Patients with rheumatoid arthritis (RA) have a high rate of cardiovascular morbidity and mortality; women, who suffer from this disease 3 times more often than men, have a 2- to 3‑fold increased risk of developing heart attack even without traditional cardiovascular risk factors.¹ Higher levels of inflammatory markers and a higher clinical score with swollen joints are associated with a higher prevalence of increased carotid intima‑media thickness and carotid plaques.² The European League Against Rheumatism recommends to multiply the cardiovascular risk by 1.5 to predict the accurate risk of heart attack in patients with RA.³ The Nurses’ Health Study⁴ found that women with RA had by 45% increased risk of dying from cardiovascular diseases (CVDs), which correlated with severity of inflammation.

Endothelial dysfunction is considered the main reason for accelerated atherosclerosis. This term reflects a complicated series of molecular, biochemical, and cellular events that upregulate translational factors (nuclear factor κB), nuclear proteins, proinflammatory cytokines, expression of cell adhesion molecules, hormones, and growth factors, which inhibit endothelial nitric oxide synthase in endothelial cells, nitric oxide (NO) synthesis and secretion, and the ability to produce, activate, and mobilize endothelial progenitor cells (EPCs).⁵ These processes generate free radicals that break down the integrity of the endothelial cells.

The paradigm today is that endothelial function reflects bioavailability of NO, which is affecting the number and function of EPCs.⁶ The mechanism to produce EPCs is impaired in patients with long‑standing high‑grade inflammation, and consequently, they experience endothelial dysfunction that can be evaluated using the brachial artery method based on plethysmography. The clinical implication is an impaired ability to regenerate damaged blood vessels, along with thrombotic events and a continuous vicious circle of endothelial cell injury by intensified production of oxidized free radicals and formation of neutrophil extracellular traps (NETs), and destruction induced by inflammatory pathways, such as interleukin 6 signaling pathway and activated interleukin 17A, a cytokine that promotes inflammation, coagulation, and thrombosis.⁷

In their work published in this issue of Polish Archives of Internal Medicine, Nowakowski et al⁸ did not find differences in endothelial function between patients with RA and controls. They did observe an impaired flow‑mediated diameter percentage change (FMD%) in the patients with RA who had hyperlipidemia. Some studies support Nowakowski’s findings, and did not find any difference in the FMD% between patients with RA and healthy controls.⁸ However, I believe that the difference depends mainly on the severity of RA and duration of the inflammatory disease. Many of the patients in Nowakowski’s study were treated with methotrexate and tumor necrosis factor (TNF) inhibitors or interleukin 6 inhibitors. These metabolic and biologic medications have been shown to decrease the inflammation severity and the CVD risk. Our experience was different. We studied a group of patients (72% women) who suffered from RA for 12 months and more, with a significant degree of activation of the inflammatory disease. We found that our group, who did not receive TNF blockers or disease modifying rheumatic drugs, had significantly impaired FMD%.⁹ The patients with the highest FMD% (good endothelial function) had the lowest clinical scores. More than that, we observed an inverse correlation between endothelial function and RA disease severity score, and suggested to use this noninvasive tool of measuring endothelial function by the brachial artery method for evaluation of the RA severity score (along with other parameters), mainly to estimate the risk of CVD development.⁹ We continued to study this phenomenon of impaired vascular reactivity in patients with RA, and found that those with long‑standing disease (>12 months and without biologic and disease‑modifying rheumatic drugs) had an impaired ability to grow colonies of EPCs, which could explain the impaired endothelial function and regenerative capability.¹⁰

A genetic link has been suggested as well. RA patients with CVD were reported to carry HLA‑DrB1*4 shared epitope alleles.¹¹ Genetic / epigenetic mechanisms may upregulate inflammatory processes that impair NO synthesis by endothelial cells, inhibit EPC production and mobilization, with clinical implications of endothelial dysfunction, accelerated atherosclerosis, and increased rate of CVD morbidity and mortality.