Rheumatoid Arthritis: Tak PP

Vervoordeldonk MJ, Aalbers CJ, Tak PP. · No affiliation provided · Ann Rheum Dis. · Pubmed #19139202 No free full text.

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de Vries N, Tak PP. · No affiliation provided · Rheumatology (Oxford). · Pubmed #15855186 links to  free full text

This publication has no abstract.

Hamilton JA, Tak PP. · Arthritis and Inflammation Research Centre, University of Melbourne and Department of Medicine, The Royal Melbourne Hospital, Parkville, Victoria, Australia. · Arthritis Rheum. · Pubmed #19404968 No free full text.

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Lebre MC, Tak PP. · Division of Clinical Immunology and Rheumatology, Academic Medical Center/University of Amsterdam, Amsterdam, The Netherlands. · Hum Immunol. · Pubmed #19236901 No free full text.

Abstract: Dendritic cells (DC) comprise a complex network of heterogeneous antigen-presenting cells (APC) that are critical not only to the initiation and regulation of adaptive immunity (Th1/Th2/Th17 responses), but also to the maintenance of both central and peripheral tolerance (regulatory T cells, peripheral T-cell deletion). Previous work has clearly indicated a role for DC subsets in the pathogenesis of rheumatoid arthritis (RA). Therefore, utilizing these cells as therapeutic agents could be beneficial in the treatment of RA. However, it remains unclear which DC should be used for tolerance-inducing immunotherapy: myeloid, plasmacytoid, or both? This review summarizes the data obtained thus far concerning the functional characterization of several DC subsets in human RA and accordingly explores their potential use for immunotherapy.

Grabiec AM, Tak PP, Reedquist KA. · Division of Clinical Immunology and Rheumatology, Academic Medical Center, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands. · Arthritis Res Ther. · Pubmed #18983693 links to  free full text

Abstract: Cellular activation, proliferation and survival in chronic inflammatory diseases is regulated not only by engagement of signal trans-duction pathways that modulate transcription factors required for these processes, but also by epigenetic regulation of transcription factor access to gene promoter regions. Histone acetyl transferases coordinate the recruitment and activation of transcription factors with conformational changes in histones that allow gene promoter exposure. Histone deacetylases (HDACs) counteract histone acetyl transferase activity through the targeting of both histones as well as nonhistone signal transduction proteins important in inflammation. Numerous studies have indicated that depressed HDAC activity in patients with inflammatory airway diseases may contribute to local proinflammatory cytokine production and diminish patient responses to corticosteroid treatment. Recent observations that HDAC activity is depressed in rheumatoid arthritis patient synovial tissue have predicted that strategies restoring HDAC function may be therapeutic in this disease as well. Pharmacological inhibitors of HDAC activity, however, have demonstrated potent therapeutic effects in animal models of arthritis and other chronic inflammatory diseases. In the present review we assess and reconcile these outwardly paradoxical study results to provide a working model for how alterations in HDAC activity may contribute to pathology in rheumatoid arthritis, and highlight key questions to be answered in the preclinical evaluation of compounds modulating these enzymes.

Gerlag DM, Tak PP. · Division of Clinical Immunology and Rheumatology, Academic Medical Centre/University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands. · Best Pract Res Clin Rheumatol. · Pubmed #18455687 No free full text.

Abstract: The analysis of synovial biomarkers is increasingly used in the context of innovative trial design in rheumatoid arthritis (RA). This approach, which is generally well tolerated by patients, has been used to provide insight into the pathogenesis of RA and the mechanism of action of therapy, as well as for screening purposes during early drug development.

Lebre MC, Tak PP. · Academic Medical Center, University of Amsterdam, Division of Clinical Immunology and Rheumatology, Amsterdam, The Netherlands. · Acta Reumatol Port. · Pubmed #18344920 links to  free full text

Abstract: Dendritic cells (DC) are now known to influence many different classes of lymphocytes (T, B, NK cells) and many types of T cell responses (Th1/Th2/Th17, regulatory T cells, peripheral T cell deletion). In rheumatoid arthritis (RA) DC have been described and their roles in RA pathogenesis have been implicated. This review summarizes the data obtained so far concerning the functional characterization of several DC subsets in human RA. Moreover, the effect of TNF-alpha blockade on DC phenotype and function is also discussed. As most of the studies on DC in experimental arthritis have been conducted using (immunomodulated/tolerogenic) DC as tools to ameliorate experimental arthritis, we give some examples of how these cells may induce tolerance in vivo. Although a lot of work has been performed so far, the specific and functional roles of DC subsets in human RA and in CIA remain to be established. Achieving a detailed understanding of specific DC functions in RA holds potential for modulating DC for immunotherapy by down-regulating the autoimmune response.

Tracey D, Klareskog L, Sasso EH, Salfeld JG, Tak PP. · Abbott Bioresearch Center, Worcester, MA, USA. · Pharmacol Ther. · Pubmed #18155297 No free full text.

Abstract: During the past 30 years, elucidation of the pathogenesis of rheumatoid arthritis, Crohn's disease, psoriasis, psoriatic arthritis and ankylosing spondylitis at the cellular and molecular levels has revealed that these diseases share common mechanisms and are more closely related than was previously recognized. Research on the complex biology of tumor necrosis factor (TNF) has uncovered many mechanisms and pathways by which TNF may be involved in the pathogenesis of these diseases. There are 3 TNF antagonists currently available: adalimumab, a fully human monoclonal antibody; etanercept, a soluble receptor construct; and infliximab, a chimeric monoclonal antibody. Two other TNF antagonists, certolizumab and golimumab, are in clinical development.The remarkable efficacy of TNF antagonists in these diseases places TNF in the center of our understanding of the pathogenesis of many immune-mediated inflammatory diseases. The purpose of this review is to discuss the biology of TNF and related family members in the context of the potential mechanisms of action of TNF antagonists in a variety of immune-mediated inflammatory diseases. Possible mechanistic differences between TNF antagonists are addressed with regard to their efficacy and safety profiles.

van Leuven SI, Franssen R, Kastelein JJ, Levi M, Stroes ES, Tak PP. · Academic Medical Center, Department of Vascular Medicine, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands. · Rheumatology (Oxford). · Pubmed #17702769 No free full text.

Abstract: Several chronic inflammatory disorders, such as systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA), and chronic infections that are associated with a chronic inflammatory state, such as human immunodeficiency virus (HIV) infection, are associated with an increased incidence of cardiovascular disease (CVD). Cardiovascular mortality is a major cause of death in patients with these disorders. Direct effects and indirect sequelae of systemic inflammation promote atherothrombotic vascular disease. Pathophysiological processes promoting atherogenesis can initiate years before the diagnosis of a chronic inflammatory disease is made, and since exposure to risk factors in this pre-clinical phase is widespread, early cardiovascular protection in these patients seems warranted.

Vierboom MP, Jonker M, Tak PP, 't Hart BA. · Department of Immunobiology, Biomedical Primate Research Centre, Rijswijk, The Netherlands. · Drug Discov Today. · Pubmed #17395093 No free full text.

Abstract: The costs for the development of new drugs have increased dramatically over the past 30 years. One of the main reasons for this increase is the low success rate of new drugs being approved for patient use, which is, in part, a consequence of the common use of rodent models for preclinical validation of efficacy. Especially in the development of biologicals, which are now successfully used in the treatment of rheumatoid arthritis, the selection of the right animal model is pivotal. Non-human primates could help to bridge the evolutionary gap between rodent models and human patients.

Cantaert T, De Rycke L, Bongartz T, Matteson EL, Tak PP, Nicholas AP, Baeten D. · University of Amsterdam, Amsterdam, The Netherlands. · Arthritis Rheum. · Pubmed #17075816 links to  free full text

This publication has no abstract.

Tak PP. · Division of Clinical Immunology and Rheumatology F4-218, Academic Medical Centre/University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands. · Best Pract Res Clin Rheumatol. · Pubmed #16980215 No free full text.

Abstract: Synovial inflammation in rheumatoid arthritis (RA) and other arthritides is, in part, dependent on migration of inflammatory cells as well as retention of these cells at the site of inflammation. Chemokines play a critical role in these processes and represent an attractive target for therapeutic intervention. Animal models of RA have shown that it is possible to induce clinical improvement by specifically targeting chemokines or their receptors. Although at present only very limited data exist, initial data suggest that it may be possible to reduce synovial inflammation in patients with RA by specific chemokine blockade. Innovative trial design may help to screen for potentially interesting chemokine antagonists in an early stage of development.

Thurlings RM, Vos K, Gerlag DM, Tak PP. · Academisch Medisch Centrum/Universiteit van Amsterdam, afd. Klinische Immunologie en Reumatologie, Postbus 22.660, 1100 DD Amsterdam. · Ned Tijdschr Geneeskd. · Pubmed #16922350 No free full text.

Abstract: Recent research has shown that the humoral response plays an important role in the pathogenesis of rheumatoid arthritis. B-cells produce rheumatoid factors and antibodies directed against cyclic citrullinated peptides (anti-CCP antibodies) and are able to present auto-antigens to T-cells. Furthermore, B-cells can produce cytokines and stimulate T-cells. B-cell depletion with rituximab, a monoclonal antibody directed against CD20, has a surprisingly strong and long-lasting therapeutic effect. After administration a sharp decrease of specific auto-antibody titres has been observed. Future developments in B-cell targeted therapy are expected to lead to further improvements in the treatment of rheumatoid arthritis and other autoimmune diseases.

Lodde BM, Baum BJ, Tak PP, Illei G. · Gene Therapy and Therapeutics Branch/NIDCR, National Institutes of Health, 10 Center Drive, Building 10, Room 1N114, Bethesda, MD 20892-1190, USA. · Ann Rheum Dis. · Pubmed #16880196 No free full text.

Abstract: Sjögren's syndrome is an autoimmune exocrinopathy, mainly affecting the lacrimal and salivary glands, and resulting in ocular and oral dryness (keratoconjunctivitis sicca and xerostomia). The aetiology and pathogenesis are largely unknown, and only palliative treatment is currently available. Data obtained from experimental animal and human studies using biological agents or gene therapeutics can offer insight into the disease process of Sjögren's syndrome. This article reviews the current literature on these approaches and assesses the lessons learnt about the pathogenesis of Sjögren's syndrome.

Adriaansen J, Vervoordeldonk MJ, Tak PP. · Clinical Immunology and Rheumatology, Academic Medical Center/University of Amsterdam, Amsterdam, The Netherlands. · Rheumatology (Oxford). · Pubmed #16510530 links to  free full text

Abstract: In recent years, significant progress has been made in the treatment of rheumatoid arthritis (RA). In addition to conventional therapy, novel biologicals targeting tumour necrosis factor-alpha have successfully entered the clinic. However, the majority of the patients still has some actively inflamed joints and some patients suffer from side-effects associated with the high systemic dosages needed to achieve therapeutic levels in the joints. In addition, due to of the short half-life of these proteins there is a need for continuous, multiple injections of the recombinant protein. An alternative approach might be the use of gene transfer to deliver therapeutic genes locally at the site of inflammation. Several viral and non-viral vectors are being used in animal models of RA. The first gene therapy trials for RA have already entered the clinic. New vectors inducing long-term and regulated gene expression in specific tissue are under development, resulting in more efficient gene transfer, for example by using distinct serotypes of viral vectors such as adeno-associated virus. This review gives an overview of some promising vectors used in RA research. Furthermore, several therapeutic genes are discussed that could be used for gene therapy in RA patients.

Vergunst CE, van de Sande MG, Lebre MC, Tak PP. · Division of Clinical Immunology and Rheumatology, Academic Medical Centre/University of Amsterdam, the Netherlands. · Scand J Rheumatol. · Pubmed #16393761 No free full text.

Abstract: The directed movement of immune cells is highly dependent on the chemokine network. Chemokines are key molecules early in the embryogenesis of lymph nodes and throughout adult life, where they regulate immune responses against pathogens. Although immune cells are best known for expressing chemokine receptors, through which they can respond to matching chemokines, endothelial cells also express chemokine receptors. The directed movement of endothelial cells facilitates angiogenesis. In chronic inflammatory conditions, such as rheumatoid arthritis (RA), chemokines are abundantly present at the site of inflammation and form a group of potential therapeutic targets. Some agents that block chemokine-chemokine receptor interaction are already under clinical investigation. The expression of chemokine receptors has also been found in cell types other than immune cells and endothelial cells. Chondrocytes, for instance, express several chemokine receptors. Elucidating their function may provide new insights into joint degradation in RA as well as in other conditions, including osteoarthritis (OA).

Bresnihan B, Baeten D, Firestein GS, Fitzgerald OM, Gerlag DM, Haringman JJ, McInnes IB, Reece RJ, Smith MD, Ulfgren AK, Veale DJ, Tak PP, Anonymous00383. · Department of Rheumatology, St. Vincent's University Hospital, Dublin, Ireland. · J Rheumatol. · Pubmed #16331792 No free full text.

Abstract: Synovial tissue analysis has considerable potential for future randomized controlled trials (RCT). The synovial membrane is the target tissue in treatment strategies of rheumatoid arthritis and other arthropathies. Effective modulation of synovitis is critical when attempting to control symptoms and signs, to prevent joint damage, and to maintain function. In RCT, the systematic evaluation of changes in synovial tissue after commencing treatment enables identification of an early therapeutic effect, using relatively small numbers of patients. This special interest group is working on establishing the evidence to have this endpoint meet the OMERACT filter criteria.

Vergunst CE, Tak PP. · Division of Clinical Immunology and Rheumatology, F4-218, Academic Medical Center/University of Amsterdam, Meibergdreef 9, NL-1105 AZ Amsterdam, The Netherlands. · Curr Rheumatol Rep. · Pubmed #16174489 No free full text.

Abstract: Chemokines are small proteins that can act on cells that express matching receptors. They are best known for their role in migration of cells, especially immune cells. Chemokine/chemokine-receptor pairs are often functionally categorized into three groups: inflammatory, homeostatic, and angiogenic/angiostatic, although functions sometimes overlap. Interfering with the interaction between chemokines and their receptors is currently under investigation as a therapeutic strategy in rheumatoid arthritis.

Smith MD, Baeten D, Ulfgren AK, McInnes IB, Fitzgerald O, Bresnihan B, Tak PP, Veale D, Anonymous00013. · Rheumatology Research Unit, Repatriation General Hospital, Adelaide, South Australia. · Ann Rheum Dis. · Pubmed #15975970 links to  free full text

Abstract: Changes in cellular infiltrate and expression of cytokines, chemokines, and cell adhesion molecules as a result of therapeutic interventions in rheumatoid arthritis can be demonstrated in the synovial membrane. However, before synovial tissue analysis can be used as an outcome measure in such studies, standardisation of the site and method of synovial tissue acquisition, methods of tissue processing, and appropriate methods of detection and measurement of cell lineage specific markers and relevant biological proteins is needed.

Haringman JJ, Oostendorp RL, Tak PP. · Division of Clinical Immunology and Rheumatology F4-218, Department of Internal Medicine, Academic Medical Center, University of Amsterdam, Meibergdreef 9, NL-1105 AZ, Amsterdam, The Netherlands. · Expert Opin Emerg Drugs. · Pubmed #15934868 No free full text.

Abstract: The development of specific targeted therapies, such as anti-TNF-alpha treatment, for chronic inflammatory disorders such as rheumatoid arthritis, has significantly improved treatment, although not all patients respond. Targeting cellular adhesion molecules and chemokines/chemokine receptors as regulators of the extravasation and migration of leukocytes may provide a novel approach for the treatment of these diseases. Moreover, the possibility of developing small-molecule antagonists offers an excellent method for the oral delivery of compounds with a short half-life.

Tak PP. · Division of Clinical Immunology and Rheumatology, Academic Medical Center/University of Amsterdam, Amsterdam, The Netherlands. · J Rheumatol Suppl. · Pubmed #15742462 No free full text.

Abstract: Several studies have shown decreased synovial inflammation after treatment of patients with rheumatoid arthritis (RA) with infliximab. Recent data indicate that these effects can be detected as soon as 48 hours after first infusion. Although there are strong indications that infliximab exerts its effects in patients with Crohn's disease by induction of apoptosis in the gut, there are as yet no studies that convincingly show the same mechanism of action in RA. Conceivably, neutralization of tumor necrosis factor-alpha may be sufficient to induce clinical improvement in RA, even without induction of apoptosis at the site of inflammation. This hypothesis could explain the observation that both infliximab and etanercept are effective in RA, whereas apoptosis induction by infliximab might be required in Crohn's disease. Future studies should focus on the evaluation of apoptosis within the first 48 hours after initiation of therapy in RA to exclude the possibility that the effects occur very early after infliximab infusion.

Tas SW, Remans PH, Reedquist KA, Tak PP. · Division of Clinical Immunology and Rheumatology, Academic Medical Center, University of Amsterdam, 1100DD Amsterdam, The Netherlands. · Curr Pharm Des. · Pubmed #15720277 No free full text.

Abstract: Many chronic inflammatory diseases are associated with deregulated intracellular signal transduction pathways. Resultant pathogenic interactions between immune and stromal cells lead to changes in cell activation, proliferation, migratory capacity, and cell survival that all contribute to inflammation. Increasing efforts are now being made in the design of novel therapeutic compounds to interfere with signaling pathways in inflammatory diseases like rheumatoid arthritis (RA). In this review we will outline the major signal transduction pathways involved in the pathogenesis of RA. We will assess advances in targeting a number of key intracellular pathways, including nuclear factor-(kappa)B (NF-(kappa)B), mitogen-associated protein kinases (MAPKs), phosphoinositide 3-kinase (PI3K)/Akt, signal transducers and activators of transcription (STATs), and reactive oxygen species (ROS) production. Finally, we will discuss recently identified lead molecules and the progress of selected compounds towards becoming new drugs for the treatment of inflammatory diseases.

Tak PP. · Division of Clinical Immunology and Rheumatology, Academic Medical Center, University of Amsterdam, 1100 DE Amsterdam, The Netherlands. · J Rheumatol Suppl. · Pubmed #15660460 No free full text.

Abstract: The synovium is the key target of the disease process in rheumatoid arthritis (RA). Examination of synovial tissue samples may provide insight into the events that take place in different phases of the disease and may help to decipher the mechanism of action of antirheumatic treatment. This review describes the features of synovitis in early RA, which clearly represent chronic inflammation. There is marked interindividual variability, suggesting that RA consists of different pathogenetic subsets. Evaluation of serial synovial tissue samples has shown that effective treatment is associated with a reduction in synovial macrophages, independent of the specific mechanism of action of the compound. This suggests that these are key effector cells in the pathogenesis. In addition, it provides a biomarker that can be used in clinical trials.

Haringman JJ, Tak PP. · Academisch Medisch Centrum/Universiteit van Amsterdam, afd. Klinische Immunologie en Reumatologie, F4-218, Meibergdreef 9, 1105 AZ Amsterdam. · Ned Tijdschr Geneeskd. · Pubmed #15495938 No free full text.

Abstract: Chemokines form a relatively new family of chemotactic cytokines that seem to play a central role in the migration and activation of leukocytes in a wide variety of immune-mediated disorders. Specific therapy targeted against these proteins may well become an effective treatment in many of these disorders. The efficacy and safety of chemokine blockade is currently being investigated in clinical trials on patients with HIV infection, multiple sclerosis, rheumatoid arthritis and other chronic inflammatory disorders. The first results have been reported in patients with rheumatoid arthritis and these seem to confirm the potency of this treatment.

Tak PP. · Division of Clinical Immunology and Rheumatology Academic Medical Center/ University of Amsterdam, The Netherlands. · Front Biosci. · Pubmed #15353352 No free full text.

Abstract: IFN-beta is a cytokine with pleiotropic effects and is expressed in rheumatoid synovial tissue. Based on in vitro work and experiments in animal models of rheumatoid arthritis (RA), the effects are mainly anti-inflammatory. Of special interest is the ability of IFN-beta to reduce the secretion of TNF-alpha, IL-1 beta, and IL-6, which are all key players in the pathogenesis of RA. At the same time IFN-beta could enhance the production of anti-inflammatory mediators like IL-1 receptor antagonist (IL-1Ra) and IL-10. Treatment of mice and monkeys with collagen-induced arthritis with daily IFN-beta injections resulted in clinical improvement, decreased synovial inflammation, and protection against joint destruction. Similar data were obtained after IFN-beta gene therapy. However, treatment of RA patients with IFN-beta has been unsuccessful so far, presumably due to pharmacokinetic issues. Novel approaches leading to constitutive IFN-beta production at the site of inflammation may be required to induce clinical efficacy in patients.