Infliximab (Remicade)
Introduced in 1998 as the first biological agent approved for treating adults and children with Crohn's disease, Infliximab is a chimeric (75% human, 25% murine) IgG1 monoclonal antibody for TNF-alpha. The U.S. Food and Drug Administration approved the drug for the treatment of moderate to severe Crohn's disease that does not respond to standard therapies (mesalamine, corticosteroids, immunosuppressive agents) and for the treatment of open, draining fistulas. Infliximab binds to both soluble and membrane bound TNF-alpha, thereby neutralizing the proinflammatory cytokine and reducing inflammation (Brookes, 2004)Brookes MJ, Green JR. Maintenance of remission in Crohn's disease: current and emerging therapeutic options. Drugs. 2004;64(10):1069-89. Review.
The ACCENT I study, which was a large randomised controlled trial (Hanauer SB et al, 2002)Hanauer SB, Feagan BG, et al; ACCENT I Study Group: Maintenance infliximab for Crohn's disease: the ACCENT I randomised trial:Lancet. 2002 May ;359(9317):1541-9.) has shown that patients with Crohn's disease who respond to an initial dose of infliximab are more likely to be in remission at weeks 30 and 54, to discontinue corticosteroids, and to maintain their response for a longer period of time, if infliximab treatment is maintained every 8 weeks. One out of every four patients who was initially on steroids was able to stop taking steroids and remain in remission when they were on infliximab maintenance therapy.
In another study, nearly 65% of refractory cases of Crohn's disease responded well to treatment with infliximab (5 mg/kg), and one third went into complete remission. Patients who relapsed after the initial response responded again to further infusions (Present DH et al, 1999)Present DH, Rutgeerts P, , et al. Infliximab for the treatment of fistulas in patients with Crohn's disease. N Engl J Med. 1999;340(18):1398-405..
Infliximab was effective in short-term closure of rectovaginal fistulas. After infusions of infliximab at weeks 0, 2, and 6, 60.7% (17 of 28) and 44.8% (13 of 29) of rectovaginal fistulas were closed at weeks 10 and 14, respectively. Among responders, 72.2% (13 of 18) of rectovaginal fistulas were no longer draining at week 14. The duration of rectovaginal fistula closure was longer in the infliximab 5-mg/kg maintenance group (median, 46 wk) than in the placebo group (33 wk) (ACCENT II study, Sands BE et al, 2004)Sands BE, Blank MA, et al; ACCENT II Study.: Long-term treatment of rectovaginal fistulas in Crohn's disease: response to infliximab in the ACCENT II Study; Clin Gastroenterol Hepatol. 2004 Oct;2(10):912-20 .
In patients with fistulizing Crohn's disease, infliximab 5 mg/kg every 8 weeks significantly reduced number of hospitalization days, mean numbers (per 100 patients) of hospitalizations, all surgeries and procedures, inpatient surgeries and procedures and major surgeries compared with those who received placebo maintenance treatment (Lichtenstein GR et al, 2005)Lichtenstein GR, Yan S, et al. Infliximab maintenance treatment reduces hospitalizations, surgeries, and procedures in fistulizing Crohn's disease. Gastroenterology. 2005 Apr;128(4):862-9 .
An added benefit of infliximab treatment is the ability to possibly taper steroids, which will decrease further adverse effects (Present DH et al, 1999;Present DH, Rutgeerts P, , et al. Infliximab for the treatment of fistulas in patients with Crohn's disease. N Engl J Med. 1999;340(18):1398-405. Targan SR et al, 1997Targan SR, Hanauer SB, et al. A short-term study of chimeric monoclonal antibody cA2 to tumor necrosis factor alpha for Crohn's disease. Crohn's Disease cA2 Study Group. N Engl J Med. Oct 9 1997;337(15):1029-35 ).
Infliximab also acts by downregulating CD40 and VCAM-1 expression in intestinal microvessels. CD40 and its ligand stimulate the production of TNF-alpha which acts as a positive feedback loop by increasing CD40 and CD40L expression. VCAM-1 is normally absent in intestinal tissue but is increased significantly in Crohn's disease. By decreasing VCAM-1 expression with Infliximab, fewer immune cells can enter the tissue which reduces inflammation (Danese S et al, 2006)Danese S, Sans M, et al. TNF-alpha blockade down-regulates the CD40/CD40L pathway in the mucosal microcirculation: a novel anti-inflammatory mechanism of infliximab in Crohn's disease. J Immunol. 2006 Feb 15;176(4):2617-24.