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Headline

Events

The Pathophysiology

CHAPTER 2

A disease with many unknowns, has many treatment challenges

Crohn’s disease – many unknowns

There is no known cause or cure for Crohn’s disease; however, with a better understanding of the pathophysiology, the ambition of treatment is no longer short-term symptom control but more targeted, long-term disease modification. 1
Recent evidence has suggested that Crohn’s disease is caused by a combination of factors including genetics, immune dysregulation, barrier dysfunction and change in microbial flora. 2

Crohn’s disease – many treatment challenges

There are high treatment failure rates with existing biologic therapies – for example, over 50 % patients do not respond to anti-TNFs.[4,5]

These patients need more effective treatment options to improve overall disease management and optimise their outcomes.3

Inappropriate immune response

  • Could be linked to increased uptake of bacteria, leading to activation of innate immune responses 6
  • Cytokines are known to play a crucial role as they control multiple aspects of the inflammatory response 7
  • Imbalance between pro-inflammatory and anti-inflammatory cytokines stops the resolution of inflammation and instead leads to disease perpetuation and tissue destruction 7

Host genetic susceptibility

  • The relative risk is elevated in first-degree relatives, higher still in dizygotic twins and highest among monozygotes 8
  • More than 160 IBD associated genes, at least 70 of which are specific to Crohn’s disease 8
  • There is an excess of pro-inflammatory cytokines, primarily IL-12 and interferon IFN-γ - these cells perpetuate the inflammatory response 8

Environmental risk factors

  • One of the strongest identified environmental risk factors is smoking 9,10
  • Light and heavy smokers have been reported to be at significantly higher risk of having active disease as well as hospitalisations due to Crohn’s disease 10
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Understanding the disease pathways at a molecular level is key

  1. A.
    When antigen-presenting cells are activated many cytokines are produced. 11,12
  2. B.
    Increased amounts of the regulatory cytokine IL 12 drive the differentiation of naïve T cells (Th0 cells) into Type 1 helper T cells (Th1 cells). 11,12
  3. C.
    Antigen-presenting cells also produce TGF-β, TL1A and IL 6, which are involved in the differentiation of Th17 cells. Increased amounts of the regulatory cytokine IL 23 promote the survival and expansion of the Th17 cell lineage. 11,12
  4. D.
    Th1 cells produce proinflammatory effector cytokines such as IFNγ, TNF and IL 6, whereas Th17 cells are a source of the proinflammatory effector cytokines IL 17A, IL 17F, IL 21 and IL 22. 11,12
  5. E.
    These proinflammatory cytokines are thought to lead to epithelial tissue damage and further activation of immune cells from local and systemic sources, contributing to uncontrolled, chronic inflammation. 7
diagram

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References:

  1. 1. Iacucchi M et al. Therap Adv Gastroenterol. 2011;4: 129–143.
  2. 2. Gyires K et al. Curr Pharm Des. 2014;20:1063–81.
  3. 3. Gordon JP et al. Eur J Gastroenterol Hepatol. 2015;27:804–12.
  4. 4. Oussalah A et al. Am J Gastroenterol. 2010; 105:2617–2625.
  5. 5. Grau-Mdel C et al. Dig Liver Dis. 2016;48:613–619.
  6. 6. Sartor RB. Nat Clin Pract Gastroenterol Hepatol. 2006;3:390–407.
  1. 7. Neurath MF. Nat Rev Immunol. 2014;14:329–42.
  2. 8. Randall CW et al. Therap Adv Gastroenterol. 2015;8:143–59.
  3. 9. Jones DT et al. Am J Gastroenterol. 2008;103:2382–93.
  4. 10. Seksik P et al. Inflamm Bowel Dis. 2009;15:734–41.
  5. 11. Melmed GY et al. Nat Rev Gastroenterol Hepatol. 2010;7: 110-117.
  6. 12. Tato CM et al. Nature. 2006;441: 166–168.
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