Impact of Glucocorticoids on Endothelial Function in RA

Cardiovascular disease (CVD) is a common comorbidity for patients with rheumatoid arthritis (RA). CVD is the top cause of death in this group, which has a 50% higher risk of mortality than the general population.¹ This elevated CVD risk is due to accelerated atherogenesis, which some evidence suggests is induced by endothelial dysfunction. A review published in Arthritis Research & Therapy examined the effect of glucocorticoids (GCs) on endothelial function, particularly in RA patients.²

When functioning normally, the endothelium acts as a physical barrier between the blood and the vessel wall, maintaining homeostasis of vascular tone. When the endothelium senses stimuli such as pressure, hormones, or locally secreted vasoactive substances, it releases endothelium-derived relaxing factors (EDRF) that “regulate vasomotor function, inflammatory processes, cell growth, and hemostasis,” wrote Frank Verhoeven, MD, of the Université Bourgogne Franche-Comté in Besançon, France, and colleagues in the review.²

Since 2002, a sizable body of research has established that endothelial dysfunction is present in both the micro- and macrovasculature in patients with RA at various stages and levels of disease activity, including those with established disease who often do not have the classic risk factors for CVD.³ This suggests that inflammation plays a key role in endothelial dysfunction, though the underlying pathways are unclear.

Since the first patient with RA was successfully treated with GCs in 1948, studies have linked oral GC (≥7.5 mg/day) therapy with an elevated risk of CVD and all-cause mortality,⁴ possibly due to an increase in CVD risk factors, such as insulin resistance or hypertension. Animal research indicates that GC use can directly affect endothelial function via a reduction in endothelial nitric oxide (NO) synthase (eNOS) activity and expression, and can increase reactive oxygen species (ROS) leading to decreased vascular NO bioavailability.⁵ Such findings, however, have not been well-supported in human research.

In contrast, GC use may decrease CVD risk by easing inflammation; additional beneficial effects may be seen when treating diseases characterized by high inflammation levels. For example, cross-sectional and longitudinal  studies of 6 patients with giant cell arteritis (GCA) found that impaired endothelial function that improved after the patients’ inflammation was reduced through corticosteroid treatment.⁶ “The mechanisms involved in the beneficial effects of GC on endothelial cells in inflammatory conditions are likely due to a decrease in endothelial expression of cytokines (interleukin [IL]-6, IL-8), granulocyte-colony stimulating factor (G-CSF), vascular endothelial growth factor (VEGF), endothelin-1, NFκB proteins, arginase 2, and cyclooxygenase (COX)-2,” explained Dr Verhoeven and colleagues.

Summary and Clinical Applicability

The authors concluded that, based on their review of available data, “there is an urgent need to perform clinical trials specifically designed to define the best GC strategy to prevent CV[D] risk in RA.” Dr Verhoeven and colleges assert this because GCs are commonly assumed to have a deleterious effect on endothelial function; however, no such data exist to suggest this effect in patients with RA.

References

1. van Halm VP, Peters MJ, Voskuyl AE, et al. Rheumatoid arthritis versus diabetes as a risk factor for cardiovascular disease: a cross-sectional study, the CARRE Investigation. Ann Rheum Dis. 2009;68:1395–1400.
2. Verhoeven F, Prati C, Maguin-Gaté K, Wendling D, Demougeot C. Glucocorticoids and endothelial function in inflammatory diseases: focus on rheumatoid arthritis. Arthrit Res Ther. 2016;18:258. doi:10.1186/s13075-016-1157-0 [ePub ahead of print]
3. Sandoo A, Carroll D, Metsios GS, Kitas GD, Veldhuijzen van Zanten JJ. The association between microvascular and macrovascular endothelial function in patients with rheumatoid arthritis: a cross-sectional study. Arthrit Res Ther. 2011;13(3):R99. doi:10.1186/ar3374
4. Gonzalez-Juanatey C, Llorca J, Garcia-Porrua C, Sanchez-Andrade A, Martín J, Gonzalez-Gay MA. Steroid therapy improves endothelial function in patients with biopsy-proven giant cell arteritis. J Rheumatol. 2006;33(1):74–78.
5. Schäfer SC, Wallerath T, Closs EI, et al. Dexamethasone suppresses eNOS and CAT-1 and induces oxidative stress in mouse resistance arterioles. Am J Physiol Heart Circ Physiol. 2005;288:H436–H444. doi:10.1152/ajpheart.00587.2004
6. Veselinovic MV, Zivkovic VI, Toncev S, et al. Carotid artery intima-media thickness and brachial artery flow-mediated vasodilatation in patients with rheumatoid arthritis. Vasa. 2012;41:343–351. doi:10.1024/0301-1526/a000220

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