Thesis (M. P. H.)--University of Hong Kong, 2006. / Also available in print.

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

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

A well-functioning immune system is of paramount importance in preventing lymphomagenesis. Both immunostimulation, which causes excessive cell turnover and increased potential for mutations, and immunosuppression, causing a decreased ability to monitor and halt aberrant cell proliferation, have been implicated in cancer development. Autoimmune diseases are characterized by excessive activation of lymphocytes due to a dysregulated response to self-antigens. The treatments for autoimmune disease therefore share a common goal of immunosuppression. While treatments have become better-targeted to specific inflammatory pathways over the last 30 years as opposed to general immunosuppression, there remains a high risk of hematologic malignancy for patients with autoimmune disease relative to the general population. There are numerous types of autoimmune disease, as well as much heterogeneity within each diagnosis from patient to patient. The focus of this thesis is Rheumatoid Arthritis (RA), a strikingly common disease affecting 0.5-1.0% of the world population and characterized by debilitating, painful, joint-deforming symptoms and difficulty in achieving remission. [1] Therapeutic intervention often necessitates a trial and error approach and various combinations of drugs, in the same way cocktails of chemotherapeutic drugs are tailored to treat cancers due to their heterogeneity. Drugs for the treatment of autoimmune diseases are collectively known as Disease-Modifying Anti-Rheumatic Drugs (DMARDs) and were only first widely used for the treatment of RA in the 1980s. This short history of widespread use, along with the great variability in manifestation of disease and treatment course, has historically limited the ability of observational studies to determine the safety of DMARDs in terms of malignancy risk. Only in the past few years has enough information been available, drawn mostly from national healthcare databases in several countries, to enable strong conclusions about the effects of DMARDs on malignancy risk. This thesis aims to provide a comprehensive review of the most recent and well-designed studies regarding currently available DMARDs for RA and their effects on the risk of lymphoma.

No description available.

M.Tech.: Chiropractic, Durban Institute of Technology, 2006. / The purpose of this pragmatic controlled clinical trial was to investigate the efficacy of low-level laser therapy (LLL T) as a part of the palliative management of the hand symptoms of rheumatoid arthritis (RA). The results were based upon subjective and objective clinical findings. LLLT may offer a viable treatment option for the hand symptoms of RA as its application theoretically supports and suggests that the physiological effects of LLL Tare biostimulation, improved metabolism, increased cell metabolism, improved blood circulation, vasodilatation, analgesic effects, anti-inflammatory and anti-edematous effects; all of which are desired in the treatment of RA (Baxter, 1994; Kahn, 1994, Liggins, 2002). There is however controversy within the literature as to the efficacy of LLLT (Asada et al., 1991; Bliddal et al., 1987; Goats. et al., 1996; Hall et al., 1994; Heussier et al., 1993; Johannsen et al., 1994; Palmagren et al., 1989; Walker et aI., 1987). This is partially attributable to the lack of consensus regarding the methodology applied in these studies. Other inconsistencies regarding the efficacy of laser in the treatment of RA exist due to the wide range of differing wavelengths and doses that have been used in the published reports, thereby making it difficult to effectively compare studies (Asada et al., 1991; Goats et al., 1996; Hall et ai., 1994; Haslett et al., 2001, Heussier et ai., 1993; Johannsen et al., 1994; Palmagren et al., 1989; Walker et al., 1987). This study included a sample of 24 patients with rheumatoid arthritis. They were divided into two groups (Group A and Group B) based on their DASH score and their primary medication. Group A (treatment group) received LLLT of the metacarpophalangeal (Mep) joints and proximal interphalangeal (PIP) joints of their more severely affected hand. Patients in Group B (placebo / M

Introduction: Patients with inflammatory polyarthritis (IP) have an excess risk of cardiovascular (CVD) mortality due to accelerated atherosclerosis. Markers identifying individuals with subclinical atherosclerosis as measured by carotid intima-medial thickness (cIMT) and plaque may allow for attenuation of CVD risk. The objective of this study was to identify associated risk markers for atheromatous plaque and cIMT in an incident cohort of patients with early IP and to assess the risk markers associated with progression of cIMT and plaque after 2 years of follow-up.Methods: From 2004 to 2008 consecutive patients with early IP (≥2 joints swollen for ≥4 weeks) aged 18-65 years, who were within 24 months of symptom onset (±6 months) were recruited as part of a primary-care-based inception cohort. Apparently healthy controls were recruited on a frequency matched 'buddy' pair system. Patients underwent joint and blood pressure examination. Patients and controls underwent BMI measurement and their medication was recorded. Patients' blood was taken for measurement of rheumatoid factor, anti-citrullinated protein antibody, C reactive protein, glucose, lipids (LDL, HDL, triglycerides, paroxonase 1, apolipoprotein A1 and B) and markers of vascular damage (E-selectin, VCAM) and adipocytokines (leptin and adiponectin). Patients and controls underwent B mode Doppler ultrasound examination of the carotid arteries to assess for cIMT and the presence of plaque. In univariate analyses we identified factors that were associated with cIMT and plaque presence after age and gender adjustment. An additive stepwise multivariable logistic regression model was created to investigate the independence of any associations.Results: The 329 IP subjects had a median (IQR) age of 51 (42-58) years and 96 (29%) were male. IP subjects were more likely to be smokers, have a family history of CVD, have diabetes, higher BP and be overweight than their apparently healthy counterparts. IP subjects with plaque at baseline often did not have prior CVD. Subjects with IP had a 2.87 fold higher plaque frequency at the baseline but a similar median cIMT relative to the controls. Traditional CVD risk markers such as age, systolic BP and LDL were associated with cIMT and plaque at baseline. Adiponectin levels were negatively associated with cIMT and positively associated with plaque. IP subjects had a significant increase in their cIMT in the first 2 years of follow-up. The rate of progression of cIMT was 1.5-2.2 fold greater in IP than reported in the general population. Novel risk factors added to the model above and beyond traditional risk factors in predicting atherosclerosis. Steroid exposure at 2 years was associated with atherosclerosis progression.Conclusion: Markers known to be associated with atherosclerosis in the general population are associated with cIMT and plaque presence in early IP prior to established inflammatory disease and therapy. While cIMT in subjects and controls was the same at baseline there was an accelerated rate of progression of cIMT in IP subjects relative to that reported in the general population.

The Canadian Arthritis and Rheumatism Society, British Columbia Division has envisaged research as an important and integral part of its objectives and in February 1951 embarked upon an intensive study of the usefulness of cortisone in long-term medical treatment of the rheumatic diseases, including a series on Rheumatoid Arthritis. A comprehensive program of medical treatment has been put into effect, including the services of social workers. It is essentially a team approach to the aim of physical rehabilitation and a return to gainful employment. The present study is directed to the evaluation of the case work treatment offered to those patients selected to participate in the Rheumatic Diseases Project, Rheumatoid Arthritis Series on Cortisone Therapy. Within a predominantly medical setting the function of the case worker has been considered from the viewpoint of what is expected of her by the medical profession and what might be expected from her as a professional social worker. Two methods of assessment were employed both based on evaluation of each case according to selected case work criteria and the premise that effectiveness of treatment depends upon the appropriate use of skills in relation to the degree of treatability of the patient. The first approach made use of the available case records as far as possible. The second was the device of a Rating Scale devised for the purpose and completed by a group of social workers for each patient worked with. The goals aimed at by the Medical Committee responsible for the project were stated as "physical rehabilitation and a return to gainful employment". Medically the cortisone therapy was successful in effecting enough physical improvement for a patient to become potentially employable. Socially results were discouraging because emotional difficulties and the non-availability of suitable positions prevented the actual return of many patients to gainful employment. The Long-standing personality problems, characterizing this group of patients, precluded the use of intensive case work techniques in roughly 75% of the cases. The evidence is that face-to-face interviewing involving the skilled use of relationship is not appropriate and that supportive technigues designed to prevent further deterioration, alone are relevant for the majority. Sound social diagnostic evaluations with the use of appropriate treatment methods are essential. It is suggested the reality of the team approach should he made available, and that more use should be made of social work skills in the selective screening of applicants for rehabilitation, and that the contributions of social work in the total team plan merits deeper exploration. / Arts, Faculty of / Social Work, School of / Graduate