Studies exploring the relationship between methotrexate use and blood pressure and arterial function in the rheumatoid arthritis population

Author: Leena Baghdadi

Baghdadi, Leena, 2017 Studies exploring the relationship between methotrexate use and blood pressure and arterial function in the rheumatoid arthritis population, Flinders University, School of Medicine

Terms of Use: This electronic version is (or will be) made publicly available by Flinders University in accordance with its open access policy for student theses. Copyright in this thesis remains with the author. You may use this material for uses permitted under the Copyright Act 1968. If you are the owner of any included third party copyright material and/or you believe that any material has been made available without permission of the copyright owner please contact with the details.


Rheumatoid arthritis (RA) is a chronic disabling inflammatory disease affecting up to 2% of the population. Methotrexate (MTX) use has been associated with reduced cardiovascular morbidity and mortality in patients with RA. Although MTX has anti-inflammatory effects, there is little evidence to support additional salutary effects of MTX on markers of cardiovascular risk such as blood pressure (BP), and markers of arterial function including arterial wave reflection (augmentation index, AIx), and pulse wave velocity (PWV). Observational studies have suggested a lower systolic BP (SBP) in MTX users; however, it is unknown whether these differences remain constant over time and whether they are independent of systemic markers of inflammation.

The studies presented in this thesis sought to determine whether there is an association between MTX and BP/arterial function in the RA patients and whether it is independent of inflammation. In addition, it explores the role of asymmetric dimethylarginine (ADMA), intracellular MTX polyglutamates (MTXPGs), and genetic polymorphism of transporters and target enzymes in modulating the effects of MTX on BP and arterial function. An initial cross-sectional study was conducted followed by a repeat cross-sectional study, where the same RA patients were followed for 8 months to examine changes in BP and arterial function. Mobil-O-Graph monitors were used to record 24-hour BP, AIx and PWV. The SphygmoCor was used to measure AIx and central BP.

The findings of these studies revealed that clinical BP was significantly lower in MTX patients compared to non-MTX patients at both baseline and 8 months. Similar differences were found for central BP and PWV. Patients treated with MTX had significant lower average 24-h and daytime, but not night-time, peripheral and central BP and PWV when compared to RA patients on other DMARDs. The changes in outcomes between visits were mostly no different between groups, although the 24-h central SBP was lowerd more in MTX than in non-MTX users. There were no significant associations between the two systemic inflammatory markers ESR and CRP and clinic SBP, or between DAS28 and clinic SBP. Heterozygous genotype of MTX ABCG2 (i.e. mutant gene) showed higher concentration of MTXPGs and was associated with lower BP and arterial function. The associations between MTX and low BP and PWV have pharmacological, genetic and preventive attractions.

Keywords: asymmetric dimethylarginine, augmentation index, blood pressure, diseasemodifying antirheumatic drugs, methotrexate, pulse wave velocity, rheumatoid arthritis, single nucleotide polymorphism

Subject: Medicine thesis

Thesis type: Doctor of Philosophy
Completed: 2017
School: School of Medicine
Supervisor: Prof Arduino Mangoni