Tumor Necrosis Factor-Alpha (TNF- α) Inhibitors

TNF- α is a pro-inflammatory cytokine that plays a pivotal role in the pathogenesis of IBD and has been found in increased concentrations in the mucosa and stool of patients with Crohn's disease. There are currently three available anti- TNF monoclonal antibodies approved for use in Crohn's disease. Infiiximab is a chimeric mouse-human IgG1 monoclonal antibody, whereas adalimumab is a humanized IgG1 antibody and certolizumab pegol is a pegylated Fab' fragment.

All three TNF inhibitors bind with high specificity and affinity to soluble and membrane-bound TNF- α , leading to neutralization of its biological activity. Infiiximab and adalimumab, but not certolizumab pegol, also induce apoptosis of TNF expressing cells.

The first randomized controlled trial of infliximab in 1997 evaluated a single infusion in 108 patients with active Crohn's disease and demonstrated clinical response at week 2 in 81 % of the infiiximab-treated patients versus 17 % of the placebo-treated patients. Subsequently, the ACCENT 1 trial evaluated the use of repeated infiiximab infusions for maintenance therapy in moderate-severe Crohn's disease. In total, 58 % of patients responded within 2 weeks to the initial infusion of infiiximab, and those randomized to receive ongoing infusions achieved a 39 % remission rate at week 30, compared with 21 % of placebo-treated patients. When all patients treated with infiiximab were pooled, the odds ratio of sustained clinical remission with infiiximab compared to placebo was 2.7 and three times as many patients in the infiiximab group were able to discontinue steroids.

Interestingly, the real life experience with infiiximab seems to be even better than the clinical trials. In a Canadian cohort of 130 patients, most on concurrent immunomodulators, 83 % maintained clinical response at 30 weeks and 64 % at 54 weeks. Another study detailing a large single center experience with infiiximab showed an 82 % response to infiiximab induction, and a 66 % sustained clinical benefit.

Infiiximab has also proven effective for treatment of fistulas in Crohn's disease. The initial study of its use for this indication included 94 patients with draining abdominal or perianal fistulas . Of the patients who received 5 mg/kg infiiximab induction dosing, 68 % had a reduction of at least 50 % in the number of draining fistulas, compared to 26 % of the placebo group, and 55 % of the patients in the infiiximab group had complete closure of their fistulas. Subsequently, the landmark ACCENT II trial demonstrated that continued infusions of infiiximab every 8 weeks was more effective than placebo in maintaining fistula closure. In this study 36 % of patients in the infiiximab arm had a complete absence of draining fistulas at week 54, a statistically significant increase from the placebo group. In this same trial, infiiximab was effective for inducing and maintaining closure of rectovaginal fistulas, and reducing the number of hospital days, surgeries, and procedures.