Management of anal fistulas in Crohn’ disease after failure of Infliximab Runnig head: Fistule anale réfractaire à l’infliximab

##plugins.themes.academic_pro.article.sidebar##

Published Apr 6, 2024
https://doi.org/10.62438/tunismed.v102i4.4699
Download
pdf
Vol. 102 No. 4 (2024): Tunis Med apr 2024

##plugins.themes.academic_pro.article.main##

Sarra Ben Azouz
Departement of Gastro-enterology, Sahloul Hospital, Sousse, Tunisia
Nour Elleuch
Department of Gastroenterology, Sahloul Hospital, Sousse, Tunisia
Wafa Dahmeni
Department of Gastroenterology, Sahloul Hospital, Sousse, Tunisia
Eya Hammami
Department of Gastroenterology, Sahloul Hospital, Sousse, Tunisia
Ahlem Braham
Department of Gastroenterology, Sahloul Hospital, Sousse, Tunisia
Hanene Jaziri
Department of Gastroenterology, Sahloul Hospital, Sousse, Tunisia
Aida Ben Slema
Department of Gastroenterology, Sahloul Hospital, Sousse, Tunisia
Mehdi Ksiaa
Department of Gastroenterology, Sahloul Hospital, Sousse, Tunisia
Ali Jmaa
Department of Gastroenterology, Sahloul Hospital, Sousse, Tunisia

Abstract

Introduction : Treatment of complex perianal fistulas in Crohn's disease remains a challenge especially after the failure of Infliximab.


Aim: Update on the different therapeutic alternatives for anal fistula in Crohn's disease after failure of Infliximab.


Methods: A research in the medical literature on PubMed and Google Scholar was carried out. We included cohort studies, reviews and randomized double-blinded therapeutic trials. Case reports and fundamental research studies have been excluded.


Results: Anti-TNF therapy, notably Infliximab remain the therapeutic option of choice. Since Infliximab efficacy has been estimated at 60%, with a significant loss-of response rate, new therapeutic strategies have been evaluated and may offer new opportunities for the management of anal fistulas: for example, Ustekinumab could be effective after failure of anti-TNF therapy, although further studies are required. Recent guidelines suggest that injection of mesenchymal stem cells is an effective and safe treatment for complex fistulas. Other surgical options have been proposed, such as endorectal advancement flap, fibrin glue injection, anal fistula plug and ligation of the intersphincteric fistula tract, but all with limited and debatable efficacy. Given the failure rate of all these options, new strategies are currently being evaluated.


Conclusion: Anal fistulas in Crohn's disease are a real therapeutic challenge. New medical and surgical therapies are currently being evaluated, with promising results.

Keywords:

Anoperineal Crohn’s disease, fistula, Infliximab, failure, treatment

##plugins.themes.academic_pro.article.details##

Creative Commons License

This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.

References

  1. Ha F, Khalil H. Crohn’s disease: a clinical update. Therap Adv Gastroenterol. 2015 Nov;8(6):352–9.
  2. Ruffolo C, Citton M, Scarpa M, et al. Perianal Crohn´s disease: is there something new? World J Gastroenterol. 2011 Apr 21;17(15):1939-46.
  3. Bouchard D, Abramowitz L, Bouguen G, et al. Anoperineal lesions in Crohn´s disease: french recommendations for clinical practice. Tech Coloproctol. sept 2017;21(9):683-91.
  4. Sandborn WJ, Fazio VW, Feagan BG, Hanauer SB. AGA technical review on perianal Crohn’s disease. Gastroenterology. 2003 Nov;125(5):1508–30.
  5. Torres J, Bonovas S, Doherty G, et al. ECCO Guidelines on Therapeutics in Crohn’s Disease: Medical Treatment. J Crohns Colitis. 2020 Jan 1;14(1):4–22.
  6. Sands BE, Anderson FH, Bernstein CN, et al. Infliximab maintenance therapy for fistulizing Crohn´s disease. N Engl J Med. 2004 Feb 26;350(9):876-85.
  7. Diffaa A, Hlili F, Eddaghai I, et al. La prise en charge des lésions anopérinéales de la maladie de Crohn: revue de la littérature. J Afr Hépato-Gastroentérologie. 2012 Mar;6(1):10–4.
  8. Lopez N, Ramamoorthy S, Sandborn WJ. Recent advances in the management of perianal fistulizing Crohn’s disease: lessons for the clinic. Expert Rev Gastroenterol Hepatol. 2019 Jun 3;13(6):563–77.
  9. Singh S, Proctor D, Scott FI, Falck-Ytter Y, Feuerstein JD. AGA Technical Review on the Medical Management of Moderate to Severe Luminal and Perianal Fistulizing Crohn’s Disease. Gastroenterology. 2021 Jun;160(7):2512-2556.e9.
  10. Colombel JF, Sandborn WJ, Reinisch W, et al. Infliximab, Azathioprine, or Combination Therapy for Crohn’s Disease. N Engl J Med. 2010 Apr 15;362(15):1383–95.
  11. Bouguen G, Siproudhis L, Gizard E, et al. Long-term Outcome of Perianal Fistulizing Crohn’s Disease Treated With Infliximab. Clin Gastroenterol Hepatol. 2013 Aug;11(8):975-981.e4.
  12. De Gregorio M, Lee T, Krishnaprasad K, Amos G, et al. P399 Higher anti-tumour necrosis factor-alpha drug levels are associated with improved radiological outcomes in patients with perianal fistulising Crohn’s disease: A retrospective multi-centre study. J Crohns Colitis. 2021 May 27;15(Supplement_1):S408–9.
  13. Yarur AJ, Kanagala V, Stein DJ, et al. Higher infliximab trough levels are associated with perianal fistula healing in patients with Crohn’s disease. Aliment Pharmacol Ther. 2017 Apr;45(7):933–40.
  14. Lichtiger S, Binion DG, Wolf DC, et al. 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 infliximab therapy. Aliment Pharmacol Ther. 2010 Nov;32(10):1228-39.
  15. Colombel JF, Schwartz DA, Sandborn WJ et al. Adalimumab for the treatment of fistulas in patients with Crohn’s disease. Gut. 2009 Jul 1;58(7):940–8.
  16. De Krijger M, Buskens CJ, Wildenberg ME, Verseijden C, De Jonge WJ, Ponsioen CY. P044 T cells expressing integrin α4β7 are abundant in fistula tracts of Crohn’s disease patients. J Crohns Colitis. 2018 Jan 16;12(supplement_1):S114–S114.
  17. Chapuis-Biron C, Bourrier A, Nachury M, et al. Vedolizumab For Perianal Crohn’s Disease: A Multicentre Cohort Study In 151 Patients. Aliment Pharmacol Ther. 2020 Apr;51(7):719-727.
  18. Feagan BG, Schwartz D, Danese S, et al. Efficacy of vedolizumab in fistulising Crohn´s disease: exploratory analyses of data from GEMINI 2. J Crohns Colitis. 2018 Apr 27;12(5):621-626.
  19. Schwartz DA, Peyrin-Biroulet L, Lasch K, Adsul S, Danese S. Efficacy and Safety of 2 Vedolizumab Intravenous Regimens for Perianal Fistulizing Crohn’s Disease: ENTERPRISE Study. Clin Gastroenterol Hepatol. 2022 May;20(5):1059-1067.e9.
  20. Biemans VBC, Van Der Meulen - De Jong AE, Van Der Woude CJ, et al. Ustekinumab for Crohn’s Disease: Results of the ICC Registry, a Nationwide Prospective Observational Cohort Study. J Crohns Colitis. 2020 Jan 1;14(1):33–45.
  21. Feagan BG, Sandborn WJ, Gasink C, et al. Ustekinumab as Induction and Maintenance Therapy for Crohn’s Disease. N Engl J Med. 2016 Nov 17;375(20):1946–60.
  22. Khorrami S, Ginard D, Marín-Jiménez I, et al. Ustekinumab for the Treatment of Refractory Crohnʼs Disease: The Spanish Experience in a Large Multicentre Open-label Cohort. Inflamm Bowel Dis. 2016 Jul;22(7):1662–9.
  23. Chapuis-Biron C, Kirchgesner J, Pariente B, et al. Ustekinumab for Perianal Crohn’s Disease: The BioLAP Multicenter Study From the GETAID. Am J Gastroenterol. 2020 Nov;115(11):1812–20.
  24. Attauabi M, Burisch J, Seidelin JB. Efficacy of ustekinumab for active perianal fistulizing Crohn’s disease: a systematic review and meta-analysis of the current literature. Scand J Gastroenterol. 2021 Jan 2;56(1):53–8.
  25. Plevris N, Fulforth J, Siakavellas S, et al. Real‐world effectiveness and safety of ustekinumab for the treatment of Crohn’s disease: the Scottish ustekinumab cohort. J Gastroenterol Hepatol. 2021 Aug;36(8):2067–75.
  26. Straatmijer T, Biemans VBC, Hoentjen F, et al. Ustekinuma b for Crohn’s Disease: Two-Year Results of the Initiative on Crohn and Colitis (ICC) Registry, a Nationwide Prospective Observational Cohort Study. J Crohns Colitis. 2021 Nov 8;15(11):1920–30.
  27. Ma C, Fedorak RN, Kaplan GG, et al. Clinical, endoscopic and radiographic outcomes with ustekinumab in medically‐refractory Crohn’s disease: real world experience from a multicentre cohort. Aliment Pharmacol Ther. 2017 May;45(9):1232–43.
  28. Fumery M, Peyrin-Biroulet L, Nancey S, et al. Effectiveness and Safety of Ustekinumab Intensification at 90 mg Every 4 Weeks in Crohn’s Disease: A Multicentre Study. J Crohns Colitis. 2021 Feb 1;15(2):222–7.
  29. Guadalajara H, Herreros D, De-La-Quintana P, Trebol J, Garcia-Arranz M, Garcia-Olmo D. Long-term follow-up of patients undergoing adipose-derived adult stem cell administration to treat complex perianal fistulas. Int J Colorectal Dis. 2012 May;27(5):595-600.
  30. Adamina M, Bonovas S, Raine T, et al. ECCO Guidelines on Therapeutics in Crohn’s Disease: Surgical Treatment. J Crohns Colitis. 2020 feb;14(2):155-68.
  31. Cao Y, Su Q, Zhang B, Shen F, Li S. Efficacy of stem cells therapy for Crohn’s fistula: a meta-analysis and systematic review. Stem Cell Res Ther. 2021 jan;12(1):32.
  32. Panés J, García-Olmo D, Van Assche G, 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. The Lancet. 2016 sept;388(10051):1281-90.
  33. Panés J, García-Olmo D, Van Assche G, et al. Long-term Efficacy and Safety of Stem Cell Therapy (Cx601) for Complex Perianal Fistulas in Patients With Crohn’s Disease. Gastroenterology. 2018 Apr;154(5):1334-1342.e4.
  34. Nguyen A, Guo J, Banyard DA, et al. Stromal vascular fraction: A regenerative reality? Part 1: Current concepts and review of the literature. J Plast Reconstr Aesthet Surg. 2016 Feb;69(2):170–9.
  35. Serrero M, Grimaud F, Philandrianos C, Visée C, Sabatier F, Grimaud JC. Long-term Safety and Efficacy of Local Microinjection Combining Autologous Microfat and Adipose-Derived Stromal Vascular Fraction for the Treatment of Refractory Perianal Fistula in Crohn’s Disease. Gastroenterology. 2019 Jun;156(8):2335-2337.e2.
  36. Barnhoorn MC, Van Halteren AGS, Van Pel M, et al. Lymphoproliferative Disease in the Rectum 4 Years After Local Mesenchymal Stromal Cell Therapy for Refractory Perianal Crohn’s Fistulas: A Case Report. J Crohns Colitis. 2019 May 27;13(6):807–11.
  37. Feitosa MR, Parra RS, Machado VF, et al. Adjunctive Hyperbaric Oxygen Therapy in Refractory Crohn’s Disease: An Observational Study. Ricci C, editor. Gastroenterol Res Pract. 2021 Apr 26;2021:1–8.
  38. Lansdorp CA, Gecse KB, Buskens CJ, et al. Hyperbaric oxygen therapy for the treatment of perianal fistulas in 20 patients with Crohn’s disease. Aliment Pharmacol Ther. 2021 Mar;53(5):587–97.
  39. Dulai PS, Gleeson MW, Taylor D, Holubar SD, Buckey JC, Siegel CA. Systematic review: the safety and efficacy of hyperbaric oxygen therapy for inflammatory bowel disease. Aliment Pharmacol Ther. 2014 Jun;39(11):1266–75.
  40. Sugrue J, Mantilla N, Abcarian A et al. Sphincter-Sparing Anal Fistula Repair: Are We Getting Better? Dis Colon Rectum. 2017 Oct;60(10):1071–7.
  41. Bondi J, Avdagic J, Karlbom U et al. Randomized clinical trial comparing collagen plug and advancement flap for trans-sphincteric anal fistula. Br J Surg. 2017 Jul 13;104(9):1160–6.
  42. Van Praag E, Stellingwerf M, Van Der Bilt J, Gecse K, Bemelman W, Buskens C. P653 Ligation of the intersphincteric fistula tract vs. endorectal advancement flap for high perianal fistulas in Crohn’s disease: a retrospective cohort study. J Crohns Colitis. 2019 Jan 25;13(Supplement_1):S445–6.
  43. Roper MT, Trinidad SM, Ramamoorthy SL, et al. Endorectal Advancement Flaps for Perianal Fistulae in Crohn’s Disease: Careful Patient Selection Leads to Optimal Outcomes. J Gastrointest Surg. 2019 Nov;23(11):2277–84.
  44. Stellingwerf ME, Van Praag EM, Tozer PJ, Bemelman WA, Buskens CJ. Systematic review and meta‐analysis of endorectal advancement flap and ligation of the intersphincteric fistula tract for cryptoglandular and Crohn’s high perianal fistulas. BJS Open. 2019 Jun;3(3):231–41.
  45. Rojanasakul A, Pattanaarun J, Sahakitrungruang C, Tantiphlachiva K. Total anal sphincter saving technique for fistula-in-ano; the ligation of intersphincteric fistula tract. J Med Assoc Thai. 2007 Mar;90(3):581-6.
  46. Sirany AME, Nygaard RM, Morken JJ. The Ligation of the Intersphincteric Fistula Tract Procedure for Anal Fistula: A Mixed Bag of Results. Dis Colon Rectum. 2015 Jun;58(6):604–12.
  47. Van Praag E, Stellingwerf M, Van Der Bilt J, Gecse K, Bemelman W, Buskens C. P653 Ligation of the intersphincteric fistula tract vs. endorectal advancement flap for high perianal fistulas in Crohn’s disease: a retrospective cohort study. J Crohns Colitis. 2019 Jan 25;13(Supplement_1):S445–6.
  48. Stellingwerf ME, Van Praag EM, Tozer PJ, Bemelman WA, Buskens CJ. Systematic review and meta‐analysis of endorectal advancement flap and ligation of the intersphincteric fistula tract for cryptoglandular and Crohn’s high perianal fistulas. BJS Open. 2019 Jun;3(3):231–41.
  49. Grimaud J, Munoz–Bongrand N, Siproudhis L et al. Fibrin Glue Is Effective Healing Perianal Fistulas in Patients with Crohn’s Disease. Gastroenterology. 2010 Jun;138(7):2275-2281.e1.
  50. Vitton V, Gasmi M, Barthet M, Desjeux A, Orsoni P, Grimaud JC. Long-term healing of Crohn’s anal fistulas with fibrin glue injection. Aliment Pharmacol Ther. 2005 Jun;21(12):1453–7.
  51. Dietz AB, Dozois EJ, Fletcher JG et al. Autologous Mesenchymal Stem Cells, Applied in a Bioabsorbable Matrix, for Treatment of Perianal Fistulas in Patients With Crohn’s Disease. Gastroenterology. 2017 Jul;153(1):59-62.e2.
  52. Senéjoux A, Siproudhis L, Abramowitz L, et al. Fistula Plug in Fistulising Ano-Perineal Crohn’s Disease: a Randomised Controlled Trial. J Crohns Colitis. 2016 Feb;10(2):141–8.
  53. Yamamoto T, Allan RN, Keighley MRB. Effect of Fecal Diversion Alone on Perianal Crohn’s Disease. World J Surg. 2000 Oct;24(10):1258–63.
  54. McCurdy JD, Reid J, Yanofsky R, et al. Fecal Diversion for Perianal Crohn Disease in the Era of Biologic Therapies: A Multicenter Study. Inflamm Bowel Dis. 2022 Feb 1;28(2):226–33.
  55. Singh S, Ding NS, Mathis KL, et al. Systematic review with meta‐analysis: faecal diversion for management of perianal Crohn’s disease. Aliment Pharmacol Ther. 2015 Oct;42(7):783–92.
  56. Wei Y, Gong JF, Zhu WM. Endoscopic closure instead of surgery to close an ileal pouch fistula with the over-the-scope clip system. World J Gastrointest Endosc. 2017;9(2):95.
  57. Yzet C, Brazier F, Sabbagh C, et al. Endoscopic Treatment of Enterocutaneous Fistulas in Crohn’s Disease. Dis Colon Rectum. 2022 May;65(5):721–6.
  58. Mennigen R, Laukötter M, Senninger N, Rijcken E. The OTSC® proctology clip system for the closure of refractory anal fistulas. Tech Coloproctology. 2015 Apr;19(4):241–6.
  59. Matano Y, Zianne M, Omura H, Hayashi N, Miwa K. Successful endoscopic closure of a refractory postoperative rectovaginal fistula. Endosc Int Open. 2019 Jun;07(06):E796–9.
  60. Wallenhorst T, Jacques J, Bouguen G, et al. Successful Closure of a Rectal Fistula of Crohn’s Disease Using Endoscopic Submucosal Dissection Combined With an Over-the-Scope Clip. Am J Gastroenterol. 2019 Sep;114(9):1416–1416.
  61. Lefevre JH, Bretagnol F, Maggiori L, et al. Operative results and quality of life after gracilis muscle transposition for recurrent rectovaginal fistula. Dis Colon Rectum 2009;52:1290-5.
  62. Ruffolo C, Scarpa M, Bassi N, Angriman I. A systematic review on advancement flaps for rectovaginal fistula in Crohn’s disease: transrectal vs transvaginal approach. Colorectal Dis 2010 Dec;12(12):1183-91.