Background:The association between cholesterol and cardiovascular disease (CVD) risk is attenuated in Rheumatoid arthritis (RA). In fact, RA patients in the lowest low-density lipoprotein (LDL) group (<70mg/dl) may experience unexpectedly high CVD risk.Objectives:We here explored whether patients with LDL<70mg/dl (Group 1) had higher coronary atherosclerosis burden compared to other LDL groups (Group 2: 70≤LDL≤130 and Group 3: LDL>130), as a reason for this risk. We further evaluated whether low LDL in group 1 associated with differences in inflammation, LDL particle composition or oxidation.Methods:One hundred fifty RA patients without symptoms or history of CVD underwent coronary atherosclerosis evaluation with computed tomography angiography. Coronary artery calcium (CAC), number of segments with plaque (segment involvement score), stenotic severity (segment stenosis score), and extensive (>4 segments with plaque) or obstructive disease (>50% stenosis) were assessed. Lipoprotein classes and subclasses were directly measured. Oxidized LDL (oxLDL) was measured with monoclonal antibody E06. Chemiluminescence Elisa quantified IgG and IgM antibodies to oxLDL (anti-oxLDL) and apoB100 immune complexes (IC). Proinflammatory cytokines were measured with Erenna Immunoassay. Robust linear and logistic regression models- adjusted for Framingham D’Agostino score, obesity, disease activity, bDMARD and statin treatment- evaluated associations between LDL groups and plaque outcomes. Similar models evaluated adjusted differences in LDL subclasses, oxLDL, anti-oxLDL, anti-ApoB100 IC, and cytokines across LDL groups.Results:Group 1 patients had higher coronary plaque burden (Figure 1A) and 2.8 times greater risk of extensive or obstructive disease (adjusted OR 2.82 [95% CI 1.12-7.17], P = 0.031) compared to LDL>70 groups. Among statin naïve patients, those with LDL<70 also had higher oxLDL (log-transformed adjusted mean 2.55 [95% CI 2.34-2.77] versus 2.27 [95% CI 2.19-2.36], P = 0.018 for LDL>70). Notably, Group 1 patients also had higher anti-oxLDL IgG and anti-ApoB100 IgG IC levels compared to other groups (Figure 1B). LDL subclass relative content in the LDL particle differed across groups (Figure 1C). Lp(a) was higher in LDL particles in Group 1 (adjusted mean 16.04% [95% CI 11.75-20.33], versus 10.48% [95% CI 8.20-12.75] in Group 2, P = 0.026 and 7.41% [95% CI 0.77-14.04] in Group 3, P = 0.033). Notably, Lp(a) content strongly associated with oxLDL overall (r = 0.83, P < 0.0001). This association was stronger for Group 1 compared to others (P < 0.005, Figure 1D). No differences in RA activity, CRP, TNF-α, IL-17A, or IL-17F were seen across groups. However, Group 1 had higher IL-6 (log-transformed adjusted mean 1.98 [95% CI 1.64- 2.32] versus 1.57 [95% CI 1.45-1.70], P = 0.028 in Group 2 and 1.32 [95% CI 0.84-1.80], P = 0.031 in Group 3). IL-6 associated with both IgG anti-oxLDL (P = 0.015) and anti-apoB100 IC (P = 0.016). Log-transformed IL-6 further associated with higher log-transformed CAC (adjusted B 0.41 [95% CI 0.01-0.81], P = 0.049).Conclusion:RA patients with LDL<70 mg/dl had higher coronary atherosclerosis burden. Low circulating LDL in that group may reflect higher oxidation; this was mostly linked to the larger Lp(a) relative content of LDL and its significantly higher oxidation potential in that group. OxLDL immune recognition was linked to higher IgG anti-oxLDL Ab and anti-ApoB100 IC levels in the LDL<70 group, which further associated with higher IL-6 elaboration and atherosclerosis burden.Disclosure of Interests:George Karpouzas Speakers bureau: Sanofi/ Genzyme/ Regeneron, Consultant of: Sanofi/ Genzyme/ Regeneron, Grant/research support from: Pfizer, Sarah Ormseth: None declared, Elizabeth Hernandez: None declared, Matthew Budoff Consultant of: Pfizer
Exploring the Lipid Paradox Theory in Rheumatoid Arthritis: Associations of Low Circulating Low‐Density Lipoprotein Concentration With Subclinical Coronary Atherosclerosis