RA patients more likely to develop atherosclerosis, but can novel drug therapy help?

Myeloid cell expansion and problems with cholesterol maintenance secondary to rheumatoid arthritis (RA) impede the regression of atherosclerotic plaques, as well as alter their progression, according to new research published in the European Heart Journal. Reconstituted high-density lipoprotein (rHDL) counteracted enhanced myelopoiesis and monocyte entry into atherosclerotic lesions in mouse models, a finding that opens the door to novel drug therapy.

“While cardiovascular disease is the number one killer of patients with RA, it’s hard for us to fully understand its genesis and [this] poses major challenges in the cardiovascular management of these patients,” said co-author Prabhakara Nagareddy, PhD, assistant professor, Department of Nutrition Sciences, University of Alabama at Birmingham.

Patients with RA are at increased risk for cardiovascular disease (CVD), and are two to three times more likely to develop atherosclerosis—separate from plasma cholesterol levels.

“RA is a chronic inflammatory disorder that significantly increases the risk of CVD independent of traditional risk factors, making CVD-risk assessment challenging,” wrote authors, led by Andrew J. Murphy, PhD, Haematopoiesis and Leukocyte Biology Laboratory, Division of Immunometabolism, Baker Heart and Diabetes Institute, Melbourne, Australia.

Mechanisms hastening the development of this atherosclerosis have yet to be elucidated, but systemic inflammation is implicated, with evidence in the literature that circulating monocytes and platelets are significantly tied to CVD in humans.

Moreover, according to the authors, studies in animals “have demonstrated a causal relationship between circulating levels of monocytes and platelets with atherogenesis and impaired atherosclerotic lesion regression.”

Cellular levels of cholesterol stockpile to effect heightened myelopoiesis. Hematopoietic stem and progenitor cells (HSPCs) plus myeloid progenitors maintain cholesterol efflux via the ATP binding cassette transporters (ABC)-A1 and ABCG1, as well as their cell intrinsic ligand apolipoprotein-E (apoE). On a related note, people with RA seem to exhibit defective cholesterol metabolism via the downregulation of cholesterol ef?ux genes such as ABCA1 and ABCG1, which may contribute to CVD.

“We hypothesized that systemic inflammation associated with RA would drive enhanced and sustained myelopoiesis, associated with a central defect in HSPC cholesterol metabolism that causes increased growth factor receptor expression,” the authors wrote. Furthermore, they suggested that altered cholesterol metabolism could then interfere with atherosclerotic plaque regression or with lesion progression in preclinical atherosclerotic models.

In two RA mouse models, the researchers observed monocytosis, neutrophilia, and thrombocytosis due to HSPC expansion in the bone marrow and spleen, which was also correlated with higher cellular cholesterol content. This increase in cellular cholesterol resulted from the downregulation of cholesterol efflux genes apoE, ABCA1, and ABCG1. Of note, these HSPCs presented with upregulation of important myeloid performing growth factor receptors.

Systemic inflammation in these mouse models impaired cellular cholesterol metabolism. Furthermore, heightened levels of myeloid cells in RA mice models were correlated with impairment in plaque regression, despite serum cholesterol levels being equal in RA vs non-RA mouse models.

“Lesions from arthritic mice exhibited a less stable phenotype as demonstrated by increased immune cell infiltration, lipid accumulation, and decreased collagen formation,” the researchers wrote.

With a lesion progression model, the team saw monocytosis, enhanced monocyte recruitment, and increased levels of plaque macrophages. This progression was switched by administration of rHDL, which has been shown to promote cholesterol efflux through passive diffusion. Importantly, the researchers found that patients with RA had expanded CD16⁺ monocyte subsets, as well as downregulated ABCA1 and ABCG1 thus suggesting that these findings translate to people.

“Rheumatoid arthritis impairs atherosclerotic regression and alters progression, which is associated with an expansion of myeloid cells and disturbed cellular cholesterol handling, independent of plasma cholesterol levels,” the researchers concluded. “Infusion of rHDL prevented enhanced myelopoiesis and monocyte entry into lesions. Targeting cellular cholesterol defects in people with RA, even if plasma cholesterol is within the normal range, may limit vascular disease.”

Specifically, the team suggests that cellular cholesterol levels could be targeted with either rHDL or statins.

“If we find out that targeting cellular cholesterol defects through rHDL in mice with RA could limit atherosclerosis progression, it will ultimately help us get closer to limiting CVD in these patients,” said study co-author, Beatriz Hanoaka, MD. “These results are getting us closer to figuring out how to manage CVD in patients with rheumatoid arthritis.”