Associations Between Methotrexate Use and the Risk of Cardiovascular Events in Patients with Elderly-onset Rheumatoid Arthritis

Widdifield, Jessica; Abrahamowicz, Michał; Paterson, J. Michael; Huang, Anjie; Thorne, John; Pope, Janet; Kuriya, Bindee; Beauchamp, Marie-Ève; Bernatsky, Sasha

doi:10.3899/jrheum.180427

Cited by 36 publications

(21 citation statements)

References 48 publications

(51 reference statements)

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“…In addition, the changes in oxLDL-C are especially relevant in patients with low LDL-C. These findings are in keeping with descriptions showing a decreased incidence of CV disease in patients treated either with methotrexate or biologic agents [62][63][64], since an increasing number of patients reach lowdisease activity and remission at present [65]. Moreover, our findings can also explain why a beneficial effect preventing cardiovascular events has not been observed with methotrexate in the general population [66] or with atorvastatin in non-selected RA patients [67].…”

Section: Discussionsupporting

confidence: 87%

Effects of disease activity on lipoprotein levels in patients with early arthritis: can oxidized LDL cholesterol explain the lipid paradox theory?

et al. 2020

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Background An increased risk of cardiovascular (CV) complications has been described in patients with rheumatoid arthritis (RA). It is the result of the combined effect of classic CV risk factors and others that are specific to the disease. Methods We assessed data from 448 early arthritis (EA) patients: 79% women, age (median [p25-p75]) at onset: 55 [44–67] years and disease duration at study entry 5 [3–8] months; and 72% fulfilled the 1987 RA criteria at 2 years of follow-up. Rheumatoid factor was positive in 54% of patients and anti-citrullinated peptide antibodies in 50%. The follow-up of patients ranged from 2 to 5 years with more than 1400 visits with lipoprotein measurements available (mean 2.5 visits/patient). Demographic- and disease-related variables were systematically recorded. Total cholesterol (TC), high-density lipoprotein (HDL-C), and low-density lipoprotein (LDL-C) levels were obtained from routine laboratory tests. Oxidized-LDL (oxLDL-C) levels were assessed using a commercial ELISA kit. We fitted population-averaged models nested by patient and visit to determine the effect of independent variables on serum levels of TC, its fractions, and oxLDL-C. Results After adjustment for several confounders, high-disease activity was significantly associated with decreased TC, HDL-C, and LDL-C levels and increased oxLDL-C levels. Standardized coefficients showed that the effect of disease activity was greater on oxLDL-C and HDL-C. Interestingly, we observed that those patients with lower levels of LDL-C showed higher oxLDL-C/LDL-C ratios. Conclusions High-disease activity in EA patients results in changes in the HDL-C and oxLDL-C levels, which in turn may contribute to the increased risk of CV disease observed in these patients.

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Section: Discussionsupporting

confidence: 87%

Effects of disease activity on lipoprotein levels in patients with early arthritis: can oxidized LDL cholesterol explain the lipid paradox theory?

et al. 2020

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“…Treatment with methotrexate and biologics is associated with a lower risk of cardiovascular events [13][14][15][16][17]. The increased use of methotrexate and biologics over time is evident in our cohort as shown in a previous study, and could explain the low AMI and IHD risk seen in RA patients diagnosed after 1998 [37].…”

Section: Discussionsupporting

confidence: 72%

“…Treatment of RA with disease-modifying anti-rheumatic drugs (DMARDs) reduces in ammation and disease activity, and is associated with a lower AMI risk [13][14][15][16][17].…”

Section: Introductionmentioning

confidence: 99%

Declining risk of ischemic heart disease over time in rheumatoid arthritis: 1821 patients from 1972 to 2017.

Alsing¹,

Nystad²,

Igland³

et al. 2021

Preprint

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Objectives: To evaluate trends of acute myocardial infarction (AMI) and ischemic heart disease (IHD) in rheumatoid arthritis (RA) patients compared with the general population over time. Methods: We performed a retrospective cohort study of 1821 RA patients diagnosed from 1972 to 2013. The total population of the same county (Hordaland, Norway) and time period was used for comparison. Information on AMI and IHD events was obtained from hospital patient administrative systems or cardiovascular registries. We estimated incidence rates and standardized event ratios (SER) compared with the general population by Poisson regression.Results: There was an average annual decline of 1.6% in age- and sex-adjusted AMI incidence rates from 1972 to 2017 (incidence rate ratio 0.984, 95% CI 0.971–0.998). Excess events in RA patients compared with the general population declined on average 1.3% per year for AMI and 2.3% for IHD from 1972 to 2014. The total RA cohort had 49% (SER 1.49, 95% CI 1.30–1.69) more AMI events and 63% (SER 1.63, 95% CI 1.52–1.74) more IHD events compared with the general population. There were no significant excess AMI and IHD events for RA patients diagnosed after 1998 compared with the general population.Conclusion: Incidence rates and excess events of AMI and IHD in RA patients declined from 1972 to 2017. There were no excess AMI or IHD events in RA patients diagnosed after 1998 compared with the general population.

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“…In contrast, recent studies revealed a beneficial effect of hydroxychloroquine (HCQ) on cardiovascular outcomes in patients with RA [ 124 , 125 ]. Other csDMARDs, such as methotrexate, could also reduce ASCVD risk [ 126 ].…”

Section: Proposed Therapeutic Strategies For Targeting Ascvd In Patients With Airdsmentioning

confidence: 99%

Autoimmune Rheumatic Diseases: An Update on the Role of Atherogenic Electronegative LDL and Potential Therapeutic Strategies

Chen

Sawamura

Dixon³

et al. 2021

JCM

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Atherosclerosis has been linked with an increased risk of atherosclerotic cardiovascular disease (ASCVD). Autoimmune rheumatic diseases (AIRDs) are associated with accelerated atherosclerosis and ASCVD. However, the mechanisms underlying the high ASCVD burden in patients with AIRDs cannot be explained only by conventional risk factors despite disease-specific factors and chronic inflammation. Nevertheless, the normal levels of plasma low-density lipoprotein (LDL) cholesterol observed in most patients with AIRDs do not exclude the possibility of increased LDL atherogenicity. By using anion-exchange chromatography, human LDL can be divided into five increasingly electronegative subfractions, L1 to L5, or into electropositive and electronegative counterparts, LDL (+) and LDL (−). Electronegative L5 and LDL (−) have similar chemical compositions and can induce adverse inflammatory reactions in vascular cells. Notably, the percentage of L5 or LDL (−) in total LDL is increased in normolipidemic patients with AIRDs. Electronegative L5 and LDL (−) are not recognized by the normal LDL receptor but instead signal through the lectin-like oxidized LDL receptor 1 (LOX-1) to activate inflammasomes involving interleukin 1β (IL-1β). Here, we describe the detailed mechanisms of AIRD-related ASCVD mediated by L5 or LDL (−) and discuss the potential targeting of LOX-1 or IL-1β signaling as new therapeutic modalities for these diseases.

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Associations Between Methotrexate Use and the Risk of Cardiovascular Events in Patients with Elderly-onset Rheumatoid Arthritis

Cited by 36 publications

References 48 publications

Effects of disease activity on lipoprotein levels in patients with early arthritis: can oxidized LDL cholesterol explain the lipid paradox theory?

Effects of disease activity on lipoprotein levels in patients with early arthritis: can oxidized LDL cholesterol explain the lipid paradox theory?

Declining risk of ischemic heart disease over time in rheumatoid arthritis: 1821 patients from 1972 to 2017.

Autoimmune Rheumatic Diseases: An Update on the Role of Atherogenic Electronegative LDL and Potential Therapeutic Strategies

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