Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0010346 (Crohn's disease)
 21,615 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Although the cause of Crohn's disease remains unknown considerable progress has been made in recent years to unravel the pathogenesis of the inflammatory processes seen in chronic idiopathic inflammatory bowel diseases (IBD). Th-1 lymphocytes seem to orchestrate the inflammation through the production of pro-inflammatory cytokines such as IFN-gamma, IL-1beta and tumor necrosis factor (TNF). After isolation and characterization of TNF and its two receptors (p55 and p75) detailed regulatory processes for transcription, secretion and post receptor actions of TNF are now rapidly being discovered. Genetically engineered monoclonal antibodies, specifically directed against TNF are only the first drugs acting against TNF, available for clinical use now in the treatment of Crohn's disease. A single IV injection of these antibodies produces very dramatic clinical, endoscopic and histological responses in a majority of refractory patients. More data on long term safety and the exact role in combination with standard therapies are being awaited. In the mean time, these drugs should be reserved for patients not responding to standard antiinflammatory therapy. The exciting "TNF story" very nicely illustrates how the benchmark of basic immunological research now provides us with very potent and rationally designed drugs. Expected and unexpected safety toxicity data should caution clinicians to a certain extent against too liberal use of these agents interfering with very basic physiological events.
 ...
PMID:Anti-TNF therapy for Crohn's disease. 1257 Aug 20

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.
 ...
PMID:Etanercept-induced systemic lupus erythematosus. 1461 25

Anti-TNFalpha agents are frequently used in the treatment of severe JIA. Etanercept, a fully human soluble recombinant tumour necrosis factor p75 receptor Fc fusion protein, has been registered for the treatment of polyarticular course JIA patients who fail to respond to or do not tolerate methotrexate (MTX). Infliximab, a chimeric human-mouse monoclonal antibody to TNFalpha, is expected to be registered soon for JIA and Crohn's disease (CD) in children. As in adults, both agents are effective in controlling inflammation and inhibiting the progression of joint destruction. Despite this good clinical efficacy, the physician must remain alert for potential side effects, especially after prolonged use. This review gives an overview of the reported adverse events.
 ...
PMID:Safety of anti-TNFalpha therapy in children with juvenile idiopathic arthritis. 1508 97

TNF-alpha plays a central role in the pathophysiology of Crohn's disease. Infliximab, a chimeric monoclonal antibody against TNF-alpha, has been shown to be effective and well-tolerated in several large placebo-controlled trials and has become a common treatment for Crohn's disease. The blockade of TNF through the infusion of infliximab is characterized by high clinical efficacy and rapid onset of action. A single infusion of infliximab results in a remission rate of 30-40%. Lack of response appears to be a stable trait even after repeated infusions, suggesting that it might be genetically determined. Mutations in the TNF-alpha gene have been extensively studied as predictors of response with various results. Polymorphisms in the TNF-alpha receptors TNF-R1 and TNF-R2 have been found not to be associated with treatment response. Similarly, the three mutations in the CARD15 gene, which are independently associated with susceptibility to Crohn's disease, have also been found not to be associated with treatment response.
 ...
PMID:The role of pharmacogenomics in the prediction of efficacy of anti-TNF therapy in patients with Crohn's disease. 1521 84

Anti-tumour necrosis factor (TNF) strategies, the most studied of biological therapies, include chimeric monoclonal (infliximab), humanized monoclonal (CDP571 and the PEGylated CDP870) and fully human monoclonal (adalimumab) antibodies, p75 fusion protein (etanercept), p55 soluble receptor (onercept) and small molecules such as MAPkinase inhibitors. The principal use of infliximab is in treating active Crohn's disease patients not responding to or intolerant of conventional therapies. Infliximab is steroid sparing. The development of antibodies against infliximab is associated with an increased risk of infusion reactions, and a reduced duration of response to treatment, and concomitant immunosuppressive therapy reduces the immunogenic response. The demonstration of the efficacy of maintenance therapy every 8 weeks with infliximab in the randomised, controlled, ACCENT I trial opened up the strategy for regular maintenance. In patients who have failed therapy with cortocosteroids and immunosuppressive therapy and are poor surgical candidates, and patients with fistulizing disease, where infliximab therapy is chosen, regular maintenance therapy with infliximab is likely to be required. On the other hand, patients with severely active, steroid-refractory disease in whom immunosuppressive therapy and infliximab are initiated together, may respond adequately and be continued on long-term immunosuppressive therapy alone. In ulcerative colitis the role of infliximab remains uncertain.
 ...
PMID:Anti-TNF therapy in Crohn's disease. 1566 43

Blockade of tumor necrosis factor (TNF) has emerged as one of the most promising therapies in rheumatoid arthritis (RA). Three agents are currently available as specific TNF antagonists, etanercept (Enbrel), infliximab (Remicade), and adalimumab (Humira). Data from noncomparative trials suggest that all 3 agents have comparable therapeutic activity in RA. Etanercept and infliximab have also demonstrated beneficial activity in other inflammatory arthritides [i.e., psoriatic arthritis and ankylosing spondylitis (both agents) and juvenile rheumatoid arthritis (etanercept only)] and inflammatory diseases (i.e., psoriasis and uveitis). Their effects in granulomatous diseases are more variable, with only infliximab demonstrating clear efficacy in the treatment of Crohn's disease, sarcoidosis, and Wegener's vasculitis. In this brief review current efficacy data are summarized and possible explanations for observed clinical differences are explored.
 ...
PMID:Differentiating the efficacy of tumor necrosis factor inhibitors. 1574 57

Treatment of chronic inflammatory conditions, such as rheumatoid arthritis and Crohn's disease, with tumor necrosis factor (TNF) targeted biologics is associated with an increased risk of infectious complications, especially tuberculosis (TB). Clinical studies have revealed that monoclonal anti-TNF antibodies (e.g., infliximab) more frequently reactivate TB than a TNF receptor p75 immunoglobulin fusion construct (etanercept). Experimental studies in mice have shown TNF to be an essential component of protective granuloma formation. Based on these studies and the known pharmacological properties of the 2 prototype TNF targeted biologic agents, this review discusses 3 hypotheses that might explain the unpredicted differential risk of infectious complications: differential induction of target cell death, differential TNF receptor signaling, and differential net inhibition of TNF bioavailability.
 ...
PMID:Why does tumor necrosis factor targeted therapy reactivate tuberculosis? 1574 63

Targeted inhibition of tumour necrosis factor-alpha (TNF-alpha) is an effective therapy in rheumatoid arthritis and Crohn's disease (CD). Infliximab, a monoclonal murine-human chimeric antibody to TNF-alpha, and etanercept, a fusion protein of two p75 chains of the TNF receptor II and the Fc portion of IgG1, are generally well tolerated. Rarely does clinically significant autoimmunity, including drug-induced lupus and vasculitis occur. Immunologic mechanisms underlying the development of autoimmunity in the presence of such powerful immunosuppressants are unknown. We describe a patient with CD, who developed cutaneous vasculitis on etanercept, which worsened significantly with switch to infliximab. Investigation of the associated systemic and local immune response demonstrated the absence of human antichimera antibodies, but mRNA for T-helper 1 cytokines, chemokines and defensins in the skin and elevated angiogenesis factors in the serum, as determined by reverse-transcriptase polymerase chain reaction and enzyme-linked immunosorbent assay. Histopathology revealed a lymphocytic vasculitis composed of T cells. A permanent B-cell line (MD-B) producing extremely high amounts of chemokines and interleukin-6 was established from this patient's peripheral blood. Lesions progressed despite discontinuation of the drugs and (40 mg/day) prednisone but almost completely resolved with single dose of (0.1 mg/kg) intravenous dexamethasone, which may be therapy of choice for this reaction. A few lesions (<10) have recurred intermittently over 4 years of follow-up, suggesting possible persistence of this TNF-inhibitor-triggered autoimmune disease.
 ...
PMID:Immunology of cutaneous vasculitis associated with both etanercept and infliximab. 1585 15

Etanercept is a commercially available pharmaceutical protein approved for treatment of rheumatoid arthritis, RA. Given subcutaneously, etanercept binds and inactivates soluble tumor necrosis factor-alpha, TNF. Etanercept has a good safety record and is of benefit in lowering pain, inflammation, and joint destruction in RA. RA is mediated by many factors, TNF among them. Malignant myeloma, MM, is a malignant clonal expansion of a post-germinal center B lymphocyte. Since TNF is a necessary growth factor for expansion and maintenance of MM cells, and etanercept binds soluble TNF and is of clinical benefit in RA, etanercept was tried experimentally in MM. Contrary to expectations, etanercept resulted in increased levels of TNF and possibly shortened survival. This paper presents an hypothesis of how this happened. There are two cognate receptors for TNF, termed R1 and R2 and two forms of TNF, soluble and transmembrane. Soluble TNF has greater affinity for TNF-R1 than for TNF-R2. Transmembrane TNF has equal affinity for the two receptors. Since TNF-R2 signaling tends to be more anti-apoptotic and activating of nuclear factor kappa B, NFkB, than is TNF-R1, and TNF-R1 tends to be more pro-apoptotic than is TNF-R2, by inactivating soluble TNF while leaving transmembrane TNF signaling relatively unchanged, etanercept changed the balance in TNF signaling from TNF-R1 towards TNF-R2 weighting. Anti-apoptosis and TNF synthesis would have been up-regulated by that shift. Early data indicates that the common generic antidepressant bupropion may ameliorate Crohn's disease course by down regulating TNF synthesis, maybe it will slow the course of MM as well.
 ...
PMID:Evidence of a mechanism by which etanercept increased TNF-alpha in multiple myeloma: new insights into the biology of TNF-alpha giving new treatment opportunities--the role of bupropion. 1596 26

Cytokines (interleukins, chemokines, and some growth factors) play an important role in cancer, metabolic disorders, autoimmune disorders and inflammatory diseases, such as rheumatoid arthritis, asthma, Crohn's disease, psoriasis, multiple sclerosis and asthma. Cytokine-based drugs and anticytokine therapies are an increasingly important class of drugs in the treatment and management of many diseases. Interferons are being used to treat viral diseases and cancers. Anti-tissue necrosis factor therapies, such as Enbrel (etanercept; Immunex Corp) and Remicade (infliximab; Centocor) have demonstrated clinical efficacy in rheumatoid arthritis and Crohn's disease. In addition, thalidomide (Celgene) is being used to treat erythema nodosum in leprosy, cancers (multiple myeloma and colon cancer) and autoimmune diseases. This conference focused on new developments in basic research, drug discovery and clinical development of cytokine-based drugs.
 ...
PMID:Cytokines as drug targets. 1601 67


<< Previous 1 2 3 Next >>