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ID PMID Title PublicationDate abstract
15103248 An update on the cytokine network in rheumatoid arthritis. 2004 May PURPOSE OF REVIEW: To update the knowledge accumulated on the contribution of cytokines to rheumatoid arthritis and related animal models. Publications from the end of 2002 and 2003 period were analyzed for a selection. RECENT FINDINGS: A better understanding of the clinical results with tumor necrosis factor-alpha inhibitors has come from studies in treated patients. The expected effect of infliximab on the apoptosis of cells expressing tumor necrosis factor-alpha was not observed in synovium biopsy specimens. The mode of action of tumor necrosis factor-alpha on bone destruction has been clarified in gene-defective mice. Tumor necrosis factor-alpha acts through osteoclasts--an effect that is inhibited with osteoprotegerin. New interleukin-1 inhibitors with a potential for increased efficacy, such as interleukin-1trap, have been manufactured and are now being tested in rheumatoid arthritis. The list of cytokines of interest for therapeutic intervention has been growing rapidly. The results with animal models have provided clues to control arthritis with natural interleukin-18 inhibitors, such as interleukin-18 BP. Additional results have been accumulated that indicate the contribution of T cell subsets in inflammation and destruction through the production of interleukin-17. Synergistic interactions with other cytokines are critical in the interleukin-17 tuning effects. Macrophage inhibitory factor was described many years ago. Its comeback is based on properties of synoviocyte activation and proliferation. SUMMARY: Such findings are critical for a better understanding of response heterogeneity in patients treated with the cytokine inhibitors now on the market. New therapeutic approaches are been planned from these results.
12697740 A mutation in a CD44 variant of inflammatory cells enhances the mitogenic interaction of F 2003 Apr Synovial fluid cells from joints of rheumatoid arthritis (RA) patients express a novel variant of CD44 (designated CD44vRA), encoding an extra trinucleotide (CAG) transcribed from intronic sequences flanking a variant exon. The CD44vRA mutant was detected in 23 out of 30 RA patients. CD44-negative Namalwa cells transfected with CD44vRA cDNA or with CD44v3-v10 (CD44vRA wild type) cDNA bound FGF-2 to an equal extent via their associated heparan sulfate chains. However, Namalwa cells, immobilizing FGF-2 via their cell surface CD44vRA, bound substantially more soluble FGF receptor-1 (FGFR-1) than did Namalwa cells immobilizing the same amount of FGF-2 via their cell surface CD44v3-v10. The former cells stimulated the proliferation of BaF-32 cells, bearing FGFR-1, more efficiently than did the latter cells. Finally, isolated primary synovial fluid cells from RA patients expressing CD44vRA bound more soluble FGFR-1 to their cell surface-associated FGF-2 than did corresponding synovial cells expressing CD44v3-v10 or synovial cells from osteoarthritis patients. The binding of soluble FGFR-1 to RA synovial cells could be specifically reduced by their preincubation with Ab's against the v3 exon product of CD44. Hence, FGF-2 attached to the heparan sulfate moiety expressed by the novel CD44 variant of RA synovium cells exhibits an augmented ability to stimulate FGFR-1-mediated activities. A similar mechanism may foster the destructive inflammatory cascade not only in RA, but also in other autoimmune diseases.
12084010 TACE inhibition: a new approach to treating inflammation. 2002 Jul Clinical trials showing the benefits of reducing the effects of TNF- alpha in rheumatoid arthritis have highlighted the key role of the cytokine TNF- alpha in this inflammatory condition. A new approach to reducing the effects of TNF- alpha is to decrease its synthesis by inhibiting TNF- alpha converting enzyme with GW3333. In rat models of arthritis, GW3333 has some beneficial effects. Further longer-term studies of GW3333 in animal models are required to determine whether its benefit is maintained. TACE inhibition may represent a new approach to treating inflammation.
15706910 [Resource and pharmacognostical study on Aralia echinocaulis]. 2004 Jun OBJECTIVE: To provide fundamental information for its exploiting. Aralia echinocaulis by the resource and identification study on. METHOD: Resource survey and various identification were carried out. RESULT: The county level distribution and ecological environment of A. echinocaulis were initially observed. It mainly distributed in the mountainous areas of the Yangtze River basin and the south, and was usually used as folk drug. This study also displayed its morphological, microscopic and chemophysical identification features. CONCLUSION: The morphological features of original plant and crude drug, and the anatomical and chemophysical characteristics of A. echinocaulis are of identification value, and the species are also of greater development and utilization potentiality, but the resource does not support the sustainable utilization. Therefore, artificial propagation is apparently crucial to its exploitation.
11833673 Validation of a new automated immunoassay for measurement of intact osteocalcin. 2002 Bone turnover is assessed indirectly by measurement of biochemical markers of bone turnover. Osteocalcin, a 49-amino-acid protein is a major noncollagenous protein of bone matrix, synthesized by osteoblasts and odontoblasts. Various assays exist for assessment of osteocalcin and concentrations in the same serum or plasma sample may vary enormously. The used antibodies may recognize intact osteocalcin and/or circulating fragments of osteocalcin. We here describe and validate a new automated immunoassay system for measurement of intact osteocalcin (DPC IMMULITE assay) using monoclonal antibodies (mouse) against the C-terminus of osteocalcin (AA 44-49). For detection polyclonal antibodies (goat) directed against the N-terminus (AA 1-17) conjugated with alkaline phosphatase are used. While different laboratory assays show marked clinical discordance, we evaluated our results comparatively to an established IRMA method (Nichols). We observed a highly significant correlation between both assays (r = 0.9352, p < 0.0001, n = 286) for healthy persons and also for patient samples (osteoporosis, diabetes type 1, rheumatoid arthritis). Very low inter- and intraassay covariance as well as highly significant linearity (analytical recovery near 100%) tested by serial dilutions were demonstrated for the DPC IMMULITE intact osteocalcin assay. We conclude that the IMMULITE assay is a useful method for assessment of intact osteocalcin giving valuable results in comparison to an established non-automated assay.
12695561 Role of macrophage inflammatory protein-3alpha and its ligand CCR6 in rheumatoid arthritis 2003 Apr We examined the expression and participation of CCR6 and its ligand MIP-3alpha in rheumatoid arthritis (RA) by ELISA, RT-PCR, real-time PCR (TaqMan) analysis, monocyte chemotaxis, and two- and four-color flow cytometry. We found that RA synovial fluid (SF) contained significantly more MIP-3alpha than osteoarthritis (OA), indicating a potential role for MIP-3alpha in RA. IL-1beta, IL-18, and TNF-alpha stimulated RA fibroblast MIP-3alpha production at 48 hours of incubation in vitro. By TaqMan analysis, there were more CCR6 mRNA transcripts in RA synovial tissue (ST) than in OA or normal (NL) ST, and elevated MIP-3alpha mRNA expression in RA compared with NL ST. By FACS analysis, there were significantly elevated percentages of CD3+/CD4+/CD45RO+/CCR6+ memory lymphocytes found in RA peripheral blood (PB) compared with NL PB or RA SF. We also found that MIP-3alpha induced monocyte chemotactic activity at 1.25 pM, consistent with concentrations of MIP-3alpha found in RA SF. Furthermore, MIP-3alpha accounted for 40% of RA SF chemotactic activity for monocytes in modified Boyden chamber assays. We confirmed that MIP-3alpha may be binding a G-coupled protein receptor because in vitro monocyte chemotaxis was inhibited by preincubation of monocytes with pertussis toxin. RA patient clinical data revealed that CD3+ lymphocyte/CCR6 expression inversely correlated with the age of the patient, indicating that CCR6 expression may be important in the development of RA at a younger age. Overall, these studies indicate that MIP-3alpha and CCR6 may function to recruit monocytes and memory lymphocytes from the RA PB to the RA joint. These results further indicate that expression of CCR6, the receptor for MIP-3alpha, can be correlated with RA development.
12187755 [Treatment of peptic ulcer related to rheumatic diseases]. 2002 Aug Rheumatic diseases often have gastrointestinal(GI) manifestations, and may present as GI bleeding and perforation due to peptic ulcer associated with high mortality. Major causes of peptic ulcer related to rheumatic diseases are drugs such as nonsteroidal anti-inflammatory drug(NSAID) and corticosteroid, and vasculitis. The analgesic effects of NSAID often mask abdominal pain until they cause GI bleeding and perforation. Therefore, it is important to make early diagnosis of peptic ulcer with upper gastrointestinal endoscope. Fundamental treatment of NSAID induced peptic ulcer is to quit it, however it is difficult because of activity of rheumatic diseases. Also, most NSAID induced peptic ulcers heal by administration of proton pump inhibitor or misoprostol. Corticosteroid pulse therapy or administration of immunosuppressant agents is effective for vasculitis induced peptic ulcer, however it is difficult to make diagnosis of it. Development of NSAID with less side effects such as cyclooxygenase-2 selective inhibitors and establishment of diagnosis and treatment of peptic ulcer related to rheumatic diseases are expected.
15249360 Multifocal electroretinographic evaluation of long-term hydroxychloroquine users. 2004 Jul OBJECTIVES: To observe the long-term effects of hydroxychloroquine sulfate on retinal electrical activity by multifocal electroretinography (mfERG) and to evaluate the regional variation of retinal dysfunction in subjects with hydroxychloroquine retinopathy. METHODS: Multifocal ERG with 103-hexagon stimulation was performed on 19 patients (36 eyes) treated with hydroxychloroquine for systemic lupus erythematosus, rheumatoid arthritis, or localized atypical scleroderma. Visual acuity testing, Amsler grid testing, and Ishihara color vision testing were also performed. In 2 of the patients, hydroxychloroquine was discontinued due to concerns about toxicity. Both of these patients had additional mfERG performed after discontinuation of medication. RESULTS: Twelve patients (19 eyes) had a normal response density in one or both eyes, including 6 patients (12 eyes) with a low lifetime dose (< or =438 g) of hydroxychloroquine who had normal response densities in both eyes. Eleven patients (17 eyes) had abnormal response densities in one or both eyes, and 2 of these patients (4 eyes) had significant attenuation of response densities in almost the whole tested field; 4 patients had a normal mfERG result for one eye but had a slight decrease of response densities for the other eye. There were 4 patterns of abnormal mfERG amplitude change observed: (1) paracentral loss, (2) foveal loss, (3) peripheral loss, and (4) generalized loss. Implicit times were abnormal for pericentral responses in 3 patients. The results of color vision and Amsler grid testing were normal, except for one patient with a generalized loss pattern. In 2 subjects in whom hydroxychloroquine toxicity was suspected, response densities improved after termination of hydroxychloroquine. CONCLUSIONS: Long-term hydroxychloroquine use may be associated with mfERG abnormalities. The mfERG appears to detect retinal physiological change earlier than visual acuity testing, color vision testing, or Amsler grid testing can. The greatest value of the mfERG is in differentiating a retinal cause and, hence, providing important evidence for hydroxychloroquine toxicity, for whatever visual field loss is apparent on perimetry.
12618865 Variations of human killer cell lectin-like receptors: common occurrence of NKG2-C deletio 2003 Mar CD94 and NKG2 are members of the NK cell receptor families, and are encoded in the natural killer gene complex (NKC) on human chromosome 12p12-13, one of the candidate chromosomal regions for rheumatic diseases. To examine a possible association between variations in CD94 and NKG2 genes and genetic susceptibility to rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE), we carried out a systematic polymorphism screening of NKG2-A (KLRC1), NKG2-C (KLRC2) and CD94 (KLRD1) genes on a population basis. In NKG2-A, previously considered to be highly conserved, 10 polymorphisms in the noncoding region and introns, as well as one rare variation leading to an amino acid substitution within the transmembrane region, c.238T>A (Cys80Ser), were detected. In NKG2-C, in addition to the previously described two nonsynonymous substitutions, c.5G>A (Ser2Asn) and c.305C>T (Ser102Phe), two polymorphisms were newly detected in the noncoding region. In CD94, only one single nucleotide substitution was identified in the 5' untranslated region. When the patients and healthy individuals were genotyped for these variations, no significant association was observed. However, although statistically not significant, NKG2-A c.238T>A (Cys80Ser) was observed in three patients with RA, but in none of the healthy individuals and the patients with SLE. Unexpectedly, in the process of polymorphism screening, we identified homozygous deletion of NKG2-C in approximately 4.3% of healthy donors; under the assumption of Hardy-Weinberg equilibrium, the allele frequency of NKG2-C deletion was estimated to be 20.7%. These results demonstrated that, although human NKG2-A, -C and CD94 are generally conserved with respect to amino acid sequences, NKG2-A is polymorphic in the noncoding region, and that the number of genes encoded in the human NKC is variable among individuals, as previously shown for the leukocyte receptor complex (LRC), HLA and Fcgamma receptor (FCGR) regions.
12296865 Mediators of inflammation are down-regulated while apoptosis is up-regulated in rheumatoid 2002 Oct The aim of the study was to determine whether collagen-polyvinylpyrrolidone (collagen-PVP) modifies some proinflammatory responses in synovium cultures from rheumatoid arthritis (RA) patients. Synovium from 10 RA patients were cultured with or without 1% collagen-PVP. Tissues on the 3rd, 5th and 7th culture day were sectioned and stained by the Herovici technique. Total collagen and type I/III collagen ratios were evaluated by the Woessner micromethod and by interrupted gel electrophoresis, respectively. Collagenolytic activity was assessed by degradation of [3H]-collagen in supernatants. TIMP-1, IL-1beta and TNF-alpha were determined in supernatants by ELISA, and the results were normalized by DNA concentration. IL-1beta, TNF-alpha, IL-6, IL-8, MMP-1, TIMP-1, Cox-1, VCAM-1, ICAM-1 and Fas/APO95 expression was evaluated by immunohistochemistry. Apoptosis was detected by TUNEL technique. The histological analysis and electrophoresis revealed a 1.7-fold increase of type III collagen in a time-dependent fashion in collagen-PVP-treated cultures. Proinflammatory cytokines (IL-1beta: 58 +/- 9 versus 22 +/- 10; TNF-alpha: 41 +/- 6 versus 11 +/- 3; IL-8: 59 +/- 12 versus 29 +/- 9; treated versus untreated), adhesion molecule (ICAM-1: 57 +/- 11 versus 29 +/- 15; VCAM-1: 49 +/- 7 versus 21 +/- 13; treated versus untreated) as well as Cox-1 (59 +/- 10 versus 20 +/- 3) expression was down-regulated in RA synovium treated. Meanwhile, TIMP-1 (36 +/- 7 versus 57 +/- 11) and Fas expression (20 +/- 10 versus 55 +/- 13) and apoptosis (14 +/- 3 versus 55 +/- 5) were up-regulated in treated cultures compared with controls. In supernatants, the collagenolytic activity, as well as IL-1beta and TNF-alpha, levels were all down-regulated in treated cultures (two, three, fourfold, respectively). The addition of collagen-PVP to synovium-induced down-modulation of some inflammatory parameters and an increase in apoptosis of synovial cells. Perhaps this mechanism could contribute to inhibit outgrowth of pannus formation and to down-regulate inflammation of joints in patients with RA.
14676202 Differential effect of transforming growth factor beta (TGF-beta) on the genes encoding hy 2004 Mar 5 Unfettered hyaluronan (HA) production is a hallmark of rheumatoid arthritis. The discovery of three genes encoding hyaluronan synthases (HASs) allows for the investigation of the signaling pathways leading to the activation of these genes. Our objective is to further understanding of the regulation of these genes as well as to find ways to prevent undesired gene activation. Human fibroblast-like synoviocytes were used in these experiments. mRNA levels of HAS were monitored by reverse transcriptase-PCR. A series of specific kinase inhibitors were used to investigate intracellular pathways leading to the up-regulation of HAS1. Our experiments, testing a series of stimuli including tumor necrosis factor alpha (TNFalpha), demonstrate that TGF-beta is the most potent stimulus for HAS1 transcription. TGF-beta activates HAS1 in a dose-dependent manner with a maximum effect at a concentration of 0.5-1 ng/ml. TGF-beta-induced HAS1 mRNA can be detected within 60 min and reaches maximal levels at 6 h. Furthermore, TGF-beta treatment leads to an increase in synthase activity as determined by HA ELISA and by in vitro HA synthase assays. In contrast to the activatory effect on HAS1, TGF-beta dose-dependently suppresses HAS3 mRNA. As to the mode of action of TGF-beta-induced HAS1 mRNA activation, our experiments reveal that blocking p38 MAPK inhibited the TGF-beta effect by 90%, blocking the MEK pathway led to an inhibition by 40%, and blocking the JNK pathway had no effect. The presented data might contribute to a better understanding of the role of TGF-beta and of HA in the pathology of diseases.
15860218 FK506 suppresses the stimulation of matrix metalloproteinase 13 synthesis by interleukin-1 2005 May 15 The aim of this study was to determine whether FK506, which has been shown to be effective for the treatment of refractory RA, affects the synthesis of matrix metalloproteinases (MMPs) in rheumatoid synovial fibroblasts. Synovial fibroblasts isolated from rheumatoid synovium were incubated in 6-well culture plates for 24 h with FK506 and interleukin-1beta, alone and in combination. Samples of supernatants were assayed by ELISA or immunoblottings using anti-MMP-13 specific antibodies. In addition, synovial fibroblasts pretreated with FK506 were stimulated with IL-1beta for 10 min and cellular lysates were subjected to anti-phospho-specific mitogen-activated protein kinase (MAPK). Unstimulated synovial fibroblasts produced low levels of MMP-3 and 13. IL-1beta-induced substantial output of these MMPs into cell supernatants. FK506 had no detectable effects on IL-1beta-induced MMP-2 induction. FK506, however, significantly suppressed MMP-13 production from IL-1beta-stimulated synovial fibroblasts. FK506 also prevented IL-1beta-stimulated JNK activation and transcriptional activation of AP-1 in these cells. Our results indicate that FK506 is capable of regulating MMP-13 synthesis via JNK pathway in rheumatoid synonvium.
12847684 Heterogeneous requirement of IkappaB kinase 2 for inflammatory cytokine and matrix metallo 2003 Jul OBJECTIVE: To investigate the potential role of IkappaB kinase 1 (IKK-1) and IKK-2 in the regulation of nuclear factor kappaB (NF-kappaB) activation and the expression of tumor necrosis factor alpha (TNFalpha), as well as interleukin-1beta (IL-1beta), IL-6, IL-8, vascular endothelial growth factor (VEGF), and matrix metalloproteinases (MMPs), in rheumatoid arthritis (RA). METHODS: Recombinant adenoviruses expressing beta-galactosidase, dominant-negative IKK-1 and IKK-2, or IkappaBalpha were used to infect ex vivo RA synovial membrane cultures and synovial fibroblasts obtained from patients with RA undergoing joint replacement surgery, or human dermal fibroblasts, human umbilical vein endothelial cells (HUVECs), and monocyte-derived macrophages from healthy volunteers. Then, their effect on the spontaneous or stimulus-induced release of inflammatory cytokines, VEGF, and MMPs from RA synovial membrane cells was examined. RESULTS: IKK-2 was not required for lipopolysaccharide (LPS)-induced NF-kappaB activation or TNFalpha, IL-6, or IL-8 production in macrophages, but was essential for this process in response to CD40 ligand, TNFalpha, and IL-1. In synovial fibroblasts, dermal fibroblasts, and HUVECs, IKK-2 was also required for LPS-induced NF-kappaB activation and IL-6 or IL-8 production. In RA synovial membrane cells, IKK-2 inhibition had no effect on spontaneous TNFalpha production but significantly reduced IL-1beta, IL-6, IL-8, VEGF, and MMPs 1, 2, 3, and 13. CONCLUSION: Our study demonstrates that IKK-2 is not essential for TNFalpha production in RA. However, because IKK-2 regulates the expression of other inflammatory cytokines (IL-1beta, IL-6, and IL-8), VEGF, and MMPs 1, 2, 3, and 13, which are involved in the inflammatory, angiogenic, and destructive processes in the RA joint, it may still be a good therapeutic target.
14994387 Expression of interleukin 12 receptor (IL-12R) and IL-18R on CD4+ T cells from patients wi 2004 Mar OBJECTIVE: Interleukin 12 (IL-12) and IL-18 synergistically induce interferon-gamma (IFN-gamma) production by T cell infiltrates in rheumatoid arthritis (RA). To investigate this synergism, we examined the expression and regulation of IL-12 receptor (IL-12R) and IL-18R on peripheral blood (PB) and synovial tissue (ST) CD4+ T cells from patients with RA. METHODS: The mRNA and cell surface expression of IL-12R and IL-18R in CD4+ T cells were determined by reverse transcriptase-polymerase chain reaction and flow cytometry, respectively. IFN-gamma and IL-4 production by CD4+ T cells stimulated with phorbol myristate acetate (PMA) and calcium ionophore A23187 was measured by intracellular cytokine staining and flow cytometry. RESULTS: Despite the negligible expression of IL-12R on fresh cells, PB CD4+ T cells from RA patients expressed higher levels of both IL-12Rbeta1 and beta2 subunits after stimulation with anti-CD3 antibody (Ab) than the cells of healthy controls. ST CD4+ T cells contained mRNA transcripts encoding IL-12Rbeta1 and beta2, and expressed detectable levels of these 2 subunits on the cell surface. Their IL-12R expression was markedly augmented by costimulation with anti-CD3 Ab and IL-18. In contrast, IL-18Ralpha was expressed on freshly isolated PB CD4+ T cells from RA patients and controls, and the level of expression was higher in RA. IL-18Ralpha+ CD4+ T cells were further increased in the ST lesion, where IL-18Rbeta mRNA was constitutively detected. IL-12Rbeta1 and beta2 were induced mainly on IL-18Ralpha+ CD4+ T cells after anti-CD3 Ab stimulation. PMA and A23187-activated ST CD4+ T cells mostly expressed IL-18Ralpha and produced high levels of IFN-gamma. CONCLUSION: These results indicate that IL-18R-expressing CD4+ T cells are accumulated in the ST of patients with RA, where the functional IL-12R is locally induced by stimuli such as CD3 activation and IL-18. Activation of both cytokine receptors may be necessary for the IFN-gamma-dominant cytokine response.
20217661 Pes planovalgus in RA: a descriptive and analytical study of foot function determined by g 2003 Mar OBJECTIVE: To compare gait and foot function between rheumatoid arthritis (RA) patients with painful pes planovalgus deformity and healthy age- and sex-matched adults. METHODS: Gait analysis was undertaken in 23 RA patients (14 female and 9 male, mean age 52.3 years, mean disease duration 6.6 years) and 23 healthy adults (14 female and 9 male, mean age 49.5 years). Gait measurements included temporal and spatial parameters, plantar pressures and three-dimensional (3D) kinematics at the ankle joint complex (AJC). The mean differences between the groups and associated confidence intervals were calculated using the t distribution. RESULTS: RA patients showed longer gait cycle (mean difference 0.15 sec and 0.14 sec for right and left limbs, respectively) and double-limb support times (mean difference 8.3% and 7.9% for right and left limbs, respectively), shorter stride length (mean difference -0.31 m for right and left limbs), slower walking speed (mean difference -0.39 m/sec) and lower cadence (mean difference -16.6 steps/min). In comparison with the normal group, RA patients had greater AJC dorsi/plantarflexion range of motion (ROM) (mean difference 5.7 ( degrees )) and inversion/eversion ROM (mean difference 2.9 ( degrees )). The frontal plane position of the AJC was more everted at specific stance periods (mean difference at heel strike -2.4 ( degrees ) and at midstance -4.0( degrees )). Furthermore, both the peak eversion (mean difference -4.1 ( degrees )) and summated eversion motion as a function of time (mean difference -313.9 ( degrees )) were greater in the RA group. The pes planovalgus foot in RA was characterized by increases in peak pressure (mean difference 34.3 kPa), pressure-time integral (mean difference 18.2 kPa.sec), peak force (mean difference 1.7 N), force-time integral (mean difference 0.7 N.sec), contact time (mean difference 9.8% roll over process) and contact area (mean group difference 3.4 cm(-2)) in the medial midfoot. Further changes in the load pattern in the forefoot were observed in the RA patients, namely increases in the peak pressure (mean difference 96.4 kPa), pressure-time integral (mean difference 58.4 kPa.sec), and contact area (mean difference 1.7 cm(-2)) in the medial forefoot region and reduction in contact area (mean difference -3.9 cm(-2)), peak force (mean difference -7.2 N) and force-time integral (mean difference -1.6 N.sec) in the lateral forefoot. CONCLUSIONS: Painful pes planovalgus deformity in RA is associated with global changes in gait, and localized structural and functional changes in the foot which can be accurately measured using clinical gait analysis.
11854121 Advanced glycation end products activate endothelium through signal-transduction receptor 2002 Feb 19 BACKGROUND: The products of nonenzymatic glycation and oxidation of proteins, the advanced glycation end products (AGEs), form under diverse circumstances such as aging, diabetes, and kidney failure. Recent studies suggested that AGEs may form in inflamed foci, driven by oxidation or the myeloperoxidase pathway. A principal means by which AGEs alter cellular properties is through interaction with their signal-transduction receptor RAGE. We tested the hypothesis that interaction of AGEs with RAGE on endothelial cells enhances vascular activation. METHODS AND RESULTS: AGEs, RAGE, vascular cell adhesion molecule-1, intercellular adhesion molecule-1, and E-selectin are expressed in an overlapping manner in human inflamed rheumatoid synovia, especially within the endothelium. In primary cultures of human saphenous vein endothelial cells, engagement of RAGE by heterogeneous AGEs or Nepsilon(carboxymethyl)lysine-modified adducts enhanced levels of mRNA and antigen for vascular cell adhesion molecule-1, intercellular adhesion molecule-1, and E-selectin. AGEs increased adhesion of polymorphonuclear leukocytes to stimulated endothelial cells in a manner reduced on blockade of RAGE. CONCLUSIONS: AGEs, through RAGE, may prime proinflammatory mechanisms in endothelial cells, thereby amplifying proinflammatory mechanisms in atherogenesis and chronic inflammatory disorders.
12782719 Inhibition of interleukin 10 signaling after Fc receptor ligation and during rheumatoid ar 2003 Jun 2 Interleukin-10 (IL-10) is a potent deactivator of myeloid cells that limits the intensity and duration of immune and inflammatory responses. The activity of IL-10 can be suppressed during inflammation, infection, or after allogeneic tissue transplantation. We investigated whether inflammatory factors suppress IL-10 activity at the level of signal transduction. Out of many factors tested, only ligation of Fc receptors by immune complexes inhibited IL-10 activation of the Jak-Stat signaling pathway. IL-10 signaling was suppressed in rheumatoid arthritis joint macrophages that are exposed to immune complexes in vivo. Activation of macrophages with interferon-gamma was required for Fc receptor-mediated suppression of IL-10 signaling, which resulted in diminished activation of IL-10-inducible genes and reversal of IL-10-dependent suppression of cytokine production. The mechanism of inhibition involved decreased cell surface IL-10 receptor expression and Jak1 activation and was dependent on protein kinase C delta. These results establish that IL-10 signaling is regulated during inflammation and identify Fc receptors and interferon-gamma as important regulators of IL-10 activity. Generation of macrophages refractory to IL-10 can contribute to pathogenesis of inflammatory and infectious diseases characterized by production of interferon-gamma and immune complexes.
15026583 Efficacy and safety of leflunomide 10 mg versus 20 mg once daily in patients with active r 2004 Jun OBJECTIVE: To compare the efficacy and safety profile of two daily maintenance doses of leflunomide, 10 mg and 20 mg, for the treatment of active rheumatoid arthritis (RA). METHODS: In this multinational, randomized, double-blind, parallel-group study, 402 RA patients were randomized equally to receive daily doses of 10 mg leflunomide (n = 202; loading dose on day 3, 100 mg) or 20 mg leflunomide (n = 200; loading dose on day 1-3, 100 mg) for 24 weeks. The study was designed to demonstrate non-inferiority of the efficacy of 10 mg compared with 20 mg by calculating 95% confidence intervals for differences in changes in tender joint count (TJC), swollen joint count (SJC) and Health Assessment Questionnaire Disability Index (HAQ DI), comparing these confidence intervals with predefined bounds. RESULTS: In the intent-to-treat population, mean improvements at the end-point in the 10 and 20 mg groups respectively were: TJC, -7.57 and -8.89 (P = 0.061); SJC, -6.38 and -6.96 (P = 0.304); and HAQ DI, 0-0.37 and 0-0.49 (P = 0.095). By American College of Rheumatology (ACR) > or =20% criteria, response rates were 49.8 and 56.6% respectively (P = 0.1724). Adverse events (AEs) resulting in treatment withdrawal were higher in the 10 mg (15.3%) than in the 20 mg treatment group (12.0%), as were serious adverse events (SAEs): 12.9 vs 10.0%. CONCLUSIONS: This study rejected the hypothesis of non-inferiority of 10 mg compared with 20 mg daily maintenance doses of leflunomide. More AEs resulting in treatment discontinuation and SAEs in patients receiving 10 mg leflunomide daily also support a better efficacy profile for the 20 mg daily dose.
12960349 Soluble IL-6 receptor governs IL-6 activity in experimental arthritis: blockade of arthrit 2003 Sep 15 Studies in IL-6-deficient (IL-6(-/-)) mice highlight that IL-6 contributes to arthritis progression. However, the molecular mechanism controlling its activity in vivo remains unclear. Using an experimental arthritis model in IL-6(-/-) mice, we have established a critical role for the soluble IL-6R in joint inflammation. Although intra-articular administration of IL-6 itself was insufficient to reconstitute arthritis within these mice, a soluble IL-6R-IL-6 fusion protein (HYPER-IL-6) restored disease activity. Histopathological assessment of joint sections demonstrated that HYPER-IL-6 increased arthritis severity and controlled intrasynovial mononuclear leukocyte recruitment through the CC-chemokine CCL2. Activation of synovial fibroblasts by soluble IL-6R and IL-6 emphasized that these cells may represent the source of CCL2 in vivo. Specific blockade of soluble IL-6R signaling in wild-type mice using soluble gp130 ameliorated disease. Consequently, soluble IL-6R-mediated signaling represents a promising therapeutic target for the treatment of rheumatoid arthritis.
15266215 Effects of the cyclooxygenase-2 specific inhibitor valdecoxib versus nonsteroidal antiinfl 2004 Jul There have been concerns that the risk of cardiovascular thrombotic events may be higher with cyclooxygenase (COX)-2-specific inhibitors than nonselective nonsteroidal antiinflammatory drugs (NSAIDs). We evaluated cardiovascular event data for valdecoxib, a new COX-2-specific inhibitor in approximately 8000 patients with osteoarthritis and rheumatoid arthritis treated with this agent in randomized clinical trials. The incidence of cardiovascular thrombotic events (cardiac, cerebrovascular and peripheral vascular, or arterial thrombotic) was determined by analyzing pooled valdecoxib (10-80 mg daily), nonselective NSAID (diclofenac 75 mg bid, ibuprofen 800 mg tid, or naproxen 500 mg bid) and placebo data from 10 randomized osteoarthritis and rheumatoid arthritis trials that were 6-52 weeks in duration. The incidence rates of events were determined in all patients (n = 7934) and in users of low-dose (< or =325 mg daily) aspirin (n = 1051) and nonusers of aspirin (n = 6883). Crude and exposure-adjusted incidences of thrombotic events were similar for valdecoxib, NSAIDs, and placebo. The risk of serious thrombotic events was also similar for each valdecoxib dose. Thrombotic risk was consistently higher for users of aspirin users than nonusers of aspirin (placebo, 1.4% vs. 0%; valdecoxib, 1.7% vs. 0.2%; NSAIDs, 1.9% vs. 0.5%). The rates of events in users of aspirin were similar for all 3 treatment groups and across valdecoxib doses. Short- and intermediate-term treatment with therapeutic (10 or 20 mg daily) and supratherapeutic (40 or 80 mg daily) valdecoxib doses was not associated with an increased incidence of thrombotic events relative to nonselective NSAIDs or placebo in osteoarthritis and rheumatoid arthritis patients in controlled clinical trials.