Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

IL-12 and IL-23 pathway inhibition in inflammatory bowel disease

Nature Reviews Gastroenterology & Hepatology volume 20, pages 433–446 (2023)Cite this article

Subjects

Abstract

Interleukin-12 (IL-12) and interleukin-23 (IL-23), which belong to the IL-12 family of cytokines, have a key role in intestinal homeostasis and inflammation and are implicated in the pathogenesis of inflammatory bowel disease. Upon their secretion by antigen-presenting cells, they exert both pro-inflammatory and anti-inflammatory receptor-mediated effects. An increased understanding of these biological effects, particularly the pro-inflammatory effects mediated by IL-12 and IL-23, has led to the development of monoclonal antibodies that target a subunit common to IL-12 and IL-23 (p40; targeted by ustekinumab and briakinumab), or the IL-23-specific subunit (p19; targeted by risankizumab, guselkumab, brazikumab and mirikizumab). This Review provides a summary of the biology of the IL-12 family cytokines IL-12 and IL-23, discusses the role of these cytokines in intestinal homeostasis and inflammation, and highlights IL-12- and IL-23-directed drug development for the treatment of Crohn’s disease and ulcerative colitis.

Key points

  • IL-12 and IL-23, which are members of the IL-12 family of cytokines, have a key role in intestinal homeostasis and inflammation, including in inflammatory bowel disease.

  • Multiple IL-12- and/or IL-23-neutralizing antibodies have been tested in immune-mediated diseases, including Crohn’s disease and ulcerative colitis.

  • In addition to demonstrated efficacy for clinical, endoscopic and histological outcomes, targeting IL-12 and/or IL-23 is a safe treatment strategy.

  • The exact positioning of such antibodies in current treatment algorithms will be influenced by ongoing head-to-head trials and evaluation of predictive molecular markers.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Cellular sources, target cells, signalling and downstream effects of IL-12.
Fig. 2: Cellular sources, target cells, signalling and downstream effects of IL-23.

Similar content being viewed by others

References

  1. Chang, J. T. Pathophysiology of inflammatory bowel diseases. N. Engl. J. Med. 383, 2652–2664 (2020).

    Article  CAS  PubMed  Google Scholar 

  2. Baumgart, D. C. & Le Berre, C. Newer biologic and small-molecule therapies for inflammatory bowel disease. N. Engl. J. Med. 385, 1302–1315 (2021).

    Article  CAS  PubMed  Google Scholar 

  3. Roda, G., Jharap, B., Neeraj, N. & Colombel, J. F. Loss of response to anti-TNFs: definition, epidemiology, and management. Clin. Transl. Gastroenterol. 7, e135 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. 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 

  5. Verstockt, B., Van Assche, G., Vermeire, S. & Ferrante, M. Biological therapy targeting the IL-23/IL-17 axis in inflammatory bowel disease. Expert. Opin. Biol. Ther. 17, 31–47 (2017).

    Article  CAS  PubMed  Google Scholar 

  6. Kobayashi, M. et al. Identification and purification of natural killer cell stimulatory factor (NKSF), a cytokine with multiple biologic effects on human lymphocytes. J. Exp. Med. 170, 827–845 (1989).

    Article  CAS  PubMed  Google Scholar 

  7. Hsieh, C. S. et al. Development of TH1 CD4+ T cells through IL-12 produced by Listeria-induced macrophages. Science 260, 547–549 (1993).

    Article  CAS  PubMed  Google Scholar 

  8. Manetti, R. et al. Natural killer cell stimulatory factor (interleukin 12 [IL-12]) induces T helper type 1 (Th1)-specific immune responses and inhibits the development of IL-4-producing Th cells. J. Exp. Med. 177, 1199–1204 (1993).

    Article  CAS  PubMed  Google Scholar 

  9. Seder, R. A., Gazzinelli, R., Sher, A. & Paul, W. E. Interleukin 12 acts directly on CD4+ T cells to enhance priming for interferon gamma production and diminishes interleukin 4 inhibition of such priming. Proc. Natl Acad. Sci. USA 90, 10188–10192 (1993).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. 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).

    Article  CAS  PubMed  Google Scholar 

  11. Brombacher, F. et al. IL-12 is dispensable for innate and adaptive immunity against low doses of Listeria monocytogenes. Int. Immunol. 11, 325–332 (1999).

    Article  CAS  PubMed  Google Scholar 

  12. Aggarwal, S., Ghilardi, N., Xie, M. H., de Sauvage, F. J. & Gurney, A. L. Interleukin-23 promotes a distinct CD4 T cell activation state characterized by the production of interleukin-17. J. Biol. Chem. 278, 1910–1914 (2003).

    Article  CAS  PubMed  Google Scholar 

  13. Tesmer, L. A., Lundy, S. K., Sarkar, S. & Fox, D. A. Th17 cells in human disease. Immunol. Rev. 223, 87–113 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Pirhonen, J., Matikainen, S. & Julkunen, I. Regulation of virus-induced IL-12 and IL-23 expression in human macrophages. J. Immunol. 169, 5673–5678 (2002).

    Article  CAS  PubMed  Google Scholar 

  15. Verreck, F. A. et al. Human IL-23-producing type 1 macrophages promote but IL-10-producing type 2 macrophages subvert immunity to (myco)bacteria. Proc. Natl Acad. Sci. USA 101, 4560–4565 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Cella, M. et al. Ligation of CD40 on dendritic cells triggers production of high levels of interleukin-12 and enhances T cell stimulatory capacity: T–T help via APC activation. J. Exp. Med. 184, 747–752 (1996).

    Article  CAS  PubMed  Google Scholar 

  17. Wesa, A. & Galy, A. Increased production of pro-inflammatory cytokines and enhanced T cell responses after activation of human dendritic cells with IL-1 and CD40 ligand. BMC Immunol. 3, 14 (2002).

    Article  PubMed  PubMed Central  Google Scholar 

  18. Ma, X. et al. The interleukin 12 p40 gene promoter is primed by interferon gamma in monocytic cells. J. Exp. Med. 183, 147–157 (1996).

    Article  CAS  PubMed  Google Scholar 

  19. Luque-Martin, R. et al. IFN-gamma drives human monocyte differentiation into highly proinflammatory macrophages that resemble a phenotype relevant to psoriasis. J. Immunol. 207, 555–568 (2021).

    Article  CAS  PubMed  Google Scholar 

  20. Shi, Q. et al. PGE2 elevates IL-23 production in human dendritic cells via a cAMP dependent pathway. Mediat. Inflamm. 2015, 984690 (2015).

    Article  Google Scholar 

  21. Geyer, C. E. et al. C-reactive protein controls IL-23 production by human monocytes. Int. J. Mol. Sci. 22, 11638 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Lim, K. S. et al. Inflammatory and mitogenic signals drive interleukin 23 subunit alpha (IL23A) secretion independent of IL12B in intestinal epithelial cells. J. Biol. Chem. 295, 6387–6400 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Macho-Fernandez, E. et al. Lymphotoxin beta receptor signaling limits mucosal damage through driving IL-23 production by epithelial cells. Mucosal Immunol. 8, 403–413 (2015).

    Article  CAS  PubMed  Google Scholar 

  24. Moschen, A. R., Tilg, H. & Raine, T. IL-12, IL-23 and IL-17 in IBD: immunobiology and therapeutic targeting. Nat. Rev. Gastroenterol. Hepatol. 16, 185–196 (2019).

    Article  CAS  PubMed  Google Scholar 

  25. Schwarz, E. & Carson, W. E. III Analysis of potential biomarkers of response to IL-12 therapy. J. Leukoc. Biol. 112, 557–567 (2022).

    Article  CAS  PubMed  Google Scholar 

  26. Grohmann, U. et al. Positive regulatory role of IL-12 in macrophages and modulation by IFN-gamma. J. Immunol. 167, 221–227 (2001).

    Article  CAS  PubMed  Google Scholar 

  27. Parham, C. et al. A receptor for the heterodimeric cytokine IL-23 is composed of IL-12Rβ1 and a novel cytokine receptor subunit, IL-23R. J. Immunol. 168, 5699–5708 (2002).

    Article  CAS  PubMed  Google Scholar 

  28. Awasthi, A. et al. Cutting edge: IL-23 receptor gfp reporter mice reveal distinct populations of IL-17-producing cells. J. Immunol. 182, 5904–5908 (2009).

    Article  CAS  PubMed  Google Scholar 

  29. Frucht, D. M. IL-23: a cytokine that acts on memory T cells. Sci. STKE 2002, pe1 (2002).

    PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  31. Glassman, C. R. et al. Structural basis for IL-12 and IL-23 receptor sharing reveals a gateway for shaping actions on T versus NK cells. Cell 184, 983–999.e924 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Thierfelder, W. E. et al. Requirement for Stat4 in interleukin-12-mediated responses of natural killer and T cells. Nature 382, 171–174 (1996).

    Article  CAS  PubMed  Google Scholar 

  33. Floss, D. M. et al. Identification of canonical tyrosine-dependent and non-canonical tyrosine-independent STAT3 activation sites in the intracellular domain of the interleukin 23 receptor. J. Biol. Chem. 288, 19386–19400 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Sun, R., Hedl, M. & Abraham, C. IL23 induces IL23R recycling and amplifies innate receptor-induced signalling and cytokines in human macrophages, and the IBD-protective IL23R R381Q variant modulates these outcomes. Gut 69, 264–273 (2020).

    Article  CAS  PubMed  Google Scholar 

  35. Becker, C. et al. Constitutive p40 promoter activation and IL-23 production in the terminal ileum mediated by dendritic cells. J. Clin. Invest. 112, 693–706 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Fuss, I. J. et al. Both IL-12p70 and IL-23 are synthesized during active Crohn’s disease and are down-regulated by treatment with anti-IL-12 p40 monoclonal antibody. Inflamm. Bowel Dis. 12, 9–15 (2006).

    Article  PubMed  Google Scholar 

  37. Kullberg, M. C. et al. IL-23 plays a key role in Helicobacter hepaticus-induced T cell-dependent colitis. J. Exp. Med. 203, 2485–2494 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Grohmann, U. et al. IL-12 acts directly on DC to promote nuclear localization of NF-κB and primes DC for IL-12 production. Immunity 9, 315–323 (1998).

    Article  CAS  PubMed  Google Scholar 

  39. Yang, R. et al. IL-12 + IL-18 cosignaling in human macrophages and lung epithelial cells activates cathelicidin and autophagy, inhibiting intracellular mycobacterial growth. J. Immunol. 200, 2405–2417 (2018).

    Article  CAS  PubMed  Google Scholar 

  40. Xing, Z., Zganiacz, A. & Santosuosso, M. Role of IL-12 in macrophage activation during intracellular infection: IL-12 and mycobacteria synergistically release TNF-α and nitric oxide from macrophages via IFN-γ induction. J. Leukoc. Biol. 68, 897–902 (2000).

    Article  CAS  PubMed  Google Scholar 

  41. Sun, R. & Abraham, C. IL23 promotes antimicrobial pathways in human macrophages, which are reduced with the IBD-protective IL23R R381Q variant. Cell Mol. Gastroenterol. Hepatol. 10, 673–697 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  42. Bastos, K. R. et al. What kind of message does IL-12/IL-23 bring to macrophages and dendritic cells? Microbes Infect. 6, 630–636 (2004).

    Article  CAS  PubMed  Google Scholar 

  43. Esplugues, E. et al. Control of TH17 cells occurs in the small intestine. Nature 475, 514–518 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Monteleone, I., Sarra, M., Pallone, F. & Monteleone, G. Th17-related cytokines in inflammatory bowel diseases: friends or foes? Curr. Mol. Med. 12, 592–597 (2012).

    Article  CAS  PubMed  Google Scholar 

  45. Punkenburg, E. et al. Batf-dependent Th17 cells critically regulate IL-23 driven colitis-associated colon cancer. Gut 65, 1139–1150 (2016).

    Article  CAS  PubMed  Google Scholar 

  46. Huber, S. et al. Th17 cells express interleukin-10 receptor and are controlled by Foxp3– and Foxp3+ regulatory CD4+ T cells in an interleukin-10-dependent manner. Immunity 34, 554–565 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Lee, J. S. et al. Interleukin-23-independent IL-17 production regulates intestinal epithelial permeability. Immunity 43, 727–738 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  49. 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 

  50. Pickert, G. et al. STAT3 links IL-22 signaling in intestinal epithelial cells to mucosal wound healing. J. Exp. Med. 206, 1465–1472 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Bauche, D. et al. IL-23 and IL-2 activation of STAT5 is required for optimal IL-22 production in ILC3s during colitis. Sci. Immunol. 5, eaav1080 (2020).

    Article  CAS  PubMed  Google Scholar 

  52. Aden, K. et al. Epithelial IL-23R signaling licenses protective IL-22 responses in intestinal inflammation. Cell Rep. 16, 2208–2218 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Powell, N. et al. Interleukin 6 increases production of cytokines by colonic innate lymphoid cells in mice and patients with chronic intestinal inflammation. Gastroenterology 149, 456–467.e15 (2015).

    Article  CAS  PubMed  Google Scholar 

  54. Peng, V., Jaeger, N. & Colonna, M. Innate lymphoid cells and inflammatory bowel disease. Adv. Exp. Med. Biol. 1365, 97–112 (2022).

    Article  PubMed  Google Scholar 

  55. Bauche, D. et al. LAG3+ regulatory T cells restrain interleukin-23-producing CX3CR1+ gut-resident macrophages during group 3 innate lymphoid cell-driven colitis. Immunity 49, 342–352 (2018).

    Article  CAS  PubMed  Google Scholar 

  56. Rankin, L. C. & Arpaia, N. Treg cells: a LAGging hand holds the double-edged sword of the IL-23 axis. Immunity 49, 201–203 (2018).

    Article  CAS  PubMed  Google Scholar 

  57. Powell, N. et al. Interleukin-22 orchestrates a pathological endoplasmic reticulum stress response transcriptional programme in colonic epithelial cells. Gut 69, 578–590 (2020).

    Article  CAS  PubMed  Google Scholar 

  58. Simmons, C. P. et al. Impaired resistance and enhanced pathology during infection with a noninvasive, attaching–effacing enteric bacterial pathogen, Citrobacter rodentium, in mice lacking IL-12 or IFN-gamma. J. Immunol. 168, 1804–1812 (2002).

    Article  CAS  PubMed  Google Scholar 

  59. Zundler, S. & Neurath, M. F. Interleukin-12: functional activities and implications for disease. Cytokine Growth Factor Rev. 26, 559–568 (2015).

    Article  CAS  PubMed  Google Scholar 

  60. 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 

  61. Pidasheva, S. et al. Functional studies on the IBD susceptibility gene IL23R implicate reduced receptor function in the protective genetic variant R381Q. PLoS ONE 6, e25038 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Di Meglio, P. et al. The IL23R R381Q gene variant protects against immune-mediated diseases by impairing IL-23-induced Th17 effector response in humans. PLoS ONE 6, e17160 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  63. Yu, R. Y., Brazaitis, J. & Gallagher, G. The human IL-23 receptor rs11209026 A allele promotes the expression of a soluble IL-23R-encoding mRNA species. J. Immunol. 194, 1062–1068 (2015).

    Article  CAS  PubMed  Google Scholar 

  64. Sivanesan, D. et al. IL23R (interleukin 23 receptor) variants protective against inflammatory bowel diseases (IBD) display loss of function due to impaired protein stability and intracellular trafficking. J. Biol. Chem. 291, 8673–8685 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Beaudoin, M. et al. Deep resequencing of GWAS loci identifies rare variants in CARD9, IL23R and RNF186 that are associated with ulcerative colitis. PLoS Genet. 9, e1003723 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. 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 

  67. Zwiers, A. et al. Cutting edge: a variant of the IL-23R gene associated with inflammatory bowel disease induces loss of microRNA regulation and enhanced protein production. J. Immunol. 188, 1573–1577 (2012).

    Article  CAS  PubMed  Google Scholar 

  68. 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 

  69. Brant, S. R. et al. Genome-wide association study identifies African-specific susceptibility loci in African Americans with inflammatory bowel disease. Gastroenterology 152, 206–217 (2016).

    Article  PubMed  Google Scholar 

  70. Huang, C. et al. Characterization of genetic loci that affect susceptibility to inflammatory bowel diseases in African Americans. Gastroenterology 149, 1575–1586 (2015).

    Article  CAS  PubMed  Google Scholar 

  71. Barrett, J. C. et al. Genome-wide association defines more than 30 distinct susceptibility loci for Crohn’s disease. Nat. Genet. 40, 955–962 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Ben-Selma, W. & Boukadida, J. IL23R(Arg381Gln) functional polymorphism is associated with active pulmonary tuberculosis severity. Clin. Vaccin. Immunol. 19, 1188–1192 (2012).

    Article  CAS  Google Scholar 

  73. Zakrzewski, M. et al. IL23R-protective coding variant promotes beneficial bacteria and diversity in the ileal microbiome in healthy individuals without inflammatory bowel disease. J. Crohns Colitis 13, 451–461 (2019).

    Article  PubMed  Google Scholar 

  74. Neurath, M. F., Fuss, I., Kelsall, B. L., Stuber, E. & Strober, W. Antibodies to interleukin 12 abrogate established experimental colitis in mice. J. Exp. Med. 182, 1281–1290 (1995).

    Article  CAS  PubMed  Google Scholar 

  75. Davidson, N. J. et al. IL-12, but not IFN-γ, plays a major role in sustaining the chronic phase of colitis in IL-10-deficient mice. J. Immunol. 161, 3143–3149 (1998).

    Article  CAS  PubMed  Google Scholar 

  76. Hue, S. et al. Interleukin-23 drives innate and T cell-mediated intestinal inflammation. J. Exp. Med. 203, 2473–2483 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. 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 

  78. 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).

    Article  CAS  PubMed  Google Scholar 

  79. Monteleone, G., Parrello, T., Luzza, F. & Pallone, F. Response of human intestinal lamina propria T lymphocytes to interleukin 12: additive effects of interleukin 15 and 7. Gut 43, 620–628 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Mannon, P. J. et al. Anti-interleukin-12 antibody for active Crohn’s disease. N. Engl. J. Med. 351, 2069–2079 (2004).

    Article  CAS  PubMed  Google Scholar 

  81. Globig, A. M. et al. Ustekinumab inhibits T follicular helper cell differentiation in patients with Crohn’s disease. Cell Mol. Gastroenterol. Hepatol. 11, 1–12 (2021).

    Article  CAS  PubMed  Google Scholar 

  82. Wiekowski, M. T. et al. Ubiquitous transgenic expression of the IL-23 subunit p19 induces multiorgan inflammation, runting, infertility, and premature death. J. Immunol. 166, 7563–7570 (2001).

    Article  CAS  PubMed  Google Scholar 

  83. Yen, D. et al. IL-23 is essential for T cell-mediated colitis and promotes inflammation via IL-17 and IL-6. J. Clin. Invest. 116, 1310–1316 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Elson, C. O. et al. Monoclonal anti-interleukin 23 reverses active colitis in a T cell-mediated model in mice. Gastroenterology 132, 2359–2370 (2007).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Izcue, A. et al. Interleukin-23 restrains regulatory T cell activity to drive T cell-dependent colitis. Immunity 28, 559–570 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Chen, L. et al. Diet modifies colonic microbiota and CD4+ T-cell repertoire to induce flares of colitis in mice with myeloid-cell expression of interleukin 23. Gastroenterology 155, 1177–1191 (2018).

    Article  CAS  PubMed  Google Scholar 

  88. He, Z. et al. Food colorants metabolized by commensal bacteria promote colitis in mice with dysregulated expression of interleukin-23. Cell Metab. 33, 1358–1371 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Eftychi, C. et al. Temporally distinct functions of the cytokines IL-12 and IL-23 drive chronic colon inflammation in response to intestinal barrier impairment. Immunity 51, 367–380 (2019).

    Article  CAS  PubMed  Google Scholar 

  90. Cox, J. H. et al. Opposing consequences of IL-23 signaling mediated by innate and adaptive cells in chemically induced colitis in mice. Mucosal Immunol. 5, 99–109 (2012).

    Article  CAS  PubMed  Google Scholar 

  91. Becker, C. et al. Cutting edge: IL-23 cross-regulates IL-12 production in T cell-dependent experimental colitis. J. Immunol. 177, 2760–2764 (2006).

    Article  CAS  PubMed  Google Scholar 

  92. Aychek, T. et al. IL-23-mediated mononuclear phagocyte crosstalk protects mice from Citrobacter rodentium-induced colon immunopathology. Nat. Commun. 6, 6525 (2015).

    Article  CAS  PubMed  Google Scholar 

  93. 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 

  94. Rutgeerts, P. et al. Efficacy of ustekinumab for inducing endoscopic healing in patients with Crohn’s disease. Gastroenterology 155, 1045–1058 (2018).

    Article  CAS  PubMed  Google Scholar 

  95. Li, K. et al. Effects of ustekinumab on histologic disease activity in patients with Crohn’s disease. Gastroenterology 157, 1019–1031 (2019).

    Article  CAS  PubMed  Google Scholar 

  96. Sands, B. E. et al. Ustekinumab versus adalimumab for induction and maintenance therapy in biologic-naive patients with moderately to severely active Crohn’s disease: a multicentre, randomised, double-blind, parallel-group, phase 3b trial. Lancet 399, 2200–2211 (2022).

    Article  CAS  PubMed  Google Scholar 

  97. Danese, S. et al. Treat to target versus standard of care for patients with Crohn’s disease treated with ustekinumab (STARDUST): an open-label, multicentre, randomised phase 3b trial. Lancet Gastroenterol. Hepatol. 7, 294–306 (2022).

    Article  PubMed  Google Scholar 

  98. D’Haens, G. et al. Risankizumab as induction therapy for Crohn’s disease: results from the phase 3 ADVANCE and MOTIVATE induction trials. Lancet 399, 2015–2030 (2022).

    Article  PubMed  Google Scholar 

  99. Ferrante, M. et al. Risankizumab as maintenance therapy for moderately to severely active Crohn’s disease: results from the multicentre, randomised, double-blind, placebo-controlled, withdrawal phase 3 FORTIFY maintenance trial. Lancet 399, 2031–2046 (2022).

    Article  CAS  PubMed  Google Scholar 

  100. Ferrante, M. et al. OP25 Patients with moderate to severe Crohn’s disease with and without prior biologic failure demonstrate improved endoscopic outcomes with risankizumab: results from phase 3 induction and maintenance trials. J. Crohns Colitis 16, i027–i028 (2022).

    Article  Google Scholar 

  101. Bossuyt, P. et al. OP40 Efficacy of risankizumab induction and maintenance therapy by baseline Crohn’s disease location: post hoc analysis of the phase 3 ADVANCE, MOTIVATE, and FORTIFY studies. J. Crohns Colitis 16, i048 (2022).

    Article  Google Scholar 

  102. Sandborn, W. J. et al. The efficacy and safety of guselkumab induction therapy in patients with moderately to severely active Crohn’s disease: week 12 interim analyses from the phase 2 GALAXI 1 study. U. Eur. Gastroenterol. 8, 64 (2020).

    Google Scholar 

  103. Sandborn, W. J. et al. Guselkumab for the treatment of Crohn’s disease: Induction results from the Phase 2 GALAXI-1 study. Gastroenterology https://doi.org/10.1053/j.gastro.2022.01.047 (2022).

    Article  PubMed  Google Scholar 

  104. Danese, S. et al. OP24 Clinical efficacy and safety of guselkumab maintenance therapy in patients with moderately to severely active Crohn’s disease: week 48 analyses from the phase 2 GALAXI 1 study. J. Crohns Colitis 16, i026–i027 (2022).

    Article  Google Scholar 

  105. Sands, B. E. et al. Efficacy and safety of MEDI2070, an antibody against interleukin 23, patients with moderate to severe Crohn’s disease: a phase 2a study. Gastroenterology 153, 77–86 (2017).

    Article  CAS  PubMed  Google Scholar 

  106. Sands, B. E. et al. 1003 — Efficacy and safety of mirikizumab (LY3074828) in a phase 2 study of patients with Crohn’s disease. Gastroenterology 156, S216 (2019).

    Article  Google Scholar 

  107. Sands, B. E. et al. Efficacy and safety of mirikizumab after 52-weeks maintenance treatment in patients with moderate-to-severe Crohn’s disease. Gastroenterology 160, S37 (2021).

    Article  Google Scholar 

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

    PubMed  Google Scholar 

  109. Sands, B. E. et al. Ustekinumab as induction and maintenance therapy for ulcerative colitis. N. Engl. J. Med. 381, 1201–1214 (2019).

    Article  CAS  PubMed  Google Scholar 

  110. Leong, R. et al. DOP55 Long-term outcomes after histologic-endoscopic mucosal healing: results from the UNIFI study in ulcerative colitis. J. Crohns Colitis 16, i102–i103 (2022).

    Article  Google Scholar 

  111. D’Haens, G. et al. OP26 Efficacy and safety of mirikizumab as induction therapy in patients with moderately to severely active ulcerative colitis: results from the phase 3 LUCENT-1 study. J. Crohns Colitis 16, i028–i029 (2022).

    Article  Google Scholar 

  112. Dignass, A. et al. OP23 The efficacy and safety of guselkumab induction therapy in patients with moderately to severely active ulcerative colitis: phase 2b QUASAR study results through week 12. J. Crohns Colitis 16, i025–i026 (2022).

    Article  Google Scholar 

  113. Sands, B. E. et al. OP36 Efficacy and safety of combination induction therapy with guselkumab and golimumab in participants with moderately-to-severely active ulcerative colitis: results through week 12 of a phase 2a randomized, double-blind, active-controlled, parallel-group, multicenter, proof-of-concept study. J. Crohns Colitis 16, i042–i043 (2022).

    Article  Google Scholar 

  114. Sandborn, W. J. et al. Safety of ustekinumab in inflammatory bowel disease: pooled safety analysis of results from phase 2/3 studies. Inflamm. Bowel Dis. 27, 994–1007 (2021).

    Article  PubMed  Google Scholar 

  115. Fiorentino, D. et al. Risk of malignancy with systemic psoriasis treatment in the Psoriasis Longitudinal Assessment Registry. J. Am. Acad. Dermatol. 77, 845–854 (2017).

    Article  PubMed  Google Scholar 

  116. Honap, S. et al. Effectiveness and safety of ustekinumab in inflammatory bowel disease: a systematic review and meta-analysis. Dig. Dis. Sci. 67, 1018–1035 (2022).

    Article  PubMed  Google Scholar 

  117. Martinez-Barricarte, R. et al. Human IFN-γ immunity to mycobacteria is governed by both IL-12 and IL-23. Sci. Immunol. 3, eaau6759 (2018).

    Article  PubMed  Google Scholar 

  118. Teng, M. W. et al. IL-12 and IL-23 cytokines: from discovery to targeted therapies for immune-mediated inflammatory diseases. Nat. Med. 21, 719–729 (2015).

    Article  CAS  PubMed  Google Scholar 

  119. Meeks, K. D., Sieve, A. N., Kolls, J. K., Ghilardi, N. & Berg, R. E. IL-23 is required for protection against systemic infection with Listeria monocytogenes. J. Immunol. 183, 8026–8034 (2009).

    Article  CAS  PubMed  Google Scholar 

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

    Article  PubMed  Google Scholar 

  121. Shih, V. F. et al. Homeostatic IL-23 receptor signaling limits Th17 response through IL-22-mediated containment of commensal microbiota. Proc. Natl Acad. Sci. USA 111, 13942–13947 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  122. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Patel, D. D. & Kuchroo, V. K. Th17 cell pathway in human immunity: lessons from genetics and therapeutic interventions. Immunity 43, 1040–1051 (2015).

    Article  CAS  PubMed  Google Scholar 

  124. Schulz, S. M. et al. Protective immunity to systemic infection with attenuated Salmonella enterica serovar enteritidis in the absence of IL-12 is associated with IL-23-dependent IL-22, but not IL-17. J. Immunol. 181, 7891–7901 (2008).

    Article  CAS  PubMed  Google Scholar 

  125. Schmitt, H. et al. Expansion of IL-23 receptor bearing TNFR2+ T cells is associated with molecular resistance to anti-TNF therapy in Crohn’s disease. Gut 68, 814–828 (2018).

    Article  PubMed  Google Scholar 

  126. Sandborn, W. et al. OP303 efficacy and safety of mirikizumab (LY3074828) in patients with moderate-to-severe ulcerative colitis in a phase 2 study. U. Eur. Gastroenterol. J. 6, A119–A120 (2018).

    Google Scholar 

  127. Doherty, M. K. et al. Fecal microbiota signatures are associated with response to ustekinumab therapy among Crohn’s disease patients. mBio 9, e02120–02117 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Sandborn, W. J. et al. Efficacy and safety of mirikizumab in a randomized phase 2 study of patients with ulcerative colitis. Gastroenterology 158, 537–549 (2020).

    Article  CAS  PubMed  Google Scholar 

  129. 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 

  130. Gisbert, J. P. & Chaparro, M. Predictors of primary response to biologic treatment [anti-TNF, vedolizumab, and ustekinumab] in patients with inflammatory bowel disease: from basic science to clinical practice. J. Crohns Colitis 14, 694–709 (2020).

    Article  PubMed  Google Scholar 

  131. Dalal, R. S. et al. Predictors and outcomes of ustekinumab dose intensification in ulcerative colitis: a multicenter cohort study. Clin. Gastroenterol. Hepatol. https://doi.org/10.1016/j.cgh.2021.03.028 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  132. Dalal, R. S., Njie, C., Marcus, J., Gupta, S. & Allegretti, J. R. Predictors of ustekinumab failure in Crohn’s disease after dose intensification. Inflamm. Bowel Dis. 27, 1294–1301 (2021).

    Article  PubMed  Google Scholar 

  133. Lefevre, P. L. C., Shackelton, L. M. & Vande Casteele, N. Factors influencing drug disposition of monoclonal antibodies in inflammatory bowel disease: implications for personalized medicine. BioDrugs 33, 453–468 (2019).

    Article  PubMed  Google Scholar 

  134. Wang, Z. et al. Population pharmacokinetic-pharmacodynamic model-based exploration of alternative ustekinumab dosage regimens for patients with Crohn’s disease. Br. J. Clin. Pharmacol. 88, 323–335 (2022).

    Article  CAS  PubMed  Google Scholar 

  135. Bots, S. J. et al. Anti-drug antibody formation against biologic agents in inflammatory bowel disease: a systematic review and meta-analysis. BioDrugs 35, 715–733 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  137. Verstockt, B. et al. Ustekinumab exposure-outcome analysis in Crohn’s disease only in part explains limited endoscopic remission rates. J. Crohns Colitis 13, 864–872 (2019).

    Article  PubMed  Google Scholar 

  138. Hanzel, J. et al. Peak concentrations of ustekinumab after intravenous induction therapy identify patients with Crohn’s disease likely to achieve endoscopic and biochemical remission. Clin. Gastroenterol. Hepatol. 19, 111–118 (2021).

    Article  CAS  PubMed  Google Scholar 

  139. Adedokun, O. J. et al. Ustekinumab pharmacokinetics and exposure response in a phase 3 randomized trial of patients with ulcerative colitis. Clin. Gastroenterol. Hepatol. 18, 2244–2255 (2020).

    Article  CAS  PubMed  Google Scholar 

  140. Alsoud, D., Vermeire, S. & Verstockt, B. Monitoring vedolizumab and ustekinumab drug levels in patients with inflammatory bowel disease: hype or hope. Curr. Opin. Pharmacol. 55, 17–30 (2020).

    Article  CAS  PubMed  Google Scholar 

  141. D’Haens, G. R. et al. 775a risankizumab induction therapy in patients with moderate-to-severe Crohn’s disease with intolerance or inadequate response to conventional and/or biologic therapy: results from the phase 3 ADVANCE study. Gastroenterology 161, e28 (2021).

    Article  Google Scholar 

  142. Sands, B. E. et al. Efficacy and safety of mirikizumab in a randomized phase 2 study of patients with Crohn’s disease. Gastroenterology 158, 537–549 (2021).

    Google Scholar 

  143. Danese, S. et al. OP28 The effect of guselkumab induction therapy on early clinical outcome measures in patients with Moderately to Severely Active Crohn’s Disease: Results from the phase 2 GALAXI 1 study. J. Crohns Colitis 15, S027–S028 (2021).

    Article  Google Scholar 

  144. Strober, B. et al. Efficacy of risankizumab in patients with moderate-to-severe plaque psoriasis by baseline demographics, disease characteristics and prior biologic therapy: an integrated analysis of the phase III UltIMMa-1 and UltIMMa-2 studies. J. Eur. Acad. Dermatol. Venereol. 34, 2830–2838 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  145. Irving, P. M. et al. OP02 Ustekinumab versus adalimumab for induction and maintenance therapy in moderate-to-severe Crohn’s disease: the SEAVUE study. J. Crohns Colitis 15, S001–S002 (2021).

    Article  Google Scholar 

  146. Singh, S. et al. Comparative efficacy and safety of biologic therapies for moderate-to-severe Crohn’s disease: a systematic review and network meta-analysis. Lancet Gastroenterol. Hepatol. 6, 1002–1014 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  147. Singh, S., Murad, M. H., Fumery, M., Dulai, P. S. & Sandborn, W. J. First- and second-line pharmacotherapies for patients with moderate to severely active ulcerative colitis: an updated network meta-analysis. Clin. Gastroenterol. Hepatol. 18, 2179–2191 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  148. Burr, N. E., Gracie, D. J., Black, C. J. & Ford, A. C. Efficacy of biological therapies and small molecules in moderate to severe ulcerative colitis: systematic review and network meta-analysis. Gut https://doi.org/10.1136/gutjnl-2021-326390 (2021).

    Article  PubMed  Google Scholar 

  149. Lasa, J. S., Olivera, P. A., Danese, S. & Peyrin-Biroulet, L. Efficacy and safety of biologics and small molecule drugs for patients with moderate-to-severe ulcerative colitis: a systematic review and network meta-analysis. Lancet Gastroenterol. Hepatol. 7, 161–170 (2022).

    Article  PubMed  Google Scholar 

  150. Guillo, L., D’Amico, F., Danese, S. & Peyrin-Biroulet, L. Ustekinumab for extra-intestinal manifestations of inflammatory bowel disease: a systematic literature review. J. Crohns Colitis 15, 1236–1243 (2021).

    Article  PubMed  Google Scholar 

  151. Li, S. J., Perez-Chada, L. M. & Merola, J. F. TNF inhibitor-induced psoriasis: proposed algorithm for treatment and management. J. Psoriasis Psoriat. Arthritis 4, 70–80 (2019).

    Article  Google Scholar 

  152. Puig, L., Morales-Munera, C. E., Lopez-Ferrer, A. & Geli, C. Ustekinumab treatment of TNF antagonist-induced paradoxical psoriasis flare in a patient with psoriatic arthritis: case report and review. Dermatology 225, 14–17 (2012).

    Article  PubMed  Google Scholar 

  153. Sandborn, W. J. et al. Five-year efficacy and safety of ustekinumab treatment in Crohn’s disease: the IM-UNITI trial. Clin. Gastroenterol. Hepatol. 20, 578–590 (2022).

    Article  CAS  PubMed  Google Scholar 

  154. Garg, R. et al. Real-world effectiveness and safety of ustekinumab in elderly Crohn’s disease patients. Dig. Dis. Sci. https://doi.org/10.1007/s10620-021-07117-9 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  155. Hayashi, M. et al. Efficacy and safety of ustekinumab treatment in elderly patients with psoriasis. J. Dermatol. 41, 974–980 (2014).

    Article  CAS  PubMed  Google Scholar 

  156. Ferrante, M. et al. Long-term safety and efficacy of risankizumab treatment in patients with Crohn’s disease: results from the phase 2 open-label extension study. J. Crohns Colitis 15, 2001–2010 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

The authors would like to thank L. M. Shackelton and S. Donegan for critical technical review and editing. B.V. is supported by the Clinical Research Fund (KOOR) at the University Hospitals Leuven and the Research Council at KU Leuven. N.V.C. is supported in part by the NIDDK-funded San Diego Digestive Diseases Research Center (P30 DK120515).

Author information

Authors and Affiliations

  1. University Hospitals Leuven, Department of Gastroenterology and Hepatology, KU Leuven, Leuven, Belgium

    Bram Verstockt & Severine Vermeire

  2. KU Leuven Department of Chronic Diseases and Metabolism, Translational Research Center for Gastrointestinal Disorders (TARGID), Leuven, Belgium

    Bram Verstockt & Severine Vermeire

  3. Inflammatory Bowel Disease Unit, Hospital Clínic de Barcelona, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Barcelona, Spain

    Azucena Salas, Julian Panes & Marisol Veny

  4. Dr. Henry D. Janowitz Division of Gastroenterology, Icahn School of Medicine at Mount Sinai, New York, NY, USA

    Bruce E. Sands & Saurabh Mehandru

  5. Department of Medicine, Yale University, New Haven, CT, USA

    Clara Abraham

  6. Zane Cohen Centre for Digestive Diseases, Division of Gastroenterology & Hepatology, Temerty Faculty of Medicine, Mount Sinai Hospital, University of Toronto, Toronto, Ontario, Canada

    Haim Leibovitzh

  7. Department of Medicine 1, University Erlangen-Nürnberg, Erlangen, Germany

    Markus F. Neurath

  8. Deutsches Zentrum Immuntherapie DZI, University Erlangen-Nürnberg, Erlangen, Germany

    Markus F. Neurath

  9. Department of Medicine, University of California San Diego, La Jolla, CA, USA

    Niels Vande Casteele

  10. Gastroenterology and Endoscopy, IRCCS Ospedale San Raffaele, Milan, Italy

    Silvio Danese

  11. University Vita-Salute San Raffaele, Milan, Italy

    Silvio Danese

  12. Amsterdam UMC, Amsterdam Medical Center, University of Amsterdam, Department of Gastroenterology and Hepatology, Amsterdam, Netherlands

    Geert D’Haens

  13. Metabolism Research Institute, Amsterdam UMC, University of Amsterdam, Amsterdam, Netherlands

    Geert D’Haens

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

    Lars Eckmann & William J. Sandborn

  15. Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA

    William A. Faubion

  16. Departments of Medicine and Epidemiology and Biostatistics, Western University, London, Ontario, Canada

    Brian G. Feagan & Vipul Jairath

  17. Division of Gastroenterology and Hepatology, Departments of Medicine and Community Health Sciences, University of Calgary, Calgary, Alberta, Canada

    Christopher Ma

  18. Precision Institute of Immunology, Icahn School of Medicine at Mount Sinai, New York, NY, USA

    Saurabh Mehandru

  19. Department of Gastroenterology, Hepatology and Nutrition, Digestive Diseases and Surgery Institute, Cleveland Clinic Foundation, Cleveland, OH, USA

    Florian Rieder

  20. Department of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH, USA

    Florian Rieder

  21. Mount Sinai Hospital IBD Centre, University of Toronto, Toronto, Ontario, Canada

    Mark S. Silverberg

  22. Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Milan, Italy

    Stefania Vetrano

  23. Laboratory of Gastrointestinal Immunopathology, IRCCS Humanitas Research Hospital — IRCCS, Rozzano, Milan, Italy

    Stefania Vetrano

Authors
  1. Bram Verstockt
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Azucena Salas
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Bruce E. Sands
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Clara Abraham
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Haim Leibovitzh
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Markus F. Neurath
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Niels Vande Casteele
    View author publications

    You can also search for this author in PubMed Google Scholar

Consortia

Alimentiv Translational Research Consortium (ATRC)

  • Silvio Danese
  • , Geert D’Haens
  • , Lars Eckmann
  • , William A. Faubion
  • , Brian G. Feagan
  • , Vipul Jairath
  • , Christopher Ma
  • , Saurabh Mehandru
  • , Julian Panes
  • , Florian Rieder
  • , William J. Sandborn
  • , Mark S. Silverberg
  • , Marisol Veny
  • , Severine Vermeire
  •  & Stefania Vetrano

Contributions

The authors contributed equally to all aspects of the article.

Corresponding author

Correspondence to Niels Vande Casteele.

Ethics declarations

Competing interests

Alimentiv Inc. is an academic gastrointestinal contract research organization (CRO), operating under the Alimentiv Health Trust. Alimentiv Inc. provides comprehensive clinical trial services, precision medicine offerings, and centralized imaging solutions for endoscopy, histopathology, and other imaging modalities. The beneficiaries of the Alimentiv Health Trust are the employees of the enterprises it holds. None of the authors is a beneficiary of the Alimentiv Health Trust. B.V., N.V.C., G.D’H., B.G.F., V.J., C.M., W.J.S. and A.S. are consultants to Alimentiv Inc. and have a primary academic appointment; they do not hold equity positions or shares in Alimentiv Inc. B.V. reports research support from AbbVie, Biora Therapeutics, Pfizer, Sossei Heptares and Takeda; speaker’s fees from Abbvie, Biogen, Bristol Myers Squibb, Celltrion, Chiesi, Falk, Ferring, Galapagos, Janssen, MSD, Pfizer, R-Biopharm, Takeda, Truvion and Viatris; and consultancy fees from Abbvie, Alimentiv, Applied Strategic, Atheneum, Biora Therapeutics, Bristol Myers Squibb, Galapagos, Guidepont, Inotrem, Inotrem, Ipsos, Janssen, Mylan, Progenity, Sandoz, Sosei Heptares, Takeda Tillots Pharma and Viatris. A.S. reports research grants from Roche-Genentech, Abbvie, GSK, Scipher Medicine, Alimentiv Inc, Boehringer Ingelheim and Origo Biopharma; consulting fees from Genentech, GSK, Pfizer, HotSpot Therapeutics, Alimentiv, Origo Biopharma and Boxer Capital. B.E.S. reports research grants from Takeda, Pfizer, Theravance Biopharma R&D and Janssen; consulting fees from 4D Pharma, Abivax, Abbvie, Alimentiv, Allergan, Amgen, Arena Pharmaceuticals, AstraZeneca, Bacainn Therapeutics, Boehringer-Ingelheim, Boston Pharmaceuticals, Bristol-Myers Squibb, Calibr, Capella Bioscience, Celgene, Celltrion Healthcare, ClostraBio, Enthera, F.Hoffmann-La Roche, Ferring, Galapagos, Gilead, GlaxoSmithKline, GossamerBio, Immunic, Index Pharmaceuticals, Innovation Pharmaceuticals, Ironwood Pharmaceuticals, Janssen, Kaleido, Kallyope, Lilly, MiroBio, Morphic Therapeutic, Oppilan Pharma, OSE Immunotherapeutics, Otsuka, Palatin Technologies, Pfizer, Progenity, Prometheus Biosciences, Prometheus Laboratories, Protagonist Therapeutics, Q32 Bio, Redhill Biopharma, Rheos Medicines, Salix Pharmaceuticals, Seres Therapeutics, Shire, Sienna Biopharmaceuticals, Sun Pharma, Surrozen, Takeda, Target PharmaSolutions, Teva Branded Pharmaceutical Products R&D, Thelium, Theravance Biopharma R&D, TLL Pharma, USWM Enterprises, Ventyx Biosciences, Viela Bio, Vivante Health and Vivelix Pharmaceuticals; and holds stock in Vivante Health and Ventyx Biosciences. M.F.N. reports consulting fees from MSD Sharp & Dohme GmbH, PPM Services, IFM Therapeutics, Sterna Biologicals, Boehringer Ingleheim GmbH and Co. KG, Janssen Cilag GmbH, Pentax Europe GmbH, Takeda, Amgen GmbH, Pfizer Pharma, Falk Foundation e.v., Abbvie and Celgene. N.V.C. reports research grants and personal fees from R-Biopharm, Takeda and UCB; and personal fees from Alimentiv, Inc (formerly Robarts Clinical Trials, Inc), Celltrion and Prometheus. These activities were all outside the submitted work. C.A. and H.L. declare no competing interests. The competing interests of the Alimentiv Translational Research Consortium Member Authors are listed in Supplementary Box 1.

Peer review

Peer review information

Nature Reviews Gastroenterology & Hepatology thanks Giovanni Monteleone and Herbert Tilg for their contribution to the peer review of this work.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Verstockt, B., Salas, A., Sands, B.E. et al. IL-12 and IL-23 pathway inhibition in inflammatory bowel disease. Nat Rev Gastroenterol Hepatol 20, 433–446 (2023). https://doi.org/10.1038/s41575-023-00768-1

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41575-023-00768-1

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing