Infliximab

Cytokines including TNF-a are critical in the inflammatory processes that characterize CD. Mucosal biopsy specimens and mononuclear cells isolated from the lamina propria of a patient with CD express high levels of TNF-a. Infliximab is a chimeric monoclonal antibody that binds to and neutralizes human TNF-a. Its infusion results in a significant reduction in inflammation, as confirmed in many randomized placebo-controlled trials.

Present et al. [57] demonstrated the efficacy of infliximab in the treatment of fistulizing CD in a placebo-controlled multicentered study in which 94

patients with active abdominal or perianal fistulae received either infliximab 5 mg/kg, infliximab 10 mg/kg, or placebo. Treatments were administrated at weeks 0,2 and 6. The primary goal was a reduction of 50% or more in the number of draining fistulae observed at two or more consecutive visits; a secondary goal was fistula-closure. Sixty-eight percent of patients on infliximab 5 mg/kg and 56% on infliximab 10 mg/kg achieved the primary goal compared to 26% on placebo. Much more notably, complete fistula healing was obtained in 55% of patients on infliximab 5 mg/kg and in 38% 10 mg/kg. The majority of fistulae closed before the third infusion and the median duration of remission was 3 months. No differences were noted with regards to duration, extent of disease, prior surgery, number of fistulae or concomitant medications.

Infliximab has also proved to maintain its efficacy in the long term. In a randomized controlled trial of 573 patients with active Crohn's disease (CDAI score of at least 220), responders to a 5 mg/kg i.v. of infliximab (335 patients) were randomly assigned to repeat infusions of placebo at weeks 2 and 6 and then every 8 weeks until week 46 (group I), or 5 mg/kg infliximab at the same timepoints (group II), or 5 mg/kg infliximab at weeks 2 and 6 followed by infliximab 10 mg/kg (group III). At week 30, 21% of the patients of group I were in remission, compared to 39% of group II and 45% of group III [58].

Sands et al. performed a multicenter randomized double-blind placebo-controlled trial to evaluate the efficacy of infliximab maintenance therapy in 306 CD patients and one or more fistulae. Initially patients received 5 mg/kg infliximab i.v. at week 0, 2 and 6. A total of 195 patients who responded at week 14 were randomized to receive infliximab or placebo. The remaining 87 patients who didn't achieve an initial response were also randomly assigned to placebo or infliximab maintenance therapy. Among the respon-ders, those assigned to maintenance infliximab had a longer time to the loss of response than those on placebo (median 40 vs. 14 weeks). At week 54,36% of the infliximab group had a complete absence of draining fistulae, compared with 19% in the placebo group. There was no difference in response between infliximab and placebo among initial non-respon-ders [59].

No consensus has been reached on the best inflix-imab regimen for the long-term treatment of CD between short-term courses and retreatment of relapses vs. maintenance therapy. Some authors sustain that infliximab should be used as a bridge therapy while awaiting the onset of effects of conventional immunosuppressive therapy [60].

In a recent analysis of Crohn's disease, patients treated with infliximab in ACCENT I, episodic and scheduled treatment strategies were compared under conditions that simulate clinical practice. Patients treated with scheduled infliximab, particularly in the 10 mg/kg group, had better symptomatic responses than those treated on demand. Both scheduled groups had fewer hospitalizations, higher rates of mucosal healing, and lower rates of antibody positiv-ity, with no increase in side effects, than those treated on demand [61].

The main argument in favour of long-term scheduled infliximab is represented by the reduced prevalence of anti-infliximab antibodies during scheduled therapy rather than during episodic therapy, and by the association of these antibodies with decreased serum infliximab concentrations, decreased clinical responsiveness, and increased risk of allergic reactions [62].

The long-term use of infliximab for fistulizing CD is still under investigation in terms both of a limited efficacy and cost-effectiveness. As for the first problem, Poritz et al found that, if clinical improvement was obtained in 18 out of 26 patients with fistulizing CD, with complete fistula closure in 6, surgery was ultimately required in 14 patients and 6 continued to have draining fistulae [63]. The problem of the cost-effectiveness of infliximab therapy has been raised by a recent cost-utility analysis [64] in which infliximab proved to be more effective then either metronida-zole or AZA, but also far more expensive. However, these results are outweighed by the consideration that patients with fistulizing Crohn's disease in the ACCENT II study who received maintenance inflix-imab had significantly fewer days of hospitalization, number of hospitalizations, surgical procedures in total, and fewer major surgical procedures compared to those who received placebo [65].

Adverse events observed in patients treated with infliximab include infusion reactions such as delayed hypersensitivity, formation of anti-chimeric antibodies and anti-dsDNA autoantibodies and, in rare cases, onset of drug-induced lupus. Approximately 3% of patients in the ACCENT I trial developed delayed hypersensitivity reactions manifested by serum-sickness-like symptoms. This may be due to the fact that a proportion of the molecule is still of murine origin and therefore potentially immuno-genic. Attempts are therefore being made to produce less immunogenic biologic agents, thereby increasing their "human" proportion (Fig. 4).

The efficacy of a humanized chimeric antibody (CDP-571) against human TNF-a in fistula closure has been assessed in a randomized placebo-controlled trial on 37 patients with actively draining fistulae [66]. Closure of at least 50% of fistulae was obtained in 12 of 24 patients on CDP-571 and in 2 of 23 on placebo. Other agents that inhibit TNF-a activity such as pen-

Monoclonal Antibodies And Immunogenicity
Fig. 4. Ideal progression in the development of engineered monoclonal antibodies from wholly-murine to wholly humane, in an attempt to reduce the immunogenicity of the molecules. In black, components of murine origin; in white, components of human origin.

toxifylline and etanercept failed to demonstrate their efficacy in CD. Moreover, some of these agents are only active in a subset of patients with highly active disease, as identified by elevated C-reactive protein. Possible explanations for the different activity of biological drugs sharing the same target may be found in their different biological actions (binding to soluble or to membrane-bound TNF, capacity to produce T-cell apoptosis, fixation of complement, induction of antibody-dependent cytotoxicity).

Two open-label studies of thalidomide, a potent inhibitor of TNF alfa, have shown some degree of efficacy in fistulizing CD [67, 68]. Together, these studies support a strategy of TNF-a inhibition as a basis for healing fistulizing CD. In addition to its well-known teratogenic effects, thalidomide has been complicated by marked somnolence and peripheral neuropathy.

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