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ID PMID Title PublicationDate abstract
15124777 Progression of radiographic changes in the temporomandibular joints of patients with rheum 2004 Feb The aim of this study was to investigate longitudinal radiographic changes in the temporomandibular joint (TMJ) with clinical involvement of rheumatoid arthritis (RA) and its relation to the blood level of inflammatory mediators and markers. Sixteen patients were investigated by computed tomography on two occasions 25-46 months apart. The radiographs were assessed independently for changes in presence of erosions, sclerosis, flattening, osteophytes, and subchondral pseudocysts. The serum (S) or plasma (P) concentrations of C-reactive protein (CRP), thrombocyte particle concentration, scrotonin (S-5-HT and P-5-HT), tumor necrosis factor alpha, interleukin-1 receptor antagonist, tumor necrosis factor soluble receptor type II, interleukin-1 soluble receptor type II (P-IL-1sRII) and interleukin 6 as well as the erythrocyte sedimentation rate (ESR) were measured. The radiographic status showed no consistent or significant change during the observation period, but the individual variation was considerable. The radiographic signs of erosion and sclerosis varied most. Regression of erosions was associated with high S-5-HT and P-IL-1sRII, while progression of erosions was associated with high P-5-HT. Regression of sclerosis was associated with an increase in P-5-HT and high ESR. Progression of flattening was associated with high CRP. In conclusion, this study indicates that the progression of radiographic changes that occurs in the TMJ of patients with well-controlled RA during a period of 25-46 months seems to be related to the blood levels of CRP, 5-HT, and IL-1sRII. However, only minor progression can be expected to occur, and with considerable individual variation.
12602959 Nitric oxide levels in Behçet's disease. 2003 Jan Behçet's disease (BD) is a chronic multisystemic disorder which is characterized by a relapsing systemic inflammatory process. In certain inflammatory conditions such as rheumatoid arthritis, over production of nitric oxide (NO) could damage host cells and tissues, either directly and/or following reaction with other free radicals, such as superoxide anion to form species including peroxynitrite or hydroxyl radicals. Excessive superoxide radical production and impaired antioxidant mechanism in both the neutrophils and plasma of patients with BD have been reported. Our study was designed to investigate the role of NO in BD. NO is an extremely unstable molecule and rapidly converted in vivo and in vitro to nitrate (NO3-) and nitrite (NO2-). For this reason serum NO2- and NO3- have been used as an index of NO generation. We measured serum nitrate + nitrite levels, by using an enzymatic one-step methodology based on the reduction of nitrate to nitrite by nitrate reductase from Aspergillus species, in the presence of beta-NADPH. When compared to healthy controls, serum nitrate + nitrite levels were found to be higher in active periods of BD patients (P < 0.01). It was concluded that increased NO production in patients with BD might have critical biological activities relevant to vasculitic events in the active period of disease.
15037469 Magic angle effects in MR neurography. 2004 Mar BACKGROUND AND PURPOSE: Magic angle effects are well recognized in MR imaging of tendons and ligaments, but have received virtually no attention in MR neurography. We investigated the hypothesis that signal intensity from peripheral nerves is increased when the nerve's orientation to the constant magnetic induction field (B(0)) approaches 55 degrees (the magic angle). METHODS: Ten volunteers were examined with their peripheral nerves at different orientations to B(0) to detect any changes in signal intensity and provide data to estimate T2. Two patients with rheumatoid arthritis also had their median nerves examined at 0 degrees and 55 degrees. RESULTS: When examined with a short TI inversion-recovery sequence with different TEs, the median nerve showed a 46-175% increase in signal intensity between 0 degrees and 55 degrees and an increase in mean T2 from 47.2 to 65.8 msec. When examined in 5 degrees to 10 degrees increments from 0 degrees to 90 degrees, the median nerve signal intensity changed in a manner consistent with the magic angle effect. No significant change was observed in skeletal muscle. Ulnar and sciatic nerves also showed changes in signal intensity depending on their orientation to B(0). Components of the brachial plexus were orientated at about 55 degrees to B(0) and showed a higher signal intensity than that of nerves in the upper arm that were nearly parallel to B(0). A reduction in the change in signal intensity in the median nerve with orientation was observed in the two patients with rheumatoid arthritis. CONCLUSION: Signal intensity of peripheral nerves changes with orientation to B(0). This is probably the result of the magic angle effect from the highly ordered, linearly orientated collagen within them. Differences in signal intensity with orientation may simulate disease and be a source of diagnostic confusion.
12832706 Comparison of the incidence rates of thromboembolic events reported for patients prescribe 2003 Nov BACKGROUND: Rofecoxib and meloxicam are classified as cyclo-oxygenase (COX)-2 selective inhibitors. The Drug Safety Research Unit (DSRU) monitored the post-marketing safety of these drugs in England using the non-interventional observational cohort technique of prescription-event monitoring (PEM). OBJECTIVES: To compare the incidence rates of selected thromboembolic (TE)(cardiovascular, cerebrovascular and peripheral venous thrombotic) events reported for patients prescribed rofecoxib and meloxicam in general practice. METHODS: Patients were identified from dispensed prescriptions written by general practitioners (GPs) for meloxicam (December 1996 to March 1997) and rofecoxib (July to November 1999). Simple questionnaires requesting details of events recorded during/after treatment, indication and potential risk factors (including age, sex and NSAIDs prescribed within 3 months of treatment) were posted to prescribing GPs approximately 9 months after the first prescription for each patient. Incidence rates of the first event within each TE group were calculated; crude and age- and sex-adjusted rate ratios (RR) obtained using regression modelling. RESULTS: During the 9 months after starting treatment, 21 (0.14%) and 19 (0.10%) patients were reported to have cardiovascular TE events, and 74 (0.48%) and 52 (0.27%) cerebrovascular TE events, and 6 (0.05%) and 20 (0.10%) were reported to have peripheral venous thrombotic events for rofecoxib and meloxicam, respectively. Regarding time to first event, there was a persistent divergence between the two drugs from the start of treatment for both the cerebrovascular TE event group (log rank test P = 0.0063) and the peripheral venous thrombotic event group (log rank test P = 0.0264). Indication and use of a NSAID within 3 months prior to starting treatment had no statistically significant effect on the relative risk estimates of the event groups and was excluded from subsequent analyses. Adjusting for the two identified risk factors of age (age2) and sex, for rofecoxib the adjusted cerebrovascular TE event group rate was higher than for meloxicam [RR 1.68 (95% CI 1.15, 2.46)]; lower than meloxicam for the peripheral venous thrombotic event group [RR 0.29 (95% CI 0.11, 0.78)], and not different for the cardiovascular TE event group [RR 1.38 (95% CI 0.71, 2.67)]. CONCLUSIONS: This study reports a relative increase in the rate of cerebrovascular TE events and a relative reduction in peripheral venous thrombotic events in users of rofecoxib compared with meloxicam. There was no difference in the rate of cardiovascular thromboembolic events. The incidence of these three groups of events reported in each of these two drug cohorts was low (less than 0.5%), therefore the relevance of our findings needs to be taken into consideration with other clinical and pharmacoepidemiological studies.
16038842 Infliximab continuation rates in patients with rheumatoid arthritis in everyday practice. 2005 Jul Infliximab is a major breakthrough in the management of rheumatoid arthritis (RA). We evaluated infliximab continuation rates and reasons for discontinuation in patients with RA. PATIENTS AND METHODS: We studied patients with RA started on infliximab at any time between March 2000 and December 2002, under the conditions of everyday practice (as opposed to clinical trial settings), as recommended by the French marketing license (3 mg/kg as an intravenous infusion at weeks 0, 2, and 6 then at 8-week intervals). The number of infliximab infusions, side effects, and nonresponse rates was recorded. The Kaplan-Meier method was used to evaluate treatment continuation. Reasons for discontinuation were studied. RESULTS: We included 41 patients, with a mean age of 54 years, a mean RA duration of 9 years, and a mean of three previous disease-modifying antirheumatic drug treatments. The total number of infliximab infusions was 461 with a mean of 10.8 per patient and a mean follow-up under treatment of 15.3 months. The proportions of patients still on infliximab were 82%, 74%, and 67% after 6, 12, and 24 months, respectively. The main reasons for discontinuation were escape phenomenon (n = 6, 42.8% of discontinuations) and allergy (n = 3); in one case each, the reason was primary ineffectiveness, severe infection, plans to start a pregnancy, poor compliance, and unavailability for follow-up. There were 59 recorded episodes of side effects, with a profile similar to that in the literature and in postmarketing databases. CONCLUSION: The infliximab continuation rate in everyday practice in patients with RA (67% after 2 years) was consistent with published data and with the results of controlled trials.
11830430 Circulating soluble E-selectin in early rheumatoid arthritis: a prospective five year stud 2002 Mar BACKGROUND: Soluble E-selectin (sE-selectin) is a marker of activation of vascular endothelium. OBJECTIVE: To examine serum levels of sE-selectin in a cohort of 85 patients with early rheumatoid arthritis (RA) followed up for five years. METHODS: sE-selectin levels were assessed annually using an enzyme linked immunosorbent assay (ELISA) and related to simultaneously obtained clinical and laboratory measures. Joint inflammation was evaluated by active joint count, functional status by Health Assessment Questionnaire (HAQ), and radiographic findings in hands and feet by the Larsen method. Laboratory tests included serum C reactive protein (CRP) level, erythrocyte sedimentation rate, blood haemoglobin level, white blood cell count (WBC), and platelet count. Area under the curve (AUC) was calculated for each variable, and Jonckheere's test for ordered alternatives was applied to assess significance of association between sE-selectin AUC tertiles and other variables. Baseline sE-selectin tertiles were related to change in Larsen score and HAQ score at five years. Odds ratios (OR) with 95% confidence interval (CI) were calculated using univariate and multivariate logistic regression. RESULTS: sE-selectin levels were associated with CRP level (p=0.012), WBC (p=0.037), active joint count (p=0.019), progression of joint destruction (p=0.038), and HAQ score at five years (p=0.021), but not with extra-articular symptoms or comorbidity. Baseline sE-selectin levels in the third tertile predicted the HAQ score at five years (OR 4.18, 95% CI 1.15 to 15.22). sE-selectin levels of patients did not differ significantly from those of healthy control subjects. CONCLUSION: The degree of activation of vascular endothelium is associated with activity and outcome of early RA.
12391319 Despite ubiquitous autoantigen expression, arthritogenic autoantibody response initiates i 2002 Oct 29 K/BxN mice develop an inflammatory joint disease with many features characteristic of rheumatoid arthritis. In this model, the KRN transgenic T cells and nontransgenic B cells both recognize the glycolytic enzyme glucose-6-phosphate-isomerase (GPI) as an autoantigen. Here, we followed the anti-GPI B cell response that naturally arises in K/BxN mice. The anti-GPI B cell response was robust and arose at the same time as the development of serum anti-GPI autoantibody and joint inflammation. Surprisingly, although GPI was expressed systemically, the anti-GPI B cell response was focused to the lymph nodes (LN) draining the distal joints where arthritis was evident. In lymphotoxin-beta receptor-Ig-treated mice, which lack LNs, the development of arthritis was completely inhibited up to 5-6 weeks. At later times, some arthritis did develop, but at a significantly reduced level. Thus, in this spontaneous model of autoimmunity, the LNs draining the distal joints are essential for both the inhibition and amplification of the arthritogenic B cell response. These findings imply that the immune physiology of a joint is unique, resulting in a local immune response to a systemic autoantigen.
12617572 Anti-inflammatory effects of opioids. 2003 In summary, therapy with opioids is an exciting new development for arthritis especially since there is the potential for fewer side effects from molecules which act outside the CNS. We found kappa-opioid drugs to be powerfully anti-inflammatory, reducing disease severity by as much as 80%; attenuating arthritis in a dose-dependent, stereoselective, antagonist-reversible manner. By contrast opioids acting at other receptors were only therapeutic at near toxic doses. The HPA-axis was found to be only partially involved, thus we investigated other neural and immune mechanisms. Results showed that the kappa-opioid anti-inflammatory actions were exerted via (i) reduced adhesion molecule expression; (ii) inhibition of cell trafficking; (iii) reduced TNF release and expression and (iv) alterations in mRNA expression and protein levels of SP and CGRP in joint tissue (Fig. 2). The ability of kappa-opioids to act at multiple sites in the inflammatory cascade, as suggested by the presence of opioid receptors at various locations throughout the cascade, may explain their powerful actions (Fig. 2). It is also relevant that during inflammatory states that enhanced peripherally directed axonal transport leads to receptor upregulation on peripheral nerve terminals in the joint. Neuropeptides (SP and CGRP) were found to be involved in the later phases of adjuvant arthritis suggesting that they are involved in the maintenance or persistence of the disease. The involvement of SP and the efficacy of neurokinin-1 (SP receptors) antagonists predicts that combined opioid- neurokinin-1 therapy has promise. Kappa-opioids are, however, powerfully therapeutic during disease onset. Thus, they most likely exert their anti-inflammatory effects via changes in cellular activation and cytokine expression. The mechanisms involved are summarized in Fig. 2. The increased potency of kappa-opioids in females is likely to be a significant advantage for treatment of inflammatory disease with these agents. Thus our work supports the findings of Stein's group, that opioids do indeed have powerful actions in the periphery via specific receptors at that site. Peripherally acting opioids may prove to be a potent new treatment for rheumatoid arthritis sufferers in the future.
15383603 Human parvovirus B19 transgenic mice become susceptible to polyarthritis. 2004 Oct 1 Human parvovirus B19 (B19) often causes acute polyarthritis in adults. In this paper, we analyzed nucleotide sequences of the B19 genome of patients with rheumatoid arthritis (RA), and then introduced the nonstructural protein 1 (NS1) gene of B19 into C57BL/6 mice that had a genetic origin not susceptible to arthritis. The transgenic mice developed no lesions spontaneously, but were susceptible to type II collagen (CII)-induced arthritis. B19 NS1 was expressed in synovial cells on the articular lesions that were histologically characteristic of granulomatous synovitis and pannus formation in cartilage and bone. Serum levels of anti-CII Abs and TNF-alpha increased in NS1 transgenic mice to the same levels as those of DBA/1 mice, which were susceptible to polyarthritis. Stimulation with CII increased secretion of Th1-type- and Th2-type cytokines in NS1 transgenic mice, indicating that a nonpermissive H-2(b) haplotype in the wild type of C57BL/6 mice can be made susceptible to polyarthritis through the expression of NS1. This study is the first to show that a viral agent from the joints in humans can cause CII-induced arthritis resembling RA.
14687710 Regulation of GRB2 and FLICE2 expression by TNF-alpha in rheumatoid synovium. 2003 Dec 15 Chronic rheumatoid arthritis (RA) is characterized by the hyperplasia of synovial tissue, which results from dysregulation of proliferative and antiapoptotic signals transduced in the synovial cells by unknown mechanisms. To identify candidate factors involved in the regulation of synovial hyperplasia, the expression profile of 205 apoptosis-related genes was compared between tissues from patients with RA and osteoarthritis (OA) using a cDNA microarray. Upregulated genes in the RA synovium included TNFR2, FLICE2, and signaling molecules involved in a MAP kinase pathway (GRB2, MAPK p38). In contrast, genes encoding SARP1 and various cell cycle regulators were down-regulated in the RA synovium relative to OA. Importantly, the expression levels of GRB2 and FLICE2 genes were remarkably enhanced in RA synoviocytes but not in OA synoviocytes in response to tumor necrosis factor (TNF)-alpha treatment. Thus, these results suggest that over-expression of GRB2 and FLICE2 in RA synovium is caused by TNF-alpha inducibility differentially regulated in RA synoviocytes and provide potential pathogenic roles of these genes in the hyperplasia of the RA synovium.
15060719 Angiogenesis inhibition by the novel VEGF receptor tyrosine kinase inhibitor, PTK787/ZK222 2004 Apr OBJECTIVE AND DESIGN: To examine the effects of PTK787/ZK222584, a novel angiogenesis inhibitor, in a series of in vivo models of arthritis and inflammation. MATERIALS: The granulomatous air pouch and antigen-induced arthritis models were established in female OFA-1 mice. Female DBA/1LacJ mice were used for the collagen-induced arthritis model and male OFA rats were used for the carrageenan oedema and hyperalgesia tests. TREATMENT: PTK787/ZK222584 was administered p.o., once daily, at various concentrations. Diclofenac (3 mg/kg) and DUP697 (0.5 mg/kg) were also given p.o, once daily. METHODS: The anti-angiogenic effects of PTK787/ZK222584 were directly assessed in the granulomatous air pouch model using the carmine red assay. The anti-arthritic effects of this compound were further examined in the mouse antigen-induced and collagen-induced models of arthritis, using macroscopic observations (calliper measurements of joints) and histological scores (as assessed by degree of cellularity, cell infiltration and erosions and proteoglycan loss). All compounds were administered orally. PTK787/ZK222584 at 10, 30, 50 and 100 mg/kg and positive control compounds, diclofenac and DUP697 at 3 mg/kg and 0.5 mg/kg, respectively. In addition, the effects of PTK787/ZK222584 in the rat carrageenan oedema model and Randall Selitto hyperalgesia test were observed. RESULTS: PTK787/ZK222584 treatment caused dose dependent reduction in the vascularity of the granulomatous air pouch model. It inhibited knee swelling by 40% in antigen-induced arthritis, at the dose of 30 mg/kg p.o., once daily (s.i.d). and inhibited both severity scores (by 51%) and global histological scores in mice with collagen-induced arthritis following oral treatment (45 mg/kg p.o.), as compared to control animals. PTK787/ZK222584 demonstrated no effects on inflammatory mediators in the VEGF-independent rat carrageenan model and displayed interesting analgesic activity in the Randall Selitto test in the acute setting. CONCLUSIONS: The anti-arthritic effects of this specific, receptor tyrosine kinase inhibitor compound appear to be mediated by anti-angiogenic actions. This study represents a new indication for PTK787/ZK222584, namely, rheumatoid arthritis and further supports the belief that angiogenesis inhibition is likely to be beneficial in the therapy of this condition.
15248213 Endothelial precursor cells in the synovial tissue of patients with rheumatoid arthritis a 2004 Jul OBJECTIVE: To find evidence for the presence of endothelial precursor cells, which can induce new vessel formation, in the synovial tissue of patients with rheumatoid arthritis (RA) and osteoarthritis (OA). METHODS: Precursor cells in the synovial tissue of 18 RA patients and 15 OA patients were identified by immunohistochemistry, morphometric analysis, and confocal laser scanning microscopy using the following phenotype markers: CD31, CD34, STRO-1, CD133, vascular endothelial growth factor receptor 2 (VEGFR-2), and CXCR4. The presence of CD31, CD34, CD133, VEGFR-2, and CXCR4 messenger RNA in the synovial tissue was determined by reverse transcriptase-polymerase chain reaction, and the message for CXCR4 was quantified by an RNase protection assay. RESULTS: A population of cells that expressed CD34 on their surface but lacked the endothelial cell marker CD31 was found in the synovial tissue of RA and OA patients. CD34+,CD31- cells were detected in close proximity to STRO-1+ and CD133+ cells, forming cell clusters in the sublining area of the synovial membrane. Within these cell clusters, CD34+,CD31- precursor cells were located on the inside surrounded by STRO-1+ cells and with CD133+ cells on the outside. CD34+ precursor cells in the cell layer expressed high levels of the chemokine receptor CXCR4, while VEGFR-2 was expressed on CD34+ and CD133+ cells, and alpha-smooth muscle actin was expressed on STRO-1+ cells. CONCLUSION: The presence of endothelial precursor cells in the synovial tissue of RA and OA patients provides evidence for vasculogenesis induced by precursor cells that arise in situ or from circulating progenitors.
15569811 Preventing venous thromboembolism in acute medical patients. 2004 Dec BACKGROUND: While extensive data support the clinical benefit and cost-effectiveness of routine thromboprophylaxis in surgical patients, the use of this approach in medical patients has been controversial. However, recent data, mainly from the MEDENOX trial, support routine thromboprophylaxis in acutely ill medical patients. AIM: To determine attitudes towards VTE prevention in such patients, in departments of internal medicine in Israel. DESIGN: Questionnaire-based survey. METHODS: A questionnaire regarding aspects of VTE prophylaxis was mailed to all heads of internal medicine departments in Israel (n = 90). The questionnaire also included data concerning VTE prevention measures in specific acute medical illnesses, based on the MEDENOX study population. RESULTS: Fifty-eight (64%) departments returned the questionnaire. Forty-seven (81%) of them considered VTE a clinical problem in their departments, but only 37 (63%) had a routine VTE prevention policy. The most frequently used modality for VTE prophylaxis was low-molecular-weight heparin. There was little agreement concerning the exact indications or risk factors in which VTE prophylaxis measures should be used, except the combination of acute medical disabling illness and previous VTE. DISCUSSION: The results emphasize the need for detailed guidelines and risk assessment models for VTE prevention treatments in acutely ill medical patients, as well as better education for physicians.
11953628 Patellar component resection arthroplasty for the severely compromised patella. 2002 Apr When severe bone loss precludes reimplantation of a new patellar component during revision knee arthroplasty, the treatment options include patellar bone grafting, patellar component resection arthroplasty, and patellectomy. The purpose of this study was to evaluate the clinical and functional results of patellar component resection arthroplasty for the severely compromised patella for which insertion of another patellar component was not possible. Thirty-five knees (31 patients) were treated with patellar component resection arthroplasty for aseptic patellar component failure associated with severely compromised patellar bone stock. Followup averaged 7.9 years (range, 2-18 years). There was a significant improvement in Knee Society pain and function scores. Pain relief was more dramatic than functional improvement. The range of motion also improved significantly and in particular preoperative extensor lag was resolved in the majority of patients. Patients treated with isolated patellar resection arthroplasty were more likely to have continuing pain and require reoperation compared with patients who had concomitant revision of the tibial and femoral components. Correct positioning and the stability of tibial and femoral components should be tested carefully at the time of patellar resection arthroplasty and considered for revision if malpositioned either axially or rotationally.
12188480 A randomised, controlled trial of cemented versus cementless press-fit condylar total knee 2002 Jul We have carried out a long-term survival analysis of a prospective, randomised trial comparing cemented with cementless fixation of press-fit condylar primary total knee replacements. A consecutive series of 501 replacements received either cemented (219 patients, 277 implants) or cementless (177 patients, 224 implants) fixation. The patients were contacted at a mean follow-up of 7.4 years (2.7 to 13.0) to establish the rate of survival of the implant. The ten-year survival was compared using life-table and Cox's proportional hazard analysis. No patient was lost to follow-up. The survival at ten years was 95.3% (95% CI 90.3 to 97.8) and 95.6% (95% CI 89.5 to 98.2) in the cemented and cementless groups, respectively. The hazard ratio for failure in cemented compared with cementless prostheses was 0.97 (95% CI 0.36 to 2.6). A comparison of the clinical outcome at ten years in 80 knees showed no difference between the two groups. The survival of the press-fit condylar total knee replacement at ten years is good irrespective of the method of fixation and brings into question the use of more expensive cementless implants.
15208176 Long term safety of methotrexate in routine clinical care: discontinuation is unusual and 2005 Feb OBJECTIVE: To analyse patients with rheumatoid arthritis, treated with methotrexate in a weekly academic rheumatology clinic over 13 years, for continuation of courses and reasons for discontinuation. METHODS: All 248 patients with an analysable longitudinal course who took methotrexate in standard care between 1990 and 2003 were studied. Continuation of courses was analysed using life tables. All abnormal and severely abnormal values for aspartate aminotransferase (AST) >40 U/l, >80 U/l, albumin <35 g/l, <30 g/l, white blood cell (WBC) count <4.0 x 10(9)/l, <3.0 x 10(9)/l, and platelet count <150 x 10(9)/l, <100 x 10(9)/l, were identified. Responses of the clinician and subsequent laboratory values were reviewed. RESULTS: Over 1007 person-years, the probability of continuing methotrexate over five years was 79% (95% confidence interval, 72% to 84%). Severe laboratory abnormalities occurred in 2.9 per 100 person-years, specifically 0.9 for AST >80 U/l, 1.1 for albumin <30 g/l, 0.7 for WBC <3.0 x 10(9)/l, and 0.3 for platelets <100 x 10(9)/l. No severe laboratory abnormality progressed to further severity or clinical disease. Permanent discontinuations of methotrexate occurred in 46 patients (19%), 26 (10% of all patients) for adverse effects, 15 (32.6%) for inefficacy; only two discontinuations resulted from laboratory abnormalities, both of WBC, possibly from other sources. CONCLUSIONS: Methotrexate was associated with a high rate of continuation, and few clinically significant laboratory abnormalities. Discontinuation primarily reflected clinical rather than laboratory findings. Vigilance for methotrexate toxicity is required but methotrexate appears among the safest treatments for rheumatoid arthritis.
12228163 Synovial macrophage-osteoclast differentiation in inflammatory arthritis. 2002 Oct BACKGROUND: Pathological bone resorption (marginal erosions and juxta-articular osteoporosis) by osteoclasts commonly occurs in rheumatoid arthritis (RA). OBJECTIVES: To define the nature of the mononuclear precursor cells from which osteoclasts are formed in inflamed synovial tissues and to determine the cellular and humoral factors which influence osteoclast differentiation. METHOD: Macrophage (CD14+), non-macrophage (CD14-), and unsorted (CD14+/CD14-) synovial cell populations from RA and inflammatory/non-inflammatory osteoarthritis (OA) synovium were cultured in the presence of receptor activator for nuclear factor kappaB ligand (RANKL) and monocyte-colony stimulating factor (M-CSF; in the presence/absence of prostaglandin E(2) (PGE(2)), interleukin 1beta (IL1beta), tumour necrosis factor alpha (TNFalpha), and IL6). Osteoclast differentiation was assessed by expression of tartrate resistant acid phosphatase (TRAP), vitronectin receptor (VNR), and lacunar resorption. RESULTS: TRAP+ and VNR+ multinucleated cells capable of lacunar resorption were only formed in cultures of CD14+-containing synovial cell populations (that is, CD14+ and CD14+/CD14- cells). No difference in the extent of osteoclast formation was noted in cultures of CD14+ cells isolated from RA, inflammatory OA, and non-inflammatory OA synovium. However, more TRAP+/VNR+ cells and more lacunar resorption was noted in CD14+/CD14- cells from RA and inflammatory OA synovial tissues. The addition of PGE(2), IL1beta, TNFalpha, and IL6 did not increase RANKL/M-CSF-induced osteoclast formation and lacunar resorption of both CD14+/CD14- and CD14+ synovial cell populations. CONCLUSIONS: Osteoclast precursors in synovial tissues are CD14+ monocyte/macrophages. The increase in osteoclast formation in cultures of CD14+/CD14- compared with CD14+ synovial cells in RA and inflammatory OA points to a role for CD14- cells in promoting osteoclast differentiation and bone resorption in inflamed synovial tissues by a mechanism which does not involve a direct effect of proinflammatory cytokines/prostaglandins on RANKL-induced macrophage-osteoclast differentiation.
14749527 High levels of soluble herpes virus entry mediator in sera of patients with allergic and a 2003 Dec 31 Herpes virus entry mediator (HVEM) is a newly discovered member of the tumor necrosis factor receptor (TNFR) superfamily that has a role in herpes simplex virus entry, in T cell activation and in tumor immunity. We generated mAb against HVEM and detected soluble HVEM (SHVEM) in the sera of patients with various autoimmune diseases. HVEM was constitutively expressed on CD4(+) and CD8(+) T cells, CD19(+) B cells, CD14(+) monocytes, neutrophils and dendritic cells. In three-way MLR, mAb 122 and 139 were agonists and mAb 108 had blocking activity. An ELISA was developed to detect sHVEM in patient sera. sHVEM levels were elevated in sera of patients with allergic asthma, atopic dermatitis and rheumatoid arthritis. The mAbs discussed here may be useful for studies of the role of HVEM in immune responses. Detection of soluble HVEM might have diagnostic and prognostic value in certain immunological disorders.
12379519 Invasive properties of fibroblast-like synoviocytes: correlation with growth characteristi 2002 Nov BACKGROUND: Matrix metalloproteinases (MMPs) have a pivotal role in the destruction of cartilage in rheumatoid arthritis (RA), which is mediated by the fibroblast-like synoviocytes (FLS). OBJECTIVE: To examine the in vitro invasiveness of synoviocytes obtained from inflamed joints of patients with arthritis in relation to the expression of MMP 1-14, 17, 19, cathepsin-K, the tissue inhibitors of matrix metalloproteinases TIMP-1 and TIMP-2 by FLS. METHODS: FLS were derived from 56 patients (30 with RA, 17 with osteoarthritis (OA), and nine with avascular necrosis (AVN)). Invasive growth of FLS through an artificial matrix (Matrigel) was measured in a transwell system. The number of cells that migrated through the matrix were counted. Proliferation rate was determined by counting the FLS after seven days of culturing. Expression of MMPs, cathepsin-K and TIMPs was investigated with reverse transcriptase-polymerase chain reaction and related to the expression of a household gene, beta-actin. RESULTS: FLS from RA showed greater invasive growth than FLS from OA and AVN. The median number of cells that grew through the matrix membrane was 4788 for RA, significantly higher than the number for OA, 1875 (p<0.001) and for AVN, 1530 (p=0.014). The median rate of proliferation of RA FLS was 0.27 per day compared with OA 0.22 per day (p= 0.012) and AVN 0.25 per day, but there was no correlation between the rate of proliferation and invasive growth in vitro. FLS from RA and OA that expressed MMP-1, MMP-3, or MMP-10 were significantly more invasive (median number of invasive cells: 3835, 4248, 4990, respectively) than cells that did not express these MMPs (1605, p=0.03; 1970, p=0.004; 2360, p=0.012, respectively). There was also a significant relationship between the expression of MMP-1 and MMP-9 and the diagnosis RA (both p=0.013). The expression levels of mRNA for MMP-1 and MMP-2 correlated with the protein levels produced by the synoviocytes as measured by an enzyme linked immunosorbent assay (ELISA). CONCLUSION: FLS of RA invade more aggressively in a Matrigel matrix than OA and AVN FLS; this is not because of a higher rate of proliferation of RA FLS. The significant correlation between the expression of MMP-1, MMP-3, and MMP-10 and invasive growth in a Matrigel transwell system suggests that these MMPs play a part in the invasive growth of FLS obtained from patients with RA.
15146413 Macrophage migration inhibitory factor up-regulates the expression of interleukin-8 messen 2004 May OBJECTIVE: Interleukin-8 (IL-8) plays an important role in the migration of inflammatory cells into the synovium and joint fluids in rheumatoid arthritis (RA). This study was undertaken to investigate the IL-8 inductive activity of the macrophage migration inhibitory factor (MIF) in RA synovial fibroblasts. The regulatory mechanism of IL-8 was compared with that of IL-1beta. METHODS: MIF-induced IL-8 and IL-1beta transcriptional activation was studied in RA synovial fibroblasts by Northern blot analysis, enzyme-linked immunosorbent assay, and electromobility shift assay. The effect of anti-MIF antibody administration on murine passive collagen-induced arthritis (CIA) was also evaluated by histologic examination and reverse transcriptase-polymerase chain reaction. RESULTS: MIF up-regulated the IL-8 messenger RNA (mRNA) and protein levels in a dose-dependent manner. The IL-8 mRNA up-regulation started 1 hour poststimulation by MIF, and reached a maximum level at 6 hours. IL-1beta mRNA was also up-regulated by MIF. The mRNA up-regulation of IL-8 and IL-1beta by MIF was inhibited by 2 tyrosine kinase inhibitors, a protein kinase C (PKC) inhibitor, an activator protein 1 (AP-1) inhibitor, and by an NF-kappaB inhibitor. A cAMP-dependent kinase inhibitor did not inhibit it. MIF enhanced AP-1 and NF-kappaB binding activities in a dose-dependent manner. Passive CIA enhanced mRNA levels of macrophage inflammatory protein 2 and cytokine-induced neutrophil chemoattractants and, moreover, migration and proliferation of inflammatory cells within the synovium, which were suppressed by administration of an anti-MIF antibody. CONCLUSION: MIF may play an important role in the migration of inflammatory cells into the synovium of rheumatoid joints via induction of IL-8. MIF up-regulates IL-8 and IL-1beta mRNA via tyrosine kinase-, PKC-, AP-1-, and NF-kappaB-dependent pathways.