Browse

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

ID PMID Title PublicationDate abstract
11454054 Nitric oxide and bone. 2001 Jul Nitric oxide (NO) is a free radical which has important effects on bone cell function. The endothelial isoform of nitric oxide synthase (eNOS) is widely expressed in bone on a constitutive basis, whereas inducible NOS is only expressed in response to inflammatory stimuli. It is currently unclear whether neuronal NOS is expressed by bone cells. Pro-inflammatory cytokines such as IL-1 and TNF cause activation of the iNOS pathway in bone cells and NO derived from this pathway potentiates cytokine and inflammation induced bone loss. These actions of NO are relevant to the pathogenesis of osteoporosis in inflammatory diseases such as rheumatoid arthritis, which are characterized by increased NO production and cytokine activation. Interferon gamma is a particularly potent stimulator of NO production when combined with other cytokines, causing very high concentrations of NO to be produced. These high levels of NO inhibit bone resorption and formation and may act to suppress bone turnover in severe inflammation. The eNOS isoform seems to play a key role in regulating osteoblast activity and bone formation since eNOS knockout mice have osteoporosis due to defective bone formation. Other studies have indicated that the NO derived from the eNOS pathway acts as a mediator of the effects of oestrogen in bone. eNOS also mediates the effects of mechanical loading on the skeleton where it acts along with prostaglandins, to promote bone formation and suppress bone resorption. Pharmacological NO donors have been shown to increase bone mass in experimental animals and preliminary evidence suggests that these agents may also influence bone turnover in man. These data indicate that the L-arginine/NO pathway represents a novel target for therapeutic intervention in the prevention and treatment of bone diseases.
9402860 Different approaches to synovial membrane volume determination by magnetic resonance imagi 1997 Nov Automated fast (5-20 min) synovial membrane volume determination by MRI, based on pre-set post-gadolinium-DTPA enhancement thresholds, was evaluated as a substitute for a time-consuming (45-120 min), previously validated, manual segmentation method. Twenty-nine knees [rheumatoid arthritis (RA) 13, osteoarthritis (OA) 16] and 17 RA wrists were examined. At enhancement thresholds between 30 and 60%, the automated volumes (Syn(x%)) were highly significantly correlated to manual volumes (SynMan) (knees: rho = 0.78-0.91, P < 10(-5) to < 10(-9); wrists: rho = 0.87-0.95, P < 10(-4) to < 10(-6)). The absolute values of the automated estimates were extremely dependent on the threshold chosen. At the optimal threshold of 45%, the median numerical difference from SynMan was 7 ml (17%) in knees and 2 ml (25%) in wrists. At this threshold, the difference was not related to diagnosis, clinical inflammation or synovial membrane volume, e.g. no systematic errors were found. The inter-MRI variation, evaluated in three knees and three wrists, was higher than by manual segmentation, particularly due to sensitivity to malalignment artefacts. Examination of test objects proved the high accuracy of the general methodology for volume determinations (maximal error 6.3%). Preceded by the determination of reproducibility and the optimal threshold at the available MR unit, automated 'threshold' segmentation appears to be acceptable when changes rather than absolute values of synovial membrane volumes are most important, e.g. in clinical trials.
9438089 The postoperative drain-clamping method for hemostasis in total knee arthroplasty. Reducin 1997 We attempted to decrease the amount of postoperative bleeding after total knee arthroplasty (TKA) by clamping the suction drain and through retrograde infusion of saline containing a low concentration of epinephrine. When TKA was completed and the sutured wound was bandaged, 50 ml of saline containing epinephrine diluted to 1:200,000 and 0.5 g of antibiotic was injected into the knee joint via the inserted suction drain. The drain was clamped for 20 hours and then unclamped to begin aspiration until 48 hours after surgery. To clarify the effectiveness of this method, patients were divided into three groups. Group I consisted of 116 knees (in 95 patients) infused with 50 ml saline containing a low dose of epinephrine: Group II was composed of 70 knees (42 patients) infused with 50 ml saline only; and Group III included 97 knees (78 patients) who did not undergo this drain-clamp method. The average amount of postoperative bleeding was 207 ml in Group I, 255 ml in Group II (p < 0.01), and 501 ml in Group III (p < 0.001). With this method of using saline with a low dose of epinephrine and sustained clamping of up to 20 hours, we have been able to operate on elderly patients with rheumatoid arthritis without blood transfusion, even in cases of simultaneous bilateral TKA. Drain-clamping with saline infusion effectively controlled postoperative bleeding after TKA, and when epinephrine was added to the saline, the hemostatic effect was even greater than that of saline alone.
10922169 Total prosthetic replacement of the TMJ: experience with two systems 1988-1997. 2000 Aug We report our experience with the Vitek VK II and the Christensen systems for total prosthetic replacement of the temporomandibular joint, in 62 patients treated between 1988 and 1997. Thirteen were treated in Birmingham and 49 in Gloucester. A total of 86 joints were replaced, of which 27 (31%) were Vitek VK II and 59 (69%) were Christensen prostheses. Just over half of the patients were treated for degenerative arthropathy or osteoarthritis, and the second most common diagnosis was rheumatoid arthritis. Twenty-five patients had had previous operations. The median follow-up was 14.5 months (range 1-120). Preoperatively only 14 patients (23%) could eat all types of food - and postoperatively this increased to 48 (77%). Thirty-nine patients (63%) reported severe pain preoperatively compared with three (5%) postoperatively. No prostheses were rejected, but four patients required replacement of Vitek VK II by Christensen prostheses; all four showed histological evidence of a foreign body giant cell reaction. The overall success rate was 58/62 patients and 81/86 joints replaced (94% in each case). However, for the Vitek VK II system alone the success rate was 14/17 patients (82%) and 24/27 joints replaced (89%).
10970168 Occupational exposure to crystalline silica and autoimmune disease. 1999 Oct Occupational exposure to silica dust has been examined as a possible risk factor with respect to several systemic autoimmune diseases, including scleroderma, rheumatoid arthritis, systemic lupus erythematosus, and some of the small vessel vasculitidies with renal involvement (e.g., Wegener granulomatosis). Crystalline silica, or quartz, is an abundant mineral found in sand, rock, and soil. High-level exposure to respirable silica dust can cause chronic inflammation and fibrosis in the lung and other organs. Studies of specific occupational groups with high-level silica exposure (e.g., miners) have shown increased rates of autoimmune diseases compared to the expected rates in the general population. However, some clinic- and population-based studies have not demonstrated an association between silica exposure and risk of autoimmune diseases. This lack of effect may be due to the limited statistical power of these studies to examine this association or because the lower- or moderate-level exposures that may be more common in the general population were not considered. Experimental studies demonstrate that silica can act as an adjuvant to nonspecifically enhance the immune response. This is one mechanism by which silica might be involved in the development of autoimmune diseases. Given that several different autoimmune diseases may be associated with silica dust exposure, silica dust may act to promote or accelerate disease development, requiring some other factor to break immune tolerance or initiate autoimmunity. The specific manifestation of this effect may depend on underlying differences in genetic susceptibility or other environmental exposures.
10902749 Determining minimally important changes in generic and disease-specific health-related qua 2000 Jul OBJECTIVE: To define clinically meaningful changes in 2 widely used health-related quality of life (HQL) instruments in studies of patients with rheumatoid arthritis (RA). METHODS: Patients with RA (n = 693) who were enrolled in 2 double-blind, placebo-controlled clinical trials completed the Short Form 36 (SF-36) modified health survey and the Health Assessment Questionnaire (HAQ) disability index at baseline and 6-week followup assessments. Data on 5 RA severity measures were also collected at baseline and at 6 weeks (patient and physician global assessments, joint swelling and tenderness counts, and global pain assessment). Comparison of changes in the SF-36 scales and HAQ scores was made between groups of patients known to differ in the level of change on each RA severity measure. RESULTS: With few exceptions, changes in the SF-36 and HAQ scores were different between patients who differed in the level of change on each RA severity measure. Changes in the SF-36 and HAQ scores were more strongly related to changes in the patient and physician global assessments and patient pain assessment than to changes in the joint swelling and tenderness counts. CONCLUSION: Based on these results, minimally important changes in the SF-36 scales and HAQ disability scores were determined, which will be useful in interpreting HQL results in clinical trials.
10376735 Localization and expression of cartilage oligomeric matrix protein by human rheumatoid and 1999 May Synovium and cartilage from patients with osteoarthritis or rheumatoid arthritis were analyzed for expression of cartilage oligomeric matrix protein. Immunostaining of synovium with antiserum to cartilage oligomeric matrix protein demonstrated positive staining in both diseases. In osteoarthritis, there was positive staining within the synovial cells and immediately subjacent connective tissue, with less intense staining in the deeper connective tissue. In rheumatoid arthritis, there was less intense staining within the synovial cells and marked intense staining in the deeper connective tissue. In situ hybridization performed with an antisense digoxigenin-labeled riboprobe to human cartilage oligomeric matrix protein confirmed the presence of cartilage oligomeric matrix protein mRNA in the cells of the synovial lining in both types of synovium. Quantitative polymerase chain reaction with a cartilage oligomeric matrix protein MIMIC demonstrated increased cartilage oligomeric matrix protein mRNA in rheumatoid cartilage and synovium as compared with osteoarthritic cartilage and synovium, respectively; mRNA levels in rheumatoid synovium were similar to those from osteoarthritic chondrocytes. As a result of the high expression of cartilage oligomeric matrix protein from rheumatoid synovium, inflammatory synovium should be considered as a potential tissue source of cartilage oligomeric matrix protein in any investigation of biological markers of cartilage metabolism. The upregulated expression of cartilage oligomeric matrix protein in inflammatory tissues suggests its in vivo regulation by cytokines.
10437642 Quantification of protease activities in synovial fluid from rheumatoid and osteoarthritis 1999 Jun 15 We have compared (using the same series of experimental samples) the levels of activity of a comprehensive range of cytoplasmic, lysosomal and matrix protease types, together with the levels of free radical-induced protein damage (determined as protein carbonyl derivative) in synovial fluid from rheumatoid (RA) and osteoarthritis (OA) cases. Many protease types showed significantly increased activity (typically by a factor of 2-3-fold) in RA compared to OA cases. Protease activity levels (including those enzyme types putatively involved in the immune response, such as dipeptidyl aminopeptidase IV) in plasma were not significantly different in RA and control cases. The level of free radical induced damage to synovial fluid proteins was approximately 2-fold higher in RA compared to OA, although there was no significant difference in total antioxidant status in synovial fluid or plasma between RA, OA or control cases. We conclude from the above that activation of proteolytic enzymes and free radicals (occurring specifically within synovial tissues) are likely to be of equal potential importance as protein damaging agents in the pathogenesis of RA, and the development of novel therapeutic strategies for the latter disorder should include both protease inhibitory and free radical scavenging elements. In addition, the protease inhibitory element should be designed to inhibit the action of a broad range of enzymic mechanistic types (cysteine, serine, metallo proteinases and peptidases).
10852288 Primary cutaneous B cell lymphoma during methotrexate therapy for rheumatoid arthritis. 2000 Jun A patient with rheumatoid arthritis developed a reversible, primary cutaneous, large B cell lymphoma during prolonged methotrexate (MTX) treatment. Regression of the skin lesions after discontinuation of the drug suggested a close relationship to MTX. Increased clinical awareness, discontinuation of MTX, and close observation are important in the initial management of this rare lymphoproliferative disorder.
10907346 Case report. Primary cutaneous histoplasmosis in an immunosuppressed patient. 2000 A case of cutaneous histoplasmosis is reported in an 80-year-old man with rheumatoid arthritis who had been treated with steroid therapy for 15 years. The patient developed a large ulcerative lesion on the back of the left hand and on the distal third of the left dorsal forearm after a slight trauma. Diagnosis was based on histological and mycological examination. Systemic involvement was not found. The lesions healed after 2 months of therapy with 100 mg day-1 fluconazole, confirmed at follow-up 1 year later.
11160188 The human endoplasmic reticulum molecular chaperone BiP is an autoantigen for rheumatoid a 2001 Feb 1 Rheumatoid arthritis (RA) is the most common, crippling human autoimmune disease. Using Western blotting and tandem mass spectroscopy, we have identified the endoplasmic reticulum chaperone BiP, a 78-kDa glucose-regulated protein, as a possible autoantigen. It preferentially stimulated increased proliferation of synovial T cells from patients with RA but not from patients with other arthritides. Mice with established collagen- or pristane-induced arthritis developed IgG Abs to BiP. Although BiP injected in CFA failed to induce arthritis in several strains of rats and mice, including HLA-DR4(+/-)- and HLA-DR1(+/+)-transgenic animals, it completely inhibited the development of arthritis when given i.v. 1 wk before the injection of type II collagen arthritis. Preimmunization with BiP suppressed the development of adjuvant arthritis in Lewis rats in a similar manner. This is the first report of a mammalian chaperone that is an autoantigen in human RA and in experimental arthritis and that can also prevent the induction of experimental arthritis. These findings may stimulate the development of new immunotherapies for the treatment of RA.
9296336 Positive correlation between levels of IL-1 or IL-2 and 1,25(OH)2D/25-OH-D ratio in synovi 1997 The present study determined the levels in synovial fluid (SF) of vitamin D metabolites (1,25-dihydroxyvitamin D (1,25(OH)2D), 24,25-dihydroxyvitamin D (24,25(OH)2D) and 25-hydroxyvitamin D (25-OH-D)), and of the cytokines. We evaluated SF from 21 patients with rheumatoid arthritis (RA) and 6 patients with osteoarthritis (OA). The levels of vitamin D metabolites in SF, as determined by two different extraction methods, were significantly correlated (p < 0.05, n=7). The levels of 3 vitamin D metabolites were significantly higher in the RA SF than in OA SF (p < 0.05). The ratio of 1,25(OH)2D/25-OH-D in RA SF, which is presumed to reflect the activity of 25-OH-D-1-hydroxylase (1-OH-ase), was positively correlated with the levels of interleukin-1alpha (IL-1alpha), IL-1beta, and IL-2 in such SF, and was significantly higher than that in sera from RA patients. This suggests an important role for these cytokines in the activation of 1-OH-ase in RA synovium. The ratio of 24,25(OH)2D/25-OH-D, which is presumed to reflect 25-OH-D-24-hydroxylase (24-OH-ase) activity, was significantly correlated with 1,25(OH)2D levels only in RA SF, but not in sera from RA patients, suggesting a local regulation of vitamin D metabolism that 1,25-(OH)2D induces 24-OH-ase as in other target cells. Our observations suggested that 1,25(OH)2D and 24,25(OH)2D are produced locally from 25-OH-D in RA synovium, and that the syntheses of 1,25(OH)2D and 24,25(OH)2D may be affected by IL-1/IL-2 and 1,25(OH)2D in RA SF, respectively.
11289656 An investigation of cell proliferation and soluble mediators induced by interleukin 1beta 2001 Feb OBJECTIVES AND DESIGN: The difference in cell proliferation and release of soluble factors in response to interleukin 1beta (IL-1beta) in fibroblasts obtained from patients with osteoarthritis (OA) and rheumatoid arthritis (RA) and from normal skin has been investigated. TREATMENT: The cells were treated with recombinant IL-1beta in the presence or absence of pharmacological agents for 24 h or 48 h. METHODS: Cell proliferation was examined by WST-1 assay, and the amounts of interleukin-6 (IL-6), interleukin-8 (IL-8), macrophage colony stimulating factor (M-CSF), vascular endothelial growth factor (VEGF), matrix metalloproteinase-1 (MMP-1), and prostaglandin E2 (PGE2) were measured by enzyme linked immunosorbent assay (ELISA). RESULTS: IL-1beta dose-dependently enhanced the proliferation of all fibroblasts. The proliferative response to IL-1beta in RA synovial fibroblasts was greater than that in OA synovial and skin fibroblasts. However, there was no difference in spontaneous levels of soluble factors between OA and RA fibroblasts, though medium concentrations of IL-1beta-released VEGF, MMP-1, and PGE2, but not cytokines, in RA were slightly higher than those in OA. Ability to release soluble mediators was pronouncedly increased at 3 h to 9 h after stimulating fibroblasts with IL-1beta for 1 h. The proliferative response to IL-1beta in all fibroblasts was inhibited by dexamethasone and the NF-kappaB inhibitor hymenialdisine but not the cyclooxygenase 2 (COX-2) inhibitor NS-398. But PGE2 prevented proliferation of RA fibroblasts when added to medium up to 3 h after IL-1beta stimulation. Dexamethasone also inhibited the release of IL-6, IL-8, and PGE2 induced by IL-1beta in both OA and RA fibroblasts. NS-398 exhibited an inhibition of IL-1beta-induced IL-6 production as well as PGE2 production. Hymenialdisine inhibited IL-6 production and reduced IL-8 production dependent on synovial cell strains. Methotrexate had no effect on the response to IL-1beta in synovial fibroblasts. CONCLUSION: The present results indicate that the activation of NF-kappaB plays an important role in the proliferative response to IL-1beta in human fibroblasts, and suggest that PGE2 acts as a modulator of cell proliferation in inflamed synovial tissue. It appears that the ability to produce soluble factors in RA synovial fibroblasts is not intrinsic. However, the response to IL-1beta in RA cells seems to be greater than that in OA cells.
11564149 Characterization of a human synovial cell antigen: VCAM-1 and inflammatory arthritis. 2001 Oct The contribution of synovial cells to the pathogenesis of rheumatoid arthritis (RA) is only partly understood. Monoclonal antibody (mAb) 1D5 is one of very few mAb ever raised against RA synovial cells in order to study the biology of these cells. Studies on the expression pattern and structural features of the 1D5 Ag suggest that 1D5 recognizes human vascular cell adhesion molecule-1 (VCAM-1), which is an intercellular adhesion molecule. Vascular cell adhesion molecule-1 may be involved in a number of crucial intercellular interactions in RA.
11043056 [Leflunomide for active rheumatoid arthritis]. 2000 Sep 25 In 1999, leflunomide was introduced for the treatment of active rheumatoid arthritis. Leflunomide is a reversible inhibitor of "de novo" synthesis of pyrimidine, resulting in a restriction of lymphocyte proliferation. The pharmacodynamics are characterized by slow elimination. Leflunomide has shown an efficacy and a pattern of mild and serious side effects similar to methotrexate and sulphasalazine. Treatment is started with a loading dose of 100 mg orally for three days followed by 20 (10) mg daily. Regular haematological measurements, determination of serum chemistry and blood pressure should be performed every second week the first six months, subsequently every sixth week. If the treatment is to be terminated abruptly, a drug elimination procedure must be performed. Leflunomide will find its place in the treatment of rheumatoid arthritis. Leflunomide should follow an unsuccessful treatment attempt with methotrexate or sulphasalazine.
9771214 Low frequency of recent parvovirus infection in a population-based cohort of patients with 1998 Jun OBJECTIVE: To determine the contribution of human parvovirus B19 infection in explaining the incidence of early inflammatory polyarthritis (IP) in a population. SETTING: The Norfolk Arthritis Register (NOAR) is a community-based programme aiming to ascertain all new cases of IP arising in a population that lead to attendance at primary care. SUBJECTS: 147 newly ascertained subjects with IP with a disease duration of less than 16 weeks. METHODS: Full clinical appraisal of all subjects who were followed up for three years. B19 IgM assayed with a third generation antibody capture enzyme immunoassay. RESULTS: Only four (2.7%) patients had evidence of recent B19 infection, only one of whom did not satisfy criteria for rheumatoid arthritis (RA). CONCLUSION: B19 infection does not explain more than a small proportion of either RA or undifferentiated IP cases occurring in the population.
10599332 Cutaneous necrotizing vasculitis. Relation to systemic disease. 1999 Cutaneous necrotizing vasculitis (CNV) is a complex multisystem disease generally involving the skin and mucous membranes, often accompanied by renal, gastrointestinal, pericardial, neurological, and articular signs and symptoms. CNV may be idiopatical or occur in association with a drug, infection, or underlying disease. CNV has been shown in patients with chronic infections (viral, bacterial, protozoa, helminthic), serum sickness, a variety of collagen vascular diseases (systemic lupus erythematous, Sjögren's syndrome, rheumatoid arthritis, Behçet's disease) hyperglobulinemic states, cryoglobulinemia, bowel bypass syndrome, ulcerative colitis, cystic fibrosis, primary biliary cirrhosis and HIV infection. Association with malignancies is not frequent. Lymphoproliferative disorders (Hodgkin's disease, mycosis fungoides, lymphosarcoma, adult T-cell leukemia, multiple mieloma) and solid tumors (lung cancer, colon carcinoma, renal, prostate, head and neck cancer and breast cancer) may be associated with CNV. Whenever possible, treatment is directed at the elimination of the cause. In other cases after adequate laboratory screening local and systemic therapy are recommended.
9255106 Selective induction of the secretion of cathepsins B and L by cytokines in synovial fibrob 1997 Jul We have investigated the potent influence of some cytokines, tumour necrosis factor-alpha (TNF-alpha), platelet-derived growth factor (PDGF), basic fibroblast growth factor (bFGF) and interferon-gamma (IFN-gamma), on the secretion of cysteine proteinases (cathepsins B and L) by cultured synovial fibroblast-like cells from patients with rheumatoid arthritis (RA). After treatment of synovial fibroblast-like cells with cytokines, culture media were evaluated for cathepsins B and L by enzyme immunoassays, and for cathepsin B and L activities using the enzymatic substrates. Z-Phe-Arg-AMC and Z-Arg-Arg-AMC, and specific inhibitors. Treatment of synovial fibroblast-like cells with TNF-alpha or PDGF resulted in a marked increase in cathepsin B secretion. Moreover, after prolonged PDGF treatment, the amount of secreted cathepsin B returned to the low control level. In contrast, bFGF led to increased cathepsin L secretion. IFN-gamma induced both cathepsin B and L secretion. Our results show that cytokines induce a selective secretion of cathepsins B and L by synovial fibroblast-like cells. This selective effect of cytokines on the secretion of cysteine proteinases suggests that synovial fibroblast-like cell-mediated articular degradation is a highly regulated process.
11053089 The pre-ligand binding assembly domain: a potential target of inhibition of tumour necrosi 2000 Nov Signalling by the tumour necrosis factor receptors (TNFR) is thought to be mediated by the binding of the trimeric ligand TNF to three monomeric subunits of the receptor. This ligand induced trimerisation model of TNFR signalling is mainly supported by crystallographic data of the p60 TNFR-1 and TNFbeta complex in which the trimeric ligand interdigitates between the individual receptor chains and prevents the receptor subunits from interacting with each other. Recently, a domain NH(2)-terminal to the ligand binding domain in the extracellular region of p60 TNFR-1, p80 TNFR-2 and Fas was identified that mediates receptor self association before ligand binding. This pre-ligand binding assembly domain or PLAD is critical for assembly of functional receptor complexes on the cell surface and may provide a potential target in the design of future novel therapeutics against diseases mediated by members of the TNFR family of receptors.
10435356 Autoantibodies in connective tissue diseases: clinical significance and analysis of target 1999 Jul Systemic connective tissue diseases are characterized by the production of a number of autoantibodies directed against various cellular constituents. These autoantibodies are closely associated with certain diseases and clinical manifestations, and are therefore useful for clinical practice such as to diagnose diseases and to predict clinical subsets, disease activity and prognosis. To understand the etiology and pathogenic mechanisms of connective tissue diseases; it is particularly important to elucidate the structure and function of target autoantigens recognized by these disease-specific autoantibodies. In recent years, the nature of many target autoantigens have been identified using molecular biology approaches. Most of them are intracellular enzymes and regulatory factors necessary for important biological function involved in gene replication, transcription, RNA processing and protein translation. Thus, the studies of autoantibodies are useful not only in clinical medicine but also in basic cellular and molecular biology.