Infliximab in Crohn disease
- Richard P MacDermott, MD
Richard P MacDermott, MD
- Emeritus Professor of Medicine, Division of Gastroenterology
- The Albany Medical College
- Gary R Lichtenstein, MD
Gary R Lichtenstein, MD
- Professor of Medicine
- Director, Center for Inflammatory Bowel Diseases
- University of Pennsylvania School of Medicine
Infliximab is a chimeric IgG 1 monoclonal antibody comprised of 75 percent human and 25 percent murine sequences, which has a high specificity for and affinity to tumor necrosis factor (TNF)-alpha. Infliximab is available for treatment of patients with moderately to severely active Crohn disease and patients with fistulizing Crohn disease, who have had an inadequate response to conventional therapy.
TNF-alpha has several biologic activities that may be directly related to the pathogenesis of inflammatory bowel disease and there is increasing evidence suggesting a central role for TNF-alpha in Crohn disease . As an example, stool TNF-alpha levels are elevated in patients with Crohn disease and correlate with disease activity . (See "Immune and microbial mechanisms in the pathogenesis of inflammatory bowel disease".)
Infliximab neutralizes the biologic activity of TNF-alpha by inhibiting binding to its receptors. However, infliximab's mechanism of action most likely involves the destruction of activated effector cells through apoptosis and/or other mechanisms [3-7]. Treatment of patients with infliximab markedly decreases endoscopic and histologic disease activity in Crohn colitis [8,9].
The role of infliximab in Crohn disease will be reviewed here. Conventional, alternative, and other types of immunomodulator therapy for Crohn disease are discussed separately (see appropriate topic reviews). The American Gastroenterological Association (AGA) guideline for glucocorticoids, immunomodulators, and infliximab in inflammatory bowel disease , as well as other AGA guidelines, can be accessed through the AGA website. In addition, the American College of Gastroenterology (ACG) has issued practice guidelines that can be accessed through the ACG website.
INDUCTION OF REMISSION IN PATIENTS WITH ACTIVE CROHN DISEASE
Multiple studies have evaluated the efficacy of infliximab in patients with active, non-fistulizing Crohn disease. Several centers have also published their clinical experience with infliximab, which provides further insight into the effectiveness of infliximab outside of the clinical trials setting. A meta-analysis found that patients treated with infliximab were less likely to fail to achieve remission than patients treated with placebo (RR 0.68) . (See 'Experience in clinical practice' below.)
- Plevy SE, Landers CJ, Prehn J, et al. A role for TNF-alpha and mucosal T helper-1 cytokines in the pathogenesis of Crohn's disease. J Immunol 1997; 159:6276.
- Braegger CP, Nicholls S, Murch SH, et al. Tumour necrosis factor alpha in stool as a marker of intestinal inflammation. Lancet 1992; 339:89.
- Scallon BJ, Moore MA, Trinh H, et al. Chimeric anti-TNF-alpha monoclonal antibody cA2 binds recombinant transmembrane TNF-alpha and activates immune effector functions. Cytokine 1995; 7:251.
- Su C, Salzberg BA, Lewis JD, et al. Efficacy of anti-tumor necrosis factor therapy in patients with ulcerative colitis. Am J Gastroenterol 2002; 97:2577.
- Lügering A, Schmidt M, Lügering N, et al. Infliximab induces apoptosis in monocytes from patients with chronic active Crohn's disease by using a caspase-dependent pathway. Gastroenterology 2001; 121:1145.
- ten Hove T, van Montfrans C, Peppelenbosch MP, van Deventer SJ. Infliximab treatment induces apoptosis of lamina propria T lymphocytes in Crohn's disease. Gut 2002; 50:206.
- Van den Brande JM, Braat H, van den Brink GR, et al. Infliximab but not etanercept induces apoptosis in lamina propria T-lymphocytes from patients with Crohn's disease. Gastroenterology 2003; 124:1774.
- van Dullemen HM, van Deventer SJ, Hommes DW, et al. Treatment of Crohn's disease with anti-tumor necrosis factor chimeric monoclonal antibody (cA2). Gastroenterology 1995; 109:129.
- D'haens G, Van Deventer S, Van Hogezand R, et al. Endoscopic and histological healing with infliximab anti-tumor necrosis factor antibodies in Crohn's disease: A European multicenter trial. Gastroenterology 1999; 116:1029.
- Lichtenstein GR, Abreu MT, Cohen R, et al. American Gastroenterological Association Institute medical position statement on corticosteroids, immunomodulators, and infliximab in inflammatory bowel disease. Gastroenterology 2006; 130:935.
- Ford AC, Sandborn WJ, Khan KJ, et al. Efficacy of biological therapies in inflammatory bowel disease: systematic review and meta-analysis. Am J Gastroenterol 2011; 106:644.
- Targan SR, Hanauer SB, van Deventer SJ, 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 1997; 337:1029.
- Hanauer SB, Feagan BG, Lichtenstein GR, et al. Maintenance infliximab for Crohn's disease: the ACCENT I randomised trial. Lancet 2002; 359:1541.
- Colombel JF, Sandborn WJ, Reinisch W, et al. Infliximab, azathioprine, or combination therapy for Crohn's disease. N Engl J Med 2010; 362:1383.
- Present DH, Rutgeerts P, Targan S, et al. Infliximab for the treatment of fistulas in patients with Crohn's disease. N Engl J Med 1999; 340:1398.
- Sands BE, Anderson FH, Bernstein CN, et al. Infliximab maintenance therapy for fistulizing Crohn's disease. N Engl J Med 2004; 350:876.
- Ochsenkühn T, Göke B, Sackmann M. Combining infliximab with 6-mercaptopurine/azathioprine for fistula therapy in Crohn's disease. Am J Gastroenterol 2002; 97:2022.
- West RL, van der Woude CJ, Hansen BE, et al. Clinical and endosonographic effect of ciprofloxacin on the treatment of perianal fistulae in Crohn's disease with infliximab: a double-blind placebo-controlled study. Aliment Pharmacol Ther 2004; 20:1329.
- Rutgeerts P, D'Haens G, Targan S, et al. Efficacy and safety of retreatment with anti-tumor necrosis factor antibody (infliximab) to maintain remission in Crohn's disease. Gastroenterology 1999; 117:761.
- Feagan BG, Yan S, Bala M, et al. The effects of infliximab maintenance therapy on health-related quality of life. Am J Gastroenterol 2003; 98:2232.
- Rutgeerts P, Feagan BG, Lichtenstein GR, et al. Comparison of scheduled and episodic treatment strategies of infliximab in Crohn's disease. Gastroenterology 2004; 126:402.
- Behm BW, Bickston SJ. Tumor necrosis factor-alpha antibody for maintenance of remission in Crohn's disease. Cochrane Database Syst Rev 2008; :CD006893.
- Lichtenstein GR, Yan S, Bala M, Hanauer S. Remission in patients with Crohn's disease is associated with improvement in employment and quality of life and a decrease in hospitalizations and surgeries. Am J Gastroenterol 2004; 99:91.
- Sartor RB. Episodic retreatment versus scheduled maintenance therapy of crohn's disease with infliximab: not so far apart. Gastroenterology 2004; 126:598.
- Lémann M, Mary JY, Duclos B, et al. Infliximab plus azathioprine for steroid-dependent Crohn's disease patients: a randomized placebo-controlled trial. Gastroenterology 2006; 130:1054.
- Kotlyar DS, Osterman MT, Diamond RH, et al. A systematic review of factors that contribute to hepatosplenic T-cell lymphoma in patients with inflammatory bowel disease. Clin Gastroenterol Hepatol 2011; 9:36.
- Kotlyar DS, Blonski W, Diamond RH, et al. Hepatosplenic T-cell lymphoma in inflammatory bowel disease: a possible thiopurine-induced chromosomal abnormality. Am J Gastroenterol 2010; 105:2299.
- Van Assche G, Magdelaine-Beuzelin C, D'Haens G, et al. Withdrawal of immunosuppression in Crohn's disease treated with scheduled infliximab maintenance: a randomized trial. Gastroenterology 2008; 134:1861.
- Beaugerie L, Brousse N, Bouvier AM, et al. Lymphoproliferative disorders in patients receiving thiopurines for inflammatory bowel disease: a prospective observational cohort study. Lancet 2009; 374:1617.
- Oussalah A, Chevaux JB, Fay R, et al. Predictors of infliximab failure after azathioprine withdrawal in Crohn's disease treated with combination therapy. Am J Gastroenterol 2010; 105:1142.
- Louis E, Mary JY, Vernier-Massouille G, et al. Maintenance of remission among patients with Crohn's disease on antimetabolite therapy after infliximab therapy is stopped. Gastroenterology 2012; 142:63.
- Van Assche G, Vermeire S, Ballet V, et al. Switch to adalimumab in patients with Crohn's disease controlled by maintenance infliximab: prospective randomised SWITCH trial. Gut 2012; 61:229.
- Lichtenstein GR, Yan S, Bala M, et al. Infliximab maintenance treatment reduces hospitalizations, surgeries, and procedures in fistulizing Crohn's disease. Gastroenterology 2005; 128:862.
- Sands BE, Blank MA, Patel K, et al. Long-term treatment of rectovaginal fistulas in Crohn's disease: response to infliximab in the ACCENT II Study. Clin Gastroenterol Hepatol 2004; 2:912.
- Hanauer SB, Lichtenstein GR, Mayer L, et al. Extraintestinal manifestations of Crohn's disease: Response to infliximab (Remicade) in the ACCENT I trial through 30 weeks (abstract). Am J Gastroenterol 2001; 96:A26.
- Colombel JF, Loftus EV Jr, Tremaine WJ, et al. The safety profile of infliximab in patients with Crohn's disease: the Mayo clinic experience in 500 patients. Gastroenterology 2004; 126:19.
- Cohen RD, Tsang JF, Hanauer SB. Infliximab in Crohn's disease: first anniversary clinical experience. Am J Gastroenterol 2000; 95:3469.
- Farrell RJ, Shah SA, Lodhavia PJ, et al. Clinical experience with infliximab therapy in 100 patients with Crohn's disease. Am J Gastroenterol 2000; 95:3490.
- Ljung T, Karlén P, Schmidt D, et al. Infliximab in inflammatory bowel disease: clinical outcome in a population based cohort from Stockholm County. Gut 2004; 53:849.
- Waugh AW, Garg S, Matic K, et al. Maintenance of clinical benefit in Crohn's disease patients after discontinuation of infliximab: long-term follow-up of a single centre cohort. Aliment Pharmacol Ther 2010; 32:1129.
- Parsi MA, Achkar JP, Richardson S, et al. Predictors of response to infliximab in patients with Crohn's disease. Gastroenterology 2002; 123:707.
- Baert F, Noman M, Vermeire S, et al. Influence of immunogenicity on the long-term efficacy of infliximab in Crohn's disease. N Engl J Med 2003; 348:601.
- Vande Casteele N, Gils A, Singh S, et al. Antibody response to infliximab and its impact on pharmacokinetics can be transient. Am J Gastroenterol 2013; 108:962.
- Jürgens M, Mahachie John JM, Cleynen I, et al. Levels of C-reactive protein are associated with response to infliximab therapy in patients with Crohn's disease. Clin Gastroenterol Hepatol 2011; 9:421.
- Ordás I, Feagan BG, Sandborn WJ. Therapeutic drug monitoring of tumor necrosis factor antagonists in inflammatory bowel disease. Clin Gastroenterol Hepatol 2012; 10:1079.
- Steenholdt C, Brynskov J, Thomsen OØ, et al. Individualised therapy is more cost-effective than dose intensification in patients with Crohn's disease who lose response to anti-TNF treatment: a randomised, controlled trial. Gut 2014; 63:919.
- Vande Casteele N, Ferrante M, Van Assche G, et al. Trough concentrations of infliximab guide dosing for patients with inflammatory bowel disease. Gastroenterology 2015; 148:1320.
- Lichtenstein GR, Olson A, Travers S, et al. Factors associated with the development of intestinal strictures or obstructions in patients with Crohn's disease. Am J Gastroenterol 2006; 101:1030.
- Lichtenstein GR, Stein R, Lewis JD, Deren J. The presence of intestinal strictures is associated with poorer responses for active or fistulizing Crohn's disease (abstract). Am J Gastroenterol 1999; 94:2676.
- Toy LS, Abittan C, Kornbluth A, et al. Complete bowel obstruction following initial response to Infliximab therapy for Crohn's disease: A series of a newly described complication (abstract). Gastroenterology 2000; 118:A569.
- Kugathasan S, Werlan SL, Aktay N, et al. Prolonged duration of response to infliximab in early pediatric Crohn's disease (CD): One year follow up (abstract). Gastroenterology 2000; 118:A566.
- Vasiliauskas EA, Schaffer S, Dezenberg CV, et al. Collaborative experience of open-label infliximab in refractory pediatric Crohn's disease (abstract). Gastroenterology 2000; 118:A178.
- Stephens MC, Shepanski MA, Mamula P, et al. Safety and steroid-sparing experience using infliximab for Crohn's disease at a pediatric inflammatory bowel disease center. Am J Gastroenterol 2003; 98:104.
- Baldassano R, Braegger CP, Escher JC, et al. Infliximab (REMICADE) therapy in the treatment of pediatric Crohn's disease. Am J Gastroenterol 2003; 98:833.
- de Ridder L, Escher JC, Bouquet J, et al. Infliximab therapy in 30 patients with refractory pediatric crohn disease with and without fistulas in The Netherlands. J Pediatr Gastroenterol Nutr 2004; 39:46.
- Markowitz J, Hyams J, Mack D, et al. Corticosteroid therapy in the age of infliximab: acute and 1-year outcomes in newly diagnosed children with Crohn's disease. Clin Gastroenterol Hepatol 2006; 4:1124.
- Hyams J, Crandall W, Kugathasan S, et al. Induction and maintenance infliximab therapy for the treatment of moderate-to-severe Crohn's disease in children. Gastroenterology 2007; 132:863.
- Lichtenstein GR, Feagan BG, Cohen RD, et al. Serious infection and mortality in patients with Crohn's disease: more than 5 years of follow-up in the TREAT™ registry. Am J Gastroenterol 2012; 107:1409.
- INDUCTION OF REMISSION IN PATIENTS WITH ACTIVE CROHN DISEASE
- INDUCTION OF REMISSION IN FISTULIZING DISEASE
- MAINTENANCE OF RESPONSE AND REMISSION
- Patients without fistulizing disease
- - Initial clinical response
- - Maintenance
- - Steroid tapering
- - Quality of life
- - Toxicity
- - Limitations
- Use of immunosuppressive agents in combination with infliximab
- Switching from infliximab to an alternative anti-TNF agent
- Patients with fistulizing disease
- - Rectovaginal fistulas
- EXTRAINTESTINAL MANIFESTATIONS
- EXPERIENCE IN CLINICAL PRACTICE
- Predictors of response
- USE IN THE SETTING OF INTESTINAL STRICTURES
- PEDIATRIC EXPERIENCE
- ADVERSE EVENTS
- ADALIMUMAB VERSUS INFLIXIMAB VERSUS CERTOLIZUMAB
- SOCIETY GUIDELINE LINKS
- INFORMATION FOR PATIENTS
- SUMMARY AND RECOMMENDATIONS