Abstract
Crohn’s disease is a chronic, disabling, inflammatory condition of the gastrointestinal tract that has a segmental distribution and can affect the entire gastrointestinal tract. Treatment of patients with Crohn’s disease represents a difficult challenge to physicians. Conventional therapy includes corticosteroids and immunosuppressants. Corticosteroids are highly effective for inducing response and remission, but the results in the long-term are disappointing and are associated with serious adverse events. Immunosuppressants are effective, but have a slow onset of action and are associated with intolerance and adverse events. In the last decade, as a result of a better understanding of the immunopathology of inflammatory bowel disease, novel therapeutic agents have been developed to target crucial components of the inflammatory cascade. Tumour necrosis factor (TNF) inhibitors (infliximab, adalimumab and certolizumab pegol) offer an effective alternative therapy, and are widely used in clinical practice for the management of Crohn’s disease and ulcerative colitis. This article focuses on the latest evidence-based data on clinical effectiveness, mucosal healing, immunogenicity, dose optimization for induction and maintenance of response and remission, and step-up versus top-down approaches of the available TNF inhibitors for the treatment of Crohn’s disease.
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References
Podolsky DK. Inflammatory bowel disease. N Engl J Med 2002; 347: 417–29
Schreiber S, Reinisch W, Colombel JF, et al. Early Crohn’s disease shows high levels of remission to therapy with adalimumab: subanalysis of CHARM. Gastroenterology 2007; 132: A–147
Travis SP, Stange EF, Lémann M, et al. European evidence based consensus on the diagnosis and management of Crohn’s disease: current management. Gut 2006; 55 Suppl.: i16–35
Mary JY, Modigliani R. Development and validation of an endoscopic index of the severity for Crohn’s disease: a prospective multicentre study. Groupe d’Etudes Therapeutiques des Affections Inflammatories du Tube Digestif (GETAID). Gut 1989; 30: 983–9
Present DH, Korelitz BI, Wisch N, et al. Treatment of Crohn’s disease with 6-mercaptopurine: a long-term, randomized, double-blind study. N Engl J Med 1980; 302: 981–7
Van Deventer SJ. Tumour necrosis factor and Crohn’s disease. Gut 1997; 40: 443–8
Reinecker HC, Steffen M, Witthoeft T, et al. Enhanced secretion of tumour necrosis factor-alpha, IL-6, and IL-1 beta by isolated lamina propria mononuclear cells from patients with ulcerative colitis and Crohn’s disease. Clin Exp Immunol 1993; 94: 174–81
Panés J, Gomollón F, Taxonera C, et al. Crohn’s disease: a review of current treatment with a focus on biologics. Drugs 2007; 67: 2511–37
Lichtenstein GR, Yan S, Bala M, et al. Infliximab maintenance treatment reduces hospitalizations, surgeries, and procedures in fistulizing Crohn’s disease. Gastroenterology 2005; 128: 862–9
Feagan BG, Panaccione R, Sandborn WJ, et al. Effects of adalimumab therapy on incidence of hospitalization and surgery in Crohn’s disease: results from the CHARM study. Gastroenterology 2008; 135: 1493–9
Schnitzler F, Fidder H, Ferrante M, et al. Long-term outcome of treatment with infliximab in 614 patients with Crohn’s disease: results from a single-centre cohort. Gut 2009; 58: 492–500
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: 1029–35
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: 761–9
Hanauer SB, Feagan BG, Lichtenstein GR, et al., ACCENT I Study Group. Maintenance infliximab for Crohn’s disease: the ACCENT I randomised trial. Lancet 2002; 359: 1541–9
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: 1398–405
Sands BE, Anderson FH, Bernstein CN, et al. Infliximab maintenance therapy for fistulizing Crohn’s disease. N Engl J Med 2004; 350: 876–85
Regueiro M, Schraut W, Baidoo L, et al. Infliximab prevents Crohn’s disease recurrence after ileal resection. Gastroenterology 2009; 136: 441–50
Hanauer SB, Sandborn WJ, Rutgeerts P, et al. Human anti-tumor necrosis factor monoclonal antibody (adalimumab) in Crohn’s disease: the CLASSIC-I trial. Gastroenterology 2006; 130: 323–33
Sandborn WJ, Hanauer SB, Rutgeerts P, et al. Adalimumab for maintenance treatment of Crohn’s disease: results of the CLASSIC II trial. Gut 2007; 56: 1232–9
Colombel JF, Sandborn WJ, Rutgeerts P, et al. Adalimumab for maintenance of clinical response and remission in patients with Crohn’s disease: the CHARM trial. Gastroenterology 2007; 132: 52–65
Sandborn WJ, Rutgeerts P, Enns R, et al. Adalimumab induction therapy for Crohn disease previously treated with infliximab: a randomized trial. Ann Intern Med 2007; 146: 829–38
Sandborn WJ, Feagan BG, Stoinov S, et al., PRECISE 1 Study Investigators. Certolizumab pegol for the treatment of Crohn’s disease. N Engl J Med 2007; 357: 228–38
Schreiber S, Khaliq-Kareemi M, Lawrance IC, et al., PRECISE 2 Study Investigators. Maintenance therapy with certolizumab pegol for Crohn’s disease. N Engl J Med 2007; 357: 239–50
Clark M, Colombel JF, Feagan BG, et al. American gastroenterological association consensus development conference on the use of biologics in the treatment of inflammatory bowel disease. Gastroenterology 2007; 133: 312–39
Behm BW, Bickston SJ. Tumor necrosis factor-alpha antibody for maintenance of remission in Crohn’s disease. Cochrane Database Syst Rev 2008; (1): CD006893
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: 935–87
Loras C, Saro C, Gonzalez-Huix F, et al. GETECCU (Grupo Español de Enfermedades de Crohn y Colitis Ulcerosa). Prevalence and factors related to hepatitis B and C in inflammatory bowel disease patients in Spain: a nationwide, multicenter study. Am J Gastroenterol 2009; 104: 57–63
Allez M, Lemann M, Bonnet J, et al. Long term outcome of patients with active Crohn’s disease exhibiting extensive and deep ulcerations at colonoscopy. Am J Gastroenterol 2002; 7: 947–53
Frøslie KF, Jahnsen J, Moum BA, et al., IBSEN Group. Mucosal healing in inflammatory bowel disease: results from a Norwegian population-based cohort. Gastroenterology 2007; 133: 412–22
Modigliani R, Mary JY, Simon JF, et al. Clinical, biological, and endoscopic picture of attacks of Crohn’s disease: evolution on prednisolone. Groupe d’Etude Thérapeutique des Affections Inflammatoires Digestives. Gastroenterology 1990; 98: 811–8
Olaison G, Sjödahl R, Tagesson C. Glucocorticoid treatment in ileal Crohn’s disease: relief of symptoms but not of endoscopically viewed inflammation. Gut 1990; 31: 325–8
D’Haens G, Geboes K, Rutgeerts P. Endoscopic and histologic healing of Crohn’s (ileo-) colitis with azathioprine. Gastrointest Endosc 1999; 50: 667–71
D’Haens G, Geboes K, Ponette E, et al. Healing of severe recurrent ileitis with azathioprine therapy in patients with Crohn’s disease. Gastroenterology 1997; 112: 1475–81
Lémann M, Mary JY, Colombel JF, et al. Groupe D’Etude Thérapeutique des Affections Inflammatoires du Tube Digestif. A randomized, double-blind, controlled withdrawal trial in Crohn’s disease patients in long-term remission on azathioprine. Gastroenterology 2005; 128: 1812–8
Colombel JF, Rutgeerts P, Reinisch W, et al. SONIC: a randomized, double-blind, controlled trial comparing infliximab and infliximab plus azathioprine to azathioprine in patients with Crohn’s disease na:ve to immunomodulators and biologic therapy. Gut 2008; 57: A1
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: 1029–34
Rutgeerts P, Diamond RH, Bala M, et al. Scheduled maintenance treatment with infliximab is superior to episodic treatment for the healing of mucosal ulceration associated with Crohn’s disease. Gastrointest Endosc 2006; 63: 433–42
Schnitzler F, Fidder H, Ferrante M, et al. Mucosal healing predicts long-term outcome of maintenance therapy with infliximab in Crohn’s disease. Inflamm Bowel Dis 2009; 15: 1295–301
Rutgeerts P, D’Haens GR, Van Assche G, et al. Adalimu-mab induces and maintains mucosal healing in patients with moderate to severe ileocolonic Crohn’s disease: first results of the extend trial. Gastroenterology 2009; 136: A–116
Hébuterne X, Colombel J, Bouhnik Y, et al. Endoscopic improvement in patients with active Crohn’s disease treated with certolizumab pegol: first results of the MUSIC clinical trial. Gut 2008; 57: A–15
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: 601–8
Vermeire S, Noman M, Van Assche G, et al. Effectiveness of concomitant immunosuppressive therapy in suppressing the formation of antibodies to infliximab in Crohn’s disease. Gut 2007; 56: 1226–31
Farrell RJ, Alsahli M, Jeen YT, et al. Intravenous hydrocortisone premedication reduces antibodies to infliximab in Crohn’s disease: a randomized controlled trial. Gastroenterology 2003; 124: 917–24
Hanauer SB, D’Haens GR, Colombel JF, et al. Sustained clinical remission in patients with moderate to severe Crohn’s disease with adalimumab, regardless of anti-TNF history or concomitant immunosuppressant therapy. Am J Gastroenterol 2006; 101: S457
Karmiris K, Paintaud G, Noman M, et al. Influence of trough serum levels and immunogenicity on long-term outcome of adalimumab therapy in Crohn’s disease. Gastroenterology 2009; 137: 1628–40
Rutgeerts P, Feagan BG, Lichtenstein GR, et al. Comparison of scheduled and episodic treatment strategies of infliximab in Crohn’s disease. Gastroenterology 2004; 126: 402–13
Domènech E, Zabana Y, Mañosa M, et al. Infliximab reintroduction is not associated to a higher rate of immune-related adverse effects in patients with inflammatory bowel disease initially treated with a three-infusion induction regimen. J Clin Gastroenterol. Epub 2009 May 4
Hanauer SB, Wagner CL, Bala M, et al. Incidence and importance of antibody responses to infliximab after maintenance or episodic treatment in Crohn’s disease. Clin Gastroenterol Hepatol 2004; 2: 542–53
Colombel JF, Sandborn WJ, Rutgeerts P, et al. Comparison of two adalimumab treatment schedule strategies for moderate-to-severe Crohn’s disease: results from the CHARM trial. Am J Gastroenterol 2009; 104: 1170–9
Regueiro M, Siemanowski B, Kip KE, et al. Infliximab dose intensification in Crohn’s disease. Inflamm Bowel Dis 2007; 13: 1093–9
Gisbert JP, Panés J. Loss of response and requirement of infliximab dose intensification in Crohn’s disease: a review. Am J Gastroenterol 2009; 104: 760–7
Schnitzler F, Fidder H, Ferrante M, et al. Flexible dosing of infliximab enables long-term maintenance of response in patients with refractory Crohn’s disease. Gut 2008; 57: A65
Oussalah A, Babouri A, Chevaux JB, et al. Adalimumab for Crohn’s disease with intolerance or lost response to infliximab: a 3-year single-centre experience. Aliment Pharmacol Ther 2009; 29: 416–23
Toruner M, Loftus EV, Harmesen WS, et al. Risk factors for opportunistic infections in patients with inflammatory bowel disease. Gastroenterology 2008; 134: 929–36
Beigel F, Jürgens M, Tillack C, et al. Hepatosplenic T-cell lymphoma in a patient with Crohn’s disease. Nat Rev Gastroenterol Hepatol 2009; 6: 433–6
Feagan BG, McDonald JW, Panaccione R, et al. A randomized trial of methotrexate in combination with infliximab for the treatment of Crohn’s disease. Gastroenterology 2008; 135: 294–5
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: 1861–8
Maser EA, Villela R, Silverberg MS, et al. Association of trough serum infliximab to clinical outcome alter scheduled maintenance treatment for Crohn’s disease. Clin Gastroenterol Hepatol 2006; 4: 1248–54
Markowitz J, Grancher K, Kohn N, et al. A multicenter trial of 6-mercaptopurine and prednisone in children with newly diagnosed Crohn’s disease. Gastroenterology 2000; 119: 895–902
Cosnes J, Nion-Larmurier I, Beaugerie L, et al. Impact of the increasing use of immunosuppressants in Crohn’s disease on the need for intestinal surgery. Gut 2005; 54: 237–41
Lémann M, Mary JY, Duclos B, et al. Groupe d’Etude Therapeutique des Affections Inflammatoires du Tube Digestif (GETAID). Infliximab plus azathioprine for steroid-dependent Crohn’s disease patients: a randomized placebo-controlled trial. Gastroenterology 2006; 130: 1054–61
D’Haens G, Baert F, van Assche G, et al. Belgian Inflammatory Bowel Disease Research Group; North-Holland Gut Club. Early combined immunosuppression or conventional management in patients with newly diagnosed Crohn’s disease: an open randomised trial. Lancet 2008; 371: 660–7
Beaugerie L, Seksik P, Nion-Larmurier I, et al. Predictors of Crohn’s disease. Gastroenterology 2006; 130: 650–6
Papi C, Festa V, Leandro G, et al. Long-term outcome of Crohn’s disease following corticosteroid-induced remission. Am J Gastroenterol 2007; 102: 814–9
Loly C, Belaiche J, Louis E. Predictors of severe Crohn’s disease. Scand J Gastroenterol 2008; 43: 948–54
Schreiber S, Hanauer S, Lichtenstein G, et al. Superior efficacy of certolizumab pegol in early Crohn’s disease is independent of CRP status. Gastroenterology 2007; 132: A–510
Acknowledgements
M.J. Etchevers and I. Ordás contributed equally to this work. No sources of funding were used in the preparation of this article. The authors have no conflicts of interest that are directly relevant to the content of this review.
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Etchevers, M.J., Ordás, I. & Ricart, E. Optimizing the Use of Tumour Necrosis Factor Inhibitors in Crohn’s Disease. Drugs 70, 109–120 (2010). https://doi.org/10.2165/11533700-000000000-00000
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DOI: https://doi.org/10.2165/11533700-000000000-00000