Methotrexate and Vasculoprotection: Mechanistic Insights and Potential Therapeutic Applications in Old Age

Abstract

Increasing age is a strong, independent risk factor for atherosclerosis and cardiovascular disease. Key abnormalities driving cardiovascular risk in old age include endothelial dysfunction, increased arterial stiffness, blood pressure, and the pro-atherosclerotic effects of chronic, low-grade, inflammation. The identification of novel therapies that comprehensively target these alterations might lead to a major breakthrough in cardiovascular risk management in the older population. Systematic reviews and meta-analyses of observational studies have shown that methotrexate, a first-line synthetic disease-modifying anti-rheumatic drug, significantly reduces cardiovascular morbidity and mortality in patients with rheumatoid arthritis, a human model of systemic inflammation, premature atherosclerosis, and vascular aging. We reviewed in vitro and in vivo studies investigating the effects of methotrexate on endothelial function, arterial stiffness, and blood pressure, and the potential mechanisms of action involved. The available evidence suggests that methotrexate might have beneficial effects on vascular homeostasis and blood pressure control by targeting specific inflammatory pathways, adenosine metabolism, and 5' adenosine monophosphate-activated protein kinase. Such effects might be biologically and clinically relevant not only in patients with rheumatoid arthritis but also in older adults with high cardiovascular risk. Therefore, methotrexate has the potential to be repurposed for cardiovascular risk management in old age because of its putative pharmacological effects on inflammation, vascular homeostasis, and blood pressure. However, further study and confirmation of these effects are essential in order to adequately design intervention studies of methotrexate in the older population.

C-reactive protein and 10-year cardiovascular risk in rheumatoid arthritis

“…First, due to the study's cross-sectional nature, a cause-effect relationship between CRP concentrations and increased cardiovascular risk as predicted by ERS-RA cannot be firmly established. Second, most of RA patients included in the CORDIS database were under immunosuppressive and anti-inflammatory therapy at enrollment, which may have mitigated the strength of the association between CRP and ERS-RA score [30][31][32][33] . In particular, in the current study, a large proportion of patients were exposed to glucocorticoids (43%) at the moment of the analysis and during the disease course (disease duration was 11.6 (8) years), a condition that may have had a significant impact both on the risk of cardiovascular events 34 and on the measured association between CRP, predicted 10-year risk and individual components of ERS-RA risk score.…”

Crosstalk between Inflammation and Atherosclerosis in Rheumatoid Arthritis and Systemic Lupus Erythematosus: Is There a Common Basis?

“…In conclusion, based on systematic reviews and meta-analyses of observational studies, MTX may have the potential to be considered for cardiovascular risk management in old RA patients [ 76 ].…”

Non-Alcoholic Fatty Liver Disease (NAFLD) in Patients with Psoriasis: A Review of the Hepatic Effects of Systemic Therapies

“…Finally, there was a positive link between FGF-23 and AST levels which suggests a possible link with liver activity [ 90 ] MTX Review of the evidence for the potential pro-atherosclerotic effects of MTX MTX improves endothelial function and vascular homeostasis, and is associated with a significant reduction in CV morbidity. These effects appear to be mediated via inhibition of pro-atherosclerotic cytokines such as TNF-α, IL-1 and IL-6 [ 91 , 92 ] CYC TGFβs plays a key role in cell growth and differentiation, modulation of immune activity and regulation of the cell cycle. The effects of CYC on TGFβ levels was determined in PSO pts treated for 12 weeks CYC significantly improved PSO symptoms and QoL of pts in this 3-month clinical study.…”

“…Methotrexate has exhibited beneficial effects on cardiovascular inflammation 91 , 92 as well as decreasing serum levels of PCSK9, which is a likely marker of improved lipid metabolism ( Table 3 ). 89 However, a large placebo-controlled RCT failed to show any benefits of methotrexate on the risk of cardiovascular events.…”

“…Assessment of hepatoprotection can be derived from several different research pathways including in vitro experiments, animal models and monitoring of potential biomarkers (Table 3). [89][90][91][92][93][94][95][96][97][98][99][100][101][102][103][104][105][106][107][108] Given the common etiology of inflammation between psoriasis and NAFLD, it might be postulated that systemic therapies for psoriasis that attenuate systemic inflammation may also have beneficial effects on NAFLD by targeting pro-inflammatory cytokines. 109 However, to date, clinical data are scarce for any direct hepatoprotective effects of systemic psoriasis treatments.…”