Investigating Methotrexate Associated Adverse Events in Patients with Rheumatoid Arthritis

Abstract

Background: Methotrexate (MTX) is the recommended first-line treatment for patients with rheumatoid arthritis (RA) due to its cost-effectiveness. Although used in most patients with new onset RA, adverse events (AEs) experienced by patients who receive MTX treatment are known to lead to treatment interruption, a decrease in adherence, and/or permanent discontinuation, and therefore posing challenges to achieving optimal disease control and positive outcomes. Aim and objectives: The overarching aim of this thesis is to provide an in-depth understanding of the occurrence and factors associated with the development of AEs in patients with RA starting MTX for the first time. This aim is addressed through four specific objectives: i) to summarise systematically the existing knowledge about the rates and predictors of AEs in patients receiving MTX; ii) to estimate the rates of AEs occurrence and identify baseline factors associated with subsequent AEs; iii) to illustrate the rates and temporal patterns of patient-recorded AEs; and iv) to examine the relationship between AEs and patient-reported health-related quality of life (HRQoL). Methods: First, the rates and factors associated with AEs were summarised in a systematic review of published literature between 2005 and 2019 with meta-analyses of reported AEs in MTX-naïve patients. The remaining three objectives were assessed using data from the Rheumatoid Arthritis Medication Study (RAMS), a national cohort of patients commencing MTX for the first time. Prevalence rates of AEs were estimated over the first year of treatment (collected by a researcher at 6- and 12-month visits) and weekly (self-recorded by patients in diaries). The associations between baseline factors and AEs were assessed using multivariable logistic regression models. Finally, the associations between the occurrence of nausea/headache and change in EQ-5D (a measure of HRQoL) were explored using random effects linear regression models. Results: Gastrointestinal AEs were the most common AEs reported in the literature with a pooled estimate of 32.7%, and while pooled estimates of neurological, mucocutaneous, and pulmonary AEs were 24.7%, 24.7%, and 30.7%, respectively. The review also identified several factors associated with AEs, such as increased BMI, higher disability, and positive auto antibody status. The estimated AEs in RAMS were comparable with the existing literature. Baseline factors associated with AEs included female gender, alcohol consumption, increased BMI, higher disability and disease activity scores, and lower MTX starting dose. An evaluation of the weekly patterns of patient-recorded AEs found that reporting peaked in the early few weeks of treatment for some AEs, such as nausea (14%) and headache (5%), but the number of patients reporting these AEs gradually declined over the year of study. Contrary to this, alopecia was reported in less than 1% of patients in the first few weeks of starting MTX but increased over the study period to a peak of 2.5%. Lastly, assessment of the relationship between AEs (nausea and headache) and HRQoL found that the experience of AEs had negative effects on HRQoL. Although less common, headache had almost double the negative impact on HRQoL compared to nausea. Conclusions: The findings presented in this thesis provide an up-to-date account on rates and factors associated with AE occurrence in patients starting MTX and highlight their potential impact on patient HRQoL.