No description available.

Introduction: The tibialis posterior (TP) tendon is vulnerable to inflammatory damage in rheumatoid arthritis (RA). TP tendon disease is frequently associated with pes pIano valgus (PPV) deformity; both inflammatory and mechanical factors are thought to contribute. Minimal evidence exists in terms of the contribution of the TP muscle, determined by electromyography (EMG), to the deformity in RA. To date this has not been combined with current multi-segment foot (MSFoot) models or diagnostic imaging. Moreover, the response of these features to intervention is currently unknown. The aim of this study was to undertake a detailed description of TP tenosynovitis and PPV in RA and to determine the effect of targeting mechanics and inflammation. Methods: Patients with RA and PPV and control participants were recruited to establish the reliability of TP EMG and the MSFoot model in the first phase of the study. A further cohort of RA patients with RA, PPV and ultrasound (US) confirmed tenosynovitis were recruited to determine the effect of targeting mechanics with customised foot orthoses (FO) and inflammation with a peri-tendinous corticosteroid injection. Results: Reliability of the MSFoot model was established barefoot and shod in five healthy controls and five patients with RA and PPV. Ten patients were recruited to the proof-of-concept study; all were issued with customised FO and four were issued with peri-tendinous corticosteroid injections in combination with FO. Differences between patients and controls were recorded across all domains. Mechanical and inflammatory intervention for three months did not significantly improve movement patterns, muscle activity or impairments and disability in the presence of highly active disease states. Improvements to levels of TP tendon pathology were recorded following targeted local corticosteroid intervention in this population. Results demonstrated response to intervention on an individual level due to high levels of disease activity. Conclusion: This study has provided an insight into muscle function in RA in the presence of active tendon disease and PPV. Suboptimal mechanics in this population are linked with increased muscle activity relative to healthy control participants and occur in conjunction with pathological tendon features on US. Technical and methodological issues adversely affected the results and the importance of disease related factors was highlighted.

The epidemiology of foot complications in patients with rheumatoid arthritis (RA) is poorly understood. A number of patients report ongoing foot-related pain, impairment, footwear restriction and activity limitation, despite developments in pharmacological disease management. Forefoot bursae (fluid filled sacks, FFB) have been previously shown to be highly prevalent and related to foot complications in patients with RA. However, the longitudinal epidemiology and clinical importance of FFB in this patient population remains unclear. It is anticipated that an improved understanding of the mechanisms by which FFB are responsive to, or contribute to, fluctuations in RA disease activity will inform future evaluation of foot health and novel therapeutic targets. Through a series of four experimental studies this work has shown that ultrasound (US) detectable FFB are highly prevalent in patients with RA compared to healthy volunteers (HV) and are clinically relevant. The natural history of FFB remains consistent longitudinally in a cohort of patients with established RA disease at baseline. US-detectable FFB were determined to be significant prognostic indicators of foot-related disability after three years. Furthermore, the distribution of US-detected FFB across forefoot sites was identified as significantly different between HV and patients with predominantly inflammatory or degenerative arthritis; uniquely patients with RA have a number of FFB within the central forefoot region, in addition to those located laterally, which were frequently present in all comparative groups. Thus, in patients with RA ~50% of US-detected FFB may be of greatest clinical relevance, due to their positioning within the central forefoot region. Detection of FFB using MRI defined a series of FFB characteristics of clinical relevance in patients with RA. The presence of plantar forefoot fluid lesions or intermetatarsal soft tissue lesions was significantly related to RA disease activity. The presence of plantar soft tissue lesions was significantly related to increased biomechanical impairment. However, a high proportion of plantar predominantly soft tissue FFB was also noted to be actively inflamed whilst other MRI-based markers of disease activity within the forefoot were minimal.

Rheumatoid arthritis (RA) is a systemic autoimmune disease characterised by chronic synovial inflammation, ultimately leading to joint destruction and permanent disability. Disease expression may be affected by genetic variations and environmental factors such as cigarette smoking. The main objective of this study was to identify some of the main determinants of poor outcome in RA, both in terms of disease severity and comorbidity. Analysis of possible interaction of genetic factors with smoking was carried out. Candidate genes included GSTM1, GSTT1, VEGFA, eNOS, MMP1, MMP2, MMP3, TGFB1 and PTPN22. Smoking was associated with seropositive RA, in particular with RF+ RA. It was associated with the development of erosive disease and with more severe functional outcome in seronegative patients. Promoter polymorphism VEGFA-2578(A/C) (rs699947) was associated with serum VEGF-A level, which may reflect a genotype-specific response to inflammation. This polymorphism was associated with disease activity, which only occurred in nonsmokers. The same polymorphism was also associated with the occurrence of IHD and MI, which may be due to an interaction with smoking. Both MMP1 (rs1799750) and MMP3 (rs679629, rs3025058) polymorphisms were independently associated with serum MMP-1 level, whereas serum MMP-3 was mainly associated with MMP3 polymorphisms. MMP3 SNPs were associated with disease activity, independent of systemic inflammation and serum MMP-3. A haplotype across the MMP1-3 loci was associated with the development of erosive disease in earlier RA. Evidence of interaction with smoking was also found regarding the above association. No association of polymorphisms in TGFB1 with serum TGF-β1 level was found. A missense polymorphism TGFB1+868(C/T) (rs1800470) was associated with the occurrence of IHD and MI, which may be explained by an interaction with smoking. The current thesis highlighted the complexity of factors associated with severity and comorbidity in RA, and showed the importance of smoking in exacerbating various aspects of disease outcome.

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.

Background: Inflammation is the natural reaction of the body to an antigen. In some conditions, this reaction continues even after the elimination of the antigen, entering a chronic stage; it targets normal cells of the body and causes extensive damage. Rheumatoid arthritis (RA) is such a condition. It associates with significant metabolic alterations that lead to changes in body composition and especially body fat (BF) increases. In the general population, increased body fat (i.e. obesity) associates with a number of health disorders such as systemic low grade inflammation and a significantly increased risk for cardiovascular disease (CVD). Both effects of obesity could have detrimental effects in RA. Increased inflammation could worsen disease activity while obesity could further increase the already high CVD risk in RA. However, obesity in RA has attracted minimal scientific attention. Aims: The present project aimed to: 1) assess whether the existing measures of adiposity are able to identify the changes in body composition of RA patients, 2) if necessary develop RA-specific measures of adiposity, 3) investigate the association of obesity with disease characteristics and CVD profile of the patients, 4) and identify factors that might affect body weight and composition in these patients. Methods: A total of 1167 volunteers were assessed. Of them 43 suffered from osteoarthritis and 82 were healthy controls. These, together with 516 RA patients were used in the first study. Their body mass index (BMI), BF, and disease characteristics were assessed. In the second, third, fourth and fifth studies a separate set of 400 RA patients was assessed. In addition to the above assessments, their cardiovascular profile and more detailed disease characteristics were obtained. For the final study, 126 RA patients were assessed for all the above and also data on their physical activity levels and their diet were collected. Results: Assessments of adiposity for the general population are not valid for RA patients. Thus, we proposed RA-specific measures of adiposity. These are able to better identify RA patients with increased BF. We were also able to find associations between obesity and disease activity. Both underweight and obese RA patients had more active disease compared to normal-weight patients. Obese patients had significantly worse CVD profile compared to normal-weight. The newly devised measures of adiposity were able to identify those at increased risk. However, not all obese individuals were unhealthy and not all normal-weight healthy. Among our patients we were able to identify subtypes of obesity with distinct phenotypic characteristics that warrant special attention. Finally, we were able to identify factors that influence body weight and composition. Cigarette smoking protected against obesity while its cessation associated with increased adiposity. Physical activity was also found to be protective against obesity while diet or inflammation of the disease failed to produce any significant results. Conclusions: Obesity is a significant threat to the health of RA patients. The measures of adiposity developed herein should be used to identify obese RA patients. Physical activity seems like the sole mode for effective weight management in this population. Health and exercise professionals should actively encourage their patients to exercise as much as they can. This study has created more questions than it answered; further research in the association of obesity and inflammation, as well as in ways to treat it, is essential.