Dissertations / Theses on the topic 'Rheumatology and arthritis'

Inflammatory arthritis (IA) types such as rheumatoid arthritis (RA), juvenile idiopathic arthritis (JIA) and psoriatic arthritis (PsA) have been shown to exhibit common clinical features. As complex diseases they have a known genetic component, some of which is known to be shared. The aim of this study was to assess the genetic overlap between 3 types of IA (RA, JIA and PsA) using genotype data generated on the Immunochip array and to select a biologically promising overlapping region for further genetic and functional investigation. Overlap analysis was performed using association data generated for a large cohort of inflammatory arthritis cases and shared controls (11,475 RA; 2816 JIA; 929 PsA respectively). 50 genetic regions were identified as being associated with more than 1 type of IA (p < 1x10-3), with several interesting similarities and differences observed between the diseases. As several of the overlapping regions detected represented novel disease associations, they required replication in an independent sample cohort. 12 variants were selected for replication in an independent RA cohort of 3879 cases and 2561 controls. Of these, 2 variants in the CTLA4 and MTMR3 regions were successfully replicated in RA at p<0.05. Bioinformatics analysis was performed for the 50 overlapping regions, with one particularly promising region, RUNX1, selected for further investigation. In this region, the same variant (rs9979383) is associated across the 3 diseases, with similar odds ratios (OR 0.8-0.9) observed in each disease. As this region represented both a novel IA association and had not been densely genotyped on the Immunochip array, fine mapping was performed by genotyping 51 SNPS in 3491 cases and 2359 controls. This resulted in replication of the association at rs9979383 (p=0.02) with no additional significant genetic effects detected, therefore this variant was selected for further functional analysis. As rs9979383 lies ~280kb upstream of the RUNX1 gene, a cis-eQTL analysis was performed to identify if the variant acts by regulation of RUNX1 gene expression. This was performed in whole blood, CD4+ and CD8+ lymphocytes from 75 (and a subset of 23) healthy volunteers respectively. No significant eQTLs were detected between rs9979383 and RUNX1 in whole blood (p =0.9) or RUNX1/LOC100506403 CD4+ and CD8+ lymphocytes (p=0.1). This study has provided insight into the genetic similarities and differences between different types of inflammatory arthritis, which can be applied to further investigations into disease susceptibility. Although no significant cis-eQTL was detected in any of these tissues with either RUNX1 or the nearby lnc-RNA LOC100506403, in cells from healthy volunteers under unstimulated conditions, these findings will direct future functional investigations into the role of this overlapping region in the susceptibility of IA.

Rheumatoid arthritis (RA) is a systemic and inflammatory disease that has been associated with an increased morbidity and mortality in cardiovascular disease (CVD). Low aerobic capacity is one of the strongest independent risk factors for CVD and all-cause mortality in the general population. In patients with longstanding RA, low aerobic capacity has been related with a worse cardiovascular profile and an increased risk of CVD mortality. As a consequence of this, low aerobic capacity might provide an additional risk factor for CVD in patients with RA. The aim of this thesis was to describe the associations between aerobic capacity and risk factors for CVD as well as disease activity in patients with early RA, and also the effects of intensive exercise therapy on traditional risk factors for CVD and disease activity in patients with longstanding RA. Paper I, a cross-sectional study including 67 patients with early RA, mean (SD) age 53.1 (14.4), assessments of aerobic capacity, CVD risk factors, disease activity and functional ability were taken. Data were analysed for the associations between aerobic capacity and CVD risk factors and disease activity. In paper II, an intervention study, including 13 patients with RA, median age (Q1-Q3) 57 (44-64) years, aerobic capacity, pulse wave analysis (PWA), CVD risk factors, and disease activity were analysed for changes after 10 weeks of intensive exercise therapy. Additional follow-up was made after 25 weeks. In paper I, the mean (SD) aerobic capacity was 31.6 (8.7) ml O2/kg/min. CVD risk factors and disease activity were all in favour of patients with higher aerobic capacity. In a multiple regression model, adjusted for age and sex, aerobic capacity was significantly associated with percent body fat (β=-0.502, 95%CI=-0.671;-0.333) and triglycerides (β=-2.365, 95%CI=-4.252;-0.479). In paper II, intensive exercise over ten weeks was shown to be a feasible method to significantly improve aerobic capacity (p=≤0.05), systolic blood pressure (p=≤0.01) and the number of tender joints (p=≤0.05). No detrimental effect on disease activity was recorded. This thesis adds further knowledge of aerobic capacity and its associations with CVD risk factors and disease activity in patients with RA. Also, intensive exercise therapy was a feasible intervention to improve CVD risk factors. To include assessment of aerobic capacity in regular clinical practice may improve patient management as well as patient outcome in patients with RA.
Bakgrund: Reumatoid artrit (RA, ledgångsreumatism) är en kronisk inflammatorisk sjukdom som i första hand angriper leder, men kan även påverka inre organ. Typiska symptom är ledsvullnad, smärta, morgonstelhet och nedsatt funktion i lederna. Patienter med RA har visat sig ha en ökad risk att insjukna i och avlida i hjärt- och kärlsjukdom. I den allmänna befolkningen har låg syreupptagningsförmåga (kondition) visat sig vara en av de starkaste riskfaktorerna för att insjukna i eller att avlida i hjärt- och kärlsjukdom. Tidigare studier har visat att patienter med RA kan ha låg kondition vilket kan utgöra en riskfaktor för hjärt- och kärlsjukdom även vid RA. Syfte: Syftet med denna avhandling var att beskriva sambanden mellan kondition och riskfaktorer för hjärt- och kärlsjukdom och sjukdomsaktivitet. Ett annat syfte var att studera hur intensiv cykelträning påverkar kondition, traditionella riskfaktorer och sjukdomsaktivitet hos patienter med RA. Metod: Studie I är en tvärsnittsstudie, bestånde av 67 patienter med tidig RA, som hade en medelålder på 53 år. De undersöktes avseende; kondition, riskfaktorer för hjärt- och kärlsjukdom och sjukdomsaktivitet för att analysera samband mellan dessa. Studie II är en träningsstudie, bestående av 13 patienter med RA, med en medianålder på 57 år. Kondition, riskfaktorer för hjärt- och kärlsjukdom och sjukdomsaktivitet analyserades för att se förändringar efter tio veckors intensiv cykelträning samt vid en uppföljning efter 25 veckor. Resultat: I studie I visade den studerade gruppen ett konditionsmedelvärde på 31.6 mL. Sambandsanalyser visade att högre kondition var relaterad till lägre grad av riskfaktorer för hjärt- och kärlsjukdom, samt lägre 10 års risk för hjärt- och kärlsjukdom och sjukdomsaktivitet. I studie II fann vi att tio veckors intensiv cykelträning kan vara en användbar metod för att förbättra kondition, blodtryck och antalet ömma leder. Ingen ökad sjukdomsaktivitet noterades. Slutsatser: Dessa studier bidrar med kunskap om samband mellan kondition och riskfaktorer för hjärt- och kärlsjukdom samt sjukdomsaktiviteten hos patienter med RA. De visar också att intensiv cykelträning kan vara en effektiv metod att förbättra kondition och blodtryck hos patienter med RA.

Ultrasound (US) imaging has made significant progress over the past 20 years in relation to its role in inflammatory arthritis, and in particular, Rheumatoid Arthritis. Modern US machines provide crisp, detailed images of superficial anatomical structures which has facilitated the uptake of US imaging as an important assessment tool within the Rheumatology department. Diagnostic and prognostic information can now assist clinicians decisions with the goal of improving patient treatment and subsequent outcome. In addition, 3D US imaging has recently been suggested as an additional imaging modality with potential benefits in the assessment of in?ammatory arthritis. Recent work has focused on providing a reliable, responsive US joint count which can be assimilated into routine care as well as providing a platform for clinical research. Thus, my first aim was to show that a defined limited US data set, including 2D and 3D imaging, shows acceptable reliability. I demonstrate that both imaging modalities are reliable in terms of reading and image acquisition when restricted to a limited US data set. My second aim, was to demonstrate that a limited US data set is responsive. Using both a physiological and pharmacological trigger, I demonstrate that both 2D and 3D imaging are responsive and that combining US endpoints with DAS28 (Disease Activity Score - 28) increased the effect size and identifies treatment effects early. Despite notable advances in musculoskeletal US research, there is still need for better understanding of the pathophysiological correlates of ultrasound imaging. Therefore my final aim was to examine the relationship of Power Doppler Signal (PDS) and gray-scale synovial thickening with histological features of synovitis at a single joint level and with an extended joint US data set. I Firstly show that the harvesting of synovial tissue, using a minimally invasive US-guided biopsy technique, is safe and well tolerated by patients and that the quality of tissue and RNA extracted is good. Using this tissue collection method, I demonstrate a good correlation of US and histological parameters of synovitis (specifically CD68+ sub-lining macrophages) at a single joint level, in both an early and established RA cohort. This relationship is maintained if the US assessment is extended to a discrete US joint data set. Furthermore, within the knee joint I demonstrated that PDS correlates well with synovial tissue expression of inflammatory mediators of neoangiogenesis and histological assessment of synovial vascular area.

Depression is a common comorbidity in rheumatoid arthritis (RA), yet it may not be adequately recognized during routine clinical care. RA symptoms may confer a risk for depression, and vice versa; depression may affect RA disease activity and response to treatment. The study aims were to compare patient- and physician-reported depression measures, evaluate the temporal bi-directional association between RA disease activity and depressive symptomology, and assess depression as a moderator of RA treatment. Patients were identified using a national RA registry sample (Consortium of Rheumatology Researchers of North America; CORRONA). Depression prevalence and incidence rates were estimated, and concordance and disagreement using measures reported separately by patients and physicians, as well as baseline cross-sectional associations between RA disease and a history of depression. A survival analysis was conducted to temporally predict the incident onset of self-reported depressive symptoms using the different metrics of RA disease activity. Also, mixed effects models were used to assess prospective changes in RA disease activity by prevalent and incident depressive symptom status. Lastly, logistic regression models compared the likelihood of clinical response to RA treatment during follow-up in those with and without depression when starting biologic disease modifying anti-rheumatic drug (DMARD) therapy. Patient-reported depression rates were much higher and significantly different from physician based comorbidity estimates. Patient and physician RA disease activity measures were associated with an increased risk for depression onset, but not laboratory-reported serum biomarkers. Similarly, depression was temporally associated with significantly slower rates of decline regarding every patient-reported disease activity measure, some physician-reported metrics, but not acute phase reactants. Moreover, there was a significantly lower probability of achieving clinical remission among those with depression on a biologic DMARD after 6 months and an analogous effect at 12-months that was slightly lower in magnitude, which did not reach statistical significance. Rheumatologists under-reported the occurrence of prevalent and incident depressive symptoms, and thus are likely unaware of its presence in their RA patients. Further, the results suggest the bi-directional effects between these conditions are related to the cognitive and behavioral aspects of depression and their interactions with disease activity, rather than shared immunological mechanisms in the context of cell-mediated immunity. When also considering the impact on clinical response to biologic DMARDS, the findings collectively imply that rheumatologists must address any challenges due to depression to provide the best care to their patients.

Aim: The aim of this thesis was to validate the 2010 American College of Rheumatology/European League Against Rheumatism classification criteria for rheumatoid arthritis (RA), in particular with respect to its construct validity and the role of autoantibodies within the criteria. Methods: This thesis used data from the Norfolk Arthritis Register, a longitudinal inception cohort of adults (16 years and over) with inflammatory polyarthritis (IP), defined as at least 2 swollen joint for at least 4 weeks. The 2010 criteria were used to define RA, firstly in a re-estimation of the incidence rates (IR) with comparisons made to incidence defined by the previous criteria set; and secondly in a study comparing mortality rates in patients with RA to those of the general population, and how these rates changed over time. Analyses were performed testing the ability of the 2010 criteria to identify those patients with IP at increased risk of mortality, disability, disease severity and radiographic damage. The levels and number of autoantibodies present were investigated as predictors of mortality in patients with IP. The association between anti-carbamylated protein (anti-CarP) antibodies and long term disease outcomes were investigated. Results: The incidence of RA was 40 per 100 000 population; baseline IRs were similar to the cumulative IRs using the previous criteria set over 5 years. Patients who were seronegative were less likely to be classified as RA by the 2010 criteria. Mortality rates in patients with RA were higher compared to the general population (standardised mortality ratio 1.16, 95 percent confidence interval (CI) 1.04-1.29) and declined over the study period at the same rate as the general population. Patients with IP who fulfilled the 2010 criteria had increased risk of early death (hazard ratio (HR) 1.35, 95 percent CI 1.13-1.64), as well as increased levels of disability (beta 0.38, 95 percent CI 0.33-0.43), disease severity (beta 1.63, 95 percent CI 1.54-1.73) and radiographic damage (beta 0.33, 95 percent CI 0.20-0.47) throughout follow up. Patients with two autoantibodies had an increased risk of early death (HR 1.35, 95 percent CI 1.09-1.68), but there was no association with early death and the levels of these antibodies. Anti-CarP antibody positivity was independently associated with worse disability (beta 0.12, 95 percent CI 0.02-0.21) and disease severity (beta 0.23, 95 percent CI 0.07-0.39) throughout follow up. Conclusions: The 2010 ACR/EULAR classification criteria for RA identify patients with IP early in their disease course and recognise those at increased risk of mortality and poor outcomes. The 2010 criteria may miss a subgroup of seronegative patients who nevertheless have a poor prognosis. Novel autoantibodies may be useful to identify this subgroup.

INTRODUCTION Rheumatoid arthritis (RA) is a disease of chronic inflammation in the joints and organs. RA patients exhibit 4-fold increased incidence of CVD, increased prevalence of insulin resistance (IR) and increased mortality. Aerobic and resistance training (RT) programs have been suggested for the management of RA symptoms and reduction of comorbidities, including insulin resistance. Exercise has been shown by recent evidence to be safe and beneficial in RA patients. RT has been documented to improve inflammation and insulin sensitivity. The present study was undertaken to examine the impact of a sixteen week intensive training regimen on disease status, body composition, markers of inflammation and indicators of insulin resistance in RA patients undergoing infliximab therapy, a potent RA treatment.METHODS30 RA patients were randomized into exercise (EX) or control (C) groups. EX patients underwent a 16-week supervised, intensive, progressive and individualized resistance training regimen. Participants were monitored by professional fitness trainers during all exercise sessions. Subjects were assessed prior to and after intervention. Assessments included disease status, strength and functional testing, anthropometrical and body composition analysis, analysis of markers of inflammation and assessment of insulin sensitivity.RESULTS EX subjects significantly increased in strength and functional ability without worsening of disease state, and increased lean mass from baseline. Fat mass was significantly reduced in EX. Glucose and resistin levels increased significantly following EX intervention. Mean IR was unchanged, but EX subjects with elevated IR did show improvement following training. Regression analysis indicates duration of infliximab therapy to be correlated with improved insulin sensitivity.CONCLUSIONS RA patients taking infliximab tolerated an intensive resistance training program. Participants increased strength and lean mass while decreasing fat mass and displayed improved functional capacity. Disease status was not worsened by the regimen. Though the mean measure of IR did not improve, those patients with the most adverse scores did show improvement following the intervention. Furthermore, regression analysis indicates that infliximab treatment duration was linked to reduced IR. In conclusion, resistance training improved strength and functional ability in RA patients taking infliximab without disease degradation, and may help reduce IR in those patients with elevated resistance.

Sjögren's syndrome (SS) and rheumatoid arthritis (RA) are characterised by breach of self-tolerance with high affinity circulating autoantibodies and peripheral B cell disturbances in the naïve and memory B cell compartments. In addition, both SS and RA develop functional ectopic B cell follicles in the respective target organs, i.e. the salivary glands and the joint synovium, whereby autoreactive B cell undergo antigen selection and affinity maturation. However, the exact stage at which errors in B cell tolerance checkpoints accumulate is unknown. In this PhD project, I amplified and sequenced Ig VH and VL gene transcripts from single B cells which were FACS sorted either from the peripheral blood of SS patients or from the RA synovium. Healthy donors (HD) were used as controls. Subsequently, I cloned and expressed recombinant monoclonal antibodies displaying identical antigenic specificity of the original B cells. Finally, I tested the poly- and autoreactivity profile of these antibodies against SS and RA-associated autoantigens. In SS, I analysed 353 VH and 293 VL sequences and obtained 114 recombinant antibodies from circulating naïve (n=66) and memory (n=48) B cells of 4 SS patients and compared their autoreactive and polyreactive profile to 45 naïve clones from 2 HD. Analysis of the VH and VL gene usage showed no significant differences between SS and HD. Conversely, I observed accumulation of circulating autoreactive naïve B cells in SS as demonstrated by Hep-2 cells, ENA, Ro/SSA and/or La/SSB reactivity. The elevated frequency of autoreactive naïve B cells in the circulation of SS patients supports the existence of early defects in B cell tolerance checkpoints in this condition In RA, I analysed the Ig gene repertoire and the VH gene somatic mutation rate of 139 VH and 175 VL sequences of synovial CD19+ B cells which demonstrated evidence of antigen selection and hypermutated alpha > gamma > mu VH chains with presence of intra-synovial clonal diversification. Recombinant antibodies from synovial B cell clones were then screened for reactivity towards citrullinated antigens with a plan for a wider analysis using autoantigen microarrays. Overall, these results highlighted the existence of B cell abnormalities and loss of tolerance for self-antigens both in the peripheral and/or lesional compartment of SS and RA. Further analysis of the fine specificity and pathogenicity of recombinant antibodies from autoreactive B cells will be invaluable in order to dissect the mechanisms and the antigens driving the development and the persistence of autoimmunity in RA and SS.

Rheumatoid arthritis (RA) is a progressive disease, often leading to disability. Because the disease course develops rapidly during the first years after diagnosis, more knowledge is needed about the early disease course to minimize later disability. This thesis describes the course of disability in early RA such as hand function, pain intensity, activity limitation and sick leave. In addition, this thesis compares disability between women and men and compares disability between RA patients and referents. This thesis is primarily based on data from the 320 patients that were included in the multi-centre project in Sweden called ‘Early interventions in rheumatoid arthritis’ (TIRA). A wide range of outcome variables was registered between 1996 and 2006 during regular follow-ups from time for diagnosis through the eight-year follow-up. Outcome regarding disease activity and disability of RA patients still remaining in TIRA at the three and five year follow-up respectively are used in this thesis. Data concerning sick leave were obtained for the patients during six years (1993-2001) – three years before and three years after diagnosis. Referents were included in two of the studies. Data regarding disability in referents were obtained according to hand function and activity limitation using the Health Assessment Questionnaire (HAQ). Data for sick leave were obtained for six years in referents, for the same period as the RA patients. For most variables, disability in RA was most pronounced at time of diagnosis but before intervention started. Disability was then reduced already at the 3-month follow-up and thereafter affected but stable during the following five years. The exception was participation, reflected by sick leave, a variable that was stable from inclusion to three years from diagnosis. Activity limitation, pain intensity and sick leave in RA that represents different aspects of disability were explained by other aspects of disability and contextual factors rather than by disease activity. RA affects women and men differently in some aspects. Women had more severe course of activity limitations than men according to HAQ. Men were more affected than women in range of motion, although the differences were small in a clinical perspective. However, pain intensity and frequency of sick leave did not differ between women and men. Patients with RA have pronounced disability in relation to referents although several variables improve soon after diagnosis. This discrepancy refers to hand function as well as activity limitations and sick leave. The frequency of sick leave increased during the year before diagnosis in relation to referents and was thereafter high compared to sick leave in referents.

Background. Rheumatoid Arthritis (RA) is an autoimmune inflammatory disease that, without powerful treatment, may lead to irreversible joint damage. During the past decade, anti-cytokine therapy has become available, e.g., infliximab, a chimeric antibody targeting the pro-inflammatory cytokine TNF that has a central role in the inflammatory process in RA patients. Systemic Lupus Erythematosus (SLE) is a systemic autoimmune disease that may affect all organs and is characterized by a massive antibody production. Chemokines, chemokine receptors and lipoprotein receptor-related protein 1(CD91) are regulators of inflammation in autoimmune diseases and T-cell migration. Objectives. The aim of this study was to get a deeper understanding how TNF blocking treatment influences inflammatory mechanisms and autoantibody formation in RA with special reference to similarities and differences with SLE. Methods. In patients with RA treated with anti-TNF, and in SLE patients (ACR criteria) clinical evaluation was performed and blood samples analyzed. Autoantibodies were analyzed using indirect immunofluorescence, ELISA and multiplex flow cytometry in samples from anti-TNF treated RA patients (n=59) followed longitudinally for 54 weeks, in pre-diseased samples from SLE patients (n=38) and matched population-based controls (n=152). T-cell expression of chemokine receptors and CD91 was analyzed by flow cytometry, whilst serum levels of chemokines were determined using ELISA in anti-TNF treated RA-patients (n=24) followed longitudinally (30 weeks), and cross-sectionally in SLE-patients (n=23). Expression of mRNA for chemokines was analyzed in T-cells from SLE-patients (n=10) using PCR. Results. After treatment with infliximab, RA patients produced ANA, anti-dsDNA and anti-nucleosome antibodies, but not anti-ENA antibodies. Although these antibodies are considered typical for SLE only one patient developed a transient lupus-syndrome. Antibodies against cell nuclear antigens, including ENA, were detected several years before the first clinical symptom of SLE; anti-SSA was the earliest detectable antibody. In RA-patients before infliximab treatment, the T-cell expression of several chemokine receptors was elevated compared with healthy controls. In contrast, only one soluble chemokine, IP-10 was elevated. After treatment the levels of soluble MIP-1β, MCP-1 and IP-10, and the T-cell expression of CCR2 were decreased. In SLE-patients MIP-1β, MCP-1, SDF-1, IP-10 and RANTES in blood were elevated, whilst expression of CXCR5 and CCR6 on T-cells was lower than in healthy controls. T-cell expression of CXCR2 and CCR1 was elevated in active disease (measured as SLEDAI index), whereas the CXCR5 and CCR2 expression was lower in inactive SLE. In SLE patients with nephritis IP-10 was lower and T-cell expression of CXCR3 and CCR3 elevated compared with patients without nephritis. The expression of CD91 was higher on T-cells from patients not responsive to infliximab treatment compared with responders. Conclusion. These findings indicate that anti-TNF (infliximab) treatment in RA-patients has a major impact on the production of autoantibodies and chemokines. The autoantibody profile in infliximab-treated patients was similar to that predating disease onset in SLE patients with the exception of anti-ENA being detectable in SLE, but the development of lupus-syndromes was rare. The expression of CD91 on T-cells may predict responsiveness to infliximab. The expression of chemokine receptors in SLE- patients seemed to be related to disease activity. Anti-nuclear antibodies were detectable years before clinical disease onset in patients who developed SLE suggesting a gradual pathogenic process.

Class of 2012 Abstract
Specific Aims: To evaluate the presence of statistical information from clinical studies in official product labeling specific for disease-modifying anti-rheumatic drugs (DMARDs) used in the treatment of rheumatoid arthritis. Methods: Data were abstracted from official product labeling DMARDs with FDA approval for treatment of rheumatoid arthritis. Each document was examined for the presence of statement regarding a priori type 1 error rate, p-values, and measures of variance. Medications were classified as either biologic or non-biologic. Main Results: A total of 14 DMARDs, 7 biologics (50%) and 7 non-biologics (50%), were found to be FDA approved for the treatment of rheumatoid arthritis. Primary outcomes consisted of American College of Rheumatology (ACR) response rates, radiographic changes, and health assessment questionnaire score (HAQ). Any measure of variance and the presence of a p-value were both found in six (43%) of the drug labels. Inclusion of p-values was found to be significantly greater in biologics compared to non-biologics for both ACR and radiographic results. Inclusion of variance was found to be significantly greater in biologics compared to non-biologics for radiographic changes only. No package inserts contained statements regarding the a priori type I error rate. Conclusions: Measures of variance are not frequently included in product labeling for either biologic or non-biologic DMARDs. However, inclusion of variance and p-values for ACR response rates and radiographic changes were more likely to be reported for biologics therapies as compared to non-biologics. A statement regarding Type 1 error rates were absent from labels regardless of outcome assessed.

Autoimmune diseases such as rheumatoid arthritis (RA) are associated with debilitating chronic inflammation, autoantibody production, articular bone erosions and systemic bone loss. The underlying mechanisms and cell types that initiate these diseases are not fully understood, and current therapies mainly address downstream mechanisms and do not fully halt disease progression in all patients. Moreover, previous studies have largely focused on the role of adaptive immunity in driving these diseases, and less attention has been given to the contribution of innate immune pathways such as DNA sensor signaling pathways in initiating and/or perpetuating autoimmunity and erosive inflammatory arthritis. Detection of microbial nucleic acids by DNA sensors such as endosomal toll-like receptors (TLRs) and cytosolic sensors is an early form of antiviral defense. Upon detection of nucleic acid, TLRs dependent on Unc93B and cytosolic sensors dependent on the adaptor stimulator of interferon genes (STING) orchestrate production of type 1 interferons and pro-inflammatory cytokines to resolve infection. Additionally, the cytosolic DNA sensor absent in melanoma 2 (AIM2), which is not dependent on STING, also recognizes microbial DNA and coordinates the cleavage of pro-IL-1β. Previous studies have largely focused on the role of these DNA sensors in macrophages and dendritic cells in the context of antiviral immunity. In recent years, however, the inappropriate recognition of host nucleic acids by these sensors has been associated with several autoimmune diseases including RA. This dissertation aims to delineate the mechanisms by which DNA sensors contribute to inflammatory arthritis and bone remodeling in the context of a murine model of autoimmunity. In DNase II deficient mice, excessive accrual of undegraded, endogenous DNA leads to robust production of type 1 interferons (IFNs) and proinflammatory cytokines. The high levels of type 1 IFNs result in anemia and embryonic lethality; therefore, the gene for the type 1 IFN receptor (IFNaR) has also been deleted so that the mice survive. DNase II-/- IFNaR-/- double knockout (DKO) mice develop erosive inflammatory arthritis, anti-nuclear antibodies, and splenomegaly not seen in the DNase II+/- IFNaR-/- (Het) control group. To evaluate whether cytosolic or endosomal DNA sensors contribute to the clinical manifestations of DKO mice, genes involved in TLR or cytosolic sensor signaling were deleted on the DKO background. Genetically altered mice include STING/DNaseII/IFNaR TKO (STING TKO), AIM2/DNase II/IFNaR TKO (AIM2 TKO), and Unc93b/DNase II/IFNaR TKO (Unc93 TKO) mice. Our hypothesis was that the STING, AIM2, and/or Unc93 pathways would contribute to the autoimmune manifestations in DNase II deficient mice. Rigorous examination of inflammation in these lines revealed important roles for both the STING and AIM2 pathways in arthritis. Despite the substantial effects of the STING and AIM2 pathways on arthritis, STING TKO and AIM2 TKO mice still exhibited prominent autoantibody production. Interestingly, inflammation persisted in Unc93 TKO mice while autoantibody production to nucleic acids was abrogated. Collectively, these data indicate that innate immune pathways contribute to the initiation/perpetuation of inflammatory arthritis and demonstrate that cytosolic and endosomal pathways play distinct roles in the manifestations of autoimmunity. Moreover, they reveal a previously undescribed role for AIM2 as a sensor of endogenous nucleic acids in inflammatory arthritis. Thus, therapeutics that target the STING and AIM2 pathways may be beneficial for the treatment of inflammatory joint diseases. While the role of hematopoietic cells in driving autoimmunity has been well established, the contribution of stromal elements to disease pathogenesis is less well understood. Therefore, we generated bone marrow chimeras to delineate the contribution of hematopoietic and non-hematopoietic cells to the various autoimmune manifestations in DKO mice. These studies revealed that both donor hematopoietic and host radioresistant cells are required for inflammation in the joint as well as for other features of autoimmunity in DKO mice, including splenomegaly, extramedullary hematopoiesis, and autoantibody production. This data demonstrates that stromal host cells play a major role in DNA-driven autoimmunity. Moreover, these results suggest that targeting not only hematopoietic but also stromal elements may be advantageous in the setting of inflammatory arthritis. In the final chapter of this thesis, a role for innate immune sensor pathways in bone is described. The majority of inflammatory arthritides have been shown to lead to systemic loss of bone. Surprisingly, however, we found that DKO mice accumulate trabecular bone in the long bones over time as well as ectopic bone in the spleens, both sites of robust DNA accrual. Moreover, deficiency of the STING pathway abrogated this bone accumulation. Collectively, these data demonstrate that DNA accrual promotes dysregulated bone remodeling through innate immune sensing pathways. These findings are the first to reveal a role for the STING pathway in bone and may unveil novel targets for the treatment of diseases associated with bone disorders.

Rheumatoid arthritis (RA) is a major cause of progressive joint damage and disability, and is associated with decline in quality of life, reduced ability to work and increased health care utilisation. The economic consequences of the disease are substantial for the individuals and their families and for the society as a whole. This thesis describes a 5-year follow up of 320 patients with early RA, enrolled between January 1996 and April 1998 in the Swedish multi-centre inception cohort TIRA (early interventions in rheumatoid arthritis). Health status, function and costs were investigated. Predictors of high costs were calculated, and an algorithm was constructed to predict future need for TNFinhibitor treatment in patients not responding to traditional disease-modifying antirheumatic drugs (DMARDs). Clinical and laboratory data, measures of functional capacity and self-reported assessments were collected regularly. In addition, patients completed biannual/annual questionnaires concerning all health care utilisation and days lost from work due to the disease. Within 3 months, improvements were seen regarding all variables assessing disease activity and functional ability, but 15% of the patients had sustained high or moderate disease activity throughout the study period. The scores of ‘health assessment questionnaire’ (HAQ) were similar for men and women at baseline, but had a less favourable course in women, who also had DMARDs more frequently prescribed. Ambulatory care accounted for 76% of the direct costs during the first year. Women had more ambulatory care visits and higher usage of complementary medicine compared to men. Men ≥65 years had low costs compared to younger men and compared to women of all ages. In multiple logistic regression tests, HAQ, high levels of IgM-class rheumatoid factor (RF), and poor hand function increased the odds of incurring high direct costs. Poor hand function and pain increased the odds of incurring high indirect costs. Indirect costs exceeded direct costs all three years. The average direct costs were €3,704 (US$ 3,297) year 1 and €2,652 (US$ 2,360) year 3. All costs decreased over the years, except those for medication and surgery. The indirect costs were €8,871 (US$ 7,895) year 1 and remained essentially unchanged, similarly for both sexes. More than 50% were on sick leave or early retirement at inclusion. Sick leave decreased but was offset by increase in early retirement. 14 patients (5%) were prescribed TNF-inhibitors at the 3- year follow up, thus increasing drug costs substantially. However, they incurred higher costs even before prescription of anti-TNF therapy. At the 5-year follow-up (2001-2003), 31 patients (12%) were prescribed TNFinhibitors. Baseline values of erythrocyte sedimentation rate, C-reactive protein, anti-CCP antibodies and morning stiffness were significantly higher in this group. These patients were also to a larger extent RF-positive and carriers of the ‘shared epitope’ (SE). Anti-TNF treated patients were significantly younger and more often women. For men, a predictive model was constructed using baseline data including SE+ and IgA-RF >100 U/L and anti-CCP >240 U/L yielding a specificity of 98% and a sensitivity of 71%. For women, disease activity score (DAS28) at the 3-month follow-up proved to be a better predictor, and the final model comprised SE+ and 3-month DAS28>5.2, giving a specificity of 95% and a sensitivity of 59%.

Background. Response to anti-tumour necrosis factor (anti-TNF) therapy in patients with rheumatoid arthritis (RA) varies between patients. Incidence of sustained remission in the UK is not known, and factors contributing to its achievement are poorly understood. Prior knowledge of response would enable better targeting of anti-TNF therapy, leading to better outcomes and reduced morbidity. Aims. This thesis aims to identify incidence of sustained remission and low disease activity (LDA) in patients with rheumatoid arthritis (RA) taking anti-TNF therapy. Clinical and demographic factors associated with sustained remission and LDA were identified. Methods. I undertook a systematic literature review of the incidence of, and factors associated with, sustained remission in patients with RA taking anti-TNF therapy. Results informed a subsequent analysis of data extracted from the British Society for Rheumatology Biologics Register for Rheumatoid Arthritis (BSRBR-RA). I used two approaches to examine sustained remission and LDA. Firstly, pre-defined DAS28 thresholds were used to identify individuals in sustained remission and LDA. Secondly, a data-driven approach used latent class mixed modelling (LCMM) to identify independent trajectories of response within the data. Results. Sustained remission and LDA occurred infrequently in the literature review (range 4.2 – 38.1% sustained remission) and was uncommon in the BSRBR-RA (14.9% and 26.3% respectively), but had improved significantly over time. Significant associations were identified between the candidate variables and sustained remission and LDA, both using pre-defined thresholds and LCMM analyses. LCMM analyses identified response at six months to be a good indicator of long-term outcomes. Conclusions. Sustained remission and LDA remains uncommon, although outcomes are improving. Clinical and demographic features are associated with achieving these outcomes, suggesting it may be possible to use phenotypic features to guide therapy. Additionally, the clear response trajectories identified at six months, suggest it may be possible to identify non-responders to anti-TNF therapy earlier than six months.

Introduction: Rheumatoid arthritis (RA) is a chronic inflammatory disease. Treatment strategies emphasize early multi-professional interventions to reduce disease activity and to prevent disability, but there is a lack of knowledge on how optimal treatment can be provided to each individual patient. Aim: To elucidate how clinical manifestations of early RA are associated to disease and disability outcomes, to strive for greater potential to establish prognosis in early RA, and to facilitate implementation of decision support through analyses of the decision-making environment in chronic care. Methods: Multivariate statistics and mathematical modelling, as well as field observations and focus group interviews. Results: Decision support: A prognostic tree that predicted patients with a poor prognosis (moderate or high levels of DAS-28) at one year after diagnosis had a performance of 25% sensitivity, 90% specificity and a positive predictive value of 76%. Implementation of a decision support application at a rheumatology unit should include taking into account incentive structures, workflow and awareness, as well as informal communication structures. Prognosis: A considerable part of the variance in disease activity at one year after diagnosis could be explained by disease progression during the first three months after diagnosis. Using different types of knowledge – different expertise – prior to standardized data mining methods was found to be a promising when mining (clinical) data for new patterns that elicit new knowledge. Disease and disability: Women report more fatigue than men in early RA, although the difference is not consistently significant. Fatigue in early RA is closely and rather consistently related to disease activity, pain and activity limitation, as well as to mental health and sleep disturbance. Conclusion: A decision tree was designed to identify patients at risk of poor prognosis at one year after the diagnosis of RA. When constructing prediction rules for good or poor prognosis, including more measures of disease and disability progressions showed promise. Using different types of knowledge – different lenses of expertise – prior to standardized data mining methods was also a promising method when mining (clinical) data for new patterns that elicit new knowledge.
Introduktion: Reumatoid artrit (RA) är en kronisk inflammatorisk sjukdom. Dagens behandlingsstrategi bygger på tidiga multiprofessionella insatser för att reducera sjukdomsaktivitet och minska risken för framtida funktionshinder. Idag finns stora datamängder tillgängliga gällande medicinering och utfall vid RA. Dessa data erbjuder möjligheter att generera ny kunskap som kan användas för att forma beslutsstöd. Syfte: Att undersöka hur olika kliniska manifestationer vid tidig RA samvarierar med funktionshinder och sjukdomsaktivitet, att pröva metoder att ställa prognos vid tidig RA, och att analysera en kontext för beslutsfattande inom vård av kroniskt sjuka. Metod: Multivariat statistik och matematisk modellering, samt observationsstudier och fokusgruppsintervjuer. Resultat: Beslutsstöd: Ett beslutsträd utformades för att bestämma vilka patienter som har dålig prognos (måttlig eller hög DAS-28) ett år efter diagnos. Beslutsträdet hade 25 % sensitivitet, 90 % specificitet och ett positivt prediktivt värde på 76 %. Vid införande av beslutsstöd på en reumatologisk klinik befanns det nödvändigt att hänsyn tas till incitamentsstrukturer, arbetsflöde och samarbetsformer. Informella kommunikationsstrukturer kan också ha stort inflytande på klinisk praxis. Prognos: En betydande del av variansen i sjukdomsaktivitet ett år efter diagnos kan förklaras av sjukdomsprogression första tre månaderna efter diagnos. Att formalisera olika experters erfarenheter före standardiserade ”data mining” metoder är en lovande ansats när man letar efter mönster i (kliniska) databaser. Funktionshinder och sjukdomsaktivitet: Kvinnor rapporterar mer trötthet än män vid tidig RA, men skillnaden är inte konsistent över tid. Trötthet vid tidig RA är nära relaterat till sjukdomsaktivitet, smärta och aktivitets begränsningar, men också till mental hälsa och sömnstörningar. Slutsats: Ett beslutsträd har utformats för att predicera patienter med dålig prognos inom tidig RA. Studier av fler mått på sjukdoms- och funktionshindersprogression behövs vid konstruktion av prediktionsregler för god eller dålig prognos framledes. Att använda sig av kunskap från olika experter – olika experters glasögon – vid sökandet efter mönster i stora datamängder för att generera ny kunskap är en lovande metodik. Implementering av beslutsstöd bör göras under övervägande av incitamentsstrukturer, arbetsflöde och samarbetsformer.

In this thesis, we have studied the immunological processes of joint inflammation that may be targets for future treatment of patients with arthritis. We focus on the immune-modulating properties of interferon-α (IFN-α) and uridine in experimental arthritis. The nucleoside uridine, which is regarded a safe treatment has anti-inflammatory properties notably by inhibiting tumor necrosis factor (TNF) release. Because the inflamed synovium in rheumatoid arthritis (RA) is characterised by pathogenic TNF-production, uridine could potentially be away to ameliorate arthritis. Systemic administration of uridine had no effect on antigeninduced arthritis (AIA), which is a T-cell dependent model where animals are immunized twice (sensitization) with bovine serum albumin (mBSA), before local triggering of arthritis by intra-articular antigen (mBSA) re-challenge. In contrast, intra-articular administration of uridine clearly down modulated development of AIA in a dose dependent manner and inhibited the expression of synovial adhesion molecules, influx of inflammatory leukocytes and synovial expression of TNF and interleukin 6, but did not affect systemic levels of proinflammatory cytokines or antigen-specific T-cell responses. Local administration of uridine may thus be a viable therapeutic option for treatment of arthritis in the future. Viral double-stranded deoxyribonucleic acid (dsRNA), a common nucleic acid found in most viruses, can be found in the joints of RA patients and local deposition of such viral dsRNA induces arthritis by activating IFN-α. Here we show that arthritis induced by dsRNA can be mediated by IFN-producing dendritic cells in the joint and this may thus explain why viral infections are sometimes associated with arthritis. Earlier, to study the effect of dsRNA and IFN-α in an arthritis model, that like RA, is dependent on adaptive immunity, dsRNA and IFN-α were administered individually during the development of AIA. Both molecules clearly protected against AIA in a type I IFN receptor-dependent manner but were only effective if administered in the sensitization phase of AIA. Here we show that the anti-inflammatory effect of IFN-α is critically dependent on signalling via transforming growth factor β (TGF-β) and the enzymatic activity of indoleamine 2,3 dioxygenase 1 (IDO). The IDO enzyme is produced by plasmacytoid DC and this cell type was critically required both during antigen sensitization and in the arthritis phase of AIA for the protective effect of IFN-α against AIA. In contrast, TGF-β and the enzymatic activity of IDO were only required during sensitization, which indicate that they are involved in initial steps of tolerogenic antigen sensitization. In this scenario, IFN- α first activates the enzymatic activity of IDO in pDC, which converts Tryptophan to Kynurenine, which thereafter activates TGF-β. Common for IDO-expressing pDC, Kyn and TGF-β is their ability to induce development of regulatory T cells (Tregs). We found that Tregs were crucial for IFN-α-mediated protection against AIA, but only in the arthritis phase. In line with this, adoptive transfer of Tregs isolated from IFN-α treated mice to recipient animals in the arthritis phase clearly protected against AIA. The numbers of Tregs were not significantly altered by IFN-α but IFN-α increased the suppressive capacity of Tregs against antigen-induced proliferation. This enhanced suppressive activity of Tregs in the arthritis phase was dependent on the earlier activated enzyme IDO1 during the sensitization phase of AIA. Thus, presence of IFN-α at the time of antigen sensitization activates the enzymatic activity of IDO, which generates Tregs with enhanced suppressive capacity that upon antigen re-challenge prevents inflammation. We have thus identified one example of how immune tolerance can be developed, that may be a future way to combat autoimmunity.

This thesis comprised patients with chronic rheumatic diseases. The studies aimed to elucidate food sensitivity by measuring mucosal inflammatory reactivity and thereby a possible link between the gut and joints. In all the studies, the mucosal path technique was used to evaluate the rectal mucosal response to rectal challenge with gluten and/or cow’s milk protein (CM). In some patients with primary Sjögren’s syndrome (pSS) and the genetic susceptibility genes HLA DQ2, mucosal reactivity measured with nitric oxide (NO) was found after rectal gluten challenge without detectable serum antibodies to gluten or transglutaminase. This gluten sensitivity was not linked to coeliac disease. After rectal CM challenge, a rectal mucosal inflammatory response measured with NO and myeloperoxidase (MPO) was detected in 38% of pSS patients, all of whom fulfilled the criteria for irritable bowel syndrome. In a questionnaire study of self-experienced adverse reactions to food, 27% of patients with rheumatoid arthritis (RA) reported intolerance to various foods and CM in particular. After rectal CM challenge performed in RA patients (n=27), strong mucosal reactivity to CM was observed in a few patients and a moderate increase in 23%. After gluten challenge, a moderate increase in mucosal reactivity was found in 35% of patients. No correlation to self-perceived intolerance and mucosal reactivity measured with NO and MPO was seen. Inflammation of the gut is a prominent feature of spondyloarthropathies (SpA). After rectal challenges with CM protein and gluten, an increase in rectal NO production was seen in 26% and 19% respectively (p<0.001). An increase in the mucosal release of MPO as a sign of neutrophil activation was seen in the CM- and gluten-sensitive patients. NO production in SpA patients was more enhanced compared with RA and pSS patients and could contribute to the increased barrier permeability described in SpA patients.

Remarkable progress has been made in the development of effective treatments for patients with rheumatoid arthritis (RA). To ensure that a patient is optimally responding to treatment, consistent monitoring of disease activity is recommended. Established composite and individual disease activity measures often cannot be computed due to missing laboratory values. Simplified measures that can be calculated without a lab value have been developed and previous studies have validated these new measures, yet differences in their performance compared with established measures remain. Therefore, the goal of my doctoral research was to examine and evaluate disease activity and composite measures to facilitate monitoring of response in clinical care settings and inclusion of patients with missing laboratory values in epidemiological research. In the first study, the validity of two composite measures, the Clinical Disease Activity Index (CDAI) and the Disease Activity Score with 28 joint count (DAS28) was examined and both were significantly associated with a rheumatologist’s decision to change therapy (CDAI OR=1.58; 95% CI: 1.42, 1.76) (DAS28 OR=1.34; 95% CI 1.27,1.56). However, further evaluation using receiver operating characteristic (ROC) analysis found that they were not strong predictors of physician decisions to change therapy (AUC=0.75, 0.76, respectively). Thus, they should not be used to guide treatment decisions in the clinic. Two measures of disease activity, erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) are often not measured and impede the computation of composite measures of disease activity. In the second study, significant factors which may predict the measurement of the ESR and CRP were identified and included physician and clinical variables but no quantitative disease activity measures. Thus the suitability of the ESR and CRP as measures of disease activity is suspect. In the final study, I created a new composite measure, the modified disease activity score with 28 joint count (mDAS28), by replacing the laboratory value in the DAS28. The mDAS28 was then validated by comparing its performance with the DAS28. The measures were strongly correlated (r=0.87), and strong agreement was found between the two measures when categorizing patients to levels of disease activity (ĸ=0.77) and treatment response (ĸ=0.73). Therefore, the mDAS28 could be used in place of the DAS28 when laboratory values needed to compute the DAS28 are missing. In summary, I found that the CDAI and DAS28 were not strong predictors of the rheumatologist’s decision to change therapy. I also found that the variability in the measurement of ESR and CRP was not associated with disease activity. I was able to modify the DAS28 by replacing the laboratory measure and create a new simplified measure, the mDAS28. I also validated the mDAS28 for use in the clinic and in epidemiological research when the DAS28 is unavailable.

La artritis reumatoide (AR) es la artropatía inflamatoria crónica más frecuente, afecta aproximadamente el 0.5% - 1% de la población general y causa una progresiva destrucción articular, discapacidad y disminución de la expectativa de vida. La etiología de la AR es desconocida y su patogenia solo parcialmente conocida al día de hoy. En los últimos años se han estudiado e identificado múltiples factores de riesgo para su desarrollo. Sabemos que intervienen factores genéticos y ambientales y que la interacción de ambos puede ser determinante en el desarrollo de la enfermedad. Entre los factores ambientales el tabaco ha sido ampliamente estudiado y actualmente se lo reconoce como el factor de riesgo no genético más importante para el desarrollo de AR, siendo este efecto particularmente importante en aquellos sujetos que presentan una susceptibilidad genética (presencia del epitopo reumatoide (ER)). Estudios más recientes ponen de manifiesto que el consumo de tabaco puede influir además en la expresión clínica de la enfermedad, determinar un curso evolutivo más grave y una mayor destrucción articular, aunque no todos los estudios son concordantes en estos últimos aspectos. El objetivo general de esta tesis fue analizar el efecto del consumo de tabaco en la expresión clínica y curso evolutivo de la artritis reumatoide en una cohorte de pacientes con artritis reumatoide de reciente comienzo. Para esto se llevó a cabo un estudio prospectivo en una cohorte de pacientes con artritis reumatoide de inicio (menos de dos años desde el inicio de los síntomas). En ellos se analizaron las características epidemiológicas, clínicas, serológicas y radiológicas basales y periódicamente, cada tres meses, hasta los dos años de evolución. Estas variables fueron comparadas entre aquellos pacientes fumadores y los no fumadores. Se observó que los pacientes con AR fumadores son con mayor frecuencia son portadores del epitopo reumatoide, lo que sugiere la existencia de una relación genético-ambiental en el desarrollo de la AR. En nuestra serie no hemos podido observar relación entre el consumo de tabaco y la presencia de ACPA. Desde el punto de vista de la expresión clínica de la AR, los pacientes fumadores presentaron un debut de su enfermedad más temprano que los no fumadores. La actividad clínica y biológica de la enfermedad y discapacidad que presentaron tanto al momento del debut de la AR como tras dos años de seguimiento fueron similares entre fumadores y no fumadores. El tabaco no parece influir en la expresión clínica de la enfermedad (a corto plazo). En cuanto a la destrucción articular, el tabaco demostró ser un factor predictor independiente de destrucción articular, junto con el sexo femenino y la presencia del ER. No obstante la magnitud de este efecto sería moderada. La prevalencia de ACPA en la población sana, tanto si son fumadores o no lo son, es del 1.9%. En grandes fumadores el consumo de tabaco no determina una mayor producción de ACPA. Sin embargo los grandes fumadores con EPOC sí tendrían una mayor predisposición a la producción de ACPA, aunque a títulos bajos. La implicación y relevancia clínica de los mismos debe ser aún estudiada en mayor profundidad.

Osteoclast-mediated focal articular bone erosion is a hallmark of rheumatoid arthritis, a disease of inflammation-induced bone loss. Inflammation in the bone microenvironment enhances osteoclast differentiation leading to bone erosion. Simultaneously, inflammation also inhibits osteoblast-mediated bone formation, further contributing to the net loss of bone. Previous studies have shown a paucity of mature osteoblasts at eroded bone surfaces correlating with suppression of bone formation and upregulation of antagonists of the Wnt pathway, a signaling cascade essential for osteoblast lineage commitment. Despite these observations, the exact pathogenesis of impaired bone formation in the setting of inflammation is not clearly understood. This dissertation aims to delineate the mechanisms by which inflammation suppresses osteoblast differentiation and activity in inflammatory arthritis. Specifically, this research elucidates how inflammation-induced alterations in the Wnt and bone morphogenetic protein (BMP) osteogenic signaling pathways contribute to bone loss and formation at distinct inflammatory microenvironments within the bone. Secondly, the means by which cellular mediators, including lymphocytes and macrophages, facilitate bone erosion and formation was addressed. Taken together, the research in this dissertation underscores the relationship between inflammation-induced bone loss and alterations in osteogenic signaling. Using an innovative murine inflammatory arthritis model, this study definitively demonstrates that resolving inflammation promotes osteoblast-mediated bone formation. Repair of erosions correlates with upregulation of synovial expression of Wnt10b, a Wnt agonist, and downregulation of sFRP1 and sFRP2, Wnt antagonists. This work also directly evaluates the contribution of sFRP1 to inflammation-induced bone destruction. Furthermore, this research demonstrates that expression of BMP3, a negative regulator of BMP signaling, is upregulated in osteoblasts by IL-17, a pro-inflammatory cytokine. BMP3-expressing osteoblasts are also observed at erosion sites in murine arthritis. Lastly, evaluation of the mediators of inflammation-induced periosteal bone formation implicates BMP2 as a means by which inflammation may positively regulate osteoblast function. This dissertation further elucidates the role of T cells and macrophages in the erosion and formation processes, respectively. In the absence of lymphocytes, bone erosion occurred normally, demonstrating that RANKL-expressing lymphocytes are not absolutely required for the bone erosion. Preliminary studies also suggest that M2 macrophages are potential mediators of bone formation via the expression of BMP2. In conclusion, this dissertation explores the ability of inflammation to act as a rheostat, which controls the fate of bone by modulating not only osteoclast differentiation, but also osteogenic signaling pathways and cellular mediators in the bone microenvironment. The soluble mediators and cell types identified in this research highlight novel mechanisms by which inflammation may regulate osteoblast activity within the bone microenvironment. Collectively, these data imply that strict control of inflammation may be necessary in order to create an anabolic environment that preserves bone architecture in diseases of inflammation-induced bone loss.

Title page, contents and summary only. The complete thesis in print form is available from the University of Adelaide Library.
"In early arthritis, it is important to make a diagnosis before structural damage has occurred, with early disease modifying therapy effective in improving long term outcomes. The first part of this thesis addresses the deficiency in our current knowledge of standardisation and reproducibility of ultrasound (US) findings. Chapter 2 describes a standardised protocol developed for assessing the metacarphphalangeal (MCP) joints and novel measurements of synovial inflammation. Chapter 3 compares early arthritis subjects to a control group, and showed significantly more US synovitis and abnormally increased measurements, with extensor tenosynovitis (ET) and power Doppler (PD_ positivity highly specific to the early arthritis group. Chapter 4 validates HRUS findings in a subset of subjects using MRI as the reference standard..Chapter 5 presents longitudinal data which suggests that clnical swelling and PD positivity at the MCP joints were the most sensitive to change as a reseult of disease-modifying therapy. Chapter 6 validates an US assessment tooldevelopedbadsed on “sentinel joints” whilst factors that may hemp to differentiate subjects with polyarthralgias from those with early RA are identified in chapter 7. The results of this study suggest that early RA needs to be redefined in the light of our US findings. The prognostic value of early US abnormalities will contlinue to be investigated." -- from Abstract.
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Thesis (Ph.D.) -- University of Adelaide, School of Medicine, 2008

"In early arthritis, it is important to make a diagnosis before structural damage has occurred, with early disease modifying therapy effective in improving long term outcomes. The first part of this thesis addresses the deficiency in our current knowledge of standardisation and reproducibility of ultrasound (US) findings. Chapter 2 describes a standardised protocol developed for assessing the metacarphphalangeal (MCP) joints and novel measurements of synovial inflammation. Chapter 3 compares early arthritis subjects to a control group, and showed significantly more US synovitis and abnormally increased measurements, with extensor tenosynovitis (ET) and power Doppler (PD_ positivity highly specific to the early arthritis group. Chapter 4 validates HRUS findings in a subset of subjects using MRI as the reference standard..Chapter 5 presents longitudinal data which suggests that clnical swelling and PD positivity at the MCP joints were the most sensitive to change as a reseult of disease-modifying therapy. Chapter 6 validates an US assessment tooldevelopedbadsed on “sentinel joints” whilst factors that may hemp to differentiate subjects with polyarthralgias from those with early RA are identified in chapter 7. The results of this study suggest that early RA needs to be redefined in the light of our US findings. The prognostic value of early US abnormalities will contlinue to be investigated." -- from Abstract.
Thesis (Ph.D.) -- University of Adelaide, School of Medicine, 2008

Mia Alessandra Nieto is an 8-year old living with Juvenile Idiopathic Arthritis (JIA) in Austin, Texas. When she was diagnosed at 10 months, she was the youngest child ever diagnosed with JIA in the state of Texas. However, it took 37 days to confirm her condition because there is an immense lack on knowledge in the field of pediatric rheumatology among general practitioners despite the fact that JIA is the most prevalent chronic condition in children in the United States with over 300,000 diagnosed. This is an overview of Mia’s story, along with information regarding the lack of knowledge on the condition not only in the general population but mainly and more importantly among the medical professionals in the United States.
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L’arthrite est l’une des causes principales de douleur et d’incapacité auprès de la population canadienne. Les gens atteints d’arthrite rhumatoïde (AR) devraient être évalués par un rhumatologue moins de trois mois suivant l’apparition des premiers symptômes et ce afin de débuter un traitement médical approprié qui leur sera bénéfique. La physiothérapie et l’ergothérapie s’avèrent bénéfiques pour les patients atteints d’ostéoarthrite (OA) et d’AR, et aident à réduire l’incapacité. Notre étude a pour but d’évaluer les délais d’attente afin d’obtenir un rendez-vous pour une consultation en rhumatologie et en réadaptation dans le système de santé public québécois, et d’explorer les facteurs associés. Notre étude est de type observationnel et transversal et s’intéresse à la province de Québec. Un comité d’experts a élaboré trois scénarios pour les consultations en rhumatologie : AR présumée, AR possible, et OA présumée ; ainsi que deux scénarios pour les consultations en réadaptation : AR diagnostiquée, OA diagnostiquée. Les délais d’attente ont été mesurés entre le moment de la requête initiale et la date de rendez-vous fixée. L’analyse statistique consiste en une analyse descriptive de même qu’une analyse déductive, à l’aide de régression logistique et de comparaison bivariée. Parmi les 71 bureaux de rhumatologie contactés, et pour tous les scénarios combinés, 34% ont donné un rendez-vous en moins de trois mois, 32% avaient une attente de plus de trois mois et 34% ont refusé de fixer un rendez-vous. La probabilité d’obtenir une évaluation en rhumatologie en moins de trois mois est 13 fois plus grande pour les cas d’AR présumée par rapport aux cas d’OA présumée (OR=13; 95% Cl [1.70;99.38]). Cependant, 59% des cas d’AR présumés n’ont pas obtenu rendez-vous en moins de trois mois. Cent centres offrant des services publics en réadaptation ont été contactés. Pour tous les scénarios combinés, 13% des centres ont donné un rendez-vous en moins de 6 mois, 13% entre 6 et 12 mois, 24% avaient une attente de plus de 12 mois et 22% ont refusé de fixer un rendez-vous. Les autres 28% restant requéraient les détails d’une évaluation relative à l’état fonctionnel du patient avant de donner un rendez-vous. Par rapport aux services de réadaptation, il n’y avait aucune différence entre les délais d’attente pour les cas d’AR ou d’OA. L’AR est priorisée par rapport à l’OA lorsque vient le temps d’obtenir un rendez-vous chez un rhumatologue. Cependant, la majorité des gens atteints d’AR ne reçoivent pas les services de rhumatologie ou de réadaptation, soit physiothérapie ou ergothérapie, dans les délais prescrits. De meilleures méthodes de triage et davantage de ressources sont nécessaires.
Arthritis is a leading cause of pain and disability in Canada. Persons with rheumatoid arthritis (RA) should be seen by a rheumatologist within three months of symptom onset to begin appropriate medical treatment and improve health outcomes. Early physical therapy (PT) and occupational therapy (OT) are beneficial for both osteoarthritis (OA) and RA and may prevent disability. The objectives of the study are to describe wait times from referral by primary care provider to rheumatology and rehabilitation consultation in the public system of Quebec and to explore associated factors. We conducted a cross-sectional study in the province of Quebec, Canada whereby we requested appointments from all rheumatology practices and public rehabilitation departments using case scenarios that were created by a group of experts. Three scenarios were developed for the rheumatology referrals: Presumed RA; Possible RA; and Presumed OA and two scenarios for the rehabilitation referrals: diagnosed RA and diagnosed OA. Wait times were evaluated as the time between the initial request and the appointment date provided. The statistical analysis consisted primarily of descriptive statistics as well as inferential statistics (bivariate comparisons and logistic regression). Seventy-one rheumatology practices were contacted. For all scenarios combined, 34% were given an appointment with a rheumatologist within three months of referral, 32% waited longer than three months and 34% were refused services. The odds of getting an appointment with a rheumatologist within three months was 13 times greater for the Presumed RA scenario versus the Presumed OA scenario (OR=13; 95% Cl[1.70;99.38]). However, 59% of the Presumed RA cases did not receive an appointment within three months. One hundred rehabilitation departments were also contacted. For both scenarios combined, 13% were given an appointment within 6 months, 13% within 6 to 12 months, 24% waited longer than 12 months and 22% were refused services. The remaining 28% were told that they would require an evaluation appointment based on functional assessment prior to being given an appointment. There was no difference with regards to diagnosis, RA versus OA, for the rehabilitation consultation. RA is prioritized over OA when obtaining an appointment to a rheumatologist in Quebec. However, the majority of persons with RA are still not receiving rheumatology or publicly accessible PT or OT intervention in a timely manner. Better methods for triage and increased resource allocation are needed.

Aims: To determine the test-retest reliability and responsiveness of a new computerized 20-item pain measure, SUPER-KIDZ, in children with juvenile idiopathic arthritis (JIA). Methods: A single centre prospective cohort study of JIA patients aged 8-18 years was performed. For each SUPER-KIDZ item, test-retest reliability analysis was done in patients expected to have stable pain, and responsiveness was evaluated after intra-articular steroid injection(s). Results: Fifty-one subjects were included. Good internal consistency (α=0.73-0.92) was demonstrated for the 3 SUPER-KIDZ domains. Acceptable test-retest reliability (intraclass correlation coefficient or kappa ≥0.80) was found for 15 SUPER-KIDZ items. At 2 weeks post-injection, 16 items were responsive to change in pain (standardized response mean=0.66-0.82, significant Wilcoxon signed rank and linear mixed model). Conclusions: The majority of the SUPER-KIDZ items have acceptable test-retest reliability and responsiveness properties. If validity is demonstrated, this measure could be implemented as a standardized comprehensive pain tool for JIA patients.

Tese no âmbito do doutoramento em Ciências da Saúde, no ramo Enfermagem, apresentada à Faculdade de Medicina da Universidade de Coimbra
Rheumatoid arthritis (RA) is the most common chronic inflammatory autoimmune arthritis characterized by persistent synovitis and destructive and symmetrical polyarthritis of the small and large joints. The development of the disease is associated with an increased risk of organ failure, persistent pain, progressive disability and reduced quality of life (QoL) as well as high social-economic impact on the individuals and on the health care system. Although the course of RA has greatly improved in the last years, there is no cure and the drugs used to reduce inflammation and to slow down the progression of joint damage carry some notable side effects, ranging from an irritated stomach, to liver damage or an increased susceptibility to serious infections. Women who wish to become pregnant and/or breastfeed often need to modify their medications to optimise the health of their baby. Given the fact of the expanding awareness of unwanted side effects of pharmaceutical treatment, there has been an increased utilization of acupuncture which has been reported as a kind of safe management. Evidence suggests that acupuncture interventions may have a positive effect on pain relief, physical function and QoL in RA patients. However, due to the heterogeneity and methodologic limitations of the randomized clinical trials, ineffective allocation of acupoints, lack of double blinding and quantification of its effects, evidence is not strong enough to produce a good practice guideline. Acupuncture has its roots in the most significant component of complementary and alternative medicine, Chinese Medicine (CM). RA patients may be divided into different CM syndromes wich different biomarkers, molecular signatures and, as such, with different reactions to certain treatments. That is why acupuncture treatments should be designed with acupoints corresponding to the CM syndrome differentiation. We aimed to assess acupuncture effects on RA based on clear allocation criteria of acupoints, objective and valid assessment of effects and, for the first time, with randomized, double-blinded controls. Several methodologies, applying the CONSORT guidelines, were used to strengthen the evidence base on acupuncture treatment and to understand its specific effects. First, in order to clearly quantify the effects of acupuncture for relieving pain and reducing inflammatory effects associated to RA, we tested a newly pressure algometry device designed to assess the pressure tolerated by RA patients with hand pain and the effects on this of acupuncture. The pressure algometry device proved to be suitable to quantify the differences between the hand pressure tolerate before and after the acupuncture treatments. After that, 190 RA patients with stable symptoms and stable conventional treatment, diagnosed by the criteria of the American College of Rheumatology, were stratified into two groups: “hand pain worsened by handgrip” or “hand pain worsened by thumb resistance”. After analysing these patients we found different features between RA patients with handgrip pain, and these differences were compatible with different CM syndromes. 79.5% of the 190 participants showed worsening hand pain by handgrip. The CM diagnosis of these patients’ group was obtained through inspection, auscultation, interrogation and palpation. CM diagnosis of RA patients with “hand pain worsened by handgrip” showed that they all had concomitant presence of imbalances and intermingled symptoms and clinical findings of the invasion of the pathogen agent algor/“cold”, namely: cold hands (62.9%), tearing and localized pain with gradual onset (82.9%), worse pain upon cold exposure (82.9%), pain relief by applying warmth to the affected area (62.9%), tongue exhibiting a hyaline (85.7%) and white coating (52.4%). In the last phase, 105 RA patients with the CM functional diagnosis of a “pivotal syndrome” or Turning point syndrome (TPS) were randomly assigned to a verum acupuncture, a control acupuncture or a waiting list group (each group n = 35). In the verum and control group the exact same number, depth and stimulation of needles was used as described previously in a double-blind assay. The double-blind experiment showed that RA patients with a TPS, that were treated with verum acupuncture significantly improved in: self-reported pain (Z = -5.099, p < 0.001), pressure algometry (Z = -5.086, p < 0.001); hand grip strength (Z = -5.086, p < 0.001) and arm strength (Z = -5.086, p < 0.001), health assessement questionnaire (p < 0.001, Z = -4.895) and 7/8 QoL survey domains. The number of swollen joints (Z = -2.862, p = 0.004) and tender joints (Z = -3.986, p < 0.001) significantly decreased in the verum acupuncture group. Patients treated with false acupuncture showed no significant changes. The waiting list group showed an overall worsening. The erythrocyte sedimentation rate and the c-reactive-protein rate remained unchanged. This first double-blind controlled study on acupuncture in RA objectively assessed specific effects supporting its integration in rheumatology and in the health care systems. The combination of disease diagnosis in biomedicine and integrative approaches such as CM diagnosis, identification of joint non-related symptoms and pathogenic external factors such as algor/“cold” can help to identify different functional diagnoses of RA and improve treatment strategies. By integrating the CM diagnosis as an inclusion criterion, there is homogenization of biomedical parameters and classification of CM diagnosis. Furthermore, it provides clear evidence about the importance of synergy that must exist between the diagnosis in CM and the respective selection of acupoints and it is essential for clinical practice because it might allocate interventions more adequately to the patient complaints.
A artrite reumatóide (AR) é a forma mais comum de artrite crónica inflamatória e auto-imune caracterizada por persistente sinovite, destruição e poliartrite simétrica das pequenas e grandes articulações. O desenvolvimento da doença está associado ao aumento do risco de falência orgânica, à dor persistente, incapacidade progressiva, redução da qualidade de vida (QV), e um alto impacto socioeconómico nos indivíduos e nos sistemas de saúde. Embora o curso da AR tenha melhorado muito nos últimos anos, não existe cura e os tratamentos farmacêuticos utilizados para reduzir a inflamação e retardar a progressão da doença provocam efeitos secundários notáveis, desde lesões ao nível do tracto gastrointestinal até danos hepáticos ou o aumento da susceptibilidade a infecções graves. As mulheres que desejam engravidar e/ ou amamentar muitas vezes necessitam de modificar a terapêutica utilizada para optimizar a saúde do recém-nascido. Dado o facto da crescente consciencialização dos efeitos colaterais indesejados da medicação utilizada, tem havido um aumento na procura dos tratamentos de acupunctura, que tem sido classificada como uma técnica segura. Evidências sugerem que as intervenções de acupunctura podem ter um efeito positivo no alívio da dor, função física e QV em pacientes com AR. No entanto, devido à heterogeneidade e limitações metodológicas dos ensaios clínicos randomizados, nomeadamente a alocação eficaz dos pontos de acupunctura, a falta de dupla ocultação e a quantificação dos seus efeitos, as evidências não são fortes o suficiente para produzir uma directriz de boas práticas. A acupunctura tem origem na componente mais significativa da medicina complementar e alternativa, a medicina chinesa (MC). Os doentes com AR podem ser divididos em diferentes síndromes segundo a MC, correspondentes a diferentes biomarcadores e mecanismos moleculares e, como tal, com diferentes reacções a determinado tratamento. Portanto, os tratamentos de acupunctura devem ser planeados com acupontos unânimes de acordo com as diferentes síndromes. O nosso objectivo foi avaliar os efeitos da acupunctura na AR com base em critérios claros de alocação dos pontos de acupunctura, avaliações objectivas e válidas dos efeitos e seguindo, pela primeira vez, um ensaio clinico randomizado e duplo-cego. Diversas metodologias, aplicando as recomendações CONSORT, foram utilizadas para fortalecer a evidência dos tratamentos de acupunctura e para entender os seus efeitos específicos. Primeiro, a fim de quantificar os efeitos da acupunctura no alívio da dor e inflamacção associadas à AR, testamos um novo algómetro projectado para avaliar a pressão tolerada pela dor na mão em pacientes com AR e os efeitos dos tratamentos de acupunctura. O algómetro de pressão demonstrou-se adequado para quantificar as diferenças entre a pressão da mão tolerada antes e após os tratamentos de acupunctura. Depois disso, 190 pacientes com AR, com sintomas e tratamento farmacológico convencional estáveis, diagnosticados pelos critérios do Colégio Americano de Reumatologia, foram estratificados em dois grupos: “pior dor ao apertar a mão” ou “pior dor provocada pela resistência do polegar”. Ao analisar estes pacientes encontrámos diferentes características entre os pacientes com AR com “pior dor ao apertar a mão” ou “pior dor provocada pela resistência do polegar”, e essas diferenças foram compatíveis com diferentes síndromes da MC. 79,5% dos 190 participantes apresentaram “pior dor ao apertar a mão”. Foi realizado o diagnóstico médico chinês deste grupo de pacientes por meio da inspeção, auscultação, interrogatório e palpação. Diagnóstico chines dos pacientes com “pior dor ao apertar a mão” revelou que todos eles apresentavam presença concomitante e intercalada de desequilíbrios diferenciados, sintomas e sinais clínicos da invasão do agente patogénico algor/“frio”, nomeadamente: mãos frias (62,9%), dor localizada, gradual e acompanhada da sensação de rasgar (82,9%), dor pior ao frio (82,9%), alívio da dor pela aplicação de calor na área afetada (62,9%), língua com hialina (85,7%) e cobertura branca (52,4%). Na última fase, 105 pacientes, com AR e com o diagnóstico funcional segundo a MC de uma “síndrome pivot” ou “ponto de viragem”, foram aleatoriamente destribuídos nos grupos acupunctura verdadeira, acupunctura falsa e lista de espera (cada grupo n = 35), aplicando exactamente o mesmo número, profundidade e estimulação de agulhas de acordo com a metodologia de dupla ocultação já descrita em trabalhos anteriores realizados pelos elementos deste grupo de investigação. O ensaio duplo-cego demostrou que os pacientes com AR com uma “síndrome pivot” e tratados com acupunctura verdadeira melhoraram significativamente: a dor auto-relatada (Z = -5,099, p < 0,001), a algometria de pressão (Z = -5,086, p <0,001), a força de preensão manual (Z = -5,086, p < 0,001) e a força do braço (Z = -5,086, p <0,001), a capacidade funcional (p = 0,000, Z = -4,895) e 7/8 dos domínios de pesquisa da QV. O número de articulações inchadas (Z = -2,862, p = 0,004) e dolorosas (Z = -3,986, p = 0,000) diminuiu significativamente. Os pacientes tratados com acupuntura falsa não apresentaram alterações significativas, e os pacientes do grupo “lista de espera” pioraram de uma forma geral os parâmetros avaliados. A taxa de sedimentação e a dosagem da proteína C reactiva não se alteraram significativamente em qualquer um dos grupos avaliados. Este é o primeiro ensaio clínico randomizado e duplo-cego que avalia os efeitos da acupuntura na AR e objetivamente avaliou os seus efeitos específicos, apoiando a sua integração na reumatologia e nos serviços de saúde. A combinação do diagnóstico biomédico com uma abordagem integrativa como o diagnóstico da MC, a identificação dos sinais e sintomas relevantes e não relacionados com as articulações e a avaliação dos factores externos patogénicos como é o caso do algor/“frio” podem ajudar a identificar diferentes diagnósticos funcionais da AR e a melhorar as estratégias de tratamento. A integração do diagnóstico da MC como um critério de inclusão, permitiu homogeneizar os parâmetros biomédicos e a respectiva relação com os parâmetros de classificação e diagnóstico segundo a MC, enfatizando a evidência clara e a importância da sinergia que deve existir entre o diagnóstico em MC e a respectiva seleção de acupontos como aspecto essencial para a investigação e para a prática clínica, pois permite alocar as intervenções de uma forma mais adequada às queixas individuais.

Theoretical foundation: Rheumatoid arthritis is a chronic system disease manifesting itself particularly by inflammatory joint impairment. The main problems confronting daily the patient include pains of the motor system and fatigue. The disease has typically long, progressive development, and although it does not cause directly the patients' death, it reduces their life by some ten years on average. The serious character of the disease consists in the fact that the motor abilities of the individual are gradually impaired. At the beginning the patients must avoid major physical activity, often give up their hobbies and sometimes even their jobs. In the most serious cases, the disease may even prevent the patients from performing basic self-service activities. Goal of the thesis: The goal of the thesis consists in mapping the level of problems of rheumatoid arthritis patients at performing daily activities. Hypotheses - H1: Rheumatoid arthritis patients feel discomfort when performing common daily activities, H2: Rheumatoid arthritis patients make use of supporting and compensation aids when performing common daily activities, H3: Rheumatoid arthritis patients make use of another person's assistance when performing common daily activities. Methodology: The research part of the thesis was implemented based on quantitative inquiry within the grant Project No. 120/2012/S ?Reflection of life quality in nursing?. The actual research made use of HAQ standardized questionnaire, distributed among the rheumatoid arthritis patients. The size of the research set was set at 200 rheumatoid arthritis patients from all over the Czech Republic. The respondents were chosen based on quota selection, striving to observe the proportion of men to women at 3:1, i.e. 150 women and 50 men. When searching the respondents, organizations associating patients with the respective diagnosis were first approached. All results obtained were statistically processed in the SASD (Statistical Analysis of Social Data) program. Descriptive statistics were used. Results: The results can be divided into three areas, by the related hypotheses. The first part of the results gave information on the degree of discomfort felt by the individuals when performing specific common daily activities. It was found out that the patients see the most difficult activity in taking down an item from a place above their head and bathing in the bathtub. The second area brought information on the aids used to perform common daily activities. The respondents named dressing aids or handgrips at the bathtub most frequently. The third and last area brought the answer to the question what activities require another person's help. The patients named reaching or opening of things most frequently. But an essential part of the patients stated not to need any help of another person in common daily activities. Based on the results, the hypotheses were evaluated as follows: H1 - Rheumatoid arthritis patients feel discomfort when performing common daily activities - confirmed, H2 - Rheumatoid patients make use of supporting and compensation aids when performing common daily activities - confirmed and H3 - Rheumatoid arthritis patients make use of another's person when performing common daily activities - not confirmed. Conclusion: The thesis provides a detailed and comprehensive view on the issues of performing common daily activities in rheumatoid arthritis patients. The results can be used both by practical nurses and by students of nursing and related disciplines. The thesis can also constitute foundation for further research. The thesis results will be also presented and published.

Contexte : Pour les patients atteints d’une polyarthrite rhumatoïde débutante (PARD), l’utilisation de médicaments antirhumatismaux à longue durée d’action améliore les résultats pour les patients de manière significative. Les patients traités par un rhumatologue ont une plus grande probabilité de recevoir des traitements et donc d’avoir de meilleurs résultats de santé. Toutefois, les délais observés entre le début des symptômes et une première visite avec un rhumatologue sont souvent supérieurs à la recommandation de trois mois énoncée par les guides de pratiques. Au Québec, le temps d’attente pour voir un rhumatologue à la suite d’une demande de consultation est généralement long et contribue aux délais totaux. Objectifs : Nous avons évalué la capacité d’un programme d’accès rapide avec un triage effectué par une infirmière à correctement identifier les patients avec PARD et à réduire leur temps d’attente, dans le but d’améliorer le processus de soin. Méthodes : Une infirmière a évalué tous les nouveaux patients référés en 2009 et 2010 dans une clinique de rhumatologie située en banlieue de Montréal. Un niveau de priorité leur a été attribué sur la base du contenu de la demande de consultation, de l’information obtenue à la suite d’une entrevue téléphonique avec le patient et, si requis, d’un examen partiel des articulations. Les patients avec PARD, avec une arthrite inflammatoire non différentiée, ou atteints d’une autre pathologie rhumatologique aiguë étaient priorisés et obtenaient un rendez-vous le plus rapidement possible. Les principales mesures de résultat étudiées étaient la validité (sensibilité et spécificité) du triage pour les patients atteints de PARD ainsi que les délais entre la demande de consultation et la première visite avec un rhumatologue. Résultats : Parmi les 701 patients nouvellement référés, 65 ont eu un diagnostic final de PARD. Le triage a correctement identifié 85,9% de ces patients et a correctement identifié 87,2% des patients avec l’une des pathologies prioritaires. Le délai médian entre la demande de consultation et la première visite était de 22 jours pour les patients atteints de PARD et de 115 pour tous les autres. Discussion et conclusion : Ce programme d’accès rapide avec triage effectué par une infirmière a correctement identifié la plupart des patients atteints de PARD, lesquels ont pu être vus rapidement en consultation par le rhumatologue. Considérant qu’il s’agit d’un programme qui requiert beaucoup d’investissement de temps et de personnel, des enjeux de faisabilités doivent être résolus avant de pouvoir implanter un tel type de programme dans un système de soins de santé ayant des ressources très limitées.
Background : In patients with early rheumatoid arthritis (ERA), use of disease-modifying anti-rheumatic drugs substantially improves patient outcomes. Patients treated by rheumatologists are more likely to receive these treatments and to have better disease outcomes. However, delays from symptoms onset to first rheumatologist visit often exceed the guideline recommendations of 3 months. Waiting time to see a rheumatologist after a referral is made, is generally long in Quebec and contributes to those delays. Objectives : We evaluated the ability of a nurse-led triage and rapid access program to identify patients with ERA and reduce their waiting time, in order to improve process of care. Methods : A nurse assessed all new referrals received between 2009 and 2010, in a suburban Montreal rheumatology clinic. Priority level was assigned based on the written content of the referral, a telephone interview with the patient and, if needed, an partial joint examination. Patients with ERA, including undifferentiated inflammatory arthritis, and other acute rheumatologic conditions were prioritized and given an appointment as early as possible. The main outcome measures were validity (sensibility and specificity) of the priority level for patients with ERA and delay from referral to first visit with rheumatologist. Results : Of 701 newly referred patients, 65 had a final diagnosis of ERA. The triage correctly identified 85.9% of patients with ERA and 87.2% of patients with other high priority conditions. The median delay between referral date and first visit was 22 days for patients with ERA and 115 days for all others. Discussion and implications : This nurse led triage and rapid access program correctly identified most patients with ERA and resulted in rapid consultation for these patients. Since this is a labor intensive program, feasibility issues need to be resolved before implementing this type of triage in a resource constrained healthcare system.

Die rheumatoide Arthritis ist eine chronisch entzündliche Gelenkentzündung, deren Ursachen bis dato ungeklärt bleibt. Der Verlauf der Erkrankung führt zu irreversiblem Zerstörung von Knorpel, Knochen und umgebenden Geweben in den betroffenen Gelenken. Es scheint jedoch klar, dass Synovialzellen, Knorpelzellen und Zytokine eine entscheidende Rolle im Fortschreiten der Erkrankung spielen. IL17 ist ein kürzlich entdecktes Zytokine, welches im besonderen Maßen mit der rheumatoiden Arthritis in Verbindung gebracht wird. Es liegt in der Synovialflüssigkeit und im Serum von Patienten mit rheumatoider Arthritis in deutlich höherer Konzentration vor als in anderen Gelenks-zerstörenden Erkrankungen wie z.B. der Osteoarthritis. Eine kürzlich entdeckte Zellpopulation konnte als chondrogene Vorläuferzellen charakterisiert werden. Da sie einen IL17-Rezeptorkomplex exprimieren, ist anzunehmen, dass eine IL17 Stimulation der chondrogenen Vorläuferzellen zu Veränderungen in deren Synthesemustern führt. Methode: Chondrogenen Vorläuferzellen konnten aus menschlichem Knorpel von Patientin mit rheumatoider Arthritis gewonnen und in Kultur gehalten werden. Die Zellen wurden mit IL17 inkubiert und deren Reaktion durch Zellkulturstudien, real-time-PCR, Immunfluoreszenz und western blot untersucht. Ergebnisse: Die IL17 Stimulation der chondrogenen Vorläuferzellen führte zu einer Suppression des Zellwachstums in den ersten Tagen der Zellkultur. Folgende mRNA Moleküle konnten erstmals in den chondrogenen Vorläuferzellen nachgewiesen werden: IL6, IL1,MMP3, MMP14,MMP15, MMP17 NFkB, , MAPK1, IL1, Aggrecan, ADAMTS-5 und TIMP3. Die IL17 Stimulation führte zu einer Erhöhung der Expression von MMP3, MMP17, IL6 und NFkB in den chondrogenen Vorläuferzellen. MMP14 und MMP15 zeigten sich nicht beeinflusst in ihrem Expressionsmuster. Anschließend konnten die Proteine MMP3 und IL6 stellvertretend in den chondrogenen Vorläuferzellen nachgewiesen werden. Ein IL17 Antikörper konnte den zuvor gezeigten Effekt von IL17 auf die IL6 Expression erfolgreich blocken. Schlussvolgerung: chondrogenen Vorläuferzellen scheinen in einem bestimmten Expressionsmuster auf die IL17 Stimulation zu reagieren. Gerade diese Reaktion scheint zum weiteren Fortschreiten der rheumatoiden Arthritis zu führen. Aufgrund der vielen bereits gezeigten Effekte von IL17 auf Gewebe in der rheumatoiden Arthritis scheint IL17 ein vielversprechendes Ziel in der zukünftigen Therapie der Erkrankung darzustellen.