Call number: LD2668 .T4 1958 M37

Background: Rheumatoid arthritis (RA) is an inflammatory disease associated with an increased risk of cardiovascular morbidity and mortality. Methotrexate is a widely used RA medication that has encouraging results for being protective from RA cardiovascular related complications. In a published meta-analysis, MTX showed a 21% reduction in cardiovascular mortality; however, this meta-analysis had multiple limitations. Arterial stiffness is considered to be one of RA's extra-articular manifestations. As a common medication, could MTX have a beneficial effect on traditional cardiovascular risk factors and arterial stiffness parameters? Aims: The aim of this thesis is to assess the effect of MTX on cardiovascular morbidity and mortality using meta-analysis and a cross sectional and longitudinal study to determine whether MTX therapy is associated with reduced blood pressure, AS parameters (measured by pulse wave velocity (PWV), augmentation index (AIX)) and other traditional cardiovascular risk factors (glucose, lipids) in rheumatoid arthritis patients in Saudi Arabia. Methods: Meta-analysis of cohort study design was conducted using combined reporting guidelines. Studies were selected using a systematic search in five databases. Meta-analysis of the effect estimate of the cohort study design was done using a fixed effect model. Another part of the thesis is a cross sectional and longitudinal study of RA patients attending the rheumatology clinic at the university hospital in Saudi Arabia that were classified into three groups: 'current-MTX', which were patients that took MTX for at least three months; 'no-MTX', which were patients that were not on MTX for at least one year; and 'new-MTX', which were patients that were due to commence MTX directly after recruitment. Arterial stiffness and central 2 blood pressure parameters were assessed in RA patients using a validated non-invasive Mobil-O-Graph device. Other cardiovascular and non-cardiovascular parameters were also assessed during patient recruitment from patient interviews, medical records and the laboratory database. Patients were followed-up with two times. Linear regression analysis was performed; a mixed model for repeated measures was done to evaluate the effect of time on differences in blood pressure and arterial stiffness between groups. Results: Nine studies were included in the meta-analysis, and MTX showed a 46% reduction in cardiovascular events. Non-significant heterogeneity was documented between studies. A total of 353 patients (mean age 49 years, female 89%, median RA duration 10 years) were recruited at baseline (March 2013 to January 2014); with 117 reassessed over 3-6 months of follow-up. Augmentation index of the 'current-MTX' group was reduced compared to the 'no-MTX' group by 1.1 (95% CI -4.7 to 2.6) %; and systolic blood pressure was increased by 2.5 (95% CI -2.3 to 7.4) mmHg in 'current-MTX', but results were not statistically significant. During follow-up, no difference was found between treatment groups or within each individual group in the longitudinal analysis. Conclusion: Methotrexate is associated with reduced cardiovascular events on meta-analysis of cohort studies. In the cross sectional setting and longitudinal analysis, methotrexate did not prove to be beneficial in reducing arterial stiffness and blood pressure parameters and other cardiovascular risk factors in rheumatoid arthritis patients in Saudi Arabia.

No description available.

published_or_final_version / abstract / Diagnostic Radiology / Master / Master of Philosophy

published_or_final_version / abstract / Medicine / Doctoral / Doctor of Philosophy

published_or_final_version / Molecular Biology / Doctoral / Doctor of Philosophy

published_or_final_version / Nursing Studies / Master / Master of Nursing

published_or_final_version / Medicine / Doctoral / Doctor of Philosophy

published_or_final_version / Paediatrics and Adolescent Medicine / Master / Master of Medical Sciences

This thesis aims to integrate functional and nutrigenomics analyses to examine how dietary polyphenols affect human platelet function and thus may contribute to the prevention of cardiovascular diseases. Initially, 26 low molecular weight phenolic compounds were screened for their effects on platelet aggregation and P-selectin expression in vitro. Only high, non-physiological concentrations of some phenolics showed anti-platelet effects. In parallel we conducted a systematic review of the literature to assess how polyphenol-rich foodstuffs, beverages, or extracts affect platelet function in humans. Cocoa-derived flavan-3-ols were the only class of dietary polyphenols that consistently showed anti-platelet effects in both, acute and chronic settings. Consequently we conducted an acute randomised-controlled human intervention study in which healthy volunteers consumed three different types of chocolates containing different amounts of flavan-3-ols. We found that flavan-3-ol-enriched dark chocolate beneficially affected ex vivo bleeding time, platelet aggregation and P-selectin expression. These effects were gender-dependent. Bioavailability of cocoa-derived flavan-3-ols, as assessed by a targeted metabolomics approach, was also gender-dependent. Using a platelet proteomics approach, we found subtle changes in platelet protein levels 2 h after consumption of flavan-3-ol-enriched chocolate in men, which may partly explain the observed anti-platelet effects. Finally, we assessed whether flavan-3-ols are internalised in platelets after consumption of dark chocolate. No internalisation could be found up to 2.5 h after chocolate ingestion, despite these compounds appearing in plasma. In conclusion, flavan- 3-ol-enriched dark chocolate beneficially affects platelet function in a gender-dependent way, but underpinning mechanisms are still unknown. Furthermore, current insights into their bioavailability cannot fully explain the ability of flavan-3-ols to affect platelet function. Successful future progress of research into the bioavailability and mechanisms of flavan-3- ols in vitro and in vivo will depend on the availability of pure standards for the major human metabolites of flavan-3-ols.