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Search for: rheumatoid arthritis    methotrexate    autoimmune disease    biomarker    gene expression    GWAS    HLA genes    non-HLA genes   

ID PMID Title PublicationDate abstract
14705213 High diagnostic value of anticalpastatin autoantibodies in rheumatoid arthritis detected b 2004 Jan OBJECTIVE: To develop a quantitative method of measuring autoantibodies against human calpastatin in rheumatoid arthritis (RA) and to determine their diagnostic value compared with other autoimmune and articular diseases. METHODS: We performed a highly sensitive ELISA for IgG and IgM anticalpastatin autoantibodies in human sera using human erythrocyte calpastatin as an antigen. Samples were diluted 1:2000 for the measurement of IgG and 1:400 for IgM. RESULTS: IgG anticalpastatin antibodies were found in the sera of 48 of 58 patients (82.8%) with RA. In contrast, IgG anticalpastatin antibodies were found in the sera of only 2 of 11 (8.3%) patients with osteoarthritis (OA). Compared to sera from patients with other autoimmune diseases, anticalpastatin antibody sensitivity for RA was better than that of systemic lupus erythematosus (5.6%), systemic sclerosis (0%), mixed connective tissue disease (0%), and Sjögren's syndrome (20%). IgG anticalpastatin antibodies also showed high specificity (96.1%) for RA. Almost 90% of patients with RA were positive for IgG or IgM anticalpastatin antibodies. CONCLUSION: We have developed a simple, sensitive, specific, and quantitative ELISA for anticalpastatin antibodies that may have a high diagnostic value for RA.
12784385 Hyaluronan inhibits matrix metalloproteinase-1 production by rheumatoid synovial fibroblas 2003 Jun OBJECTIVE: To study the inhibitory effects of hyaluronan (HA) on the production of matrix metalloproteinase-1 (MMP-1) by rheumatoid synovial fibroblasts (RSF) stimulated by proinflammatory cytokines, tumor necrosis factor-a (TNF-a), and interleukin-1beta (IL-1beta). METHODS: HA of various sizes at various concentrations was added to monolayer cultures of RSF in the presence of TNF-a or IL-1beta, with or without pretreatment with a monoclonal antibody against CD44, OS/37. Concentrations of MMP-1 in cell lysates and conditioned media and of CD44 on RSF were assayed by immunoblotting. MMP-1 expression was analyzed by reverse transcriptase-polymerase chain reaction. Binding of HA to RSF was evaluated by confocal microscopy using fluorescein-conjugated HA and OS/37. RESULTS: Treatment with HA (0.3 approximately 3.0 mg/ml) resulted in a significant decrease in the production of MMP-1 induced by TNF-a and IL-1beta, in a dose-dependent manner. HA of 250 approximately 2300 kDa at 3 mg/ml was found to suppress the induction of MMP-1 by TNF-a. HA decreased the cytokine-induced MMP-1 synthesis in RSF at mRNA and protein levels. The monoclonal antibody, which showed abundant expression of CD44 on RSF by immunofluorescein cytochemistry, partially blocked the binding of fluorescein-conjugated HA to RSF. Pretreatment with OS/37 reversed the inhibition of MMP-1 production in TNF-a or IL-1beta-stimulated RSF caused by HA. CONCLUSION: HA suppresses the production of MMP-1 by TNF-a or IL-1beta-stimulated RSF. Based on data from anti-CD44 treatment, HA binding to CD44 is directly involved in the suppression of MMP-1 production. Those results provide the rationale for a therapeutic role of HA in treatment of rheumatoid joints.
15546803 Strategies using functional genomics in rheumatic diseases. 2004 Nov For functional genomics of inflammatory disorders and infection, rheumatic diseases offer unique features to analyse the transition from infection to chronic inflammation, autoimmunity and immunopathology, both systemic and tissue specific. The diseases are frequent and of considerable socio-economic impact. Well-defined cohorts of patients are available. The tissues and cells involved are readily accessible for molecular analysis. Both genetic predisposition and infection are involved in the aetiopathogenesis of rheumatic diseases. The number of susceptibility and severity genes has been estimated to be at least 30, but only few of them have been identified so far. There is an urgent need for developing new therapies adapted to genetic risk and based on a functional genetic and molecular understanding of chronic inflammation. It is evident that gene analysis in inflammatory rheumatic diseases will not only be beneficial for the large number of patients involved, but will also lead to a better understanding of other inflammatory disorders, thereby possibly leading to novel diagnostic and therapeutic strategies in this important group of disorders.
14991230 Calcaneus bone mineral density in Japanese women with rheumatoid arthritis. 2005 Apr OBJECTIVES: The aim of this study was to investigate the relationships among bone mineral densities (BMD) in the calcaneus and leg activity of daily living (L-ADL) in rheumatoid arthritis (RA) patients. METHODS: We measured and compared calcaneus BMD using single X-ray absorptiometry and lumbar spine and femoral neck BMD using dual X-ray absorptiometry in 158 Japanese female outpatients with RA and 358 normal controls (NC). RESULTS: Regardless of whether the women were premenopausal or postmenopausal, calcaneus and femoral neck BMDs in the RA group were significantly lower than in the NC group. Calcaneus BMD correlated with the modified health assessment questionnaire, L-ADL score, and 10-m walking time, regardless of whether the patients were premenopausal or postmenopausal (P<0.01). CONCLUSIONS: We conclude that calcaneus BMD reflects the L-ADL of RA patients very well and allows us to perform the same level of BMD evaluation as that with current BMD measurement methods.
12102476 Serum complexes of immunoglobulin A-alpha1 proteinase inhibitor in rheumatoid arthritis: a 2002 May OBJECTIVE: To investigate whether high levels of serum immunoglobulin A-alpha1 proteinase inhibitor (IgA-alpha1PI) complexes are primarily associated with cigarette smoking or the rheumatoid arthritis (RA) disease process itself. METHODS: A case-control study consisting of 231 RA cases and 83 healthy hospital workers. A smoking history was taken for the study groups. The serum IgA-alpha1PI complex levels (arbitrary units, au) were determined using a sandwich ELISA. Erythrocyte sedimentation rate (ESR) and rheumatoidfactor (RF) measurements were recorded in each of the RA cases. The serum complex levels were compared between RA cases and controls matched for smoking history and between smokers and non-smokers in the RA cases and controls. RESULTS: Mean serum IgA-alpha1PI complex levels were significantly higher in RA current smokers than in non-smoking RA patients (17.4 v 11.9 a.u., p = 0.0001). Similarly, mean serum complex levels were significantly higher in control current smokers than control non-smokers (18.8 v 11.5 a.u., p = 0.003). Seropositive RA cases had significantly higher complex levels than seronegative cases. Patients with erosive disease had higher levels than non-erosive patients, although significance was lost after correction for current smoking and RF positivity. There was an association between ESR and serum IgA-alpha1PI complex levels which was independent of current smoking. Overall, there was no significant difference in complex levels between RA cases and controls after correction for current smoking. CONCLUSION: Raised serum IgA-alpha1PI complex levels are associated with current smoking in both RA and healthy controls. ESR levels in RA patients are also associated with serum complex levels independently of current smoking. Our data suggest that high IgA-alpha1PI complex levels can be generated either as a result of current smoking, or by an active disease process in RA patients.
14686883 Unmitigated communion, social constraints, and psychological distress among women with rhe 2004 Feb The personality trait of unmitigated communion, an extreme focus on relationships that has been associated with self-neglect, has been linked to poorer outcomes for both men and women, but is more common among women. This longitudinal study is the first to examine the influence of unmitigated communion on adaptation to a chronic illness that affects a much greater proportion of women to men. Women with rheumatoid arthritis completed measures of unmitigated communion, social constraints, and psychological distress at study entry and repeated the distress measure one year later. As expected, unmitigated communion was associated with psychological distress. Cross-sectional moderation analyses indicated that low social constraints buffered the negative effects of unmitigated communion.
15238080 Citrullination of self-proteins and autoimmunity. 2004 Jul Citrullination (deimination is an enzymatic, posttranslational conversion of arginine residues to citrulline residues) of joint-associated self-proteins may be a possible mechanism in the induction of autoimmune CD4 T-cell responses in rheumatoid arthritis. We have studied the immune response to normal or deiminated human fibrinogen (hFBG) in mouse strains expressing major histocompatibility complex (MHC) class II antigens similar to either RA-susceptible or non-susceptible HLA-DR4 alleles. Upon immunization with deiminated hFBG, all mouse strains analysed produced high amounts of anti-FBG antibodies, while relatively low levels of anti-citrulline antibodies and little or no anti-FBG antibodies crossreactive with mouse FBG (mFBG) were obtained. Mice immunized with normal hFBG also produced high amounts of anti-hFBG antibodies. However, whereas mice with MHC class II molecules similar to RA-non-susceptible HLA-DR4 alleles produced low levels of anti-hFBG antibodies with crossreactivity to mFBG, mouse strains with RA-susceptible HLA-DR4-equivalent MHC class II molecules contained high levels of such crossreactive anti-mFBG antibodies. Similar results were obtained with HLA-DR4*0401, human CD4-double-transgenic mice. However, none of the more than 600 mice investigated developed arthritis. These data indicate that the quality and/or quantity of anti-FBG autoantibodies or of anti-citrulline antibodies, produced in the studied mouse strains, are insufficient to induce arthritis.
15259375 Presence of secretory group IIa and V phospholipase A2 and cytosolic group IValpha phospho 2004 Both secretory and cytosolic phospholipase A2 enzymes have been implicated in the pathogenesis of arthritis in animal models, but the exact expression patterns of the enzymes in diseased human joint tissue are uncertain. We investigated the messenger RNA expression of group IIa, IValpha and V phospholipase A2 and localized the presence of group IIa and IValpha phospholipase A2 at protein levels in articular cartilage from patients with rheumatoid arthritis, osteoarthritis and patients with non-arthritic joints. Both group IIa phospholipase A2 messenger RNA and protein were detected in all samples independent of diagnosis, but were far more prominent in cartilage from rheumatoid arthritis samples. In cartilage with rheumatoid arthritis, the enzyme was detected both within the chondrocytes and in the extracellular matrix, whereas only few osteoarthritic cartilage samples showed positive staining in the matrix. In the cartilage matrix of non-arthritic controls, group IIa phospholipase A2 was totally absent. Messenger RNA for the group IValpha and V phospholipase A2 was, except for one osteoarthritic cartilage sample, exclusively detected in rheumatoid arthritic cartilage. For group IValpha phospholipase A2 this was also confirmed at the protein level. These results suggest that each phospholipase A2 enzyme has distinct roles in both healthy and diseased joint tissue, and that the diversity and amount of enzyme correlate with the grade of inflammation and disease severity.
11779752 The rheumatoid arthritis articular damage score: first steps in developing a clinical inde 2002 Jan OBJECTIVE: To design and validate a clinical method for scoring irreversible long term articular damage in rheumatoid arthritis (RA). METHODS: The rheumatoid arthritis articular damage score (RAAD score) is based on examination of 35 large and small joints. Concise definitions were formulated to score each joint on a three point scale (0, no irreversible damage; 1, partially damaged; 2, severe damage, ankylosis, or prosthesis). The RAAD score was determined for 121 patients with RA with a large range of disease duration. Interobserver agreement was studied in 39 patients scored by three observers. Data on disease duration, Health Assessment Questionnaire, disease activity score, and Larsen score were collected for 121, 78, 47, and 45 patients, respectively. RESULTS: The RAAD score correlated well with the Larsen score (r(s)=0.81) and disease duration (r(s)=0.68) and (as intended) not with disease activity (r(s)=0.10). Good interobserver agreement was found for total scores and individual joints. The wide range of RAAD scores for patients with the same disease duration suggested good discriminating power, especially after >10 years. CONCLUSION: The RAAD score is a quick and feasible method for measuring the long term articular damage in large RA populations. It has good reliability and construct validity and deserves further study to assess its discriminant validity.
12379637 Integrin alpha V beta 3 as a target for treatment of rheumatoid arthritis and related rheu 2002 Nov A substantial and persuasive body of data now exists that supports the view that integrin alpha V beta 3 plays a critical part in activated macrophage dependent inflammation, osteoclast development, migration, and bone resorption, and inflammatory angiogenesis. All of these processes play an important part in the pathogenesis of rheumatoid arthritis (RA) and related arthropathies. Animal arthritis model data further support these concepts and also suggest that therapeutic antagonism of integrin alpha V beta 3 is worthy of further investigation in RA and related arthropathies. To this end, Vitaxin, also known as MEDI-522, has been developed. Vitaxin is a humanised monoclonal IgG1 antibody that specifically binds a conformational epitope formed by both the integrin alpha V and beta 3 subunits. It blocks the interaction of alpha V beta 3 with various ligands such as osteopontin and vitronectin. Clinical trials with Vitaxin in patients with RA are in progress.
12595628 The -308 polymorphism in the tumour necrosis factor (TNF) gene promoter region and ex vivo 2003 Feb OBJECTIVE: To investigate the association of the -308 polymorphism in the promoter region of the tumour necrosis factor (TNF) gene with susceptibility to the development of RA. We also explored the expression and cytotoxicity of TNF in relation to the -308 polymorphism. METHODS: We recruited 92 RA patients and 42 healthy control subjects. Genotyping for the TNF promoter was performed by polymerase chain reaction-restriction fragment length polymorphism analysis. To study the overexpression of TNF we used a whole-blood culture system. TNF cytotoxicity was assessed in the L929 cell line. RESULTS: The TNF2 allele was found in 23% of RA patients and 10% of controls. Although both groups showed high variability in serum TNF concentration, in the lipopolysaccharide-induced TNF level and in the cytotoxicity of the cytokine in the L929 cell line, these differences were not associated with the -308 TNF polymorphism. CONCLUSION: No associations were found between the -308 TNF promoter polymorphism, serum and ex vivo TNF levels and the cytotoxic activity of TNF in RA patients.
12020179 Lower risk of thromboembolic cardiovascular events with naproxen among patients with rheum 2002 May 27 BACKGROUND: Naproxen strongly inhibits platelet aggregation. OBJECTIVE: To examine the risk of acute thromboembolic cardiovascular events (TCEs) (myocardial infarction, sudden death, and stroke) with current naproxen use among patients with rheumatoid arthritis. METHODS: We studied patients aged 40 to 79 years with rheumatoid arthritis in the British General Practice Research Database, excluding those with a prior TCE and potentially confounding conditions. We matched up to 4 controls by sex, age, and site of medical practice to cases with first incident TCEs. The case diagnosis date was designated as the index date for each case and his or her controls. We categorized naproxen according to the most recent prescription prior to the index date as being current (< or =30 days), past (> 30 days but < 365 days), or none (> or =365 days before index date). Using conditional logistic regression, we conducted a matched case-control analysis with adjustment for potential confounders. RESULTS: We identified 809 cases. Current naproxen use was more common among controls (5.7%) than cases (3.2%). Adjusting for calendar year of treatment start, systemic corticosteroid use, diabetes, and comorbidity, we found that the odds ratio (95% confidence interval) for current naproxen use was 0.61 (0.39-0.94) while that for past use was 0.87 (0.65-1.16). Secondary and sensitivity analyses supported these results. CONCLUSIONS: In this case-control study, patients with rheumatoid arthritis and a current prescription for naproxen had a reduced risk of acute major TCEs relative to those with no naproxen prescription in the past year. These results are consistent with the ability of naproxen to inhibit platelet aggregation.
15172044 Infliximab treatment of rheumatoid arthritis. 2004 May Infliximab was the first anti-TNF agent used to treat rheumatoid arthritis to provide proof of concept of the role of TNF-alpha in this condition. It has become widely used since, principally as an effective treatment in combination with methotrexate, but also as monotherapy for the treatment of Crohn's disease, ankylosing spondylitis,and psoriatic arthritis. The benefits of infliximab in controlling signs and symptoms, improving quality of life, preventing structural joint damage, and possible healing of bone provide an important option for the treatment of rheumatoid arthritis.
14964790 The hand X-ray in rheumatology. 2004 Jan X-ray of the hands is the most valuable imaging modality in rheumatology. Joint disease may be identified by individual features such as joint space narrowing, erosions, new bone formation, subluxation and deformity, which may be diagnostic. In diseases such as rheumatoid arthritis presence of erosions on hand X-ray give a valuable measure of disease progression and response to therapy.
11994686 [Leflunomide in the treatment of rheumatoid arthritis]. 2002 Feb Leflunomide is a new second-line drug for rheumatoid arthritis. This compound with long half-life inhibits proliferation of activated T lymphocytes. Phase III studies have demonstrated a clinical efficacy superior to placebo and identical to comparators (salazopyrine, methotrexate) with a faster onset of response. Improvement of inflammatory paramaters and functional capacity (HAQ) were observed as well as slowing of structural damage evaluated by X-rays. Global tolerance is fair, but possibility of hepatic involvement, although unfrequent, needs a regular survey.
14749714 A review of the MHC genetics of rheumatoid arthritis. 2004 May Rheumatoid arthritis is a common complex genetic disease, and, despite a significant genetic element, no gene other than HLA-DRB1 has been clearly demonstrated to be involved in the disease. However, this association accounts for less than half the overall genetic susceptibility. Investigation of other candidate genes, in particular those that reside within the major histocompatibility complex, are hampered by the presence of strong linkage disequilibrium and problems with study design.
12082280 COX-1, COX-2 and articular joint disease: a role for chondroprotective agents. 2002 It is widely accepted that whilst exhibiting clinically useful anti-inflammatory and analgesic activity, the application of non-steroidal anti-inflammatory drugs (NSAIDs) does not affect the underlying pathogenesis of articular diseases such as rheumatoid arthritis. The demonstration of a role for COX-2 in the resolution of inflammation may partly underly the lack of disease modifying activity seen with NSAIDs in long term use in these inflammatory joint diseases. This has led to the suggestion that the anti-arthritic efficacy of these agents may be improved by altering prescribing practice such that they are not given during periods of disease remission, which may be difficult to achieve in the clinic. Alternatively, they may benefit from concomitant administration of chondroprotective agents, such as diacetylrhein, which may protect against the deleterious effects of traditional NSAIDs on cartilage degradation and, further, inhibit additional pathways such as cytokine elaboration which are important in joint destruction.
12956655 Measurement of both native and inactivated forms of alpha1 proteinase inhibitor in human i 2003 Sep BACKGROUND: Inactivation of the elastase inhibitor, alpha1 proteinase inhibitor (alpha1PI), may be of pathogenic significance in inflammatory diseases like periodontal disease. Two key mechanisms of inactivation appear to be (a) the formation of an alpha1PI-elastase complex and (b) proteolytic cleavage by elastase or other enzymes such as metalloproteinases of host origin or enzymes of bacterial origin. Based on the different heat stabilities of the intact, complexed and proteolytically cleaved forms of alpha1PI, an enzyme-linked immunosorbent assay (ELISA) that allowed the simultaneous measurement of native and inactive forms of alpha1PI was developed. METHODS: The ELISA method described employs a commercially available antibody and represents a rapid, reproducible and sensitive method for studying alpha1PI inactivation in human inflammatory diseases. The assay was applied to normal human plasma and to human extracellular fluids obtained from patients with inflammatory diseases such as adult periodontitis and rheumatoid arthritis. Samples from patients with osteoarthritis, a "non-inflammatory" joint disease, were also studied. RESULTS: The findings expressed as the mean percentage (+/-SD) of the total alpha1PI that was inactivated were as follows: gingival crevicular fluid from adult periodontitis patients: 73.5+/-16.6% (n=12); normal human plasma: 8.4+/-4.9% (n=13); knee-joint synovial fluid (SF) from rheumatoid arthritis patients: 12.5+/-4.5% (n=15); plasma from rheumatoid arthritis patients: 8.0+/-1.8% (n=15); knee-joint SF from osteoarthritis patients: 8.6+/-8.2% (n=14); plasma from osteoarthritis patients: 5.7+/-4.8% (n=14). The results obtained by ELISA were in good agreement with those obtained by the semi-quantitative method of SDS-PAGE and Western blotting. CONCLUSIONS: We have shown that the differential heat stability of alpha1PI may be utilised as the basis for a rapid, sensitive and reproducible ELISA assay of alpha1PI inactivation. In gingival crevicular fluid from periodontal disease patients, alpha1PI is mainly inactivated and the extent of this inactivation is much higher than in inflammatory fluids from other chronic diseases such as rheumatoid arthritis. This assay could be useful in monitoring the progression of periodontal disease.
14673618 Radon therapy for the treatment of rheumatic diseases--review and meta-analysis of control 2005 Apr OBJECTIVE: The aim of this study was to analyze the effect of radon therapy on pain in rheumatic diseases. METHODS: MEDLINE and MedKur databases were searched for the terms radon plus therapy, rheum, arthritis, and osteo. Radon therapy centers and experts in the field were contacted, proceedings hand-searched, and bibliographies checked for references of potential importance. Included were all prospective randomized controlled clinical trials that compared clinical effects of radon therapy with other interventions in patients with rheumatic diseases and studied pain intensity. Information concerning patients, interventions, results, and methodology were extracted in a standardized manner by all authors independently and summarized descriptively. Reports on pain reduction were pooled for meta-analysis. RESULTS: Five clinical trials with a total of 338 patients and comparing the effect on pain of radon baths (three trials) or radon speleotherapy (two trials) with control intervention in degenerative spinal disease (two trials), rheumatoid arthritis (one trial) and ankylosing spondylitis (two trials) met the inclusion criteria. In meta-analysis, the pooled data showed no difference immediately after treatment (P=0.13) but significantly better pain reduction in the radon group than the control group at 3 months (P=0.02) and 6 months (P=0.002) after treatment. CONCLUSIONS: The existing trials suggest a positive effect of radon therapy on pain in rheumatic diseases. With respect to the potential clinical effect and given the increasing public interest in radon therapy, there is an urgent need for further randomized controlled clinical investigations with long-term follow-up.
12430576 Severe neutropenia due to naproxen therapy in rheumatoid arthritis: a case report and revi 2002 Aug Rheumatoid arthritis is a chronic inflammatory disease that primarily affects the joints and is often treated with non-steroidal anti-inflammatory drugs (NSAIDs) on demand and disease-modifying antirheumatic drugs (DMARDs), with a relatively low risk of side effects. Although an infrequent side effect, neutropenia has been described as a sequel of NSAIDs. We report a case of neutropenia proven (by rechallenge) to be due to naproxen therapy. The literature on neutropenia during treatment with NSAIDs and DMARDs is briefly reviewed.