Medical Therapy of Perianal Crohn's Disease

Thomas Klag, Martin Goetz, Eduard F Stange, Jan Wehkamp, Thomas Klag, Martin Goetz, Eduard F Stange, Jan Wehkamp

Abstract

Background: Development of perianal fistulas are a common feature of Crohn's disease (CD). Consequences are severe impairment of quality of life as well as potentially life-threatening complications like abscess formation or bacterial sepsis. Therefore, appropriate treatment is an important task in the management of CD.

Methods: This review describes the epidemiology, pathogenesis, diagnosis, and conservative medical treatment of perianal CD with regard to the available literature. In February 2015, a PubMed search was performed with the following terms (combined and separate): 'Crohn's disease management', 'Crohn's disease complications', 'perianal Crohn's disease', 'fistulizing Crohn's disease', 'perianal fistulas', 'fistula healing', 'fistula closure'. From the search results, 36 articles were chosen as core elements of this review.

Results: Pelvic magnetic resonance imaging and rectal endosonography are established diagnostic approaches to evaluate perianal fistulas in conjunction with endoscopy. Antibiotics, thiopurines, and calcineurin inhibitors are useful agents in the management of perianal CD. The availability of anti-TNF-alpha therapies has substantially changed the prospects and goals of medical treatment, and fistula healing seems to be possible in a substantial proportion of patients.

Conclusion: Antibiotics and several immunosuppressive drugs have improved the treatment of fistulizing CD and should be combined with surgical measures.

Keywords: Anti-TNF-alpha therapy; Crohn's disease; Crohn's disease complications; Inflammatory bowel disease; Perianal fistula.

Figures

Fig. 1
Fig. 1
A Distal (perianal) orifice of a fistula tract, gastrointestinal lumen at 5 o'clock (arrow). B Anorectal stenosis with stigmata of chronic inflammation (ulceration and wall thickening). C Balloon dilatation of the intestinal stenosis to promote fistula healing in addition to medical therapy.
Fig. 2
Fig. 2
Diagnostic and therapeutic algorithm for the management of perianal Crohn's disease.
Fig. 3
Fig. 3
Magnetic resonance imaging (MRI) scan of perianal fistulas in a patient with Crohn's disease. A Arrows indicate complex fistula tracks. B Arrow indicates a big pararectal abscess that was treated by computed tomography-guided drainage 1 day later, before anti-TNF-alpha therapy with infliximab was initiated. MRI imaging with the kind assistance of Prof. Niolaou and PD Dr. C. Schraml, Department of Radiology, University of Tübingen.

References

    1. Fakhoury M, Negrulj R, Mooranian A, Al-Salami H. Inflammatory bowel disease: clinical aspects and treatments. J Inflamm Res. 2014;7:113–120.
    1. Nielsen OH, Rogler G, Hahnloser D, Thomsen O. Diagnosis and management of fistulizing Crohn's disease. Nature Clin Pract Gastroenterol Hepatol. 2009;6:92–106.
    1. Hellers G, Bergstrand O, Ewerth S, Holmström B. Occurrence and outcome after primary treatment of anal fistulae in Crohn's disease. Gut. 1980;21:525–527.
    1. Vavricka SR, Rogler G. Fistula treatment: the unresolved challenge. Dig Dis. 2010;28:556–564.
    1. Schwartz DA, Loftus EV, Jr, Tremaine WJ, Panaccione R, Harmsen WS, Zinsmeister AR, Sandborn WJ. The natural history of fistulizing Crohn's disease in Olmsted County, Minnesota. Gastroenterology. 2002;122:875–880.
    1. Marzo M, Felice C, Pugliese D, Andrisani G, Mocci G, Armuzzi A, Guidi L. Management of perianal fistulas in Crohn's disease: an up-to-date review. World J Gastroenterol. 2015;21:1394–1403.
    1. Seifarth C, Kreis ME, Gröne J. Indications and specific surgical techniques in Crohn's disease. Viszeralmedizin. 2015;31:273–279.
    1. Klag T, Stange EF, Wehkamp J. Defective antibacterial barrier in inflammatory bowel disease. Dig Dis. 2013;31:310–316.
    1. Bataille F, Klebl F, Rümmele P, et al. Morphological characterisation of Crohn's disease fistulae. Gut. 2004;53:1314–1321.
    1. Leeb SN, Vogl D, Gunckel M, Kiessling S, Falk W, Wild PJ, Fürst A, Hofstädter F, Schölmerich J, Herfarth H, Rogler G. Reduced migration of fibroblasts in inflammatory bowel disease: role of inflammatory mediators and focal adhesion kinase. Gastroenterology. 2003;125:1341–1354.
    1. Tarnawski AS. Cellular and molecular mechanisms of gastrointestinal ulcer healing. Dig Dis Sci. 2005;50:24–33.
    1. Dignass AU. Mechanisms and modulation of intestinal epithelial repair. Inflamm Bowel Dis. 2001;7:68–77.
    1. West RL, Van der Woude CJ, Endtz HP, Hansen BE, Ouwedijk M, Boelens HA, Kusters JG, Kuipers EJ. Perianal fistulas in Crohn's disease are predominantly colonized by skin flora: implications for antibiotic treatment? Dig Dis Sci. 2005;50:1260–1263.
    1. Gecse K, Khanna R, Stoker J, Jenkins JT, Gabe S, Hahnloser D, D'Haens G. Fistulizing Crohn's disease: diagnosis and management. United European Gastroenterol J. 2013;1:206–213.
    1. Law PJ, Bartram CI. Anal endosonography: technique and normal anatomy. Gastrointest Radiol. 1989;14:349–355.
    1. Navarro-Luna A, Garcia-Domingo MI, Rius-Macias J, Marco-Molina C. Ultrasound study of anal fistulas with hydrogen peroxide enhancement. Dis Colon Rectum. 2004;47:108–114.
    1. Siddiqui MR, Ashrafian H, Tozer P, Daulatzai N, Burling D, Hart A, Athanasiou T, Phillips RK. A diagnostic accuracy meta-analysis of endoanal ultrasound and MRI for perianal fistula assessment. Dis Colon Rectum. 2012;55:576–585.
    1. Haggett PJ, Moore NR, Shearman JD, Travis SP, Jewell DP, Mortensen NJ. Pelvic and perianal complications of Crohn's disease: assessment using magnetic resonance imaging. Gut. 1995;36:407–410.
    1. Halligan S, Stoker J. Imaging of fistula in ano. Radiology. 2006;239:18–33.
    1. Schwartz DA, Wiersema MJ, Dudiak KM, Fletcher JG, Clain JE, Tremaine WJ, Zinsmeister AR, Norton ID, Boardman LA, Devine RM, Wolff BG, Young-Fadok TM, Diehl NN, Pemberton JH, Sandborn WJ. A comparison of endoscopic ultrasound, magnetic resonance imaging and exam under anesthesia for evaluation of Crohn's perianal fistulas. Gastroenterology. 2001;121:1064–1072.
    1. Buchanan GN, Halligan S, Bartram CI, Williams AB, Tarroni D, Cohen CR. Clinical examination, endosonography and MR imaging in preoperative assessment of fistula in ano: comparison with outcome-based reference standard. Radiology. 2004;233:674–681.
    1. Sparberg M, Kirnser JB. Long-term corticosteroid therapy for regional enteritis: an analysis of 58 courses in 54 patients. Am J Dig Dis. 1966;11:865–880.
    1. Malchow H, Ewe EK, Brandes JW, Goebell H, Ehms H, Sommer H, Jesdinsky H. European Cooperative Crohn's Disease Study (ECCDS): results of drug treatment. Gastroenterology. 1984;86:249–266.
    1. Bressler B, Sands BE. Review article: medical therapy for fistulizing Crohn's disease. Aliment Pharmacol Ther. 2006;24:1283–1293.
    1. Pascua M, Su C, Lewis JD, Brensinger C, Lichtenstein GR. Meta-analysis: factor predicting post-operative recurrence with placebo therapy in patients with Crohn's disease. Aliment Pharmacol Ther. 2008;28:545–556.
    1. Bernstein LH, Frank MS, Brandt LJ, Boley SH. Healing of perianal Crohn's disease with metronidazole. Gastroenterology. 1980;79:357–365.
    1. Brandt LJ, Bernstein LH, Boley SJ, Frank MS. Metronidazole therapy for perianal Crohn's disease: a follow-up study. Gastroenterology. 1982;83:383–387.
    1. Jakobovits J, Schuster MM. Metronidazole therapy for Crohn's disease and associated fistulae. Am J Gastroenterol. 1984;79:533–540.
    1. Turunen U, Farkkila M, Seppala K. Long-term treatment of peri-anal or fistulous Crohn's disease with ciprofloxacin. Scand J Gastronterol. 1989;24(suppl 48):144.
    1. Wolf J. Ciprofloxacin may be useful in Crohn's disease. Gastroenterology. 1990;98:A212. abstract.
    1. Solomon M, McLeod R, O'Connor B, Steinhart A, Greenberg G, Cohen Z. Combination ciprofloxacin and metronidazole in severe perianal Crohn's disease. Can J Gastroenterol. 1993;7:571–573.
    1. Thia KT, Mahadevan U, Feagan BG, Wong C, Cockeram A, Bitton A, Bernstein CN, Sandborn WJ. Ciprofloxacin or metronidazole for the treatment of perianal fistulas in patients with Crohn's disease: a randomized, double-blind, placebo-controlled pilot study. Inflamm Bowel Dis. 2009;15:17–24.
    1. McDonald JW, Feagan BG, Jewell D, Brynskov J, Stange EF, Macdonald JK. Cyclosporine for induction of remission in Crohn's disease. Cochrane Database Syst Rev. 2005;18:CD000297.
    1. Present DH, Lichtiger S. Efficacy of cyclosporine in treatment of fistula of Crohn's disease. Dig Dis Sci. 1994;39:374–380.
    1. Egan LJ, Sandborn WJ, Tremaine WJ. Clinical outcome following treatment of refractory inflammatory and fistulising Crohn's disease with intravenous cyclosporine. Am J Gastroenterol. 1998;93:442–448.
    1. Hanauer SB, Smith MB. Rapid closure of Crohn's disease fistulas with continuous intravenous cyclosporine. Am J Gastroenterol. 1993;88:646–649.
    1. Nakase H, Yoshino T, Matsuura M. Role of calcineurin inhibitors for inflammatory bowel disease in biologics era: when and how to use. Inflamm Bowel Dis. 2014;20:2151–2156.
    1. Sandborn WJ, Present DH, Isaacs KL, Wolf DC, Greenberg E, Hanauer SB, Feagan BG, Mayer L, Johnson T, Galanko J, Martin C, Sandler RS. Tacrolimus for the treatment of fistulas in patients with Crohn's disease: a randomized, placebo-controlled trial. Gastroenterology. 2003;125:380–388.
    1. González-Lama Y, Abreu L, Vera MI, Pastrana M, Tabernero S, Revilla J, Durán JG, Escartin P. Long-term oral tacrolimus therapy in refractory to infliximab fistulizing Crohn's disease. Inflamm Bowel Dis. 2005;11:8–15.
    1. Bär F, Sina C, Fellermann K. Thiopurines in inflammatory bowel disease revisited. World J Gastroenterol. 2013;19:1699–1706.
    1. Pearson DC, May GR, Fick GH, Sutherland LR. Azathioprine and 6-mercaptopurine in Crohn's disease: a meta-analysis. Ann Intern Med. 1995;123:132–142.
    1. Present DH, Korelitz BI, Wisch N, Glass JL, Sachar DB, Pasternack BS. Treatment of Crohn's disease with 6-mercaptopurine: a long-term, randomized, double-blind study. N Eng J Med. 1980;302:981–987.
    1. Present DH, Rutgeerts P, Targan S, Hanauer SB, Mayer L, van Hogezand RA, Podolsky DK, Sands BE, Braakman T, DeWood KL, Schaibl TF, van Deventer SJ. Infliximab for the treatment of fistulas with Crohn's disease. N Engl J Med. 1999;340:1398–1405.
    1. Sands BE, Anderson FH, Bernstein CN, Chey WY, Feagan BG, Fedorak RN, Kamm MA, Korzenik JR, Lashner BA, Wild G, Wolf DC, Marsters PA, Travers SB, Blank MA, van Deventer SJ. Infliximab maintenance therapy for fistulizing Crohn's disease. N Engl J Med. 2004;350:876–885.
    1. Sands BE, Blank MA, Diamond RH, Barrett JP, van Deventer SJ. Maintenance infliximab does not result in increased abscess development in fistulizing Crohn's disease: results from the ACCENT II study. Aliment Pharmacol Ther. 2006;23:1127–1136.
    1. Colombel JF, Sandborn WJ, Rutgeerts P, Enns R, Hanauer SB, Panaccione R, Schreiber S, Byczkowski D, Li J, Kent JD, Pollack PF. Adalimumab for maintenance of clinical response and remission in patients with Crohn's disease: the CHARM trial. Gastroenterology. 2007;132:52–65.
    1. Lichtiger S, Binion DG, Wolf DC, Present DH, Bensimon AG, Wu E, Cardoso AT, Chao J, Mulani PM, Lomax KG, Kent JD. The CHOICE trial: adalimumab demonstrates safety, fistula healing improved quality of life and increased work productivity in patients with Crohn's disease who failed prior to infliximab therapy. Aliment Pharmacol Ther. 2010;32:1228–1239.
    1. Hanauer SB, Sandborn WJ, Rutgeerts P, Fedorak RN, Lukas M, MacIntosh D, Panaccione R, Wolf D, Pollack P. Human anti-tumor necrosis factor monoclonal antibody (adalimumab) in Crohn's disease: the CLASSIC-I trial. Gastroenterology. 2006;130:323–333.
    1. Sandborn WJ, Rutgeerts P, Enns R, Hanauer SB, Colombel JF, Panaccione R, D'Haens G, Li J, Rosenfeld MR, Kent JD, Pollack PF. Adalimumab induction therapy for Crohn disease previously treated with infliximab: a randomized trial. Ann Intern Med. 2007;146:829–838.
    1. Sandborn WJ, Feagan BG, Stoinov S, Honiball PJ, Rutgeerts P, Mason D, Bloomfield R, Schreiber S. Certolizumab pegol for the treatment of Crohn's disease. N Engl J Med. 2007;357:228–238.
    1. Schreiber S, Khaliq-Kareemi M, Lawrance IC, Thomson O, Hanauer SB, McColm J, Bloomfield R, Sandborn WJ. Maintenance therapy with certolizumab pegol for Crohn's disease. N Engl J Med. 2007;357:239–250.
    1. Schreiber S, Lawrance IC, Thomsen OØ, Hanauer SB, Bloomfield R, Sandborn WJ. Randomised clinical trial: certolizumab pegol for fistulas in Crohn's disease – subgroup results from a placebo-controlled study. Aliment Pharmacol Ther. 2011;33:185–193.
    1. West RL, van der Woude CJ, Hansen BE, Felt-Bersma RJ, van Tilburg AJ, Drapers JA, Kuipers J. 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;20:1329–1336.
    1. Dewint P, Hansen BE, Verhey E, Oldenburg B, Hommes DW, Pierik M, Ponsioen CI, van Dullemen HM, Russel M, van Bodegraven AA, van der Woude CJ. Adalimumab combined with ciprofloxacin is superior to adalimumab monotherapy in perianal fistula closure in Crohn's disease: a randomised, double-blind, placebo controlled trial (ADAFI) Gut. 2014;63:292–299.
    1. Dejaco C, Harrer M, Waldhoer T, Miehsler W, Vogelsang H, Reinisch W. Antibiotics and azathioprine for the treatment of perianal fistulas in Crohn's disease. Aliment Pharmacol Ther. 2003;18:1113–1120.
    1. Tozer P, Ng SC, Siddiqui MR, Plamondon S, Burling D, Gupta A, Swatton A, Tripoli S, Vaizey CJ, Kamm MA, Phillips R, Hart A. Long-term MRI-guided combined anti-TNF-a and thiopurine therapy for Crohn's perianal fistulas. Inflamm Bowel Dis. 2012;18:1825–1834.
    1. Poole R. Vedolizumab: first global approval. Drugs. 2014;74:1293–1303.

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