Background RA is reported to be an independent risk factor for morbidity and mortality, but there is little data from inception cohorts. Part of this excess risk appears to be driven by systemic inflammation. This MD thesis is divided into two parts. The first is an analysis of eo-morbidity and mortality in RA, especially cardiovascular disease (CVD), in an established inception cohort. The second is a study to examine clinical and sub clinical features of CVD in early RA in greater detail. Methods The Early RA Study (ERAS) is an inception cohort (n=1460) with up to 23yrs follow up. Clinical, laboratory and radiological assessments were made yearly. Outcomes included functional and work disability, joint damage, disease activity, treatment effects, extra-articular manifestations, eo-morbidity and mortality. 50 early RA patients were recruited into a separate study using the ERAS model, but additionally included clinical CVD risk factors and laboratory CRP and endothelial biomarkers. Results Increased and early mortality was found in the ERAS cohort (573, 39%), mainly due to CVD (40%). Baseline prevalence of major co-morbidities was 32% (respiratory 7.5%, CVD 5%). Cumulative incidence of several eo morbid conditions was increased, especially CVD and respiratory (2111000 each). The main risk factors for all cause and cardiovascular mortality were similar and included older age, men, disease activity and worse HAQ. Cc-morbidity was associated with functional and work disability. In the sub study, only one endothelial biomarker was elevated (E- Selectin) and was associated with disease activity. Conclusion Cc-morbidity and mortality were increased and manifested early in the course of RA, mainly due to CVD and respiratory conditions. Co-morbidity was associated with disease activity and severity, and worse outcomes. Endothelial cell activation was not expressed at disease onset. Assessment of eo-morbidity and CVD risk should be part of an annual review in RA.

Disease-related foot pathology is recognised to have a significant impact on mobility and functional capacity in the majority of people with rheumatoid arthritis (RA). The forefoot is widely affected and the metatarsophalangeal (MTP) joints are the most common site of symptoms. The plantar plate is a fibrocartilaginous structure found on the plantar aspect of the MTP joint and has a role in maintaining the structural integrity of the forefoot. Damage to the plantar plates is a plausible mechanism therefore, through which the forefoot presentation, commonly described as 'walking on pebbles'. may develop in patients with RA. The hypothesis of this thesis was that plantar plate pathology of the lesser (2nd-5th)MTP joints is associated with pain and structural change in the forefoot of patients with RA. The aims of this thesis were to report the prevalence of plantar plate pathology in the painful forefoot of patients with RA, to explore associations with inflammatory and mechanical features of disease and identify predictors of plantar plate pathology. To this end high resolution 3T magnetic resonance imaging and high resolution ultrasound scanning in patients and controls, and histological analysis of cadaveric specimens was undertaken. The results demonstrate that the distribution of plantar plate pathology at the lesser MTP joints in RA differs from that seen in otherwise healthy subjects and is associated with related features of disease severity. Findings from a two year longitudinal study indicated that longer disease duration, a radiographic Larsen score> I and higher peak plantar pressure at baseline were associated with the increased odds of developing or deteriorating plantar plate pathology. Further work is now required to establish the contribution of plantar plate pathology to forefoot pain in patients with RA. In summary, damage to the plantar plates of the lesser MTP joints and progression of pathology is associated with features of disease severity and mechanical changes in the forefoot of patients with RA.

The aim of this thesis was to identify and compare objective measures and predictors of remission. This was done in a cohort of patients with established RA, early RA and very early undifferentiated arthritis with poor prognostic markers. The objective markers used to define the remission state included clinical (remission scores, clinical examination, inflammatory markers and antibody status), imaging (ultrasound [US] assessment for power Doppler [PD] activity) and immunology (assessment of T cell subtypes) assessments. In patients with established RA treated with combination TNF blocker therapy and disease modifying anti-rheumatic therapy [DMARD] therapy, the remission state is associated with longer disease duration, shorter time in remission, worse health assessment questionnaire [HAQ] scores and comparable PD activity when compared to patients in remission treated with DMARDs. When TNF blocker treated patients with established RA were compared to those with early RA, there were no differences in PD activity, but patients with early RA were significantly more likely to sustain remission after cessation of TNF blocker therapy. In patients with early disease, predictors of successful cessation were short duration of symptoms and a pattern of T cell subtypes that is associated with normalisation of the immune system and recapitulation of thymic activity. It was then proposed to use TNF blocker therapy to induce longstanding remission and prevent the evolution to RA; however a short course of infliximab was not successful. Clinical prognostic markers were able to predict the evolution into the RA phenotype in this cohort. In summary, this thesis aimed to improve the management of patients in remission by objectively defining the remission state. Combinations of standard clinical and objective measures of remission are required to accurately diagnose remission and to identify patients who can safely withdraw therapy.

Rheumatoid Arthritis (RA) is a chronic inflammatory disease characterized by progressive joint inflammation that results in bony erosions and cartilage damage. Until recently only 2 genes were unambiguously correlated with disease risk: the HLA-DRB1 and the protein tyrosine phosphatase non-receptor 22 (PTPN22). Several genome wide scans conducted in populations from UK, USA and Sweden have suggested other risk loci including TNFAIP3-OLIG3, TRAF1-C5 and STAT4. The search for genetic regions associated with complex diseases such as RA is an important challenge that could lead to better diagnosis and treatment directed at the cause of the disease.

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No description available.

This thesis is about what people can do with their hands in the early stages of rheumatoid arthritis (RA). The wrist and hand are affected early in RA. Wrist and hand joint swelling, pain and deformity are all likely to contribute to the functional performance of the hand. Static splinting alongside joint protection education and active exercise is one of the most common conservative intervention strategies used by therapists. Splinting attempts to reduce local inflammation and pain, correctly position joints, minimise the occurrence or progression of deformity and maintain hand function. This thesis reviews the impact that RA can have on the hands and upper limb, examines what factors may influence function and compares the outcome measures that are used to measure this. A clinical effectiveness randomised controlled trial, examining the effectiveness of static hand splinting in early RA is described. A total of one hundred and sixteen patients with early RA were recruited onto the main trial and randomly allocated to either a splint or non-splint group. Assessments were carried out at baseline, six and 12- months. There was insufficient evidence from the results of this 12 month randomised controlled trial to suggest that using static splinting alongside standardised occupational therapy intervention was any more effective than standardised occupational therapy intervention alone in the maintenance of hand functional ability. However, when male and female participants were analysed separately young male participants could potentially experience clinically significant deleterious effects when issued with static resting splints.

The benefits of exercise for people with rheumatoid arthritis (RA) are now well-established. However, RA patients are less active than the general population. This may result from previous negative views surrounding the effects of exercise on joint health and limitations in current empirical evidence. Thesis Summary The aims of this thesis were to explore patient perceptions relating to exercise and joint health, alongside determining the physiological effects of acute exercise and exercise training on novel markers of joint health. Firstly, focus group methodology was used to collect qualitative data, offering a preliminary description of patient perceptions. This data was then used to develop a questionnaire which was distributed to a large population of RA patients. Patients showed an awareness that exercise was beneficial, but were concerned about joint health, how they should exercise and perceived uncertainty amongst health professionals. The factorial validity of the new measure was established and the quantitative data confirmed findings on a larger scale. To enhance the information available to health professionals, and consequently RA patients, the second part of the thesis explored the effects of exercise per se on joint health. Intensive aerobic and resistance exercise showed no acute effect on absolute serum cartilage oligomeric matrix protein, C-reactive protein and minor effects on synovial inflammation (as assessed by colour fraction using colour Doppler ultrasound). The third part of the thesis investigated the effects of continued intensive training on these outcome variables. Following an eight-week aerobic and resistance exercise training intervention, improvements in aerobic fitness and strength were demonstrated, with no detrimental effects on joint health. Overall, it is anticipated that the findings from this series of studies will provide further information for health professionals when prescribing exercise and help to alleviate the fears of patients. This may well help to increase exercise participation in this population.

Rheumatoid arthritis (RA) patients have an increased prevalence of cardiovascular disease (CVD). Traditional cardiovascular risk factors do not fully explain this increased incidence. Cardio-respiratory fitness and obesity are acknowledged CVD risk factors; however these are generally excluded when assessing CVD risk in RA patients. This PhD thesis aims to investigate the association between cardio-respiratory fitness and traditional CVD risk factors in RA patients and establish whether exercise can improve these CVD risk factors. To determine cardio-respiratory fitness of RA patients a simple submaximal step test was validated (n=24). A cross sectional study was then carried out with 100 RA patients who underwent assessments of fitness (step test), RA disease, CVD risk factors and body composition. RA patient fitness level was poor (22 ± 6 ml·kg-1·min-1). Traditional CVD risk factors were not obviously elevated but poor fitness was strongly associated with poor body composition. Thirty-five patients were unable to complete the step test. These patients rated their arthritis as worse, more painful, disabling and had a greater prevalence of obesity. This study highlighted two important modifiable CVD risk factors (poor fitness and obesity) that are not routinely measured. An 8 week exercise intervention (n= 10) designed to increase cardio-respiratory fitness was then implemented and improved cardiovascular health (systolic blood pressure), body composition (body fat, waist and hip circumference) and RA disease (p < 0.05). RA patients are suffering from the effects of being unfit and overweight. Not only are they independent CVD risk factors, they impact considerably on patients disease perception and functional ability. These risk factors should be considered as part of RA care and information should be provided to help patients improve their cardiovascular health and general wellbeing. Regular exercise can help improve the above CVD risk factors as shown in this thesis.

Key components of the innate immune response to infections are the Toll-like receptors (TLRs), which are able to detect invading pathogens and subsequently generate inflammatory responses. Many details of the signalling pathways of TLRs have emerged from gene targeted mice or inhibition studies in transformed cell lines. However, the signalling pathways activated in primary human cells and disease tissues are less well understood. Previous studies identified differences in TLR signalling between human cells of myeloid- and non-myeloid origin. While over-expression of a dominant negative construct of the TLR adaptor molecule MyD88 inhibited TLR4 signalling in HUVECs it had no effect on TLR4 signalling in macrophages. Based on this observation, this thesis examined the function of MyD88 in primary human monocyte derived dendritic cells (DCs). Unexpectedly, over-expression of MyD88 dn resulted in the activation of DCs. Subsequent experiments, provided evidence for a DC specific inhibitory mechanism, which depends on endogenous MyD88 and is disrupted by TIR domain over-expression. To further investigate the mechanism, the function of SIGIRR in human DCs was examined. SIGIRR is a member of the TIR domain containing receptor family that has been shown to be expressed in murine and human DCs but not macrophages. However, results in this thesis show that SIGIRR is expressed by human DCs as well as macrophages. While SIGIRR has been studied in murine models, nothing is known about its function in primary human cells. Therefore, an adenoviral construct encoding wild-type SIGIRR was generated and over-expressed in DCs and macrophages, which impaired TLR2, TLR3, TLR4, TLR5, TLR7/8 and IL-1R but not TNFα signalling. In accordance with these results, siRNA knock down of SIGIRR in macrophages led to an increase of TLR3, TLR4, TLR7/8 and IL-1R but not TNFα induced cytokine production. Therefore, SIGIRR seems to be an inhibitor of TIR domain dependent signalling, affecting the MyD88 dependent as well as the TRIF dependent signalling pathway. Furthermore, immunoprecipitation studies of SIGIRR with MyD88 suggest, that SIGIRR interacts with MyD88 constitutively through TIR domain interaction, indicating that SIGIRR inhibits TLR/IL-1R signalling by sequestering MyD88. Given the potency of SIGIRR to inhibit TLR/IL-1R signalling in human DCs and macrophages, this thesis further investigated its role in rheumatoid arthritis disease models. Over-expression of SIGIRR wt in human RA synovial membrane cultures inhibited the spontaneous secretion of cytokines by those cells. In contrast, SIGIRR deficient mice were resistant to collagen induced arthritis (CIA). SIGIRR null mice immunised with CIA showed a loss in IgG2a anti-collagen antibody production as well as reduced Th1 and Th17 immune responses but increased Th2 immunity. Subsequent results indicated that SIGIRR is able to regulate CD4+ T cell development through the inhibition of ST2/IL-33 signalling. Therefore, while SIGIRR inhibits pro-inflammatory cytokine release during the progression stages of RA, it may also regulate the development of Th2 development, thereby reducing CIA incidence. These studies highlight the importance of investigating signalling pathways in physiologically relevant cells in order to fully understand the roles TLRs and specific signalling molecules play in the human immune system and human disease process.