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

PMID	Title	PublicationDate	abstract
8207219	Overexpression of zinc-finger transcription factor Z-225/Egr-1 in synoviocytes from rheuma	1994 Jun 15	In rheumatoid arthritis (RA) the proliferation of synovial lining cells appears to be one of the initial pathologic changes that contributes to the destruction of articular joints. To understand the pathomechanisms involved in these functional changes, we analyzed the transcriptional regulation of the zinc-finger gene 225 (Z-225/Egr-1), a transcription factor expressed in the immediate early events of cellular activation. We found that Z-225 transcripts were significantly up-regulated in RA synoviocytes. In primary and long term culture Z-225 was spontaneously transcribed at elevated levels. In situ hybridization of zinc-finger probe showed characteristic Z-225 transcripts in RA synovial tissues. Identity of these signals to the Z-225 gene product were confirmed in freshly isolated synovial tissue by enzymatic amplification of cDNA by the PCR technique. Z-225 transcripts were also detected and characterized in a cDNA library established from a RA synovial explant. We therefore conclude that RA synoviocytes spontaneously produce Z-225 gene products at elevated levels. Because early growth response gene Z-225 is involved in the regulation of expression of other genes such as proto-oncogenes c-ras and c-sis, which are also up-regulated in the RA synovium, activation of Z-225 transcription in RA may represent a key event in articular joint destruction.
7518519	Administration of an anti-CD5 immunoconjugate to patients with rheumatoid arthritis: effec	1994 Apr	OBJECTIVE: An immunoconjugate, CD5 Plus, composed of ricin A chain and murine IgG1 anti-CD5 monoclonal antibody is under investigation for treatment of rheumatoid arthritis. To understand better the mechanism of action of this agent, alterations in immune function and lymphocyte subpopulations were assessed in a subset of patients consecutively enrolled in 2-phase II clinical trials. METHODS: Flow cytometric and in vitro functional analyses of peripheral blood mononuclear cells from 12 patients receiving 5 daily intravenous infusions of CD5 Plus at doses of 0.20 or 0.33 mg/kg were performed before, during and after treatment. RESULTS: Peripheral CD3+ T cells were significantly depleted (p < 0.01) during treatment on Days 2 and 5 and returned towards baseline on Days 15 to 29; changes in CD5+ B cells occurred in parallel. There was no significant treatment effect on monocytes. All T cell subsets examined, including CD4, CD8, CD45RA, CD45RO, HLA-DR+, TCR-alpha beta and TCR-gamma delta, were affected equally through Day 15. On Day 29, the median CD4:CD8 ratio, elevated before treatment, was significantly decreased (p < 0.01), approaching the ratio observed in healthy controls. Proliferative responses to antigenic, allogeneic and mitogenic stimuli in vitro were depressed but detectable during the time of maximal T cell depletion and normalized to baseline values with recovery of T cell number. Spontaneous and pokeweed mitogen induced immunoglobulin secretion were unaffected in these patients. CONCLUSION: Treatment associated effects of CD5 Plus were observed for both T and B cell populations which bear the CD5 antigen, and were reversible, as measured by in vitro assays of immune cell function, phenotype and number.
8295173	Cytokine production by helper T cell populations from the synovial fluid and blood in pati	1993 Oct	OBJECTIVE: Our study was undertaken to determine the phenotypic changes and cytokine production from the synovial fluid (SF) and blood of patients with rheumatoid arthritis (RA). METHODS: Blood and SF purified T cells were stained with monoclonal antibodies using standard, indirect immunofluorescence technique for the determination of T cell receptor (TcR) TcR alpha beta and TcR gamma delta antigen expressions, CD25, CD38, CD71, HLA-DR activation antigens, and for percentage distribution of CD4+CD29+ and CD4+CD45RA+ subsets. The production of interleukin 2 (IL-2), IL-4 and IL-6 by various T cell compartments was determined by the bioassay or enzyme linked immunosorbent assay methods. RESULTS: Highly elevated percentage of CD3+TcR gamma delta and CD4+CD29+ T cell subsets were detected in SF and blood of RA. The CD4+CD29+ T cell subsets produced elevated levels of IL-4 and IL-6 but deficient levels of IL-2. IL-6 cytokine induced CD4+CD29+ subsets were found to provide effective helper function to B cells in IgG and IgM synthesis. CONCLUSION: The IL-6 production and IL-6 induced CD4+CD29+ T cell subset function in B cell antibody synthesis may be important in B cell hyperactivity and antibody synthesis in RA. Our studies suggest that CD4+CD29+ subsets bearing TcR gamma delta antigens are increased at inflammation site (SF) in RA and is implicated in immunopathology and autoantibody production of this inflammatory condition in humans.
7779664	New therapies for rheumatoid arthritis.	1995 May	There are two major thrusts in the development of effective treatments in RA: the use and development of entirely new drugs; and the more effective usage of the currently available drugs. This represents a comprehensive review of the pharmacological agents that have been recently developed or will be available in the near future.
1458788	Effects of different regimes of corticosteroid treatment on calcium and bone metabolism in	1992 Sep	A clinical study of 30 patients with rheumatoid arthritis was undertaken in order to assess the acute effects of corticosteroids on calcium and bone metabolism. The patients were randomly divided into 3 groups. The first group was not treated with corticosteroids, the second group was treated with 3 oral pulses of 100 mg prednisolone and the third group received 3 intravenous pulses of 1000 mg methylprednisolone (MP) on alternate days during one week. In both steroid treated groups the serum parathyroid hormone concentration tended to increase. In the MP treated group an increase in the 1,25-dihydroxyvitamin D concentration after the first pulse was followed by a significant drop; this effect was also seen, but somewhat retarded and less distinct, in the orally treated group. In the MP treated group the urinary calcium excretion raised significantly 6 hrs after the first pulse and then dropped significantly. In all groups no changes were found in the serum calcium level and the urinary excretion of hydroxyproline. We conclude that, acute changes in calcium and bone metabolism occur during treatment with intravenous pulses of methylprednisolone and with oral pulses of prednisolone. These changes are small and reversible in a few days.
7871965	[Low dosage methotrexate treatment in chronic polyarthritis].	1994	30 patients with rheumatoid arthritis were treated with a weekly low dose of Methotrexate for a period of 12 months. In the course of treatment there was significant improvement in pain and mobility, in the number of inflamed joints and use of steroids. There was a fall in erythrocyte sedimentation rate and hemoglobin content rose significantly. 81% of the patients improved. Of these 14% had a complete clinical remission. There were 19% non-responders. Adverse reactions developed in 13 patients (43.3%, gastrointestinal symptoms, elevated liver enzymes, loss of hair, stomatitis). After decreasing or temporary discontinuing in 10 of them the drug was taken again later on. It had to be withdrawn in 3 patients (10%). All recovered when Methotrexate was discontinued. It is concluded that low dose Methotrexate is effective in the long term treatment of chronic rheumatoid arthritis.
7555618	Somatostatin 14 and joint inflammation: evidence for intraarticular efficacy of prolonged	1995	Previous studies with intraarticular administration of somatostatin (SST14) in rheumatoid arthritis showed an antiinflammatory and analgesic effect. The aim of the present study was to demonstrate the efficacy and tolerability of SST14 in rheumatoid arthritis (RA) patients for a longer period of treatment than previously scheduled. Forty-one patients with RA of the knee were treated with a cycle of intraarticular injection of 750 micrograms of SST14, every 15 days. The efficacy of SST14 was evaluated by determining acute phase parameters (erythrocyte sedimentation rate, C-reactive protein [CRP]) and by clinical assessment (pain at rest and on movement, joint tenderness, morning stiffness, spontaneous pain). Additionally, telethermography was performed to evaluate the intensity of the joint inflammation. The tolerability of the treatment was also assessed both by patients and physicians. SST14 produced a reduction in all parameters; this was already statistically significant after the second injection in terms of pain at rest and on movement, and after the third injection for all other symptoms. The treatment showed an excellent tolerability, both local and systemic. Our results indicate the analgesic property of SST14 and demonstrate its capacity to reduce progressively joint inflammation confirmed by thermography and by reduction of pain, after a month of therapy.
7835011	Lymphoedema of the limbs in rheumatoid arthritis.	1994 Sep	The lymphoedema of the extremities is a rare complication of rheumatoid arthritis (RA); it does not appear to be correlated with positivity for rheumatoid factor nor with the clinical activity of the disease. The authors describe 6 cases of lymphoedema in patients affected by RA; in 3 of them the lymphoedema was localized in the upper and in the remaining cases in the lower limbs. Four patients, (one of whom has been subjected to a lymphoangiography which demonstrates an obstruction of the deep lymphatics), presented an increase of the plasma fibrinogen degradation products (FDP). This could confirm the hypothesis according to which the lymphoedema could be attributable to an obstruction of the lymphatics caused by fibrin and other degradation products of the coagulation system. In one case the authors underscore the therapeutic effectiveness of lymphodrainage associated with administration of diuretics.
8921926	Circulating transferrin receptor during erythropoietin medication of anemic patients with	1996	Serum levels of the transferrin receptor (TfR) were monitored in 12 anemic patients with rheumatoid arthritis (RA) undergoing treatment with recombinant human erythropoietin (rHuEPO) for a 24-week period. Measurement of TfR was performed using an enzyme immunoassay. Compared to a mean pretreatment level of 4.2 mg/l (range 2.1-6.1 mg/l), there was an increase in the mean TfR concentrations from 2 weeks of treatment onwards to a maximum of 7.7 mg/l (range 2.1-12.3 mg/l) at 12 weeks (p < 0.01). Nine of the 12 patients responded to rHuEPO with an increase in blood hemoglobin concentration of 15 g/l or more. An increase in TfR levels was documented not only in the responders but also in the 3 nonresponders. We conclude that in anemic RA patients exogenous erythropoietin induces a swift and sustained increase in the serum concentration of TfR, which probably reflects increased expression of TfR on erythroblasts. This sustained elevation of TfR seems to occur even in patients who do not have an increase in their hemoglobin level.
7763113	Interleukin-1 receptor antagonist production in cultured synovial cells from patients with	1995 Apr	OBJECTIVE: To measure the amounts of interleukin-1 receptor antagonist (IL-1ra) protein produced by cultured synovial cells obtained from patients with rheumatoid arthritis (RA) and osteoarthritis (OA). METHODS: Synovial cells obtained from patients with either RA or OA were cultured and the supernatants were measured for IL-1ra by enzyme linked immunosorbent assay. RESULTS: The synovial cells obtained from patients with RA produced significantly smaller amounts of IL-1ra than did those obtained from patients with OA, in a late passage (third to fifth) without stimulation and a first passage both with and without stimulation (p < 0.025, respectively). In addition, when the patients with RA were divided into two groups according to the maximum number of lining cell layers, the amounts of IL-1ra produced by the proliferative type were smaller than those produced by the less proliferative type (p < 0.025). CONCLUSIONS: The above findings suggest that IL-1ra production in RA synovial cells is suppressed, and that reduced IL-1ra protein production is one of the causes which leads to the proliferation of lining cells and persistent joint inflammation.
7738951	Detection of insulin-like growth factor I and II in synovial tissue specimens of patients	1995 Feb	OBJECTIVE: To study the expression of insulin-like growth factor I and II (IGF I and II) in synovial tissue specimen of patients with rheumatoid arthritis (RA) and osteoarthritis (OA). METHODS: Synovial tissue sections were examined for the expression of IGF I and II by in situ hybridization using digoxigenin labeled antisense and sense RNA probes. RESULTS: The antisense probe of IGF I reacted with all specimens. IGF II mRNA was expressed in 7/7 RA and 4/5 OA tissues. Cells of the synovial lining and subsynovial layer bound both antisense probes, whereas inflammatory infiltrates of RA tissues were labeled rarely. CONCLUSION: The significant number of cells in the synovium that express IGF I and II mRNA suggests a role of IGF in repair mechanisms of articular cartilage in response to injury and effects on fibroblast growth within the synovium.
7979586	Serum transferrin receptors in rheumatoid arthritis.	1994 Oct	OBJECTIVE: Serum transferrin receptors (sTfR) were determined in patients affected by rheumatoid arthritis (RA) to verify a possible relationship with the degree of anaemia and with the severity of the inflammatory disease. METHODS: sTfR, IL1-b, TNF-a and common parameters of iron metabolism were studied in 72 patients with active RA. Anaemia (Hb < 12 g/dl) was present in 51 patients. Twenty normal healthy subjects and 40 iron-deficient anaemic patients without chronic inflammatory, infective or malignant diseases were studied as controls. RESULTS: In patients with RA sTfR levels were significantly higher than in the normal group but lower than in iron-deficient anaemic patients and correlated positively with ESR and IL1-b and negatively with Hb. Anaemic patients with RA were divided into two groups. Group A (56%) showed a possible iron deficiency (TSI < 16 and ferritin < 50 ng/ml); group B did not show iron deficiency (TSI > 16 and ferritin > 50 ng/ml). No significant difference in sTfR was observed in the two groups. CONCLUSION: sTfR appear to be elevated and related to the degree of anaemia and to the inflammatory process in RA. Reduced sTfR levels in patients with RA compared with patients with iron-deficiency anaemia may indicate a reduced erythropoietic activity in RA.
8108662	Localisation of interleukin 8 in the synovial membrane, cartilage-pannus junction and chon	1994	Interleukin-8 (IL-8) may play an important role in the development of synovitis in rheumatoid arthritis (RA), in that it is a powerful chemoattractant for neutrophils and T cells. The aim of this study was to examine the distribution of IL-8 in the synovial membrane and cartilage, from RA, osteoarthritis (OA) and normal joints. By immunohistochemical techniques, IL-8 was shown to be present in the lining layer cells in RA (87%) and in OA (62%). By contrast, only a few of the normal synovial lining layer cells (14%) contained IL-8. Deeper in the membrane the number of IL-8 positive cells decreased. Only vessels were highly positive for IL-8. At the RA cartilage-pannus junction 26% of the cells contained IL-8, whereas at the OA cartilage-pannus junction 8% of the cells were IL-8 positive (P < 0.05). Chondrocytes present in joint surface cartilage stained positive for IL-8 in an average of 20% of the cells of both RA and OA. These results provide histological evidence that IL-8 is present in the arthritic synovial tissue and cartilage, and is distributed in a manner that may form a chemotactic gradient, which favours localisation of neutrophils to the joint lumen.
7905924	The use of the disease activity score in the analysis of clinical trials in rheumatoid art	1993 Nov	OBJECTIVE: To ascertain how well the disease activity score discriminates drug from placebo treated patients. METHODS: Three placebo controlled trials in rheumatoid arthritis (RA) were reanalyzed using the disease activity score: DAS = 0.53938 x SQRT (Ritchie index) + 0.06465 x (# swollen joints) + 0.330 x 1n (erythrocyte sedimentation rate) + 0.224. RESULTS: Patient groups receiving methotrexate, high dose D-penicillamine and sulfasalazine had the statistically greatest improvement vs placebo treated groups; patient groups receiving gold sodium thiomalate (GSTM) and low dose D-penicillamine also showed statistically significant improvement versus placebo treated groups. Patients receiving sulfasalazine or GSTM were deemed to benefit compared to placebo treated patients in this analysis, unlike the results presented in the initial analyses of this trial. CONCLUSION: The disease activity score is a simple and effective measure of inflammation that can discriminate between active drug and placebo treated patient groups. Use of this composite measure may improve analysis of clinical trials and also be applicable to clinical care.
1429034	Analysis of HLA DP, DQ, and DR alleles in adult Italian rheumatoid arthritis patients.	1992 Jun	We analyzed the distribution of DRB1, DQA1, DQB1, and DPB1 allelic variants in 48 rheumatoid arthritis (RA) patients, compared with 109 Italian random controls, using PCR amplification and hybridization with specific oligonucleotides. We confirm the previously reported increase of DR4 specificity, in comparison with healthy Italian individuals. In particular, we find a statistically significant positive association of DRB10401 and DRB10404 alleles with RA. However, when we compare the DR4+ groups, none of the DRB104 alleles is increased in the RA group. By sequence analysis, performed on 10 patients, we demonstrate that the DRB104 genes of RA show no difference from the DRB104 sequences previously published. From the molecular analysis of the other DRB1 polymorphic variants, we find a trend of positive association of DRB10101 in DR4-negative patients versus DR4-negative healthy controls and, in the group of DR4-negative and/or DR1-negative patients, a similar increase of DRB106. Also, we observe in RA patients a statistically significant increase of DQA10301 and DQB10302 accompanied by a significant decrease of DQA10201, DQA10501 and DQB10201. Finally, from the analysis of DPB1 gene, it can be assessed that the distribution of DPB1 alleles does not differ significantly between RA patients and healthy controls.
1593573	Cyclosporine nephrotoxicity in rheumatoid arthritis: no effect of short term misoprostol t	1992 Apr	We assessed the effect of the prostaglandin E1 analog misoprostol on cyclosporine nephrotoxicity in patients with rheumatoid arthritis (RA). Thirteen patients with RA were given cyclosporine with misoprostol tablets, 800 micrograms/day for one week in a randomized, double blind, placebo controlled crossover trial. All had cyclosporine nephrotoxicity, documented by an increase in serum creatinine of at least 15% over the values before the start of cyclosporine treatment. Mean glomerular filtration rate (GFR) (single shot 51Cr-EDTA plasma clearance) at baseline was 77.3 ml/min (SD, 22.0). After misoprostol, it was 80.0 ml/min (SD, 18.9); after placebo, 79.1 ml/min (SD, 20.0). None of these changes were statistically significant. Serum creatinine levels and whole blood cyclosporine levels were also unchanged. Power to detect at least a 5 ml/min rise in GFR was 0.92. Short term misoprostol treatment does not improve the GFR of patients with RA on cyclosporine.
1347295	Changes in normal glycosylation mechanisms in autoimmune rheumatic disease.	1992 Mar	To investigate potential mechanisms controlling protein glycosylation we have studied the interrelationship between lymphocytic galactosyltransferase (GTase) activity and serum agalactosylated immunoglobulin G levels (G(0)) in healthy individuals and patients with rheumatoid arthritis and non-autoimmune arthritis. In RA there was reduced GTase activity and increased G(0). A positive linear correlation between B and T cell GTase was found in all individuals. The relationship between GTase and G(0) was found to be positive and linear in the control population and negative and linear in the RA population. Sulphasalazine therapy maintained normal levels of GTase and caused a reduction in G(0) in the RA population. IgG anti-GTase antibodies (abs) were significantly increased in the RA population, whereas IgM anti-GTase abs were significantly decreased in both the RA and the non-autoimmune arthritis groups. These data describe a defect in RA lymphocytic GTase, with associated abnormal G(0) changes, which is corrected by sulphasalazine. A possible regulatory mechanism controlling galactosylation in normal cells is suggested, in which there is parallel control of B and T cell GTase. IgM anti-GTase abs may be integrated into this normal regulatory process. This is disrupted in RA, where the positive feedback between GTase and G(0) is lost and there is an associated increase in IgG anti-GTase abs, which may result from isotype switching as IgM anti-GTase abs are reduced. We suggest that these mechanisms are of relevance to the pathogenesis of RA, and that their manipulation may form part of a novel therapeutic approach.
1642656	The immunoglobulin kappa light chain repertoire expressed in the synovium of a patient wit	1992 Aug	OBJECTIVE: To analyze the nature of the B cell response in the synovial tissue of a patient with rheumatoid arthritis (RA). Specifically, we sought to determine if the pattern of immunoglobulin expression was consistent with polyclonal stimulation of B cells or an antigen-driven response. METHODS: We generated an unrestricted complementary DNA (cDNA) library from the diseased synovium of a rheumatoid factor (RF)-positive patient with an 18-year history of RA. A random sample of kappa light chain recombinants was identified, and sequence analysis was performed. The variable domains were compared with an extensive database of germline and cDNA kappa sequences. RESULTS: We found a light chain repertoire enriched for kappa transcripts containing 2 V kappa gene segments (Humkv325 and Humkv328) that are frequently associated with paraproteins expressing RF activity. Kappa variable domains from synovium contained numerous somatic mutations which resulted in frequent replacement of amino acids that encode the classic antigen-binding site. Unexpectedly, many of these kappa transcripts contained non-germline-encoded nucleotides (N regions) at the site of V kappa-J kappa joining. The combination of N-region addition and variation in the sites of V kappa-J kappa splicing generated unusually long complementarity-determining region 3 regions and charged amino acids near the V kappa-J kappa splice site. CONCLUSION: The pattern of somatic mutations found in this patient sample supports the hypothesis that these synovium-derived plasma cells are the product of immunoglobulin receptor-dependent (i.e., antigen-driven) selection. The extent of N-region addition raised the additional possibility that these antibodies derive from an unusual set of B lymphocytes that have escaped normal regulation.
7722963	Life events and the onset of rheumatoid arthritis.	1994 Nov	This study used the Life Events and Difficulties Schedule to assess whether an excess of life events occurred prior to onset of rheumatoid arthritis (RA) in 60 consecutive out-patients. There was no evidence of an excess of events of any kind during the 12 months before onset of RA. There was no difference between seropositive and seronegative RA or between those with and without a family history. There was a non-significant trend for an excess of events before onset compared with after; this may be explained by the reduction of events after onset as a consequence of disabling disease. The prevalence of psychiatric disorder measured using the Psychiatric Assessment Schedule was 13.3% at the time of interview.
7639807	Effects of high-dose fish oil on rheumatoid arthritis after stopping nonsteroidal antiinfl	1995 Aug	OBJECTIVE: To determine the following: 1) whether dietary supplementation with fish oil will allow the discontinuation of nonsteroidal antiinflammatory drugs (NSAIDs) in patients with rheumatoid arthritis (RA); 2) the clinical efficacy of high-dose dietary omega 3 fatty acid fish oil supplementation in RA patients; and 3) the effect of fish oil supplements on the production of multiple cytokines in this population. METHODS: Sixty-six RA patients entered a double-blind, placebo-controlled, prospective study of fish oil supplementation while taking diclofenac (75 mg twice a day). Patients took either 130 mg/kg/day of omega 3 fatty acids or 9 capsules/day of corn oil. Placebo diclofenac was substituted at week 18 or 22, and fish oil supplements were continued for 8 weeks (to week 26 or 30). Serum levels of interleukin-1 beta (IL-1 beta), IL-2, IL-6, and IL-8 and tumor necrosis factor alpha were measured by enzyme-linked immunosorbent assay at baseline and during the study. RESULTS: In the group taking fish oil, there were significant decreases from baseline in the mean (+/- SEM) number of tender joints (5.3 +/- 0.835; P < 0.0001), duration of morning stiffness (-67.7 +/- 23.3 minutes; P = 0.008), physician's and patient's evaluation of global arthritis activity (-0.33 +/- 0.13; P = 0.017 and -0.38 +/- 0.17; P = 0.036, respectively), and physician's evaluation of pain (-0.38 +/- 0.12; P = 0.004). In patients taking corn oil, no clinical parameters improved from baseline. The decrease in the number of tender joints remained significant 8 weeks after discontinuing diclofenac in patients taking fish oil (-7.8 +/- 2.6; P = 0.011) and the decrease in the number of tender joints at this time was significant compared with that in patients receiving corn oil (P = 0.043). IL-1 beta decreased significantly from baseline through weeks 18 and 22 in patients consuming fish oil (-7.7 +/- 3.1; P = 0.026). CONCLUSION: Patients taking dietary supplements of fish oil exhibit improvements in clinical parameters of disease activity from baseline, including the number of tender joints, and these improvements are associated with significant decreases in levels of IL-1 beta from baseline. Some patients who take fish oil are able to discontinue NSAIDs without experiencing a disease flare.