Anti-CXCR3 IgG Linked to Carotid Atherosclerosis in RA
Key Takeaways
- Anti-CXCR3 IgG levels were lower in early and established rheumatoid arthritis, clinically suspect arthralgia, and Sjögren disease than in their respective healthy-control groups.
- Lower antibody levels were associated with carotid plaque in early RA after adjustment for cardiovascular risk factors and statin use.
- Adding antibody tertiles to mSCORE improved classification of existing atherosclerosis in early RA, principally among participants with plaque.
- Lower baseline antibody levels accompanied poorer csDMARD response in early RA.
Miranda-Prieto and colleagues’ Frontiers in Immunology study was observational and primarily cross-sectional, with recruitment associated with Asturias, Spain. Cohorts included early RA at diagnosis before disease-modifying antirheumatic drug (DMARD) exposure, clinically suspect arthralgia, established RA of more than a year’s duration, SjD, and respective healthy controls. The Results and figure report 82 early RA participants; 14 participants had clinically suspect arthralgia. Investigators measured serum anti-CXCR3 IgG with a commercial assay and assessed carotid plaque presence and number by Doppler ultrasound. Models accounted for sex, age, hypertension, diabetes, smoking, and dyslipidemia, with statins considered separately. Investigators also compared antibody tertiles with modified SCORE (mSCORE), performed targeted serum proteomics, and examined public gene-expression datasets from different participants.
Antibody levels were reduced across early and established RA, clinically suspect arthralgia, and SjD relative to their respective controls. In early RA, lower levels accompanied carotid plaque presence and extent; the statin-adjusted plaque-presence association was OR 0.940 (95% CI 0.885–0.992), p=0.020. Plaque number also showed an adjusted association. In established RA, the comparison concerned a history of cardiovascular disease (CVD)—including non-ischemic manifestations—rather than ultrasound-detected plaque; in SjD, lower levels accompanied atherosclerosis. Lower baseline antibody levels accompanied poorer response to conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) at 6 and 12 months, without establishing that the antibodies influenced treatment response.
Antibody levels alone provided modest discrimination of existing atherosclerosis. Adding antibody tertiles to mSCORE yielded a reported difference between areas of 0.164 (0.008–0.247), p<0.001. Reclassification was principally among plaque-positive early RA participants, not a forecast of future cardiovascular events. Serum proteomics linked antibody levels to immune activation and, among participants with plaque, to apoptosis, chemotaxis, and adhesion pathways. Separate public datasets showed increased synovial CXCR3 expression and reduced systemic expression in RA, along with increased target-tissue expression in SjD. These molecular associations did not establish antibody function.
The cross-sectional vascular comparisons cannot establish causality, and cumulative inflammation may confound the observed associations. No study-specific receptor-binding, signaling, antibody subclass-function, or migration assays determined how the measured antibodies act. Public expression datasets were not matched to serum participants. The clinically suspect arthralgia and tumor necrosis factor (TNF) inhibitor follow-up groups were exploratory. The mSCORE comparison classified prevalent atherosclerosis; prospective prediction of major adverse cardiovascular events remains untested in these cohorts from Spain.
The authors concluded that lower circulating anti-CXCR3 IgG accompanies systemic autoimmunity and vascular disease in the studied cohorts. Its biological role and value for prospective cardiovascular classification remain unresolved.
Clinician Questions
Do anti-CXCR3 IgG levels track rheumatoid arthritis activity or disease-associated autoantibodies?
In early RA, anti-CXCR3 IgG levels were not associated with measured disease activity, symptom duration, rheumatoid factor, or anti-citrullinated protein antibodies. Antinuclear antibody positivity, however, accompanied lower anti-CXCR3 levels.
Did anti-TNF treatment change anti-CXCR3 IgG in biologic-naïve rheumatoid arthritis?
In an exploratory group of 13 biologic-naïve RA patients assessed before and three months after starting a TNF inhibitor, anti-CXCR3 IgG levels did not change significantly, regardless of clinical outcome. The small group and short follow-up limit what this treatment-exposure observation establishes.
Recommended Reading
- For more on Sjögren disease pathophysiology: Sjögren’s Myth Busters: Can You Detect Fact from Fiction on Emerging Therapies?