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ID PMID Title PublicationDate abstract
15535831 Infliximab therapy in rheumatoid arthritis and ankylosing spondylitis-induced specific ant 2004 Treatment of rheumatoid arthritis (RA) with infliximab (Remicade) has been associated with the induction of antinuclear autoantibodies (ANA) and anti-double-stranded DNA (anti-dsDNA) autoantibodies. In the present study we investigated the humoral immune response induced by infliximab against organ-specific or non-organ-specific antigens not only in RA patients but also in patients with ankylosing spondylitis (AS) during a two-year followup. The association between the presence of autoantibodies and clinical manifestations was then examined. The occurrence of the various autoantibodies was analyzed in 24 RA and 15 AS patients all treated with infliximab and in 30 RA patients receiving methotrexate but not infliximab, using the appropriate methods of detection. Infliximab led to a significant induction of ANA and anti-dsDNA autoantibodies in 86.7% and 57% of RA patients and in 85% and 31% of AS patients, respectively. The incidence of antiphospholipid (aPL) autoantibodies was significantly higher in both RA patients (21%) and AS patients (27%) than in the control group. Most anti-dsDNA and aPL autoantibodies were of IgM isotype and were not associated with infusion side effects, lupus-like manifestations or infectious disease. No other autoantibodies were shown to be induced by the treatment. Our results confirmed the occurrence of ANA and anti-dsDNA autoantibodies and demonstrated that the induction of ANA, anti-dsDNA and aPL autoantibodies is related to infliximab treatment in both RA and AS, with no significant relationship to clinical manifestations.
12522051 Simultaneous detection of 15 human cytokines in a single sample of stimulated peripheral b 2003 Jan Cytokines secreted by cells of the immune system can alter the behavior and properties of immune or other cells. At a site of inflammation, sets of cytokines interact with immune cells, and their combined effect is often more important than the function of one isolated component. Conventional techniques, such as enzyme-linked immunosorbent assays, generally require large quantities of cells to characterize a complete cytokine profile of activated lymphocytes. The Bio-Plex system from Bio-Rad Laboratories combines the principle of a sandwich immunoassay with the Luminex fluorescent-bead-based technology. We developed a multiplex cytokine assay to detect different cytokines simultaneously in culture supernatant of human peripheral blood mononuclear cells stimulated with antigen and with mitogen. Fifteen human cytokines (interleukin 1alpha [IL-1alpha], IL-1beta, IL-2, IL-4, IL-5, IL-6, IL-8, IL-10, IL-12p70, IL-13, IL-15, IL-17, IL-18, gamma interferon, and tumor necrosis factor alpha) were validated with a panel of healthy individuals, rheumatoid arthritis patients, and juvenile idiopathic arthritis patients. Comparing the multiplex assay with a regular enzyme-linked immunosorbent assay technique with this donor panel resulted in correlation coefficients for all cytokines ranging from 0.75 to 0.99. Intra-assay variance proved to be less then 10%, whereas interassay variability ranged between 10 and 22%. This multiplex system proved to be a powerful tool in the quantitation of cytokines. It will provide a more complete picture in differences between activated lymphocyte cytokine profiles from healthy individuals and those from patients with chronic inflammatory diseases.
12620173 What are the risks of long-term NSAIDs and COX-2 inhibitors? 2003 Mar This review presents an interesting new analysis of cyclo-oxygenase-2 (COX-2) inhibitor safety, concluding that long-term use results in more serious adverse events than traditional nonsteroidal anti-inflammatory drugs (NSAIDs). The nonsystematic and retrospective properties of this analysis limit its validity. However, the fact that an evaluation of long-term data found some small harm to COX-2 inhibitors relative to traditional NSAIDs (number needed to harm=78 over 9 months) should give clinicians pause. Until better meta-analyses or new safety data are published, clinicians should prescribe COX-2 inhibitors long-term only for those patients deemed to be at high risk of ulcer complications.
14531954 Lessons learned in the use of tumor necrosis factor-alpha inhibitors in the treatment of r 2003 Aug Tumor necrosis factor-alpha (TNFa) plays a central role in rheumatoid arthritis (RA) pathogenesis. There are currently three available anti-TNFa agents for the treatment of RA--adalimumab, etanercept, and infliximab. These targeted therapies have select advantages over traditional disease-modifying antirheumatic drugs (DMARDs), agents that have long been the mainstay of RA treatment. Compared with conventional DMARDs, TNFa inhibitors display a rapid onset of action and have shown a significant effect in retarding the radiographic joint destruction that often characterizes RA disease progression. Although anti-TNFa drugs represent an important advance in RA treatment, postmarketing reports of serious infections, as well as other adverse events, highlight the need for continued postmarketing vigilance with the use of these agents. This review evaluates the unique attributes of the available TNFa inhibitors, focusing specifically on recent reports providing important insight into the understanding of drug-related efficacy and toxicity.
12115219 Treatment of rheumatoid arthritis with methotrexate and hydroxychloroquine, methotrexate a 2002 May OBJECTIVE: To compare the efficacy of combination therapy with methotrexate (MTX) and hydroxychloroquine (HCQ), MTX and sulfasalazine (SSZ), and MTX, HCQ, and SSZ in patients with rheumatoid arthritis (RA). METHODS: RA patients (n = 171) who had not previously been treated with combinations of the study medications were randomized to receive 1 of the 3 treatment combinations in this 2-year, double-blind, placebo-controlled protocol. HCQ was given at a dosage of 200 mg twice a day. The dosage of MTX was accelerated from 7.5 mg/week to 17.5 mg/week in all patients who were not in remission. Similarly, the dosage of SSZ was escalated from 500 mg twice a day to 1 gm twice a day in patients who were not in remission. The primary end point of the study was the percentage of patients who had a 20% response to therapy according to the American College of Rheumatology (ACR) criteria at 2 years. RESULTS: Intent-to-treat analysis revealed that patients receiving the triple combination responded best, with 78% achieving an ACR 20% response at 2 years, compared with 60% of those treated with MTX and HCQ (P = 0.05) and 49% of those treated with MTX and SSZ (P = 0.002). Similar trends were seen for the ACR 50% response, with 55%, 40%, and 29% of patients in the 3 treatment groups, respectively, achieving these results at 2 years (P = 0.005 for the triple combination group versus the MTX and SSZ group). All combination treatments were well-tolerated. Fourteen patients (evenly distributed among the 3 groups) withdrew from the protocol because of symptoms that were potentially related to the study medication. CONCLUSION: The triple combination of MTX, SSZ, and HCQ is well-tolerated, and its efficacy is superior to that of the double combination of MTX and SSZ and is marginally superior to that of the double combination of MTX and HCQ.
11920335 Bucillamine induces membranous glomerulonephritis. 2002 Apr A variety of renal histopathologic lesions, such as amyloidosis, mesangial proliferative glomerulonephritis, and membranous glomerulonephritis (MGN), are associated with rheumatoid arthritis (RA). Bucillamine (BCL), a disease-modifying antirheumatic drug, has a chemical structure and side-effect profile similar to that of d-penicillamine, which can induce MGN in RA. There are a few reports of MGN occurring in association with BCL treatment. However, lacking detailed analyses of immunoglobulin deposition in glomerular lesions, these studies did not elucidate the pathogenesis of BCL-induced MGN. We evaluated seven biopsy specimens from six patients with RA who had undergone BCL treatment with a mean BCL dose of 72.5 g before the appearance of proteinuria. Light microscopic evaluation showed mild to moderate mesangial proliferation. Two biopsy specimens showed spikes along glomerular capillary walls. Granular deposition of immunoglobulin G (IgG) along glomerular capillary walls was seen in all cases, and five specimens showed deposition of IgG2 and/or IgG3 components, in addition to IgG4. Furthermore, subepithelial dense deposits were distributed segmentally in four biopsy specimens on electron microscopy. IgG4, reported to be the predominant IgG subclass deposited, is distributed diffusely in idiopathic MGN. Thus, there were obvious differences between BCL-induced and idiopathic MGN in regard to both IgG subclasses deposited and deposition pattern within the glomerulus. Because IgG3 has the strongest affinity for C1q, these findings suggest that BCL-induced MGN activates the classical pathway more efficiently than idiopathic MGN and that the pathogenesis is different between these two diseases.
15500109 [Sivelestat sodium hydrate was effective for ARDS in a patient suffering from chronic rheu 2004 Sep Sivelestat sodium hydrate (ELASPOL) was effective for ARDS in a fifty-year-old female patient suffering from chronic rheumatoid arthritis with acute exacerbation, after failing to respond to high dose steroid pulse therapy. In ICU, the patient had bilateral lung opacities, especially of the upper lobes, respiratory acidosis, hypercapnea (PaCO2 89 mmHg), and poor oxygenation (P/F ratio 193). High dose steroid pulse therapy had been performed, but oxygenation was not improved, and a low level of oxygenation (P/F ratio 155) persisted. Sivelestat was started two days after finishing the steroid pulse therapy. The butterfly shadow on chest X ray and impaired oxygenation were markedly improved from the third day of sivelestat administration. Respiratory support was terminated with P/F ratio 300. Plasma concentrations of SP-A and SP-D decreased after sivelestat administration, but concentration of KL-6 was still elevated. In this case, sivelestat was effective for ARDS in the patient not responding to steroid pulse therapy, and clinical finding and plasma concentrations of SP-A and SP-D were correlated well.
15361391 Predominance of Th1 cytokine in peripheral blood and pathological tissues of patients with 2004 Oct OBJECTIVE: To determine the type 1 T helper (Th1)/type 2 T helper (Th2) balance in the peripheral blood (PB) and pathological tissues of patients with active untreated adult onset Still's disease (AOSD). METHODS: The percentages of interferon gamma (IFNgamma)- and interleukin (IL)4-producing Th cells in the PB of 20 patients with active untreated AOSD, 20 patients with active rheumatoid arthritis (RA), and 20 healthy controls were determined by intracellular staining and flow cytometry. Serum levels of IL18 and soluble IL2 receptor were measured by enzyme linked immunosorbent assay. Levels of IFNgamma and IL4 messenger (m) RNA expression were examined by real time quantitative polymerase chain reaction in biopsy specimens of evanescent rash and synovitis from 8 patients with AOSD. RESULTS: Significantly higher IFNgamma-producing Th cells and Th1/Th2 ratio in PB were found in patients with AOSD than in healthy controls. Percentages of IFNgamma-producing Th cells and Th1/Th2 ratio in PB correlated significantly with clinical activity score and serum IL18 levels in patients with AOSD. Increased ratio of Th1/Th2 cytokine transcripts was seen in the biopsy specimens of evanescent rash and synovitis from patients with AOSD compared with normal skin controls and patients with OA. Th cell cytokine pattern in PB and cytokine mRNA expression in synovium were similar for patients with AOSD and with RA. After 3 months' treatment, clinical remission was associated with a marked decrease in the percentages of cytokine-producing Th1 cells, but not of the Th2 cells. CONCLUSION: A predominance of Th1 cytokine may precipitate the pathogenesis of AOSD.
12913938 Expression of granzyme B in human articular chondrocytes. 2003 Aug OBJECTIVE: To investigate the expression of granzyme B (GrB) in normal and rheumatoid arthritis (RA) articular cartilage, and to analyze the relationship between the expression of GrB and apoptotic chondrocytes in RA cartilage. METHODS: Normal cartilage samples were obtained from 9 resected joints and RA cartilage samples were obtained from 12 patients with RA during joint replacement surgery. Cartilage sections were analyzed by immunohistochemistry for the presence of GrB, and the mRNA expression of GrB in chondrocytes was analyzed by in situ hybridization and nonquantitative and semiquantitative reverse transcriptase-polymerase chain reaction (RT-PCR). The expression of perforin (PFN) was also assessed. Apoptotic chondrocytes were detected using TUNEL staining and their morphology was examined using electron microscopy. RESULTS: The immunohistochemical analyses revealed GrB and PFN expression in normal chondrocytes and a larger number of GrB and PFN-positive chondrocytes in RA cartilage. In situ hybridization and RT-PCR confirmed the expression of GrB and PFN mRNA, and semiquantitative RT-PCR showed elevated concentrations of GrB and PFN expression in RA chondrocytes. The distribution of GrB and PFN-positive cells in the RA cartilage samples was similar to that of apoptotic cells. CONCLUSION: GrB and PFN expression is present in normal human articular chondrocytes and elevated in RA chondrocytes. The targets and precise functions of GrB expressed in chondrocytes remain to be determined, but GrB may be involved in the remodeling mechanism of matrix macromolecules and the endogenous degradation of RA cartilage.
12064793 Up-regulation of CD11a (LFA-1) expression on peripheral CD4+ T cells in primary biliary ci 2002 Jun Up-regulation of CD11a expression on CD4+ T lymphocytes is considered to be one of the mechanisms involved in the initiation of the Th-1-mediated immune response. In this study, peripheral blood mononuclear cells from patients with primary biliary cirrhosis (PBC) were evaluated for CD11a(high) CD2(low) T cells and populations of type 1 (Th-1) and type 2 (Th-2) helper T cells. CD11a(high) CD2(low) T cells were found in PBC (7/15) and in active rheumatoid arthritis (4/4), but not in chronic hepatitis C (0/5) or in healthy subjects (0/6). The population of Th-1 had a positive correlation with that of CD4+ CD11a(high) CD2+ cells in patients with PBC (P = 0.034). The serum levels of interferon-gamma also had a weak correlation with the population of CD4+ CD11a(high) CD2(low) cells (P = 0.050). There was no statistically significant correlation of Th-2 population (P = 0.295) or serum interleukin-4 level (P = 0.685) with the population of CD4+ CD11a(high) CD2(low) cells. These results suggest that CD4+ CD11a(high) cells play a role in Th-1-predominance and in the autoimmune process of PBC.
12707342 Naive T cell recruitment to nonlymphoid tissues: a role for endothelium-expressed CC chemo 2003 May 1 Naive T cells are usually excluded from nonlymphoid tissues. Only when such tertiary tissues are subjected to chronic inflammation, such as in some (but not all) autoimmune diseases, are naive T cells recruited to these sites. We show that the CCR7 ligand CC chemokine ligand (CCL)21 is sufficient for attracting naive T cells into tertiary organs. We performed intravital microscopy of cremaster muscle venules in T-GFP mice, in which naive T cells express green fluorescent protein (GFP). GFP(+) cells underwent selectin-dependent rolling, but no firm adherence (sticking). Superfusion with CCL21, but not CXC chemokine ligand 12, induced integrin-dependent sticking of GFP(+) cells. Moreover, CCL21 rapidly elicited accumulation of naive T cells into sterile s.c. air pouches. Interestingly, a second CCR7 ligand, CCL19, triggered T cell sticking in cremaster muscle venules, but failed to induce extravasation in air pouches. Immunohistochemistry studies implicate ectopic expression of CCL21 as a mechanism for naive T cell traffic in human autoimmune diseases. Most blood vessels in tissue samples from patients with rheumatoid arthritis (85 +/- 10%) and ulcerative colitis (66 +/- 1%) expressed CCL21, and many perivascular CD45RA(+) naive T cells were found in these tissues, but not in psoriasis, where CCL21(+) vessels were rare (17 +/- 1%). These results identify endothelial CCL21 expression as an important determinant for naive T cell migration to tertiary tissues, and suggest the CCL21/CCR7 pathway as a therapeutic target in diseases that are associated with naive T cell recruitment.
11940234 Association of antigen specificity and migratory capacity of memory T cells in rheumatoid 2002 Mar Among the T cell pool of multiple specificities in the rheumatoid synovial tissues (ST) we have previously shown a lack of proliferative response of T cells to Acanthamoeba polyphaga [1]. In contrast, peripheral blood (PB) derived T cells proliferate to the antigen. The aim of the present study was to establish whether there is a preferential migration of some T cell specificities to the joint in rheumatoid arthritis (RA) patients dependent on the chemokine system, and to identify which chemokine receptors are involved in the migratory process. For this purpose, PB-derived T cell lines and clones from RA patients specific for A. polyphaga, herpes simplex virus (HSV) and Campylobacter jejuni were developed. Their migratory capacities towards ST-derived chemokine supernatants were analysed. Expression of CCR1, CCR2, CCR5, CCR6, CCR7, CXCR3 and CXCR4 were analysed by FACS, and attracting chemokines were identified by blocking studies. We found that the migratory capacities of T cells specific for C. jejuni and HSV were markedly higher against synovial chemokines than T cells specific for A. polyphaga. CCR5 and CXCR3 were expressed by all high-migrating T cell lines and clones. CCR2 was expressed at higher levels on the high-migrating T cell lines compared with the low-migrating A. polyphaga lines. Neutralization of RANTES (regulated upon activation normal T cell expressed and secreted) in the ST cell-derived supernatant reduced T cell migration of all T cell lines and clones by 60-90%, while neutralization of MCP-1 reduced the migratory capacity of CCR2-expressing T cells by 45-80%. In conclusion, the ability of T cells to migrate towards chemokines produced by ST cells is associated with the T cell specificity. Blocking of single chemokines substantially reduced the migratory capacity of memory T cells to ST cell-derived supernatant indicating unique roles for each chemokine receptor in the process of T cell migration.
15996569 [Current concepts on the physiopathology of adult-onset Still's disease]. 2005 Jul PURPOSE: Adult-onset Still's disease (AOSD) is a rare systemic inflammatory disorder of unknown origin. It is characterized by hectic fever, evanescent rash, polyarthralgias or polyarthritis, sore throat, hepatosplenomegaly, lymphadenopathy, polynuclear leukocytosis, liver cytolysis, and high serum level of ferritin with low glycosylated fraction. CURRENT KNOWLEDGE AND KEY POINTS: An increased serum level of ferritin, IL-8, IL-6, IL-18 and TNF-alpha indicates that macrophages are highly activated in AOSD. Interleukin 18 (IL-18) seems to be a key cytokine in the pathogenesis of AOSD. Serum IL-18 levels are increased in AOSD patients compared to other systemic inflammatory diseases such as rheumatoid arthritis and they are well correlated with serum ferritin levels and disease activity. IL-18 could cause acute liver injury and arthritis. Macrophages could be activated by infectious agents such as viruses and by an inadequate control of T cell response secondary to depressed Natural Killer lymphocyte function, similarly to that observed in systemic juvenile idiopathic arthritis. Sustained macrophage activation can lead to the hemophagocytic syndrome, a severe complication of both AOSD and systemic juvenile idiopathic arthritis. FUTURE PROSPECTS: Cytotoxic cell functions should be probably studied in AOSD as they were in the hemophagocytic syndrome and systemic juvenile idiopathic arthritis because AOSD, characterised by a marked macrophage activation may be related to an immunological deficiency.
12465029 Glycopeptide specificity of helper T cells obtained in mouse models for rheumatoid arthrit 2002 Dec 2 Five protected analogues of beta-D-galactosyl-(5R)-5-hydroxy-L-lysine were prepared, in which the galactosyl moiety was modified by monodeoxygenation or inversion of stereochemistry at C-4. The building blocks were used in the solid-phase synthesis of a set of glycopeptides related to the peptide fragment CII256-273 from type II collagen. Evaluation of the glycopeptides revealed that T-cell hybridomas obtained in collagen-induced arthritis (CIA), which is a common mouse model for rheumatoid arthritis, recognized the galactosyl moiety with high specificity for individual hydroxy groups. Moreover, T-cell hybridomas obtained in a humanized variant of CIA were also found to recognize the glycopeptides in an equally carbohydrate-specific manner. The results allowed the generation of models of the complexes formed between the appropriate class II major histocompatibility complex (MHC) molecule, glycopeptide, and the T-cell receptor, that is, of an interaction that is critical for the stimulation of T cells in the arthritis models. In the structural models, peptide side chains anchor the glycopeptide in pockets in the class II MHC molecule, whereas the galactosylated hydroxylysine residue forms the key contacts with the T-cell receptor. Importantly, the results also suggest that a T-cell response towards glycopeptide fragments from type II collagen could play an important role in the development of rheumatoid arthritis in humans.
12444152 A potent and selective nonpeptide antagonist of CXCR2 inhibits acute and chronic models of 2002 Dec 1 Much evidence implicates IL-8 as a major mediator of inflammation and joint destruction in rheumatoid arthritis. The effects of IL-8 and its related ligands are mediated via two receptors, CXCR1 and CXCR2. In the present study, we demonstrate that a potent and selective nonpeptide antagonist of human CXCR2 potently inhibits (125)I-labeled human IL-8 binding to, and human IL-8-induced calcium mobilization mediated by, rabbit CXCR2 (IC(50) = 40.5 and 7.7 nM, respectively), but not rabbit CXCR1 (IC(50) = >1000 and 2200 nM, respectively). These data suggest that the rabbit is an appropriate species in which to examine the anti-inflammatory effects of a human CXCR2-selective antagonist. In two acute models of arthritis in the rabbit induced by knee joint injection of human IL-8 or LPS, and a chronic Ag (OVA)-induced arthritis model, administration of the antagonist at 25 mg/kg by mouth twice a day significantly reduced synovial fluid neutrophils, monocytes, and lymphocytes. In addition, in the more robust LPS- and OVA-induced arthritis models, which were characterized by increased levels of proinflammatory mediators in the synovial fluid, TNF-alpha, IL-8, PGE(2), leukotriene B(4), and leukotriene C(4) levels were significantly reduced, as was erythrocyte sedimentation rate, possibly as a result of the observed decreases in serum TNF-alpha and IL-8 levels. In vitro, the antagonist potently inhibited human IL-8-induced chemotaxis of rabbit neutrophils (IC(50) = 0.75 nM), suggesting that inhibition of leukocyte migration into the knee joint is a likely mechanism by which the CXCR2 antagonist modulates disease.
14770029 Systemic inflammatory diseases and silicone breast prostheses: report of a case of adult s 2004 Feb There has been a debate about the possibility of a link between silicone breast implants and the onset of systemic connective tissue diseases (eg, scleroderma, systemic lupus erythematosus, rheumatoid arthritis) and other inflammatory pathologies, such as silicone implant associated syndrome and adult Still disease. We report a case of adult Still disease in a patient with a silicone gel breast implant. The disease regressed with steroidal treatment, and the patient is now no longer steroid-dependent, although the implant is still in place.
14558081 Monitoring by rheumatologists for methotrexate-, etanercept-, infliximab-, and anakinra-as 2003 Oct OBJECTIVE: To determine what monitoring protocols rheumatologists use to identify adverse events in rheumatoid arthritis (RA) patients treated with methotrexate (methotrexate), etanercept (etanercept), infliximab (infliximab), and anakinra (anakinra), how often rheumatologists encounter treatment-altering adverse events in their RA patients receiving these treatments, and how they feel about and comply with the current monitoring guidelines. METHODS: Three hundred ten physician members of the American College of Rheumatology (ACR) were notified by e-mail of a survey that was posted on our rheumatology Web site. Questions were closed-ended and multiple choice in format. RESULTS: One hundred twenty-three responses were received (40%). Most rheumatologists reported that they utilize the ACR recommended screening tests at baseline before methotrexate treatment is initiated. Seventy-nine percent reported that treatment-altering abnormalities had occurred in <5% of their methotrexate-treated RA patients, and 88% reported that such abnormalities had occurred in <10% of such patients, in the previous 3 years. Forty-one percent believed liver function monitoring guidelines need to be changed; 59% said they would agree with new guidelines that would include a recommendation for liver function monitoring every 3-4 months. Most rheumatologists were not aware of any guidelines for monitoring by blood tests in RA patients treated with biologic agents, yet the majority reported that they order blood tests before patients start these therapies and on followup. CONCLUSION: Our survey indicates that treatment-altering liver function abnormalities in methotrexate-treated RA patients are rare, and more than half of rheumatologists agree that a less stringent monitoring regimen should be considered. Rheumatologists and pharmaceutical companies might work together to develop guidelines for monitoring of patients treated with biologic agents.
15167967 Induction of cyclooxygenase-1 in cultured synovial cells isolated from rheumatoid arthriti 2004 Jun OBJECTIVE AND DESIGN: The aim of this study was to confirm the involvement of cyclooxygenase (COX)-1 in rheumatoid arthritis (RA). MATERIALS AND SUBJECTS: Synovial cells isolated from arthritic patients were cultured primarily and consecutively for 8 passages. TREATMENT: The cultured synovial cells were incubated with 10 ng/ml of interleukin-1alpha (IL-1alpha) for 6 h. METHODS: The effects of either COX-1 or COX-2 selective inhibitor on prostaglandin E2 (PGE2) production was estimated by enzyme-linked immunosorbent assay (ELISA) and the expression of COX-1 and COX-2 were determined by Western blotting and immunocytochemistry. RESULTS: IL-1alpha-induced PGE2 production in synovial cells isolated from RA in primary culture was inhibited by mofezolac, a selective inhibitor of COX-1, as well as NS-398, a specific inhibitor of COX-2. The similar inhibitory patterns were obtained in the RA-derived synovial cells within 3 passages. However, COX activity in the RA-derived synovial cells after 5 passages was inhibited by NS-398, but not by mofezolac. In contrast, COX activity in primary and consecutively cultured synovial cells isolated from osteoarthritis (OA) or normal arthritis was inhibited by NS-398, but not by mofezolac. Western blot and immunocytochemical analyses of COX-1 and COX-2 in the synovial cells isolated from RA patients within 3 passages showed an induction in both COX-1 and COX-2 expression by IL-1alpha. The induction of both COX-1 and COX-2 was inhibited by dexamethasone. CONCLUSIONS: These experiments demonstrate COX-1 induction in synovial cells isolated from RA patients, suggesting that COX-1 is involved in the progression of RA.
15272075 Critical role for granulocyte colony-stimulating factor in inflammatory arthritis. 2004 Aug 3 Granulocyte colony-stimulating factor (G-CSF) is a well known regulator of granulopoiesis, but the role of endogenous G-CSF in inflammatory joint disease has not been explored. We studied the response of G-CSF-deficient mice in experimental models of joint inflammation. We show that G-CSF deficiency protects mice from acute and chronic arthritis. Reduced severity was associated with blunted mobilization of granulocytic cells from the bone marrow and less cellular infiltrate and cellular activation in inflamed joints. We also demonstrate that G-CSF blockade in established collagen-induced arthritis in WT mice markedly reduces disease manifestations and is as effective as tumor necrosis factor blockade. Our results reveal a critical role for G-CSF in driving joint inflammation and highlight G-CSF as a potential therapeutic target in inflammatory joint diseases, such as rheumatoid arthritis.
12811506 Generation of three-dimensional pannus-like tissues in vitro from single cell suspensions 2004 Mar Using single cell suspensions from synovial fluid cells of arthritis patients, we observed differentiation of three-dimensional tissues in vitro. This new model of pannus-like tissue (PLT) might be useful to study pannus tissue formation and differentiation. In the PLT cultures, we observed two cell types, fibroblast-like and macrophage-like cells, defined by their distinct morphology and major histocompatibility complex (MHC) by human leukocyte antigen (HLA) class II expression. We could discriminate several intermediate steps of differentiation which finally led to 3D villi-like structures. Secretion of interferon gamma, interleukin-10, and tumor necrosis factor alpha was measured in the culture supernatants. Using methotrexate at various concentrations, the growth of PLT could be inhibited. We describe definite intermediate steps of differentiation. The present approach could be a suitable model for the in vitro study of pannus tissue formation.