Reduced circulating anti-CXCR3 antibodies as a common hallmark bridging systemic autoimmunity and atherosclerosis.

Introduction: immune dysregulation underlies cardiovascular risk excess in systemic autoimmune diseases, such as rheumatoid arthritis (RA) and Sjögren disease (SjD). However, exact mediators are unknown. Regulatory autoantibodies targeting G protein-coupled receptors, including CXCR3, have emerged as modulators of immune and vascular homeostasis, but their role in autoimmunity remains ill-defined. Our aim was to evaluate anti-CXCR3 levels in systemic autoimmunity and their potential value as biomarkers. Methods: anti-CXCR3 IgG serum levels were quantified in early RA (n=84), clinically-suspect arthralgia (n=14), and controls (n=65). Established RA (n=103) and SjD (n=44) were recruited for validation. Atherosclerosis was assessed by carotid ultrasound. Cytokines were measured by multiplex immunoassays. Cardiometabolic-related proteins were evaluated using high-throughput targeted proteomics. Publicly available datasets were used for validation. Results: anti-CXCR3 antibodies were significantly reduced in early RA and clinically-suspect arthralgia compared with controls, independently of disease activity, autoantibodies, or systemic inflammation. This finding was confirmed in the validation cohort. Equivalent results were also observed in SjD. Anti-CXCR3 were negatively associated with good therapeutic outcomes upon csDMARD at 6 and 12 months in early RA. Lower anti-CXCR3 levels were independently associated with atherosclerosis occurrence and extent across conditions. Incorporating anti-CXCR3 into mSCORE improved risk stratification. Anti-CXCR3 were related to proteomic signatures linked to immune activation and to apoptosis, chemotaxis, and cell adhesion in an atherosclerosis-dependent manner in RA and SjD. Transcriptomic analyses indicated compartment-specific CXCR3 dysregulation both in RA and SjD. Conclusion: reduced anti-CXCR3 antibodies represent a shared hallmark bridging systemic autoimmunity and atherosclerosis burden, shaping our understanding on the regulatory role of antibodies at the vascular-immune interface. Clinical translation of anti-CXCR3 antibodies hold promise to improve risk stratification.