226 research outputs found

    Why golimumab in the treatment of psoriatic arthritis, ankylosing spondylitis and rheumatoid arthritis?

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    Golimumab is an anti-TNF monoclonal antibody administred subcutaneously once a month and produced with an innovative technology that minimizes immunogenicity. This paper reviews and updates the main studies on the efficacy, safety and pharmacoeconomic aspects of treatment with golimumab of psoriatic arthritis, ankylosing spondylitis and rheumatoid arthritis

    Turning data into decisions : clinical decision support in orthopaedic oncology

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    Background: The treatment of patients with skeletal metastases is predicated on each patient’s estimated survival. In order to maximize function and quality of life, orthopaedic surgeons must carefully avoid over- or undertreatment of the disease. Unfortunately, physician estimates are notoriously inaccurate and there are no validated means by which to estimate patient survival in patients with long-bone skeletal metastases. The purpose of this thesis is to apply machine learning (ML) approaches to (1) develop a clinical decision support (CDS) tool capable of estimating survival in patients with operable skeletal metastases, and (2) establish guidelines so that this approach may be used in other relevant topics within the field of orthopaedics. Methods: We first defined the scope of the problem using data from the Karolinska Skeletal Metastasis Registry. We then developed objective criteria by which to estimate patient survival using data gleaned from the Memorial Sloan-Kettering Skeletal Metastasis Database (n=189). We employed ML techniques to find patterns within the data associated with short- and long-term survival. We chose three and 12 months because they are widely accepted to guide orthopaedic surgical decisionmaking. We developed an Artificial Neural Network (ANN), a Bayesian Belief Network (BBN), and a traditional Logistic Regression (LR) model. Each resulting model was internally validated and compared using Receiver Operator Characteristic (ROC) analysis. In addition, we performed decision analysis to determine which model, if any, was suited for clinical use. Next, we externally validated the models using Scandinavian Registry data (n=815), and again using data collected by the Societ. Italiana di Ortopedia e Traumatologia (SIOT) (n=287). We then created a web-based CDS tool as well as the infrastructure to collect prospective data on a global scale, so the models could be improved over time. Finally, we used BBN modeling to describe the hierarchical relationships between features associated with the treatment of highgrade soft tissue sarcomas (STS), and codify this complex information into a graphical representation to promote a more thorough understanding of the disease process. Results: We found that implant failures in patients with skeletal metastases remain relatively common—even in the revision setting—as patients outlive their implants. On the other hand, perioperative deaths are relatively common, indicating that an estimation of life expectancy should be part of the surgical decision making process. Using ML approaches, we found several criteria that can be used to estimate longevity in this patient population. When compared to other techniques, the ANN model was most accurate, and also resulted in highest net benefit on decision analysis, compared to the BBN and LR models. However, the BBN is the best suited to accommodate missing data, which is common in the clinical setting. The three- and 12-month BBN models were successfully externally validated using the SSMR database (Area under the ROC curve (AUC) of 0.79 and 0.76, respectively), and again using SIOT data (AUC 0.80 and 0.77). In the setting of high-grade, completely excised STS, BBN Modeling identified the first-degree associates of disease-specific survival to be the size of the primary tumor, and the presence and timing of local and distant recurrence. Conclusions: We successfully developed and validated a CDS tool designed to estimate survival in patients with operable skeletal metastases. In addition, we made this tool available to orthopaedic surgeons, worldwide, at www.pathfx.org. We also created an international skeletal metastasis registry to continue to collect data on patients with skeletal metastases. Within this framework, prognostic models have the capacity to improve over time, as treatment philosophies evolve and more effective systemic therapies become available. These techniques may now be applied to other disciplines, in an effort to turn quality data into decision support tools

    CLINICAL AND BIOLOGICALLY-BASED APPROACHES FOR CLASSIFYING AND PREDICTING EARLY OUTCOMES OF CHRONIC CHILDHOOD ARTHRITIS

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    Background: Juvenile idiopathic arthritis (JIA) comprises a heterogeneous group of conditions that share chronic arthritis as a common characteristic. Current classification criteria for chronic childhood arthritis have limitations. Despite new treatment strategies and medications, some continue to have persistently active and disabling disease as adults. Few predictors of poor outcomes have been identified. Objectives: This thesis comprises two complementary studies. The objective of the first study was to identify discrete clusters comprising clinical features and inflammatory biomarkers in children with JIA and to compare them with the current JIA categories that have been proposed by the International League of Associations for Rheumatology. The second study aimed to identify predictors of short-term arthritis activity based on clinical and biomarker profiles in JIA patients. Methods: For both studies we utilized data that were collected in a Canadian nation-wide, prospective, longitudinal cohort study titled Biologically-Based Outcome Predictors in JIA. Clustering and classification algorithms were applied to the data to accomplish both study objectives. Results: This research identified three clusters of patients in visit 1 (enrolment) and five clusters in visit 2 (6-month). Clusters revealed in this analysis exposed different and more homogenous subgroups compared to the seven conventional JIA categories. In the second study, the presence or absence of active joints, physician global assessments, and Wallace criteria were chosen as outcome variables 18 months post-enrolment. Among 112 variables, 17 were selected as the best predictors of 18-month outcomes. The panel predicted presence or absence of active arthritis, physician global assessment, and Wallace criteria of inactive disease 18 months after diagnosis with 79%, 82%, and 71% accuracy and 0.83, 0.86, 0.82 area under the curve (AUC), respectively. The accuracy and AUC values were higher compared to when only clinical features were used for prediction. Conclusion: Results of this study suggest that certain groups of patients within different JIA categories are more aligned pathobiologically than their separate clinical categorizations suggest. Further, the research found a small number of clinical and inflammatory variables at diagnosis can more accurately predict short-term arthritis activity in JIA than clinical characteristics only

    Assessment of the complexities of genetic contributions to Ankylosing Spondylitis

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    Objectives This research assesses whether structural variations can predict disease expression and whether gene-environment interactions can predict radiographic severity and progression. Methods In a cohort of 896 AS patients the associations of UGT2B17 CNV with HLA B*27 and extra-­‐articular features were compared using the Chi-­‐ Squared test. A second cohort of 76 AS patients were assessed using multiple linear regression analysis of serial radiographic assessments and SNPs from three genes related to smoking metabolism. Results No association was found between having UGT2B17 CNV 2 and IBD (p-value = 0.155), psoriasis (p-value = 0.481), uveitis (p-value = 0.466) or HLA-B*27 positivity (pvalue = 0.118). Two SNPs from CHRNA7 were associated with radiographic severity: rs11071593 and rs7178176 (p-value = 0.0005). Two SNPs from CHRNA7 were associated with radiographic progression: rs2337506 and rs12910885 (p-value < 0.0001). Conclusion No association was found between UGT2B17 CNVs and disease expression; however, we have demonstrated an association between CHRNA7 SNPs and AS radiographic severity and progression

    Spondyloarthritis in Colombia

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    Spondyloarthritis comprises a heterogeneous group of distinct disorders including ankylosing spondylitis, non-radiographic axial spondyloarthritis, psoriatic arthritis, arthritis related to inflammatory bowel disease and reactive arthritis. Spondyloarthritis is the second most prevalent form of chronic inflammatory arthritis, with an estimated prevalence of about 0.5-1.5%. The studies presented in this thesis cover many aspects related to Spondyloarthritis in Colombia. The following topics were addressed. First, the analyses and performance of the different classification criteria and the factors important in the decision of the rheumatologist to order an MRI or HLA-B27 test in the diagnostic work-up of spondyloarthritis in the context of the clinical rheumatology setting. Second, a better insight was obtained with regard to the presence of comorbidities and risk factors of patients with spondyloarthritis. This included also a case control study to evaluate the relationship between periodontitis and spondyloarthritis. Third, the translation and cross-cultural adaptation to Spanish of the ASAS-HI was performed. Adittionally, the implementation of the domains and instruments of the ASAS core set in clinical trials have been evaluated. Finally, we discuss the potential unmet needs in the field of rheumatology in Colombia and we propose a research agenda for the upcoming years.LUMC / Geneeskund

    Epidemiological, aetiological and prognostic aspects of canine primary bone cancer, with a view to its human counterpart

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    Osteosarcoma (OSA) is the most common histological subtype of primary bone cancer in both humans and dogs. The importance of this relatively rare malignancy in humans is underlined by the fact that it typically affects children and adolescents, constituting about 5% of paediatric cancers (<15 years (y) of age). Although a rare disease in the canine population as well, certain breeds of dogs have a lifetime risk approaching 10%, thereby affecting a large proportion of these dogs. Hence, OSA has a major impact on the health within such breeds. The overall incidence rate in canines outnumbers that of the human population, inspiring the use of dogs with naturally occurring OSA as models for its human counterpart. Furthermore, similar clinical and epidemiological features of this disease are seen in the 2 species. Knowledge regarding risk factors for developing OSA is scarce in both dogs and humans. A better understanding of the aetiology and pathogenesis could generate ideas for novel treatment options, and identifying markers for progression of the disease may help optimise individualised therapy.Osteosarkom (OSA) er den vanligste histologiske formen for primær benkreft hos både mennesker og hunder. Viktigheten av denne relativt sjeldne kreftformen understrekes av at den hovedsakelig rammer barn og ungdom; den utgjør omtrent 5 % av kreftsykdommene som rammer barn under 15 år. Osteosarkom er sjelden hos hunder også, men rammer opp til 10 % av hunder innen visse raser i løpet av livet. Sykdommen får derfor store konsekvenser for helsen til disse rasene. Alt i alt er OSA vanligere hos hund enn menneske, noe som har ført til bruk av hunder med naturlig forekomst av OSA som modeller for tilsvarende sykdom hos mennesker. Dette komparative aspektet styrkes av kliniske og epidemiologiske likheter ved denne kreftformen hos de to artene. Kunnskap om risikofaktorer for utviklingen av denne sykdommen er mangelfull hos både hund og menneske. En bedre forståelse av årsaksfaktorer for utvikling av OSA kan generere hypoteser som fører til nye behandlingsformer, samt identifisere markører som kan indikere progresjon av sykdommen og tilrettelegge for individuelle behandlingsprotokoller

    Differences in osteoclast activity between rheumatoid arthritis and ankylosing spondylitis

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    Tese de doutoramento, Ciências Biomédicas (Biologia Celular e Molecular), Universidade de Lisboa, Faculdade de Medicina, 2016In many inflammatory diseases, such as rheumatoid arthritis (RA) and ankylosing spondylitis (AS), bone is a target for immune cells unbalancing bone remodeling. RA typically presents as a symmetric polyarthritis, affecting more women than men and is linked with the presence of autoantibodies in the serum such as anti-citrullinated protein antibodies (ACPA) and rheumatoid factor (RF). Human leukocyte antigen (HLA)-DR genes are strongly associated with the disease. Chronic inflammation in RA leads to cartilage and bone destruction, which is typically recognized as erosive disease on x-rays. In contrast, AS is characterized by axial disease involving the sacroiliac joints and the spine. AS affects more men than women and is strongly associated with HLA-B27 haplotypes. The long-term outcome is characterized by ankylosis of the spine and sacroiliac joints. While RA is a disease characterized by destruction of bone and cartilage, the predominant finding in AS is bone formation rather than its destruction. In this work, we hypothesize that the inability of osteoclasts (OC) or its precursors to respond to osteoclastogenic stimuli in AS patients contributes to the excessive bone formation characteristic of this disease. Therefore, the aim of this thesis was the characterization of OC circulating precursors (monocytes) in RA and AS, as well as their ability to differentiate in resorbing OC when cultured in vitro. Moreover, we also aimed to understand the effect of therapies, such as methotrexate (MTX) and tumor necrosis factor inhibitors (TNFi), in the OC precursors in RA and AS patients. We first investigated whether cytokines were dysregulated in very early rheumatoid arthritis patients with less than 6 weeks of disease duration (VERA) before and after treatment with corticosteroids and MTX. Pro-inflammatory cytokines were quantified in the serum of VERA and established RA patients and compared with other very early arthritis (VEA) and healthy controls. Patients were also analyzed after therapy. Synovial fluid (SF) from RA and osteoarthritis (OA) patients was also analyzed. VERA patients had increased serum levels of cytokines promoting Th17 polarization (IL-1β and IL-6), as well as IL-8 and Th17-derived cytokines (IL-17A and IL-22) known to promote the chronicity of inflammation. These cytokines are also associated with the promotion of osteoclastogenesis. In established RA this pattern was more evident within the SF. Early treatment with MTX or corticosteroids led to clinical improvement but without an impact on the cytokine pattern. VERA patients already display increased levels of cytokines related with Th17 polarization and osteoclastogenesis, a deregulation also found in SF of established RA, suggesting that a cytokine-milieu favoring Th17 and OC activity is an early event in RA pathogenesis. We then aimed to assess the effect of MTX on circulating OC precursors and OC differentiation in RA patients. RA patients were assessed before therapy and at least 6 months after the introduction of MTX therapy and results controlled with healthy donors. We determined receptor activator of NF-κB (RANK) ligand (RANKL) surface expression on circulating leukocytes and frequency and phenotype of monocyte subpopulations. Quantification of serum levels of bone turnover markers and cytokines and in vitro OC differentiation were also performed. We found that serum RANKL, classical activation monocytes markers (C-C chemokine receptor 2 - CCR2, CD86, HLA-DR) and RANK were increased in RA patients with active disease compared to healthy donors, and after MTX exposure these parameters normalized to control levels. Although we found no differences in OC number, cells differentiated from RA patients showed higher resorption activity than from healthy donors. Again, after MTX treatment, osteoclasts resorption activity was normalized. The results of this work suggested that MTX plays an important role in downregulating OC function through the decrease in RANK surface expression in monocytes. We then proceeded to study the effect of TNFi in osteoclastogenesis in RA patients. RA patients treated with TNFi were analyzed at baseline and after a minimum follow-up period of 6 months. Results were controlled with healthy donors. After TNFi therapy, RANKL surface expression was downregulated in B lymphocytes and the frequency of circulating OC precursors was also decreased. Cells from TNFi treated patients had decreased osteoclast numbers and resorption activity as well as decreased expression of specific genes important for osteoclastogenesis, like tumour necrosis factor receptorassociated factor (TRAF6), fos-related antigen 2 (FRA-2) and for bone resorption like cathepsin K. Therefore, we suggest that in RA TNFi decreases bone resorption through the direct reduction of the number of circulating precursors and the inhibition of intracellular signalling pathways acting through TRAF6. After exploring OC precursor behavior in untreated and treated RA patients we aimed to characterize bone remodeling and pro-osteoclastogenesis inflammatory environment, monocytes phenotype and in vitro OC differentiation in AS patients. xli Patients with active AS without any ongoing therapy and age and gender matched healthy donors were recruited. We observed that pro-inflammatory cytokine levels were higher in a cohort of untreated AS patients when compared to healthy donors, but CD51/CD61 expression (integrin αvβ3 or vitronectin receptor, important for osteoclast attachment to the bone matrix) was downregulated in the classical OC precursors. No differences in the in vitro osteoclastogenesis or bone resorption was observed when compared to healthy donors, however we found low expression of colony stimulating factor 1 receptor (CSF1R), RANK and nuclear factor of activated T cell c1 (NFATc1) in AS osteoclast precursors that consequently led to a decreased expression of important resorption genes such as cathepsin K. These findings showed us that despite the high levels of proinflammatory cytokines present in AS patients, circulating monocytes have low OC specific gene expression supporting our hypothesis of an impaired response of OC precursors to pro-osteoclastogenic stimuli in AS patients. In an effort to understand the effects of TNFi therapy in circulating OC precursors and their differentiation ability from AS patients, we followed up a cohort of patients before and after therapy. Results were controlled with healthy donors. We found that IL-17A and IL-23 circulating levels decreased after TNFi treatment. OC number was decreased in AS patients before treatment when compared to control. However, no differences in OC precursor frequency or in the number OC in culture were found after treatment. RANK, CSF1R and NFATc1 expression was downregulated in circulating OC precursors after TNFi treatment. However, when cultured in OC differentiated from AS TNFi-treated patients showed higher resorption activity than cells from patients before treatment. These results showed us that in AS patients, TNFi treatment reduces systemic proosteoclastogenic stimuli but when OC precursors are exposed to TNFi therapy they have increased in vitro activity in response to osteoclastogenic stimuli. From this work we were able to understand some of the mechanisms by which MTX and TNFi therapies act on circulating OC precursors in RA and AS patients. Although RA and AS are two chronic immune mediated diseases their effect on bone metabolism is different. The work here discussed shows that RA and AS OC precursors have a different behaviour in vitro, even coming from a similar pro-inflammatory milieu. Our findings support the hypothesis that OC from AS patients have impairment in their activity when compared both to RA patients or healthy controls. This difference can be partially explained by an intrinsic inability to respond to osteoclastogenic stimuli and by downregulation of key OC differentiation and activity genes in AS patients.Projeto,“Differences in Bone Cell Activity Between Rheumatoid Arthritis and Ankylosing Spondylitis” financiado pela Merck Sharp & Dohme Corp - Merck_P08574

    Efficacy, Safety and Clinical Outcomes of Biologic Drugs in the Treatment of Rheumatoid Arthritis

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    Rheumatoid Arthritis (RA) is an autoimmune disease, which is treated with anti-inflammatory and immunosuppressive medication comprising synthetic disease-modifying anti-rheumatic (sDMARDs) and biologic drugs. In this thesis all published randomized controlled trials studying the efficacy and safety of biologic drugs based on the inhibition of tumor necrosis factor (TNF) were identified, evaluated and pooled in using a systematic review including a meta-analysis. Then we pursued a cross-sectional overview on disease activity and medical treatment of patients with RA treated wthin the Finnish specialized healthcare. Finally, we executed two cohort studies in which we combined longitudinal patient data with information on the incidence of serious infections, malignancies and joint replacement operations retrieved from national registers. Forty-one articles reporting on 26 RCTs of TNF-inhibitors were included in the systematic review and meta-analysis. TNF-inhibitors as a monotherapy were more efficacious than placebo but comparable to methotrexate (MTX). TNF-inhibitor and MTX combination was superior to either MTX or TNF-inhibitor alone. TNF-inhibitors were relatively safe as compared to either MTX or placebo. The cross-sectional study revealed 91%, 58% and 21% of patients as concurrent users of (sDMARDs), glucocorticoids and biologics, respectively. The cohort studies showed that the adjusted incidence rate ratios (aIRRs) of infections compared to sDMARD users were 0.9 (95% CI 0.6-1.4) and 1.1 (95% CI 0.59-1.9) for the users of TNF-inhibitors and rituximab, respectively. The aIRRs of malignancies were similar between the sDMARD and biologics users. There were more primary joint replacement operations per 100 patient years among the users of biologic drugs (3.89, 95% CI 3.41 4.41) vs. DMARD (2.63, 2.35 2.94) users but slightly fewer revisions (0.65, 0.46 0.88 vs. 0.83, 0.68 1.01). Efficacy and safety of TNF-inhibitors are comparable to MTX and only few differences were observed between individual agents. Currently, more than 20% of Finnish RA patients are using biologic drugs, with a majority of them in combination therapy with sDMARDs. The incidence of serious infections and malignancies is comparable between the users of sDMARDs, TNF-inhibitors and rituximab. Compared to sDMARD users, biologic drugs users had a higher incidence of joint replacement operations while the durability of the prostheses were similar.Nivelreuma on autoimmuunisairaus, jonka oireisiin kuuluu reumatulehduksesta johtuvaa nivelarkuutta- ja turvotusta erityisesti käsissä ja jaloissa. Nivelreuman diagnoosi perustuu lääkärin tekemään arvioon potilaan voinnista, potilaan omaan arvioon oireistaan sekä laboratorio- ja kuvantamistutkimuksiin. Nivelreuman hoito perustuu tulehdusreaktion hillintään ja sen tavoitteena on oireeton tauti. Suomalaisten hoitosuositusten mukaisesti lääkehoito aloitetaan metotreksaatilla tai tarvittaessa metotreksaatin, sulfasalatsiinin ja hydroksiklorokiinin sekä pieniannoksisen prednisolonin yhdistelmähoidolla. Mikäli näillä tavanomaisilla reumalääkkeillä ei saavuteta riittävää hoitovastetta tai ne ovat vasta-aiheisia potilaalla, voidaan hoitoa jatkaa biologisilla lääkkeillä. Väitöskirjatutkimuksen ensimmäisessä vaiheessa etsittiin, arvioitiin ja yhdistettiin kaikki Tuumorinekroosifaktorin estoon perustuvia biologisen lääkkeitä koskevat satunnaistetut kontrolliryhmän sisältävät tutkimukset niiden tehon ja turvallisuuden selvittämiseksi. Seuraavaksi tehtiin poikkileikkaustutkimus erikoissairaanhoidon piirissä olevista nivelreumapotilaista, jotta tiedettäisiin suomalaisten nivelreumapotilaiden tyypillinen tautiaktiivisuus ja heillä käytetty lääkitys. Lopuksi tehtiin kaksi kohorttitutkimusta, joissa selvitettiin biologisen lääkehoidon aikaisten vakavien infektioiden ja syöpien ilmaantuvuutta sekä biologisen lääkehoidon vaikutusta tekonivelkururgian tarpeeseen ja uusintaleikkaustarpeeseen. Tulosten perusteella biologiset lääkkeet ovat satunnaistetuissa verrokkiryhmän sisältävissä tutkimuksissa olleet vähintään yhtä tehokkaita ja turvallisia kuin metotreksaatti. Yhdistelmähoitona metotreksaatin kanssa ne ovat tehokkaampia, mutta yhtä turvallisia kuin kumpikaan vaihtoehto yksinään. Biologisilla lääkkeillä hoidetut suomalaiset nivelreumapotilaat eivät saaneet enempää vakavia infektioita tai syöpiä kuin pelkästään tavanomaisilla reumalääkkeillä hoidetut potilaatkaan. Biologista lääkehoitoa saavilla potilailla oli enemmän tekonivelleikkauksia kuin tavanomaisten reumalääkkeiden käyttäjillä, mikä saattoi johtua biologisten lääkkeiden käyttäjien vaikeammasta taudista ja pidemmälle edenneistä niveleroosiosta
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