Browse

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

ID PMID Title PublicationDate abstract
11968556 [Influence of implant position of a hip prosthesis on alignment exemplified by the CLS sha 2002 Jan We performed a clinical and radiological analysis to evaluate the significance of the stem position of cementless CLS components with respect to function and survival. We used patient material from a multi-center study of 3,732 CLS stems with a mean follow-up of 43 months (range: 12-142 months). The clinical outcome was assessed using Merle D'Aubigné Scores and stem alignment was determined as the deviation of the longitudinal stem axis from the longitudinal femur axis. We found no correlation between stem alignment and function, survival, implant migration or periprosthetic radiolucent lines. In patients with rheumatoid arthritis and hip ankylosis the neutral stem position was less often achieved than in patients with other diagnoses. The results of our study cast doubt on whether the varus position of the femoral component of cementless tapered CLS-type stem designs is as critical as in cemented total hip arthroplasty.
15468354 Multisegment foot motion during gait: proof of concept in rheumatoid arthritis. 2004 Oct OBJECTIVE: To test a multisegment foot model for kinematic analysis during barefoot walking in patients with well established rheumatoid arthritis (RA) and foot impairments. METHODS: Five healthy adult subjects and 11 RA patients with advanced disease were studied. Foot impairments were assessed using standardized outcomes and clinical examination techniques. A 6-camera 60 Hz video-based motion analysis system was used to measure motion of the shank, rearfoot, forefoot, and hallux segments and the vertical displacement of the navicular. Face validity and estimates of repeatability were determined. Motion patterns were calculated and comparisons were made between healthy subjects and patients with RA. Relationships between clinical impairment and abnormal motion were determined through inspection of individual RA cases. RESULTS: Across the motion variables, the within-day and between-day coefficient of multiple correlation values ranged from 0.677 to 0.982 for the healthy subjects and 0.830 to 0.981 for RA patients. Based on previous studies, motion parameters for the healthy subjects showed excellent face validity. In RA patients, there was reduced range of motion across all segments and all planes of motion, which was consistent with joint stiffness. In the RA patients, rearfoot motion was shifted towards eversion and external rotation and peak values for these variables were increased, on average, by 7 degrees and 11 degrees, respectively. Forefoot range of motion was reduced in all 3 planes (between 31% and 53%), but the maximum and minimum angles were comparable to normal. The navicular height, during full foot contact, was on average 3 mm lower in the RA patients in comparison to normal. The hallux was less extended in the RA subjects in comparison to normal (21 degrees vs 33 degrees) during the terminal stance phase. Individual cases showed abnormal patterns of motion consistent with their clinical impairments, especially those with predominant forefoot pain or pes planovalgus. CONCLUSION: In RA, multisegment foot models may provide a more complete description of foot motion abnormalities where pathology presents at multiple joints, leading to complex and varied patterns of impairment. This technique may be useful to evaluate functional changes in the foot and to help plan and assess logical, structurally based corrective interventions.
15637808 The assessment of cartilage degradation in vivo: development of an immunoassay for the mea 2004 Nov A monoclonal antibody has been developed which recognizes a neoepitope in type II collagen which is generated by the intrahelical cleavage of collagenases. Antibody reactivity is directed at the carboxyl-terminus of the TCA or 3/4 piece of the degraded alpha1(II) chain. Reactivity is dependent upon hydroxylation of proline. Evidence is provided suggesting that epitope binding involves the recognition of a conformational neoepitope. Using an ELISA, we show that this neoepitope can be detected in the urines and sera of nonarthritic persons and patients with rheumatoid arthritis (RA). An increased content is observed in the sera and urines of patients. The assay may be of value in studying cartilage type II degradation both in vitro and in vivo such as in those with arthritis.
12173276 Clinical experience with cyclooxygenase-2 inhibitors. 2002 Apr Rheumatoid arthritis (RA) and osteoarthritis (OA) are chronic conditions requiring long-term therapy for pain relief. Currently prescribed non-steroidal anti-inflammatory drugs (NSAIDs) provide symptomatic efficacy, but are frequently associated with gastrointestinal (GI) toxicities such as dyspepsia and ulcerations. In a small but significant number of cases, complications including perforations and massive bleeding develop and these may be fatal. A desirable therapeutic strategy would maintain efficacy while minimizing gastric intolerance. Two potential approaches have been suggested: (i) administration of NSAIDs in combination with gastroprotective compounds; or (ii) administration of potentially safer anti-inflammatory compounds which act via selective inhibition of cyclooxygenase-2 (COX-2). The selective COX-2 inhibitors rofecoxib and celecoxib consistently demonstrate efficacy comparable to conventional NSAIDs in patients with RA and OA, but have a significantly reduced propensity to cause GI toxicity. In many cases, the gastric effects of therapeutically active doses of COX-2 inhibitors are indistinguishable from placebo. The safety benefits of COX-2 inhibitors given alone appear similar to combined therapy with conventional NSAIDs and gastroprotective agents. Findings warrant the consideration of COX-2 inhibitors as first-line therapy in patients requiring long-term pain relief.
15170916 Variability of precision in scoring radiographic abnormalities in rheumatoid arthritis by 2004 Jun OBJECTIVE: To determine the extent of precision and sources of variability among experts on scoring radiographic abnormalities in rheumatoid arthritis. METHODS: Radiographic scores from 6 datasets in which 2 or more readers had scored film sets were analyzed. Datasets included scores by 11 different readers, 6 of whom scored films by both the Larsen (global) and Sharp (composite) methods. Scores of each possible combination of 2 readers were compared in calculating the smallest detectable difference (SDD) on raw scores and on scores normalized for each individual reader (nSDD). Intraclass correlation (ICC), Pearson's r, and the correlation between differences in score and their mean scores were determined. Agreement on progression of radiographic damage scores was also examined. RESULTS: Variability among readers was greater than previous studies suggested. Agreement was better for intra- than interreader comparisons; average intrareader SDD was 24.4 for the composite method and 9.0 for the global. The larger SDD for the composite method reflect their greater range of possible scores. When normalized scores were used to adjust for the range difference, there was minimal difference in the SDD; nSDD was 10.1 for the composite method, 8.0 for the global. Interreader variability was larger: SDD of 53.7 for the composite method and 23.3 for the global; nSDD 12.9 and 14.4, respectively. ICC varied between 0.465 and 0.999, with all but one value below 0.925 occurring in composite scores with a range below 100. Differences in repeated scores were frequently associated with the mean of those scores and this was greater for inter- than for intrareader comparisons. Agreement between progression scores showed a similar pattern. The SDD was better for intrareader comparisons and smaller for global scores: compare 13.7 (composite, intrareader) and 5.4 (global, intrareader) to 18.1 (composite, interreader) and 8.7 (global, interreader). The ICC was lower for progression scores than for raw scores, averaging between 0.661 and 0.885. CONCLUSION: The variability in scoring radiographic abnormalities is considerable among this group of 11 expert readers. This has important implications for power calculations in comparison studies such as therapeutic trials and for cross-trial comparisons. The correlation between the difference in repeated scores and their means indicates systematic error (bias), which, if corrected, may improve the detection of treatment effects when using a responder-type analysis. These and other design and analysis issues are discussed.
15693607 Bone lysis and inflammation. 2004 Nov Over the past decade there have been major advances in our understanding of the factors that regulate osteoclast formation and activity. It is now apparent that receptor activator NFkappaB (RANK), its ligand, RANKL (also known as TRANCE, osteoclast differentiation factor and osteoprotegerin (OPG) ligand) and the natural RANKL inhibitor, OPG, are the key factors regulating osteoclast formation in normal bone physiology. The molecular interactions of these molecules regulate osteoclast formation and subsequent bone loss in disease and there is now strong evidence that the bone loss associated with inflammatory diseases, such as rheumatoid arthritis, periodontal disease and peri-implant loosening, is regulated by the action of RANK, RANKL, and OPG. These molecules are targets for the pharmacological regulation of severe bone loss in several common inflammatory diseases.
15560380 [Legionella pneumonia which occurred in a private whirlpool bath user]. 2004 Oct A 88 year old female with active rheumatoid arthritis treated by low dose of prednisolone and methotrexate was admitted to our hospital because of severe bilateral pulmonary infiltration and acute respiratory distress syndrome. On admission, she had consciousness disturbance and was intubated because of severe respiratory failure. We heard from her family of her habit she had taking a private whirlpool bath 2 or 3 times everyday. So, we suspected a Legionella pneumophila infection. We started intravenous erythromycin (EM) (1,500mg/day) and methylprednisolone pulse therapy (1,000mg x 3days) and full controlled mechanical ventilation supported with PEEP. Her respiratory failure was gradually improved and she was discharged on the 44 the hospital day. Legionella pneumophila (serogroup 6) was isolated in her sputum by B-CYE alpha culture. Legionella pneumophila (serogroup 6) was isolated in her private whirlpool bath too. Both samples revealed the same by genetic analysis with pulse field gel electrophoresis (PFGE). This is the first adult case of Legionella pneumophila pneumonia infected from a private whirlpool bath confirmed by genetic analysis. We should always suspect Legionella pneumonia as one of the severe community-acquired pneumonia, because Legionella pneumophila were frequently detected among various water sources including the private whirlpool bath.
12522839 Trajectory of assistive device usage and user and non-user characteristics: long-handled b 2002 Dec 15 OBJECTIVES: To examine use of an assistive device, a long-handled bath sponge (LHBS) in patients with rheumatoid arthritis and osteoarthritis to describe use from the time of in-hospital prescription to the 2- and 12-month followups, and to describe the characteristics of those who became device users and non-users. METHODS: Patients (n = 102) who were prescribed a LHBS during hospitalization were followed prospectively. The clinical and psychosocial assessment included disease, physical and psychosocial factors, and disability. RESULTS: The overall usage rate for the LHBS was 86%. When compared with users, non-users had fewer arthritic joints, perceived greater control over their disability and pain, and had less favorable perceptions of the LHBS. Characteristics that did not differentiate non-users from users were sociodemographic variables, disease duration, movement capability, level of disability and pain, and general perceptions of assistive devices. CONCLUSION: The results support the early identification of patients who are likely to become non-users so that acceptable alternative interventions can be planned.
11879539 Cytokine-stimulated T cells induce macrophage IL-10 production dependent on phosphatidylin 2002 IL-10 is an anti-inflammatory cytokine produced in the joint in rheumatoid arthritis by macrophages and infiltrating blood lymphocytes. Regulation of its expression is poorly understood, but previous findings have suggested that physical interactions with T cells may play a role. This report investigates signalling mechanisms involved in the production of macrophage IL-10 upon interaction with fixed, cytokine-stimulated T cells (Tck). Elutriated monocytes were differentiated to macrophages by macrophage-colony-stimulating factor (M-CSF) and co-cultured with fixed T cells chronically stimulated in a cytokine cocktail of IL-2/IL-6/tumour necrosis factor (TNF)-alpha in the presence or absence of wortmannin and LY294002, inhibitors of phosphatidylinositol 3-kinase (PI3K), or of rapamycin, an inhibitor of p70 S6-kinase (p70S6K). Spontaneous IL-10 production by rheumatoid arthritis synovial-membrane mononuclear cells (RA-SMCs) and co-cultures of rheumatoid arthritis T cells (RA-Ts) and macrophages was also assessed. RA-T and Tck induction of macrophage IL-10 production was suppressed by cell separation and inhibition of PI3K and p70S6K. PI3K involvement was also shown by phosphorylation of the downstream effector protein kinase B. Spontaneous IL-10 production by RA-SMCs was also inhibited by LY294002 and depletion of the nonadherent (T-cell-enriched) fraction of the cell population. IL-10 production in RA-SMCs and M-CSF-primed macrophages, activated by interaction with Tck, is PI3K- and p70S6K-dependent.
15148945 Anakinra: new preparation. Weakly effective in rheumatoid arthritis. 2004 Apr (1) There is no consensus on the best treatment option for rheumatoid arthritis when a first-line agent fails (most often methotrexate). Among the recent immunosuppressants, etanercept should be used before infliximab. (2) Anakinra, an interleukin-1 type 1 receptor antagonist, was recently authorised in the European Union as a second-line treatment for rheumatoid arthritis in combination with methotrexate. (3) There are no published trials comparing anakinra with other slow-acting antirheumatic drugs (especially infliximab and etanercept). In one clinical trial in patients who did not respond adequately to methotrexate, the combination anakinra + methotrexate was more effective than methotrexate + placebo on ACR 20%, ACR 50% and ACR 70% criteria, but the clinical relevance of these results is doubtful. (4) An indirect comparison suggests that etanercept is more effective than anakinra + methotrexate. (5) In a placebo-controlled trial of anakinra, 75% of patients had reactions at the injection site. Serious infections, neutropenia and anti-anakinra antibodies were also reported. There is no evidence that anakinra is any safer than etanercept. (6) Anakinra + etanercept offers no gains in efficacy, just an increased risk of severe infections. (7) Subcutaneous injections of anakinra are required daily (twice-weekly subcutaneous injections for etanercept). (8) In short, there is no argument for using anakinra as a second-line treatment for rheumatoid arthritis; it does not improve disease management.
14644866 Distribution of lymphatic vessels in normal and arthritic human synovial tissues. 2003 Dec OBJECTIVES: To investigate the distribution of lymphatic vessels in normal, rheumatoid arthritis (RA) and osteoarthritis (OA) synovium. METHODS: Synovial tissues from 5 normal controls, 14 patients with RA, and 16 patients with OA were studied. Lymphatic vessels were identified by immunohistochemistry using antibodies directed against the lymphatic endothelial hyaluronan receptor (LYVE-1) and recognised blood vessel endothelial markers (factor VIII, CD34, CD31). RESULTS: Lymphatic vessels were found in all zones of the normal, OA, and RA synovial membrane. Few lymphatic vessels were seen in the sublining zone in normal and OA synovium which did not show villous hypertrophy. However, in both RA synovium and OA synovium showing villous hypertrophy and a chronic inflammatory cell infiltrate, numerous lymphatic vessels were seen in all zones of the synovial membrane, including the sublining zone of the superficial subintima. CONCLUSIONS: Lymphatic vessels are present in normal and arthritic synovial tissues and are more numerous and prominent where there is oedema and an increase in inflammatory cells in the subintima, particularly in RA. This may reflect increased transport of hyaluronan and leucocyte trafficking in inflamed synovial tissues.
15330027 Stability of cemented all-polyethylene keeled glenoid components. A radiostereometric stud 2004 Aug We studied the stability of cemented all-polyethylene keeled glenoid components by radiostereometric analysis (RSA) in 16 shoulders which had received a total shoulder replacement. There were 14 women (one bilateral) and one man with a mean age of 64 years. The diagnosis was osteoarthritis in eight and rheumatoid arthritis in seven. Two of the shoulders were excluded from the RSA study because of loosening of the tantalum markers. Three tantalum markers were inserted in the glenoid socket, two in the coracoid process and two in the acromion. The polyethylene keeled glenoid component was marked with three to five tantalum markers. Conventional radiological and RSA examinations were carried out at five to seven days, at four months and at one and two years after operation. Radiolucent lines were found in all except three shoulders. Migration was most pronounced in the distal direction and exceeded 1 mm in four shoulders. In ten shoulders rotation exceeded 2 degrees in one or more axes with retroversion/anteversion being most common. No correlation was found between migration and the presence of radiolucencies on conventional radiographs.
15181749 [Evaluation of magnetostimulation effectiveness in physiotherapy--questionnaire research]. 2004 The anonymous questionnaires which had been filled in by patients were analysed after the end of the magnetostimulation applied with Viofor JPS. The applicator in form of a mattress with maximum induction 45 microT was used. In the analysed group of 1742 patients, 5% of patients suffered from rheumatoid arthritis, 16% from central nervous system illnesses, 9% from injuries, 1.5% from allergies, 2% from infections, 5.4% from vessel illnesses, 1% from skin illnesses. 0.5% of the patients used monotherapy. 8% suffered from radicular symptoms, 30.7% from pseudoradicular symptoms, 17.4% from arthrosis, and 3.4% patients suffered from migraines and headaches. The complete abatement of complaints or the improvement was noted in 95.5% of patients, no improvement in 4.3% and 0.2% of patients became worse--82% of deteriorated patients were the ones that suffered from infections. The strongest analgesic action and the most frequent abatement were noted in patients after injuries and patients with headaches.
12364634 Repeat-cycle study of high-dose intravenous 4162W94 anti-CD4 humanized monoclonal antibody 2002 Oct OBJECTIVE: Results of an earlier open-label pilot study showed that 4162W94 was a relatively non-depleting anti-CD4 monoclonal antibody that induced >80% down-modulation of CD4 molecules from the surface of T lymphocytes. This placebo-controlled repeat-cycle study was conducted in active rheumatoid arthritis (RA) patients to determine the duration of CD4 blockade required to achieve lasting clinical benefit. METHODS: Following DMARD washout, 48 patients (i.e. three cohorts of 16 patients) with ACR-defined RA were to be dosed with 1 (cohort 1), 2 (cohort 2) or 3 (cohort 3) cycles of 5x300 mg 4162W94 or placebo (12 and 4 patients per cohort respectively) at monthly intervals. There was at least 3 months of follow-up after dosing. Clinical outcome was assessed in evaluable patients (receiving at least 80% of each dose course) using ACR20 criteria (required on two consecutive visits). CD4 lymphocyte counts and adverse events were also monitored. RESULTS: Sixteen patients were dosed in each of the first two cohorts; however, the dose was reduced in cohort 3 after five patients had received up to two dose cycles due to accumulating evidence of a high frequency of skin rash. These patients were analysed according to the number of cycles received. A further eight patients received 5x100 mg for one to three cycles prior to stopping the study for administrative reasons. Four of 13 (P=0.119 vs placebo) and 7/13 (P=0.015 vs placebo) in cohorts 1 and 2 respectively achieved ACR20 response on at least two consecutive occasions. No patient receiving 5x100 mg/day or placebo achieved ACR20. Four patients were still responding at the end of the 3-month follow-up period. CD4 lymphocyte suppression (<0.2x10(9)/l on at least two successive occasions) occurred in 11/34 patients who received 4162W94 vs none on placebo. Rash occurred in 21/34 monoclonal antibody-treated patients, including one case of biopsy-confirmed cutaneous vasculitis and 1/11 placebo patients. CONCLUSION: 4162W94 demonstrated significant clinical efficacy in this study. However, because of unacceptable CD4 lymphopenia and rash, the original hypothesis that prolonged CD4 blockade would give lasting clinical benefit was not tested.
15658544 [Immunological features of rheumatoid arthritis in patients infected with viruses of hepat 2004 AIM: To specify immunological features of rheumatoid arthritis (RA) associated with hepatitis B, C viruses (HBV, HCV) and cryoglobulinemia (CGE). MATERIAL AND METHODS: Four groups of patients with verified RA were examined immunologically: infected with HCV, infected with HBV, with CGE diagnosed by the capillary method, free of HBV, HCV, CGE. CGE was estimated by the spectrophotometric method, functional activity of the complement components--by hemolytic micromethod. Polymerase chain reaction, identification of serological markers of viral hepatitides B and C were conducted with application of commercial kits produced in Russia. RESULTS: In RA patients infected with HBV and HCV, functional activity of the complement was significantly reduced. RA patients with hepatitis C and CGE showed hypoactivity of all the complement components. A classic course of RA was associated with elevated levels of C1 and C3 components in normal values of C1q, C2, C4 and C5 components. CGE was highest in RA+HCV and RA+CGE groups. CONCLUSION: The study of immunological features of RA associated with HCV, HBV and CGE is important not only in scientific but also in practical aspect as it indicates the necessity of treating the above conditions with drugs which do not suppress complement system significantly.
12114282 Somatotropic, lactotropic and adrenocortical responses to insulin-induced hypoglycemia in 2002 Jun Neuroendocrine mechanisms have been suggested to play an important role in the onset and progression of rheumatoid arthritis (RA). The aim of this study was to evaluate hypothalamic-pituitary functions in RA patients by measurement of hormone responses to insulin-induced hypoglycemia. Insulin-hypoglycemia (Actrapid HM 0.1 IU/kg, i.v. as a bolus) was induced in 17 male patients and in 11 age-, gender-, and weight-matched healthy subjects. Concentrations of growth hormone (GH), prolactin (PRL) and cortisol were analyzed in plasma. PRL release after thyreoliberin stimulation (TRH, 200 g, i.v.) was determined in 21 patients with active forms of RA and in 12 control subjects to evaluate pituitary lactotropic response. In RA patients, basal concentrations of glucose, GH, PRL, and cortisol were in the normal range and they were comparable to those in the control group. Stress of hypoglycemia induced significant elevation of GH, PRL, and cortisol concentrations in all groups. Cortisol responses to hypoglycemia were comparable in patients and in control subjects. GH release during hypoglycemia was increased (p < 0.05) and PRL response was attenuated (p < 0.05) in RA patients versus control subjects. After TRH administration, PRL response was the same in patients as in healthy subjects. In conclusion, the present study revealed an altered hypothalamic-pituitary function in patients with RA, namely, an enhanced somatotropic and reduced lactotropic activation in response to insulin-induced hypoglycemia. Basal hormone levels and cortisol release during hypoglycemia were similar to those in healthy subjects.
12632607 [Use of grommet for Swanson flexible hinge toe implant arthroplasty for hallux valgus defo 2002 Dec OBJECTIVES: We reviewed the results of arthroplasty of the great toe with hallux valgus in rheumatoid patients, using a Swanson flexible hinge toe implant protected by grommet. MATERIALS AND METHODS: Sixteen patients (26 feet) with rheumatoid arthritis were operated on from 1996 to 1999. (fifteen women, one man). The average age was 59.8 years (range, 48-73 years). The average follow-up period was 3.0 years (range, 1.0-4.5 years). In each patient, the hallux valgus angle (HVA) was measured before and after surgery, and implant breakage and radiolucency around the implant were evaluated on radiographs. RESULTS: Average HVA was 47.7 degrees preoperatively and 19.3 degrees postoperatively. No implant breakage was observed in 76.9% of the feet. Radiolucency of more than 2 mm was observed in only 3.8% of the feet. CONCLUSIONS: These findings suggest that arthroplasty using a Swanson flexible hinge toe implant with a grommet is useful for treatment of hallux valgus in rheumatoid patients.
14558085 Synovial fluid neutrophils transcribe and express class II major histocompatibility comple 2003 Oct OBJECTIVE: To investigate a potential interaction between neutrophils and T cells in rheumatoid arthritis (RA), by defining the optimal conditions for induction of class II major histocompatibility complex (MHC) expression on peripheral blood neutrophils in vitro and investigating the capacity for neutrophils to express class II MHC molecules in RA. METHODS: Surface expression of class II MHC and costimulatory molecules by peripheral blood and synovial fluid (SF) neutrophils obtained from healthy controls and patients with RA was measured by flow cytometry and fluorescence microscopy. Intracellular class II MHC protein and messenger RNA (mRNA) were detected by Western blotting and Northern blotting, respectively. RESULTS: Freshly isolated peripheral blood neutrophils from controls did not express surface class II MHC; expression was induced by culture with appropriate cytokines. Freshly isolated peripheral blood neutrophils from patients with RA expressed mRNA, but there was no surface expression of class II MHC. Freshly isolated SF neutrophils from patients with RA contained high levels of class II MHC mRNA, did not express surface class II MHC, but did have large intracellular amounts of this protein as detected by Western blotting. After culture for 20 hours in vitro, SF neutrophils from RA patients expressed large amounts of surface class II MHC but very low levels of costimulatory molecules CD80 and CD86. Fluorescence microscopy localized surface class II MHC to discrete areas on the neutrophil. Class II MHC-expressing neutrophils stimulated T cell proliferation. CONCLUSION: Peripheral blood neutrophils from patients with RA but not healthy controls express class II MHC mRNA. SF neutrophils in RA synthesize and express large amounts of class II MHC but not costimulatory molecules. This might underlie a novel interaction with T cells that is important in terms of disease pathology.
12233875 Coexpression of microsomal prostaglandin E synthase with cyclooxygenase-2 in human rheumat 2002 Sep OBJECTIVE: Recently, microsomal prostaglandin (PG) E synthase (mPGES) was cloned as a terminal enzyme catalyzing PGH2 to PGE2. We investigated mPGES as well as cyclooxygenase (COX)-2, catalyzing arachidonic acid to PGH2, in synovial cells from patients with rheumatoid arthritis (RA). The effect of dexamethasone on mPGES expression was also studied. METHODS: Synovial cells were treated with interleukin 1beta (IL-1beta) and dexamethasone under various conditions, and expression of mPGES mRNA and protein was analyzed by Northern blot and Western blot, respectively. Conversions of arachidonic acid or PGH2 to PGE2 were measured by ELISA. Subcellular localization of mPGES and COX-2 was determined by immunofluorescent microscopic analysis. RESULTS: mPGES mRNA and protein expression were significantly upregulated by IL-1beta in synovial cells. COX-2 mRNA and protein were also upregulated by IL-1beta, but with a different time course from that of mPGES. Conversion of PGH2 to PGE2 increased by IL-1beta and was correlated with mPGES expression. Increased conversion of arachidonic acid to PGE2 was maintained when mPGES and COX-2 were coexpressed. Subcellular localization of mPGES and COX-2 overlapped in the perinuclear region in IL-1beta stimulated synovial cells. Dexamethasone inhibited mRNA and protein expression for mPGES and increased conversion of arachidonic acid to PGE2, but inhibition of mPGES was weaker compared with that of COX-2 in IL-1beta stimulated cells. CONCLUSION: The results suggest that abundant PGE2 production at inflammation sites such as rheumatoid synovia is caused by the coordinated upregulation of mPGES and COX-2. Thus mPGES might be a potential new target for therapeutic strategies to control PGE2 synthesis specifically in patients with RA and other inflammatory diseases.
12874786 Synovial fibroblasts and synovial macrophages from patients with rheumatoid arthritis and 2003 Sep Chromosomal aberrations were investigated in nuclei extracted from synovial tissue and first-passage synovial fibroblasts (P-1 SFB, 98% enrichment) or macrophages (P-1 Mphi) from patients with rheumatoid arthritis (n=10). The findings were compared with those in other rheumatic diseases (osteoarthritis, n=14; reactive arthritis, n=1), as well as with those in chronic obstructive pulmonary disease (n=8). Controls were paired peripheral blood lymphocytes from arthritic patients, synovial tissue or SFB/Mphi from joint trauma/normals (n=9), and peripheral blood monocytes from normal donors (n=10). GTG banding of metaphase chromosomes and interphase fluorescence in situ hybridization with centromere-specific probes were used. Comparable chromosomal aberrations were observed in synovial tissue and P-1 SFB of patients with rheumatoid arthritis, osteoarthritis, and reactive arthritis (polysomy 7 and aneusomies of chromosomes 4, 8, 9, 12, and 18). Notably, aneusomies of chromosomes 4, 6, 7, 8, 9, 11, 12, and/or X were also detected in P-1 synovial Mphi from rheumatoid arthritis (90% of the cases), osteoarthritis (93%), and reactive arthritis (1/1), as well as bronchial Mphi from chronic obstructive pulmonary disease (25%). No aberrations were detected in paired peripheral blood lymphocytes (except for one osteoarthritis case with a karyotype 45,X[10]/46,XX[17]), or in peripheral blood monocytes and synovial tissue of normals/joint trauma. Because Mphi aberrations were common to chronic joint and pulmonary disease, chronic inflammatory stress may induce chromosomal aberrations with potential functional relevance in local mesenchymal cells and infiltrating leukocytes in an organ-independent fashion.