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ID PMID Title PublicationDate abstract
15840673 Development of glomerulonephritis during anti-TNF-alpha therapy for rheumatoid arthritis. 2005 Jul BACKGROUND: Treatment of rheumatoid arthritis with anti-tumour necrosis factor alpha (TNFalpha) agents may lead to autoantibody formation and flares of vasculitis, but renal complications are rare. METHODS: We report the clinical and pathologic findings in five patients with longstanding rheumatoid arthritis (duration of rheumatoid arthritis, 10-30 years; mean, 23 years) who developed new onset of glomerular disease after commencing therapy with anti-TNFalpha agents (duration of therapy, 3-30 months; median, 6 months). RESULTS: At presentation, three patients were receiving etanercept, one adalimumab and one infliximab. Two subjects presented with acute renal insufficiency, haematuria, nephrotic-range proteinuria, positive lupus serologies, and hypocomplementemia, and renal biopsies showed proliferative lupus nephritis. Two individuals presented with new onset renal insufficiency, haematuria and proteinuria, and renal biopsies showed pauci-immune necrotizing and crescentic glomerulonephritis. One of these subjects, who had anti-myeloperoxidase autoantibodies, also developed pulmonary vasculitis. The fifth patient presented with nephrotic syndrome and renal biopsy findings of membranous glomerulonephritis, associated with immune complex renal vasculitis. A pathogenic role for anti-TNFalpha therapy is suggested by the close temporal relationship with development of glomerular disease, and by the improvement in clinical and laboratory abnormalities after drug withdrawal and initiation of immunosuppressive therapy in most cases. CONCLUSIONS: Rheumatoid arthritis patients receiving anti-TNFalpha agents may develop glomerulonephritis via the induction of rheumatoid arthritis-related nephropathy or de novo autoimmune disorders.
16362366 The effect of circulating nitric oxide level on axial bone mineral density in postmenopaus 2006 Jul The aim is to investigate the differences in the circulating nitric oxide (NO) levels of rheumatoid arthritis (RA) patients, healthy controls and osteoporotic (OP) patients. We also examined whether the circulating NO levels may be correlated with bone mineral density (BMD) in RA patients. Forty-five patients with RA, 30 healthy women and 30 osteoporotic patients were recruited from the outpatient clinic. All the subjects were female and postmenopausal. Serum NO levels were measured (Nitrite/Nitrate, calorimetric method 1746081, Roche diagnostics, Mannheim, Germany) and BMD was measured at the spine and hip using dual energy X-Ray absorbtiometry (DEXA, Norland XR-46). Height and weight were measured and body mass index was calculated. Circulating NO levels were significantly higher in RA patients than other groups. Moreover, the RA group showed significantly higher BMD at lumbar spine and femoral neck regions compared to osteoporotic patients. However, the RA group showed significantly lower BMD at all sites than the controls. There was no correlation between circulating NO levels and BMD in all groups. We suggest that, unlike postmenopausal osteoporosis, inflammation induced osteoporosis is associated with RA is characterised by relatively preserved bone mass at the axial bone regions, and circulating NO levels as a parameter or determinant of inflammation are not correlated with axial BMD in RA patients.
17289546 What is after cytokine-blocking therapy, a novel therapeutic target--synovial Epstein-Barr 2007 Jan There has been significant progress in cytokine-blocking therapy for treatment of rheumatoid arthritis (RA) However, inhibition of cytokines involved in immune defense raises severe side effects. The cost of cytokine-blocking treatment is another major issue. Why are levels of inflammatory cytokines increased in RA patients? We have a large amount of circumstantial and direct evidence for the presence of Epstein-Barr virus (EBV) in RA synovial cells. Here, we provide an overview of the implications for novel approaches to therapy for RA patients, based on the most recent available evidences of anti-viral agents.
16309380 Sensitive immunoassays for the autoantibodies reacting against citrullinated carboxy-termi 2005 We developed sensitive assay methods for autoantibodies recognizing the citrullinated synthetic peptides derived from type I and type II collagens in patients with rheumatoid arthritis (RA). These peptides were tested with the chemiluminescence method (Nichols Advantage System). In 44 RA patients out of 120, the sera showed increased binding of citrullinated synthetic C-telopeptide derived from the alpha1 chain of type I collagen (p=0.003 compared to controls). For a corresponding C-telopeptide pair from the alpha1 chain of type II collagen, 35 patient sera bound the citrullinated peptide more strongly than the arginine peptide, but the difference compared to the controls was not significant (p=0.074). Correlation between the two carboxy-telopeptides was r=0.473 (p<0.001). The anti-CCP assay (antibodies against citrullinated filaggrin sequence-derived peptides) was positive in 59% of our RA patients. There was no relationship between the anti-CCP results and the antibodies against collagen C-telopeptides, but both are increased in RA patients. We demonstrated autoantibodies in RA patients that bound citrullinated C-telopeptides derived from type I and type II collagen antigens. The peptide sequences detected (-YYXA and -YMXA) were different from that based on the cyclic filaggrin antigen (-STXG-, where X represents citrulline).
15763460 Improvement of refractory rheumatoid arthritis-associated constrictive bronchiolitis with 2005 Apr Rheumatoid arthritis (RA)-associated constrictive bronchiolitis is a severe condition with no established efficient treatment. A 55-year-old woman with seropositive RA developed rapidly progressive constrictive bronchiolitis confirmed by lung biopsy. Her clinical condition worsened despite steroids and azathioprine. Treatment with etanercept-a tumor necrosis factor (TNF)-alpha inhibitor-combined with methotrexate, resulted in a marked improvement of both her clinical condition and pulmonary function tests. Treatment with TNF-alpha inhibitors and methotrexate may be proposed in RA-associated constrictive bronchiolitis, a severe condition hitherto not amenable to improvement.
15708880 Increased C reactive protein in response to acute stress in patients with rheumatoid arthr 2005 Sep OBJECTIVE: To assess the effects of acute stress on inflammatory, haemostatic, rheological, and haemodynamic activity in patients with rheumatoid arthritis (RA) in comparison with patients with osteoarthritis (OA). METHODS: 21 patients with RA and 10 with OA underwent a brief mental stress task while standing. Inflammatory, haemostatic, rheological, and haemodynamic variables were measured at baseline, during the task, and at recovery. RESULTS: At baseline, erythrocyte sedimentation rate and fibrinogen were higher in RA than OA. White blood cell count, fibrinogen, blood pressure, and pulse rate increased, whereas prothrombin time and plasma volume decreased during the task in both patient groups. The stress task increased C reactive protein (CRP) only in patients with RA, and more specifically in those patients with RA with high disease activity. CONCLUSIONS: The increase in the inflammatory marker CRP, which was specific to patients with RA, combined with the haemostatic, rheological, and haemodynamic reactions to the stress task, over and above the already high baseline levels, could underlie the increased risk for myocardial infarction in this vulnerable patient group.
16783865 Most rheumatologists are conservative in active rheumatoid arthritis despite methotrexate 2006 Jul OBJECTIVE: To evaluate the proportion of patients with rheumatoid arthritis (RA) visiting office-based rheumatologists for persistently active RA despite past or current methotrexate (MTX) treatment, and to describe the management of these patients in France in 2003. METHODS: All French rheumatologists were invited to participate in a cross-sectional postal survey. During a predetermined week, they were to include the first 2 patients seen for RA with a history of past or current MTX treatment. Adequacy of current treatment was assessed based on the 28-joint Disease Activity Score 28 (DAS28) and on current MTX and corticosteroid regimens. RESULTS: Of the 1800 French rheumatologists, 492 returned 838 assessable patient questionnaires. Mean patient age was 58 years and mean time since RA diagnosis was 10 years; 77% of patients were currently taking MTX, and 51% a corticosteroid. High dosages were noted for MTX (> 15 mg/week) in 20% of patients and for corticosteroid therapy (> 10 mg/day) in 5%. Nevertheless, 41% of patients had active RA (DAS28 score 3.2 to 5.1) and 7% had very active RA (DAS28 score > 5.1). The treatment was left unchanged in 78% of patients, and biological therapy was contemplated in only 16% of patients. CONCLUSION: Although half of MTX-treated patients with RA visiting office-based rheumatologists had active or very active disease, a change in treatment was rarely considered.
15319231 Decreased prolactin response to hypoglycaemia in patients with rheumatoid arthritis: corre 2005 Mar OBJECTIVE: To compare basal and stimulated prolactin levels between patients with rheumatoid arthritis and healthy controls, and to assess the effects of antirheumatic treatment on prolactin concentrations. METHODS: Serum prolactin was assessed under basal conditions and during an insulin tolerance test (ITT) in 20 patients with recently diagnosed active rheumatoid arthritis and 20 age and sex matched controls. The patients were reassessed after two weeks' treatment with naproxen and after six months' additional treatment with either sulfasalazine or methotrexate. Disease activity was assessed by the disease activity score (DAS). RESULTS: Basal levels of prolactin were not significantly different between patients with rheumatoid arthritis and controls. Prolactin responses to hypoglycaemia were less in untreated rheumatoid patients than in controls. DAS scores correlated negatively with the area under the curve (AUC) for prolactin concentrations during the ITT. Treatment with naproxen for two weeks did not influence either basal or stimulated prolactin levels. After six months of antirheumatic treatment, prolactin responses to hypoglycaemia increased significantly to levels observed in controls. At the same time point, DAS had improved considerably. The improvement correlated with the increase in AUC of prolactin during the ITT (r = 0.48; p = 0.05). CONCLUSIONS: Patients with active rheumatoid arthritis have a decreased prolactin response to hypoglycaemia induced stress. The response recovers following treatment with antirheumatic drugs.
16571961 Atlantoaxial subluxation in different intraoperative head positions in patients with rheum 2006 Apr BACKGROUND: Disorders of the cervical spine are often observed in patients with rheumatoid arthritis (RA). However, the best head position for RA patients with atlantoaxial subluxation in the perioperative period is unknown. This study investigated head position during general anesthesia for the patients with RA and proven atlantoaxial subluxation. METHODS: During anesthesia of patients with RA and proven atlantoaxial subluxation, the authors used fluoroscopy to obtain a lateral view of the upper cervical spine in four different positions: the mask position, the intubation position, the flat pillow position, and the protrusion position. Copies of the still fluoroscopic images were used to determine the anterior atlantodental interval, the posterior atlantodental interval, and the angle of atlas and axis (C1-C2 angle). RESULTS: The anterior atlantodental interval was significantly smaller in the protrusion position (2.3 mm) than in the flat pillow position (5.1 mm) (P < 0.05). The posterior atlantodental interval was significantly greater in the protrusion position (18.9 mm) than in the flat pillow position (16.2 mm) (P < 0.05). The C1-C2 angle was, on average, 9.3 degrees greater in the protrusion position than in the flat pillow position (P < 0.05). CONCLUSION: This study showed that the protrusion position using a flat pillow and a donut-shaped pillow during general anesthesia reduced the anterior atlantodental interval and increased the posterior atlantodental interval in RA patients with atlantoaxial subluxation. This suggests that the protrusion position, which involves support of the upper cervical spine and extension at the craniocervical junction, might be advantageous for these patients.
15838239 Hypoxia and angiogenesis in rheumatoid arthritis. 2005 May PURPOSE OF REVIEW: Angiogenesis is a prominent feature of rheumatoid synovitis. Although new blood vessels deliver oxygen to the augmented inflammatory cell mass, the neovascular network is dysfunctional and fails to restore tissue oxygen homeostasis, so that the rheumatoid joint remains a markedly hypoxic environment. The purpose of this review is to discuss the role of hypoxia and angiogenesis in the pathogenesis of rheumatoid arthritis. RECENT FINDINGS: Vascular pathologic change, in the form of angiogenesis, is important in the perpetuation of rheumatoid arthritis and, in the form of endothelial dysfunction, contributes to associated cardiovascular comorbidity. Recent data suggest that tumor necrosis factor-alpha blockade may modify the vascular pathologic changes in rheumatoid arthritis. Angiogenesis is a prominent feature of rheumatoid synovitis. Emerging evidence based on ultrasonographic vascular imaging and angiogenic biomarkers implicates angiogenesis in the active phase of erosive disease. Many factors contribute to the profoundly hypoxic environment that can arise within the joint affected by rheumatoid arthritis. At a cellular level, hypoxia is detected by a mechanism that regulates cytoplasmic concentrations of hypoxia-inducible factor-1alpha. After translocation to the nucleus, hypoxia-inducible factor-1alpha binds its partner hypoxia-inducible factor-1beta to form a heterodimeric, functional transcription factor, hypoxia-inducible factor-1, which activates a gene program associated with angiogenesis, glycolysis, and adaptation to pH. SUMMARY: Despite the luxuriant vasculature associated with rheumatoid arthritis synovitis, the joint affected by rheumatoid arthritis is hypoxic. Repetitive cycles of hypoxia and reoxygenation together with oxidants produced by phagocytic cells promote chronic oxidative stress within the microenvironment of the affected joint, leading to the generation of reactive oxygen species with the potential to contribute to tissue damage.
15941729 Coping and psychological adjustment in recent-onset inflammatory polyarthritis: the role o 2005 Sep OBJECTIVES: To examine the role of gender, age and coping in psychological adjustment of patients with early inflammatory polyarthritis (IP). METHODS: One hundred and twelve patients with IP of up to 18 months' duration from the Norfolk Arthritis Register completed questionnaires measuring coping, anxiety, disability and pain. RESULTS: Thirty-six per cent of the patients were at risk of depressive symptoms. Women had significantly higher levels of depression and anxiety than men. Regression analyses showed that pain and (low) illness acceptance predicted levels of depression. Younger age, wishful thinking and covering up predicted anxiety levels. CONCLUSIONS: The study found higher levels of depression and anxiety for women than men with early IP. Psychological distress was predicted by younger age, specific coping strategies and high levels of pain.
17110315 Autoantibodies to citrullinated antigens in (early) rheumatoid arthritis. 2006 Nov Rheumatoid arthritis (RA) is a common, systemic autoimmune disease characterized by chronic inflammation of the synovium, that can lead to progressive joint destruction and in many cases results in severe disability and poor quality of life. With the availability of more sophisticated and effective therapies and with increasing evidence that the first few months of disease represent an unique therapeutic opportunity and that such early therapeutic intervention is crucial in preventing irreversible joint damage, it is widely accepted that early and accurate diagnosis of RA is critical in disease management. Within the last three years a growing number of publications have reported that the second generation anti-CCP (cyclic citrullinated peptide) test may become the marker of choice for diagnosing early RA as it appears to be highly specific for the disease with a sensitivity comparable to the widely used but less specific rheumatoid factor test. Additionally, anti-CCP2 positivity can predict future development of RA in both asymptomatic individuals and in patients with undifferentiated arthritis. Furthermore, antibody levels at presentation can correlate with progression to erosive disease.
16296806 Drug delivery strategies for cathepsin inhibitors in joint diseases. 2005 Nov Cathepsins play important roles in the development of joint and bone diseases such as osteoporosis, rheumatoid arthritis (RA) and osteoarthritis (OA). Cathepsin inhibitors are presently in development and clinical testing for use as novel disease-modifying drugs for the improved treatment of osteoporosis. They may also be applicable for the treatment of joint diseases. However, some barriers still hamper their clinical applications in these indications. Based on pathophysiological features of RA and OA, the authors discuss six potential drug delivery strategies for the effective delivery of cathepsin inhibitors or other antiarthritic drugs to the arthritic joint tissue. Successful application of these strategies may significantly contribute to a more effective and safe treatment of RA and OA.
16947383 Differential tissue expression and activation of p38 MAPK alpha, beta, gamma, and delta is 2006 Sep OBJECTIVE: Activation of p38 MAPK is a key signaling step in chronic inflammation. Inhibition of p38 MAPK is considered to be a promising future strategy to control inflammatory diseases, but studies of compounds to inhibit this kinase have so far been limited to investigation of their side effects. We undertook the present study to investigate which specific molecule, among 4 different isoforms of p38 MAPK (alpha, beta, gamma, and delta), is predominantly expressed and activated in inflammation. Such knowledge could allow more specific targeting of p38 MAPK in inflammatory disease. METHODS: Studies were performed on inflamed tissue from patients with rheumatoid arthritis, as a prototype of inflammatory disease. The expression and activation of the alpha, beta, gamma, and delta isoforms of p38 MAPK were examined by immunoblotting, immunoprecipitation, and immunohistochemistry. RESULTS: Immunoblot analysis revealed that alpha and gamma were the predominantly expressed p38 MAPK isoforms, whereas the other 2 isoforms were less frequently present. By immunohistochemistry, the expression of all p38 MAPK isoforms was localized to the synovial lining layer as well as to blood vessels. Colabeling with cell-specific markers revealed that macrophages expressed the alpha and gamma isoforms, synovial fibroblasts the beta and gamma isoforms, and granulocytes the delta isoform, whereas T lymphocytes were rarely positive for any p38 MAPK isoform. Double-labeling with isoform-specific antibody and pan-p38 antibody against the phosphorylated form of p38 MAPK showed activation of the alpha and gamma isoforms. Occasional activation of the beta isoform was also noted in the synovial lining and the endothelium, whereas the delta isoform, although expressed in pericytes around blood vessels, was not phosphorylated. This phosphorylation pattern was confirmed in immunoprecipitation studies in which activated p38 MAPK from synovial tissue extracts was identified as p38 MAPKalpha and -gamma but not p38 MAPKbeta or -delta. CONCLUSION: These data show that the alpha and gamma isoforms of p38 MAPK dominate in chronic inflammation. Effective strategies to inhibit p38 MAPK should therefore aim to specifically target either or both of these isoforms.
15769663 Angiogenesis in rheumatoid arthritis. 2005 May 1 Endothelial cells lining the lumina of blood vessels are involved in leukocyte extravasation underlying inflammatory states, such as rheumatoid arthritis (RA). New vessel formation, termed angiogenesis, is also crucial for leukocyte extravasation during inflammatory synovitis. The outcome of neovascularization in the RA synovium is highly dependent on the balance or imbalance between angiogenic mediators and inhibitors. There have been several attempts to therapeutically interfere with the cellular and molecular mechanisms underlying RA-associated neovascularization. Most studies have been performed using animal models of arthritis. In addition, a limited number of human clinical trials gave promising results. In this review, authors summarize some relevant information on those angiogenic and angiostatic agents, which have also been studied in context with RA. In addition, further perspectives of anti-angiogenic therapy in arthritis are also discussed. Specific targeting of angiogenesis may be useful in the future management of various inflammatory, as well as malignant, diseases.
16724807 T cell activation as starter and motor of rheumatic inflammation. 2006 Rheumatic inflammation is driven by sustained specific immunity against self-antigens, resulting in local inflammation and cellular infiltration and, subsequently, in tissue damage. Although the specific autoantigen(s) eliciting the detrimental immune reactions in rheumatic diseases have rarely been defined, it has become clear that the mechanisms resulting in the destruction of tissue and the loss of organ function during the course of the diseases are essentially the same as in protective immunity against invasive microorganisms. Of fundamental importance in initiating, controlling, and driving these specific immune responses are CD4 T cells. Currently available data provide compelling evidence for a major role of CD4 T cells in the initiation and perpetuation of chronic rheumatic inflammation. Consequently, T cell-directed therapies have been employed with substantial clinical success in the treatment of rheumatic diseases. Here, we review current knowledge based on which CD4 T cells can be implicated as the motor of rheumatic inflammation.
15860511 Combination treatment strategies in early rheumatoid arthritis. 2005 Sep Combinations of disease modifying antirheumatic drugs (DMARDs) are increasingly being used in patients with early rheumatoid arthritis (RA) when long term results with sequential DMARD monotherapy are disappointing. Combination DMARD therapy may be more effective than monotherapy, and has no additional short term adverse events. The evidence for using combination DMARD therapy is still weak, however, and further trials are needed.
16277696 Gene therapy for arthritis--where do we stand? 2005 The successful use of biologicals in the treatment of rheumatoid arthritis, psoriatic arthritis and spondyloarthritis has had a major impact on the management of these conditions. The challenge in the development of gene therapy as an alternative to these current treatments is to demonstrate that such therapy is more advantageous for patients from the therapeutic and safety points of view. Also, it will need to be demonstrated that gene therapy for the arthritides is economically feasible and that patient populations worldwide will be able to access these treatments.
16870102 An increased frequency of gallbladder stones in rheumatoid arthritis patients. Factors rel 2006 May OBJECTIVE: In this study, we determined the frequency of gallbladder stone (GBS) in rheumatoid arthritis (RA) patients and evaluated factors which could affect the formation of GBS--such as lipids and the GB motilities of the patients. METHODS: One hundred and thirteen RA patients (92F, 21M, mean disease duration: 8.9 years) and 117 healthy controls (94F, 23M) were included. In all RA patients, the clinical findings were recorded down; biochemical parameters and body mass index (BMI) were determined; and, abdominal ultrasonography was performed. In addition, 16 RA patients and 20 controls who were age-matched were randomly chosen for GB emptying monitored by ultrasound at 30-minute intervals for 2 hours after a mixed meal. Fasting volume (FV), residual volume (RV) and ejection fraction (EF) for all GBs were assessed. RESULTS: There was a tendency towards a higher frequency of GBS including cholecystectomy (11 GBS, 11 cholecystectomy, 19.5%) in RA patients when compared to controls (8 GBS, 5 cholecystectomy, 11.1%) (p = 0.08). The frequency of GBS plus cholecyctectomy in female RA patients (22.8%) was significantly higher than the control group (11.7%, p = 0.044). Logistic regression analysis showed that only older age was significantly associated with the presence of GBS in RA (OR:1.05, p = 0.048). There was no difference between the 2 groups in FV (p > 0.05). RV, PRV and EF were significantly higher in RA patients than in the control group (p < 0.05). CONCLUSION: We diagnosed a higher frequency of GBS in female RA patients when compared to controls. Impaired GB motility in RA patients might contribute to an increased incidence of GBS development.
15319232 Silica exposure is associated with increased risk of developing rheumatoid arthritis: resu 2005 Apr OBJECTIVE: To study the association between silica exposure and rheumatoid arthritis and how it is modified by cigarette smoking. METHODS: Data were analysed from 276 male cases and 276 male controls aged 18 to 70 years, included in a Swedish population based study between May 1996 and June 2001. A case was defined as a person recently diagnosed with rheumatoid arthritis according to the ACR criteria. Controls were selected from the study base as a stratified random sample accounting for age, sex, and residency. Men with a self reported history of work with rock drilling, stone crushing, or exposure to stone dust in general were defined as silica exposed. Rheumatoid factor (RF) status among cases was recorded. RESULTS: Silica exposed men had increased risk of rheumatoid arthritis, with an odds ratio (OR), adjusted for age, residential area, and smoking, of 2.2 (95% confidence interval, 1.2 to 3.9) among men aged 18 to 70 years, and 2.7 (1.2 to 5.8) among those aged 50 to 70 years. Men who had worked with rock drilling or stone crushing (regarded as highly exposed) had a slightly greater increase in risk of rheumatoid arthritis than silica exposed men in general, with an OR of 3.0 (1.2 to 7.6). The joint effects of silica exposure and smoking were compatible with synergy between these two exposures in the development of rheumatoid arthritis but this was not conclusive. CONCLUSIONS: Silica exposure is associated with increased risk of developing rheumatoid arthritis. This association is not explained by smoking habits.