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Investigational therapies in the medical management of Crohn disease

Joshua R Korzenik, MD
Section Editor
Paul Rutgeerts, MD, PhD, FRCP
Deputy Editor
Kristen M Robson, MD, MBA, FACG


Crohn disease (CD) is the focus of unprecedented interest for new potential therapeutics. Since the approval of infliximab for the treatment of CD in 1998, CD has been viewed as an excellent proving ground for anti-inflammatory biologics.

Despite increasing available therapies, the approved therapies have limited efficacy, and there continues to be concern related to their safety. Thus, a large unmet need exists for the treatment of CD. Mesalamine, though used widely in CD, has a minor role with little data supportive of a significant benefit, if any, for the treatment of CD. Glucocorticoids, while clinically useful, do not completely control the disease in many patients and have no role for maintenance. While some patients respond to the available anti-tumor necrosis factor (TNF) agent, many fail to respond or lose response over time. Thus, newer approaches are being evaluated.

The dramatic advances in mucosal immunology have revealed a broad set of new targets to resolve the inflammation and symptoms of the disease. The prevailing understanding of CD suggests that the intestinal inflammation is initiated by an aberrant innate immune response, which eventuates in a T-cell driven process, characterized by a T-helper cell 1 type cytokine profile. Many new treatments focus on inhibiting, suppressing, or altering T-cell differentiation. With the identification of a T-cell subset, Th17, which may be responsible for much of the inflammatory process and production of inflammatory cytokines, a new set of therapeutic antibodies are in early phase of testing. The importance of Treg (a T-cell subset that regulates other T cells) has also opened other potential avenues for influencing activated T cells such as targeting SMAD7. (See "Normal B and T lymphocyte development", section on 'Th17 cells'.)

In addition to efforts to manipulate T cells, T-cell products, or inflammatory pathways, other therapeutics are being investigated that take very different theoretical approaches. Examples include the administration or cytokines to stimulate innate immunity, or the use of prebiotics, complex carbohydrates to alter the gut flora. With the approval of vedolizumab, the approach of selective adhesion molecule antagonist is also a focus of considerable effort for new therapies for CD.

This topic review will discuss experimental treatments for CD. None of the treatments that will be discussed is currently approved for routine clinical application. Furthermore, because many of these agents are in early stages of development, information regarding their efficacy and safety is derived largely from unpublished sources of data.


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Literature review current through: Jul 2017. | This topic last updated: Aug 15, 2017.
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  1. Sandborn WJ, Feagan BG, Hanauer SB, et al. An engineered human antibody to TNF (CDP571) for active Crohn's disease: a randomized double-blind placebo-controlled trial. Gastroenterology 2001; 120:1330.
  2. Sandborn WJ, Feagan BG, Radford-Smith G, et al. CDP571, a humanised monoclonal antibody to tumour necrosis factor alpha, for moderate to severe Crohn's disease: a randomised, double blind, placebo controlled trial. Gut 2004; 53:1485.
  3. Feagan BG, Sandborn WJ, Baker JP, et al. A randomized, double-blind, placebo-controlled trial of CDP571, a humanized monoclonal antibody to tumour necrosis factor-alpha, in patients with corticosteroid-dependent Crohn's disease. Aliment Pharmacol Ther 2005; 21:373.
  4. Hanauer S, Present D, Targan SR, et al. CDP571, a humanized monoclonal antibody to TNFA, a well tolerated alternative in Crohn's disease patients who have experienced hypersensitivity reactions to infliximab (abstract). Gastroenterology 2003; :Abstract ID 106362.
  5. D'Haens G, Swijsen C, Noman M, et al. Etanercept in the treatment of active refractory Crohn's disease: a single-center pilot trial. Am J Gastroenterol 2001; 96:2564.
  6. Sandborn WJ, Hanauer SB, Katz S, et al. Etanercept for active Crohn's disease: a randomized, double-blind, placebo-controlled trial. Gastroenterology 2001; 121:1088.
  7. Rutgeerts P, Lemmens L, Van Assche G, et al. Treatment of active Crohn's disease with onercept (recombinant human soluble p55 tumour necrosis factor receptor): results of a randomized, open-label, pilot study. Aliment Pharmacol Ther 2003; 17:185.
  8. Rutgeerts P, Sandborn WJ, Fedorak RN, et al. Onercept for moderate-to-severe Crohn's disease: a randomized, double-blind, placebo-controlled trial. Clin Gastroenterol Hepatol 2006; 4:888.
  9. Neovacs Announces Kinoid Trial Results. http://www.dddmag.com/news-Neovacs-Announces-Kinoid-Trial-Results-12810.aspx (Accessed on December 13, 2010).
  10. Feagan BG, Choquette D, Ghosh S, et al. The challenge of indication extrapolation for infliximab biosimilars. Biologicals 2014; 42:177.
  11. Hommes D, van den Blink B, Plasse T, et al. Inhibition of stress-activated MAP kinases induces clinical improvement in moderate to severe Crohn's disease. Gastroenterology 2002; 122:7.
  12. Dotan I, Rachmilewitz D, Schreiber S, et al. A randomised placebo-controlled multicentre trial of intravenous semapimod HCl for moderate to severe Crohn's disease. Gut 2010; 59:760.
  13. Vasiliauskas EA, Kam LY, Abreu-Martin MT, et al. An open-label pilot study of low-dose thalidomide in chronically active, steroid-dependent Crohn's disease. Gastroenterology 1999; 117:1278.
  14. Ehrenpreis ED, Kane SV, Cohen LB, et al. Thalidomide therapy for patients with refractory Crohn's disease: an open-label trial. Gastroenterology 1999; 117:1271.
  15. Lazzerini M, Martelossi S, Magazzù G, et al. Effect of thalidomide on clinical remission in children and adolescents with refractory Crohn disease: a randomized clinical trial. JAMA 2013; 310:2164.
  16. Mansfield JC, Parkes M, Hawthorne AB, et al. A randomized, double-blind, placebo-controlled trial of lenalidomide in the treatment of moderately severe active Crohn's disease. Aliment Pharmacol Ther 2007; 26:421.
  17. Plamondon S, Ng SC, Kamm MA. Thalidomide in luminal and fistulizing Crohn's disease resistant to standard therapies. Aliment Pharmacol Ther 2007; 25:557.
  18. Panaccione R, Sandborn WJ, Gordon GL, et al. Briakinumab for treatment of Crohn's disease: results of a randomized trial. Inflamm Bowel Dis 2015; 21:1329.
  19. Mannon PJ, Fuss IJ, Mayer L, et al. Anti-interleukin-12 antibody for active Crohn's disease. N Engl J Med 2004; 351:2069.
  20. Burakoff R, Barish CF, Riff D, et al. A phase 1/2A trial of STA 5326, an oral interleukin-12/23 inhibitor, in patients with active moderate to severe Crohn's disease. Inflamm Bowel Dis 2006; 12:558.
  21. Feagan BG, Sandborn WJ, D'Haens G, et al. Induction therapy with the selective interleukin-23 inhibitor risankizumab in patients with moderate-to-severe Crohn's disease: a randomised, double-blind, placebo-controlled phase 2 study. Lancet 2017; 389:1699.
  22. Reinisch W, Hommes DW, Van Assche G, et al. A dose escalating, placebo controlled, double blind, single dose and multidose, safety and tolerability study of fontolizumab, a humanised anti-interferon gamma antibody, in patients with moderate to severe Crohn's disease. Gut 2006; 55:1138.
  23. Reinisch W, de Villiers W, Bene L, et al. Fontolizumab in moderate to severe Crohn's disease: a phase 2, randomized, double-blind, placebo-controlled, multiple-dose study. Inflamm Bowel Dis 2010; 16:233.
  24. Yamamoto M, Yoshizaki K, Kishimoto T, Ito H. IL-6 is required for the development of Th1 cell-mediated murine colitis. J Immunol 2000; 164:4878.
  25. Atreya R, Mudter J, Finotto S, et al. Blockade of interleukin 6 trans signaling suppresses T-cell resistance against apoptosis in chronic intestinal inflammation: evidence in crohn disease and experimental colitis in vivo. Nat Med 2000; 6:583.
  26. Ito H, Takazoe M, Fukuda Y, et al. A pilot randomized trial of a human anti-interleukin-6 receptor monoclonal antibody in active Crohn's disease. Gastroenterology 2004; 126:989.
  27. Hueber W, Sands BE, Vandemeulebroecke M, et al. Inhibition of IL-17A by secukinumab is ineffective for Crohn's disease (CD) (abstract #10). Abstracts of the 6th Congress of the European Crohn's and Colitis Organisation, Dublin, Ireland 2011. Available at: http://www.ecco-ibd.eu/index.php/congress/8-6business-meetings/detail/46-5 (Accessed on January 27, 2012).
  28. Autschbach F, Braunstein J, Helmke B, et al. In situ expression of interleukin-10 in noninflamed human gut and in inflammatory bowel disease. Am J Pathol 1998; 153:121.
  29. van Deventer SJ, Elson CO, Fedorak RN. Multiple doses of intravenous interleukin 10 in steroid-refractory Crohn's disease. Crohn's Disease Study Group. Gastroenterology 1997; 113:383.
  30. Buruiana FE, Solà I, Alonso-Coello P. Recombinant human interleukin 10 for induction of remission in Crohn's disease. Cochrane Database Syst Rev 2010; :CD005109.
  31. Schreiber S, Fedorak RN, Nielsen OH, et al. Safety and efficacy of recombinant human interleukin 10 in chronic active Crohn's disease. Crohn's Disease IL-10 Cooperative Study Group. Gastroenterology 2000; 119:1461.
  32. Fedorak RN, Gangl A, Elson CO, et al. Recombinant human interleukin 10 in the treatment of patients with mild to moderately active Crohn's disease. The Interleukin 10 Inflammatory Bowel Disease Cooperative Study Group. Gastroenterology 2000; 119:1473.
  33. Steidler L, Hans W, Schotte L, et al. Treatment of murine colitis by Lactococcus lactis secreting interleukin-10. Science 2000; 289:1352.
  34. Braat H, Rottiers P, Hommes DW, et al. A phase I trial with transgenic bacteria expressing interleukin-10 in Crohn's disease. Clin Gastroenterol Hepatol 2006; 4:754.
  35. Vermeire S, Rutgeerts PJ, D'Haens GR, et al. A phase 2a randomized placebo-controlled double-blind multi-center dose escalation study to evaluate the safety, tolerability, pharmacodynamics and efficacy of AG011 in patients with moderately active ulcerative colitis (abstract #46). Gastroenterology 2010; 138 Suppl 1:S9.
  36. Du X, Williams DA. Interleukin-11: review of molecular, cell biology, and clinical use. Blood 1997; 89:3897.
  37. Qiu BS, Pfeiffer CJ, Keith JC Jr. Protection by recombinant human interleukin-11 against experimental TNB-induced colitis in rats. Dig Dis Sci 1996; 41:1625.
  38. Sands BE, Bank S, Sninsky CA, et al. Preliminary evaluation of safety and activity of recombinant human interleukin 11 in patients with active Crohn's disease. Gastroenterology 1999; 117:58.
  39. Sands BE, Winston B, Salzberg B, et al. A randomized, double-masked, placebo-controlled study of recombinant human interleukin eleven (RHIL-11) in Crohn's disease subjects not receiving prednisone (abstract). Gastroenterology 1999; 116:G3518.
  40. Herrlinger KR, Witthoeft T, Raedler A, et al. Randomized, double blind controlled trial of subcutaneous recombinant human interleukin-11 versus prednisolone in active Crohn's disease. Am J Gastroenterol 2006; 101:793.
  41. Panés J, Sandborn WJ, Schreiber S, et al. Tofacitinib for induction and maintenance therapy of Crohn's disease: results of two phase IIb randomised placebo-controlled trials. Gut 2017; 66:1049.
  42. Sandborn WJ, Ghosh S, Panes J, et al. A phase 2 study of tofacitinib, an oral Janus kinase inhibitor, in patients with Crohn's disease. Clin Gastroenterol Hepatol 2014; 12:1485.
  43. Vermeire S, Schreiber S, Petryka R, et al. Clinical remission in patients with moderate-to-severe Crohn's disease treated with filgotinib (the FITZROY study): results from a phase 2, double-blind, randomised, placebo-controlled trial. Lancet 2017; 389:266.
  44. http://www.glpg.com/docs/view/58349050acf95-en (Accessed on March 13, 2017).
  45. Hommes DW, Targan SR, Dignass A, et al. Visilizumab therapy in subjects with moderate-to-severe, refractory Crohn's disease. Gastroenterology 2007; 132:A157.
  46. Abreu MT, Von Tirpitz C, Mannon PJ, et al. Extracorporeal photoimmune therapy for refractory moderately active Crohn's disease: a multicenter, open-label study. Gastroenterology 2007; 132:A157.
  47. Baumgart DC, Lowder JN, Targan SR, et al. Transient cytokine-induced liver injury following administration of the humanized anti-CD3 antibody visilizumab (HuM291) in Crohn's disease. Am J Gastroenterol 2009; 104:868.
  48. Sandborn WJ, Colombel JF, Frankel M, et al. Anti-CD3 antibody visilizumab is not effective in patients with intravenous corticosteroid-refractory ulcerative colitis. Gut 2010; 59:1485.
  49. Hanauer SB, Sandborn WJ, Sands BE, et al. A randomized placebo-controlled trial of abatacept for moderately-to-severely active Crohn's disease (CD) (abstract #649). Gastroenterology 2010; 138:S86.
  50. D'Haens G, Sandborn WJ, Colombel JF, et al. A phase II study of laquinimod in Crohn's disease. Gut 2015; 64:1227.
  51. Vermeire S, O'Byrne S, Keir M, et al. Etrolizumab as induction therapy for ulcerative colitis: a randomised, controlled, phase 2 trial. Lancet 2014; 384:309.
  52. Anti-MAdCAM-1 antibody (PF-00547659) for active refractory Crohn's disease: results of the OPERA study. Crohns Colitis 2015; :S14.
  53. Askari FK, McDonnell WM. Antisense-oligonucleotide therapy. N Engl J Med 1996; 334:316.
  54. Monteleone G, Neurath MF, Ardizzone S, et al. Mongersen, an oral SMAD7 antisense oligonucleotide, and Crohn's disease. N Engl J Med 2015; 372:1104.
  55. Malizia G, Calabrese A, Cottone M, et al. Expression of leukocyte adhesion molecules by mucosal mononuclear phagocytes in inflammatory bowel disease. Gastroenterology 1991; 100:150.
  56. Yacyshyn BR, Bowen-Yacyshyn MB, Jewell L, et al. A placebo-controlled trial of ICAM-1 antisense oligonucleotide in the treatment of Crohn's disease. Gastroenterology 1998; 114:1133.
  57. Schreiber S, Nikolaus S, Malchow H, et al. Absence of efficacy of subcutaneous antisense ICAM-1 treatment of chronic active Crohn's disease. Gastroenterology 2001; 120:1339.
  58. Yacyshyn B, Chey WY, Wedel MK, et al. A randomized, double-masked, placebo-controlled study of alicaforsen, an antisense inhibitor of intercellular adhesion molecule 1, for the treatment of subjects with active Crohn's disease. Clin Gastroenterol Hepatol 2007; 5:215.
  59. Bekker P, Schreiber S, Keshav S, et al. PROTECT-1, prospective randomized oral therapy evaluation of CCX282-B (TRAFICET-EN) in Crohn's disease. Gut 2007; 56:A23.
  60. Keshav S, Johnson D, Schall T, Bekker P. Chemokine receptor antagonist CCX282-B (Traficet-En) maintained remission of Crohn’s disease in PROTECT-1 study (abstract #647). Gastroenterology 2010; 138:S86.
  61. Buchman AL, Katz S, Fang JC, et al. Teduglutide, a novel mucosally active analog of glucagon-like peptide-2 (GLP-2) for the treatment of moderate to severe Crohn's disease. Inflamm Bowel Dis 2010; 16:962.
  62. Turner D, Zlotkin SH, Shah PS, Griffiths AM. Omega 3 fatty acids (fish oil) for maintenance of remission in Crohn's disease. Cochrane Database Syst Rev 2007; :CD006320.
  63. Feagan BG, Sandborn WJ, Mittmann U, et al. Omega-3 free fatty acids for the maintenance of remission in Crohn disease: the EPIC Randomized Controlled Trials. JAMA 2008; 299:1690.
  64. Prajapati DN, Knox JF, Emmons J, et al. Leflunomide treatment of Crohn's disease patients intolerant to standard immunomodulator therapy. J Clin Gastroenterol 2003; 37:125.
  65. Margalit M, Israeli E, Shibolet O, et al. A double-blind clinical trial for treatment of Crohn's disease by oral administration of Alequel, a mixture of autologous colon-extracted proteins: a patient-tailored approach. Am J Gastroenterol 2006; 101:561.
  66. Smith JP, Stock H, Bingaman S, et al. Low-dose naltrexone therapy improves active Crohn's disease. Am J Gastroenterol 2007; 102:820.
  67. Smith JP, Bingaman SI, Ruggiero F, et al. Therapy with the opioid antagonist naltrexone promotes mucosal healing in active Crohn's disease: a randomized placebo-controlled trial. Dig Dis Sci 2011; 56:2088.
  68. Reinisch W, Panés J, Lémann M, et al. A multicenter, randomized, double-blind trial of everolimus versus azathioprine and placebo to maintain steroid-induced remission in patients with moderate-to-severe active Crohn's disease. Am J Gastroenterol 2008; 103:2284.
  69. Slonim AE, Bulone L, Damore MB, et al. A preliminary study of growth hormone therapy for Crohn's disease. N Engl J Med 2000; 342:1633.
  70. Korzenik JR, Dieckgraefe BK. Is Crohn's disease an immunodeficiency? A hypothesis suggesting possible early events in the pathogenesis of Crohn's disease. Dig Dis Sci 2000; 45:1121.
  71. Korzenik J, Pittler A, Diekgraefe B. Immunostimulation in Crohn's disease: retreatment and maintenance therapy with GM-CSF (abstract). Gastroenterology 2002; 122 (Suppl):A423.
  72. Korzenik JR, Dieckgraefe BK. An open-labelled study of granulocyte colony-stimulating factor in the treatment of active Crohn's disease. Aliment Pharmacol Ther 2005; 21:391.
  73. Korzenik JR, Dieckgraefe BK, Valentine JF, et al. Sargramostim for active Crohn's disease. N Engl J Med 2005; 352:2193.
  74. Dieckgraefe BK, Korzenik JR. Treatment of active Crohn's disease with recombinant human granulocyte-macrophage colony-stimulating factor. Lancet 2002; 360:1478.
  75. Roth L, Macdonald JK, McDonald JW, Chande N. Sargramostim (GM-CSF) for induction of remission in Crohn's disease. Cochrane Database Syst Rev 2011; :CD008538.
  76. Morgan KL. Johne's and Crohn's. Chronic inflammatory bowel diseases of infectious aetiology? Lancet 1987; 1:1017.
  77. Burnham WR, Lennard-Jones JE, Stanford JL, Bird RG. Mycobacteria as a possible cause of inflammatory bowel disease. Lancet 1978; 2:693.
  78. Feller M, Huwiler K, Stephan R, et al. Mycobacterium avium subspecies paratuberculosis and Crohn's disease: a systematic review and meta-analysis. Lancet Infect Dis 2007; 7:607.
  79. Hulten K, El-Zimaity HM, Karttunen TJ, et al. Detection of Mycobacterium avium subspecies paratuberculosis in Crohn's diseased tissues by in situ hybridization. Am J Gastroenterol 2001; 96:1529.
  80. Sechi LA, Scanu AM, Molicotti P, et al. Detection and Isolation of Mycobacterium avium subspecies paratuberculosis from intestinal mucosal biopsies of patients with and without Crohn's disease in Sardinia. Am J Gastroenterol 2005; 100:1529.
  81. Autschbach F, Eisold S, Hinz U, et al. High prevalence of Mycobacterium avium subspecies paratuberculosis IS900 DNA in gut tissues from individuals with Crohn's disease. Gut 2005; 54:944.
  82. Bentley RW, Keenan JI, Gearry RB, et al. Incidence of Mycobacterium avium subspecies paratuberculosis in a population-based cohort of patients with Crohn's disease and control subjects. Am J Gastroenterol 2008; 103:1168.
  83. Suenaga K, Yokoyama Y, Nishimori I, et al. Serum antibodies to Mycobacterium paratuberculosis in patients with Crohn's disease. Dig Dis Sci 1999; 44:1202.
  84. Naser SA, Ghobrial G, Romero C, Valentine JF. Culture of Mycobacterium avium subspecies paratuberculosis from the blood of patients with Crohn's disease. Lancet 2004; 364:1039.
  85. Parrish NM, Radcliff RP, Brey BJ, et al. Absence of mycobacterium avium subsp. paratuberculosis in Crohn's patients. Inflamm Bowel Dis 2009; 15:558.
  86. Lowry PW, Sandborn WJ, Lipsky JJ. Mycophenolate mofetil for Crohn's disease? Lancet 1999; 354:3.
  87. Elliott PR, Burnham WR, Berghouse LM, et al. Sulphadoxine-pyrimethamine therapy in Crohn's disease. Digestion 1982; 23:132.
  88. Graham DY, Al-Assi MT, Robinson M. Prolonged remission in Crohn's disease following therapy for Mycobacterium paratuberculosis infection (abstract). Gastroenterology 1995; 108:A826.
  89. Afdhal NH, Long A, Lennon J, et al. Controlled trial of antimycobacterial therapy in Crohn's disease. Clofazimine versus placebo. Dig Dis Sci 1991; 36:449.
  90. Kelleher D, O'Brien S, Weir DG. Preliminary trial of clofazimine in chronic inflammatory bowel disease (abstract). Gut 1982; 23:A449.
  91. Prantera C, Kohn A, Mangiarotti R, et al. Antimycobacterial therapy in Crohn's disease: results of a controlled, double-blind trial with a multiple antibiotic regimen. Am J Gastroenterol 1994; 89:513.
  92. Shaffer JL, Hughes S, Linaker BD, et al. Controlled trial of rifampicin and ethambutol in Crohn's disease. Gut 1984; 25:203.
  93. Swift GL, Srivastava ED, Stone R, et al. Controlled trial of anti-tuberculous chemotherapy for two years in Crohn's disease. Gut 1994; 35:363.
  94. Borgaonkar M, MacIntosh D, Fardy J, Simms L. Anti-tuberculous therapy for maintaining remission of Crohn's disease. Cochrane Database Syst Rev 2000; :CD000299.
  95. Borgaonkar MR, MacIntosh DG, Fardy JM. A meta-analysis of antimycobacterial therapy for Crohn's disease. Am J Gastroenterol 2000; 95:725.
  96. Selby W, Pavli P, Crotty B, et al. Two-year combination antibiotic therapy with clarithromycin, rifabutin, and clofazimine for Crohn's disease. Gastroenterology 2007; 132:2313.
  97. Summers RW, Elliott DE, Urban JF Jr, et al. Trichuris suis therapy in Crohn's disease. Gut 2005; 54:87.
  98. Croese J, O'neil J, Masson J, et al. A proof of concept study establishing Necator americanus in Crohn's patients and reservoir donors. Gut 2006; 55:136.
  99. Söderholm JD, Malm C, Juliusson G, Sjödahl R. Long-term endoscopic remission of crohn disease after autologous stem cell transplantation for acute myeloid leukaemia. Scand J Gastroenterol 2002; 37:613.
  100. Kashyap A, Forman SJ. Autologous bone marrow transplantation for non-Hodgkin's lymphoma resulting in long-term remission of coincidental Crohn's disease. Br J Haematol 1998; 103:651.
  101. Lopez-Cubero SO, Sullivan KM, McDonald GB. Course of Crohn's disease after allogeneic marrow transplantation. Gastroenterology 1998; 114:433.
  102. Oyama Y, Craig RM, Traynor AE, et al. Autologous hematopoietic stem cell transplantation in patients with refractory Crohn's disease. Gastroenterology 2005; 128:552.
  103. Burt RK, Craig RM, Milanetti F, et al. Autologous nonmyeloablative hematopoietic stem cell transplantation in patients with severe anti-TNF refractory Crohn disease: long-term follow-up. Blood 2010; 116:6123.
  104. Hasselblatt P, Drognitz K, Potthoff K, et al. Remission of refractory Crohn's disease by high-dose cyclophosphamide and autologous peripheral blood stem cell transplantation. Aliment Pharmacol Ther 2012; 36:725.
  105. Duijvestein M, Vos AC, Roelofs H, et al. Autologous bone marrow-derived mesenchymal stromal cell treatment for refractory luminal Crohn's disease: results of a phase I study. Gut 2010; 59:1662.
  106. 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; 60:788.
  107. 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; 149:918.
  108. 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. Lancet 2016; 388:1281.
  109. Ayabe T, Ashida T, Taniguchi M, et al. A pilot study of centrifugal leukocyte apheresis for corticosteroid-resistant active ulcerative colitis. Intern Med 1997; 36:322.
  110. Kawamura A, Saitoh M, Yonekawa M, et al. New technique of leukocytapheresis by the use of nonwoven polyester fiber filter for inflammatory bowel disease. Ther Apher 1999; 3:334.
  111. Reinisch W, Nahavandi H, Santella R, et al. Extracorporeal photochemotherapy in patients with steroid-dependent Crohn's disease: a prospective pilot study. Aliment Pharmacol Ther 2001; 15:1313.
  112. Sands BE, Katz S, Wolf DC, et al. A randomised, double-blind, sham-controlled study of granulocyte/monocyte apheresis for moderate to severe Crohn's disease. Gut 2013; 62:1288.
  113. Lindsay JO, Whelan K, Stagg AJ, et al. Clinical, microbiological, and immunological effects of fructo-oligosaccharide in patients with Crohn's disease. Gut 2006; 55:348.
  114. Benjamin JL, Hedin CR, Koutsoumpas A, et al. Randomised, double-blind, placebo-controlled trial of fructo-oligosaccharides in active Crohn's disease. Gut 2011; 60:923.