Inflammation and immunomodulatory therapies influence the relationship between ATP-binding cassette A1 membrane transporter-mediated cholesterol efflux capacity and coronary atherosclerosis in rheumatoid arthritis

George A Karpouzas; Bianca Papotti; Sarah R Ormseth; Marcella Palumbo; Elizabeth Hernandez; Maria Pia Adorni; Francesca Zimetti; Matthew J Budoff; Nicoletta Ronda

doi:10.1016/j.jtauto.2023.100209

Inflammation and immunomodulatory therapies influence the relationship between ATP-binding cassette A1 membrane transporter-mediated cholesterol efflux capacity and coronary atherosclerosis in rheumatoid arthritis

J Transl Autoimmun. 2023 Jul 18:7:100209. doi: 10.1016/j.jtauto.2023.100209. eCollection 2023 Dec.

Authors

George A Karpouzas¹, Bianca Papotti², Sarah R Ormseth¹, Marcella Palumbo², Elizabeth Hernandez³, Maria Pia Adorni⁴, Francesca Zimetti², Matthew J Budoff⁵, Nicoletta Ronda²

Affiliations

¹ Division of Rheumatology, Harbor-UCLA and The Lundquist Institute, Torrance, CA, USA.
² Department of Food and Drug, University of Parma, Parco Area delle Scienze 27/A, 43124, Parma, Italy.
³ The Lundquist Institute, 1124 W Carson Street, Torrance, CA, 90502, USA.
⁴ Department of Medicine and Surgery, University of Parma, Parma, Italy.
⁵ Division of Cardiology, Harbor-UCLA and The Lundquist Institute, Torrance, CA, USA.

Abstract

Objectives: High-density lipoprotein (HDL) removes cholesterol from cells in atherosclerotic lesions, a function known as cholesterol efflux capacity (CEC). ATP-binding-cassette A1 (ABCA1) membrane transporter starts cholesterol transfer from macrophages to HDL particles. In rheumatoid arthritis (RA), methotrexate and biologic disease modifying drugs (bDMARDs) are atheroprotective whereas corticosteroids and C-reactive protein (CRP) are proatherogenic. We evaluated the influence of these factors on the relationship of ABCA1-CEC with atherosclerosis and cardiovascular events.

Methods: Atherosclerosis was evaluated with computed tomography angiography in 140 patients with RA and repeated in 99 after 6.9 ± 0.3 years. Events including acute coronary syndromes, stroke, cardiovascular death, claudication, revascularization, and heart failure were recorded. ABCA1-CEC was quantified in J774A.1 murine macrophages and reported as percentage of effluxed over intracellular cholesterol.

Results: Higher ABCA1-CEC associated with (i) more calcified plaques at baseline only in patients with CRP>7 mg/L (median) (p-interaction = 0.001) and methotrexate nonusers (p-interaction = 0.037), and more partially-calcified plaques only in bDMARD nonusers (p-interaction = 0.029); (ii) fewer new calcified plaques in patients with below-median but not higher time-averaged CRP (p-interaction = 0.028); (iii) fewer new total and calcified plaques in prednisone unexposed but not patients exposed to prednisone during follow-up (p-interaction = 0.034 and 0.004) and (iv) more new plaques in baseline bDMARD nonusers and fewer in bDMARD users (p-interaction $\leq$ 0.001). Also, ABCA1-CEC associated with greater cardiovascular risk only in baseline prednisone users (p-interaction = 0.027).

Conclusion: ABCA1-CEC associated with decreased atherosclerosis in patients with below-median baseline and time-averaged CRP and bDMARD use. Conversely, ABCA1-CEC associated with increased plaque in those with higher CRP, corticosteroid users, methotrexate nonusers, and bDMARD nonusers. While in well-treated and controlled disease ABCA1-CEC appears atheroprotective, in uncontrolled RA its action may be masked or fail to counteract the inflammation-driven proatherogenic state.

Keywords: ABCA1; Cardiovascular events; Cholesterol efflux capacity; Coronary atherosclerosis; Corticosteroids; Rheumatoid arthritis.