Protective Effects of Methotrexate against Proatherosclerotic Cytokines: A Review of the Evidence

Abstract

There is good epidemiological evidence that patients with autoimmune rheumatic disease states, particularly rheumatoid arthritis, have an increased risk of cardiovascular morbidity and mortality when compared to the general population. The presence of a chronic systemic proinflammatory state in this patient group disrupts the structural and functional integrity of the endothelium and the arterial wall, favouring the onset and progression of atherosclerosis. A significant role in the detrimental effects of inflammation on endothelial function and vascular homeostasis is played by specific proatherosclerotic cytokines such as tumour necrosis factor-alpha (TNF-α), interleukin-1 (IL-1), and interleukin-6 (IL-6). Recent systematic reviews and meta-analyses have shown that treatment with methotrexate, a first-line disease-modifying antirheumatic drug (DMARD), is associated with a significant reduction in atherosclerosis-mediated cardiovascular events, such as myocardial infarction and stroke, and mortality, when compared to other DMARDs. This suggests that methotrexate might exert specific protective effects against vascular inflammation and atherosclerosis in the context of autoimmune rheumatic disease. This review discusses the available evidence regarding the potential antiatherosclerotic effects of methotrexate through the inhibition of TNF-α, IL-1, and IL-6 and provides suggestions for future experimental and human studies addressing this issue.

Plasma from Patients with Rheumatoid Arthritis Reduces Nitric Oxide Synthesis and Induces Reactive Oxygen Species in A Cell-Based Biosensor

“…In term of inflammation, all RA patients in this study have active disease and high levels of inflammation as 58% of RA patients had elevated levels of hs-CRP, 40% exhibited high levels of IL-6 and 55% had high levels of sVCAM-1. It is known that systemic inflammation has detrimental effects in several tissues, particularly in the endothelium where stimulates atherosclerosis [30]. Several biomarkers of systemic inflammation have been associated with endothelial dysfunction and atherosclerosis, for example, IL-6 and CRP have been inversely correlated with the thickness of the intima media of the carotid in RA patients [30,31].…”

“…It is known that systemic inflammation has detrimental effects in several tissues, particularly in the endothelium where stimulates atherosclerosis [30]. Several biomarkers of systemic inflammation have been associated with endothelial dysfunction and atherosclerosis, for example, IL-6 and CRP have been inversely correlated with the thickness of the intima media of the carotid in RA patients [30,31]. Consistent with our results, CRP levels were higher in patients with high ROS production and low NO synthesis than healthy volunteers with normal ROS or NO.…”

Correlation of cytokines, BDNF levels, and memory function in patients with opioid use disorder undergoing methadone maintenance treatment

“…NSAIDs might also affect the responses of IL-2, IL-6, IL-8, and monocyte chemoattractant protein-1 (Lisboa et al, 2017). DMARDs inhibit the induction of cytokines in monocytes and macrophages (Bondeson, 1997) and interfere with IL-6 and TNF-α expression (Mangoni et al, 2017). Therefore, the current study excluded patients taking anti-inflammatory agents.…”

The relationship of the immune response mediator genes’ polymorphic variants with the methotrexate efficacy in juvenile idiopathic arthritis

“…At the same time, p50/p65 heterodimers exhibit proinflammatory properties and stimulate the transcription of the corresponding cytokine genes, including TNFA [36][37][38]. Methotrexate has been shown to inhibit the p65 phosphorylation and thereby to downregulate the expression of TNFA [39,40]. It is assumed that the NFKB1 rs28362491*D allele may cause a decrease in the NFKB1 expression and, accordingly, the p50 production; the decrease in the p50/p50 homodimer levels most likely exceeds the decrease in the p50/p65 heterodimer levels, which leads to the increased proinflammatory cytokine production in these patients [37,38,41].…”