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Zentralbl Chir 2023; 148(03): 220-227
DOI: 10.1055/a-2063-3673
Übersicht

Stammzelltherapie bei komplexen perianalen Fisteln bei Morbus Crohn: Aktuelle Evidenz und Ausblick

Stem Cell Therapy for Complex Anal Fistula in Crohn`s Disease: Current Evidence and Future Perspectives
Oliver Schwandner
1   Abteilung für Proktologie, Krankenhaus Barmherzige Brüder, Regensburg, Deutschland
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Zusammenfassung

Trotz Weiterentwicklungen in interdisziplinärer Diagnostik und Therapie stellen komplexe Analfisteln bei Morbus Crohn weiterhin eine Herausforderung für medikamentöse und chirurgische Therapiekonzepte dar. Konventionelle chirurgische Techniken (u. a. Flap, LIFT) sind mit relativ hohen Persistenz- und Rezidivraten vergesellschaftet. Vor diesem Hintergrund zeigen Ergebnisse der Stammzelltherapie eine vielversprechende, sphinkterschonende Therapieoption. Insbesondere die allogene mesenchymale Stammzelltherapie (Darvadstrocel) konnte im Rahmen der randomisierten ADMIRE-CD-Studie eine hohe Wirksamkeit bei komplexen Crohn-Fisteln zeigen, die auch in limitierten „Real-World“-Daten reproduziert werden konnte. Die aktuelle Evidenz der allogenen mesenchymalen Stammzellen hat hierbei auch Einzug in internationale Leitlinien erhalten. Inwieweit die allogene mesenchymale Stammzelltherapie in Zukunft eine effektive Therapieoption im interdisziplinären Management der komplexen perianalen Fistel bei Morbus Crohn darstellt, kann derzeit noch nicht definitiv bewertet werden.

Abstract

Despite progress in multidisciplinary diagnostic and therapeutic strategies, complex anal fistulas associated with Crohn’s disease remain a challenge for both medical and surgical management. Conventional surgical techniques such as flap procedures or LIFT are still associated with considerable persistence and recurrence rates. Based on this background, results of stem cell therapy for Crohn’s anal fistula have shown promising results and are a sphincter-preserving technique. In particular, adipose-derived, allogeneic stem cell therapy (Darvadstrocel) has shown encouraging healing rates within the randomised controlled ADMIRE-CD trial, which were reproducible in “real world” data of limited clinical studies. The current evidence has led to the integration of allogeneic stem cell therapy into international guidelines. To date, the definitive status of allogeneic stem cells in the multidisciplinary treatment algorithm for complex anal fistulas associated with Crohn’s disease cannot be evaluated.

Schlüsselwörter

Analfistel - M. Crohn - mesenchymale Stammzellen - Darvadstrocel - Evidenz

Keywords

anal fistula - Crohn`s disease - mesenchymal stem cells - darvadstrocel - evidence


Publication History

Received: 04 March 2023

Accepted: 25 March 2023

Article published online:
02 June 2023

© 2023. Thieme. All rights reserved.

Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany

 

  • Literatur

  • 1 Kelley KA, Kaur T, Tsikitis VL. Perianal Crohn’s disease: challenges and solutions. Clin Exp Gastroenterol 2017; 10: 39-46
    CrossrefPubMedSearch in Google Scholar
  • 2 Scharl M, Rogler G. Pathophysiology of fistula formation in Crohn’s disease. World J Gastroenterol Pathophysiol 2014; 5: 205-212
    CrossrefPubMedSearch in Google Scholar
  • 3 Panes J, Reinisch W, Rupniewska F. et al. Burden and outcomes for complex perianal fistulas in Crohn’s disease: systematic review. World J Gastroenterol 2018; 24: 4821-4834
    CrossrefPubMedSearch in Google Scholar
  • 4 Lightner AL. Perianal Crohn’s disease. Dis Colon Rectum 2020; 63: 1023-1026
    CrossrefPubMedSearch in Google Scholar
  • 5 Sandborn WJ, Fazio VW, Feagan BG. et al. ; American Gatroenterological Association Clinical Practice Committee. AGA technical review on perianal Crohn’s disease. Gastroenterology 2003; 125: 1508-1530
    CrossrefPubMedSearch in Google Scholar
  • 6 Zabot GP, Cassol O, Saad-Hossne R. et al. Modern surgical strategies for perianal Crohn’s disease. World J Gastroenterol 2020; 26: 6572-6581
    CrossrefPubMedSearch in Google Scholar
  • 7 Meima-van Praag EM, Buskens CJ, Hompes R. et al. Surgical management of Crohn’s disease: a state of the art review. Int J Colorectal Dis 2021; 36: 1133-1145
    CrossrefPubMedSearch in Google Scholar
  • 8 Schwandner O. Qualitätsindikatoren bei der Therapie der Analfisteln. Chirurg 2019; 90: 270-278
    CrossrefPubMedSearch in Google Scholar
  • 9 Sugrue J, Mantilla N, Abcarian A. et al. Sphincter-sparing anal fistula repair: are we getting better?. Dis Colon Rectum 2017; 60: 1071-1077
    CrossrefPubMedSearch in Google Scholar
  • 10 Malakorn S, Sammour T, Khomvilai S. et al. Ligation of intersphincteric fistula tract for fistula in ano: lessons learned from a decade of experience. Dis Colon Rectum 2017; 60: 1065-1070
    CrossrefPubMedSearch in Google Scholar
  • 11 Rojanasakul A. LIFT procedure: a simplified technique for fistula-in-ano. Tech Coloproctol 2009; 13: 237-240
    CrossrefPubMedSearch in Google Scholar
  • 12 Sirany AM, Nygaard RM, Morken JJ. The ligation of the intersphincteric fistula tract procedure for anal fistula: a mixed bag of results. Dis Colon Rectum 2015; 58: 604-612
    CrossrefPubMedSearch in Google Scholar
  • 13 Stellingwerf ME, van Praag EM, Tozer PJ. et al. 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; 3: 231-241
    CrossrefPubMedSearch in Google Scholar
  • 14 Ratto C, Grossi U, Litta F. et al. Contemporary surgical practice in the management of anal fistula: results from an international survey. Tech Coloproctol 2019; 23: 729-741
    CrossrefPubMedSearch in Google Scholar
  • 15 van Praag EM, Stellingwerf ME, van der Bilt JDW. et al. Ligation of the intersphincteric fistula tract and endorectal advancement flap for high perianal fistulas in Crohn’s disease: a retrospective cohort study. J Crohns Colitis 2020; 14: 757-763
    CrossrefPubMedSearch in Google Scholar
  • 16 Garcia-Olmo D, Guadalajara H, Rubio-Perez I. et al. Recurrent anal fistulae: limited surgery supported by stem cells. World J Gastroenterol 2015; 21: 3330-3336
    CrossrefPubMedSearch in Google Scholar
  • 17 Eberspacher C, Mascagni D, Ferent IC. et al. Mesenchymal Stem Cells for Cryptoglandular Anal Fistula: Current State of Art. Front Surg 2022; 9: 815504
    CrossrefPubMedSearch in Google Scholar
  • 18 Carvello M, Lightner A, Yamamoto T. et al. Mesenchymal Stem Cells for Perianal Crohn’s Disease. Cells 2019; 8: 764
    CrossrefPubMedSearch in Google Scholar
  • 19 Williams P, Klersy C, Karki C. et al. Mesenchymal Stem Cell Therapy Awareness, Knowledge, and Use for the Treatment of Fistulizing Crohn’s Disease: An International Survey Among Gastroenterologists and Colorectal Surgeons. Adv Ther 2022; 39: 2761-2777
    CrossrefPubMedSearch in Google Scholar
  • 20 Cheng F, Huang Z, Li Z. Mesenchymal stem-cell therapy for perianal fistulas in Crohn’s disease: a systematic review and meta-analysis. Tech Coloproctol 2019; 23: 613-623
    CrossrefPubMedSearch in Google Scholar
  • 21 Guadalajara H, García-Arranz M, Herreros MD. et al. Mesenchymal stem cells in perianal Crohn’s disease. Tech Coloproctol 2020; 24: 883-889
    CrossrefPubMedSearch in Google Scholar
  • 22 Buscail E, Le Cosquer G, Gross F. et al. Adipose-Derived Stem Cells in the Treatment of Perianal Fistulas in Crohn’s Disease: Rationale, Clinical Results and Perspectives. Int J Mol Sci 2021; 55: 9967
    CrossrefPubMedSearch in Google Scholar
  • 23 EMA (European Medicines Agency). Alofisel-epar-product-information_ de.pdf. Accessed March 04, 2023 at: https://www.ema.europa.eu/en/medicines/human/EPAR/alofisel
    PubMed
  • 24 Takeda. Fachinformation Alofisel®, Stand 23.01.2023. Accessed March 04, 2023 at: https://www.takeda-produkte.de/system/files/produkt-info/fachinformation-alofiselr.pdf
    PubMed
  • 25 Paul-Ehrlich-Institut. Schulungsmaterial Alofisel. Accessed March 04, 2023 at: https://www.pei.de/schulungsmaterial/alofisel
    PubMed
  • 26 Panés J, García-Olmo D, Van Assche G. et al. ; ADMIRE CD Study Group Collaborators. Expanded allogenic adipose-derived mesenchymal stem cells (Cx601) for complex perianal fistulas in Crohn’s disease: a phase 3 randomised, double-blind controlled trial. Lancet 2016; 388: 1281-1290
    CrossrefPubMedSearch in Google Scholar
  • 27 Panés J, García-Olmo D, Van Assche G. et al. ; ADMIRE CD Study Group Collaborators. Long-term efficacy and safety of stem cell therapy (Cx601) for complex perianal fistulas in patients with Crohn’s disease. Gastroenterology 2018; 154: 1334-1342
    CrossrefPubMedSearch in Google Scholar
  • 28 Garcia-Olmo D, Gilaberte I, Binek M. et al. Follow-up study to evaluate the long-term safety and efficacy of darvadstrocel (mesenchymal stem cell treatment) in patients with perianal fistulizing Crohn’s disease: ADMIRE-CD phase 3 randomized controlled trial. Dis Colon Rectum 2022; 65: 713-720
    CrossrefPubMedSearch in Google Scholar
  • 29 Panés J, Bouma G, Ferrante M. et al. INSPECT: a retrospective long-term effectiveness and safety of darvadstrocel in patients with perianal fistulizing Crohn’s disease treated in the ADMIRE-CD trial. Inflamm Bowel Dis 2022; 28: 1737-1745
    CrossrefPubMedSearch in Google Scholar
  • 30 Furukawa S, Mizushinma T, Nakaya R. et al. Darvadstrocel for complex perianal fistulas in Japanese adults with Crohn’s disease: a phase 3 study. J Crohns Colitis 2022;
    CrossrefPubMedSearch in Google Scholar
  • 31 Cabalzar-Wondberg D, Turina M, Bidermann L. et al. Allogeneic expanded adipose-derived mesenchymal stem cell therapy for perianal fistulas in Crohn’s disease: a case series. Colorectal Dis 2021; 23: 1444-1450
    CrossrefPubMedSearch in Google Scholar
  • 32 Schwandner O. Stem cell injection for complex anal fistula in Crohn’s disease: a single-center experience. World J Gastroenterol 2021; 27: 3643-3653
    CrossrefPubMedSearch in Google Scholar
  • 33 Fathallah N, Akaffou M, Haouari MA. et al. Deep remission improves the quality of life of patients with Crohn’s disease and anoperineal fistula treated with darvadstrocel: results of a French pilot study. Tech Coloproctol 2023;
    CrossrefPubMedSearch in Google Scholar
  • 34 Adamina M, Bonovas S, Raine T. et al. ECCO Guidelines on Therapeutics in Crohn’s Disease: Surgical Treatment. J Crohns Colitis 2020; 14: 155-168
    CrossrefPubMedSearch in Google Scholar
  • 35 Sturm A, Atreya R, Bettenworth D. et al. Aktualisierte S3-Leitlinie „Diagnostik und Therapie des Morbus Crohn“ der Deutschen Gesellschaft für Gastroenterologie, Verdauungs- und Stoffwechselkrankheiten (DGVS) – August 2021 – AWMF-Registernummer: 021–004. Z Gastroenterol 2022; 60: 332-418
    Thieme ConnectPubMedSearch in Google Scholar
  • 36 Gaertner WB, Burgess PL, Davids JS. et al. The American Society of Colon and Rectal Surgeons Clinical Practice Guidelines for the Management of Anorectal Abscess, Fistula-in-Ano, and Rectovaginal Fistula. Dis Colon Rectum 2022; 65: 964-985
    CrossrefPubMedSearch in Google Scholar
  • 37 Schwandner O. Video-assisted anal fistula treatment (VAAFT) combined with advancement flap repair in Crohn’s disease. Tech Coloproctol 2013; 17: 221-225
    CrossrefPubMedSearch in Google Scholar
  • 38 Emile SH, Elfeki H, Shalaby M. et al. A systematic review and meta-analysis of the efficacy and safety of video-assisted anal fistula treatment (VAAFT). Surg Endosc 2018; 32: 2084-2093
    CrossrefPubMedSearch in Google Scholar
  • 39 Hindryckx P, Jairath V, Zou G. et al. Development an Validation of a Magnetic Resonance Index for Assessing Fistulas in Patients With Crohn’s Disease. Gastroenterology 2019; 157: 1233-1244
    CrossrefPubMedSearch in Google Scholar
  • 40 Van Rijn KL, Meima-van Praag EM, Bossuyt PM. et al. Fibrosis and MAGNIFI-CD Activity Index at Magnetic Resonance Imaging to Predict Treatment Outcome in Perianal Fistulizing Crohn’s Disease Patients. J Crohns Colitis 2022; 16: 708-716
    CrossrefPubMedSearch in Google Scholar
  • 41 Geldorf J, Iqbal N, LeBlanc JF. et al. Classifying perianal fistulising Crohn’s disease: an expert consensus to guide decision-making in daily practice and clinical trials. Lancet Gastroenterol Hepatol 2022; 7: 576-584
    CrossrefPubMedSearch in Google Scholar
  • 42 Panés J, Rimola J. Perianal fistulizing Crohn’s disease: pathogenesis, diagnosis and therapy. Nat Rev Gastroenterol Hepatol 2017; 14: 652-664
    CrossrefPubMedSearch in Google Scholar
  • 43 Sugrue J, Nordenstam J, Abcarian H. et al. Pathogenesis and persistence of cryptoglandular anal fistula: a systematic review. Tech Coloproctol 2017; 21: 425-432
    CrossrefPubMedSearch in Google Scholar
  • 44 Verstockt B, Ferrante M, Vermeire S. et al. New treatment options for inflammatory bowel diseases. J Gastroenterol 2018; 53: 585-590
    CrossrefPubMedSearch in Google Scholar
  • 45 Parks AG, Gordon PH, Hardcastle JD. A classification of fistula-in-ano. Br J Surg 1976; 63: 1-12
    CrossrefPubMedSearch in Google Scholar
  • 46 Schwandner O, Wedel T. Analabszess und Analfistel. In: Schwandner O. Proktologische Diagnostik. BerlinHeidelberg: Springer; 2016: 79-102
    Search in Google Scholar