Crohn's disease

Introduction

Crohn’s disease (CD), along with ulcerative colitis (UC), are the main subtypes of a group of conditions known as inflammatory bowel diseases (IBDs).

CD is a chronic, relapsing, inflammatory disease of the gastrointestinal tract that most commonly affects the distal ileum and the colon.1,2

Inflammation extends through all layers of the gut wall (transmural) and often occurs in a discontinuous pattern.1

Symptoms commonly include diarrhea, abdominal cramping, fever, anemia, weight loss,  and fatigue.1

CD is often diagnosed between the ages of 15 and 40.1

The course of disease typically involves periods of relapse and remission with recurrent cycles of inflammation leading to development of complications such as strictures and intestinal fistulas.3

CD and UC share similar characteristics and symptoms; however, the location and depth of inflammation varies. CD is characterized by discontinuous, transmural inflammation, whereas UC is typically associated with superficial inflammation, typically confined to the colon mucosa and following a continuous pattern.1

Some patients have features of both CD and UC, and are given a diagnosis of indeterminate colitis.4

Pathophysiology

In the healthy gut, mucin-covered epithelium provides an important barrier between commensal gut microbiota and host immune cells. In CD, however, damage to the mucinous layer increases permeability of the epithelial barrier thereby allowing commensal bacterial and microbial products to cross the gut lumen into the bowel wall.5

This results in acute intestinal inflammation accompanied by immune-cell activation and cytokine production. If initial acute inflammation is not resolved, chronic inflammation ensues, which can cause disease complications and tissue destruction, driven by mucosal cytokine responses.1

Cytokines play a central role in the pathogenesis of CD, where they exert various proinflammatory functions in the inflamed mucosa.1

 

IEC, intestinal epithelial cell; IL, interleukin; ILC, intestinal lymphoid cell; NK, natural killer; TGFβ, transforming growth factor beta; TNF, tumor necrosis factor.

Adapted from Neurath, 2014.1

Burden

IBD can result in lower health-related quality of life (HRQoL) and personal burden. Factors associated with lower HRQoL in patients with CD include work disability, increased disease activity, number of relapses, corticosteroid treatment, and hospitalization rate.6

CD affects 3.1 to 20.2 per 100 000 individuals per year.1

IBD is slightly more prevalent in women than in men (relative risk 1.53).7

In the last 50 years, there has been a steady increase in the incidence in Western countries and newly industrialized countries, possibly reflecting the westernization of diets and lifestyles.8

Impact

CD can be classified by disease activity (mainly the CD activity index [CDAI]), disease phenotype [Montréal classification], extent of disease, and response to therapy, for example, ‘steroid-refractory’ or steroid-dependent’ (http://www.e-guide.ecco-ibd.eu/diseaseinfo/classification). The CDAI is the gold standard for assessing disease activity in CD; however, due to its complexity, it is difficult to apply in everyday practice, therefore it is generally used in the research setting.

Classification by disease activity

SeverityCDAI equivalentExample clinical features
Mild 150–220 Ambulatory, eating and drinking, <10% weight loss. No features of obstruction, fever, dehydration, abdominal mass, or tenderness. C-reactive protein usually increased above the limit of normal
Moderate 220–450 Intermittent vomiting, or weight loss >10%. Treatment for mild disease ineffective, or tender mass. No overt obstruction. C-reactive protein elevated above the upper limit of normal
Severe >450 Cachexia (body mass index <18 kg/m2) or evidence of obstruction or abscess. Persistent symptoms despite intensive treatment

CDAI, Crohn's disease activity index. 

Source: http://www.e-guide.ecco-ibd.eu/diseaseinfo/classification.

The European Crohn’s and Colitis Organisation (ECCO) advocates the subtyping of CD according to the Montréal classification, which is based on the age at which the disease began, the location of lesions, and lesion behaviour (ABL).

Montréal classification

A (Age): A1: <16 years
A2: 17–40 years
A3: >40 years
L (Location): L1: Terminal ileum
L2: Colon
L3: Ileocolon
L4: Upper gastrointestinal tract
B (Behavior): B1: Non-stenosing and non-penetrating form of CD
B2: Stenosing form of CD
B3: Penetrating form, fistulising of CD
Existence of perianal disease P is added to B1–B3 when concomitant perianal disease is present

 

CD is considered localized where there is a total of ≤30 cm of disease, while extensive disease reflects a total of ≥100 cm of disease (http://www.e-guide.ecco-ibd.eu/diseaseinfo/classification).

CD is termed steroid-refractory when there is active disease despite >4 weeks high-dose steroid therapy. Steroid-dependent CD reflects a requirement for at least prednisolone 10 mg/day or budesonide 3 mg/day for at least 3 months to maintain remission, or relapse within 3 months of stopping steroid therapy (http://www.e-guide.ecco-ibd.eu/diseaseinfo/classification).

Extraintestinal manifestations are observed in 25% to 40% of patients with IBD.9

The most common manifestations involve the musculoskeletal and dermatologic systems. Other manifestations involve other organs, such as the liver, pancreas, kidneys, lungs, and eyes.

Treatment

Treatment for CD depends on its subtype, disease activity and severity, presence of complications and extra intestinal manifestations, but typically follows a ’step-up‘ approach.

 

TNF, tumor necrosis factor.

Modified from Sandborn et al, 2014.10

The reverse ‘top-down’ approach of starting treatment with a more potent agent is gaining acceptance among gastroenterologists. The ‘top-down’ approach is currently recommended by the ECCO for patients suffering from active disease.11

Biologics are administered when the patient no longer responds to, or experiences adverse events with, alternative treatment options. They are designed to inhibit specific components of the inflammatory immune response. Biologics targeting tumor necrosis factor (TNF)-α have become a central strategy in the treatment of CD.

Anti-TNFs

Anti-TNFs, such as adalimumab and infliximab, bind soluble and transmembrane TNF-α, preventing it from interacting with its two receptors (TNFRI and TNFRII), and preventing TNF-α mediated signaling. This may affect various cells of the immune system. The most prominent effects of anti-TNF are suppression of T-cells in the inflamed mucosa and resolution of granulomas, which are common in patients with CD.12

Additional, non-TNFR modes of action require binding of the anti-TNF to the transmembrane form of TNF-α and most often result in the death of the target cell.13


IBD, inflammatory bowel disease; MoA, mode of action; mAb, monoclonal antibody; s/tmTNF, soluble/transmembrane tumor necrosis factor receptor.  

Adapted from Vande Casteele and Sandborn, 2015.13

Anti-TNF agents have demonstrated high clinical efficacy, tolerability, and positive impact on patient’s quality of life in the clinic.11

Other targets

Another biologic agent approved for the treatment of CD is ustekinumab, a monoclonal antibody targeting p40 subunit of interleukin (IL)-12 and IL-23, thereby preventing signaling via these cytokines. IL-12 and IL-23 proinflammatory cytokines induce T-cell proliferation and activation and are linked to the pathophysiological changes accompanying CD and other immune-mediated inflammatory diseases.14

Guidelines

Guidelines for the treatment of CD are available from ECCO: (https://www.ecco-ibd.eu/publications/ecco-guidelines-science/published-ecco-guidelines.html).11

  • The therapeutic goal for CD is to induce and maintain clinical remission
  • The ECCO guidelines recommend a ‘step-up’ approach of adding therapies if first-line approaches are unsuccessful within an appropriate period is commonly used
  • Decisive treatment with a potent agent (‘top down’ approach) at an early stage may be preferred by a patient with symptoms of active disease
  • The choice of steroid or anti-TNF strategy at induction depends on the activity, extent, location and behaviour of disease

Support

Additional information

You can find additional information about CD by following these links:

European Crohn’s and Colitis Organisation:

https://www.ecco-ibd.eu/

NHS Choices:

https://www.nhs.uk/conditions/crohns-disease/

Crohn’s & Colitis UK:

https://www.crohnsandcolitis.org.uk/

European Federation of Crohn's & Ulcerative Colitis Associations

http://www.efcca.org/en

1. Neurath MF. Nat Rev Immunol. 2014;14:32942.

2. Ponder A, Long MD. Clin Epidemiol. 2013;5:23747.

3. Adegbola SO, et al. Int J Mol Sci. 2018;19(8) pii: E2244.

4. Magro F, et al. J Crohns Colitis. 2017;11:64970.

5. Baumgart DC, Sandborn WJ. Lancet. 2012;380:1590605.

6. van der Have M, et al. J Crohns Colitis. 2014;8:93106.

7. Betteridge JD, et al. Inflamm Bowel Dis. 2013;19(7):14217.

8. Kaplan GG, Ng SC. Gastroenterology. 2017;152:313321.e2.

9. Levine JS, Burakoff R. Gastroenterol Hepatol (N Y). 2011;7(4):23541.

10. Sandborn WJ, et al. J Crohns Colitis. 2014;8(9):92735.

11. Gomollón F, et al. J Crohns Colitis. 2017;11(1):325.

12. Timmermans WMC, et al. Clin Transl Immunol. 2016;5(12):e118.

13. Vande Casteele N, Sandborn WJ. Nat Rev Gastroenterol Hepatol. 2015;12:37374.

14. Engel T, Kopylov U. Ther Adv Chronic Dis. 2016;7(4):20814.

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