Review Article | Published:

The current state of the art for biological therapies and new small molecules in inflammatory bowel disease

Mucosal Immunology (2018) | Download Citation



The emergence of biologic therapies is arguably the greatest therapeutic advance in the care of inflammatory bowel disease (IBD) to date, allowing directed treatments targeted at highly specific molecules shown to play critical roles in disease pathogenesis, with advantages in potency and selectivity. Furthermore, a large number of new biologic and small-molecule therapies in IBD targeting a variety of pathways are at various stages of development that should soon lead to a dramatic expansion in our therapeutic armamentarium. Additionally, since the initial introduction of biologics, there have been substantial advances in our understanding as to how biologics work, the practical realities of their administration, and how to enhance their efficacy and safety in the clinical setting. In this review, we will summarize the current state of the art for biological therapies in IBD, both in terms of agents available and their optimal use, as well as preview future advances in biologics and highly targeted small molecules in the IBD field.

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  1. 1.

    Fiocchi, C. Inflammatory bowel disease: etiology and pathogenesis. Gastroenterology 115, 182–205 (1998).

  2. 2.

    Ungaro, R., Mehandru, S., Allen, P. B., Peyrin-Biroulet, L. & Colombel, J. F. Ulcerative colitis. Lancet 389, 1756–1770 (2017).

  3. 3.

    Torres, J., Mehandru, S., Colombel, J. F. & Peyrin-Biroulet, L. Crohn’s disease. Lancet 389, 1741–1755 (2017).

  4. 4.

    Sandborn, W. J. The present and future of inflammatory bowel disease treatment. Gastroenterol. Hepatol. 12, 438–441 (2016).

  5. 5.

    Gomollon, F. et al. 3rd European evidence-based consensus on the diagnosis and management of Crohn’s disease 2016: part 1: diagnosis and medical management. J. Crohns Colitis 11, 3–25 (2017).

  6. 6.

    Harbord, M. et al. Third European evidence-based consensus on diagnosis and management of ulcerative colitis. Part 2: current management. J. Crohns Colitis 11, 769–784 (2017).

  7. 7.

    Kornbluth, A. Infliximab approved for use in Crohn’s disease: a report on the FDA GI Advisory Committee conference. Inflamm. Bowel Dis. 4, 328–329 (1998).

  8. 8.

    Morrow, T. & Felcone, L. H. Defining the difference: what makes biologics unique. Biotechnol. Healthc. 1, 24–29 (2004).

  9. 9.

    Neurath, M. F. & Travis, S. P. Mucosal healing in inflammatory bowel diseases: a systematic review. Gut 61, 1619–1635 (2012).

  10. 10.

    Fernandes, C., Allocca, M., Danese, S. & Fiorino, G. Progress with anti-tumor necrosis factor therapeutics for the treatment of inflammatory bowel disease. Immunotherapy 7, 175–190 (2015).

  11. 11.

    Vavricka, S. R., Scharl, M., Gubler, M. & Rogler, G. Biologics for extraintestinal manifestations of IBD. Curr. Drug Targets 15, 1064–1073 (2014).

  12. 12.

    Lichtenstein, G. R. et al. Serious infection and mortality in patients with Crohn’s disease: more than 5 years of follow-up in the TREAT registry. Am. J. Gastroenterol. 107, 1409–1422 (2012).

  13. 13.

    Nyboe Andersen, N. et al. Association between tumor necrosis factor-alpha antagonists and risk of cancer in patients with inflammatory bowel disease. JAMA 311, 2406–2413 (2014).

  14. 14.

    Lemaitre, M. et al. Association between use of thiopurines or tumor necrosis factor antagonists alone or in combination and risk of lymphoma in patients with inflammatory bowel disease. JAMA 318, 1679–1686 (2017).

  15. 15.

    Hyams, J. S. et al. Infliximab is not associated with increased risk of malignancy or hemophagocytic lymphohistiocytosis in pediatric patients with inflammatory bowel disease. Gastroenterology 152, 1901–14 e3 (2017).

  16. 16.

    Targan, S. R. et al. A short-term study of chimeric monoclonal antibody cA2 to tumor necrosis factor alpha for Crohn’s disease. Crohn’s Disease cA2 Study Group. New Engl. J. Med. 337, 1029–1035 (1997).

  17. 17.

    van Dullemen, H. M. et al. Treatment of Crohn’s disease with anti-tumor necrosis factor chimeric monoclonal antibody (cA2). Gastroenterology 109, 129–135 (1995).

  18. 18.

    Hanauer, S. B. et al. Maintenance infliximab for Crohn’s disease: the ACCENT I randomised trial. Lancet 359, 1541–1549 (2002).

  19. 19.

    Sands, B. E. et al. Infliximab maintenance therapy for fistulizing Crohn’s disease. New Engl. J. Med. 350, 876–885 (2004).

  20. 20.

    Rutgeerts, P. et al. Infliximab for induction and maintenance therapy for ulcerative colitis. New Engl. J. Med. 353, 2462–2476 (2005).

  21. 21.

    Hanauer, S. B. et al. Human anti-tumor necrosis factor monoclonal antibody (adalimumab) in Crohn’s disease: the CLASSIC-I trial. Gastroenterology 130, 323–333 (2006). quiz 591.

  22. 22.

    Colombel, J. F. et al. Adalimumab for maintenance of clinical response and remission in patients with Crohn’s disease: the CHARM trial. Gastroenterology 132, 52–65 (2007).

  23. 23.

    Rutgeerts, P. et al. Adalimumab induces and maintains mucosal healing in patients with Crohn’s disease: data from the EXTEND trial. Gastroenterology 142, 1102–11 e2 (2012).

  24. 24.

    Sandborn, W. J. et al. Adalimumab induces and maintains clinical remission in patients with moderate-to-severe ulcerative colitis. Gastroenterology 142, 257–265 (2012). e1-3.

  25. 25.

    Sandborn, W. J. et al. Certolizumab pegol for the treatment of Crohn’s disease. New Engl. J. Med. 357, 228–238 (2007).

  26. 26.

    Schreiber, S. et al. Maintenance therapy with certolizumab pegol for Crohn’s disease. New Engl. J. Med. 357, 239–250 (2007).

  27. 27.

    Hebuterne, X. et al. Endoscopic improvement of mucosal lesions in patients with moderate to severe ileocolonic Crohn’s disease following treatment with certolizumab pegol. Gut 62, 201–208 (2013).

  28. 28.

    Schreiber, S. et al. Randomised clinical trial: certolizumab pegol for fistulas in Crohn’s disease - subgroup results from a placebo-controlled study. Aliment. Pharmacol. Ther. 33, 185–193 (2011).

  29. 29.

    Sandborn, W. J. et al. Subcutaneous golimumab induces clinical response and remission in patients with moderate-to-severe ulcerative colitis. Gastroenterology 146, 85–95 (2014).

  30. 30.

    Sandborn, W. J. et al. Subcutaneous golimumab maintains clinical response in patients with moderate-to-severe ulcerative colitis. Gastroenterology 146, 96–109 e1 (2014).

  31. 31.

    Moreland, L. W. et al. Etanercept therapy in rheumatoid arthritis. A randomized, controlled trial. Ann. Intern. Med. 130, 478–486 (1999).

  32. 32.

    Van den Brande, J. M. et al. Infliximab but not etanercept induces apoptosis in lamina propria T-lymphocytes from patients with Crohn’s disease. Gastroenterology 124, 1774–1785 (2003).

  33. 33.

    Perrier, C. et al. Neutralization of membrane TNF, but not soluble TNF, is crucial for the treatment of experimental colitis. Inflamm. Bowel Dis. 19, 246–253 (2013).

  34. 34.

    Mitoma, H. et al. Infliximab induces potent anti-inflammatory responses by outside-to-inside signals through transmembrane TNF-alpha. Gastroenterology 128, 376–392 (2005).

  35. 35.

    ten Hove, T., van Montfrans, C., Peppelenbosch, M. P. & van Deventer, S. J. Infliximab treatment induces apoptosis of lamina propria T lymphocytes in Crohn’s disease. Gut 50, 206–211 (2002).

  36. 36.

    Ueda, N. et al. The cytotoxic effects of certolizumab pegol and golimumab mediated by transmembrane tumor necrosis factor alpha. Inflamm. Bowel Dis. 19, 1224–1231 (2013).

  37. 37.

    Nesbitt, A. et al. Mechanism of action of certolizumab pegol (CDP870): in vitro comparison with other anti-tumor necrosis factor alpha agents. Inflamm. Bowel Dis. 13, 1323–1332 (2007).

  38. 38.

    Butcher, E. C. & Picker, L. J. Lymphocyte homing and homeostasis. Science 272, 60–66 (1996).

  39. 39.

    Akiyama, S. K. Integrins in cell adhesion and signaling. Hum. Cell 9, 181–186 (1996).

  40. 40.

    Berlin, C. et al. alpha 4 integrins mediate lymphocyte attachment and rolling under physiologic flow. Cell 80, 413–422 (1995).

  41. 41.

    Ley, K., Rivera-Nieves, J., Sandborn, W. J. & Shattil, S. Integrin-based therapeutics: biological basis, clinical use and new drugs. Nat. Rev. Drug Discov. 15, 173–183 (2016).

  42. 42.

    Berlin, C. et al. Alpha 4 beta 7 integrin mediates lymphocyte binding to the mucosal vascular addressin MAdCAM-1. Cell 74, 185–195 (1993).

  43. 43.

    Miller, D. H. et al. A controlled trial of natalizumab for relapsing multiple sclerosis. New Engl. J. Med. 348, 15–23 (2003).

  44. 44.

    Targan, S. R. et al. Natalizumab for the treatment of active Crohn’s disease: results of the ENCORE Trial. Gastroenterology 132, 1672–1683 (2007).

  45. 45.

    Sandborn, W. J. et al. Natalizumab induction and maintenance therapy for Crohn’s disease. New Engl. J. Med. 353, 1912–1925 (2005).

  46. 46.

    Kleinschmidt-DeMasters, B. K. & Tyler, K. L. Progressive multifocal leukoencephalopathy complicating treatment with natalizumab and interferon beta-1a for multiple sclerosis. New Engl. J. Med. 353, 369–374 (2005).

  47. 47.

    Van Assche, G. et al. Progressive multifocal leukoencephalopathy after natalizumab therapy for Crohn’s disease. New Engl. J. Med. 353, 362–368 (2005).

  48. 48.

    Honey, K. The comeback kid: TYSABRI now FDA approved for Crohn disease. J. Clin. Invest. 118, 825–826 (2008).

  49. 49.

    Bellaguarda, E. et al. Prevalence of antibodies against JC virus in patients with refractory Crohn’s disease and effects of natalizumab therapy. Clin. Gastroenterol. Hepatol. 13, 1919–1925 (2015).

  50. 50.

    Kempster, S. L. & Kaser, A. alpha4beta7 integrin: beyond T cell trafficking. Gut 63, 1377–1379 (2014).

  51. 51.

    Feagan, B. G. et al. Vedolizumab as induction and maintenance therapy for ulcerative colitis. New Engl. J. Med. 369, 699–710 (2013).

  52. 52.

    Sandborn, W. J. et al. Vedolizumab as induction and maintenance therapy for Crohn’s disease. New Engl. J. Med. 369, 711–721 (2013).

  53. 53.

    Bryant, R. V., Sandborn, W. J. & Travis, S. P. Introducing vedolizumab to clinical practice: who, when, and how? J. Crohns Colitis 9, 356–366 (2015).

  54. 54.

    Colombel, J. F. et al. The safety of vedolizumab for ulcerative colitis and Crohn’s disease. Gut 66, 839–851 (2017).

  55. 55.

    Feagan, B. G. et al. Ustekinumab as induction and maintenance therapy for Crohn’s disease. New Engl. J. Med. 375, 1946–1960 (2016).

  56. 56.

    Langley, R. G. et al. Long-term efficacy and safety of ustekinumab, with and without dosing adjustment, in patients with moderate-to-severe psoriasis: results from the PHOENIX 2 study through 5 years of follow-up. Br. J. Dermatol. 172, 1371–1383 (2015).

  57. 57.

    Papp, K. et al. Safety surveillance for ustekinumab and other psoriasis treatments from the psoriasis longitudinal assessment and registry (PSOLAR). J. Drugs Dermatol. 14, 706–714 (2015).

  58. 58.

    Abraham, C., Dulai, P. S., Vermeire, S. & Sandborn, W. J. Lessons learned from trials targeting cytokine pathways in patients with inflammatory bowel diseases. Gastroenterology 152, 374–88 e4 (2017).

  59. 59.

    Lund, R. J., Chen, Z., Scheinin, J. & Lahesmaa, R. Early target genes of IL-12 and STAT4 signaling in th cells. J. Immunol. 172, 6775–6782 (2004).

  60. 60.

    Monteleone, G. et al. Interleukin 12 is expressed and actively released by Crohn’s disease intestinal lamina propria mononuclear cells. Gastroenterology 112, 1169–1178 (1997).

  61. 61.

    Yawalkar, N., Karlen, S., Hunger, R., Brand, C. U. & Braathen, L. R. Expression of interleukin-12 is increased in psoriatic skin. J. Invest Dermatol. 111, 1053–1057 (1998).

  62. 62.

    Cua, D. J. et al. Interleukin-23 rather than interleukin-12 is the critical cytokine for autoimmune inflammation of the brain. Nature 421, 744–748 (2003).

  63. 63.

    Murphy, C. A. et al. Divergent pro- and anti-inflammatory roles for IL-23 and IL-12 in joint autoimmune inflammation. J. Exp. Med. 198, 1951–1957 (2003).

  64. 64.

    Duerr, R. H. et al. A genome-wide association study identifies IL23R as an inflammatory bowel disease gene. Science 314, 1461–1463 (2006).

  65. 65.

    Oppmann, B. et al. Novel p19 protein engages IL-12p40 to form a cytokine, IL-23, with biological activities similar as well as distinct from IL-12. Immunity 13, 715–725 (2000).

  66. 66.

    Ivanov, I. I. et al. The orphan nuclear receptor RORgammat directs the differentiation program of proinflammatory IL-17 + T helper cells. Cell 126, 1121–1133 (2006).

  67. 67.

    Gaffen, S. L., Jain, R., Garg, A. V. & Cua, D. J. The IL-23-IL-17 immune axis: from mechanisms to therapeutic testing. Nat. Rev. Immunol. 14, 585–600 (2014).

  68. 68.

    Buonocore, S. et al. Innate lymphoid cells drive interleukin-23-dependent innate intestinal pathology. Nature 464, 1371–1375 (2010).

  69. 69.

    Abraham, C. & Cho, J. Interleukin-23/Th17 pathways and inflammatory bowel disease. Inflamm. Bowel Dis. 15, 1090–1100 (2009).

  70. 70.

    Lee, Y. et al. Induction and molecular signature of pathogenic TH17 cells. Nat. Immunol. 13, 991–999 (2012).

  71. 71.

    Yosef, N. et al. Dynamic regulatory network controlling TH17 cell differentiation. Nature 496, 461–468 (2013).

  72. 72.

    Ahern, P. P. et al. Interleukin-23 drives intestinal inflammation through direct activity on T cells. Immunity 33, 279–288 (2010).

  73. 73.

    Eken, A., Singh, A. K., Treuting, P. M. & Oukka, M. IL-23R + innate lymphoid cells induce colitis via interleukin-22-dependent mechanism. Mucosal Immunol. 7, 143–154 (2014).

  74. 74.

    Zenewicz, L. A. et al. Innate and adaptive interleukin-22 protects mice from inflammatory bowel disease. Immunity 29, 947–957 (2008).

  75. 75.

    Ben-Horin, S., Vande Casteele, N., Schreiber, S. & Lakatos, P. L. Biosimilars in inflammatory bowel disease: facts and fears of extrapolation. Clin. Gastroenterol. Hepatol. 14, 1685–1696 (2016).

  76. 76.

    Paramsothy, S., Cleveland, N. K., Zmeter, N. & Rubin, D. T. The role of biosimilars in inflammatory bowel disease. Gastroenterol. Hepatol. 12, 741–751 (2016).

  77. 77.

    Beck, A. Biosimilar, biobetter and next generation therapeutic antibodies. MAbs 3, 107–110 (2011).

  78. 78.

    Danese, S., Gomollon, F. & Governing, B., Operational Board of ECOO. ECCO position statement: the use of biosimilar medicines in the treatment of inflammatory bowel disease (IBD). J. Crohns Colitis 7, 586–589 (2013).

  79. 79.

    Park, S. H. et al. Post-marketing study of biosimilar infliximab (CT-P13) to evaluate its safety and efficacy in Korea. Expert Rev. Gastroenterol. Hepatol. 9(Suppl 1), 35–44 (2015).

  80. 80.

    Gecse, K. B. et al. Efficacy and safety of the biosimilar infliximab CT-P13 treatment in inflammatory bowel diseases: a prospective, multicentre, nationwide cohort. J. Crohns Colitis 10, 133–140 (2016).

  81. 81.

    Jorgensen, K. K. 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 389, 2304–2316 (2017).

  82. 82.

    Laharie, D. et al. Ciclosporin versus infliximab in patients with severe ulcerative colitis refractory to intravenous steroids: a parallel, open-label randomised controlled trial. Lancet 380, 1909–1915 (2012).

  83. 83.

    Sands, B. E., Van Assche, G., Tudor, D. & Tan, T. Y. Ne-jj Vedolizumab in combination with steroids for induction therapy in Crohn’s disease: an exploratory analysis of the GEMINI 2 and GEMINI 3 studies. J. Crohns Colitis 12, S068 (2018).

  84. 84.

    Tarabar, D. et al. Combination therapy of cyclosporine and vedolizumab is effective and safe for severe, steroid-resistant ulcerative colitis patients: a prospective study. J. Crohns Colitis 12, S065 (2018).

  85. 85.

    Tadbiri, S. et al. Impact of vedolizumab therapy on extra-intestinal manifestations in patients with inflammatory bowel disease: a multicentre cohort study nested in the OBSERV-IBD cohort. Aliment. Pharmacol. Ther. 47, 485–493 (2018).

  86. 86.

    Lichtenstein, G. R. et al. ACG Clinical Guideline: management of Crohn’s disease in adults. Am. J. Gastroenterol. 113, 481–517 (2018).

  87. 87.

    Adedokun, O. J. et al. Pharmacokinetics and exposure response relationships of ustekinumab in patients with Crohn’s disease. Gastroenterology 154, 1660–1671 (2018).

  88. 88.

    Colombel, J. F., Narula, N. & Peyrin-Biroulet, L. Management strategies to improve outcomes of patients with inflammatory bowel diseases. Gastroenterology 152, 351–61 e5 (2017).

  89. 89.

    Vermeire, S., Gils, A., Accossato, P., Lula, S. & Marren, A. Immunogenicity of biologics in inflammatory bowel disease. Ther. Adv. Gastroenterol. 11, 1756283X17750355 (2018).

  90. 90.

    Rutgeerts, P. et al. Comparison of scheduled and episodic treatment strategies of infliximab in Crohn’s disease. Gastroenterology 126, 402–413 (2004).

  91. 91.

    Hanauer, S. B. et al. Incidence and importance of antibody responses to infliximab after maintenance or episodic treatment in Crohn’s disease. Clin. Gastroenterol. Hepatol. 2, 542–553 (2004).

  92. 92.

    Stein, D. J. et al. Impact of prior irregular infliximab dosing on performance of long-term infliximab maintenance therapy in Crohn’s disease. Inflamm. Bowel Dis. 16, 1173–1179 (2010).

  93. 93.

    Mould, D. R. The pharmacokinetics of biologics: a primer. Dig. Dis. 33(Suppl 1), 61–69 (2015).

  94. 94.

    Colombel, J. F., Feagan, B. G., Sandborn, W. J., Van Assche, G. & Robinson, A. M. Therapeutic drug monitoring of biologics for inflammatory bowel disease. Inflamm. Bowel Dis. 18, 349–358 (2012).

  95. 95.

    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 153, 835–57 e6 (2017).

  96. 96.

    Yarur, A. J. et al. Higher infliximab trough levels are associated with perianal fistula healing in patients with Crohn’s disease. Aliment. Pharmacol. Ther. 45, 933–940 (2017).

  97. 97.

    Rakowsky, S., Papamichail, K. & Cheifetz, A. S. Infliximab concentration thresholds during maintenance therapy vary based on the therapeutic outcome of interest in inflammatory bowel disease. Gastroenterology 152(5 Supplement 1), S382 (2017).

  98. 98.

    Papamichael, K. & Cheifetz, A. S. Therapeutic drug monitoring in IBD: the new standard-of-care for anti-TNF therapy. Am. J. Gastroenterol. 112, 673–676 (2017).

  99. 99.

    Vande Casteele, N. et al. Trough concentrations of infliximab guide dosing for patients with inflammatory bowel disease. Gastroenterology 148, 1320–9 e3 (2015).

  100. 100.

    D’Haens, G. et al. Increasing infliximab dose based on symptoms, biomarkers, and serum drug concentrations does not increase clinical, endoscopic, or corticosteroid-free remission in patients with active luminal Crohn’s disease. Gastroenterology 154, 1343-1351 e1 (2018).

  101. 101.

    Shale, M., Kanfer, E., Panaccione, R. & Ghosh, S. Hepatosplenic T cell lymphoma in inflammatory bowel disease. Gut 57, 1639–1641 (2008).

  102. 102.

    Beaugerie, L. Lymphoma: the bete noire of the long-term use of thiopurines in adult and elderly patients with inflammatory bowel disease. Gastroenterology 145, 927–930 (2013).

  103. 103.

    Magro, F. et al. Extra-intestinal malignancies in inflammatory bowel disease: results of the 3rd ECCO Pathogenesis Scientific Workshop (III). J. Crohns Colitis 8, 31–44 (2014).

  104. 104.

    Colombel, J. F. et al. Infliximab, azathioprine, or combination therapy for Crohn’s disease. New Engl. J. Med. 362, 1383–1395 (2010).

  105. 105.

    Panaccione, R. et al. Combination therapy with infliximab and azathioprine is superior to monotherapy with either agent in ulcerative colitis. Gastroenterology 146, 392–400 e3 (2014).

  106. 106.

    Colombel, J. F. et al. Higher levels of infliximab may alleviate the need of azathioprine comedication in the treatment of patients with Crohn’s disease: a sonic post hoc analysis. Gastroenterology 152(5 Supplement 1), S37–S38 (2017).

  107. 107.

    Peyrin-Biroulet, L. et al. Selecting therapeutic targets in inflammatory bowel disease (STRIDE): determining therapeutic goals for treat-to-target. Am. J. Gastroenterol. 110, 1324–1338 (2015).

  108. 108.

    Colombel, J. F. et al. Effect of tight control management on Crohn’s disease (CALM): a multicentre, randomised, controlled phase 3 trial. Lancet 390, 2779–2789 (2018).

  109. 109.

    De Cruz, P. et al. Crohn’s disease management after intestinal resection: a randomised trial. Lancet 385, 1406–1417 (2015).

  110. 110.

    D’Haens, G. et al. Early combined immunosuppression or conventional management in patients with newly diagnosed Crohn’s disease: an open randomised trial. Lancet 371, 660–667 (2008).

  111. 111.

    Rubin, D. T., Uluscu, O. & Sederman, R. Response to biologic therapy in Crohn’s disease is improved with early treatment: an analysis of health claims data. Inflamm. Bowel Dis. 18, 2225–2231 (2012).

  112. 112.

    Danese, S., Fiorino, G., Fernandes, C. & Peyrin-Biroulet, L. Catching the therapeutic window of opportunity in early Crohn’s disease. Curr. Drug Targets 15, 1056–1063 (2014).

  113. 113.

    Romberg-Camps, M. J. et al. Influence of phenotype at diagnosis and of other potential prognostic factors on the course of inflammatory bowel disease. Am. J. Gastroenterol. 104, 371–383 (2009).

  114. 114.

    D’Haens, G. R. et al. The London Position Statement of the World Congress of Gastroenterology on Biological Therapy for IBD with the European Crohn’s and Colitis Organization: when to start, when to stop, which drug to choose, and how to predict response? Am. J. Gastroenterol. 106, 199–212 (2011). quiz 3.

  115. 115.

    Beaugerie, L. & Sokol, H. Clinical, serological and genetic predictors of inflammatory bowel disease course. World J. Gastroenterol. 18, 3806–3813 (2012).

  116. 116.

    Siegel, C. A. et al. A validated web-based tool to display individualised Crohn’s disease predicted outcomes based on clinical, serologic and genetic variables. Aliment. Pharmacol. Ther. 43, 262–271 (2016).

  117. 117.

    Torres, J. et al. Systematic review of effects of withdrawal of immunomodulators or biologic agents from patients with inflammatory bowel disease. Gastroenterology 149, 1716–1730 (2015).

  118. 118.

    Louis, E. et al. Maintenance of remission among patients with Crohn’s disease on antimetabolite therapy after infliximab therapy is stopped. Gastroenterology 142, 63–70 e5 (2012). quiz e31.

  119. 119.

    Sandborn, W. J. et al. Efficacy and safety of abrilumab (AMG 181/MEDI 7183) therapy for moderate to severe Crohn’s disease. Gastroenterology 152(5 Supplement 1), S598 (2017).

  120. 120.

    Sandborn, W. J. et al. Efficacy and safety of abrilumab in subjects with moderate to severe ulcerative colitis: results of a phase 2B, randomized, double-blind, multiple-dose, placebocontrolled study. Gastroenterology 152(5 Supplement 1), S198 (2017).

  121. 121.

    Stefanich, E. G. et al. A humanized monoclonal antibody targeting the beta7 integrin selectively blocks intestinal homing of T lymphocytes. Br. J. Pharmacol. 162, 1855–1870 (2011).

  122. 122.

    Vermeire, S. et al. Etrolizumab as induction therapy for ulcerative colitis: a randomised, controlled, phase 2 trial. Lancet 384, 309–318 (2014).

  123. 123.

    Vermeire, S. et al. Anti-MAdCAM antibody (PF-00547659) for ulcerative colitis (TURANDOT): a phase 2, randomised, double-blind, placebo-controlled trial. Lancet 390, 135–144 (2017).

  124. 124.

    Panaccione, R. et al. Briakinumab for treatment of Crohn’s disease: results of a randomized trial. Inflamm. Bowel Dis. 21, 1329–1340 (2015).

  125. 125.

    Sands, B. E. 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 153, 77–86 e6 (2017).

  126. 126.

    Feagan, B. 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 389, 1699–1709 (2017).

  127. 127.

    Yamaoka, K. et al. The Janus kinases (Jaks). Genome Biol. 5, 253 (2004).

  128. 128.

    Danese, S., Grisham, M., Hodge, J. & Telliez, J. B. JAK inhibition using tofacitinib for inflammatory bowel disease treatment: a hub for multiple inflammatory cytokines. Am. J. Physiol. Gastrointest. Liver Physiol. 310, G155–G162 (2016).

  129. 129.

    Fleischmann, R. et al. Placebo-controlled trial of tofacitinib monotherapy in rheumatoid arthritis. New Engl. J. Med. 367, 495–507 (2012).

  130. 130.

    van Vollenhoven, R. F. et al. Tofacitinib or adalimumab versus placebo in rheumatoid arthritis. New Engl. J. Med. 367, 508–519 (2012).

  131. 131.

    Sandborn, W. J. et al. Tofacitinib as induction and maintenance therapy for ulcerative colitis. New Engl. J. Med. 376, 1723–1736 (2017).

  132. 132.

    Vermeire, S. 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 389, 266–275 (2017).

  133. 133.

    Sandborn, W. J. 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 Supplement 1), S1308–S1309 (2017).

  134. 134.

    De Vries, L. C. S., Wildenberg, M. E., De Jonge, W. J. & D’Haens, G. R. The future of Janus kinase inhibitors in inflammatory bowel disease. J. Crohns Colitis 11, 885–893 (2017).

  135. 135.

    Mandala, S. et al. Alteration of lymphocyte trafficking by sphingosine-1-phosphate receptor agonists. Science 296, 346–349 (2002).

  136. 136.

    Rosen, H., Stevens, R. C., Hanson, M., Roberts, E. & Oldstone, M. B. Sphingosine-1-phosphate and its receptors: structure, signaling, and influence. Annu. Rev. Biochem. 82, 637–662 (2013).

  137. 137.

    Kappos, L. et al. A placebo-controlled trial of oral fingolimod in relapsing multiple sclerosis. New Engl. J. Med. 362, 387–401 (2010).

  138. 138.

    Sandborn, W. J. et al. Ozanimod induction and maintenance treatment for ulcerative colitis. New Engl. J. Med. 374, 1754–1762 (2016).

  139. 139.

    Houslay, M. D., Schafer, P. & Zhang, K. Y. Keynote review: phosphodiesterase-4 as a therapeutic target. Drug Discov. Today 10, 1503–1519 (2005).

  140. 140.

    Papp, K. et al. Apremilast, an oral phosphodiesterase 4 (PDE4) inhibitor, in patients with moderate to severe plaque psoriasis: results of a phase III, randomized, controlled trial (Efficacy and Safety Trial Evaluating the Effects of Apremilast in Psoriasis [ESTEEM] 1). J. Am. Acad. Dermatol. 73, 37–49 (2015).

  141. 141.

    Deeks, E. D. Apremilast: a review in psoriasis and psoriatic arthritis. Drugs 75, 1393–1403 (2015).

  142. 142.

    Danese, S. et al. Apremilast for active ulcerative colitis: a phase 2, randomised, double-blind, placebo-controlled induction study. J. Crohns Colitis 12, S004–S005 (2018).

  143. 143.

    Yan, X., Liu, Z. & Chen, Y. Regulation of TGF-beta signaling by Smad7. Acta Biochim. Biophys. Sin. 41, 263–272 (2009).

  144. 144.

    Briones-Orta, M. A., Tecalco-Cruz, A. C., Sosa-Garrocho, M., Caligaris, C. & Macias-Silva, M. Inhibitory Smad7: emerging roles in health and disease. Curr. Mol. Pharmacol. 4, 141–153 (2011).

  145. 145.

    Monteleone, G. et al. Mongersen, an oral SMAD7 antisense oligonucleotide, and Crohn’s disease. New Engl. J. Med. 372, 1104–1113 (2015).

  146. 146.

    Feagan, B. G. et al. Effects of mongersen (GED-0301) on endoscopic and clinical outcomes in patients with active Crohn’s disease. Gastroenterology 154, 61–4 e6 (2018).

  147. 147.

    Tew, G. W. et al. Association between response to etrolizumab and expression of integrin alphaE and granzyme A in colon biopsies of patients with ulcerative colitis. Gastroenterology 150, 477–87 e9 (2016).

  148. 148.

    West, N. R. et al. Oncostatin M drives intestinal inflammation and predicts response to tumor necrosis factor-neutralizing therapy in patients with inflammatory bowel disease. Nat. Med. 23, 579–589 (2017).

  149. 149.

    Ananthakrishnan, A. N. et al. Gut microbiome function predicts response to anti-integrin biologic therapy in inflammatory bowel diseases. Cell Host Microbe 21, 603–10 e3 (2017).

  150. 150.

    Gordon, K. B. et al. Long-term safety experience of ustekinumab in patients with moderate to severe psoriasis (Part II of II): results from analyses of infections and malignancy from pooled phase II and III clinical trials. J. Am. Acad. Dermatol. 66, 742–751 (2012).

  151. 151.

    Khanna, R. & Feagan, B. G. Safety of infliximab for the treatment of inflammatory bowel disease: current understanding of the potential for serious adverse events. Expert Opin. Drug Saf. 14, 987–997 (2015).

  152. 152.

    Hirten, R. P., Iacucci, M., Shah, S., Ghosh, S. & Colombel, J. F. Combining biologics in inflammatory bowel disease and other immune mediated inflammatory disorders. Clin. Gastroenterol. Hepatol. (2018).

  153. 153.

    Weinblatt, M. et al. Selective costimulation modulation using abatacept in patients with active rheumatoid arthritis while receiving etanercept: a randomised clinical trial. Ann. Rheum. Dis. 66, 228–234 (2007).

  154. 154.

    Genovese, M. C. et al. Combination therapy with etanercept and anakinra in the treatment of patients with rheumatoid arthritis who have been treated unsuccessfully with methotrexate. Arthritis Rheum. 50, 1412–1419 (2004).

  155. 155.

    Greenwald, M. W. et al. Evaluation of the safety of rituximab in combination with a tumor necrosis factor inhibitor and methotrexate in patients with active rheumatoid arthritis: results from a randomized controlled trial. Arthritis Rheum. 63, 622–632 (2011).

  156. 156.

    Hirten, R., Longman, R. S., Bosworth, B. P., Steinlauf, A. & Scherl, E. Vedolizumab and infliximab combination therapy in the treatment of Crohn’s disease. Am. J. Gastroenterol. 110, 1737–1738 (2015).

  157. 157.

    Fischer, S. et al. Long-term combination therapy with anti-TNF plus vedolizumab induces and maintains remission in therapy-refractory ulcerative colitis. Am. J. Gastroenterol. 112, 1621–1623 (2017).

  158. 158.

    Bethge, J. et al. Combination therapy with vedolizumab and etanercept in a patient with pouchitis and spondylarthritis. BMJ Open Gastroenterol. 4, e000127 (2017).

  159. 159.

    Yzet, C., Dupas, J. L. & Fumery, M. Ustekinumab and anti-TNF combination therapy in patients with inflammatory bowel disease. Am. J. Gastroenterol. 111, 748–749 (2016).

  160. 160.

    Sands, B. E. et al. Safety and tolerability of concurrent natalizumab treatment for patients with Crohn’s disease not in remission while receiving infliximab. Inflamm. Bowel Dis. 13, 2–11 (2007).

  161. 161.

    Fossiez, F. et al. T cell interleukin-17 induces stromal cells to produce proinflammatory and hematopoietic cytokines. J. Exp. Med. 183, 2593–2603 (1996).

  162. 162.

    Griffin, G. K. et al. IL-17 and TNF-alpha sustain neutrophil recruitment during inflammation through synergistic effects on endothelial activation. J. Immunol. 188, 6287–6299 (2012).

  163. 163.

    Langley, R. G. et al. Secukinumab in plaque psoriasis--results of two phase 3 trials. New Engl. J. Med. 371, 326–338 (2014).

  164. 164.

    Mease, P. J. et al. Secukinumab inhibition of interleukin-17A in patients with psoriatic arthritis. New Engl. J. Med. 373, 1329–1339 (2015).

  165. 165.

    Baeten, D. et al. Secukinumab, an interleukin-17A inhibitor, in ankylosing spondylitis. New Engl. J. Med. 373, 2534–2548 (2015).

  166. 166.

    Hueber, W. et al. Secukinumab, a human anti-IL-17A monoclonal antibody, for moderate to severe Crohn’s disease: unexpected results of a randomised, double-blind placebo-controlled trial. Gut 61, 1693–1700 (2012).

  167. 167.

    Targan, S. R. et al. A randomized, double-blind, placebo-controlled phase 2 study of brodalumab in patients with moderate-to-severe Crohn’s disease. Am. J. Gastroenterol. 111, 1599–1607 (2016).

  168. 168.

    Ogawa, A., Andoh, A., Araki, Y., Bamba, T. & Fujiyama, Y. Neutralization of interleukin-17 aggravates dextran sulfate sodium-induced colitis in mice. Clin. Immunol. 110, 55–62 (2004).

  169. 169.

    O’Connor, W. Jr. et al. A protective function for interleukin 17A in T cell-mediated intestinal inflammation. Nat. Immunol. 10, 603–609 (2009).

  170. 170.

    Maxwell, J. R. et al. Differential roles for interleukin-23 and interleukin-17 in intestinal immunoregulation. Immunity 43, 739–750 (2015).

  171. 171.

    Puel, A. et al. Chronic mucocutaneous candidiasis in humans with inborn errors of interleukin-17 immunity. Science 332, 65–68 (2011).

  172. 172.

    Colombel, J. F., Sendid, B., Jouault, T. & Poulain, D. Secukinumab failure in Crohn’s disease: the yeast connection? Gut 62, 800–801 (2013).

  173. 173.

    Whitlock, S. M. et al. Management of psoriasis in patients with inflammatory bowel disease: from the Medical Board of the National Psoriasis Foundation. J. Am. Acad. Dermatol. 78, 383–394 (2018).

  174. 174.

    Reich, K. et al. Inflammatory bowel disease among patients with psoriasis treated with ixekizumab: a presentation of adjudicated data from an integrated database of 7 randomized controlled and uncontrolled trials. J. Am. Acad. Dermatol. 76, 441–8 e2 (2017).

  175. 175.

    Gurcan, H. M. et al. A review of the current use of rituximab in autoimmune diseases. Int. Immunopharmacol. 9, 10–25 (2009).

  176. 176.

    Gerner, R. R., Moschen, A. R. & Tilg, H. Targeting T and B lymphocytes in inflammatory bowel diseases: lessons from clinical trials. Dig. Dis. 31, 328–335 (2013).

  177. 177.

    Goetz, M., Atreya, R., Ghalibafian, M., Galle, P. R. & Neurath, M. F. Exacerbation of ulcerative colitis after rituximab salvage therapy. Inflamm. Bowel Dis. 13, 1365–1368 (2007).

  178. 178.

    El Fassi, D., Nielsen, C. H., Kjeldsen, J., Clemmensen, O. & Hegedus, L. Ulcerative colitis following B lymphocyte depletion with rituximab in a patient with Graves’ disease. Gut 57, 714–715 (2008).

  179. 179.

    Varma, P., Falconer, J., Aga, A., Prince, H. M. & Pianko, S. Rituximab-induced Crohn’s disease. Scand. J. Gastroenterol. 52, 606–608 (2017).

  180. 180.

    Shahmohammadi, S. et al. A presentation of ulcerative colitis after rituximab therapy in a patient with multiple sclerosis and literature review. Mult. Scler. Relat. Disord. 22, 22–26 (2018).

  181. 181.

    Leiper, K. et al. Randomised placebo-controlled trial of rituximab (anti-CD20) in active ulcerative colitis. Gut 60, 1520–1526 (2011).

  182. 182.

    Calderon-Gomez, E. & Panes, J. Rituximab in active ulcerative colitis. Gastroenterology 142, 174–176 (2012).

  183. 183.

    Gupta, A., De Felice, K. M., Loftus, E. V. Jr & Khanna, S. Systematic review: colitis associated with anti-CTLA-4 therapy. Aliment. Pharmacol. Ther. 42, 406–417 (2015).

  184. 184.

    Schubert, D. et al. Autosomal dominant immune dysregulation syndrome in humans with CTLA-4 mutations. Nat. Med. 20, 1410–1416 (2014).

  185. 185.

    Kim, J. et al. Anti-PD-1 induced colitis: a case series of 25 patients. Gastroenterology 152(5 Supplement 1) S811 (2017).

  186. 186.

    Yanai, S., Nakamura, S. & Matsumoto, T. Nivolumab-induced colitis treated by infliximab. Clin. Gastroenterol. Hepatol. 15, e80–e81 (2017).

  187. 187.

    Uhlig, H. H. et al. The diagnostic approach to monogenic very early onset inflammatory bowel disease. Gastroenterology 147, 990–1007 e3 (2014).

  188. 188.

    Uhlig, H. H. & Muise, A. M. Clinical genomics in inflammatory bowel disease. Trends Genet. 33, 629–641 (2017).

  189. 189.

    Bader-Meunier, B. et al. Mevalonate kinase deficiency: a survey of 50 patients. Pediatrics 128, e152–e159 (2011).

  190. 190.

    Levy, M. et al. Severe early-onset colitis revealing mevalonate kinase deficiency. Pediatrics 132, e779–e783 (2013).

  191. 191.

    Lo, B. et al. Autoimmune disease. Patients with LRBA deficiency show CTLA4 loss and immune dysregulation responsive to abatacept therapy. Science 349, 436–440 (2015).

  192. 192.

    Amininejad, L. et al. Analysis of genes associated with monogenic primary immunodeficiency identifies rare variants in XIAP in patients with Crohn’s disease. Gastroenterology 154, 2165-2177 (2018).

  193. 193.

    Uhlig, H. H. & Booth, C. Inflammatory bowel disease and immune defects: a spectrum of genetic variants and clinical pathogenicity. Gastroenterology 154, 2022-2024 (2018).

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The authors like to thank Jill Gregory, Associate Director of Instructional Technology at the Icahn School of Medicine at Mount Sinai for creating the figure illustrations. This work was supported by the following grants: Mt Sinai (New York) SUCCESS fund - GCO14-0560 (JFC), Takeda Pharmaceuticals Investigator Initiated Research Grant (JFC), NIH/NIDDK R01 DK112296 (SM), Rainin Foundation Synergy Award (SM). Additionally, A.K.R. was supported by the Digestive Disease Research Foundation (DDRF).

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  1. Division of Gastroenterology, Icahn School of Medicine at Mount Sinai, New York, NY, USA

    • Sudarshan Paramsothy
    • , Adam K. Rosenstein
    • , Saurabh Mehandru
    •  & Jean-Frederic Colombel
  2. PrIISM Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA

    • Adam K. Rosenstein
    •  & Saurabh Mehandru


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S.P., S.M., and J.F.C. planned the manuscript. S.P. and A.K.R. drafted the manuscript. S.M. and J.F.C. reviewed the manuscript for its intellectual content.

Competing interests

S.P., A.K.R., and S.M. declare no competing interests. J.F.C. has served as consultant or advisory board member for AbbVie, Amgen, Boehringer-Ingelheim, Arena Pharmaceuticals, Celgene Corporation, Celltrion, Enterome, Eli Lilly, Ferring Pharmaceuticals, Genentech, Janssen and Janssen, Medimmune, Merck & Co., Nextbiotix, Novartis Pharmaceuticals Corporation, Otsuka Pharmaceutical Development & Commercialization, Inc., Pfizer, Protagonist, Second Genome, Gilead, Seres Therapeutics, Shire, Takeda, Theradiag; speaker for AbbVie, Ferring, Takeda, Celgene Corporation. He has stock options with Intestinal Biotech Development and Genefit; he has research grants from AbbVie, Takeda, Janssen and Janssen.

Corresponding author

Correspondence to Jean-Frederic Colombel.

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