In rheumatoid arthritis (RA), the risk of cardiovascular death is 50% higher compared to the general population. This increased risk is partly due to the systemic inflammation characteristic of RA and changes in the lipoprotein profiles. This study investigated plasma lipid levels, lipid ratios, and the composition and functionality of high-density lipoprotein (HDL) in control individuals and RA subjects based on the disease’s inflammatory score (DAS28). This study included 50 control (CTR) individuals and 56 subjects with RA, divided into remission/low-activity disease (DAS28 < 3.2; n = 13) and active disease (DAS28 ≥ 3.2; n = 43). Plasma lipids (total cholesterol, TC; triglycerides, TG) and the HDL composition (TC; TG; phospholipids, PL) were determined using enzymatic methods; apolipoprotein B (apoB) and apoA-1 were measured by immunoturbidimetry. HDL-mediated cholesterol efflux and anti-inflammatory activity were assessed in bone marrow-derived macrophages. Comparisons were made using the Mann–Whitney test, and binary logistic regression was used to identify the predictors of active RA. A p-value < 0.05 was considered significant. TC, HDLc, and the TC/apoB ratio were higher in RA subjects compared to the CTR group. Subjects with active disease exhibited higher levels of TG and the TG/HDLc ratio and lower levels of HDLc, the TG/apoB ratio, TC, and apoA-1 in HDL particles compared to those with remission/low-activity RA. Increased levels of HDLc [odds ratio (OR) 0.931, 95% CI = 0.882–0.984], TC/apoB (OR 0.314, 95% CI = 0.126–0.78), HDL content in TC (OR 0.912, 95% CI = 0.853–0.976), PL (OR 0.973, 95% CI = 0.947–1.000), and apoA-1 (OR 0.932, 95% CI = 0.882–0.985) were associated with a decreased risk of active disease, but BMI (OR 1.169, 95% CI = 1.004–1.360) and TG (OR 1.031, 95% CI = 1.005–1.057) were positively associated with active disease. A reduction in HDL-mediated cholesterol efflux increased the OR for active RA by 26.2%. The plasma levels of HDLc, along with the composition and functionality of HDL, influence the inflammatory score in RA and may affect the development of cardiovascular disease.

Autoimmune rheumatic diseases (ARDs) exhibit an elevated incidence of cardiovascular disease (CVD). The elevation of inflammatory and immune stress accompanying ARDs contributes to atherosclerosis development and alterations in lipid metabolism and lipoprotein profile add to cardiovascular (CV) risk. The plasma concentration of high‐density lipoprotein cholesterol (HDLc) is inversely related to CVD and serves as a discriminator of CV risk. However, this association is not unequivocal, and changes in HDL functionality appear to emerge as a better indicator of CV risk, albeit difficult to measure and monitor clinically. The modulation of HDLc itself can bring benefits in controlling autoimmunity and reducing ARD activity. Understanding HDL function and each peculiarity involved in ARDs enables to seek means to prevent ischemic outcomes associated with CVD, in the face of the residual CV risk persisting even with controlled disease activity and classic risk factors. By comprehending HDL’s structural and functional nuances, it will be possible to develop more effective strategies to manage the evolution and outcomes of ARDs. It is also necessary to standardize diagnostic methods and establish different markers for each specific disease allowing the design of intervention strategies to restore HDL functionality, reduce residual CV, and prevent, alleviate, or even suppress ARD activity.