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

PMID	Title	PublicationDate	abstract
2510617	Immunoglobulin heavy chain constant region variants in rheumatoid arthritis.	1989 Oct	Polymorphisms within the immunoglobulin heavy chain constant region at switch (S)mu and S alpha 1 loci were studied in patients with rheumatoid arthritis (RA) and controls in parallel with Gm and A2m allotyping. S mu and S alpha 1 restriction fragment length polymorphisms were defined using a S mu probe which was hybridised to SstI digests of DNA extracted from circulating white cells. There were no differences in S mu and S alpha 1 gene or phenotype frequencies between RA and control groups nor within the RA population between DR4 positive and negative subjects. The Gm allotype G1m(x), coded for by genes at the gamma-1 locus, was found in 29/92 (32%) of DR4 positive and 5/52 (10%) of DR4 negative subjects with RA, as compared with 25/115 (22%) cf controls. The A2m allotype A2m(2), coded for by the alpha 2 locus, was found in 11/92 (12%) of DR4 positive subjects with RA, zero of 52 DR4 negative subjects, and 5/115 (4%) of controls. These results exclude a major effect of genes within the heavy chain constant region linked to mu or alpha 1 loci on susceptibility to RA, but suggest that further study of variants closely linked to the alpha 2 locus is indicated.
2062181	Plasma vitamin B12 binding proteins correlate with disease activity in patients with rheum	1991 Jan	The unsaturated vitamin B12 (cobalamin) binding capacity (UB12BC), transcobalamin (TC) I, II and III were measured in plasma and synovial fluid of 55 patients (10 men and 45 women, 25-60 years of age) with rheumatoid arthritis. The vitamin B12 binding proteins in 55 clinically and haematologically normal subjects of similar age group and sex were also studied as controls. The mean plasma concentrations of UB12BC, TCI, II and III were all significantly raised in patients with rheumatoid arthritis (RA) as compared to the normal controls. The increase of all vitamin B12 binding proteins in these patients showed a positive correlation with the increase of total proteins and globulin concentrations, and a negative (inverse) correlation with the albumin concentrations in the plasma, suggesting that these biochemical changes may be systemic consequences of the inflammatory and immunological processes characteristic of rheumatoid arthritis. The UB12BC, TC I and TC III concentrations in the synovial fluid were significantly higher than the corresponding plasma concentrations of these vitamin B12 binding proteins in patients with RA. Vitamin B12 binding proteins in the synovial fluid in these patients were probably at least partly produced locally by inflammatory cells. The mean levels of plasma transcobalamins in patients with severe disease activity were significantly higher than in patients with median or least disease activity. Therefore these proteins may be further studied as possible additional markers of disease activity in patients with RA.
1934868	Homocysteine levels in patients with rheumatoid arthritis treated with low-dose methotrexa	1991 Nov	Plasma homocysteine levels were determined in patients who participated in a randomized, double-blind placebo-controlled trial of folate supplementation (1 mg/day) during methotrexate therapy for rheumatoid arthritis. Plasma and red blood cell folate levels before methotrexate therapy were significantly negatively correlated with homocysteine levels. Homocysteine levels were not significantly correlated with the initial C1 index (an assay that measures the folate status of blood mononuclear cells) or the C1 index during methotrexate therapy. There was no significant difference in homocysteine levels between pretreatment and levels drawn at 3 or 6 months. Initial homocysteine levels were predictive of toxicities, such as gastrointestinal intolerance and elevations of liver enzymes in the placebo group. There was no significant correlation between occurrence of toxicity and initial homocysteine levels in the folic acid-supplemented group. Homocysteine levels were not predictive of the efficacy of methotrexate therapy. We conclude that plasma homocysteine levels are correlated with plasma and red blood cell folate levels before methotrexate therapy but is not correlated with folate status in blood mononuclear cells.
3199396	Methotrexate kinetics in rheumatoid arthritis: is there an interaction with nonsteroidal a	1988 Sep	Pharmacokinetic drug interaction between methotrexate (MTX) and nonsteroidal anti-inflammatory drugs (NSAID) has been implicated in several case reports of MTX related toxicity. We therefore studied the kinetics of low dose (15 mg) oral MTX with and without concomitant NSAID therapy after preliminary determination of the systemic bioavailability of commercial tablets. Fourteen patients with rheumatoid arthritis, age range 44-77 years, participated in paired kinetic studies performed 1-4 weeks apart. The Abbott TDx fluorescence polarization immunoassay was used to measure serum levels and urinary excretion of MTX over 72 h after a single dose. The mean systemic bioavailability was 73% for the 15 mg oral dose. Area under the serum concentration versus time curve for a 50 mg oral dose was 1.1-2.7 times that of the 15 mg oral dose indicating dose dependent absorption. Mean kinetic variables after oral MTX did not differ significantly with and without NSAID therapy despite apparent interactions in individual patients. Renal clearance of MTX correlated with creatinine clearance (r = 0.8, p less than 0.01).
2383057	Anaemia of rheumatoid arthritis: serum erythropoietin concentrations and red cell distribu	1990 Jun	Immunoreactive serum erythropoietin concentrations were measured in 35 patients with anaemia associated with active rheumatoid arthritis. Based on an evaluation of stainable iron in the bone marrow (marrow iron grade 0-4) and serum ferritin concentrations (concentrations less than or equal to 60 micrograms/l compatible with iron deficiency) the anaemia was found to be complicated by iron deficiency in 19/35 (54%) of the patients. The mean serum erythropoietin level (57.6 (SD) 27.3) U/l) was sufficiently raised for the degree of anaemia irrespective of the size of the marrow iron stores. Thus the data do not support the contention that suppressed secretion of erythropoietin is involved in the pathogenesis of anaemia of chronic disorders. There was a significant inverse correlation between the haemoglobin concentration and log serum erythropoietin in the patients with rheumatoid arthritis. In the patients with adequate iron stores, but not in the iron depleted patients, there was a tendency for serum erythropoietin concentrations to correlate positively both with C reactive protein and erythrocyte sedimentation rate. Red cell distribution width (mean (SD) 16.3 (1.8)%) was above normal (11.5-14.5%) both in the iron replete and the iron depleted patients, and the mean red cell distribution width values did not differ significantly among the two subpopulations. The plasma lactoferrin concentration (mean (SD) 137.6 (109.9) micrograms/l) was normal and did not differ significantly between the iron deficient patients and those with adequate iron.
3776361	[Significance of physical activity for the patient with rheumatism--some psychosomatic ref	1986 Jul	Psychosomatic studies in patients with rheumatic diseases have shown the great importance of physical activity. Both educational and constitutional factors play a major role. The early inhibition of physical activity and the suppression of aggressive impulses are responsible for a typical personality structure of the patients. Physical activity is considered to be a substitute for impaired aggressivity and a defense mechanism against depressivity. These factors are clarified by a case report of a patient with rheumatoid arthritis. Practical implications for the management of patients with rheumatic diseases are demonstrated.
2042011	[Osteolytic forms of rheumatoid polyarthritis. Personal cases and review of the literature	1991 Feb	The authors report eight personal cases of severe and multiple osteolysis in rheumatoid arthritis. 42 other cases were found in the international literature. Osteolytic rheumatoid arthritis concern almost exclusively women, often with small stature. Lesions prevail on upper limbs. All peripheric joints can be involved, except knees, ankles and tarses. The most typical and the most constant aspect is the "opera glass hands". Extra-articular manifestations occur in the same rate as for common rheumatoid arthritis. Rheumatoid factor are present in 2/3 of the cases. Pathogeny of these osteolyses remains unknown and a neurologic mecanism is inprobable.
2168825	The effect of recombinant tumor necrosis factor-alpha on superoxide and metalloproteinase	1990 Jul	We studied the effect of recombinant tumor necrosis factor-alpha (rTNF-alpha) on the production of superoxide and metalloproteinase by rheumatoid synovial cells or osteoarthritis chondrocytes. rTNF-alpha significantly inhibited superoxide generation by osteoarthritis chondrocytes and rheumatoid synovial cells at a concentration of 23 U/ml. On the other hand, rTNF-alpha at a concentration of 1500 U/ml significantly enhanced superoxide production by rheumatoid synovial cells, osteoarthritis synovial cells and osteoarthritis chondrocytes, respectively. Metalloproteinase released by rheumatoid synovial cells and chondrocytes derived from osteoarthritis patients were stimulated by rTNF-alpha at a concentration of 94 U/ml. rTNF-alpha at the highest concentration (15000 U/ml) significantly inhibited metalloproteinase release by rheumatoid synovial cells. The enhancing effect of rTNF-alpha at higher concentrations on superoxide production by rheumatoid synovial cells and osteoarthritis chondrocytes was time dependent. These results suggest that rTNF-alpha has a biphasic effect on superoxide and metalloproteinase production, and hence may play an important role in the pathogenesis of inflammatory joint diseases.
3437418	Longterm followup of treatment with D-penicillamine for rheumatoid arthritis: effectivity	1987 Dec	To assess therapeutic effect and toxicity of D-penicillamine in relation to HLA antigens, 111 consecutive patients with rheumatoid arthritis (RA) were followed for a period of 7-9 years. Side effects occurred in 60% and were the main reason for withdrawal in 52%. HLA typing was performed in 86; overall frequencies were comparable with those found in other studies in patients with RA. Drug induced proteinuria (5 patients) was associated with HLA-B8/DR3 (60 vs 9%), and thrombocytopenia (23 patients) with HLA-DR4 (94 vs 67%). Therapeutic effect was good in 26 (23%), and moderate in 30 (27%). No single variable, including HLA antigens, was predictive of effectiveness. It is concluded that although some of the side effects were associated with HLA antigens, HLA typing is not useful in predicting the outcome of treatment with D-penicillamine.
2339014	Dynamic training and circulating levels of corticotropin-releasing factor, beta-lipotropin	1990 Jan	The study aimed at evaluating the effects of a dynamic training program on circulating levels of corticotropin-releasing factor (CRF), beta-lipotropin (beta-LPH), and beta-endorphin (beta-EP) in 8 patients (5 females and 3 males, aged 39-65 years) with classical/definite rheumatoid arthritis (RA). Blood samples were collected immediately before, in the middle of, and after a 6-week high-intensity training period as well as after a subsequent 1-year period of low-intensity training. In addition, baseline data were obtained 3 weeks before the start of the training program. Use of multivariate analyses of variance, and of analyses of variance of contrast variables, indicated a short-term effect of the high-intensity training program for beta-EP with increased levels (P less than 0.05) between the 3rd and the 6th weeks, no significant differences being obtained for CRF or beta-LPH here. Corresponding analyses with regard to the combined high and low-intensity training program revealed CRF (P less than 0.01), and beta-LPH (P less than 0.01) levels to increase over time, no long-term effect being found for beta-EP. Despite the intensity of the dynamic training program, no change was found in pain experience as measured on a visual analogue scale.
1795330	Rheumatoid arthritis antirheumatic drug trials. III. Setting the delta for clinical trials	1991 Dec	Defining the minimum clinically important difference or delta to be detected in a clinical trial depends on a number of factors including the research hypothesis, patient characteristics, the nature of the intervention and the trial design. In 2 previous studies, we have developed standardized procedures for conducting outcome measurement based on current Food and Drug Administration and European League Against Rheumatism guidelines for RA clinical trials, and thereafter, determined the standard deviation for these outcome measures. In the final component of this series of studies, we employed a Delphi technique to establish estimates for delta and calculated the sample size requirements under different conditions of Type I and Type II error probabilities.
3358797	Abnormal glycosylation of serum IgG from patients with chronic inflammatory diseases.	1988 Mar	Results of carbohydrate analysis of serum IgG from patients with rheumatoid arthritis (RA) confirmed an earlier report that IgG from patients with RA is galactosylated to a lesser extent than IgG from healthy individuals. In contrast to the previous report, we found that the content of galactose in IgG from controls and RA patients was negatively correlated with age (P = 0.026 and P = 0.010, respectively). In RA patients, the IgG content of galactose was also negatively correlated with the pain index (P less than 0.05) and was lower in the presence of rheumatoid factor (P less than 0.05). No correlation was found between the galactose deficiency of IgG from RA patients and sex, race, duration of disease, packed red blood cell volume, radiographic grade, disability index, extraarticular manifestations, articular erosions, or treatment with steroids. Furthermore, no correlation was found between the galactose content of IgG and serum levels of IgM rheumatoid factor or the ability of IgG to bind IgM rheumatoid factor in vitro. Significant galactose deficiency was also detected in IgG from patients with systemic lupus erythematosus and Crohn's disease, which suggests that the defect in the galactosylation of IgG is a feature common to a variety of chronic inflammatory diseases. The biologic significance of this observation remains unclear.
2059081	Activation of inflammatory cells by immune complexes containing IgE in serum and synovial	1991 Jun	Neutrophil and monocyte activation by immune complexes containing IgE from serum and synovial fluid of patients with rheumatoid arthritis is reported. Activation of the inflammatory cells was measured by stimulation of the respiratory burst with production of intracellular hydrogen peroxide. Generation of hydrogen peroxide was analysed by a flow cytometric method, using the fluorochrome dichlorofluorescein. The technique was modified to allow measurement of cell activation of both neutrophils and monocytes by immune complexes in suspension. Ten of 14 polyethylene glycol precipitates from serum of patients with rheumatoid arthritis and 10/16 synovial fluids of these patients could activate neutrophils. A positive relation was found between the activation of neutrophils and the total concentration of immune complexes, the presence of IgG, and the presence of IgE in the immune complexes. Activation of monocytes was also shown, but to a lesser extent (8/14 rheumatoid serum samples and 8/16 rheumatoid synovial fluids activated monocytes). There was a weak correlation between the concentration of IgE immune complexes and the intensity of fluorescence measured in the monocytes.
3791708	Acute and chronic pharmacokinetic studies of slow release ketoprofen (Oruvail) in rheumato	1986 Jul	Slow release preparations of non-steroidal anti-inflammatory drugs are used to simplify dose regimes in the treatment of rheumatoid arthritis with the aim of improving patients compliance. This study examines the acute and chronic pharmacokinetics of slow release ketoprofen in 13 rheumatoid patients with a mean age of 59.8 years. Pharmacokinetic parameters following the first dose including Tmax which was 6.92 h (s.e.m. = 0.80), Cmax 3.87 micrograms/ml (s.e.m. = 0.54), apparent half-life 8.8 h (s.e.m. = 1.0) and AUC 41.92 micrograms.h/ml (s.e.m. = 4.02) were not significantly different from those following the last dose after 3 months of chronic treatment, when these were Tmax 6.38 h (s.e.m. = 0.84) Cmax 3.57 micrograms/ml (s.e.m. = 0.33) apparent half-life 8.8 h (s.e.m. = 1.1) and AUC 43.18 micrograms.h/ml (s.e.m. = 5.34) respectively. These results show that no accumulation of ketoprofen occurred with chronic treatment. Clinical assessments were performed in an open design and showed significant improvement in pain, articular index, grip strength and duration of morning stiffness when these parameters were compared to treatment with paracetamol during an initial washout. The drug was well tolerated although there was a trend for the haemoglobin to fall and this parameter should be monitored during therapy with ketoprofen.
2688185	[Open clinical study of liposomal superoxide dismutase in severe rheumatoid arthritis. Stu	1989 Jul	An open clinical study of treatment of severe rheumatoid arthritis (7 cases) with liposomal bovine copper superoxide dismutase is described. The drug was administered by intramuscular injection twice a week for three months and was well tolerated. Of the seven cases five showed good or very good results with significant amelioration. The absence of toxicity indicates that liposomal superoxide dismutase may be used in future trials with a greater number of patients.
3607378	Cervical myelopathy complicating multiple joint replacement in rheumatoid disease.	1987 Aug	The incidence of cervical myelopathy and subluxation was investigated in 48 patients with rheumatoid disease who had three or more major lower limb joint replacements. Eight (17%) developed cervical myelopathy requiring cervical fusion. This was the subsequent cause of death in two. Four further patients demonstrated clinical features of myelopathy. Cervical subluxation was present in 29 of 44 (66%) in whom adequate radiographs were available. The development of cervical symptoms and signs could not have been predicted from the sex, age of onset, duration of disease or steroid therapy. Radiographic changes in the cervical spine were independent of major lower limb joint destruction and were often not present when planning a programme of joint replacement. Fifty-one control patients were studied. Cervical myelopathy occurred in 2 (4%) and subluxation in 24 (47%). The development of rheumatoid changes in the cervical spine was unrelated to involvement of the hip or knee joints in the control group. There was a significant (p less than 0.05) increase in the incidence of cervical myelopathy in patients with multiple lower limb joint replacements compared with the control population.
1996048	[Contact radiotherapy in rheumatoid lesions of the knee joint using Au-198].	1991	An instrumental-calculation method of assessment of an absorbed dose of radiation in the synovial tissue of the knee joint in radionuclide therapy with 198Au using directly measured topometric parameters was used for patients with rheumatoid arthritis. A group of 294 knee joint of 138 patients was considered by way of a retrospective analysis. Dosimetric indices in all cases (except stage IV arthritis) showed values which were not contrary to clinical assessment of the patients: status after therapy.
2363736	Dietary fish oil and olive oil supplementation in patients with rheumatoid arthritis. Clin	1990 Jun	Forty-nine patients with active rheumatoid arthritis completed a 24-week, prospective, double-blind, randomized study of dietary supplementation with 2 different dosages of fish oil and 1 dosage of olive oil. Clinical evaluations were performed at baseline and every 6 weeks thereafter, and immunologic variables were measured at baseline and after 24 weeks of study. The 3 groups of patients were matched for age, sex, disease severity, and use of disease-modifying antirheumatic drugs (DMARDs). Subjects continued receiving DMARDs and other background medications without change during the study. Twenty patients consumed daily dietary supplements of n3 fatty acids containing 27 mg/kg eicosapentaenoic acid (EPA) and 18 mg/kg docosahexaenoic acid (DHA) (low dose), 17 patients ingested 54 mg/kg EPA and 36 mg/kg DHA (high dose), and 12 patients ingested olive oil capsules containing 6.8 gm of oleic acid. Significant improvements from baseline in the number of tender joints were noted in the low-dose group at week 24 (P = 0.05) and in the high-dose group at week 18 (P = 0.04) and 24 (P = 0.02). Significant decreases from baseline in the number of swollen joints were noted in the low-dose group at weeks 12 (P = 0.003), 18 (P = 0.002), and 24 (P = 0.001) and in the high-dose group at weeks 12 (P = 0.0001), 18 (P = 0.008), and 24 (P = 0.02). A total of 5 of 45 clinical measures were significantly changed from baseline in the olive oil group, 8 of 45 in the low-dose fish oil group, and 21 of 45 in the high-dose fish oil group during the study (P = 0.0002). Neutrophil leukotriene B4 production decreased by 19% from baseline in the low-dose fish oil group (P = 0.0003) and 20% in the high-dose group (P = 0.03), while macrophage interleukin-1 production decreased by 38.5% in the olive oil group (P not significant), 40.6% in the low-dose group (P = 0.06), and 54.7% in the high-dose group (P = 0.0005). Tritiated thymidine incorporation in peripheral blood mononuclear cells after stimulation with concanavalin A increased significantly in all 3 groups after 24 weeks, compared with baseline values. We conclude that the clinical benefits of dietary supplementation with omega-3 fatty acids are more commonly observed in patients consuming higher dosages of fish oil for time intervals that are longer than those previously studied. Dietary supplementation with olive oil is also associated with certain changes in immune function, which require further investigation.
3766133	Immunocytochemical study on the immune complex and germinal center of synovial tissue of r	1986 Jun	To analyze the immunological role of lymphoid germinal centers and follicular dendritic cells (FDC) in synovial tissue of rheumatoid arthritis (RA), we tried to detect the immune complex in germinal centers by light and electron microscopic immunocytochemistry with special emphasis on immunoglobulin, complement components, RA factor, and DRC-1 antigen. Immunoglobulins mainly distributed intercellularly in the germinal center in a lacy network pattern, and show partial intracytoplasmic localization in some germinal center lymphoid cells. Early complement components of classical pathway (C1q, C4, C3c, and C3d) and RA factor distributed lacily similarily to immunoglobulin, but intracytoplasmic positivity is never observed. These coexistent positive sites are identical to DRC-1 positive sites which are the surface of extended processes of FDC membrane. A similar finding is observed in primary follicles or lymphoid aggregates less often than germinal centers. These results indicate that some germinal centers trap the immune complex, including RA factor at least closely related with FDCs, and also RA factor is one of the triggers of antigen as well as developing germinal centers.
1724096	Platelet-derived growth factors and heparin-binding (fibroblast) growth factors in the syn	1991 Dec	The pathology of rheumatoid arthritis (RA) is characterized by massive tumor like hyperplasia of synovial connective tissues. Fibroblast like cells and microvascular endothelial cells are the predominant cell types present in this invasive tissue, particularly at sites of bone erosions. Identification of growth factors or cytokines that drive this process is an important goal of current research. Here we review evidence that platelet-derived growth factor (PDGF)-like and heparin-binding fibroblast growth factor (HBGF)-like polypeptides play a significant role in this process. For example, messenger RNA transcripts for PDGF-A, PDGF-B, HBGF-1, and HBGF-2 are present in RA synovial tissue specimens, and immunoreactive PDGF-like and HBGF-1- and -2-like polypeptides are present in RA synovia. Levels of expression are significantly higher in RA synovia than in osteoarthritis (OA) synovia, and their expression correlates with the extent and intensity of mononuclear cell infiltration. Similarly, PDGF-receptor expression is elevated in RA synovia compared with OA synovia. High levels of tyrosine phosphorylation and Fos and Myc expression are also characteristic of RA synovia and occur in cells after PDGF- and HBGF-receptor interaction. These and other observations strongly support the view that PDGF-like and HBGF-like factors are involved in stimulating the proliferative and invasive phenotype of RA synovial connective tissue cells.