Infliximab | place in therapy review Table 5 | Complications associated with the use of biologic agents in inflammatory bowel diseasesa Disease mechanism Immunosuppression Immunogenicity Clinical equivalent Infections, malignancy Loss of response Infusion reactions Induction of autoantibodies Demyelinization neurotoxicity Toxicity in diseased cardiac muscle Drug-induced lupus arthralgias Central/peripheral neuropathy Optic neuritis Progressive cardiac failure Drugs observed with Infliximab Adalimumab, certolizumab-pegol Natalizumab Infliximab MLN-02 Natalizumab Infliximab Infliximab Infliximab Preventive strategies Screening for latent infections Physicians’ awareness Humanization of therapeutic Ab Systematic maintenance treatment Concomitant immunomodulators/steroids Screening past history Physicians’ awareness Contraindicated in NYHA grade III–IV cardiac failure aOnly infliximab has been approved by the Food and Drug Administration and European Medicines Agency for use in ulcerative colitis. Data for this agent are deducted from clinical trial and postmarketing experience. The risk of malignancy in patients treated with biologic agents is still debated and so far no increase over the incidence in the general population has been formally documented. NYHA, New York Heart Association. group. Neurologic events occurred in three infliximab recipients and one patient exposed to infliximab developed drug- induced lupus. Patients with UC resistant to intravenous steroids enrolled in the Scandinavian controlled trial had no specific safety issues when exposed to infliximab (Järnerot et al. 2005). Of note, two patients in the placebo group had a septic complication after colectomy, which confirms the association of postoperative complications with high-dose steroids rather than with infliximab or purine analogs. UC carries a limited but intrinsic risk of colorectal cancer, which is thought to develop from dysplasia originating in chronically inflamed mucosa. Since one of the aims of medical therapies such as anti-TNF agents is to prevent colectomy, particularly in patients with fulminant disease, saving the colon may expose patients to a higher dysplasia risk in the long term. On the other hand, mucosal healing and regression of inflammation, as has been shown with anti-TNF therapy, should counterbalance this increased risk of neoplasia (Rutter et al. 2004, 2006). Also, the risk of colorectal cancer in patients with longstanding UC reported in recent patient cohorts is considerably lower than what has been reported before (Jess et al. 2006). This observation cannot be explained by increased colectomy rates, but the exact role of improved disease control with medical therapy in the apparent decrease of the cancer risk is also not clear. The dysplasia and rectal cancer cases in the ACT trials both occurred in infliximab-treated patients, but the trials were not powered to study the influence of infliximab on rare events such as dysplasia. In patients with fulminant colitis, particularly those with pancolitis, the risk of developing cancer when the colon is saved and preserved long term, has not been specifically studied and cannot be weighed against surgical morbidity with colectomy. As long as this question remains unresolved, it appears prudent to apply surveillance programs to patients with longstanding UC controlled with any form of medical therapy, including anti-TNF antibodies. Core Evidence 2007;2(3) Resource utilization No published data on direct assessments of resource utilization with the use of infliximab in UC are known to the authors. However, the ACT-1 and ACT-2 trials show that scheduled maintenance therapy with infliximab for 1 year reduces the need for hospitalization (Rutgeerts et al. 2005). Hospitalization and surgery contribute heavily to the cost of treatment in these patients. There appear to be no long-term data on colectomy rates in patients successfully treated with infliximab. Total colectomy abolishes the need for further treatment in UC patients and most patients have a good quality of life after colectomy. Since biologic agents such as infliximab weigh significantly on the direct drug cost to induce remission in UC patients, further studies exploring prevention of hospitalization and colectomy, of the ability to work, and of added quality-adjusted life-years are crucial. These outcomes have been achieved with infliximab in Crohn’s disease, but specific data are needed in patients with UC. Dosage, administration, and fomulations The label for infliximab for use in patients with moderate to severe UC granted by both the European Medicines Agency and the Food and Drug Administration allows both induction and maintenance therapy in patients with treatment-refractory active colitis. Induction therapy consists of intravenous infliximab 5 mg/kg at week 0, 2, and 6. In scheduled maintenance therapy, infliximab is administered intravenously at a dose of 5 mg/kg every 8 weeks. Studies in Crohn’s disease have shown that scheduled maintenance is superior to periodic therapy during disease flare in the prevention of immunogenicity to the chimeric antibody, and is considered the optimal strategy (Hanauer et al. 2002; Rutgeerts et al. 2004; Sands et al. 2004). However, no direct comparison between the two modalities of treating patients long term has been performed in UC. 159