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Crohn’s disease

An Author Correction to this article was published on 19 June 2020

An Author Correction to this article was published on 20 May 2020

A Publisher Correction to this article was published on 06 April 2020

This article has been updated

Abstract

Crohn’s disease is an inflammatory bowel disease that is characterized by chronic inflammation of any part of the gastrointestinal tract, has a progressive and destructive course and is increasing in incidence worldwide. Several factors have been implicated in the cause of Crohn’s disease, including a dysregulated immune system, an altered microbiota, genetic susceptibility and environmental factors, but the cause of the disease remains unknown. The onset of the disease at a young age in most cases necessitates prompt but long-term treatment to prevent disease flares and disease progression with intestinal complications. Thus, earlier, more aggressive treatment with biologic therapies or novel small molecules could profoundly change the natural history of the disease and decrease complications and the need for hospitalization and surgery. Although less invasive biomarkers are in development, diagnosis still relies on endoscopy and histological assessment of biopsy specimens. Crohn’s disease is a complex disease, and treatment should be personalized to address the underlying pathogenetic mechanism. In the future, disease management might rely on severity scores that incorporate prognostic factors, bowel damage assessment and non-invasive close monitoring of disease activity to reduce the severity of complications.

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Fig. 1: Causes of Crohn’s disease.
Fig. 2: Extraintestinal manifestations and complications in Crohn’s disease.
Fig. 3: Proposed recommendations for surveillance for colitis-associated dysplasia in patients with CD.
Fig. 4: Treatment approaches in Crohn’s disease.
Fig. 5: Factors that affect QOL domains in Crohn’s disease.

Change history

  • 19 June 2020

    An amendment to this paper has been published and can be accessed via a link at the top of the paper.

  • 20 May 2020

    An amendment to this paper has been published and can be accessed via a link at the top of the paper.

  • 06 April 2020

    An amendment to this paper has been published and can be accessed via a link at the top of the paper.

References

  1. Ng, S. C. et al. Worldwide incidence and prevalence of inflammatory bowel disease in the 21st century: a systematic review of population-based studies. Lancet 390, 2769–2778 (2018). This study provides a comprehensive analysis of the global IBD epidemiology.

    Article  Google Scholar 

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

    Article  PubMed  Google Scholar 

  3. Thia, K. T., Sandborn, W. J., Harmsen, W. S., Zinsmeister, A. R. & Loftus, E. V. Risk factors associated with progression to intestinal complications of Crohn’s disease in a population-based cohort. Gastroenterology 139, 1147–1155 (2010).

    Article  PubMed  Google Scholar 

  4. Fiorino, G., Bonifacio, C., Peyrin-Biroulet, L. & Danese, S. Preventing collateral damage in Crohn’s disease: the Lémann index. J. Crohns Colitis 10, 495–500 (2016). This study clearly shows the importance of assessing bowel damage in a very early inflammatory stage of CD. The authors demonstrate that the presence of bowel damage in early CD is associated with a worse outcome.

    Article  PubMed  PubMed Central  Google Scholar 

  5. Zeng, Z. et al. Incidence and clinical characteristics of inflammatory bowel disease in a developed region of Guangdong province, China: a prospective population-based study. J. Gastroenterol. Hepatol. 28, 1148–1153 (2013).

    Article  PubMed  Google Scholar 

  6. Zhao, J. et al. First prospective, population-based inflammatory bowel disease incidence study in mainland of China: the emergence of ‘western’ disease. Inflamm. Bowel Dis. 19, 1839–1845 (2013).

    PubMed  Google Scholar 

  7. Ng, S. C. et al. Incidence and phenotype of inflammatory bowel disease based on results from the Asia-Pacific Crohn’s and Colitis Epidemiology Study. Gastroenterology 145, 158–165.e2 (2013).

    Article  PubMed  Google Scholar 

  8. Kim, H. J. et al. Incidence and natural course of inflammatory bowel disease in Korea, 2006-2012: a nationwide population-based study. Inflamm. Bowel Dis. 21, 623–630 (2015).

    Article  PubMed  Google Scholar 

  9. Park, S. H. et al. A 30-year trend analysis in the epidemiology of inflammatory bowel disease in the Songpa-Kangdong district of Seoul, Korea in 1986–2015. J. Crohns Colitis 13, 1410–1417 (2019).

    Article  PubMed  Google Scholar 

  10. Ananthakrishnan, A. N. et al. Environmental triggers in IBD: a review of progress and evidence. Nat. Rev. Gastroenterol. Hepatol. 15, 39–49 (2018).

    Article  PubMed  Google Scholar 

  11. Bernstein, C. N. et al. Increased burden of psychiatric disorders in inflammatory bowel disease. Inflamm. Bowel Dis. 25, 360–368 (2019).

    Article  PubMed  Google Scholar 

  12. Moradkhani, A., Beckman, L. J. & Tabibian, J. H. Health-related quality of life in inflammatory bowel disease: psychosocial, clinical, socioeconomic, and demographic predictors. J. Crohns Colitis 7, 467–473 (2013).

    Article  PubMed  Google Scholar 

  13. Shah, S. C., Colombel, J.-F., Sands, B. E. & Narula, N. Systematic review with meta-analysis: mucosal healing is associated with improved long-term outcomes in Crohn’s disease. Aliment. Pharmacol. Ther. 43, 317–333 (2016).

    Article  CAS  PubMed  Google Scholar 

  14. Kaplan, G. G. & Ng, S. C. Globalisation of inflammatory bowel disease: perspectives from the evolution of inflammatory bowel disease in the UK and China. Lancet Gastroenterol. Hepatol. 1, 307–316 (2016).

    Article  PubMed  Google Scholar 

  15. Ng, S. C. et al. Geographical variability and environmental risk factors in inflammatory bowel disease. Gut 62, 630–649 (2013).

    Article  PubMed  Google Scholar 

  16. Yen, H.-H. et al. Epidemiological trend in inflammatory bowel disease in Taiwan from 2001 to 2015: a nationwide population-based study. Intest. Res. 17, 54–62 (2019).

    Article  PubMed  Google Scholar 

  17. Ng, S. C. et al. Epidemiology of inflammatory bowel disease from 1981 to 2014: results from a territory-wide population-based registry in Hong Kong. Inflamm. Bowel Dis. 22, 1954–1960 (2016).

    Article  PubMed  Google Scholar 

  18. Mansour-Ghanaei, F. et al. Epidemiologic features of inflammatory bowel disease in Guilan province, north of Iran, during 2002-2012. Middle East. J. Dig. Dis. 7, 69–74 (2015).

    PubMed  PubMed Central  Google Scholar 

  19. Linares de la Cal, J. A., Cantón, C., Hermida, C., Pérez-Miranda, M. & Maté-Jiménez, J. Estimated incidence of inflammatory bowel disease in Argentina and Panama (1987–1993). Rev. Esp. Enferm. Dig. 91, 277–286 (1999).

    CAS  PubMed  Google Scholar 

  20. Piovani, D. et al. Environmental risk factors for inflammatory bowel diseases: an umbrella review of meta-analyses. Gastroenterology 157, 647–659.e4 (2019).

    Article  PubMed  Google Scholar 

  21. Lakatos, P. L. et al. Is current smoking still an important environmental factor in inflammatory bowel diseases? Results from a population-based incident cohort. Inflamm. Bowel Dis. 19, 1010–1017 (2013).

    Article  PubMed  Google Scholar 

  22. Kondo, K. et al. The association between environmental factors and the development of Crohn’s disease with focusing on passive smoking: a multicenter case-control study in Japan. PLoS One 14, e0216429 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Ng, S. C. et al. Environmental risk factors in inflammatory bowel disease: a population-based case-control study in Asia-Pacific. Gut 64, 1063–1071 (2015).

    Article  PubMed  Google Scholar 

  24. Levine, A., Sigall Boneh, R. & Wine, E. Evolving role of diet in the pathogenesis and treatment of inflammatory bowel diseases. Gut 67, 1726–1738 (2018).

    Article  CAS  PubMed  Google Scholar 

  25. Khalili, H. et al. Adherence to a Mediterranean diet is associated with a lower risk of later-onset Crohn’s disease: results from two large prospective cohort studies. Gut https://doi.org/10.1136/gutjnl-2019-319505 (2020).

    Article  PubMed  Google Scholar 

  26. Ortizo, R. et al. Exposure to oral contraceptives increases the risk for development of inflammatory bowel disease: a meta-analysis of case-controlled and cohort studies. Eur. J. Gastroenterol. Hepatol. 29, 1064–1070 (2017).

    Article  CAS  PubMed  Google Scholar 

  27. Ananthakrishnan, A. N. et al. Aspirin, nonsteroidal anti-inflammatory drug use, and risk for Crohn disease and ulcerative colitis: a cohort study. Ann. Intern. Med. 156, 350–359 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  28. Moninuola, O. O., Milligan, W., Lochhead, P. & Khalili, H. Systematic review with meta-analysis: association between acetaminophen and nonsteroidal anti-inflammatory drugs (NSAIDs) and risk of Crohn’s disease and ulcerative colitis exacerbation. Aliment. Pharmacol. Ther. 47, 1428–1439 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Ungaro, R. et al. Statins associated with decreased risk of new onset inflammatory bowel disease. Am. J. Gastroenterol. 111, 1416–1423 (2016).

    Article  CAS  PubMed  Google Scholar 

  30. Green, N., Miller, T., Suskind, D. & Lee, D. A review of dietary therapy for IBD and a vision for the future. Nutrients 11, E947 (2019).

    Article  PubMed  CAS  Google Scholar 

  31. Halfvarson, J., Bodin, L., Tysk, C., Lindberg, E. & Järnerot, G. Inflammatory bowel disease in a Swedish twin cohort: a long-term follow-up of concordance and clinical characteristics. Gastroenterology 124, 1767–1773 (2003).

    Article  PubMed  Google Scholar 

  32. Hugot, J. P. et al. Association of NOD2 leucine-rich repeat variants with susceptibility to Crohn’s disease. Nature 411, 599–603 (2001).

    Article  CAS  PubMed  Google Scholar 

  33. Ogura, Y. et al. A frameshift mutation in NOD2 associated with susceptibility to Crohn’s disease. Nature 411, 603–606 (2001).

    Article  CAS  PubMed  Google Scholar 

  34. Yamazaki, K. et al. Single nucleotide polymorphisms in TNFSF15 confer susceptibility to Crohn’s disease. Hum. Mol. Genet. 14, 3499–3506 (2005).

    Article  CAS  PubMed  Google Scholar 

  35. Huang, H. et al. Fine-mapping inflammatory bowel disease loci to single-variant resolution. Nature 547, 173–178 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Ellinghaus, D. et al. Analysis of five chronic inflammatory diseases identifies 27 new associations and highlights disease-specific patterns at shared loci. Nat. Genet. 48, 510–518 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Jostins, L. et al. Host-microbe interactions have shaped the genetic architecture of inflammatory bowel disease. Nature 491, 119–124 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Ogura, Y. et al. Expression of NOD2 in Paneth cells: a possible link to Crohn’s ileitis. Gut 52, 1591–1597 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Sidiq, T., Yoshihama, S., Downs, I. & Kobayashi, K. S. Nod2: a critical regulator of ileal microbiota and Crohn’s disease. Front. Immunol. 7, 367 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  40. Hampe, J. et al. A genome-wide association scan of nonsynonymous SNPs identifies a susceptibility variant for Crohn disease in ATG16L1. Nat. Genet. 39, 207–211 (2007).

    Article  CAS  PubMed  Google Scholar 

  41. Liu, J. Z. et al. Association analyses identify 38 susceptibility loci for inflammatory bowel disease and highlight shared genetic risk across populations. Nat. Genet. 47, 979–986 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Hong, M. et al. Immunochip meta-analysis of inflammatory bowel disease identifies three novel loci and four novel associations in previously reported loci. J. Crohns Colitis 12, 730–741 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  43. Zhu, L. et al. IL-10 and IL-10 receptor mutations in very early onset inflammatory bowel disease. Gastroenterology Res. 10, 65–69 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Uniken Venema, W. T., Voskuil, M. D., Dijkstra, G., Weersma, R. K. & Festen, E. A. The genetic background of inflammatory bowel disease: from correlation to causality. J. Pathol. 241, 146–158 (2017).

    Article  PubMed  Google Scholar 

  45. Cleynen, I. et al. Inherited determinants of Crohn’s disease and ulcerative colitis phenotypes: a genetic association study. Lancet 387, 156–167 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  46. Peterson, L. W. & Artis, D. Intestinal epithelial cells: regulators of barrier function and immune homeostasis. Nat. Rev. Immunol. 14, 141–153 (2014).

    Article  CAS  PubMed  Google Scholar 

  47. Zeissig, S. et al. Changes in expression and distribution of claudin 2, 5 and 8 lead to discontinuous tight junctions and barrier dysfunction in active Crohn’s disease. Gut 56, 61–72 (2007).

    Article  CAS  PubMed  Google Scholar 

  48. Weber, C. R., Nalle, S. C., Tretiakova, M., Rubin, D. T. & Turner, J. R. Claudin-1 and claudin-2 expression is elevated in inflammatory bowel disease and may contribute to early neoplastic transformation. Lab. Invest. 88, 1110–1120 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Odenwald, M. A. & Turner, J. R. The intestinal epithelial barrier: a therapeutic target? Nat. Rev. Gastroenterol. Hepatol. 14, 9–21 (2017).

    Article  CAS  PubMed  Google Scholar 

  50. Wehkamp, J. et al. NOD2 (CARD15) mutations in Crohn’s disease are associated with diminished mucosal alpha-defensin expression. Gut 53, 1658–1664 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Cadwell, K. et al. A key role for autophagy and the autophagy gene Atg16l1 in mouse and human intestinal Paneth cells. Nature 456, 259–263 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Thachil, E. et al. Abnormal activation of autophagy-induced crinophagy in Paneth cells from patients with Crohn’s disease. Gastroenterology 142, 1097–1099.e4 (2012).

    Article  PubMed  Google Scholar 

  53. Zhang, Q. et al. Commensal bacteria direct selective cargo sorting to promote symbiosis. Nat. Immunol. 16, 918–926 (2015).

    Article  CAS  PubMed  Google Scholar 

  54. Kaser, A. et al. XBP1 links ER stress to intestinal inflammation and confers genetic risk for human inflammatory bowel disease. Cell 134, 743–756 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Adolph, T. E. et al. Paneth cells as a site of origin for intestinal inflammation. Nature 503, 272–276 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Tschurtschenthaler, M. et al. Defective ATG16L1-mediated removal of IRE1α drives Crohn’s disease-like ileitis. J. Exp. Med. 214, 401–422 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Willson, T. A., Jurickova, I., Collins, M. & Denson, L. A. Deletion of intestinal epithelial cell STAT3 promotes T-lymphocyte STAT3 activation and chronic colitis following acute dextran sodium sulfate injury in mice. Inflamm. Bowel Dis. 19, 512–525 (2013).

    Article  PubMed  Google Scholar 

  58. Diamanti, M. A. et al. IKKα controls ATG16L1 degradation to prevent ER stress during inflammation. J. Exp. Med. 214, 423–437 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Zhou, C., Qiu, Y. & Yang, H. CD4CD8αα IELs: they have something to say. Front. Immunol. 10, 2269 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Regner, E. H. et al. Functional intraepithelial lymphocyte changes in inflammatory bowel disease and spondyloarthritis have disease specific correlations with intestinal microbiota. Arthritis Res. Ther. 20, 149 (2018).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  61. Catalan-Serra, I., Sandvik, A. K., Bruland, T. & Andreu-Ballester, J. C. Gammadelta T cells in Crohn’s disease: a new player in the disease pathogenesis? J. Crohns Colitis 11, 1135–1145 (2017).

    Article  PubMed  Google Scholar 

  62. Hosomi, S. et al. Intestinal epithelial cell endoplasmic reticulum stress promotes MULT1 up-regulation and NKG2D-mediated inflammation. J. Exp. Med. 214, 2985–2997 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Allez, M., Skolnick, B. E., Wisniewska-Jarosinska, M., Petryka, R. & Overgaard, R. V. Anti-NKG2D monoclonal antibody (NNC0142-0002) in active Crohn’s disease: a randomised controlled trial. Gut 66, 1918–1925 (2017).

    Article  CAS  PubMed  Google Scholar 

  64. Kaser, A., Zeissig, S. & Blumberg, R. S. Inflammatory bowel disease. Annu. Rev. Immunol. 28, 573–621 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Abraham, C. & Cho, J. H. Inflammatory bowel disease. N. Engl. J. Med. 361, 2066–2078 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Ouellette, A. J. Paneth cells and innate mucosal immunity. Curr. Opin. Gastroenterol. 26, 547–553 (2010).

    Article  PubMed  Google Scholar 

  67. de Souza, H. S. P. & Fiocchi, C. Immunopathogenesis of IBD: current state of the art. Nat. Rev. Gastroenterol. Hepatol. 13, 13–27 (2016).

    Article  PubMed  CAS  Google Scholar 

  68. Uhlig, H. H. & Powrie, F. Translating immunology into therapeutic concepts for inflammatory bowel disease. Annu. Rev. Immunol. 36, 755–781 (2018).

    Article  CAS  PubMed  Google Scholar 

  69. Pazmandi, J., Kalinichenko, A., Ardy, R. C. & Boztug, K. Early-onset inflammatory bowel disease as a model disease to identify key regulators of immune homeostasis mechanisms. Immunol. Rev. 287, 162–185 (2019).

    Article  CAS  PubMed  Google Scholar 

  70. Cooney, R. et al. NOD2 stimulation induces autophagy in dendritic cells influencing bacterial handling and antigen presentation. Nat. Med. 16, 90–97 (2010).

    Article  CAS  PubMed  Google Scholar 

  71. Travassos, L. H. et al. Nod1 and Nod2 direct autophagy by recruiting ATG16L1 to the plasma membrane at the site of bacterial entry. Nat. Immunol. 11, 55–62 (2010).

    Article  CAS  PubMed  Google Scholar 

  72. Segal, A. W. The role of neutrophils in the pathogenesis of Crohn’s disease. Eur. J. Clin. Invest. 48, e12983 (2018).

    Article  PubMed  CAS  Google Scholar 

  73. Geremia, A. & Arancibia-Cárcamo, C. V. Innate lymphoid cells in intestinal inflammation. Front. Immunol. 8, 1296 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  74. Bernink, J. H. et al. Interleukin-12 and -23 control plasticity of CD127+ group 1 and group 3 innate lymphoid cells in the intestinal lamina propria. Immunity 43, 146–160 (2015).

    Article  CAS  PubMed  Google Scholar 

  75. van der Gracht, E., Zahner, S. & Kronenberg, M. When insult is added to injury: cross talk between ILCs and intestinal epithelium in IBD. Mediators Inflamm. 2016, 9765238 (2016).

    PubMed  PubMed Central  Google Scholar 

  76. Uhlig, H. H. et al. Differential activity of IL-12 and IL-23 in mucosal and systemic innate immune pathology. Immunity 25, 309–318 (2006).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  78. 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).

    Article  CAS  PubMed  Google Scholar 

  79. 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).

    Article  CAS  PubMed  Google Scholar 

  80. Sarin, R., Wu, X. & Abraham, C. Inflammatory disease protective R381Q IL23 receptor polymorphism results in decreased primary CD4+ and CD8+ human T-cell functional responses. Proc. Natl Acad. Sci. USA 108, 9560–9565 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Fantini, M. C. et al. Smad7 controls resistance of colitogenic T cells to regulatory T cell-mediated suppression. Gastroenterology 136, 1308–1316 (2009).

    Article  CAS  PubMed  Google Scholar 

  83. Lo Presti, A. et al. Fecal and mucosal microbiota profiling in irritable bowel syndrome and inflammatory bowel disease. Front. Microbiol. 10, 1655 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  84. Vich Vila, A. et al. Gut microbiota composition and functional changes in inflammatory bowel disease and irritable bowel syndrome. Sci. Transl Med. 10, eaap8914 (2018).

    Article  PubMed  CAS  Google Scholar 

  85. Pascal, V. et al. A microbial signature for Crohn’s disease. Gut 66, 813–822 (2017).

    Article  CAS  PubMed  Google Scholar 

  86. Palmela, C. et al. Adherent-invasive Escherichia coli in inflammatory bowel disease. Gut 67, 574–587 (2018).

    Article  CAS  PubMed  Google Scholar 

  87. Sokol, H. et al. Faecalibacterium prausnitzii is an anti-inflammatory commensal bacterium identified by gut microbiota analysis of Crohn disease patients. Proc. Natl Acad. Sci. USA 105, 16731–16736 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Barnich, N. & Darfeuille-Michaud, A. Adherent-invasive Escherichia coli and Crohn’s disease. Curr. Opin. Gastroenterol. 23, 16–20 (2007).

    Article  PubMed  Google Scholar 

  89. Simpson, K. W. et al. Adherent and invasive Escherichia coli is associated with granulomatous colitis in boxer dogs. Infect. Immun. 74, 4778–4792 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Yilmaz, B. et al. Microbial network disturbances in relapsing refractory Crohn’s disease. Nat. Med. 25, 323–336 (2019).

    Article  CAS  PubMed  Google Scholar 

  91. Libertucci, J. et al. Inflammation-related differences in mucosa-associated microbiota and intestinal barrier function in colonic Crohn’s disease. Am. J. Physiol. Gastrointest. Liver Physiol. 315, G420–G431 (2018).

    Article  CAS  PubMed  Google Scholar 

  92. Vieira-Silva, S. et al. Quantitative microbiome profiling disentangles inflammation- and bile duct obstruction-associated microbiota alterations across PSC/IBD diagnoses. Nat. Microbiol. 4, 1826–1831 (2019).

    Article  CAS  PubMed  Google Scholar 

  93. Norman, J. M. et al. Disease-specific alterations in the enteric virome in inflammatory bowel disease. Cell 160, 447–460 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Pérez-Brocal, V. et al. Study of the viral and microbial communities associated with Crohn’s disease: a metagenomic approach. Clin. Transl. Gastroenterol. 4, e36 (2013).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  95. Imai, T. et al. Characterization of fungal dysbiosis in Japanese patients with inflammatory bowel disease. J. Gastroenterol. 54, 149–159 (2019).

    Article  CAS  PubMed  Google Scholar 

  96. Feuerstein, J. D. & Cheifetz, A. S. Crohn disease: epidemiology, diagnosis, and management. Mayo Clin. Proc. 92, 1088–1103 (2017).

    Article  CAS  PubMed  Google Scholar 

  97. Gomollón, 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).

    Article  PubMed  Google Scholar 

  98. Kuriyama, M. et al. Specific gastroduodenoscopic findings in Crohn’s disease: comparison with findings in patients with ulcerative colitis and gastroesophageal reflux disease. Dig. Liver Dis. 40, 468–475 (2008).

    Article  CAS  PubMed  Google Scholar 

  99. Sawczenko, A. & Sandhu, B. K. Presenting features of inflammatory bowel disease in Great Britain and Ireland. Arch. Dis. Child. 88, 995–1000 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Peyrin-Biroulet, L., Loftus, E. V., Colombel, J.-F. & Sandborn, W. J. The natural history of adult Crohn’s disease in population-based cohorts. Am. J. Gastroenterol. 105, 289–297 (2010). This comprehensive article describes the natural history of CD.

    Article  PubMed  Google Scholar 

  101. Fiorino, G. et al. Prevalence of bowel damage assessed by cross-sectional imaging in early Crohn’s disease and its impact on disease outcome. J. Crohns Colitis 11, 274–280 (2017).

    Article  PubMed  Google Scholar 

  102. Safroneeva, E. et al. Impact of the early use of immunomodulators or TNF antagonists on bowel damage and surgery in Crohn’s disease. Aliment. Pharmacol. Ther. 42, 977–989 (2015).

    Article  CAS  PubMed  Google Scholar 

  103. Peyrin-Biroulet, L. et al. Perianal Crohn’s disease findings other than fistulas in a population-based cohort. Inflamm. Bowel Dis. 18, 43–48 (2012).

    Article  PubMed  Google Scholar 

  104. Ott, C. & Schölmerich, J. Extraintestinal manifestations and complications in IBD. Nat. Rev. Gastroenterol. Hepatol. 10, 585–595 (2013).

    Article  CAS  PubMed  Google Scholar 

  105. Park, S. H. et al. Update on the natural course of fistulizing perianal Crohn’s disease in a population-based cohort. Inflamm. Bowel Dis. 25, 1054–1060 (2019).

    Article  PubMed  Google Scholar 

  106. Freeman, H. J. Natural history and long-term clinical course of Crohn’s disease. World J. Gastroenterol. 20, 31–36 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  107. Danese, S. et al. Development of red flags index for early referral of adults with symptoms and signs suggestive of Crohn’s disease: an IOIBD initiative. J. Crohns Colitis 9, 601–606 (2015).

    Article  PubMed  Google Scholar 

  108. Vavricka, S. R. et al. Frequency and risk factors for extraintestinal manifestations in the Swiss inflammatory bowel disease cohort. Am. J. Gastroenterol. 106, 110–119 (2011).

    Article  PubMed  Google Scholar 

  109. Jang, H.-J., Kang, B. & Choe, B.-H. The difference in extraintestinal manifestations of inflammatory bowel disease for children and adults. Transl. Pediatr. 8, 4–15 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  110. Peyrin-Biroulet, L., Loftus, E. V., Colombel, J.-F. & Sandborn, W. J. Long-term complications, extraintestinal manifestations, and mortality in adult Crohn’s disease in population-based cohorts. Inflamm. Bowel Dis. 17, 471–478 (2011). This comprehensive article describes long-term outcomes in patients with CD.

    Article  PubMed  Google Scholar 

  111. Pennazio, M. et al. Small-bowel capsule endoscopy and device-assisted enteroscopy for diagnosis and treatment of small-bowel disorders: European Society of Gastrointestinal Endoscopy (ESGE) clinical guideline. Endoscopy 47, 352–376 (2015).

    Article  PubMed  Google Scholar 

  112. Koulaouzidis, A., Rondonotti, E. & Karargyris, A. Small-bowel capsule endoscopy: a ten-point contemporary review. World J. Gastroenterol. 19, 3726–3746 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  113. Dionisio, P. M. et al. Capsule endoscopy has a significantly higher diagnostic yield in patients with suspected and established small-bowel Crohn’s disease: a meta-analysis. Am. J. Gastroenterol. 105, 1240–1248 (2010).

    Article  PubMed  Google Scholar 

  114. Magro, F. et al. European consensus on the histopathology of inflammatory bowel disease. J. Crohns Colitis 7, 827–851 (2013).

    Article  CAS  PubMed  Google Scholar 

  115. Annese, V. et al. European evidence based consensus for endoscopy in inflammatory bowel disease. J. Crohns Colitis 7, 982–1018 (2013).

    Article  PubMed  Google Scholar 

  116. Tontini, G. E., Vecchi, M., Neurath, M. F. & Neumann, H. Advanced endoscopic imaging techniques in Crohn’s disease. J. Crohns Colitis 8, 261–269 (2014).

    Article  PubMed  Google Scholar 

  117. Allocca, M., Fiorino, G. & Danese, S. Cross-sectional imaging modalities in Crohn’s disease. Dig. Dis. 31, 199–201 (2013).

    Article  PubMed  Google Scholar 

  118. Chatu, S., Subramanian, V. & Pollok, R. C. G. Meta-analysis: diagnostic medical radiation exposure in inflammatory bowel disease. Aliment. Pharmacol. Ther. 35, 529–539 (2012).

    Article  CAS  PubMed  Google Scholar 

  119. Horsthuis, K., Bipat, S., Bennink, R. J. & Stoker, J. Inflammatory bowel disease diagnosed with US, MR, scintigraphy, and CT: meta-analysis of prospective studies. Radiology 247, 64–79 (2008).

    Article  PubMed  Google Scholar 

  120. Panés, J. et al. Systematic review: the use of ultrasonography, computed tomography and magnetic resonance imaging for the diagnosis, assessment of activity and abdominal complications of Crohn’s disease. Aliment. Pharmacol. Ther. 34, 125–145 (2011).

    Article  PubMed  Google Scholar 

  121. Sahni, V. A., Ahmad, R. & Burling, D. Which method is best for imaging of perianal fistula? Abdom. Imaging 33, 26–30 (2008).

    Article  PubMed  Google Scholar 

  122. Allocca, M. et al. Comparative accuracy of bowel ultrasound versus magnetic resonance enterography in combination with colonoscopy in assessing Crohn’s disease and guiding clinical decision-making. J. Crohns Colitis 12, 1280–1287 (2018).

    Article  PubMed  Google Scholar 

  123. Magro, F. et al. Third European evidence-based consensus on diagnosis and management of ulcerative colitis. part 1: definitions, diagnosis, extra-intestinal manifestations, pregnancy, cancer surveillance, surgery, and ileo-anal pouch disorders. J. Crohns Colitis 11, 649–670 (2017).

    Article  PubMed  Google Scholar 

  124. Vermeire, S., Schreiber, S., Sandborn, W. J., Dubois, C. & Rutgeerts, P. Correlation between the Crohn’s disease activity and Harvey-Bradshaw indices in assessing Crohn’s disease severity. Clin. Gastroenterol. Hepatol. 8, 357–363 (2010).

    Article  PubMed  Google Scholar 

  125. Best, W. R. Predicting the Crohn’s disease activity index from the Harvey-Bradshaw index. Inflamm. Bowel Dis. 12, 304–310 (2006).

    Article  PubMed  Google Scholar 

  126. Mitsuyama, K. et al. Antibody markers in the diagnosis of inflammatory bowel disease. World J. Gastroenterol. 22, 1304–1310 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Gu, P. et al. Serological, genetic and clinical associations with increased health-care resource utilization in inflammatory bowel disease. J. Dig. Dis. 19, 15–23 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  128. Plevy, S. et al. Combined serological, genetic, and inflammatory markers differentiate non-IBD, Crohn’s disease, and ulcerative colitis patients. Inflamm. Bowel Dis. 19, 1139–1148 (2013).

    Article  PubMed  Google Scholar 

  129. Maaser, C. et al. ECCO-ESGAR guideline for diagnostic assessment in IBD part 1: initial diagnosis, monitoring of known IBD, detection of complications. J. Crohns Colitis 13, 144–164 (2019).

    Article  PubMed  Google Scholar 

  130. Vermeire, S., Van Assche, G. & Rutgeerts, P. C-reactive protein as a marker for inflammatory bowel disease. Inflamm. Bowel Dis. 10, 661–665 (2004).

    Article  PubMed  Google Scholar 

  131. Vermeire, S., Van Assche, G. & Rutgeerts, P. Laboratory markers in IBD: useful, magic, or unnecessary toys? Gut 55, 426–431 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. Solem, C. A. et al. Correlation of C-reactive protein with clinical, endoscopic, histologic, and radiographic activity in inflammatory bowel disease. Inflamm. Bowel Dis. 11, 707–712 (2005).

    Article  PubMed  Google Scholar 

  133. Cellier, C. et al. Correlations between clinical activity, endoscopic severity, and biological parameters in colonic or ileocolonic Crohn’s disease. A prospective multicentre study of 121 cases. The Groupe d’Etudes Thérapeutiques des Affections Inflammatoires Digestives. Gut 35, 231–235 (1994).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  134. Lakatos, P. L. et al. Serum lipopolysaccharide-binding protein and soluble CD14 are markers of disease activity in patients with Crohn’s disease. Inflamm. Bowel Dis. 17, 767–777 (2011).

    Article  PubMed  Google Scholar 

  135. Kwon, J. H. et al. Disease phenotype, activity and clinical course prediction based on C-reactive protein levels at diagnosis in patients with Crohn’s disease: results from the CONNECT study. Gut Liver 10, 595–603 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  136. Carroccio, A. et al. Diagnostic accuracy of fecal calprotectin assay in distinguishing organic causes of chronic diarrhea from irritable bowel syndrome: a prospective study in adults and children. Clin. Chem. 49, 861–867 (2003).

    Article  CAS  PubMed  Google Scholar 

  137. Diamanti, A. et al. Diagnostic work-up of inflammatory bowel disease in children: the role of calprotectin assay. Inflamm. Bowel Dis. 16, 1926–1930 (2010).

    Article  CAS  PubMed  Google Scholar 

  138. Goutorbe, F. et al. Endoscopic factors influencing fecal calprotectin value in Crohn’s disease. J. Crohns Colitis 9, 1113–1119 (2015).

    Article  CAS  PubMed  Google Scholar 

  139. van Rheenen, P. F., Van de Vijver, E. & Fidler, V. Faecal calprotectin for screening of patients with suspected inflammatory bowel disease: diagnostic meta-analysis. BMJ 341, c3369 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  140. Suray, N. de et al. Close monitoring of CRP and fecal calprotectin is able to predict clinical relapse in patients with Crohn’s disease in remission after infliximab withdrawal. a sub-analysis of the Stori study. Gastroenterology 142, S-149 (2012).

    Article  Google Scholar 

  141. Orlando, A. et al. The role of calprotectin in predicting endoscopic post-surgical recurrence in asymptomatic Crohn’s disease: a comparison with ultrasound. Eur. Rev. Med. Pharmacol. Sci. 10, 17–22 (2006).

    CAS  PubMed  Google Scholar 

  142. Guo, S. et al. A simple fecal bacterial marker panel for the diagnosis of Crohn’s disease. Front. Microbiol. 10, 1306 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  143. Marlicz, W., Skonieczna-Żydecka, K., Dabos, K. J., Łoniewski, I. & Koulaouzidis, A. Emerging concepts in non-invasive monitoring of Crohn’s disease. Ther. Adv. Gastroenterol. 11, 1756284818769076 (2018).

    Article  Google Scholar 

  144. Somineni, H. K. et al. Blood-derived DNA methylation signatures of Crohn’s disease and severity of intestinal inflammation. Gastroenterology 156, 2254–2265.e3 (2019).

    Article  CAS  PubMed  Google Scholar 

  145. Leong, R. W. et al. Full-spectrum endoscopy improves surveillance for dysplasia in patients with inflammatory bowel diseases. Gastroenterology 152, 1337–1344.e3 (2017).

    Article  PubMed  Google Scholar 

  146. Stidham, R. W. & Higgins, P. D. R. Colorectal cancer in inflammatory bowel disease. Clin. Colon. Rectal Surg. 31, 168–178 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  147. Tontini, G. E., Vecchi, M., Pastorelli, L., Neurath, M. F. & Neumann, H. Differential diagnosis in inflammatory bowel disease colitis: state of the art and future perspectives. World J. Gastroenterol. 21, 21–46 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  148. He, Y. et al. Development and validation of a novel diagnostic nomogram to differentiate between intestinal tuberculosis and Crohn’s disease: a 6-year prospective multicenter study. Am. J. Gastroenterol. 114, 490–499 (2019).

    Article  PubMed  Google Scholar 

  149. Bae, J. H. et al. Development and validation of a novel prediction model for differential diagnosis between Crohn’s disease and intestinal tuberculosis. Inflamm. Bowel Dis. 23, 1614–1623 (2017).

    Article  PubMed  Google Scholar 

  150. Lee, S. K., Kim, B. K., Kim, T. I. & Kim, W. H. Differential diagnosis of intestinal Behçet’s disease and Crohn’s disease by colonoscopic findings. Endoscopy 41, 9–16 (2009).

    Article  CAS  PubMed  Google Scholar 

  151. Valenti, S., Gallizzi, R., De Vivo, D. & Romano, C. Intestinal Behçet and Crohn’s disease: two sides of the same coin. Pediatr. Rheumatol. Online J. 15, 33 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  152. Kedia, S. et al. Differentiating Crohn’s disease from intestinal tuberculosis. World J. Gastroenterol. 25, 418–432 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  153. Oliveira, S. B. & Monteiro, I. M. Diagnosis and management of inflammatory bowel disease in children. BMJ 357, j2083 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  154. Amre, D. K., Lu, S.-E., Costea, F. & Seidman, E. G. Utility of serological markers in predicting the early occurrence of complications and surgery in pediatric Crohn’s disease patients. Am. J. Gastroenterol. 101, 645–652 (2006).

    Article  PubMed  Google Scholar 

  155. Gisbert, J. P., Marín, A. C. & Chaparro, M. Systematic review: factors associated with relapse of inflammatory bowel disease after discontinuation of anti-TNF therapy. Aliment. Pharmacol. Ther. 42, 391–405 (2015).

    Article  CAS  PubMed  Google Scholar 

  156. 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).

    Article  CAS  PubMed  Google Scholar 

  157. van Deen, W. K. et al. Value redefined for inflammatory bowel disease patients: a choice-based conjoint analysis of patients’ preferences. Qual. Life Res. 26, 455–465 (2017).

    Article  PubMed  Google Scholar 

  158. Loy, L. et al. Detection and management of early stage inflammatory bowel disease: an update for clinicians. Expert Rev. Gastroenterol. Hepatol. 13, 547–555 (2019).

    Article  CAS  PubMed  Google Scholar 

  159. Bewtra, M. et al. Inflammatory bowel disease patients’ willingness to accept medication risk to avoid future disease relapse. Am. J. Gastroenterol. 110, 1675–1681 (2015).

    Article  PubMed  Google Scholar 

  160. Torres, J. et al. Predicting outcomes to optimize disease management in inflammatory bowel diseases. J. Crohns Colitis 10, 1385–1394 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  161. Beaugerie, L., Seksik, P., Nion-Larmurier, I., Gendre, J.-P. & Cosnes, J. Predictors of Crohn’s disease. Gastroenterology 130, 650–656 (2006).

    Article  PubMed  Google Scholar 

  162. Loly, C., Belaiche, J. & Louis, E. Predictors of severe Crohn’s disease. Scand. J. Gastroenterol. 43, 948–954 (2008).

    Article  CAS  PubMed  Google Scholar 

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

    Article  PubMed  PubMed Central  Google Scholar 

  164. Mao, R. et al. Fecal calprotectin in predicting relapse of inflammatory bowel diseases: a meta-analysis of prospective studies. Inflamm. Bowel Dis. 18, 1894–1899 (2012).

    Article  PubMed  Google Scholar 

  165. Ghaly, S. et al. High vitamin D-binding protein concentration, low albumin, and mode of remission predict relapse in Crohn’s disease. Inflamm. Bowel Dis. 22, 2456–2464 (2016).

    Article  PubMed  Google Scholar 

  166. Qin, G. et al. Serum albumin and C-reactive protein/albumin ratio are useful biomarkers of Crohn’s Disease activity. Med. Sci. Monit. 22, 4393–4400 (2016).

    Article  CAS  PubMed  Google Scholar 

  167. Allez, M. et al. Long term outcome of patients with active Crohn’s disease exhibiting extensive and deep ulcerations at colonoscopy. Am. J. Gastroenterol. 97, 947–953 (2002).

    PubMed  Google Scholar 

  168. Nahon, S. et al. Diagnostic delay in a French cohort of Crohn’s disease patients. J. Crohns Colitis 8, 964–969 (2014).

    Article  PubMed  Google Scholar 

  169. Maconi, G. et al. The impact of symptoms, irritable bowel syndrome pattern and diagnostic investigations on the diagnostic delay of Crohn’s disease: a prospective study. Dig. Liver Dis. 47, 646–651 (2015).

    Article  PubMed  Google Scholar 

  170. Vavricka, S. R. et al. Systematic evaluation of risk factors for diagnostic delay in inflammatory bowel disease. Inflamm. Bowel Dis. 18, 496–505 (2012).

    Article  PubMed  Google Scholar 

  171. Schoepfer, A. M. et al. Diagnostic delay in Crohn’s disease is associated with a complicated disease course and increased operation rate. Am. J. Gastroenterol. 108, 1744–1753 (2013).

    Article  PubMed  Google Scholar 

  172. Peyrin-Biroulet, L. et al. Development of the Paris definition of early Crohn’s disease for disease-modification trials: results of an international expert opinion process. Am. J. Gastroenterol. 107, 1770–1776 (2012). This is the first description of early CD, a category of the disease defined by prognostic factors that predict a favourable response to early aggressive treatment.

    Article  PubMed  Google Scholar 

  173. 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).

    Article  CAS  PubMed  Google Scholar 

  174. Høivik, M. L. et al. Work disability in inflammatory bowel disease patients 10 years after disease onset: results from the IBSEN study. Gut 62, 368–375 (2013).

    Article  PubMed  Google Scholar 

  175. Frøslie, K. F., Jahnsen, J., Moum, B. A., Vatn, M. H. & IBSEN Group. Mucosal healing in inflammatory bowel disease: results from a Norwegian population-based cohort. Gastroenterology 133, 412–422 (2007).

    Article  PubMed  Google Scholar 

  176. 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).

    Article  Google Scholar 

  177. Peyrin-Biroulet, L. et al. Clinical disease activity, C-reactive protein normalisation and mucosal healing in Crohn’s disease in the SONIC trial. Gut 63, 88–95 (2014).

    Article  PubMed  Google Scholar 

  178. 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).

    Article  CAS  PubMed  Google Scholar 

  179. Doherty, G. et al. European Crohn’s and Colitis Organisation topical review on treatment withdrawal [‘exit strategies’] in inflammatory bowel disease. J. Crohns Colitis 12, 17–31 (2018).

    Article  PubMed  Google Scholar 

  180. Munkholm, P., Langholz, E., Davidsen, M. & Binder, V. Frequency of glucocorticoid resistance and dependency in Crohn’s disease. Gut 35, 360–362 (1994).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  181. Modigliani, R. et al. Clinical, biological, and endoscopic picture of attacks of Crohn’s disease. Evolution on prednisolone. Gastroenterology 98, 811–818 (1990).

    Article  CAS  PubMed  Google Scholar 

  182. Lamb, C. A. et al. British Society of Gastroenterology consensus guidelines on the management of inflammatory bowel disease in adults. Gut 68, s1–s106 (2019).

    Article  PubMed  Google Scholar 

  183. Panés, J. et al. Early azathioprine therapy is no more effective than placebo for newly diagnosed Crohn’s disease. Gastroenterology 145, 766–774.e1 (2013).

    Article  PubMed  CAS  Google Scholar 

  184. Beaugerie, L. et al. Risk of new or recurrent cancer under immunosuppressive therapy in patients with IBD and previous cancer. Gut 63, 1416–1423 (2014).

    Article  PubMed  Google Scholar 

  185. Cosnes, J. et al. Early administration of azathioprine vs conventional management of Crohn’s disease: a randomized controlled trial. Gastroenterology 145, 758–765.e2 (2013).

    Article  CAS  PubMed  Google Scholar 

  186. Chande, N., Townsend, C. M., Parker, C. E. & MacDonald, J. K. Azathioprine or 6-mercaptopurine for induction of remission in Crohn’s disease. Cochrane Database Syst. Rev. 10, CD000545 (2016).

    PubMed  Google Scholar 

  187. Chatu, S., Subramanian, V., Saxena, S. & Pollok, R. C. G. The role of thiopurines in reducing the need for surgical resection in Crohn’s disease: a systematic review and meta-analysis. Am. J. Gastroenterol. 109, 23–34 (2014).

    Article  CAS  PubMed  Google Scholar 

  188. Herfarth, H. H., Kappelman, M. D., Long, M. D. & Isaacs, K. L. Use of methotrexate in the treatment of inflammatory bowel diseases. Inflamm. Bowel Dis. 22, 224–233 (2016).

    Article  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  190. Dulai, P. S. et al. The real-world effectiveness and safety of vedolizumab for moderate-severe Crohn’s disease: results from the US VICTORY consortium. Am. J. Gastroenterol. 111, 1147–1155 (2016).

    Article  CAS  PubMed  Google Scholar 

  191. Kariburyo, M. F., Xie, L., Teeple, A., Tan, H. & Ingham, M. Predicting pre-emptive discussions of biologic treatment: results from an openness and preference survey of inflammatory bowel disease patients and their prescribers. Adv. Ther. 34, 1398–1410 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  192. Sands, B. E. et al. Vedolizumab versus adalimumab for moderate-to-severe ulcerative colitis. N. Engl. J. Med. 381, 1215–1226 (2019).

    Article  CAS  PubMed  Google Scholar 

  193. Vande Casteele, N. et al. The relationship between infliximab concentrations, antibodies to infliximab and disease activity in Crohn’s disease. Gut 64, 1539–1545 (2015).

    Article  CAS  PubMed  Google Scholar 

  194. Nanda, K. S., Cheifetz, A. S. & Moss, A. C. Impact of antibodies to infliximab on clinical outcomes and serum infliximab levels in patients with inflammatory bowel disease (IBD): a meta-analysis. Am. J. Gastroenterol. 108, 40–47; quiz 48 (2013).

    Article  CAS  PubMed  Google Scholar 

  195. Seinen, M. L., De Boer, N. K. & van Bodegraven, A. A. Key insights from therapeutic drug monitoring in Crohn’s disease patients. Expert Opin. Drug Metab. Toxicol. 15, 399–406 (2019).

    Article  CAS  PubMed  Google Scholar 

  196. Restellini, S., Khanna, R. & Afif, W. Therapeutic drug monitoring with ustekinumab and vedolizumab in inflammatory bowel disease. Inflamm. Bowel Dis. 24, 2165–2172 (2018).

    Article  PubMed  Google Scholar 

  197. D’Amico, F., Fiorino, G., Furfaro, F., Allocca, M. & Danese, S. Janus kinase inhibitors for the treatment of inflammatory bowel diseases: developments from phase I and phase II clinical trials. Expert Opin. Investig. Drugs 27, 595–599 (2018).

    Article  PubMed  CAS  Google Scholar 

  198. Peyrin-Biroulet, L., Christopher, R., Behan, D. & Lassen, C. Modulation of sphingosine-1-phosphate in inflammatory bowel disease. Autoimmun. Rev. 16, 495–503 (2017).

    Article  CAS  PubMed  Google Scholar 

  199. Ma, C., Jairath, V., Khanna, R. & Feagan, B. G. Investigational drugs in phase I and phase II clinical trials targeting interleukin 23 (IL23) for the treatment of Crohn’s disease. Expert Opin. Investig. Drugs 27, 649–660 (2018).

    Article  CAS  PubMed  Google Scholar 

  200. Prideaux, L., Kamm, M. A., De Cruz, P. P., Chan, F. K. L. & Ng, S. C. Inflammatory bowel disease in Asia: a systematic review. J. Gastroenterol. Hepatol. 27, 1266–1280 (2012).

    Article  PubMed  Google Scholar 

  201. Prideaux, L. et al. Comparison of clinical characteristics and management of inflammatory bowel disease in Hong Kong versus Melbourne. J. Gastroenterol. Hepatol. 27, 919–927 (2012).

    Article  PubMed  Google Scholar 

  202. Gálvez, J. Role of Th17 cells in the pathogenesis of human IBD. ISRN Inflamm. 2014, 928461 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  203. 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).

    Article  CAS  PubMed  Google Scholar 

  204. van der Giessen, J. et al. Modulation of cytokine patterns and microbiome during pregnancy in IBD. Gut 69, 473–486 (2020).

    Article  PubMed  Google Scholar 

  205. van der Giessen, J., Huang, V. W., van der Woude, C. J. & Fuhler, G. M. Modulatory effects of pregnancy on inflammatory bowel disease. Clin. Transl. Gastroenterol. 10, e00009 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  206. Maunder, R. G., Cohen, Z., McLeod, R. S. & Greenberg, G. R. Effect of intervention in inflammatory bowel disease on health-related quality of life: a critical review. Dis. Colon Rectum 38, 1147–1161 (1995).

    Article  CAS  PubMed  Google Scholar 

  207. Chen, X.-L. et al. Inflammatory bowel disease-specific health-related quality of life instruments: a systematic review of measurement properties. Health Qual. Life Outcomes 15, 177 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  208. Kaplan, G. G. The global burden of IBD: from 2015 to 2025. Nat. Rev. Gastroenterol. Hepatol. 12, 720–727 (2015).

    Article  PubMed  Google Scholar 

  209. Cohen, R. D. The quality of life in patients with Crohn’s disease. Aliment. Pharmacol. Ther. 16, 1603–1609 (2002).

    Article  CAS  PubMed  Google Scholar 

  210. López Blanco, B., Moreno-Jiménez, B., Devesa Múgica, J. M. & Rodríguez Muñoz, A. Relationship between socio-demographic and clinical variables, and health-related quality of life in patients with inflammatory bowel disease. Rev. Esp. Enferm. Dig. 97, 887–898 (2005). This study reveals the effect of IBD on QOL, which needs to be considered in clinical practice.

    Article  PubMed  Google Scholar 

  211. Blondel-Kucharski, F. et al. Health-related quality of life in Crohn’s disease: a prospective longitudinal study in 231 patients. Am. J. Gastroenterol. 96, 2915–2920 (2001).

    Article  CAS  PubMed  Google Scholar 

  212. Andersson, P., Olaison, G., Bendtsen, P., Myrelid, P. & Sjödahl, R. Health related quality of life in Crohn’s proctocolitis does not differ from a general population when in remission. Colorectal Dis. 5, 56–62 (2003).

    Article  CAS  PubMed  Google Scholar 

  213. Bernklev, T. et al. Course of disease, drug treatment and health-related quality of life in patients with inflammatory bowel disease 5 years after initial diagnosis. Eur. J. Gastroenterol. Hepatol. 17, 1037–1045 (2005).

    Article  PubMed  Google Scholar 

  214. Casellas, F., López-Vivancos, J., Badia, X., Vilaseca, J. & Malagelada, J. R. Impact of surgery for Crohn’s disease on health-related quality of life. Am. J. Gastroenterol. 95, 177–182 (2000).

    Article  CAS  PubMed  Google Scholar 

  215. Romberg-Camps, M. J. L. et al. Fatigue and health-related quality of life in inflammatory bowel disease: results from a population-based study in the Netherlands: the IBD-South Limburg cohort. Inflamm. Bowel Dis. 16, 2137–2147 (2010).

    Article  CAS  PubMed  Google Scholar 

  216. Schirbel, A. et al. Impact of pain on health-related quality of life in patients with inflammatory bowel disease. World J. Gastroenterol. 16, 3168–3177 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  217. Katz, L. et al. Mechanisms of quality of life and social support in inflammatory bowel disease. J. Clin. Psychol. Med. Settings 23, 88–98 (2016).

    Article  PubMed  Google Scholar 

  218. Reinink, A. R., Lee, T. C. & Higgins, P. D. R. Endoscopic mucosal healing predicts favorable clinical outcomes in inflammatory bowel disease: a meta-analysis. Inflamm. Bowel Dis. 22, 1859–1869 (2016).

    Article  PubMed  Google Scholar 

  219. Peyrin-Biroulet, L. et al. Defining disease severity in inflammatory bowel diseases: current and future directions. Clin. Gastroenterol. Hepatol. 14, 348–354.e17 (2016).

    Article  PubMed  Google Scholar 

  220. Pariente, B. et al. Development of the Crohn’s disease digestive damage score, the Lémann score. Inflamm. Bowel Dis. 17, 1415–1422 (2011).

    Article  PubMed  Google Scholar 

  221. Siegel, C. A. et al. Development of an index to define overall disease severity in IBD. Gut 67, 244–254 (2018). This study discusses the development of severity indices to allow assessment of disease severity and bowel damage progression in the future.

    Article  PubMed  Google Scholar 

  222. Rieder, F. & Fiocchi, C. Intestinal fibrosis in inflammatory bowel disease - current knowledge and future perspectives. J. Crohns Colitis 2, 279–290 (2008).

    Article  PubMed  Google Scholar 

  223. Burke, J. P. et al. Fibrogenesis in Crohn’s disease. Am. J. Gastroenterol. 102, 439–448 (2007).

    Article  CAS  PubMed  Google Scholar 

  224. Allen, P. B., Gower-Rousseau, C., Danese, S. & Peyrin-Biroulet, L. Preventing disability in inflammatory bowel disease. Ther. Adv. Gastroenterol. 10, 865–876 (2017).

    Article  Google Scholar 

  225. McGovern, D. Personalized medicine in inflammatory bowel disease. Gastroenterol. Hepatol. 10, 662–664 (2014).

    Google Scholar 

  226. 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).

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

Work in the laboratory of A.K. is supported by the Wellcome Trust (Senior Investigator Award 106260/Z/14/Z) and the European Research Council (Consolidator Grant 648889).

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Authors and Affiliations

Authors

Contributions

Introduction (G.R., L.P.-B. and S.D.); Epidemiology (S.C.N.); Mechanisms/pathophysiology (A.K.); Diagnosis, screening and prevention (P.G.K. and M.A.); Management (R.P.); Quality of life (G.R., A.S., L.P.-B. and S.D.); Outlook (G.R., A.S., L.P.-B. and S.D.).

Corresponding author

Correspondence to Silvio Danese.

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S.D. has served as a speaker, consultant and advisory board member for Schering-Plough, AbbVie, Merck Sharp & Dohme, UCB Pharma, Ferring, Cellerix, Takeda Pharmaceutical Company, Nycomed, Pharmacosmos, Actelion, Alpha Wasserman, Genentech, Grünenthal, Pfizer, AstraZeneca, Novo Nordisk, Cosmo Pharmaceuticals, Vifor, Johnson & Johnson and Nikkiso Europe GmbH. L.P.-B. has received consulting fees from AbbVie, Amgen, Biogaran, Boehringer Ingelheim, Bristol-Myers Squibb, Celltrion, Ferring, Genentech, HAC Pharma, Hospira, Index Pharmaceuticals, Janssen, Lilly, Merck, Mitsubishi, Norgine, Pfizer, Pharmacosmos, Pilege, Sandoz, Takeda, Therakos, Tillotts, UCB Pharma and Vifor and lecture fees from AbbVie, Ferring, HAC Pharma, Janssen, Merck, Mitsubishi, Norgine, Takeda, Therakos, Tillotts and Vifor. A.S. has acted as a consultant or speaker for Ethicon, Olympus, Frankenman, Transenterix (not active), Tigenyx, Pfizer, Takeda and Sandoz. P.G.K has been a lecturer for AbbVie, Janssen, Pfizer and Takeda and is a member of the advisory board of AbbVie, Pfizer and Takeda. A.K. has served as an adviser to Boehringer Ingelheim, Ferring, Genentech, GlaxoSmithKline, Gilead, Hospira, Janssen, Pfizer, and VHSquared. R.P. has received consultant and/or lecture fees from AbbVie, Amgen, AstraZeneca, Axcan Pharma (now Aptalis), Biogen Idec, Bristol-Myers Squibb, Centocor, ChemoCentryx, Eisai Medical Research Inc., Elan Pharmaceuticals, Ferring, Genentech, GlaxoSmithKline, Janssen, Merck Sharp & Dohme, Millennium Pharmaceuticals (now Takeda Oncology), Ocera Therapeutics Inc., Otsuka America Pharmaceutical, Pfizer, Shire Pharmaceuticals, Prometheus Laboratories, Schering-Plough Corporation, Synta Pharmaceuticals Corp., Teva, UCB Pharma and Warner Chilcott. S.C.N. has received consulting and speaker fees from AbbVie, Ferring, Janssen, Menarini and Takeda, has served as a scientific advisory board member for AbbVie, Ferring and Takeda and has received research grants from AbbVie, Ferring and Janssen. The other authors declare no competing interests.

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Nature Reviews Disease Primers thanks B.D. Ye, A. Forbes, J. Gisbert, G. Monteleone, A. Regueiro and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Roda, G., Chien Ng, S., Kotze, P.G. et al. Crohn’s disease. Nat Rev Dis Primers 6, 22 (2020). https://doi.org/10.1038/s41572-020-0156-2

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