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ID PMID Title PublicationDate abstract
15589430 Signal transduction pathways: new targets for treating rheumatoid arthritis. 2004 Nov Biotherapies and other new treatments introduced over the last few years have considerably enriched the therapeutic armamentarium for rheumatoid arthritis. Nevertheless, primary refractoriness or secondary escape phenomenon may occur, indicating a need for identifying new treatment targets. Promising candidates can be found among compounds involved in signal transduction pathways, most notably protein kinases (mitogen-activated protein kinase, MAPK and phosphatidylinositol-3 protein kinase, PI3) and transcription factors (nuclear factor kappa B, NF-kappaB; activating protein 1, AP-1; CCAAT/enhancer-binding protein, C/EBP and signal transducer and activator of transcription, STAT). Inhibition of signal transduction pathways may be achievable via three main strategies: pharmacological inhibitors, anti-sense or more specific inhibitors such as oligionucleotides or interfering mRNA, and induced overexpression of naturally occurring inhibitors. Clinical trials are under way to evaluate pharmacological inhibitors such as p38 MAPK. Although the preliminary results are promising, proof of safety has not yet been obtained. Signal transduction pathways are involved in normal processes, whose inhibition might produce untoward effects.
11981322 Autoantigenic posttranslational modifications of proteins: does it apply to rheumatoid art 2002 May There are many posttranslational modifications of proteins of which all are homeostatically important either to carry out a particular structural or functional role or to allow efficient recycling of the amino acid constituents. An important feature of the modified proteins is the acquisition of autoantigenicity. That notion should have been recognized for years with the modifications of immunoglobulin G that constitute new targets for rheumatoid factors. Citrullination or the deimination of arginine residues in proteins creates epitopes that are targeted by rheumatoid autoantibodies with a diagnostic sensitivity and specificity of 40% to 70% and 92% to 99%, respectively. The how, when, and why of the responsible break in tolerance are largely speculative but apoptosis, multiple genetic and environmental influences are likely required. Identifying citrullinated proteins as autoantigens has resulted in new diagnostic and prognostic autoantibody markers for RA and studying the citrullination process and its nature and role in cell biology has provided new insights into its pathogenesis.
14685718 [Imaging techniques in rheumatology: scoring methods in rheumatoid arthritis]. 2003 Dec This is a critical overview of existing scoring methods including their basis, their measurement systems, their advantages and disadvantages. Conventional radiography is still-since available everywhere, interpretable and cost effective-the best imaging method to evaluate the course of RA. Scoring methods are designed to semiquantitatively measure radiographically visible changes, especially erosive destruction and-in part-cartilage loss. These methods are well validated, reproducible, and yield similar results in clinical trials. Most methods overestimate early changes and have a clear ceiling effect. Within the time frame of clinical trials radiographic evaluation is not very sensitive to change since the progression of destruction in RA is relatively slow. Moreover, small erosions cannot be detected if they are not at the margin of the bone or if they are superimposed by other bones. Within the Larsen method the definition of grade 1 by soft tissue swelling is disadvantageous: soft tissue swelling is difficult to identify on X-rays, it is a measure of disease activity and not of destruction and is quickly reversible. Joint space narrowing, measured with Sharp's method and its modifications, may be caused by misprojection due to soft tissue swelling with flexion or subluxation of the joint rather than cartilage loss. Since the measurement error of a scoring method is very much dependent on the severity of the disease of the patient population and on the quality of the radiographs, the measurement error and thereby the minimal detectable change (MDC) should be stated for every single clinical trial. Conventional radiographs and scoring methods are still indispensable to measure the influence of treatment on radiographic progression in RA. A future task will be to include in scoring methods the rating of reparative changes which cannot be scored so far.
12058953 What can we learn from the synovium in early rheumatoid arthritis? 2002 Apr Rheumatoid arthritis (RA) affects approximately 1% of the population and is a chronic inflammatory joint disease resulting in joint destruction, increased morbidity and mortality. Although the aetiology of this disease is unknown, the pivotal role played by cytokines and degradative enzymes in mediating inflammation and joint destruction, particularly early in the disease process, has been the focus of recent literature and will be the focus of this review. Up until recently, studies on early RA were limited as there was an inherent delay in patients reaching the rheumatologist's care and initial diagnostic confusion may have compounded these problems. In particular, the observation that early intervention improves outcome, has driven the study of early RA. It is difficult to define early RA but most studies have defined this as disease duration of less than 12 months from symptom onset. Clearly, it is important to study the synovial membrane in early disease, in particular to try and answer the important questions: (1) What are the earliest changes to occur in the RA synovium? (2) Can we distinguish RA on the basis of synovial membrane pathology? (3) Can synovial immunopathology predict outcome? (4) What is the role of arthroscopic biopsy in early RA?
12435165 Pharmacological management of early rheumatoid arthritis--does combination therapy improve 2002 Nov Treatments for rheumatoid arthritis (RA) have involved a variety of single agent and combination therapies with one paramount goal, to slow disease progression and bone destruction. However, data indicate that not all drug combinations are equally efficacious in all patients with RA, and toxicity levels can be difficult to manage. In addition to these concerns, studies are difficult to compare because of methodologic differences and differing drug doses and schedules, for example. To more accurately discern how to best manage early RA, and because treating RA within 3 months of diagnosis appears crucial for improved outcomes, this review summarizes studies that compared combination to monotherapies in early RA, while attempting to consider factors that could complicate the results. These reports utilized disease modifying antirheumatic drugs (DMARD) with known efficacy among patients with RA, but more importantly a number also used varying levels of glucocorticoids as well. Collectively, these data are beginning to shed light on how to best treat early RA, suggesting that DMARD work best when given very early.
11845011 Influence of cigarette smoking on disease outcome in rheumatoid arthritis. 2002 Mar Cigarette smoking is a well-known risk factor for rheumatoid arthritis. However, the influence of smoking on disease outcome has only been investigated very recently, and the data are not clear-cut. Smoking has a number of important effects on the immune system and sex hormones that may influence disease pathogenesis. Smoking has also been shown to affect disease outcome in other inflammatory diseases. The major focus of this review is to explore the relationship between smoking and severity of rheumatoid arthritis in detail.
14969064 Aggressive rheumatoid arthritis registry in Italy. Characteristics of the early rheumatoid 2003 Sep The Italian Society of Rheumatology in the year 2000 decided to sponsor the creation of a data base (Registry) of consecutive patients who fulfilled the diagnosis of rheumatoid arthritis (RA) according to the American College of Rheumatology (ACR) criteria. The registry is designed to collect data on the "aggressive" type of RA all over the country in order to determine the percentage of patients who satisfy the established criteria among incident cases of RA and to define the therapeutic approach according to the characteristics of the enrolled patients. Predefined criteria set up by eight recognized opinion leaders on the disease were used by all the centers to create the database. The GIARA registry (Gruppo Italiano Artrite Reumatoide Aggressiva) has now enrolled 706 patients who will be followed up for 24 months. They have been divided into two major subsets--patients with early (< 4 months' disease duration) and late (> 4 months) RA--with the aim of establishing whether differences in clinical, serological, radiographic and therapeutic (DMARDs: disease modifying antirheumatic drugs) parameters may distinguish the two subsets. The major conclusion of this preliminary analysis is that an overall tendency to undertreatment is discernable.
12421093 Advances in understanding the genetic basis of rheumatoid arthritis and osteoarthritis: im 2002 Rheumatoid arthritis (RA) and osteoarthritis (OA) are polygenic diseases. Polymorphisms in candidate genes have been studied for possible association with susceptibility to disease development. Aside from HLA polymorphisms, of particular interest are those in genes encoding cytokines, signaling molecules, and enzymes involved in the production and catabolism of oxygen and nitrogen radicals. Cytokines are involved in the modulation of the pathological process and have been the target for novel therapeutic interventions. Evidence for their involvement in RA and OA has been provided from genetic analyses in patient populations as well as from animal models of disease. Intracellular signaling cascades control cellular responses and thus regulate many aspects of the pathology manifested in rheumatic diseases. Deciphering the organization and activity of such signaling pathways in disease is underway. Polymorphisms have been identified in gene promoter regions regulating efficient binding of transcription factors, and in coding regions of genes whose products are involved in signal cascades relevant to RA. Among these are the NF-kappaB pathway, steroid receptors and the p53 tumor suppressor gene. Both reactive oxygen species (ROS) and reactive nitrogen species (RNS) have also been implicated in rheumatic diseases. It is thought that excess, damaging, ROS/RNS may arise from an imbalance between the production and removal of these chemical species. Polymorphisms in genes that encode enzymes involved in either generating or degrading ROS/RNS may contribute to such an imbalance. In the last few years, polymorphisms in such genes have indeed been identified as risk factors for rheumatic diseases.
15053450 Methodological issues in conducting and analyzing longitudinal observational studies in rh 2004 Mar This article discusses 5 methodological issues that arise in the course of conducting longitudinal observational studies: generalizability, missing data, repeated measures on the same individual, measures taken at varying time points from symptom onset, and assessing the effect of treatment. Methods discussed include general estimating equations and propensity scores. The points are illustrated by examples from the Norfolk Arthritis Register dataset.
15575425 [Moderate intensive exercise has a positive effect in rheumatoid arthritis]. 2004 Nov 4 Rheumatoid arthritis (RA) often confers disability and increased risk of coronary heart disease and premature death. Decreased body functions and psychological obstacles in the individual with RA, and health care workers' fear of causing short-term and long-term aggravation of the disease, might represent barriers to starting and maintaining physical activity. However, there is now good evidence for the safety and benefit of moderately intensive exercise for individuals with RA. Thus, these people should be recommended, and actively supported in, physical activity.
12435162 Evidence supporting the benefit of early intervention in rheumatoid arthritis. 2002 Nov Numerous challenges confront the rheumatologist in identifying the earliest possible time during which the patient will have persistent rheumatoid arthritis (RA) or risk factors for severe RA. The first challenge is that of accurate diagnosis: clinical assessments are nonspecific and current diagnostic criteria lack sensitivity. Further compounding the problem, the patient may not seek medical attention, or may not be referred to a rheumatologist, until symptoms have been present for some time. Studies indicate that initiating treatment with disease modifying antirheumatic drugs (DMARD) as soon as possible after diagnosis produces significant clinical and functional benefit and appears to retard the rate of radiographic progression of erosions. Delaying treatment by as little as 8 or 9 months sets the stage for damage that cannot be reversed.
15589429 Clinical and pathophysiological significance of the autoimmune response to citrullinated p 2004 Nov Rheumatoid arthritis (RA) is the most frequent human autoimmune disease, affecting about 1% of the adult population worldwide. A better knowledge of the autoimmune mechanisms involved is essential. We identified the epithelial targets of various autoantibodies specifically associated to RA, as variants of (pro)filaggrin. We also showed that these targets correspond to deiminated ("citrullinated") proteins, of which arginyl residues have been posttranslationally transformed into citrullyl residues by a peptidylarginine deiminase (PAD). Moreover, we and others established that citrullyl residues are indispensable elements of the epitopes recognized by these autoantibodies but only in the context of specific aminoacid sequences. We also demonstrated that these autoantibodies to citrullinated proteins (ACPA) are secreted by plasma cells of the synovial tissue and that their major targets correspond to citrullinated forms of the alpha- and beta-chains of fibrin, abundant in the tissue. These results have allowed the development of new efficient immunochemical methods for the detection of ACPA. Some of them are already commercially available. These new methods have permitted the high diagnostic value of ACPA which are present very early in the course of the disease, and also their prognostic value, to be confirmed. ACPA detection should therefore prove to be also a very valuable tool to guide the choice of therapeutic strategies, from the earliest stages of the disease. The synthesis of ACPA in the rheumatoid synovial tissue and the existence therein of a specific antigenic target constitute a strong argument for the involvement of this specific immunological conflict in the pathophysiology of RA. Indeed, it could lead to activation of effector mechanisms with pro-inflammatory effects, thus to formation in the tissue of new fibrin deposits, secondarily citrullinated. We therefore, propose a new pathophysiological model accounting for the self-maintenance and chronicity of rheumatoid inflammation. Numerous questions about the pathophysiological significance of the autoimmune response to deiminated proteins in RA remain to be answered to confirm this model.
14531956 Early rheumatoid arthritis: toward tailor-made therapy. 2003 Aug Therapeutic possibilities for the treatment of early rheumatoid arthritis (RA) have expanded largely. New treatment modalities appear very effective with respect to relevant outcomes, such as radiographic progression. At the same time, the costs of disease-modifying antirheumatic drugs (DMARDs) have exponentially increased so that--given the rather high prevalence of RA--cost may become a limiting factor in the treatment of patients with RA. Therefore, there is a need to define the profile of those patients that should be treated with the most effective, and, unfortunately, the most costly, DMARDs. The authors describe herewith the heterogeneity of RA with respect to its most important outcomes, as well as the inability to predict those outcomes appropriately at the individual patient level. This heterogeneity of RA is not acknowledged in the modern landmark clinical trials that the authors base therapeutic decisions on, and the external validity of those trials is at stake. In this article, the authors discuss the consequences of the heterogeneity of RA in light of the perceived lack of external validity of evidence-generating landmark trials. The authors propose the following solutions to overcome this discrepancy: 1) earlier recognition of RA, and 2) appropriate prediction of treatment efficacy, because the most challenging scientific efforts may be taken in the near future in order to arrive at a tailor-made therapy for every individual presenting with RA.
15201945 [Disability and quality of life of patients with rheumatoid arthritis: assessment and pers 2004 Jan Functional disability and quality of life in rheumatoid arthritis (RA) are key outcomes that determine patient's demand for care, and influence their compliance and satisfaction with treatment. In the recent years the demand to collect outcome data is ever increasing as a means for the validation of quality care, and the development of effective outcome measures has become a major thrust of health research and has contributed to better understanding the relationship between outcomes and specific elements of health care. There are several disease-generic and specific instruments available that have proven valuable in outcome testing in RA. The first instruments provide a broad picture of health status across a range of conditions, whereas the latter are more sensitive to the disorder under consideration and are therefore more likely to reflect clinically important changes. When necessary, this kind of scales can be supplemented with specialised domain-specific scales (for the assessment of psychological well-being, social role functioning, or other). As in other fields, these measurement instruments mainly focus on: a) clinical signs and symptoms (physiologic and biologic); b) physical and/or cognitive functioning; c) well-being and emotional functioning; d) social functioning; e) satisfaction with care and other personal constructs (life satisfaction, spirituality, etc.); f) health-related quality of life (HRQOL). Over the past 20 years, there has been a better recognition of the patient's point of view as an important component in the assessment of health care outcomes, and an increasing interest in HRQOL as an important area of research, due to the rising burden of chronic diseases, longer expectation of life, the growing number of health intervention alternatives, and greater emphasis on humanising health care. In addition, decision-making on issues of cost-effectiveness across health inputs and resource allocation across health programs is likely to be more sound if informed by HRQOL evidence. This paper reviews the literature and discusses the major issues regarding mainly measures of physical function (e.g., mobility or daily activities) and health status, including some so called HRQOL instruments.
15142643 Could rheumatoid arthritis result from an abnormal T cell response towards lubricin/superf 2004 The lack of some suppressor T cells (including TCD4+CD25+(high) positively selected first in thymic medulla) specific to a restricted set of autoantigens may be the common link between all patterns of rheumatoid arthritis. In other words, instead of a 'peak' of TCD4+ effector T cells common to all patients with rheumatoid arthritis (which has so far never been demonstrated), a 'hole' in TCD4+CD25+(high) responses towards a limited set of autoantigens responsible for the normal maintenance of tolerance within the joints may be shared by many patients with rheumatoid arthritis. The hallmark of this disorder is the involvement of tissues subjected to friction stress bathed in a lubricating fluid (rheumatoid nodules and bursae, tendinous sheaths, pleura, pericardium, sclera, and joints covered by hyaline cartilage). Consequently, autoantigens shared by all forementioned places may be better candidates than autoantigens restricted to the hyaline cartilage (like collagen II). Tenosynovitis, bursitis and rheumatoid nodules can herald rheumatoid arthritis, and rheumatoid pericarditis is very frequent at the histological level. Lubricin and superficial zone protein (SZP), which are closely related products of the megacaryocyte stimulating factor (MSF) gene, are among the best candidate autoantigens for such a positive selection of suppressor T cells. Lubricin is responsible for most of the lubricating properties of synovial fluid, and SZP (expressed by the superficial articular chondrocytes from diarthrodial cartilages and lining cells of synovial villi) also shares lubricating and cytoprotective properties. Moreover, the expression of lubricin is very probable in pericardium and pleura, and can be induced by friction stress. Although this mucinous glycoprotein may already share close similarities at the antigenic levels with mucins previously demonstrated in Hassall's corpuscles of the thymus, evidence for the ectopic expression of lubricin/SZP within normal human thymus may further support this hypothesis. The prenatal positive selection within the thymus of a functional pool of TCD4+CD25+(high) clones specific for most peripheral tissues is critical (at least in mice) for the quality of tolerance for the rest of the organism's lifespan. Therefore, a poor expression of lubricin/SZP early in life within the human thymus may also favour a lack of suppressor T cells specific to tissues bathed with synovial fluid, i.e. the onset of rheumatoid arthritis later on in life. As studies of human thymus long before the onset of rheumatoid arthritis are hampered for obvious reasons, studies of murine thymus could be a first step. In as much as the human counterpart of lubricin is expressed in the thymic medulla of mice, the generation of knocked-out mice for its expression within the thymus could be one of the best models to test the above hypothesis. The stimulation of TCD4+CD25+(high) clones specific for immunodominant epitopes from the joints/synovial fluid (belonging perhaps to lubricin or SZP) could help restore a normal balance between effector T cells and suppressor T cells in rheumatoid arthritis patients.
15355747 Aspirin, NSAIDs, and COX-2 inhibitors in cardiovascular disease: possible interactions and 2004 Oct Aspirin, nonsteroidal antiinflammatory drugs (NSAIDs), and cyclooxygenase-2 (COX-2) inhibitors are widely used in patients with rheumatoid arthritis. Aspirin has the largest and most persuasive body of randomized trial evidence to support its use in secondary prevention for cardiovascular disease (CVD) and primary prevention for myocardial infarction. There is, however, a possible deleterious interaction between aspirin and NSAIDs on CVD that requires further research. Aspirin, NSAIDs, and to a lesser extent COX-2 inhibitors are associated with increased gastrointestinal side effects and bleeding, alone and in combination. The more widespread and appropriate use of aspirin in patients with rheumatoid arthritis will avoid many premature deaths in secondary prevention for CVD and first myocardial infarctions in primary prevention.
12734918 MCID/Low Disease Activity State Workshop: low disease activity state in rheumatoid arthrit 2003 May The MCID (minimal clinically important difference) module of OMERACT 5 developed a research agenda that led to the conclusion that a state of low disease activity for rheumatoid arthritis (RA) would need to be defined. To develop such a definition the various concepts and terminologies, the process for developing an operational definition, and the availability and design of longitudinal datasets for validation needed to be considered. This article describes the process of the MCID/Low Disease Activity State Workshop at OMERACT 6 to develop such a definition.
15292530 Rheumatoid cachexia: metabolic abnormalities, mechanisms and interventions. 2004 Oct We have previously identified the phrase 'rheumatoid cachexia' to describe the loss of body cell mass (BCM) that may occur among patients with rheumatoid arthritis (RA). Specifically, rheumatoid cachexia is characterized by altered energy and protein metabolism (reduced total energy expenditure, increased resting energy expenditure and increased whole-body protein catabolism) and increased inflammatory cytokine production (interleukin-1beta and tumour necrosis factor-alpha). Patients with rheumatoid cachexia consistently have a diet that appears adequate in protein and calories (based on US Dietary Reference Intakes), but with reduced physical activity. These phenomena are similar to some of the metabolic abnormalities that occur with normal ageing, but the aetiology appears to be different in RA. This review will focus on describing the metabolic abnormalities observed in rheumatoid cachexia, identifying potential mechanisms for loss of BCM and discussing strategies for intervention.
12794794 Effects of disease management programs on functional status of patients with rheumatoid ar 2003 Jun 15 OBJECTIVE: To perform a systematic review of the published literature on disease management of rheumatoid arthritis (RA) and to use meta-analysis to estimate the magnitude of benefit these programs have on functional status in patients with RA. METHODS: Computerized databases for English articles from 1966 to September 2001 were searched. Two reviewers evaluated 1,029 published titles, identified 11 studies meeting explicit inclusion criteria, and extracted data about study characteristics, interventions used, and outcomes measured. Pooled effect sizes for functional status were calculated using a random-effects model. RESULTS: Four out of 8 disease management programs showed significant improvements in functional status; however, the pooled effect size (ES) was small and statistically non-significant (ES 0.27; 95% confidence interval [95% CI] -0.01, 0.54). Studies with longer intervention durations (>5 weeks) had significantly improved patient functional status (ES 0.49; 95% CI 0.12, 0.86), compared with studies with shorter intervention durations (
12724502 Association of depression and rheumatoid arthritis. 2003 May This study assessed the relative strength of the association of physical characteristics and social stresses with a diagnosis of depression in patients with rheumatoid arthritis. Depression and social difficulties were assessed in 74 patients with rheumatoid arthritis by using standardized research interviews. Rheumatoid arthritis activity, damage related to rheumatoid arthritis, and subjective functional disability were assessed with well-validated methods. Twenty-nine patients (39.2%) were depressed. Compared to nondepressed patients, depressed patients had more marked social difficulties related to rheumatoid arthritis (72.4% versus 46.7%, respectively) and more marked social difficulties independent of rheumatoid arthritis (55.2% versus 31.1%, respectively). With logistic regression, social difficulties, independent of rheumatoid arthritis, was the only variable significantly associated with depression. Demographic characteristics and rheumatoid arthritis were not associated with a diagnosis of depression. Recognition by clinicians of the importance of social stresses, independent of disease state, should lead to more appropriate and specific psychological and social treatment of depression in rheumatoid arthritis.