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.

Approximately 18 months ago, an Arthritis Men's Group was started by the Social Work Department at the Vancouver Arthritis Centre. Having identified the need for such a group, interim objectives were proposed for the group which was still in the pilot stage of its development. The purpose of the study was to conduct a formative evaluation of the Men's Group to take a closer look at what was happening in the sessions, to examine the feasibility of the objectives and whether these objectives were being achieved. This information would be used by the planners to improve and/or modify the program. The underlying conceptual approach to the study was 'naturalistic'. In the context of this framework, several data collection methods were used including: interviews, quantitative measures, monitoring and narrative descriptions of group sessions. The findings suggested that interim objectives were being met in the sessions which focussed specifically on psycho-social issues. In addition, other sessions were serving an important 'informational' function which was recognized and valued by group members. Interviews with core-group members did indicate the perceived acceptance and usefulness of open discussions on psycho-social issues. However, over the short duration of the monitoring period no significant changes were found on the measures pre to post so that the positive or negative effects of the achievement of higher levels of emotional openness is not known. The study did provide a good preliminary data base on the nature of the group process and the heterogeneity of the membership. Useful information was gathered both on the kind of group process which may facilitate the achievement of the specific program objectives as well as the informational function of the group. Overall, group members seemed satisfied with group process and content and wanted to see the group continue. / Arts, Faculty of / Social Work, School of / Graduate

Juvenile idiopathic arthritis, JIA, is used as an umbrella term covering a heterogeneous group of chronic arthritis forms in children, many of which have important differences compared to adult arthritis, while others possibly represent similar diseases among children and adults. Classification aims to give a better understanding of the pathogenesis, patterns, disease trajectories and treatment responses. For the juvenile psoriatic arthritis, JPsA, the classification criteria are currently being debated. The distribution of affected joints in JIA differs greatly and it is unknown why some joints appear to be more affected than others. The temporomandibular joint (TMJ) can be affected early in the course of the disease and often the symptoms are mild and without obvious swelling. This thesis has its origin in the Nordic Study Group of Paediatric Rheumatology and the population-based prospective study of 510 children with newly diagnosed JIA included between 1997 and 1999. Totally 440 children were included in the eight-year follow-up, and in the TMJ study 265 patients were examined and underwent cone-beam computed tomography, CBCT, 17 years after onset. After eight years a considerable proportion of the children with definite psoriasis were classified as undifferentiated JIA based on the exclusion criteria in the ILAR classification. Our data also presents the heterogenicity of JPsA and the development over time of clinical variables supporting a psoriatic diathesis, as well as the overlap between JPsA and enthesitis-related arthritis in a group of patients.  We found that extensive symptoms and dysfunctions of the TMJ are seen in JIA 17 years after disease onset, even in patients registered with inactive disease or remission. Individuals with substantial condylar damage on CBCT were found in all JIA categories. The deeper understanding of a chronic disease over time is crucial for research initiatives to improve care as well as for clinical decisions and planning of the health care. Our findings suggest a need for a more appropriate classification of JPsA and also that aspects of TMJ involvement should be included in the general health assessment in JIA.

京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第22644号 / 医博第4627号 / 新制||医||1066(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 松田 秀一, 教授 古川 壽亮, 教授 中山 健夫 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

Thesis (M.S.)--Boston University

No description available.

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. / Dance

Die Rheumatoide Arthritis ist eine Autoimmunerkrankung, die mit grundlegenden Veränderungen im CD4+ T-Zellpool einhergeht. Viele Studien konnten zeigen, dass die Gruppe der T-Helferzellen bei erkrankten Personen vermehrt Anzeichen von replikativer Seneszenz und das adaptive Immunsystem deutliche Zeichen der Immunoseneszenz aufweisen. Als zum Teil ursächlich hierfür konnte ein reduzierter Thymusoutput festgestellt werden. Das Ziel der vorliegenden Studie war es, aufbauend auf Erkenntnissen von Six und Kollegen anhand einer Lymphozytenvorläuferzelle, die im peripheren Blut zirkuliert, in vivo in der Lage ist, den Thymus zu besiedeln und sich in reife T-Zellen zu entwickeln, den Thymusinput abzuschätzen, um eine defiziente Thymusbesiedlung als eventuelle Ursache des reduzierten Thymusoutput festzustellen. Hierzu wurde das Blut von 28 Patienten mit Rheumatoider Arthritis und altersentsprechenden gesunden Kontrollen mittels Durchflusszytometrie auf mehrere relevante reife T-Helferzellpopulationen, naive CD4+ T-Zellen und benannte lymphozytäre Vorläuferzelle untersucht. Es konnten dann direkte Vergleiche des prozentualen Anteils bestimmter T-Helferzellgruppen zwischen Erkrankten und Gesunden gezogen sowie Korrelationen verschiedener Zellgruppen untereinander hergestellt werden. Die gewonnenen Ergebnisse wurden mit der hierzu vorliegenden Literatur verglichen und diskutiert.

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Die Rheumatoide Arthritis (RA) ist eine chronisch-entzündliche Systemerkrankung des Bindegewebes mit autoimmunem Charakter. In dieser Studie wurden 7 Kandidatengene, welche in zentrale Abläufe der Apoptose involviert sind (CFLAR, XIAP, NFKB1, RELA, BCL2L1, FAS, FASLG), selektiert. Innerhalb dieser Gene wurden 23 Einzel-Basen-Polymorphismen (single nucleotide polymorphisms bzw. SNPs) sowie ein Insertions-Deletions-Polymorphismus in 300 französich-kaukasischen Individuen (100 RA-Trio-Familien) mittels Einzelbasenverlängerung (Single Base Extension bzw. SBE) in einer massenspektrometrischen Analyse durch MALDI-TOF-MS (Matrix Assisted Laser Desorption/Ionization–Time Of Flight Mass Spectrometry) genotypisiert. Die Auswahl der zu untersuchenden genetischen Polymorphismen erfolgte dabei unter Berücksichtigung einer möglichen funktionellen Bedeutung, bekannter Assoziationen mit RA oder anderer Autoimmunerkrankungen, der Lage im Gen sowie der genetischen Variabilität. Die Ergebnisse der Genotypisierung wurden genutzt um die Polymorphismen bzw. Kandidatengene mit Hilfe verschiedener statistischer Methoden auf ihre Assoziation mit RA hin zu untersuchen. Die statistischen Analysen des SNPs CFLAR-rs7583529 zeigten hierbei einen nicht signifikanten Trend, wobei das minor Allel A gehäuft in RA Patienten vorkam. Das Ergebnis des Genotypen-Tests (Lathrop) für FAS-rs1800682 belegte einen protektiven Effekt für homozygote Träger des major Allels C (Lathrop pval = 0.045). Unterstützung für die gefundenen Trends bzw. Assoziationen von CFLAR-rs7583529 und FAS-rs1800682 boten Vergleiche mit Daten genomweiter Studien (NARAC/EIRA- und WTCCC-Studie). In den Assoziationsanalysen von BCL2L1-rs3181073 zeigte sich ein protektiver Effekt des minor Allels A (TDT pval = 0.008, OR = 0.51 [0.3 – 0.9], OR pval = 0.014). Der Risikoeffekt des major Allels C spiegelte sich entsprechend im Lathroptest wider, welcher eine signifikante Anreicherung des homozygoten C/C-Genotyps in den Fällen anzeigte (Lathrop pval = 0.021). Die gefundenen Assoziationen von FAS und BCL2L1 mit RA gehen mit der Hypothese konform, dass veränderte Abläufe sowohl im intrinsischen mitochondrialen (BCL2L1) als auch im extrinsischen (FAS) Weg der Apoptose in die Ätiologie der RA involviert sind. Die Ergebnisse dieser Arbeit sollten in einer zweiten unabhängigen Kohorte repliziert werden. In Folgestudien wäre es ebenfalls interessant, weitere SNPs der Kandidatengene zu genotypisieren, um die genetische Variabilität anhand der Haplotypen genauer zu analysieren. Sollten sich die o. g. Assoziationen bestätigen, sind im Weiteren funktionelle Studien bezüglich unterschiedlicher Genexpression oder verändertem Apoptoseverhalten von Zellen oder synovialem Gewebe von großem Interesse. / Rheumatoid arthritis (RA) is a chronic inflammatory systemic disease of the connective tissue with autoimmune character. In this study, 7 candidate genes that are known to be involved in key processes of apoptosis (CFLAR, XIAP, NFKB1, REAL, Bcl2l1, FAS, FASLG) were selected. Within these genes, 23 single nucleotide polymorphisms (SNPs) and one insertion/deletion polymorphism were genotyped in a sample of 300 French Caucasian individuals (100 RA trio families) by means of Single Base Extension (SBE) and MALDI-TOF (Matrix Assisted Laser Desorption /Ionization–Time Of Flight) mass spectrometry analysis. The possible functional significance, known associations with RA or other autoimmune diseases, the location in the gene and genetic variability were taken into account during the selection of genetic polymorphisms. The SNP genotyping results were used to analyse associations of polymorphisms or candidate genes with RA by applying various statistical methods. Analysis of the SNP CFLAR-rs7583529 showed a non-significant trend toward increased frequency of the minor allele A in RA patients. The genotypic test (Lathrop) of FAS-rs1800682 revealed a protective effect for homozygous carriers of major allele C (Lathrop pval = 0.045). Data of genome-wide studies (NARAC/EIRA- and WTCCC study) provided further support for association of CFLAR-rs7583529 and FAS-rs1800682 like confirmed in this study. Association analysis of Bcl2l1-rs3181073 showed a protective effect of the minor allele A (TDT pval = 0.008, OR = 0.51 [0.3 - 0.9], pval OR = 0.014). The genotypic Lathrop-test in turn revealed a corresponding risk effect for homozygous C/C genotype carriers (Lathrop pval = 0.021). Within this study, associations of the apoptosis genes FAS and Bcl2l1 with RA were found out. These results further indicate that changes of the intrinsic mitochondrial (Bcl2l1) and extrinsic (FAS) apoptosis pathway are possibly involved in the etiology of RA. For confirmation, results of this study should be replicated in a larger independent cohort. It would also be of interest to analyze the genetic variability based on specific haplotypes of additional SNPs within candidate genes. If the aforementioned associations are confirmed, functional studies with regard to different gene expression or changed apoptosis initiation in cells or synovial tissue would be of interest.