Higher frequencies of age-associated B-cells in early arthritis are linked to atherosclerosis and immune circuits—a potential role as a biomarker for risk stratification

Abstract Objective Immune dysregulation may play a role in cardiovascular (CV) risk excess in RA. However, exact mediators are unknown. Age-associated B-cells (ABCs) have emerged as multi-faceted pro-inflammatory mediators, also in the atherosclerosis microenvironment, but their role in autoimmunity is ill-defined. Our aim was to evaluate ABCs frequencies in the earliest stages of inflammatory arthritis and their potential role as biomarkers of atherosclerosis. Methods ABCs were quantified by flow cytometry in 58 early RA patients, 11 individuals with clinically suspect arthralgia (CSA) and 33 healthy controls (HC). Atherosclerosis occurrence was measured by Doppler-ultrasound. Cytokines were measured by multiplex immunoassays. Cardiometabolic-related proteins were evaluated using high-throughput targeted proteomics. Results Circulating ABCs were increased in RA patients compared with HC within the CD19+ and PBMCs pools (P = 0.013 and P < 0.001, respectively). Higher ABCs median frequency was found in CSA. ABCs frequency was unrelated to disease features and traditional CV risk factors but negatively associated with good therapeutic outcomes upon csDMARD at 6 and 12 months. ABCs frequency was positively correlated with pro-inflammatory cytokines (IFNγ, TNF, IL-6 and IL-21) and proteomic signatures related to B- and T-cell responses as well as cellular pathways linked to atherosclerosis. ABCs predicted atherosclerosis burden in RA patients after adjusting for confounders. Furthermore, adding ABCs strata significantly improved risk stratification over conventional instruments. Conclusions Higher frequencies of ABCs are an early event along arthritis course, linked to therapeutic outcomes, inflammatory milieu and atherosclerosis burden. ABCs may be a missing link between humoral responses and atherosclerosis in autoimmunity.