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Novel Therapies and Treatment Strategies for Patients with Inflammatory Bowel Disease

  • Inflammatory Bowel Disease (G Lichtenstein, Section Editor)
  • Published:
Current Treatment Options in Gastroenterology Aims and scope Submit manuscript

Abstract

Purpose of review

This article reviews current treatment options and strategies and provides an update on the status of drug development programs of new therapeutic agents for inflammatory bowel diseases (IBD).

Recent findings

In the past two decades, tumor necrosis factor antagonist therapy has given clinicians better treatment options. However, not all patients respond to induction therapy with these agents, and of those initially responding, up to 40% ultimately lose response due to suboptimal drug exposure (e.g., caused by immunogenicity), side effects, or other poorly characterized mechanisms. Recently, additional therapies, such as vedolizumab, an integrin blocker that prevents T cell trafficking to the gut, and ustekinumab, an antibody blocking the common p40 subunit of interleukin (IL)-12 and 23, were introduced to the market. In addition, other agents including novel anti-trafficking therapies (e.g., anti-β7 and sphingosine-1-phosphate receptor modulators), antibodies against p19 (unique to IL-23), and small molecules including Janus kinase inhibitors are under investigation in phase II and III trials.

Furthermore, the management of IBD has evolved from targeting control of symptoms to suppression of mucosal inflammation. This shift in thinking has been accompanied by the early use of highly effective therapy in poor prognosis patients, accelerated treatment escalation and utilization of a treat to target paradigm approach, and adoption of therapeutic drug monitoring.

Summary

The treatment landscape for IBD is rapidly evolving with the recent approval of novel biologics as well as several other agents in late phase of clinical development. Moreover, we have started to use agents more intelligently with a focus on risk stratification and early use of highly effective therapy in high-risk patients, treat to target using patient-reported outcomes (PROs), biomarkers, endoscopy, and therapeutic drug monitoring.

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References and Recommended Reading

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. Abraham C, Cho JH. Inflammatory bowel disease. N Engl J Med. 2009;361(21):2066–78.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Peyrin-Biroulet L, Loftus EV Jr, Colombel JF, Sandborn WJ. Long-term complications, extraintestinal manifestations, and mortality in adult Crohn’s disease in population-based cohorts. Inflamm Bowel Dis. 2011;17(1):471–8.

    Article  PubMed  Google Scholar 

  3. Van Deventer SJ. Tumour necrosis factor and Crohn’s disease. Gut. 1997;40(4):443–8.

    Article  PubMed  PubMed Central  Google Scholar 

  4. •• Peyrin-Biroulet L, Sandborn W, Sands BE, Reinisch W, Bemelman W, Bryant RV, et al. Selecting therapeutic targets in inflammatory bowel disease (STRIDE): determining therapeutic goals for treat-to-target. Am J Gastroenterol. 2015;110(9):1324–38. This article provides evidence- and consensus-based recommendations for selecting the goals for treat-to-target strategies in patients with IBD.

    Article  CAS  PubMed  Google Scholar 

  5. Wang Y, Parker CE, Bhanji T, Feagan BG, JK MD. Oral 5-aminosalicylic acid for induction of remission in ulcerative colitis. Cochrane Database Syst Rev. 2016;4:CD000543.

    PubMed  Google Scholar 

  6. Wang Y, Parker CE, Feagan BG, MacDonald JK. Oral 5-aminosalicylic acid for maintenance of remission in ulcerative colitis. Cochrane Database Syst Rev. 2016;(5):Cd000544.

  7. Lim WC, Wang Y, JK MD, Hanauer S. Aminosalicylates for induction of remission or response in Crohn’s disease. Cochrane Database Syst Rev. 2016;7:CD008870.

    PubMed  Google Scholar 

  8. Sherlock ME, Seow CH, Steinhart AH, Griffiths AM. Oral budesonide for induction of remission in ulcerative colitis. Cochrane Database Syst Rev. 2010;10:CD007698.

    Google Scholar 

  9. Sandborn WJ, Travis S, Moro L, Jones R, Gautille T, Bagin R, et al. Once-daily budesonide MMX(R) extended-release tablets induce remission in patients with mild to moderate ulcerative colitis: results from the CORE I study. Gastroenterology. 2012;143(5):1218–26 e1–2.

    Article  CAS  PubMed  Google Scholar 

  10. Travis SP, Danese S, Kupcinskas L, Alexeeva O, D’haens G, Gibson PR, et al. Once-daily budesonide MMX in active, mild-to-moderate ulcerative colitis: results from the randomised CORE II study. Gut. 2014;63(3):433–41.

    Article  CAS  PubMed  Google Scholar 

  11. Lichtenstein GR, Bengtsson B, Hapten-White L, Rutgeerts P. Oral budesonide for maintenance of remission of Crohn’s disease: a pooled safety analysis. Aliment Pharmacol Ther. 2009;29(6):643–53.

    Article  CAS  PubMed  Google Scholar 

  12. Waljee AK, Rogers MA, Lin P, Singal AG, Stein JD, Marks RM, et al. Short term use of oral corticosteroids and related harms among adults in the United States: population based cohort study. BMJ. 2017;357:j1415.

    Article  PubMed  Google Scholar 

  13. Benchimol EI, Seow CH, Steinhart AH, Griffiths AM. Traditional corticosteroids for induction of remission in Crohn’s disease. Cochrane Database Syst Rev. 2008;2:CD006792.

    Google Scholar 

  14. D’Haens G, Baert F, van Assche G, Caenepeel P, Vergauwe P, Tuynman H, et al. Early combined immunosuppression or conventional management in patients with newly diagnosed Crohn’s disease: an open randomised trial. Lancet. 2008;371(9613):660–7.

    Article  PubMed  Google Scholar 

  15. JW MD, Tsoulis DJ, Macdonald JK, Feagan BG. Methotrexate for induction of remission in refractory Crohn’s disease. Cochrane Database Syst Rev. 2012;12:CD003459.

    Google Scholar 

  16. Feagan BG, Rochon J, Fedorak RN, Irvine EJ, Wild G, Sutherland L, et al. Methotrexate for the treatment of Crohn’s disease. The North American Crohn’s Study Group Investigators. N Engl J Med. 1995;332(5):292–7.

    Article  CAS  PubMed  Google Scholar 

  17. Soon SY, Ansari A, Yaneza M, Raoof S, Hirst J, Sanderson JD. Experience with the use of low-dose methotrexate for inflammatory bowel disease. Eur J Gastroenterol Hepatol. 2004;16(9):921–6.

    Article  CAS  PubMed  Google Scholar 

  18. Panés J, López-SanRomán A, Bermejo F, García-Sánchez V, Esteve M, Torres Y, et al. Early azathioprine therapy is no more effective than placebo for newly diagnosed Crohn’s disease. Gastroenterology. 2013;145(4):766–74.e1.

    Article  PubMed  Google Scholar 

  19. Cosnes J, Bourrier A, Laharie D, Nahon S, Bouhnik Y, Carbonnel F, et al. Early administration of azathioprine vs conventional management of Crohn’s Disease: a randomized controlled trial. Gastroenterology. 2013;145(4):758–65.e2. quiz e14–5

  20. Vande Casteele N, Herfarth H, Katz J, Falck-Ytter Y, Singh S. American Gastroenterological Association Institute technical review on the role of therapeutic drug monitoring in the management of inflammatory bowel diseases. Gastroenterology. 2017;153(3):835–57. e6

  21. Lichtenstein GR, Feagan BG, Cohen RD, Salzberg BA, Diamond RH, Langholff W, et al. Drug therapies and the risk of malignancy in Crohn’s disease: results from the TREAT Registry. Am J Gastroenterol. 2014;109(2):212–23.

    Article  CAS  PubMed  Google Scholar 

  22. Kotlyar DS, Lewis JD, Beaugerie L, Tierney A, Brensinger CM, Gisbert JP, et al. Risk of lymphoma in patients with inflammatory bowel disease treated with azathioprine and 6-mercaptopurine: a meta-analysis. Clin Gastroenterol Hepatol. 2015;13(5):847–58 e4.

    Article  CAS  PubMed  Google Scholar 

  23. Smith MA, Irving PM, Marinaki AM, Sanderson JD. Review article: malignancy on thiopurine treatment with special reference to inflammatory bowel disease. Aliment Pharmacol Ther. 2010;32(2):119–30.

    Article  CAS  PubMed  Google Scholar 

  24. Hanauer SB, Feagan BG, Lichtenstein GR, Mayer LF, Schreiber S, Colombel JF, et al. Maintenance infliximab for Crohn’s disease: the ACCENT I randomised trial. Lancet. 2002;359(9317):1541–9.

    Article  CAS  PubMed  Google Scholar 

  25. Schreiber S, Khaliq-Kareemi M, Lawrance IC, Thomsen OO, Hanauer SB, McColm J, et al. Maintenance therapy with certolizumab pegol for Crohn’s disease. N Engl J Med. 2007;357(3):239–50.

    Article  CAS  PubMed  Google Scholar 

  26. Colombel JF, Sandborn WJ, Rutgeerts P, Enns R, Hanauer SB, Panaccione R, et al. Adalimumab for maintenance of clinical response and remission in patients with Crohn’s disease: the CHARM trial. Gastroenterology. 2007;132(1):52–65.

    Article  CAS  PubMed  Google Scholar 

  27. Sandborn WJ, Feagan BG, Marano C, Zhang H, Strauss R, Johanns J, et al. Subcutaneous golimumab induces clinical response and remission in patients with moderate-to-severe ulcerative colitis. Gastroenterology. 2014;146(1):85–95. quiz e14–5

  28. Baert F, Moortgat L, Van Assche G, Caenepeel P, Vergauwe P, De Vos M, et al. Mucosal healing predicts sustained clinical remission in patients with early-stage Crohn’s disease. Gastroenterology. 2010;138(2):463–8. quiz e10–1

  29. Behm BW, Bickston SJ. Tumor necrosis factor-alpha antibody for maintenance of remission in Crohn’s disease. Cochrane Database Syst Rev. 2008;1:CD006893.

    Google Scholar 

  30. Danese S, Fiorino G, Reinisch W. Review article: Causative factors and the clinical management of patients with Crohn’s disease who lose response to anti-TNF-alpha therapy. Aliment Pharmacol Ther. 2011;34(1):1–10.

    Article  CAS  PubMed  Google Scholar 

  31. Singh JA, Wells GA, Christensen R, Tanjong Ghogomu E, Maxwell L, Macdonald JK, et al. Adverse effects of biologics: a network meta-analysis and Cochrane overview. Cochrane Database Syst Rev. 2011;2:CD008794.

    Google Scholar 

  32. Yoo DH, Hrycaj P, Miranda P, Ramiterre E, Piotrowski M, Shevchuk S, et al. A randomised, double-blind, parallel-group study to demonstrate equivalence in efficacy and safety of CT-P13 compared with innovator infliximab when coadministered with methotrexate in patients with active rheumatoid arthritis: the PLANETRA study. Ann Rheum Dis. 2013;72(10):1613–20.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Park W, Hrycaj P, Jeka S, Kovalenko V, Lysenko G, Miranda P, et al. A randomised, double-blind, multicentre, parallel-group, prospective study comparing the pharmacokinetics, safety, and efficacy of CT-P13 and innovator infliximab in patients with ankylosing spondylitis: the PLANETAS study. Ann Rheum Dis. 2013;72(10):1605–12.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. •• Jorgensen KK, Olsen IC, Goll GL, Lorentzen M, Bolstad N, Haavardsholm EA, et al. Switching from originator infliximab to biosimilar CT-P13 compared with maintained treatment with originator infliximab (NOR-SWITCH): a 52-week, randomised, double-blind, non-inferiority trial. Lancet. 2017;389(10086):2304–16. First prospective randomized trial on switching from originator infliximab to biosimilar.

    Article  PubMed  Google Scholar 

  35. Khanna R, Zou G. Is a biosimilar interchangeable with an originator? Gastroenterology. 2017;153(4):1160–2.

    Article  PubMed  Google Scholar 

  36. FDA. Considerations in demonstrating interchangeability with a reference product. 2017.

  37. Bloomgren G, Richman S, Hotermans C, Subramanyam M, Goelz S, Natarajan A, et al. Risk of natalizumab-associated progressive multifocal leukoencephalopathy. N Engl J Med. 2012;366(20):1870–80.

    Article  CAS  PubMed  Google Scholar 

  38. Berlin C, Berg EL, Briskin MJ, Andrew DP, Kilshaw PJ, Holzmann B, et al. Alpha 4 beta 7 integrin mediates lymphocyte binding to the mucosal vascular addressin MAdCAM-1. Cell. 1993;74(1):185–95.

    Article  CAS  PubMed  Google Scholar 

  39. Feagan BG, Rutgeerts P, Sands BE, Hanauer S, Colombel JF, Sandborn WJ, et al. Vedolizumab as induction and maintenance therapy for ulcerative colitis. N Engl J Med. 2013;369(8):699–710.

    Article  CAS  PubMed  Google Scholar 

  40. Sandborn WJ, Feagan BG, Rutgeerts P, Hanauer S, Colombel JF, Sands BE, et al. Vedolizumab as induction and maintenance therapy for Crohn’s disease. N Engl J Med. 2013;369(8):711–21.

    Article  CAS  PubMed  Google Scholar 

  41. Sands BE, Feagan BG, Rutgeerts P, Colombel JF, Sandborn WJ, Sy R, et al. Effects of vedolizumab induction therapy for patients with Crohn’s disease in whom tumor necrosis factor antagonist treatment had failed. Gastroenterology. 2014;147(3):618–27 e3.

    Article  CAS  PubMed  Google Scholar 

  42. Khanna R, Zou G, Stitt L, Feagan BG, Sandborn WJ, Rutgeerts P, et al. Responsiveness of endoscopic indices of disease activity for Crohn’s disease. Am J Gastroenterol. 2017;

  43. Duerr RH, Taylor KD, Brant SR, Rioux JD, Silverberg MS, Daly MJ, et al. A genome-wide association study identifies IL23R as an inflammatory bowel disease gene. Science. 2006;314(5804):1461–3.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Wang X, Wu T, Zhou F, Liu S, Zhou R, Zhu S, et al. IL12p40 regulates functional development of human CD4+ T cells: enlightenment by the elevated expressions of IL12p40 in patients with inflammatory bowel diseases. Medicine (Baltimore). 2015;94(10):e613.

    Article  CAS  Google Scholar 

  45. Maxwell JR, Zhang Y, Brown WA, Smith CL, Byrne FR, Fiorino M, et al. Differential roles for interleukin-23 and interleukin-17 in intestinal immunoregulation. Immunity. 2015;43(4):739–50.

    Article  CAS  PubMed  Google Scholar 

  46. •• Feagan BG, Sandborn WJ, Gasink C, Jacobstein D, Lang Y, Friedman JR, et al. Ustekinumab as induction and maintenance therapy for Crohn’s disease. N Engl J Med. 2016;375(20):1946–60. Phase III results on ustekinumab for CD.

    Article  CAS  PubMed  Google Scholar 

  47. • Gottlieb AB, Kalb RE, Langley RG, Krueger GG, de Jong EM, Guenther L, et al. Safety observations in 12,095 patients with psoriasis enrolled in an international registry (PSOLAR): experience with infliximab and other systemic and biologic therapies. J Drugs Dermatol. 2014;13(12):1441–8. Safety observations obtained in an international registry (PSOLAR) concerning biologic therapy.

    CAS  PubMed  Google Scholar 

  48. Papp KA, Griffiths CE, Gordon K, Lebwohl M, Szapary PO, Wasfi Y, et al. Long-term safety of ustekinumab in patients with moderate-to-severe psoriasis: final results from 5 years of follow-up. Br J Dermatol. 2013;168(4):844–54.

    Article  CAS  PubMed  Google Scholar 

  49. Tillack C, Ehmann LM, Friedrich M, Laubender RP, Papay P, Vogelsang H, et al. Anti-TNF antibody-induced psoriasiform skin lesions in patients with inflammatory bowel disease are characterised by interferon-gamma-expressing Th1 cells and IL-17A/IL-22-expressing Th17 cells and respond to anti-IL-12/IL-23 antibody treatment. Gut. 2014;63(4):567–77.

    Article  CAS  PubMed  Google Scholar 

  50. Deepak P, Sandborn WJ. Ustekinumab and anti-interleukin-23 agents in Crohn’s disease. Gastroenterol Clin N Am. 2017;46(3):603–26.

    Article  Google Scholar 

  51. Thomas S, Baumgart DC. Targeting leukocyte migration and adhesion in Crohn’s disease and ulcerative colitis. Inflammopharmacology. 2012;20(1):1–18.

    Article  CAS  PubMed  Google Scholar 

  52. •• Vermeire S, O’Byrne S, Keir M, Williams M, Lu TT, Mansfield JC, et al. Etrolizumab as induction therapy for ulcerative colitis: a randomised, controlled, phase 2 trial. Lancet. 2014;384(9940):309–18. Phase II results on etroluzimab for UC.

    Article  CAS  PubMed  Google Scholar 

  53. Mullershausen F, Zecri F, Cetin C, Billich A, Guerini D, Seuwen K. Persistent signaling induced by FTY720-phosphate is mediated by internalized S1P1 receptors. Nat Chem Biol. 2009;5(6):428–34.

    Article  CAS  PubMed  Google Scholar 

  54. Cohen JA, Barkhof F, Comi G, Hartung HP, Khatri BO, Montalban X, et al. Oral fingolimod or intramuscular interferon for relapsing multiple sclerosis. N Engl J Med. 2010;362(5):402–15.

    Article  CAS  PubMed  Google Scholar 

  55. Camm J, Hla T, Bakshi R, Brinkmann V. Cardiac and vascular effects of fingolimod: mechanistic basis and clinical implications. Am Heart J. 2014;168(5):632–44.

    Article  CAS  PubMed  Google Scholar 

  56. •• Sandborn WJ, Feagan BG, Wolf DC, D’Haens G, Vermeire S, Hanauer SB, et al. Ozanimod induction and maintenance treatment for ulcerative colitis. N Engl J Med. 2016;374(18):1754–62. Phase II results on ozanimod for UC.

    Article  CAS  PubMed  Google Scholar 

  57. Fuss IJ, Becker C, Yang Z, Groden C, Hornung RL, Heller F, et al. Both IL-12p70 and IL-23 are synthesized during active Crohn’s disease and are down-regulated by treatment with anti-IL-12 p40 monoclonal antibody. Inflammatory Bowel Diseases. 2006;12(1):9–15.

    Article  PubMed  Google Scholar 

  58. Coskun M, Vermeire S, Nielsen OH. Novel targeted therapies for inflammatory bowel disease. Trends Pharmacol Sci. 2017;38(2):127–42.

    Article  CAS  PubMed  Google Scholar 

  59. Teng MW, Bowman EP, JJ ME, Smyth MJ, Casanova JL, Cooper AM, et al. IL-12 and IL-23 cytokines: from discovery to targeted therapies for immune-mediated inflammatory diseases. Nat Med. 2015;21(7):719–29.

    Article  CAS  PubMed  Google Scholar 

  60. •• Feagan BG, Sandborn WJ, D’Haens, G, Panes J, Kaser A, Ferrante M, 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. Phase II results on risankizumab for CD.

  61. •• Sands BE, Chen J, Feagan BG, Penney M, Rees WA, Danese S, 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(1):77–86 e6. Phase II results on brazikumab for CD.

    Article  CAS  PubMed  Google Scholar 

  62. Jostins L, Ripke S, Weersma RK, Duerr RH, DP MG, Hui KY, et al. Host-microbe interactions have shaped the genetic architecture of inflammatory bowel disease. Nature. 2012;491(7422):119–24.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Ghoreschi K, Laurence A, O’Shea JJ. Janus kinases in immune cell signaling. Immunol Rev. 2009;228(1):273–87.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Boland BS, Vermeire S. Janus kinase antagonists and other novel small molecules for the treatment of Crohn’s disease. Gastroenterol Clin N Am. 2017;46(3):627–44.

    Article  Google Scholar 

  65. •• Sandborn WJ, Su C, Sands BE, D’Haens GR, Vermeire S, Schreiber S, et al. Tofacitinib as induction and maintenance therapy for ulcerative colitis. N Engl J Med. 2017;376(18):1723–36. Phase III results on tofacitinib for UC.

    Article  CAS  PubMed  Google Scholar 

  66. •• Vermeire S, Schreiber S, Petryka R, Kuehbacher T, Hebuterne X, Roblin X, 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(10066):266–75. Phase II results on filgotinib for CD.

    Article  CAS  PubMed  Google Scholar 

  67. Sandborn WJ, Feagan BG, Panes J, D’Haens GR, Colombel JF, Zhou Q, et al. Safety and efficacy of ABT-494 (upadacitinib), an oral Jak1 inhibitor, as induction therapy in patients with Crohn’s disease: results from Celest. Gastroenterology. 152(5):S1308–S9.

  68. Peyrin-Biroulet L, Panes J, Sandborn WJ, Vermeire S, Danese S, Feagan BG, et al. Defining disease severity in inflammatory bowel diseases: current and future directions. Clin Gastroenterol Hepatol. 2016;14(3):348–54.e17.

    Article  PubMed  Google Scholar 

  69. Guizzetti L, Zou G, Khanna R, Dulai PS, Sandborn WJ, Jairath V, et al. Development of clinical prediction models for surgery and complications in Crohn’s disease. J Crohns Colitis. 2017.

  70. Beaugerie L, Seksik P, Nion-Larmurier I, Gendre JP, Cosnes J. Predictors of Crohn’s disease. Gastroenterology. 2006;130(3):650–6.

    Article  PubMed  Google Scholar 

  71. Loly C, Belaiche J, Louis E. Predictors of severe Crohn’s disease. Gastroenterol Clin N Am. 2007;132(Suppl 2):A-17.

    Google Scholar 

  72. Khanna R, Jairath V, Feagan BG. The evolution of treatment paradigms in Crohn’s disease: beyond better drugs. Gastroenterol Clin N Am. 2017;46(3):661–77.

    Article  Google Scholar 

  73. Van Assche G, Dignass A, Panes J, Beaugerie L, Karagiannis J, Allez M, et al. The second European evidence-based Consensus on the diagnosis and management of Crohn’s disease: definitions and diagnosis. J Crohns Colitis. 2010;4(1):7–27.

    Article  PubMed  Google Scholar 

  74. Yarur AJ, Strobel SG, Deshpande AR, Abreu MT. Predictors of aggressive inflammatory bowel disease. Gastroenterol Hepatol (N Y). 2011;7(10):652–9.

    Google Scholar 

  75. Solberg IC, Vatn MH, Hoie O, Stray N, Sauar J, Jahnsen J, et al. Clinical course in Crohn’s disease: results of a Norwegian population-based ten-year follow-up study. Clin Gastroenterol Hepatol. 2007;5(12):1430–8.

    Article  PubMed  Google Scholar 

  76. Jess T, Riis L, Vind I, Winther KV, Borg S, Binder V, et al. Changes in clinical characteristics, course, and prognosis of inflammatory bowel disease during the last 5 decades: a population-based study from Copenhagen, Denmark. Inflamm Bowel Dis. 2007;13(4):481–9.

    Article  PubMed  Google Scholar 

  77. Schreiber S, Reinisch W, Colombel JF, Sandborn WJ, Hommes DW, Robinson AM, et al. Subgroup analysis of the placebo-controlled CHARM trial: increased remission rates through 3 years for adalimumab-treated patients with early Crohn’s disease. J Crohns Colitis. 2013;7(3):213–21.

    Article  CAS  PubMed  Google Scholar 

  78. Colombel JF, Sandborn WJ, Reinisch W, Mantzaris GJ, Kornbluth A, Rachmilewitz D, et al. Infliximab, azathioprine, or combination therapy for Crohn’s disease. N Engl J Med. 2010;362(15):1383–95.

    Article  CAS  PubMed  Google Scholar 

  79. • Khanna R, Bressler B, Levesque BG, Zou G, Stitt LW, Greenberg GR, et al. Early combined immunosuppression for the management of Crohn’s disease (REACT): a cluster randomised controlled trial. Lancet. 2015;386(10006):1825–34. This prospective study demonstrates that although early combinedimmunosuppression (TNF antagonist and antimetabolite) was not more effective than conventional management for controlling Crohn’s disease symptoms, the risk of major adverse outcomes was lower.

    Article  PubMed  Google Scholar 

  80. Khanna R, Zou G, DHaens G, Feagan BG, Sandborn WJ, Vandervoort MK, et al. A retrospective analysis: the development of patient reported outcome measures for the assessment of Crohn’s disease activity. Aliment Pharmacol Ther. 2015;41(1):77–86.

    Article  CAS  PubMed  Google Scholar 

  81. Jairath V, Khanna R, Zou GY, Stitt L, Mosli M, Vandervoort MK, et al. Development of interim patient-reported outcome measures for the assessment of ulcerative colitis disease activity in clinical trials. Aliment Pharmacol Ther. 2015;42(10):1200–10.

    Article  CAS  PubMed  Google Scholar 

  82. Froslie KF, Jahnsen J, Moum BA, Vatn MH, Group I. Mucosal healing in inflammatory bowel disease: results from a Norwegian population-based cohort. Gastroenterology. 2007;133(2):412–22.

    Article  PubMed  Google Scholar 

  83. Colombel JF, Rutgeerts PJ, Sandborn WJ, Yang M, Camez A, Pollack PF, et al. Adalimumab induces deep remission in patients with Crohn’s disease. Clin Gastroenterol Hepatol. 2014;12(3):414–22.e5.

    Article  CAS  PubMed  Google Scholar 

  84. • Shah SC, Colombel JF, Sands BE, Narula N. Mucosal healing is associated with improved long-term outcomes of patients with ulcerative colitis: a systematic review and meta-analysis. Clin Gastroenterol Hepatol. 2016;14(9):1245–55 e8. A meta-analysis showing that mucosal healing is with long-term clinical remission, avoidance of colectomy, and corticosteroid-free clinical remission.

    Article  PubMed  Google Scholar 

  85. Colombel JF, Rutgeerts P, Reinisch W, Esser D, Wang Y, Lang Y, et al. Early mucosal healing with infliximab is associated with improved long-term clinical outcomes in ulcerative colitis. Gastroenterology. 2011;141(4):1194–201.

    Article  CAS  PubMed  Google Scholar 

  86. Bryant RV, Burger DC, Delo J, Walsh AJ, Thomas S, von Herbay A, et al. Beyond endoscopic mucosal healing in UC: histological remission better predicts corticosteroid use and hospitalisation over 6 years of follow-up. Gut. 2016;65(3):408–14.

    Article  CAS  PubMed  Google Scholar 

  87. • Christensen B, Hanauer SB, Erlich J, Kassim O, Gibson PR, Turner JR, et al. Histologic normalization occurs in ulcerative colitis and is associated with improved clinical outcomes. Clin Gastroenterol Hepatol. 2017. Histological remission better predicts lower rates of corticosteroid use and acute severe colitis requiring hospitalization, over a median of 6 years of follow-up.

  88. Mosli MH, Feagan BG, Zou G, Sandborn WJ, D’Haens G, Khanna R, et al. Development and validation of a histological index for UC. Gut. 2017;66(1):50–8.

    Article  PubMed  Google Scholar 

  89. 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(2):262–7.

    Article  PubMed  Google Scholar 

  90. Mojtahed A, Khanna R, Sandborn WJ, D’Haens GR, Feagan BG, Shackelton LM, et al. Assessment of histologic disease activity in Crohn’s disease: a systematic review. Inflamm Bowel Dis. 2014;20(11):2092–103.

    Article  PubMed  Google Scholar 

  91. Brennan GT, Melton SD, Spechler SJ, Feagins LA. Clinical implications of histologic abnormalities in ileocolonic biopsies of patients with Crohn’s disease in remission. J Clin Gastroenterol. 2017;51(1):43–8.

    Article  PubMed  Google Scholar 

  92. Solem CA, Loftus EV Jr, Tremaine WJ, Harmsen WS, Zinsmeister AR, Sandborn WJ. Correlation of C-reactive protein with clinical, endoscopic, histologic, and radiographic activity in inflammatory bowel disease. Inflammatory Bowel Disease. 2005;11(8):707–12.

    Article  Google Scholar 

  93. Mosli MH, Zou G, Garg SK, Feagan SG, MacDonald JK, Chande N, et al. C-reactive protein, fecal calprotectin, and stool lactoferrin for detection of endoscopic activity in symptomatic inflammatory bowel disease patients: a systematic review and meta-analysis. Am J Gastroenterol. 2015;110(6):802–19. quiz 20

  94. Jones J, Loftus EV Jr, Panaccione R, Chen LS, Peterson S, McConnell J, et al. Relationships between disease activity and serum and fecal biomarkers in patients with Crohn’s disease. Clin Gastroenterol Hepatol. 2008;6(11):1218–24.

    Article  PubMed  Google Scholar 

  95. • Colombel JF, Panaccione R, Bossuyt P, Lukas M, Baert F, Vanasek T, et al. Effect of tight control management on Crohn’s disease (CALM): a multicentre, randomised, controlled phase 3 trial. Lancet. 2018;390(10114):2779–89. The first study to show that timely escalation with an anti-tumor necrosis factor therapy on the basis of clinical symptoms combined with biomarkers in patients with early CD results in better clinical and endoscopic outcomes than symptom-driven decisions alone.

    Article  PubMed  Google Scholar 

  96. • Feuerstein JD, Nguyen GC, Kupfer SS, Falck-Ytter Y, Singh S, American Gastroenterological Association Institute Clinical Guidelines C. American Gastroenterological Association Institute guideline on therapeutic drug monitoring in inflammatory bowel disease. Gastroenterology. 2017;153(3):827–34. Current guideline of the American Gastroenterological Association Institute on therapeutic drug monitoring in IBD.

    Article  PubMed  Google Scholar 

  97. Coskun M, Steenholdt C, de Boer NK, Nielsen OH. Pharmacology and optimization of thiopurines and methotrexate in inflammatory bowel disease. Clin Pharmacokinet. 2016;55(3):257–74.

    Article  CAS  PubMed  Google Scholar 

  98. Bortlik M, Duricova D, Malickova K, Machkova N, Bouzkova E, Hrdlicka L, et al. Infliximab trough levels may predict sustained response to infliximab in patients with Crohn’s disease. J Crohn’s Colitis. 2013;7(9):736–43.

    Article  Google Scholar 

  99. Adedokun OJ, Sandborn WJ, Feagan BG, Rutgeerts P, Xu Z, Marano CW, et al. Association between serum concentration of infliximab and efficacy in adult patients with ulcerative colitis. Gastroenterology. 2014;147(6):1296–307 e5.

    Article  CAS  PubMed  Google Scholar 

  100. American Gastroenterological A. Therapeutic drug monitoring in inflammatory bowel disease: clinical decision support tool. Gastroenterology. 2017;153(3):858–9.

    Article  Google Scholar 

  101. Beigel F, Friedrich M, Probst C, Sotlar K, Goke B, Diegelmann J, et al. Oncostatin M mediates STAT3-dependent intestinal epithelial restitution via increased cell proliferation, decreased apoptosis and upregulation of SERPIN family members. PloS One. 2014;9(4):e93498.

    Article  PubMed  PubMed Central  Google Scholar 

  102. • West NR, Hegazy AN, Owens BMJ, Bullers SJ, Linggi B, Buonocore S, et al. Oncostatin M drives intestinal inflammation and predicts response to tumor necrosis factor-neutralizing therapy in patients with inflammatory bowel disease. Nat Med. 2017;23(5):579–89. This study shows that high expression of oncostatin M is strongly associated with failure of anti-TNF therapy.

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Authors and Affiliations

  1. Robarts Clinical Trials, San Diego, CA, USA

    Marjolijn Duijvestein MD, PhD, Robert Battat MD & Niels Vande Casteele PharmD, PhD

  2. Division of Gastroenterology, University of California San Diego, La Jolla, CA, USA

    Marjolijn Duijvestein MD, PhD, Robert Battat MD, Niels Vande Casteele PharmD, PhD & William J. Sandborn MD

  3. Academic Medical Center, Amsterdam, Netherlands

    Marjolijn Duijvestein MD, PhD & Geert R. D’Haens MD, PhD

  4. Robarts Clinical Trials, Amsterdam, Netherlands

    Geert R. D’Haens MD, PhD

  5. Robarts Clinical Trials, London, Canada

    Reena Khanna MD, Vipul Jairath MD, PhD & Brian G. Feagan MD

  6. Department of Medicine, University of Western Ontario, London, ON, Canada

    Reena Khanna MD, Vipul Jairath MD, PhD & Brian G. Feagan MD

  7. Department of Epidemiology and Biostatistics, University of Western Ontario, London, Canada

    Brian G. Feagan MD

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  1. Marjolijn Duijvestein MD, PhD
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  2. Robert Battat MD
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  3. Niels Vande Casteele PharmD, PhD
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  4. Geert R. D’Haens MD, PhD
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  5. William J. Sandborn MD
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  6. Reena Khanna MD
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  7. Vipul Jairath MD, PhD
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  8. Brian G. Feagan MD
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Corresponding author

Correspondence to Vipul Jairath MD, PhD.

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Conflict of Interest

Robert Battat declares no conflict of interest.

Marjolijn Duijvestein reports nonfinancial support from Dr. Falk Pharma and personal fees from Janssen, Merck & Co., Inc., Pfizer, and Tillotts Pharam.

Niels Vande Casteele reports personal fees from Janssen, Pfizer, Takeda, UCB Pharma, and Boehringer Ingelheim.

Geert R. D’Haens reports grants from Photophill and grants and personal fees from Abbvie, Ferring, Dr. Falk Pharma, Johnson and Johnson, Millenium/Takeda, MSD, Mundipharma, and Prometheus laboratories/Nestle.

Dr. D’Haens also received personal fees from Ablynx, Amaken, Amgen, AM Pharma, Avaxia, Biogen, BMS, Celgene, Boerhinger Ingelheim, Celltrion, Cosmo, Covidien/Medtronics, Eli Lilly, Engene, Galapagos, Genentech/Roche, GSK, Gilead, Lycera, Medimetrics, MitsubishiPharma, Nextbiotics, Novonordisk, Norgine, Otsuka, Pfizer, Protagonist, Receptos/Celgene, Salix, Sandoz, Setpoint, Shire, TEVA, Tigenix, Tillotts, Versant, and Vifor.

William J. Sandborn reports personal fees and nonfinancial support from Robarts Clinical Trials (wholey owned by Western University, London, Ontario, Canada). Dr. Sandborn has also received grants and personal fees from Prometheus Laboratories, AbbVie, Boehringer Ingelheim, Takeda, Atlantic Pharmaceuticals, Janssen, Bristol-Myers Squibb, Genentech, and Nutrition Science Partners and personal fees from Kyowa Hakko Kirin, Millennium Pharmaceuticals, Celgene Cellular Therapeutics, Santarus, Salix Pharmaceuticals, Catabasis Pharmaceuticals, Vertex Pharmaceuticals, Warner Chilcott, Gilead Sciences, Cosmo Pharmaceuticals, Ferring Pharmaceuticals, Sigmoid Biotechnologies, Tillotts Pharma, Am Pharma BV, Dr. August Wolff, Avaxia Biologics, Zyngenia, Ironwood Pharmaceuticals, Index Pharmaceuticals, Nestle, Lexicon Pharmaceuticals, UCB Pharma, Orexigen, Luitpold Pharmaceuticals, Baxter Healthcare, Ferring Research Institute, Amgen, Novo Nordisk, Mesoblast Inc., Shire, Ardelyx Inc., Actavis, Seattle Genetics, MedImmune (AstraZeneca), Actogenix NV, Lipid Therapeutics Gmbh, Eisai, Qu Biologics, Toray Industries Inc., Teva Pharmaceuticals, Eli Lilly, Chiasma, TiGenix, Adherion Therapeutics, Immune Pharmaceuticals, Celgene, Arena Pharmaceuticals, Ambrx Inc., Akros Pharma, Vascular Biogenics, Theradiag, Forward Pharma, Regeneron, Galapagos, Seres Health, Ritter Pharmaceuticals, Theravance, Palatin, and Biogen. In addition, Dr. Sandborn has a patent Topical azathioprine to treat inflammatory bowel disorders (US 5,691,343) issued, a patent Topical formulations of azathioprine to treat inflammatory bowel disorders (US 5,905,081) issued, a patent Colonic delivery of nicotine to treat inflammatory bowel disease (South African patent 97/1020; US 5,846,983, 5,889,028, and 6,166,044; Mexico patent 209,636; Europe patents 0954337 and 893,998; Hong Kong patent HK1019043; China patent ZL97192177; Czech patent 293,616; Canada patent 2,246,235) issued, a patent The use of azathioprine to treat Crohn’s disease (US 5,733,915) issued, a patent Azathioprine compositions for colonic administration (New Zealand patent 306062; Singapore patent 45647; Australia patent 707168; Czech patent 290428) issued, a patent Intestinal absorption of nicotine to treat nicotine responsive conditions (Australia patent 718052; US 6,238,689) issued, a patent The use of topical azathioprine and thioguanine to treat colorectal adenomas (US 6,166,024) issued, a patent Enema and enterically coated oral dosage forms of azathioprine (US 6,432,967) issued, a patent A pharmaceutical composition for the treatment of inflammatory bowel disease (US 7,341,741) issued, a patent Intestinal absorption of nicotine to treat nicotine responsive conditions (Canada patent 2,260,909) issued, and a patent Obesity treatment and device (US 7,803,195 B2) licensed to Enteromedics.

Reena Khanna reports personal fees from AbbVie, Janssen, Pfizer, Shire, and Takeda.

Vipul Jairath reports personal fees from Janssen, Takeda, Abbvie, Ferring, and Pfizer.

Brian G. Feagan reports grants and personal fees from AbbVie, Amgen, Astra Zeneca, Bristol-Meyers Squibb (BMS), Janssen Biotech/Centocor, JnJ/Janssen, Pfizer, Receptos, and Takeda. Dr. Feagan also reports personal fees from Actogenix, Akros, Albireo Pharma, Allergan, Avaxia Biologics Inc., Avir Pharma, Atlantic Pharma, Baxter Healthcare Corporation, Biogen Idec, Boehringer-Ingelheim, Calypso Biotech, Celgene, Elan/Biogen, EnGene, Ferring, Genentech/Roche, GiCare Pharma, Gilead, Given Imaging, GSK, Ironwood, Kyowa Kakko Kirin Co Ltd., Lilly, Lycera Biotech, Merck, Mesoblast Pharma, Millennium, Nestles, Novo Nordisk, Novartis, Prometheus Therapeutics & Diagnostics, Protagonist, Salix, Shire, Sigmoid Pharma, Synergy Pharma, Teva Pharma, TiGenix, Tillotts, UCB, Vertex, VHsquared, Wyeth, Zealand, Zyngenia, Galapagos, Inception IBD Inc., Lexicon, Vivelix Pharma, Japan Tobacco Company, Ablynx, Progenity, and NextBiotix. Dr. Feagan has also received a grant from Sanofi and is Senior Scientific Officer, Robarts Clinical Trials Inc., Western University, London, Ontario, Canada.

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This article does not contain any studies with human or animal subjects performed by any of the authors.

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This article is part of the Topical Collection on Inflammatory Bowel Disease

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Duijvestein, M., Battat, R., Vande Casteele, N. et al. Novel Therapies and Treatment Strategies for Patients with Inflammatory Bowel Disease. Curr Treat Options Gastro 16, 129–146 (2018). https://doi.org/10.1007/s11938-018-0175-1

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