Investigating changes in disease activity as a mediator of cardiovascular risk reduction with methotrexate use in rheumatoid arthritis

Johnson, Tate M.; Sayles, Harlan; Baker, Joshua F.; George, Michael; Roul, Punyasha; Zheng, Cheng; Sauer, Brian C.; Liao, Katherine P.; Anderson, Daniel R.; Mikuls, Ted R.; England, Bryant R.

doi:10.1136/annrheumdis-2021-220125

Cited by 25 publications

(22 citation statements)

References 46 publications

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“…Moreover, the demonstration that in our study the favourable effects on endothelial homeostasis seem to be at least partly independent of the reduction of systemic inflammation fits well with this hypothesis and confirms the results of recent in vitro and population-based studies [ 24 , 33 ]. In fact, in a cohort of patients with the CV risk profile, MTX therapy did not reduce the levels of some inflammatory cytokines, such as TNFα, IL-1β and IL-6 [ 46 ].…”

Section: Discussionsupporting

confidence: 92%

“…Methotrexate (MTX) represents the gold standard and first-line drug in the treatment of RA patients interfering with multiple inflammatory and metabolic pathways, such as homocysteine and nucleic acid metabolism [ 23 ]. Interestingly, long-term MTX therapy has been also associated with a 28% overall lower risk of major CV events, in particular, myocardial infarction, a 57% reduction of hospitalization for heart failure and with reduced CV mortality in RA patients [ 24 , 25 ]. This probably reflects the reduction of the systemic inflammatory burden by MTX treatment, with a consequent decrease in atherosclerotic CV risk.…”

Section: Introductionmentioning

confidence: 99%

“…Taken together, these results suggest a protective, anti-inflammatory activity of MTX on endothelial layer integrity and function. However, the positive effect on endothelial homeostasis and the reduced risk of CV events in RA seem to be partly independent from MTX-induced improvement of disease activity, suggesting that alternative mechanisms may contribute to the improvement of endothelial function and reduction of CV risk [ 24 , 33 ]. The effect of MTX on biomarkers and cell subsets of endothelial damage and repair has been poorly explored.…”

Section: Introductionmentioning

confidence: 99%

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Methotrexate improves endothelial function in early rheumatoid arthritis patients after 3 months of treatment

et al. 2022

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Background Endothelial dysfunction contributes to increased cardiovascular (CV) disease in rheumatoid arthritis (RA). Angiogenic T cells (Tang) are a key regulator of vascular function via their interaction with endothelial progenitor cells (EPCs). Methotrexate (MTX) has been associated to reduced CV disease risk, but its effects on endothelial homeostasis have been poorly explored. We investigated MTX effects on endothelial homeostasis in early, treatment-naïve RA patients. Methods Fifteen untreated, early RA patients and matched healthy controls (HC) were enrolled. RA patients with long-standing disease in remission or low disease activity treated with MTX for at least 6 months were selected as controls. Circulating CD28+ and CD28null Tang cell, endothelial microparticle (EMP), EPC and soluble vascular cell adhesion molecule (sVCAM)-1 levels were measured. Results Tang percentage was higher in early RA than in HCs and significantly increased after 3-month MTX treatment. Tang cells in RA were characterized by higher percentage of CD28null and lower CD28-positive cells than HCs. MTX restored a Tang cell phenotype similar to HCs. Altered sVCAM-1, EMP and EPC were restored to levels similar to HCs after a 3-month MTX. Biomarker levels after 3 months of MTX were not different to those of patients with long-standing treatment. Conclusions MTX has a positive effect on Tang, sVCAM-1, EPCs and EMPs in RA. Restoration of imbalance between CD28 + and CD28null Tang by MTX may be one of the mechanisms underlying its favourable effects on endothelial dysfunction. These effects seem to be long-lasting and independent from systemic inflammation reduction, suggesting a direct effect of MTX on the endothelium.

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Section: Discussionsupporting

confidence: 92%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Methotrexate improves endothelial function in early rheumatoid arthritis patients after 3 months of treatment

et al. 2022

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“…These findings suggest that CVD risk may be modulated by alternative methotrexate-related mechanisms in this population. 104 …”

Section: Cvd Risk Management In Imidsmentioning

confidence: 99%

“…These findings suggest that CVD risk may be modulated by alternative methotrexaterelated mechanisms in this population. 104 Hydroxychloroquine is an antimalarial drug, particularly effective in RA and SLE. It is beneficial for the metabolic profile and, to a lesser extent, for reducing the rates of CVD events in patients with RA.…”

Section: Conventional Dmardsmentioning

confidence: 99%

Monitoring and Managing Cardiovascular Risk in Immune Mediated Inflammatory Diseases

Anyfanti¹,

Dara²,

Angeloudi³

et al. 2021

JIR

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Cardiovascular disease (CVD) is common in immune-mediated inflammatory diseases (IMIDs) and it is predominately attributed to the interplay between chronic inflammation and traditional CVD risk factors. CVD has significant impact on the survival of patients with IMIDs as it is associated with increased morbidity and mortality. Despite recommendations for monitoring and managing CVD in patients with IMIDs, the individual CVD risk assessment remains problematic as CVD risk calculators for the general population consistently underestimate the risk in patients with IMIDs. Application of new technologies utilizing artificial intelligence techniques have shown promising potential for tailoring predictive medicine to the individual patient, but further validation of their role in clinical decision-making is warranted. In the meantime, individuals with IMIDs should be encouraged to adopt behavioral interventions targeting at modifiable lifestyle CVD risk factors, whereas rheumatologists need to be well aware of the unfavorable effects of antirheumatic medication on various CVD risk factors and outcomes. In the current paper, we aim to provide an overview of current and emerging strategies for mitigating CVD risk in patients with IMIDs, based on a practical approach.

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Circulating Adipokines and Associations With Incident Cardiovascular Disease in Rheumatoid Arthritis

Federico

Johnson

England

et al. 2022

Arthritis Care & Research

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Objective. To assess whether circulating levels of adiponectin, leptin, and fibroblast growth factor 21 (FGF-21) are associated with incident cardiovascular disease (CVD) in rheumatoid arthritis (RA).Methods. Adipokines were measured using banked enrollment serum from patients with RA and dichotomized above/ below the median value. Incident CVD events (coronary artery disease [CAD], stroke, heart failure [HF] hospitalization, venous thromboembolism, CVD-related deaths) were identified using administrative data and the National Death Index. Covariates were derived from medical record, biorepository, and registry databases. Multivariable Cox models were generated to quantify associations between adipokine concentrations and CVD incidence. Five-year incidence rates were predicted.Results. Among 2,598 participants, 639 (25%) had at least 1 CVD event over 19,585 patient-years of follow-up. High adiponectin levels were independently associated with HF hospitalization (hazard ratio [HR] 1.39 [95% confidence interval (95% CI) 1.07-1.79], P = 0.01) and CVD-related death (HR 1.49 [95% CI 1.16-1.92], P = 0.002) but not with other CVD events. High leptin was independently associated with CVD-related death (HR 1.44 [95% CI 1.05-1.97], P = 0.02). High FGF-21 levels were independently associated with lower rates of CAD (HR 0.75 [95% CI 0.58-0.97], P = 0.03). In subgroup analyses, associations between high adiponectin and leptin levels with CVD-related death were driven by strong associations in nonobese patients.Conclusion. Adipokines are associated with HF hospitalization and CVD-related death in patients with RA, with stronger associations in nonobese participants. These findings suggest that adipokines effectively predict clinically important outcomes in RA perhaps through an association with body composition and metabolic health. Further study is needed to determine whether adipokine measures might augment existing tools to identify RA patients at increased risk of CVD.

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Investigating changes in disease activity as a mediator of cardiovascular risk reduction with methotrexate use in rheumatoid arthritis

Cited by 25 publications

References 46 publications

Methotrexate improves endothelial function in early rheumatoid arthritis patients after 3 months of treatment

Methotrexate improves endothelial function in early rheumatoid arthritis patients after 3 months of treatment

Monitoring and Managing Cardiovascular Risk in Immune Mediated Inflammatory Diseases

Circulating Adipokines and Associations With Incident Cardiovascular Disease in Rheumatoid Arthritis

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