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ID PMID Title PublicationDate abstract
9818651 The longterm outcomes of rheumatoid arthritis: Work disability: a prospective 18 year stud 1998 Nov OBJECTIVE: Work disability is a common outcome of rheumatoid arthritis (RA). Yet there have been no longitudinal, longterm, prospective studies of work disability in this illness. This 18 year longitudinal study investigates the rate of work disability, its concomitants, and its predictors, using a large series of clinical, laboratory, and self-report measures. METHODS: In 1974, a computerized database was developed for the contemporaneous entry of all patient visits. Data included clinical, laboratory, and self-report information. Patients were also assessed by mailed questionnaires at 6 month intervals. In 1994, patients with RA were interviewed in detail about lifetime work status and work disability. RESULTS: Work disability was estimated to occur in 25% at 6.4 years and 50% at 20.9 years after disease onset, and most disability occurred late in the course of disease. Work disability was predicted by almost every demographic and clinical variable. Education level, body mass index (BMI), erythrocyte sedimentation rate, rheumatoid factor, pain, Health Assessment Questionnaire (HAQ) disability, and physical demands of the job were independently associated with disability. Over the course of their illness, the work disabled had a 35% reduction in family income, and had more abnormal scores for joint counts, grip strength, sedimentation rate, pain, global severity, HAQ disability, and anxiety and depression. Except for BMI, the results were essentially similar in a subset of 156 patients seen first with a disease duration of less than one year. CONCLUSION: Work disability can be predicted by patient and work characteristics present at the first clinic visit, but it is persistent abnormalities of sedimentation rate, HAQ disability, and pain, which may be detected in longitudinal followup, that best predict work disability after work and demographic characteristics are accounted for.
11716398 Evolution of the rotating hinge for complex total knee arthroplasty. 2001 Nov Initial rotating hinge total knee designs were associated with a high failure rate. More recent designs have improved the patellofemoral articulation and the rotating hinge mechanism, added modular canal filling slotted fluted stems and metaphyseal sleeves, and improved the articulation between the mobile-bearing element and the tibial component. A series of patients with complex problems was studied. They underwent knee arthroplasty using a second generation rotating hinge component incorporating the design features listed above. Indications for surgery included medial collateral ligament disruption, revision of a previous hinged component with a massive bone loss, comminuted distal femur fracture or distal femoral nonunion in elderly patients, extensor mechanism disruption requiring reconstruction in an unstable knee, and ankylosis requiring femoral peel exposure with moderate residual flexion extension gap imbalance. A series of 23 knees in 22 patients was evaluated at the 2- to 9-year followup. The clinical results, range of motion, and satisfaction were comparable with that of a standard condylar revision knee arthroplasty despite the fact that the cases were more complex. These results warrant continued investigation of the role of rotating hinge in complex total knee arthroplasty.
11323107 Production of neuropeptide substance P by synovial fibroblasts from patients with rheumato 2001 May 11 We examined the production of substance P (SP) in synovial fibroblasts derived from patients with rheumatoid arthritis (RA) and osteoarthritis (OA). Immunoreactive SP was observed in non-stimulated RA fibroblasts. The expression of beta-preprotachykinin-A (beta-PPT-A) mRNA was confirmed by reverse transcription-polymerase chain reaction analysis. SP contents in culture medium were increased by treatment of RA fibroblasts with transforming growth factor-beta (TGFbeta) (10 ng/ml). Levels of SP release were elevated at 12 h after TGFbeta stimulation whereas the expression of beta-PPT-A mRNA was enhanced at 3 h. Furthermore, SP production in response to TGFbeta was dose-dependently enhanced by basic fibroblast growth factor (bFGF). OA fibroblasts also significantly released SP in the presence of TGFbeta (10 ng/ml) plus bFGF (50 ng/ml). These results suggest that SP produced by synovial fibroblasts may participate in joint diseases.
11791468 Regulation of apoptosis of synovial fibroblasts. 2001 In 1992, the first gene to cause systemic autoimmune disease in mice was identified as the Fas gene that is mutated in lymphoproliferative (lpr mice). These mice exhibited a defect in activation-induced cell death of T cells and B cells in vivo. This leads to the failure of proper clearance and removal of immune cells and defective downmodulation of an immune response. This then leads to the speculation that apoptosis defects, including defects in Fas, Fas ligand and Fas apoptosis signaling, may play a role in defective downmodulation of the hyperimmune response observed in human autoimmune diseases. Over the past 7 years, many scientists have analyzed different proapoptotic genes such as Fas, Fas ligand, Bcl-X, caspases as well as antiapoptosis pathways including defects in Fas and Fas ligand, Bcl-2 and caspase inhibitors. Potential genetic defects have been analyzed at the RNA, protein and functional level in humans with autoimmune disease. Somewhat surprisingly, most studies indicate that there is excessive apoptosis of PBMCs in autoimmune disease and human autoimmune disease suggesting that human autoimmune disease is not due to defective apoptosis of immune cells. Some studies indicate that there is decreased apoptosis of parenchymal cells such as RASF that undergo hyperplasia. Gene therapy and other modulators of apoptosis, such as wortmannin, can be used to faciliate apoptosis of RASF.
9002020 Antibodies to Klebsiella, Proteus, and HLA-B27 peptides in Japanese patients with ankylosi 1997 Jan OBJECTIVE: To determine whether patients with ankylosing spondylitis (AS) and patients with rheumatoid arthritis (RA) from Japan have antibodies to Klebsiella pneumoniae and Proteus mirabilis and to assess whether such antibodies are activated against peptides sharing sequences with HLA-B27. METHODS: Serum samples from 152 Japanese patients, 52 with AS, 50 with RA, and 50 healthy controls, were tested against 3 bacteria (K. pneumoniae, P. mirabilis, and Escherichia coli) and 3 synthetic peptides (HLA-B27, pullulanase-D, and scrambled pullulanase-D control peptide) by ELISA under coded conditions. Samples were tested for elevations in IgG, IgA, and IgM antibody classes in patients with active AS or RA, in patients with RA with probable disease, and in patients with inactive AS. Disease activity was determined by an elevated serum C-reactive protein (> 10 mg/l) level and elevated erythrocyte sedimentation rate (> 20 mm/h). RESULTS: Patients with active AS showed specific elevations in serum IgA antibody levels against K. pneumoniae compared to patients with RA and controls (p < 0.001). No such elevation was seen in the IgG and IgM antibody classes. Patients with inactive AS showed no elevation in any class of antibody against K. pneumoniae compared to controls or patients with RA. Patients with active or probably active RA showed significant elevations in IgG antibody levels against P. mirabilis compared to AS and controls (p < 0.001). Patients with AS (active or inactive), RA (active or probably active), and controls showed no elevations in any antibody class to E. coli. Both active and inactive AS patients had specific autoantibodies against HLA-B27 peptide compared to patients with RA and controls (active AS: IgG, IgA, IgM, p < 0.001; inactive AS: IgG and IgA, p < 0.001). Patients with active AS had IgG and IgA antibodies against pullulanase-D peptide, which contains a sequence that cross reacts with HLA-B27 compared to controls (p < 0.001). CONCLUSION: These results provide the first evidence of AS and RA patients in Japan having specific elevations of antibody to K. pneumoniae and P. mirabilis, respectively. This suggests that K. pneumoniae in AS and P. mirabilis in RA may play a role in triggering and/or exacerbating these diseases.
11205697 Evaluation of iron status in anemic patients with rheumatoid arthritis using an automated 2000 Dec We have evaluated a newly introduced immunoturbidimetric transferrin receptor assay (IdeA TfR-IT, Orion Diagnostica, Finland) in healthy subjects and in a study population consisting of patients with rheumatoid arthritis and juvenile chronic arthritis. The IdeA TfR-IT assay was found to provide reproducible results which were in good agreement with the ELISA assays from Orion Diagnostica (IDeA-ELISA, correlation R2=0.8, n=102) and R&D systems (Quantikine TfR ELISA assay, correlation R2=0.95, n=39). The analysis of the patient samples suggested that, on the basis of serum transferrin receptor and ferritin concentrations, in approximately one third of patients with rheumatoid arthritis anemia is due to the depletion of iron stores. Apparently, in all patients with rheumatoid arthritis iron deficiency must be considered as a potential cause of the anemia. Now, that assays which are suitable for automated analyzers have become available for the measurement of serum transferrin receptor, this analyte has the potential to become a part of the routine evaluation of iron status.
9541473 Evidence of ED-B+ fibronectin synthesis in human tissues by non-radioactive RNA in situ hy 1998 Mar The splicing variant of fibronectin containing the ED-B domain (oncofoetal fibronectin) occurs in foetal tissues, reparative processes, organ fibrosis and in tumour tissues. Consequently, a supportive effect of ED-B+ fibronectin for tissue remodelling and tumour progression is assumed. A non-radioactive RNA-RNA in situ hybridization protocol for the investigation of ED-B+ fibronectin synthesis applicable in human tissues is introduced. The ED-B+ fibronectin synthesis was investigated in human disease processes, for which the occurrence of ED-B+ fibronectin is well demonstrated by immunohistochemistry (rheumatoid arthritis, oral squamous cell carcinoma, invasive ductal carcinoma of the breast and nodular palmar fibromatosis). The ED-B+ fibronectin synthesis could be shown in lining cells and in endothelial cells of synovial villi in rheumatoid arthritis, in stromal cells of oral squamous cell carcinoma and invasive ductal carcinoma and in fibro-/myofibroblasts in the proliferative and early involutional phase of nodular palmar fibromatosis. By means of double labelling (alpha-smooth muscle actin immunostaining - ED-B+ fibronectin in situ hybridization), the ED-B+ fibronectin synthesis could be shown to be a typical feature of myofibroblasts. In contrast to the often diffuse ED-B+ fibronectin immunostaining, only a few synthetically active stromal cells were observed focally accentuated within the tumour, which were interpreted as hot spots of tumour-stroma interaction.
11454637 Focal sialadenitis in patients with ankylosing spondylitis and spondyloarthropathy: a comp 2001 Aug OBJECTIVES: To investigate the occurrence of and risk factors for focal sialadenitis in patients with rheumatoid arthritis (RA), mixed connective tissue disease (MCTD), ankylosing spondylitis (AS), and spondyloarthropathy (SpA). METHODS: A total of 85 patients (25 with RA, 19 with MCTD, 19 with AS, 22 with SpA) participated in the study. Each patient filled out a questionnaire for eye and oral symptoms and for the use of medication, and was interviewed; other tests included Schirmer's test, laboratory tests, collection of unstimulated and stimulated whole saliva, and minor salivary gland biopsy. A focus score of > or =1 was regarded as an indicator of focal sialadenitis. RESULTS: Focal sialadenitis was observed in 68% (57/84) of all patients. It affected 80% (20/25) of the patients with RA, 94% (17/18) of those with MCTD, 58% (11/19) of those with AS, and 41% (9/22) of those with SpA (chi(2) test, p=0.0013). Salivary secretion correlated negatively with the focus scores-that is, severity of focal sialadenitis. Patients with focal sialadenitis had both decreased salivary secretion and decreased tear secretion significantly more often than did patients without (chi(2) test, p=0.0074 and p=0.048 respectively). Patients with positive rheumatoid factor (RF), antinuclear antibodies (ANA), or SSA or SSB antibodies had sialadenitis significantly more often than did patients with negative antibodies. In the subgroup of patients with AS or SpA, no associations were found between focal sialadenitis and the presence of these antibodies. CONCLUSION: In addition to patients with RA or MCTD, focal sialadenitis also affects a very high proportion of patients with AS or SpA. Focus scores are significantly higher in patients with RA or MCTD than in those with AS or SpA. A significant association exists between focal sialadenitis and RF, ANA, SSA and SSB. However, in the subgroup of patients with AS or SpA, no associations were found between focal sialadenitis and serological markers or clinical symptoms.
11053088 Etanercept (Enbrel): update on therapeutic use. 2000 Nov Tumour necrosis factor (TNF) is an important inflammatory disease mediator in a wide spectrum of articular diseases, including adult and juvenile rheumatoid arthritis (RA, JRA). Etanercept (Enbrel), approved in the United States and in Europe for use in patients with RA and JRA, is an effective inhibitor of TNF that has been shown to provide rapid and sustained improvement in both of these diseases. Long term studies continue to show that etanercept controls signs and symptoms of RA and JRA with no change in rate or type of adverse event over time. To demonstrate that etanercept is effective as first line treatment for patients with early active RA who have not been previously treated with methotrexate, and to examine the effect of etanercept on radiographic progression, a double blind, placebo controlled study was recently conducted, comparing etanercept with methotrexate (median dose 20 mg per week). Both etanercept 25 mg twice weekly and rapidly escalated methotrexate were effective in reducing the signs and symptoms of RA, and etanercept was significantly better than methotrexate in slowing the rate of radiographic erosions. In patients with severe psoriatic arthritis (PsA), a double blind, placebo controlled study demonstrated that etanercept was also effective in reducing disease activity in PsA. Etanercept has been well tolerated in all of these clinical trials and offers an important new treatment option to patients with inflammatory articular diseases.
10555023 Cost effectiveness of replacing diclofenac with a fixed combination of misoprostol and dic 1999 Nov OBJECTIVE: To estimate the costs and health consequences of replacing treatment with diclofenac 50 mg with a fixed combination of diclofenac 50 mg and misoprostol 0.2 mg 3 times a day in patients with rheumatoid arthritis (RA). METHODS: A decision tree was developed to simulate 6 months of nonsteroidal antiinflammatory drug (NSAID) treatment for RA. The probabilities of the clinical outcomes were based on a literature review. A survey of Norwegian rheumatologists was undertaken to explore their clinical management of dyspepsia in RA patients taking NSAIDs. Valuation of health states was based on results of the Short Form 36 health survey. RESULTS: In female RA patients without any risk factors associated with serious gastrointestinal (GI) complications, the incremental cost of replacing diclofenac with the fixed misoprostol/diclofenac combination therapy was $72,700 per quality-adjusted life-year gained. For patients with 1 risk factor, the cost was less than $16,000. With 2 or 3 risk factors, the use of misoprostol was cost saving. The cost-effectiveness ratios in males were approximately 20% higher than in females. CONCLUSION: Replacing diclofenac with a fixed diclofenac/misoprostol combination is cost effective when restricted to RA patients at increased risk of serious GI events.
11083278 Annexin I surface binding sites and their regulation on human fibroblast-like synoviocytes 2000 Nov OBJECTIVE: Annexin I is a glucocorticoid-inducible protein whose expression in rheumatoid synovium and inhibitory actions in animal models of arthritis suggests its involvement in human arthritis. The present study explored the potential for annexin I to mediate its antiinflammatory actions via specific cell-surface binding sites on human fibroblast-like synoviocytes (FLS). METHODS: Annexin I binding sites on cultured FLS from patients with osteoarthritis (OA) and rheumatoid arthritis (RA) were determined by ligand-binding flow cytometry. Phospholipase A2 (PLA2) activity was determined by arachidonic acid release. RESULTS: FLS exhibited saturable, concentration-dependent cell-surface annexin I binding, with >99% of the OA FLS exhibiting binding at an annexin I concentration of 10 microM. Annexin I binding of RA FLS was significantly lower than that of OA FLS. FLS annexin I binding sites were not affected by elastase or a specific elastase inhibitor, and elastase release did not differ between RA and OA cells. In contrast, collagenase significantly increased annexin I binding sites on OA FLS and approached a significant effect on RA FLS. Tumor necrosis factor alpha increased annexin I binding sites on OA and RA FLS. Similarly, interleukin-1beta significantly increased annexin I binding on OA FLS; but the increased binding on RA FLS was not significant. Dexamethasone exerted no significant effect on OA or RA FLS annexin I binding sites. Treatment of RA FLS with an annexin I N-terminal peptide significantly inhibited RA FLS PLA2 activity. CONCLUSION: This is the first description of the expression, regulation, and function of cell surface annexin I binding sites on FLS. Reduced annexin I binding sites in RA FLS may impair the sensitivity of certain proinflammatory events to glucocorticoids.
11453467 Pro-inflammatory--anti-inflammatory cytokine dynamics mediated by cytokine-receptor dynami 2001 Jun Many of the major human diseases, both infectious (septic shock syndromes) and idiopathic (for example, rheumatoid arthritis), are driven by the production of the pro-inflammatory cytokines interleukin-1 (IL-1) and tumour necrosis factor-alpha (TNF-alpha) produced by monocytes and macrophages. These key pro-inflammatory cytokines can, in turn, stimulate the production of additional cytokines which, in totality, generate tissue pathology. A major deactivator of activated, cytokine-producing monocytes and macrophages is the anti-inflammatory cytokine interleukin-10 (IL-10). It is known that the interactions between these three cytokines are pivotal in terms of health and pathology, but almost nothing is known of the dynamics of these interactions. In this study we have modelled the autocrine interactions of TNF-alpha, IL-1 and IL-10 with monocytes. The model constructed is a six-dimensional, continuous-time dynamical system, with free IL-1 and IL- 10 concentrations in the cell's vicinity, and the proportions of bound and free IL-1 and IL-10 cell-surface receptors, which transduce the cell's response to stimulation, as the state variables. The monocyte is assumed to be initially in a quiescent state, and it is stimulated to produce IL-1 by an external stimulus (e.g. exposure to TNF-alpha or lipopolysaccharide, LPS). This in turn invokes an autocrine IL-1 response, and also induces the production of the anti-inflammatory cytokine IL-10, which acts to downregulate IL-1 production. These responses are mediated by specific cell-surface receptors, the concentrations of which may also be subject to stimulated upregulation. We analyse a reduced, four-dimensional version of the model, and explore its asymptotic states. We find a variety of possible outcomes: runaway IL-1 production, multiple stable equilibria, stable limit cycles, and, exceptionally, quasi-periodic behaviour. These behaviours depend crucially on the form of the cell's response functions. The possible biological implications of these phenomena are discussed.
9710893 Methotrexate and emerging therapies. 1998 Aug It is likely that all new therapeutic interventions will be used with methotrexate in combination therapy. These combinations may yield real therapeutic advances. The potential for end organ toxicity, opportunistic infection, and malignancy will need to be carefully monitored with long-term, meticulously conducted observational studies. Expense, ease of use, and perceived benefit-to-risk ratio will determine which new agents become most commonly prescribed with methotrexate.
9117172 Comparative cytokine gene expression in synovial tissue of early rheumatoid arthritis and 1997 Jan Interleukin 1-beta (IL-1 beta), IL-2, IL-4, IL-5, IL-6, IL-8, tumour necrosis factor-alpha (TNF-alpha), transforming growth factor-beta (TGF-beta) and granulocyte-macrophage colony-stimulating factor (GM-CSF) gene expression was determined in knee synovium of 16 patients with rheumatoid arthritis (RA) and 16 patients with seronegative spondyloarthropathies (SSP), by using polymerase chain reaction (PCR) amplification. The pattern of cytokines observed in RA synovium is of the macrophage-fibroblast type, with the highest expression of IL-1 beta and TGF-beta. GM-CSF and IL-2 bands were visualized in a minority of patients. Neither IL-4 nor IL-5 could be detected. No significant differences were observed in the cytokine profile between patients with early (< 12 months) and more advanced disease. No differences were observed according to gender, age, rheumatoid factor status and the duration of knee synovitis. The pattern of cytokines in the synovium of SSP patients is similar to that observed in RA patients and does not change in relation to disease duration. IL-2 was the only T-cell cytokine observed. These data provide evidence that the macrophage-fibroblast cells have an important role in early and more advanced rheumatoid synovitis, and show that this is also true for SSP peripheral synovitis.
9068289 Use of monoclonal antibodies to detect disease associated HLA-DRB1 alleles and the shared 1997 Feb OBJECTIVE: To use a panel of monoclonal antibodies (Mab) which recognise HLA class II alleles associated with rheumatoid arthritis for fluorescence activated cell sorter (FACS) analysis of peripheral blood mononuclear cells (PBMNC) from patients with early and established rheumatoid arthritis and to compare these results against DNA oligotyping of HLA class II molecules in the same patients. METHODS: 27 patients (18 from an early arthritis clinic, nine with established rheumatoid arthritis) were studied using both techniques. PBMNC were stained with Mab which recognise the shared epitope, the HLA-DRB1*04 molecule and its* 0401, *0404 subtypes in the presence of bound peptide. Mab stained cells were analysed by FACS. Genomic DNA was prepared from PBMNC and use for DNA oligotyping and sequencing by standard methods. RESULTS: FACS analysis of Mab stained PBMNC gave identical results to those obtained by DNA oligotyping in 26/27 patients. The antibodies identified the shared epitope in 14/14 cases and the presence of an HLA-DRB1*04 molecule in 12/12 cases. HLA-DRB1*0404 was identified in 4/4 cases. HLA-DRB1*0401 was identified in 5/6 cases. One patient oligotyped as HLA-DRB1*0401, but consistently failed to react with the *0401 Mab. DNA sequencing of the second exon of the HLA-DRB1*0401 allele in this patient confirmed a normal HLA-DRB1*0401 genotype. CONCLUSIONS: FACS analysis of PBMNC stained with Mab recognising the shared epitope and rheumatoid arthritis associated HLA susceptibility molecules provides a rapid, reliable, and more accessible alternative to DNA oligotyping. The apparent discordance between phenotypic and genetic analysis of HLA-DRB1*0401 in one patient, may reflect variability in HLA-DRB1*0401 gene expression or in class II peptide presentation.
9556353 Heat shock proteins and arthritis--new readers start here. 1997 The possible roles of heat shock proteins in the pathogenesis of inflammatory arthritis have been discussed for a number of years, and investigated intensively in both animal models and human disease. This review surveys evidence which has pointed, on the one hand, to hsp as targets of a pathogenic immune response, and on the other, to an immunoregulatory role for T cell recognition of self hsp. The extent to which findings in experimental animals have led to further insights applicable to human disease is also emphasised.
17195512 [Styles of interpersonal conflict in patients with panic disorder, alcoholism, rheumatoid 2000 May OBJECTIVE: Conflict and conflict resolution in intimate relationships are not only among the most important factors influencing relationship satisfaction but are also seen in association with clinical symptoms. Styles of conflict will be assessed in patients suffering from panic disorder with and without agoraphobia, in alcoholics and in patients suffering from rheumatoid arthritis. METHODS: 176 patients and healthy controls filled out the Styles of Conflict Inventory and questionnaires concerning severity of clinical symptoms. RESULTS: A cluster analysis revealed 5 types of conflict management. Healthy controls showed predominantely assertive and constructive styles, patients with panic disorder showed high levels of cognitive and/or behavioral aggression. Alcoholics showed high levels of repressed aggression, and patients with rheumatoid arthritis often did not exhibit any aggression during conflict. CONCLUSIONS: 5 Clusters of conflict pattern have been identified by cluster analysis. Each patient group showed considerable different patterns of conflict management.
10342392 The lack of associations between rheumatoid arthritis and both nulliparity and infertility 1999 Apr OBJECTIVES: Rheumatoid arthritis (RA) is an autoimmune disease that occurs more commonly in women and frequently onsets in women of childbearing age. Pregnancy often causes disease remission, with a subsequent flare postpartum. Nulliparity may be a risk factor for RA, but the literature does not consistently report this finding. There may be a production of antibodies in women with RA that could lead to infertility, and subsequent nulliparity, but this has not been proved. We wanted to determine whether there was a relationship between nulliparity, infertility, oral contraceptive use, and adverse pregnancy outcome in women with newly diagnosed RA. METHODS: Through a case control study, using a mailed questionnaire, we compared the fertility and pregnancy outcome histories of 34 women between the ages of 19 and 44 years with recent-onset RA with 68 healthy controls matched for age and marital status. The response rate was 97%. A review of the literature also was performed to study the associations between RA and infertility and nulliparity, using Medline searching key references. RESULTS: We found no association between infertility and the onset of RA. Seventy-one percent of women with RA and 68% of controls had been pregnant. There was a trend toward increased nulliparity in these patients, but the result was not statistically significant (odds ratio [OR], 1.4; P<.6). There were no differences in the number of children (2.6 v. 2.7; P<.6) and parity outcomes in the two groups. Age at first pregnancy was younger in the women with RA (22.6 v. 25.5 years; P<.008), but the education level was higher in the controls (P<.0001), which may explain these differences. Oral contraceptive use was lower in the RA women, but more RA women had long-term use (greater than or equal to 5 years), and neither result was statistically significant. Literature review shows that at best, there are weak negative associations between current estrogen use and RA, and no association with nulliparity and infertility. CONCLUSIONS: It appears that infertility, the number of pregnancies, and pregnancy outcome are not strongly associated with the risk of developing RA in women of childbearing age. However, in this study there may have been selection biases in the women with RA and the controls that differentially could have affected their reproductive outcomes. Thus, a true association could have been missed. Most other published studies find no association between nulliparity and RA.
10366100 Dominant-negative p53 mutations in rheumatoid arthritis. 1999 Jun OBJECTIVE: Studies were performed to determine if p53 mutations identified in rheumatoid arthritis (RA) synovial tissue are dominant negative. METHODS: Site-directed mutagenesis was used to produce 2 RA-derived mutants: asparagine-->serine at codon 239 (N239S) and arginine-->stop at codon 213 R213*). HS68 dermal fibroblasts were transfected with either empty vector, wild-type p53 cDNA (wt), or the N239S or R213* mutant p53 cDNA clones. Interleukin-6 (IL-6) and bax gene expression were determined by Northern blot analysis. Bax transcription was determined using a bax promoter/reporter gene construct (bax-luc). RESULTS: Transfection of HS68 cells with wt increased bax mRNA levels. This process was blocked by cotransfection with either mutant. The mutant p53 genes also increased IL-6 gene expression. Low levels of bax promoter activity were detected in HS68 cells co-transfected with bax-luc and empty vector, N239S, or R213*, indicating that the RA mutants lacked transcriptional activity. Transfection with wt and bax-luc led to a 10-fold increase in luciferase expression. When the wt gene was cotransfected with either of the mutants, there was a dose-dependent inhibition of bax promoter activity. CONCLUSION: These data indicate that at least 2 of the p53 mutants identified in RA joint samples are dominant negative and suppress endogenous wild-type p53 function.
9469643 The effects of a newly developed nonsteroidal anti-inflammatory drug (M-5011) on arachidon 1997 Dec M-5011 (d-2-[4-(3-methyl-2-thienyl)phenyl]propionic acid) is a newly developed nonsteroidal anti-inflammatory drug (NSAID) that displays potent anti-inflammatory and analgesic properties with low ulcerogenic activities in animal models. In this study, the effects of M-5011 on arachidonic acid (AA) metabolism in synovial fibroblasts from patients with rheumatoid arthritis were evaluated and compared with those of other NSAIDs in vitro. Either M-5011 or ketoprofen potently inhibited prostaglandin (PG) E2 production by cyclooxygenase (COX)-2 from exogenous AA in interleukin-1beta (IL-1beta)-stimulated cells. The IC50 values of M-5011 and ketoprofen were 4.4 x 10(-7) and 5.9 x 10(-7) M, respectively. However, diclofenac and indomethacin were one order less potent. Although the latter two drugs exhibited time-dependent and irreversible inhibition on COX-2 in IL-1beta-stimulated cells, the inhibitory effects of M-5011 and ketoprofen were reversible. PGE2 production by COX-1 from exogenous AA in non-stimulated cells was also inhibited by M-5011 with a potency less than that of ketoprofen. In addition, M-5011 inhibited [14C]AA release from prelabeled synovial cells stimulated with bradykinin. However, ketoprofen hardly affected the [14C]AA release. It is likely that the effects of M-5011 on AA metabolism are, in part, responsible for its in vivo efficacy and safety profile.