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Anti-Citrullinated Protein Antibody Specificities, Rheumatoid Factor Isotypes, and Incident Cardiovascular Events in
Helga Westerlind1, Johan Rönnelid2, Monika Hansson3
1Karolinska Institutet, Stockholm, Sweden.
Insights
Rheumatoid factor (RF) isotypes and anti-citrullinated protein antibodies (ACPAs) are linked to increased cardiovascular (CV) event risk in rheumatoid arthritis (RA) patients. ACPA levels and subspecificities, not specific types, are key predictors, independent of smoking.
Area of Science:
- Rheumatology
- Cardiology
- Immunology
Background:
- Rheumatoid arthritis (RA) is an autoimmune disease associated with an increased risk of cardiovascular (CV) disease.
- Anti-citrullinated protein antibodies (ACPAs) and rheumatoid factor (RF) are key serological markers in RA pathogenesis.
- The specific contribution of different ACPA subspecificities and RF isotypes to incident CV events in RA remains incompletely understood.
Purpose of the Study:
- To investigate the association between ACPAs, specific ACPA subspecificities, RF isotypes, and the risk of incident CV events in patients with new-onset RA.
- To determine if ACPA levels and the number of ACPA subspecificities are more significant predictors of CV events than specific ACPA types.
- To explore the impact of adjusting for baseline factors like DAS28, smoking, and income on these associations.
Main Methods:
- Serum samples from 2,814 Swedish patients with new-onset RA were analyzed for anti-cyclic citrullinated peptide 2 (anti-CCP2) antibodies, 20 ACPA subspecificities, and RF isotypes.
- Patients were followed longitudinally for incident acute coronary syndrome (ACS), stroke, CV-related death, and major adverse CV events (MACE).
- Cox proportional hazards models were used to assess associations between serological markers and CV outcomes, with adjustments for clinical and demographic factors.
Main Results:
- Anti-CCP2 occurrence/levels were associated with increased risk of ACS, stroke, CV-related death, and MACE.
- A higher number of ACPA subspecificities correlated with CV risk, but no single subspecificity was uniquely identified.
- IgM-RF was linked to most CV endpoints (except ACS), IgA-RF to CV-related death, and both RF isotypes and ACPAs were associated with all-cause mortality.
Conclusions:
- RF isotypes and ACPAs are significant predictors of future CV events in RA patients.
- ACPA levels and the breadth of ACPA reactivity (number of subspecificities) are more critical than specific ACPA subspecificities for CV risk prediction.
- These associations persist even after accounting for smoking history, DAS28, and income, highlighting their independent role in RA-related cardiovascular risk.
Objective:
To investigate the relationship between anti-citrullinated protein antibodies (ACPAs), specific ACPA subspecificities, rheumatoid factor (RF) isotypes, and incident cardiovascular (CV) events in patients with rheumatoid arthritis (RA).
Methods:
Serum samples from Swedish patients with new-onset RA (diagnosed within 1 year of symptom onset between 1996 and 2009) were centrally typed for anti-cyclic citrullinated peptide 2 (anti-CCP2) antibodies, 20 ACPA subspecificities, and RF isotypes. Patients were followed up longitudinally in nationwide registers to monitor the occurrence of acute coronary syndrome (ACS), stroke, CV-related death, and major adverse CV events (MACE). The association between each serologic marker and CV outcome, and the impact of adjustment for the Disease Activity Score in 28 joints (DAS28), smoking status, and income at baseline, were assessed using Cox proportional hazards models. In addition, associations of serologic markers with all-cause mortality were explored.
Results:
In total, 2,814 patients with RA were included in the study. The median follow-up was 13 years, during which the CV end points of ACS, stroke, or CV-related death were reported to occur in 375 patients. Occurrence and/or levels of anti-CCP2 were associated with risk of incident ACS (hazard ratio [HR] 1.46, 95% confidence interval [95% CI] 1.03-2.06), stroke (HR 1.47, 95% CI 1.03-2.10), CV-related death (P = 0.024 for association with anti-CCP2 levels), and MACE (HR 1.34, 95% CI 1.06-1.70). Similarly, an association with the number of ACPA subspecificities was observed; however, this could not be attributed to any individual or group of ACPA subspecificities. Presence of IgM-RF was associated with all CV end points except ACS, and IgA-RF was exclusively associated with CV-related death. Adjustment for smoking status, income, and DAS28 scores decreased most of the HRs, whereas IgA-RF remained associated with CV-related death (HR 1.61, 95% CI 1.05-2.48). All of the assessed serologic makers were associated with all-cause mortality.
Conclusion:
RF isotypes and ACPAs are associated with future CV events in patients with RA. ACPA levels and number of subspecificities seem more important than the occurrence of particular subspecificities, and these associations were not explained by a history of ever smoking.
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