Introduction: Juvenile idiopathic arthritis is a chronic inflammatory arthritis of childhood which often results in chronic, persistent and disabling foot impairments. Modern day clinical guidelines recommend early and aggressive therapeutic intervention in order to arrest inflammatory disease activity and preserve function. For these reasons, this thesis focuses on the development and evaluation of a contemporary new foot care programme. The programme of care comprises rapid access to targeted, individualised therapies informed by a sensitive imaging technique, and delivered by a multi disciplinary team. This is a logical and advanced extension of previous research within the field of paediatric rheumatology. Aims: The primary aim of the present work was to investigate the key methodological and procedural issues associated with evaluating a new foot care intervention under trial conditions for patients with JIA. Secondary aims were to estimate the levels of agreement between clinical and ultrasound examinations of foot disease, and the prevalence of sub- clinical foot disease in JIA. A discrete choice experiment questionnaire capable of eliciting and quantifying preferences for foot care was to be developed. The clinical and cost- effectiveness of this newly developed foot care programme were also explored. Methods: An experimental foot care programme was developed according to current evidence of best practice and expert opinion. An exploratory phase II non-pharmacological randomised-controlled trial and a full economic analysis were conducted in order to compare the experimental intervention with the current 'usual care' alternative. Patients with a definitive diagnosis of JIA and a history of foot and ankle arthritis were recruited from a paediatric rheumatology hospital outpatient clinic and randomised to 12 months of care in either treatment arm. At trial baseline, clinical and ultrasound examinations data from a pre- determined subset of participants were compared to estimate levels of agreement and subclinical disease. The primary outcome was change to the levels of foot-related impairments and disability which were assessed following 6 and 12 months of exposure to the interventions. A discrete choice experiment designed according to published design efficiency criteria was administered at baseline to determine parental preferences and willingness -to-pay for foot care. Costs of both interventions were estimated, and costs in relation to changes in foot function and quality of life outcomes were compared. Results: Of 126 patients identified, 85 were eligible, 44 were recruited, and 41 completed the study. 21 participants were allocated to receive the experimental intervention while 23 participants were allocated to receive 'usual care'. 3 participants in the 'usual care' arm self- withdrew prior to final follow up. The present work demonstrated that further phase I modelling and pre-clinical research is required prior to the implementation of a phase III definitive trial to evaluate similar experimental interventions. Multidisciplinary foot care appeared to be no more effective than 'usual care' for improving levels of foot impairments and disability. In terms of foot care service provision for children with HA, parents appear to prefer improvements in health outcomes over non-health outcomes and service process attributes. The experimental intervention was more costly over a 12 month period and thus non-cost-effective relative to the alternative intervention. Ultrasound and clinical examinations of foot disease were frequently discordant, and subclinical foot disease appears common in JIA. Conclusions: The primary fmdings from this thesis highlight areas requiring development through feasibility studies prior to the implementation of defmitive trials of multidisciplinary foot care. Secondary fmdings suggest that there were no sustainable improvements in functional outcomes following a programme of multidisciplinary foot care received by patients with established disease. Persistent levels of foot impairments and disability were exhibited despite targeted interventions. It is recommended that earlier intervention of this kind should be implemented in order to improve outcomes. The findings of this project provide an important foundation for future research into the optimisation of foot care for children and adolescents with JIA.

Reactive arthritis (ReA) is a sterile joint inflammation triggered by bacterial infection and is associated with the MHC class I molecule HLA-B27. Bacterial antigens have been detected in synovial tissues from ReA patients, but how they are transported to the joints from the site of infection is not known. In this project, we have tested the role of infected macrophages and dendritic cells as carriers of bacterial antigens in a mouse model for ReA. Bone marrow derived macrophages (BMMac) and dendritic cells (BMDC) were infected with Salmonella, a known causative agent of ReA, and adoptively transferred to HLA-B27 transgenic mice. We found a differential migration profile for Salmonella infected macrophages vs dendritic cells. In contrast to their uninfected counterparts, both populations emigrated significantly from the peritoneal cavity after intraperitoneal (i.p.) injection. Salmonella-infected BMDC showed a significantly increased ability to migrate to secondary lymphoid organs (SLO) (spleen and mesenteric lymph nodes). Moreover, results from CCR7 deficient mouse clearly showed that the migration of infected BMDC to the mesenteric lymph nodes (MLN), but not the spleen, was mediated by CCR7. Unlike BMDC, Salmonella infected BMMac were prone to migrate to inflamed joints. Although both BMDC and BMMac were able to present bacterial-derived peptides and stimulate antigen experienced cytotoxic T cells in vitro, only BMDC were capable of activating antigen specific naive T cells. By co-transfer HLA-B27 transgenic BMDC and naive T cells from GRb transgenic mice, which express a HLA-B27-restricted TCR specific for an influenza peptide, BMDC infected with recombinant Salmonella expressing the flu epitope were shown to induce T cells activation in vivo. The results of this study suggest distinct roles for macrophages and dendritic cells as antigen transporters following Salmonella infection, and have implications for both the pathogenesis of ReA, and the generation of anti-Salmonella immunity.

The emerging role of protease-activated receptor-2 (PAR2) in chronic joint inflammation may present therapeutic opportunities for the treatment of diseases such as rheumatoid arthritis (RA). The central hypothesis examined in this thesis was that PAR2pathways playa key role in the pathogenesis of RA. Although there is increasing interest in the involvement of PAR2in joint inflammation, the proinflammatory mechanisms and the importance of this receptor in RA remain unclear. The role of PAR2 was investigated in vivo with the specific aim of characterising the upstream activation mechanisms and downstream proinflammatory mechanisms of PAR2 in joint inflammation, and assessing whether PAR2-dependent pathways present a novel therapeutic avenue in a T cell driven, murine model of rheumatoid arthritis. Chapter 3 explores endogenous and exogenous activators of PAR2 in the context of joint inflammation. Agonist responses are characterised and used to assess the potency and specificity of the first PAR2 antagonist (ENMD-1068). This was an important prelude to work presented later in the thesis and the conclusion of these studies was that ENMD-1 068 is a selective but low-potency antagonist for PAR2. Although earlier proof of concept studies have shown the presence of functional PAR2 to be crucial to the chronicity of a murine model of RA, the therapeutic potential of inhibiting PAR2in a highly relevant model of the disease has yet to be assessed. The studies presented in chapter 4 show not only that a novel PAR2 antagonist, ENMD1068, has therapeutic efficacy in ameliorating collagen-induced murine arthritis (CIA), but also, importantly, that PAR2antagonism suppresses release of the proinflammatory cytokine TNFa by T cells in this model of RA. Mast cells and PAR2 are independently reported to be important in models of RA but the mechanisms by which they contribute to the disease require elucidation. Since mast cells are known to be abundant in the inflamed j oint and are capable of releasing tryptase, a potent and preferential activator of PAR2, a functional link between mast cells and PAR2 seemed plausible. Indeed, mast cell tryptase is a likely candidate as a key endogenous activator of PAR2in arthritis. Chapter 5 explores the relationship between mast cells, tryptase and PAR2, and presents the first evidence for a functional link between mast cells and PAR2in the context of the joint. In addition these studies sought to clarify the downstream proinflammatory mechanisms of PAR2and demonstrates that prostaglandins are, in part, responsible for the pro-inflammatory actions of PAR2in the murine joint. Collectively the studies presented in this thesis support a key role for PAR2in arthritis, and extend the field by providing novel insights into the mechanisms by which PAR2 pathways contribute to joint inflammation. Perhaps most importantly, this work advances the case for the therapeutic potential of inhibiting PAR2pathways and supports progression towards future clinical trials of PAR2 inhibiting agents.

One of the major characteristics of both rheumatoid and osteoarthritis is aberrant matrix metalioproteinase (MMP) -1 and -13 induction leading to irreversible cartilage breakdown. MMP-1 and 13 induction is known to be mediated by interleukin -1 (IL-1) within the arthritic joint, furthermore it is also known that oncostatin M (OSM) potentiates the effects of IL-1 in a synergistic manner. Although the phenomenon of synergy with IL-1+0SM is well documented, little data exist explaining the precise underlying mechanism.

Arthritis is a common disease characterised by chronic inflammation as well as bone and cartilage destruction. Proinflammatory cytokines such as interieukin-17( IL-17), aT cell derived cytokine, and Oncostatin M (OSM) a microphage cytokine, are elevated in rheumatoid arthritis (RA). The aim of this study was to characterise the effects of IL-17 and OSM on the expression of receptor activator of NF-kappaBl and (RANKL) and its decoy receptoro steoprotegeri(nO PG)by mesenchymalil neage cells in vitro, in particular synovial fibroblasts and the human osteo sarcoma cell line (MG-63 and SaOS-2) that are potentially involved in this process as they regulate osteoclastogenesis. In addition, the ability of IL-17 to support osteoclastogenesinis vitro was assessed. Human synovial fibroblasts( SFB)from RA and OA patients were contrasted with cell lines MG-63 and SaOS-2 and were treated with IL-17 and/or OSM for up to 48 hr. The expression and production of RANKL and OPG over a time course was assessed in these cells. To investigate osteoclastogenesis peripheral blood mononuclea cells (PBMCs)were cultured with IL-17 either alone or with Macrophage colony stimulating factor (M-CSF). Osteoclastogenesis was analyzed after 21 days by tartrate-resistant acid phosphatase (TRAP),positive multinucleated cell counts, and resorption of ivory slices. This study demonstrated a direct role for IL- 17 in bone and cartilage catabolism through the induction of RANKL and OPG mRNA levels at 6 hr and 48 hr in SFB RA and OA, MG-63 and SaOS-2. Furthermore the combination of IL-17 and OSM showed that the expression of RANKL and OPGw as down-regulated. Co-incubation of IL-17 with or without M-CSF significantly enhanced TRAP+ve multinucleated cell formation. Furthermore cultures of PBMC with IL-17 on ivory slices showed significantly increased resorption and when cocultured with synovial fibroblasts from RA and OA patients further significant resorption. The addition of OPG to IL-17 cultures significantly inhibited the formation of resorption lacunae. The effect of IL-17 on bone resorption in vitro is mostly RANKL-dependent. This finding may lead to the conclusion that IL-17 significantly induces osteoclasto genesis in vitro. Therefore,I L-17 represents a key cytokine involved in the exacerbation of inflammatory joint disease and is an important target for anti-cytokine therapies. Also these results provide proof of the concept that OPG production can result in effective therapies.

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Psoriatic Arthritis (psA) is an inflammatory joint disease with a predilection for sites within the lower limb and foot. In particular the entheseal attachments of the Achilles tendon, the plantar fascia and the posterior tibial tendon are most commonly affected, reasons for this are unknown. These sites naturally deal with high compressive loads and stresses during gait and it has been theorised that abnormal biomechanics in people with PsA may play a role in the initiation of enthesitis at these sites. The aim of this thesis is three-fold; firstly to identify the frequency and severity of foot involvement in people with PsA. Secondly to develop a new seven segment foot model and test its reliability characteristics in people with PsA and matched controls, and thirdly to investigate the gait characteristics of PsA participants with clinical and ultrasound evidence of enthesopathy compared to PsA participants with no evidence of enthesopathy and a matched control group. The method employed for this body of work is split into three phases. Phase 1 is a clinical survey with a convenience sample of 104 participants. Phase 2 is a within and between day reliability study with 9 PsA and 9 matched control participants tested at two time points with the newly developed seven segment foot model and Phase 3 is an exploratory case control study with 29 PsA participants and 10 control participants. Results from Phase 1 highlight high levels of foot pain comparable to established Rheumatoid Arthritis (RA) despite low clinical signs of disease activity. High levels of impairment and disability and low provision of foot care with only one in five participants in receipt of foot care were also found. Phase 2 highlighted that within day reliability was excellent and between day reliability was excellent for some variables but poorer for others. Phase 3 highlighted differences in gait characteristics between the groups with statistically significant results for stride length (psA positive and control group), ankle power (psA positive and control positive group) and midfoot abduction (psA positive and control negative group). In conclusion, foot involvement in people with PsA is high and the provision of foot care is low It is therefore imperative to consider routine foot screening for all people with PsA in order to identify foot complications early and manage them accordingly. Further investigations into gait characteristics in people with PsA are vital to understand what, if any, abnormal biomechanics contribute to the presence of enthesitis.

Aim: This study aimed to explore the experiences of young people receiving treatment for and living with Juvenile Idiopathic Arthritis (JIA). More specifically, it explored their experience of long term treatment, what this told us about treatment adherence and their experience of being an adolescent with a chronic illness. Conclusion: The findings are discussed in relation to the current literature on JIA, chronic illness and treatment adherence. The study highlighted that even those apparently managing their treatment may still be experiencing difficulties. The results have implications for clinical services in developing existing provision of support and several avenues for future research were identified.

No description available.