Saudi Cultural Missions Theses & Dissertations
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Item Restricted Investigating Methotrexate Associated Adverse Events in Patients with Rheumatoid Arthritis(Saudi Digital Library, 2023-11-17) Sherbini, Ahmad; Verstappen, SBackground: 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.20 0Item Restricted COMPLEMNT ACTIVATION DOES NOT PLAY A DIRECT ROLE IN MODEL CHEMOTHERAPUTIC- INDUCED MUCOSITIS(2023-07-31) Aljamei, Hanan; Stadnyk, AndrewChemotherapeutic agents are highly efficient in the treatment of various cancers; however, many of the drugs also lead to unwanted toxicities. “Mucositis” describes the injury caused by these cytotoxic agents to the healthy mucosa of the digestive tract. Depending on the dose regimen and drug, mucositis afflicts a significant fraction of patients, from 40-100%. Currently, the underlying molecular mechanism(s) responsible for mucositis are not fully understood and there are no efficient treatments. Research into the mechanism underlying mucositis has identified superoxide radicals early followed by changes in mediators of inflammation and subsequent tissue injury. It was previously reported that complement becomes activated in the jejunum of mice injected with 5-fluorouracil to elicit mucositis and that properdin deficient mice, which should have compromised alternative pathway activation, were protected though in a complement-activation-independent mechanism. While that discovery implicated properdin in the inflammation, the experiment did not rule-out other pathways of complement activation possibly contributing to the inflammation. Therefore, the objective of this study was to determine whether activation of complement by other routes contributes to mucositis, and the hypothesis; that preventing complement activation would protect mice from mucositis. Mice were injected daily with 5-fluorouracil or methotrexate for 5 days then euthanized one day later. Each mouse’s jejunum, colon, tongue and cheek mucosae were harvested for histopathological analysis. To determine whether the lectin pathway was involved, mice lacking mannose binding lectins 1 and 2 were used. Deficient mice responded similar to wildtype mice to 5-fluorouracil and methotrexate, showing weight loss at the same rate and similar pathological features in both the jejunum and colon. Neither strain of mouse manifested with oral mucositis. Having ruled-out the mannose-binding lectin pathway, it was decided to use mice deficient in the molecule central to complement, C3. C3 deficient mice were bred with wild type mice, then the heterozygous offspring bred to a second generation which were used in experiments. The stool bacteria showed a pattern consistent with the F2 generation mice becoming more similar though different from their parent’s. C3 deficient and C3 wildtype drug-treated mice lost weight to a similar extent, while C3 heterozygotes lost weight beginning on the third day of the experiment. All the mice had similar histopathological features in their jejunums and colons after the treatments. No mice developed oral mucositis. One experiment extending the period of time the mice were treated was conducted but none of the mice developed oral mucositis. I conclude that complement activation does not contribute mechanistically to mucositis.8 0