Dissertations / Theses on the topic 'Arthritis'

This study was designed to investigate the experience of having arthritic pain from the children's perspective. Previous research on how Canadian children perceive and manage arthritic pain and how it affects their daily lives is nonexistent. Therefore the purpose of this qualitative descriptive study was to explore and describe the arthritic pain experience of school age children with juvenile rheumatoid arthritis (JRA) and to understand the impact/influence of various factors on the construction of that experience. Ten children, aged 10 to 13 years, with either early (at 2 to 4 years) or late (at 7 to 11 years) onset arthritis participated in this study. Descriptive data were obtained during two open-ended in depth interviews with the children in their homes. Using content analysis, data were analyzed for themes and their elements. An analytical framework of themes and their elements was developed that reflected the children's descriptions of and explanations for arthritic pain in the context of their day to day in the context of their day to day living with arthritis, both in the past and currently. The children perceived pain to be synonymous with arthritis and the mediating factor in how they functioned. They described arthritic pain in relation to distinguishing factors: intensity, duration, and frequency. Intermittent arthritic pain was attributed to cessation of medications, arthritis "flare-ups," inactivity, and activity. A current concern for most children was pain attributed to activity because it meant limitations in activities with peers. The children identified strategies they used to manage pain and cope with pain's unpredictability. The findings of this study were discussed in relation to selected research studies that either supported or refuted the findings of this study. Implications for nursing practice and research were addressed.
Applied Science, Faculty of
Nursing, School of
Graduate

Dance
M.A.
This Master of Arts thesis is based on research that I conducted on dancers who have the auto-immune disease of Rheumatoid Arthritis. Rheumatoid Arthritis is a long-term autoimmune disease that causes inflammation in the joints and the surrounding tissues. Dancers with arthritis feel pain the joints that can be minor or severe, depending on how they are moving their bodies. This research investigates how dancers with an arthritic body can dance without the experiencing pain in their joints. Arthritis impairs movement because it is a disease that affects the joints. In this thesis, I created movements that could enable arthritic dancers the opportunity to continue dancing. I have identified a movement vocabulary, movement methods, and strategies for arthritic dancers who want and need to move with minimal pain. Movements have been created specifically for the arthritic body. I use my own experiences and challenges as an arthritic dancer to inform this study. My experiences helped me to create movements specifically for arthritic dancers because I am an advocate for those who suffer from arthritis.
Temple University--Theses

Multimedia - Wort des Jahres 1995 - taucht als populärer Begriff in allen Bereichen unserer Gesellschaft auf. Auch an Universitäten erhofft man sich durch die Einführung von computerunterstützten Lernformen eine höhere Qualität der Lehre sowie Kosteneinsparungen. Nach ersten Versuchen in den 60er Jahren war das Neue in den 90ern die realitätsnahe, multimediale Simulation von Entscheidungssituationen. Auf dem Gebiet der Rheumatologie ist derzeit jedoch noch ein Mangel an deutschsprachigen Softwaretiteln zu erkennen. Ziel war die Erstellung eines multimedialen Kompendiums über die rheumatoide Arthritis für den Einsatz in der universitären und postgraduierten Lehre. Das System soll als elektronisches Nachschlagewerk und als Basis für interaktive Diashows geeignet sein. Mit Hilfe eines Apple Macintosh und der Autorensoftware Macromedia Director wurde eine CD-ROM entwickelt, die sowohl für Macintosh- als auch für Windows-Computer geeignet ist. Die Beschreibung der Symptome der rheumatoiden Arthritis und der erforderlichen Untersuchungstechniken nimmt mit 31% der Bildschirmseiten den größten Teil des vorliegenden Multimedia-Kompendiums ein. Weitere Schwerpunkte wurden auf Pathogenese (19%), bildgebende Verfahren (14%), Differentialdiagnosen (11%), Therapie (10%) und Laboruntersuchungen (7%) gelegt. Videos und Animationen dienen der Illustration zellulärer Vorgänge und der Zusammenfassung klinischer Untersuchungstechniken. Etablierte Kriterienkataloge für elektronische Medien dienten der Qualitätssicherung im Entwicklungsprozeß. Eine parallel durchgeführte formative Evaluation lieferte erste Erkenntnisse über Praxistauglichkeit und Stabilität des Programmes, ohne jedoch eine fundierte summative Evaluation ersetzen zu können. Multimedia-Lehrbücher wie das vorliegende Kompendium stellen für den konventionellen Unterricht eine ideale Ergänzung zum klassischen Lehrbuch dar und dienen für die problemorientierte Ausbildung als schnell zur Verfügung stehende Wissensbasis. Jedoch blieben bei der fakultativen Nutzung von computerbasierten Lernmöglichkeiten in Lernzentren die Ergebnisse bisher hinter den Erwartungen zurück. Es ist zu diskutieren, inwieweit die Vorteile der Multimedia-Technologie durch gezielte Integration in das Curriculum an deutschen Hochschulen zu Kosten- und Zeitersparnissen führen können.
Multimedia - word of the year 1995 in Germany - is a popular term cropping up in all areas of society. Universities, too, hope to improve the quality of teaching and to cut costs by introducing computer-based forms of learning. Following initial attempts in the sixties, a new aspect introduced in the nineties was the life-like multimedia simulation of decision-making situations. In medicine, there still is a lack of German-language software packages in rheumatology. The aim of the present project was to develop a multimedia compendium on rheumatoid arthritis for teaching at the university and postgraduate level. The system was intended to serve both as an electronic work of reference and as a basis for interactive slide presentations. Using the authoring tool Macromedia Director on an Apple Macintosh computer, a CD-ROM was developed that can be run on Macintosh and Windows computers alike. The largest part of the multimedia compendium now available (31% of the screen pages) is dedicated to the description of the symptoms of rheumatoid arthritis and examination techniques. Other main areas are pathogenesis (19%), imaging modalities (14%), differential diagnoses (11%), therapy (10%), and laboratory tests (7%). Videos and animations serve to illustrate cellular processes and to summarize the clinical examination techniques. Catalogues of established criteria for electronic media were adhered to during development to assure quality. A simultaneously performed formative evaluation yielded initial results about the practicability and stability of the program but cannot replace a thorough summative evaluation. Multimedia textbooks such as the compendium presented here are ideal supplements to classical textbooks in conventional teaching, providing a rapidly accessible knowledge base for problem-oriented training. However, the results achieved with computer-based learning tools available for optional use at teaching centers have so far lagged behind expectations. It remains to be discussed to what extent the advantages of multimedia technology can save both cost and time by being selectively integrated into the curriculum at German universities.

The goal of the study was to explore and describe how arthritis patients experience the influence of arthritis on their quality of life after commencing with biologic arthritis medication. In order to achieve this goal, a qualitative research approach was adopted in an attempt to understand what the arthritis patients experience their quality of life to be while taking biologic arthritis medication. To achieve the research goal, the collective case study guided the research. Individual interviews, specifically semi-structured one-to-one interviews, with an interview schedule, were used as method of data collection. The researcher made use of Creswell’s (1998) qualitative data analysis process to analyse and to interpret the qualitative data. The trustworthiness of the data interpretation was confirmed through credibility, transferability, dependability and conformability. An analysis of the literature and transcripts of interviews was undertaken to answer the following research question: What is the influence of biologic arthritis medication on the quality of life of arthritis patients? The key findings of the study can be stipulated as follows: (1) Several signs and symptoms are associated with an arthritis patient, such as pain and fatigue; (2) Arthritis patients often visit several medical practitioners which can even be over a period of years before an official diagnosis of arthritis can be made; (3) A decrease of arthritis symptoms may be experienced during pregnancy, but increases again after the delivery; (4) Several types of arthritis treatments are available for managing the arthritis condition, ranging from traditional methods, such as anti-inflammatory medication, to biologic medication, such as Adalimumab (Humira); (5) A lack of knowledge pertaining to certain levels of medical doctors causes a mistrust amongst patients towards medical personnel; (6) Quality of life is a variable construct that is influenced by a patient’s culture and values; (7) Arthritis affects the patient’s ability to perform daily activities, such as washing; (8) Employment is important in making the patient feel human and therefore patients tend to hide their condition or to make adjustments at work, just to keep on working; (9) Biologic medication is seen as a miracle drug, albeit not totally without side effects, as patients are able to do things that were previously impossible; (10) Relationships are important in the life of an arthritis patient to enable coping, whether it be family, friends or the relationship with their medical practitioner; (11) Support provided by patients amongst themselves was also found to be important in order to facilitate coping with the disease; (12) Arthritis patients are encouraged to participate in physical exercise as it increases joint mobility; and lastly, (13) Biologic medication is quite expensive and patients are reliant on medical aids for funding of the treatment. In strengthening the role of social workers to assist arthritis patients to manage their disease better, the following recommendations are offered: (1) An awareness campaign facilitated by social workers, with experience in arthritic conditions, in collaboration with other health care workers in order to create awareness at different levels of society; (2) Social workers working in the field of arthritis should continuously strive toward improving the quality of life of arthritis patients they work with by setting up support networks and facilitating programmes that aim toward empowering those living with arthritis; (3) Social workers are encouraged to partner with rheumatology practices during which social workers are able to support newly diagnosed patients from the point of diagnosis. Social work support services could be in the form of counselling, or group support programmes; (4) A “fit for life” programme is recommended that is facilitated by social workers working with patients suffering from arthritic conditions with the goal of providing a safe environment where patients can be encouraged to be physically active. The aim will be to improve the patients’ quality of life experience, but also to create a safe environment for patients to support each other. (5) It is recommended that social workers working in the field of arthritis set up a database of patients that have proved to be involved in support programmes and shared their desire to provide guidance to newly diagnosed arthritis patients. The aim is then to partner a newly diagnosed arthritis patient with a more “senior” patient with a similar diagnosis and characteristics in order to establish a buddy support system. A context can then be created where the “senior” patient can share surviving techniques to the newly diagnosed patient but also provide assistance, for example picking up the children from school. Social workers are encouraged to then work closely with these buddies in order to provide further therapeutic support should it be required (6) Social workers working in the field of arthritis should always seek to advocate for arthritis patients when presenting at conferences and workshops (7) Investigate current, refine, or develop, policy related to the management and treatment of arthritis. Such policy should address aspects, including but not limited to, the employment conditions of people living with arthritis and securing the employment of people once diagnosed with the disease, medical aid and the requirements patients need to comply with in order to receive the full benefit provided to patients by medical aids, and thirdly, aspects related to the pricing (i.e., affordability) of disability insurance (8) The design and implementation of a continuous professional development programme is recommended to enable all health care workers to be continuously up to date with the latest developments related to arthritis research and management, in order to ensure that first line practitioners, for example physio-therapists and general practitioners, be equipped with the necessary skills to identify possible arthritis signs and symptoms which will ensure that patients are referred to specialist intervention as soon as possible. The sooner the patient receives the adequate level of care, the less joint deterioration may be sustained, and the higher the possibility to enjoy a good quality of life Future research could focus on initiating a research study that covers a more extensive geographical area, which is also more representative of the ethnic diversity in South Africa. Such a study could also cover more of the biologic medication used in the treatment of arthritis in order to reach a more holistic picture.
Dissertation (MSW)--University of Pretoria, 2014.
tm2015
Social Work and Criminology
MSW
Unrestricted

Background Rheumatoid arthritis (RA) is associated with both local and systemic inflammation which influences the function of the whole body as well as local tissues in the joints. Significant consequences of this are changes in metabolism. Hence, we hypothesised that chronic inflammation alters metabolism and that the metabolic profile of an individual patient with early inflammatory arthritis predicts the subsequent course of disease. Furthermore, we suggested that these metabolic changes would identify biomarkers of response to treatment in inflammatory arthritis and provide novel insights into disease mechanisms. Methods Using NMR spectroscopy of serum, urine and synovial fibroblasts we derived metabolic profiles and subjected these to multi-parameter analyses to identify metabolic differences associated with inflammation. Results We were able to predict outcome in patients with early arthritis using material derived from cultured synovial fibroblasts but were unable to do so using serum. There was a significant association between CRP levels in the patients’ serum and the metabolic profile of their synovial fibroblasts and their serum. There was also a significant association between the metabolomic fingerprint of synovial fibroblasts and the fibroblasts’ IL6 production. We found differences in metabolites between urine samples of RA and psoriatic arthritis (PsA) patients and were able to predict responses to anti-TNF therapy in patients with RA. Discussion Our results demonstrate that underlying inflammatory processes drive significant changes in metabolism that can be measured in the peripheral blood, synovial fibroblasts and urine samples in patients with inflammatory arthritis.

The literature is replete with reports of osteoporosis in rheumatoid arthritis, but the mechanism of bone loss remains obscure. This is probably due to the overlap with bone loss of aging and the menopause, whose exact mechanisms are also poorly understood. Against this background, a study was designed to evaluate generalised bone loss in young, premenopausal (if female), patients with rheumatoid arthritis. The protocol was designed to record demographic data, as well as information pertaining to the disease. Cortical bone mass was measured at the metacarpals and left femur, using an automated, computer-controlled technique. Trabecular bone was evaluated at the left femur (Singh index) as well as at the 3rd lumbar vertebra (Saville index). Bone kinetics were studied by the measurement of urinary excretion of calcium, phosphate and hydroxy-praline (resorption) and serum alkaline phosphatase (formation). Disease activity was measured clinically and with laboratory indices. Physical activity was indirectly measured by quantitating the disability, using the Keitel function test as well as a modified health assessment questionnaire (HAQ). The radiograph of the right wrist was scored by the Larsen index. The carpometacarpal ratio was also calculated from the radiograph. Numerous statistical techniques were applied in the analysis of the data. Healthy volunteers were used as controls. Patients with SLE were also studied, in order to compare the 2 inflammatory diseases. Patients with RA had generalised cortical bone loss (metacarpal and femur) (p < 0.001). Trabecular bone measurements were not significantly different from normals, using the crude radiographic techniques. Duration of disease was the most important clinical determinant of this bone loss. The relative contributions of disease activity and lack of physical activity to the loss of bone could not be adequately separated using conventional statistical techniques. Corticosteroid therapy did not promote metacarpal bone loss in these subjects, but may have contributed to thinning of the femoral cortex. Nonsteroidal anti-inflammatory drugs and disease modifying agents did not seem to influence the extent of the bone loss. Nutritional status and skinfold thickness did not correlate with bone mass. Dietary factors played no role in the genesis of bone loss, but may have had some effect on disease activity. Metacarpal measurements showed a sensitivity of 80% and specificity of 85% in discriminating between osteopaenic and normopaenic groups with RA. Osteopaenia could not be adequately predicted in the absence of metacarpal measurements. Metacarpal bone loss in RA was due to endosteal resorption, while in SLE it was due to periosteal resorption. The semi-automatic technique for measurement of metacarpal bone mass showed good reproducibility among 5 observers and at 2 different centres. The pathogenesis of bone loss in RA was multifactorial, the largest contribution probably coming from a humoral factor in the circulation, closely related to disease activity. Ionised calcium was elevated in 55% of RA patients, but only 5% of SLE patients. Serum PTH levels were normal in 99% of the RA subjects. Elevations in alkaline phosphatase. (25%) probably reflected disease activity rather than increased bone formation. Factor analysis of 27 variables showed that disease activity was central to the development of OP in RA. CS therapy tended to be used in the presence of active disease. Disability was not an important determinant of bone loss in RA, but may be a useful measure of activity of the disease. This study did not evaluate the relationships with sex hormonal status or vitamin D metabolism. Future research should aim at cohort analysis at 2 different periods, in order to improve our understanding of the pathogenesis of bone loss in RA.

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.

Rheumatoid arthritis (RA) is a chronic, autoimmune, inflammatory disease that affects synovial joints. A key characteristic of RA is hyperplasia of fibroblast-like synoviocytes (FLS) which develop a stable, auto-aggressive phenotype that augments tissue destruction. It is unknown how this phenotype is stably maintained; however, epigenetic changes have been implicated. Histone deacetylation is one proposed method; a process controlled by histone deacetylases (HDACs). However, there have recently been reports publishing conflicting data regarding the expression of HDACs in RA synovium and FLS. The objective of this thesis is to determine the role of HDACs in regulating the auto-aggressive phenotype of RA through studies in FLS and in mice. Real time-quantitative PCR was used to assess the levels of HDAC1-11 in RA compared to osteoarthritis (OA) FLS. Immunohistochemistry and western blotting were used to assess protein expression of HDAC1 in RA and OA synovial tissue and FLS. HDAC1 was found to be overexpressed in RA compared to OA. HDAC1 was knocked down in RA FLS, then cell proliferation, migration and invasion were assessed by using tritiated thymidine, a scratch assay and a Matrigel invasion assay respectively. All three functions were significantly reduced following HDAC1 knockdown. An Illumina BeadChip (47,000 transcripts) was used to analyse global gene expression changes after knockdown. This revealed significant gene changes in important functional clusters, such as proliferation and migration. HDAC1 knockout is embryonic lethal in mice, so the in vivo role of HDAC1 was investigated in a mouse model of collagen-induced arthritis (CIA) using in vivo siRNAs. Clinical scores of CIA were measured daily and HDAC1 knockdown mice showed a significantly reduced clinical score compared to controls, comparable to dexamethasone-treated mice. The bones were analysed using a microCT scanner and histology. Knocking down HDAC1 showed reduced bone erosion, joint inflammation and cartilage degradation compared to controls. Overall, this study shows that HDAC1 is dysregulated in RA and it has a significant role in the autoaggressive phenotype shown in RA FLS and collagen-induced arthritis. The novel data shown in this thesis demonstrates that inhibiting HDAC1 may provide a powerful new target for treating RA.

These findings suggest that systemic and vascular wall levels of matrix metalloproteinase-9, related to inflammation at the joint site, may play a prominent role in the development of vascular dysfunction in this experimental model. This thesis goes someway to elucidating the potential mechanisms of vascular dysfunction in rheumatoid arthritis.

Psoriatic arthritis (PsA) has a strong genetic predilection with the first-degree relatives of PsA cases having an increased risk of developing the disease and the sibling recurrence risk (?s) estimated to be as high as 55. Due to the" overlap of PsA with psoriasis aTid other inflammatory arthritis (lA) such as rheumatoid arthritis (RA), in order to dissect out genetic factors contributing to the aetiology of PsA over and above those that contribute to psoriasis alone and lA alone, a unique study design was used whereby allele frequencies for the genetic polymorphisms tested were compared between patients with PsA and three control cohorts: psoriasis alone, lA alone and healthy controls.

Genetic as well as environmental factors are believed to be of importance in the etiology of rheumatoid arthritis (RA). There are a number of previous studies of genetic markers in RA, but so far no genetic linkage and only a few associations have been found. Of the associations only one (with the HLA antigen DR4) appears to be well documented. In most previous association studies the patients have not been divided according to sex and family history of RA. In this investigation the HLA antigens A, B and DR and five serum protein systems (Bf, C3, Pi, Hp and Tf) were studied in patients with erosive rheumatoid arthritis (RA), from northern Sweden. Special attention was paid to variations in the strength of associations accord­ing to sex and family history of polyarthritis. The following results were found:  The frequency of the HLA antigen B27 was significantly increased in the North-Swedish population (16.6%) and among patients with a family history of polyarthritis (42.6%). In agree­ment with previous investigations a significantly increased frequency of the DR4 antigen was found in the RA patients.  In the properdin factor B (Bf) system the S phenotype was found to be significantly in­creased in male patients and in patients with a family history of polyarthritis, more severe form of RA and high titres of rheumatoid factor.  No significant differences with respect to phenotype or gene frequencies were found in the C3 complement system. Thus, the association between RA and C3 found in previous investiga­tions was not confirmed.  A significant increase of rare alpha-1-antitrypsin (Pi) types (MS, MZ, MF and SZ) was found among RA patients. However, the increase concerned mainly Z heterozygotes and was more strongly pronounced among male patients.  In the haptoglobin system a significant increase of the Hp^ gene and the Hp2-2 type was found among patients with a family history of polyarthritis, more pronounced among males.  A significant increase of the transferrin gene and of the 2 type was found among male RA patients, more pronounced among patients with a family history of polyarthritis. In 6 out of 8 gene loci studied significant associations were found, which is in agreement with a multifactorial etiology of RA. The results were largely in agreement with the hypothesis that associations would be expected to be stronger in males and in patients with a family history of polyarthritis. A notable finding was the high frequency of first degree relatives (around 40%) with symmetric peripheral polyarthritis of which more than 70% had a diagnosis of RA verified by hospital records.

Diss. (sammanfattning) Umeå : Umeå universitet, 1985, härtill 6 uppsatser.

digitalisering@umu

Biologic therapies have revolutionized the treatment of rheumatoid arthritis, a common chronic inflammatory disease, mainly characterized by the chronic inflammation of the joints. The activity and progression of the disease are highly variable, both between subjects and between the successive assessments for the same subject. Standardized assessments of clinical variables have been developed to reflect the disease activity and evaluate new therapies. Pharmacokinetics-pharmacodynamic (PKPD) models and methods for analyzing the generated time-course data are needed to improve the interpretation of the clinical trials’ outcomes, and to describe the variability between subjects, including patients characteristics, disease factors and the use of concomitant treatments that may affect the response to treatment. In addition, good simulation properties are also desirable for predicting clinical responses for various populations or for different dosing schedules. The aim of this thesis was to develop methods and models for analyzing pharmacokinetic and pharmacokinetic-pharmacodynamic (PKPD) data from rheumatoid arthritis patients, illustrated by treatment with a new anti-TNFα biologic drug under clinical development, certolizumab pegol. Two models were developed that characterized the relationship between the exposure to the drug and the efficacy ACR variables that represent improvement of the disease; a logistic-type Markov model for 20% improvement (ACR20) and a continuous-type Markov model for simultaneous analysis of 20% (ACR20), 50% (ACR50) and 70% (ACR70) improvement. Both models accounted for the within-subjects correlation in the successive clinical assessments and were able to capture the observed ACR responses over time. Simulations from these models of the ACR20 response rate supported dosing regimens of 400 mg at weeks 0, 2 and 4 to achieve a rapid onset of response to the treatment, followed by 200 mg every 2 weeks, or alternative maintenance regimen of 400 mg every 4 weeks. The immunogenicity induced by the biologic drug was characterized by a time to event model describing the time to appearance of antibodies directed against the drug. The immunogenicity was predicted to appear mainly during the first 3 months following the start of the treatment and to be reduced at higher trough concentrations of CZP, as well as with concomitant administration of MTX. The full time-course of sequential events, such as dose-exposure-efficacy relations, is most accurately described by a simultaneous analysis of all data. However, due to the complexity and runtime limitations of such an analysis, alternatives are often used. In this thesis, a method, IPPSE, was developed and compared to the reference simultaneous method and to existing alternative methods. The IPPSE method was shown to provide accuracy and precision of estimates similar to the simultaneous method, but with easier implementation and shorter run times. In conclusion, two PKPD models and one immunogenicity model were developed for evaluation of the response of a biologic drug against rheumatoid arthritis that allowed accurate analysis and simulation of clinical trial data, as well as serving as examples for how a model-informed basis for decisions about biological drugs can be created.

Psoriatic arthritis is an inflammatory arthritis affecting a fifth of patients with skin psoriasis. Inflammation of the joints and tendons causes pain, stiffness, reduced function and disability. Work disability is increasingly recognised as an important, patient centred, functional measure of disease yet little is known about work disability in psoriatic arthritis. The overall aim of my thesis is to examine patient reported work disability in psoriatic arthritis by undertaking the following; • A systematic review of the relevant literature • Classification of a cohort of patients to study • Validation of a commonly used work outcome measure used in other rheumatic diseases • Selection of a suitable measure of structural damage to inflamed joints for investigating the associations of work disability in longitudinal observational studies. The results of the systematic review identified limited data reporting high levels of work disability associated with a wide variety of disease and non-disease related factors. The review also identified the lack of a validated outcome measure for use in psoriatic arthritis. I report the classification of a large single centre longitudinal cohort of patients with psoriatic arthritis and evidence supporting the retrospective application of a psoriatic arthritis classification criterion. Subsequently I report a preliminary validation study of the work productivity and activity impairment questionnaire to measure work disability in psoriatic arthritis and a further study comparing the existing measures of structural damage in psoriatic arthritis. Finally I developed and supervised a multicentre observational study to examine the associations of work disability in psoriatic arthritis. The study identified reduced work effectiveness to be associated with measures of disease activity, whereas unemployment was associated with recent disease onset, greater age and worse physical function. The study will provide a valuable cohort for prospective study of work disability and the effect of medical treatment and will form part of my planned post-doctoral studies.

Background: Psoriatic arthritis (PsA) is a chronic heterogenous inflammatory arthritis with five phenotypes. The two least studied phenotypes are investigated in this thesis, including: psoriatic spondyloarthropathy (PsSpA) and psoriatic arthritis mutilans (PAM). The aims of this thesis were to determine the prevalence, clinical characteristics and radiographic characteristics of PsSpA and PAM in a cohort of PsA patients, and serum-soluble bone- turnover biomarkers of these phenotypes. Aims: Comparisons were made with PsA patients without axial disease (pPsA), and ankylosing spondylitis (AS) patients. Methods: A prospective single-centre cross-sectional study was conducted of PsA and AS patients. Serum on psoriasis-only patients (PsC) and healthy controls (HC) were also obtained. Multivariate clinical, radiographic, genetic and serum biomarker comparisons were made between these five groups of subjects. Results: The study enrolled 201 PsA and 201 AS patients, who were then reclassified as 118 PsSpA, 127 pPsA and 157 AS cases, alongside 200 PsC and 50 HC subjects. Several clinical biomarkers, imaging biomarkers, serum-soluble biomarkers and genetic biomarkers were identified that differentiate PsSpA from pPsA and AS. PsSpA affected a significant proportion of PsA patients, and was not a milder version of AS. PsSpA involvement was as disabling and clinically impactful as AS. PAM was found to be associated with PsSpA, and clinical biomarkers of PAM occurrence and radiographic progression were identified. Conclusions: In conclusion, this thesis indicates that PsSpA is on a spectrum of musculoskeletal disease, in between pPsA and AS; with PsSpA comprising a continuum itself, and with a phenotype expression related to disease duration. These findings may prompt the inception of an international-consensus classification system for PsSpA, for which there is a great clinical need. Given that PsSpA has its own discrete clinical and biomarker signature, its clinical management and research should be tailored from that of pPsA and AS. Ultimately this may further the effort for stratified and personalised medicine.

Rheumatoid arthritis (RA) is a chronic inflammatory condition with poorly understood pathophysiology and increased cardiovascular risk. The mechanisms for increased cardiovascular risk are not fully known, however one novel mechanism explored in this thesis is autonomic nervous system (ANS) dysfunction. The thesis comprises of: a systematic literature review; two case-control studies (n=30 RA patients, n=34 controls; a longitudinal case-study (n=1 RA patient)); a cohort study (n=112 RA patients); and a randomised placebo controlled crossover study (n=10 healthy controls). The work presented in this thesis demonstrates that ANS dysfunction is prevalent in ~60 % of RA patients and characterised by heightened sympathetic outflow to the peripheral vasculature (determined by muscle sympathetic nerve activity using microneurography), depressed baroreflex control of heart rate (determined using the modified Oxford technique), depressed heart rate variability and heightened vascular responses to stressors (cold pressor test and mental stress). Inflammation was associated with ANS dysfunction, and may well contribute to the increased cardiovascular risk seen in RA. Further studies are required to: confirm these findings; determine whether therapeutic strategies to restore ANS function improve prognosis in RA; and further explore the precise mechanisms by which inflammatory cytokines may influence ANS function in health and disease.

Identification of the role of T cells and their interaction with other cell types remains a major challenge to our understanding of the pathogenesis of rheumatoid arthritis. In this study we have investigated the regulation of the response of T cells infiltrating the rheumatoid joint to IL-6. Furthermore we have investigated the level of T cell activation in the early stages of rheumatoid arthritis. Interleukin-6 is an important regulator of T cell differentiation and survival. It exerts its biological function by either directly binding to the complete IL-6 receptor consisting of CD126 CD130 or via transsignaling, when sIL6R-IL6 complexes bind to CD130. This study addresses the expression and regulation of these receptor components on the T cells infiltrating the rheumatoid joint. While compared to blood T cells, CD126 expression was found at low levels on synovial fluid and tissue T cells, expression of CD130 on synovial tissue T cells was comparable to that of blood T cells, with lower levels in synovial fluid T cells, both at protein and mRNA level. When exposed to sIL6R-IL6 complexes, tissue derived T cells responded with a higher level of STAT3 phosphorylation compared to cells incubated with IL-6, suggestive of transsignaling. High CD130 expression was demonstrable in T cells in the perivascular cuff area. Among a range of cytokines tested, IL-6 reduced CD126 and CD130 expression while IL-10, which is expressed at high levels in the perivascular infiltrate, induced expression of CD130. Taken together these data suggest that the inflammatory microenvironment maintains responsiveness to IL-6 transsignalling by cytokine driven CD130 expression on CD4 positive T cells. To address the question whether the role of T cells changes during the course of progression of RA, we analysed the expression of T cells activation markers on synovial fluid and peripheral blood T cells from patients at the very early stage of disease (within 3 months of disease onset) compared to patients with established or self resolving arthritis. Expression of CD69, CD71 and HLA-DR was upregulated on synovial fluid T cells compared to peripheral blood but there were no differences between the different groups of patients. Furthermore, we quantified the proportion of T cells expressing the invariant TCR Vα24Jα18 in synovial fluid and blood of the same groups of patients. We found a lower frequency of iNKT cells in the synovial fluid of very early arthritis patients compared to other patients. While this is a preliminary result, it suggests that there may be a role for these cells in the regulation of disease susceptibility.

The principle aim of this study was to test the hypothesis that heavy smoking is an aetiological factor in RA and generates a distinct subgroup of the disease definable in terms of clinical phenotype, particularly severity. A second aim was to investigate possible molecule mechanisms linking smoking with RA and what I believe to be candidate mechanisms involving the detoxifying glutathione S transferase Mu 1 (GST M1) gene and oxidative damage to alpha 1 proteinase (alpha1 PI). These studies involved a review of the literatures regarding the link between RA and both smoking and alpha1 PI deficiency. I investigated the relationship between heavy cigarette smoking and hospital based, more severely affected RA patients. Additionally, the age of onset and smoking history was compared in familial and sporadic RA cases. Regarding smoking and severity of RA, a cohort of RA patients were studied to determine if smoking was an independent risk factor for severe RA and whether this effect was influenced by the presence (GSTM1-1) or absence (GSTM1-0) of the GST M1 gene. Oxidative damage in RA to the alpha1 PI protein was studied in relation to rheumatoid disease activity, GST M1 and cigarette smoking. The oxidative damage to alpha1 PI was measured in terms of serum levels of Immunoglobulin A-1 PI was measured in terms of serum levels of Immunoglobulin A-alpha1 PI (IgA-alpha1 PI). In summary, I have shown that heavy smoking is strongly associated with hospital based RA. Secondly, that familial RA presents at an earlier age than sporadic RA in individuals smoking at disease onset only, and that sporadic RA patients are significantly more likely to smoke at disease onset that familial RA patients. I have confirmed previous findings that raised serum IgA-alpha1 PI levels are associated with erosive as opposed to non-erosive RA cases.

Psoriatic arthritis (PsA) is an inflammatory arthritis associated with psoriasis. Psoriasis is a dermatological condition that affects 1-2% of the population. Approximately 10-15% of patients with skin manifestations of psoriasis develop PsA and 0.3-1% of the general population. Moll and Wright defined PsA as psoriasis associated with inflammatory arthritis and usually a negative serological test for rheumatoid factor (RF).

Thesis: S.B. in Art and Design, Massachusetts Institute of Technology, Department of Architecture, May, 2020
Cataloged from PDF version of thesis.
Includes bibliographical references (pages 34-36).
The purpose of this thesis is to investigate and create more responsive and adaptive assistive technology for patients with rheumatoid arthritis (RA), using computational design methods to embed individualized data within the design and materiality. Rheumatoid arthritis is a chronic, autoimmune disease that attacks the joints and causes progressive deformity and bone erosion directed mostly at joint linings and cartilage. Living with RA means sudden flare-ups of pain and inflammation that can last anywhere from hours to months and dramatically impact the ability to accomplish ordinary tasks. While there is no cure, the disease can be slowed down through intensive drugs and or mitigated with assistive wearable devices such as braces, splints, and compressive gloves. These wearables are used to minimize swelling in affected joints, lessen ulnar deviating forces, and reduce pain. However, many people are unwilling to wear these devices because they can be quite obtrusive and hinder patients' lifestyles. Most wearables are only available in set sizes, and when sized incorrectly can aggravate pain and symptom flare-up or have no healing benefits. This thesis asks whether and how computational design methods can be applied to alleviating unique pain points faced daily by people with chronic health issues such as RA and other physical joint or musculature needs. Given that each person suffering from rheumatoid arthritis manifests the debilitating effects of the disease in different ways, this leads to the question of how more effective and personalized assistive devices can be designed using computational design methods that do not put the onus on the user to perform corrective action, but rather automatically offer responsive support as needed.
by Jierui Fang.
S.B. in Art and Design
S.B.inArtandDesign Massachusetts Institute of Technology, Department of Architecture

As rheumatoid arthritis (RA) is a heterogeneous disease whose course and treatment response varies between patients, a stratified approach to its management is required. This thesis aimed to facilitate the risk prediction that underpins stratified medicine in RA. Its primary aim was to improve the knowledge of which clinical and genetic factors predict RA’s onset, disease course and treatment responses. Its secondary aim was to develop a prediction modelling framework that harnessed these factors to inform clinical care. There were five key findings. Firstly, it demonstrated a significant inverse association between alcohol consumption and RA development when the evidence across published studies was pooled using meta-analytical techniques. This suggests alcohol may protect against RA. Secondly, it demonstrated that only HLA RA susceptibility variants associated with radiological progression in a clinical trial cohort of early, active RA patients. This suggests the non-HLA genetic architectures of RA susceptibility and severity may, at least partially, differ. Thirdly, it provided evidence that anti-citrullinated protein antibodies (ACPA) can identify patients with early, active RA that are most likely to benefit from combination treatments. Fourthly, it demonstrated that estimating an asymptomatic individual’s risk of RA is possible, through developing and validating a risk prediction model that uses computer simulation to improve upon the discriminative abilities of existing RA prediction models. Finally, it highlighted the importance of considering RA’s heterogeneity when assessing its predictive factors; alcohol’s likely protective effect was predominantly seen in ACPA-positive disease and genetic and environmental factors had different impacts on the risk of developing younger and older onset RA. In conclusion this thesis has contributed to stratified medicine in RA by better characterising which predictive factors are relevant to its development, severity, treatment needs and responses and developing a risk prediction modelling framework that may be applicable to many aspects of stratified care.

Inflammatory arthritis (IA) refers to a group of diseases that affect up to 3% of the population. Characterized by joint pain, swelling, and loss of function, examples of IA include rheumatoid arthritis (RA), psoriatic arthritis (PsA), ankylosing spondylitis (AS) and other forms of spondyloarthritis (SpA). In spite of significant advances in treatment over the past few decades, international studies have shown that many patients with IA continue to experience musculoskeletal pain. Untreated and under treated pain are well known to negatively impact overall well-being and increase disability. There are many contributing factors to the suboptimal pain management of patients with IA. Despite extraordinary advances in the understanding of pain mechanisms at the molecular level, there remains a lack of understanding about what actually causes joint pain. In addition, pain generating mechanisms are dynamic as well as influenced by a multiplicity of factors such as sleep, mood, past pain experiences, cultural background, and genetics of the individual. Hence, for clinicians assessing pain in patients with IA, the exact aetiology, influencers and resultant impact can often be difficult to elucidate. When managing patients with IA, clinicians have also traditionally focused on disease activity outcome measures. However, the correlation between pain intensity and measures of disease activity is poor. In fact pain has been shown to be one of the most significant predictors of discordance between patient and physician global assessment scores. This can lead to a physician believing the patient has very well controlled disease, while at the same time their patient feels that it is poorly controlled. Such miscommunications may explain why despite apparent disease control, patients continue to report pain as their predominant impairment, and pain management as their highest priority. Yet, despite being a frequent and important issue, there has been a paucity of research evaluating the prevalence, severity, impact or best management of pain in modern day patients with IA. Clinicians have had to rely upon clinical experience and inferences of therapeutic potential of pain medications from other patient groups to guide best management. This is clearly suboptimal. To understand the magnitude of the problem in Australia, the first aim of this thesis was to describe the prevalence, severity and impact of persistent pain in modern day patients with the most common IA condition, rheumatoid arthritis (RA). Data from the Australian Rheumatology Association Database (ARAD) was analysed and revealed that 95% adult patients with RA reported persistent pain in the last week, with a high proportion reporting moderate (39%) or severe (19%) levels of pain. Patients with higher levels of pain were found to have higher levels of disability and lower quality of life scores. After adjusting for confounders, the strongest associations with moderate to severe levels of pain were current use of opioid, paracetamol and non-steroidal anti-inflammatory drugs (NSAIDs), joint pain, lower level of education, presence of concurrent back pain, higher disability and female sex. To better understand the current management of persistent pain in patients with IA, the second aim of this thesis was to describe the analgesic medications currently being used by patients to manage their pain. A review of ARAD data revealed that in patients with RA, paracetamol (60%) and non-steroidal anti-inflammatory drugs (37%) were the most frequently used analgesics, however, surprisingly the prevalence of opioid use was also very high (26%). Overall, there was significant variation in the number and types of analgesics being used by these patients reflecting the lack of evidence and guidelines available to guide front line clinicians and patients in best practice. The third aim, prompted by the unexpected prevalence of opioid use, was to explore the longitudinal patterns of opioid use and factors associated with starting and stopping their use. This analysis showed that the prevalence of opioid use was stable over time, but there was a linear trend for an increase in high potency opioid use from 6.1% prior to 2008 to 11.2% after 2012. This was accompanied by a concomitant decrease in low potency only opioid use. Another significant finding was that those who commenced opioids, on average, continued them for almost two years. Younger baseline age, higher pain scores, HAQ scores and oral glucocorticoid use were important determinants of change in opioid use, associated with both a higher probability of commencing opioid use, and a lower probability of cessation. Of note, use of bDMARDs was not associated with a discontinuation of opioid use. Opioid use was also associated with an increased mortality risk unrelated to opioid overdose. The fourth aim of this thesis was to review the evidence for the efficacy and safety of medications found to be commonly used to treat persistent pain in patients with IA. As part of a body of work that contributed to the international 3e (Evidence, Expertise, Exchange) initiative, four Cochrane systematic literature reviews (SLRs) for patients with RA and four SLRs in patients with IA were performed to evaluate antidepressants, neuromodulators, muscle relaxants, and opioids. This complemented other 3e research that reviewed the evidence for paracetamol, NSAIDs and corticosteroids. The SLRs evaluating antidepressants versus placebo or an active intervention comprised eight randomized controlled trials (RCTs) (652 participants) in patients with RA and one RCT in patients with AS (100 participants). All trials evaluated tricyclic antidepressants and 2 studies included a selective serotonin uptake inhibitor. All studies were small and deemed to have a high or unclear risk of bias so no reliable conclusions about efficacy were able to be drawn. In terms of safety, use of antidepressants was associated with adverse events which were generally mild and did not lead to cessation of treatment. Based on these SLRs, there was insufficient evidence to support the routine prescription of antidepressants as analgesics. A research gap was also identified with a need for more high quality trials in this area. The SLRs evaluating neuromodulators identified only four RCTs in patients with RA, with two evaluating oral nefopam and one trial each evaluating topical capsaicin with placebo and oromucosal cannabis with placebo. All trials were determined to have a high risk of bias. The review found weak evidence that oral nefopam, topical capsaicin and oromucosal cannabis were all superior to placebo in modestly reducing pain in patients with RA. However, each agent was associated with a significant side effect profile so routine use was not recommended. The SLRs evaluating muscle relaxants identified six small RCTs (126 participants) evaluating the benzodiazepines diazepam and triazolam, as well as the non-benzodiazepine zopiclone in patients with RA. No trial was longer than 2 weeks and 3 single-dose trials assessed outcomes at 24 hours only. Overall, the included trials failed to find evidence of a beneficial effect of muscle relaxants over placebo or in addition to nonsteroidal anti-inflammatory drugs on pain intensity, function, or quality of life. Data from two trials of longer than 24-hour duration found that participants who received a muscle relaxant had significantly more adverse events compared with those who received placebo. These were predominantly central nervous system side effects including dizziness and drowsiness. The reviews found there was insufficient evidence to support the use of muscle relaxants for pain management in patients with RA. The SLRs evaluating the efficacy and safety of opioids found eleven RCTs in patients with RA (672 participants) only. The risk of bias in all studies was high and no study was longer than 6 weeks in duration. Based on the available evidence, the review found that treating RA patients with weak opioids for up to six weeks may offer clinically-relevant improvement in pain, however adverse effects such as constipation, dizziness, nausea, and vomiting were common. There was insufficient evidence to draw conclusions regarding the regular use of weak oral opioids for longer than 6 weeks, the use of strong opioids for any duration, or the role of opioids in IA other than RA. Based on the available evidence for many patients, benefits of weak opioids are unlikely to outweigh the harms. Following the completion of the SLRs, the fifth aim of this thesis was to combine this evidence with expert opinion to develop national pragmatic, evidence-based guidelines to aid practitioners in the management of pain in patients with IA. The evidence from the SLRs was presented to 46 Australian and New Zealand rheumatologists for discussion. Using this evidence, their expert opinion and a Delphi process, 10 Australian and New Zealand recommendations regarding the use of pharmacotherapy for pain management in adult patients with IA were formulated. These Australian and New Zealand national recommendations, in addition to the recommendations from 16 other nations, contributed to the formation of multi-national guidelines for pain management by pharmacotherapy in patients with IA. There are numerous strengths of this thesis. This work has addressed a research gap to a prevalent problem and provided the first insights into the magnitude and severity or persistent pain in Australian patients with IA. Use of the national ARAD database allowed large numbers of real world, Australian patients with IA from a wide variety of backgrounds to be included and ensured the patient perspective was captured. This ensured that the results were meaningful, patient centric, and generalisable to the broader Australian IA population. This work was also the first to evaluate such an extensive array of potential predictors of persistent pain in patients with RA and has also thrown a spotlight, for the first time, on the unrecognised and concerning problem of high levels of use of opioid medication use in this patient population. The methodology used in the SLRs and development of the guidelines was robust. In the systematic appraisals of the evidence for the efficacy and safety of various analgesic agents in this patient population, a rigorous, reproducible, Cochrane methodological approach was used. The reviews contained in this thesis are the first published work to evaluate the efficacy and safety of anti-depressants, neuromodulators, muscle relaxants and opioids in patients with IA. In the development of the national and multinational evidence based guidelines, the inclusion of a broad range of rheumatologists and the use of a formal modified Delphi voting process ensured, that a wide range of expertise was captured, relevance of the recommendations to a broad audience and that promotion for the implementation of the guidelines occurred on a large scale. In presenting the work contained in this thesis at state, national, and international conferences and publishing the work in high impact journals, this thesis has also contributed significantly to the collaborative effort to educate the broader community about the significant issue of persistent pain in patients with IA, how it is optimally managed, and the large research gap that currently exists in this area. The guidelines are the first Australian and New Zealand evidence based guidelines published to assist front line clinicians managing pain in patients with IA. Limitations of the work included the lack of disease activity measures (ESR, CRP, tender joint count (TJC), swollen joint count (SJC)) and qualitative data present in the ARAD database to further understand the aetiology of the pain being reported by patients. The reliance on self-reporting of analgesic medications and lack of dosages of medications recorded, or indication for treatment means that accuracy of the data may be affected by recall bias, and relies on the patient’s understanding of why they are taking their pain medications. Commonly used antidepressants, neuromodulators and muscle relaxants such a duloxetine, sertraline, fluoxetine, citalopram, gabapentin, amitryptiline, pregabalin, diazepam were not specifically asked about and are likely to have been under-reported. In the SLRs, there were few high quality trials present, and the populations included were not reflective of current day patients with IA. The scope of this thesis is limited to pharmacotherapy and so non pharmacological interventions for pain management in IA have not been reviewed. The findings in this thesis highlight the need for further research to better understand the aetiology of pain as well as the optimal use of analgesic agents in patients with IA. A need for new pain management approaches taking into account current immunomodulatory strategies, novel analgesic drugs and a modern understanding of measurement and neurobiology of pain is also clear. In summary, the work contained in this thesis has shown that the prevalence of moderate to severe pain in Australian patients with IA is high, and has a significant impact on their disability and quality of life. Opioid use in this patient group is frequent and prolonged despite evidence suggesting harms outweigh the benefits. To assist front line clinician’s in managing this complex, multi-dimensional symptom, pragmatic, evidence and expertise-based Australian and New Zealand have been published. The work contained in this thesis also significantly contributed to the first published multi-national guidelines for pain management by pharmacotherapy in patients with IA. A clear research agenda to address the large knowledge gaps in this area has also been identified.