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.

BACKGROUND: Rheumatoid arthritis (RA) is an autoimmune disease that causes inflammatory polyarthritis, typically of the small joints. Obesity, a serious global epidemic, has been shown to increase systemic inflammatory biomarkers, several of which are related to RA pathophysiology. Associations have been observed between obesity and worsened RA disease activity outcomes in crosssectional studies. Limited longitudinal studies investigated the effects of weight change on RA disease activity measures. Surgical interventions for weight loss in RA patients showed marked improvement in RA disease activity measures and outcomes but typical weight change in a clinical setting has not been investigated. OBJECTIVE: To investigate the impact of typical weight change on RA disease activity measures. METHODS: We conducted a retrospective cohort study on 178 RA patients seen in typical clinical practice that met the inclusion criteria for the study, which included patients with a minimum of two clinical disease activity assessments (CDAI) with corresponding body mass index (BMI) measures. Medical record review was conducted for each clinic visit where CDAI and BMI were measured, and at each of these visits, sociodemographic, lifestyle, medication usage, questionnaire data, RA characteristics, laboratory values, and comorbidities were collected. Linear regression was used to analyze the association between ΔBMI and ΔCDAI, defined at the dates of minimum and maximum BMI for each subject, adjusting for confounders including sex, age, disease duration, smoking status, serologic status, and steroid usage. Logistic regression was performed to evaluate whether ΔBMI was associated with low/remission RA disease activity according to accepted CDAI cutoffs. RESULTS: Unadjusted linear regression was performed on all 178 subjects to analyze the overall trend within the sample population. For every 1 kg/m2 increase in BMI, CDAI increased by 0.49 points, but these results were not statistically significant (p=0.155, 95%CI -0.176, 1.097). Subjects were stratified into BMI gain, stable, and loss groups. Within the BMI loss group (defined as those whose BMI decreased by more than 1 kg/m2), a significant association was found with ΔCDAI (β= -2.61 [p=0.028, 95%CI -4.91, -0.298]). Unadjusted linear regression on the BMI gain and stable groups was found to be not statistically significant. This association remained significant after adjusting for sex, age, disease duration, smoking status, serologic status, and steroid usage (β=-2.499 [p=0.044, 95%CI -4.94, -0.061]). There was no association between ΔBMI and low/remission RA disease activity (OR 0.990, (95%CI 0.855, 1.146). When stratified by BMI gain, stable, and loss groups there was no significant association with low/remission RA disease activity. CONCLUSION: These results suggest that weight loss may be associated with improved disease activity among patients with RA seen in a typical clinical setting. Weight loss has the potential to be a non-pharmacologic intervention to improve RA disease activity. Prospective studies of weight loss and RA disease activity are necessary to replicate these results.

Osteoarthritis (OA) currently affects 41 million Americans, and knee OA (KOA) alone causes the highest risk of mobility disability of any medical condition in people 65 years and older. There are no current treatments to reverse the degenerative changes of KOA, and research is aimed at finding biomarkers of KOA progression to aid in the development of effective therapies. Osteophytes are a hallmark feature of KOA and may act as a biomarker of joint space loss and pain progression. MR imaging, which is an accurate and non-invasive method to monitor KOA disease status, may aid in clarifying the role of osteophytes in KOA, especially using semi-automated quantitative software methods to accurately and efficiently calculate osteophyte volume in longitudinal studies. This study investigated the association of osteophyte volume change with joint space narrowing and pain progression in a randomized sample of 505 subjects from the FNIH OA Biomarker Consortium Project, a case-control study based on a larger longitudinal study of patients with KOA. We also aimed to further validate a software method that measured osteophyte volume in MRI. We found a moderate and significant association with osteophyte volume and joint space narrowing, but no significant association with pain progression. The software was further validated as responsive and efficient method to measure KOA osteophyte volume change.

The skeleton is a dynamic organ that undergoes a continual process known as bone remodeling. Bone remodeling is necessary to maintain structural integrity, heal micro-fractures caused by from daily wear and tear, and to store and release essential ions and minerals. Remodeling is a highly regulated process, with bone resorption precisely balanced by bone formation under homeostatic conditions. In the setting of rheumatoid arthritis (RA), an inflammatory condition affecting joints, this balance is lost and bone around inflamed joints is eroded. These so-called "bone erosions" compromise joint function, causing disability. Osteoclasts, multinucleated cells of hematopoietic origin, are the only cells known to resorb bone. Osteoclasts are found at erosion sites in human joints, and data from mouse models of inflammatory arthritis suggest that osteoclasts are required for erosions to form in bone. The canonical pathway of osteoclast differentiation requires stimulation of myeloid precursors by the cytokine Receptor Activator of NF-Kappa B ligand (RANKL) through its receptor, RANK. In the inflamed joint, RANKL expression can be induced on mesenchymal lineage cells by inflammatory cytokines such as tumor necrosis factor alpha (TNF alpha). Surprisingly, our lab observed bone erosions and osteoclast formation in a mouse model of RA in the absence of RANK. Thus we hypothesized that in addition to RANKL expression, the cytokine milieu in RA may directly stimulate osteoclast formation. It was recently reported that the inflammatory cytokines TNF alpha and interleukin-6 (IL-6) in combination stimulate osteoclast differentiation, independent of exogenous RANKL. We have reproduced these results and shown that these osteoclast-like cells form entirely independently of RANK signaling. However, TNF alpha/IL-6 induced osteoclast formation still requires the transcription factor Nuclear Factor of Activated T cells (NFATc1), a master regulator of RANK-mediated osteoclast differentiation, as well as co-stimulatory signaling provided by the immunoreceptor tyrosine based activation motif (ITAM)-containing DNAX-activating protein (DAP12) molecules. We also showed that TNF alpha/IL-6 induced osteoclast formation requires activity of IL-6 receptor (IL-6R), as osteoclast formation can be inhibited through co-culture with an IL-6R blocking antibody (MR16-1). Finally, using an in vivo mouse model of RA in RANK-deficient mice, we tested whether blocking IL-6R with MR16-1 antibody protects against the formation of periarticular bone erosions. Our results suggest that a RANK-independent pathway of osteoclast formation contributes to inflammatory bone erosions. Targeting this pathway may improve outcomes for RA patients.

Introdução: A Artrite Idiopática Juvenil (AIJ) inicia-se principalmente no intervalo etário de oito a catorze anos, podendo estar associada a déficit de crescimento e atraso puberal. O estadiamento de Tanner e a avaliação ultrassonográfica da pelve podem detectar atrasos no desenvolvimento puberal. Objetivos: Comparar a maturação sexual das meninas com AIJ a controles saudáveis, por meio da avaliação clínica dos estágios de Tanner e dos parâmetros da ultrassonografia (US) pélvica e relacionar esses achados aos níveis de hormônios sexuais e fatores relacionados à doença. Comparar, também, os dados antropométricos e a idade da menarca entre os dois grupos e relacioná-los a fatores de risco ligados à AIJ. Delineamento: Estudo transversal com grupo controle Metodologia: O estudo foi realizado com 44 meninas com AIJ e 59 controles com idades entre seis e dezoito anos incompletos, sem uso de glicocorticoides há no mínimo seis meses e sem outras doenças crônicas concomitantes. O diagnóstico de AIJ foi realizado de acordo com critérios da Liga Internacional das Associações de Reumatologia (ILAR). Foi realizada avaliação antropométrica, e a maturação sexual foi avaliada por meio dos estádios de Tanner. A US pélvica abdominal foi utilizada para avaliar as medidas do útero dos ovários e o índice de pulsatilidade das artérias uterinas (IP). Foram medidos níveis hormonais de FSH, LH, estrógeno, progesterona e IGF-1 nas meninas com AIJ. Resultados: Os parâmetros da US pélvica foram correlacionados aos estágios de Tanner no grupo controle (p <0,001). Todas as medidas de útero e ovários foram menores nas meninas com AIJ quando comparadas ao grupo controle. A média do IP das artérias uterinas foi maior nas meninas com AIJ. Estratificando-se por idade, o volume do útero foi menor nas meninas com AIJ na faixa etária de 10-11 anos (p < 0,004) e 14-15 anos (p=0,042), e a relação corpo/cérvice AP foi menor no intervalo de 10-11 anos (p=0,007). Os níveis de LH e estradiol foram fortemente relacionados ao aumento dos órgãos pélvicos (p<0,001) e inversamente com IP médio das artérias uterinas (p<0.01). O escore z do IMC e da estatura foi menor nas meninas com AIJ em relação ao grupo controle (p=0,032 e p=0,041 respectivamente). As meninas com AIJ poliarticular e com maior dose cumulativa de glicocorticoide apresentaram a maior chance de ter baixa estatura. Não houve diferença entre os grupos AIJ e controles com relação à idade da menarca. A altura final e a diferença entre essa altura e a altura-alvo familiar não foi diferente entre as meninas com AIJ e as do grupo controle. Conclusão: Nosso estudo mostrou que, mesmo sem uso de glicocorticoide há mais de seis meses, as crianças com formas mais graves de AIJ e que necessitaram de doses maiores de glicocorticoide estão mais suscetíveis ao retardo no crescimento e atraso no início da puberdade. A US pélvica demonstrou ser um exame sensível para avaliação da maturação sexual de meninas, identificando atrasos nas meninas com AIJ não percebidas por meio da avaliação clínica pelos estágios de Tanner. / Introduction: Juvenile Idiopathic Arthritis (JIA) manifests at the 8 to 14-year age span and is often associated with growth deficit and puberty delay. Tanner staging and pelvic ultrasonography (US) can be used to detect pubertal delays. Objectives: To compare sexual maturation in JIA girls and healthy controls (HC) by clinical evaluation with Tanner stages and pelvic US parameters and to correlate these findings with sexual hormone levels and disease related factors. Additionally, to compare anthropometric data and menarche age between groups and to correlate such findings with disease related risk factors in JIA patients. Study design: Cross-sectional study. Methods: 44 JIA and 59 healthy girls, aged six to 18 years, free of steroid use in the last six months and with no concomitant chronic diseases were included the study. JIA was diagnosed after the International League of the Rheumatology Associations (ILAR) criteria. Anthropometric and sexual development evaluations by Tanner staging were performed Pelvic US was performed to measure uterus, endometrial thickness, ovaries and uterine artery pulsatility index. Sexual hormone levels were measured in JIA girls. Results: Pelvic US parameters correlated with Tanner stages in HC (p <0.001). All uterine and ovarian measurements were smaller in JIA girls than in HC. Mean uterine artery PI was greater in JIA girls. Uterine volume was smaller in JIA girls at the 10 to 11 (P=0.004) and 14 to 15 year (p=0.042) age strata and the anteroposterior body cervix ratio was smaller in JIA girls the 10 to 11 year stratum (p=0.007). LH and estradiol levels were strongly correlated with pelvic organ size. (P<0.001) and inversely correlated with mean uterine artery PI (p<0.01) BMI and height for age z scores were smaller in JIA girls than in HC. Polyarticular JIA girls and those that had received greater steroid doses had the largest chance to have short stature. There was no difference between JIA girls and HC regarding menarche age. Final height and the final height/target height difference was not different between JIA girls and HC. Conclusion: The current study showed that JIA girls from the most severe subtypes and those that had received the largest steroid cumulative doses were more susceptible to growth and puberty delays, even six months after drug withdrawal. Pelvic US was a sensitive tool in detecting sexual development in girls, being able to identify puberty delays, unsuspected by Tanner stage evaluation.

Objectives: The purpose of this study is to advance the understanding of secondary conditions experienced by persons aging with the long-term disabilities of polio and rheumatoid arthritis and the consequences of these declines in health and function on disability bed days. Additionally, it explores the effects of the timing and severity of onset of disability characteristics on the frequency and consequences of secondary conditions. A life course conceptual framework with the Institute of Medicine’s model of disablement is used to frame and anchor disability and life events. Methods: In-depth structured in-home interviews were conducted on 216 individuals with polio and 186 individuals with rheumatoid arthritis. They consisted of objective and subjective self-reports of current status and prior condition. The survey was a regional crosssectional, group comparison design with a cross-sequential sampling and data analytic framework. Scale development for data reduction was utilized to obtain parsimonious measures for the models. Linear regression was then performed to test the models for three outcome variables (number of chronic secondary conditions, increases in functional limitations and number of disability bed days in six months) in a theorized order for the polio and RA samples individually. Results: There was partial support for within-sample hypotheses for both polio and rheumatoid arthritis regarding interrelationships and disability bed days in past six months. No significant differences were found across subsamples for the effects of timing and severity of onset of disability characteristics, predicting chronic secondary conditions, predicting increase in functional limitations, and the number of disability bed days in six months. Similarities were found between the two samples when examining subgroup predictors on the three outcomes above. Chronic secondary conditions predicted (p<.05 for both subsamples) increase in functional limitations and increase in mobility was a significant predictor (p<.001 for both subsamples) of increase in functional limitations. Discussion: There were limited findings for these data. Judgment must be withheld with respect to the hypotheses. The analyses did not yield enough predictive strength to make comparisons possible across subsamples. Likewise, in examining similarities, only general, descriptive statements could be made. The subjective nature of disability is an immense challenge in cross disability research for comparability within disabilities and across disabilities.

RA is a chronic and disabling disease with no known cure. The disease has a strong genetic component and modern genetic studies have successfully identified over 100 loci associated with the onset of RA. Despite the number of associations identified, the full genetic component of RA is not known, and for the majority of the loci the causal variant remains unknown. The overall aim of this study was to utilise well-powered genetic data, in order to identify novel loci, refine genetic associations, and generate robust evidence for the causal SNP and causal gene at a selected RA locus. An initial analysis was undertaken utilising 3870 RA cases and 8430 controls from the UK-ImmunoChip, a study designed for comprehensive fine-mapping of confirmed RA susceptibility loci. Analysis of the UK-ImmunoChip data identified a novel finding with the TYK2 locus, and proved informative to refining association signals, illustrating the utility of fine-mapping and implicated SNPs with putative regulatory function. The UK-ImmunoChip was subsequently expanded to incorporate samples from five additional cohorts in a study led by Dr. Stephen Eyre. In additional to novel loci discovery, this study provided evidence for SNPs putatively associated with RA (P smaller or equal to5E-05 < 5E-08). In a combined meta-analysis of 17,581 cases and 20,160 controls, convincing evidence was obtained for two novel RA loci, BACH2 and RAD51B.The newly identified genes implicate two novel pathways in RA (B-cell differentiation and DNA repair) and add to the growing number of loci associated with multiple AIDs. These findings are important to aid comprehensive pathway analysis and add to the knowledge of RA risk genes. The third most associated RA locus in both serological subtypes of disease, with an uncharacterised protein, ANKRD55, was subsequently selected for in-depth characterisation. Utilising genetic and haplotypic analysis the association at this locus was refined to a single signal, with four SNPs in strong LD (r2 > 0.8). Through bioinformatic analysis, two SNPs rs6859219 and rs10065637 showed evidence for functional activity, with evidence of being located in an enhancer element, supported by histone marks, DNAse hypersensitivity, evidence of transcription factor binding and eQTL. The use of RNA and ChIP experiments have established a testable hypothesis that the presence of the putative causal variants rs6859219 and rs10065637, act to weaken the strength of the enhancer element in which they are located, (evidenced by diminished H3k4me1 modification), which in turn down-regulates the transcriptional output of the target gene ANKRD55 (evidenced by eQTL in both whole blood and CD4+ T cells).In summary this study has led to the identification of three novel loci, highlighted the importance of fine-mapping and developed a successful systemic strategy for the characterisation of the 5q11 risk locus associated with RA.

Abstract   Introduction Failure in the mechanism of self-tolerance in T or B cells can lead to autoimmunity. One of the autoimmune diseases is rheumatoid arthritis (RA), which is a chronic inflammatory disease of unknown cause and is characterized by systemic inflammation, autoantibodies and joint destruction. Serology is crucial for the classification of this disease. The first autoantibody found in RA patients was Rheumatoid factor (RF). However, anti-citrullinated peptide antibodies (ACPAs), a relatively new group of autoantibodies found in 70-90% of RA patients, are diagnostically more specific than RF. Type II collagen (CII) is the most abundant protein in human cartilage. In RA patients, immunity against CII leads to cartilage degradation and loss of joint function. Already from the 1970s, antibodies to CII (anti-CII) were found in RA sera, suggesting that CII autoimmunity might be pathogenetically important. Previous studies from our group show that a subgroup of patients with high levels of anti-CII at the time of diagnosis at the same time have high levels of inflammation in the joints. This is probably caused by anti-CII immune complexes (IC) inducing pro-inflammatory cytokines from macrophages. Although anti-CII positive patients have high inflammatory activity early on, as anti-CII levels decrease during the first year, the associated inflammation also diminishes. Thus, anti-CII positive patients have a rather good prognosis. Moreover, it is assumed that since anti-CII positive patients have a better prognosis than ACPA positive, patients with elevated anti-CII at the time of diagnosis might benefit from different and milder treatment. Previous studies from the group were performed on stored patient samples from the time before modern treatments with biologic agents (1995-2005). In this study, we aimed to investigate patients belonging to a more recent RA cohort, diagnosed between 2005-2014, with the aim to investigate whether patients with the anti-CII-associated RA phenotype would respond differently depending on the use of different modern RA therapies. Patients and Methods The primary cohort consisted of 2335 RA patients and 480 non-RA controls from the Epidermiological Investigations in Rheumatoid Arthritis (EIRA) case-control study. As we run into methodological problems two subgroups with 62 and 40 RA patients from the previous anti-CII studies were investigated when modifying the ELISA procedure, as well as a group of earlier investigated patients with non-specific ELISA reactivity. Totally 2776 RA patients were investigated. All investigated patients fulfilled the American College of Rheumatology classification criteria. To measure the anti-CII levels in RA patients and healthy controls anti-CII ELISA was performed. During the experiments, several different sources of CII from human, rat and bovine origin, and two different alternative coating buffers were used. The optical density (OD) was measured at 450 nm and anti-CII concentrations were calculated against the standard curve from an RA patient with high anti-CII levels.   Results My first analysis of the EIRA cohort showed that anti-CII are higher in RA patients than in controls, but could not confirm the association with acute onset RA. This was an unexpected finding and changed the focus of this master thesis project, to modify the measurement of anti-CII. Re-investigation of EIRA I showed that a proprietary coating buffer is important in the assay. Moreover, when different samples from RA patients were tested with bovine, rat and three different lots of human CII, correlation tests with clinical measures showed that bovine collagen and a new lot of human CII- prepared by the supplying company solely for this project- showed the strongest associations. Thereafter the EIRA cohort was re-investigated with two ELISAs, using bovine and human CII coated with the proprietary buffer. At the time of thesis writing almost all of the EIRA samples have been re-analysed, and results from both the modified ELISAs show the awaited clinical associations to early inflammation.   Conclusion Keeping the integrity of triple helical collagen is very important for the identification anti-native CII in RA patients. Our results show that the use of the proprietary coating buffer appears to be instrumental in this assay, irrespective of what source of CII was used. The new lot of human CII shows significant associations with the clinical measures, but associations are somewhat stronger with bovine CII. After finalising the re-investigations, we will be able to conclude which of the two analyses is most appropriate, and the corresponding dataset will then be merged with data from the first part of the EIRA study investigated previously by other group members. As anti-CII analysis shows the association to disease activity and prognosis, it can be used for predicting prognosis of RA and choosing the appropriate therapy in newly diagnosed RA patients, which might be clinically useful for rheumatologists. Our hypothesis is that as anti-CII positive patients have strong early inflammatory response but good long-term prognosis, they might benefit from other and perhaps short-term treatment compared to other RA patients.  If this is correct, our finding can have impact on the economy as it can define the patients who will not need expensive long-term medications. As modern anti-rheumatic therapies carry the risk of infections, such individualized therapies might also benefit anti-CII positive patients.

No description available.

O objetivo deste estudo foi adaptar e validar o Foot Health Status Questionnaire (FHSQ) avaliando suas propriedades de medida. Este instrumento foi traduzido, traduzido de volta para o inglês, avaliado por comitê multidisciplinar e submetido a pré-teste, gerando o FHSQ-Br. O FHSQ-Br foi submetido a teste de campo em um grupo de estudo composto por 65 pacientes com Artrite Reumatóide (AR) para avaliar a confiabilidade teste-reteste, a consistência interna e a validade do construto. A validade do construto foi testada correlacionando os escores do instrumento com dados clínicos e laboratoriais usados para avaliar a AR. Este estudo demonstrou que o FHSQ-Br é um instrumento confiável, consistente e válido, útil na avaliação da saúde dos pés, sendo passível de adaptação para diferentes culturas / The purpose of this study was to conduct a cross-cultural adaptation and validation of the Foot Health Status Questionnaire (FHSQ) evaluating its measurement properties. All ten domains of the FHSQ were translated into Portuguese by two Brazilian translators creating Version 1. This version was back-translated by two native English-speaking teachers who made suggestions for Version 1, creating Version 2. A multidisciplinary committee was formed to test the instrument’s semantic, idiomatic, experiential and conceptual equivalences. After being reformulated and approved by the committee, Version 3 was pre-tested on a group of patients from the Rheumatology Service of the Hospital das Clínicas. They answered this version and made suggestions for the better understanding of the instructions, questions and response option. The FHSQ-Br was then created. The translated and adapted version was submitted to field test on a study group composed of sixty-five Rheumatoid Arthritis (RA) patients to evaluate test-retest reliability, internal consistency and construct validity. The construct validity of the FHSQ-Br was tested correlating the scores to clinical and laboratory parameters commonly used to assess RA (Health Assessment Questionnaire; Numbered Rating Scale for foot pain; foot X-rays; erythrocyte sedimentation rate and C-reactive protein). The cultural adaptation of the FHSQ was successfully accomplished, since patients suggested changes in only three items of the instrument during the pre-test phase. In the field test, the intra-class correlation coefficients showed high reliability for both intra- and inter-observer correlations. Internal consistency coefficients were statistically significant (p<0.05) for all domains. As for the evaluation of the construct validity, each domain revealed correlations with a specific group of parameters, according to what the domains were intended to measure. The FHSQ was cross-culturally adapted generating a reliable, consistent and valid instrument. This study has proven the FHSQ-Br to be a useful tool to evaluate foot health in systemic diseases and is easily adaptable to different cultures