Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Perianal fistulizing Crohn's disease: pathogenesis, diagnosis and therapy

Nature Reviews Gastroenterology & Hepatology volume 14, pages 652–664 (2017)Cite this article

Subjects

Key Points

  • Factors involved in fistulizing perianal disease pathogenesis include a genetically determined altered immune response with increased production of cytokines, leading to upregulation of matrix metalloproteinases and epithelial-to-mesenchymal transition

  • Essential evaluation of fistulas includes a clinical assessment of external openings, endoscopic assessment of proctitis and MRI to determine the anatomy of fistula tracts and presence of abscesses

  • A top-down approach with medical therapy might provide maximal benefit for treatment of this aggressive manifestation of Crohn's disease

  • Local injection of mesenchymal stem cells can induce remission in patients not responding to medical therapies, or avoid the exposure to systemic immunosuppression

  • Surgery is still required in a high proportion of patients and should not be delayed when criteria of drug failure is met

Abstract

Perianal fistulizing Crohn's disease has a major negative effect on patient quality of life and is a predictor of poor long-term outcomes. Factors involved in the pathogenesis of perianal fistulizing Crohn's disease include an increased production of transforming growth factor β, TNF and IL-13 in the inflammatory infiltrate that induce epithelial-to-mesenchymal transition and upregulation of matrix metalloproteinases, leading to tissue remodelling and fistula formation. Care of patients with perianal Crohn's disease requires a multidisciplinary approach. A complete assessment of fistula characteristics is the basis for optimal management and must include the clinical evaluation of fistula openings, endoscopic assessment of the presence of proctitis, and MRI to determine the anatomy of fistula tracts and presence of abscesses. Local injection of mesenchymal stem cells can induce remission in patients not responding to medical therapies, or to avoid the exposure to systemic immunosuppression in patients naive to biologics in the absence of active luminal disease. Surgery is still required in a high proportion of patients and should not be delayed when criteria for drug failure is met. In this Review, we provide an up-to-date overview on the pathogenesis and diagnosis of fistulizing Crohn's disease, as well as therapeutic strategies.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Proposed pathogenesis of perianal fistulas.
Figure 2: Classifications of perianal fistulas in patients with Crohn's disease.
Figure 3: Classifications of perianal fistulas.
Figure 4: Simple perianal fistula.
Figure 5: Complex perianal fistula.
Figure 6: Injection of mesenchymal stem cells in perianal fistulas.
Figure 7: Treatment algorithm for perianal fistulizing disease.

Similar content being viewed by others

References

  1. Penner, A. & Crohn, B. B. Perianal fistulae as a complication of regional ileitis. Ann. Surg. 108, 867–873 (1938).

    CAS  PubMed  PubMed Central  Google Scholar 

  2. Kasparek, M. S. et al. Long-term quality of life in patients with Crohn's disease and perianal fistulas: influence of fecal diversion. Dis. Colon Rectum 50, 2067–2074 (2007).

    PubMed  Google Scholar 

  3. Beaugerie, L., Seksik, P., Nion-Larmurier, I., Gendre, J. P. & Cosnes, J. Predictors of Crohn's disease. Gastroenterology 130, 650–656 (2006).

    PubMed  Google Scholar 

  4. Sandborn, W. J., Fazio, V. W., Feagan, B. G., Hanauer, S. B. & American Gastroenterological Association Clinical Practice Committee. AGA technical review on perianal Crohn's disease. Gastroenterology 125, 1508–1530 (2003).

    PubMed  Google Scholar 

  5. Lewis, R. T. & Bleier, J. I. Surgical treatment of anorectal Crohn disease. Clin. Colon Rectal Surg. 26, 90–99 (2013).

    PubMed  PubMed Central  Google Scholar 

  6. Schwartz, D. A. et al. The natural history of fistulizing Crohn's disease in Olmsted County, Minnesota. Gastroenterology 122, 875–880 (2002).

    PubMed  Google Scholar 

  7. Eglinton, T. W., Barclay, M. L., Gearry, R. B. & Frizelle, F. A. The spectrum of perianal Crohn's disease in a population-based cohort. Dis. Colon Rectum 55, 773–777 (2012).

    PubMed  Google Scholar 

  8. Hellers, G., Bergstrand, O., Ewerth, S. & Holmstrom, B. Occurrence and outcome after primary treatment of anal fistulae in Crohn's disease. Gut 21, 525–527 (1980).

    CAS  PubMed  PubMed Central  Google Scholar 

  9. Fields, S., Rosainz, L., Korelitz, B. I., Panagopoulos, G. & Schneider, J. Rectal strictures in Crohn's disease and coexisting perirectal complications. Inflamm. Bowel Dis. 14, 29–31 (2008).

    PubMed  Google Scholar 

  10. Buchmann, P., Keighley, M. R., Allan, R. N., Thompson, H. & Alexander-Williams, J. Natural history of perianal Crohn's disease. Ten year follow-up: a plea for conservatism. Am. J. Surg. 140, 642–644 (1980).

    CAS  PubMed  Google Scholar 

  11. Makowiec, F., Jehle, E. C. & Starlinger, M. Clinical course of perianal fistulas in Crohn's disease. Gut 37, 696–701 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  12. Bell, S. J. et al. The clinical course of fistulating Crohn's disease. Aliment. Pharmacol. Ther. 17, 1145–1151 (2003).

    CAS  PubMed  Google Scholar 

  13. Michelassi, F., Melis, M., Rubin, M. & Hurst, R. D. Surgical treatment of anorectal complications in Crohn's disease. Surgery 128, 597–603 (2000).

    CAS  PubMed  Google Scholar 

  14. Molendijk, I., Nuij, V. J., van der Meulen-de Jong, A. E. & van der Woude, C. J. Disappointing durable remission rates in complex Crohn's disease fistula. Inflamm. Bowel Dis. 20, 2022–2028 (2014).

    PubMed  Google Scholar 

  15. Schwartz, D. A. & Herdman, C. R. Review article: The medical treatment of Crohn's perianal fistulas. Aliment. Pharmacol. Ther. 19, 953–967 (2004).

    CAS  PubMed  Google Scholar 

  16. Iesalnieks, I. et al. Fistula-associated anal adenocarcinoma in Crohn's disease. Inflamm. Bowel Dis. 16, 1643–1648 (2010).

    PubMed  Google Scholar 

  17. Baars, J. E. et al. Malignant transformation of perianal and enterocutaneous fistulas is rare: results of 17 years of follow-up from The Netherlands. Scand. J. Gastroenterol. 46, 319–325 (2011).

    PubMed  Google Scholar 

  18. Papaconstantinou, I., Mantzos, D. S., Kondi-Pafiti, A. & Koutroubakis, I. E. Anal adenocarcinoma complicating chronic Crohn's disease. Int. J. Surg. Case Rep. 10, 201–203 (2015).

    PubMed  PubMed Central  Google Scholar 

  19. Siegmund, B. et al. Results of the Fifth Scientific Workshop of the ECCO (II): Pathophysiology of Perianal Fistulizing Disease. J. Crohns Colitis 10, 377–386 (2016).

    PubMed  Google Scholar 

  20. Scharl, M. et al. Interleukin-13 and transforming growth factor β synergise in the pathogenesis of human intestinal fistulae. Gut 62, 63–72 (2013).

    CAS  PubMed  Google Scholar 

  21. Nieto, M. A., Huang, R. Y., Jackson, R. A. & Thiery, J. P. Emt: 2016. Cell 166, 21–45 (2016).

    CAS  PubMed  Google Scholar 

  22. Frei, S. M. et al. A role for tumor necrosis factor and bacterial antigens in the pathogenesis of Crohn's disease-associated fistulae. Inflamm. Bowel Dis. 19, 2878–2887 (2013).

    PubMed  Google Scholar 

  23. Scharl, M. et al. Potential role for SNAIL family transcription factors in the etiology of Crohn's disease-associated fistulae. Inflamm. Bowel Dis. 17, 1907–1916 (2011).

    PubMed  Google Scholar 

  24. Frei, S. M. et al. The role for dickkopf-homolog-1 in the pathogenesis of Crohn's disease-associated fistulae. PLoS ONE 8, e78882 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  25. Scharl, M. et al. Epithelial-to-mesenchymal transition in a fistula-associated anal adenocarcinoma in a patient with long-standing Crohn's disease. Eur. J. Gastroenterol. Hepatol. 26, 114–118 (2014).

    PubMed  Google Scholar 

  26. von Lampe, B., Barthel, B., Coupland, S. E., Riecken, E. O. & Rosewicz, S. Differential expression of matrix metalloproteinases and their tissue inhibitors in colon mucosa of patients with inflammatory bowel disease. Gut 47, 63–73 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  27. Castaneda, F. E. et al. Targeted deletion of metalloproteinase 9 attenuates experimental colitis in mice: central role of epithelial-derived MMP. Gastroenterology 129, 1991–2008 (2005).

    CAS  PubMed  Google Scholar 

  28. Kirkegaard, T., Hansen, A., Bruun, E. & Brynskov, J. Expression and localisation of matrix metalloproteinases and their natural inhibitors in fistulae of patients with Crohn's disease. Gut 53, 701–709 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Seow-Choen, F., Hay, A. J., Heard, S. & Phillips, R. K. Bacteriology of anal fistulae. Br. J. Surg. 79, 27–28 (1992).

    CAS  PubMed  Google Scholar 

  30. Yassin, N. A. et al. The gut microbiome–immune system interaction as an aetiological factor for fistulising perianal Crohn's disease. J. Crohns Colitis 9, S81–S82 (2015).

    Google Scholar 

  31. Cleynen, I. et al. Genetic factors conferring an increased susceptibility to develop Crohn's disease also influence disease phenotype: results from the IBDchip European Project. Gut 62, 1556–1565 (2013).

    CAS  PubMed  Google Scholar 

  32. Henckaerts, L. et al. Genetic risk profiling and prediction of disease course in Crohn's disease patients. Clin. Gastroenterol. Hepatol. 7, 972–980.e2 (2009).

    CAS  PubMed  Google Scholar 

  33. Kaur, M. et al. Perianal Crohn's disease is associated with distal colonic disease, stricturing disease behavior, IBD-associated serologies and genetic variation in the JAK–STAT pathway. Inflamm. Bowel Dis. 22, 862–869 (2016).

    PubMed  PubMed Central  Google Scholar 

  34. Parks, A. G., Gordon, P. H. & Hardcastle, J. D. A classification of fistula-in-ano. Br. J. Surg. 63, 1–12 (1976).

    CAS  PubMed  Google Scholar 

  35. Spencer, J. A., Ward, J., Beckingham, I. J., Adams, C. & Ambrose, N. S. Dynamic contrast-enhanced MR imaging of perianal fistulas. AJR Am. J. Roentgenol. 167, 735–741 (1996).

    CAS  PubMed  Google Scholar 

  36. Morris, J., Spencer, J. A. & Ambrose, N. S. MR imaging classification of perianal fistulas and its implications for patient management. Radiographics 20, 623–635 (2000).

    CAS  PubMed  Google Scholar 

  37. Tozer, P. et al. Long-term MRI-guided combined anti-TNF-α and thiopurine therapy for Crohn's perianal fistulas. Inflamm. Bowel Dis. 18, 1825–1834 (2012).

    PubMed  Google Scholar 

  38. Sheedy, S. P., Bruining, D. H., Dozois, E. J., Faubion, W. A. & Fletcher, J. G. MR imaging of perianal Crohn disease. Radiology 282, 628–645 (2017).

    PubMed  Google Scholar 

  39. Irvine, E. J. Usual therapy improves perianal Crohn's disease as measured by a new disease activity index. McMaster IBD Study Group. J. Clin. Gastroenterol. 20, 27–32 (1995).

    CAS  PubMed  Google Scholar 

  40. Allan, A., Linares, L., Spooner, H. A. & Alexander-Williams, J. Clinical index to quantitate symptoms of perianal Crohn's disease. Dis. Colon Rectum 35, 656–661 (1992).

    CAS  PubMed  Google Scholar 

  41. Ng, S. C. et al. Prospective evaluation of anti-tumor necrosis factor therapy guided by magnetic resonance imaging for Crohn's perineal fistulas. Am. J. Gastroenterol. 104, 2973–2986 (2009).

    CAS  PubMed  Google Scholar 

  42. Horsthuis, K. et al. Evaluation of an MRI-based score of disease activity in perianal fistulizing Crohn's disease. Clin. Imag. 35, 360–365 (2011).

    Google Scholar 

  43. Van Assche, G. et al. Magnetic resonance imaging of the effects of infliximab on perianal fistulizing Crohn's disease. Am. J. Gastroenterol. 98, 332–339 (2003).

    PubMed  Google Scholar 

  44. Horsthuis, K., Lavini, C., Bipat, S., Stokkers, P. C. & Stoker, J. Perianal Crohn disease: evaluation of dynamic contrast-enhanced MR imaging as an indicator of disease activity. Radiology 251, 380–387 (2009).

    PubMed  Google Scholar 

  45. Karmiris, K. et al. Long-term monitoring of infliximab therapy for perianal fistulizing Crohn's disease by using magnetic resonance imaging. Clin. Gastroenterol. Hepatol. 9, 130–136 (2011).

    CAS  PubMed  Google Scholar 

  46. Savoye-Collet, C., Savoye, G., Koning, E., Dacher, J. N. & Lerebours, E. Fistulizing perianal Crohn's disease: contrast-enhanced magnetic resonance imaging assessment at 1 year on maintenance anti-TNF-α therapy. Inflamm. Bowel Dis. 17, 1751–1758 (2011).

    CAS  PubMed  Google Scholar 

  47. Schwartz, D. A. et al. A comparison of endoscopic ultrasound, magnetic resonance imaging, and exam under anesthesia for evaluation of Crohn's perianal fistulas. Gastroenterology 121, 1064–1072 (2001).

    CAS  PubMed  Google Scholar 

  48. Fichera, A., Zoccali, M. & Crohn's & Colitis Foundation of America, Inc. Guidelines for the surgical treatment of Crohn's perianal fistulas. Inflamm. Bowel Dis. 21, 753–758 (2015).

    PubMed  Google Scholar 

  49. Schwartz, D. A. et al. Guidelines for the multidisciplinary management of Crohn's perianal fistulas: summary statement. Inflamm. Bowel Dis. 21, 723–730 (2015).

    PubMed  Google Scholar 

  50. Gecse, K. B. et al. A global consensus on the classification, diagnosis and multidisciplinary treatment of perianal fistulising Crohn's disease. Gut 63, 1381–1392 (2014).

    PubMed  Google Scholar 

  51. Schwartz, D. A., Ghazi, L. J. & Regueiro, M. Guidelines for medical treatment of Crohn's perianal fistulas: critical evaluation of therapeutic trials. Inflamm. Bowel Dis. 21, 737–752 (2015).

    PubMed  Google Scholar 

  52. Gomollon, F. et al. 3 rd European evidence-based consensus on the diagnosis and management of Crohn's disease 2016: Part 1: diagnosis and medical management. J. Crohns Colitis 11, 3–25 (2017).

    PubMed  Google Scholar 

  53. Hinterleitner, T. A. et al. Combination of cyclosporine, azathioprine and prednisolone for perianal fistulas in Crohn's disease. Z. Gastroenterol. 35, 603–608 (1997).

    CAS  PubMed  Google Scholar 

  54. Lennard-Jones, J. E. Toward optimal use of corticosteroids in ulcerative colitis and Crohn's disease. Gut 24, 177–181 (1983).

    CAS  PubMed  PubMed Central  Google Scholar 

  55. Brandt, L. J., Bernstein, L. H., Boley, S. J. & Frank, M. S. Metronidazole therapy for perineal Crohn's disease: a follow-up study. Gastroenterology 83, 383–387 (1982).

    CAS  PubMed  Google Scholar 

  56. Solomon, M. J. et al. Combination of ciprofloxacin and metronidazole in severe perianal Crohn's disease. Can. J. Gastroenterol. 7, 571–573 (1993).

    Google Scholar 

  57. Thia, K. T. et al. 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. 15, 17–24 (2009).

    PubMed  Google Scholar 

  58. Maeda, Y. et al. Randomized clinical trial of metronidazole ointment versus placebo in perianal Crohn's disease. Br. J. Surg. 97, 1340–1347 (2010).

    CAS  PubMed  Google Scholar 

  59. West, R. L. 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. 20, 1329–1336 (2004).

    CAS  PubMed  Google Scholar 

  60. Dewint, P. et al. 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 63, 292–299 (2014).

    CAS  PubMed  Google Scholar 

  61. Pearson, D. C., May, G. R., Fick, G. H. & Sutherland, L. R. Azathioprine and 6-mercaptopurine in Crohn disease. A meta-analysis. Ann. Intern. Med. 123, 132–142 (1995).

    CAS  PubMed  Google Scholar 

  62. Dejaco, C. et al. Antibiotics and azathioprine for the treatment of perianal fistulas in Crohn's disease. Aliment. Pharmacol. Ther. 18, 1113–1120 (2003).

    CAS  PubMed  Google Scholar 

  63. Sandborn, W. J. et al. Tacrolimus for the treatment of fistulas in patients with Crohn's disease: a randomized, placebo-controlled trial. Gastroenterology 125, 380–388 (2003).

    CAS  PubMed  Google Scholar 

  64. Hart, A. L., Plamondon, S. & Kamm, M. A. Topical tacrolimus in the treatment of perianal Crohn's disease: exploratory randomized controlled trial. Inflamm. Bowel Dis. 13, 245–253 (2007).

    PubMed  Google Scholar 

  65. Hanauer, S. B. & Smith, M. B. Rapid closure of Crohn's disease fistulas with continuous intravenous cyclosporin A. Am. J. Gastroenterol. 88, 646–649 (1993).

    CAS  PubMed  Google Scholar 

  66. Present, D. H. & Lichtiger, S. Efficacy of cyclosporine in treatment of fistula of Crohn's disease. Dig. Dis. Sci. 39, 374–380 (1994).

    CAS  PubMed  Google Scholar 

  67. Mahadevan, U., Marion, J. F. & Present, D. H. Fistula response to methotrexate in Crohn's disease: a case series. Aliment. Pharmacol. Ther. 18, 1003–1008 (2003).

    CAS  PubMed  Google Scholar 

  68. Schroder, O., Blumenstein, I., Schulte-Bockholt, A. & Stein, J. Combining infliximab and methotrexate in fistulizing Crohn's disease resistant or intolerant to azathioprine. Aliment. Pharmacol. Ther. 19, 295–301 (2004).

    CAS  PubMed  Google Scholar 

  69. Present, D. H. et al. Infliximab for the treatment of fistulas in patients with Crohn's disease. N. Engl. J. Med. 340, 1398–1405 (1999).

    CAS  PubMed  Google Scholar 

  70. Sands, B. E. et al. Infliximab maintenance therapy for fistulizing Crohn's disease. N. Engl. J. Med. 350, 876–885 (2004).

    CAS  PubMed  Google Scholar 

  71. Hanauer, S. B. et al. Human anti-tumor necrosis factor monoclonal antibody (adalimumab) in Crohn's disease: the CLASSIC-I trial. Gastroenterology 130, 323–333 (2006).

    CAS  PubMed  Google Scholar 

  72. Sandborn, W. J. et al. Adalimumab induction therapy for Crohn disease previously treated with infliximab: a randomized trial. Ann. Intern. Med. 146, 829–838 (2007).

    PubMed  Google Scholar 

  73. Colombel, J. F. et al. Adalimumab for the treatment of fistulas in patients with Crohn's disease. Gut 58, 940–948 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  74. Sandborn, W. J. et al. Certolizumab pegol for the treatment of Crohn's disease. N. Engl. J. Med. 357, 228–238 (2007).

    CAS  PubMed  Google Scholar 

  75. Schreiber, S. et al. Maintenance therapy with certolizumab pegol for Crohn's disease. N. Engl. J. Med. 357, 239–250 (2007).

    CAS  PubMed  Google Scholar 

  76. Schreiber, S. et al. Randomised clinical trial: certolizumab pegol for fistulas in Crohn's disease - subgroup results from a placebo-controlled study. Aliment. Pharmacol. Ther. 33, 185–193 (2011).

    CAS  PubMed  Google Scholar 

  77. Bouguen, G. et al. Long-term outcome of perianal fistulizing Crohn's disease treated with infliximab. Clin. Gastroenterol. Hepatol. 11, 975–981.e1-4 (2013).

    CAS  PubMed  Google Scholar 

  78. Sandborn, W. J. et al. Vedolizumab as induction and maintenance therapy for Crohn's disease. N. Engl. J. Med. 369, 711–721 (2013).

    CAS  PubMed  Google Scholar 

  79. Ehrenpreis, E. D., Kane, S. V., Cohen, L. B., Cohen, R. D. & Hanauer, S. B. Thalidomide therapy for patients with refractory Crohn's disease: An open-label trial. Gastroenterology 117, 1271–1277 (1999).

    CAS  PubMed  Google Scholar 

  80. Lavy, A. et al. Hyperbaric oxygen for perianal Crohn's disease. J. Clin. Gastroenterol. 19, 202–205 (1994).

    CAS  PubMed  Google Scholar 

  81. Colombel, J. F. et al. Hyperbaric oxygenation in severe perineal Crohn's disease. Dis. Colon Rectum 38, 609–614 (1995).

    CAS  PubMed  Google Scholar 

  82. Weisz, G. et al. Modification of in vivo and in vitro TNF-α, IL-1, and IL-6 secretion by circulating monocytes during hyperbaric oxygen treatment in patients with perianal Crohn's disease. J. Clin. Immunol. 17, 154–159 (1997).

    CAS  PubMed  Google Scholar 

  83. Fukuda, Y. et al. Oral spherical adsorptive carbon for the treatment of intractable anal fistulas in Crohn's disease: a multicenter, randomized, double-blind, placebo-controlled trial. Am. J. Gastroenterol. 103, 1721–1729 (2008).

    PubMed  Google Scholar 

  84. Reinisch, W. et al. AST-120 (spherical carbon adsorbent) in the treatment of perianal fistulae in mild-to-moderate Crohn's disease: FHAST-1, a phase 3, multicenter, placebo-controlled study. Inflamm. Bowel Dis. 20, 872–881 (2014).

    PubMed  PubMed Central  Google Scholar 

  85. Bernardo, M. E., Locatelli, F. & Fibbe, W. E. Mesenchymal stromal cells. Ann. NY Acad. Sci. 1176, 101–117 (2009).

    CAS  PubMed  Google Scholar 

  86. Nauta, A. J. & Fibbe, W. E. Immunomodulatory properties of mesenchymal stromal cells. Blood 110, 3499–3506 (2007).

    CAS  PubMed  Google Scholar 

  87. Gonzalez-Rey, E., Gonzalez, M. A., Rico, L., Buscher, D. & Delgado, M. Human adult stem cells derived from adipose tissue protect against experimental colitis and sepsis. Gut 58, 929–939 (2009).

    CAS  PubMed  Google Scholar 

  88. Panes, J., Ordas, I. & Ricart, E. Stem cell treatment for Crohn's disease. Expert Rev. Clin. Immunol. 6, 597–605 (2010).

    CAS  PubMed  Google Scholar 

  89. Garcia-Olmo, D. et al. A phase I clinical trial of the treatment of Crohn's fistula by adipose mesenchymal stem cell transplantation. Dis. Colon Rectum. 48, 1416–1423 (2005).

    PubMed  Google Scholar 

  90. Garcia-Olmo, D. et al. Expanded adipose-derived stem cells for the treatment of complex perianal fistula: a phase II clinical trial. Dis. Colon Rectum. 52, 79–86 (2009).

    PubMed  Google Scholar 

  91. Guadalajara, H. et al. Long-term follow-up of patients undergoing adipose-derived adult stem cell administration to treat complex perianal fistulas. Int. J. Colorectal Dis. 27, 595–600 (2012).

    PubMed  Google Scholar 

  92. Ciccocioppo, R. et al. Autologous bone marrow-derived mesenchymal stromal cells in the treatment of fistulizing Crohn's disease. Gut 60, 788–798 (2011).

    PubMed  Google Scholar 

  93. de la Portilla, F. et al. Expanded allogeneic adipose-derived stem cells (eASCs) for the treatment of complex perianal fistula in Crohn's disease: results from a multicenter phase I/IIa clinical trial. Int. J. Colorectal Dis. 28, 313–323 (2013).

    CAS  PubMed  Google Scholar 

  94. Molendijk, I. et al. Allogeneic bone marrow-derived mesenchymal stromal cells promote healing of refractory perianal fistulas in patients with Crohn's disease. Gastroenterology 149, 918–927.e6 (2015).

    PubMed  Google Scholar 

  95. Panes, J. et al. Expanded allogeneic adipose-derived mesenchymal stem cells (Cx601) for complex perianal fistulas in Crohn's disease: a phase 3 randomised, double-blind controlled trial. Lancet 388, 1281–1290 (2016).

    PubMed  Google Scholar 

  96. Dietz, A. B. et al. Autologous mesenchymal stem cells, applied in a bioabsorbable matrix, for treatment of perianal fistulas in patients with Crohn's disease. Gastroenterology 153, 59–62.e2 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  97. Solomon, M. J. Fistulae and abscesses in symptomatic perianal Crohn's disease. Int. J. Colorectal Dis. 11, 222–226 (1996).

    CAS  PubMed  Google Scholar 

  98. Regueiro, M. & Mardini, H. 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 (2003).

    PubMed  Google Scholar 

  99. Sciaudone, G. et al. Treatment of complex perianal fistulas in Crohn disease: infliximab, surgery or combined approach. Can. J. Surg. 53, 299–304 (2010).

    PubMed  PubMed Central  Google Scholar 

  100. Parks, A. G. & Stitz, R. W. The treatment of high fistula-in-ano. Dis. Colon Rectum 19, 487–499 (1976).

    CAS  PubMed  Google Scholar 

  101. Hyder, S. A., Travis, S. P., Jewell, D. P., McC Mortensen, N. J. & George, B. D. Fistulating anal Crohn's disease: results of combined surgical and infliximab treatment. Dis. Colon Rectum 49, 1837–1841 (2006).

    PubMed  Google Scholar 

  102. van Koperen, P. J., Safiruddin, F., Bemelman, W. A. & Slors, J. F. Outcome of surgical treatment for fistula in ano in Crohn's disease. Br. J. Surg. 96, 675–679 (2009).

    CAS  PubMed  Google Scholar 

  103. Williams, J. G., Rothenberger, D. A., Nemer, F. D. & Goldberg, S. M. Fistula-in-ano in Crohn's disease. Results of aggressive surgical treatment. Dis. Colon Rectum 34, 378–384 (1991).

    CAS  PubMed  Google Scholar 

  104. de Parades, V. et al. Seton drainage and fibrin glue injection for complex anal fistulas. Colorectal Dis. 12, 459–463 (2010).

    CAS  PubMed  Google Scholar 

  105. Gaertner, W. B. et al. Results of combined medical and surgical treatment of recto-vaginal fistula in Crohn's disease. Colorectal Dis. 13, 678–683 (2011).

    CAS  PubMed  Google Scholar 

  106. Abel, M. E., Chiu, Y. S., Russell, T. R. & Volpe, P. A. Autologous fibrin glue in the treatment of rectovaginal and complex fistulas. Dis. Colon Rectum 36, 447–449 (1993).

    CAS  PubMed  Google Scholar 

  107. Zmora, O. et al. Fibrin glue sealing in the treatment of perineal fistulas. Dis. Colon Rectum 46, 584–589 (2003).

    PubMed  Google Scholar 

  108. Loungnarath, R. et al. Fibrin glue treatment of complex anal fistulas has low success rate. Dis. Colon Rectum 47, 432–436 (2004).

    PubMed  Google Scholar 

  109. Lindsey, I., Smilgin-Humphreys, M. M., Cunningham, C., Mortensen, N. J. & George, B. D. A randomized, controlled trial of fibrin glue versus conventional treatment for anal fistula. Dis. Colon Rectum 45, 1608–1615 (2002).

    PubMed  Google Scholar 

  110. Grimaud, J. C. et al. Fibrin glue is effective healing perianal fistulas in patients with Crohn's disease. Gastroenterology 138, 2275–2281.e1 (2010).

    CAS  PubMed  Google Scholar 

  111. Singer, M. et al. Treatment of fistulas-in-ano with fibrin sealant in combination with intra-adhesive antibiotics and/or surgical closure of the internal fistula opening. Dis. Colon Rectum 48, 799–808 (2005).

    PubMed  Google Scholar 

  112. O'Riordan, J. M., Datta, I., Johnston, C. & Baxter, N. N. A systematic review of the anal fistula plug for patients with Crohn's and non-Crohn's related fistula-in-ano. Dis. Colon Rectum 55, 351–358 (2012).

    CAS  PubMed  Google Scholar 

  113. Senejoux, A. et al. Fistula plug in fistulising ano-perineal Crohn's disease: a randomised controlled trial. J. Crohns Colitis 10, 141–148 (2016).

    CAS  PubMed  Google Scholar 

  114. Soltani, A. & Kaiser, A. M. Endorectal advancement flap for cryptoglandular or Crohn's fistula-in-ano. Dis. Colon Rectum 53, 486–495 (2010).

    PubMed  Google Scholar 

  115. Gionchetti, P. et al. 3rd European evidence-based consensus on the diagnosis and management of Crohn's disease 2016: Part 2: Surgical management and special situations. J. Crohns Colitis 11, 135–149 (2016).

    PubMed  Google Scholar 

  116. Rojanasakul, A. LIFT procedure: a simplified technique for fistula-in-ano. Tech. Coloproctol. 13, 237–240 (2009).

    CAS  PubMed  Google Scholar 

  117. Gingold, D. S., Murrell, Z. A. & Fleshner, P. R. A prospective evaluation of the ligation of the intersphincteric tract procedure for complex anal fistula in patients with Crohn's disease. Ann. Surg. 260, 1057–1061 (2014).

    PubMed  Google Scholar 

  118. D'Haens, G. R. et al. Early lesions of recurrent Crohn's disease caused by infusion of intestinal contents in excluded ileum. Gastroenterology 114, 262–267 (1998).

    CAS  PubMed  Google Scholar 

  119. Yamamoto, T., Allan, R. N. & Keighley, M. R. Effect of fecal diversion alone on perianal Crohn's disease. World J. Surg. 24, 1258–1262; discussion 1262–1263 (2000).

    CAS  PubMed  Google Scholar 

  120. Singh, S. et al. Systematic review with meta-analysis: faecal diversion for management of perianal Crohn's disease. Aliment. Pharmacol. Ther. 42, 783–792 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  121. Gaertner, W. B. et al. Does infliximab infusion impact results of operative treatment for Crohn's perianal fistulas? Dis. Colon Rectum 50, 1754–1760 (2007).

    PubMed  Google Scholar 

  122. Gecse, K. B. et al. Results of the Fifth Scientific Workshop of the ECCO [II]: clinical aspects of perianal fistulising crohn's disease-the unmet needs. J. Crohns Colitis 10, 758–765 (2016).

    PubMed  Google Scholar 

Download references

Acknowledgements

The author's work is supported in part by grant 2015/ 66379-R from Ministerio de Economia y Competitividad, Spain, and the Helmsley Trust (to J.P.), and grant PI16/00721 from Ministerio de Sanidad, Spain (to J.R.)

Author information

Authors and Affiliations

  1. Department of Gastroenterology, Hospital Clínic de Barcelona, Institut d'Investigació Biomèdica August Pi i Sunyer (IDIBAPS), Centro de Investigación Biomédica en Red Enfermedades Hepaticas y Digestivas (CIBERehd), Villarroel 170, Barcelona, 08036, Spain

    Julián Panés

  2. Department of Radiology, Hospital Clínic de Barcelona, Institut d'Investigació Biomèdica August Pi i Sunyer (IDIBAPS), Centro de Investigación Biomédica en Red Enfermedades Hepaticas y Digestivas (CIBERehd), Villarroel 170, Barcelona, 08036, Spain

    Jordi Rimola

Authors
  1. Julián Panés
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jordi Rimola
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

J.P. conceived the structure of the article, J.R. performed the literature review. J.P. and J.R. contributed equally to writing the manuscript and to reviewing and/or editing of the manuscript before submission.

Corresponding author

Correspondence to Julián Panés.

Ethics declarations

Competing interests

J.P. has received consulting fees from Abbvie, Almirall, Boehringer-Ingelheim, Celgene, Ferring, Janssen, MSD, Novartis, Pfizer, Robarts, Roche, Second Genome, Shire, Takeda, TiGenix and Topivert; and speaker fees from Abbvie, Biogen, Ferring, Janssen, MSD and Pfizer. J.R. has received consulting and speaker fees from Abbvie, Bioclinica, Boehringer-Ingelheim, MSD, Robarts Clinical Trials, Roche, Takeda, and TiGenix.

Supplementary information

Supplementary Information S1

Controlled trials on treatments for perianal fistulizing Crohn's disease (PDF 103 kb)

PowerPoint slides

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Panés, J., Rimola, J. Perianal fistulizing Crohn's disease: pathogenesis, diagnosis and therapy. Nat Rev Gastroenterol Hepatol 14, 652–664 (2017). https://doi.org/10.1038/nrgastro.2017.104

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrgastro.2017.104

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing