Diss. (sammanfattning) Göteborg : Göteborgs universitet, 2007. / Härtill 3 uppsatser.

Thesis (Ph.D.)--University of Adelaide, Dept. of Pathology, 2003. / "January 2003" Errata slip inserted inside front cover. Includes bibliographical references (leaves 282-313).

Thesis (M.Sc.)--Victoria University of Wellington, 2009. / "Malaghan Institute of Medical Research." Includes bibliographical references.

Thesis (M. Med. Sc.)--University of Hong Kong, 2004. / Also available in print.

Thesis (doctoral)--Katholieke Universiteit te Nijmegen.

Thesis (M.S.)--University of Wisconsin--Madison, 1981. / Typescript. eContent provider-neutral record in process. Description based on print version record. Includes bibliographical references (leaves 52-54).

Würzburg, Univ., Diss., 2004.

Introduction: Rheumatoid arthritis (RA) is a multisystem disease associated with early mortality. Methotrexate (MTX) is the first-line therapy in RA but is associated with significant adverse events and response is not universal. There is, therefore, a need to identify early those patients with RA unlikely to respond or develop toxicity to MTX. One of the major influences on drug response is adherence and MTX can cause a range of side effects known to impact on adherence such as pneumonitis (MTX-P). The gold standard measurement of adherence would be direct detection of MTX or its metabolites in a biochemical assay. Currently, there are no reliable markers that predict response to MTX but some studies have suggested measurement of MTX levels may predict response. Previous studies have suggested that MTX-P may occur in individuals genetically predisposed to the disease. The aims of this research are to i) develop an assay to measure MTX levels; ii) test the ability of the assay to measure adherence; iii) investigate if MTX levels are associated with response; and iv) conduct a genome wide association study (GWAS) investigating MTX-P. Methods: An assay to measure MTX and 7-OH-MTX in urine and plasma was developed using HPLC-SRM-MS and the assay was used to measure levels in a cohort of RA patients to develop a pharmacokinetic model. Simulations of the model were used to determine the ability of the assay to monitor adherence and the model was validated in a separate cohort of patients with RA. An observational study of RA patients was used to measure MTX and 7-OH-MTX levels to investigate if levels are associated with response. Finally, a GWAS investigating MTX-P was conducted. Results: Results of the pharmacokinetic model demonstrated that MTX is the preferred analyte to monitor adherence. The model was validated in a separate cohort of patients with RA demonstrating the ability of the assay to measure adherence. MTX levels were not associated with disease response in this cohort. A GWAS of MTX-P demonstrated three SNPs associated with disease (p <5 x 10-5) with subsequent bioinformatics analysis showing a potential functional role for rs7514182.ConclusionAdherence to MTX may be a significant barrier to patients achieving full response to therapy. The development of a direct test to detect adherence based on measuring MTX levels using HPLC-SRM-MS has been developed in urine and blood. The assay was shown to be accurate in several domains from EMA guidelines and was validated in a separate cohort of patients. Finally, this program of work has investigated genetic markers associated with MTX-P. The results demonstrated a potential SNP associated with disease which demonstrates a functional role in the development of pulmonary fibrosis.

Rheumatoid Arthritis (RA) is an autoimmune disease characterized by chronic inflammation, pain and joint remodeling. Existing RA therapies such analgesics and anti-inflammatories can treat symptoms. More recent strides in disease modifying anti-rheumatic drugs (DMARDs) can slow progression of disease. However, there is still no therapeutic that can reverse disease damage and there is no cure for RA. Resolvin E1 (RvE1) is an endogenous lipid initially identified as a key pro-resolving mediator. By tamping down expression of pro-inflammatory cytokines, tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β), RvE1 is able to down-modulate inflammation and return an inflamed tissue to a homeostatic state. More recently, RvE1 has been shown to act directly to inhibit inflammatory pain through central and peripheral nervous system mechanisms. RvE1 has also been shown to restore bone homeostasis by balancing osteoclast and osteoblast activity. In contrast to current therapeutics that treat symptoms and slow disease progression, a RvE1 pathway agonist has the potential to reverse RA by resolving inflammation, reversing bone remodeling and returning joints to normal homeostasis.

Thesis (Ed.D.)--Boston University