Browse

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

ID PMID Title PublicationDate abstract
12498812 Retroviral gene therapy of collagen-induced arthritis by local delivery of IL-4. 2002 Dec Rheumatoid arthritis (RA) is an autoimmune arthritis, for which treatment options remain limited. This study investigated the potential role of adoptive cellular gene therapy as a novel means for treating the RA animal model collagen-induced arthritis (CIA). Adoptive transfer of antigen-specific T-cell hybridomas retrovirally transduced to express IL-4 1 day before booster immunization significantly reduced the number of inflamed joints. Cell transfer after clinical onset of disease had no therapeutic effect. Bioluminescence imaging showed that the hybridomas migrated to the inflamed joints, thus delivering the regulatory protein locally at the site of inflammation. The homing was, at least in part, due to chemotaxis in response to proinflammatory chemokines that are expressed in inflamed joints. There were no significant changes in the cytokine milieu of the draining lymph nodes, nor in the systemic levels of anti-collagen antibodies in treated mice. We conclude that the beneficial clinical effects observed in our model were most likely based on the local action(s) of IL-4 in the inflamed joints and that the local delivery (and effects) of regulatory cytokines, like IL-4, constitutes a novel and effective method of preventing organ-specific autoimmune disease and of minimizing systemic adverse effects.
12858186 Electro-gene therapy of collagen-induced arthritis by using an expression plasmid for the 2003 Aug Tumor necrosis factor (TNF) is a proinflammatory cytokine involved in the pathogenesis of rheumatoid arthritis, and antagonism of TNF may reduce the activity of the disease. Among a number of techniques for gene transfer in vivo, the direct injection of plasmid DNA into muscle is simple, inexpensive, and safe. In this study, we attempted to treat collagen-induced arthritis (CIA) with anti-TNF gene therapy by transferring the plasmid encoding soluble p75 TNF receptor linked to the Fc portion of human IgG1 (sTNFR:Fc) using in vivo electroporation. DBA/1 mice were immunized with bovine type II collagen and boosted with the same antigen. At 2 days after boosting, the plasmid vector containing cDNA for the sTNFR:Fc was injected into one selected site in the gastrocnemius muscle followed by electroporation. Serum levels of sTNFR:Fc reached 2.3 ng/ml on day 5 when gene expression reached its peak. Macroscopic analysis of paws for redness, swelling and deformities showed that the onset of moderate-to-severe CIA in mice treated with sTNFR:Fc was prevented on a significant level compared with the control mice (P<0.05). The beneficial effect of sTNFR:Fc DNA transfer lasted for at least 18 days following treatment. In addition, both the synovitis and the erosion of cartilage in the knee joints were dramatically reduced in mice treated with sTNFR:Fc (P<0.05). The expression of IL-1beta and IL-12 in the paw was also decreased by sTNFR:Fc treatment (P<0.01) while there was little change in the levels of IL-17 and vWF. These data showed that sTNFR:Fc expression plasmid was effective in the prevention of CIA, and in vivo electroporation-mediated gene transfer may provide a new approach to cytokine therapy in autoimmune arthritis.
15331127 The importance of timing of adrenergic drug delivery in relation to the induction and onse 2004 Nov Stressful events often precede onset and exacerbate established rheumatic diseases. There are numerous reports of abnormal autonomic function in rheumatoid arthritis (RA) patients. Targeting the sympathetic nervous system (SNS) with adrenergic receptor (AR) drugs in RA patients and animal models of the disease have revealed mixed results, with treatments inhibiting and exacerbating disease pathology. We tested the hypothesis that variability in disease outcome following adrenergic drug treatment is due to different roles played by the SNS at different disease stages. The contribution of beta2- and alpha-AR subtypes to disease pathology was studied at different disease stages in adjuvant-induced arthritis (AA), an animal model of RA. Lewis rats were given twice-daily intraperitoneal (i.p.) injections of an alpha-AR antagonist (phentolamine: 500 microg/kg) or a beta2-AR agonist (terbutaline: 1200 microg/day), initiated at adjuvant challenge or disease onset, and continued through severe disease. Both adrenergic therapies, when initiated at adjuvant challenge exacerbated disease pathology. In contrast, SH1293, an adrenergic drug that targets both alpha- and beta-AR (300 microg/day; twice-daily), initiated at adjuvant challenge did not exacerbate disease severity. Additionally, the same treatment regimen of phentolamine, terbutaline or SH1293 initiated at disease onset attenuated joint-inflammation and dramatically reduced bone destruction in the arthritic hind limbs. These data support the SNS playing different roles in disease pathology preclinically and after disease onset. Given current drug therapies are not effective in preventing bone destruction, these data support using adrenergic drugs as bone sparing treatments in RA.
12472659 Conserved TCR beta chain usage in reactive arthritis; evidence for selection by a putative 2002 Oct Previous work suggested that expanded CD8+ T-cell clones in the synovial fluid (SF) of HLA-B27+ patients with reactive arthritis (ReA) preferentially use the T-cell receptor variable region (TCRBV) 1, similar CDR3 sequences, and joining region (BJ) 2S3. To determine the range of conservation and disease-specificity of CDR3-sequences, we analyzed the TCRBV1-J2S3 repertoire from 33 healthy HLA-B27+ individuals, patients with various types of spondyloarthropathies (SpA), and with rheumatoid arthritis (RA) by CDR3-spectratyping. After collection and database submission of all available TCRB-CDR3 from HLA-B27-restricted or SpA-derived T cells, we systematically screened the entire human sequence database for sequences similar to the B27/SpA-related CDR3. Spectratyping revealed expanded T cell clones using conserved TCRBV1J2S3 in the SF from 5/6 of the patients with acute ReA but not among the controls. In database searches, 50 HLA-B27 or SpA-related CDR3-sequences generated similar clusters of matched sequences, and matched reciprocally. Identical or closely related sequences were identified in 15 different individuals and a canonical ReA-associated TCRB was defined [BV1-CASSVG(V/I/L)(Y/F)STDTQYF-J2S3]. All but one patient-derived conserved sequences originated from acute stage ReA-patients, and were not present among approximately 3800 other human TCRB sequences in the database. Five of the conserved sequences originated from T cell clones that recognized uninfected cells in an HLA-B27-restricted fashion, implying a role of HLA-B27-restricted CD8+ T cells specific for a ubiquitous self- or cross-reactive microbial determinant in the early phase of ReA. Related sequences were independently identified in four different laboratories. The consensus TCRB motif could be a helpful diagnostic marker in HLA-B27-associated 'undifferentiated arthritis'.
14630345 Responses of C-fiber low threshold mechanoreceptors and nociceptors to cold were facilitat 2003 Dec Cold allodynia is an annoying symptom in conditions of chronic inflammation such as rheumatoid arthritis. To examine whether primary afferent nerve activities are changed in association with hypersensitivity to cold, we recorded single nerve activities from the sural nerve in persistently inflamed rats in vivo. Inflammation was induced by an injection of complete Freund's adjuvant (CFA) solution into the tibio-tarsal joint. Inflamed rats showed an increased number of paw shakes to paw immersion in 25 degrees C water (pre-inflammation: 1.15+/-0.58, 2-week inflammation: 4.70+/-1.15). We also recorded cutaneous C-fiber activities under pentobarbital anesthesia and studied their responses to thermal and mechanical stimuli. The response of C-low threshold mechanoreceptors to cooling (total discharges between 27 and 23 degrees C) increased 1.8-fold (control group: 5.17+/-1.04 impulses, inflamed group: 9.38+/-1.47 impulses). In addition, the proportion of C-nociceptor units responding to cold down to 2 degrees C was significantly greater in the inflamed group (9 out of 18 units; threshold: 10.0+/-2.6 degrees C) than in the intact group (1 out of 14 units; threshold: 4.0 degrees C). These results suggest that the facilitated responses of these primary afferents are associated with cold hypersensitivity in chronically inflamed conditions.
11838859 Ethnic differences in risk for pediatric rheumatic illness in a culturally diverse populat 2002 Feb OBJECTIVE: To analyze the differences of occurrence of pediatric rheumatic disease among various ethnic groups in a culturally diverse isolated geographic area. METHODS: A retrospective study of pediatric rheumatic diseases in a multiethnic area during a 6 year period. RESULTS: A group of 922 patients was categorized based on predominant ethnicity, and their risk of having acute rheumatic fever (ARF), juvenile rheumatoid arthritis (JRA), and systemic lupus erythematosus (SLE) was studied. Odds ratios (OR) were computed for each illness with Caucasians as the reference group. Results indicated that Polynesians were overrepresented among patients with ARF, having elevated OR that were significantly different from Caucasians (22.5-120.7, p < 0.0001). For SLE, the highest OR were obtained for Samoans, Filipinos, and Japanese. In contrast, for JRA, Filipinos and Japanese had OR less than one, and no Samoans were diagnosed with JRA, possibly indicating a protective effect against developing JRA. CONCLUSION: This unique retrospective study examined the ethnic variations of expression of certain rheumatic diseases in an isolated region. Results reveal that certain ethnic groups are at risk for ARF and SLE, but are protected against JRA. These findings suggest investigating possible immunogenetic similarities and differences in these illnesses.
12215390 An ELISA avoiding interference by heterophilic antibodies in the measurement of components 2002 Oct 15 Endogenous heterophilic antibodies in blood are known to interfere with two-site enzyme-linked immunosorbent assays (ELISAs) evoking false positive signals. In the present study, we describe an assay for the assessment of components of the plasminogen activation system (uPA, tPA and PAI-1, and their complexes) in blood which is not susceptible to interference by heterophilic antibodies. In the ELISA format, two avian (duck, chicken) antibodies are employed in the pre-analyte and two mammalian (rabbit, goat) antibodies in the post-analyte stage. The assay is compared to our earlier reported ELISA for measuring uPA, tPA and PAI-1 components in tumor tissue extracts. Applying the so-called "nonsense formats", designed against non-existent components, to the NIBSC reference preparation of rheumatoid factor (RF), no response was found with the new assay, whereas a clear RF dose-dependent interfering signal was observed with the original assay designed for tumor tissue extracts. Analysis of tumor-tissue based international reference preparations (RBG EORTC 101094 and 040297), human anti-mouse antibodies (HAMA) containing sera, and sera from patients with rheumatoid arthritis (RA), also displayed no false positive signals. In conclusion, we have developed an ELISA that permits the determination of blood levels of components in the urokinase system, free from disturbance by endogenous heterophilic antibodies.
16388216 Reye's syndrome. 2003 Apr Five and half years male child with one day history of pain abdomen and vomiting who was on aspirin for suspected rheumatoid arthritis presented initially with acute gastritis. Next day, however he developed the signs of encephalopathy with altered liver function.
15485106 Pregnancy in patients with rheumatic diseases: obstetric management and monitoring. 2004 The obstetric management of the pregnant rheumatic patient is largely dictated by the specific disease and the degree to which it is associated with recognizable and treatable adverse obstetric outcomes, maternal or fetal. This review will cover the obstetric management of women with systemic lupus erythematosus (SLE), antiphospholipid syndrome (APS), rheumatoid arthritis (RA) and systemic sclerosis (SSc). Most experts agree that a co-ordinated management effort on the part of obstetricians and rheumatologists will likely yield the optimal achievable results.
14613583 Cancer cachexia. 2003 Nov 5 In recent years many efforts of researchers and clinicians were made to improve our knowledge of cachexia syndrome. Not only cancer, but also many chronic or end-stage diseases such as AIDS, chronic obstructive pulmonary disease (COPD), rheumatoid arthritis, tuberculosis and Crohn's disease are associated with cachexia, a condition of abnormally low weight, weakness, and general bodily decline which deteriorates quality of life and reduces the prognosis of the patients who suffer from it. In the present editorial we will focus cachexia related on cancer and provide some insight into this prognosis-limiting syndrome.
12800055 Recent chymase inhibitors and their effects in in vivo models. 2002 Dec Recent efforts to discover novel chymase inhibitors have produced orally bioavailable compounds. Studies using such inhibitors have shed light on the pathophysiological roles of chymase, eg, a chymase inhibitor has prevented atherosclerosis, restenosis and myocardial infarction in respective animal models. In these cardiovascular diseases, angiotensin I is likely involved as a substrate for chymase. The studies using chymase inhibitors have also shown the potential role of chymase in other diseases, including atopic dermatitis, tissue fibrosis and rheumatoid arthritis; a chymase inhibitor also reduced ischemic reperfusion injury in the small intestine. These results suggest the existence of physiological substrates for chymase other than angiotensin I. Chymase inhibitors are promising for the treatment of cardiovascular as well as inflammatory diseases.
12793032 Subcutaneous granuloma annulare in an adult. 2003 May 15 A 38-year-old female presented with a history of recurrent multiple deep dermal nodules located on the dorsa of the feet, over the ankle joints and lower pretibial area. Laboratory investigation excluded rheumatoid arthritis. Histopathological examination showed changes in the deep dermis: histiocytes in palisades around foci consisting of degenerated bundles of collagen, mucin, fibrin and "nuclear dust". The diagnosis of subcutaneous granuloma annulare was made on the basis of the clinical and histological features. Treatment with dapsone was successful, and in the course of two months the nodules disappeared.
12207199 [Vomiting]. 2002 Aug Vomiting, the culminating sign of nausea, is primarily a protective reflex occurring in a wide variety of vertebrates. Even tough nausea and vomiting are among the most basic neural reflexes, they remain poorly understood. Poorly understood are the pathogenetic mechanisms from the anatomic receptor and neuroendocrine point of view. This is the reason why drugs are useful in some types of vomiting but not in others. The aim of this paper is to summarize current knowledge about anatomy of vomiting reflex, neurotransmitter receptor subtypes, agonists and antagonists of serotonin and substance P. Particularly in the treatment of post-chemotherapy and postoperative vomiting. It is pointed out that nausea an vomiting may be field of neurochemical and neuropharmacological research. Finally, in clinical research drugs for vomiting therapy may be useful in other pathologies (migraine, rheumatoid arthritis, bronchial asthma).
19807415 Cost-effectiveness of replacing NSAIDs with coxibs: diclofenac and celecoxib in rheumatoid 2002 Jun Cyclooxygenase-2 inhibitors exhibit the same effectiveness on rheumatic symptoms as nonsteroidal anti-inflammatory drugs, have fewer gastrointestinal side effects, but a higher price. Based on cost and healthcare utilization in Norway, this paper explores what factors are most important for the cost-effectiveness of cyclooxygenase-2 inhibitors and points to patient groups that may be most relevant for prescribing coxibs instead of nonsteroidal anti-inflammatory drugs.
14872511 Ameliorative effects of follistatin-related protein/TSC-36/FSTL1 on joint inflammation in 2004 Feb OBJECTIVE: To clarify the in vivo function of follistatin-related protein (FRP)/TSC-36/FSTL1 in rheumatoid arthritis (RA), we investigated the roles of FRP in a mouse model of arthritis. METHODS: Arthritis was induced in BALB/c mice by injecting anti-type II collagen monoclonal antibody and lipopolysaccharide. Mice were treated with daily intraperitoneal injections of 20 microg of recombinant FRP. Development of arthritis was assessed by the clinical score and footpad swelling. Histologic examination of affected paws was performed on day 21 after the onset of arthritis. The gene expression profiles of affected paws in FRP-treated and untreated mice were compared using commercially available complementary DNA (cDNA) arrays. The difference in gene expression was confirmed by real-time quantitative reverse transcription-polymerase chain reaction. RESULTS: Treatment with recombinant FRP showed significant amelioration of the arthritis severity. Histologic analyses confirmed this finding and revealed the alleviation of cellular infiltration into the synovium as well as cartilage damage. The significant decrease in the amount of urinary deoxypyridinoline also indicated the ameliorative effect of FRP on joint destruction. Moreover, cDNA array analysis of the gene expression profile in FRP-treated arthritic lesions revealed a reduced expression of the c-fos, ets-2, IL6, MMP3, and MMP9 genes, some of which are thought to be associated with synovial inflammation and joint destruction. CONCLUSION: These findings from in vivo experiments suggest that FRP could be one of the key molecules in the treatment of inflammatory joint diseases such as RA.
13130487 Vegfb gene knockout mice display reduced pathology and synovial angiogenesis in both antig 2003 Sep OBJECTIVE: To determine the role of vascular endothelial growth factor B (VEGF-B) in 2 mouse models of arthritis, antigen-induced arthritis (AIA) and collagen-induced arthritis (CIA). METHODS: For AIA studies, monarticular AIA was induced by methylated bovine serum albumin (mBSA) priming of Vegfb gene knockout (Vegfb(-/-)) and wild-type (Vegfb(+/+)) mice, followed by intraarticular injection of mBSA or saline control 8 days later. CIA was induced in Vegfb(-/-) and Vegfb(+/+) mice by intradermal injection of chick type II collagen in adjuvant. Arthritis was monitored in both models using defined criteria (clinical and histologic). Angiogenesis was measured by synovial vessel density in diseased and control joints. RESULTS: In AIA studies, Vegfb(+/+) mice displayed significant knee joint swelling and synovial inflammation 7 days after intraarticular injection of antigen. Synovial inflammation was associated with angiogenesis, since vessel density in AIA synovium was significantly higher in arthritic than in control joints from the same animal. Knee joint swelling, synovial inflammation, and inflammation-associated vessel density in arthritic joints were reduced in Vegfb(-/-) mice compared with arthritic joints from Vegfb(+/+) mice. Similarly, in CIA, both disease incidence and mean clinical severity scores were significantly reduced in Vegfb(-/-) mice compared with Vegfb(+/+) mice. Mean histologic severity scores and mean synovial vessel density were reduced in diseased joints from Vegfb(-/-) mice when compared with diseased joints from Vegfb(+/+) mice. CONCLUSION: The reduction in inflammation-associated synovial angiogenesis in Vegfb(-/-) mice implicates VEGF-B in pathologic vascular remodeling in inflammatory arthritis. VEGF-B may be an attractive target in the design of anti-angiogenic therapies for rheumatoid arthritis.
12709543 Suppressive effects of PG201, an ethanol extract from herbs, on collagen-induced arthritis 2003 May OBJECTIVE: PG201 has been formulated using 12 herbs known to have anti-inflammatory and protective effects on damaged tissue and bone among other functions. The present study was done in order to assess the therapeutic effects of PG201 in collagen-induced arthritis (CIA) in mice. METHODS: DBA/1 mice were immunized with bovine type II collagen. After a second collagen immunization, mice were treated with PG201 orally at 10 mg/kg once a day for 18 days. Paws were evaluated macroscopically for redness, swelling and deformities. The levels of TNF-alpha and IL-1beta in the ankle were examined. The severity of arthritis within the knee joints was evaluated by histological assessment of cartilage destruction and pannus formation. Molecular indicators related to CIA pathology were analysed by measuring the serum levels of matrix metalloproteinase 2 (MMP-2), tissue inhibitor of matrix metalloproteinase 2 (TIMP-2) and the anti-inflammatory cytokines interleukin (IL)-4 and IL-10. RESULTS: Administration of PG201 significantly suppressed the progression of CIA and inhibited the production of TNF-alpha and IL-1beta in the paws. The erosion of cartilage was dramatically reduced in mouse knees after treatment with PG201. In the serum of PG201-treated mice, the level of TIMP-2 and the ratio of TIMP-2 to MMP-2 were significantly elevated, and the level of IL-4, but not of IL-10, was increased. CONCLUSION: Administration of PG201 has therapeutic effects on CIA. Protection of cartilage was particularly prominent. PG201 is a potential therapy for rheumatoid arthritis.
17608990 Review of the selective COX-2 inhibitors celecoxib and rofecoxib: focus on clinical aspect 2002 Jul The selective cyclooxygenase-2 (COX-2) inhibitors celecoxib and rofecoxib were designed to have similar efficacy but less gastrointestinal toxicity than traditional nonsteroidal anti-inflammatory drugs (NSAIDs). Their efficacy has been demonstrated in the treatment of osteoarthritis, rheumatoid arthritis, ankylosing spondylitis, postoperative dental pain and dysmenorrhea. These agents produce fewer endoscopic ulcers, symptomatic ulcers and gastrointestinal bleeds than traditional NSAIDs; although the absolute benefit is small and the gastropreserving effect is negated by concurrent use of low-dose aspirin for cardiovascular risk reduction. Nephrotoxicity and hyptertension remain concerns with COX-2 inhibitors, as they are with traditional NSAIDs. COX-2 inhibitors may be safe alternatives to traditional NSAIDs for patients with aspirin-sensitive asthma.
16088549 Pulmonary hypertension in the collagen vascular diseases. 2003 Jun Pulmonary hypertension is increasingly recognized as a complication of the collagen vascular diseases. Both isolated and secondary forms of the disease may be appreciated. Pulmonary hypertension is observed with high prevalence in scleroderma and mixed connective tissue disease. It is less commonly seen in systemic lupus erythematosus, and is a rare clinical finding in rheumatoid arthritis. The diagnosis and treatment of pulmonary hypertension associated with the collagen vascular diseases mirror diagnosis and treatment for pulmonary hypertension of any etiology. Vasodilator therapy may play a particularly important role in patients with the isolated form of disease, which is most frequently associated with scleroderma.
15775151 [Leflunomide: clinical effectiveness and mechanism of action]. 2003 Jun Leflunomide is a new immunomodulatory agent by selectively inhibiting the de novo pyrimidine synthesis. Its active metabolite (A77 1726) is highly bound to plasma protein and has a long half life. Through several large trials describing its efficacy and safety including retardation of radiographic progression in comparison with both sulfasalazine and methotrexate and with placebo have been published in Europe and the United States, leflunomide was shown to improve primary and secondary outcome measures with satisfactory safety profile. The most common treatment-related adverse reactions were diarrhea, nausea, and abnormal plasma liver enzyme levels. Leflunomide may be a useful addition to the current management of rheumatoid arthritis.