Abstract
Background
Stenoses and fistulas are frequent complications in patients with Crohn’s disease (CD). They represent a major diagnostic and therapeutic challenge and surgical intervention is often required. The availability of novel, anti-TNF strategies for therapy has raised the question as to what extent these new treatment options have impact on the clinical decision-making process regarding the necessity for surgery.
Discussion
A short overview of the current pathophysiological understanding of CD, focusing on the immunology of the intestinal mucosa, is given. Then the problems of proper clinical management of stenoses and fistulas are addressed. With regard to symptomatic stenoses, attention will be given to novel diagnostic tools for the distinction between inflammatory and fibrotic stenoses, and our clinical experience with the treatment of symptomatic inflammatory stenoses with infliximab will be discussed. With regard to fistulizing CD, the data that are currently available for medical therapy are summarized with special reference to the studies on the efficacy of anti-TNF treatment.
Conclusion
With regard to moderately and severe inflammatory stenoses, medical treatment with infliximab may be an option after careful assessment of the inflammatory nature of the stenosis and exclusion of a septic focus. With regard to fistulas, anti-TNF treatment is a valuable option that is likely to improve the clinical outcome. Based on the available data, however, anti-TNF treatment cannot yet replace surgical intervention when necessary. Prospective trials of medical therapy and a combination of medical and surgical therapy for complex fistulas and internal fistulas are needed to define the potential and the limitations of these novel therapeutic approaches.
References
Shivananda S et al (1996) Incidence of inflammatory bowel disease across Europe. Is there a difference between North and South. Gut 39:690–697
Farmer RG, Hawk WA, Turnbull RBJ (1975) National cooperative Crohn’s disease study: extraintestinal manifestations and perianal complications. Gastroenterology 77:914–920
Steinberg DM, Cooke WT, Alexander-Williams J (1973) Abscess and fistulae in Crohn’s disease. Gut 14:865–869
Holtmann M et al (2002) Das mukosale Immunsystem. Wie klar ist die Pathogenese. Internist 43:1343–1353
Hugot JP et al (2001) Association of NOD2 leucine-rich repeat variants with susceptibility to Crohn’s disease. Nature 411:599–603
Ogura Y et al (2001) A frameshift mutation in NOD2 associated with susceptibility to Crohn’s disease. Nature 411:603–606
Neurath MF, Finotto S, Glimcher LH (2002) The role of Th1/Th2 polarization in mucosal immunity. Nat Med 8:567–573
Holtmann M et al (2002) Functional relevance of soluble and transmembrane TNF and TNF-signal transduction in gastrointestinal diseases with special reference to inflammatory bowel diseases. Z Gastroenterol 40:587–600
Siegel SA et al (1995) The mouse/human chimeric monoclonal antibody cA2 neutralizes TNF in vitro and protects transgenic mice from cachexia and TNF lethality in vivo. Cytokine 7:15–25
Knight DM et al (1993) Construction and initial characterization of a mouse-human chimeric anti-TNF antibody. Mol Immunol 30:1443–1453
Scallon BJ et al (1995) Chimeric anti-TNF-alpha monoclonal antibody cA2 binds recombinant transmembrane TNF-alpha and activates immune effector functions. Cytokine 7:251–259
Luegering A et al (2001) Infliximab induces apoptosis in monocytes from patients with chronic active Crohn’s disease by using a caspase-dependent pathway. Gastroenterology 121:1145–1157
Ewe K et al (1993) Azathioprine combined with prednisolone or monotherapy with prednisolone in active Crohn’s disease. Gastroenterology 105:367–372
Candy S et al (1995) A controlled double blind study of azathioprine in the management of Crohn’s disease. Gut 37:674–678
Sandborn WJ, Sutherland L, Pearson DC, May GR, Modigliani R, Prantera C (1999) Azathioprine or 6-mercaptopurine for inducing remission of Crohn’s disease. The Cochrane Library. Update Software, Oxford
Pearson DC et al (2000) Azathioprine for maintaining remission of Crohn’s disease. Cochrane Database Syst Rev 2(Ia):CD000067
Tiede I et al (2003) CD28-dependent Rac1 activation is the molecular target of azathioprine in primary human CD4+ T lymphocytes. J Clin Invest 111:1133–1145
Neurath MF, Stange E (2000) Evidenzbasierte Immunsuppression bei chronisch entzündlichen Darmerkrankungen. Dtsch Ärztebl 97:A1977
Fazio VW et al (1989) Stricture-plasty in Crohn’s disease. Ann Surg 210:621–625
Fazio VW et al (1996) Effect of resection margins on the recurrence of Crohn’s disease in the small bowel. Ann Surg 224:563–573
Van Dullemen HM et al (1995) Treatment of Crohn’s disease with anti-tumor necrosis factor chimeric monoclonal antibody (cA2). Gastroenterology 109:129–135
Targan SR et al (1997) 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 337:1029–1035
Schunk K et al (2000) Hydro-MRI in Crohn’s disease: appraisal of disease activity. Invest Radiol 35:431–437
Schunk K et al (2000) Assessment of inflammatory activity in Crohn disease with hydro-MRI. Röfo Fortschr Geb Röntgenstr Neuen Bildgeb Verfahr 172:153–160
Bartenstein P et al (1997) Central motor processing in Huntington’s disease. A PET study. Brain 120:1553–1567
Bicik I et al (1997) Inflammatory bowel disease activity measured by positron-emission tomography. Lancet 350:262
Neurath MF et al (2002) Non-invasive assessment of Crohn’s disease activity: a comparison of 18F-fluoro-deoxy-glucose-positron emission tomography. Hydromagnetic resonance imaging and granulocyte scintigraphy with labelled antibodies. Am J Gastroenterol 97:1878–1885
Holtmann M et al (2003) Anti-TNF antibodies in the treatment of inflammatory intestinal stenoses in Crohn’s disease. Z Gastroenterol 41:11–17
Jones JH, Lennard-Jones JF (1966) Corticosteroids and corticotropin in the treatment of Crohn’s disease. Gut 7:181–187
Malchow H et al (1984) European cooperative Crohn’s disease study (ECCDS): results of drug treatment. Gastroenterology 86:249–266
Brandt LJ et al (1982) Metronidazole therapy for perineal Crohn’s disease: a follow-up study. Gastroenterology 83:383–387
Bernstein LH et al (1980) Healing of perineal Crohn’s disease with metronidazole. Gastroenterology 79:357–365
Schneider MU et al (1985) Metronidazol in der Behandlung des Morbus Crohn. Dtsch Med Wochenschr 110:1724–1730
Turunen U, Farkkila M, Seppala K (1989) Long-term treatment of perianal or fistulous Crohn’s disease with ciprofloxacin. Scand J Gastroenterol 24:144
Present DH et al (1980) Treatment of Crohn’s disease with 6-mercaptopurine: a long-term randomized double blind study. N Engl J Med 302:981–987
Korelitz BI, Present DH (1985) Favorable effect of 6-mercaptopuine on fistulae of Crohn’s disease. Dig Dis Sci 30:58–64
O’Brien JJ, Bayless TM, Bayless JA (1991) Use of azathioprine or 6-mercaptopurine in the treatment of Crohn’s disease. Gastroenterology 101:39–46
Present DH et al (1999) Infliximab for the treatment of fistulas in patients with Crohn’s disease. N Engl J Med 340:1398–1405
Sands BE et al (2004) Infliximab maintenance therapy for fistulizing Crohn’s disease. N Engl J Med 350:934–936
Sandborn WJ et al (2001) An engineered human antibody to TNF (CDP571) for active Crohn’s disease: a randomized, double-blind placebo-controlled trial. Gastroenterology 120:1330–1338
Feagan BG et al (2000) A randomized, double-blind, placebo-controlled, multi-center trial of the engineered human antibody to TNF (CDP571) for steroid sparing and maintenance of remission in patients with steroid-dependent Crohn’s disease [abstract]. Gastroenterology 118:A655
Bell SJ et al (2003) Response of fistulating Crohn’s disease to infliximab treatment assessed by magnetic resonance imaging. Aliment Pharmacol Ther 17:387–393
Van Bodegraven AA et al (2002) Endosonographic evidence of persistence of Crohn’s disease-associated fistulas after infliximab treatment, irrespective of clinical response. Dis Colon Rectum 45:39–45
Rasul I et al (2004) Clinical and radiological responses after infliximab treatment for perianal fistulizing Crohn’s disease. Am J Gastroenterol 99:82–88
Marks CG, Ritchie JK, Lockhart-Mummery HE (1981) Anal fistulas in Crohn’s disease. Br J Surg 68:525–527
Bernard D, Morgan S, Tasse D (1986) Selective surgical management of Crohn’s disease of the anus. Can J Surg 29:318–321
Williamson P et al (1995) Twenty year review of the surgical management of perianal Crohn’s disease. Dis Colon Rectum 38:389–392
Nordgren S, Fasth S, Hulten L (1992) Anal fistulas in Crohn’s disease: incidence and outcome of surgical treatment. Int J Colorectal Dis 7:214–218
Williams J et al (1991) Fistula-in-ano in Crohn’s disease. Dis Colon Rectum 34:378–384
White R et al (1990) Seton management of complex anorectal fistulas in patients with Crohn’s disease. Dis Colon Rectum 33:587–589
Pearl RK et al (1993) Role of the seton in the management of anorectal fistulas. Dis Colon Rectum 39:573–577
Scott H, Northover J (1996) Evaluation of surgery for perianal Crohn’s fistulas. Dis Colon Rectum 39:1039–1043
Regueiro M, Mardini H (2003) Treatment of perianal fistulizing Crohn’s disease with infliximab alone or as an adjunct to exam under anesthesia with seton placement. Inflamm Bowel Dis 9:98–103
Topstad DR et al (2003) Combined seton placement, infliximab infusion, and maintenance immunosuppressives improve healing rate in fistulizing anorectal Crohn’s disease: a single center experience. Dis Colon Rectum 46:577–583
Poritz LS, Rowe WA, Koltun WA (2002) Remicade does not abolish the need for surgery in fistulizing Crohn’s disease. Dis Colon Rectum 45:771–775
Broe PO, Bayless TM, Cameron JL (1982) Crohn’s disease: are enteroenteral fistulas an indication for surgery? Surgery 91:249–253
Radcliffe A et al (1988) Anavaginal and rectovaginal fistulas in Crohn’s disease. Dis Colon Rectum 31:94–99
Scott N, Nair A, Hughes L (1992) Anorectal and rectovaginal fistula with Crohn’s disease. Br J Surg 79:1379–1380
Joo JS et al (1998) Endorectal advancement flap in perianal Crohn’s disease. Am Surg 64:147–150
Hesterberg R et al (1993) Treatment of anovaginal fistulas with an anocutaneous flap in patients with Crohn’s disease. Int J Colorectal Dis 1993:51–54
Ozuner G et al (1996) Long-term analysis of the use of transanal rectal advancement flaps for complicated anorectal/vaginal fistulas. Dis Colon Rectum 39:10–14
Hanauer SB, Smith MB (1993) Rapid closure of Crohn’s disease fistulas with continuous intravenous cyclosporin. Am J Gastroenterol 88:646–649
Game X et al (2003) Infliximab treatment of Crohn disease ileovesical fistula. Scand J Gastroenterol 38:1097–1098
Beart F et al (2003) Influence of immunogenicity on the long-term efficacy of infliximab in Crohn’s disease. N Engl J Med 348:601–608
Keane J et al (2001) Tuberculosis associated with infliximab, a tumor necrosis factor alpha-neutralizing agent. N Engl J Med 345:1098–1104
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Holtmann, M.H., Neurath, M.F. Anti-TNF strategies in stenosing and fistulizing Crohn’s disease. Int J Colorectal Dis 20, 1–8 (2005). https://doi.org/10.1007/s00384-004-0634-0
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00384-004-0634-0