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Clin Colon Rectal Surg
DOI: 10.1055/s-0044-1786543
Review Article

Perianal Fistulizing Crohn's Disease: Outcomes of Surgical Repairs and Current State of Stem Cell-Based Therapies

Aaron J. Dawes
1   Section of Colon & Rectal Surgery, Department of Surgery, Stanford University School of Medicine, Stanford, California
2   Stanford-Surgery Policy Improvement Research and Education Center, Department of Surgery, Stanford University School of Medicine, Stanford, California
,
Amy L. Lightner
3   Department of General Surgery, Scripps Clinic, La Jolla, California
4   Department of Molecular Medicine, Scripps Research Institute, La Jolla, CA
› Author Affiliations Funding Research reported in this publication was supported by the National Center for Advancing Translational Sciences of the National Institutes of Health under Award Number KL2TR003143 (salary support for A.J.D.). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
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Abstract

Perianal fistulizing Crohn's disease is one of the most disabling phenotypes of Crohn's disease, due to the severe impairment in quality of life including social and personal wellbeing. A multimodal approach with patient-tailored care is the key to optimal management of this condition. Medical therapy is needed to optimize the luminal disease, and surgical intervention is required to control any associated perianal sepsis and attempt palliative or definitive fistula repair. While several medical and surgical options are available, the majority of patients continue to have symptomatic disease. Fortunately, this continues to drive novel innovations which are revolutionizing the treatment and outcomes of perianal fistulizing Crohn's disease. However, there continues to be a need for randomized trials and consistent metrics utilized for classification and treatment outcomes in order to accurately describe optimal treatment outcomes.

Keywords

perianal fistulas - Crohn's disease - multidisciplinary approach - surgical intervention


Publication History

Article published online:
15 May 2024

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  • References

  • 1 Schwartz DA, Loftus Jr EV, Tremaine WJ. et al. The natural history of fistulizing Crohn's disease in Olmsted County, Minnesota. Gastroenterology 2002; 122 (04) 875-880
    CrossrefPubMedGoogle Scholar
  • 2 Schwartz DA, Tagarro I, Carmen Díez M, Sandborn WJ. Prevalence of fistulizing Crohn's disease in the United States: estimate from a systematic literature review attempt and population-based database analysis. Inflamm Bowel Dis 2019; 25 (11) 1773-1779
    CrossrefPubMedGoogle Scholar
  • 3 Shivashankar R, Tremaine WJ, Harmsen WS, Loftus Jr EV. Incidence and prevalence of Crohn's disease and ulcerative colitis in Olmsted County, Minnesota from 1970 through 2010. Clin Gastroenterol Hepatol 2017; 15 (06) 857-863
    CrossrefPubMedGoogle Scholar
  • 4 Hellers G, Bergstrand O, Ewerth S, Holmström B. Occurrence and outcome after primary treatment of anal fistulae in Crohn's disease. Gut 1980; 21 (06) 525-527
    CrossrefPubMedGoogle Scholar
  • 5 Schnitzler F, Friedrich M, Wolf C. et al. The NOD2 single nucleotide polymorphism rs72796353 (IVS4+10 A>C) is a predictor for perianal fistulas in patients with Crohn's disease in the absence of other NOD2 mutations. PLoS One 2015; 10 (07) e0116044
    CrossrefPubMedGoogle Scholar
  • 6 Beaugerie L, Seksik P, Nion-Larmurier I, Gendre JP, Cosnes J. Predictors of Crohn's disease. Gastroenterology 2006; 130 (03) 650-656
    CrossrefPubMedGoogle Scholar
  • 7 Karki C, Athavale A, Abilash V. et al. Multi-national observational study to assess quality of life and treatment preferences in patients with Crohn's perianal fistulas. World J Gastrointest Surg 2023; 15 (11) 2537-2552
    CrossrefPubMedGoogle Scholar
  • 8 Longworth L, Fountain D, Singh J. et al. Elicitation of health-related utility in perianal fistula in Crohn's disease. Patient 2019; 12 (03) 339-348
    CrossrefPubMedGoogle Scholar
  • 9 Adegbola SO, Dibley L, Sahnan K. et al. Burden of disease and adaptation to life in patients with Crohn's perianal fistula: a qualitative exploration. Health Qual Life Outcomes 2020; 18 (01) 370
    CrossrefPubMedGoogle Scholar
  • 10 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; 32 (10) 1228-1239
    CrossrefPubMedGoogle Scholar
  • 11 Panés J, Rimola J. Perianal fistulizing Crohn's disease: pathogenesis, diagnosis and therapy. Nat Rev Gastroenterol Hepatol 2017; 14 (11) 652-664
    CrossrefPubMedGoogle Scholar
  • 12 Gecse KB, Bemelman W, Kamm MA. et al; World Gastroenterology Organization, International Organisation for Inflammatory Bowel Diseases IOIBD, European Society of Coloproctology and Robarts Clinical Trials, World Gastroenterology Organization International Organisation for Inflammatory Bowel Diseases IOIBD European Society of Coloproctology and Robarts Clinical Trials. A global consensus on the classification, diagnosis and multidisciplinary treatment of perianal fistulising Crohn's disease. Gut 2014; 63 (09) 1381-1392
    CrossrefPubMedGoogle Scholar
  • 13 Sandborn WJ, Fazio VW, Feagan BG, Hanauer SB. American Gastroenterological Association Clinical Practice Committee. AGA technical review on perianal Crohn's disease. Gastroenterology 2003; 125 (05) 1508-1530
    CrossrefPubMedGoogle Scholar
  • 14 Schratter-Sehn AU, Lochs H, Vogelsang H, Schurawitzki H, Herold C, Schratter M. Endoscopic ultrasonography versus computed tomography in the differential diagnosis of perianorectal complications in Crohn's disease. Endoscopy 1993; 25 (09) 582-586
    Article in Thieme ConnectPubMedGoogle Scholar
  • 15 Wells K, Wise PE. Hereditary colorectal cancer syndromes. Surg Clin North Am 2017; 97 (03) 605-625
    CrossrefPubMedGoogle Scholar
  • 16 Siddiqui MR, Ashrafian H, Tozer P. et al. A diagnostic accuracy meta-analysis of endoanal ultrasound and MRI for perianal fistula assessment. Dis Colon Rectum 2012; 55 (05) 576-585
    CrossrefPubMedGoogle Scholar
  • 17 Schwartz DA, Wiersema MJ, Dudiak KM. et al. A comparison of endoscopic ultrasound, magnetic resonance imaging, and exam under anesthesia for evaluation of Crohn's perianal fistulas. Gastroenterology 2001; 121 (05) 1064-1072
    CrossrefPubMedGoogle Scholar
  • 18 Buchanan G, Halligan S, Williams A. et al. Effect of MRI on clinical outcome of recurrent fistula-in-ano. Lancet 2002; 360 (9346) 1661-1662
    CrossrefPubMedGoogle Scholar
  • 19 Spradlin NM, Wise PE, Herline AJ, Muldoon RL, Rosen M, Schwartz DA. A randomized prospective trial of endoscopic ultrasound to guide combination medical and surgical treatment for Crohn's perianal fistulas. Am J Gastroenterol 2008; 103 (10) 2527-2535
    CrossrefPubMedGoogle Scholar
  • 20 Wiese DM, Beaulieu D, Slaughter JC. et al. Use of endoscopic ultrasound to guide adalimumab treatment in perianal Crohn's disease results in faster fistula healing. Inflamm Bowel Dis 2015; 21 (07) 1594-1599
    CrossrefPubMedGoogle Scholar
  • 21 Gecse KB, Sebastian S, Hertogh Gd. et al. Results of the Fifth Scientific Workshop of the ECCO [II]: clinical aspects of perianal fistulising Crohn's disease-the unmet needs. J Crohn's Colitis 2016; 10 (07) 758-765
    CrossrefPubMedGoogle Scholar
  • 22 Caron B, D'Amico F, Danese S, Peyrin-Biroulet L. Endpoints for perianal Crohn's disease trials: past, present and future. J Crohn's Colitis 2021; 15 (08) 1387-1398
    CrossrefPubMedGoogle Scholar
  • 23 Irvine EJ. Usual therapy improves perianal Crohn's disease as measured by a new disease activity index. McMaster IBD Study Group. J Clin Gastroenterol 1995; 20 (01) 27-32
    CrossrefPubMedGoogle Scholar
  • 24 Present DH, Rutgeerts P, Targan S. et al. Infliximab for the treatment of fistulas in patients with Crohn's disease. N Engl J Med 1999; 340 (18) 1398-1405
    CrossrefPubMedGoogle Scholar
  • 25 Van Assche G, Vanbeckevoort D, Bielen D. et al. Magnetic resonance imaging of the effects of infliximab on perianal fistulizing Crohn's disease. Am J Gastroenterol 2003; 98 (02) 332-339
    CrossrefPubMedGoogle Scholar
  • 26 Savoye-Collet C, Savoye G, Koning E, Dacher JN, Lerebours E. Fistulizing perianal Crohn's disease: contrast-enhanced magnetic resonance imaging assessment at 1 year on maintenance anti-TNF-alpha therapy. Inflamm Bowel Dis 2011; 17 (08) 1751-1758
    CrossrefPubMedGoogle Scholar
  • 27 Tozer P, Ng SC, Siddiqui MR. et al. Long-term MRI-guided combined anti-TNF-α and thiopurine therapy for Crohn's perianal fistulas. Inflamm Bowel Dis 2012; 18 (10) 1825-1834
    CrossrefPubMedGoogle Scholar
  • 28 Hindryckx P, Jairath V, Zou G. et al. Development and validation of a magnetic resonance index for assessing fistulas in patients with Crohn's disease. Gastroenterology 2019; 157 (05) 1233-1244.e5
    CrossrefPubMedGoogle Scholar
  • 29 Adegbola SO, Dibley L, Sahnan K. et al. Development and initial psychometric validation of a patient-reported outcome measure for Crohn's perianal fistula: the Crohn's Anal Fistula Quality of Life (CAF-QoL) scale. Gut 2021; 70 (09) 1649-1656
    CrossrefPubMedGoogle Scholar
  • 30 Sahnan K, Tozer PJ, Adegbola SO. et al; ENiGMA collaborators. Developing a core outcome set for fistulising perianal Crohn's disease. Gut 2019; 68 (02) 226-238
    CrossrefPubMedGoogle Scholar
  • 31 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; 160 (07) 2512-2556.e9
    CrossrefPubMedGoogle Scholar
  • 32 Sands BE, Anderson FH, Bernstein CN. et al. Infliximab maintenance therapy for fistulizing Crohn's disease. N Engl J Med 2004; 350 (09) 876-885
    CrossrefPubMedGoogle Scholar
  • 33 Colombel JF, Sandborn WJ, Rutgeerts P. et al. Adalimumab for maintenance of clinical response and remission in patients with Crohn's disease: the CHARM trial. Gastroenterology 2007; 132 (01) 52-65
    CrossrefPubMedGoogle Scholar
  • 34 Colombel JF, Schwartz DA, Sandborn WJ. et al. Adalimumab for the treatment of fistulas in patients with Crohn's disease. Gut 2009; 58 (07) 940-948
    CrossrefPubMedGoogle Scholar
  • 35 Sandborn WJ, Rutgeerts P, Enns R. et al. Adalimumab induction therapy for Crohn disease previously treated with infliximab: a randomized trial. Ann Intern Med 2007; 146 (12) 829-838
    CrossrefPubMedGoogle Scholar
  • 36 Feagan BG, Schwartz D, Danese S. et al. Efficacy of vedolizumab in fistulising Crohn's disease: exploratory analyses of data from GEMINI 2. J Crohn's Colitis 2018; 12 (05) 621-626
    CrossrefPubMedGoogle Scholar
  • 37 Sands BE, Chen J, Feagan BG. et al. Efficacy and safety of MEDI2070, an antibody against interleukin 23, in patients with moderate to severe Crohn's disease: a phase 2a study. Gastroenterology 2017; 153 (01) 77-86.e6
    CrossrefPubMedGoogle Scholar
  • 38 Thia KT, Mahadevan U, Feagan BG. 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 2009; 15 (01) 17-24
    CrossrefPubMedGoogle Scholar
  • 39 West RL, van der Woude CJ, Hansen BE. 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 2004; 20 (11–12): 1329-1336
    CrossrefPubMedGoogle Scholar
  • 40 Dewint P, Hansen BE, Verhey E. 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 2014; 63 (02) 292-299
    CrossrefPubMedGoogle Scholar
  • 41 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 2003; 9 (02) 98-103
    CrossrefPubMedGoogle Scholar
  • 42 Wasmann KA, de Groof EJ, Stellingwerf ME. et al. Treatment of perianal fistulas in Crohn's disease, seton versus anti-TNF versus surgical closure following anti-TNF [PISA]: a randomised controlled trial. J Crohn's Colitis 2020; 14 (08) 1049-1056
    CrossrefPubMedGoogle Scholar
  • 43 Ferrante M, Sabino J. Efficacy of JAK inhibitors in ulcerative colitis. J Crohn's Colitis 2020; 14 (Suppl. 02) S737-S745
    CrossrefPubMedGoogle Scholar
  • 44 Ng KS, Kwok AMF, Young CJ. Factors associated with healing, reoperation and continence disturbance in patients following surgery for fistula-in-ano. Colorectal Dis 2020; 22 (12) 2204-2213
    CrossrefPubMedGoogle Scholar
  • 45 Meima-van Praag EM, van Rijn KL, Wasmann KATGM. et al. Short-term anti-TNF therapy with surgical closure versus anti-TNF therapy in the treatment of perianal fistulas in Crohn's disease (PISA-II): a patient preference randomised trial. Lancet Gastroenterol Hepatol 2022; 7 (07) 617-626
    CrossrefPubMedGoogle Scholar
  • 46 Graf W, Andersson M, Åkerlund JE, Börjesson L. Swedish Organization for Studies of Inflammatory Bowel Disease. Long-term outcome after surgery for Crohn's anal fistula. Colorectal Dis 2016; 18 (01) 80-85
    CrossrefPubMedGoogle Scholar
  • 47 Michelassi F, Melis M, Rubin M, Hurst RD. Surgical treatment of anorectal complications in Crohn's disease. Surgery 2000; 128 (04) 597-603
    CrossrefPubMedGoogle Scholar
  • 48 Sangwan YP, Schoetz Jr DJ, Murray JJ, Roberts PL, Coller JA. Perianal Crohn's disease. Results of local surgical treatment. Dis Colon Rectum 1996; 39 (05) 529-535
    CrossrefPubMedGoogle Scholar
  • 49 Williams JG, Rothenberger DA, Nemer FD, Goldberg SM. Fistula-in-ano in Crohn's disease. Results of aggressive surgical treatment. Dis Colon Rectum 1991; 34 (05) 378-384
    CrossrefPubMedGoogle Scholar
  • 50 Papaconstantinou I, Kontis E, Koutoulidis V, Mantzaris G, Vassiliou I. Surgical management of fistula-in-ano among patients with Crohn's disease: analysis of outcomes after fistulotomy or seton placement-single-center experience. Scand J Surg 2017; 106 (03) 211-215
    CrossrefPubMedGoogle Scholar
  • 51 van Koperen PJ, Safiruddin F, Bemelman WA, Slors JF. Outcome of surgical treatment for fistula in ano in Crohn's disease. Br J Surg 2009; 96 (06) 675-679
    CrossrefPubMedGoogle Scholar
  • 52 Lee MJ, Heywood N, Adegbola S. et al; ENiGMA Collaborators. Systematic review of surgical interventions for Crohn's anal fistula. BJS Open 2017; 1 (03) 55-66
    CrossrefPubMedGoogle Scholar
  • 53 Lindsey I, Smilgin-Humphreys MM, Cunningham C, Mortensen NJ, George BD. A randomized, controlled trial of fibrin glue vs. conventional treatment for anal fistula. Dis Colon Rectum 2002; 45 (12) 1608-1615
    CrossrefPubMedGoogle Scholar
  • 54 Vidon M, Munoz-Bongrand N, Lambert J. et al. Long-term efficacy of fibrin glue injection for perianal fistulas in patients with Crohn's disease. Colorectal Dis 2021; 23 (04) 894-900
    CrossrefPubMedGoogle Scholar
  • 55 Grimaud JC, Munoz-Bongrand N, Siproudhis L. et al; Groupe d'Etude Thérapeutique des Affections Inflammatoires du Tube Digestif. Fibrin glue is effective healing perianal fistulas in patients with Crohn's disease. Gastroenterology 2010; 138 (07) 2275-2281 , 2281.e1
    CrossrefPubMedGoogle Scholar
  • 56 Abramowitz L, Brochard C, Pigot F. et al. Surgical closure, mainly with glue injection and anti-tumour necrosis factor α, in fistulizing perianal Crohn's disease: a multicentre randomized controlled trial. Colorectal Dis 2022; 24 (02) 210-219
    CrossrefPubMedGoogle Scholar
  • 57 Nasseri Y, Cassella L, Berns M, Zaghiyan K, Cohen J. The anal fistula plug in Crohn's disease patients with fistula-in-ano: a systematic review. Colorectal Dis 2016; 18 (04) 351-356
    CrossrefPubMedGoogle Scholar
  • 58 O'Riordan JM, Datta I, Johnston C, Baxter NN. A systematic review of the anal fistula plug for patients with Crohn's and non-Crohn's related fistula-in-ano. Dis Colon Rectum 2012; 55 (03) 351-358
    CrossrefPubMedGoogle Scholar
  • 59 Aho Fält U, Zawadzki A, Starck M, Bohe M, Johnson LB. Long-term outcome of the Surgisis® (Biodesign® ) anal fistula plug for complex cryptoglandular and Crohn's fistulas. Colorectal Dis 2021; 23 (01) 178-185
    CrossrefPubMedGoogle Scholar
  • 60 Senéjoux A, Siproudhis L, Abramowitz L. et al; Groupe d'Etude Thérapeutique des Affections Inflammatoires du tube Digestif [GETAID]. Fistula plug in fistulising ano-perineal Crohn's disease: a randomised controlled trial. J Crohn's Colitis 2016; 10 (02) 141-148
    CrossrefPubMedGoogle Scholar
  • 61 Rothenberger DA, Christenson CE, Balcos EG. et al Endorectal advancement flap for treatment of simple rectovaginal fistula. Dis Colon Rectum 1982; 25 (04) 297-300
    CrossrefPubMedGoogle Scholar
  • 62 Dawes AJ, Jensen CC. Rectovaginal fistulas secondary to obstetrical injury. Clin Colon Rectal Surg 2021; 34 (01) 28-39
    Article in Thieme ConnectPubMedGoogle Scholar
  • 63 Soltani A, Kaiser AM. Endorectal advancement flap for cryptoglandular or Crohn's fistula-in-ano. Dis Colon Rectum 2010; 53 (04) 486-495
    CrossrefPubMedGoogle Scholar
  • 64 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; 3 (03) 231-241
    CrossrefPubMedGoogle Scholar
  • 65 Mizrahi N, Wexner SD, Zmora O. et al. Endorectal advancement flap: are there predictors of failure?. Dis Colon Rectum 2002; 45 (12) 1616-1621
    CrossrefPubMedGoogle Scholar
  • 66 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; 23 (11) 2277-2284
    CrossrefPubMedGoogle Scholar
  • 67 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; 90 (03) 581-586
    PubMedGoogle Scholar
  • 68 Gingold DS, Murrell ZA, Fleshner PR. A prospective evaluation of the ligation of the intersphincteric tract procedure for complex anal fistula in patients with Crohn's disease. Ann Surg 2014; 260 (06) 1057-1061
    CrossrefPubMedGoogle Scholar
  • 69 Wood T, Truong A, Mujukian A, Zaghiyan K, Fleshner P. Increasing experience with the LIFT procedure in Crohn's disease patients with complex anal fistula. Tech Coloproctol 2022; 26 (03) 205-212
    CrossrefPubMedGoogle Scholar
  • 70 Mujukian A, Truong A, Fleshner P, Zaghiyan K. Long-term healing after complex anal fistula repair in patients with Crohn's disease. Tech Coloproctol 2020; 24 (08) 833-841
    CrossrefPubMedGoogle Scholar
  • 71 D'Haens GR, Geboes K, Peeters M, Baert F, Penninckx F, Rutgeerts P. Early lesions of recurrent Crohn's disease caused by infusion of intestinal contents in excluded ileum. Gastroenterology 1998; 114 (02) 262-267
    CrossrefPubMedGoogle Scholar
  • 72 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; 42 (07) 783-792
    CrossrefPubMedGoogle Scholar
  • 73 Kasparek MS, Glatzle J, Temeltcheva T, Mueller MH, Koenigsrainer A, Kreis ME. Long-term quality of life in patients with Crohn's disease and perianal fistulas: influence of fecal diversion. Dis Colon Rectum 2007; 50 (12) 2067-2074
    CrossrefPubMedGoogle Scholar
  • 74 Yamamoto T, Allan RN, Keighley MR. Effect of fecal diversion alone on perianal Crohn's disease. World J Surg 2000; 24 (10) 1258-1262 , discussion 1262–1263
    CrossrefPubMedGoogle Scholar
  • 75 Toma JG, Akhavan M, Fernandes KJ. et al. Isolation of multipotent adult stem cells from the dermis of mammalian skin. Nat Cell Biol 2001; 3 (09) 778-784
    CrossrefPubMedGoogle Scholar
  • 76 Wang HS, Hung SC, Peng ST. et al. Mesenchymal stem cells in the Wharton's jelly of the human umbilical cord. Stem Cells 2004; 22 (07) 1330-1337
    CrossrefPubMedGoogle Scholar
  • 77 Yoshimura K, Shigeura T, Matsumoto D. et al. Characterization of freshly isolated and cultured cells derived from the fatty and fluid portions of liposuction aspirates. J Cell Physiol 2006; 208 (01) 64-76
    CrossrefPubMedGoogle Scholar
  • 78 Le Blanc K, Frassoni F, Ball L. et al; Developmental Committee of the European Group for Blood and Marrow Transplantation. Mesenchymal stem cells for treatment of steroid-resistant, severe, acute graft-versus-host disease: a phase II study. Lancet 2008; 371 (9624) 1579-1586
    CrossrefPubMedGoogle Scholar
  • 79 Sun L, Wang D, Liang J. et al. Umbilical cord mesenchymal stem cell transplantation in severe and refractory systemic lupus erythematosus. Arthritis Rheum 2010; 62 (08) 2467-2475
    CrossrefPubMedGoogle Scholar
  • 80 Lee RH, Pulin AA, Seo MJ. et al. Intravenous hMSCs improve myocardial infarction in mice because cells embolized in lung are activated to secrete the anti-inflammatory protein TSG-6. Cell Stem Cell 2009; 5 (01) 54-63
    CrossrefPubMedGoogle Scholar
  • 81 Yamout B, Hourani R, Salti H. et al. Bone marrow mesenchymal stem cell transplantation in patients with multiple sclerosis: a pilot study. J Neuroimmunol 2010; 227 (1–2): 185-189
    CrossrefPubMedGoogle Scholar
  • 82 García-Olmo D, García-Arranz M, Herreros D, Pascual I, Peiro C, Rodríguez-Montes JA. A phase I clinical trial of the treatment of Crohn's fistula by adipose mesenchymal stem cell transplantation. Dis Colon Rectum 2005; 48 (07) 1416-1423
    CrossrefPubMedGoogle Scholar
  • 83 Gharibi T, Ahmadi M, Seyfizadeh N, Jadidi-Niaragh F, Yousefi M. Immunomodulatory characteristics of mesenchymal stem cells and their role in the treatment of multiple sclerosis. Cell Immunol 2015; 293 (02) 113-121
    CrossrefPubMedGoogle Scholar
  • 84 Kimbrel EA, Kouris NA, Yavanian GJ. et al. Mesenchymal stem cell population derived from human pluripotent stem cells displays potent immunomodulatory and therapeutic properties. Stem Cells Dev 2014; 23 (14) 1611-1624
    CrossrefPubMedGoogle Scholar
  • 85 Sebbagh AC, Rosenbaum B, Péré G. et al. Regenerative medicine for digestive fistulae therapy: benefits, challenges and promises of stem/stromal cells and emergent perspectives via their extracellular vesicles. Adv Drug Deliv Rev 2021; 179: 113841
    CrossrefPubMedGoogle Scholar
  • 86 Ryan JM, Barry F, Murphy JM, Mahon BP. Interferon-gamma does not break, but promotes the immunosuppressive capacity of adult human mesenchymal stem cells. Clin Exp Immunol 2007; 149 (02) 353-363
    CrossrefPubMedGoogle Scholar
  • 87 Meisel R, Zibert A, Laryea M, Göbel U, Däubener W, Dilloo D. Human bone marrow stromal cells inhibit allogeneic T-cell responses by indoleamine 2,3-dioxygenase-mediated tryptophan degradation. Blood 2004; 103 (12) 4619-4621
    CrossrefPubMedGoogle Scholar
  • 88 Horton JA, Hudak KE, Chung EJ. et al. Mesenchymal stem cells inhibit cutaneous radiation-induced fibrosis by suppressing chronic inflammation. Stem Cells 2013; 31 (10) 2231-2241
    CrossrefPubMedGoogle Scholar
  • 89 Pezato R, de Almeida DC, Bezerra TF. et al. Immunoregulatory effects of bone marrow-derived mesenchymal stem cells in the nasal polyp microenvironment. Mediators Inflamm 2014; 2014: 583409
    CrossrefPubMedGoogle Scholar
  • 90 Anbazhagan M, Geem D, Venkateswaran S. et al. Characterization of intestinal mesenchymal stromal cells from patients with inflammatory bowel disease for autologous cell therapy. Stem Cells Transl Med 2023; 12 (02) 112-122
    CrossrefPubMedGoogle Scholar
  • 91 García-Olmo D, García-Arranz M, García LG. et al. Autologous stem cell transplantation for treatment of rectovaginal fistula in perianal Crohn's disease: a new cell-based therapy. Int J Colorectal Dis 2003; 18 (05) 451-454
    CrossrefPubMedGoogle Scholar
  • 92 Wang H, Jiang HY, Zhang YX, Jin HY, Fei BY, Jiang JL. Mesenchymal stem cells transplantation for perianal fistulas: a systematic review and meta-analysis of clinical trials. Stem Cell Res Ther 2023; 14 (01) 103
    CrossrefPubMedGoogle Scholar
  • 93 Panés J, García-Olmo D, Van Assche G. et al; ADMIRE CD Study Group Collaborators. 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 2016; 388 (10051): 1281-1290
    CrossrefPubMedGoogle Scholar
  • 94 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 (05) 1334-1342.e4
    CrossrefPubMedGoogle Scholar
  • 95 Lightner AL, Reese J, Ream J. et al. A phase IB/IIA study of ex vivo expanded allogeneic bone marrow-derived mesenchymal stem cells for the treatment of perianal fistulizing Crohn's disease. Dis Colon Rectum 2023; 66 (10) 1359-1372
    CrossrefPubMedGoogle Scholar
  • 96 Lightner AL, Reese JS, Ream J. et al. A phase IB/IIA study of ex vivo expanded allogeneic bone marrow-derived mesenchymal stem cells for the treatment of rectovaginal fistulizing Crohn's disease. Surgery 2024; 175 (02) 242-249
    CrossrefPubMedGoogle Scholar
  • 97 Lightner AL, Otero-Pineiro A, Reese J. et al. A Phase I study of ex vivo expanded allogeneic bone marrow-derived mesenchymal stem cells for the treatment of pediatric perianal fistulizing Crohn's disease. Inflamm Bowel Dis 2023; 29 (12) 1912-1919
    CrossrefPubMedGoogle Scholar
  • 98 Lightner AL. Management of fistulas in patients with Crohn's disease. Gastroenterol Hepatol (N Y) 2021; 17 (11) 533-535
    PubMedGoogle Scholar
  • 99 Panés J, Bouma G, Ferrante M. et al. INSPECT: A retrospective study to evaluate 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 (11) 1737-1745
    CrossrefPubMedGoogle Scholar
  • 100 Barnhoorn MC, Wasser MNJM, Roelofs H. et al. Long-term evaluation of allogeneic bone marrow-derived mesenchymal stromal cell therapy for Crohn's disease perianal fistulas. J Crohn's Colitis 2020; 14 (01) 64-70
    CrossrefPubMedGoogle Scholar
  • 101 Lightner AL, Ashburn JH, Brar MS. et al. Fistulizing Crohn's disease. Curr Probl Surg 2020; 57 (11) 100808
    CrossrefPubMedGoogle Scholar
  • 102 Gómez-Ferrer M, Amaro-Prellezo E, Dorronsoro A. et al. HIF-overexpression and pro-inflammatory priming in human mesenchymal stromal cells improves the healing properties of extracellular vesicles in experimental Crohn's disease. Int J Mol Sci 2021; 22 (20) 11269
    CrossrefPubMedGoogle Scholar
  • 103 Pak H, Hadizadeh A, Heirani-Tabasi A. et al. Safety and efficacy of injection of human placenta mesenchymal stem cells derived exosomes for treatment of complex perianal fistula in non-Crohn's cases: clinical trial phase I. J Gastroenterol Hepatol 2023; 38 (04) 539-547
    CrossrefPubMedGoogle Scholar
  • 104 Garcia-Olmo D, Herreros D, Pascual I. et al. Expanded adipose-derived stem cells for the treatment of complex perianal fistula: a phase II clinical trial. Dis Colon Rectum 2009; 52 (01) 79-86
    CrossrefPubMedGoogle Scholar
  • 105 Cho YB, Lee WY, Park KJ, Kim M, Yoo HW, Yu CS. Autologous adipose tissue-derived stem cells for the treatment of Crohn's fistula: a phase I clinical study. Cell Transplant 2013; 22 (02) 279-285
    CrossrefPubMedGoogle Scholar
  • 106 Lee WY, Park KJ, Cho YB. et al. Autologous adipose tissue-derived stem cells treatment demonstrated favorable and sustainable therapeutic effect for Crohn's fistula. Stem Cells 2013; 31 (11) 2575-2581
    CrossrefPubMedGoogle Scholar
  • 107 Cho YB, Park KJ, Yoon SN. et al. Long-term results of adipose-derived stem cell therapy for the treatment of Crohn's fistula. Stem Cells Transl Med 2015; 4 (05) 532-537
    CrossrefPubMedGoogle Scholar
  • 108 Ciccocioppo R, Bernardo ME, Sgarella A. et al. Autologous bone marrow-derived mesenchymal stromal cells in the treatment of fistulising Crohn's disease. Gut 2011; 60 (06) 788-798
    CrossrefPubMedGoogle Scholar
  • 109 de la Portilla F, Alba F, García-Olmo D, Herrerías JM, González FX, Galindo A. 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 2013; 28 (03) 313-323
    CrossrefPubMedGoogle Scholar
  • 110 Molendijk I, Bonsing BA, Roelofs H. et al. Allogeneic bone marrow-derived mesenchymal stromal cells promote healing of refractory perianal fistulas in patients with Crohn's disease. Gastroenterology 2015; 149 (04) 918-27.e6
    CrossrefPubMedGoogle Scholar
  • 111 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; 153 (01) 59-6 -2.e2
    CrossrefPubMedGoogle Scholar
  • 112 Lightner AL, Reese J, Ream J. et al. A phase IB/IIA study of allogeneic, bone marrow-derived, mesenchymal stem cells for the treatment of refractory ileal-anal anastomosis and peripouch fistulas in the setting of Crohn's disease of the pouch. J Crohn's Colitis 2023; 17 (04) 480-488
    CrossrefPubMedGoogle Scholar