Aim: To describe the predictive validity of reaching low disease activity (LDA) at 1 year on future disability and joint damage in patients with early rheumatoid arthritis (ERA). Methods: First a systematic literature review of prognostic studies assessing the association between disease activity and functional or radiographic outcomes in ERA was performed. Then data from the Study Of New-Onset RA (SONORA) were used to evaluate the impact of year-one LDA on 3-year disability and 2-year radiographic progression using multivariate regression analyses. Results: Our review demonstrated evidence for relationship between baseline disease activity and future disability and join damage. However evidence for the impact of early treatment response on long-term outcomes in ERA is sparse. Analysis of 984 patients showed year one LDA predicts lower HAQ (p<.0001) and less damage (p=0.04) in future. Conclusion: Reaching LDA early is associated with better long-term functional and radiographic outcomes in patients with early RA.

Aim: To describe the predictive validity of reaching low disease activity (LDA) at 1 year on future disability and joint damage in patients with early rheumatoid arthritis (ERA). Methods: First a systematic literature review of prognostic studies assessing the association between disease activity and functional or radiographic outcomes in ERA was performed. Then data from the Study Of New-Onset RA (SONORA) were used to evaluate the impact of year-one LDA on 3-year disability and 2-year radiographic progression using multivariate regression analyses. Results: Our review demonstrated evidence for relationship between baseline disease activity and future disability and join damage. However evidence for the impact of early treatment response on long-term outcomes in ERA is sparse. Analysis of 984 patients showed year one LDA predicts lower HAQ (p<.0001) and less damage (p=0.04) in future. Conclusion: Reaching LDA early is associated with better long-term functional and radiographic outcomes in patients with early RA.

Commercial composite aerospace structure is required to be designed and managed under the damage tolerant principle. Airworthiness is maintained through a process of regulated inspections and if required maintenance. Currently inspections use visual and assisted visual (non-destructive inspection - NDI) techniques. Damage tolerant operation is therefore reliant on inspectability. Unlike metal structure composite and adhesively bonded structure may show few if any recognisable indicators prior to rapid failure, either visually or using NDI. Although stringent manufacturing processes are demanded to best ensure components are fit for service strategies such as reducing stresses by oversizing components or in the case of bonded features additional mechanical fasteners may be included to allow operation with this potential structural uncertainty. Structural Heath Monitoring (SHM) uses data from in-situ sensors to assess the condition of the structure. If via SHM any uncertainty associated with difficult to inspect components could be eliminated less reliance would be required of additional structure or features allowing lighter and more efficient structure to be viable with no impact on current airworthiness demands. Despite much previous research no SHM system is in use with in-service composite or bonded aerospace components. When operating a structure under Damage-tolerance operational requirements damage must be positively identified to allow repairs to be made whist ensuring appropriate airworthiness demands are maintained. Such demands must also be met by structure inspected using SHM. Unlike previous studies this research combines the process of structural design and in-situ monitoring to address the issues identified. Termed SHM enabled design this approach allows the implementation of monitoring technology and the potential for benefits including the reduced reliance on inefficient additional structure to be viably included in actual structure ... [cont.].

Rheumatoid Arthritis (RA) is a chronic auto-immune disease that causes in ammation in the joints. Left uncontrolled, this prolonged in ammation can lead to pain and structural damage, resulting in erosions to the bones and total breakdown of the surrounding cartilage. Structural joint damage, measured by plain radiographs, is an important outcome measure of RA. It provides an objective marker of disease activity to assess any improvements or failures of treatments in controlling for the disease. Increased long-term joint damage has been linked with increased functional disability and decreased quality of life for RA patients. While a range of studies have looked at radiographic outcomes from observational data, they tend to be restricted to historical cohorts, with little long-term data on how radiographic progression may have changed in line with changes in clinical management. Additionally, these studies have not used the appropriate statistical methods to account for non-normal data distributions and within-patient variation over time. As a result, the main aim of this thesis is to investigate the long-term progression of structural joint damage in patients with early RA. The speci c objectives were to; (1) investigate the current evidence base to identify common methods in measuring and analysing radiographic outcomes, (2) assess what statistical methods are most appropriate in modelling long-term radiographic data, (3) use these models to understand the natural progression of radiographic damage using data from two UK inception cohorts, and nally, (4) expand these models to investigate the long-term relationship of radiographic damage with two important clinical outcomes; disease activity and functional disability. The analysis is based on longitudinal data from two UK prospective, multi-centre, early RA observational cohorts. These cohorts represent two distinct eras in the management and treatment of RA, making them invaluable for investigating how key RA outcomes have progressed in clinical practice over time. Using multi-level count models, precise rates of radiographic progression for both cohorts are presented. The models look at how seropositive RA and increased disease activity are related to increased radiographic progression, and what impact this has on functional disability. The results show that rates of radiological damage have declined dramatically in recent years. Possible attributable factors to these declines include both milder disease and more e ective treatment strategies. Analysis of the earlier cohort (1986-2001) shows how seropositive RA and increased disease activity lead to clinically meaningful increases in radiological damage. Conversely, their impact on patients in the more recent cohort (2002-2011) suggest that their e ect on radiographic progression is reduced, where increases in radiological damage were not larger than clinically meaningful thresholds. This has large implications on the debate around the use of biologic therapies in patients with less severe RA. However more data is sorely needed, particularly long-term radiographic data from those patients on biologics treatments, before any de nitive conclusions can be made. The possible impact of these declines on functional disability appears to be relatively small. The analysis shows that radiographic damage is more strongly associated with functional disability in later disease, but there is little evidence to indicate that declines in radiographic damage has lead to large improvements in long-term functional disability. These ndings are explored within the framework of a dual-pathway model, which suggests that functional disability is caused by two distinct mechanisms, either structural joint damage, or through increased pain. Research so far has predominantly focused on pharmacological treatments in reducing in ammation. More research is needed to explore the role of psychosocial factors and pain perception in order to create a more holistic treatment programme for RA patients.

Inflammatory processes are infamous for their destructive effects on tissues and joints in a variety of diseases. Within the body, inflammation is a highly regulated biological response whose purpose is to promote tissue regeneration following injury. However, in certain settings, inflammation persists and leads to progressive tissue destruction. This thesis focused on modulating inflammatory signaling in both contexts. Part I investigated the effects of a model pro-inflammatory cytokine, tumor necrosis factor-alpha (TNF-α), on the in vitro osteogenic differentiation of mesenchymal stem cells (MSCs). In contrast, Part II describes the development and in vivo evaluation of the first intra-articular controlled release system for the temporomandibular joint (TMJ), which silences inflammatory signaling and thus mitigates the painful joint damage seen in inflammatory TMJ disease. The following specific aims were addressed: (1) to determine the concentration of TNF-α that enhances in vitro osteogenic differentiation of MSCs; (2) to determine the temporal pattern of TNF-α delivery that enhances in vitro osteogenic differentiation of MSCs; (3) to determine the impact of bone-like extracellular matrix (ECM) on the concentration and temporal pattern of TNF-α delivery that enhances in vitro osteogenic differentiation of MSCs; (4) to evaluate the biocompatibility of intra-articular microparticles in the rat TMJ; (5) to develop a microparticle-based formulation for sustained release of a model anti-inflammatory small interfering ribonucleic acid (siRNA); and (6) to evaluate the therapeutic efficacy of intra-articular microparticles delivering siRNA in an animal model of TMJ inflammation. These studies led to the development of powerful strategies to rationally control inflammation to promote bone regeneration and mitigate joint damage in the setting of disease, both of which will ultimately improve the quality and specificity of therapies available in modern medicine. / Only volume 2 has been digitized.