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ID PMID Title PublicationDate abstract
7818568 Rheumatoid arthritis treated with tenidap and piroxicam. Clinical associations with cytoki 1995 Jan OBJECTIVE: To compare the effects of tenidap and piroxicam on acute-phase protein and cytokine levels in the blood of rheumatoid arthritis (RA) patients and to explore their associations with clinical disease activity. METHODS: A double-blind, randomized, crossover trial in 49 patients with active RA compared 6 weeks of treatment with tenidap (120 mg/day) versus 6 weeks of treatment with piroxicam (20 mg/day). RESULTS: Median values for C-reactive protein (CRP), Westergren erythrocyte sedimentation rate (ESR), serum amyloid A (SAA) protein, and interleukin-6 (IL-6) were significantly lower after tenidap treatment compared with piroxicam treatment, even in the presence of stable background treatment with prednisone, methotrexate, or prednisone plus methotrexate. The median within-patient treatment differences (after tenidap minus after piroxicam) in the CRP, ESR, SAA, and IL-6 values were -1.7 mg/dl, -10.0 mm/hour, -22.0 micrograms/ml, and -3.7 pg/ml, respectively, and represent -60.4%, -17.7%, -35.5%, and -26.1% of the respective baseline levels. IL-6 levels were positively correlated with CRP and SAA. Plasma IL-1 beta was generally below the level of detection. Tumor necrosis factor alpha levels were similar after tenidap and after piroxicam. Treatment differences for 4 of 7 clinical parameters favored tenidap, but did not reach statistical significance. IL-6, CRP, and ESR were significantly correlated with clinical treatment differences. Tenidap and piroxicam toleration were similar, although tenidap-treated patients exhibited a reversible increase in urinary protein excretion. CONCLUSION: Tenidap was differentiated from piroxicam by lower levels of acute-phase proteins, ESR, and IL-6 after tenidap treatment. These treatment differences were significantly correlated with clinical parameters.
8853229 Flow cytometric characterisation of the "false naive" (CD45RA+, CD45RO-, CD29 bright+) per 1996 The aim of this study was to quantify and characterize the CD4+ and CD8+, CD45RA+, CD45RO- T-lymphocytes that paradoxically expressed the CD29 bright+ phenotype in health and in rheumatoid arthritis. We further evaluated their clinical implications. Blood samples were obtained from 100 patients with rheumatoid arthritis and 40 age- and sex-matched controls. Cell surface antigens and interleukin-2 (IL-2) binding were detected on CD4+ and CD8+ peripheral blood T-lymphocytes (T-PBL) by three-colour flow cytometry. One-third of the patients were clinically evaluated at the time of blood sampling. In healthy donors, we found 16 +/- 14% of CD29 bright+ cells among CD4+, CD45RA+, RO- T-PBL. These "false naive" CD4+ T-PBL were Leu-8+, and a majority expressed the CD25/p55 receptor (IL-2R alpha chain), while a minority showed the CD11a bright+, CD69+ and/or CD122/p75+ (IL-2R beta chain) phenotype, and few cells were CD31 bright+ and HLA-DR+. In rheumatoid arthritis, their proportion among CD4+, CD45RA+, RO- cells increased to 25 +/- 15% (P < 0.001, compared with controls). In patients, the reductions in CD31 and CD38 expression (P < 0.05 for both), as well as the enhanced CD25 expression (P < 0.001) on CD4+, CD45RA+, RO- T-PBL reflected a more differentiated phenotype. The occurrences of CD25 and CD122 were increased on false naive CD4+ T-PBL (0.01 < P < 0.001); however, the binding of IL-2 remained very low (in contrast to the binding of IL-2 on CD45RO+ T-PBL). Furthermore, a major subset of CD8+, CD45RA+, RO- T-PBL (45 +/- 17% in controls) expressed the CD29 bright+ phenotype. These "false naive" CD8+ T-PBL included a great many of CD11b+, CD28- cells, while a minority showed the HLA-DR+, CD69+ and/or CD122+ phenotypes. Patients with low levels of IgM rheumatoid factors (IgM-RF; but with active disease) had an elevated proportion of CD45RA+, RO- cells among the CD8+ T-PBL, in part due to an increased proportion of false naive cells (P < 0.05). In patients, the false naive CD8+ T-PBL showed down-regulated CD11b and an increased expression of IL-2 receptor chains (CD25 and CD122; 0.05 < P < 0.01), but without a significant increase in IL-2 binding. More CD69 on false naive CD8+ T-PBL was found in patients with high levels of IgM-RF (P < 0.005 compared to patients with low IgM-RF). Finally, both false naive CD4+ and CD8+ T-PBL correlated with the clinical process and outcome variables (0.05 < P < 0.01). The levels of activated false naive (CD4+ T-PBL (CD25+ and/or CD122+) or CD8+ T-PBL (CD69+ and/or CD122+) were associated with clinical parameters of disease activity (0.05 < P < 0.01). Thus, in rheumatoid arthritis, false naive T-PBL showed important qualitative differences. The levels of activated false naive T-PBL could be particularly interesting for monitoring disease evolution.
1494743 [Effects of methotrexate on leukotriene and derivated lipoxygenase synthesis in polynuclea 1992 Oct Methotrexate (MTX) has been proved to be effective in rheumatoid arthritis (RA). The mechanism of action of MTX in this disease remains unelucidated but may involve inhibition of the enzyme 5-lipoxygenase. Arachidonic acid metabolites were studied in eight patients with active RA immediately prior to and 24 hours after the first intramuscular injection of 10 mg MTX. None of the patients were taking corticosteroids. Nonsteroidal antiinflammatory drugs were withdrawn four days before the study. Reverse phase high-performance liquid chromatography was used to quantitate metabolites produced by 5-lipoxygenase (5-LO) and 12-LO in plasma (full spectrum of blood cells) and purified neutrophils (PN) after stimulation with calcium ionophore A 21387 (50 microM for 30 minutes and 5 microM for 5 minutes, respectively). LTB4 production by PNs was significantly decreased (-32%, p < 0.01) 24 hours after MTX administration. A moderate (-17%), nonsignificant (NS) fall in LTB4 omega-oxidation products (wP) was seen. Production of 5-HETE was also slightly decreased (-15%, NS). Findings in plasma were comparable, with a significant decrease in total LTB4 (-29.8%, p < 0.01) and moderate falls in wP (-18.8%, NS) and in 5-HETE production (-17%, NS). Production of 12-HETE was unchanged. These findings suggest that MTX in a single dose is responsible for a decrease in the synthesis of LTB4 and 5-LO products in neutrophils and other blood cells in RA patients but does not affect 12-LO activity.
7913675 Interim monitoring of bivariate responses using repeated confidence intervals. 1994 Jun A method for interim monitoring is described for bivariate response data arising in clinical trials. This procedure centers on a sequence of rectangular joint confidence regions obtained by inverting the hypothesis testing-confidence interval relationship when the testing procedure is governed by a bivariate group sequential design described by Cook and Farewell [4]. The advantage of this type of design over other possible multivariate sequential designs is that the marginal analyses are maintained throughout the trial. This approach proves to be particularly advantageous for active control trials in which a region of therapeutic equivalence is specified for two responses related to efficacy. Two examples illustrate the design and analysis aspects of this approach. The procedure is presented in the context of normally distributed responses; however, adaptations to handle bivariate binary and bivariate failure time data are indicated. Generalizations of this procedure to handle multivariate response data are straightforward.
8463125 Defective signal transduction via T-cell receptor-CD3 structure in T cells from rheumatoid 1993 Feb T cells from patients with active RA are known to produce low levels of IL-2 and proliferate poorly in response to various mitogenic stimuli. The present work shows that cross-linking of CD3 antigen on patients' T-cell surface induces two- to threefold lower Ca2+ response than in T cells from age-matched controls. Immunofluorescence studies indicate that the attenuated signal may be due to the suppressed expression of CD3 and/or CD45 molecules on patients' T cells. In the majority of the patients, the level of CD45 expression is reduced by 60%-70% as compared with that in the control T cells. Therefore, the poor mitogenic response of patient cells is apparently due to a defect in early stages of signal transduction through the T-cell receptor (TCR-CD3).
8200971 Rheumatoid cachexia: cytokine-driven hypermetabolism accompanying reduced body cell mass i 1994 Jun The cytokines IL-1 beta and TNF-alpha cause cachexia and hypermetabolism in animal models, but their role in human inflammation remains controversial. The relationship between in vitro cytokine production and metabolism was examined in 23 adults with RA and 23 healthy control subjects matched on age, sex, race, and weight. Body composition was measured by multicompartmental analysis of body cell mass, water, fat, and bone mass. Resting energy expenditure (REE) was measured by indirect calorimetry. Cytokine production by PBMC was measured by radioimmunoassay. Usual energy intake, physical activity, disability scores, medication use, and other confounders were also measured. Body cell mass was 13% lower (P < 0.00001), REE was 12% higher (P < 0.008), and physical activity was much lower (P < 0.001) in subjects with RA. Production of TNF-alpha was higher in RA than controls, both before and after stimulation with endotoxin (P < 0.05), while production of IL-1 beta was higher with endotoxin stimulation (P < 0.01). In multivariate analysis, cytokine production was directly associated with REE (P < 0.001) in patients but not in controls. While energy and protein intake were similar in the two groups and exceeded the Recommended Dietary Allowances, energy intake in subjects with RA was inversely associated with IL-1 beta production (P < 0.005). In this study we conclude that: loss of body cell mass is common in RA; cytokine production in RA is associated with altered energy metabolism and intake, despite a theoretically adequate diet; and TNF-alpha and IL-1 beta modulate energy metabolism and body composition in RA.
8016129 Expression of HLA-DR4 and human CD4 transgenes in mice determines the variable region beta 1994 Jun 21 Inherited susceptibility to rheumatoid arthritis is associated with genes encoding the human major histocompatibility complex class II molecule HLA-DR4. To study the immune function of HLA-DR4 and attempt to generate a murine model of rheumatoid arthritis we have produced triple transgenic mice expressing HLA-DRA*0101, -DRB1*0401, and human CD4. The expression of the HLA transgenes is driven by the promoter of the murine major histocompatibility complex class II I-E alpha gene and was found on murine cells that normally display major histocompatibility complex class II molecules. The expression of the human CD4 transgene is driven by the murine CD3 delta-promoter, and therefore its gene product was found on cells that express murine CD3. In contrast to other HLA-DR and HLA-DQ transgenic mouse lines, the transgenes are functional in our mice. In H-2 I-E-negative transgenic mice, T cells expressing variable region beta chain (V beta) 3, 5, 6, 7, 9, 11, 12, or 13 were either absent or significantly reduced, in contrast to H-2 I-E-negative nontransgenic littermates. In addition, the peptide antigen influenza A virus hemagglutinin 307-319, which binds to the HLA-DRA*0101/-DRB1*0401 heterodimer with high affinity and induces an HLA-DR-restricted and CD4+ T-cell response in humans, also induced a T-cell response in the triple transgenic mice but not in nontransgenic littermates. Thus, these transgenic mice should permit extensive testing of the antigen-presentation capabilities of the HLA-DRA*0101/-DRB1*0401 molecule.
1522232 Enhanced production of monocyte chemoattractant protein-1 in rheumatoid arthritis. 1992 Sep Cells within the synovial tissue may recruit mononuclear phagocytes into the synovial fluid and tissues of arthritic patients. We investigated the production of the chemotactic cytokine monocyte chemoattractant protein-1 (MCP-1) using sera, synovial fluid, synovial tissue, as well as macrophages and fibroblasts isolated from synovial tissues from 80 arthritic patients. MCP-1 levels were significantly higher (P less than 0.05) in synovial fluid from RA patients (mean 25.5 +/- 8.1 ng/ml [SE]) compared to synovial fluid from osteoarthritis (OA) patients (0.92 +/- 0.08), or from patients with other arthritides (2.9 +/- 1.5). MCP-1 levels in RA sera (8.44 +/- 2.33) were significantly greater than MCP-1 in normal sera (0.16 +/- 0.06). The quantities of RA synovial fluid IL-8, which is chemotactic for neutrophils and lymphocytes, and MCP-1 were strongly positively correlated (P less than 0.05). To examine the cellular source of MCP-1, RA synovial tissue macrophages and fibroblasts were isolated. Synovial tissue fibroblasts did not express MCP-1 mRNA, but could be induced to produce MCP-1 by stimulation with either IL-1 beta, tumor necrosis factor-alpha (TNF-alpha), or LPS. In contrast, unlike normal peripheral blood monocytes or alveolar macrophages, RA synovial tissue macrophages constitutively expressed MCP-1 mRNA and antigen. Immunohistochemical analysis of synovial tissue showed that a significantly greater percentage of RA macrophages (50 +/- 8%) as compared to either OA macrophages (5 +/- 2) or normal macrophages (1 +/- 0.3) reacted with anti-MCP-1 antibodies. In addition, the synovial lining layer reacted with MCP-1 in both RA and OA synovial tissues. In contrast, only a minority of synovial fibroblasts (18 +/- 8%) from RA synovium were positive for immunolocalization of MCP-1. These results suggest that synovial production of MCP-1 may play an important role in the recruitment of mononuclear phagocytes during inflammation associated with RA and that synovial tissue macrophages are the dominant source of this cytokine.
1347492 Evidence for the presence of activated CD4 T cells with naive phenotype in the peripheral 1992 Mar We have investigated whether T cell activation in rheumatoid arthritis (RA) preferentially engages distinct T cell subpopulations in the peripheral blood (PB) and in the synovial fluid. We found that CD25 expression was enhanced among PB CD4 T cells of RA patients as compared with CD4 cells of patients with reactive arthritis, degenerative joint disease or of healthy controls. Within the CD4 T lymphocytes subset we found that the CD45RO- (naive) cells selectively in RA displayed higher levels of CD25 protein and of interferon-gamma mRNA expression when compared with the respective subset of all other investigated groups. These results show that in the PB of RA, but not in the PB of the other arthropathies or healthy controls, CD45RO-CD4 T lymphocytes exist which display well-defined signs of activation.
1380043 Alpha 4/beta 1 integrin (VLA-4) ligands in arthritis. Vascular cell adhesion molecule-1 ex 1992 Aug 15 Expression of vascular cell adhesion molecule-1 (VCAM-1) in synovial tissue was determined using the immunoperoxidase technique. Normal, rheumatoid arthritis (RA), and osteoarthritis (OA) synovia bound VCAM-1 antibodies in the intimal lining as well as blood vessels. The amount of VCAM-1 was significantly greater in the synovial lining of RA and OA tissues compared with normal synovium (p less than 0.002). There was also a trend toward greater levels of VCAM-1 staining in blood vessels of arthritic tissue (RA greater than OA greater than normal). Because VCAM-1 staining was especially intense in the synovial lining, VCAM-1 expression and regulation was studied on cultured fibroblast-like synoviocytes (FLS) derived from this region. Both VCAM-1 and intercellular adhesion molecule 1 were constitutively expressed on FLS. VCAM-1 expression was further increased by exposure to IL-1 beta, TNF-alpha, IL-4, and IFN-gamma. These cytokines (except for IL-4) also induced intercellular adhesion molecule 1 expression on FLS. ELAM was not detected on resting or cytokine-stimulated FLS. The specificity of VCAM-1 for FLS was demonstrated by the fact that only trace amounts were detected on normal and RA dermal fibroblasts. Cytokines induced intercellular adhesion molecule 1 display on dermal fibroblasts but had minimal effect on VCAM-1 expression. Finally, in adherence assays, Jurkat cell binding to resting FLS monolayers was inhibited by antibody to alpha 4/beta 1 integrin (VLA-4), CS-1 peptide from alternatively spliced fibronectin (which is another VLA-4 ligand), and, to a lesser extent, anti-VCAM-1 antibody. After cytokine stimulation of FLS, Jurkat-binding significantly increased, and this increase was blocked by anti-VCAM-1 antibody. Therefore, both CS-1 and VCAM-1 participate in VLA-4-mediated adherence to resting FLS in vitro, and VCAM-1 is responsible for the increase in Jurkat binding mediated by cytokines.
9114902 The influence of renal function on the enantioselective pharmacokinetics and pharmacodynam 1993 Sep 1. Single oral doses of 100 mg racemic ketoprofen were given to 15 patients (age range: 51-79 years) with rheumatoid arthritis and a range of creatinine clearances (CLCR) from 26 to 159 ml min-1. 2. The fractions unbound of (R)- and (S)-ketoprofen in plasma were determined for each subject after in vitro addition of rac-ketoprofen (enantiomer range: 1.00-6.00 micrograms ml-1) to pre-dose plasma. 3. An index of the antiplatelet effect of ketoprofen in vitro was measured as inhibition of platelet thromboxane B2 (TXB2) generation during the controlled clotting of whole blood (pre-dose) spiked with rac-ketoprofen. 4. In vivo studies revealed significant associations (P < 0.05) between the reciprocal of AUC for both unbound and total (bound plus unbound) (S)-ketoprofen and CLCR. Corresponding relationships were also observed for the (R)-enantiomer of ketoprofen. In addition, the half-life of each enantiomer was negatively correlated with CLCR. There was a positive relationship between the 24 h urinary recovery of combined non-conjugated and conjugated (R)-ketoprofen and CLCR while that for the (S)-stereoisomer failed to reach statistical significance (P > 0.05). 5. There was no difference between AUC for (R)- and (S)-ketoprofen for either unbound or total drug. 6. The mean +/- s.d. percentage unbound of (S)-ketoprofen in plasma (0.801 +/- 0.194%) exceeded (P < 0.05) the corresponding value for its optical antipode (0.724 +/- 0.149%). The percentage unbound of the (S)-enantiomer was higher at 6.00 micrograms ml-1 than that at enantiomer concentrations of 3.50 micrograms ml-1 and below, where it was invariant. The percentage unbound of (R)-ketoprofen was independent of plasma concentration up to 6.00 micrograms ml-1. There were no correlations between the percentage unbound of each enantiomer and either serum albumin concentration or CLCR. 7. The relationship between the serum concentration of unbound (S)-ketoprofen and the percentage inhibition of platelet TXB2 generation was described by a sigmoidal Emax equation for each patient. There was no correlation between the unbound concentration of (S)-ketoprofen in serum required to inhibit platelet TXB2 generation by 50% (EC50) and CLCR. The mean +/- s.d. EC50 was 0.216 +/- 0.143 ng ml-1. 8. These data indicate that diminished renal function is associated with an increased exposure to unbound (S)-ketoprofen, presumably due to regeneration of parent aglycone arising from the hydrolysis of accumulated acyl-glucuronide conjugates. The apparent sensitivity of platelet cyclo-oxygenase to the inhibitory effect of (S)-ketoprofen was not influenced by renal function.
1376343 A monoclonal anti-idiotype specific for human polyclonal IgM rheumatoid factor. 1992 Jun 15 One of the hallmarks of rheumatoid arthritis (RA) is the production of high titers of rheumatoid factor (RF) antibody directed against the Fc portion of IgG. Anti-Id that recognize the majority of monoclonal RF from patients with B cell dyscrasias are reactive with only 1 to 2% of these polyclonal RF from RA patients. We describe a new monoclonal anti-Id, 4C9, that recognizes a L chain determinant on polyclonal IgM RF from patients with RA but does not recognize a panel of monoclonal RF from patients with B cell malignancies. 4C9 reactivity is found in the serum of 34/43 RF-positive RA patients and in 12/12 RF-positive synovial fluids, but in only 1/14 RF-negative sera from RA patients and 1/22 sera containing monoclonal IgM RF. 4C9 reactivity is highly enriched in purified IgM RF from nine RA patients and represents a variable percentage of total IgM RF up to a maximum of 23%. Furthermore, 4C9 reactivity is enriched in the synovial fluid of three of five RA patients compared with serum, suggesting that 4C9-reactive IgM RF are synthesized within the joint. IgG RF from RA synovial fluids are not 4C9 reactive, indicating either that different genes are used to encode IgM and IgG RF in RA patients, or that IgG RF have somatically mutated away from idiotypic reactivity.
7837160 Intermittent cyclic therapy with etidronate in the prevention of corticosteroid induced bo 1994 Oct OBJECTIVE: To assess the potential efficacy of intermittent cyclic therapy (ICT) with etidronate in the treatment of patients with corticosteroid induced osteoporosis. METHODS: Cohort study in a tertiary care university affiliated hospital in corticosteroid treated patients, with polymyalgia rheumatica, asthma, systemic lupus erythematosus, rheumatoid arthritis, or temporal arteritis, examining the effects of ICT etidronate. Patients were included if they were taking corticosteroids for a minimum of one year. Comparison patients were those who had been taking corticosteroids for a minimum of one year and who had not been treated with etidronate or other medication which might alter bone metabolism. A total of 68 patients were included from 253 considered. The mean (SD) dose of prednisone in the ICT etidronate treated patients was 9.3 (6.2) mg and in the comparison patients 9.4 (5.9) mg. The duration of prednisone therapy was 7.8 (5.8) years and 3.4 (4.2) years, respectively (p2 < 0.001). An analysis of covariance demonstrated that this difference did not alter our primary outcome measure. The primary outcome measure was the difference in the percentage change from baseline to one year of followup in bone mineral density (BMD) of the lumbar spine between treatment and comparison groups. RESULTS: ICT etidronate resulted in a statistically significant and clinically important increase in BMD. The BMD of the lumbar spine increased by 3.82% (0.65%), [95% confidence interval (CI), 2.51 to 5.14%] in the 35 ICT etidronate treated patients and decreased by 1.78% (0.76%), [95% CI, -3.34 to -0.23%] in the 33 comparison patients after 12 months (p2 < 0.0001). CONCLUSIONS: ICT etidronate prevented loss of vertebral bone density in patients with corticosteroid induced osteoporosis. Controlled, double blind, prospective trials with longer followup are needed to confirm these results and to demonstrate that increases in bone mass translate into decreased fracture rates.
7481075 T-cell repertoires in healthy and diseased human tissues analysed by T-cell receptor beta- 1995 Feb Many examples of oligoclonal T-cell expansion in infiltrated diseased tissues have been reported. However, it remains to be established whether such observations can be generalized and to what extent oligoclonal patterns obtained after in vitro culture of T-cell infiltrates reflect in vivo situations. Using new high resolution analysis which requires no in vitro cellular expansion, we detected such oligoclonal T-cell expansions in 7/7 melanoma tumour biopsies, 3/3 biopsies of inflammatory skin during acute graft versus host disease (aGVHD) after allogeneic bone marrow transplantation (alloBMT) and 7/7 synovial membranes from patients with rheumatoid arthritis. Thus, oligoclonal T-cell expansions are readily observed when a sufficiently sensitive detection method is used, suggesting that similar expansions are the rule among T-cell infiltrates in different diseases. This observation and the monitoring of the in vivo evolution of such expansion during the course of the disease and during in vitro culture should have important clinical implications.
1380241 Interleukin-6 and its receptor in autoimmunity. 1992 Apr Interleukin-6 (IL-6) is a multifunctional cytokine which acts on a wide variety of cells, regulating immune response, acute phase reaction and hematopoiesis. In accordance with its pleiotropic functions, IL-6 is indicated to be involved in the pathogenesis of several diseases including autoimmunities, lymphoid malignancies and inflammations. An elevated level of IL-6 is demonstrated in patients with rheumatoid arthritis and cardiac myxoma, which can explain symptoms of these diseases, such as autoantibody production and increase in acute phase proteins. Therefore, inhibitors of IL-6 production or IL-6 receptor-mediated signal transduction may be used for treatment of IL-6-related diseases. The IL-6 receptor system consists of two membrane proteins, a ligand-binding chain (IL-6R) and a non-ligand-binding signal transducer, gp130, both of which belong to the cytokine receptor family. Binding of IL-6 to IL-6R triggers the association of IL-6R and gp130, and gp130 in turn transduces the signal. A nuclear factor for controlling IL-6 gene expression (NF-IL6) is also involved in the transcriptional regulation of various acute-phase protein genes. IL-6-stimulation of hepatocytes, through modification of pre-existing NF-IL6 protein, leads to binding of NF-IL6 to IL-6-responsive elements and activation of acute-phase protein genes. NF-IL6 is shown to recognize the enhancer core sequence of several viruses, suggesting a possible relationship of virus infection and IL-6 expression.
8070822 Subcutaneous nodules in acute rheumatic fever--an analysis of age old dictums. 1993 Nov It is assumed that subcutaneous nodule (SCN), one of the major criteria in acute rheumatic fever (ARF), is rare and whenever these nodules appear, they are invariably associated with carditis. Further large number of nodules appear in crops and they are evanescent. This prospective study of 42 cases of ARF with SCN attempts to analyse the accuracy of such statements. The group comprised of 12.5% of 336 consecutive cases of ARF. Other major criteria associated with SCN were carditis in 38 (90.4%), arthritis in 33 (78.5%) and chorea in two (4.7%). No evidence of carditis could be found in 4 (9.5%). When a detailed study of SCN was done the average number of nodules found in the group was 18 (range 4-49). Thirteen (30.9%) had less than 10 nodules and 5 (11.9%) had only 4-5 nodules. With initiation of treatment SCN disappeared within 4 weeks in 29 (69%), within next 5-8 weeks in 8 (19%) and within 9-12 weeks in 3 (7.1%). In two cases (4.7%) multiple nodules were observed 12 weeks later when all other evidences of activity had disappeared. The study shows a comparative high incidence of SCN in ARF, not all being associated with carditis. Number of nodules appearing in ARF might be quite small and they could persist for long inspite treatment.
7504102 Microvascular substance P binding to normal and inflamed rat and human synovium. 1993 Nov The regulatory peptide substance P has been implicated in the development and persistence of inflammatory synovitis. The authors used quantitative in vitro receptor autoradiography to compare synovial binding of 125Iodine-Bolton Hunter-labeled substance P ([125I]BH-SP) in rats and humans and between uniflamed and persistently inflamed synovium. [125I]BH-SP binding to microvascular endothelium paralleled the distribution of substance P-immunoreactive nerves and had characteristics of the neurokinin (NK) 1 class of tachykinin receptor. Specific binding was inhibited by the selective NK1 receptor antagonist, FK888, and the dual NK1/NK2 receptor antagonist FK224, with Hill coefficients near unity. FK888 was > 1000 times and FK224 > 10 times more potent at inhibiting binding in human compared with rat synovium. Synovium from patients and rats with chronic arthritis contained heterogeneously distributed inflammatory cell infiltrates. For the 10 microvessels with the densest [125I]BH-SP binding in each section, no significant differences in binding density, affinity, or Ki values for substance P, FK888 or FK224 were found between synovium from naive and monoarthritic rats, nor between that from patients with rheumatoid arthritis or osteoarthritis. However, in both rat and human specimens, microscopic examination suggested that microvascular [125I]BH-SP binding in intensely infiltrated regions of synovium was less dense than in adjacent, less infiltrated areas. It was concluded that NK1 receptors are similarly distributed in rat and human synovium but show major differences in selectivity for antagonists such as FK888. NK1 receptors in synovium may mediate proinflammatory actions of locally released substance P; defective neurovascular regulation may contribute to the persistence of chronic arthritis.
1351318 Tyrosine kinase signal transduction in rheumatoid synovitis. 1992 Apr Explants of synovial cells in rheumatoid arthritis display a transformed phenotype with focus formation and anchorage-independent growth. Many of the cytokines that activate these fibroblasts mediate their action through tyrosine kinase growth factor receptors. Mechanisms of signal transduction via such tyrosine kinases are therefore relevant to the pathogenesis of rheumatoid lesions. Data are presented using the neu oncogene product p185neu as a model system to explore signal transduction by receptor tyrosine kinases. Evidence is shown that increased tyrosine kinase activity in the oncogenic form of this protein may result from dimerization of the tyrosine kinase receptor. In the normal cellular counterpart of p185neu, dimerization appears to be mediated by the action of an as yet unidentified ligand. Dimerization also appears to be important in signal transduction mediated by epidermal growth factor, platelet-derived growth factor, and colony-stimulating factor 1. These cytokines also alter the phenotype of rheumatoid synovial fibroblasts to resemble transformed fibroblasts. Additionally, preliminary data that suggest increased tyrosine kinase activity in rheumatoid arthritis synovia compared with osteoarthritis synovia are presented. Molecular characterization of tyrosine kinase receptors will be an important direction for future studies of the pathogenesis of rheumatoid disease.
7522685 Soluble P-selectin in the plasma of patients with connective tissue diseases. 1994 Oct We measured the soluble P-selectin (sP-selectin) in plasma of 54 patients with connective tissue diseases and 12 normal controls by a 2-step sandwich enzyme immunoassay. Our purpose was 2-fold: to determine (1) whether the level of sP-selectin of such patients is higher than normal, and (2), if it is, whether it correlates with any of the laboratory data currently available. The mean levels in patients with systemic lupus erythematosus (SLE), mixed connective tissue disease (MCTD) and rheumatoid arthritis (RA) were 306, 1,048 and 844 ng/ml, respectively, compared with 220 ng/ml for controls. The mean levels in patients with SLE and nephropathy, MCTD and either nephropathy or thrombosis, and malignant RA were 351, 1,116 and 1,721 ng/ml, respectively. No correlation was found between the levels of sP-selectin and other laboratory data (WBC, CRP, ESR, antinuclear antibody, RF, aCL) except the number of platelets (y = 0.057, r = 0.37). In the clinical course of patients with lupus nephritis and MCTD with nephropathy, sP-selectin became a sensitive parameter. Thus, the level of sP-selectin is higher than normal in patients with connective tissue diseases, especially when complications exist, and it does not correlate with any of the laboratory data currently available except the number of platelets. Measurement of sP-selectin levels should be included in the laboratory tests of patients with connective tissue diseases, especially when complicated by nephropathy or thrombosis.
8436825 Cartilage degradation by cocultures of transformed macrophage and fibroblast cell lines. A 1993 Mar 1 A number of human and mouse macrophage and fibroblast cell lines were examined for their ability to degrade cartilage proteoglycan in an attempt to establish a cell culture model of cartilage degradation. The mouse transformed macrophage cell line J774A.1 alone or in combination with the mouse transformed fibroblast cell line 10ME HD A.5R.1 were the only cell lines capable of extensively degradating cartilage proteoglycan. Incubation of the macrophage cell line J774A.1 on heat-killed cartilage disks resulted in the release of 36% +/- 8 (mean +/- SEM, n = 5) of the radiolabeled cartilage proteoglycan. The fibroblast cell line 10ME HD A.5R.1 alone did not degrade cartilage. However, cocultures of J774A.1 macrophages and 10ME HD A.5R.1 fibroblasts incubated on cartilage discs resulted in the release of 69% +/- 6 (mean +/- SEM, n = 5) of radiolabeled proteoglycan. There was little degradation of cartilage by macrophage/fibroblast cocultures during the first 3 days of culture. Cartilage degradation increased with each subsequent day in culture from 7% +/- 2 on day 4 to 68% +/- 3 (n = 3) by day 7. Supernatants from the macrophage/fibroblast cocultures were incubated with cartilage discs in the presence of general class-specific proteinase inhibitors. The metalloproteinase inhibitors 1,10 phenanthroline, EDTA, and recombinant tissue inhibitor of metalloproteinase were the only inhibitors that significantly blocked cartilage degradation by coculture supernatant. The cartilage degrading metalloproteinase in the macrophage/fibroblast coculture supernatant eluted as a broad peak on Sephacryl S-200HR with an estimated molecular mass between 22 and 55 kDa. These studies suggest that the macrophage/fibroblast coculture model of cartilage degradation may be a useful experimental system for the study of metalloproteinase-mediated connective tissue degradation.