Background: Changes in serum cholesterol loading capacity (CLC) on macrophages overtime were linked to coronary atherosclerosis progression in rheumatoid arthritis (RA) [1]. Disease-related inflammation, LDL oxidation and autoantibodies were shown to influence macrophage cholesterol loading and coronary plaque burden both directly and indirectly [2]. Oxidized LDL readily formed complexes with beta-2-glycoprotein-1— a protein with antiatherogenic properties readily present in both serum and plaque— in both RA and controls. The complex can be subsequently bound by anti-beta-2-glycoprotein-1 antibodies (anti-b2GPI Ab). We recently reported that anti-b2GPI Ab specifically of the IgA isotype, independently contributed to coronary atherosclerosis progression in RA; yet the precise mechanisms remain speculative [3].

Objectives: We hypothesized that anti-b2GPI IgA may promote atherosclerosis progression by influencing oxidized LDL-mediated cholesterol loading on arterial macrophages.

Methods: Coronary computed tomography angiography evaluated atherosclerosis (noncalcified, mixed or fully calcified plaques) in 100 patients without cardiovascular disease at baseline and follow-up 6.9±0.4 years later. Presence of five or more coronary plaques in a patient and lesions rendering greater than 50% luminal stenosis were considered extensive and obstructive disease respectively. CLC was measured as intracellular cholesterol content in serum treated human THP-1 monocyte-derived macrophages with a fluorimetric assay both at baseline and follow-up assessments. Serum anti-b2GPI IgA were measured with ELISA at baseline visit and positivity was confirmed 12 weeks later. Multivariable negative binomial regression and logistic regression evaluated the influence of anti-b2GPI IgA on the relationship between CLC change and number of new plaques and likelihood of noncalcified plaque formation and new extensive or obstructive disease respectively.

Results: A significant interaction between CLC change and anti-b2GPI IgA titers on plaque progression indicated that the influence of increasing anti-b2GPI IgA titers on atherosclerosis progression varied across levels of CLC change. Specifically, increasing anti-b2GPI IgA titers associated with greater number of new plaques overall (p-for-interaction=0.005), a higher likelihood of new noncalcified plaque formation (p-for-interaction=0.023) and new extensive or obstructive disease (p-for-interaction=0.043) only at the highest tertile of CLC change (Figure 1). This suggested that anti-b2GPI IgA may be actively involved in macrophage cholesterol loading by oxidized LDL in a dose-dependent manner. Presence of anti-b2GPI IgA may also determine the composition of newly formed plaques in the context of increasing CLC change (Figure 2). Specifically, in the presence of anti-b2GPI IgA, CLC change associated with greater likelihood of higher-risk noncalcified plaque progression (odds ratio [OR] 2.82, 95% confidence interval [95%CI] 1.40-5.67, p=0.004 and p-for-interaction=0.005), but not progression of fully-calcified plaque (p=0.364). In contrast, in the absence of anti-b2GPI IgA, CLC change associated with a greater likelihood of lower-risk fully-calcified plaque progression (OR 1.48, 95%CI 1.19-1.84, p<0.001 and p-for-interaction=0.046), but not noncalcified plaque progression (p=0.658)

Conclusion: Anti-b2GPI IgA antibodies may facilitate cholesterol loading onto macrophages and influence coronary atherosclerosis progression and plaque composition in a dose dependent manner, specifically at high levels of CLC change. Our results support a potential mechanism that may involve anti-b2GPI IgA binding of oxidized LDL/b2GP1 complexes to FcA receptors on arterial macrophages, that promotes cholesterol loading and clinically translates to atherosclerosis progression in vivo.

REFERENCES: [1] Karpouzas GA et al. RMD Open. 2024 Dec 24;10(4):e004991

[2] Karpouzas GA et al. Rheumatology (Oxford). 2023 Mar 1;62(3):1254-1263.

[3] Karpouzas GA et al. Semin Arthritis Rheum. 2021 Feb;51(1):20-27.

Acknowledgements: NIL.

Disclosure of Interests: George Karpouzas Scipher, Janssen, Pfizer, Scipher, Bianca Papotti: None declared , Sarah Ormseth: None declared , Marcella Palumbo: None declared , Matthew Budoff: None declared , Nicoletta Ronda: None declared .

© The Authors 2025. This abstract is an open access article published in Annals of Rheumatic Diseases under the CC BY-NC-ND license ( http://creativecommons.org/licenses/by-nc-nd/4.0/ ). Neither EULAR nor the publisher make any representation as to the accuracy of the content. The authors are solely responsible for the content in their abstract including accuracy of the facts, statements, results, conclusion, citing resources etc.