Age-associated B-cells are expanded in early arthritis linked to atherosclerosis and immune circuits - a potential role as a biomarker for risk stratification

Objective

immune dysregulation may play a role in cardiovascular (CV) risk excess in rheumatoid arthritis (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 levels 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 clinical-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). Numerically higher ABCs levels were 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 proinflammatory cytokines (IFNg, 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 were independently associated with atherosclerosis occurrence and extent in RA patients. Furthermore, adding ABCs levels significantly improved risk stratification over conventional instruments.

Conclusions

ABCs expansion is 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.