Rheumatoid Factor Isotypes, ACPAs Show Strong Associations With Future Cardiovascular Events in RA

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Rheumatoid factor isotypes and anticitrullinated protein antibodies are strongly associated with future cardiovascular events in rheumatoid arthritis.

Rheumatoid factor (RF) isotypes and anticitrullinated protein antibodies (ACPA) are strongly associated with future cardiovascular (CV) events, including acute coronary syndrome (ACS) and stroke, in patients with rheumatoid arthritis (RA), according to study results published in Arthritis and Rheumatology.

The study cohort included patients from the Swedish Epidemiological Investigation of RA who received a diagnosis of RA between 1996 and 2009 (N=2814). Using these cases, researchers centrally typed baseline serologic data based on the anticyclic citrullinated peptide test (anti-CCP2), 20 ACPA subspecificities, and RF isotypes. Patients were followed over a median 13-year follow-up period through the Swedish national patient register and cause of death register until the first event of ACS, stroke, CV-related mortality, or major adverse CV event (MACE). The association between each serologic marker and CV outcome was examined and adjustments were made for baseline Disease Activity Score in 28 joints (DAS28), smoking, and income level.

During the follow-up period, a total of 375 first ACS, stroke, and CV death events occurred. There was an association between anti-CCP2 positivity and risk for incident ACS (hazard ratio [HR], 1.46; 95% CI, 1.03-2.06; P =.035), stroke (HR, 1.47; 95% CI, 1.03-2.10; P =.034), and MACE (HR, 1.34; 95% CI, 1.06-1.70; P =.014). A similar nonsignificant association was found between anti-CCP2 positivity and CV death (HR, 1.48; 95% CI, 0.94-2.31; P =.087).

Immunoglobulin M (IgM) RF was associated with stroke (HR, 1.42; 95% CI, 1.01-2.01; P =.045) and MACE (HR, 1.40; 95% CI, 1.11-1.76; P =.0045). The researchers also observed a significant association between IgA RF and an increased risk for CV mortality (HR, 1.88; 95% CI, 1.22-2.88; P =.0038). After adjustment for smoking, income, and DAS28, IgA RF remained associated with CV mortality (HR, 1.61; 95% CI, 1.05-2.48). In analyses stratified by smoking status, IgA and IgG RF were associated with CV mortality and IgG and IgM RF were associated with MACE in patients who had never smoked.

Strong associations were found between all-cause mortality and anti-CCP2 positivity, anti-CCP2 level, autoantibody load, the majority of the ACPA subspecificities, and each RF isotype.

A limitation of this study was the lack of adjustment for lipid profile, family history of cardiovascular disease, physical activity, and comorbid conditions.

The researchers suggested that with regard to the risk for CV events, patients with “high anti-CPP2 levels or presence of IgA or IgG RF at diagnosis are at higher risk and might benefit from closer monitoring from a cardio preventative perspective.”

Disclosure: Several study authors declared affiliations with the pharmaceutical industry. Please see the original reference for a full list of authors’ disclosures.


Westerlind H, Rönnelid J, Hansson M, et al. Anti-citrullinated protein antibody specificities, rheumatoid factor isotypes and incident cardiovascular events in patients with rheumatoid arthritis [published online May 31, 2020]. Arthritis Rheumatol. doi:10.1002/art.41381