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ID PMID Title PublicationDate abstract
10886401 Interleukin-15 up-regulates the expression of CD154 on synovial fluid T cells. 2000 Jun To investigate the role of the CD40-CD154 interaction in rheumatoid arthritis (RA), we analysed the expression of CD154 on CD3+ and CD4+ T cells in synovial fluid (SF) from patients with RA and in peripheral blood (PB) from patients and normal controls. As interleukin (IL)-15 is a potent activator of synovial T cells we wanted to study whether IL-15 also regulated the expression of CD154 on these T cells. Freshly isolated synovial T cells did not express significant levels of CD154, as evaluated using flow cytometry, whereas the expression of CD86 and human leucocyte antigen (HLA)-DR was significantly elevated on SF T cells when compared with PB T cells from patients or controls. Synovial T cells could up-regulate their CD154 expression following activation with phorbol 12-myristate 13-acetate (PMA) + ionomycin or anti-CD3 + anti-CD28 monoclonal antibodies (mAbs), but the maximal level of expression remained lower than in control T cells. IL-15 significantly increased the expression of CD154 on SF and PB T cells from patients, whereas IL-2 had minimal effects. Furthermore, IL-15 induced extensive proliferation in SF T cells. Our results show that SF T cells up-regulate the expression of CD154 in the presence of IL-15, a cytokine present in the synovium of patients with RA. These results further emphasize the role of IL-15 in the pathogenesis of RA.
9225870 T cell receptor (V beta) bias in the response of rheumatoid arthritis synovial fluid T cel 1997 T cell receptor (V beta) use in the response to type II collagen and cartilage proteoglycans was analysed in peripheral blood and synovial fluid T cells from RA patients. T cells from RA patients with an immune response to connective tissue antigens, and paired PB and SF samples were stimulated in vitro with type II collagen, high density aggrecan proteoglycans (PG), and the T cell mitogen concanavalin A. After short term culture, mRNA was extracted from cells and a reverse transcription-polymerase chain reaction was performed, using primers specific for eight TCR V beta determinants. Blood cells stimulated with ConA generated strong bands with virtually all the V beta primers tested, but the TCR (V beta) expression by SF T cells stimulated with mitogen was biased, suggesting a selection process during joint infiltration. The V beta phenotypes of cells responding to PG was restricted in individual RA patients, but the pattern of V beta use in the the RA population was not consistent. In contrast, the V beta phenotypes of SF cells responding to CII was highly biased in both individual patients and the RA population, with V beta 14, V beta 17, and V beta 8 phenotypes predominant. We conclude that the T cell response to connective tissue antigens is restricted compared with mitogen stimulation, with the highest degree of TCR bias seen in the response of SF T cells to stimulation with type II collagen.
11212173 Regulation of angiogenesis by the C-X-C chemokines interleukin-8 and epithelial neutrophil 2001 Jan OBJECTIVE: Angiogenesis, the growth of new blood vessels, is vital to the ingress of inflammatory leukocytes in rheumatoid arthritis (RA) synovial tissue and to the growth and proliferation of RA pannus. The factors that mediate the growth of new blood vessels have not been completely defined. This study examined the ability of Glu-Leu-Arg (ELR)-containing chemokines to induce angiogenesis in the RA joint. METHODS: To reflect angiogenic activity in vivo, we selected a model using whole human synovial tissue rather than isolated cells. Tissues were examined by immunohistochemistry and enzyme-linked immunosorbent assay, and tissue homogenates were immunoneutralized and assayed for their ability to induce endothelial cell chemotaxis and rat corneal neovascularization. RESULTS: Cells expressing interleukin-8 (IL-8) and epithelial neutrophil activating peptide 78 (ENA-78) were located in proximity to factor VIII-related antigen-immunopositive endothelial cells. RA homogenates produced more IL-8 and ENA-78 compared with normal synovial tissue homogenates. Moreover, homogenates from RA synovial tissue produced significantly more chemotactic activity for endothelial cells in vitro and angiogenic activity in the rat cornea in vivo than did normal synovial tissue homogenates. The effects of IL-8 and ENA-78 accounted for a significant proportion of the chemotactic activity of endothelial cells and angiogenic activity found in RA synovial tissue homogenates. CONCLUSION: These results indicate that the ELR-containing chemokines IL-8 and ENA-78 are important contributors to the angiogenic activity found in the inflamed RA joint. It is possible that efforts aimed at down-regulating these chemokines offer a novel targeted therapy for the treatment of RA.
11558558 Characterization of secretory type IIA phospholipase A2 (sPLA2-IIA) as a glycyrrhizin (GL) 2001 Sep By means of heparin-affinity and glycyrrhizin (GL)-affinity column chromatographies (HPLC), a GL-binding phospholipase A2 (gbPLA2) was selectively purified from the synovial fluids of patients with rheumatoid arthritis. This purified gbPLA2 was identified as a secretory type IIA PLA2 (sPLA2-IIA) since it was crossreacted with anti-sPLA2-IIA serum. The activity of purified sPLA2-IIA was inhibited by glycyrrhetinic acid (GA) and a GA derivative (oGA) in a dose-dependent manner, but it was more sensitive to GA than GL. Furthermore, it was found that (i) purified sPLA2-IIA is phosphorylated by casein kinase II (CK-II) in vitro; (ii) this phosphorylation induces in a significant stimulation of PLA2 activity; and (iii) oGA at one-tenth the concentration of GL inhibits the CK-II-mediated stimulation of sPLA2-IIA activity. These results show that (i) sPLA2-IIA is a GL-binding protein; and (ii) CK-II mediates stimulation of its PLA2 activity in vitro.
11304658 Cox-2-specific inhibitors: definition of a new therapeutic concept. 2001 Jan Nonsteroidal anti-inflammatory drugs have been a mainstay in the treatment of inflammatory diseases such as rheumatoid arthritis. However, these agents can result in severe and occasionally life-threatening adverse effects that can limit therapeutic benefit. Progress toward safer anti-inflammatory therapy was aided by the discovery that cyclooxygenase (COX) exists as two isozymes, COX-1 and COX-2. Both isozymes form prostaglandins that support physiologic functions; however, the formation of proinflammatory prostaglandins is catalyzed by COX-2. Inhibition of COX-2 accounts for the anti-inflammatory and analgesic action of NSAIDs; however, concurrent inhibition of COX-1 inhibits prostaglandin-dependent mechanisms such as gastroduodenal mucosal defense and platelet aggregation. This inhibition is the basis of the gastrointestinal toxicity and bleeding characteristic of these drugs. These findings led to the hypothesis that agents that selectively inhibit COX-2 would possess anti-inflammatory and analgesic action but would spare COX-1, thereby avoiding adverse effects in the gastrointestinal tract and platelets. Selective COX-2 inhibitors are now available. The novelty of these agents has raised questions in the medical community as to what constitutes selectivity for COX-2. This review outlines the criteria that must be met to characterize a compound as COX-2-specific. Clinical evidence of clear improvement in gastrointestinal tolerability and safety must be demonstrated in addition to complementary evidence of COX-2 selectivity obtained from enzyme, biochemical, and clinical pharmacology evaluations.
9701291 The mammalian homologue of Prp16p is overexpressed in a cell line tolerant to Leflunomide, 1998 Aug Prp2p, Prp16p, Prp22p, and Prp43p are members of the DEAH-box family of ATP-dependent putative RNA helicases required for pre-mRNA splicing in Saccharomyces cerevisiae. Recently, mammalian homologues of Prp43p and Prp22p have been described, supporting the idea that splicing in yeast and man is phylogenetically conserved. In this study, we show that a murine cell line resistant to the novel immunoregulatory drug Leflunomide (Arava) overexpresses a 135-kDa protein that is a putative DEAH-box RNA helicase. We have cloned the human counterpart of this protein and show that it shares pronounced sequence homology with Prp16p. Apart from its N-terminal domain, which is rich in RS, RD, and RE dipeptides, this human homologue of Prp16p (designated hPrp16p) is 41% identical to Prp16p. Significantly, homology is not only observed within the phylogenetically conserved helicase domain, but also in Prp16p-specific sequences. Immunofluorescence microscopy studies demonstrated that hPrp16p co-localizes with snRNPs in subnuclear structures referred to as speckles. Antibodies specific for hPrp16p inhibited pre-mRNA splicing in vitro prior to the second step. Thus, like its yeast counterpart, hPrp16p also appears to be required for the second catalytic step of splicing. Taken together, our data indicate that the human 135-kDa protein identified here is the structural and functional homologue of the yeast putative RNA helicase, Prp16p.
9002011 Chloroquine and hydroxychloroquine equally affect tumor necrosis factor-alpha, interleukin 1997 Jan OBJECTIVE: The efficacy of both chloroquine and hydroxychloroquine in rheumatoid arthritis (RA) has been proved in controlled clinical trials. Despite similar chemical characteristics, it is believed the clinical efficacy of chloroquine is superior to that of hydroxychloroquine in patients with RA. Excessive production of proinflammatory cytokines was shown to contribute to the pathogenesis of RA. From different studies testing either chloroquine or hydroxychloroquine, it could be concluded that both drugs differentially inhibit cytokine production. METHODS: We compared the effects of both chloroquine and hydroxychloroquine on stimulated peripheral blood mononuclear cells (PBMC) with respect to cytokine production. Therefore, PBMC were tested for tumor necrosis factor-alpha (TNF-alpha), interleukin 6 (IL-6), and interferon-gamma (IFN-gamma) by specific ELISA, after stimulation with phytohemagglutinin (PHA) or lipopolysaccharide (LPS) in the presence or absence of different concentrations of chloroquine or hydroxychloroquine. RESULTS: We observed that chloroquine and hydroxychloroquine equally inhibit PHA induced TNF-alpha and IFN-gamma production, and LPS induced TNF-alpha and IL-6 production, while PHA induced IL-6 production was not affected. CONCLUSION: Chloroquine and hydroxychloroquine display similar effects on PHA and LPS induced cytokine production by PBMC under identical in vitro conditions. These findings may help in understanding the mechanism of action of these drugs on RA.
11826744 [New basic therapeutic drugs from the viewpoint of evidence-based therapy]. 2001 Dec Leflunomide, infliximab and etanercept belong to a new generation of disease-modifying antirheumatic drugs: they achieve a sustained improvement of clinical as well as biochemical parameters of the disease activity. Consecutively, indices of life quality become better and they are essentially able to prevent structural joint damage. The therapeutic rating of these new agents in early and advanced RA compared to the commonly used DMARDs and combination therapies has to be evaluated in further trials. Controlled studies are the basis of evidence-based therapy. But also the daily clinical experience as well as costs of therapy may have an impact on decision making. The focus of antirheumatic therapy should be on the achievement of an early and sustained remission in RA patients.
10688389 Tolerability and efficacy of nabumetone and naproxen in the treatment of rheumatoid arthri 2000 Jan OBJECTIVE: The purpose of this study was to compare the tolerability and efficacy of nabumetone and naproxen in the treatment of patients with rheumatoid arthritis (RA). The occurrence of gastrointestinal (GI) adverse events was compared. BACKGROUND: Nonsteroidal anti-inflammatory drugs (NSAIDs) have similar efficacy at equipotent doses, but the therapeutic response to various NSAIDs often differs in individual patients. METHODS: This was a 3-month, randomized, double-blind, multicenter, parallel-group study conducted in adult patients with RA. The study had 2 phases: a 3- to 14-day washout period and a 12-week treatment period. During the treatment phase, the tolerability and efficacy of nabumetone 2000 mg/d were compared with those of naproxen 1000 mg/d. The change from baseline in efficacy variables, including global assessments, number of tender or swollen joints, and pain, was evaluated. The study was sized to provide an 80% power to detect a 15% difference in the percentage improvement on the physician's global assessment (alpha = 0.05). GI safety was assessed by monitoring the occurrence of clinically important adverse GI events. RESULTS: A total of 346 RA patients at 31 US rheumatology centers were randomly assigned to treatment (173 patients per group). The study population was predominantly white (87.0%) and female (70.5%), with a mean age of 54 years. Both treatments improved the signs and symptoms of RA, with no statistically significant differences between groups for any efficacy variables. No serious GI adverse events occurred with either NSAID. The most frequent treatment-related adverse events in both groups were predominantly GI in origin, as were those that resulted in withdrawal from the study. Diarrhea with lower abdominal pain was the most common adverse event in the nabumetone group; upper abdominal pain was the most common adverse event in the naproxen group. The only significant difference between the 2 groups was a higher incidence of diarrhea (P < 0.01) in patients receiving nabumetone. CONCLUSIONS: Nabumetone 2000 mg/d was as effective as naproxen 1000 mg/d in relieving the signs and symptoms of RA. In this study, no serious GI adverse events were observed with either NSAID, but nabumetone was associated with a higher incidence of diarrhea.
9418624 Survivorship of cemented total knee arthroplasty. 1997 Dec The survivorship method of analysis was used to compare the failure rate and overall success of 2629 cemented primary total knee arthroplasties during a 22-year period by the senior surgeon. There were 215 Total Condylar prostheses with a polyethylene tibia, 265 of the Posterior Stabilized type with an all polyethylene tibia, 2036 Posterior Stabilized with a metal backed tibial component, 49 Posterior Stabilized with modular augmented components, and 64 with the Constrained Condylar system. Failure was considered revision or planned revision. The Total Condylar series had an average annual failure rate of 0.46% and a 21-year success rate of 90.77%. The Posterior Stabilized prosthesis with an all polyethylene tibia had an average annual rate of failure of 0.38% and a 16-year success rate of 94.10%, and this prosthesis with a metal backed tibial component had an annual failure rate of 0.14% and a 14-year success rate of 98.10%. The Posterior Stabilized series with modular components had an average annual rate of failure of 0.59% and a 10-year success rate of 93.63%. The Constrained Condylar knee series had an average annual failure rate of 0.26% and a 7-year success rate of 98.12%. This review represents a retrospective analysis of consecutive series of cemented, total knee arthroplasties, whose annual failure and success rates were done during differing time spans. The overall success rate was not influenced by gender, age, diagnosis, or percentage of ideal body weight. Failure was considered revision or planned revision. The best and worse case scenarios were calculated for each series. Long term results of cemented, total knee arthroplasty with a relatively conforming articular surface has been shown to be a reliable procedure with excellent survivorship.
9079801 Cytokine stimulation of T lymphocytes regulates their capacity to induce monocyte producti 1997 Mar Previous studies in the laboratory have shown that the pro-inflammatory cytokine tumor necrosis factor (TNF)-alpha plays a pivotal role in the pathogenesis of rheumatoid arthritis (RA). The mechanisms involved in regulating monocyte/macrophage cytokine production are not yet fully understood, but are thought to involve both soluble factors and cell/cell contact with other cell types. We and others have previously demonstrated that T cells activated through the T cell receptor/CD3 complex induce monocyte TNF-alpha production by contact-mediated signals. In this report, we investigated further whether T cells activated by cytokines in the absence of T cell receptor stimulation also regulate monocyte cytokine production. T cells were activated in an antigen-independent manner using the cytokines interleukin (IL)-15 or IL-2 alone, or in combination with IL-6 and TNF-alpha. Subsequently, T cells were fixed and incubated with monocytes. Fixed, cytokine-stimulated T cells induced monocytes to secrete TNF-alpha in a dose-dependent manner, but did not induce secretion of IL-10, a potent endogenous down-regulator of TNF-alpha and other pro-inflammatory cytokines. Stimulation of monocyte TNF-alpha was markedly inhibited when T cells were physically separated from monocytes within the tissue culture well, confirming that T cell contact is necessary. T cell acquisition of monocyte-activating capacity was shown to be dependent on the period of cytokine stimulation, with T cells activated for 8 days more effective than T cells activated for shorter periods. Addition of interferon-gamma or granulocyte/macrophage colony-stimulating factor to the T cell/monocyte cultures enhanced T cell induction of monocyte TNF-alpha by threefold and ninefold, respectively. The results from this model of cognate interaction suggest that cytokine-stimulated T cells, interacting with macrophages in the rheumatoid synovial membrane, may contribute to the continuous excessive production of TNF-alpha observed in the RA joint, and to the imbalance of pro-inflammatory cytokines over anti-inflammatory cytokines.
11299057 IL-17 derived from juxta-articular bone and synovium contributes to joint degradation in r 2001 The origin and role of IL-17, a T-cell derived cytokine, in cartilage and bone destruction during rheumatoid arthritis (RA) remain to be clarified. In human ex vivo models, addition of IL-17 enhanced IL-6 production and collagen destruction, and inhibited collagen synthesis by RA synovium explants. On mouse cartilage, IL-17 enhanced cartilage proteoglycan loss and inhibited its synthesis. On human RA bone explants, IL-17 also increased bone resorption and decreased formation. Addition of IL-1 in these conditions increased the effect of IL-17. Blocking of bone-derived endogenous IL-17 with specific inhibitors resulted in a protective inhibition of bone destruction. Conversely, intra-articular administration of IL-17 into a normal mouse joint induced cartilage degradation. In conclusion, the contribution of IL-17 derived from synovium and bone marrow T cells to joint destruction suggests the control of IL-17 for the treatment of RA.
9427064 Glucocorticoid modulation of human monocyte/macrophage function: control of TNF-alpha secr 1997 Nov Glucocorticoids suppress many functions in activated monocyte/macrophages, including the release of TNF-alpha. This is likely to contribute to the efficacy of glucocorticoids in some inflammatory diseases, such as rheumatoid arthritis, where TNF-alpha contributes to pathogenesis. Glucocorticoids suppress the activity of reporters which include TNF-alpha promoter regions and modify the activity of NF-kappa B family transcription factors in activated human monocytic cell lines, suggesting effects of glucocorticoids on TNF-alpha gene transcription. In addition, glucocorticoids have been reported to antagonise the enhanced translational efficiency of TNF-alpha mRNA which occurs at least after stimulation of murine monocytic cells. It is likely, therefore, that glucocorticoids act at several points in stimulated monocyte/ macrophages to reduce TNF-alpha secretion. Understanding glucocorticoid control of TNF-alpha secretion may explain some of the variability in response to GC in inflammatory diseases and may reveal means of inducing glucocorticoid-like anti-inflammatory effects in monocyte/macrophages without exposing other tissues to the adverse effects of glucocorticoids.
9751091 Preliminary study of the safety and efficacy of SC-58635, a novel cyclooxygenase 2 inhibit 1998 Sep OBJECTIVE: To investigate the efficacy and safety of SC-58635 (celecoxib), an antiinflammatory and analgesic agent that acts by selective cyclooxygenase 2 (COX-2) inhibition and is not expected to cause the typical gastrointestinal (GI), renal, and platelet-related side effects associated with inhibition of the COX-1 enzyme. METHODS: Four phase II trials were performed: a 2-week osteoarthritis efficacy trial, a 4-week rheumatoid arthritis efficacy trial, a 1-week endoscopic study of GI mucosal effects, and a 1-week study of effects on platelet function. RESULTS: The 2 arthritis trials identified SC-58635 dosage levels that were consistently effective in treating the signs and symptoms of arthritis and were distinguished from placebo on standard arthritis scales. In the upper GI endoscopy study, 19% of subjects receiving naproxen (6 of 32) developed gastric ulcers, whereas no ulcers occurred in subjects receiving SC-58635 or placebo. The study of platelet effects revealed no meaningful effect of SC-58635 on platelet aggregation or thromboxane B2 levels, whereas aspirin caused significant decreases in 2 of 3 platelet aggregation measures and thromboxane B2 levels. In all 4 trials, SC-58635 was well tolerated, with a safety profile similar to that of placebo. CONCLUSION: SC-58635 achieves analgesic and antiinflammatory efficacy in arthritis through selective COX-2 inhibition, without showing any evidence of 2 of the toxic effects of COX-1 inhibition associated with nonsteroidal antiinflammatory drugs.
11491492 Intra-articular injection of hyaluronate (SI-6601D) improves joint pain and synovial fluid 2001 Jul OBJECTIVE: The relationship between clinicalfeatures and biochemical parameters of synovialfluid after serial intra-articular injections of sodium hyaluronate (SI-6601D) was investigated. METHODS: SI-6601D (sodium hyaluronate with an average molecular weight of 8.4 x 10(5); 25mg/2.5ml/syringe) was injected intra-articularly into the knees of 25 patients with rheumatoid arthritis (RA) every week for 5 consecutive weeks. Clinical and biochemical parameters were monitored before and after injection. Clinicalfindings included pain, as a summation of 3 categories (pain at rest, pain in motion and pain in passive motion, each assessed on a 4-step rating scale), and inflammation, also as a summation of 3 categories (swelling, patellar ballotement and local warmth, each assessed on a 4-step rating scale). Pain on walking of patient was qualitatively assessed by visual analogue scale (VAS). The aspirated volume of synovialfluid (SFV) was recorded and levels of prostaglandin (PG) E2, transforming growth factor beta-1, tumor necrosis factor alpha, interleukin I receptor antagonist, chondroitin 4-sulfate (C4S) and chondroitin 6-sulfate were measured. RESULTS: Significant improvement in pain symptoms (p < 0.0001), inflammation (p < 0.0001), VAS pain (p < 0.001) and SFV (p < 0.05) were observed after the 5 injections. Levels of PGE2 (p < 0.05) and C4S (p < 0.05) in the synovialfluid were significantly decreased. DISCUSSION: SI-6601D improved local clinical symptoms in RA patients by suppressing PGE2 and, therefore, may be a useful treatment for local inflammation in RA.
10339777 Evaluation of the efficacy of etidronate therapy in preventing glucocorticoid-induced bone 1999 Apr The prevention and treatment of glucocorticoid-induced osteoporosis is a major concern for rheumatologists since inflammatory joint disease is among the most common reasons for long-term glucocorticoid therapy. We used a randomized placebo-controlled design to evaluate the efficacy of one-year cyclical etidronate therapy in preventing bone loss in 83 glucocorticoid-treated patients with rheumatoid arthritis, polymyalgia rheumatica, or giant cell arteritis. Glucocorticoid treatment duration was shorter than three months, and the starting dose was greater than 7.5 mg of prednisone-equivalent per day. Etidronate was given according to the standard cyclical schedule, i.e. 400 mg/d for periods of 14 days separated by 76-day intervals during which patients took 500 mg of supplemental calcium per day. The primary evaluation criterion was the change in lumbar spine bone mineral density after one year of etidronate therapy. Bone mineral density decreased by 1.94 +/- 0.61% in the placebo group and increased by 0.86 +/- 0.6% in the etidronate group, yielding a between-group difference of 2.8 +/- 0.86% (P = 0.002). The difference was largest in postmenopausal women (3.38 +/- 1.11%; P = 0.004). At the femoral neck, there was a smaller bone mineral density decrease in the etidronate than in the placebo group, but the difference (1.11 +/- 1.13%) was not statistically significant. The most common side effects were gastrointestinal symptoms and showed no difference between the two groups. Four fractures (including one vertebral fracture) occurred in the placebo group versus two (including one vertebral) in the etidronate group. Etidronate prevents glucocorticoid-induced lumbar spine bone loss in patients with rheumatoid arthritis, polymyalgia rheumatica, or giant cell arteritis.
11596589 Tuberculosis associated with infliximab, a tumor necrosis factor alpha-neutralizing agent. 2001 Oct 11 BACKGROUND: Infliximab is a humanized antibody against tumor necrosis factor alpha (TNF-alpha) that is used in the treatment of Crohn's disease and rheumatoid arthritis. Approximately 147,000 patients throughout the world have received infliximab. Excess TNF-alpha in association with tuberculosis may cause weight loss and night sweats, yet in animal models it has a protective role in the host response to tuberculosis. There is no direct evidence of a protective role of TNF-alpha in patients with tuberculosis. METHODS: We analyzed all reports of tuberculosis after infliximab therapy that had been received as of May 29, 2001, through the MedWatch spontaneous reporting system of the Food and Drug Administration. RESULTS: There were 70 reported cases of tuberculosis after treatment with infliximab, for a median of 12 weeks. In 48 patients, tuberculosis developed after three or fewer infusions. Forty of the patients had extrapulmonary disease (17 had disseminated disease, 11 lymph node disease, 4 peritoneal disease, 2 pleural disease, and 1 each meningeal, enteric, paravertebral, bone, genital, and bladder disease). The diagnosis was confirmed by a biopsy in 33 patients. Of the 70 reports, 64 were from countries with a low incidence of tuberculosis. The reported frequency of tuberculosis in association with infliximab therapy was much higher than the reported frequency of other opportunistic infections associated with this drug. In addition, the rate of reported cases of tuberculosis among patients treated with infliximab was higher than the available background rates. CONCLUSIONS: Active tuberculosis may develop soon after the initiation of treatment with infliximab. Before prescribing the drug, physicians should screen patients for latent tuberculosis infection or disease.
9146015 [Clinical features of Sjögren syndrome]. 1997 Apr Between 1985 and 1995, 134 patients presented to our clinic with complaints of either dry mouth, decreased salivary flow or salivary gland swelling of unknown origin. These patients were diagnosed retrospectively based on the criteria established by the Sjögren's disease research committee (1977), and 30 patients were definitively diagnosed with Sjögren's disease while 23 were considered suspect. The gender distribution of these 30 patients was 25 female (83%) and 5 male (17%). The average patient age was 55.8 years for females and 42.6 years for males. Of 30 patients, 10 (33.3%) had only sicca syndrome and the other 20 (66.7%) had various complications such as collagen diseases, autoimmune diseases, and malignant lymphoid infiltration. Subjects included 14 cases of rheumatoid arthritis (RA), 1 case of systemic lupus erythematosus (SLE), 1 case of RA with periarteritis nodosa (PN), 1 case of progressive systemic sclerosis (PSS) with SLE, 1 case of PSS with Hashimoto disease, 1 case of malignant lymphoma and 1 case of RA with Waldenström's macroglobulinemia. Positive blood tests showed a relatively high incidence of elevated erythrocyte sedimentation ratios (ESR) (75%), elevated IgG levels (69.2%), positive anti-nuclear antibody (52.3%), positive anti SS A antibody (75%) and positive anti-SS B antibody (50%).
11012629 Tumour necrosis factor-alpha (TNF-alpha) enhances lymphocyte migration into rheumatoid syn 2000 Oct Adhesion mechanisms play a major role in the recruitment of peripheral blood lymphocytes (PBL) which characteristically infiltrate rheumatoid arthritis (RA) synovium and other chronically inflamed tissues. Through a sequential series of complex integrated adhesion and signalling events, 'multistep model of migration', specific subsets of PBL are recruited into inflamed tissues. In this process both leucocyte receptors and microvascular endothelial (MVE) counter-receptors play a critical role. The MVE in particular, during an inflammatory state, is the target of various inflammatory mediators that cause the up-regulation of several cell adhesion molecules (CAM). One of the most important factors known to be a powerful inducer of MVE CAM is TNF-alpha. Conversely, blocking TNF-alpha causes a down-modulation of CAM expression. To test directly the capacity of TNF-alpha to induce cell migration into RA synovium we adapted a model in which synovial grafts were implanted into SCID mice subcutaneously. Using this model we demonstrate that: (i) transplants remain viable and become vascularized and fed by mouse subdermal vessels; (ii) the mouse vasculature connects to the transplant vasculature which maintains the ability to express human CAM; (iii) intragraft injections of TNF-alpha up-regulate the expression of human CAM, following the down-regulation which occurred 4 weeks post-transplantation; and (iv) the up-regulation of graft CAM is associated with increased human PBL migration into the transplants. This study provides direct evidence in vivo of the capacity of TNF-alpha to induce cell migration. In addition, it provides the experimental background for the optimal use of this model.
10903334 15-deoxy-delta(12,14)-PGJ(2) induces synoviocyte apoptosis and suppresses adjuvant-induced 2000 Jul Peroxisome proliferator-activated receptors (PPARs) are members of the nuclear hormone receptor superfamily and have a dominant regulatory role in adipocyte and monocyte differentiation. PPAR-gamma agonists are also negative regulators of macrophage activation and have modulatory effects on tumorigenesis. In this study we demonstrate that synovial tissue localized expression of PPAR-gamma in patients with rheumatoid arthritis (RA). We detected markedly enhanced expression of PPAR-gamma in macrophages, as well as modestly enhanced expression in the synovial lining layer, fibroblasts, and endothelial cells. Activation of the PPAR-gamma by 15-deoxy-Delta(12,14)-prostaglandin J(2) (15d-PGJ(2)) and the synthetic PPAR-gamma ligand (troglitazone) induced RA synoviocyte apoptosis in vitro. Moreover, intraperitoneal administration of these PPAR-gamma ligands ameliorated adjuvant-induced arthritis with suppression of pannus formation and mononuclear cell infiltration in female Lewis rats. Anti-inflammatory effects of 15d-PGJ(2) were more potent than troglitazone. These findings suggest that PPAR-gamma may be an important immunoinflammatory mediator and its ligands, especially 15d-PGJ(2), may be useful in the treatment of RA.