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ID PMID Title PublicationDate abstract
11093433 Antiproliferative and antiinflammatory effects of methotrexate on cultured differentiating 2000 Nov OBJECTIVE: We investigated the antiproliferative and antiinflammatory effects of methotrexate (MTX) on differentiating/differentiated cells, namely cultured human monocytic myeloid cells (THP-1), and primary cultures of synovial macrophages from patients with rheumatoid arthritis (RA). METHODS: We evaluated early and late apoptosis as well as natural cytokine inhibitor production, such as the interleukin 1 (IL-1) receptor antagonist (IL-1ra) and the soluble tumor necrosis factor receptor (sTNFr). RESULTS: Within THP-1 cells we observed a significant (p < 0.001) dose-dependent inhibition of proliferation (at 24-48 and 72-96 h) and a significant presence of apoptosis (at 24-48 h) with MTX concentrations of 500, 100, and 75 microg/ml compared with untreated controls. No significant changes were observed with 5 microg/ml or 500 to 50, and 5 ng/ml. A significant increase of IL-1ra (p < 0.001) was observed with MTX concentrations of 5 microg (51.43 +/- 2.53 vs 16.22 +/- 5.19 pg/ml control) and 500 ng (36.43 +/- 3.3 vs 16.22 +/- 5.19 pg/ml control) at all the tested times. No significant changes were observed for the sTNFr p75. Evaluating the RA synovial macrophages, we obtained no significant effects on cell proliferation and apoptosis with MTX treatment at 24 h and at the concentration of 50 microg/ml (achievable in the serum with low dose MTX treatment in RA). No significant changes were observed for the IL-1ra and no detectable levels for the sTNFr p75 were detected after treatment with MTX. CONCLUSION: This study shows that the antiproliferative and antiinflammatory effects of MTX on human cultured monocytes are dose-dependent. The antiproliferative activity seems to be mediated by cell apoptosis and the antiinflammatory activity seems to be related to cytokine inhibitor release.
9182920 The synovial expression and serum levels of interleukin-6, interleukin-11, leukemia inhibi 1997 Jun OBJECTIVE: To determine the expression of interleukin-6 (IL-6), IL-11, leukemia inhibitory factor (LIF), and oncostatin M (OSM) and their major cellular sources in the joints of rheumatoid arthritis (RA) patients, as well as the correlation of circulating levels of these IL-6-type cytokines and C-reactive protein (CRP). METHODS: Messenger RNA (mRNA) and protein levels for IL-6, IL-11, LIF, and OSM were determined by using reverse transcription-polymerase chain reaction and enzyme-linked immunosorbent assay, respectively. RESULTS: Cells isolated from the synovium of RA patients expressed mRNA for IL-6, IL-11, LIF, and OSM at higher levels than did synovial cells from osteoarthritis (OA) patients, and spontaneously released greater quantities of these proteins in culture. Fibroblast cell lines derived from RA synovium were able to produce IL-6, IL-11, and LIF, but not OSM, when stimulated with IL-1 and tumor necrosis factor alpha. OSM was found to be produced spontaneously by synovial tissue macrophages. IL-6, IL-11, LIF, and OSM were present in synovial fluid from the RA patients; levels of IL-6, LIF, and OSM were present in significantly greater quantities in RA patients than in OA patients. However, only IL-6 was significantly elevated in the serum of RA patients and correlated with the serum CRP level, while other IL-6-type cytokines were not detected. CONCLUSION: IL-6, IL-11, LIF, and OSM are all produced in large amounts at the site of disease activity, but IL-6 derived from synovial fibroblasts may be the major hormone-like mediator that induces the hepatic synthesis of acute-phase proteins in RA.
11194886 [Ulcers of the colon in association with nonsteroidal anti-inflammatory drugs (NSAID)--a r 2000 Dec Although adverse side effects of nonsteroidal anti-inflammatory drugs (NSAID) can affect the whole gastrointestinal tract, most reports refer to upper gastrointestinal tract complications. We report on 3 patients with lower gastrointestinal bleeding (patient 1 and 2) respectively detectable fecal blood loss (patient 3) after the use of NSAID. Patient 1 and 3 were taking NSAID over at least 6 months for the treatment of rheumatic diseases while patient 2 reported a single use of 2 g acetylsalicylic acid. Colonoscopy showed a single ulcer of the colon in patients 1 and 2. Due to acute bleeding patient 1 required interventional endoscopic treatment. Colonoscopy of patient 3 revealed multiple colonic ulcerations. Gastroduodenoscopy also detected adverse NSAID-effects on the upper gastrointestinal tract in patient 1 and 3 (ulcers of the stomach, erosive duodenitis). NSAID-medication was discontinued in all patients and, additionally, mesalazine was administered to patient 3. Consecutively, symptoms and lesions disappeared. Our cases stress the clinical importance of NSAID-toxicity distal to the small intestine which may exist concomitantly to lesions of the upper gastrointestinal tract and is not obligatory dose-dependent.
11592358 Two-year, blinded, randomized, controlled trial of treatment of active rheumatoid arthriti 2001 Sep OBJECTIVE: Three 6-12-month, double-blind, randomized, controlled trials have shown leflunomide (LEF; 20 mg/day, loading dose 100 mg x 3 days) to be effective and safe for the treatment of rheumatoid arthritis (RA). This analysis of the North American trial assessed whether the clinical benefit evident at month 12 was sustained over 24 months of treatment with LEF as compared with the efficacy and safety of methotrexate (MTX), an equivalent disease-modifying antirheumatic drug, at 24 months. METHODS: The year-2 cohort, comprising patients continuing into the second year of treatment with > or = 1 dose of study medication and > or = 1 followup visit after week 52, consisted of 235 patients (LEF n = 98; placebo n = 36; MTX n = 101). The mean (+/- SD) maintenance dose of LEF was 19.6 +/- 1.99 mg/day in year 2 and that of MTX was 12.6 +/- 4.69 mg/week. Statistical analyses used an intent-to-treat (ITT) approach. Statistical comparisons of the active treatments only were prospectively defined in the protocol. RESULTS: In total, 85% and 79% of LEF and MTX patients, respectively, who entered year 2 completed 24 months of treatment. From month 12 to month 24, the American College of Rheumatology improvement response rates of > or = 20% (LEF 79% versus MTX 67%; P = 0.049), > or = 50% (LEF 56% versus MTX 43%; P = 0.053), and > or = 70% (LEF 26% versus MTX 20%; P = 0.361) were sustained in both of the active treatment groups. The mean change in total Sharp radiologic damage scores at year 2 compared with year 1 and baseline (LEF 1.6 versus MTX 1.2) showed statistically equivalent sustained retardation of radiographic progression in the active treatment groups. Maximal improvements evident at 6 months in the Health Assessment Questionnaire (HAQ) disability index (HAQ DI) and the physical component score of the Medical Outcomes Survey 36-item short form were sustained over 12 months and 24 months; improvement in the HAQ DI with LEF4(-0.60) was statistically significantly superior to that with MTX (-0.37) at 24 months (P = 0.005). Over 24 months in the ITT cohort, serious treatment-related adverse events were reported in 1.6% of the LEF-treated patients and 3.7% of the MTX-treated patients. Frequently reported adverse events included upper respiratory tract infections, diarrhea, nausea and vomiting, rash, reversible alopecia, and transient liver enzyme elevations. CONCLUSION: The safety and efficacy of LEF and MTX were maintained over the second year of this 2-year trial. Both active treatments retarded radiographic progression over 24 months. LEF was statistically significantly superior to MTX in improving physical function as measured by the HAQ DI over 24 months of treatment. Results indicate that LEF is a safe and effective initial treatment for active RA, with clinical benefit sustained over 2 years of treatment without evidence of new or increased toxicity.
11816834 Etanercept Immunex. 2001 Feb Immunex has developed and launched etanercept, a soluble TNF receptor (TNFR) fusion protein, for the treatment of early and moderate to severely active rheumatoid arthritis (RA). Etanercept was launched as a first-line agent in the US for the treatment of moderate-to-severe active RA in June 2000 [375481]. It can also be used in conjunction with methotrexate (MTX) in patients who do not respond adequately to MTX alone [303266], [310436]. It was launched in the EU in November 2000 [388846]. Enbrel was also launched for the treatment of polyarticular-course juvenile RA (JRA) patients who have an inadequate response to one or more disease-modifying antirheumatic drugs (DMARDs) in May 1999. Additionally, it is in phase III trials for psoriatic arthritis and a BLA filing for this indication is expected for the first half of 2001 [364948]. Etanercept was launched in the US in November 1998, for the treatment of moderate-to-severe RA in patients with inadequate responses to one or more DMARDs, or in combination with MTX in patients who do not respond adequately to MTX alone [306175]. The drug was subsequently approved by the US FDA for use as a first-line therapy to treat patients with moderately to severely active RA [375481]. In February 2000, Wyeth Europe received clearancefor etanercept in 15 EU countries by the EMEA for the treatment of active arthritis in adults when the response to DMARDs has been inadequate [354844]. It has since been launched in the UK (June 2000) [388840], and by October 2000 had been launched in all EU member states [388846]. In November 1998, the company filed a supplemental BLAfor the treatment of children and teenagers with moderately to severely active polyarticular course JRA. In May 1999, etanercept was approvedfor this indication by the US FDA and approvedfor this indication in Europe in February 2000 [307061], [310436], [326379]. The increasing understanding of the role of TNF in a number of other diseases has led to its clinical assessment in these areas. Following positive clinical results in phase II studies [317562], [315793], (320666], (359789], (373980] in patients with chronic heart failure, etanercept entered phase III trials for this indication in June 1999 [330068], and a BLA filing for this indication is expected in 2003 [396110]. Additionally, Immunex initiated a phase III trial of etanercept in psoriatic arthritis in March 2000, and as of May 2000, the company was planning a BLA filing for this indication in the first half of 2001 [364948]. An open-label trialfor the treatment of Crohn's disease is in progress in Belgium [367,039], and results from this trial were presented at Digestive Disease Week in May 2000 [379907]. While WO-09103553 claims the recombinant human receptor, the fusion protein consisting of the etanercept domain and the immunoglobulin region was disclosed in WO-09406476. In February 1997, US-05605690 was issued to Immunex for methods of using etanercept to treat diseases mediated by TNF. The patent also claims methods of using recombinant etanercept to decrease the levels of TNF in RA patients [235456]. In June 1999, Immunex strengthened its patent estate covering the product with a patent licensing agreement for Genentech's immunoadhesin patents covering the product [327250]. A royalty agreement with Serono SA and Immunex on sales of etanercept was agreed in 1999. The agreement reflected the strength of Ares-Serono's intellectual property status [352813]. In June 1999, Lehman Brothers predicted Immunex's sales at US $300 million in 1999, rising to peak annual sales of US $1.5 billion [328701]. Salesfor the drug's first full quarter on the market in 1999 were US $59.7 million [330068]. By November 1999 the drug had made sales of US $500 million; Immunex expects the drug will generate over US $2 billion in annual sales by 2004 [353185]. In September 2000, Merrill Lynch reported that if sales of the drug continue at the present rate then it is likely that demand will temporarily outstrip supply in 2001. Resolution of the supply issue is expected by 2002. Also in September 2000, Merrill Lynch lowered their estimate of ENBREL sales in 2001 from US $1 billion to $927 million. In the long-term, Merrill Lynch believe that the drug has the potential to exceed US $5 billion in sales in the US [382577].
10491033 Advantage of the uncemented total hip system with three spiked socket. 1999 Sep Atotal hip arthroplasty was performed on 112 joints of 110 patients from November 1983 to January 1998 using three different types of uncemented total hip systems with a three spiked socket. The clinical results of 87 joints of 85 patients, followed up 5 years or more after operation, were evaluated with the comparison among the three different types (original type [JIAT] in 6, type Y in 24, and type Y2 in 57). In 73 of the 87 patients, the age at the time of the operation was more than 60. The preoperative diagnosis was osteoarthritis with acetabular hypoplasia in 61, rapidly destructive coxarthrosis in 17, and so on. We have been receiving excellent clinical results of patients who were implanted with type Y2 compared with the other types. There was no different clinical results between patients who were less than 60 and patients who were over 60. Injuries of neurovascular bundle relating to the penetration of the tip of the spike, which was a concern in this type of socket, were not encountered. The type Y2 uncemented total hip system shows an indication of being successful even if the patients have poor bone stock in acetabulum or are elderly.
11290777 Impaired Fas signaling pathway is involved in defective T cell apoptosis in autoimmune mur 2001 Apr 15 Proteoglycan (PG)-induced arthritis (PGIA) is a novel autoimmune murine model for rheumatoid arthritis induced by immunization with cartilage PG in susceptible BALB/c mice. In this model, hyperproliferation of peripheral CD4(+) T cells has been observed in vitro with Ag stimulation, suggesting the breakdown of peripheral tolerance. Activation-induced cell death (AICD) is a major mechanism for peripheral T cell tolerance. A defect in AICD may result in autoimmunity. We report in this study that although CD4(+) T cells from both BALB/c and B6 mice, identically immunized with human cartilage PG or OVA, express equally high levels of Fas at the cell surface, CD4(+) T cells from human cartilage PG-immunized BALB/c mice, which develop arthritis, fail to undergo AICD. This defect in AICD in PGIA may lead to the accumulation of autoreactive Th1 cells in the periphery. The impaired AICD in PGIA might be ascribed to an aberrant expression of Fas-like IL-1beta-converting enzyme-inhibitory protein, which precludes caspase-8 activation at the death-inducing signaling complex, and subsequently suppresses the caspase cascade initiated by Fas-Fas ligand interaction. Moreover, this aberrant expression of Fas-like IL-1beta-converting enzyme-inhibitory protein may also mediate TCR-induced hyperproliferation of CD4(+) T cells from arthritic BALB/c mice. Our data provide the first insight into the molecular mechanism(s) of defective AICD in autoimmune arthritis.
9608331 The role of nitric oxide in articular cartilage breakdown in osteoarthritis. 1998 May It is increasingly appreciated that mediators typically associated with inflammatory arthritis, such as catabolic cytokines and nitric oxide, are produced by synovium and cartilage in osteoarthritis. The role that such mediators play in the progression of cartilage degradation in osteoarthritis is under intensive investigation. Nitric oxide is a highly reactive, cytotoxic free radical that has been implicated in tissue injury in a variety of diseases. Cartilage obtained from patients with osteoarthritis produces significant amounts of nitric oxide ex vivo, even in the absence of added stimuli such as interleukin-1 or lipopolysaccharide. In vitro, nitric oxide exerts detrimental effects on chondrocyte functions, including the inhibition of collagen and proteoglycan synthesis, enhanced apoptosis, and an inhibition of B1 integrin-dependent adhesion to the extra-cellular matrix. This paper reviews recent observations regarding the role of nitric oxide in osteoarthritis and presents evidence suggesting that the inhibition of nitric oxide production could be a desirable future therapeutic strategy.
11055824 Elevated nitric oxide production in patients with primary Sjögren's syndrome. 2000 Nitric oxide (NO) production is elevated in patients with inflammatory disorders. We have previously shown increased NO production in patients with rheumatoid arthritis and systemic lupus erythematosus. In this study we used nitrite and citrulline levels as surrogate markers of NO production in patients with primary Sjögren's syndrome (SS) and measured their levels by spectrophotometry. Fifteen patients and 15 age- and sex-matched controls were studied. Mean nitrite levels in patients were 582.3+/-208.3 nmol/ml, but those in controls were significantly lower, at 203.2-106.9 nmol/ml (p<0.001). Citrulline levels were 2820.4+/-933.9 nmol/ml in patients and were significantly higher than 217.4+/-144.8 nmol/ml, the levels in controls (p<0.0001). Mean levels of both nitrite and citrulline were significantly higher in patients with arthritis than in those who had no joint manifestations (p<0.05). There was no correlation between NO production and other variables, such as age, disease duration, drug therapy and antinuclear antibodies or rheumatoid factor positivity. Increased NO production may be partly a reflection of the presence of arthritis in five patients. It is concluded that there is increased NO production in patients with primary SS, especially if they have associated arthritis.
10048290 Erythropoietin treatment for non-uremic patients: a personal view. 1999 Jan The correction of anemia in patients with chronic renal failure (CRF) has become the most important application of recombinant human erythropoietin (rHuEpo). The merits of rHuEpo therapy in patients with CRF are overt. Firstly, patients with CRF have an absolute deficiency in endogenous erythropoietin production and a relatively low maintenance dose of rHuEpo (often less than 100 IU/kg body weight per week) is effective in avoiding regular transfusions in the majority of the patients with CRF. Secondly, rHuEpo is able to avoid long-term complications of frequent transfusions (hemochromatosis, transfusion-transmissible diseases). Thirdly, patients with uremia notice a considerable improvement in quality of life (QOL) after initiation of rHuEpo. These advantages justify administration of this costly drug in CRF patients. The use of rHuEpo outside the setting of uremia do, however, not cover the complete spectrum of beneficial effects as compared to its use in (pre)dialysis patients. The aim of this overview is to provide some annotations on recently approved (cisplatin-induced anemia, preoperative anemia, zidovudine-related anemia) and possibly future (several types of malignancy and inflammation) indications for rHuEpo in non-uremic patients, leaving out the correction of anemia due to relatively uncommon disorders in the Dutch population (such as sickle cell anemia and thalassemia).
9793376 [Detection of isotype-specific autoantibodies to calpastatin in sera from patients with rh 1998 Aug To detect immunoglobulin isotype-specific autoantibodies to native human calpastatin in patients with rheumatic diseases, we performed immunoblot analysis using the heated HeLa cell extracts to enrich heat-resistant calpastatin. The calpastatin molecule that was apparently migrated to 110 kD by SDS-PAGE was confirmed to react with monoclonal anti-human calpastatin antibody in immunoblotting. IgG antibodies to calpastatin were detected in 22 of 48 sera (46%) from patients with RA, whereas only 20% (5/25), 11% (2/19) and 13% (2/15) of sera from SLE, SSc and PM/DM had IgG anti-calpastatin antibodies, respectively. IgM antibodies were also found in 40% (19/48) of RA and 12% (3/25) of SLE patients but not detected in sera from patients with other rheumatic diseases. IgA antibodies were found in only one RA and one SLE serum. In RA, 7 of 48 sera (15%) had IgM antibodies alone, but all SLE sera with IgM antibodies had IgG antibodies. Thus, anti-calpastatin autoantibodies were detected by using the native human calpastatin. Although these autoantibodies were found in patients with various rheumatic diseases, they were present in RA patients at the highest frequency. In particular, the presence of IgM antibodies appeared to be more specific in RA patients.
11072605 Isotretinoin-induced adult onset Still's disease. 2000 Sep We describe a 21-year old man who was diagnosed as having adult onset Still's disease (AOSD) in association with isotretinoin treatment for acne conglobata. The patient was febrile, with a macular salmon pink rash, arthritis, hepatosplenomegaly, and axial lymphadenopathy. Laboratory results showed leukocytosis, mild liver dysfunction and negative rheumatoid factor and antinuclear antibodies. Isotretinoin, an orally active derivative of vitamin A, has been associated with various rheumatologic conditions such as arthralgia, myalgia, vasculitis and arthritis. The etiology of rheumatic disorders associated with retinoids is still obscure; however, it is presumed that immunomodulation by several mechanisms (such as an alteration of the cytokine balance) is probably ascribable to this interesting association.
9780213 Oxidized alpha2-macroglobulin (alpha2M) differentially regulates receptor binding by cytok 1998 Oct 15 Alpha2M binds specifically to TNF-alpha, IL-1beta, IL-2, IL-6, IL-8, basic fibroblast growth factor (bFGF), beta-nerve growth factor (beta-NGF), platelet-derived growth factor (PDGF), and TGF-beta. Since many of these cytokines are released along with neutrophil-derived oxidants during acute inflammation, we hypothesize that oxidation alters the ability of alpha2M to bind to these cytokines, resulting in differentially regulated cytokine functions. Using hypochlorite, a neutrophil-derived oxidant, we show that oxidized alpha2M exhibits increased binding to TNF-alpha, IL-2, and IL-6 and decreased binding to beta-NGF, PDGF-BB, TGF-beta1, and TGF-beta2. Hypochlorite oxidation of methylamine-treated alpha2M (alpha2M*), an analogue of the proteinase/alpha2M complex, also results in decreased binding to bFGF, beta-NGF, PDGF-BB, TGF-beta1, and TGF-beta2. Concomitantly, we observed decreased ability to inhibit TGF-beta binding and regulation of cells by oxidized alpha2M and alpha2M*. We then isolated alpha2M from human rheumatoid arthritis synovial fluid and showed that the protein is extensively oxidized and has significantly decreased ability to bind to TGF-beta compared with alpha2M derived from plasma and osteoarthritis synovial fluid. We, therefore, propose that oxidation serves as a switch mechanism that down-regulates the progression of acute inflammation by sequestering TNF-alpha, IL-2, and IL-6, while up-regulating the development of tissue repair processes by releasing bFGF, beta-NGF, PDGF, and TGF-beta from binding to alpha2M.
11312119 Interleukin-18 is a unique cytokine that stimulates both Th1 and Th2 responses depending o 2001 Mar IL-18 is a potent proinflammatory cytokine able to induce IFNgamma, GM-CSF, TNFalpha and IL-1 in immunocompetent cells, to activate killing by lymphocytes, and to up-regulate the expression of certain chemokine receptors. IL-18 is also essential to host defences against severe infections. In particular, the clearance of intracellular bacteria, fungi and protozoa requires the induction of host-derived IFNgamma, which evokes effector molecules such as nitric oxide. Also, IL-18 plays a part in the clearance of viruses, partly by the induction of cytotoxic T cells, and the expulsion of viruses is impaired in IL-18-deficient mice. IL-18 also enhances tumour rejection by its potent capacity to augment the cytotoxic activity of NK and T cells in vivo. In contrast, recent studies also demonstrate a convincing role for IL-18 in atopic responses, including atopic asthma. IL-18 induces naive T cells to develop into Th2 cells. Moreover, IL-18 also induces IL-13 and/or IL-4 production by NK cells, mast cells and basophils. Therefore, IL-18 should be seen as a unique cytokine that enhances innate immunity and both Th1- and Th2-driven immune responses.
10955322 Complement mediated vascular endothelial injury in rheumatoid nodules: a histopathological 2000 Aug OBJECTIVE: To evaluate morphologically and immunohistochemically the role of IgM rheumatoid factor (RF) immune complexes and complement activation in rheumatoid nodule vascular injury, a typical extraarticular manifestation of rheumatoid arthritis. METHODS: Histological features such as cellular infiltration, endothelial alteration, fibrinoid degeneration, and basement membrane alterations were observed in the small vessels in rheumatoid nodules. An immunohistochemical study was also carried out. RESULTS: Distinct colocalization of IgM RF and terminal complement complexes (TCC: C5b-9) was observed on the luminal surface in some of the damaged endothelial cells. Immuno-electron microscopy revealed endothelial vesiculation, typical of the in vitro protective mechanism against complement attack, with deposition of not only TCC but also IgM RF. Most TCC positive endothelial cells simultaneously expressed the major complement regulatory factor, CD59. CONCLUSION: These data suggest that, in rheumatoid nodules, vascular injury mediated by complement activation involves the assembly of IgM RF on the endothelial cell surface.
10716877 Regulation of CS1 fibronectin expression and function by IL-1 in endothelial cells. 2000 Feb 25 VLA-4 is a critical adhesion molecule that regulates mononuclear cell trafficking to sites of inflammation. VCAM-1 is a primary ligand of VLA-4, although alternatively spliced fibronectin (FN) containing the CS1 region (CS1 FN) also binds to VLA-4. CS1 FN is expressed by rheumatoid arthritis (RA) synovial endothelial cells, but the factors that regulate CS1 FN expression are not known. We incubated human umbilical vein endothelial cells (HUVEC) with IL-1 (0.1-10 ng/ml) for 8-48 h and determined total FN and CS1 FN mRNA by Northern blot analysis. Both were constitutively expressed by HUVEC, and IL-1 increased total FN mRNA and the CS1-containing isoform (P < 0.05). IL-1 also increased CS1 FN protein expression on HUVEC as determined by Western blot analysis. An adhesion assay using (51)Cr-labeled Jurkat cells and IL-1-stimulated HUVEC was used to determine if IL-1-induced CS1 FN mediates cell binding. Cyclic CS1 peptide (10 microg/ml) blocked 49 +/- 5% of IL-1-induced Jurkat cell adhesion to HUVEC (P < 0.01), whereas anti-VCAM-1 antibody inhibited binding by only 35 +/- 5% (P < 0.01). CS1 peptide and anti-VCAM antibody treatment were not additive (50 +/- 7% inhibition), and 38 +/- 6% of new VLA-4-mediated adhesion to IL-1-treated HUVEC was due to an increase in CS1 FN. These data show that IL-1 increases CS1 FN expression by HUVEC and increases CS1-mediated cell adhesion. CS1 mimetics might have therapeutic efficacy by blocking recruitment of VLA-4-bearing cells.
11212162 Rheumatoid arthritis synovial macrophages express the Fas-associated death domain-like int 2001 Jan OBJECTIVE: The chronic inflammation and progressive joint destruction observed in rheumatoid arthritis (RA) are mediated in part by macrophages. A paucity of apoptosis has been observed in RA synovial tissues, yet the mechanism remains unknown. The present study sought to characterize the expression of Fas, Fas ligand (FasL), and Fas-associated death domain-like interleukin-1beta-converting enzyme-inhibitory protein (FLIP), and to quantify the apoptosis induced by agonistic anti-Fas antibody, using mononuclear cells (MNC) isolated from the peripheral blood (PB) and synovial fluid (SF) of RA patients. METHODS: The expression of Fas, FasL, and FLIP and apoptosis induced by agonistic anti-Fas antibody in MNC from the PB and SF of RA patients were determined by flow cytometry. Immunohistochemistry employing a monospecific anti-FLIP antibody was performed on RA and osteoarthritis (OA) synovial tissue. RESULTS: CD14-positive monocyte/macrophages from normal and RA PB and from RA SF expressed equivalent levels of Fas and FasL. Furthermore, unlike the CD14-positive PB monocytes, RA SF monocyte/macrophages were resistant to the addition of agonistic anti-Fas antibody. In contrast, both CD14-positive PB and SF monocyte/macrophages were sensitive to apoptosis mediated by a phosphatidylinositol 3-kinase inhibitor. Intracellular staining of the caspase 8 inhibitor, FLIP, in CD14-positive SF monocyte/macrophages revealed a significant up-regulation of FLIP compared with normal and RA PB monocytes. Immunohistochemical analysis of synovial tissue from RA and OA patients revealed increased FLIP expression in the RA synovial lining compared with the OA synovial lining. Furthermore, FLIP expression was observed in the CD68positive population in the RA synovial lining. Forced reduction of FLIP by a chemical inhibitor resulted in RA SF macrophage apoptosis that was enhanced by agonistic anti-Fas antibody, indicating that FLIP is necessary for SF macrophage survival. CONCLUSION: These data suggest that up-regulation of FLIP in RA macrophages may account for their persistence in the disease. Thus, the targeted suppression of FLIP may be a potential therapeutic strategy for the amelioration of RA.
10576739 Arthritis provoked by linked T and B cell recognition of a glycolytic enzyme. 1999 Nov 26 The hallmark of rheumatoid arthritis (RA) is specific destruction of the synovial joints. In a mouse line that spontaneously develops a disorder with many of the features of human RA, disease is initiated by T cell recognition of a ubiquitously expressed self-antigen; once initiated, pathology is driven almost entirely by immunoglobulins. In this study, the target of both the initiating T cells and pathogenic immunoglobulins was identified as glucose-6-phosphate isomerase, a glycolytic enzyme. Thus, some forms of RA or related arthritides may develop by a mechanism fundamentally different from the currently popular paradigm of a joint-specific T cell response.
10860137 Treatment options for rheumatoid arthritis: celecoxib, leflunomide, etanercept, and inflix 2000 Jun OBJECTIVE: To review new pharmacologic agents approved for use in the management of rheumatoid arthritis (RA). DATA SOURCES: A MEDLINE search (1966-January 2000) was conducted to identify English-language literature available on the pharmacotherapy of RA, focusing on celecoxib, leflunomide, etanercept, and infliximab. These articles, relevant abstracts, and data provided by the manufacturers were used to collect pertinent data. STUDY SELECTION: All controlled and uncontrolled trials were reviewed. DATA EXTRACTION: Agents were reviewed with regard to mechanism of action, efficacy, drug interactions, pharmacokinetics, dosing, precautions/contraindications, adverse effects, and cost. DATA SYNTHESIS: Traditional pharmacologic treatments for RA have been limited by toxicity, loss of efficacy, or both. Increasing discoveries into the mechanisms of inflammation in RA have led to the development of new agents in hopes of addressing these limitations. With the development of celecoxib, a selective cyclooxygenase-2 inhibitor, the potential exists to minimize the gastrotoxicity associated with nonsteroidal antiinflammatory drugs. Leflunomide has been shown to be equal to or less efficacious than methotrexate, and may be beneficial as a second-line disease-modifying antirheumatic drug (DMARD). The biologic response modifiers, etanercept and infliximab, are alternatives that have shown benefit alone or in combination with methotrexate. However, they should be reserved for patients who fail to respond to DMARD therapy. Further studies should be conducted to evaluate the long-term safety and efficacy of these agents as well as their role in combination therapy. CONCLUSIONS: Celecoxib, leflunomide, etanercept, and infliximab are the newest agents approved for RA. Clinical trials have shown that these agents are beneficial in the treatment of RA; however, long-term safety and efficacy data are lacking.
9041934 Involvement of nuclear factor kappa B in the regulation of cyclooxygenase-2 expression by 1997 Feb OBJECTIVE: To evaluate involvement of the transcription factor nuclear factor kappa B (NF-kappa B) in the increased expression of cyclooxygenase-2 (COX-2) stimulated by interleukin-1 beta (IL-1 beta) in primary rheumatoid synoviocytes. METHODS: We treated early-passage rheumatoid synoviocytes with IL-1 beta and examined the time course of NF-kappa B translocation to the nucleus by Western blot analysis, as well as NF-kappa B binding to the COX-2 promoter/enhancer by electrophoretic mobility shift assay. We correlated the time course of NF-kappa B binding with expression of COX-2 messenger RNA (mRNA) and protein. Synoviocytes were then treated with either sense or antisense phosphorothioate-modified oligonucleotides derived from the transcription start site of the human NF-kappa B p65 RNA. We analyzed NF-kappa B binding to the COX-2 promoter and COX-2 protein levels after these treatments. RESULTS: IL-1 beta rapidly stimulated the translocation of the p65, p50, and c-rel NF-kappa B subunits from the cytoplasm to the nucleus. Electrophoretic mobility shift assay demonstrated binding to 2 NF-kappa B sites within the COX-2 promoter/enhancer, with a time course identical to that of nuclear localization of NF-kappa B. Supershift analysis revealed that binding activity was due primarily to the p65-p50 heterodimer and the p50 homodimer. With appropriate lag time after NF-kappa B binding, COX-2 mRNA and protein were increased. Pretreatment of RA synoviocytes with NF-kappa B p65 antisense oligonucleotides resulted in decreased binding to the COX-2 promoter and decreased COX-2 protein expression. CONCLUSION: These data demonstrate that signaling via the NF-kappa B pathway is involved in regulation of COX-2 expression induced by IL-1 beta in RA synoviocytes.