A artrite reumatoide (AR) Ã uma condiÃÃo autoimune caracterizada por uma inflamaÃÃo das articulaÃÃes. As medicaÃÃes mais utilizadas no tratamento da AR sÃo drogas antireumÃticas modificadoras da doenÃa (DMARD), como o metotrexato (MTX) e agentes biolÃgicos, dentre estes os inibidores do fator de necrose tumoral alfa (anti-TNF-α). Trabalhos recentes relacionam estes fÃrmacos a um maior acometimento de infecÃÃes. O objetivo do estudo foi avaliar a ocorrÃncia de inflamaÃÃo, dor, cicatrizaÃÃo e presenÃa de infecÃÃes apÃs exodontias em pacientes com AR sob tratamento com anti-TNF-α e MTX que fizeram uso prÃ-operatÃrio ou pÃs-operatÃrio de amoxicilina. Os pacientes com AR foram distribuÃdos, de forma randÃmica, em dois grupos: grupo A (profilaxia antibiÃtica â utilizaram 4 cÃpsulas de 500mg de amoxicilina uma hora antes do procedimento) e grupo B (cobertura antibiÃtica- fizeram uso de uma cÃpsula de 500mg de amoxicilina de 8 em 8 horas por 5 dias). AlÃm desses, para fins de controle, um terceiro grupo foi formado por pacientes sem AR e sem prescriÃÃo de antibiÃticos. ApÃs avaliaÃÃo de exames hematolÃgicos e radiogrÃficos, foram realizadas 30 exodontias (13 pacientes com AR e 12 do grupo controle) por um mesmo operador nos 3 grupos. Esse operador, assim como os pacientes dos grupos A e B, desconhecia qual esquema de medicaÃÃo empregada. AvaliaÃÃes periÃdicas (24 horas, 72 horas, 7 dias, 14 dias e 30 dias apÃs o procedimento) foram feitas para identificar sinais clÃnicos e radiogrÃficos de infecÃÃo e de inflamaÃÃo. A avaliaÃÃo da cicatrizaÃÃo da ferida cirÃrgica foi feita atravÃs de mediÃÃes com um paquÃmetro nos intervalos de 24 horas, 72 horas, 7 dias e 14 dias. Para verificaÃÃo da sintomatologia dolorosa, utilizou-se uma escala visual analÃgica (VAS) que foi entregue aos pacientes apÃs a exodontia. Todos os pacientes fizeram 3 radiografias periapicais (antes da exodontia, com 24 horas e apÃs 30 dias) que foram digitalizadas e analisadas pelo software ImageJÂ com intuito de verificar o perÃodo cicatricial radiogrÃfico por meio da modificaÃÃo da Ãrea radiolÃcida alveolar. A maioria dos pacientes participantes foi mulheres, tanto no grupo controle (58,3%) quanto nos grupos A e B (83,3% e 100% respectivamente). Os nÃveis de plaquetas dos pacientes dos grupos A e B foram superiores aos do grupo controle (p=0,008). No que se refere aos sinais inflamatÃrios e de infecÃÃo, nÃo houve diferenÃa significativa entre os trÃs grupos, assim como nos Ãndices de dor e na cicatrizaÃÃo Ãssea avaliada radiograficamente, diferentemente dos Ãndices de cicatrizaÃÃo tecidual, onde os grupos A e B apresentaram menores Ãreas das feridas cirÃrgicas e melhor contraÃÃo das feridas que o grupo controle (p=0,005). Os pacientes dos grupos A e B apresentaram reparo Ãsseo, Ãndice de inflamaÃÃo e de infecÃÃo semelhantes ao grupo controle, entretanto, os parÃmetros de cicatrizaÃÃo tecidual nos grupos A e B foram superiores quando comparados ao grupo controle. Com isso, sugere-se que o uso da amoxicilina de forma profilÃtica seja o mais adequado e racional, uma vez que nÃo houve diferenÃa entre os esquemas antibiÃticos empregados. / Rheumatoid arthritis (RA) is an autoimmune condition characterized by an inflammation of the joints. The medications most commonly used in the treatment of RA are disease modifying antirheumatic drugs (DMARDs) such as methotrexate (MTX) and biological agents such as tumor necrosis factor alpha inhibitors (anti-TNF-α). These drugs are immunosuppressive and they are related to a higher incidence of infections. The aim of this study was to evaluate the occurrence of inflammation, pain, scarring, and the presence of infections after tooth extraction in patients with RA treated with anti-TNF-α and MTX that used pre or postoperative amoxicillin. The RA patients were divided randomly into two groups: Group A (antibiotic prophylaxis â a single dose of amoxicillin 2g orally, 1h prior to the procedure) and group B (postoperatively antibiotic - 500mg of amoxicillin 8/8h for 5 days). In addition, a third group was created for control purposes that consisted of patients without RA and with no prescription of antibiotics. After evaluation of hematologic and radiographic parameters were performed 30 extractions (13 patients with RA and 12 in control group) by a single operator. The distribution of medications was made randomly and double-blind. Periodic evaluation (1,3,7,14 and 30 days after the procedure) were taken in order to identify clinical and radiographic signs of infection, inflammation. The evaluation of wound healing was done through measurement with a caliper at intervals of 24 hours, 72 hours, 7 days, and 14 days. A visual analogue scale (VAS) was used for verification of painful symptoms which was delivered to the patients after the extractions. All patients had 3 periapical radiographs (before extraction, with 24 hours and after 30 days) that were digitized and analyzed by ImageJÂ software to verify radiographic healing period by modifying the alveolar radiolucent area. Most participants were women in control group (58.3%) and in groups A and B (83.3% and 100% respectively). Platelet levels of patients in groups A and B were higher than the control group (p = 0.008). In regard to inflammatory and infection signs, there was no significant difference between the three groups, as well as in pain levels and bone regeneration assessed radiographically, unlike tissue healing rates, where the groups A and B showed smaller areas of surgical wounds and the wounds contraction better than the control group (p = 0.005). Patients in groups A and B showed bone healing, inflammation and infection rate similar to the control group, however, the tissue healing parameters in groups A and B were higher when compared to the control group. In conclusion, it might be wise to suggest the use of amoxicillin prophylaxis considering rational antimicrobial use, since there was no difference between antibiotic regimens employed.

Rheumatoid arthritis (RA) is a complex autoimmune disease affecting approximately 1% of the population. Multiple factors contribute to the development of RA, with genetic factors accounting for around 60% of the disease risk. Over the last few years, genome-wide association studies (GWAS) have successfully been used to identify regions of the genome predisposing to complex disease. There are now 101 confirmed RA risk loci, but for the vast majority of these loci the causal gene and causal variant remain unidentified and therefore, their function in disease is unexplored. The majority of genetic variants, or single nucleotide polymorphisms (SNPs), associated with disease map to non-coding enhancer regions, which may regulate transcription through long-range interactions with their target genes. The aims of this project were to identify the causal genes within an RA locus, pinpoint the causal variants and elucidate the mechanisms by which the variants modify gene function. Capture Hi-C (CHi-C) was carried out with the aim of identifying long range interactions between disease-associated SNPs and genes in four related autoimmune diseases. Many long-range interactions were identified which implicated novel candidate genes, interactions involving multiple genetic loci which had a common target, and interactions with loci which had previously been implicated in disease. Complex interaction patterns were observed in many of the disease associated loci, particularly in the 6q23 locus which is associated with a number of autoimmune diseases and is the focus of the present thesis. Within the 6q23 locus, associated SNPs lie a large distance from any gene (>180kb) making it difficult to pinpoint the exact causal gene. Results from CHi-C and chromosome conformation capture (3C-qPCR) experiments indicated that restriction fragments containing disease associated intergenic SNPs could display genotype-specific interactions with genes associated with autoimmunity (IL20RA and IFNGR1). Interactions could also be detected with long non-coding RNAs (lncRNAs), The lead SNP in the 6q23 region is in tight LD with eight other SNPs which are equally likely to be causal. Bioinformatics analysis suggested that the most plausible causal SNP in the 6q23 intergenic region was rs6927172, as it maps to an enhancer in both B-cells and T-cells, is in a DNaseI hypersensitivity cluster, shows transcription factor binding and is in a conserved region. Chromatin immunoprecipitation (ChIP) demonstrated binding of chromatin marks of active enhancers (H3K4me1 and H3K27ac) and the transcription factors BCL3 and NF-κB to the rs6927172 SNP target site in Jurkat T-cells and GM12878 B-cells, suggesting the risk allele could be associated with increased regulatory activity. In conclusion, these results show that CHi-C can help identify novel GWAS causal genes with the potential to suggest novel therapeutic targets. For example IL20RA is already a target for a monoclonal antibody which has been shown to be effective in treating RA in clinical trials. This project has also provided compelling evidence that the autoimmune risk variant in the 6q23 locus, rs6927172, is within a complex gene regulatory region, involving multiple immune genes and regulatory elements, such as lncRNAs.

Abstract Rheumatoid arthritis (RA) is a systemic autoimmune disease with symmetrical articular manifestations. The etiology of the disease is unknown. The prevalence of RA is approximately 0.5–1.0% in adults. In Finland, the annual incidence is 39/100 000. RA is about three times more common in females than in males. Most commonly the disease affects first the joints of feet and fingers. Chronic inflammation leads to erosions of cartilage, bone and tendons and may destroy the whole joint. The diagnosis of RA is mainly based on the clinical features of the disease. The American College of Rheumatology (ACR) 1987 revised classification criteria of RA have commonly been used for diagnosis. No specific diagnostic test is available. Rheumatoid factor (RF) has traditionally been used in the diagnosis, but only 70 to 80% of RA patients have RF in their serum. Other antibodies found in RA are the antiperinuclear factor (APF), the anti-keratin antibody (AKA) and the antibodies to cyclic citrullinated peptide (CCP), which recognize the citrulline-containing antigenic filaggrin protein. Citrulline is an amino acid that is post-translationally formed from arginine by peptidylarginine deiminase enzymes (PADs). Autoantibodies to citrullinated proteins are more specific for RA than RF. There is no filaggrin in joints, which indicates that the autoantibodies reacting with this protein most probably only reflect immunological cross-reaction. It has been postulated that autoimmunity against collagens might be involved in the pathogenesis of RA. There are antibodies binding to collagen in cartilage (type II collagen) and in bone (type I collagen). They have been tested by using collagen preparations rendered soluble by pepsin digestion. This digestion removes the carboxyterminal (C-terminal) telopeptides of collagen. Autoantibodies to the C-telopeptides of type I and II collagens were studied in this doctoral research. Autoantibodies to the citrullinated C-telopeptides of type I and II collagens were found in the serum of patients with RA. ELISA, CLIA and inhibition ELISA were used to detect these autoantibodies. Automatic CLIA gives a more than twofold number of positive findings compared to previous ELISA. Currently the best method for the detection of these autoantibodies is inhibition ELISA. These autoantibodies are specific for citrulline in the peptide sequence. Autoantibodies that bind the normal C-telopeptides of type I and II collagens were not inhibited by soluble normal or citrullinated telopeptides. However, the antibodies that bind only citrullinated telopeptides could be inhibited by corresponding citrullinated telopeptides. Autoantibodies binding the citrullinated telopeptides of type II collagen and anti-CCP predict synergistically the development of seropositive RA. / Tiivistelmä Nivelreuma (arthritis rheumatoides) on krooninen autoimmuunisairaus, jonka aiheuttajaa ei tunneta. Nivelreuman esiintyvyys aikuisilla on 0.5–1.0 prosenttia. Siihen sairastuu vuosittain 39/100 000 suomalaista aikuista. Naiset sairastavat nivelreumaa kolme kertaa yleisemmin kuin miehet. Sairaus alkaa tavallisesti päkiöistä ja sormien nivelistä. Nivelreuma aiheuttaa ruston, luun ja nivelsiteiden syöpymistä ja voi lopulta tuhota koko nivelen. Nivelreuman diagnoosi perustuu pääasiassa taudin kliinisiin piirteisiin. Yhdysvaltain reumajärjestön (American College of Rheumatology, ACR) vuonna 1987 esittämät luokittelukriteerit ovat yleisesti käytössä. Taudin toteamiseen ei ole spesifistä laboratoriotestiä. Perinteisesti käytettyä reumatekijää esiintyy 70–80 prosentilla potilaista. Muita nivelreumapotilaan seerumista esiintyviä vasta-aineita ovat antiperinukleriaaritekijä (APF), keratiinivasta-aineet (AKA) ja vasta-aineet sykliseen sitrullinisoituneeseen peptidiin (CCP). Sitrulliini on aminohappo, jonka peptidyyliarginiini deiminaasi -entsyymit (PAD) ovat muokanneet arginiinista posttranslationaalisesti. Sitrullinisoituneiden proteiinien autovasta-aineet ovat spesifisempiä nivelreumassa kuin reumatekijä. Nivelissä ei ole filaggriinia, mikä viittaa siihen, että todetut vasta-aineet perustuvat immunologiseen ristireaktioon. On epäilty, että nivelreuman patogeneesiin voisi liittyä autoimmuniteettia kollageeniin. Aiemmin tutkitut luun ja ruston (tyypin I ja II) kollageenivasta-aineet eivät ole olleet sitrullinisoituneita. Autovasta-ainetesteissä on käytetty pepsiinidigestiota, jolla kollageeni on saatu liukoiseksi. Pepsiinidigestio tuhoaa kuitenkin kollageenin karboksyyliterminaaliset (C-terminal) telopeptidit. Tässä väitöskirjatutkimuksessa tutkittiin tyypin I ja II kollageenien C-telopeptidejä. Nivelreumapotilaiden seerumissa todettiin autovasta-aineita, jotka sitoutuvat sitrullinisoituneisiin tyypin I ja II kollageeneihin. Todettuja vasta-aineita voidaan osoittaa ELISA-, CLIA- ja inhibitio-ELISA-menetelmillä. Automaattisella CLIA:lla saadaan kaksi kertaa enemmän positiivisia löydöksiä kuin aiemmin kehitetyllä ELISA:lla. Tällä hetkellä paras menetelmä näiden autovasta-aineiden osoittamiseen on inhibitio-ELISA. Todetut vasta-aineet ovat spesifisiä peptidin sekvenssissä olevaan sitrulliiniin. Vasta-aineita, jotka sitoutuvat normaaliin tyypin I ja II kollageenien C-telopeptidiin, ei voida inhiboida liukoisella normaalilla eikä sitrullinoidulla telopeptidillä. Kuitenkin vasta-aineita, jotka sitoutuvat vain sitrullinisoituihin telopeptideihin, voidaan inhiboida vastaavalla liukoisella sitrullinisoidulla telopeptidillä. Autovasta-aineet, jotka sitoutuvat samanaikaisesti sitrullinisoituneeseen tyypin II kollageenin C-telopeptidiin ja anti-CCP:hen ennustavat seropositiivista nivelreumaa.

Magister Psychologiae - MPsych / This study explored women's perceptions of how their illness (Rheumatoid Arthritis- RA) affects their relationship with their intimate life partner. RA is a chronic, inflammatory, auto-immune illnes, which mainly affects the synovial membranes of multiple joints. This highly inflammatory poly-arthritis may lead to joint destruction, chronic pain, deformity and loss of functioning as unfortunate outcomes of the established illness. RA affects key life domains such as psychological well-being, social well-being, family and couple relationships, employment, loss of independence and restrictions in daily functioning. / South Africa

Rheumatoid Arthritis (RA) is the most common type of chronic inflammatory arthritis (Thompson, 1998). When appropriately prescribed, therapeutic exercise is useful in the care of patients with RA (Semble et aI., 1990). A pre-test - post-test randomized groups design was adopted for the study to compare the effects of a land- and water-based exercise programme in RA patients. A total of ten subjects, diagnosed with RA functional class I or II according to Steinbrocker, were assigned to either a group performing water-based exercises (W, n=4), a group performing land-based exercises (L, n=4), or a control group, who were requested to continue with their present sedentary lifestyle (C, n=2). For inclusion in the study, subjects were required to be on stable medication. Categories of dependent variables measured, were disease activity, haematology, functional and psychological status as well as physical status. There was a reduction in total swollen and tender joint counts in both experimental groups, but not the control group. The reduction was greater in group W than group L. Total tender joint count (DC) decreased by 53% (p<0.1O) and the total swollen joint count (SJC) decreased by 31% (p>0.05) in group W. In group L, the total TIC decreased by 4,7% (p>0.05) and the total SIC decreased by 8,5% (p>0.05). The haematological values remained globally unchanged in all three groups concerning the hemolglobin (Hb) values. There were changes in the erythrocyte sedimentation rate (ESR) in the groups, however changes were not significant (p>0.05). The ESR decreased by 29% in group Wand by 33% in group C. There was a slight increase in group L's ESR (11,9%) but values remained within the normal range. There was an improvement in the patients self-assessed disability and psychological status in the experimental groups while there was a deterioration in the control group's. Health Assessment Questionnaire (HAQ) scores improved by 15% in group W (p>0.05), 18% in group L (p>0.05) and deteriorated by 13% in group C (p>0.05). There was no change in the total Profile of Mood States (POMS) score of the control group, however, significant (p<0.05) improvements were observed in the experimental groups. There was a 163% improvement in group L's and a 990/0 improvement in group W's affective states. As far as physical condition is concerned, in genera~ there was an improvement in group Wand group L's physical condition, while there was no improvements noted in group C. Group W showed the following changes in physical condition: Body mass decreased by 9,2% (p>0.05). Mean blood pressure values remained unchanged. 50-ft walk time improved by 18% (p<0.05). Right and left grip strength increased by 18% and 35% respectively, (p<0.05). Absolute VO2max increased by 28% and relative VO2max increased by 30% (p<0.05). Right knee flexor strength increased by 43% (p<0.05) and left knee flexor strength by 24% (p>0.05). Increases in right and left knee extensor strength were 32% (p>0.05) and 34% (p>0.05) respectively. Improvement in joint mobility was also noted. There was a significant (p<0.05) improvement in both right and left wrist extension range of motion(ROM). Right wrist extension ROM improved by 49% and left wrist extension ROM improved by 31%. Improvements were also noted in wrist flexion ROM however changes were not significant (p>0.05). There was an 12% and 19% increase in right and left wrist flexion ROM respectively. In addition, there was a 12% (p<0.05) increase in right knee flexion ROM and a 14% increase in left knee flexion ROM (p<0.05). Mean body mass and blood pressure remained unchanged. 50-ft walk test time improved by 15% (p<0.05). Right and left grip strength increased by 4,8% and 16.1% respectively (p>0.05). Relative VO2max increased by 16.6% and absolute VO2max by 31% (p<0.05). Right knee flexor strength increased by 22.1% and left knee flexor strength by 23.8% (p>O.05). Increase in right and left knee extensor strength was 9% and 2,4% respectively (p>O.05). Right wrist extension ROM increased by 20.7% and left wrist extension ROM increased by 15,7% (p>0.05). There was a significant (p<0.05) increase in left wrist flexion (7,6%), but right wrist flexion ROM decreased by 2.6% (p>0.05). Improvements in right and left knee flexion ROM were also significant (p<0.05), 9,2% and 7,4%, respectively. Group C showed the following changes in physical condition: Mean body mass increased by 2% (p>O.05), while blood pressure and 50-ft walk time remained globally unchanged. Left grip strength decreased by 16% (p>O.05) and right grip strength remained the same. Although not significant (p>O.05), there was a 11% decrease in relative VO2max and a 6,7% decrease in absolute VO2max. Muscle strength also showed deterioration in group C. Right and left knee flexor strength decreased by 1,8% and 12%, respectively (p>0.05). Left knee extensor strength remained unchanged while right knee extensor strength decreased by 9,7% (p>0.05). Right wrist extension ROM decreased by 4.7% and left wrist extension ROM increased by 6.7%, although the increase was not significant (p>O.05). While right wrist flexion ROM decreased by 1,3% and left wrist flexion ROM decreased by 21% (p>0.05). There were no significant (p>O.05) changes in group C's right and left knee flexion ROM. Right knee flexion ROM decreased by 1,2% and left knee flexion ROM increased by 1,2%. Based on the above results of the study, both exercise interventions are beneficial in the treatment of RA. Appropriate land-based exercises do not appear to enhance disease activity, however, the water-based exercise programme was superior in controlling the disease activity. Further research is required, using larger samples and evaluating the long-term effects of various exercise interventions. / Dissertation (MA (Human Movement Sciences))--University of Pretoria, 2006. / Biokinetics, Sport and Leisure Sciences / unrestricted

AimThe broad aim of this thesis was to explore the risk of malignancy in people with rheumatoid arthritis (RA), treated with anti-tumour necrosis factor (TNF) drugs.MethodsThis thesis used data from patients with RA registered with the British Society of Rheumatology Biologics Register-RA. The risk of cancer in biologic-naive patients treated with traditional disease modifying drugs (nbDMARD) was compared to that in the general population by calculating standardised incidence ratios (SIR). The influence of anti-TNF on cancer risk was then explored by comparing the risk in the anti-TNF cohort to that in the nbDMARD cohort using Cox proportional hazard models.ResultsThe risk of cancer was increased in the nbDMARD cohort by 28% compared to the general population (SIR 1.28, 95% confidence interval (CI) 1.10, 1.48). Risks of lung cancer (SIR 2.39, 95% CI 1.75, 3.19), Hodgkin lymphoma (SIR 12.82, 95% CI 4.16, 29.92) and Non-Hodgkin Lymphoma (SIR 3.12, 95% CI 1.79, 5.07) were increased compared to the general population and both prostate cancer and cancers of the female genital organs reduced; SIRs 0.35 (95% CI 0.11, 0.82) and 0.35 (95% CI 0.10, 0.90) respectively. There was no difference in the risk of cancer in patients treated with anti-TNF compared to nbDMARD, after adjusting for differences in baseline characteristics; Hazard ratio for lymphoma: 1.00 (95% CI 0.49, 2.05); cancers of the solid organs: 0.83 (95% CI 0.64, 1.07); and keratinocyte skin cancer: basal cell carcinoma 1.06 (95% CI 0.64, 1.75), squamous cell carcinoma 1.62 (95% CI 0.44, 5.90). ConclusionsSubjects with RA, treated with nbDMARD were at increased risk of cancer compared to the general population. In particular, lung cancer, lymphoma and KSC were increased. Treatment with the TNF inhibitors ETA, INF or ADA was not associated with a difference in relative risk of lymphoma, solid cancer or skin cancers when compared to nbDMARD.

Introduction: Involvement of the forefoot is common among patients with Rheumatoid Arthritis. It results in severe deformities with significant disabilities. Aim: The aim of this study was to compare and assess in patients with Rheumatoid Arthritis in a South African population the outcomes of severe forefoot deformity reconstruction surgery in the short- to medium-term and in particular focusing on radiological, clinical, and functional outcomes. Patients and Methods: A retrospective review of 19 patients who received reconstructive forefoot surgery for forefoot deformities resulting from Rheumatoid Arthritis was undertaken. They all underwent Modified Hoffman Surgical Reconstruction (first MTPJ fusion and lesser toe resection arthroplasty). The patient records between 2013 and 2016 were reviewed. Pre-operative and post-operative outcome scores were collected. Final postoperative radiographs were analyzed. Patients completed Short Form 36 and AOFAS forefoot scores. Post-operative scores were collected 6 months post-op. Results: There were 19 patients in the study with a minimum 6 months follow up. Of the 19 patients 17 (89.5%) were females and 2 (10.5%) males. The mean age was 54.9 ± 9.6 years (range: 34 – 69 years). Most patient outcomes (SF36, AOS alignment, VAS Pain percentage, and VAS Disability percentage) significantly improved with a p value < 0.05, when comparing the pre-operative versus post-operative variable scores. However, only AOS Alignments showed no significant difference between pre-operative and post-operative scores (p>0.05). Conclusion: Reconstructive forefoot surgery with the Modified Hoffman Surgical Reconstruction provides marked radiological correction, with significant improvements in the quality of life of the cohort of patients.

京都大学 / 新制・課程博士 / 博士(医学) / 甲第24190号 / 医博第4884号 / 新制||医||1060(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 伊藤 能永, 教授 安達 泰治, 教授 椛島 健治 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

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