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ID PMID Title PublicationDate abstract
16211338 Rheumatoid lung nodulosis and osteopathy associated with leflunomide therapy. 2006 May BACKGROUND: Leflunomide (LEF) is indicated in adults for the treatment of active rheumatoid arthritis (RA). LEF inhibits dehydroorotate dehydrogenase, a key enzyme of the pyrimidine synthesis in activated lymphocytes. Among rare adverse effects, fatal interstitial lung disease has been recently reported during treatment of RA with LEF in Japan. Clinical trials outside Japan do not suggest that LEF causes an excess of pulmonary adverse effects. Development and increase of peripheral rheumatoid nodules in typical sites of RA patients following LEF therapy has been recently reported. OBJECTIVES: Two cases with new and accelerated development of rheumatoid lung nodulosis during LEF therapy were described in this study. METHODS: LEF treatment was administered to two male patients (77 and 66 years old) with long-standing active seropositive nodular RA with failure of multiple second line drugs and without lung involvement. Clinical and laboratory assessment using the American College of Rheumatology response criteria, chest computed tomography (CT), quantification of serum rheumatoid factor (RF), and monocyte count of peripheral blood along with routine laboratory follow up were performed on both patients before and during therapy. In case 1, a bone scan was performed due to sustained limbs pain. Open lung biopsy was performed in case 1 and core lung biopsy in case 2. RESULTS: Both patients achieved full clinical remission during 2 months of LEF therapy. In case 1, the first complaints were limbs pain after 10 months of treatment associated with intensive bone uptake on a bone scan consistent with hypertrophic pulmonary osteopathy. Productive cough developed after 3 months of the therapy in case 2. Initially, these complaints were not attributed to therapy. New lung disease was present on CT with cherry-like progressive cavitary nodules, predominantly involving the basal segments of the right lung. The first lung lesions were found by CT 13 months (case 1) and 7 months (case 2) after the beginning of therapy and were erroneously related to bronchiectasia in case 2. In both cases, the lung biopsy showed necrosis surrounded by epithelioid mononuclear inflammation with giant cells, consistent with rheumatoid lung node. The time that elapsed between the beginning of the first symptoms to LEF discontinuation was very long: 13 months in case 1 and 24 months in case 2. Discontinuation of LEF therapy was followed by an arrest in growth of lung nodules, resolution of limb pain, and gradual improvement of bone scan. A significant decrease of monocyte count and RF level in peripheral blood was observed during LEF therapy in both cases. CONCLUSION: For the first time, we described rheumatoid lung nodulosis as complication of successful LEF therapy for RA. Hypertrophic pulmonary osteopathy with severe limbs pain and dry cough were the first manifestations of the lung nodulosis. Monocytopenia during LEF therapy is proposed to be involved in pathogenesis of this rare complication of LEF therapy.
17299838 Corticosteroid use in rheumatoid arthritis: prevalence, predictors, correlates, and outcom 2007 Apr OBJECTIVE: To determine the rate of current and lifetime use of corticosteroids, the degree of association between corticosteroids and rheumatoid arthritis (RA) activity and outcome, corticosteroid initiation and discontinuation rates, and the predictors associated with initiation and discontinuation. METHODS: A total of 12,749 patients with RA were evaluated semiannually as to corticosteroid use, RA activity measures, RA outcomes, and predictors of initiation and discontinuation of corticosteroids. RESULTS: Current corticosteroid use was 35.5% and lifetime use was 65.5%. Rheumatologists varied substantially in their use of corticosteroids. The primary patient-derived determinant of corticosteroid initiation, current use, and discontinuation was symptom severity, although 21-25% of patients in remission or with minimal disease activity continued taking corticosteroids. Within the pool of current users, 24.3% [95% confidence interval (CI) 23.2-25.3%] discontinued corticosteroids yearly, and among patients newly starting corticosteroids this rate was 56.9% (95% CI 53.4-60.7%). Corticosteroid initiation occurred at a rate of 8.9% (95% CI 8.4-9.3%) per year. Among corticosteroid users, persistent use (> 5 years) occurs in about one-third of patients. Corticosteroid use and duration of use is associated with severe outcomes for current and past users. For current users versus non-current users, covariate adjusted outcomes were: mortality 5.7% versus 2.6%, work disability 28.4% versus 17.2%, and total joint replacement 18.5% versus 13.0%. CONCLUSION: Corticosteroid use is dynamic and is associated with RA severity. Corticosteroid use is also associated with adverse longterm outcomes, but the ability to discern causal associations is severely limited by confounding by indication. The idea of "once on corticosteroids, always on corticosteroids" is incorrect and applies to only a minority of patients.
16881105 Frequency of osteoporosis in 187 men with rheumatoid arthritis followed in a university ho 2006 Aug OBJECTIVE: Although there is relevant information on frequency of osteoporosis in women with rheumatoid arthritis (RA), data about male patients are limited. We evaluated the frequency of osteoporosis in a group of Spanish men with RA followed in a university hospital. METHODS: From the database of our bone densitometry unit, we searched for men with RA evaluated between January 1991 and December 2004 and identified 187 patients, 156 of whom were older than 50 years. Previously recorded demographic, disease, and treatment-related variables were collected. Bone mineral density (BMD) was measured by dual x-ray absorptiometry (DEXA). Osteoporosis was defined according to the criteria of the World Health Organization (WHO), recommended for postmenopausal Caucasian women, as a T score
17429637 Development of acute inflammatory arthritis by granulocyte-macrophage colony-stimulating f 2007 Oct Hematopoietic growth factors (HGFs) are now known to influence the function of mature myeloid cells as well as their traditional roles as regulators of hematopoiesis. It became apparent that they could take part in inflammatory and immune responses by activating monocytes/macrophages to release mediators of such responses. We describe a 53-year-old male who developed acute inflammatory arthritis by granulocyte-macrophage colony-stimulating factor (GM-CSF) following autologous stem cell transplantation for cryoglobulinemia. Arthritis improved dramatically soon after GM-CSF was withdrawn and steroid therapy was admitted. This case may lead to further attention for this potential problem since HGFs are frequently used in a variety of clinical settings.
17934092 Thoughts on health economics in rheumatoid arthritis. 2007 Nov In this manuscript we discuss the reasons why and how health economics is important, the type of economic studies that are relevant in healthcare to different stakeholders in general, and what analyses can and have been performed in the field of rheumatoid arthritis (RA). We will thus specifically address costs and outcome measurements in RA, as well as the need for modelling in chronic progressive diseases.
18261665 Synovial hypoxia as a cause of tendon rupture in rheumatoid arthritis. 2008 Jan PURPOSE: Hypoxia and angiogenesis are now recognized as being important events in the perpetuation of joint destruction in rheumatoid arthritis (RA). In 50% of patients with RA, however, the disease also involves inflammation of the synovial tissue surrounding the tendons, which is associated with multiple ruptures and poor prognosis for long-term hand function. The aim of this study was to determine whether hypoxia and angiogenesis may also play a role in RA tendon disease. METHODS: Matched in vivo synovial oxygen measurements (invasive and encapsulating tenosynovium and joint synovium) were taken intraoperatively using a microelectrode technique in patients having elective hand surgery for RA. Patients having elective hand surgery for indications other than inflammatory synovitis were recruited as controls. In parallel, RA synovial tissue was harvested and stained for vascular endothelial growth factor (VEGF) and hypoxia-inducible factor-2alpha. Tissue was also cultured under either hypoxic (1% O(2)) or normoxic (21% O(2)) conditions to investigate the effect of hypoxia on the expression of VEGF and its soluble receptor, as well as on the key cytokines interleukin (IL)-6, IL-8, IL-10 and the chemokine monocyte chemoattractant protein-1. RESULTS: Invasive tenosynovium was observed to be significantly more hypoxic than either noninvasive tenosynovium or joint synovium in the same patients. Furthermore, RA tenosynovium was shown to be more hypoxic than tenosynovium in patients without RA. This hypoxia was accompanied by expression of VEGF and hypoxia-inducible factor-2alpha. Using in vitro joint synovial cell cultures, upregulation of VEGF expression was shown to be a consequence of this in vivo hypoxia. Furthermore, hypoxia downregulated release of monocyte chemoattractant protein-1 and the immunoregulatory cytokine IL-10. CONCLUSIONS: These data demonstrate that hypoxia is a feature of rheumatoid tendon disease and differentially regulates angiogenesis and the inflammatory cascade in RA.
18513326 FLIP and MAPK play crucial roles in the MLN51-mediated hyperproliferation of fibroblast-li 2008 Jul One of the characteristic features of the pathogenesis of rheumatoid arthritis is synovial hyperplasia. We have reported previously that metastatic lymph node 51 (MLN51) and granulocyte-macrophage colony-stimulating factor (GM-CSF) are involved in the proliferation of fibroblast-like synoviocytes in the pathogenesis of rheumatoid arthritis. In this study, we have found that: (1) GM-CSF-mediated MLN51 upregulation is attributable to both transcriptional and post-translational control in rheumatoid arthritis fibroblast-like synoviocytes; (2) p38 mitogen-activated protein kinase plays a key role in the upregulation of MLN51; and (3) FLICE-inhibitory protein is upregulated downstream of MLN51 in response to GM-CSF, resulting in the proliferation of fibroblast-like synoviocytes. These results imply that GM-CSF signaling activates mitogen-activated protein kinase, followed by the upregulation of MLN51 and FLICE-inhibitory protein, resulting in fibroblast-like synoviocyte hyperplasia in rheumatoid arthritis.
18848912 Tyrosine kinases as targets in rheumatoid arthritis. 2009 Jan Rheumatoid arthritis (RA) is an autoimmune disease characterized by the accumulation and proliferation of inflammatory cells in the synovial (joint) lining, resulting in the formation of pannus tissue, which invades and destroys adjacent cartilage and bone. In RA macrophages, B cells, mast cells, fibroblast-like synoviocytes (FLSs) and CD4+ T lymphocytes become activated and contribute to synovial inflammation and joint destruction. It has been showed that different tyrosine kinases participate in the activation of those cells having important participation in the physiopathology of RA. Therefore, the tyrosine kinases inhibitors could be the next step in the treatment of patients with RA. This review focuses on recent advances on the role of tyrosine kinases and their inhibitors in the physiopathology of RA.
18270849 Whither autoimmunity: the lessons of anti-CCP and B cell depletion. 2008 Feb The most difficult component to understand in autoimmune disease has been the issue of causation. In contrast, there have been enormous gains in improved diagnostics as well as improved therapy. Indeed, the use of biologics have changed the profile of numerous autoimmune diseases. In this issue, we discuss two such aspects. Firstly, we place in perspective the use of anti-citrullinated protein antibodies in rheumatoid arthritis. Second, we discuss the increasing use of B cell depletion in the treatment of autoimmunity. Clinical Reviews in Allergy and Immunology is a unique venue for these themes because it covers the spectrum of allergy through autoimmunity. Indeed, we also present a special paper on the relationships of the hepatitis B virus and autoimmunity. Although the Th1 to Th2 dichotomy is well known to both murine and human immunologists, it is really in the study of specific inflammatory responses that they are correctly placed in the perspective of the continuum of immunopathology.
18035650 Improving patient care: measurement of outcome in rheumatoid arthritis. 2007 Sep 13 Although most people who are seen in rheumatology clinics are suffering from fatigue, pain, functional disability and/or psychological distress, fewer than 15% of healthcare professionals collect any formal quantitative information concerning these problems. In contrast with acute disease in hospital settings where quantitative data concerning functional status or pain are unnecessary, as success or failure of the treatment is obvious within a short period, chronic diseases form a different challenge. Patient-reported outcomes are an attractive option in a busy medical practice, as the time burden is transferred from the clinician to the patient. Furthermore, such information is critical in the documentation of patient outcomes and results of care. This work was carried out to analyse a developed version of a multi-dimensional health assessment questionnaire. This questionnaire has been edited in a 'patient-friendly' format and its applicability is for standard use in a nurse-led clinical practice to monitor patients suffering from chronic inflammatory conditions in a busy rheumatology unit of a district general hospital.
18957487 Progression of radiographic joint damage in rheumatoid arthritis: independence of erosions 2009 Oct OBJECTIVE: To compare the progression of erosions and joint space narrowing (JSN) in patients with early active rheumatoid arthritis (RA) using data obtained in the "Active-controlled Study of Patients receiving Infliximab for the treatment of Rheumatoid arthritis of Early onset" (ASPIRE) study. METHODS: This was a post hoc analysis of patients in ASPIRE who received placebo plus methotrexate (MTX) or infliximab (3 or 6 mg/kg) plus MTX. Radiographs of the hands (870 patients) and feet (871 patients) were obtained at baseline and week 54 and scored using the van der Heijde/Sharp method. In total, 7160 joints in the placebo plus MTX group and 18,908 joints in the combined infliximab plus MTX group were included in this analysis. RESULTS: At baseline, 83.4% of joints in the placebo plus MTX group had no radiographic damage, 8.5% had only erosions, 4.4% had only JSN and 3.7% had both. The distribution was similar in the infliximab plus MTX group. In the placebo plus MTX group, the majority of joints did not have development or progression of radiographic damage from baseline to week 54; among joints that did have development or progression of damage at week 54, erosions occurred more often than JSN. The same pattern was observed in the infliximab plus MTX group, although the proportions of joints with damage at week 54 were generally larger in the placebo plus MTX group. There was a tendency for joints with existing erosions or JSN to have progression of damage, rather than development of new damage. CONCLUSIONS: Erosions were the predominant type of damage observed in both treatment groups. Erosions and JSN are related but partly independent processes.
17355733 Effects of clarithromycin in patients with active rheumatoid arthritis. 2007 Mar OBJECTIVE: To evaluate the clinical efficacy, safety, and tolerability of clarithromycin in patients with rheumatoid arthritis. RESEARCH DESIGN AND METHODS: This was a 6-month, monocenter, randomized, double-blind, placebo-controlled study. A total of 81 patients with early rheumatoid arthritis were treated with either once-daily oral clarithromycin (500 mg) or daily oral placebo for 6 months. MAIN OUTCOME MEASURES: The primary efficacy variable was the percentage of patients who had a 20% improvement according to American College of Rheumatology (ACR) criteria (an ACR 20 response) at 6-months. Secondary outcome measures were 50% improvement and 70% improvement according to ACR criteria (an ACR 50 response and an ACR 70 response, respectively). RESULTS: A significantly greater percentage of patients treated with 500 mg clarithromycin met the ACR 20 response at 6 months compared with patients who received placebo (59 vs. 33%; p < 0.001). Greater percentages of patients treated with 500 mg clarithromycin also achieved ACR 50 responses (34 vs. 10%; p < 0.001) and ACR 70 responses (20 vs. 3%; p = 0.003) compared with patients who received placebo, respectively. Clarithromycin was well tolerated. There were no dose-limiting toxic effects. CONCLUSIONS: In patients with early active rheumatoid arthritis, treatment with clarithromycin significantly improved the signs and symptoms of rheumatoid arthritis. Clarithromycin has been shown to be effective against rheumatoid arthritis.
17967187 Aminotransferases are associated with insulin resistance and atherosclerosis in rheumatoid 2007 Oct 29 BACKGROUND: Serum aminotransferase concentrations are reportedly strongly associated with insulin resistance, an established cardiovascular risk factor that is not routinely assessed in clinical practice. We therefore explored the possibility that serum aminotransferase concentrations are as closely related to large artery disease as insulin resistance in rheumatoid arthritis (RA). METHODS: Carotid artery plaque (ultrasonography), insulin resistance and liver enzymes (prior to methotrexate (MTX) were determined in 77 consecutive patients with RA (43 with and 34 without MTX). RESULTS: Serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were associated with insulin resistance in univariate analysis (R = 0.54, p < 0.0001 and R = 0.36, p = 0.001, respectively) and after adjustment for age, gender and waist circumference (partial R = 0.43, p = 0.0001 and partial R = 0.37, p = 0.001, respectively). ALT and AST concentrations were higher in patients with plaque as compared to in those without plaque (ALT (u/l): 27 2223242526272829303132 versus 20 181920212223, p = 0.02; AST (u/l): 25 2122232425262728 versus 20 19202122, p = 0.02). The odds ratios [95% CI] for plaque were 1.92 [1.14-3.24] (p = 0.01), 1.93 [1.17-3.16] (p = 0.009) and 1.82 [1.13-2.93] (p = 0.01) for 1 SD increase in ALT (~10 u/l) and AST (approximately 6 u/l) concentrations and in logarithmically transformed homeostasis model assessment of insulin resistance (HOMA-IR) (~0.2 uU.mmol/ml.l), respectively. After adjustment for the potentially confounding characteristics of age, sex, hypertension and hypothyroidism in logistic regression models, ALT (p = 0.049) and AST concentrations (p = 0.027) remained associated with plaque whereas the HOMA-IR did not (p = 0.08). AST concentrations (p = 0.049) were associated with plaque independent of insulin resistance whereas the HOMA-IR (p = 0.1) was not associated with plaque independent of AST concentrations. CONCLUSION: Within currently recommended reference ranges, serum aminotransferase concentrations may be strongly associated with insulin resistance and atherosclerosis in patients with RA. The measurement of aminotransferase concentrations could be a useful tool in cardiovascular risk stratification in patients with RA.
17767741 Vasculopathy and disordered angiogenesis in selected rheumatic diseases: rheumatoid arthri 2007 Angiogenesis is important in the pathogenesis of systemic inflammatory rheumatic diseases, a family of related disorders that includes rheumatoid arthritis and systemic sclerosis. Rheumatoid arthritis is the rheumatic disease in which the role of angiogenesis has been studied most extensively. However, whereas rheumatoid arthritis is characterized by excessive angiogenesis, the situation is not as clear cut in other rheumatic diseases. For example, systemic sclerosis is characterized by reduced capillary density with insufficient angiogenic responses. Results with angiogenesis inhibitors are controversial, and there is--in parallel--a wide range of upregulated angiogenic factors such as vascular endothelial growth factor. Dysregulation of angiogenesis in systemic sclerosis is accompanied by other pathogenic processes, including fibrosis, autoimmunity and vasculopathy. Animal models with at least partial features of the vasculopathy observed in systemic sclerosis include wound healing models, graft versus host disease models and, in particular, the University of California at Davis line 200 chicken model of systemic sclerosis.
18177689 Antigen-specific tolerogenic and immunomodulatory strategies for the treatment of autoimmu 2008 Dec OBJECTIVES: To review various antigen-specific tolerogenic and immunomodulatory approaches for arthritis in animal models and patients in regard to their efficacy, mechanisms of action, and limitations. METHODS: We reviewed the published literature in Medline (PubMed) on the induction of antigen-specific tolerance and its effect on autoimmune arthritis, as well as the recent work on B-cell-mediated tolerance from our laboratory. The prominent key words used in different combinations included arthritis, autoimmunity, immunotherapy, innate immunity, tolerance, treatment, and rheumatoid arthritis (RA). Although this search spanned the years 1975 to 2007, the majority of the short-listed articles belonged to the period 1990 to 2007. The relevant primary as well as cross-referenced articles were then collected from links within PubMed and reviewed. RESULTS: Antigen-specific tolerance has been successful in the prevention and/or treatment of arthritis in animal models. The administration of soluble native antigen or an altered peptide ligand intravenously, orally, or nasally, and the delivery of the DNA encoding a particular antigen by gene therapy have been the mainstay of immunomodulation. Recently, the methods for in vitro expansion of CD4+CD25+ regulatory T-cells have been optimized. Furthermore, interleukin-17 has emerged as a promising new therapeutic target in arthritis. However, in RA patients, non-antigen-specific therapeutic approaches have been much more successful than antigen-specific tolerogenic regimens. CONCLUSION: An antigen-specific treatment against autoimmune arthritis is still elusive. However, insights into newly emerging mechanisms of disease pathogenesis provide hope for the development of effective and safe immunotherapeutic strategies in the near future.
17642236 [Antibody to IL-1 or IL-15]. 2007 Jul There have recently been fewer publications written in Japanese describing inflammatory cytokines in rheumatoid arthritis (RA) other than tumor necrosis factor and interleukin (IL) -6. Interleukins such as IL-1 and IL-15 are thought to play an important role, at least in part, in pathogenesis of RA. In this review, the two interleukins above were mentioned from mainly RA point of view, respectively. Monoclonal antibody to each cytokine might be brought to the clinic in the future.
17100402 Role of apheresis in rheumatoid arthritis. 2006 Apheresis, a therapeutic procedure that has been available for decades, has recently been added to the long-term management of rheumatoid arthritis (RA). It is a procedure whereby blood is removed from the body and divided into its various components. With the development of specific instrumentation, it has become possible to target the specific cellular or humoral components to be removed or altered. RA is a destructive, chronic progressive disease with high morbidity and significant mortality if it is not treated. Recently, combinations of disease-modifying pharmacotherapeutic agents have successfully been brought to bear on this serious disease. This approach of combining potent anti-inflammatory, disease-modifying antirheumatic drugs (DMARDs), chemotherapy and biologicals continues with some success but not without significant dangers of severe adverse toxicity, including the risks of sepsis, immunopathology and malignancy. In the setting of RA, various apheresis procedures, with and without these combination modalities, have been tested with variable success. This article reviews that experience as an overall approach to better, safer RA disease management.
17031485 Poor relationship between joint swelling detected on physical examination and effusion dia 2007 Jun The purpose of this study was to assess the relationship between swelling detected on physical examination and effusion diagnosed by ultrasonography (US) in glenohumeral (GH) joints in patients with rheumatoid arthritis (RA). Fifty consecutive patients with RA entered the study and 20 healthy control persons formed a control group. Altogether 100 GH joints of the RA patients and 40 of the controls were evaluated. The clinical assessments were carried out by one doctor and the US investigations by another, and they were blinded to each other's results. The clinical examination and US gave similar results in 70 GH joints, whereas they differed in the remaining 30 GH joints. The kappa coefficient between these investigations was 0.202, showing poor agreement. These results showed poor agreement between the clinical assessment of swelling and effusion detected by US in GH joints. Therefore, US may considerably improve the accuracy of diagnosis of effusion in GH joints, which usually means synovitis in patients with RA.
18571968 Rituximab: a new therapeutic alternative in rheumatoid arthritis. 2008 Oct Rituximab is a chimeric anti-CD20 monoclonal antibody targeting B cells, which play numerous pathogenic roles in rheumatoid arthritis (RA). This review summarises the results of three controlled studies using rituximab in RA and the data regarding tolerance and repeated treatment in 1053 patients included in the clinical studies. These studies demonstrated the efficacy of rituximab in patients with RA, including those who had been unresponsive or intolerant to one or more TNF inhibitor therapies. Rituximab was globally well-tolerated. The current informations on the efficacy and the tolerance of rituximab led us to propose recommendations for the screening of patients, the use of rituximab, and the follow-up of patients. A longer follow-up duration and data from off-trial patients, included in registries, are now required.
18078614 Serum IL-1beta levels are associated with the presence of erosions in recent onset rheumat 2007 Sep OBJECTIVE: To study interleukin (IL)-1beta levels in recent onset RA patients treated either with combination DMARD therapy (sulfasalazine, methotrexate, hydroxychloroquine) or a single DMARD therapy. METHODS: Serum IL-1beta levels were measured before the treatment and 6 months after the institution of either single or combination DMARD therapy using a high sensitivity ELISA method. Radiographic evaluation of the hands and feet was performed at 0 and 24 months. RESULTS: Significant correlations (r = 0.28, 95% CI 0.10-0.45) were found between IL-1beta levels measured at 0 and 6 months. The IL-1beta levels at 0 months correlated significantly (r = 0.23, 95% CI 0.03-0.4, p= 0.021) with the baseline number of eroded joints at 0 months but not with radiographic joint damage at 24 months. The baseline level of IL-1beta was a better indicator for the presence of eroded joints than the baseline level of serum CRP. No significant changes in IL-1beta levels were observed during the first 6 months of anti-rheumatic treatment in either group. No statistically significant difference between IL-1beta levels in the patients with or without the shared epitope could be observed. CONCLUSIONS: The serum IL-1beta level is significantly associated with the presence of erosions at the onset of RA but its predictive value is attenuated or lost when single or combination DMARD medication is instituted. Measuring IL-1beta at the time of diagnosis in a single patient cannot be used to estimate the erosive nature of the disease or the prognosis.