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ID PMID Title PublicationDate abstract
8596141 Occurrence of antineutrophil cytoplasmic and antineutrophil (peri)nuclear antibodies in rh 1995 Nov OBJECTIVE: To elucidate whether sera from patients with rheumatoid arthritis (RA) contain antineutrophil cytoplasmic antibodies (ANCA) or granulocyte specific antinuclear antibodies (GS ANA), or both, and to analyze possible correlations with different clinical and laboratory data. METHODS: Forty-seven consecutive outpatients with RA were included. Control sera were obtained from patients with well defined rheumatic diseases and from healthy individuals. Serum samples were examined by indirect immunofluorescence (IIF) on both ethanol and paraformaldehyde fixed neutrophils and by ELISA using as substrates myeloperoxidase (MPO), proteinase 3, and a purified extract of alpha-granules. ANA were detected by IIF using cultured HEp-2 cells. RESULTS: Twenty-three patients (49%) had a perinuclear pattern (p-ANCA) by ethanol fixation, of which only 2 became cytoplasmic on paraformaldehyde fixed cells. These 2 patients also had a positive myeloperoxidase ELISA, while none of the remaining 45 had a positive result from the 3 ELISA performed. All 21 patients (45%) with a p-ANCA pattern that was not modified by paraformaldehyde fixation had a specific immunostaining upon examination at high power magnification; we termed this GS ANA specific pattern. The specificity of this pattern was further confirmed by a doubled blind test performed by 2 independent observers. In our study, all GS ANA pattern positive sera fulfilled the previously known definition of these antibodies. We found no relationship between GS ANA and variables such as disease duration and activity, rheumatoid factor, and vasculitis. Notably, 2 RA patients with "true" ANCA (anti-MPO antibodies) had an associated pulmonary-renal syndrome (microscopic polyangiitis). CONCLUSION: Most p-ANCA in our series of patients with RA did not seem to correspond to "true" ANCA but to antibodies directed against nuclear or perinuclear antigenic constituents of the neutrophils (GS ANA). The observation of their distinctive and specific immunostaining pattern, when screening patients for the presence of ANCA by IIF, may alert us to the possible presence of RA.
8325086 Extrinsic nonvalvular mitral obstruction due to large epicardial hematoma. 1993 Jul A case of extrinsic nonvalvular mitral obstruction due to a large epicardial hematoma in a patient with rheumatoid constrictive pericarditis is described. The patient had longstanding rheumatoid arthritis and a mitral diastolic murmur developed. Mitral obstruction was confirmed by a hemodynamic study. Coronary angiography and left ventricular angiography showed severely diseased coronary arteries and a distorted left ventricular cavity. Autopsy demonstrated rheumatoid arthritis, a normal mitral valve, thickened pericardium, and epicardial hematoma surrounding both ventricles at the atrioventricular junctional level.
8808287 Serum IgE concentration and other immune manifestations of treatment with gold salts are l 1996 Jan 1 A subset of patients with rheumatoid arthritis occasionally develops skin reactions and glomerulonephritis and exhibits an increase in serum IgE concentration when treated with gold salts. Brown-Norway (BN) rats injected with aurothiopropanolsulfonate (ATPS) also manifest an autoimmune glomerulonephritis and increased serum IgE concentration, whereas Lewis (LEW) rats are resistant to complications. Here, we show linkage between responses to ATPS in a (BN x LEW) F2 cohort and the major histocompatibility complex (RT1) on rat chromosome 20 and between markers in the region of IL4 and other candidate genes on rat chromosome 10. Recently, human serum IgE concentration has been reported to be linked to the IL-4 region. Taken together, these findings raise the possibility that homologous genes could be implicated in ATPS manifestations in the rat and in the regulation of IgE levels in the human.
7612411 Animal models in rheumatoid arthritis. 1995 May Two new models for the study of rheumatoid arthritis have been established. SCID (severe combined immunodeficient) mice implanted with human synovial tissues and human HLA-DR4-CD4 transgenic mice represent novel and important approaches to the use of animal models in pathogenetic studies. New studies of streptococcal cell wall arthritis in rats demonstrated that beta 1 integrin-mediated cell-matrix interactions are involved in the induction and perpetuation of inflammatory synovitis and that systemic administration of interleukin-4 selectively suppresses established synovitis, presumably by effects on monocyte function. The importance of nitric oxide as a mediator of synovial inflammation was confirmed in the adjuvant-induced model of rheumatoid arthritis. In the collagen-induced arthritis model, interesting new data have implicated gamma delta T cells in the pathogenesis of arthritis, and the antineoplastic drug taxol was shown to have anti-inflammatory effects.
8835247 IgG glycosylation in association with tropical infections and rheumatoid arthritis in the 1995 Nov Studies conducted in Europe suggest an association between IgG glycosylation abnormalities and rheumatoid arthritis (RA). Glycosylation abnormalities have been shown in other inflammatory diseases such as tuberculosis, systemic lupus erythematosus (SLE) and Crohn's disease. These observations led us to study glycosylation abnormalities among patients with RA and healthy controls in the tropics (sub-Saharan Africa). Using a lectin binding assay, we found that glycosylation differences were present in both groups when compared with British rheumatoid and healthy controls. This suggests that IgG glycosylation abnormalities may occur in association with chronic infections in the tropics.
9065055 [Intra-articular B-cells in the pathogenesis of rheumatoid arthritis]. 1996 B-cells of the rheumatoid synovial tissue are constant and in some cases dominant elements of the inflammatory infiltrate and are located near to the site of tissue destruction. The pattern of B-cell distribution, the pattern and the relationship to the corresponding antigen presenting cells (follicular dendritical reticulum cells; FDC's) shows a great variation: B cells exhibit a follicular organisation forming secondary follicles, follicle like patterns with irregular formed FDC's networks and a diffuse pattern of and isolated FDC's. Molecular analysis of immunoglobulin genes from synovial B-cell clones and synovial tissue demonstrates the occurrence of immunoglobulin gene hypermutation as well as germline configuration. The FDC formations in the synovial tissue may therefore serve as an environment for B-cell maturation which is involved in the generation of autoantibodies. An autoantibody may be only defined as "pathogenic" if the antibody fulfills the Witebsky-Rose-Koch criteria for classical autoimmune disease: definition of the autoantibody, induction of the disease by transfer of the autoantibody and isolation of the autoantibody from the disease specific lesion. B-cells of rheumatoid synovial tissue show specificity for FcIgG, collagen 2, sDNA, tetanus toxoid, mitochondrial antigens (M2) and bacterial HSP's and the contribution of these antibodies to the pathogenesis of RA are still hypothetic. Antibody with specificity for bacterial HSP's which have arose during contact with an infectious agent and may due to crossreactivity with eukaryotic HSP of synovial tissue perpetuate the local inflammatory process. The characteristic pattern, the localisation within the area of tissue destruction and the exclusive function of B-cells to recognize conformation dependent antigens suggests a central role of B-cells in the inflammatory process. The analyzation of the synovial tissue B-cell therefore will help to characterise antigens which are responsible for the pathogenesis of RA.
7758572 Fatal pulmonary hypertension and rheumatoid vasculitis. 1995 Feb A 51 year old man with mild rheumatoid arthritis developed pulmonary hypertension in the absence of interstitial lung disease. A cutaneous vasculitis subsequently responded to immunosuppressive therapy, but the lung disease was refractory to treatment. In patients with rheumatoid arthritis, dyspnoea should be investigated at an early stage, even in the absence of obvious pleural or interstitial lung disease.
7590814 Monoclonal anti-TNF alpha antibody as a probe of pathogenesis and therapy of rheumatoid di 1995 Apr Rheumatoid arthritis is a common cause of chronic disability for which current therapies are of limited value in controlling the disease process and outcome. Our initial approach to understanding the pathogenesis of RA and defining a novel therapeutic target was to investigate the role of cytokines by blocking their action with antibodies on cultured synovial-derived mononuclear cells in vitro. These investigations suggested that neutralization of TNF alpha with antibodies significantly inhibited the generation of other pro-inflammatory cytokines also over-produced, such as, IL-1, GM-CSF, IL-6 and IL-8. The implication that blockade of a single cytokine, TNF alpha might have far-reaching effects on multiple cytokines and thereby exert significant anti-inflammatory and protective effects on cartilage and bone of joints, was tested in arthritic DBA/1 mice immunized with collagen II. Impressive amelioration of joint swelling and joint erosions in this model encouraged clinical trials with a monoclonal anti-TNF alpha antibody. The cA2 chimeric anti-TNF alpha high-affinity antibody was initially tested in an open-label study at a dose of 20 mg/kg on 20 patients, with substantial and universal benefit. Subsequently, a randomized placebo-controlled double-blind trial was performed on 73 patients comparing a single intravenous injection of placebo (0.1% human serum albumin) with two doses of cA2. Using a composite disease activity index, at 4 weeks post infusion, 8% of patients receiving placebo improved compared with 44% receiving 1 mg/kg cA/2 and 79% receiving 10 mg/kg. Between 2 to 4 repeated cycles of cA2 were administered to 7 patients and all patients showed improvement of a similar magnitude with each cycle. These data support our proposition that TNF alpha is implicated in the pathogenesis of RA, and is thus a key therapeutic target. Monoclonal anti-TNF alpha antibodies control disease flares and are candidate agents for longer-term control of RA, although repeated therapy with cA2 is associated with anti-idiotypic responses in 50% of patients and a trend toward shortening of the duration of response. In the DBA/1 arthritic mice, synergy of action of anti-TNF and anti-CD4 is observed together with suppression of an anti-globulin response, indicating one way in which benefit might be augmented in the future.
8581516 Production of PAF-acether by synovial fluid neutrophils in rheumatoid arthritis. 1995 Aug PAF-acether (PAF) is a pro-inflammatory phospholipid molecule potentially involved in the pathogenesis of arthritis. PAF and related metabolites have been isolated in the synovial fluid from patients with arthritis. The aim of this study was to determine fluid and blood in patients with rheumatoid arthritis. Blood neutrophils from normal donors were also studied for their capacity to form PAF. Neutrophils were stimulated with the calcium ionophore A23187 (2 microM) for 1 to 60 min. PAF released in the medium and PAF associated to cells were measured. In synovial fluid neutrophils. PAF production began as soon as 1 min of stimulation (16.1 +/- 6.3 pmol per 1 x 10(6) cells) and reached a maximum at 20 min: 29.2 +/- 2.8 pmol per 1 x 10(6) cells (mean +/- SEM, n = 5). The amount of PAF released in the supernatant increased with the length of stimulation, similar amounts of PAF were produced by blood neutrophils isolated from the joint had a lower capacity to produce PAF than blood neutrophils from the same patients. The present results demonstrate the synthesis and release of PAF by synovial fluid neutrophils. They suggest that neutrophils may be source of PAF locally present in the joint. Newly synthesized PAF could participate in the amplification of the local inflammatory reaction.
8803911 The use of antimalarials in combination with other disease modifying agents in rheumatoid 1996 Jun A significant proportion of patients with rheumatoid arthritis have an aggressive, severe disease that may contribute to excess mortality. It has been suggested that early, aggressive therapy might improve the prognosis of these patients with active, severe rheumatoid arthritis. Combinations of disease modifying anti-rheumatic drugs including antimalarials are increasingly used in patients with active disease. While several open trials showed encouraging results, some controlled studies gave less support for the use of combination therapy. Ongoing controlled trials of double or triple combination therapy, such as hydroxychloroquine, methotrexate and sulphasalazine, should help define its place in treating patients with rheumatoid arthritis.
8997919 The use of trained patient educators with rheumatoid arthritis to teach medical students. 1996 Aug OBJECTIVE: To assess whether patients with rheumatoid arthritis (RA) trained as educators can enhance the integration of clinical and basic science education among second-year medical students during their rheumatology sequence. METHODS: Twenty patients with RA and strong communication skills were extensively trained to teach students how to perform the whole-body joint examination. Each arthritis educator taught three 2-hour small group sessions and participated in a concluding 2-hour panel discussion with the entire class. Changes in student knowledge and attitudes were assessed in a pre-post evaluation design. RESULTS: There were statistically and educationally significant gains in knowledge, confidence, and attitudes related to psychosocial aspects of arthritis in each of the 2 years the program was implemented. One-year followup data indicated substantial retention of these gains. CONCLUSIONS: Patients trained in arthritis education can effectively teach fundamental musculoskeletal examination skills and encourage the development of sensitivity to the impact of chronic arthritis on the daily life of other patients.
7981439 On whole blood viscosity measurements in healthy individuals and in rheumatoid arthritis p 1994 Jul Different methods of measuring whole blood viscosity using a couette rotational viscometer were compared to establish its use in clinical rheumatological practice. The relationship between blood viscosity and hematocrit was approximately exponential and no significant differences in the slopes were found between healthy controls and rheumatoid arthritis patients. Correction of native blood viscosity to a standard hematocrit of 40% by extrapolation from a standard regression curve, established by concentration/dilution of samples from healthy persons to correct for hematocrit differences and at shear rate 92s-1, was the best method for differentiating between viscosities of patients and controls. It was also the least laborious method, requiring the smallest amounts of blood and having the lowest method error. Native blood viscosity, corrected blood viscosity, plasma viscosity and red cell aggregation were all significantly higher and hematocrit significantly lower in rheumatoid arthritis patients than in controls.
7571613 [Concentration of serum sulphydryl groups in patients with rheumatoid arthritis dependent 1994 Sep In 67 patients with classical or certain (according to the ARA criteria) rheumatoid arthritis, the concentration of serum sulphydryl groups (SH) was studied. A statistically significantly decreased concentration of these groups was found in the patients with rheumatoid arthritis (397.1 +/- 31.7 mumol/l). Besides that the studies demonstrated that the concentration of serum SH groups depended on the age of the patients and duration of the disease. For example, in time range of disease duration from one to 15 years, the concentration of SH groups was 395.9 +/- 28.5 mumol/l, from 16 to 20 years: 337.0 +/- 32.0 mumol/l, and from 26 to 30 years: 290.0 +/- 17.2 mumol/l. The changes of the concentration of serum SH groups in patients with rheumatoid arthritis may become, according to many researchers, a very sensitive biochemical index in the assessment of the course of the inflammatory process.
8535641 Combination of sulphasalazine and methotrexate in the management of rheumatoid arthritis-- 1995 Nov Over the past fifteen years, there has been increasing interest in the use of combinations of medications to better suppress the inflammatory process that leads to progressive disability in most rheumatoid arthritis patients. We have been evaluating the combination of sulphasalazine and methotrexate for the last 8 years. Although these data are uncontrolled, our experience would suggest that this combination is well tolerated. Furthermore, flares of disease occurring with attempts to withdraw either of the two agents suggest that the combination may be effective when the use of these agents individually has not.
8596139 HLA-DR1, DR4, and DRB1 disease related subtypes in rheumatoid arthritis. Association with 1995 Nov OBJECTIVE: To determine the relationship of DR1, DR4, and DR4 subtypes with disease severity in patients with rheumatoid arthritis (RA). METHODS: We studied a cohort of 103 Caucasian patients with an onset of disease in 1985, and 6 to 7 years of disease at the time of the study. All rheumatologists in Edmonton participated in the city wide study which included hospital and community based patients with mild and severe disease. HLA status was determined using polymerase chain reaction amplification and amplified fragment length polymorphism typing. Outcome measures included joint counts, radiological scores, and physical functional status. RESULTS: Fifty-six patients (54%) were DR4 positive, (OR = 2.3, 95% CI 1.4-3.6, compared to controls). This association was only statistically significant for seropositive patients (OR = 2.8 in seropositive patients and OR = 1.5 in seronegative patients). A higher risk was observed for DR1/DR4 heterozygotes (OR = 6.8 in seropositive patients and OR = 1.7 in seronegative patients). No significant differences were observed in disease activity, joint counts, radiological scores, or functional status among patients carrying 1, 2 or no disease related alleles, although the prevalence of rheumatoid factor (RF) showed a linear association with allele dose (0, 1, or 2). CONCLUSION: DR4 and in particular DR1/DR4 heterozygosity were related to susceptibility to RA only in seropositive patients. RF was a better predictor of severity than disease related HLA subtypes. These findings suggest that the effect of these alleles on severity may be related to seropositivity, or that perhaps, seropositive and seronegative RA are genetically distinct entities. The results of our study suggest that in community based settings, which include patients with milder disease, DR1 and DR4 disease related alleles increase susceptibility for RA, but are not clinically useful as predictors of longer term outcome.
8620657 Immunologic mechanisms in common rheumatologic diseases. 1996 May Rheumatoid arthritis and seronegative spondyloarthropathies are rheumatologic diseases that likely are caused by inflammatory reactions occurring in genetically predisposed individuals mounting an immune response to the antigen. Understanding the immunopathology of these diseases provides insight into their etiology, pathogenesis, and a rationale for therapies targeting immune component interactions. Although the antigen in rheumatoid arthritis is not known, several bacterial antigens have been associated with seronegative spondyloarthropathies. These antigens result in an interaction between the human leukocyte antigen-B27 restricted CD8 positive T lymphocytes and the antigen presenting cell, producing an inflammatory response. Rheumatoid factors are autoantibodies directed against the fragment crystallizable portion of the immunoglobulin G. Rheumatoid factor immunoglobulin G immune complexes contribute to the inflammatory events in the rheumatoid joint, and may play an important role in antigen presentation. A novel antigen capture enzyme linked immunosorbent assay was developed that mimicked B cell surface expressed rheumatoid factor. Conversely, a direct binding enzyme linked immunosorbent assay mimicked secreted rheumatoid factor. Comparison of rheumatoid binding enzyme linked immunosorbent assays showed that the physical state of rheumatoid factor can affect binding characteristics. The state of glycosylation of immunoglobulin G may contribute to its antigenic structure. These physical characteristics may be important in rheumatoid factor's pathogenic role in rheumatoid arthritis.
8549823 Novel synthetic retinoic acid inhibits rat collagen arthritis and differentially affects s 1996 Jan 8 Retinoids affect many biological processes such as cell proliferation, differentiation and morphogenesis, but their effects on arthritic patients and animal models of arthritis are controversial. We tested the effect of a novel synthetic retinoic acid, Am-80 (4-[(5,6,7,8-tetrahydro-5,5,8,8,-tetramethyl-2-naphthalenyl) carbamoyl] benzoic acid), on type-II collagen (CII)-induced arthritis (CIA) in rats. Am-80 markedly suppressed the incidence of arthritis, hindpaw swelling and bone destruction. In contrast, 13-cis-retinoic acid (13-cis-RA) hardly inhibited these CIA symptoms. Moreover, Am-80, but not 13-cis-RA, strongly reduced the serum level of anti-CII antibody and differentially affected the levels of immunoglobulin (Ig) subclasses in vivo: IgG1 and IgG2a levels were decreased, while IgA level was increased without any change in the IgM level. These findings indicate that Am-80 may be one of the lead retinoic acids of a new class of anti-inflammatory agents.
7660686 [TNF inhibitors: a new therapeutic perspective in chronic inflammatory diseases in rheumat 1995 May Interleukin 1 (IL-1) and tumor necrosis factor alpha (TNF alpha) have been identified as important mediators of chronic immuno-inflammatory disease states such as rheumatoid arthritis. Effector cells are triggered by these cytokines to release molecules involved in synovitis and rheumatoid joint destruction, namely prostanoids, leukotrienes, adhesion molecules and metalloproteinases. Modifications of natural inhibitors of IL-1 and TNF alpha, which have been shown to maintain the homeostasis of the cytokine system, are now available by DNA technology. Monoclonal antibodies to TNF and the TNF receptor fusion proteins TNFR 55-IgG and TNFR 75-IgG are currently under clinical investigation in rheumatoid arthritis, inflammatory bowel disease and septic shock. Preliminary results from clinical trials in rheumatoid arthritis suggest that TNF inhibition represents a promising novel interventional strategy providing anti-inflammatory activity and inhibition of effector molecules of structural joint damage.
8744678 Interleukin 10 inhibits interleukin 6 production and acute phase response in rheumatoid ar 1995 To evaluate the effect of interleukin 10 (IL-10) on acute phase response, we determined serum levels of IL-10, interleukin 6 (IL-6), C-reactive protein (CRP), alpha-1-acid glycoprotein (AGP), alpha-1-anti-chymotrypsin (ACT) in 34 rheumatoid arthritis (RA) patients. IL-10 and IL-6 levels were evaluated using an enzyme-linked immunoassay (ELISA). CRP, AGP and ACT levels were measured using rocket immunoelectrophoresis. The results showed that IL-10 serum level was increased in RA patients as compared to controls (60.0 +/- 17.5 pg/ml vs. 7.2 +/- 1.9 pg/ml). IL-6 level was significantly elevated (87.3 +/- 32.7 pg/ml vs. 45 +/- 19 pg/ml, p < 0.05). CRP was significantly increased as compared to healthy controls (34 +/- 19 mg/1 vs. 3 +/- 2 mg/1, p < 0.05). AGP and ACT serum levels were increased in RA patients, but we did not find these changes to be statistically significant. A good negative correlation between IL-10 and IL-6 serum level was found (r = -0.73, p < 0.05). A positive significant correlation between IL-6 serum level and CRP (r = 0.62, p < 0.05), AGP (r = 0.74, p < 0.05) and ACT (r = 0.45, p < 0.05) was established. Moreover, a negative correlation between IL-10 and serum level of CRP (r = -0.76, p < 0.05), AGP (r = -0.60, p < 0.05) and ACT (r = -0.37, p < 0.05) was also shown. According to the data thus far obtained it seems that IL-10 decreases IL-6 production, and by that indirectly affects acute phase response, decreasing CRP, AGP and ACT synthesis.
1503634 Specific and non-specific autoreactive immunity. 1992 Apr Most autoimmune diseases are HLA-associated which supports the notion that they are dependent upon specific immune activation of a limited set of T cell clones. Findings which imply that induction of autoimmune reactivity probably does not differ from normal immune responses are discussed. The possibility of transferring autoimmune disease using T cell clones indicates that target structures for auto-immune attack are also present in healthy individuals. In the present article, it is argued that autoimmune reactions and immunity against nominal conventional antigens in principle are effected and regulated by similar mechanisms. It is assumed that persistent tissue damage occurs if immune attack is directed against tissues that cannot be regenerated, such as in diabetes, or are only slowly reconstituted, such as in rheumatoid arthritis. Normal immune responses are regulated by various inflammatory mediators and cytokines/interleukins. The joint of patients with rheumatoid arthritis is discussed as a model for propagation of immune reactions and tissue destruction in autoimmune disease. Of the different cytokines which are present in the synovial fluid or produced by cells in the synovial tissue, most are presumed to have originated in macrophages/monocytes such as IL-1, IL-6, IL-8, TNF-alpha and TGF-beta. Even so, T cells are believed to have an important role for the continued reactivity associated with autoimmune disease. This discrepancy can be explained in different ways. T cell products might escape detection because they are short-lived, they are immediately consumed or they are produced only during short time intervals.(ABSTRACT TRUNCATED AT 250 WORDS)