Drugs 1998 Sep;56(3):299-305
[Medline record in process]
Tumour necrosis factor-alpha (TNF alpha) is thought to play a central role in the immunopathology of Crohn's disease, particularly since its levels are raised in all types of cells, tissues and secretory fluids of these patients and in animal models of the disease. In addition, TNF alpha has been found to modulate a number of different processes within the network of inflammatory reactions and therefore has become a target molecule for intervention studies. In the past few years several compounds have been developed which neutralise or impair the production of TNF alpha, e.g. monoclonal antibodies [infliximab (cA2), CDP-571], TNF receptor p75-Fc fusion protein, pentoxifylline (oxpentifylline), p65 antisense oligonucleotides and metalloproteinase inhibitors, thereby counteracting the deleterious effects of this proinflammatory cytokine. At present, successful treatment of active 'refractory' and fistulising Crohn's disease has been reported with anti-TNF alpha antibodies; more clinical studies are in progress or will be performed with substances that intervene in the activation, production and processing of TNF alpha. Although important aspects of this type of immune-intervention therapy still need to be elucidated, e.g. long term effects, mechanism(s) of action, identification of responders and nonresponders, etc., it is obvious that the integration of basic and clinical research brings us to a new era of specific cytokine-directed therapy in Crohn's disease.
PMID: 9777308, UI: 98450471
N Engl J Med 1997 Oct 9;337(15):1029-35
BACKGROUND: Studies in animals and an open-label trial have suggested a role for antibodies to tumor necrosis factor alpha, specifically chimeric monoclonal antibody cA2, in the treatment of Crohn's disease. METHODS: We conducted a 12-week multicenter, double-blind, placebo-controlled trial of cA2 in 108 patients with moderate-to-severe Crohn's disease that was resistant to treatment. All had scores on the Crohn's Disease Activity Index between 220 and 400 (scores can range from 0 to about 600, with higher scores indicating more severe illness). Patients were randomly assigned to receive a single two-hour intravenous infusion of either placebo or cA2 in a dose of 5 mg per kilogram of body weight, 10 mg per kilogram, or 20 mg per kilogram. Clinical response, the primary end point, was defined as a reduction of 70 or more points in the score on the Crohn's Disease Activity Index at four weeks that was not accompanied by a change in any concomitant medications. RESULTS: At four weeks, 81 percent of the patients given 5 mg of cA2 per kilogram (22 of 27 patients), 50 percent of those given 10 mg of cA2 per kilogram (14 of 28), and 64 percent of those given 20 mg of cA2 per kilogram (18 of 28) had had a clinical response, as compared with 17 percent of patients in the placebo group (4 of 24) (p<0.001 for the comparison of the cA2 group as a whole with placebo). Thirty-three percent of the patients given cA2 went into remission (defined as a score below 150 on the Crohn's Disease Activity Index), as compared with 4 percent of the patients given placebo (P=0.005). At 12 weeks, 41 percent of the cA2-treated patients (34 of 83) had had a clinical response, as compared with 12 percent of the patients in the placebo group (3 of 25) (P=0.008). The rates of adverse effects were similar in the groups. CONCLUSIONS: A single infusion of cA2 was an effective short-term treatment in many patients with moderate-to-severe, treatment-resistant Crohn's disease.
Gastroenterology 1995 Jul;109(1):129-35
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.