Plasma metabolomics and incident major adverse cardiovascular events in patients with rheumatoid arthritis

Patients with RA have excess cardiovascular risk beyond traditional factors. We evaluated associations between plasma metabolites and incident major adverse cardiovascular events (MACEs) in RA and compared findings with matched controls.

We studied 1271 Mass General Brigham Biobank participants with RA, without known cardiovascular disease and no statin use at blood draw. 1H NMR metabolomics quantified 168 metabolites spanning lipoprotein particles and contents, fatty acids, amino acids and glycolysis. Incident MACE (myocardial infarction, stroke, transient ischaemic attack or death) was identified using ICD codes. Multivariable Cox models with false discovery rate correction assessed associations. Findings were compared with a 1:2 matched non-RA control cohort.

The mean age was 62 years, 80% were women and 8% experienced incident MACE over a median follow-up of 7.8 years. Twenty-five plasma metabolites were significantly associated with MACE. Lower MACE risk was primarily associated with higher levels of small HDL particle concentration and lipid content, as well as circulating albumin and select amino acids. In contrast, higher MACE risk was strongly associated with triglyceride-rich and remnant-like lipoprotein measures. When compared with controls, several associations were unique to the RA patients, who demonstrated a distinct metabolomic risk profile, involving triglyceride-rich VLDL and HDL particles.

In this first metabolomic study in RA, we identified a distinct cardiovascular risk profile. Higher levels of large HDL particles were associated with increased risk, whereas small HDL particles were associated with lower risk, with potential implications for inflammation-targeted and HDL-modifying therapies.