Infliximab (IFX) (Remicade) is a chimeric anti-TNF monoclonal antibody with potent anti-inflammatory effects, possibly dependent on apoptosis of inflammatory cells, which has become the best choice in both active and fistulising CD unresponsive to standard therapy.
Additionally, TNA-a plays a crucial role in the inflammatory process in UC. In this disease, high levels of TNF-a are mainly found in the superficial colonic layers, as opposed to CD, where it is found deeper in the mucosa or submucosa. Normally the inflammatory response to TNF-a is counterbalanced by inhibitors, and there is evidence that the production of TNF-a inhibitors is down-regulated in IBD.
It has been shown that TNF-a blocking agents probably do not act by binding and inactivating TNF-a, but rather by inducing the apoptosis of TNF-expressing inflammatory cells, as proven by the inef-ficacy of etanercept. Resistance to apoptosis has been shown in both CD and UC, but with different mechanisms. The defect in CD occurs in the mitochondrial pathway of apoptosis (imbalance of mitochondrial bcl-2 bax), whereas in UC it derives from the overexpression of FLICE-inhibitory protein (FLIP) and impairment of the caspase mediated apoptosis.
These data support the use of IFX in UC, mainly in steroid-refractory or severely ill patients. Open trials on such patients suggested an effect in 50-75% of cases, which was maintained long-term in 25% of cases [66-68]. Concomitant use of anti-metabolites was associated with a lower rate of relapse.
Recently, two large multicentre placebo-controlled studies—Active Ulcerative Colitis 1 and 2 (ACT 1 and 2)—evaluated the efficacy of IFX for induction and maintenance of remission in UC patients . Three hundred and sixty-four patients with moderate to severe active UC according to the Mayo Index despite concurrent medications (corti-costeroids alone or in combination with AZA/6-MP, in ACT 1, or with AZA/6-MP and 5-ASA in ACT 2), were randomised to receive placebo or IFX 5 mg/kg or 10 mg/kg intravenously at weeks 0, 2 and then every 8 weeks through week 46 (in ACT 1) or week 22 (in ACT2). In both studies, a clinical response was obtained in 69% of IFX 5 mg and 61-69% IFX 10 mg, compared to 29-37% in the placebo group, with no difference between patients who are or are not steroid-refractory. At week 30 in both studies, IFX patients were more likely to have a clinical response than controls, and showed a clear steroid-sparing effect. In fact, while at baseline, 56% of patients were on steroids, by week 30, 22% of them discontinued steroids while maintaining remission. Long-term studies will clarify whether these promising results and the cost-effectiveness of this medical approach in avoiding colectomy will be maintained over the years.
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