Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0003864 (arthritis)
 69,039 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The hyperimmunoglobulinemia D and periodic fever (hyper-IgD) syndrome is typified by recurrent febrile attacks with abdominal distress, joint involvement (arthralgias/arthritis), headache, skin lesions, and an elevated serum IgD level (> 100 U/mL). This familial disorder has been diagnosed in 59 patients, mainly from Europe. The pathogenesis of this febrile disorder is unknown, but attacks are joined by an acute-phase response. Because this response is considered to be mediated by cytokines, we measured the acute-phase proteins C-reactive protein (CRP) and soluble type-II phospholipase A2 (PLA2) together with circulating concentrations and ex vivo production of the proinflammatory cytokines interleukin-1 alpha (IL-1 alpha), IL-1 beta, IL-6, and tumor necrosis factor alpha (TNF alpha) and the inhibitory compounds IL-1 receptor antagonist (IL-1ra), IL-10, and the soluble TNF receptors p55 (sTNFr p55) and p75 (sTNFr p75) in 22 patients with the hyper-IgD syndrome during attacks and remission. Serum CRP and PLA2 concentrations were elevated during attacks (mean, 213 mg/L and 1,452 ng/mL, respectively) and decreased between attacks. Plasma concentrations of IL-1 alpha, IL-1 beta, or IL-10 were not increased during attacks. TNF alpha concentrations were slightly, but significantly, higher with attacks (104 v 117 pg/mL). Circulating IL-6 values increased with attacks (19.7 v 147.9 pg/mL) and correlated with CRP and PLA2 values during the febrile attacks. The values of the antiinflammatory compounds IL-1ra, sTNFr p55, and sTNFr p75 were significantly higher with attacks than between attacks, and there was a significant positive correlation between each. The ex-vivo production of TNF alpha, IL-1 beta, and IL-1ra was significantly higher with attacks, suggesting that the monocytes/macrophages were already primed in vivo to produce increased amounts of these cytokines. These findings point to an activation of the cytokine network, and this suggests that these inflammatory mediators may contribute to the symptoms of the hyper-IgD syndrome.
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PMID:Cytokine activation during attacks of the hyperimmunoglobulinemia D and periodic fever syndrome. 778 Jan 42

Our work has shown that TNF alpha is produced by cultured mononuclear cells from rheumatoid arthritis joints and appears to regulate the production of IL-1. Immunohistochemical examination has shown the presence of TNF alpha in the synovium, e.g. in the lining layer, some endothelial cells and most importantly, in the cells in the cartilage pannus junction. TNF receptors (both p55 and p75) have a similar distribution, thereby suggesting that TNF has the potential for autocrine and paracrine activity in the joint. The concept that TNF alpha is pathogenic in inflammatory arthritis has been validated by showing that neutralizing monoclonal anti-TNF antibodies significantly attenuate collagen-induced arthritis in mice. In preliminary trials in rheumatoid patients anti-TNF appears to have an impressive effect on indices of disease activity including C-reactive production and serum amyloid-A production. TNF alpha appears to be a relevant therapeutic target in rheumatoid disease.
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PMID:TNF-alpha in rheumatoid arthritis and prospects of anti-TNF therapy. 839 52

Collagen-induced arthritis can be transferred into severe combined immunodeficiency (SCID) mice by spleen cells from diseased DBA/1 mice. The development of arthritis in SCID animals can be prevented by infection ex vivo of DBA/1 spleen cells with retroviruses expressing the monomeric soluble human p75 tumor necrosis factor (TNF) receptor (TNF-R). In addition, a vector engineered to express a polycystronic mRNA with TNF-R and the herpes simplex virus thymidine kinase (HSVtk) gene, while producing low levels of TNF-R, had a limited effect which could be blocked by treating the animals with ganciclovir. A retroviral vector expressing the HSVtk gene alone had no effect on this arthritis transfer model with or without ganciclovir. Serum levels of TNF-R did not correlate with clinical signs, however, lower anti-collagen antibody levels corresponded with lack of clinical symptoms. These results indicate that local production of cytokine inhibitor is essential for therapeutic purposes while systemic levels may not be required.
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PMID:Inhibition of transfer of collagen-induced arthritis into SCID mice by ex vivo infection of spleen cells with retroviruses expressing soluble tumor necrosis factor receptor. 875 12

Recent studies have demonstrated that the treatment of mice with anti-gp39 antibodies impairs T-cell functions in the murine collagen type II-induced arthritis model, in acute semi-allogenic graft-versus-host disease, and in the allo-specific CTL-reaction, that is, reactions that are believed to be mediated by Th1-type T cells. On the other hand, the administration of anti-gp39 antibody did not influence Th2 T-cells responses, suggesting that CD40-CD40L interactions are more crucial for Th1 than Th2 T-cell development. Recent studies also demonstrate that dendritic cells (DC) are capable of driving a Th1 T-cell response that is mediated by IL-12. In addition, stimulation of CD40 on human monocytes results in IL-12 production, suggesting that activated T cells expressing CD40L may directly induce the production of IL-12 by antigen-presenting cells, thus allowing for the generation of a Th1 T-cell response in the absence of intracellular pathogens. We investigated whether the CD40-CD40L interaction was important in the production of IL-12 by DCs in an in vitro system that allowed precise control of cytokine concentrations. Initially we showed that FACS-purified mouse spleen DCs produce high amounts of IL-12 p40 in response to CD40 crosslinking by CD40L-expressing fibroblasts. We then demonstrate that DCs also produce IL-12 p40 in a more physiologic system using purified DCs pulsed with ovalbumin (OVA) and then cultured with LECAM-1hi T cells from ovalbumin T-cell receptor transgenic mice. Finally, we show that IL-10 has a potent capacity to shut down CD40-induced IL-12 p40 secretion; and, in addition, IL-4 partially inhibits CD40-induced IL-12 p40 secretion and enhances IL-10-mediated inhibition in an additive fashion. We also investigated the in vivo relevance of this interaction in an experimental model for a Th1-mediated disease, the hapten reagent (TNBS)-induced colitis. The administration of anti-gp39 (CD40L) antibodies during the induction phase of the Th1 response completely prevented IFN-gamma production by CD4 T cells from the intestinal lamina propria and also the clinical and histological evidence of disease. In further studies we showed that the prevention of disease activity was due to an inhibition of IL-12 secretion. Thus, the injection of recombinant IL12 p75 heterodimer into TNBS + anti-gp39-treated mice reversed the effect of anti-gp39 and resulted in severe disease activity. In conclusion, these findings suggest that DCs produce IL-12 in response to CD40 signaling, that a mechanism by which IL-4 may induce Th2 development is by acting with IL-10 to inhibit IL-12 production by DCs, and that the CD40L-CD40 interaction is crucial for the IL-12-dependent priming of Th1 T cells in vivo.
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PMID:Interleukin-12 production by dendritic cells. The role of CD40-CD40L interactions in Th1 T-cell responses. 895 22

Tumor necrosis factor (TNF) induces the production of two forms of soluble receptor (p55 and p75) that are present in human serum at concentrations that increase greatly in inflammatory rheumatic disease, as well as varying among healthy individuals. The purpose of this study was to evaluate the usefulness of soluble TNF receptors in distinguishing different forms of arthritis. Serum from patients with gout, rheumatoid arthritis, and osteoarthritis, and normal control subjects was analyzed for p55, p75, and TNF-alpha by enzyme-linked immunosorbent assay. Patients with gout had the highest level of soluble TNF receptor p55, while there was no significant difference in the level of this receptor between rheumatoid arthritis patients and controls. Both rheumatoid arthritis and gout patients had higher soluble TNF receptor p75 levels than osteoarthritis patients and control subjects, but there was no difference in the p75 level between rheumatoid arthritis and gout patients. Osteoarthritis patients had higher levels of p55 and lower levels of p75 than control subjects. The level of TNF-alpha in rheumatoid arthritis patients was higher than in osteoarthritis patients, gout patients, and control subjects. Determination of soluble TNF receptor levels, especially p55, might enable differentiation of rheumatoid arthritis from osteoarthritis and gout. The level of p75 cannot be utilized to differentiate rheumatoid arthritis and gout, in contrast to the results of previous investigations.
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PMID:Soluble tumor necrosis factor receptor in serum of patients with arthritis. 929 Feb 65

Collagen type II-induced arthritis (CIA) in DBA/1 mice can be passively transferred to SCID mice with spleen B- and T-lymphocytes. In the present study, we show that infection ex vivo of splenocytes from arthritic DBA/1 mice with a retroviral vector, containing cDNA for the soluble form of human p75 receptor of tumour necrosis factor (TNF-R) before transfer, prevents the development of arthritis, bone erosion and joint inflammation in the SCID recipients. Assessment of IgG subclass levels and studies of synovial histology suggest that down-regulating the effector functions of T helper-type 1 (Th1) cells may, at least in part, explain the inhibition of arthritis in the SCID recipients. In contrast, the transfer of splenocytes infected with mouse TNF-alpha gene construct resulted in exacerbated arthritis and enhancement of IgG2a antibody levels. Intriguingly, infection of splenocytes from arthritic DBA/1 mice with a construct for mouse IL-10 had no modulating effect on the transfer of arthritis. The data suggest that manipulation of the immune system with cytokines, or cytokine inhibitors using gene transfer protocols can be an effective approach to ameliorate arthritis.
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PMID:Prevention of collagen-induced arthritis by gene delivery of soluble p75 tumour necrosis factor receptor. 1002 37

One of the most important and changing areas of research in paediatric rheumatology is the optimum approach to the treatment of children with chronic arthritis. Until recently all medications for children with arthritis were nonspecific in terms of our understanding, albeit poor, of the pathogenesis of these diseases. Of current therapies, low dose, once-a-week methotrexate has emerged as the therapeutic agent of choice for children who fail to respond adequately to administration of a nonsteroidal anti-inflammatory drug. Thereby, it has displaced the more traditional slower acting anti-rheumatic drugs, although one or more of them are often combined with methotrexate in the polypharmaceutical approach to childhood arthritis. Better and more specific agents are needed, especially for systemic onset disease, unremitting polyarticular involvement, and certain complications such as resistant chronic uveitis. At this time the introduction of the cyclo-oxygenase 2 inhibitors and etanercept (soluble tumour necrosis factoralpha.p75 fusion protein) may herald an era of more specific and effective therapy.
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PMID:Medical management of children with juvenile rheumatoid arthritis. 1059 64

Etanercept, a tumor necrosis factor receptor p75 Fc fusion protein (TNFR:Fc; Enbrel), has preliminarily been shown to be effective in the management of methotrexate-resistant polyarticular juvenile idiopathic arthritis (JIA). Reported side-effects have been minor, for example injection site reactions and upper respiratory tract infections, not necessitating discontinuation of the medication (1, 2). We report on 2 patients who developed an urticaria-like rash with prurigo appearing bilaterally on the extensor surfaces of the elbows subsequent to etanercept injections.
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PMID:Etanercept and urticaria in patients with juvenile idiopathic arthritis. 1094 36

To study the role of nerve growth factor (NGF) in local inflammation, we investigated the expression of NGF and its receptors, trkA and p75, in the ankle joints of adjuvant-induced arthritic rats. Infiltrated mononuclear cells revealed a positive immunoreactivity for NGF and trkA; they were also positive for immunostaining for W3/25 and ED1, which mainly stain T cells and macrophages, respectively. Changes in the ratios of NGF-positive cells to mononuclear cells showed a relatively similar pattern for trkA-positive cells, which peaked at weeks 2 to 3 after the adjuvant injection. In double-immunofluorescence staining, 80% and 65% of NGF-positive cells stained for W3/25 and ED1, respectively. Similarly, 67% and 80% of trkA-positive cells also corresponded to W3/25- and ED1-positive cells, respectively. However, p75 immunoreactivity localized on the nerve fibers but not on the cells of the ankle joints. Dense meshworks of p75-positive nerve fibers with numerous terminal varicosities were observed at weeks 2 to 4. The present findings suggest that infiltrated mononuclear cells may secrete NGF in an autocrine or paracrine manner in the inflamed synovium. An upregulation of NGF in these mononuclear cells and an increase in density of the synovial nerve fibers may be involved in the development of adjuvant arthritis in rats.
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PMID:Immunohistochemical study of NGF and its receptors in the synovial membrane of the ankle joint of adjuvant-induced arthritic rats. 1120 6

Immunex has developed and launched etanercept, a soluble TNF receptor (TNFR) fusion protein, for the treatment of early and moderate to severely active rheumatoid arthritis (RA). Etanercept was launched as a first-line agent in the US for the treatment of moderate-to-severe active RA in June 2000 [375481]. It can also be used in conjunction with methotrexate (MTX) in patients who do not respond adequately to MTX alone [303266], [310436]. It was launched in the EU in November 2000 [388846]. Enbrel was also launched for the treatment of polyarticular-course juvenile RA (JRA) patients who have an inadequate response to one or more disease-modifying antirheumatic drugs (DMARDs) in May 1999. Additionally, it is in phase III trials for psoriatic arthritis and a BLA filing for this indication is expected for the first half of 2001 [364948]. Etanercept was launched in the US in November 1998, for the treatment of moderate-to-severe RA in patients with inadequate responses to one or more DMARDs, or in combination with MTX in patients who do not respond adequately to MTX alone [306175]. The drug was subsequently approved by the US FDA for use as a first-line therapy to treat patients with moderately to severely active RA [375481]. In February 2000, Wyeth Europe received clearancefor etanercept in 15 EU countries by the EMEA for the treatment of active arthritis in adults when the response to DMARDs has been inadequate [354844]. It has since been launched in the UK (June 2000) [388840], and by October 2000 had been launched in all EU member states [388846]. In November 1998, the company filed a supplemental BLAfor the treatment of children and teenagers with moderately to severely active polyarticular course JRA. In May 1999, etanercept was approvedfor this indication by the US FDA and approvedfor this indication in Europe in February 2000 [307061], [310436], [326379]. The increasing understanding of the role of TNF in a number of other diseases has led to its clinical assessment in these areas. Following positive clinical results in phase II studies [317562], [315793], (320666], (359789], (373980] in patients with chronic heart failure, etanercept entered phase III trials for this indication in June 1999 [330068], and a BLA filing for this indication is expected in 2003 [396110]. Additionally, Immunex initiated a phase III trial of etanercept in psoriatic arthritis in March 2000, and as of May 2000, the company was planning a BLA filing for this indication in the first half of 2001 [364948]. An open-label trialfor the treatment of Crohn's disease is in progress in Belgium [367,039], and results from this trial were presented at Digestive Disease Week in May 2000 [379907]. While WO-09103553 claims the recombinant human receptor, the fusion protein consisting of the etanercept domain and the immunoglobulin region was disclosed in WO-09406476. In February 1997, US-05605690 was issued to Immunex for methods of using etanercept to treat diseases mediated by TNF. The patent also claims methods of using recombinant etanercept to decrease the levels of TNF in RA patients [235456]. In June 1999, Immunex strengthened its patent estate covering the product with a patent licensing agreement for Genentech's immunoadhesin patents covering the product [327250]. A royalty agreement with Serono SA and Immunex on sales of etanercept was agreed in 1999. The agreement reflected the strength of Ares-Serono's intellectual property status [352813]. In June 1999, Lehman Brothers predicted Immunex's sales at US $300 million in 1999, rising to peak annual sales of US $1.5 billion [328701]. Salesfor the drug's first full quarter on the market in 1999 were US $59.7 million [330068]. By November 1999 the drug had made sales of US $500 million; Immunex expects the drug will generate over US $2 billion in annual sales by 2004 [353185]. In September 2000, Merrill Lynch reported that if sales of the drug continue at the present rate then it is likely that demand will temporarily outstrip supply in 2001. Resolution of the supply issue is expected by 2002. Also in September 2000, Merrill Lynch lowered their estimate of ENBREL sales in 2001 from US $1 billion to $927 million. In the long-term, Merrill Lynch believe that the drug has the potential to exceed US $5 billion in sales in the US [382577].
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PMID:Etanercept Immunex. 1181 34


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