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ID PMID Title PublicationDate abstract
8774548 The role of T-lymphocytes and cytokines in rheumatoid arthritis. 1996 In this review the involvement of T cells, in addition to that of the monocyte/macrophage lineage, in the pathogenesis of rheumatoid arthritis is discussed. The evidence for the pathogenetic importance of T cells is based upon their state of activation in the synovial membrane and the cytokines produced. These cytokines can be detected in synovial fluids as well as in the synovial membrane by both immunohistochemistry and in situ hybridization. However, cytokine production can be detected only in a minor fraction of the T cells which contrasts the number of non-T cells observed to synthesize cytokines. Nevertheless, it can be assumed that the small amount of lymphokines is sufficient to activate a cytokine cascade derived from other cells. The cytokine profile secreted is indicative for a T cell response that primarily involves Th1-like cells.
8765007 Role of tumor necrosis factor-alpha and platelet-activating factor in neoangiogenesis indu 1996 Aug The aim of the present study was to investigate in vivo in a mouse model the stimulation of neoangiogenesis by synovial fluids of patients with rheumatoid arthritis (RA) and to determine the role of tumor necrosis factor (TNF)-alpha and platelet-activating factor (PAF) in the formation of new vessels. Angiogenesis was studied in a mouse model in which Matrigel, injected subcutaneously, was used as a vehicle for the delivery of potential angiogenic stimuli. Synovial fluids of patients with RA but not with osteoarthritis (OA) were shown to induce neoangiogenesis. Since synovial fluid of patients with RA contained significantly higher levels of TNF-alpha-like bioactivity and of PAF than that of patients with OA, the role of these mediators was evaluated by using an anti-TNF-alpha neutralizing monoclonal antibody (mAb) and a PAF receptor antagonist, WEB 2170. When added to Matrigel, anti-TNF-alpha mAb and particularly WEB 2170 significantly reduced neoangiogenesis induced by synovial fluids of RA patients. Moreover, PAF extracted and purified from synovial fluid induced angiogenesis. These results suggest that the neoangiogenesis observed in rheumatoid synovitis may be due, at least in part, to the angiogenic effect of locally produced TNF-alpha and PAF.
8269782 [Experimental method and clinical significance of hidden rheumatoid factors]. 1993 Aug Hidden rheumatoid factor (HRF) was detected in rheumatoid arthritis (RA) serum with ELISA after separation and dissociation of immune complex (IC). It was found that 60% of the patients with active RA has positive latex fixation test, whereas 96% of them has been demonstrated to have IgM hidden rheumatoid factor (HIgMRF) and 70% of them IgG hidden rheumatoid factor (HIgGRF). When the disease was controlled, HIgMRF and HIgGRF was found in 24% and 12% respectively. The difference was significant with P < 0.01. Our results show that the presence of HRF in RA patients is related with the activity of the disease, but not with duration of disease, sex and age.
7543654 Angiogenesis mediated by soluble forms of E-selectin and vascular cell adhesion molecule-1 1995 Aug 10 Endothelial adhesion molecules facilitate the entry of leukocytes into inflamed tissues. This in turn promotes neovascularization, a process central to the progression of rheumatoid arthritis, tumor growth and wound repair. Here we test the hypothesis that soluble endothelial adhesion molecules promote angiogenesis. Human recombinant soluble E-selectin and soluble vascular cell adhesion molecule-1 induced chemotaxis of human endothelial cells in vitro and were angiogenic in rat cornea. Soluble E-selectin acted on endothelial cells in part through a sialyl Lewis-X-dependent mechanism, while soluble vascular cell adhesion molecule-1 acted on endothelial cells in part through a very late antigen (VLA)-4 dependent mechanism. The chemotactic activity of rheumatoid synovial fluid for endothelial cells, and also its angiogenic activity, were blocked by antibodies to either soluble E-selectin or soluble vascular cell adhesion molecule-1. These results suggest a novel function for soluble endothelial adhesion molecules as mediators of angiogenesis.
8849347 The genotypic distribution of shared-epitope DRB1 alleles suggests a recessive mode of inh 1995 Dec OBJECTIVE: To test whether the genotypic distribution of rheumatoid arthritis (RA)-associated DRB1 alleles suggests that the DRB1-associated disease-susceptibility gene has a recessive or additive (dominant) mode of inheritance. METHODS: Caucasian patients with RA and control subjects were recruited from a faculty outpatient practice. DRB1 typing was done by several DNA-based techniques: polymerase chain reaction (PCR), followed by dot-blot hybridization with sequence-specific oligonucleotides, conventional and PCR-based restriction fragment length polymorphisms (RFLPs), and a multiplex amplification-refractory mutation RFLP system. The genotypic distribution of shared-epitope DRB1 alleles was analyzed by antigen genotype frequency among patients. The analytical method postulates a linkage-disequilibrium model with a disease locus close to a marker locus and a marker allele in linkage disequilibrium with the disease-susceptibility allele. In this instance, the marker allele was defined alternatively by any DR4-group allele, by any DR4-group or DR1-group allele, by any DR4-group shared-epitope allele, by any DR4-group shared-epitope allele plus DRB1*0101, or by any shared-epitope DRB1 allele. Observed numbers were compared with those predicted for recessive mode or additive (dominant) mode of inheritance of the DRB1-associated RA disease-susceptibility gene. RESULTS: The genotypic distribution of shared-epitope DRB1 alleles (DRB1*0401, *0404, *0405, *0408, *0101, *0102, or *1001) fit that predicted for a recessive mode of inheritance and was significantly different from that predicted for an additive (dominant) mode. When the analysis was restricted to shared-epitope DR4 alleles alone (DRB1*0401, *0404, *0405, or *0408), the observed genotype numbers fit the recessive mode best. When DR1-group alleles were added to DR4-group alleles, or alternatively, when the major shared-epitope DR1 allele (*0101) was added to DR4-group shared-epitope alleles, there was a less significant deviation from the additive mode of inheritance. The reason for this was derived by comparison of observed genotype frequencies to those expected under Hardy-Weinberg equilibrium; there was a deficit of persons with DRB1*0401, *0101 and an excess of *0101,X. CONCLUSION: The genotypic distribution of shared-epitope DRB1 marker alleles suggests that the mode of inheritance of the DRB1-associated disease susceptibility gene must be recessive and not additive (dominant).
8738976 A structural model for TCR recognition of the HLA class II shared epitope sequence implica 1996 Apr HLA molecules associated with rheumatoid arthritis (RA) contain a discrete structural element known as the shared epitope, a set of conserved amino acid residues located on the alpha helical portion of the class II beta chain. Each of the different HLA molecules associated with RA contain the same shared epitope sequence, although they may vary markedly in other regions of the class II structure, which also determine peptide-class II interactions. Previous mutagenesis studies and structural modelling indicate that key polymorphic amino acid side chains within the shared epitope sequence are in locations likely to contact the T cell receptor (TCR) during the trimolecular activation reaction between the HLA-peptide complex and TCR. We have evaluated the potential structural basis for such shared epitope recognition by analysing detailed molecular models of the arthritis-associated DRB1*0404 molecule and a T cell receptor from T cell clone EM025, specific for HLA-DR4 molecules which carry the shared epitope. A likely orientation for the trimolecular complex was deduced in which the EM025 alpha chain interacts with the DR alpha chain and the EM025 beta chain interacts with the DR beta chain; residues Q70 and R71 within the DR beta chain shared epitope region are positioned for hydrogen bond interactions directly with Q97 of the TCR beta CDR3 region, D30 of the TCR beta CDR1 region, and possibly N51 of the TCR beta CDR2 region, indicating a degree of specific selection and interaction which encompasses multiple TCR contacts. These findings suggest a structural basis for the genetic associations with the HLA shared epitope and the potential contribution of this region to oligoclonal T cell selection and expansion in RA.
7945467 Increased frequency of V beta 17-positive T cells in patients with rheumatoid arthritis. 1994 Oct OBJECTIVE: To identify the T lymphocytes that mediate disease in rheumatoid arthritis (RA). METHODS: A panel of monoclonal antibodies reactive with T cell receptor (TCR) V beta gene products was used to analyze the RA T cell repertoire. RESULTS: Of 5 TCR V beta gene products studied, only V beta 17-positive T cells were increased in peripheral blood and synovial fluid (SF) from RA patients, compared with controls (P < 0.01 and P = 0.0006, respectively). Thirty-one percent of the 49 RA SF samples and none of the 19 non-RA SF samples contained > 10% V beta 17-positive T cells. Activated (Tac-positive) T cells were enriched among V beta 17-positive synovial T cells. CONCLUSION: The selective increase of V beta 17-positive T cells suggests a role for those T cells in the pathogenesis of RA.
8393676 Circulating soluble tumor necrosis factor receptors, interleukin-2 receptors, tumor necros 1993 Aug OBJECTIVE: To assess whether circulating concentrations of soluble tumor necrosis factor receptors (sTNFR; p55 and p75), soluble interleukin-2 receptors (sIL-2R), tumor necrosis factor alpha (TNF alpha), and interleukin-6 (IL-6) reflect clinical response and whether changes are dependent on the drug used in rheumatoid arthritis (RA) patients taking methotrexate (MTX) or azathioprine (AZA). METHODS: These cytokines and soluble receptors were assessed in 20 control subjects and serially for up to 48 weeks in 61 RA patients, by bioassay (IL-6) and immunoassays (sTNFR, sIL-2R, TNF alpha, and IL-6). RESULTS: Concentrations of p55 and p75, sIL-2R, and TNF alpha (but not IL-6) were significantly higher in RA patients than in controls. Significant decreases in sIL-2R and p55 concentrations were associated with clinical improvement and were observed in patients treated with MTX, but not AZA. Both treatments induced decreases in IL-6 concentrations, but circulating AZA (or its metabolites) appears to interfere with the measurement of IL-6 bioactivity. TNF alpha and p75 levels did not show significant changes. CONCLUSION: Measurement of circulating sIL-2R, p55, and IL-6 may be useful in the evaluation of RA disease activity and response to therapy. Interference by circulating levels of drugs must be ruled out when bioassays are used to evaluate cytokine levels.
7946890 [Prevalence of pericardial effusion in subjects with rheumatoid arthritis: an echocardiogr 1994 Jul We used echocardiography to determine the prevalence of pericardial effusion in rheumatoid arthritis (RA) patients without cardiac systems and compared our results to those obtained in a control group of age-matched subjects. Thirty-six patients with RA (6 men, 30 women; mean age 51 +/- 11 years) were selected from a patient population in treatment at our outpatient Rheumatology Clinic. None of the patients had any symptoms of cardiac disease, and all patients with signs and/or systems of extracardiac disease were excluded from the study. The control group consisted of 60 volunteers (mean age 51 +/- 12 years) randomly selected from a larger group of subjects with neither symptoms, signs and/or clinical findings of extracardiac disease nor symptoms of cardiac disease. Standard two-dimensional and M-mode echocardiography was carried out on all subjects. In the RA patients, we found a high prevalence of pericardial involvement, especially minimal pericardial effusion. There was no statistically significant difference among subgroups of RA patients based on stage and duration of disease respectively. There was no correlation between pericardial involvement and inflammatory indexes or drug therapy. The minimal pericardial effusion found in our patients could be caused by the extra-articular inflammatory process and might be one aspect of a more complex picture characterized by silent cardiac involvement. The potential for symptomless pericardial alterations documented in our patients indicates that careful cardiac evaluation should be given high priority in the assessment and management of subjects with RA.
7488284 Predictors of work disability in rheumatoid arthritis patients. A five-year followup. 1995 Nov OBJECTIVE: To evaluate regression models that include social, attitudinal, work structure, health status, and family characteristics, with regard to their prediction of work disability in a national sample of patients with rheumatoid arthritis (RA). METHODS: Four hundred ninety-eight employed RA patients were recruited from a national sample of private rheumatology practices. Three hundred ninety-two remained in the study after 5 years. Data were collected from patients by telephone interview, and patients' physicians provided written clinical assessments. Only variables on which information was obtained in year 1 were used to predict work status in year 5, using hierarchical multiple logistic regression analysis. RESULTS: The significant predictors of work disability were age (odds ratio [OR] 1.04), number of deformed joints (OR 1.26), number of joints with flare (OR 1.23), the complexity of working with things at work (OR 0.88), and the desire to remain employed (OR 2.3). The risk of work disability increased with increasing age, more severe disease, greater complexity of involvement with things at work, reduced work hours, and desire to not be working outside the home. CONCLUSION: The risk of becoming work disabled in 5 years was predicted more by clinical status at entry into the study than by work structure. These results, which contradict previous research on work disability in arthritis, prompt a rethinking of future studies of work disability in RA.
1440040 Spontaneous fracture of the odontoid process in rheumatoid arthritis. 1992 Oct Six cases of spontaneous fracture of the odontoid process in rheumatoid arthritis are presented. Fifty-one patients with atlantoaxial subluxation in rheumatoid arthritis underwent surgery between 1981 and 1990. This included six patients (in 10%) who had subluxation accompanied by fracture of the odontoid without apparent trauma. The mean patient age was 58 years and all had a long history of rheumatoid arthritis. No trauma was considered to be the cause of the fracture. This is a fracture caused by erosion and osteoporosis of the odontoid process due to rheumatoid synovitis, aging and steroid therapy. In addition, another cause is a dynamic load produced from the instability accompanying atlantoaxial subluxation working on the odontoid in cervical extension. It is important remember that the odontoid process is susceptible to spontaneous fracture.
8081655 Use of human sera containing autoantibodies for an immunochemical study of some ribosomal 1994 Jul Sera from human subjects affected by autoimmune connective tissue diseases and containing antiribosomal autoantibodies were used to analyze by immunoblotting ribosomal proteins from trout (Oncorhynchus mykiss) liver, mussel (Mytilus edulis) hepatopancreas and whole fly maggots (Calliphora vomitoria). As usual in medical analysis of autoantibodies, the reference antigen preparation was extracted from rat liver. With the used sera, six known ribosomal proteins from rat liver were characterized: P0, P1, P2, p30, p25 and p20. These six proteins were all targeted in trout; moreover an important 40 kDa fraction, undetectable in rat pattern, was seen. p30 and p20 were undetected in mussel and fly maggot; but p25, undetected in mussel, is clearly characterized in fly maggot. The interest of these data to infer phylogenic relationships is discussed.
8489540 Analysis of immunoglobulin gamma heavy chain expression in synovial tissue of a patient wi 1993 May OBJECTIVE: To gain insight into mechanisms underlying local immune responses in rheumatoid arthritis (RA), we analyzed the utilization of variable-region heavy chain (VH), diversity (DH), and joining (JH) gene segments expressed in synovial tissue of a patient with RA. METHODS: An unrestricted complementary DNA (cDNA) library was generated from unselected cells extracted from synovial tissue obtained at the time of joint replacement. Southern blot analysis for VH, JH, and C gamma subclass utilization was performed on the first 50 C gamma- and JH-positive recombinants for which phage DNA was isolated. Eighteen of the clones were selected at random for sequence analysis. The VH gene segments were compared with an extensive database of germline and cDNA sequences. RESULTS: All transcripts utilized gene segments from the VH1 (28%), VH3 (56%), and VH4 (15%) families. There was a predominance of JH4, JH5, and JH6 gene segment utilization. Fourteen of 18 randomly sequenced clones contained sufficient VH-region information for analysis. Eight (57%) were most closely related to VH gene segments that are preferentially expressed in human fetal liver or that encode antibodies with self-reactivity. The variable domains were heavily mutated, and replacement-to-silent substitution ratios (R:S ratios) in the antigen-binding domains (complementarity-determining regions [CDRs]) were disproportionately high. CDR3 lengths were quite variable, due to extensive N-region addition and 5'-exonuclease activity in the VH-DH-JH joins. CONCLUSION: Plasma cells in this synovial tissue sample appear to express VH gene segments that are preferentially utilized during fetal development or in autoantibodies. The JH repertoire is similar to that seen in adult peripheral blood lymphocytes, but much different from that found during fetal development. The large number of somatic mutations and the high R:S ratios in the CDRs suggest an antigen-driven response.
1610764 Morphometric analysis of the angioarchitecture of the synovial membrane in rheumatoid arth 1992 Apr Using three different immunohistochemical methods we measured the number of vessels, vessel area and diameter and their form factor in the synovial membrane of 102 patients suffering from different joint disease. The variables were evaluated by means of immunomorphometric analysis. We found UEA (Ulex europeus) immunostaining to be the optimal method for quantification of data characterizing the vasculature of the synovial membrane. Irrespective of causes of the given joint disease, we found increases in the number of vessels, vessel perimeter, vessel area and the product of the number of vessels and vessel area over and against the control group (patients without arthritis). Consequences are discussed regarding local bioavailability of medicaments in the synovial membrane.
7748019 Shared amino acid sequences between major histocompatibility complex class II glycoprotein 1995 Mar OBJECTIVES: To show molecular similarity between two sequences of Proteus mirabilis (haemolysin--ESRRAL; urease--IRRET) with HLA-DR antigens (EQRRAA) which are associated with rheumatoid arthritis (RA) and type XI collagen (LRREI), respectively; and, in patients with RA, to measure levels of antibody against a 16-mer synthetic peptide containing the ESRRAL sequence, and the haemolysin and urease proteins of Proteus mirabilis. METHODS: The homologous sequences EQRRAA and ESRRAL were modelled with Alchemy III, using the crystalline structure of DRB1*0101 (HLA-DR1). Sera from 40 patients with RA, 30 with ankylosing spondylitis (AS), and 30 controls were tested against synthetic ESRRAL peptide and the haemolysin of Proteus mirabilis by enzyme linked immunosorbent assay. Similar tests were also carried out on sera from 20 patients with RA, 40 with AS, and 15 controls, against Proteus mirabilis urease. RESULTS: Molecular modelling of the homologous sequences ESRRAL/EQRRAA and IRRET/LRREI showed stereochemical similarities. Antibodies to the 16-mer synthetic peptide containing the ESRRAL sequence, the haemolysin, and urease proteins were significantly increased in RA patients compared with AS patients (p < 0.001) and healthy controls (p < 0.001). No such increases were observed with three control peptides including the EDERAA sequence of DRB1*0402 (HLA-DR4/Dw10), the haemolysin proteins of Streptococcus pyogenes and Vibrio parahaemolyticus, and the urease of Bacillus pasteurii. CONCLUSION: The additive effect of the immune responses to the two Proteus mirabilis antigens, haemolysin (ESRRAL) and urease (IRRET), could be relevant in the aetiopathogenesis of RA.
1616361 Opinions of patients with rheumatoid arthritis about their own functional capacity: how va 1992 Jun Self assessment health status questionnaires are increasingly used to measure health status or the effect of treatment in patients with rheumatoid arthritis (RA). Most of these questionnaires measure functional (physical) disabilities. The question arises, however, as to how well self assessment questionnaires reflect the true functional status of patients or whether they only reflect their imaginary functional capacities. How valid is the opinion of patients with RA about their own functional capacity? To answer this question an investigation was performed in 80 patients with RA. Forty Dutch and 40 Belgian patients with RA completed the functional items of the DUTCH-AIMS, the Dutch version of the Arthritis Impact Measurement Scales (AIMS), a self assessment questionnaire specific to arthritis. Their scores on the functional scales were compared with the scores on the same scales completed by two experienced physiotherapists after evaluation of the functional ability of these patients. This was achieved by observing the patients perform the tasks given in the questionnaire. Correlation coefficients between the scores of the patients and the physiotherapists were highly significant for all the scales. No significant differences were found between the patients' and physiotherapists' mean scale scores except for the mobility scale in the Dutch patients. The strength of agreement (Cohen's kappa) of most scale scores of the patients and physiotherapists was substantial. The estimates of the overall functional capacity (the mean of the five scale scores) of the Belgian and Dutch patients show high correlations between the patients and the physiotherapists. It is concluded that patients' opinion about their functional ability is valid in that it is in agreement with their real functional abilities. This study provides further evidence for the validity of the DUTCH-AIMS as a measure of functional disability and health status in Dutch and Belgian patients with RA.
7589031 Population pharmacokinetics of zileution, a selective 5-lipoxygenase inhibitor, in patient 1995 The pharmacokinetics of zileuton, a novel selective 5-lipoxygenase inhibitor, were studied in 37 patients with rheumatoid arthritis after administration of 200 mg, 400 mg, and 600 mg, zileuton for 4 weeks. Patients had 6-h pharmacokinetic evaluation of zileuton on day 14. Plasma zileuton concentrations were quantitated using HPLC. Zileuton pharmacokinetic parameters were estimated using standard noncompartmental methods. A population analysis of zileuton pharmacokinetics was also performed with the NONMEM computer program. The pharmacokinetics of zileuton in patients with rheumatoid arthritis were similar to those previously estimated in normal healthy humans. The peak concentrations and the areas under the curves during the dosing interval were dose proportional. The noncompartmental means of the CL/f, terminal-phase half-life, and V/f of zileuton were approximately 545 ml min-1, 1.4 h, and 64.3 1, respectively. The estimate of population typical values of the CL/f for a 70-kg person (540 ml min-1) and V/f for a 70-kg person (64.8 1) from the NONMEM analysis were in agreement with the noncompartmental estimates. Differences in body weight, but not age or gender, helped explain some of the variability in the pharmacokinetics of zileuton in patients. Therefore, there is no pharmacokinetic basis for alteration of the zileuton dose size or the dosing schedule in patients with rheumatoid arthritis.
8344674 [Syndrome of T gamma lymphoproliferation of Fc gamma RIII- positive lymphocytes in rheumat 1993 Apr A T gamma-lymphoproliferative syndrome is described in a 69-year-old woman with seropositive rheumatoid arthritis. The phenotype of this non-clonally increased large granular lymphocyte (LGL) population is unusual: LGL are CD56- Fc gamma RIII+(CD16+) and 30% coexpress gamma/delta-T-cell receptor.
8327381 Laser therapy: scientific basis and clinical role. 1993 May The ability of laser irradiation to destroy tissue is well known. Less well known is the fact that the same radiation, at much lower intensities, can non-destructively alter cellular function. This latter phenomenon, which occurs in the absence of significant heating, is now a basis for the conservative treatment of a variety of musculoskeletal, neurological, and soft tissue conditions in many parts of the world. This review first examines the 25-year history and scientific basis of "laser therapy." Clinical applications are discussed and the reasons for its relative lack of acceptance in the US are examined. The article concludes with an overview of current research and the impact it will have on laser therapy's role in US clinical practice.
8147924 Variation among rheumatologists in the use of prednisone and second-line agents for the tr 1994 Apr OBJECTIVE: To test for and estimate variation among rheumatologists in their prescribing of prednisone and second-line agents for the treatment of rheumatoid arthritis (RA), after taking into account the characteristics of their patients. METHODS: Multiple logistic regression incorporating random effects for rheumatologists, with adjustment for patient characteristics. RESULTS: Values for the likelihood-ratio statistic provided strong evidence of such variation. Random-effect variance estimates showed that the variation is of great magnitude. CONCLUSION: Even after patient characteristics have been taken into account, the data show that the rheumatologist may strongly influence the use of prednisone and second-line agents by a patient.