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Archief afgeronde projecten
Een overzicht van projecten die voor 2012 zijn afgerond
Completed in 2011
Identification of novel lipid mediators in the joints of arthritic patients by metabolomics
Projectleader: Dr.A. Ioan-Facsinay
University: LUMC Leiden
E-mail: A.Ioan@lumc.nl
The aim of this study was to identify and measure lipid mediators present in synovial fluid and fat/adipocyte-conditioned medium from RA en OÁ patients and to study differences between lean and obese individuals.
The researchers have identified several lipid classes in SF and ACM of arthritis patients. Some fatty acids were higher in obese/overweight than lean OA patients. Also lipids that have been associated with the pathogenes of osteoarthritis were detected in different concentrations in SF and FCM.
Follow-up research will be focused on investigating the immunomodulatory function of the identified lipids and identification of novel lipid mediators in OA en RA.
Lymph nodes: the primary site of initiation of RA-
specific autoimmunity?
Projectleader: prof. dr. P.P. Tak
University: AMC Amsterdam
E-mail: p.p.tak@amc.uva.nl
In this study the researchers investigated the differences in cellular composition and functional aspects of lymph nodes in different phases of RA. They investigated lymph nodes in early arthritis patients and compared this with autoantibody positive individuals without arthritis (pre-clinical RA). The researchers found that T- en B-cell HECs can be detected in synovial tissue and lymph nodes of early RA patients. Up to 40% of the HECs in the synovial tissue are also found in the lymph node.
These results may be explained by circulation of clones between the synovium and the lymph node and suggest local retention of clones in the synovial tissue. The results also suggest increased CD8+ T cell activation within lymph nodes of early arthritis patients as well as in autoantibody positive individuals who are at risk of developing RA.
The role of dendritic cell subsets in arthritis: an in vivo study
Projectleader: prof. dr. P.P.Tak
University: AMC Amsterdam
E-mail: p.p.tak@amc.uva.nl
The unraveling of the functional roles of two main DC subsets in the pathogenesis of arthritis was the focus of this researchproject. Animal experiments show that there is an important role for these subsets in arthritis. But key experiments must pinpoint there exact contribution in arthritis and at which timepoint their contribution is crucial. When that information is available it will be time to develop gene-based or small cell-permeable peptides to restore DC function.
Antisense proteinase 3 (PR3):a link between Staphylococcus aureus and PR3-ANCA associated vasculitis?
Projectleader: prof. dr. C.G.M. Kallenberg
University: UMC Groningen
E-mail: c.g.m.kallenberg@reuma.umcg.nl
The main goal of the project was to investigate whether anti-cPR3 antibodies are present in a Groningen cohort of patients with PR3-ANCA associated vasculitis. No increased anti-cPR3 reactivity in patients with PR3-ANCA associated vasculitis was found. Also the possible role of Toll-like receptors (TLR) and TLR-signaling in patients with ANCA-associated vasculitis was investigated. These studies are being finalized.
Defining the role of the intracellular suppressor-of-cytokine signalling (SOCS)-3 protein in cartilage pathology
Projectleader: dr. A.A.J. van de Loo
University: UMC st Radboud Nijmegen
E-mail: a.vandeloo@reuma.umcn.nl
This research showed that increased expression of SOCS3 in chondrocytes, whether or not by stimulation with IL-1 by adenoviral overexpression of SOCS3, can lead to insensitivity of these cells for IGF-1, one of the most important growth factors for chrondrocytes.
The cell type specific contribution of the different RcgR gene family members in the development of arthritis
Projectleader: Dr. J.S.Verbeek
University: LUMC Leiden
E-mail: j.s.verbeek@lumc.nl
The pilot experiments of this one-year project are the first analysis in its kind of the cell type specific role of the different FcgR in immune-complex driven disease models such as CIA using newly generated type specific FcgR KO mice on pure B6 background. The researchers could redefine the role of FcgRIIB and therefore solve a 10 year-on existing controverse.
The Nijmegen randomised controlled trial on the effectiveness of a multidisciplinary treatment programme in patients with OA of the Hands (NOAH)
Projectleader: dr. C.H.M. van den Ende
Institute: Sint Maartenskliniek Nijmegen
E-mail: e.vandenende@maartenskliniek.nl
In this study the researchers investigated the effectiveness of a multidimensional (a combination of education, exercise therapy, compensatory strategies and self management) treatment program. As compared with a monodisciplinairy intervention.150 patients were included in the study. The results are not yet reported or published and are expected at the end of 2011.
The contribution of antibody-facilitated immune effector systems in the pathogenis of RA
Projectleader: prof.dr. T.W.J. Huizinga
University: LUMC Leiden
E-mail: t.w.j.huizinga@lumc.nl
This project aimed to delineate the contribution of antibody-facilitated immune effector systems and the pathogenesis of RA through the genetic analyses.
The researchers performed several genetic studies in complement and Fc-Receptors genes and identified several significant associations to the predisposition to rheumatoid arthritis. It enhanced the knowledge of a very relevant locus and formed the basis for which new applications have been written.
Clinical and molecular classification of very early rheumatoid arthritis
Projectleader: prof. dr. P.P. Tak
University: AMC Amsterdam
E-mail: p.p.tak@amc.nl
In this study the researchers looked at the events in the earliest phases of the disease to discover novel potential diagnostic and prognostic markers.
Some results. All but one autoantibody-positive individuals (n=55) showed very low scores for phenotypic markers, adhesion molecules, and vascularity, all in the same range as those in normal controls. Based on these results the researchers conclude that subclinical inflammation of the synovium does not coincide with the appearance of serum auto-antibodies during the pre-RA stage. Suggesting that a 'second hit' is involved.
So this study supports the rationale for exploring preventive strategies aimed at interfering with the humoral immune response before synovial inflammation develops.
Completed in 2010
Keeping the balance in chronic inflammation : heat shock proteins for the induction of T regulatory cells in Juvenile Idiopathic Arthritis and other paediatric autoimmune diseases
Projectleader: Dr. B.J. Prakken
University: UMC Utrecht
E-mail: b.prakken@umcutrecht.nl
In this project the researchers investigated human regulatory T cells as targets for therapeutic intervention in autoimmune diseases.
They have clearly demonstrated that there are important differences between human and murine Treg function. And conclude that in vitro suppression assays, which have so far been considered the golden standard for determining Treg suppressive function, are not sufficient to predict Treg suppressive function in vivo.
Therefore, human Treg suppressive capacity should be analyzed in vivo in humanized mouse models.
Immune modulation through HSP upregulation in the gut as a novel therapeutic target in Juvenile Idiopathic Arthritis
Projectleader: Dr. W. van Eden
University: UMCU Utrecht:
E-mail: w.vaneden@uu.nl
The aim of this project was to obtain 'proof of principle' that the induction of cell stress at the level of the gut (mucosa) can contribute to HSP dependent T cell regulation.
The researchers have shown that carvacrol obtained from the herb oregano is e powerful co-inducer of stress proteins, active through the mucosal route of administration. Given the nature of carvacrol as a regular food constituent, these findings may add to a rapid and safe development of this compound as novel, orally active, anti-rheumatic drugs.
In addition carvacrol and related compounds may be used for development of novel functional foods or neutraceuticals that may support immune regulation by facilitating the cellular production of stress proteins and subsequent induction of anti-inflammatory T-cell regulation.
Does local fat contribute to joint fibrosis?
Projectleader: dr. G.J.V.M. van Osch
University: Erasmus MC Rotterdam
E-mail: g.vanosch@erasmusmc.nl
The research in this project provided, under more, the knowledge that factors released from the intrapatellar fat pad (IPFP) from OA patients have the potential to induce fibrotic processes in the knee joint and that the IPFP can possibly contribute to the synovial fibrosis often seen in OA patients. Taken together, this study might have consequences for guidelines to remove the IPFP during total joint replacement. This decision is now surgeon dependent and not based on scientific evidence.
Novel mouse models to study auto-reactive B cells in rheumatic diseases
Projectleader: Dr. R.W. Hendriks
University: Erasmus MC Rotterdam
E-mail: r.hendriks@erasmusmc.nl
The hypothesis in this project was that pathological activation of a particular population of self-reactive SLC+LC+-B cells is a crucial step in the etiology of rheumatic disease, such as RA and SLE.
After research the main conclusions are:
• Altered BCR signaling due to the presence of SLC-Tg enhances the autoimmune phenotype of Bcl2-Tg or FcãRIIB KO mice, but the effect is clearly dependent on the SLC expression level and the genetic background.
• Increased BCR signaling, due to transgenic Btk overexpression, is sufficient to induce autoimmune disease.
• The CD19-Btk-Tg mouse is a good model for human SLE.
Implementation of a multidisciplinary care program for tailored cognitive-behavioral therapy in fibromyalgia patients at risk
Projectleaders: Mw. Dr A.W.M. Evers
University: UMC st Radboud Nijmegen
E-mail: a.evers@mps.umcn.nl
The results of this implementation project show that the implementation of this type of treatment is feasible.
In addition, in line with the results of the previous effect study, the results of this project showed that when implemented in different centers in various regions of the Netherlands, this treatment is effective in improving physical and psychological functioning and impact of FM in high-risk patients with FM. Therefore, the results of this implementation project offers several possibilities for patients, health professionals, researchers, and society.
The treatment of patients with fibromyalgia (FM), a highly prevalent condition characterized by chronic widespread pain without a clear biomedical cause, poses a great challenge for clinicians because of the lack of optimal treatment options.
In a previous study, the efficacy of a tailored multidisciplinary treatment for FM patients at risk with a high impact of the condition on daily life was shown. This group treatment consisted of 16 sessions of cognitive-behavioral therapy and physical exercise training over 10 weeks and one booster sessions three months after treatment and was tailored to the patients cognitive-behavioral pattern of pain-avoidance or pain-persistence. However, this effective specialized type of tailored multidisciplinary care for patients at risk was not yet available in regular care.
The goal of the present implementation project was the try-out of a systematic implementation of this type of tailored multidisciplinary care for FM patients at risk in several centers in different regions in the Netherlands.
Mesenchymal stromal cells (MSC) in Juvenile Idiopathic Arthritis (JIA): In vitro immunomodulatory effect of MSC derived from bone marrow and pulpa of deciduous teeth of patients with JIA versus healthy controls
Projectleader: Dr. R. ten Cate
University: LUMC Leiden
E-mail: R.ten_Cate@lumc.nl
The aim of this study was to investigate the biological and immunological properties of mesenchymal stromal cells (MSC) derived from bone marrow and dental pulpa of patients with juvenile idiopathic arthritis (JIA) compared to healthy pediatric controls.
This is the first study describing the biological characteristics of MSC in a moderately large cohort of children with JIA.
From these experiments it can be concluded that MSC of patients with JIA do not differ in their immunomodulatory capacity from healthy age matched controls. This is a first step towards the clinical use of MSC in patients with JIA or other AID.
The use of dental pulpa is a suitable alternative to study the immune modulatory effect of MSC of patient cohorts when lacking approval or an indication for a bone marrow biopsy.
This preclinical research could be a first step towards clinical implementation.
Does joint distraction in treatment of osteoarthritis result in cartilage tissue repair?
Projectleader: Dr. F.P.J.G. Lafeber
University: UMC Utrecht
E-mail: F.Lafeber@umcutrecht.nl
Joint distraction results in less cartilage damage and less pain (based on normalization of loading of the affected knee) in a canine model of experimentally induced osteoarthritis. The results of this animal in vivo study corroborate the observed cartilage repair and clinical benefit in human studies.
These results will encourage a broad implementation of joint distraction, enabling more people to profit from this novel treatment for severe OA at an early age.
Furthermore, although the study is currently for 2/3 executed the first results show that intrinsic cartilage repair activity indeed is possible. This will be the basis for further studies in vitro and in vivo to get more insight in the mechanisms underlying the cartilage repair after joint distraction.
Also this will provide novel targets to improve distraction treatment, to develop new treatment modalities for OA, and to find an explanation for the 30% failure of joint distraction in the human clinical trials.
Natural course of hand osteoarthritis
Projectleader: Dr. M. Kloppenburg
University: LUMC Leiden
E-mail: G.Kloppenburg@lumc.nl
The researchers investigated the clinical and radiographic disease course of hand OA and determinants of poor clinical outcome and radiographic progression after six years in 289 hand OA patients.
In contrast to the ongoing radiographic progression which was present in 53% of the patients, both clinical deterioration and improvement were observed.
Poor clinical outcome after six years was associated with high levels of pain and functional limitations at baseline. More pain, structural abnormalities and the presence of erosive OA and nodal OA were associated with a higher risk of radiographic progression over six years. Change in symptoms and radiographic progression were not related.
These findings enable the clinician to provide the patient with more accurate information on the disease prognosis. From a scientific point of view these findings imply that the clinical and radiographic course of hand OA are distinct, making development of structure modifying treatments with clinical benefit difficult.
Pre-clinical evaluation of the role of interleukin-7 in joint inflammation and -destruction in RA patients
Projectleader: Dr. F.P.J.G. Lafeber
University: UMC Utrecht
E-mail: F.Lafeber@umcutrecht.nl
In this project evidence is provided that indicates that interleukin-7 (IL-7) and thymic stromal lymphopoietin (TSLP) are stimuli that might contribute to loss of self-tolerance which can lead to the development of autoimmune disease like rheumatoid arthritis (RA).
These results indicate that in particular patients that have failed to anti-TNFa therapy might benefit from anti-IL-7 or anti-IL-7R therapy.
IL-32, A novel Challenge in Rheumatoid Arthritis
Projectleader: Dr. L.A. B. Joosten
University: UMC st Radboud Nijmegen
E-mail: l.joosten@aig.umcn.nl
The goal of this project was to elucidate the role of IL-32 in RA and to investigate the therapeutic value of IL-32 inhibition. The research in this project has revealed that synovial macrophages, fibroblasts, endothelial and T-cells are capable of producing IL-32.
IL-32 is important intracellular protein which can amplify TLR/NOD signalling which results in making the cells more sensitive against bacterial stimuli and is one of the crucial factors in the inflammatory loop that exists in RA synovial tissue. Reducing endogenous IL-32 expression in the synovial lining of RApatients by silencing via siRNA technology could be a promising therapy for RA.
From genotype to phenotype: the role of genetic polymorphisms to predict prognosis in JIA
Projectleader: Mw. Dr. R. ten Cate
University: LUMC Leiden
E-mail: r.ten_cate@lumc.nl
The aim of the study was to determine genetic factors that are associated with the course of disease in different subtypes of juvenile idiopathic arthritis (focusing on the subtypes oligoarthritis (persistent and extended) and polyarthritis).
The researchers have generated a DNA-bank containing DNA of 698 Caucasian JIA patients, 892 parents (in total 446 trios (set of patient and both parents)) and 1300 healthy controls and started genetic association studies and a clinical study. In the clinical study they analyzed the disease activity in the first two years in detail and the prognostic value of clinical parameters regarding the clinical course in the following three years.
Change in chondrocyte TGFß signaling as a cause for osteoartritis
Projectleader: dr. P.M. van der Kraan
University: UMC st Radboud, Nijmegen
E-mail: p.vanderKraan@reuma.umcn.nl
The researchers have elucidated ALK1 as a potential target for OA therapy. ALK1 overexpression increases MMP13 expression. In human OA cartilage MMP13 expression is strongly correlated with ALK1 expression.
Knowing the PAD to treat RA
Projectleader: Dr. G.J.M. Pruijn
University: Radboud Universiteit, Nijmegen
E-mail: g.pruijn@ncmls.nl
The results of this project have demonstrated that PAD6 is a deiminase that is not likely to play a role in protein citrullination in RA. The implication of this is that therapeutic strategies aimed at interfering with protein citrullination should be directed to the other PADs, in particular PAD2, which appeared to be responsible for the majority of citrullination in all tissues analysed.
Projecten afgerond in 2009
Perpetuating factors of chronic fatique in Rheumatoid Arthritis
Projectleader: prof. dr. P.L. van Riel
University: UMC St Radboud Nijmegen
E-mail:p.vanriel@reuma.umcn.nl
This study leads to better understanding and recognition of fatique in arthritis. And gives an instrument to measure fatique.
Understanding the pathways by which CD49b+ regulatory T cells expanded by immature dendritic cells mediate protection against arthritis
Projectleader: dr. R.E.M. Toes
University: LUMC Leiden
E-mail: r.e.m.toes@lumc.nl
More knowledge on these cells could in future lead to new treatments against arthritis.
Why not change the medication in RA? Eliciting rheumatologists' and patients' most important reasons to change or not to change treatment
Projectleader: prof. dr. P. van Riel
University: UMC st Radboud Nijmegen
E-mail: p.vanriel@reuma.umcn.nl
Most important reasons for rheumatologists to change the patient's medication are: the number of swollen joints, the DAS28 outcome, the jointdamage, diseaseactivity in comparison with 3 months ago and the doctors opinion on the diseaseactivity.
The patients' most important reasons are now subject of research.
Emotions as triggers of symptoms in patients with fibromyalgia and the modulating role of emotion regulation
Projectleader: Prof. dr. R. Geenen
University: Universiteit Utrecht
E-mail: r.geenen@uu.nl
This study shows that emotions influence the severity of fibromyalgia.
Selective modulation of IL-18 pathways for tailor made treatment of rheumatoid arthritis
Projectleader: prof. dr. W.B. van den Berg
University: Radboud UMC Nijmegen
E-mail: w.vandenberg@reuma.umcn.nl
In this study the researchers demonstrated that IL-18 has a much broader range of properties during an immune response. The results show that IL-18 also has anti-inflammatory capacities besides the well-described pro-inflammatory properties. Altogether these data identifie sIL-18Rb as a new immunomodulator of IL-18 signaling and also highlight the complexity of IL-18 in the immune response.
The role of cytokine genes in the onset of Osteoarthritis
Projectleader: mw. dr. I. Meulenbelt
University: LUMC Leiden
E-mail: i.meulenbelt@lumc.nl
Main goal of the project was to establish the relation between cytokine regulation and Osteoartritis onset and progression by genetic and associaton studies.
The pathogenic potential of anti-CCP antibodies
Projectleader: mw. dr. A. Ioan-Facsinay
University: LUMC Leiden
E-mail: A.Ioan@lumc.nl
Autoantibodies are a hallmark of rheumatoid arthritis (RA). Anti-CCP antibodies were shown to be highly specific and predictive for (erosive) RA. Moreover, studies in several mouse models reveal an important role for autoantibodies in induction/progression of arthritis.
Together, these data point to the possible involvement of CCP-specific antibodies in the pathogenesis of RA. The presence of human anti-CCP antibodies could not induce or aggravate arthritis in the models in this study. Therefore, the biological mechanisms involved in their pathogenicity could not be studied.
The identification of human Th17 cells in rheumatoid arthritis, a one-year pilot study
Projectleader: dr. E. Lubberts
University: Erasmus MC, Rotterdam
E-mail: e.lubberts@erasmusmc.nl
The results found in this project clarify that Th17 cells are present in RA. These data are of direct relevance and applicable for the human arthritis situation. Data from this pilot study are used in a new DAA-project, where the contribution of this specific T cell subset in the development of RA and other chronic inflammatory arthropathies will be unraveled.
Premature atherosclerosis in patients with ankylosing spondylitis
Projectleader: mw.dr. I.E. van der Horst-Bruinsma
University: VU MC Amsterdam
E-mail: IE.vanderHorst@vumc.nl
This study is the first to demonstrate that AS is associated with subclinical atherosclerosis and an increased carotid pulse pressure. These differences were not attributable to CV risk factors, suggesting that AS should be regarded as independent atherosclerotic risk factor.
An MRI-based diagnostic test for primary neuropsychiatric systemic lupus erythematosus
Projectleader: prof. dr. M.A. van Buchem
University: LUMC, Leiden
Email: m.a.van_buchem@lumc.nl
The researchers demonstrated that changes in clinical status in NPSLE patients are reflected in changes in MTR parameters. This finding increased the relevance of MTR analysis as a biomarker for NPSLE.
Adverse pregnancy outcome in RA; an extraarticular vascular complication of this disease
Projectleader: dr. R.J.E.M. Dolhain
University: Erasmus MC Rotterdam
E-mail: r.dolhain@erasmusmc.nl
The pregnancy outcome of RA-patients is in general comparable with general population. Higher disease activity of the mother during pregnancy was independently associated with lower birth weight. The negative association between prednisone use during pregnancy and birth weight was mediated through gestational age. Women with prednisone use during pregnancy delivered on average one week earlier compared with non-prednisone using women.
I(RCT): International Randomized Clinical Trial of Rheumatoid Craniocervical Treatment. An Intervention-Prognostic Trial comparing 'early' surgery with a 'wait and see' strategy
Projectleader: dr. W.C. Peul
University: LUMC Leiden
E-mail: w.c.peul@lumc.nl
This trial is still ongoing. It started in twenty seven rheumatological centers and several surgical centers in the Netherlands, several international centers across Europe and North-America.
More information on: http://www.thedelphitrial.com/
The role of collagen breakdown products in Osteoarthritis
Projectleader: dr. A.H. van Houwelingen
University: UMCU Utrecht
Email: a.h.vanhouwelingen@uu.nl
In this pilot-project, the involvement of PGP (Proline-glycine-proline) and GPP in arthritis development was investigated. Effects on cartilage degradation and cell infiltration were studied by histological methods.
The results are indicating that chondrocytes do not respond to the collagen breakdown products.
Although the fragments are present in high amount (compared to IL-8), their role in OA or RA remain to be unknown at this moment. Further research has to be performed in order to speculate about the role of these fragments in OA and RA.
Identification of protein biomarkers predictive of rheumatoid arthritis disease progression and therapy response
Projectleader: mw. dr. M.J.H. Coenen
University: UMC st Radboud Nijmegen|
Email: m.coenen@antrg.umcn.nl
This pilot project shows that it is possible to identify protein expression profile differences related to RA diseaseactivity als well as treatment response. As the experiments are performed with a limited number of patients we will repeat the experiments with a larger set of patients to reduce the number of false-positive identified protein expression differences.
Prognostic factors for cartilage degeneration after meniscectomy and cruciate ligament injuries. A prospective observational MRI cohort study during 8-9 years
Projectleader: prof. dr. R.G.H.H. Nelissen
University: LUMC, Leiden
Email: r.g.h.h.nelissen@lumc.nl
The results of this study show that anterior cruciate ligament (ACL), medial meniscus (MM) and lateral meniscus (LM) ruptures play a role in the development of the radiologic knee. The results also support the opinion that MRI provides a more detailed and complete picture of OA related changes than X-ray.
To obtain insight in possible genetic predisposition of knee OA, DNA samples are collected and will be analyzed. Furthermore, family history and hand radiographs will be analyzed.
Projecten afgerond in 2008
Imaging of subclinical synovitis by macrophage targeting with positron emission tomography in patients with rheumatoid arthritis in clinical remission.
Projectleader: dr. C. J. van der Laken
University: VUMC Amsterdam
Email: : j.vanderlaken@vumc.nl
In this researchproject subclinical synovitis was visualized by ® [11C]PK11195 PET in 77% of RA patients in clinical remission. In most of these patients, the uptake level of the used macrophage traces was high in at least one hand of wrist joint. PET was compared with Doppler signal.
The comparison of imaging data with clinical follow-up revealed an important finding: all patients developing an exacerbation of RA in the follow-up period up to one year had a positive PET scan at inclusion, at the stage of remission.
However, to obtain a reliable judgement on the positive and negative predictive value of PET for exarcerbation of disease, a langer follow-up study is needed preferably with a large group of patients.
Pathophysiological Consequences of T Lymphocyte Oxidate Stress in Rheumatoid Artritis
Projectleader: dr. K. A. Reedquist
University: AMC Amsterdam
Email: k.a.reedquist@amc.uva.nl
Results show that elevated ROS production is a general feature of RA synovial fluid (SF) T cells and that ROS production in RA SF T cells does not lead to mitogenic hyporesponsiveness: T cell receptor signalling is intact in RA T cells.
Published hyporesponsiveness of RA SF T cells is due to spontaneous, ROS-independend apoptosis ex vivo.Prednisolone globally targets oxidatively stressed T cell subsets for apoptosis. And constitutive activation of Rap1 in murine T cells prevents inflammation and joint destruction in experimental arthritis.
Color coded shape mapping in early arthritis patients: application of a novel MRI technique
Projectleader: dr. M.Maas,
University: AMC Amsterdam
Email: m.maas@amc.uva.nl
In this study the researchers compared MRI with synovial tissue biopsy samples, the gold standard to evaluate synovitis. The results are promising.
If this technique proves to be highly sensitive to change, it might be used as a non-invasive objective marker in evaluating treatment effect in small proof-of-principles studies or larger phase 3 clinical trials. The technique has to be further validated.
The role of CD44 splice-variants in reumatoïde arthritis
Projectleader: prof. dr. P.P. Tak
University: AMC Amsterdam
Email: p.p.tak@amc.uva.nl
The research goals in this project were to obtain insight into the role of CD44 isoforms in experimental arthritis and to dissect the dual roleof CD44 as a receptor for extracellular matrix molecules (ECM) and as a receptor for growth factors/cytokines. At the end of this project the material still has to be processed and will be further evaluated.
Pregnancy-induced remission in rheumatoid arthritis
Projectleader: dr. R. Dolhain
University: Erasmus MC Rotterdam
Email: R.Dolhain@ erasmusmc.nl
The researchers observed no association between MBL genotype groups and the improvement of RA during pregnancy or pregnancy outcome in women with RA. A clear association with improvement of RA during pregnancy and the postpartum flare was observed with IgG-0.
However this was not related to MBL production genotypes. T3 and T4 are able to induce MBL production in vitro in cultured hepatocytes. In healthy controls an association between high MBL production genotype and shorter gestational age could be appreciated.
Growing up with Juvenile Idiopathic Arthritis: the development of a counseling method ajusted to the adolescent's own perspective
Projectleader: mw. dr. G. Sinnema
University: WKZ UMCU Utrecht
Email: g.sinnema@umcutrecht.nl
Providing accurate and skilful psychosocial care to patients suffering from JIA should start from an appreciation of what it is like to live with this illness. In this study the researchers wanted to go beyond the more traditional lines of psychological research in to JIS en to open up an more thorough way of approaching the adolescent's perception.
Main goal is to integrate the patient's own perspectives in the treatment of JIA by developing a new dialogical counselling methode. But while the research is done, the analysis in still ongoing and must be completed somewhere in autumn 2008.
DMARD Resistance
Projectleader: dr. G. Jansen
University: VUMC Amsterdam
Email: g.jansen@vumc.nl
The goal of this project was to delineate the molecular basis of diminished responsiveness/resistance to DMARD's that the majority of RA patients face either before treatment or along the duration of treatment.
The project demonstrated that expression of Multidrug resistance-related proteins, in particular Pgp, MRP1, MRP4 and MRP7 is up-regulated in DMARD non-responding RA patients. The project also demonstrated that for cell entry of MTX, different types of folate transport systems are operative in peripheral blood lymphocytes and synovial tissue macrophages.
Toll-like receptor (TLR) expression determines chronicity of joint inflammation
Projectleader: dr. L.A.B. Joosten
University: Radboud Universiteit Nijmegen
email: l.joosten@reuma.umcn.nl
In this project the researchers investigated the role of TLR signaling in the development of chronic destructive joint inflammation. They have revealed that the expression of TLR2,3,4 and 7 is significantly higher in synovial tissue from RA patients compared to that of healthy controls.
A novel approach to stimulate cartilage repair: targetting collagen turnover
Projectleader: mw. dr. G.J. V.M. van Osch
University: Erasmus MC Rotterdam
Email: g.vanosch@erasmusmc.nl
The goal of the project was to search for novel ways to modulate collagen synthesis and assembly, in order to promote cartilage repair. For this, the researchers have used several approaches to modulate the formation and function of a collagen network in vitro and thus improve our understanding of cartilage repair mechanisms: growth factors, collagen crosslinking, COMP and proteoglycans.
Tolerantie-inductie door regulatoire T-cellen voor de behandeling van auto-immuunziekten
Projectleader: dr. R.E.M. Toes
University: LUMC Leiden
Email: r.e.m.toes@lumc.nl
The original research goal addressed by this project was whether regulatory T-cells can be used to prevent of stop chronic arthritis, and if so, by which mechanisms this is achieved.The researchers showed that CD4+CD25+ Treg cells are not only playing a role in the inhibition of arthritis induction, but also that they van be used to treat the disease following adoptive transfer.
Ras family GTPase regulation of fibroblast-like Synoviocyte Function in Rheumatoid Arthritis
Projectleader: dr.K.A. Reedquist
University: AMC Amsterdam
Email: k.a.reedquist@amc.uva.nl
In this project the researchers were unable to find data to supporting the original hypotheses, that changes in Ras protein expression or signalling might lead to ROS-dependent genotoxic damage of tumor surpressor genes.
However, the studies have identified specific contibutions of Ras regulatory proteins and downstream signalling targets to destructive MMP production, joint erosion, and disease progression in RA.The researchers hope that their studies will further invite efforts to develop RasGRF1 inhibitory compounds. And that they will provide some new biomarkers.
Autologous bone marrow-derived mononuclear cell transplantation for shoulder muscle function improvement in patient with fatty and/or artropic degeneration of the rotator cuff muscles
Projectleader: prof.dr. R.G.H.H. Nelissen
University: LUMC Leiden
Email: r.g.h.h.nelissen@lumc.nl
The goal of this pilot study was to evaluate the improvement of shoulder muscles function following transplantation of the mononuclear cell fraction (MNCs) of the adult bone marrow (BM). The primary objective was the assessment of the safety and feasibility of intramuscular injection of BM-derived MNC's in the shoulder cuff muscle of patients following shoulder arthroplasty.
It was not possible tot meat the primary objective because of problems with the CT analysis and muscle biopsies. These technique must be improved first.
The second goal was to assess muscle improvement of the shoulder cuff muscle and/or improvement of the shoulder functionality. Compared to the preoperative evaluation, patients scored significantly higher on SF-36 at 3 and 6 month following shoulder arthroplasty and MNC transplantation. Also scores on DASH and Oxford shoulder increased significantly.
Inhibition of inflammatory cell migration; a novel approach in the treatment of rheumatoid arthritis
Projectleader: dr. P.L. Hordijk
Institute: Sanquin Research/AMC, Amsterdam
Email: p.hordijk@sanquin.nl
The ultimate goal in this project was to develop a complete new approach for the treatment of RA. That finally could result in new or additional therapeutic approaches for RA patients who are not or poorly responding to the current therapies.
However, since the researchers only could observe an effect on pawswelling and not on two important other hallmarks of arthritis, inflammation and bone/cartage destruction, after treatment with the Rac-1 c-terminal peptide, these experiments do not support at this stage further development of this peptide for clinical applications in patients with RA.
But, on scientific point of view these experiments have given a lot of insight in the working mechanism of these kind of peptides in vivo and in vitro. The data will be used for follow-up research on small GTPase inhibitors.
Projecten afgerond in 2007
Tailored behavioural and cognitive treatment in recently diagnosed fibromyalgia patients at risk: a randomized, controlled trial
Projectleader: mw. dr. A.W.M. Evers
University: UMC st Radboud Nijmegen
Email: a.evers@mps.umcn.nl
In this randomized, controlled trial, the efficacy of a tailored multidisciplinary treatment for FM patients at risk, consisting of tailored cognitive behaviour therapy and physical exercise training, was subsequently shown. As part of a 4-year project, the 3rd year was financed by the Reumafonds.
As a follow up on this research, in june 2008 an implementationproject was started, granted by the Reumafonds. This is necessary because this specialized type of tailored multidisciplinary care for patients at risk is not yet available in the regular care in the Netherlands.
Effectiveness, acceptance and costs of sterling silver finger and prefabricated thermoplastic fingersplints for swan neck deformity in patients with rheumatoid arhritis: a randomised cross-over study
Projectleader: mw. dr. T.P.M. Vliet Vlieland
University: LUMC Leiden
Email: t.p.m.vliet_vlieland@lumc.nl
The researchers compared two fingersplints for swan neck deformity.Preliminary conclusions: there were no significant differences in clinical effectiveness between sterling silver finger splints and prefab thermoplastic finger splints in patients with RA and swanneck deformities.
Both swan-neck orthoses improved dexterity and pain. There is more data forthcoming.
Ontkoppelen TGF's-Beta's "Bright side" en "Dark side"
Projectleader: dr. P.M. van der Kraan
University: Radboud University Nijmegen
Email: p.vander kraan@reuma.umcn.nl
We show that blocking TGF beta activity in the synovial lining can inhibit synovial fibrosis without interfering with the positive effects of TGF beta on cartilage. The secondary mediators of TGF beta CTGF and BMP2, do not appear to play a crucial role in the induction of persistent fibrosis or in early osteophyte information.
Identification of down stream mediators of macrophage FcyRI activation involved in cartilage erosion
Projectleader: dr. P.L.E.M. van Lent
University: Radboud UMC Nijmegen
Email: p.vanlent@reuma.umcn.nl
In this one year project we performed microarray studies. The goal was to identify genes involved in cartilage destruction and particularly regulated by FcγRI.
Analysing the microarray data it came out that particularly two families of genes may be involved in FcγRI mediated cartilage destruction. First the S100 family with important members S100A8 and A9 and secondly the protein convertase family with as important representative PACE-4.
The research can lead to new therapeutic possibilities to inhibit erosions in RA patients. A follow-up on this project will start in 2007.
Towards exvivo siRNA therapeutic approach of osteoartritic cartilage
Projectleader: mw. dr. G. J.V.M. van Osch
University: Erasmus MC Rotterdam
Email: g.vanosch@erasmusmc.nl
Projecten afgerond in 2006
Development of in vivo gene therapy for Sjögrens's syndrome (SS)
Projectleader: prof. dr. P.P. Tak
University: AMC Amsterdam
Email: p.p.tak@amc.uva.nl
We have shown that the NOD mouse model, an established model for type I diabetes, develops an exocrinopathy characterized by diminished salvary flow that is age and gender dependent. The latter charateristic, which is lacking in all other SS animal model to date, makes it the most suitbale candidate for the development of a pre-clinical testing model for SS.
Local gene transfer to the salivary glands is quite straightforward. The expirements in this study provide the rationale for further optimization of the gene constructs, aiming at clinical development for patients with SS.
The role of DC-SIGN expression in Rheumatoid Arthritis
Projectleader: dr. P.L.E.M. van Lent
University: University Medical Center, Nijmegen
E-mail: p.vanlent@reuma.umcn.nl
The following questions are investigated:
1.Does DC-SIGN and FcγRIIb expression on synovial macrophages /dendritic cells of RA patients lead to excessive TNF and enzyme production and thereby to more severe cartilage destruction?
2.Does a high DC-SIGN and FcγRIIb expression on mature DC lead to promotion of 'autoimmunity'?
Experimental studies have shown that the inhibitory FcγRIIb is of crucial importance in the regulation of increased immunity which leads to severe inflammation and cartilage destruction during experimental arthritis. In dendritic cells of RA patients FcγRIIb is high expressed, but it is only low on macrophages. Increase of FcγRIIb on dendritic cells might lead to a disturbed T cell response which inhibits macrophage activation.
On the contrary, decrease of FcγRIIb on macrophages leads to activation of this cell via the stimulation with immune complexes. In summary, it seems that a disturbed FcγRIIb regulation on crucial cells involved in RA could be an important cause of inflammation and cartilage destruction. Further studies are at present directed to develop therapeutic strategies to restore the disturbed FcγRIIb expression on the dendritic cell and macrophage.
Nonmyeloablative conditioning and allogeneic stem cell transplantation as platform for adoptive cellular therapy of arthritis
Projectleader: dr. J.M. van Laar
University: LUMC Leiden
Email: j.m.van_laar@lumc.nl
The results from this project lend support to the development of nonmyeloablative conditioning and allogenic stem cell transplantation as a treatment option for severe autoimmune diseases, including refractory RA.
The results suggest that this treatment may provide an effective en relatively non-toxic means of eradicating autoaggressive T and B lymphocytes from a patient, while maintaining immunocompetence due to rapid engraftment of donor stem cells.
The finding that donor NK-cells play a key role in establishing donor chimerism in haploidentical transplant settings opens avenues for adoptive cell therapy.
Is it possible to prevent progression to rheumatoid arthritis by a 1-year course of methothrexate in a group of patients with undifferentiated arthritis that exists less than two years?
Projectleader: prof. dr. T.W.J. Huizinga
University: LUMC Leiden
Email: T.W.J.Huizinga@lumc.nl
This study indicates that a window of opportunity is present duren the time that patients with probable RA progress into RA that meets the ACR criteria. A strategy in which a 1 year course of MTX is given to patients with probable RA is beneficial with respect to less progression to RA.
Moreover, less joint destruction was observed in the patients treated with MTX then in the patients treated with placebo. The presence of autoantibodies precedes RA als well as predicts evolvement in to RA from UA. The differences in outcome measures were most pronounced in patientes with anti-CCP antibodies.
Computer-assisted radiological measurement of joint damage in Reumatoid Arthritis
Projectleader: dr. H. J. Bernelot Moens
University: Universiteit Twente
Email: h.moens@zgt.nl
Dr. Bernelot Moens aimed tot develop an automated system fort the measurement of joint damage by rheumatoid arthritis on digitized X-rays of hand and feet. His group developed a system to recognize individual joints automatically on hand X-rays.
International cooperation has been set up in the Omeract Special Interest group for measurement of joint damage. Within this framework, the system developed was tested and compared with other systems from around the world.
Breaking the vicious cicle of joint degeneration in OA: targeting Toll-like receptors -a 1 year pilot study-
Projectleader: dr. J. DeGroot
Researchinstitute: TNO Quality of Life Leiden
Email: J.deGroot@pg.tno.nl
In this pilot project dr. de Groot aimed at obtaining proof-of-principle that (combinations of) in vivo occurring extracellular matrix fragments activate TLRs and thereby contribute tot amplification and progression of cartilage destruction in OA, and may therefore serve as targets for therapy. After the experiments, this principle could not be proven.
Biomarkers of Radiographic Progression in Ankylosing Spondylitis
Projectleader: dr. R. Landewé
University: AZM Maastricht
Email: r.lan@sint.azm.nl
The researchers were able to measure sera from 100 OASIS patients and urine samples of 86 OASIS patients, of whom they had data about the level of damage and subsequent 2-year progression. A panel of biomarkers was measured in the sera and two biomarkers were measured in the urine.
In the analysis phase, biomarkers were correlated with acute phase reactants, disease activity measures and variables reflecting radiographic damage and progression