Browse

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

ID PMID Title PublicationDate abstract
10562301 A proinflammatory role for IL-18 in rheumatoid arthritis. 1999 Nov IL-18 is a novel cytokine with pleiotropic activities critical to the development of T-helper 1 (Th1) responses. We detected IL-18 mRNA and protein within rheumatoid arthritis (RA) synovial tissues in significantly higher levels than in osteoarthritis controls. Similarly, IL-18 receptor expression was detected on synovial lymphocytes and macrophages. Together with IL-12 or IL-15, IL-18 induced significant IFN-gamma production by synovial tissues in vitro. IL-18 independently promoted GM-CSF and nitric oxide production, and it induced significant TNF-alpha synthesis by CD14(+) macrophages in synovial cultures; the latter effect was potentiated by IL-12 or IL-15. TNF-alpha and IFN-gamma synthesis was suppressed by IL-10 and TGF-beta. IL-18 production in primary synovial cultures and purified synovial fibroblasts was, in turn, upregulated by TNF-alpha and IL-1beta, suggesting that monokine expression can feed back to promote Th1 cell development in synovial membrane. Finally, IL-18 administration to collagen/incomplete Freund's adjuvant-immunized DBA/1 mice facilitated the development of an erosive, inflammatory arthritis, suggesting that IL-18 can be proinflammatory in vivo. Together, these data indicate that synergistic combinations of IL-18, IL-12, and IL-15 may be of importance in sustaining both Th1 responses and monokine production in RA.
9209358 HTLV-I env-pX transgenic rats: prototype animal model for collagen vascular diseases. 1997 Apr To evaluate the function of HTLV-I env-pX gene in vivo, we developed two lines of transgenic rats (env-pX rats) that expressed env-pX gene products, under control of own LTR promotor. In various tissues of the rats, env and pX mRNAs were constitutively expressed, irrespective of age. At age 5 weeks, swelling of the bilateral ankle joints histologically showing synovial lining hyperplasia, severe chronic inflammation, erosion of the joint cartilage, and bone destruction with pannus formation began to develop in these env-pX rats. These histologic features resemble those of rheumatoid arthritis (RA) in man. High titered rheumatoid factors and low anti-dsDNA antibodies and hyper-gamma globulinemia were detected. Necrotizing arteritis resembling polyarteritis nodosa, polymyositis, myocarditis and Sjögren syndrome-like sialoadenitis developed, together with RA-like arthritis even in one individual animal. Thymic atrophy with low body weight was also observed. The evidence indicates that env-pX rats appear to be suitable animal models for elucidating pathogenetic mechanisms involved in not only HTLV-I related diseases but also various collegen vascular and autoimmune diseases of unknown etiology in man.
12010565 Transcriptional regulation of collagenase (MMP-1, MMP-13) genes in arthritis: integration 2002 Matrix metalloproteinase (MMP)-1, MMP-8 and MMP-13 are interstitial collagenases that degrade type II collagen in cartilage; this is a committed step in the progression of rheumatoid arthritis and osteoarthritis. Of these enzymes, the expression of MMP-1 and MMP-13 is substantially increased in response to IL-1 and tumor necrosis factor-alpha, and elevated levels of these collagenases are observed in arthritic tissues. Therefore, cytokine-mediated MMP-1 and MMP-13 gene regulation is an important issue in arthritis research. In this review, we discuss current models of MMP-1 and MMP-13 transcriptional regulation, with a focus on signaling intermediates and transcription factors that may be future targets for the development of new arthritis drugs.
11523352 [Clinico-immunological aspects of renal lesions in rheumatoid arthritis]. 2001 The aim of this study was to examine the incidence of different renal lesions in rheumatoid arthritis (RA) and to determine their relationships with the type of previous drug therapy and with the specific features of immune disorders. Ninety four patients, 84 (89.9%) females and 10 (10.6%) males) with RA whose mean age was 45.2 +/- 11.9 years and duration of the disease 7.5 +/- 6.5 years were examined. Most of them had degrees 2 and 3 PA (62.7 and 24.4%, respectively). Systemic manifestations were encountered in 60 (63.8%) patients. Eighty one patients took nonsteroidal antiinflammatory drugs (NSAID) continuously: 18 patients for a year, 32 for 5 years, 14 for 6 to 10 years, and 17 for over 10 years. All the patients underwent clinical, laboratory, and instrumental study of partial functions of the kidney. Immunological study involved solid-phase immunoassay of IgA and IgM rheumatoid factor, von Willebrand factor antigens (WF:Ag), C-reactive protein. The serum concentrations were measured by the Mancini method. Changes in urinalysis and/or signs of decreased glomerular and tubular functions were found in 69 (73.%) patients, 25 (26.6%) had arterial hypertension. Tubular dysfunctions were more common [31 (32.9%) patients]. Signs of early renal failure were detected in 20 (21.2%) patients. There were no cases of acute renal failure. Amyloidosis, glomerulonephritis, pyelonephritis were diagnosed in 5 (5.3%), 16 (17%), and 13 (13.8%) patients, respectively. The above renal lesions were concurrent in some patients. Renal lesion correlated with the progression and severity of RA, the presence of systemic manifestations, and age. There was no relationship of both 5- and 10-year use of NSAID to the symptoms of renal disease. The use of these drugs for over 10 years was concurrent with the signs of chronic renal failure and arterial hypertension. Analyzing immunological disorders showed an association of increased erythrocytic sedimentation rates and WF:Ag with amyloidosis, that of higher IgA concentrations with proteinuria and tubular dysfunctions. It is concluded that renal lesion is common in RA, there is a predominance of tubular interstitial changes. In rare cases nephropathy is characterized by a benign course and fails to result in uremia. The symptoms of renal diseases are largely associated with RA progression and severity and the patients' age. Prolonged continuous use of NSAID may contribute to the development of renal failure. Different immune mechanisms are involved in the pathogenesis of glomerular and tubular nephropathy in RA.
10765917 Involvement of Fcgamma receptor IIIA genotypes in susceptibility to rheumatoid arthritis. 2000 Apr OBJECTIVE: To investigate a possible association of Fcgamma receptor IIIA (FcgammaRIIIA) gene polymorphism at position 158 with susceptibility to, and the outcome of, rheumatoid arthritis (RA). METHODS: One hundred seventeen RA patients and 142 unrelated healthy control subjects from the same geographic area were studied. Genotyping for FcgammaRIIIA-158V/F was performed by a method based on polymerase chain reaction (PCR) and restriction fragment length polymorphism analysis using amplification-created restriction sites. HLA-DRB1 typing by PCR-sequence-specific oligonucleotide hybridization (reverse hybridization) was also performed. RESULTS: Allele and genotype distributions in healthy controls were similar to those reported in other populations. The overall distribution of genotypes in the patients was significantly different from that in the controls (P = 0.023, by chi-square test from 3 x 2 contingency table). An overrepresentation of the FcgammaRIIIA-158FF genotype in the patients was observed (for 158FF versus non-158FF P = 0.01, odds ratio [OR] 1.98, 95% confidence interval [95% CI] 1.16-3.4). However, the FcgammaRIIIA-158VF genotype was increased in controls (for 158VF versus non-158VF P = 0.021, OR 0.54, 95% CI 0.32-0.92). No associations were found with any of a series of clinical parameters. Analysis of FcgammaRIIIA-158FF along with shared epitope showed that the presence of both factors increased the susceptibility to RA (P = 0.0009, OR 3.6, 95% CI 1.63-8.01); however, they probably do not interact to produce this effect. CONCLUSION: These results indicate that the FcgammaRIIIA-158 genotypes confer differential susceptibility to RA in our study population. Further studies to elucidate the role of this polymorphism in the pathogenesis of RA and other autoimmune diseases are warranted.
11229460 Rheumatoid arthritis in southern Spain: toward elucidation of a unifying role of the HLA c 2001 Feb OBJECTIVE: To evaluate the contributions of HLA-DQ and -DR polymorphisms to susceptibility to rheumatoid arthritis (RA) in a population in southern Spain, and to compare the value of the shared epitope (SE) and RA protection (RAP) models in accounting for the HLA class II region's contribution to RA predisposition. METHODS: One hundred sixty RA patients and 153 healthy controls were typed for HLA-DRB1 and -DQB1 using high-resolution DNA techniques. Distributions of predisposing DRB1 alleles in patients and control subjects according to the SE model were compared with distributions of predisposing DQ and protective DERAA-positive DRBI alleles according to the RAP model. RESULTS: DQ3 (DQBI*03 and *04 combined with DQA1*03) and DQ5 (DQB1*0501/DQA1*0101) alleles predisposed individuals to RA independently of SE-positive DRB1 alleles. DQ3/3-homozygous individuals had the strongest risk of developing RA. DQ3 molecules predisposed to RA more than did DQ5 molecules. The weaker predisposition mediated by DQ5 included the DRB1*1001-carrying haplotype; no DRB1*1001-homozygous patients were observed. DRBI*0401 played a unique role in the contribution of DQ3-DR4 haplotypes to RA, in spite of its low frequency in southern Spain. CONCLUSION: The low prevalences of RA and of mild disease observed in Spain, and in southern Europe in general, can be explained in great part by the low frequency of DQ3-DR4 haplotypes, especially those carrying DRB1*0401. However, the overall distribution of HLA-DQ and -DR alleles in RA patients compared with control subjects is similar to that in other European and North American populations. A model involving both DQ and DR can best account for the contribution of HLA to RA.
9360303 Comparative study of monoclonal immunoglobulin M and rheumatoid immunoglobulin M by differ 1997 Aug Thermal denaturation of monoclonal immunoglobulin M (IgM) and rheumatoid immunoglobulin M (IgM-RF) and their Fab- and (Fc)5-fragments was studied by differential scanning microcalorimetry. The melting of IgM-RF started at a higher temperature than that of IgM and the maximum temperature of its main asymmetric peak of heat absorption was higher by 4 degrees C. At equal values of enthalpy, the thermal denaturation of IgM-RF and IgM consisted of four and five individual transitions, respectively, between pairs of states. The comparison of thermal denaturation parameters of Fab- and (Fc)5-fragments of IgM-RF and IgM showed a thermodynamic similarity of (Fc)5-fragments of both proteins, while their Fab-fragments differed in the interaction between VL-CL and VH-CH domains.
11196690 Immuno- and genetic therapy in autoimmune diseases. 2000 Jun Animal models of autoimmune disease have been developed that mimic some aspects of the pathophysiology of human disease. These models have increased our understanding of possible mechanisms of pathogenesis at the molecular and cellular level and have been important in the testing, development and validation of new immunotherapies. The susceptibility to develop disease in the majority of these models is polygenic as is the case in humans. The exceptions to this rule are gene knock outs and transgenic models of particular genes which, in particular genetic backgrounds, have also contributed to the understanding of single gene function and their possible contribution to pathogenesis. Gene therapy approaches that target immune functions are being developed with encouraging results, despite the polygenic nature of these diseases. Basically this novel immuno-genetic therapy harnesses the knowledge of immunology with the myriad of biotechnological breakthroughs in vector design and delivery. Autoimmune disease is the result of genetic dysregulation which could be controlled by gene therapy. Here we summarize the genetic basis of these human diseases as well as some of the best characterized murine models. We discuss the strategies for their treatment using immuno- and gene therapy.
9710886 Biologic agents and immunotherapy in rheumatoid arthritis. Progress and perspective. 1998 Aug Advances in our understanding of rheumatoid synovitis have been coupled with increasingly refined methods from biotechnology to produce promising therapeutic agents. Monoclonal antibodies (MoAbs), recombinant cytokines, cytokine receptor fusion proteins and other biologics have been elevated from the status of novel reagents applied in phase I toxicity trials to, in some cases, substantially evaluated and validated tools awaiting federal regulatory approval. Biologic agents will soon be released for the treatment of patients with RA. We review some of the most promising preclinical work that supports a position of optimism regarding the future of RA. We also speculate on the potential role for biologics in future management of patients with RA.
16320552 Measuring disability: application of the Rasch model to activities of daily living (ADL/IA 2001 This paper describes a comparative analysis of (ADL) and (IADL) items administered to two samples, 4,430 persons representative of older Americans, and 605 persons representative of patients with rheumatoid arthrisit (RA). Responses are scored separately using both Likert and Rasch measurement models. While Likert scoring seems to provide information similar to Rasch, the descriptive statistics are often contrary if not contradictory, and estimates of reliability from Likert are inflated. The test characteristic curves derived from Rasch are similar despite differences between the levels of disability with the two samples. Correlations of Rasch item calibrations across three samples were .71, .76, and .80. The fit between the items and the samples, indicating the compatibility between the test and subjects, is seen much more clearly with Rasch with more than half of the general population measuring the extremes. Since research on disability depends on measures with known properties, the superiority of Rasch over Likert is evident.
9606177 Clonally-related immunoglobulin VH domains and nonrandom use of DH gene segments in rheuma 1998 Apr BACKGROUND: Synovia of patients with long-standing rheumatoid arthritis (RA) are typically infiltrated with B lymphocytes and plasma cells that secrete large amounts of immunoglobulin. The CDR3 of an immunoglobulin heavy chain is composed of the VH-DH-JH join, with interposed N region addition, and thus defines clonal relatedness. Furthermore, the CDR3 lies at the center of the antigen binding site, so its length and composition influence antigen binding. We sought definitive evidence of an antigen-driven B cell response (i.e., clones derived from the same VH, DH, and JH gene segments with shared somatic mutations) in RA synovial mRNA transcripts, and to characterize CDR3 intervals at the target of inflammation in this autoimmune disease. MATERIALS AND METHODS: We screened a cDNA library generated from unselected cells from the knee joint of a 62-year-old white female with long-standing RA. This technique does not have the potential bias of selecting for antibodies that express a particular reactivity such as rheumatoid factor. C gamma recombinants were sequenced and progenitor VH, DH, and JH gene segments were assigned and somatic mutations determined by comparison to germline sequences. Analyses of DH reading frame utilization and hydropathy characteristics of CDR3s were performed. RESULTS: Two of 67 recombinants were derived from the same VH (V3-11) and JH gene segments, demonstrated shared mutations, and contained nearly identical VH-DH-JH joins, including N region addition. Three other recombinants contained identical sequence throughout the variable domain. We also found preferential utilization of a limited number of VH and DH gene segments and marked preference for a DH reading frame encoding predominantly hydrophilic residues. CONCLUSIONS: Analysis of expressed heavy chain variable domains strongly supports the hypothesis that the B cell response in RA synovium is at least in part antigen driven and oligoclonal.
9465625 [A case of rheumatoid lung exacerbated by acetaminophen-induced pneumonitis]. 1997 Oct A 57-year-old man was admitted with a high fever, dry cough, severe dyspnea and an interstitial shadow bilaterally on chest roentogenogram. Although his illness was not diagnosed, he was treated with a high dose of methylprednisolone (1 g/day for 3 days) for acute interstitial lung disease. As the 3-day treatment was not effective, high-dose methylprednisolone therapy was repeated. Subsequently, he was treated with prednisolone (60 mg/day), after which his condition improved. After 8 months, the patient caught cold for which he was treated. Subsequently his previous lung disease appeared again. His illness, improved after steroid therapy. The patient had been treated with Shin-Ruru-A tablets during his first admission. A lymphocyte stimulation test for Shin-Ruru-A-Tablet, PL granule, and acetaminophen (which is the common constituent of the former two drugs), was positive. Polyarthralgia, bone lesions joint swelling, and a positive rheumatoid factor test were present on first admission. Therefore, his illness was diagnosed as rheumatoid arthritis (RA). As the interstitial shadow remained after treatment of the lung disease, a thoracoscopic lung biopsy was performed. The specimen revealed an intensive lymphocytic infiltration, perivasculatitis, and thickening of the alveolar septa. These findings corresponded with those of lung disease associated with RA. The results suggest that lung disease associated with collagen vascular diseases may be exacerbated by drug-induced pneumonitis.
9375887 Elevated levels of hyaluronic acid in the sera of women with fibromyalgia. 1997 Nov OBJECTIVE: To evaluate serum levels of hyaluronic acid (HA) in patients with fibromyalgia (FM). METHODS: HA serum levels were evaluated by a radiometric assay in 42 women with FM (ACR criteria), 27 female patients with rheumatoid arthritis (RA) and 36 healthy female controls matched for age. RESULTS: HA serum levels (mean microg/l +/- SEM) were 41 +/- 8.7 in healthy controls; 113 +/- 15.9 in RA: and 420 +/- 26 in FM. CONCLUSION: HA serum levels in women with FM were significantly elevated compared to healthy controls and patients with RA. This observation suggests that FM is associated with a biochemical abnormality and that serum HA could be a laboratory marker for its diagnosis.
10331121 Pharmacologic management of the arthritic foot and ankle. 1999 Apr The arthritides discussed are presented with many drug therapies because of a not fully understood and accepted cause of the disease process. Similarly, the drug therapies offered are diverse and have mechanisms that are not always fully understood. Because of the destruction and disability the arthritides are capable of and the realization that destruction may be reversible early in the course of the disease, physicians are initiating earlier, aggressive treatment with DMARDs. Long-term outcome studies of the early institution of DMARDs, combination therapies, and newer medications need to be evaluated to produce the most efficient treatment regimens.
12567457 [Autoantibodies to the heterogeneous nuclear ribonucleoproteins and the autoimmune disease 1999 Aug Autoantibodies to the heterogeneous nuclear ribonucleoproteins (hnRNP) have a great role in the diagnosis of rheumatic diseases. hnRNP-A/B proteins are the main autoantigens in Rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), and mixed connective tissue disease (MCTD). Anti-RA33 autoantibodies which target the hnRNP proteins A2, B1, B2 (the 'RA33 complex') help to the diagnosis of RA at early stage. Therefore, anti-hnRNP autoantibodies are not only valuable diagnostic markers but may also allow deep insights into the pathogenetic mechanisms of rheumatic diseases.
9004373 Direct and buffer effects of social support and personal coping resources in individuals w 1997 Feb The direct and buffer effects of various aspects of social support and personal coping resources on depressive symptoms were examined. The study concerned a community-based sample of 1690 older persons aged 55-85 yrs, of whom 719 had no chronic disease, 612 had mild arthritis and 359 had severe arthritis. Persons with arthritis reported more depressive symptoms than persons with no chronic diseases. Irrespective of arthritis, the presence of a partner, having many close social relationships, feelings of mastery and a high self-esteem were found to have direct, favourable effects on psychological functioning. Mastery, having many diffuse social relationships, and receiving emotional support seem to mitigate the influence of arthritis on depressive symptoms, which is in conformity with the buffer hypothesis. Favourable effects of these variables on depressive symptomatology were only, or more strongly, found in persons suffering from severe arthritis.
11369787 Major histocompatibility complex class I-recognizing receptors are disease risk genes in r 2001 May 21 Rheumatoid arthritis (RA) is a heterogeneous syndrome of which a subset of patients develops vascular inflammation. The genetic determinants that confer risk for rheumatoid vasculitis are not known, but patients with vascular complications are known to have an expansion of CD4(+)CD28(null) T cells, a cell population potentially involved in endothelial damage. CD4(+)CD28(null) T cell clones isolated from RA patients with vasculitis were found to express killer cell immunoglobulin-like receptors (KIRs) with the stimulatory KIR2DS2 often present in the absence of opposing inhibitory receptors with related specificities. To test the hypothesis that the KIR2DS2 gene is involved in the development of vasculitis, association studies were performed. The KIR2DS2 gene was significantly enriched among patients with rheumatoid vasculitis compared with normal individuals (odds ratio 5.56, P = 0.001) and patients with RA but no vasculitis (odds ratio 7.96, P = 0.001). Also, the distribution of human histocompatibility leukocyte antigen (HLA)-C, the putative ligand for KIRs, was significantly different in patients with rheumatoid vasculitis in comparison with the control populations. These data suggest that HLA class I-recognizing receptors and HLA class I genes are genetic risk determinants that modulate the pattern of RA expression. Specifically, KIR2DS2 in conjunction with the appropriate HLA-C ligand may have a role in vascular damage by regulating CD4(+)CD28(null) T cells.
9487244 Production of T-cell cytokines at the single-cell level in patients with inflammatory arth 1998 Jan We used a newly developed, sensitive ELISPOT technique in order to estimate the number of cells producing interferon-gamma (IFN-gamma) and interleukin-4 (IL-4) in synovial fluid mononuclear cells (SFMC) and peripheral blood mononuclear cells (PBMC) in patients with rheumatoid arthritis (RA) and other inflammatory arthritides, and to correlate the results with clinical and laboratory parameters of disease activity. SFMC and PBMC were cultured either without stimuli or with a standardized dose of phytohaemagglutinin (PHA) for 6 h. Twenty-nine patients, 16 with RA and 13 with other inflammatory joint diseases, were investigated and compared to PBMC from 25 healthy controls. The mean number of IFN-gamma-producing cells was 37.1/10(5) plated SFMC (range 0-121.5). The corresponding value for PBMC was 5.1 (0-39). The difference was highly significant (P = 0.0033 for RA patients, P = 0.0050 for non-RA patients and P < 0.0001 for all patients). Forty-five per cent of SFMC samples (range for all samples 0-38.5 SFC/10(5) MNC) and 25% of PBMC samples (0-20.5) exhibited spontaneous IL-4 production, yielding a significant difference for all patients treated collectively (P = 0.021). Although the cells that spontaneously secrete these cytokines are relatively few, quantification of these cells thus shows increased functional T-cell activation and decreased ratio of cells spontaneously producing IL-4 vs IFN-gamma in the joint fluid as compared to blood of arthritis patients.
11450808 Drugs versus diets: disillusions with Dutch health care. 2001 Biology incorporated into other disciplines is often distorted, alarmingly so in some areas of medicine. Together with other forms of bias, this may have detrimental effects for patients depending on medical research for their health. A case study concerning omeprazole (Losec), one of the acid-suppressive drugs against gastric ulcers, and NSAIDs, non-steroid anti-inflammatory drugs, confirms that distorted biology together with biased health care policies foster disasters in current biomedicine and medical practice. In our country, The Netherlands, omeprazole is presumably the most commonly used medication. NSAIDs are also used in large quantities, increasingly since they have become available as analgesic over-the-counter drugs. Unofficial and official sources tend to inform the general public that the drugs promote human health. We argue that their being used on a massive scale is actually a medical disaster. The health of many patients would be served better if the drugs they take were replaced by proper forms of diet, but the pharmaceutical industry, the most potent force affecting medication policies, appears to prevent a shift in the balance from over-medicalization towards healthy life styles. The shift should come from government agencies responsible for regulation in the medication market. Policies of these agencies are now a dismal failure.
10853046 Survival of cementless and cemented porous-coated anatomic knee replacements: retrospectiv 2000 Jun AIM: To evaluate the effect of cement use in porous-coated anatomic (PCA) total knee prosthesis on its survival. METHODS: The study was a retrospective analysis of 142 PCA total condylar arthroplasties performed in 124 patients from 1985 to 1991. Uncemented prostheses were used in 87 knees, the prostheses were cemented in 44 knees, and hybrid prosthesis components were used in 11 knees. The average follow-up time was 88 months (range 66-140). The survival of prosthesis was assessed using the Kaplan-Meier's method. The Baltimore score was evaluated as a measure of clinical performance in 115 replacements. RESULTS: The overall cumulative survival rate of a PCA total knee prosthesis was 77% over the average follow-up period of 88 months. No significant differences in survival rates among cementless, cemented, or hybrid fixations could be demonstrated. The survival rate of the prostheses in patients with rheumatoid arthritis (82.5%) was significantly higher than in patients with osteoarthritis (73.8%). Revision was necessary in 29 (20.4%) replacements. CONCLUSION: The survival of PCA endoprosthesis, regardless of the components used for implantation, is not satisfactory.