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

Many different factors can lead to inflammatory changes within temporomandibular joint tissues. This investigation examined if the expression of TNF-alpha and its receptors was altered in TMJ tissues during inflammation. Adult male rats were injected bilaterally with complete Freund's adjuvant (CFA) into the TMJ or served as uninjected controls and were killed two days after CFA treatment. TMJ tissues were removed, and expression of TNF-alpha and its receptors was examined via gene microarray analysis, RT-PCR, Western blot, and ELISA. Gene microarray analysis provided evidence for changes in gene expression, notably that TNF-alpha and TNF-R1, but not TNF-R2, were significantly elevated in CFA-treated TMJ tissues. However, protein levels of TNF-alpha, TNF-R1, and TNF-R2 were all significantly increased in CFA-treated TMJ tissues. These results indicate that the pro-inflammatory cytokine TNF-alpha may play a significant role in the onset of inflammatory conditions associated with adjuvant-induced arthritis of the TMJ.
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PMID:A determination of tumor necrosis factor expression in TMJ inflammation with the use of microarray analysis. 1451 61

The innervation of the temporomandibular joint (TMJ) has attracted particular interest because of the close association with complex mandibular movement. Although the pathological changes of disk innervation may have a crucial role in the development of TMJ pain, the innervation of the TMJ disk by experimentally induced arthritis has rarely been examined in detail. Arthritic rats were induced by injection with 0.1ml solution of Complete Freund's adjuvant (CFA). We investigated three-dimensional distribution of nerve fibers in the TMJ disk using immunohistochemistry for protein gene product-9.5 (PGP-9.5) and calcitonin gene-related peptide (CGRP) in naive and arthritic rats. To clarify the possible role of nerve growth factor (NGF) and its receptor on changes in peripheral innervation of the TMJ, the expressions of trkA and p75 receptor in trigeminal ganglia were examined. Although PGP-9.5 and CGRP immunoreactive (ir) fibers were seen in the peripheral part of the TMJ disk, they were not seen in its central part. The total length and the length density of PGP-9.5 ir and CGRP ir nerve fibers increased in arthritic rats. The innervation area of fibers proliferating in the rostro-medial part merged with that of fibers in the rostro-lateral part in the arthritic rats. In addition, the ratio of trkA- and p75-positive small- and medium-sized cells increased in trigeminal ganglia. It is assumed that increasing innervation of the TMJ disk may be important for the pathophysiology of TMJ pain. NGF and its receptors are likely involved in pathological changes of the TMJ disk.
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PMID:Nerve terminals extend into the temporomandibular joint of adjuvant arthritic rats. 1457 62

Chlamydia trachomatis (Ct)-induced arthritis (CtIA) is characterized by persistent Ct infection, which stimulates secretion of cytokines in vitro. We therefore investigated whether CtIA patients have a unique cytokine profile in synovial fluid or serum in vivo. Because underlying Ct infection is overlooked in a high percentage of patients with initially diagnosed undifferentiated oligoarthritis (UOA), we examined whether determination of cytokines might also be of diagnostic relevance for this arthritis form. Matched serum and synovial fluid specimens from 26 patients with CtIA were analyzed and compared to those from 34 patients with UOA in whom Ct infection was excluded and those of nine patients with rheumatoid arthritis (RA). In 15 CtIA patients, Ct DNA from synovial fluid could be amplified by polymerase chain reaction. The following cytokine or cytokine antagonists were measured by enzyme-linked immunosorbent assay: interleukin (IL)-1beta, tumor necrosis factor (TNF)-alpha, IL-6, IL-1 receptor antagonist, and soluble TNF receptor p75. No statistically significant differences in cytokine levels between patients with CtIA or the other arthritis forms were detected. Also, comparison between CtIA patients with (n = 17) and without Chlamydia DNA (n = 9) in synovial fluid revealed no significant differences for these cytokines. Cytokine levels in serum and synovial fluid were not different between CtIA, UOA without Ct infection, and RA patients. The intracellular presence of Ct was not associated with a specific profile of these cytokines in vivo.
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PMID:Cytokine profile in serum and synovial fluid of arthritis patients with Chlamydia trachomatis infection. 1459 90

Tumour necrosis factor (TNF) is a pro-inflammatory cytokine with a role in the pathogenesis of a number of conditions including rheumatoid arthritis, psoriasis, psoriatic arthritis, ankylosing spondylitis and Crohn's disease. Etanercept (Enbrel; Immunex Corp., Seattle, WA, USA) is a recombinant soluble fusion protein of TNF-alpha type II receptor and IgG which acts by blocking the action of TNF-alpha. It is licensed for use in rheumatoid arthritis and juvenile chronic arthritis. A number of studies report the development of antinuclear and anti-double-stranded DNA antibodies in patients treated with TNF antagonists for rheumatoid arthritis. There are few reports of the development of clinical features of discoid, subacute or systemic lupus erythematosus. We present one of the first reported cases of etenercept-induced systemic lupus erythematosus and review the literature of lupus and TNF antagonists.
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PMID:Etanercept-induced systemic lupus erythematosus. 1461 25

TNF-alpha has been found to play a pivotal role in the pathogenic mechanisms of rheumatoid arthritis (RA). The overexpression of TNF-alpha in RA synovium, the data from in vitro synovial cell cultures with the use of anti-TNF-alpha antibody and the results from TNF-alpha blockade in animal models of arthritis argued for the importance of this cytokine in RA. Drugs targeting TNF-alpha have been developed to neutralise the deleterious effects of this inflammatory cytokine. There are currently three drugs available in the treatment of RA patients with active disease, which was refractory to conventional treatments including methotrexate, infliximab (a chimeric mouse/human monoclonal antibody), etanercept (a fusion protein combining 2 p75 TNF receptors with a Fc fragment of human IgG (1)) and adalimumab (a fully human monoclonal antibody). These three drugs have proved to be effective and safe in appropriate and well conducted clinical trials and showed effectiveness in slowing and even arresting the progression of radiographic damage. With the long-term surveillance of these drugs serious adverse events were described, particularly intracellular organism infections such as tuberculosis. Other drugs targeting TNF-alpha are in development and include monoclonal antibody (CDP571), pegylated molecules (CDP870 and PEG-r-Hu-sTNF-RI) or soluble p55 TNF receptor construct (lenercept). These new biological therapies blocking TNF-alpha undoubtedly constitute a considerable advance in the management of RA, but careful evaluation at the initiation of the treatment and long-term surveillance of the patients receiving such drugs remains necessary.
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PMID:The use of TNF-alpha blocking agents in rheumatoid arthritis: an overview. 1501 27

Therapeutic options for patients suffering from the more severe spondyloarthritides (SpA) have been rather limited in the last decades. Evidence is now accumulating that anti-tumour necrosis factor (TNF) therapy is highly effective in SpA, especially in ankylosing spondylitis (AS) and psoriatic arthritis (PsA). Based on the data recently published concerning more than 1000 patients with AS and PsA, this treatment seems to be even more effective than in rheumatoid arthritis (RA). The anti-TNFalpha agents currently available, infliximab (Remicade), etanercept (Enbrel) and adalimumab (Humira), are approved for the treatment of RA in the USA and Europe. The situation for SpA is different from RA because there is an unmet medical need, especially in AS, since no therapies with disease-modifying anti-rheumatic drugs (DMARDs) are available for severely affected patients, especially those with spinal disease. Thus, TNF blockers may even be considered a first-line treatment in a patient with active AS and PsA whose condition is not sufficiently controlled with non-steroidal anti-inflammatory drugs (NSAIDs) in the case of axial disease, and sulphasalazine or methotrexate in the case of peripheral arthritis. For infliximab, a dose of 5 mg/kg is required, and intervals of between 6 and 12 weeks are necessary to constantly suppress disease activity-also a major aim for long-term treatment. The standard dosage of etanercept is 2 x 25 mg subcutaneously per week. There are almost no studies yet on adalimumab (standard dose in RA, 20-40 mg subcutaneously every 1-2 weeks) in SpA. Infliximab and etanercept are now both approved for AS in Europe. The efficacy of etanercept was first demonstrated in PsA, and it is now approved for this indication in the USA and Europe. There is preliminary evidence that both agents also work in other SpA, such as undifferentiated SpA (uSpA). Studies should be performed to document the long-term efficacy of this treatment. There is hope that ankylosis may be preventable, but it remains to be shown whether patients benefit from long-term anti-TNF therapy and whether radiological progression and ankylosis can be stopped. Severe adverse events have remained rare. Complicated infections including tuberculosis have been reported. These can largely be prevented by appropriate screening. As it stands now, the benefits of anti-TNF therapy in AS seem to outweigh these shortcomings.
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PMID:Biological therapies in the spondyloarthritides--the current state. 1518 39

The marrow stromal cell is the principal source of the key osteoclastogenic cytokine receptor activator of NF-kappaB (RANK) ligand (RANKL). To individualize the role of marrow stromal cells in varying states of TNF-alpha-driven osteoclast formation in vivo, we generated chimeric mice in which wild-type (WT) marrow, immunodepleted of T cells and stromal cells, is transplanted into lethally irradiated mice deleted of both the p55 and p75 TNFR. As control, similarly treated WT marrow was transplanted into WT mice. Each group was administered increasing doses of TNF-alpha. Exposure to high-dose cytokine ex vivo induces exuberant osteoclastogenesis irrespective of in vivo TNF-alpha treatment or whether the recipient animals possess TNF-alpha-responsive stromal cells. In contrast, the osteoclastogenic capacity of marrow treated with lower-dose TNF-alpha requires priming by TNFR-bearing stromal cells in vivo. Importantly, the osteoclastogenic contribution of cytokine responsive stromal cells in vivo diminishes as the dose of TNF-alpha increases. In keeping with this conclusion, mice with severe inflammatory arthritis develop profound osteoclastogenesis and bone erosion independent of stromal cell expression of TNFR. The direct induction of osteoclast recruitment by TNF-alpha is characterized by enhanced RANK expression and sensitization of precursor cells to RANKL. Thus, osteolysis attending relatively modest elevations in ambient TNF-alpha depends upon responsive stromal cells. Alternatively, in states of severe periarticular inflammation, TNF-alpha may fully exert its bone erosive effects by directly promoting the differentiation of osteoclast precursors independent of cytokine-responsive stromal cells and T lymphocytes.
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PMID:Marrow stromal cells and osteoclast precursors differentially contribute to TNF-alpha-induced osteoclastogenesis in vivo. 1547 24

Our objective was to clarify the heterogeneity in response to infliximab treatment in rheumatoid arthritis (RA); to this end, a bioassay was designed to explore the contribution of circulating tumour necrosis factor (TNF)-alpha bioactivity and its possible link to response. The bioassay is based on the induction of IL-6 and osteoprotegerin (OPG) production by synoviocytes in response to TNF-alpha. RA synoviocytes were cultured with TNF-alpha (5 ng/ml) and 42 RA plasma samples collected just before starting therapy. Levels of IL-6 and OPG were measured in supernatants. In 20 of the patients, plasma samples collected before and 4 hours after the first and the ninth infusions were tested in the same way. Plasma concentrations of TNF-alpha and p55 and p75 soluble receptors were measured using ELISA. TNF-alpha induced IL-6 and OPG production by synoviocytes, which was further increased with patient plasma dilutions and inhibited by infliximab. With plasma samples obtained before the first infusion, the IL-6-induced production was greater in patients with a good clinical response than in the poor responders (44.4 +/- 23.3 ng/ml versus 27.4 +/- 20.9 ng/ml; P = 0.05). This high circulating TNF-alpha bioactivity was strongly inhibited with the first infliximab infusion. The difference between IL-6 levels induced with plasma samples obtained before and 4 hours after the first infusion was greater in patients with a good clinical response (40.0 +/- 23.7 ng/ml versus 3.4 +/- 10.0 ng/ml; P = 0.001). Similar findings were obtained for OPG production (7.0 +/- 6.2 ng/ml versus 0.0 +/- 3.0 ng/ml; P < 0.05). Levels of circulating TNF-alpha bioactivity were predictive of clinical response to TNF-alpha inhibition, confirming a key role for TNF-alpha in these RA patients.
Arthritis Res Ther 2005
PMID:Circulating tumour necrosis factor-alpha bioactivity in rheumatoid arthritis patients treated with infliximab: link to clinical response. 1564 35

Etanercept (Enbrel, Wyeth Pharmaceuticals) is a fusion protein composed of a soluble TNF alpha receptor issued from bio-technology. It is a member of TNF alpha's family with two others marked infliximab (Remicade, Scheringh Plough Laboratory), chimeric monoclonal antibody (25 p. 100 mouse) and adalimumab (Humira, Abbott France Laboratory), humanized monoclonal antibody (100 p. 100 human). In United States, etanercept is approved by Food and Drug Administration, since 1998, to treat rheumatoid arthritis showing an inadequate response to prior therapy with other disease-modifying antirheumatic drugs (DMARDS). In France, the MA (Marketing Authorization) is more recent, in 2000, etanercept to treat active rheumatoid arthritis who showed an inadequate response to others DMARDS (like methotrexate for example), with opportunity, in 2002, to administer etanercept in active, severe RA, in first line treatment without previous use of methotrexate. Others MA have been obtained in ankylosing spondylitis (2004) polyarticular-course juvenile rheumatoid arthritis (2000), and in the treatment of psoriasic arthritis (2002). Request of MA have been realised to treat cutaneous mild to severe psoriasis in adult, which failed to respond, contradication or no tolerance with systemic treatment as methotrexate, cyclosporine or phototherapy. Among the others anti-TNF therapy, only infliximab can be prescribed, in dermatology, to treat psoriatic arthritis in France. Encouraging good results were the subject of cases report, but lacking clinical trial, predicting probably administration of etanercept in others indications in future. TNF alpha is a proinflammatory cytokine and plays an important role in the physiopathology of large inflammatory diseases. Logically, in future, we should increased prescription of biotherapy, particularly anti-TNF alpha. We have to mind short or mild-term adverse events, widely described in the literature, but long-term side effects remained unknown. Moreover, these biotherapic agents have a high cost and should be estimate.
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PMID:[Etanercept]. 1632 16

Tumor necrosis factor (TNF), initially discovered as a result of its antitumor activity, has now been shown to mediate tumor initiation, promotion, and metastasis. In addition, dysregulation of TNF has been implicated in a wide variety of inflammatory diseases including rheumatoid arthritis, Crohn's disease, multiple sclerosis, psoriasis, scleroderma, atopic dermatitis, systemic lupus erythematosus, type II diabetes, atherosclerosis, myocardial infarction, osteoporosis, and autoimmune deficiency disease. TNF, however, is a critical component of effective immune surveillance and is required for proper proliferation and function of NK cells, T cells, B cells, macrophages, and dendritic cells. TNF activity can be blocked, either by using antibodies (Remicade and Humira) or soluble TNF receptor (Enbrel), for the symptoms of arthritis and Crohn's disease to be alleviated, but at the same time, such treatment increases the risk of infections, certain type of cancers, and cardiotoxicity. Thus blockers of TNF that are safe and yet efficacious are urgently needed. Some evidence suggests that while the transmembrane form of TNF has beneficial effects, soluble TNF mediates toxicity. In most cells, TNF mediates its effects through activation of caspases, NF-kappaB, AP-1, c-jun N-terminal kinase, p38 MAPK, and p44/p42 MAPK. Agents that can differentially regulate TNF expression or TNF signaling can be pharmacologically safe and effective therapeutics. Our laboratory has identified numerous such agents from natural sources. These are discussed further in detail.
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PMID:TNF blockade: an inflammatory issue. 1633 57


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