Rheumatoid Arthritis: Netherlands

van der Woude D, Huizinga TW. · Leiden University Medical Center, Department of Rheumatology, Albinusdreef 2, 2300 RC Leiden, The Netherlands. <> · Best Pract Res Clin Rheumatol. · Pubmed #18455686 No free full text.

Abstract: Findings from basic research in combination with precise clinical observations of the disease course in rheumatoid arthritis (RA) have led to the development of a multistage model to explain the pathophysiology of RA. Different cellular and soluble mediators, which play principal roles at different phases of the disease, have been identified. New therapeutic agents, which specifically target these factors, now allow us to intervene at several levels of the pathogenesis. This has already resulted in significant improvements for patients suffering from RA, and the development of new promising agents continues at a high pace. However, many questions concerning the optimal use of the new therapies remain unanswered. Combined efforts of basic research and clinical trials investigating the optimal timing and combination of the new treatments will be necessary to allow them to achieve their full potential and to result in the maximum benefit for patients.

van Hagen PM, Dalm VA, Staal F, Hofland LJ. · Department of Immunology, Erasmus Medical School, Rotterdam, The Netherlands. · Mol Cell Endocrinol. · Pubmed #18450367 No free full text.

Abstract: Cortistatin (CST) is a recently described neuropeptide that shares high homology with somatostatin (somatotropin release-inhibiting factor, SRIF) and binds with high affinity to all somatostatin (sst) receptor subtypes. CST is currently known to have a widespread distribution in many human organs including the immune system. The activities specific to CST may be partially attributable to its binding to the growth hormone secretagogue (GHS)-receptor (GHS-R) and the orphan G-protein-coupled receptor MrgX2. Human immune cells produce CST, whereas macrophage lineage and activated endothelium express sst2, and human lymphocytes express sst3. The human thymus expresses sst1, 2, 3, MrgX2 and almost all immune cells express GHS-R. Moreover, at this very moment promising research with CST in experimental animal models is being performed. On the basis of these promising results, studies aiming to further evaluate the possibilities of CST as a therapeutic agent in human immune-mediated inflammatory diseases are warranted.

Geusens P. · Internal Medicine and Rheumatology, University Hospital, Maastricht, The Netherlands. · Minerva Med. · Pubmed #18431325 No free full text.

Abstract: Clinical features associated with osteoporotic fractures include increased morbidity (pain, physical impairment, decreased quality of life), increased risk for new fractures (even within short-term) and increased mortality. Readily recognizable clinical features that indicate a high risk for fracture include age, gender, low body weight, history of fracture, familial history of fracture, severe immobilization, smoking, rheumatoid arthritis, use of glucocorticoids and clinical risks for falls. In addition, many patients with fractures and osteoporosis have pre-existing contributors to secondary osteoporosis, many of which are correctable.

Takken T, van Brussel M, Engelbert RH, Van der Net J, Kuis W, Helders PJ. · University Medical Center Utrecht, Department of Pediatric Physical Therapy & Exercise Physiology, Room Kb 02.056.0, POBox 85090, Utrecht, Netherlands, 3508 AB. · Cochrane Database Syst Rev. · Pubmed #18425929 No free full text.

Abstract: BACKGROUND: Exercise therapy is considered an important component of the treatment of arthritis. The efficacy of exercise therapy has been reviewed in adults with rheumatoid arthritis but not in children with juvenile idiopathic arthritis (JIA). OBJECTIVES: To assess the effects of exercise therapy on functional ability, quality of life and aerobic capacity in children with JIA. SEARCH STRATEGY: The Cochrane Central Register of Controlled Trials (CENTRAL), Cochrane Database of Systematic Reviews (The Cochrane Library), MEDLINE (January 1966 to April 2007), CINAHL (January 1982 to April 2007), EMBASE (January 1966 to October 2007), PEDro (January 1966 to October 2007), SportDiscus (January 1966 to October 2007), Google Scholar (to October 2007), AMED (Allied and Alternative Medicine) (January 1985 to October 2007), Health Technologies Assessment database (January 1988 to October 2007), ISI Web Science Index to Scientific and Technical Proceedings (January 1966 to October 2007) and the Chartered Society of Physiotherapy website (http://www.cps.uk.org) were searched and references tracked. SELECTION CRITERIA: Randomised controlled trials (RCTs) of exercise treatment in JIA. DATA COLLECTION AND ANALYSIS: Potentially relevant references were evaluated and all data were extracted by two review authors working independently. MAIN RESULTS: Three out of 16 identified studies met the inclusion criteria, with a total of 212 participants. All the included studies fulfilled at least seven of 10 methodological criteria. The outcome data of the following measures were homogenous and were pooled in a meta-analysis: functional ability (n = 198; WMD -0.07, 95% CI -0.22 to 0.08), quality of life (CHQ-PhS: n = 115; WMD -3.96, 95% CI -8.91 to 1.00) and aerobic capacity (n = 124; WMD 0.04, 95% CI -0.11 to 0.19). The results suggest that the outcome measures all favoured the exercise therapy but none were statistically significant. None of the studies reported negative effects of the exercise therapy. AUTHORS' CONCLUSIONS: Overall, based on 'silver-level' evidence (www.cochranemsk.org) there was no clinically important or statistically significant evidence that exercise therapy can improve functional ability, quality of life, aerobic capacity or pain. The low number of available RCTs limits the generalisability. The included and excluded studies were all consistent about the adverse effects of exercise therapy; no short-term detrimental effects of exercise therapy were found in any study. Both included and excluded studies showed that exercise does not exacerbate arthritis. The large heterogeneity in outcome measures, as seen in this review, emphasises the need for a standardised assessment or a core set of functional and physical outcome measurements suited for health research to generate evidence about the possible benefits of exercise therapy for patients with JIA. Although the short-term effects look promising, the long-term effect of exercise therapy remains unclear.

van der Helm-van Mil AH, Huizinga TW. · Department of Rheumatology, Leiden University Medical Center, PO Box 9600, 2300RC Leiden, The Netherlands. · Arthritis Res Ther. · Pubmed #18394179 links to  free full text

Abstract: In the past few years considerable advances have been made in the genetics of susceptibility to rheumatoid arthritis (RA). For decades the HLA-DRB1 alleles were the only extensively replicated genetic factor, but more genetic risk factors have now been identified that predispose to RA. Interestingly, several of the observed genetic variants conferred risk to anticitrulline-peptide antibody (ACPA)-positive RA and two variants may be restricted to ACPA-negative RA, pointing to the need for subclassification of RA. The current manuscript reviews recently identified genetic factors predisposing to ACPA-positive RA and ACPA-negative RA. Additionally, although being scarcely explored, genetic variants affecting the severity of disease course are discussed.

van der Kooij SM, Allaart CF, Dijkmans BA, Breedveld FC. · Leiden University Medical Center, Leiden, The Netherlands. · Curr Opin Rheumatol. · Pubmed #18388520 No free full text.

Abstract: PURPOSE OF REVIEW: The present review provides an update on novel treatment strategies striving for remission in patients with recent onset of rheumatoid arthritis. RECENT FINDINGS: As early treatment is crucial to achieve optimal results, identifying patients with rheumatoid arthritis early is imperative to achieve clinical remission. Patients with early arthritis who will progress to rheumatoid arthritis can be identified, and treating these patients can postpone the diagnosis of rheumatoid arthritis and retard the progression of structural damage. The best way to achieve remission is by adjusting treatments at regular intervals using predetermined response criteria. Specific treatments to rapidly induce remission include disease modifying antirheumatic drugs combinations, especially combined with glucocorticoids or tumor necrosis factor antagonists. The prediction of joint damage progression, or the response to specific drugs is not yet accurately possible. The early institution of tumor necrosis factor antagonists followed by discontinuation leads to sustained clinical benefit. SUMMARY: Early treatment of patients with rheumatoid arthritis with strategies aiming at remission results in the best outcomes. Until the prediction of a severe disease course and treatment response becomes possible, a promising strategy would be to rapidly induce remission using an effective combination of drugs followed by tapering and discontinuation. Tumor necrosis factor antagonists have proven to be highly effective in this approach.

Folkerts G, Kraneveld AD, Nijkamp FP. · Division of Pharmacology and Pathophysiology, Utrecht Institute for Pharmaceutical Sciences, University of Utrecht, 3508 TB Utrecht, The Netherlands. <> · Trends Pharmacol Sci. · Pubmed #18353448 No free full text.

Abstract: Chronic respiratory inflammation is caused by a sustained influx of macrophages and neutrophils, which leads to tissue remodeling and collagen breakdown. Recently, we have identified collagen-breakdown products that can activate and attract inflammatory cells via the CXC (two cysteines with an inverting amino acid)1 and CXC2 receptors (CXCR1 and CXCR2). By using a technique called 'inverted hydropathy', small peptides were synthesized that interact specifically with the responsible collagen-breakdown products and inactivate them. After inactivation, the collagen-breakdown products are no longer able to bind to their receptors. These neutralizing peptides inhibited neutrophil influx, heart hypertrophy and lung emphysema in animal models, and they are likely to be useful in other diseases that are characterized by a chronic inflammation, such as rheumatoid arthritis and inflammatory bowel diseases, where neutrophils are potential target cells. In this opinion article we will present a new hypothesis through which the chronicity and remodeling of tissue of several inflammatory diseases could be explained.

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.

Hamdy NA. · Department of Endocrinology & Metabolic Diseases, Leiden University Medical Center, Leiden, The Netherlands. · Drugs Today (Barc). · Pubmed #18301800 No free full text.

Abstract: Receptor activator of nuclear factor-kB (RANK), its ligand (RANKL) and its decoy receptor osteoprotegerin (OPG) together play a key role in osteoclastogenesis. Alterations in the RANKL/ OPG ratio are central in the pathogenesis of bone loss, from osteoporosis in all its forms to malignancy-induced bone loss. This fact has led to the search for drugs capable of targeted RANKL inhibition in the management of skeletal disorders associated with bone loss. Promising preclinical data using OPG have paved the way for the development of the new agent denosumab, a high-affinity, high-specificity, fully human monoclonal antibody to RANKL, shown to be able to induce a dose-dependent, rapid, profound and sustained inhibition of bone resorption lasting for months after a single subcutaneous injection in healthy postmenopausal women, men and patients with multiple myeloma or metastatic breast cancer. Data from a phase II study in postmenopausal women with low bone mineral density (BMD) demonstrate that the sustained inhibition of bone resorption induced by three or six monthly subcutaneously administered denosumab was associated with significant increases in BMD for up to two years of treatment. Antifracture efficacy and long-term skeletal and extraskeletal safety of denosumab are being addressed in ongoing phase III trials. The potential of denosumab to prevent bone loss has also been demonstrated in malignancy-induced bone loss. Ongoing studies in rheumatoid arthritis are also promising.

van Beijnum JR, Buurman WA, Griffioen AW. · Angiogenesis Laboratory, Department of Pathology, Research Institute for Growth and Development (GROW), Maastricht University, P.O. Box 5800, 6202 AZ, Maastricht, The Netherlands. · Angiogenesis. · Pubmed #18264787 No free full text.

Abstract: Sustained proinflammatory responses in rheumatoid arthritis, atherosclerosis, and diabetic retinopathy, as well as in cancer, are often associated with increased angiogenesis that contributes to tissue disruption and disease progression. High mobility group B1 (HMGB1) has been recognized as a proinflammatory cytokine and more recently, as a proangiogenic factor. HMGB1 can either be passively released from necrotic cells or actively secreted in response to angiogenic and inflammatory signals. HMGB1 itself may signal through the receptor for advanced glycation end products (RAGE), and via toll-like receptors, TLR2 and TLR4. Activation of these receptors results in the activation of NFkappaB, which induces the upregulation of leukocyte adhesion molecules and the production of proinflammatory cytokines and angiogenic factors in both hematopoietic and endothelial cells, thereby promoting inflammation. Interestingly, HMGB1 seems to be involved in a positive feedback mechanism, that may help to sustain inflammation and angiogenesis in several pathological conditions, thereby contributing to disease progression. Endothelial cells express HMGB1, as well as the receptors RAGE, TLR2, and TLR4, and in diverse pathologies HMGB1 and its receptors are overexpressed. Furthermore, HMGB1-induced signaling can activate NFkappaB, which can subsequently induce the expression of HMGB1 receptors. Thus, HMGB1 can mediate amplification of inflammation and angiogenesis through increased secretion of HMGB1 and increased expression of the receptors it can interact with. In this review, we discuss signaling cascades that HMGB1 can induce via TLRs and RAGE, as well as its contribution to pathologies involving endothelial cells.

Van den Ende CH, Vliet Vlieland TP, Munneke M, Hazes JM. · NIVEL, Netherlands Institute of Primary Health Care, PO Box 1568, Utrecht, Netherlands 3500 BN. · Cochrane Database Syst Rev. · Pubmed #18253972 No free full text.

Abstract: BACKGROUND: Rheumatoid arthritis (RA) is a chronic inflammatory disease affecting the musculoskeletal system. Inflammation of the joints and tendons results in pain, swelling and restricted movement, eventually leading to radiological changes and deformities. Exercise therapy is considered to be an important cornerstone of the treatment of RA in all stages of the disease. OBJECTIVES: To assess the effects of dynamic exercise therapy in improving joint mobility, muscle strength, aerobic capacity and daily functioning in patients with rheumatoid arthritis (RA). In addition, possible unwanted effects such as an increase in pain, disease activity and radiological progression were studied. SEARCH STRATEGY: We searched the Cochrane Musculoskeletal trials register, the Cochrane Controlled trials Register, MEDLINE, EMBASE and SCISEARCH databases up to May 1997 in order to controlled trials on the effect of exercise therapy. SELECTION CRITERIA: Randomized trials on the effect of dynamic exercise therapy in RA patients with an exercise program fulfilling the following criteria: a) intensity level such that heart rates exceeded 60% of maximal heart rate during at least 20 minutes, b) exercise frequency of two sessions per week, and c) duration of intervention of greater than six weeks DATA COLLECTION AND ANALYSIS: Two blinded reviewers independently selected eligible studies, rated the methodological quality and extracted data. MAIN RESULTS: Six out of 30 identified controlled trials met the inclusion criteria. Four of the six included studies fulfilled at least seven out of 10 methodological criteria. Due to heterogeneity in outcome measures, data could not be pooled. The results suggest that dynamic exercise therapy is effective at increasing aerobic capacity and muscle strength. No detrimental effects on disease activity and pain were observed. The effects of dynamic exercise therapy on functional ability and radiological progression are unclear. AUTHORS' CONCLUSIONS: The results suggest that dynamic exercise therapy is effective at increasing aerobic capacity and muscle strength. No detrimental effects on disease activity and pain were observed. The effects of dynamic exercise therapy on functional ability and radiological progression are unclear.Dynamic exercise therapy has a positive effect on physical capacity. Research on the long-term effect of dynamic exercise therapy on radiological progression and functional ability is needed.

Toonen EJ, Barrera P, Radstake TR, van Riel PL, Scheffer H, Franke B, Coenen MJ. · Department of Human Genetics, Radboud University Nijmegen Medical Centre, PO Box 9101, 6500 HB Nijmegen, The Netherlands. · Ann Rheum Dis. · Pubmed #18250114 No free full text.

Abstract: Over the last years microarray technologies have generated new perspectives for the high-throughput analysis of biological systems. Nowadays, it is possible to monitor thousands of genes in a single experiment. This molecular profiling technology combined with standardised and validated clinical measurements can allow a more precise characterisation of a patient's phenotype, and may lead to the design of therapeutic protocols and procedures better tailored to an individual patient's needs. In this report we provide an overview of expression profiling studies in rheumatoid arthritis (RA). RA is a chronic inflammatory disease in which both genetic and environmental factors are involved. The precise molecular mechanisms underlying RA are not fully understood. A systematic literature search revealed nine array-based expression profiling studies in patients with RA. Findings from these studies were compared with those of linkage and genome-wide association (GWA) studies. Although we observed many differences in study design, analysis and interpretation of results between the different studies, we extracted two sets of genes: (1) those differentially expressed in more than one study, and (2) genes differentially expressed in at least one of the reviewed studies and present in RA linkage or GWA loci. We suggest that both sets of genes include interesting candidate genes for further study in RA.

Plasqui G. · Department of Human Biology, Maastricht University, PO Box 616, 6200 MD Maastricht, The Netherlands. · Physiol Behav. · Pubmed #18234247 No free full text.

Abstract: Rheumatoid arthritis (RA) is a chronic inflammatory auto-immune disease, causing progressive damage to the musculoskeletal system. Many patients with RA also suffer from accelerated muscle loss or cachexia, which contributes to the loss of physical function and quality of life. Physical activity plays a central role in the management of the disease as it is essential to maintain muscle strength and endurance, range of motion and the ability to perform activities of daily life. On the other hand, given the nature of the disease, there is always an increased risk for injury. There is a large amount of literature investigating the effect of exercise interventions on muscle function and disease activity. These studies show that exercise clearly improves muscle function without affecting disease activity. Studies including radiographic evaluation of joint damage as an endpoint also show that there is no evidence that exercise, even high-intensity exercise, increases inflammation or joint damage, although care should be taken with patients with severe baseline damage. Regarding daily physical activity (exercise is only one component of physical activity) there is hardly any research done showing either that physical activity is indeed decreased in patients or whether or not there is a relation between daily physical activity and disease activity. The results from studies looking at the effect of exercise on muscle mass or the ability to prevent or reverse cachexia are somewhat contradictory, but it seems that when the training dose is sufficiently large, gains in muscle mass can be achieved.

Nurmohamed MT. · Department of Internal Medicine, VU University Medical Centre, Amsterdam, The Netherlands. · Vasc Health Risk Manag. · Pubmed #18200805 links to  free full text

Abstract: Cardiovascular morbidity and mortality are enhanced in rheumatoid arthritis, which might be due to an increased prevalence of cardiovascular risk factors such as dyslipidemia. The dyslipidemia observed in RA appears to be dependent on disease activity, ie, a higher disease activity is associated with lower total cholesterol levels and even more depressed high density lipoprotein levels, leading to a higher (ie, unfavorable) atherogenic index. It appears that this dyslipidemia is already present long before the clinical onset of rheumatoid arthritis. Antirheumatic drug treatment with disease modifying antirheumatic drugs as well TNF-blocking agents has, in general, favorable, albeit moderate, effects on the lipid profile. Therefore, it is unlikely that the observed beneficial effects of antirheumatic drug treatment on cardiovascular morbidity and cardiovascular mortality in rheumatoid arthritis is mediated through effects on the lipid metabolism. Management of dyslipidemia in rheumatoid arthritis should be part of a general cardiovascular risk management. Hence, in addition to the assessment of the lipid profile, other cardiovascular risk factors should be determined and appropriate treatment installed when indicated. Lower treatment thresholds should be considered in view of the enhanced cardiovascular risk in rheumatoid arthritis and guidelines should be developed based on epidemiological data.

Wessels JA, Huizinga TW, Guchelaar HJ. · Department of Clinical Pharmacy and Toxicology, Leiden University Medical Center, PO Box 9600, 2300 RC Leiden, The Netherlands. · Rheumatology (Oxford). · Pubmed #18045808 No free full text.

Abstract: This review presents recent data supporting the methotrexate (MTX) mechanisms of action, which are likely to account for its anti-proliferative and immunosuppressive effects in rheumatoid arthritis (RA). The effects of MTX in vivo may be mediated by reducing cell proliferation, increasing the rate of apoptosis of T cells, increasing endogenous adenosine release, altering the expression of cellular adhesion molecules, influencing production of cytokines, humoral responses and bone formation. Several reports indicate that the effects of MTX are influenced by genetic variants, specific dynamic processes and micro-environmental elements such as nucleotide deprivation or glutathione levels. The challenge for the future will be linking biological and genetic markers relevant to the response to MTX in RA.

Lubberts E. · Department of Rheumatology, Erasmus Medical Center, Dr. Molewaterplein 50, 3015 GE Rotterdam, The Netherlands. · Cytokine. · Pubmed #18039580 No free full text.

Abstract: Interleukin-17A (IL-17A) contributes to the pathogenesis of arthritis. Data from experimental arthritis indicate IL-17 receptor signaling as a critical pathway in turning an acute synovitis into a chronic destructive arthritis. The identification of six IL-17 family members (IL-17A-F) may extend the role of this novel cytokine family in the pathogenesis of chronic destructive joint inflammation. Whether the successful anti-IL-17A cytokine therapy in murine arthritis can be effectively translated to human arthritis need to be tested in clinical trials in humans. Interestingly, IL-17A and IL-17F are secreted by the novel T helper subset named Th17. This novel pathogenic T cell population induces autoimmune inflammation in mice and is far more efficient at inducing Th1-mediated autoimmune inflammation in mice than classical Th1 cells (IFN-gamma). In addition to IL-17A and IL-17F, Th17 cells are characterized by expression of IL-6, TNF, GM-CSF, IL-21, IL-22 and IL-26. Th17 cells have been established as a separate lineage of T helper cells in mice distinct from conventional Th1 and Th2 cells. Whether this also applies to human Th17 and whether RA is a Th1 or a Th17 mediated disease is still not clear. This review summarizes the findings about the role of IL-17 in arthritis and discusses the impact of the discovery of the novel Th17 cells for arthritis. Further studies are needed to unravel the role of Th17 cells and the interplay of IL-17 and other Th17 cytokines in the pathogenesis of arthritis and whether regulating Th17 cell activity will have additional value compared to neutralizing IL-17A activity alone. This might help to reach the ultimate goal not only to treat RA patients but to prevent the development of this crippling disease.

Meijer JM, Pijpe J, Bootsma H, Vissink A, Kallenberg CG. · Department of Oral and Maxillofacial Surgery, University Medical Center Groningen, University of Groningen, The Netherlands. · Clin Rev Allergy Immunol. · Pubmed #17992596 links to  free full text

Abstract: The gain in knowledge regarding the cellular mechanisms of T and B lymphocyte activity in the pathogenesis of Sjögren's syndrome (SS) and the current availability of various biological agents (anti-TNF-alpha, IFN- alpha, anti-CD20, and anti-CD22) have resulted in new strategies for therapeutic intervention. In SS, various phase I and II studies have been performed to evaluate these new strategies. Currently, B cell-directed therapies seem to be more promising than T cell-related therapies. However, large, randomized, placebo-controlled clinical trials are needed to confirm the promising results of these early studies. When performing these trials, special attention has to be paid to prevent the occasional occurrence of the severe side effects.

Landewé R. · Department of Internal Medicine/Division of Rheumatology and Caphri Research Institute, University Hospital Maastricht, Maastricht, The Netherlands. · J Rheumatol Suppl. · Pubmed #17985418 No free full text.

Abstract: The emphasis in rheumatoid arthritis (RA) management today is on early diagnosis and intervention, but the choice of intervention has become increasingly complex. The number of disease modifying antirheumatic drugs available for treatment of RA has increased significantly. The efficacy, toxicity, and cost of those agents vary widely. And the progression of joint damage in RA is highly unpredictable and variable, ranging from self-limited disease to rapid progressive destruction. Prognostic markers that could identify patients with aggressive, rapidly progressing disease and predict the response to therapy would provide a rational basis for early, aggressive treatment. They would also protect patients with less aggressive disease from possible overtreatment and toxicities, and could have a significant influence on allocation of healthcare resources. The search for predictive markers of arthritis outcome has been and undoubtedly will continue to be the subject of many studies. This article will review both established and emerging predictive markers in RA.

Sutmuller R, Garritsen A, Adema GJ. · Target Discovery Oss, NV Organon, 5340 BH Oss, The Netherlands. · Ann Rheum Dis. · Pubmed #17934105 No free full text.

Abstract: Regulatory T cells (Treg) play a crucial role in maintaining control of leucocytes. Several studies have shown that in vivo Treg depletion results in autoimmune syndromes like thyroiditis, gastritis, diabetes mellitus and colitis, but at the same time, may also result in improved anti-tumour vaccination. Although Treg are recognised to maintain peripheral tolerance in healthy individuals, recent research has shown that Treg also suppress immune responses during infections to prevent tissue damage. How the Treg themselves are regulated is still under investigation. Their suppressive activity must be regulated in order to allow for the effective elimination of pathogens. Until recently, this control of Treg function was found to be through modulation via cytokines or by stimulation via co-stimulatory molecules on antigen-presenting cells. It is now demonstrated, however, that the presence of pathogens can be communicated to Treg directly through toll-like receptors (TLRs). Up until now, Treg have been reported to respond to ligands for TLR2, 4, 5 and 8, and different TLRs can have alternative effects on Treg resulting in more suppression or, in contrast, abrogation of suppression. As TLRs can also recognise endogenous proteins, such as heat shock proteins, it is tempting to speculate on the role of these proteins in modulating Treg function during chronic inflammation. In this review, we will discuss the implications of TLR engagement on Treg and any consequences this may have for chronic autoinflammatory diseases like rheumatoid arthritis (RA).

Bakker MF, Jacobs JW, Verstappen SM, Bijlsma JW. · University Medical Center Utrecht, Department of Rheumatology & Clinical Immunology, F02.127, PO Box 85500, 3508 GA Utrecht, The Netherlands. · Ann Rheum Dis. · Pubmed #17934098 No free full text.

Abstract: OBJECTIVE: To evaluate the available evidence on the efficacy and feasibility of the new concept of tight control in randomised trials in patients with rheumatoid arthritis (RA). Tight control is a treatment strategy tailored to the individual patient with RA, which aims to achieve a predefined level of low disease activity or remission within a certain period of time. METHODS: The literature database PubMed was searched and yielded four trials: the FIN-RACo trial, the TICORA study, the BeSt study and the CAMERA study. RESULTS: Tight control resulted in greater improvement and a higher percentage of patients meeting the preset aim of low disease activity or remission when compared to the control intervention. In the FIN-RACo trial, analysing the subset of patients completing the study, 68% in the tight control group achieved remission (DAS28<2.6) verus 41% in the contrast group [corrected] In the TICORA study, 65% of patients in the tight control group versus 16% of the contrast group achieved remission, based on DAS<1.6 (p<0.0001). In the CAMERA study, 50% of patients in the tight control group using a computer decision model achieved remission, versus 37% in the contrast group (p = 0.029). The BeSt study consisted of only tight control groups aimed at a DAS<1.6; remission was achieved in 38-46% of patients. This is higher than the range of remission in earlier trials of 13-36%. CONCLUSION: Tight control aiming for low disease activity or even better still, remission, seems a promising option in treating patients with RA in clinical trials and probably also in daily practice.

van den Berg WB, van Lent PL, Joosten LA, Abdollahi-Roodsaz S, Koenders MI. · Rheumatology Research and Advanced Therapeutics, Radboud University Nijmegen Medical Center, Geert Grooteplein 26, 6525 GA Nijmegen, The Netherlands. · Ann Rheum Dis. · Pubmed #17934095 No free full text.

Abstract: Rheumatoid arthritis (RA) is a systemic autoimmune disease characterised by chronic joint inflammation and variable degrees of bone and cartilage erosion. Studies in animal models of arthritis provide insight into elements which can amplify destructive features. The presence of immune complexes in the joint makes arthritis more erosive. Although considerable bone erosion still occurs in the absence of FcgammaR triggering by immune complexes, through cytokine-induced RANKL and direct osteoclast activation, cartilage erosion is heavily dependent on the FcgammaR pathway. T cell factors such as IFNgamma and IL17 further amplify erosion through upregulation of the damaging FcgammaRI and stimulation of the influx of granulocytes, respectively. Apart from immune elements, environmental pressure and components of tissue damage contribute through innate pathways. Spontaneous T cell-dependent arthritis in IL1Ra-/- mice is absent under germ-free conditions, and markedly suppressed in TLR4-deficient mice. Moreover, TLR4 blocking with a receptor antagonist suppresses erosive arthritis.

van Riel PL, Fransen J. · Radboud University Nijmegen Medical Centre, Department of Rheumatology, PO Box 9101, 6500HB Nijmegen, The Netherlands. · Best Pract Res Clin Rheumatol. · Pubmed #17870029 No free full text.

Abstract: Clinical assessment of established rheumatoid arthritis (RA) can have several purposes. It can be used to evaluate prognosis, disease course or interventions at both the individual and the group level (i.e. in a clinical trial), over the short or long term. The instruments used for the different purposes are not always the same. For example, information on prognosis is very useful when assessing the risk:benefit ratio of early aggressive pharmacotherapy; however, established prognostic factors are currently of limited use in individual patients with established RA. As, at the individual patient level, disease activity, disability and joint damage have variable courses, the course of the disease should be evaluated regularly both with process (i.e. erythrocyte sedimentation rate, joint counts) and with outcome (i.e. radiological progression, sum of past process) measures. For the evaluation of interventions, 'core sets' of valid measures to assess disease activity, outcome and specific criteria for improvement are used; these can, to some extent, be useful in clinical practice.

van de Merwe JP. · Erasmus MC, University Medical Center Rotterdam, Departments of Immunology and Internal Medicine, Dr Molewaterplein 50, Rotterdam, The Netherlands. · Nat Clin Pract Urol. · Pubmed #17823601 No free full text.

Abstract: The cause of interstitial cystitis, a chronic disease that affects the bladder, is unknown. Autoantibodies, such as those against nuclear and bladder epithelium antigens, have been found in patients with interstitial cystitis, but these are likely to be secondary to the disease. No data support a direct causal role of autoimmune reactivity in the pathogenesis of interstitial cystitis. Indirect evidence, however, does support a possible autoimmune nature of interstitial cystitis, such as the strong female preponderance and the clinical association between interstitial cystitis and other known autoimmune diseases within patients and families. The strongest association occurs between interstitial cystitis and Sjögren's syndrome. Increasing evidence suggests a possible role of autoantibodies to the muscarinic M3 receptor in Sjögren's syndrome. The M3 receptor is also located on the detrusor muscle cells of the bladder and mediates cholinergic contraction of the urinary bladder and other smooth muscle tissues. Autoantibodies to the M3 receptor might be important in both the early noninflammatory and the late inflammatory features of interstitial cystitis.

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.

Vliet Vlieland TP. · Department of Rheumatology, C1-R, Leiden University Medical Center, P.O. Box 9600, 2300 RC Leiden, The Netherlands. · Rheumatology (Oxford). · Pubmed #17586864 No free full text.

Abstract: Non-pharmacological treatment modalities are often recommended, prescribed and used in addition to drug treatment in patients with rheumatoid arthritis (RA). This article provides a review of the literature on their effectiveness. Currently, a considerable number of systematic reviews summarising the available studies for non-drug care interventions in RA are available. The evidence of effectiveness varies among the different non-pharmacological modalities, with relatively strong support for exercise and self-management interventions, and modest support for joint protection programmes, specific orthoses and comprehensive care interventions. Overall, the evidence for effectiveness of massage and electro-physical modalities is absent or weak. In general, few studies in patients with early RA, studies comparing different attributes of non-pharmacological modalities or comprehensive care models and economic evaluations have been performed, so that the optimal timing, intensity, duration and mode of delivery often remain unclear. The results of this review indicate a need for further investigation into the most clinically and cost-effective strategies to deliver individual non-pharmacological treatment modalities as well as comprehensive arthritis service delivery models for RA patients in different stages of the disease.