ABSTRACT All members registered on the managed care database for the chronic condition Rheumatoid Arthritis (RA), for the period 01 January 2003 to 30 June 2003, were evaluated to determine the prescribing pattern of the cyclo-oxygenase (COX) II inhibitors and non-selective non-steroidal anti-inflammatory (NSAIDs). A total of 2818 members were registered on the managed care database of the chronic condition RA and 1372 members were identified as using COX II inhibitors and 827 members were using nonsteroidal anti-inflammatory (NSAIDs). The prescribing frequency determined for the COX II inhibitors were 48.60% and 29.35% for the NSAIDs. The members identified as either using a COX II inhibitor or a NSAIDs were divided into two groups. The prescribing patterns of each group such as age, gender, co-morbid conditions, concomitant medication use and frequency were analysed and compared to the national institute of clinical excellence (NICE) and the South African Rheumatism and Arthritis Association (SARAA) guidelines for the appropriate prescribing of the COX II inhibitors. Celecoxib was the most frequently prescribed COX II inhibitor accounting for 46% of all the COX II inhibitors identified and diclofenac was the most frequently prescribed NSAID accounting for 34% of all the NSAIDs prescriptions. COX II inhibitors were prescribed more frequently to females with a mean age of 55 years than males. A similar prescribing trend was found with the NSAIDs. The COX II inhibitors were frequently prescribed to patients over the age of 56 with co morbid gastro-oesophageal disease and concomitant warfarin and steroid use. The prescribing patterns found in the managed care environment were similar to those recommended by the NICE and SARAA guidelines. The managed care data showed that the COX II inhibitors, which are supposed to have less gastric adverse side effects, were frequently used in combination with gastroprotective agents (GPA’s). This study indicates that even though COX II inhibitors were prescribed more frequently than NSAIDs in the managed care environment the recommended clinical guidelines and protocols employed by the managed care environment were adhered to. However, there v is a need to closely monitor patients on concomitant GPA’s treatment and COX II inhibitors. This study helped to evaluate the current prescribing patterns of COX II inhibitors in the managed health care environment. This study confirmed that guidelines and protocols were adhered to. These are excellent tools to be used in the managed health care environment to ensure effective and appropriate prescribing.

Ultrasound (US) imaging has made significant progress over the past 20 years in relation to its role in inflammatory arthritis, and in particular, Rheumatoid Arthritis. Modern US machines provide crisp, detailed images of superficial anatomical structures which has facilitated the uptake of US imaging as an important assessment tool within the Rheumatology department. Diagnostic and prognostic information can now assist clinicians decisions with the goal of improving patient treatment and subsequent outcome. In addition, 3D US imaging has recently been suggested as an additional imaging modality with potential benefits in the assessment of in?ammatory arthritis. Recent work has focused on providing a reliable, responsive US joint count which can be assimilated into routine care as well as providing a platform for clinical research. Thus, my first aim was to show that a defined limited US data set, including 2D and 3D imaging, shows acceptable reliability. I demonstrate that both imaging modalities are reliable in terms of reading and image acquisition when restricted to a limited US data set. My second aim, was to demonstrate that a limited US data set is responsive. Using both a physiological and pharmacological trigger, I demonstrate that both 2D and 3D imaging are responsive and that combining US endpoints with DAS28 (Disease Activity Score - 28) increased the effect size and identifies treatment effects early. Despite notable advances in musculoskeletal US research, there is still need for better understanding of the pathophysiological correlates of ultrasound imaging. Therefore my final aim was to examine the relationship of Power Doppler Signal (PDS) and gray-scale synovial thickening with histological features of synovitis at a single joint level and with an extended joint US data set. I Firstly show that the harvesting of synovial tissue, using a minimally invasive US-guided biopsy technique, is safe and well tolerated by patients and that the quality of tissue and RNA extracted is good. Using this tissue collection method, I demonstrate a good correlation of US and histological parameters of synovitis (specifically CD68+ sub-lining macrophages) at a single joint level, in both an early and established RA cohort. This relationship is maintained if the US assessment is extended to a discrete US joint data set. Furthermore, within the knee joint I demonstrated that PDS correlates well with synovial tissue expression of inflammatory mediators of neoangiogenesis and histological assessment of synovial vascular area.

Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease which predominantly affects the synovial joints. Local gene therapy represents an approach to produce therapeuticmolecules (i.e. soluble TNF receptor (sTNFR)-Fc and interleukin-1 receptor antagonist (IL-1Ra)) directly in arthritic joints. Gene therapy could be designed to link the level of therapeutic gene expression directly to disease activity, through the use of transcriptional and posttranscriptional regulatory elements. The experiments in this thesis describe the construction of multi-responsive, composite synthetic promoters, comprised of the binding sites for an array of transcription factors activated in arthritic joints. Optimal spatial arrangements of binding sites in relation to each other and to the TATA box were determined by Assembly PCR cloning and the functionality of the resulting synthetic promoters revealed additive or synergistic induction of luciferase reporter gene expression in response to combined stimulation. Candidate synthetic promoters were cloned into a lentiviral vector between insulator elements and displayed significantly enhanced induction, in excess of 1,500 fold in response to combined stimulation. Inflammation-specific activation of lentiviral synthetic promoters was confirmed in a carrageenan-induced paw inflammation mouse model, which demonstrated the strong correlation between local luciferase gene expression and paw inflammation. Post-transcriptional gene regulation was also investigated by exploiting the differential expression of endogenous miR-23b during inflammation. Insertion of miR-23b target sites into the 3’UTR of the luciferase gene subjected luciferase mRNA to regulation by miR-23b. Experiments demonstrated that high basal gene expression driven by constitutive and inducible promoters was significantly downregulated by miR-23b without significantly impairing high gene expression upon stimulation. Overall, the experiments in this thesis have confirmed the induction of inflammation-specific gene expression, regulated by inflammationresponsive endogenous transcriptional and post-transcriptional elements.

Bone makes up a framework that provides protection for internal body organs. The homeostasis of bone is maintained by a balanced process involving old bone degradation and new bone formation. However, this balance can be altered in pathophysiological conditions such as in postmenopausal osteoporosis and in patients with rheumatoid arthritis (RA). In recent years, new therapies have been developed to reduce bone resorption. However, there is disparity in patients’ response to these therapies. The reasons are unclear although age, gender, ethnic background and lifestyle have all been suggested to play a part. For patients with chronic inflammatory conditions, treatment was revolutionised by the discovery and application of biologic therapies that target pro-inflammatory proteins and/or pathways. However, whilst the anti-inflammatory effect of these biologic agents is well-established, their effect on bone loss is just emerging. In RA, it is not clear whether the beneficial anti-inflammatory effects of biologic anti-tumour necrosis factor alpha (TNFα) agents are accompanied by parallel improvements in bone erosion/density, whether there are differences between patient groups and what factors influence the response. In order to address these issues, a database on the factors that influence responsiveness of patients with osteoporosis to bisphosphonates, a treatment that suppresses bone resorption, was established. Based on the outcome of this study, the influence of the key factor(s) that affect bone response to treatment in combination with excess pro-inflammatory cytokine production on bone response in RA patients was determined. Significant improvement in bone mineral density (BMD) and plasma levels of bone biomarkers has been shown in this study with biologic anti-TNFα agents. The improvement in BMD was not always consistent with improvement the clinical response to treatment as assessed by changes in disease activity score 28(DAS28). The study also provides a mechanistic explanation for how blockade of TNFα in patients can reverse the balance of bone loss in patients with RA. Thus, the data show that treatment of patients with biologic anti-TNFα agents reduces the number of osteoclast precursors (OCs) in the blood.

Rheumatoid arthritis (RA) is a chronic inflammatory disease of autoimmune origin affecting approximately 1% of adult population worldwide. The clinical course of RA is highly variable, ranging from self-limiting to severe disease, with considerable individual and socio-economic implications. It is now well acknowledged that early diagnosis and treatment equates to better long-term outcomes. However, despite major therapeutic advances in recent decades, the management of RA remains challenging as a significant proportion of patients presents with active disease despite maximization of therapy. It is also difficult to predict which patients will respond adequately to various treatment regimens. The identification of biomarkers of clinical outcome capable of stratifying patients into accurate prognostic categories and guide pharmacological intervention is therefore urgently needed. Notably, along with clinical variability, RA is characterised by high biological heterogeneity at the tissue level. The cellular infiltrate of the RA synovium can be distinguished into at least three main patterns according to the degree and organisation of the immune cells: the 'Lymphoid' pattern characterised by predominant B and T lymphocytes which tend to cluster in discrete aggregates resembling ectopic lymphoid structures; the 'Myeloid' pattern characterised by absence of lymphocytic aggregates but significant expression of sublining macrophages; the 'Pauci-immune' pattern, that hardly shows any infiltrating immune cells. The hypothesis of this thesis was to determine whether these distinct synovial pathotypes may define specific disease subsets and predict response to therapy in patients with RA. Specifically, this work aims at: 1. evaluating whether the synovial pathotype associates with the presence of specific clinical, serological, radiological and ultrasonographic findings in an early RA cohort (< 1 year onset); 2. exploring the potential role of the synovial pathotype as a predictor of response to conventional synthetic disease-modifying antirheumatic drugs (csDMARD) after 6 months in an early RA cohort; 3. exploring the potential role of the synovial pathotype as a predictor of response to anti-TNFα treatment after 3 months in a csDMARD-failure established RA cohort.

Rheumatoid arthritis (RA) is a chronic, heterogeneous, autoimmune disease that causes inflammation of synovial joints leading to pain, stiffness and swelling. If left untreated, RA results in irreversible joint destruction and long term disability. Initial treatment with glucocorticoids and other immunosuppressive agents suppresses inflammation. However, many of these drugs are not well-tolerated due to extensive side effects or are simply ineffective. The discovery of tumour necrosis factor-α (TNF) as a key mediator of inflammation in RA led to the development of monoclonal anti-TNF antibody therapy. Since then, other biologic drugs targeting immune pathways have been developed for RA, including interleukin-6 (IL-6) blockade, B cell depletion, and T cell co-stimulation blockade. Not all patients will respond to their first biologic drug and currently there is no way to predict which patient will respond to each different class of drug. Generally, 3 – 6 months are required to determine clinical efficacy, during which time joint inflammation proceeds. Therefore, discovering biomarkers to predict treatment response is a research priority. Biologic drugs target immune pathways. As single cell technology advances and has increasing capacity to identify subtle changes in many cell subsets, I hypothesise that studying the blood immune cell landscape will define cellular biomarker profiles relevant to each individual patient’s disease.

No description available.

Abstract not available

"January 2003" Errata slip inserted inside front cover. Includes bibliographical references (leaves 282-313)

"January 2003" / Errata slip inserted inside front cover. / Includes bibliographical references (leaves 282-313) / xxx, 313 leaves : ill. ; 30 cm. / Title page, contents and abstract only. The complete thesis in print form is available from the University Library. / Thesis (Ph.D.)--University of Adelaide, Dept. of Pathology, 2003