Methotrexate in Atherogenesis and Cholesterol Metabolism

Coomes, E. N.; Chan, Edwin S. L.; Reiss, Allison B.

doi:10.1155/2011/503028

Cited by 49 publications

(38 citation statements)

References 56 publications

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“…coexistent cardiometabolic risk factors, may explain the association between cardiovascular diseases and psoriasis . Targeted anti‐inflammatory therapy holds promise in the prevention and treatment of atherothrombotic disease and results from on‐going trials of such strategies in patients with high risk of cardiovascular events are awaited and could have a major clinical impact . Along this line, an association between systemic anti‐inflammatory treatments, including biological drugs, and reduced risk of cardiovascular events has been demonstrated in patients with rheumatoid arthritis .…”

Section: Discussionmentioning

confidence: 99%

Cardiovascular outcomes and systemic anti‐inflammatory drugs in patients with severe psoriasis: 5‐year follow‐up of a Danish nationwide cohort

Ahlehoff

Skov

Gislason

et al. 2014

Acad Dermatol Venereol

168

157

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Systemic anti-inflammatory treatment with methotrexate was associated with significantly lower rates of cardiovascular events during long-term follow-up compared to patients treated with other antipsoriatic therapies. The treatment strategy in patients with severe psoriasis may have an impact on cardiovascular outcomes and randomized trials to evaluate the cardiovascular safety and efficacy of systemic antipsoriatic therapies are called for.

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Section: Discussionmentioning

confidence: 99%

Cardiovascular outcomes and systemic anti‐inflammatory drugs in patients with severe psoriasis: 5‐year follow‐up of a Danish nationwide cohort

Ahlehoff

Skov

Gislason

et al. 2014

Acad Dermatol Venereol

168

157

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“…These observed reductions are suggestive of a protective effect due to the anti-inflammatory properties of MTX, whereas MTX has previously been reported to affect cholesterol transport (Coomes et al. , 2011). However, administration of the highest dose caused minimal liver fibrosis and biliary hyperplasia suggesting enhanced toxicity of MTX in the context of NASH.…”

Section: Discussionmentioning

confidence: 99%

Systems Level Metabolic Phenotype of Methotrexate Administration in the Context of Non-alcoholic Steatohepatitis in the Rat

Kyriakides

Hardwick

Jin

et al. 2014

Toxicological Sciences

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Adverse drug reactions (ADRs) represent a significant clinical challenge with respect to patient morbidity and mortality. We investigated the hepatotoxicity and systems level metabolic phenotype of methotrexate (MTX) in the context of a prevalent liver disease; non-alcoholic steatohepatitis (NASH). A nuclear magnetic resonance spectroscopic-based metabonomic approach was employed to analyze the metabolic consequences of MTX (0, 10, 40, and 100 mg/kg) in the urine and liver of healthy rats (control diet) and in a model of NASH (methionine-choline deficient diet). Histopathological analysis confirmed baseline (0 mg/kg) liver necrosis, liver inflammation, and lipid accumulation in the NASH model. Administration of MTX (40 and 100 mg/kg) led to liver necrosis in the control cohort, whereas the NASH cohort also displayed biliary hyperplasia and liver fibrosis (100 mg/kg), providing evidence of the synergistic effect of MTX and NASH. The complementary hepatic and urinary metabolic phenotypes of the NASH model, at baseline, revealed perturbation of multiple metabolites associated with oxidative and energetic stress, and folate homeostasis. Administration of MTX in both diet cohorts showed dose-dependent metabolic consequences affecting gut microbial, energy, nucleobase, nucleoside, and folate metabolism. Furthermore, a unique panel of metabolic changes reflective of the synergistic effect of MTX and NASH was identified, including the elevation of hepatic phenylalanine, urocanate, acetate, and both urinary and hepatic formiminoglutamic acid. This systems level metabonomic analysis of the hepatotoxicity of MTX in the context of NASH provided novel mechanistic insight of potential wider clinical relevance for further understanding the role of liver pathology as a risk factor for ADRs.

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“…With regard to experimental data, mechanistic studies suggest that atheroprotective effects of low-dose methotrexate may accrue in part from enhanced release of adenosine and a consequent facilitation of cholesterol efflux and reverse cholesterol transport from arterial wall foam cells via upregulated expression of cholesterol 27-hydroxylase (HY27) and the ATP-binding cassette transporter (ABCA1)38,39. Low-dose methotrexate also appears to have effects on apoptosis and on the suppression of adhesion molecule function.…”

Section: Moving Beyond Jupiter Part Ii: Cirt and Low-dose Methotrexatementioning

confidence: 99%

Moving Beyond JUPITER: Will Inhibiting Inflammation Reduce Vascular Event Rates?

Ridker

2012

Curr Atheroscler Rep

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The recent JUPITER trial demonstrated that potent statin therapy reduces by 50 percent the risk of heart attack and stroke among men and women with low levels of LDL-cholesterol who are at increased vascular risk due to elevated levels of CRP, a biomarker of low-grade systemic inflammation. In JUPITER, both absolute risk and the absolute risk reduction with statin therapy in JUPITER were related to the level of CRP whereas no such relationship was observed for LDL-C. Further, on-treatment levels of CRP and LDL-C were independently associated with residual risk, and the genetic determinants of statin-induced CRP reduction differed from the genetic determinants of statin-induced LDL reduction. Despite these data, it is impossible in any statin trial to establish whether the clinical benefits of treatment are due to LDL-reduction alone, to inflammation inhibition, or to a combination of both processes To address the hypothesis that lowering inflammation will lower vascular event rates, two large-scale placebo controlled trials using targeted anti-inflammatory agents for the secondary prevention of myocardial infarction have been initiated. The first trial, the Canakinumab Anti-Inflammatory Thrombosis Outcomes Study (CANTOS) is evaluating whether interleukin-1 (IL-1 ) inhibition as compared to placebo can reduce rates of recurrent myocardial infarction, stroke, and cardiovascular death among stable coronary artery disease patients who remain at high vascular risk due to persistent elevations of hsCRP (≥2 mg/L) despite contemporary secondary prevention strategies. The second trial, the Cardiovascular Inflammation Reduction Trial (CIRT) has been funded by the NHLBI and will evaluate whether low dose methotrexate (target dose 20 mg/week) as compared to placebo will reduce major vascular events among a group of post-myocardial infarction patients with either diabetes or metabolic syndrome, groups known to have high risk on the basis of a persistent proinflammatory response. Together, CANTOS and CIRT represent a core test of the inflammation hypothesis of atherothrombosis and the exploration of a potential new phase for cardiovascular therapeutics.

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Methotrexate in Atherogenesis and Cholesterol Metabolism

Cited by 49 publications

References 56 publications

Cardiovascular outcomes and systemic anti‐inflammatory drugs in patients with severe psoriasis: 5‐year follow‐up of a Danish nationwide cohort

Cardiovascular outcomes and systemic anti‐inflammatory drugs in patients with severe psoriasis: 5‐year follow‐up of a Danish nationwide cohort

Systems Level Metabolic Phenotype of Methotrexate Administration in the Context of Non-alcoholic Steatohepatitis in the Rat

Moving Beyond JUPITER: Will Inhibiting Inflammation Reduce Vascular Event Rates?

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