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

ID PMID Title PublicationDate abstract
8250611 Complement activating properties of monoreactive and polyreactive IgM rheumatoid factors. 1993 Nov OBJECTIVES: To estimate the complement activating properties of monoclonal, monoreactive, and polyreactive IgM rheumatoid factors derived from Epstein-Barr virus transformed B cells isolated from peripheral blood and synovial tissue of patients with rheumatoid arthritis (RA). METHODS: An enzyme linked immunosorbent assay (ELISA) was used to measure the activation of the classical pathway of complement by monoclonal IgM rheumatoid factor. Monoclonal IgM rheumatoid factor was bound to IgG Fc adsorbed onto microtitre plates and then reacted with diluted normal human serum as a source of complement. The activation and binding of C4 were measured with F(ab')2 antibody to human C4. The complement activating property of IgM rheumatoid factor bound to IgG Fc was tentatively expressed as the ratio of the amount of bound C4 to the amount of bound IgM rheumatoid factor. RESULTS: The complement activating property of monoreactive IgM rheumatoid factor was shown to be about three times higher than that of polyreactive IgM rheumatoid factor. CONCLUSIONS: Monoreactive IgM rheumatoid factor with the higher complement activating property would result in a greater degree of complement dependent inflammation and might have a more important pathogenic role in RA than polyreactive IgM rheumatoid factor.
8484698 Adjuvant oestrogen treatment increases bone mineral density in postmenopausal women with r 1993 Apr OBJECTIVES: The beneficial effect of oestrogens on bone mineral density in women with osteoporosis is well known. Patients with rheumatoid arthritis (RA) are at risk for osteoporosis. A study was therefore set up to investigate the effects of adjuvant oestrogen treatment on bone metabolism and bone mineral density in postmenopausal women with RA. METHODS: Forty postmenopausal women with active RA were admitted to a placebo controlled, double blind study investigating the beneficial effect of adjuvant oestradiols or placebo on bone metabolism and bone mineral density. Thirty three patients completed 52 weeks of treatment. RESULTS: At the start both treatment groups were comparable for all parameters. In the oestrogen group serum concentrations of osteocalcin decreased and concentrations of sex hormone binding globulin increased during the study. Bone mineral density measured by dual energy x ray absorptiometry increased significantly in the lumbar vertebral spine and femoral neck in the oestrogen group compared with the placebo group. CONCLUSIONS: This study shows that the use of adjuvant oestrogens in post-menopausal women with active RA increases bone mineral density.
8983286 Rheumatoid arthritis and cancer risk. 1996 Sep The aim of this study was to examine the cancer pattern in a large group of patients with rheumatoid arthritis (RA). A follow-up study of cancer incidence in RA was conducted within a cohort of 20,699 patients recorded in the Danish Hospital Discharge Register during 1977-1987 by linkage with the Danish Cancer Registry through 1991. There were consistent excesses of non-Hodgkin's lymphoma and Hodgkin's disease in both sexes and during both early and late periods of follow-up. Risks for lung cancer and non-melanoma skin cancer were also increased, with no predilection for any specific histological subtype, while risks for colorectal cancer and female breast cancer were reduced. The cancer pattern seen among Danish RA patients largely supports findings from two earlier Nordic investigations. Thus, there seem to be consistent positive associations between RA and non-Hodgkin's lymphoma, Hodgkin's disease and lung cancer and a consistent negative association with colorectal cancer.
8157289 Persistence of gamma/delta T cell oligoclonality in the peripheral blood of rheumatoid art 1994 Feb The peripheral blood of patients with rheumatoid arthritis (RA) contains oligoclonal gamma/delta T cell populations which may contribute to the pathogenesis of the disease. To investigate whether there is persistent gamma/delta T cell oligoclonality in RA peripheral blood, we screened polymerase chain reaction-amplified T cell receptor (TCR) cDNA, derived from peripheral blood mononuclear cells (PBMC) of four RA patients, with sequence specific oligonucleotides (SSO). The SSO used were specific for TCR variable (V) delta 1, V delta 2 and V gamma 9 transcripts comprising V-joining (J) junctions found over-represented in PBMC of the same RA patients, when bled up to 3 years previously. The dominant transcripts were expressed in the new PBMC samples, although in most cases at a lower frequency than was originally detected. In one patient there was almost 100% oligoclonality of V gamma 9-(N)-J gamma 2 junctional region sequences among the V gamma 9 cDNA clones, progressing from 55% oligoclonality in 15 months. These results indicate the persistence of clonally expanded gamma/delta T cells in the peripheral blood of RA patients. Whether this reflects continual endogenous or exogenous antigenic stimulation remains to be investigated. The findings presented in this report may have important therapeutic implications in view of the potential for immuno-intervention for the treatment of human autoimmune disorders, like RA.
8291449 Recurred Castleman's disease containing a fibrohistiocytic nodular lesion with vascular oc 1993 Oct A recurring case of Castleman's disease containing a fibrohistiocytic nodular lesion is presented. The recurred tumor was found in the mediastinum of a 40 year old Japanese female who had undergone the extirpation of a mediastinal tumor 18 years previously and had been suffering from rheumatoid arthritis 5 years after the initial removal. Microscopically, the present tumor and the initial removed tumor fulfilled the morphologic criteria for the hyaline-vascular type of Castleman's disease. A well-demarcated nodular lesion (1.5 cm in diameter) was located in the present tumor. It consisted of interlacing oval to short spindle-shaped cells positive for factor XIIIa and vimentin, merging with lymphocytes, plasma cells, macrophages and capillaries lined by swollen endothelial cells. Mitotic figures were not noted. Foci of hemorrhage and necrosis were also not detected. The stenosis or occlusion of the large vessels due to intimal fibrosis and medial hypertrophy was observed around the nodular lesion.
8809436 Elastase activity in cartilage extracts and synovial fluids from subjects with osteoarthri 1996 May OBJECTIVE: Polymorphonuclear leukocyte (PMN) elastase is able to degrade the extra-cellular matrix components of cartilage. However, in vitro several proteinases can degrade elastin. The purpose of this study was to evaluate the role of the serine proteinases and metalloproteinases in the elastase activity measured in cartilage extracts from patients with osteoarthritis (OA), as well as in synovial fluid (SF) from patients with rheumatoid arthritis (RA) and OA. METHODS: Elastase activity was determined using synthetic low molecular weight substrates and radiolabelled insoluble elastin. Aminophenyl mercuric acetate was used to activate the prometalloproteinases. RESULTS: Elastase activity, measured using synthetic substrates, was higher in BA SF (0.76 + 0.03 microU/ml, n = 12) than in OA SF (0.14 + 0.04 microU/ml, n = 12) (p < 0.001). This activity was inhibited by metal chelating agents: 86% inhibition in OA and 75% inhibition in RA. However, in RA SF the inhibitor of serine proteinase (PMSF) also induced a 40% inhibition. Elastase activity, measured using radiolabelled elastin, in OA SF and RA SF samples and in OA cartilage extract was very low, but increased following activation by mercurial agents. Again this activity was inhibited by metal chelating agents. CONCLUSIONS: Taken together these results indicate that elastase activity (measured by standard methods) in OA and RA SF is mainly due to metalloenzymes.
7783056 Isolated microscopic hematuria in patients with rheumatoid arthritis compared with age and 1995 Mar OBJECTIVE: To evaluate the prevalence and causes of isolated microscopic hematuria in patients with rheumatoid arthritis (RA). METHODS: An unselected population of 1018 patients with RA (810 women, 208 men) were studied prospectively (n = 604) or retrospectively (n = 414), and the results were compared with an age and sex matched control population (n = 457; 352 women, 105 men). Hematuria was defined as a positive dipstick result in 2 urine samples, and was regarded as isolated when no concomitant proteinuria was found (urine protein excretion < or = 0.15 g/24 h). To investigate the urological causes of isolated hematuria, urine cytology, renal ultrasound, and urethrocystoscopy were undertaken. Renal biopsy was performed when no urological lesions were found. RESULTS: There was no difference in the prevalence of isolated hematuria between patients with RA and controls (women 10 and 9%, men 5 and 6%, respectively; total 9% for both). Mild mesangial glomerulopathy was the most common renal biopsy finding in patients with RA with isolated hematuria, found in 13 of 15 adequate renal biopsy specimens. The cause of hematuria remained uncertain or unknown in 52% of the patients with RA and in 61% of controls. CONCLUSION: The prevalence of isolated microscopic hematuria was not significantly more frequent in patients with RA than in age and sex matched controls. This result was independent of the definition or grade of hematuria. Mesangial glomerulopathy was the most common renal biopsy finding in patients with RA with isolated hematuria.
8199454 New directions for biological therapy in rheumatoid arthritis. 1994 Advances in our understanding of the pathogenesis of rheumatoid arthritis (RA), together with developments in hybridoma and molecular technology have opened the way for more directed therapy in this disease. In reviewing the experience so far with T-cell-directed biological agents, we show that the early promise displayed by anti-CD4 monoclonal antibodies in open clinical trials has not been sustained in controlled studies. This outcome provides a challenge to the concept that CD4+ T cells are of prime importance in RA, and prompts a search for alternative therapeutic targets. Agents directed towards other leucocyte antigens such as CD5, CDw52 or the receptor for interleukin 2 have induced clinical responses in early studies, but at the expense of significant toxicity. Newer therapies targeting the monokines tumour necrosis factor alpha (TNF-alpha), IL-1 and IL-6, and the leucocyte adhesion molecule intercellular adhesion molecule 1 (ICAM-1) have provided encouraging clinical improvements and, in the case of anti-TNF-alpha and anti-IL-6, impressive modulation of the acute-phase response. Strategies allowing long-term blockade of such molecules, including antibody reshaping and the use of soluble cytokine receptors are discussed. Finally, the potential for using biological agents in combination with other therapies is outlined.
7504913 Characterisation of the rat oesophagus epithelium antigens defined by the so-called 'antik 1993 Oct OBJECTIVES: An attempt was made to characterise the antigens recognised by serum IgG antibodies directed to the stratum corneum of rat oesophagus epithelium, the so-called 'antikeratin antibodies', which were shown to be highly specific for rheumatoid arthritis (RA) and thus to have an actual diagnostic value. METHODS: Immunoblotting was performed with RA serum samples on different extracts of rat oesophagus epithelium separated by various monodimensional and two dimensional electrophoreses. RESULTS: Three low-salt-soluble antigens sensitive to proteinase K and, therefore, of protein nature were identified. Two proteins, with apparent molecular masses of 210 and 120-90 kilodaltons, shared isoelectric points ranging from 5.8 to 8.5; the third protein exhibited isoelectric points from 4.5 to 7.2 while its molecular mass ranged from 130 to 60 kilodaltons. Immunoadsorption of RA serum samples onto cytokeratins extracted from the stratum corneum of rat oesophagus epithelium did not change their immunoreactivity towards the three antigenic proteins. Widely used deglycosylation and dephosphorylation methods failed to modify either the electrophoretic migration of the proteins or their immunoreactivity with RA serum samples. CONCLUSION: The so-called 'antikeratin antibodies' do not react with cytokeratins. They specifically recognise three late epithelial differentiation proteins which had not been previously described. These proteins may be related to (pro)filaggrin.
8737716 Microheterogeneity of alpha 1-antitrypsin in relation to the concentration of its complex 1996 Mar OBJECTIVE: Serum alpha 1-antitrypsin (alpha 1AT) is an acute-phase glycoprotein which contains three carbohydrate side chains, N-glycosidically linked to the asparagine molecules (Asn46, Asn83 and Asn247) of the single polypeptide unit. "Microheterogeneity", which is a varying proportion of bi- or triantennary heteroglycans attached to the glycosylation sites, has been observed in various inflammatory states including rheumatoid arthritis (RA), and may influence the properties of alpha 1AT. METHODS: In this study, we used affinity immunoelectrophoresis with the lectin concanavalin A (ConA) to investigate the possible role of alpha 1AT microheterogeneity in IgA-alpha 1AT complex formation. The concentrations of alpha 1AT and its glycosylation variants, the level of immunoglobulin A (IgA), and concentration of IgA-alpha 1AT complex were determined in the sera of 43 patients with RA. RESULTS: In seven patients, high concentrations of the IgA-alpha 1AT complex were found. This group did not differ from the remaining patients in sex, age, or disease activity. However, significantly higher concentrations of both the alpha 1AT variant 1a+1b (with a predominance of triantennary heteroglycan side chains) and IgA were found in patients with an elevated complex compared to those with low serum levels of IgA-alpha 1AT complex (p < 0.05 for both variables). In the entire group, there was a significant correlation between the IgA-alpha 1AT complex level and both serum IgA and the concentrations of alpha 1AT variants 1a+1b and 2 (r = 0.3473, p < 0.05; r = 0.4604, p < 0.005; r = 0.3176, p < 0.05, respectively). CONCLUSION: The results suggest that the microheterogeneity of alpha 1AT may play a part in the formation of the IgA-alpha 1AT complex in RA.
7939138 Tolerability of methotrexate starting with 15 or 25 mg/week for rheumatoid arthritis. 1994 The objective of the present study was to assess the rate of side-effects and dose-limiting toxicity in patients with rheumatoid arthritis (RA) receiving methotrexate (MTX) at an initial dose of 15 or 25 mg/week. One hundred and eighty-five patients with active RA were enrolled into a prospective non-blind trial over 12 months and randomized to start at a dose of 15 mg/week with subsequent increases if necessary (group A) or 25 mg/week with subsequent dose reductions according to effect (group B). With 168 patients eligible for evaluation 74% of patient in group A and 73% of patients in group B were on MTX after 12 months. Withdrawal due to side-effects amounted to 16% of patients in group A and 18% in group B, and decreases in dose due to side-effects amounted to 10% in group A and 9% in group B. The higher dose of MTX elicited a significantly higher rate of gastrointestinal side-effects (28% versus 17%, P < 0.05) and a tendency towards a higher rate of liver enzyme elevations (47% versus 39%). The frequencies of other side-effects did not differ significantly between the groups. We concluded that starting MTX treatment at a dose of 25 mg/week was associated with a higher rate of minor but not major toxicity as compared with 15 mg/week. With this profile of tolerability it is possible to examine the therapeutic potential of MTX doses exceeding 15 mg/week.
9296920 [The use of low doses of sodium aurothiomalate in the treatment of rheumatoid arthritis. C 1996 Dec We studied 20 patients suffering from rheumatoid arthritis treated with small doses of sodium aurothiomalate (20 mg/month, seldom 40 mg/month) for a mean time of 6.1 years (range 2.7-10.6). 16 subjects were women and 4 men; their mean age was 58 years (range 35-77). 9 patients (45%) were affected by seropositive RA; the mean duration of disease was 1.5 years (range 0.3-7.3). 14 patients achieved the grade 1 of disease activity, evaluated by Mallya and Mace's (1981) criteria: 9 subjects after 3-9 months and 5 subjects after 2-5 years. The mean length of this remission state was 4.3 years (range 0.9-9.9). Side dermatological effects (skin rashes, pruritus, exfoliative dermatitis) were observed in 3 patients (15%); 1 patient (5%) was withdrawn from the study. We have discussed the numerous advantages of low doses of sodium aurothiomalate monotherapy, although this therapy has to be employed only in patients selected by prognostic features. Moreover we briefly mention the actual opinions in R.A. therapy that discuss the traditional pyramidal approach in favour of more aggressive therapy with combination of various disease-modifying drugs in many R.A. patients.
7488292 Rheumatoid synovial fibroblast adhesion to human articular cartilage. Enhancement by neutr 1995 Nov OBJECTIVE: To determine if preexposure of human articular cartilage to activated neutrophils alters rheumatoid synovial fibroblast adhesion to human articular cartilage. METHODS: Human articular cartilage was exposed to either activated neutrophils, interleukin-1, or supernatants obtained from activated neutrophils that had been treated with different protease inhibitors. Radiolabeled rheumatoid synovial fibroblasts were then incubated with the cartilage and the number of counts associated with the cartilage was determined. RESULTS: Pretreatment of human articular cartilage with either activated neutrophils or supernatants obtained from activated neutrophils enhanced subsequent rheumatoid synovial fibroblast adhesion. In contrast, interleukin-1 treatment of cartilage did not alter the adhesion of synovial fibroblasts. The enhanced adhesion could be attenuated by pretreatment of the neutrophil supernatants with either diisopropylfluorophosphonate or EGTA and almost completely abolished by using both inhibitors. CONCLUSION: This study demonstrates that adhesion of rheumatoid synovial fibroblasts to human articular cartilage can be enhanced by exposing the cartilage to proteases released by neutrophils. These results suggest that neutrophil products may play a role in enhancing adhesion of rheumatoid synovium to cartilage in vivo.
8641702 Allele-specific quantification of TNFA transcripts in rheumatoid arthritis. 1996 Jun Clinical and laboratory studies have suggested a pivotal role for tumor necrosis factor alpha (TNFA) in the pathogenesis of rheumatoid arthritis (RA). Interindividual variation in the expression of TNFA indicates the existence of functionally distinct TNFA alleles that could play a role in susceptibility to TNFA-associated diseases such as RA. In order to determine whether differential TNFA gene expression is present in RA, we studied the relative contribution of TNFA alleles to the total amount of steady-state mRNA in peripheral blood mononuclear cells of RA patients and healthy individuals. Moreover, allelic TNFA mRNA expression was analyzed in synovial biopsy material of RA patients. For this purpose, we used the recently identified C-insertion polymorphism located in the 5' untranslated region of the first exon. The location of this polymorphism within a part of the gene that is transcribed into mRNA allowed us to discriminate between the contribution of each allele to the total amount of TNFA mRNA in heterozygous individuals. The results of this study do not indicate the existence of variation at the level of mRNA transcribed from each TNFA allele by in vitro and physiological stimulation conditions in RA patients. Therefore, our data do not suggest a role for transcriptionally distinct TNFA alleles in the susceptibility to RA.
8411760 [Clinical significance of microalbuminuria in patients with rheumatoid arthritis]. 1993 Jul In order to make an estimate of clinical significance of microalbuminuria (MAU) in patients with rheumatoid arthritis (RA), we studied MAU in 138 patients with RA without macroalbuminuria. MAU was assayed by double-antibody RIA in the ambulatory urine. Moreover, urinary (U) beta 2-microglobulin (BMG) and N-acetyl-beta-D-glucosaminidase (NAG) were simultaneously measured. The values for MAU/U-creatinine (U-Alb index) in patients with RA, osteoarthropathy (OA) and normal controls were 25.7 +/- 38.2, 11.4 +/- 11.5 and 7.7 +/- 3.5, respectively, and U-Alb indices in patients with RA were significantly higher than U-Alb indices in patients with OA and normal controls. Especially, in patients with RA receiving lovenzarit disodium and gold sodium thiomalate (GST), U-Alb indices were elevated. U-Alb indices were not correlated with clinical findings in RA. Also, U-Alb indices were not correlated with U-BMG indices and U-NAG indices in patients with RA. In serial measurements of U-Alb index, U-BMG index and U-NAG index in a patient with RA who developed massive macroalbuminuria during GST therapy, it was found that U-Alb index was elevated first, followed by U-NAG index and finally U-BMG index was elevated. These results indicate that U-Alb indices are elevated in patients with RA without macroalbuminuria, and serial measurements of MAU in patients with RA, especially receiving disease modifying antirheumatic drugs, are useful for the detection of subclinical glomerular injury.
8991986 The B7 cross reactive group and spondyloarthropathies: an epidemiological approach. 1995 Oct OBJECTIVE: To study the association between the B7 cross reactive group (B7, B40) and spondyloarthropathy (SpA), taking into account patients with atypical features. METHODS: We studied the main clinical and paraclinical features of 51 patients with rheumatoid arthritis, 55 with SpA, 120 with mechanical diseases, and 160 with inflammatory rheumatism not fulfilling the diagnostic criteria currently used. This descriptive analysis was performed using multiple correspondence factorial analysis to identify subgroups among unclassified patients and select SpA variants. We compared HLA frequencies among these groups versus a control group. RESULTS: We identified a subgroup close to the axial SpA and related to B7 (OR:5.91, p = 0.0008), whereas B40 is related to patients close to the peripheral SpA. CONCLUSION: B7 is related to axial SpA variants manifested by inflammatory low back pain according to Calin's criteria, with either extraarticular signs or sacroiliitis. Followup of such patients is required to determine whether their disease is a new entity or can be considered SpA.
1563757 [Circulating CD8 as an indicator of inflammatory rheumatic disease]. 1992 Feb An enzyme-linked immunoassay detecting soluble CD8 (s-CD8) was applied to study activation of CD8(+)-(suppressor/cytotoxic) T-cells in patients with rheumatic diseases. Compared with normals, s-CD8 levels were elevated in patients with rheumatoid arthritis, ankylosing spondylitis, and polymyositis. In contrast, low s-CD8 values were observed in patients with progressive systemic sclerosis/scleroderma. In systemic lupus erythematosus (SLE), s-CD8 values were correlated with C-reactive protein. This finding and an association with other parameters of clinical activity were confirmed by longitudinal studies. In summary, our findings support the view that implication of CD8(+)-T-cell activation is different in the pathogenesis of each rheumatic disease. Elevated s-CD8 indicates active disease, and can be used to monitor CD8(+)-T-cell activation in SLE while determination of s-CD8 seems to be of little clinical value in the other rheumatic diseases studied.
1385154 Integrins and other adhesion molecules on lymphocytes from synovial fluid and peripheral b 1992 Nov Cell and matrix adhesion of lymphocytes participates in homing, migration and accumulation of these cells in inflamed tissues as well as in the generation of immune and inflammatory responses. In inflamed joints of rheumatoid arthritis (RA) patients, lymphocytes accumulate in the synovial membrane and the synovial fluid. In the present study we have analyzed the expression of integrins and other adhesion molecules in synovial fluid lymphocytes (RA-SFL) and paired peripheral blood lymphocytes (RA-PBL) from 21 RA patients by immunofluorescence flow cytometry. We have also investigated the expression of these adhesion molecules on peripheral blood lymphocytes obtained from 13 sex- and age-matched healthy controls (CO-PBL). RA-SFL, which consisted mostly of T cells, showed higher expression of the integrin subunits beta 1 (CD29), VLA-1 alpha, -3 alpha, -4 alpha, -5 alpha and -6 alpha when compared to RA-PBL. In turn, RA-PBL showed lower expression of these molecules than CO-PBL. The expression of the immunoglobulin-related molecules CD2, CD54 (ICAM-1) and CD58 (LFA-3) was higher on RA-SFL when compared to RA-PBL or CO-PBL, and similar results were obtained with the beta 2 integrin subunits CD11a and CD18. In contrast, L-selectin (LECAM-1) and ICAM-2 were expressed at much lower levels on RA-SFL than on RA-PBL or CO-PBL. CD44, a receptor for hyaluronic acid and collagen, was expressed by most RA-SFL, RA-PBL and CO-PBL cells but at higher density on RA-SFL. The results indicate that RA-SFL express a distinct array of adhesion molecules, similar to the one of memory T lymphocytes. This characteristic phenotype may contribute to the lymphocytic infiltration of the synovium and to the pathogenesis of RA.
7559821 The operative repair of chronic nontraumatic extensor tendon subluxations in the hand. 1995 Aug The authors study the literature and the surgical treatment in chronic nonrheumatoid cases. Their technique employs one-half of the extensor digitorum communis tendon as a tether on the central extensor tendon, recentralizing it over the metacarpophalangeal joint.
7524018 [Biochemical markers in RA]. 1994 Inflammatory activity is usually (but not always) accompanied by increases in the plasma concentrations of acute-phase reactants such as C-reactive protein (CRP), fibrinogen etc. The most widely used and most sensitive variable is the CRP value. Increase in the concentrations of acute-phase reactants is accompanied by increase in the ESR (erythrocyte sedimentation rate), though increase in ESR may also be secondary to hypergammaglobulinaemia and anaemia without co-existing inflammation. The measurement of various connective tissue markers in the blood, synovial fluid and urine has opened up the way to new possibilities for evaluating synovial inflammation, pannus formation, and cartilage and bone destruction.