Pathophysiology

Learn about the mechanism by which Crohn’s disease may develop, its clinical presentation, and how unmet needs in symptom management can contribute to the way in which the condition impacts patients.

Pathogenesis

Crohn’s disease is caused by a failure to defend against intestinal microbes, this failure arises from (Matricon et al., 2010):

  • impairment of the epithelial mucosal barrier
  • altered host immune responses.

There are three stages (Matricon et al., 2010):

Figure 4. Pathogenesis of Crohn’s disease.

Figure 4. Pathogenesis of Crohn’s disease (Matricon et al., 2010).

Intestinal permeability can be increased via a range of means, such as changes to tight junctions between cells in the epithelium, with intestinal permeability being increased in 36% of Crohn’s disease patients (Matricon et al., 2010). In Crohn’s disease, other changes may include defective production of antimicrobial defensins from Paneth cells (Wehkamp et al., 2016), while pathogenic strains of Escherichia coli have been associated with the mucosa (Matricon et al., 2010).

Inflammatory responses to invading bacteria arise through both innate and adaptive immunity (Wehkamp et al., 2016). The genetic profile of the host can also affect such responses (Matricon et al., 2010).

Under normal physiological conditions, the intestinal lamina propria contains immune cells and cytokines. Anti-inflammatory molecules, such as transforming growth factor β (TGF-β) and interleukin-10 (IL-10) downregulate immune responses, while pro-inflammatory mediators reduce entry of gut flora and defend against pathogens, with a balance between regulatory (Treg) and T helper (Th) cells being maintained (Abraham and Cho, 2009).

Figure 5. The intestinal immune system.

Figure 5. The intestinal immune system (adapted from Abraham and Cho, 2009). α4β7, Integrin α4β7; Th2, T helper 2 cell; Th17, T helper 17 cell; Treg, Regulatory T cell.

However, within the intestinal mucosa of patients with Crohn’s disease, there are increased levels of the pro-inflammatory cytokines IL-17, IFNγ and TNFα (Abraham and Cho, 2009). Furthermore, IL-23, which promotes activation of JAK-STAT-mediated transcription, is also elevated in the colonic mucosa (Abraham and Cho, 2009). This increase in pro-inflammatory cytokine expression in Crohn’s disease could be a consequence of defects in T cell tolerance. Crohn’s disease has been linked to various polymorphisms of autophagy genes which have been linked to alterations in regulatory T cell development, function and the body’s ability to respond to them (Abraham and Cho, 2009).

Further details of the inflammatory pathways in IBD can be found in the sections of this Knowledge Centre that describe the pathology of ulcerative colitis and inflammatory targets.

Clinical presentation

Crohn’s disease is a chronic condition in which inflammation often affects all the layers of the bowel wall (Abraham and Cho, 2009). Any part of the gastrointestinal tract can be involved, but the pathology is generally discontinuous (Abraham and Cho, 2009; Feuerstein and Cheifitz, 2017). In addition to inflammation, patients may have strictures or fistulae (Abraham and Cho, 2009; Feuerstein and Cheifitz, 2017); surgery may be required (Feuerstein and Cheifitz, 2017).

Common symptoms of Crohn’s disease (Feuerstein and Cheifitz, 2017; Neurath, 2014):

  • diarrhoea
  • abdominal pain
  • fever
  • fatigue.

Endoscopy remains a key tool for the physical examination and diagnosis of Crohn’s disease. The below animation allows you to take a virtual tour through mild, moderate and severe Crohn’s disease, highlighting the characteristic skip lesions and cobblestone appearance. As the disease progresses towards a more severe phenotype, watch as increased inflammation results in greater colonic involvement and the development of additional complications such as strictures.

  • Crohn's disease

    Take a virtual journey through the bowel of a patient with Crohn’s disease. This animation is taken from the Gastro Ex app that allows gastroenterologists from all around the world to virtually diagnose conditions and perform life-like interventional procedures. Free for healthcare providers, the app can be downloaded from the App Store or on Google Play.

Compare this to a virtual journey through the bowel of a patient with ulcerative colitis here.

Symptoms are not always limited to the gastrointestinal tract and extra-intestinal manifestations can sometimes occur (Feuerstein and Cheifitz, 2017) including effects on the (Vavricka et al., 2015):

  • skin (e.g. erythema nodosum, pyoderma gangrenous)
  • joints (e.g. peripheral and axial arthropathies)
  • eyes (e.g. episcleritis, uveitis).

While some extra-intestinal manifestations are common to Crohn’s disease and ulcerative colitis, others are significantly more common in one of the IBD presentation. A prospective study of 566 IBD patients observed that erythema nodosum and peripheral arthritis were significantly more common in Crohn’s disease than ulcerative colitis. Meanwhile, the opposite was true for hepatobiliary manifestations, venous thromboembolism and arthralgias (Mendoza JL et al., 2015).

Treatment and unmet needs

Treatment of Crohn’s disease is determined by disease severity, location, subtype (i.e. inflammatory, structuring or penetrating) and risk of aggressive disease. A significant issue with the management of Crohn’s disease is that a considerable number of patients, approximately 30%, require surgery within just 5 years of diagnosis (Feuerstein and Cheifitz, 2017).

Treatment of Crohn’s disease aims to achieve remission and delay/prevent the need for surgery. Traditionally, this treatment has involved the use of conventional medications such as (Feuerstein and Cheifitz, 2017):  

  • 5-aminosalicylates
  • corticosteroids
  • thiopurines
  • classic immunosuppressive drugs.

Mesalamine, or 5-aminosalicyclic acid, is still commonly prescribed for Crohn’s disease despite studies suggesting it is in ineffective and should not be used. Meanwhile, thiopurines, such as azathioprine (AZA), are immunosuppressants that can be used to maintain remission in Crohn’s disease. While their use remains in guideline recommendations their efficacy has also been questioned recently. In addition to efficacy concerns, use of thiopurines is also limited by their side effect profile with 15–20% of patients discontinuing them due to adverse events (Feuerstein and Cheifitz, 2017).

With many conventional therapies offering no or limited efficacy and significant side effects, biological agents targeting tumour necrosis factor (TNF) have become a preferred option (Feuerstein and Cheifitz, 2017). However, even with these, as many as 30% of patients may not respond when initially treated, and in almost half, responses can decrease over time (Roda et al., 2016). A number of mechanisms have been proposed to explain the loss of response to anti-TNFα. In approximately 60% of patients exposed to infliximab, anti-drug antibodies can be detected, however, 25% of patients who lose response to infliximab have no detectable anti-drug antibodies indicating more than one mechanism is responsible. Possible mechanisms to explain the loss of response in the absence of anti-drug antibodies include increased antibody degradation by matrix metalloproteinases and mucosal cells, loss of antibody through the inflamed mucosa resulting in increased excretion, and presence of a pro-inflammatory state as a consequence of certain comorbidities such as obesity (Scaldaferri et al., 2016).

Uncontrolled disease is liable to be associated with substantial morbidity, adversely affecting patients’ quality of life and impairing their ability to work (Neurath, 2014). In the search for other treatments, attention has thus been directed towards the range of inflammatory targets that may drive pathogenesis.