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Thesis (Masters Degree( Medical Technology) --Cape Technikon, Cape Town,1996 / Intensive investigations in many different populations over the last decade, have indicated a failure to understand the inheritance of rheumatoid arthritis (RA). It was hoped that genes within the class IT region of the major histocompatibility complex (MHq could shed some light on the inheritance of this autoimmune disease and which are now known without doubt, to confer susceptibility to the disease. Genetic studies of RA have concentrated primarily on its autoimmune nature and several investigations of MHC class IT molecules, have demonstrated an association between specific HIA alleles and susceptibility to RA, in particular the DRBI*04 and DRBI*01 alleles. - The HIA system is known to be associated with many diseases involving an immune aetiology. The structural features of specific DR and DQ genes give clues to the molecular mechanisms by which these alleles are associated with RA It has been found by many investigators that there is more than one susceptibility allele for RA at the DRBI locus. Questions arise whether the DRBI molecule itself directly contributes to the pathogenesis ofRA and why some DRBI genes carrying DRBI*04 alleles, are not associated withRA Animal studies have emphasised the critical importance of T-cells in the pathogenesis of RA Immune responsiveness is thought to be controlled by specific allelic variation by determining the ability of specific T-cell receptors (fCRs) to be triggered by recognition of class IT molecules during the induction of the immune response. In a disease such as RA, however, where multiple alleles are thought to confer risk, it is not yet known whether each of these alleles shares some common structural feature triggering a single T-cell pathway or whether each allele represents an alternative recognition site which triggers different T-cell clones, all of which lead to a similar clinical syndrome.

Rheumatoid arthritis (RA) is a systemic, inflammatory disease, which predominantly affects multiple joints. RA is characterized by swollen joints and peri-articular bone erosion. Conventional RA treatments have shown to reduce inflammation and slow down bone erosion, but repair of bone erosion is limited. Additionally, failure to repair for bone erosion in rheumatoid arthritis (RA) is caused by inadequate osteoblast-mediated bone formation resulting from focal inflammatory environment. Hence, there is immediate need to facilitate greater insight and develop a new therapeutic strategy to aid osteoblast -mediated repair of bone loss in RA. CKIP-1 is an intracellular inhibitor, that can negatively regulate osteoblast lineage cells differentiation and activity. CKIP-1 levels were found to be aberrantly over expressed in bone specimens from RA patients and arthritis mice, which was associated with reduced bone formation and increased disease severity. By genetic approach, overexpressed CKIP-1 in osteoblast exacerbated bone erosion and articular inflammation in CIA mice, whereas deficiency of CKIP-1 in osteoblast alleviates bone erosion in CIA mice. By pharmacological approach, RNA interference-based silencing of osteoblastic CKIP-1 led to bone formation-mediated reparative process at erosive site and reduced articular inflammation in arthritis induced mice. To extend above findings to a more relevant species that more closely resemble humans, we aimed to investigate the role of osteoblastic Casein kinase-2 interacting protein-1 (CKIP-1) in failure to repair bone erosion in non-human primate (NHP) arthritis model in this study. We found that CKIP-1 mRNA expression in osteoblasts of arthritic NHP was significantly suppressed by CKIP-1 siRNA treatment. Moreover, silencing of CKIP-1 in osteoblast of arthritis monkey improved clinical signs such as reduction in arthritis score, joint swelling and increase in body weight. Similarly, suppression of osteoblastic CKIP-1 resulted in better organized bony and articular structure with, fewer bone erosion sites as observed in x ray and micro CT images. Moreover, we found increase in bone mass, bone formation parameters such as BFR/BS and MAR and histological examination revealed attenuation of peri articular bone erosion and intraarticular inflammation in CKIP-1 siRNA treated arthritis monkeys. Taken together, these data strongly suggest that highly expressed osteoblastic CKIP-1 plays an important role in failure to repair articular bone erosion by inhibiting bone formation in RA. Targeting osteoblastic CKIP-1 could serve as a new therapeutic strategy by bone repair augmentation in RA.

Aim: The aim of this thesis was to validate the 2010 American College of Rheumatology/European League Against Rheumatism classification criteria for rheumatoid arthritis (RA), in particular with respect to its construct validity and the role of autoantibodies within the criteria. Methods: This thesis used data from the Norfolk Arthritis Register, a longitudinal inception cohort of adults (16 years and over) with inflammatory polyarthritis (IP), defined as at least 2 swollen joint for at least 4 weeks. The 2010 criteria were used to define RA, firstly in a re-estimation of the incidence rates (IR) with comparisons made to incidence defined by the previous criteria set; and secondly in a study comparing mortality rates in patients with RA to those of the general population, and how these rates changed over time. Analyses were performed testing the ability of the 2010 criteria to identify those patients with IP at increased risk of mortality, disability, disease severity and radiographic damage. The levels and number of autoantibodies present were investigated as predictors of mortality in patients with IP. The association between anti-carbamylated protein (anti-CarP) antibodies and long term disease outcomes were investigated. Results: The incidence of RA was 40 per 100 000 population; baseline IRs were similar to the cumulative IRs using the previous criteria set over 5 years. Patients who were seronegative were less likely to be classified as RA by the 2010 criteria. Mortality rates in patients with RA were higher compared to the general population (standardised mortality ratio 1.16, 95 percent confidence interval (CI) 1.04-1.29) and declined over the study period at the same rate as the general population. Patients with IP who fulfilled the 2010 criteria had increased risk of early death (hazard ratio (HR) 1.35, 95 percent CI 1.13-1.64), as well as increased levels of disability (beta 0.38, 95 percent CI 0.33-0.43), disease severity (beta 1.63, 95 percent CI 1.54-1.73) and radiographic damage (beta 0.33, 95 percent CI 0.20-0.47) throughout follow up. Patients with two autoantibodies had an increased risk of early death (HR 1.35, 95 percent CI 1.09-1.68), but there was no association with early death and the levels of these antibodies. Anti-CarP antibody positivity was independently associated with worse disability (beta 0.12, 95 percent CI 0.02-0.21) and disease severity (beta 0.23, 95 percent CI 0.07-0.39) throughout follow up. Conclusions: The 2010 ACR/EULAR classification criteria for RA identify patients with IP early in their disease course and recognise those at increased risk of mortality and poor outcomes. The 2010 criteria may miss a subgroup of seronegative patients who nevertheless have a poor prognosis. Novel autoantibodies may be useful to identify this subgroup.

Introduction: Rheumatoid arthritis (RA) is known to be associated with an increased risk of cardiovascular disease (CVD), resulting in excess mortality. Dyslipidaemia has been identified as a major CVD risk factor in the general population. Current evidence would suggest that lipid metabolism is altered in RA due to inflammation, and that use of anti-inflammatory therapy may reverse some of these changes. However, the impact of such lipid changes on CVD in RA remains unknown. Data regarding the effects of RA/drug therapy on lipid structure and function are sparse. Genetic factors are important in the pathogenesis of RA and play a central role in the regulation of lipid metabolism. To date, no studies have assessed the impact of genetic polymorphisms on lipids in RA.The aim of this thesis is to: 1) assess the prevalence of dyslipidaemia in RA and the CVD risk this confers 2) establish the effects of inflammation on lipid levels and lipid ratios 3) assess the impact of anti-inflammatory drug therapy (anti-TNF, rituximab and intravenous glucocorticoids) on lipid levels, structure and function 4) assess the prevalence and associations of particular genetic polymorphisms (RA susceptibility and lipid metabolism regulating genes) with lipids in RA.Methods: Data from 400 RA patients were used to address aims 1, 2 and 4 in cross-sectional studies. All patients had a clinical assessment and fasting blood taken. Blood was processed to provide data on the lipid profile, ESR, CRP and DNA was extracted for genotyping. Aim 2 and 4 also utilised a retrospective longitudinal cohort of 550 RA patients and the DNA from 400 healthy controls, respectively. Aim 3 was addressed using a longitudinal cohort including: patients due to commence anti-TNF (n=35), rituximab (n=10), intravenous glucocorticoids (n=12); 15 RA controls on stable therapy; and 40 healthy controls. Assessments and blood samples were taken at baseline, 2 weeks and 3 months. Results: Dyslipidaemia was highly prevalent (56.8%), but undertreated in many RA patients at risk of developing CVD. Systemic inflammation associated with many of the changes in lipid levels and structure. Lipid ratios were found to be less susceptible to fluctuations due to inflammation. The use of anti-inflammatory drug therapy produced changes in lipid structure and function through both generic suppression of inflammation and drug specific mechanisms (particularly in the case of glucocorticoids). The prevalence of cholesterol ester transfer protein (CETP) and Apolipoprotein C3 genetic polymorphisms differed between RA patients and local population controls. RA susceptibility genes (HLA-DRB1-SE and TRAF1C5) and several ’lipid metabolism genes’ (Apolipoprotein E, ATP-binding cassette transporter 1 (ABCA1) and CETP) were found to associate with lipid levels within the RA population. Conclusion: Dyslipidaemia is highly prevalent in RA and currently undertreated. Dyslipidaemia in RA is regulated by numerous factors including inflammation, drug therapy and genetic factors. Further longitudinal studies are required to assess whether these findings have an impact on hard CVD endpoints.

Introduction: Rheumatoid arthritis (RA) is a systemic autoimmune condition, characterised by an inflammatory arthritis. It is associated with a 50% increased risk of cardiovascular (CV) mortality. Chronic inflammation is thought to lead to accelerated atherosclerosis in RA. There is some evidence to suggest that patients have a more inflammatory, unstable atherosclerotic plaque phenotype. The impact of advances in RA treatment, on cardiovascular co-morbidity remains unclear. The aims of the current study were to employ non-invasive imaging techniques to test the hypothesis that RA patients have more inflammatory, unstable atherosclerotic plaques compared to unaffected individuals and that treatment of active arthritis would lead to alterations in plaque composition and inflammation. Secondary aims were to evaluate the association of clinical phenotype and potential serological biomarkers of CV risk with plaque presence and phenotype. Methods: A prospective pilot study of patients with active RA and age and sex matched controls was conducted. Subjects underwent clinical and serological evaluation, then carotid artery ultrasound was performed to screen for carotid plaque. Dynamic contrast enhanced magnetic resonance imaging (DCE-MRI) was performed on those with suitable plaque. A subgroup of patients had a carotid artery positron emission tomography (PET) scan. Patients were followed up with repeat clinical, serological and DCE-MRI assessments. The primary outcome evaluated was difference in plaque inflammation measured on DCE-MRI between patients and controls and in patients longitudinally. Secondary outcomes included differences in plaque composition on DCE-MRI, plaque inflammation on PET and the relationship of clinical, serological and imaging findings. Results: 130 patients and 52 controls were recruited and screened for carotid plaque. There was a higher prevalence of plaque on ultrasound in the patient group (53% vs 36%) and plaque was independently associated with high sensitivity c reactive protein (hsCRP). Carotid DCE- MRI data was analysed in 15 patients and 5 controls. There was no significant difference in plaque inflammation on DCE-MRI between the groups. However there was a significantly higher rate of plaque calcification in patients, despite similar plaque burden in both groups (73.3% vs 20%, p=0.038). All 15 patients exhibited features of high-risk plaque. Plaque inflammation was seen in all 13 patients in whom PET imaging was undertaken. No significant improvement in plaque inflammation was detected on DCE-MRI over time, which was in keeping with the lack of clinical improvement found in most cases. ConclusionsIncreased prevalence of atherosclerosis and differences in plaque phenotype were observed in this study and findings would support the hypothesis that patients have a more high-risk plaque phenotype. The high prevalence of calcified lesions in RA is a novel finding which warrants further investigation. The study was underpowered to detect significant changes in plaque inflammation, measured on DCE-MRI, between the groups and in patients over time. However, this study provides valuable data with which to plan a larger study to investigate the effects of anti-inflammatory therapy on atherosclerosis in RA in the future.

Objectives: The aim of this thesis was to evaluate the clinical use of rituximab (RTX) in rheumatoid arthritis (RA) patients treated in routine clinical practice in the UK, taking account of the previous therapies (anti-tumour necrosis factor (anti-TNF) therapies).Methods: The analysis involved RA patients registered with the British Society for Rheumatology Biologics Register. Kaplan-Meier survival analysis was used to study the persistence with anti-TNF therapies. Drug persistence was compared across the anti-TNF therapies and according to the most common concomitant non-biological disease modifying anti-rheumatic drugs (nbDMARDs) for up to five years. Adjusted multivariate Cox proportional hazard models were used to compare drug persistence across the subgroups. Change in Disease Activity Score (DAS28) and European League Against Rheumatism (EULAR) response were used to assess the clinical effectiveness of RTX while change in Health Assessment Questionnaire (HAQ) score was used to assess the physical function of the patients six months after starting RTX. Logistic regression was used to compare EULAR response and achieving a minimal clinically important difference (MCID) in HAQ (at least 0.22) between patients who started RTX and those who switched to a second alternative anti-TNF after failing a first anti-TNF therapy. Multivariate regression analyses were used to identify factors associated with the clinical effectiveness and the improvements in physical function six months after starting RTX. The models included baseline demographics, disease characteristics, baseline quality of life and previous drug history. Results: Among 10,396 RA patients receiving their first anti-TNF therapy, five-year drug persistence (95% CI) was 42% (41%: 43%). Infliximab was the most likely discontinued anti-TNF therapy. Compared to methotrexate (MTX), patients receiving no nbDMARD, leflunomide or sulfasalazine were more likely to discontinue their first anti-TNF therapy while patients receiving MTX in combination with other nbDMARDs showed superior persistence with their anti-TNF therapy. After failing the first anti-TNF therapy, patients who switched to RTX were significantly more likely to achieve EULAR response and MCID in HAQ; odds ratio (95% CI) 1.31 (1.02: 1.69) and 1.49 (1.07: 2.08) respectively compared to those who switched to an alternative anti-TNF therapy. In a cohort of 646 RA patients who started RTX, the mean DAS28 scores significantly improved six months after starting RTX with mean (95% CI) change of -1.42 (-1.53: -1.30). 17% of the patients achieved a good EULAR response and 43% achieved a moderate response. Higher baseline DAS28 score and positive rheumatoid factor (RF) status were significantly associated with a decrease in disease activity, while females and patients with higher baseline HAQ score were less likely to respond to RTX. In a cohort of 484 patients receiving RTX, the mean HAQ scores significantly improved by -0.12 (-0.16: -0.09) units. High baseline HAQ score was significantly associated with six months improvement in HAQ. Older patients, females, current smokers and patients receiving concurrent steroids were less likely to show an improvement in their HAQ scores. Conclusions: Compared to MTX, concomitant use of two or three nbDMARDs combinations including MTX with anti-TNF therapies resulted in better persistence with the anti-TNF therapies. After failing the first anti-TNF therapy, starting RTX may be of more benefit than switching to an alternative anti-TNF therapy. RTX has proven to be effective in improving both the clinical and patients' reported outcomes in routine clinical practice in the UK. Response to RTX was influenced by baseline DAS28, RF status, baseline HAQ, age, gender, smoking, and concurrent use of steroids.

京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第22644号 / 医博第4627号 / 新制||医||1066(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 松田 秀一, 教授 古川 壽亮, 教授 中山 健夫 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

Thesis (M.S.)--Boston University

published_or_final_version / abstract / toc / Clinical Psychology / Master / Master of Social Sciences