Browse

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

ID PMID Title PublicationDate abstract
17929126 Effects of low-dosage simvastatin on rheumatoid arthritis through reduction of Th1/Th2 and 2007 The objective of this study was to assess both the anti-inflammatory and immunomodulatory effects of low-dosage simvastatin on rheumatoid arthritis (RA). In each patient, simvastatin at 10 mg/day was administered for 12 weeks. The other treatments were unchanged at least 3 months before simvastatin administration to the end of the study. Patients were assessed for the improvement in clinical, laboratory, and immunological parameters of RA and for adverse events. Twenty-four patients with RA were enrolled. Clinical symptoms, including patient's assessment of pain and disease activity on visual analog scale (VAS), the swollen joint and tender joint counts, and handgrip strength significantly improved. Physician's assessment of disease activity on VAS, a period of morning stiffness and modified health assessment questionnaire showed a tendency of improving after administration of low-dosage of simvastatin. Of special interest was that the median levels of erythrocytes sedimentation rate, C-reactive protein, and rheumatoid factor were significantly decreased from 54.0 mm/h to 45.5 mm/h, from 1.50 mg/dl to 0.85 mg/dl, and from 57.0 IU/ml to 28.0 IU/ml, respectively, after administration of simvastatin. ACR20 and ACR50 responses were achieved in 62% and 38%, respectively, of simvastatin-treated patients for 12 weeks. Immunological assessment in peripheral blood revealed that the Th1/Th2 and CD4/CD8 ratios were significantly reduced by simvastatin. No adverse events were reported during simvastatin treatment. Immunomodulation through the alteration of Th1/Th2 and CD4/CD8 ratios may be a pharmacological mechanism in the anti-rheumatic effect of low-dosage simvastatin. Although it is necessary to evaluate the long-term effects of statins, low-dosage statins appear to be good as additional therapeutic agents.
16511915 Simvastatin inhibits production of interleukin 6 (IL-6) and IL-8 and cell proliferation in 2006 Mar OBJECTIVE: Rheumatoid arthritis (RA) is a chronic inflammatory disease in which the synovial environment is characterized by intense immunological activity. Evidence suggests that statins modulate immune functions and may have a beneficial effect on patients with RA. We investigated whether simvastatin could inhibit the expression of interleukin 6 (IL-6) and IL-8 and cell proliferation induced by tumor necrosis factor-alpha (TNF-alpha) in fibroblast-like synoviocytes (FLS) obtained from RA patients undergoing joint replacement therapy. METHODS: RA FLS were cultured with or without 0.05-10 microM simvastatin for 12 h. Cytokine mRNA expression and secretion levels were detected using real-time PCR and ELISA, respectively. Cell proliferation of FLS induced by TNF-alpha was determined by MTT assay. RESULTS: Real-time PCR analysis revealed that the levels of IL-6 and IL-8 mRNA expressed by FLS were reduced by simvastatin in a dose-dependent manner. Levels of IL-6 and IL-8 in FLS culture supernatants were decreased by simvastatin in a time-dependent and dose-dependent manner. MTT assay revealed that simvastatin could inhibit proliferation of FLS induced by TNF-alpha. These effects of simvastatin on IL-6 and IL-8 production and cell proliferation were reversed in the presence of mevalonic acid or geranylgeranyl-pyrophosphate, but not with farnesyl-pyrophosphate. CONCLUSION: Our results suggest that the beneficial effect of simvastatin in RA patients may involve inhibition of IL-6 and IL-8 production, as well as reduction of cell proliferation.
17054880 Cytokine-induced osteoclastic bone resorption in charcot arthropathy: an immunohistochemic 2006 Oct BACKGROUND: Charcot arthropathy is a chronic, progressive destructive process affecting bone architecture and joint alignment in people lacking protective sensation. The etiologic factors leading to progressive bone resorption have not been elucidated. The purpose of this study was to histologically examine surgical specimens with Charcot arthropathy for cell type and immunoreactivity of known cytokine mediators of bone resorption. METHODS: Tissue samples of 20 specimens with known Charcot arthropathy were stained for Hematoxylin and Eosin (H&E) to quantify cell type. Nine of the specimens were stained with interleukin-1 (IL-1) antibody, nine with tumor necrosis factor (TNF) alpha antibody, and nine with interleukin-6 (IL-6) antibody. Distribution of staining was graded as focal (less than 10% of cells), moderate (10% to 50% of cells), and diffuse (more than 50% of cells) by two independent investigators. Inflammatory cells in tissue sections of rheumatoid synovium served as a positive control. RESULTS: Osteoclasts were seen in excessive numbers lining the resorptive bone lacunae. There was a disproportionate increase in osteoclasts to osteoblasts in the Charcot-reactive bone. In each case, osteoclasts demonstrated immunoreactivity for IL-1, IL-6 and TNF-alpha with a grade of moderate or diffuse reactivity. CONCLUSION: The findings of excessive osteoclastic activity in the environment of cytokine mediators of bone resorption (IL-1, IL-6, and TNF-alpha) suggest enhanced bone resorption through the stimulation of osteoclastic progenitor cells as well as mature osteoclasts. Alteration in the synthesis, secretion, or activity of these important regulatory molecules through the use of pharmacologic agents may, in turn, alter bone remodeling and loss and lead to accelerated healing without collapse or malalignment.
17015691 RANTES modulates TLR4-induced cytokine secretion in human peripheral blood monocytes. 2006 Oct 15 Monocytes are the key regulators of joint inflammation and destruction in rheumatoid arthritis; hence, suppression of their recruitment into the joint may be therapeutically beneficial. Chemokines, including RANTES, are highly expressed in the joints of patient with rheumatoid arthritis, and they promote leukocyte trafficking into the synovial tissue. Because endogenous TLR4 ligands are expressed in the rheumatoid joint, the TLR4 ligand LPS was used to characterize the effects of RANTES on the TLR4-mediated induction of TNF-alpha and IL-6. Using peripheral blood (PB) monocytes, RANTES decreased LPS-induced IL-6 transcriptionally, whereas TNF-alpha was suppressed at the posttranscriptional level. RANTES signaled through p38 MAPK, and this signaling was further enhanced by LPS stimulation in PB monocytes, resulting in the earlier and increased secretion of IL-10. Inhibition of p38 by short-interfering RNA or a chemical inhibitor, as well as neutralization of IL-10, reversed the RANTES-mediated suppression of LPS-induced IL-6 and TNF-alpha. Further, when rheumatoid arthritis synovial fluid was added to PB monocytes, the neutralization of RANTES in fluid reduced the LPS-induced IL-10 and increased TNF-alpha. In conclusion, the results of this study suggest that RANTES down-regulates TLR4 ligation-induced IL-6 and TNF-alpha secretion by enhancing IL-10 production in PB monocytes. These observations suggest that the therapeutic neutralization of RANTES, in addition to decreasing the trafficking of leukocytes, may have a proinflammatory effect at the site of established chronic inflammation.
18456562 Synovial VLA-1+ T cells display an oligoclonal and partly distinct repertoire in rheumatoi 2008 Jul VLA-1 integrin expressing T cells are more frequent in inflammatory synovial fluids (SF) compared to peripheral blood. Recent studies suggest that VLA-1 expression mainly marks IFNgamma+ T cells while excluding both IL-4+ and regulatory FoxP3+ T cells. To further characterize the TCR repertoire of the potentially pathogenic VLA-1+ IFNgamma+ T cells, isolated from SF of adult patients with rheumatoid and psoriatic arthritis, we determined the complementarity determining region (CDR)3 spectratypes. Here we show in a cohort of 9 patients that VLA-1+ T cells display a perturbed repertoire that, moreover, differs from that of VLA-1- synovial T cells and even VLA-1+ PB T cells. Importantly, random sequencing of the CDR3 region of the TCR variable beta (BV) 6.1 gene of both VLA-1+ and VLA-1- synovial T cells, in one patient, revealed that their sequences were by and large different (29 out of 33 clones). Thus, our results imply that VLA-1+ T cells that infiltrate into inflamed joints represent a partly distinct and highly oligoclonal population of Th1 cells, probably selected by unique antigens.
17611980 The effect of low-dose aspirin on the decreased risk of development of dyspepsia and gastr 2007 Aug OBJECTIVE: To evaluate the risk of gastrointestinal (GI) symptoms and ulcers associated to the use of low-dose aspirin (ASA) among patients with rheumatoid arthritis (RA) and osteoarthritis (OA) treated with cyclooxygenase-2 (COX-2) drugs, to clarify the controversy in the literature. METHODS: Using a longitudinal databank, a prospective study using Cox proportional hazards models was performed in patients receiving COX-2 therapy for RA or OA to examine the effect of ASA on GI events. In 4 separate analyses patients reported dyspeptic symptoms and GI ulcers at semiannual intervals for up to 3 years. Ulcers were validated by review of medical records. RESULTS: Among 4240 patients taking COX-2-specific inhibitors, with no ulcer at study start, the age- and sex-adjusted hazard ratios for the effect of ASA on the development of epigastric pain, heartburn, nausea, and ulcers, without these previous events, were 1.11 (95% CI 0.97-1.29), 1.00 (95% CI 0.88-1.15), 1.32 (95% CI 1.13-1.54), and 1.27 (95% CI 0.78-2.05). The use of a propensity score to account for the risk of ASA prescription showed an even lower effect of ASA among all GI variables. This risk occurs within the setting of no prior GI symptoms or GI events, and independently of the use of proton pump inhibitors, other GI drugs, other nonsteroidal antiinflammatory drugs, prednisone, or methotrexate. CONCLUSION: In actual practice, the use of low-dose ASA has a small effect on the risk of developing dyspeptic symptoms in a group of patients with rheumatic disease.
17185418 IL-33, the IL-1-like cytokine ligand for ST2 receptor, is a chromatin-associated nuclear f 2007 Jan 2 Recent studies indicate that IL-1alpha functions intracellularly in pathways independent of its cell surface receptors by translocating to the nucleus and regulating transcription. Similarly, the chromatin-associated protein HMGB1 acts as both a nuclear factor and a secreted proinflammatory cytokine. Here, we show that IL-33, an IL-1-like cytokine that signals via the IL-1 receptor-related protein ST2 and induces T helper type 2-associated cytokines, is an endothelium-derived, chromatin-associated nuclear factor with transcriptional repressor properties. We found that IL-33 is identical to NF-HEV, a nuclear factor preferentially expressed in high endothelial venules (HEV), that we previously characterized. Accordingly, in situ hybridization demonstrated that endothelial cells constitute a major source of IL-33 mRNA in chronically inflamed tissues from patients with rheumatoid arthritis and Crohn's disease. Immunostaining with three distinct antisera, directed against the N-terminal part and IL-1-like C-terminal domain, revealed that IL-33 is a heterochromatin-associated nuclear factor in HEV endothelial cells in vivo. Association of IL-33 with heterochromatin was also observed in human and mouse cells under living conditions. In addition, colocalization of IL-33 with mitotic chromatin was noted. Nuclear localization, heterochromatin-association, and targeting to mitotic chromosomes were all found to be mediated by an evolutionarily conserved homeodomain-like helix-turn-helix motif within the IL-33 N-terminal part. Finally, IL-33 was found to possess transcriptional repressor properties, associated with the homeodomain-like helix-turn-helix motif. Together, these data suggest that, similarly to IL1alpha and HMGB1, IL-33 is a dual function protein that may function as both a proinflammatory cytokine and an intracellular nuclear factor with transcriptional regulatory properties.
17289553 Autoimmune inflammation from the Th17 perspective. 2007 Jan Recent studies demonstrated an IL-17-producer CD4+ T cell subpopulation, termed Th17, distinct from Th1 and Th2. It represents a different pro-inflammatory Th-cell lineage. This notion is supported by gene-targeted mice studies. Mice lacking IL-23 (p19-/-) do not develop experimental autoimmune encephalomyelitis (EAE) or collagen-induced arthritis (CIA), while knockout mice for the Th1 cytokine IL-12 (p35-/-) strongly develop both autoimmune diseases. Disease resistance by IL-23 knockout mice correlates well with the absence of IL-17-producing CD4(+) T lymphocytes in target organs despite normal presence of antigen-specific-IFN-gamma-producing Th1 cells. This finding may thus explain previous contradictory reports showing that anti-IFN-gamma-treated mice, IFN-gamma- or IFNR-deficient mice develop CIA or EAE. TGF-beta, IL-6 and IL-1 are the differentiation factors of Th17 cells. IL-23 is dispensable for this function, but necessary for Th17 expansion and survival. The master regulator that directs the differentiation program of Th17 cells is the orphan nuclear receptor RORgammat. IL-27, a member of the IL-12/IL-23 family, potently inhibits Th17 development. Evidence suggesting rheumatoid arthritis and multiple sclerosis as primarily IL-17 autoimmune inflammatory-mediated diseases is rapidly accumulating. The IL-17/23 axis of inflammation and related molecules may rise as therapeutic targets for treating these and perhaps other autoimmune diseases.
17696279 Vanadate, an inhibitor of stromelysin and collagenase expression, suppresses collagen indu 2007 Sep OBJECTIVE: Collagen induced arthritis (CIA) is a model of chronic inflammatory synovitis with pannus, neovascularization, and joint destruction similar to rheumatoid arthritis (RA). Matrix metalloproteinases (MMP) are involved in degradation of the extracellular matrix and joint destruction in RA. c-fos and c-jun are protooncogenes whose products combine to form activating protein (AP-1), a regulatory protein that is required for cell proliferation and the transcription of a variety of genes, including MMP such as collagenase and stromelysin. Administration of vanadium compounds suppresses c-fos/c-jun expression and AP-1 activity, resulting in inhibition of MMP expression in response to factors such as interleukin 1 (IL-1). We evaluated whether a vanadium AP-1 inhibitor could reduce MMP expression and subsequent joint damage in CIA. METHODS: Vanadate [bis (maltolato) oxovanadium (IV) (BMOV; 10 mg/kg/day)] and the reducing agent N-acetyl cysteine (NAC; 100 mg/kg/day) were given subcutaneously daily in an attempt to suppress established CIA in rats. NAC in combination with vanadate appeared to increase the efficacy of c-fos/c-jun inhibition, while decreasing toxicity. Controls were given NAC alone. Clinical, radiographic, and histologic measures were evaluated as well as synovial MMP and IL-1a expression. RESULTS: BMOV therapy, initiated on the day of onset of clinical arthritis, significantly reduced clinical arthritis within 2 days (p <0.05) compared to controls. Significance was maintained to the termination of the study on Day 18 post-arthritis onset (p < 0.005), with a maximum difference seen on Day 5 (p < 0.00001). Blinded radiographic scores at the completion of the protocols indicated less joint destruction in the experimental group compared to the control group (p < 0.005). Scanning and transmission electron microscopy confirmed the preservation of articular cartilage with therapy. In BMOV-treated rats, synovial mRNA expression of collagenase, stromelysin, and IL-la were reduced by 78%, 58%, and 85%, respectively, compared to controls. CONCLUSION: This is the first study of vanadate as a potential antirheumatic agent. Further study of this AP-1 and MMP inhibitor may lead to new treatment options in RA.
16331802 An evidence-based approach to prescribing nonsteroidal antiinflammatory drugs. Third Canad 2006 Jan OBJECTIVE: To revisit our previous evidence-based recommendations on the appropriate prescription of nonsteroidal antiinflammatory drugs (NSAID) with particular emphasis on cyclooxygenase-2 selective inhibitors (coxibs). METHODS: Needs assessments were conducted among Canadian physicians to determine their educational needs surrounding NSAID/coxibs. A survey of patients with arthritis was also conducted. Consensus participants reviewed articles relating to NSAID/coxibs in peer-reviewed journals between January 2000 and December 2004. At the consensus meeting, held January 21-23, 2005, participants discussed selected topics, after which recommendations were formulated and debated. Results. At the time of the meeting, it was agreed that emerging cardiovascular data were not clear enough to decide whether unanticipated cardiovascular events associated with coxibs represent a class effect or an effect of an individual drug. However, publications that appeared shortly after the meeting, as well as data presented at both the Joint Meeting of the Arthritis Advisory Committee and the Drug Safety and Risk Management Advisory Committee of the US Food and Drug Administration, February 16-18, 2005, and Health Canada's Expert Advisory Panel on the Safety of Cox-2 Selective NSAID, June 9-10, 2005, clarified that all available coxibs do carry some degree of cardiovascular risk, denoting a class effect. Our consensus group made the following specific recommendations: (1) Patients should be fully informed about treatment options, including the need to balance between cardiovascular risks and gastrointestinal (GI) benefits of NSAID/coxibs. (2) Coxibs are as effective as nonselective NSAID and superior to acetaminophen for the symptoms of arthritis. Topical NSAID may also be beneficial. (3) Coxibs are associated with fewer severe GI complications than nonselective NSAID. A proton pump inhibitor (PPI) should be prescribed if an NSAID must be used in a patient at increased GI risk. (4) The renal/blood pressure (BP) impact of coxibs is similar to that of NSAID. (5) In individuals at risk, creatinine clearance and BP should be determined at baseline and shortly after treatment begins. (6) In the geriatric population, use of nonpharmacological therapies should be maximized, and special caution is required before prescribing oral NSAID/coxibs. (7) Patients taking rofecoxib have been shown to have an increased risk of cardiovascular events. Current data suggest that this increased cardiovascular risk may be an effect of the NSAID/coxib class. (8) Although the data are limited, coxibs may be more cost-effective for patients at high GI risk than nonselective NSAID plus proprietary PPI. CONCLUSION: Coxibs continue to be an option in the treatment armamentarium. Given the evolving cardiovascular information, physicians and patients should weigh the benefits and risks of NSAID/coxib treatment. This concern emphasizes the need to routinely reassess patients' risks. These recommendations, which were formulated according to the Appraisal of Guidelines for Research and Evaluation, are intended to be used as guidelines to supplement, but not replace, the physician's judgment in clinical decision-making.
17369772 [IgA, an essential part of the immune system: selected issues]. 2006 Immunoglobulin class A is the main protein of the mucosal immune system. The daily production of this isotype exceeds the synthesis of all other classes of immunoglobulins. Because the mucosal surface area of the human organism is about 400 m2, the role of IgA in the defense of this surfaces from harmful agents from the external environment is extremely essential. Any changes connected with a lack or an overproduction of this immunoglobulin can manifest as different clinical diseases. In this paper some selected issues on the heterogeneity of the IgA are presented, its structure and significance for the human organism, the formation of IgA immunity during ontogenesis on one hand and antigenic stimulation on the other, as well as disorders connected with abnormal synthesis or structure of these molecules.
18353171 Resting CD4+ effector memory T cells are precursors of bystander-activated effectors: a su 2008 BACKGROUND: Previously we described a system whereby human peripheral blood T cells stimulated for 8 days in a cytokine cocktail acquired effector function for contact-dependent induction of proinflammatory cytokines from monocytes. We termed these cells cytokine-activated (Tck) cells and found that the signalling pathways elicited in the responding monocytes were identical whether they were placed in contact with Tck cells or with T cells isolated from rheumatoid arthritis (RA) synovial tissue. METHODS: Here, using magnetic beads and fluorescence-activated cell sorting, we extensively phenotype the Tck effector cells and conclude that effector function resides within the CD4+CD45RO+, CCR7-, CD49dhigh population, and that these cells are derived from the effector memory CD4+ T cells in resting blood. RESULTS: After stimulation in culture, these cells produce a wide range of T-cell cytokines, undergo proliferation and differentiate to acquire an extensively activated phenotype resembling RA synovial T cells. Blocking antibodies against CD69, CD18, or CD49d resulted in a reduction of tumour necrosis factor-alpha production from monocytes stimulated with CD4+CD45RO+ Tck cells in the co-culture assay. Moreover, blockade of these ligands also resulted in inhibition of spontaneous tumour necrosis factor-alpha production in RA synovial mononuclear cell cultures. CONCLUSION: Taken together, these data strengthen our understanding of T-cell effector function, highlight the multiple involvement of different cell surface ligands in cell-cell contact and, provide novel insights into the pathogenesis of inflammatory RA disease.
17034427 Major histocompatibility complex class II (DR) antigen and costimulatory molecules on in v 2006 Dec We have previously shown that normal human peripheral blood polymorphonuclear neutrophils (PMNs) contain cytoplasmic 'stores' of three key molecules normally associated with antigen presentation and T-cell costimulation, i.e. major histocompatibility complex class II (DR) antigen, CD80 (B7-1) and CD86 (B7-2). These cytoplasmic molecules were found to translocate to the cell surface within a few minutes following cross-linking (X-L) of Mac-1: an early neutrophil activation signal. In this study we have compared X-L of Mac -1 in parallel with four other well documented in vitro neutrophil activators: phorbol myristate acetate, N-formyl methionyl leucyl phenylalanine, lipopolysaccharide, and phagocytosis of immunoglobulin G-Latex particles. In addition, we have used paired samples of neutrophils obtained from peripheral blood (as a control) and synovial fluid from patients with rheumatoid arthritis as a source of in vivo activated cells. With the exception of phagocytosis, all activators resulted in the rapid (within 30 min) generation of two populations of activated neutrophils (designated P1 and P2) based on flow-cytometry measurements of size, granularity and phenotype. Significant up-regulation of DR and costimulatory molecules was observed, predominantly on P2 cells, with all activators except phagocytosis. CD80 and CD86 were noted to respond to the various activation signals in a different pattern suggesting that their intracellular granule location may be different. Dual-staining confocal laser microscopy studies showed that CD80 is largely confined to secretory vesicles (SVs) while CD86 appears to have a much wider distribution being found in SVs and within secondary (specific) and primary (azurophilic) granules. Increased surface expression of these antigens was also observed on P2 synovial fluid neutrophils appearing as large heterogeneous clusters on the cell surface when visualized by confocal laser microscopy.
16984635 Novel insights in the regulation of CCL18 secretion by monocytes and dendritic cells via c 2006 Sep 19 BACKGROUND: The T cell attracting chemokine CCL18 is produced by antigen presenting cells and a role for CCL18 has been suggested in the pathogenesis of a variety of diseases. Rheumatoid arthritis (RA) is one of these conditions, in which abundant CCL18 production is present. Although Th2 cytokines and IL-10 are known to have an effect on CCL18 production, there are several gaps in our knowledge regarding the exact regulation of CCL18 secretion, both in general and in RA. In this study we provide new insights in the regulation of CCL18 secretion by monocytes and dendritic cells. RESULTS: In contrast to a large panel of pro-inflammatory stimuli (IL-1beta, TNF-alpha, IL-10, IL-13, IL-15, IL-17, IL-18, IFN-gamma), T cell mimicking molecules (RANKL, CD40L) or TLR driven maturation, the anti-inflammatory IL-10 strongly stimulated DC to secrete CCL18. On freshly isolated monocytes, CCL18 secretion was induced by IL-4 and IL-13, in strong synergy with IL-10. This synergistic effect could already be observed after only 24 hours, indicating that not only macrophages and dendritic cells, but also monocytes secrete CCL18 under these stimulatory conditions. A high CCL18 expression was detected in RA synovial tissue and incubation of monocytes with synovial fluid from RA patients clearly enhanced the effects of IL-4, IL-13 and IL-10. Surprisingly, the effect of synovial fluid was not driven by IL-10 of IL-13, suggesting the presence of another CCL18 inducing factor in synovial fluid. CONCLUSION: In summary, IL-10 synergistically induces CCL18 secretion in combination with IL-4 of IL-13 on monocytes and monocyte derived cells. The effects of IL-14, IL-13 and IL-10 are strongly enhanced by synovial fluid. This synergy may contribute to the high CCL18 expression in RA.
18173921 Polymorphism of genes related to cardiovascular disease in patients with rheumatoid arthri 2007 Nov OBJECTIVE: To analyze candidate genes, related to cardiovascular disease (CVD) in general, and potentially involved in the inflammatory process, in RA patients from northern Sweden. METHODS: Four hundred and sixty-seven individuals (345 females; 122 males) with RA (ACR criteria), having a mean age of 61.8 +/- 13.0 years and mean disease duration of 16.2 +/- 12.1 years, were consecutively recruited and followed-up for 3 years. The prevalence of CVD, [(ischemic heart disease (IHD), deep vein thromboses/pulmonary embolism (DVT/PE) and/or stroke/TIA] and hypertension was registered. Candidate genes encoding for Beta-fibrinogen (G-455A), Factor XIIIA (Val34Leu), plasminogen activator inhibitor type-1 (PAI-1 4G/5G), and tumor necrosis factor receptor (TNFR)II (M196R) were analysed. Controls (n = 672) were randomly selected according to age and gender from the Medical Biobank of Northern Sweden. Polymorphisms were genotyped using a TaqMan 9700HT and the 5'nuclease allelic discrimination assay. RESULTS: The genotypes, carriers and alleles did not differ in distribution between patients and controls. Carriage of the TNFRII R variant was more frequent among patients with hypertension (p = 0.018). The genotype distribution of PAI-1 in patients with IHD differed significantly (p = 0.002) because carriage of 4G was more frequent (p = 0.024). Combined carriage of TNFRII 196R variant and Beta-fibrinogen-455A was a stronger predictor for hypertension than each genotype separately. The distribution of FXIIIA genotypes deviated significantly in RA patients with DVT/PE (p = 0.028) with an increased frequency of the Leu34 variant. CONCLUSION: The unusual alleles of TNFRII, PAI-1 and FXIIIA were associated with CVD in RA patients. The combination of several of the rare types further increased the predictive values for CVD.
18057361 A randomised controlled trial of cemented versus cementless press-fit condylar total knee 2007 Dec We report the long-term survival of a prospective randomised consecutive series of 501 primary knee replacements using the press-fit condylar posterior cruciate ligament-retaining prosthesis. Patients received either cemented (219 patients, 277 implants) or cementless (177 patients, 224 implants) fixation. Altogether, 44 of 501 knees (8.8%) underwent revision surgery (24 cemented vs 20 cementless). For cemented knees the 15-year survival rate was 80.7% (95% confidence interval (CI) 71.5 to 87.4) and for cementless knees it was 75.3% (95% CI 63.5 to 84.3). There was no significant difference between the two groups (cemented vs cementless; hazard ratio (HR) 0.83, 95% CI 0.45 to 1.52, p = 0.55). When comparing the covariates there was no significant difference in the rates of survival between the side of operation (HR 0.58, p = 0.07), age (HR 0.97, p = 0.10) and diagnosis (HR 1.25 p = 0.72). However, there was a significant gender difference, with males having a higher failure rate with cemented fixation (HR 2.48, p = 0.004). Females had a similar failure rate in both groups. This single-surgeon series, with no loss to follow-up, provides reliable data of the revision rates of one of the most commonly-used total knee replacements. The survival of the press-fit condylar total knee replacement remained good at 15 years, irrespective of the method of fixation.
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.
17635334 Methods to enhance the safety of methotrexate prescribing. 2007 Aug The treatment of chronic inflammatory conditions often involves a difficult balance between the benefits of disease modification and the risks attendant with the use of disease-modifying agents. Methotrexate is a useful and commonly used disease-modifying agent but has a particularly notable reputation for causing morbidity and mortality. We explore ways in which the safety of methotrexate prescribing may be improved. There has been considerable debate as to the whether some of the side-effects can be mitigated by co-prescription of folate with methotrexate. Whereas no definitive conclusion can yet be reached, evidence suggests that the improvement in side-effect profile is limited to fewer elevations of liver enzymes, but that this may be at the expense of decreased methotrexate efficacy. The question remains as to whether the improved tolerability more than compensates for the decreased efficacy or whether folic acid should be used in a more circumspect way. However, a very specific danger arises from the fact that methotrexate is prescribed once weekly for inflammatory conditions, leading to errors at both the prescription and patient level. We highlight simple ways of improving safety to decrease such errors.
16951119 Revision total elbow arthroplasty for prosthetic fractures. 2006 Sep BACKGROUND: Fractures of total elbow arthroplasty components are uncommon, and the literature provides little guidance regarding the management and outcomes of treatment of these complications. The goal of this report was to investigate the prevalence and management of fractures of ulnar and humeral components following total elbow arthroplasty and to review our experience with cement-within-cement reconstruction for revision following such fractures. METHODS: Between 1979 and 2003, twenty-four patients with a total of twenty-seven fractured total elbow arthroplasty components (seventeen ulnar and ten humeral) of different designs presented to our institution. Twenty-six implants underwent subsequent revision elbow arthroplasty at our institution. Fourteen of those revisions were done with a cement-within-cement technique, and twelve, with traditional methods. Twenty-one patients (twenty-three implants) were available for final follow-up, and data that had been acquired prospectively and entered into the institutional arthroplasty database were reviewed retrospectively. At the time of final follow-up, the Mayo Elbow Performance Score (MEPS) was calculated and preoperative, postoperative, and most recent radiographs were examined for bone loss, bushing wear, and integrity of the bone-cement interface. RESULTS: The prevalences of humeral and ulnar component fracture following primary total elbow arthroplasties performed at our institution were 0.65% and 1.2%, respectively. At a mean of 5.1 years following revisions for those fractures, the MEPS was excellent for eight patients, good for five, fair for six, and poor for two. The average MEPS was 82 points following the revision total elbow arthroplasties done with the cement-within-cement technique and 78 points following the revisions done with the traditional method of cement removal and insertion of a revision component. Complications included seven intraoperative cortical perforations; five nerve injuries, two of which were permanent; three triceps avulsions; and one deep infection. CONCLUSIONS: Implant fractures following total elbow arthroplasty are uncommon. They occur for several reasons, such as notch sensitivity, component design, and high stresses due to bone deficiency. Revision techniques, such as cement-within-cement reimplantation, are reliable for relieving pain and restoring function; however, the rate and spectrum of complications are a cause for concern. LEVEL OF EVIDENCE: Therapeutic Level IV.
17607547 Selective activation of mast cells in rheumatoid synovial tissue results in production of 2007 Jun OBJECTIVES AND DESIGN: To study the consequences of mast cell activation in human synovial tissue. METHODS: Synovial tissue was obtained from 18 RA patients and mast cells was selectively activated in synovial tissue explant cultures. Expression of TNF-alpha, IL-1beta and IL-1Ra were determined and tissue distribution of IL-1beta was studied. RESULTS: Compared to untreated synovia, selective activation of synovial mast cells increased significantly the production of TNF-alpha (0.49 +/- 0.88 vs. 4.56 +/- 3.18 pg/mg wet tissue, p < 0.001) and IL-1beta (0.058 +/- 0.032 vs. 2.55 +/- 1.98 pg/mg wet tissue, p = 0.013). The expression of TNF-alpha and IL-1beta mRNA increased significantly (19-fold (p = 0.009) and 13-fold (p = 0.031), respectively). Mast cell activation induced IL-1beta expression in particular in nearby CD68 positive synovial macrophages. Secretion of IL-1Ra was also increased but to a lesser degree than that of IL-1beta. CONCLUSIONS: Synovial mast cells produce proinflammmatory cytokines and may thus contribute to the inflammation in RA.