Infliximab | place in therapy review patients and sustained clinical improvement was observed for at least 4 months. Consecutively, a placebo-controlled, multicenter trial was terminated prematurely due to slow patient enrollment. The study was scheduled to enroll 60 patients in severe, active, steroid- refractory UC, but eventually enrolled just 11 patients; eight in the infliximab group (5, 10, or 20 mg/kg for one infusion) and three in the placebo group (Sands et al. 2001). Four patients treated with infliximab improved after 2 weeks versus none receiving placebo. The precise implication of these data is hard to define due to the limited size of the patient population. More recently the results of a Scandinavian placebo-controlled trial confirmed the initial findings. In this trial, patients with moderate to severe UC failing to respond to hospital treatment with intravenous steroids (betamethasone 4 mg/day) were randomized to receive infliximab 5 mg/kg in one infusion or placebo (Järnerot et al. 2005). Patients were eligible either because of fulminant colitis [assessed with the Sweden index (Seo et al. 2002)] at day 4 after starting intravenous steroids, or because they had more moderate disease activity but failed to improve from day 4 until day 8. Mesalamine therapy was started or continued in all patients and azathioprine was initiated at the discretion of the investigator. In total 45 patients were included, of whom 24 received infliximab, over a period of 3.5 years. Sixty-two percent of patients in both groups were included on the basis of the fulminant colitis index in both groups. Of note, more patients in the placebo group were experiencing their first attack of UC (43% vs 12% in the infliximab group). The primary endpoint of the trial was defined as colectomy or death within 90 days from baseline. Significantly more patients in the placebo group met this endpoint (67% vs 29%, P<0.02; odds ratio 4.9; 95% CI 1.4, 17). The cumulative proportion of patients not needing colectomy after 90 days was 71% in the infliximab group versus 33% in the placebo group (P<0.05). Interestingly, the difference in colectomy rates between the two groups was not significant for the patient groups recruited on the basis of fulminant disease activity at day 4, but only for those with more moderate disease at that time point. Severe endoscopic lesions at baseline, however, were not associated with poor prognosis. In summary, this trial provides evidence of the potential of infliximab to prevent colectomy in hospitalized patients with steroid-refractory UC, but long-term outcome data on the patient population included in this trial are needed to define the precise role of infliximab in the setting of fulminant colitis. Safety of long-term infliximab therapy Biologic agents are selective and powerful therapies for patients with IBD. Although the experience with infliximab has shown a beneficial benefit-to-risk ratio, some specific complications need to be addressed (Table 5). The chimeric nature of the monoclonal antibody infliximab gives rise to antibodies to infliximab (ATIs) in humans. ATIs are 158 associated with acute infusion reactions and loss of response, and with delayed hypersensitivity reactions and secondary loss of response. Acute infusion reactions are manifested by shortness of breath, chest pain, palpitations, flushing, headache, and sometimes urticaria and hypotension. They are in most cases easily managed with slowing of the infusion and administration of antihistamines and/or hydrocortisone. Patients who have experienced acute infusion reactions should receive prophylactic hydrocortisone before subsequent infusions. The delayed infusion reactions or serum sickness-like reactions occur typically 4–9 days after an infusion and are characterized by arthralgias (which may include unusual locations such as the jaw), back pain, myalgias, fever, skin rash, and leukocytosis. These delayed reactions need management with high doses of steroids for 4–7 days. The risk of serious infections, particularly with intracellular pathogens such as Myobacterium tuberculosis is increased in infliximab-treated patients and has been related to mortality. In patients with Crohn’s disease and rheumatoid arthritis, no clear increase in lymphoma incidence has been found in controlled clinical trials. A recent meta analysis of clinical trials with infliximab and adalimumab for rheumatoid arthritis suggested an increased risk of malignancy in patients receiving higher (≥6 mg/kg) doses of infliximab (odds ratio 4.3; 95% CI 1.6, 11.8) (Bongartz et al. 2005). For patients treated with infliximab in rheumatoid arthritis, the number needed to harm was 59 for serious infections, and 154 for malignancy. From clinical trials and from postmarketing surveillance, no increased risk of malignancy has become apparent with the use of infliximab (Biancone et al. 2006; Lichtenstein et al. 2006). Nevertheless, infliximab in combination with azathioprine has been associated with rare cases of gamma/delta T-cell hepatosplenic lymphoma in 10 young patients, nine of whom had Crohn’s disease, and one with unclassified colitis (Anon. 2007). Although it is impossible to define the relative role of both drugs in these lymphoma cases, they illustrate the need for postmarketing safety surveillance. In this respect, the North American TREAT registry has not revealed an increased risk for malignancies related to the use of infliximab in patients with Crohn’s disease thus far (Lichtenstein et al. 2006). An in-silico model of the benefit-to-risk ratio with the use of infliximab based on experience in clinical trials and in large patient cohorts came up with a beneficial effect of an infliximab-based strategy over non- infliximab-based management. More specifically, surgery-free remission was clearly increased in the putative infliximab- treated patient group. However, this came with the price of an increased mortality and lymphoma risk (Siegel et al. 2006). In the ACT-1 and ACT-2 trials the total number of adverse events and the proportion of patients with adverse events was similar in placebo- and infliximab-treated patients (Rutgeerts et al. 2005). The proportion of patients with a serious adverse event or with an infectious event was also similar in the three groups, but in ACT-1 significantly more patients in the combined infliximab group had an infectious event necessitating antibiotic treatment. In both studies combined, four neoplasias were found in the infliximab-treated patients versus one in the placebo © 2007 Core Medical Publishing Limited