Search for: rheumatoid arthritis methotrexate autoimmune disease biomarker gene expression GWAS HLA genes non-HLA genes
| ID | PMID | Title | PublicationDate | abstract |
|---|---|---|---|---|
| 18562787 | Chondrogenic potential of mesenchymal stem cells from patients with rheumatoid arthritis a | 2009 | BACKGROUND: Mesenchymal stem cells (MSCs) have the potential to differentiate into distinct mesenchymal tissues; including cartilage and bone, they can be an attractive cell source for cartilage tissue engineering approaches. Our objective here was to compare the in vitro chondrogenic potential of MSCs isolated from patients with rheumatoid arthritis (RA) and osteoarthritis (OA) with cells from normal donors. METHODS: Marrow samples were removed during bone surgery and adherent cell cultures were established. The cells were then passed into a newly developed microaggregate culture system in a medium containing transforming growth factor beta3, insulin, dexamethasone and/or demineralized bone matrix. In vitro chondrogenic activity was measured as metabolic sulfate incorporation and type II collagen expression in pellet cultures. RESULTS: Culture-expanded MSCs from RA and OA patients did not differ significantly from the normal population with respect to their chondrogenic potential in vitro. Capability of total protein and proteoglycan synthesis as well as collagen II mRNA expression by cell aggregates was similar for all cell preparations in the presence of the appropriate growth and differentiation factors. Chondroprotective drugs such as chondroitin sulfate and glucosamine enhanced, whereas chloroquine inhibited chondrogenesis in normal donor-derived or patient-derived MSC cultures. Galectin-1, a beta-galactoside-binding protein with marked anti-inflammatory activity, stimulated the chondrogenic differentiation of mesenchymal cells in low (<2 microg/ml) concentration. DISCUSSION: These findings show that MSCs from RA and OA patients possess similar chondrogenic potential as MSCs isolated from healthy donors, therefore these cells may serve as a potential new prospect in cartilage replacement therapy. | |
| 18795393 | Repeated tuberculin skin testing following therapy with TNF-alpha inhibitors. | 2009 Feb | To determine the rate of true tuberculin skin test (TST) response in a cohort of patients with rheumatic disease treated with tumor necrosis factor inhibitors (TNFi). The study population included consecutive patients with rheumatoid arthritis (RA), ankylosing spondylitis (AS), and psoriatic arthritis (PsA) treated with TNFi for at least 3 months. Patients with a positive TST at screening who began Tb prophylaxis before the beginning of TNFi therapy were excluded. All patients underwent a second TST. True TST response was defined as an increase of 6 mm of induration between the screening test and the second test. Forty patients (12 men and 28 women) were included. Mean age was 51.2 years. Of them, 27 (67.5%) had RA, eight (20%) had PsA, and five patients (12.5%) had AS. At pre-treatment TST, 15 patients had a TST > or = 5 mm. A significantly higher percent of patients with TST > or = 5 mm was seen among men compared with women (75% vs. 21%, p = 0.012) and patients with PsA compared with patients with RA (75% vs. 22%, p = 0.014). At the second test, eight (20%) had an increase of 6 mm between readings with four having an increase of 10 mm or more. Four patients received infliximab and the other four were treated with etanercept. Seven of these eight patients had RA and one was a patient with PsA. Patients with true TST response were significantly older and non-smokers with elevated sedimentation rate and a higher rate of anemia. Nationality, comorbid conditions, treatment with immunosuppressives, and BCG vaccination status had no significant influence on the TST response. Serial TST testing in patients receiving TNFi is indicated to identify patients with reactivation of latent tuberculosis infection or those exposed to mycobacterium. | |
| 20100913 | A proof-of-concept and drug-drug interaction study of pamapimod, a novel p38 MAP kinase in | 2010 Sep | This study evaluated the potential pharmacokinetic interaction of pamapimod, a p38 mitogen-activated protein kinase inhibitor, and methotrexate (MTX) when administered concomitantly in patients with rheumatoid arthritis (RA); the study also evaluated the pharmacodynamic effects of pamapimod. Twenty-two RA patients on a stable regimen of MTX (10-25 mg/wk; administered on days 1 and 8) were randomized to receive 300 mg of pamapimod (n = 17) or placebo (n = 5) once daily (qd) for 10 days (days 5-14). Blood and urine samples were collected pre- and postdose on days 1 (MTX alone), 7 (pamapimod alone), and 8 (MTX and pamapimod coadministered). No clinically significant changes were observed in plasma exposures and renal clearance of pamapimod, MTX, or their metabolites, whether administered separately or concomitantly. The combination of pamapimod (300 mg qd) for 10 days and weekly MTX was generally well tolerated. Parameters of RA disease--namely, tender joint count, swollen joint count, erythrocyte sedimentation rate, and C-reactive protein--generally decreased between days 5 and 14. The results of this study suggest that dose adjustments for either drug are not necessary when concomitantly administered and that pamapimod can decrease pharmacodynamic markers of disease activity. | |
| 20541791 | Comparison of symptoms, treatment, and outcomes of coronary artery disease among rheumatoi | 2010 Dec | OBJECTIVE: Rheumatoid arthritis (RA) is associated with an increased prevalence of coronary artery disease (CAD). We investigated the presenting symptoms of CAD, coronary anatomy (single versus multi-vessel CAD), and treatment among a group of subjects undergoing percutaneous coronary intervention (PCI) with angioplasty and/or stenting. METHODS: We evaluated a retrospective cohort of 43 RA subjects and 43 matched non-RA subjects undergoing PCI at 2 academic referral centers. RA subjects were matched to non-RA subjects on age, gender, history of coronary artery bypass grafting, date of PCI, and interventional cardiologist. We compared cardiac risk factors, presentation, treatment, and outcomes. RESULTS: The mean age of the study cohort was 71 ± 10 years, and the distribution of traditional cardiac risk factors was similar in the subjects with RA compared with the matched non-RA subjects (all P values > 0.05). Seventy-four percent of subjects with RA compared with 67% of those without RA presented with an acute coronary syndrome before PCI (P = 0.48). All subjects in this cohort undergoing PCI had at least 1 stenosis in a major epicardial vessel and similar percentages of subjects with RA (44%) and without RA (40%) had multi-vessel CAD (P = 0.66). The administration of cardiac medications both at PCI and at hospital discharge was not different among subjects with RA compared with matched non-RA subjects. CONCLUSIONS: Among this cohort with significant CAD undergoing PCI, clinical characteristics, presentation, severity of CAD, treatment modalities, and outcomes were similar in subjects with RA and well-matched non-RA subjects. | |
| 19698994 | Aberrant integrin activation induces p38 MAPK phosphorylation resulting in suppressed Fas- | 2009 Oct | Delayed Fas-mediated apoptosis in T cells is associated with inflammatory diseases including rheumatoid arthritis (RA). CD3(+) T cells in RA synovia expressed high amounts of phospho-p38 MAPK. Exposure to RA synovial fluid or soluble collagen, a degradation product of extracellular matrix abundant in RA synovium, induced the phosphorylation of p38 MAPK in Jurkat T cells accompanied by resistance against Fas-mediated apoptosis. Blocking beta1 integrin by antibody diminished this effect. In addition, ectopic expression of auto-activated beta1 integrin variant in T cells profoundly induced the phosphorylation of p38 MAPK. Suppression of p38 MAPK sensitized T cells to Fas-mediated apoptosis and increased caspase-8 and caspase-3 cleavage. A physical interaction of p38 MAPK and caspase-8 was demonstrated by using confocal microscopic imaging and co-immunoprecipitation assay. RA synovial fluid markedly increased the formation of phospho-p38 MAPK/caspase-8 complex in Jurkat T cells. In conclusion, abnormal activation of p38 MAPK to prevent Fas-mediated apoptosis may represent a common survival mechanism of RA synovial T cells contributing to the persistent inflammation of affected synovium. | |
| 19519545 | A new approach to the inflammatory/autoimmune diseases. | 2009 Jun | Extracellular adenosine 5 -triphosphate (eATP) is an important mediator of cell-to-cell interactions in the nervous, vascular and immune system. Its low release by different cells, as mast cells, platelets, red blood cells, T cells and also by nerve terminals, requires different mechanisms and especially occurs in physiologic conditions. However, in pathologic conditions, as inflammation, eATP can highly increase, following its release by damaged cells. Elevated levels of eATP provoke the activation of some purinergic receptors, mainly the P2XR, which are located on mononuclear phagocytes, T cells and endothelial cells. The activation by eATP of inflammatory/immune cells leads to their release of some inflammatory mediators, such as the cytokines IL-1beta and TNFalpha. These cytokines are able to further activate other cells, as endothelial cells, favouring their increased expression of adhesion molecules; such process enhances circulating cell recruitment to the inflamed tissue. The blockade of the purinergic-mediated activation of the inflammatory/immune cells might represent a useful tool to reduce the spreading of the inflammatory/immune response. This review will summarize the beneficial effects of the use of periodate oxidized ATP (oATP), an inhibitor of P2XR, in the treatment of some experimental models of inflammatory/immune diseases. The article is a short review of recent patents related to the anti-inflammatory/analgesic/antiangiogenic effects of oATP and to its role in the autoimmune diseases. | |
| 19723901 | Positive conversion of tuberculin skin test and performance of interferon release assay to | 2009 Oct | OBJECTIVES: To evaluate tuberculin skin tests (TST) and interferon-gamma (IFN-gamma) assay in the detection of latent tuberculosis (TB) infection during tumor necrosis factor (TNF) antagonist treatment in Korean patients with initial negative TST result. METHODS: Eighty-six patients with rheumatic diseases who had received anti-TNF agents for over one year were investigated. Clinical data were obtained from medical records. All patients received followup TST, and IFN-gamma assay was performed in 64. RESULTS: The study population consisted of 40 rheumatoid arthritis (RA), 34 ankylosing spondylitis (AS), 9 juvenile rheumatoid arthritis (JRA), and 3 other patients. The TST converted to positive in 28 (32.6%) patients. There was no significant variation between TST conversion rate and all risk factors. Although there was no statistical significance, the odds of the TST conversion rate tended to increase with the duration of TNF antagonist administration. Nine (14.1%) of 64 patients who performed an IFN-gamma assay had positive results. Among 28 TST positive conversion cases, 4 patients with AS and 1 with psoriatic arthritis had positive IFN-gamma assay results, and one of them developed miliary TB. However, none of the 4 RA patients with positive IFN-gamma assay showed TST conversion. There was 68.6% agreement (kappa = 0.29, p = 0.02) between TST and IFN-gamma assay results. CONCLUSION: Serial TST with IFN-gamma assay may be useful to identify false-negative response to cases of latent Mycobacterium tuberculosis infection and new TB infections in patients with immune mediated inflammatory diseases during longterm anti-TNF therapy, especially in areas with intermediate TB burden. | |
| 19541526 | Hairy-cell leukemia with inaugural joint manifestations. | 2009 Jul | Hairy-cell leukemia is a chronic B-cell malignancy seen in adults. The presenting manifestations consist of splenomegaly, pancytopenia, and characteristic monocyte depletion. The presence in peripheral blood or bone marrow of hairy cells exhibiting the CD19(+) CD20(+) CD25(+) CD11c(+) phenotype establishes the diagnosis. Rarely, patients present with inaugural joint manifestations related either to the hematological malignancy or to immune dysfunction. The resulting polymorphic polyarticular symptoms may cause diagnostic wanderings. Monocytopenia is a valuable diagnostic clue. The identification of hairy cells in the joint fluid establishes the diagnosis of leukemia-related arthritis. The treatment rests on purine analogs. One of the main differential diagnoses is Felty's syndrome, which combines rheumatoid arthritis, splenomegaly, and neutropenia. Felty's syndrome is usually caused by T-cell lymphoproliferative disorders. Among 27 patients with hairy-cell leukemia managed at our institution, 1 presented with joint manifestations. We describe this case. | |
| 20409410 | [A cutaneous infection by Mycobacterium chelonae in a patient with rheumatoid arthritis]. | 2010 Apr 15 | There are no pathognomonic findings for cutaneous infection caused by Mycobacterium chelonae. The type and duration of therapy varies considerably among reports and no single antibiotic is considered the treatment of choice. A 61-year-old patient, suffering from rheumatoid arthritis (treated with metotrexate and salazopyrine), presented with violaceous nodules of the right leg that had been evolving for 6 months. She was underwent several skin biopsies. Tissue culture of the last showed an atypical mycobacteria, identified as M. chelonae. Despite improvement after a two-week course of treatment with clarithromycin, a switch to ciprofloxacin was made because of gastrointestinal intolerance. After 3 months, only slight improvement of the lesions was achieved and clarithromycin was reintroduced; significant clinical improvement occurred by the third month. Clarithromycin was continued a further two months until the patient quit on her own and. no recurrence was observed. Infections caused by M. chelonae frequently occur in the setting of immunological impairment. Contaminated water is the natural reservoir, but we were unable to establish the source of contamination. As was previously described, there was a significant delay between clinical presentation and diagnosis. Thus, a high index of suspicion and multiple biopsies with culture are of paramount importance to confirming the diagnosis. | |
| 19543670 | Development of the rehabilitation patient experiences questionnaire: data quality, reliabi | 2009 Jun | OBJECTIVE: To develop the Rehabilitation Patient Experiences Questionnaire for patients undergoing rehabilitation for rheumatological disorders. METHODS: Development of the instrument was based on literature review and adaptation of the Patient Experiences Questionnaire. The instrument was piloted and then administered in a multicentre cohort study of 12 rehabilitation units. RESULTS: The survey included 435 patients, of which 412 (94.7%) responded to the Rehabilitation Patient Experiences Questionnaire. Following principal component analysis, the initial 27 items were reduced to 18 items and 4 scales: rehabilitation care and organization, information and communication, availability of staff, and social environment. Item--total correlations ranged from 0.77 to 0.87. Cronbach's alpha exceeded the criterion of 0.7, and was 0.87, 0.86, 0.78, and 0.77 for the 4 scales, respectively. Construct validity was supported by correlations between the 4 scales and responses to individual questions, which were largely in the direction as hypothesized. Overall, patients reported good experiences. There were statistical differences across the rehabilitation settings in staff availability (p = 0.001) and social environment (p = 0.002), but no difference in care and organization and information/communication (p > 0.05). CONCLUSION: The 18-item Rehabilitation Patient Experiences Questionnaire is a promising outcome measure of experiences related to rehabilitation in patients with rheumatic diseases across different clinical settings. : | |
| 19413182 | Non-steroidal anti-inflammatory drugs and the risk of cardiovascular diseases: are we goin | 2009 Apr | The use of non-steroidal anti-inflammatory drugs (NSAID) is associated with a number of gastrointestinal and other adverse effects. Introduction of selective cyclooxygenase-2 (COX-2) inhibitors at the end of the 20th century raised hopes for a substantial reduction in the rate of serious events such as upper gastrointestinal ulcers, bleeding and perforations. In 2004 and 2005, predictions of some pharmacologists were confirmed when the Adenomatous Polyp Prevention on VIOXX trial (APPROVE) and other randomized, double-blind, placebo-controlled trials with COX-2 inhibitors showed an increased rate of thrombotic vascular events, including myocardial infarction, in patients treated with coxibs. So far, only limited long-term data on cardiovascular risk associated with non-selective NSAID have been available; however, some studies have suggested that both selective COX-2 inhibitors and traditional NSAID increase the risk of cardiovascular events. For patients at high cardiovascular risk, contradictory warnings and recommendations have been published recently by the American Heart Association, Food and Drug Administration, and by independent experts. The current paper reviews these recommendations and discusses the therapeutic challenge to minimize the risk of serious adverse events associated with the use of NSAID. | |
| 19177265 | The regulatory role of nerve growth factor and its receptor system in fibroblast-like syno | 2009 May | OBJECTIVES: Investigating the role of nerve growth factor (NGF) and its receptors (NGF-R) in inflammatory diseases is an active field of research. Inflammatory diseases of the joint are the commonest cause of human morbidity but very little is known about the effect of NGF on synovial tissue biology. Here we have studied NGF/NGF-R and their functional significance on cultured fibroblast-like synovial cells (FLS) collected from the synovial tissue of five healthy subjects. METHODS: NGF/NGF-R expression was determined in the basal condition and after stimulation with tumour necrosis factor (TNF)alpha and interleukin (IL)-1beta by enzyme-linked immunosorbent assay (ELISA) and fluorescence-activated cell sorting (FACS). Proliferation studies were performed by cell count, hexosaminidase assay, and the MTT assay. The synovial fluid (SF) NGF level was studied by ELISA in 12 psoriatic arthritis (PsA), 14 rheumatoid arthritis (RA), and 10 osteoarthritis (OA) patients. RESULTS: FACS studies showed that unstimulated FLS expressed low levels of NGF and the high-affinity NGF-tyrosine kinase receptor TrkA, and TNFalpha and IL-1beta increased NGF and TrkA expression in FLS. NGF (100 ng/mL) increased FLS proliferation by 400% compared to the control (medium only). The NGF level was significantly higher in the PsA group (365.5+/-85.2 pg/mL) than in the RA (120+/-35 pg/mL) and OA groups (30+/-6 pg/mL). CONCLUSIONS: Upregulation of NGF/TrkA in proinflammatory cytokine-activated FLS, the mitogenic effect of NGF on FLS, and the increased NGF level in SF of inflammatory arthritis suggest that there is cross-talk between NGF/NGF-R and FLS. These results also suggest that dysregulated production of NGF may lead to synovial cell proliferation and thus could influence the inflammatory and proliferative cascades of inflammatory arthritis. | |
| 21181220 | Th-17 associated cytokines in patients with reactive arthritis/undifferentiated spondyloar | 2011 Jun | We and others have previously shown that IL-17 is elevated in the synovial fluid of patients with reactive arthritis (ReA)/undifferentiated spondyloarthropathy (uSpA) having acute synovitis. Major source for IL-17 is Th17 cells, which differentiate from Th0 cells under the influence of TGF-β and IL-6, IL1-β and are maintained by IL-21 and 23. There is a paucity of data on these cytokines in ReA/uSpA. Thus, we measured the levels of Th-17 differentiating and maintaining cytokines in synovial fluid of patients with ReA and uSpA. Fifty patients with ReA/uSpA (ReA 24, uSpA 26), 19 patients with rheumatoid arthritis (RA) and 11 patients with osteoarthritis (OA) were included in the study. Synovial fluid (SF) were collected from knee joint and stored at -80°C until analysis. Cytokines were assayed using ELISA in SF specimens. The median IL-17A levels were significantly elevated in ReA (48.3 pg/ml) and uSpA (32.5 pg/ml) as compared to non-inflammatory OA controls (<7.8 pg/ml; p < 0.0001), while comparable to RA (57.9 pg/ml). Further, IL-6 median values were higher in ReA (25.2 ng/ml) and uSpA (13.6 ng/ml) as compared to OA (0.76 ng/ml; p < 0.0001), and comparable to RA (15.8 ng/ml). The median levels of IL-1β, IL-21 levels were elevated in ReA, uSpA and RA as compared to OA but were not statistically significant. TGF-β levels in ReA and uSpA were similar to OA but lower than in RA (4340 pg/ml; p < 0.05). IL-23 was not detectable in any synovial fluid sample. However, levels of these cytokines did not correlate with disease activity parameters. Significant positive correlation was observed between IL-17 and IL-1β (r = 0.38, p < 0.005), IL-17 and IL-6 (r = 0.659, p < 0.0001), and IL-1β and IL-6 (r = 0.391, p < 0.0001) in ReA and uSpA group. Inflammatory synovitis in ReA/uSpA is mediated by pro-inflammatory cytokines like IL-17, IL-6, IL-1β, and IL-21. However, IL-23 was not detectable in SF. Good correlation between IL-17, IL-6, and IL 1β suggest that either they are co-regulated or they regulate each other. | |
| 19734303 | PI3Kgamma regulates cartilage damage in chronic inflammatory arthritis. | 2009 Dec | The gamma isoform of phosphoinositide 3-kinase (PI3Kgamma) has been viewed as restricted to leukocytes mediating the regulation of chemokine-induced migration and recruitment of neutrophils, monocytes, and macrophages. In line with the observation that PI3Kgamma-deficient mice display defects in adaptive immunity, inhibition of PI3Kgamma reduces synovial inflammation in the collagen-induced arthritis mouse model of inflammatory arthritis [rheumatoid arthritis (RA)], which has been attributed to reduced influx of inflammatory cells. Challenging the concept of leukocyte-restricted PI3Kgamma function, we report here a novel, nonredundant function of PI3Kgamma as an important regulator of fibroblast-induced cartilage destruction during chronic destructive arthritis. We show that in human tumor necrosis factor transgenic mice, the loss of PI3Kgamma leads to a milder inflammatory arthritis. Interestingly, PI3Kgamma deficiency does not alter the recruitment of inflammatory cells, but significantly reduces cartilage damage through reduced expression of matrix metalloproteinases in fibroblasts and chondrocytes. In vitro analyses demonstrate that the decreased invasiveness of fibroblasts is mediated by reduced phosphorylation of Akt and extracellular signal-regulated kinase. Using a PI3Kgamma specific inhibitor, these data are confirmed in human synovial fibroblasts from patients with RA who exhibit a disease-specific up-regulation of PI3Kgamma. Our data indicate that in addition to mediating the recruitment of inflammatory cells, PI3Kgamma is an important regulator of fibroblast-mediated joint destruction in RA and suggest that specific inhibitors of PI3Kgamma will interfere with the activation of RA synovial fibroblasts and reduce cartilage destruction in RA. | |
| 19139846 | Predicting range of movement after knee replacement: the importance of posterior condylar | 2009 May | We have attempted to quantify the influence of clinical, radiological and prosthetic design factors upon flexion following knee replacement. Our study examined the outcome following 101 knee replacements performed in two prospective randomized trials using similar cruciate retaining implants. Multivariate analyses, after adjusting for age, sex, diagnosis and the type of prosthesis revealed that the only significant correlates for range of movement at 12 months were the difference in posterior condylar offset ratio (p < 0.001), tibial slope (p < 0.001) and preoperative range of movement (p = 0.025). We found a moderate correlation between 12-month range of movement and posterior tibial slope (R = 0.58) and the difference of post femoral condylar offset (i.e, post-operative minus preoperative posterior condylar offset, R = 0.65). Posterior condylar offset had the greatest impact upon final range of movement highlighting this as an important consideration for the operating surgeon at pre-operative templating when choosing both the design and size of the femoral component. | |
| 19884297 | A network meta-analysis of randomized controlled trials of biologics for rheumatoid arthri | 2009 Nov 24 | BACKGROUND: We sought to compare the benefits and safety of 6 biologics (abatacept, adalimumab, anakinra, etanercept, infliximab and rituximab) in patients with rheumatoid arthritis. METHODS: In this network meta-analysis, we included all completed and updated Cochrane reviews on biologics for rheumatoid arthritis. We included data from all placebo-controlled trials that used standard dosing regimens. The major outcomes were benefit (defined as a 50% improvement in patient- and physician-reported criteria of the American College of Rheumatology [ACR50]) and safety (determined by the number of withdrawals related to adverse events). We used mixed-effects logistic regression to carry out an indirect comparison of the treatment effects between biologics. RESULTS: Compared with placebo, biologics were associated with a clinically important higher ACR50 rate (odds ratio [OR] 3.35, 95% confidence interval [CI] 2.62-4.29) and a number needed to treat for benefit of 4 (95% CI 4-6). However, biologics were associated with more withdrawals related to adverse events (OR 1.39, 95% CI 1.13-1.71), with a number needed to treat for harm of 52 (95% CI 29-152). Anakinra was less effective than all of the other biologics, although this difference was statistically significant only for the comparison with adalimumab (OR 0.45, 95% CI 0.21-0.99) and etanercept (OR 0.34, 95% CI 0.14-0.81). Adalimumab, anakinra and infliximab were more likely than etanercept to lead to withdrawals related to adverse events (adalimumab OR 1.89, 95% CI 1.18-3.04; anakinra OR 2.05, 95% CI 1.27-3.29; and infliximab OR 2.70, 95% CI 1.43-5.26). INTERPRETATION: Given the limitations of indirect comparisons, anakinra was less effective than adalimumab and etanercept, and etanercept was safer than adalimumab, anakinra and infliximab. This summary of the evidence will help physicians and patients to make evidence-based choices about biologics for the treatment of rheumatoid arthritis. | |
| 19146971 | Plasma 3-nitrotyrosine is a biomarker in animal models of arthritis: Pharmacological disse | 2009 May | The contribution of inducible nitric oxide synthase (iNOS) to oxidative/nitrative stress is well-documented in inflammation, but difficult to quantify. Using a novel, recently developed assay for 3-nitrotyrosine (3-NT), we characterized iNOS activity and its inhibition in preclinical models of inflammation. In particular, we utilized the 3-NT assay to assess the role of iNOS in the disease pathology as well as for proof of pharmacology of iNOS inhibitors in an acute endotoxin challenge model, in models of rheumatoid arthritis (RA) such as rat adjuvant- and collagen-induced arthritis (AIA and CIA) and a model of osteoarthritis (OA) such as rat sodium monoiodoacetate-induced arthritis (MIA). Quantification of nitrotyrosine was performed using immuno-affinity 2-D LC-MS/MS assay. This assay is a very specific and reproducible and is amenable to a number of biological fluids. Plasma levels of 3-NT were significantly elevated in an acute model of inflammation (rat LPS) and in models of rheumatoid arthritis (adjuvant- and collagen-induced arthritis), and osteoarthritis (monoiodoacetate-induced arthritis). Plasma 3-NT correlated with the severity of the inflammatory response; thus, a 20-fold increase was observed in the rat LPS model, a 10-fold increase in AIA, and only a 2.5-fold elevation in CIA. Pharmacological intervention with iNOS inhibitors decreased 3-NT levels and associated pathology. 3-NT determination allowed for better elucidation of the role of iNOS in RA and OA disease pathology and provided proof of pharmacology for NOS inhibitors in animal models of RA and OA. | |
| 20713496 | Red blood cell methotrexate polyglutamates emerge as a function of dosage intensity and ro | 2010 Dec | OBJECTIVE: MTX is a prodrug producing anti-arthritic effects through a folylpolyglutamate synthase-mediated activation to MTX polyglutamates (MTXPGs). Our objective was to characterize the pharmacokinetics of intracellular MTXPGs and the factors associated with their accumulation in adult RA patients treated with MTX weekly. METHODS: MTX pharmacokinetics were evaluated in 47 MTX-naïve patients enrolled in an MTX dose-escalation study for an average of 20 weeks and 223 patients enrolled in a cross-sectional study under long-term MTX therapy. Short-chain (MTXPG1-2), long-chain (MTXPG3) and very long-chain (MTXPG4-5) concentrations were measured in circulating red blood cells using liquid chromatography. Statistical analyses consisted of non-linear mixed models, multivariate regression analyses and Wilcoxon signed-rank test. RESULTS: The accumulation of MTXPG1-5 was sigmoidal and steady-state concentrations were achieved after 7 weeks of therapy. However, additional exposure and MTX dosage escalation produced a selective redistribution towards longer chain MTXPGs at the expense of shorter chain MTXPGs. Age, glomerular filtration rate and route of MTX administration were the most important predictors of MTXPG accumulation. In 10 patients, a switch from oral to parenteral MTX was associated with a 37% increase in long-chain MTXPGs, a 132% increase in very long-chain MTXPGs and a concomitant 31% reduction in disease activity (P<0.02). CONCLUSION: The selective emergence of long-chain MTXPGs is function of dose, time of exposure and hence dosage intensity. Switching from oral to parenteral MTX produces a selective accumulation of longer chain MTXPGs that are known to be more potent inhibitors of de novo purine biosynthesis than shorter chain MTXPGs. | |
| 19765361 | NSAIDs and the gastrointestinal tract. | 2009 Oct | NSAIDs incur significant gastrointestinal (GI) side effects. The complication risk increases with history of peptic ulcer or older age. Helicobacter pylori infection and cardioprotective aspirin have independent and additive risks in the presence of NSAID use. NSAID enteropathy is increasingly recognized. Cardiovascular and GI risk stratification and H. pylori infection testing should be done before initiating NSAIDs. An NSAID combined with a proton pump inhibitor (PPI) is comparable to cyclooxygenase (COX)-2 inhibitors for gastroprotection, but for high-risk patients, COX-2 plus PPI should be considered. Aspirin and COX-2 inhibitors are associated with reduced colon adenoma risk, but higher dose and longer duration of treatment with aspirin appears effective. Hence, patients at high risk of colorectal cancer (with significant family or personal history of premalignant adenoma) must be identified, and cardiovascular and GI risk must be assessed before using these agents as chemopreventive drugs. | |
| 19629605 | Tailor-made Surgical Guide Reduces Incidence of Outliers of Cup Placement. | 2010 Apr | Malalignment of the cup in total hip arthroplasty (THA) increases the risks of postoperative complications such as neck cup impingement, dislocation, and wear. We asked whether a tailor-made surgical guide based on CT images would reduce the incidence of outliers beyond 10 degrees from preoperatively planned alignment of the cup compared with those without the surgical guide. We prospectively followed 38 patients (38 hips, Group 1) having primary THA with the conventional technique and 31 patients (31 hips, Group 2) using the surgical guide. We designed the guide for Group 2 based on CT images and fixed it to the acetabular edge with a Kirschner wire to indicate the planned cup direction. Postoperative CT images showed the guide reduced the number of outliers compared with the conventional method (Group 1, 23.7%; Group 2, 0%). The surgical guide provided more reliable cup insertion compared with conventional techniques. LEVEL OF EVIDENCE: Level II, therapeutic study. See the Guidelines for Authors for a complete description of levels of evidence. |