Re: Remicade/TNF-alpha

[Guest guest]

Folks,

raised the subject of Remicade, a relatively new drug that is part of

a class called chimeric monoclonal antibody antagonists. This class, which

also includes Infliximab (being used successfully for Crohns Disease), block

the overproduction of a proinflammatory chemical produced by the body -- a

protein called Tumor Necrosis Factor-alpha.

In a July 1999 article published in the journal Hepatology, Lindor and

his Mayo colleague Angulo note that " The strong association between PSC

and Irritable Bowel Disease has suggested portal bacteremia as a potential

antigen source in genetically predisposed individuals. Absorption of

intestinal bacteria endotoxins through a diseased bowel mucosa may lead to

activation of Kupffer cells in the liver, with the consequent increased

production of tumor necrosis factor. Overproduction of tumor necrosis factor

has been associated with hepatobiliary lesions in rats with bile duct

destruction and proliferation resembling PSC in humans " [ " Primary Sclerosing

Cholangitis, " 326].

Below are two abstracts I found in Medline. I believe there is adequate basis

for hoping that Remicade or Infliximab may help to quell the inflammatory

process in PSC. Ezra

Gastroenterology 1999 Jan;116(1):22-8 Related Articles, Books, LinkOut

Tumor necrosis factor alpha antibody (infliximab) therapy profoundly

down-regulates the inflammation in Crohn's ileocolitis.

Baert FJ, D'Haens GR, Peeters M, Hiele MI, Schaible TF, Shealy D, Geboes K,

Rutgeerts PJ

Department of Gastroenterology, University Hospital Gasthuisberg, Leuven,

Belgium.

BACKGROUND & AIMS: Anti-tumor necrosis factor alpha monoclonal antibody

treatment (infliximab) reduces clinical signs and symptoms in patients with

Crohn's disease. The effects of infliximab on mucosal histopathologic

abnormalities in Crohn's ileocolitis were studied. METHODS: Thirteen patients

with steroid-refractory Crohn's disease were treated with a single infusion

of infliximab (5-20 mg/kg), and 5 were treated with placebo. Ileal and

colonic biopsy specimens of all patients were collected before and 4 weeks

after therapy. Severity of inflammation was assessed by a histological score.

Immunohistochemical stainings with antibodies against HLA-DR, CD68, tumor

necrosis factor alpha, intercellular adhesion molecule 1, lymphocyte

function-associated antigen, CD4, CD8, and interleukin 4 were performed.

RESULTS: Total histological activity score was reduced significantly in both

ileitis and colitis after infliximab. This is caused by a virtual

disappearance of the neutrophils and a reduction of mononuclear cells.

Mucosal architecture returned to normal in 4 patients at 4 weeks. The number

of lamina propria mononuclear cells decreased because of a global reduction

of CD4(+) and CD8(+) T lymphocytes and CD68(+) monocytes. Aberrant colonic

epithelial HLA-DR expression completely disappeared. The percentage of

intercellular adhesion molecule 1 and lymphocyte function-associated antigen

1-expressing and interleukin 4- and tumor necrosis factor-positive lamina

propria mononuclear cells sharply decreased. CONCLUSIONS: Infliximab

dramatically decreases histological disease activity in Crohn's ileocolitis.

Signs of active inflammation nearly disappear accompanied by a profound

down-regulation of mucosal inflammatory mediators.

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Gastroenterology 1995 Jul;109(1):129-35 Related Articles, Books, LinkOut

Treatment of Crohn's disease with anti-tumor necrosis factor chimeric

monoclonal antibody (cA2).

van Dullemen HM, van Deventer SJ, Hommes DW, Bijl HA, Jansen J, Tytgat GN,

Woody J

Department of Hepatogastroenterology, Academic Medical Center, Amsterdam, The

Netherlands.

BACKGROUND & AIMS: Increased concentrations of tumor necrosis factor (TNF), a

potent proinflammatory cytokine, can be shown in the mucosa of patients with

active Crohn's disease. Neutralization of TNF has been shown to decrease

recruitment of inflammatory cells and granuloma formation in several animal

models. The aim of this study was to investigate the safety and potential

efficacy of an anti-TNF monoclonal antibody in the treatment of active

Crohn's disease. METHODS: Ten patients with active Crohn's disease that was

unresponsive to therapy were administered a single infusion of an anti-TNF

human/mouse chimeric monoclonal antibody (cA2) in an open-label treatment

protocol while the baseline anti-inflammatory therapy was continued. RESULTS:

Eight patients showed normalization of Crohn's Disease Activity Index scores

and healing of ulcerations as judged by colonoscopy within 4 weeks after

treatment. One patient had a perforation after colonoscopy and recovered

completely after surgery. One elderly patient showed a poor response. The

average duration of response after a single infusion was 4 months. No adverse

experiences related to cA2 were observed. CONCLUSIONS: The results support

the hypothesis that TNF is of major importance in the pathogenesis of Crohn's

disease. Treatment with cA2 was safe and may be useful in patients with

Crohn's disease that is unresponsive to steroid treatment.