Serum concentrations of tumour necrosis factor alpha in childhood chronic inflammatory bowel disease.

Serum tumour necrosis factor alpha (TNF alpha) concentrations were measured by enzyme linked immunoadsorbent assay in 31 normal children and during 65 episodes of clinical remission and 54 episodes of relapse in 92 children with chronic inflammatory bowel disease. An appreciable rise in TNF alpha was found only in children in relapse of ulcerative colitis and colonic Crohn's disease. The group of children with small bowel Crohn's disease in relapse did not show increases of TNF alpha above control concentrations, despite an equivalent rise in disease indices. Height velocity was depressed in children with relapse of large bowel Crohn's disease and ulcerative colitis compared with the equivalent condition in remission. The impairment of growth velocity was significantly greater in relapse of large bowel Crohn's disease and ulcerative colitis than in small bowel Crohn's disease alone, although for the subgroups in stage 1 puberty (prepubertal) the differences were not significant. Inadequate growth in chronic inflammatory bowel disease is currently ascribed to inadequate nutrition and TNF alpha may contribute to this through its cachexia inducing effects. It may, in addition, diminish pituitary growth hormone release. These results suggest that production of TNF alpha may be associated with growth failure in relapse of colonic inflammatory bowel disease.     

Raised pro-inflammatory cytokines interleukin 6 and tumour necrosis factor alpha in coeliac disease mucosa detected by immunohistochemistry.

The levels of two pro-inflammatory cytokines, interleukin 6 (IL-6) and tumour necrosis factor alpha (TNF-alpha), in coeliac disease were studied by immunohistochemistry. Jejunal biopsy specimens from patients with untreated disease, (n = 11), treated disease (n = 9), and normal controls, (n = 11) were stained to detect IL-6, TNF-alpha, CD45 (pan-leukocyte), and CD68 (macrophage surface antigen). Positive cells were identified in the epithelium (per 100 enterocytes) and in the lamina propria (per unit area). There was a significant increase in median IL-6 and TNF-alpha staining in both the lamina propria and the epithelium of untreated coeliac disease patients (lamina propria, 16.2 and 13.0 respectively; epithelium, 0.86 and 1.21, all p < 0.05) when compared with treated coeliac disease patients (lamina propria; 6.0 and 6.2, epithelium; 0.60 and 0.60) and controls (lamina propria; 6.5 and 7.5, epithelium; 0.58 and 0.60). A significant increase in the number of CD45 positive cells was found in the untreated coeliac disease lamina propria and epithelium (p < 0.05) but this was accompanied by a significant rise in CD68 positive cells in the lamina propria only (p < 0.05). Increased IL-6 and TNF-alpha in the lamina propria and epithelium of patients with untreated coeliac disease further supports their role in the immune pathogenesis of this disorder.     

Secretion imbalance between tumour necrosis factor and its inhibitor in inflammatory bowel disease

BACKGROUND: Tumour necrosis factor (TNF) alpha and TNF-beta are soluble ligands binding to TNF receptors with similar activities; soluble TNF receptors neutralise TNF activity by acting as inhibitors. Little is known about the cytokine/soluble receptor role in inflammatory bowel disease (IBD). AIMS: To test the hypothesis that an imbalance in secretion between TNF and TNF inhibitors plays a role in gut inflammation in patients with IBD. METHODS: The secretion of TNF-alpha, TNF-beta, and soluble TNF receptors was compared in the culture supernatants of colonic biopsy specimens and isolated lamina propria mononuclear cells from patients with active colonic IBD. RESULTS: Spontaneous secretion of TNF-alpha in involved IBD mucosa was higher than in normal control and self limited colitis mucosa. Secretion of TNF-beta was higher in patients with Crohn's disease than in those with ulcerative colitis. Soluble TNF receptor in IBD mucosa inhibited TNF activity. Type 2 soluble receptor release from IBD mucosa was increased in active inflammation; release from lamina propria cells was not increased. Mucosal TNF-alpha production correlated with severity of disease. CONCLUSIONS: Results showed enhanced secretion of TNF-alpha but failure to release enhanced amounts of soluble TNF receptor in lamina propria mononuclear cells of patients with IBD. An imbalance in secretion between TNF and TNF inhibitor may be implicated in the pathogenesis of IBD.     

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炎症性肠病(inflammatory bowel disease,IBD)包括溃疡性结肠炎(ulcerative colitis,UC)和克罗恩病(Crohn's diseases,CD).其病因和发病机制尚不清楚,与遗传、环境、微生物、免疫等多个因素密切相关,其中免疫因素引起人们极大关注.     

Optimizing anti-tumor necrosis factor strategies in inflammatory bowel disease

The introduction of infliximab, a mouse/human chimeric monoclonal antibody to tumor necrosis factor (TNF), is an important advance in the treatment of Crohn’s disease. Infliximab is effective for induction and maintenance of remission in patients with inflammatory luminal and fistulizing disease. The development of human antichimeric antibodies (HACAs) has led to infusion reactions and loss of efficacy in patients treated with infliximab. Strategies to reduce the frequency of HACA formation include induction of immunologic tolerance with a three-dose regimen at 0, 2, and 6 weeks followed by systematic maintenance dosing every 8 weeks; concomitant immunosuppressive therapy with azathioprine, 6-mercaptopurine, or methotrexate; and premedication with intravenous corticosteroids. Humanized or fully human anti-TNF biotechnologic agents, including CDP571, CDP870, etanercept, adalimumab, and onercept, are theoretically less immunogenic than the chimeric antibody infliximab. Etanercept is not effective for Crohn’s disease. CDP571 is not effective in unselected patients with active Crohn’s disease, but it may be effective in patients with elevated C-reactive protein. The efficacy of CDP870, adalimumab, and onercept is under investigation. The different mechanisms of action of these anti-TNF agents may account for their variable efficacy. Their benefits, however, must be considered in the context of their risks, including infusion reaction; delayed hypersensitivitylike reaction; new onset of autoimmunity, with rare cases of drug-induced lupus and new-onset demyelination; and the potential for rare but serious infections.     

Paradoxical psoriasiform reactions of anti‐tumour necrosis factor therapy in inflammatory bowel disease patients

Anti‐tumour necrosis factor (TNF) agents have demonstrated efficacy in inflammatory bowel disease (IBD). Cutaneous reactions such as new onset psoriasis or psoriasiform‐like reactions are among the most common adverse reactions. We retrospectively identified cases of anti‐TNF‐induced psoriasis or psoriasiform manifestations in IBD patients at a tertiary centre in Australia. A total of 10 (six females) of 270 (3.7%) IBD patients treated with anti‐TNF therapy developed drug‐induced psoriatic or psoriasiform‐like reactions: five patients were treated with infliximab and five with adalimumab; nine had Crohn disease. The time from initiation of anti‐TNF agent to onset of rash was 7.5 months on average. The most frequent distributions were the scalp (7/10) and extremities (6/10). Three patients discontinued anti‐TNF treatment with resolution of the rash. Topical treatment of the lesions allowed continued use of biological agent in the majority. Paradoxical psoriatic lesions are recognised adverse events associated with anti‐TNF therapy, but discontinuation of therapy due to dermatological complications is required only rarely, even in patients with psoriasiform lesions.     

Safety of anti-tumor necrosis factor therapy in inflammatory bowel disease

Inflammatory bowel disease （IBD）, in particular Crohn＇s disease refractory to conventional therapy, fistulizing Crohn＇s disease and chronic active ulcerative colitis,generally respond well to anti-tumor necrosis factor（TNF） therapy. However, serious side effects do occur,necessitating careful monitoring of therapy. Potentialside effects of anti-TNF therapy include opportunistic infections, which show a higher incidence whenconcomitant immunosuppression is used. Furthermore,antibody formation against anti-TNF is associated with decreased efficacy and an increased frequency of infusion reactions. The hypothesis of a slightlyincreased risk of lymphomas in IBD patients treated with anti TNF-therapy is debatable, since most studieslack the specific design to properly address this issue.Alarmingly, the occurrence of hepatosplenic T-cell lymphomas coincides with combined immunosuppressive therapy. Despite the potential serious side effects, anti-TNF therapy is an effective and relatively safe treatment option for refractory IBD. Future research is needed to answer important questions, such as the long-term risk of malignancies, safety during pregnancy, when to discontinue and when to switch anti-TNF therapy, as well as to determine the balance between therapeutic and toxic effects.     

Antitumor necrosis factor treatment for pediatric inflammatory bowel disease

Infliximab, adalimumab, and certolizumab are monoclonal antibodies against tumor necrosis factor-α (TNFα), a proinflammatory cytokine with an increased expression in the inflamed tissues of inflammatory bowel disease (IBD) patients. Currently, infliximab is the only anti-TNF drug that has been approved for use in refractory pediatric Crohn's disease (CD). Nevertheless, adalimumab and certolizumab have been used off-label to treat refractory pediatric IBD. Over the past 10 years, anti-TNF treatment has been of great benefit to many pediatric IBD patients, but their use is not without risks (infections, autoimmune diseases, malignancies). Despite the growing experience with these drugs in children with IBD, optimal treatment strategies still need to be determined. The purpose of this review is to summarize the current knowledge on the use of anti-TNF drugs in pediatric IBD and to discuss the yet-unsolved issues.     

Study of tumor necrosis factor receptor in the inflammatory bowel disease

Ulcerative colitis(UC) and Crohn’s disease(CD) are part of Inflammatory Bowel Diseases(IBD) and have pathophysiological processes such as bowel necrosis and enteric neurons and enteric glial cells.In addition,the main inflammatory mediator is related to the tumor necrosis factor-alpha(TNF-α).TNF-α is a mediator of the intestinal inflammatory processes,thus being one of the main cytokines involved in the pathogenesis of IBD,however,its levels,when measured,are present in the serum of patients wit...     

Thalidomide reduces tumour necrosis factor alpha and interleukin 12 production in patients with chronic active Crohn's disease.

BACKGROUND: Thalidomide improves clinical symptoms in patients with therapy refractory Crohn's disease, as shown in two recent studies. The mechanism of this effect however is still unknown. Suppression of tumour necrosis factor alpha (TNF-alpha) by thalidomide has been suggested as a possible mechanism. However, effects on other cytokines have not been adequately investigated. AIM: The aim of our study was to investigate the effects of thalidomide on cytokine production in patients with inflammatory bowel disease (IBD). METHODS: Ten patients with therapy refractory IBD (nine Crohn's disease, one ulcerative colitis) received thalidomide 300 mg daily in a 12 week open label study. Production of TNF-alpha, interleukin (IL)-1 beta, IL-6, and IL-12 was investigated in short term cultures of stimulated colonic lamina propria mononuclear cells (LPMC) and peripheral blood monocytes (PBMC) before and after 12 weeks of treatment. LPMC were also cultured with graded doses of thalidomide. RESULTS: Three patients discontinued treatment because of sedative side effects. In the other patients, disease activity decreased significantly, with four patients achieving remission. Production of TNF-alpha and IL-12 decreased during treatment with thalidomide: LPMC (TNF-alpha: 42.3 (8.3) pg/ml v 16.4 (6.3); IL-12: 9.7 (3.3) v 5.0 (2.5); p<0.04) and PBMC (TNF-alpha: 62.8 (14.6) v 22.5 (9.2); p<0.02). Production of IL-1 beta and IL-6 did not change significantly. Culturing of LPMC with thalidomide showed a dose dependent decrease in TNF-alpha and IL-12 production. CONCLUSION: The clinical effects of thalidomide in Crohn's disease may be mediated by reduction of both TNF-alpha and IL-12.     

Anaemia of chronic disease in rheumatoid arthritis: in vivo effects of tumour necrosis factor alpha blockade

Anaemia of chronic disease (ACD) is a common feature of active rheumatoid arthritis (RA). Inflammatory cytokines, particularly tumour necrosis factor alpha (TNF-alpha), interleukin-1 (IL-1) and interleukin- 6 (IL-6), are thought to contribute to the pathogenesis of ACD, possibly by inhibiting erythropoietin (EPO) production. In this study, we examined the in vivo effects of TNF-alpha blockade with a chimeric monoclonal antibody, cA2, on erythropoiesis in RA patients with ACD. Administration of cA2 led to a dose-dependent increase in haemoglobin levels compared to placebo and these changes were accompanied by a reduction in both EPO and IL-6 levels. The data support the notion that TNF-alpha is important in the causation of ACD, but suggest a mechanism independent of EPO suppression. Instead, TNF-alpha may act directly on bone marrow red cell precursors.      

New concepts in anti-tumor necrosis factor therapy for inflammatory bowel disease

Crohn's disease is a T helper type 1 response immune disease characterized by increased production of interleukin-12 tumor necrosis factor-a (TNF-a), and interferon-g. Clinical trials have demonstrated that inhibition of TNF is effective for the treatment of Crohn's disease. Adverse events reported in patients treated with anti-TNF agents include immunogenicity, acute infusion reactions, delayed hypersensitivity-type reactions, autoimmune diseases including drug-induced lupus and demyelination, and infection. This article reviews new concepts in the treatment of Crohn's disease and ulcerative colitis with a variety of anti-TNF biologic therapies: infliximab, adalimumab, CDP870, CDP571, etanercept, and onercept.     

Practical guidelines for treating inflammatory bowel disease safely with anti‐tumour necrosis factor therapy in Australia

Anti‐tumour necrosis factor (TNF) therapy is an effective but expensive option for treating inflammatory bowel disease (IBD). Its use is generally reserved for patients with severe refractory disease, often involving long‐term administration. Anti‐TNF therapy has the potential to be associated with various adverse effects, such as infection, malignancy and immunogenicity. Clinicians and patients should be familiar with these possibilities and adopt appropriate precautions prior to and during treatment to minimize risk. Guidelines have been developed for Australian prescribers intending to use anti‐TNF therapy in IBD by a Working Party commissioned by IBD‐Australia, a Special Interest Group affiliated with the Gastroenterology Society of Australia.     

Therapeutic drug monitoring of tumor necrosis factor antagonists in inflammatory bowel disease

Although tumor necrosis factor (TNF) antagonists have shown clear benefits over conventional treatments for inducing and maintaining clinical remission in both Crohn's disease and ulcerative colitis, a high proportion of patients lose response over time. Given the scarce alternative of treatments when treatment failure occurs, it is highly desirable to optimize both initial response and long-term continuation of TNF antagonists. One of the most well-characterized factors associated with loss of response to these agents is the development of immunogenicity, whereby the production of neutralizing antidrug antibodies accelerates drug clearance, leading to subtherapeutic drug concentrations and, ultimately, to treatment failure. However, other patient-related factors, such as sex and/or body size, and disease severity, including TNF burden and serum albumin concentration among others, also may influence the pharmacokinetics of these agents. Nevertheless, the evidence generated to date about these complex interactions is scarce, and further prospective studies evaluating their influence on the pharmacokinetics of TNF antagonists are needed. Drug adjustment empirically based on clinical symptoms often is inaccurate and may lead to suboptimal outcomes. Recent evidence shows that maintenance of an optimal therapeutic drug concentration is associated with improved clinical outcomes. Therefore, incorporation of therapeutic drug monitoring into clinical practice may allow clinicians to optimize treatment by maintaining effective drug concentrations over time.