRP and anti-CCP status. The concentrations of anti-cit fibrinogen therefore provided information additional to anti-CCP in identifying which RA patients had CAD, Hejblum and colleagues said.
They added that the study may explain why some previous reports did not find associations between anti-cit-fibrinogen and surrogate measures of CV risk: “While we detected a significant association between all anti-cit-fibrinogens with CAD, the signal appeared to be driven by a group of targets within the large fibrinogen molecule. Thus, if a particular ACPA assay does not measure antibodies targeting specific regions of fibrinogen, an association with CAD, may not be detected.”
A limitation to the study, the team noted, was the collection of samples in patients with prevalent CAD, thus not permitting an estimation of the value of anti-cit-fibrinogen in predicting future CAD risk.
Funding was provided by the Rheumatology Research Foundation.
Robert Jasmer, MD Associate Clinical Professor of Medicine, University of California, San Francisco and Dorothy Caputo, MA, BSN, RN, Nurse Planner