Browse

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

ID PMID Title PublicationDate abstract
9485082 ATP and UTP activate calcium-mobilizing P2U-like receptors and act synergistically with in 1998 Feb OBJECTIVE: To pharmacologically and functionally characterize calcium-mobilizing purine receptors on adherent human rheumatoid synovial cells. METHODS: Fura-2-loaded synovial cells were screened for changes in cytosolic calcium concentration after the addition of purine receptor agonists. Release of interleukin-1 (IL-1) and prostaglandin E2 (PGE2) was assessed by enzyme-linked immunosorbent assay (ELISA) and radioimmunoassay, respectively. The effect of IL-1 prestimulation on purine-mediated PGE2 release was determined. RESULTS: ATP (1-100 microM) and UTP (1-100 microM), but not 2-methylthio-ATP or adenosine, stimulated mobilization of calcium from intracellular stores in synovial cells. ATP and UTP stimulated a small, but significant, increase in PG release from resting synoviocytes and a dramatic increase in PG release from synoviocytes prestimulated with recombinant human IL-1alpha. Neither ATP nor UTP stimulated synoviocyte release of IL-1 as measured by specific ELISA. The effects of ATP and UTP on PG secretion were mimicked by phorbol 12-myristate 13-acetate and thapsigargin, and blocked by BAPTA buffering of cytosolic calcium. CONCLUSION: Adherent human rheumatoid synovial cells mobilize intracellular calcium via a P2U-like purine receptor. P2U receptor agonists stimulate PGE2 release from synoviocytes, an effect that is greatly enhanced by IL-1alpha prestimulation and blocked by intracellular calcium buffering.
9122163 Discovery and analysis of inflammatory disease-related genes using cDNA microarrays. 1997 Mar 18 cDNA microarray technology is used to profile complex diseases and discover novel disease-related genes. In inflammatory disease such as rheumatoid arthritis, expression patterns of diverse cell types contribute to the pathology. We have monitored gene expression in this disease state with a microarray of selected human genes of probable significance in inflammation as well as with genes expressed in peripheral human blood cells. Messenger RNA from cultured macrophages, chondrocyte cell lines, primary chondrocytes, and synoviocytes provided expression profiles for the selected cytokines, chemokines, DNA binding proteins, and matrix-degrading metalloproteinases. Comparisons between tissue samples of rheumatoid arthritis and inflammatory bowel disease verified the involvement of many genes and revealed novel participation of the cytokine interleukin 3, chemokine Gro alpha and the metalloproteinase matrix metallo-elastase in both diseases. From the peripheral blood library, tissue inhibitor of metalloproteinase 1, ferritin light chain, and manganese superoxide dismutase genes were identified as expressed differentially in rheumatoid arthritis compared with inflammatory bowel disease. These results successfully demonstrate the use of the cDNA microarray system as a general approach for dissecting human diseases.
10460184 Does social disadvantage contribute to the excess mortality in rheumatoid arthritis patien 1999 Sep BACKGROUND: Socioeconomic deprivation is associated with increased mortality from cardiovascular causes and malignancy. The influence of disadvantage in patients with rheumatoid arthritis (RA), who are known to have premature mortality, has not been ascertained. AIM: To assess the relation between the level of patient deprivation and mortality in RA patients. METHODS: 200 RA patients, enrolled in a study comparing sulfasalazine and penicillamine in 1984-85, have been followed up prospectively for 12 years. Subjects were categorised into Carstairs groups with deprivation scores ranging from 1 (most affluent) to 7 (most deprived). Information about deaths was obtained from the Registrar General in Scotland, death certificates and GP/hospital records. RESULTS: There were more RA patients in the deprived areas then expected compared with the West of Scotland and England and Wales. Some 47.5% of the RA patients had died by 12 years-the majority of cardiorespiratory causes or malignancy. There were no differences in the median age or disease duration in the various Carstairs groups at study entry, but the percentage of deaths was higher in the more deprived groups after 12 years (36% dead in most affluent area compared with 61% in the most deprived, that is, in groups 6 and 7). CONCLUSION: In patients with RA increasing deprivation was associated with premature mortality. If confirmed elsewhere these findings have implications for rheumatological management strategies, for researchers involved in collaborative studies of patients from different socioeconomic backgrounds and for resource allocation.
9667618 Isometric muscle strength is an indicator of self-reported physical functional disability 1998 Jun The objective of our study was to examine (1) whether isometric muscle strength contributes to the explanation of the physical functional disability of a rheumatoid arthritis (RA) patient population after accounting for other disease parameters and demographic variables and (2) whether change in isometric muscle strength is an indicator of change in physical functional disability. Sixty-five consecutive patients fulfilling the American Rheumatism Association 1987 revised criteria for RA were included in the study. Isometric muscle strength was measured with a validated Muscle Strength Index (MSI) calculated as the mean score of standardized isometric extension and flexion strength of the knee and elbow joints. Physical functional disability was measured with the physical dimension of the Health Assessment Questionnaire (HAQ). For 56 patients, we could obtain 1 yr follow-up data. Cross-sectionally, there was a significant correlation (r = -0.51, P < 0.01) between the MSI and the HAQ. Muscle strength remained a significant determinant of the HAQ in multivariate analysis accounting for disease and demographic variables. Longitudinally, change in MSI explained additional variance of change in HAQ after accounting for change in pain, the most important correlate of change in HAQ.
9209794 Correlation between blood antioxidant levels and lipid peroxidation in rheumatoid arthriti 1997 Jun OBJECTIVES: To investigate the relationship between lipid peroxidation and certain antioxidant parameters in the blood of rheumatoid arthritis patients. METHODS AND RESULTS: In the present study, significantly increased lipid peroxidation, measured as malondialdehyde (MDA), was demonstrated in the plasma of rheumatoid arthritis patients (p < 0.01). The activities of erythrocyte antioxidant enzymes, superoxide dismutase and catalase remained unaltered. However, erythrocyte glutathione and plasma ceruloplasmin levels were significantly higher in patients (p < 0.001). Moreover, a positive correlation was also observed between these two parameters and MDA levels in the patient group but not in controls. Interestingly, a significant positive correlation also existed between red cell glutathione and plasma ceruloplasmin levels. CONCLUSION: These results suggest that increased oxidant stress present in rheumatoid arthritis may lead to compensatory changes in the levels of some antioxidants, viz. glutathione and ceruloplasmin. These changes, in turn, may provide additional protection against lipid peroxidation in rheumatoid arthritis.
11496741 [C-reactive protein and defect in lipid transport blood system in patients with rheumatoid 2001 In 88 patients with rheumatoid arthritis lipid-protein spectrum of the blood serum were determined biochemically and by means of nefelometric technique, C-reactive protein (CRP) was measured with enzyme immunoassay. An increase in CRP concentration was associated with lowering of apoA1 and HDL FL, triglycerides. Thus, elevation of CRP in RA reflects not only activity of inflammation but also defects in serum lipid-transport system by the atherogenic type.
9283612 ICAM-1/LFA-1 expression in acute osteodestructive joint lesions in collagen-induced arthri 1997 Sep Collagen-induced arthritis in rats is a widely used model of rheumatoid arthritis (RA). However, the joint immunohistopathology is less well characterized. The objective of this study was therefore to analyze whole ankle joints for markers known to mediate inflammatory mechanisms in RA. Indirect immunohistochemistry was performed on undecalcified cryostat sections for intercellular adhesion molecule-1 (ICAM-1, clone 1A 29) and leukocyte function-associated antigen-1 (LFA-1, clone WT.1) expression, for CD4+ lymphocytes (clone W3/25), B-cells (clone HIS 14), and macrophages (clone ED2). Acute, osteodestructive arthritis (n = 8) induced with bovine collagen Type II was verified by clinical and radiological measures. LFA-1 expression was found almost exclusively at sites associated with cartilage erosion or osteodestruction. ICAM-1 was similarly expressed in the vicinity of tissue degradation but also by blood vessels in peripheral areas of joint swelling. CD4+ lymphocytes and macrophages were more ubiquitous. B-cells were infrequent. In control animals (n = 4) ICAM-1 was expressed by synovial blood vessels. Macrophages were identified at the synovial lining. The results suggest that LFA-1 and ICAM-1 mediate important inflammatory events in this model. Similar findings in human RA synovium provide further arguments that collagen-induced arthritis in rats might be regarded as a comparable disease.
9676753 Clinical and immunologic effects of a PRIMATIZED anti-CD4 monoclonal antibody in active rh 1998 Jul OBJECTIVE: The goal of this single infusion, dose escalation study was to evaluate the safety of the PRIMATIZED anti-CD4 monoclonal antibody (Mab), IDEC-CE9.1, in patients with rheumatoid arthritis (RA). METHODS: Twenty-five patients received single infusions of IDEC-CE9.1 in dose escalation form (0.03 to 4 mg/kg). Cohorts consisted of 3 patients each with seropositive RA. Following treatment, patients were monitored for 2 weeks before initiation of treatment of the next cohort. Peripheral blood samples were taken during and after treatment to measure immune function. Flow cytometry of peripheral blood mononuclear cells and in vitro proliferative responses to antigens and recall antigens were assessed pre and post-treatment. Cell surface markers CD3, CD4 (OKT4 and Leu 3a), CD8, CD20, CD25, CD45Ro, CD45Ra and DR were analyzed, and proliferation to mitogens and recall antigens was measured. RESULTS: No infusion related adverse events were noted and other drug related adverse events were mild. Reduction in peripheral CD4 T cell number was brief (3 to 7 days) and not associated with infection. CD4 cell surface antigen downmodulation was observed postinfusion. Suppression of CD25 expression was associated with a positive clinical response. In vitro proliferative responses to mitogens and antigen were inhibited for up to one month with no association to positive clinical response. CONCLUSION: IDEC-CE9.1 appears to have a benign safety profile and may modulate immune function rather than deplete CD4+ T cells.
9710881 Triple therapy with methotrexate, sulfasalazine, and hydroxychloroquine in patients with r 1998 Aug Combinations of DMARDs are currently used to treat rheumatoid arthritis by almost all rheumatologists. This article reviews the published data on the triple combination of methotrexate, sulfasalazine, and hydroxychloroquine, discusses caveats for clinical use, compares efficacy of different combinations, and speculates on future combination therapies.
9623733 Cytokines in thyroid eye disease: potential for anticytokine therapy. 1998 May Interactions between between orbital fibroblasts and immunocompetent cells that infiltrate or reside within the orbit are thought to be important in the pathogenesis of thyroid eye disease (TED). These interactions are mediated primarily by cytokines; interferon-gamma, tumor necrosis factor-alpha, interleukin-1alpha and leukoregulin are of particular interest in this regard. These mediators induce or enhance the in vitro expression of immunomodulatory proteins in orbital fibroblasts, and stimulate proliferative and metabolic activities of these cells. The stimulation by particular cytokines of glycosaminoglycan synthesis in orbital fibroblasts is an important factor in the development of the clinical disease. A similarly important pathophysiological role for cytokines has been defined in rheumatoid arthritis. In this disease, the chronic erosive changes in the cartilage and bone of the joints result from cytokine-stimulated production of collegenases and other neutral proteases by synovial cells and articular chondrocytes. Advances in the understanding of the pathogenesis of rheumatologic joint disease has led to treatment trials aimed at immune-modulation, including trials of anticytokine therapy. Lessons learned in early clinical trials using these biological therapies in the treatment of rheumatoid arthritis can be applied to studies of similar agents in the treatment of TED.
11503269 [Current opinions on immunological processes in rheumatoid arthritis during pregnancy]. 2001 Jun The essential in pathogenesis of RA is induction of incorrect immunological response against synovial and connective tissue antigens, which depends of CD4+ T-cells activation by specific antigen. This stimulation leads to releasing Th1 lymphokines. The most important cytokine is TNF-alpha. An increased level of TNF-alpha, IL-1, IL-6, GM-CSF, IL-8 was observed in patients with RA. PDGF, FGF, TGF, C-X-C a chemokines (IL-GRO-alpha, ENA78) and CCb chemokines (RANTES, MCP1 MIP1 alpha) are also involved in synovial hyperplasia in RA. During a pregnancy a clinical improvement in women with RA is frequent. The reason of this fact is probably connected with Th2 predominance (IL-4, IL-10) caused by presence of fetal tissues. Specific, cell-mediated immunity is suppressed and changed to Th2 by progesterone and PGE2. During a pregnancy a higher sensitivity of lymphocytes to progesterone was found. Progesterone stimulates T cells to PIBF production, which decreases NK activity. Th2 cytokines (Il-6, IL-10, IL-13, TGF) are expressed on decidua and inhibit secretion of Th1 cytokines (IL-2, INF gamma, TNF-alpha, IL-1 alpha, IL-1 beta). Immunosuppression caused by pregnancy probably decreases inflammatory and destructive reactions in tissues women with RA. The first attack of this disease frequently observed during puerperium is connected with a high level of prolactin and a low of estrogens, which causes a increased release of IL-2 and has a main influence on initiation and increasing of inflammatory process in RA.
11324776 Preference for disclosure of information among patients with rheumatoid arthritis. 2001 Apr OBJECTIVE: To quantify preference for disclosure of information among patients with rheumatoid arthritis (RA) and to examine sex-specific correlates of information preference. METHODS: We interviewed patients with RA and assessed preference for disclosure of information using 4 questions from the previously validated "Information Preference Seeking Scale." Three questions addressed preference for disclosure of side effects and 1 question addressed preference for disclosure of therapeutic options. Associations between preference for information and patient characteristics were examined using stepwise multiple linear regression. RESULTS: One hundred RA patients (mean age 68+/-12 years; 73% female) were interviewed; 89 respondents agreed or strongly agreed with all 4 statements reflecting a preference for full disclosure, and an additional 8 respondents agreed or strongly agreed with 3 of the 4 statements. The mean score (+/- SD) for information preference was 86+/-13, on a scale from 0 to 100 where 100 reflected a strong preference for full disclosure. In bivariate analyses, female sex and current employment were associated with stronger preferences for being informed (mean score for women 88+/-11, for men 80+/-15 [P = 0.02]; for employed 92+/-11, for unemployed 84+/-13 [P = 0.04]). Multivariate sex-specific analyses demonstrated that current employment and higher education level were positively associated with preference for disclosure among women and men, respectively. CONCLUSION: The results of our survey suggest that RA patients want to be fully informed about the risks associated with medications and about alternative options. The challenge remaining for rheumatologists is how to effectively communicate the risks and benefits related to the many options that are currently available for RA patients.
10464549 Impaired diastolic function in active rheumatoid arthritis. Relationship with disease dura 1999 Jul OBJECTIVE: Using digitized M-mode and Doppler echocardiography, we evaluated left ventricular (LV) function in 54 patients (43 women and 11 men; mean age 50 years) suffering from active rheumatoid arthritis (RA) without obvious cardiovascular disease, and compared them with 54 age- and sex-matched normal subjects. RESULTS: No differences were found in LV end-diastolic diameter, systolic function and parietal thickness between the patients and controls. However, a significant reduction in various indexes of LV diastolic function was found, including E/A (ratio of early to late filling waves of mitral inflow Doppler) and the peak lengthening rate of the LV diameter (an index of LV relaxation evaluated by M-mode echocardiography). The former was correlated with patient age and was independent of disease duration, while the latter was more markedly correlated with disease duration than with patient age. CONCLUSION: The relationship between diastolic impairment and disease duration in active RA may open new perspectives in the study of RA-associated cardiovascular disease.
10235032 [Methotrexate pneumonitis]. 1999 Mar 25 A 72 year old female with rheumatoid arthritis was treated with methotrexate for nine months. Four days before admission she complained of dyspnea NYHA III. Chest-X-ray revealed diffuse interstitial pneumopathy. Pulmonary infection was excluded by several microbiological samples. A pulmonary manifestation of rheumatoid arthritis is usually more chronic. Methotrexate-induced pneumonitis remained the most probable diagnosis. We halted methotrexate and initiated therapy with glucocorticoids. This treatment led to rapid clinical improvement and complete resolution of radiological changes.
11083273 The role of catastrophizing in the pain and depression of women with fibromyalgia syndrome 2000 Nov OBJECTIVE: Although 2 recent studies have found associations between catastrophizing and poor medical outcomes in patients with fibromyalgia syndrome (FMS), neither assessed these findings in comparison with a similar group of patients with chronic pain. Our study examined the complex relationships between depression, catastrophizing, and the multidimensional aspects of pain in women with FMS and compared these relationships with those in women with rheumatoid arthritis (RA). METHODS: Sixty-four FMS patients and 30 RA patients completed the Coping Strategies Questionnaire (CSQ), the Beck Depression Inventory II (BDI-II), and the McGill Pain Questionnaire. RESULTS: Compared with subjects with RA, FMS subjects scored significantly higher on the catastrophizing subscale of the CSQ. FMS patients also earned higher scores on overall depression and on the cognitive subscale of the BDI-II. Furthermore, the relationship between catastrophizing and depression was significant in the FMS group only. Regression analyses revealed that in FMS, catastrophizing as a measure of coping predicted patients' perception of pain better than demographic variables such as age, duration of illness, and education. CONCLUSION: Cognitive factors, such as catastrophizing and depressive self-statements, have a more pronounced role in the self-reported pain of patients with FMS than in patients with RA. Clinically, this indicates that treating pain and depression in FMS by adding cognitive therapy and coping skills components to a comprehensive treatment program may improve the outcomes obtained with pharmacologic interventions.
10328139 The role of tumor necrosis factor antagonism in clinical practice. 1999 May The armamentarium for the treatment of rheumatoid arthritis (RA) includes several classes of therapeutics that induce symptomatic relief and reduce disease activity. The early addition of disease modifying antirheumatic drugs (DMARD) is now the standard of care in treatment. Methotrexate (MTX) is a cornerstone of contemporary management of RA, and the treatment paradigm for RA includes the early use of MTX and combination DMARD. Unfortunately, second-line treatments alone or in combination rarely induce complete disease remission. Advances in the understanding of the pathogenesis of RA have opened the way for more directed therapy, and new therapies that target the cytokine tumor necrosis factor alpha (TNF-alpha) have demonstrated rapid action and substantial benefit with few adverse effects. This article discusses the pivotal role of MTX in combination with DMARD. The use of leflunomide and cyclosporine as single agents and with MTX is evaluated. The role of TNF-alpha antagonism in the treatment of rheumatologic illnesses is examined, with particular attention to etanercept, a recombinant human TNF receptor (p75)-Fc fusion protein, and infliximab, a chimeric TNF monoclonal antibody (CA2). Data on the efficacy and toxicity of etanercept and infliximab are summarized, including their use in combination therapy with MTX.
9034984 Efficacy and safety of meloxicam in patients with rheumatoid arthritis. 1997 Feb OBJECTIVE: To evaluate the efficacy and safety of meloxicam, a new acidic enolic nonsteroidal anti-inflammatory drug, at doses of 7.5 and 15 mg once daily in patients with rheumatoid arthritis (RA). METHODS: Meloxicam 15 and 7.5 mg daily was administered for 21 days in this double blind, randomized, placebo controlled study. 159 patients received meloxicam 7.5 mg, 162 received meloxicam 15 mg, and 147 received placebo. RESULTS: Meloxicam 15 mg once daily was significantly superior (p < 0.05) to placebo in 3 of the 4 primary endpoints (disease activity assessed by the investigator, disease activity assessed by the patient, and reduction of the number of tender/painful joints). No difference was observed regarding number of swollen joints. The difference between meloxicam 7.5 mg once daily and placebo reached statistical significance in 2 of the 4 primary endpoints, disease activity assessed by the patient and number of tender/painful joints. A statistically significant difference between meloxicam 1.5 mg and 7.5 mg was not observed for any primary endpoint. The rating of global tolerance by investigators and patients at the end of the study was similar in the 3 treatment groups, indicating that meloxicam and placebo were generally similarly well tolerated. However, there was a slightly higher incidence of gastrointestinal (GI) disturbances reported by patients receiving meloxicam 15 mg. GI adverse events were reported by 11, 11, and 16% of patients in the placebo, meloxicam 7.5 mg, and meloxicam 15 mg groups, respectively. None were serious. CONCLUSION: Meloxicam in daily doses of 7.5 and 15 mg is effective in treating the signs and symptoms of RA.
11263012 [Help status and help prospects of severely handicapped patients with rheumatoid arthritis 2001 Feb Although increased efforts have been made, rheumatoid arthritis still leads to severe disability and dependence on external help in about one-third of the patients. Relatively little is known on how help-dependent RA patients manage everyday life, to what extent they need help, by whom the help is given, what the patients' future help perspectives are and what kind of patient- and resource-related characteristics are associated with unmet need. METHODS: By means of standardized interviews a representative sample of severly disabled RA patients was investigated with respect to present life situation, functional capacity, amount of help needed, relationship of caregiver and patient, health status of caregiver, stability of the help situation, housing preferences and help-seeking behaviour. The patients were classified as being either in definite need of help or independent of external help. RESULTS: Patients with comparable disabilities living on their own had only one-third of the help of those living together with others. They received help slightly more often from non-family caregivers, such as visiting nurses or privately paid household help, than from family members. Although many patients had rather uncertain perspectives for the future, the majority vehemently rejected living in a retirement home or in a home for the disabled. This refusal to live in an institution was independent of functional capacity, adequacy of the present help situation and the financial situation. Unmet need was highly associated with the age and health status of the caregiver as well as the help-seeking behaviour of the dependent person, but not with functional status or available resources. CONCLUSION: Given an appropriate home, the majority of conditions for a self-determined life for help-dependent RA patients are satisfied by the present outpatient help and care systems in Germany, but patients and their care givers need to be encouraged to take advantage of the available help and care facilities.
11212177 Association between rheumatoid arthritis and polymorphism of tumor necrosis factor recepto 2001 Jan OBJECTIVE: Tumor necrosis factor (TNF) is a powerful mediator of inflammation in rheumatoid arthritis (RA). In vivo, its acute effects are limited by binding to soluble receptors (TNFR), suggesting that TNFR genes could be important candidate risk factors. The present study was undertaken to investigate association of polymorphisms of TNFRI and TNFRII with RA in subjects in the UK. METHODS: Unrelated Caucasian RA patients (n = 291) and healthy Caucasian controls (n = 143) were genotyped for A/G polymorphism in exon 1 of TNFRI. From this sample, 240 of the patients and 137 controls were also typed for a single-nucleotide polymorphism (SNP) in exon 6 of the TNFRII gene. In followup studies, DNA samples from UK Caucasian RA patients with a positive family history (n = 149) and UK Caucasian patients with sporadic RA (n = 208) were also typed for the exon 6 TNFRII polymorphism. RESULTS: TNFRI polymorphism was not associated with RA (odds ratio [OR] for GG genotype 0.93, 95% confidence interval [95% CI] 0.54-1.60). For TNFRII, in the initial study group, patients with RA were significantly more likely to be positive for both the G allele and GG genotype than were controls (OR for GG genotype 2.55, 95% CI 1.11-5.86). The association appeared to be confined to those with a family history of RA. This finding was replicated in an independent cohort of patients with familial RA. CONCLUSION: The results of this study provide evidence of association between an SNP in the TNFRII gene and RA, the strongest association being observed in patients with a family history. No evidence of association between RA and TNFRI was demonstrated.
10962872 [Prognostic value of Sharp's index in the clinical and laboratory response to an intraveno 2000 Mar BACKGROUND: No reliable variables to predict clinical or laboratory response to treatment in patients with rheumatoid arthritis were available until recently. AIM: To asses the potential predictive value of the Sharp's modified radiographic joint damage index for the assessment of clinical and laboratory response to a methylprednisolone i.v. pulse. PATIENTS AND METHODS: Twenty-two patients suffering from rheumatoid arthritis received a single i.v. pulse of 1 g of methylprednisolone. Hand X-rays were taken at baseline and blindly scored by two trained radiologists. Clinical and laboratory variables were assessed at baseline and at weekly intervals up to 30 days plus a 60 days final evaluation. Improvement was defined as a 50% amelioration in 4 variables. RESULTS: Assessment of radiographic scores had a high correlation between and within observers (intraclass correlation = 0.998). Sharp score did not reach statistical significance as global predictor for the inflammatory variable response to methylprednisolone. However, when the number of swollen joints was taken into account, patients with a low erosive score (Sharp < or = 50) had a more prolonged clinical response, than patients with higher erosive score (Sharp > 50) (Fisher test p = 0.023). It is of clinical importance to point out that among patients with high Sharp score there were also responders who reached a high level of improvement. A statistically significant correlation between the basal PCR serum titers and the radiographic score (p < 0.02) was observed. CONCLUSIONS: The number of swollen joints and other variables that consider joint structural changes should be considered for the assessment of rheumatoid arthritis patients.