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TainaSipponen

Crohn's Disease

Essentials

  • The most common symptoms are abdominal pain, diarrhoea, fever, weight loss and blood in the stools.
  • Symptoms usually develop gradually.
  • The responsibility of the primary care is to recognise the possibility of Crohn's disease and refer the patient for further investigations.
  • The aim of treatment is the absence of symptoms, sustained remission without glucocorticoid medication, mucosal healing and the prevention of complications and relapses.
  • Patients with Crohn's disease should be encouraged to give up smoking.
  • Severe disease requires management in a hospital with expertise in Crohn's disease.

Epidemiology

  • The prevalence of Crohn's disease is high in the Nordic countries, Western Europe, North America and Australia.
  • Smoking increases the risk of onset of Crohn's disease, the activity of the disease and the likelihood of having to undergo surgery.
  • The age of onset for Crohn's disease is usually 20-30 years.

Clinical presentation

  • Clinical presentation and the development of complications are determined by
    • the behaviour of the disease
    • the location of the disease in the intestinal tract.
  • The disease is limited to the small bowel in about 30% of patients and to the large bowel in 25-30% of patients. In 40% of cases, the disease is ileocolonic.
    • Pathological changes may occur in any part of the intestinal tract.
    • Approximately one third of the patients have perianal fistulae.
  • Extraintestinal involvement occurs in some patients (e.g. peripheral arthritis, sacroiliitis, erythema nodosum, uveitis, episcleritis, cholangitis).
  • Early age at disease onset, widespread inflammation, smoking, perianal problems and the need for glucocorticoid treatment are predictive factors for high risk of progression.
  • Symptoms
    • Abdominal pain
    • Diarrhoea
    • Low-grade fever
    • Bleeding from the rectum
    • Weight loss
    • Signs of intestinal obstruction
    • Perianal problems
    • Growth retardation in children
  • Clinical findings
    • Abdominal tenderness, resistance in palpation
    • Perianal fissures and fistulae
    • Oral aphthae
  • The disease is classified as being either inflammatory, structuring or fistulating (penetrating), but the behaviour of the disease may change over the years.
  • Possible complications
    • Bowel obstructions
    • Abscesses
    • Fistulae
    • Intestinal bleeding

Diagnosis and investigations

  • Common laboratory findings
    • Increased ESR and CRP
    • Mild anaemia
    • Leucocytosis and thrombocytosis
    • Increased faecal calprotectin
    • Decreased plasma albumin concentration
  • Ileocolonoscopy with biopsies for histology is the first line investigation.
  • Endoscopic findings
    • Segmental or patchy inflammation
    • Cobblestone appearance of the mucous membranes
    • Aphthous ulcers or larger, often longitudinal or fissural ulcers
    • Strictures.
  • Histological findings include chronic inflammation that extends deep into the submucosa or even through the entire bowel wall as well as granulomas, which are quite rarely detected in mucosal biopsies.
  • Capsule endoscopy (not suitable for people with obstruction symptoms) or imaging studies, mainly magnetic resonance imaging, can be used for assessing the small bowel.
  • Gastroscopy is performed on patients with upper abdominal symptoms.
  • In 10-15% of cases it is not possible to make a differential diagnosis between ulcerative colitis and Crohn's disease ("IBD unclassified", or IBDU).

Differential diagnosis

  • Ulcerative colitis Ulcerative Colitis
  • Functional diarrhoea Functional Bowel Disorders and the Irritable Bowel Syndrome (IBS) (normal inflammatory markers, normal faecal calprotectin)
  • Infectious colitis Prolonged Diarrhoea in Adults (stool cultures, serological investigations, endoscopic or histological findings as necessary)
  • Clostridioides difficile colitis Clostridioides Difficile Diarrhoea (history of antimicrobial drug use, detection of Cl. difficile from stools)
  • Intestinal tuberculosis (medical history, detection of tuberculosis from mucosal samples, endoscopic and histological findings)
  • Ischaemic colitis (patients over 50 years of age, vascular risk factors present, endoscopic and histological findings)
  • Post radiotherapy colitis (may occur several years after treatment, endoscopic and histological findings)
  • Mucosal changes caused by NSAIDs (history of NSAID use, location of the changes, histology)

Arrangement of treatment

  • The responsibility of the primary care is to be able to suspect the possibility of Crohn's disease, start basic investigations and refer the patient on the basis of these, as necessary, for further investigations.
  • Diagnosis and treatment are usually the responsibility of the specialized care.
  • The management of a patient with severe Crohn's disease requires a hospital that can provide gastroenterological expertise, adequate out of hours investigations and facilities for emergency surgery.
  • In a non-acute phase, the monitoring can also be carried out in primary care.
    • The primary care must be provided with adequate care instructions by the specialized care.

Pharmacotherapy Budesonide for Maintenance of Remission in Crohn's Disease, Aminosalicylates for Induction of Remission or Response in Crohn's Disease, Azathioprine or 6-Mercaptopurine for Inducing Remission of Crohn's Disease, Oral 5-Aminosalicylic Acid for Maintenance of Medically-Induced Remission in Crohn's Disease

Immunomodulating drugs commonly used in the treatment of Crohn's disease

DrugLaboratory monitoringDoseTherapeutic indications
Immunosuppressants
AzathioprineWeeks 0, 2, 4, 6 and 8 and thereafter every 3 months: CBC (complete blood count), ALT (alanine aminotransferase), ALP (alkaline phosphatase)
After the first year of treatment in a stable situation, every 6 months 		2-2.5 mg/kg/dayMaintenance of remission, fistulae
6-mercaptopurineWeeks 0, 2, 4, 6 and 8 and thereafter every 3 months: CBC, ALT, ALP
After the first year of treatment in a stable situation, every 6 months 		1-1.5 mg/kg/dayMaintenance of remission, fistulae
MethotrexateWeeks 0, 2, 4, 6 and 8 and thereafter every 3-4 months: CBC, ALT, ALP, plasma creatinine15-25 mg per weekMaintenance of remission
Cytokine-mediated effect
InfliximabCBC, ALT, CRP before each infusion5 mg/kg by intravenous infusion at induction (0 and 2 weeks) and thereafterfrom week 6 onwards 120 mg subcutaneously every 2 weeksInduction and maintenance of remission, fistulae Infliximab for Maintenance of Medically Induced Remission in Crohn's Disease
AdalimumabMonths 0 and 1: CBC, ALT, CRP and thereafter every 3-6 months: CBC, ALT, CRP40 mg by subcutaneous injection every 2 weeks after an initial dose (160-80 mg)Induction and maintenance of remission, fistulae
VedolizumabCBC, ALT, CRP before each infusion300 mg by intravenous infusion at induction (0 and 2 weeks) and from week 6 onwards subcutaneously 108 mg every 2 weeksInduction and maintenance of remission, fistulae
UstekinumabCBC, ALT, CRP before initial infusion and thereafter 3-4 months after the startInduction by 6 mg/kg initial infusion, thereafter 90 mg subcutaneously 8 weeks after the infusion. Maintenance therapy: 90 mg subcutaneously every 12(-8) weeks.Induction and maintenance of remission, fistulae
RisankizumabCBC, ALT, CRP before initial infusion and 12 weeks after the start600 mg by intravenous infusion at weeks 0, 4 and 8, followed at week 12 after the start by 360 mg subcutaneously every 8 weeksRemission induction and maintenance
JAK inhibitors
UpadacitinibCBC, ALT, ALP, CRP, plasma creatinineat the starting point and 4-8 weeks after the start, thereafter every 3-6 months
Lipids 8-12 weeks after the start, thereafter every 12 months		45 mg orally once a day for 12 weeks, maintenance treatment 15-30 mg daily according to the individual needRemission induction and maintenance
  • The treatment is not curative but can reduce symptoms and complications.
  • Treatment choices are based on the site, extent, severity and behaviour of the disease.
  • An active phase of mild disease can be managed with glucocorticoids for the induction of remission (primarily budesonide in disease affecting the distal part of the ileum or the right side of the large bowel).
  • Medically induced remission can be achieved in moderate to severe disease with budesonide in decreasing doses Budesonide for Induction of Remission in Crohn's Disease starting with the initial dose of 9 mg/day, or prednisolone starting with 40-60 mg/day.
  • Biological drugs and the JAK inhibitor upadasitinib are used for remission induction and maintenance therapy in moderate to severe Crohn's disease.
  • Rapid start of TNF-alpha inhibitor therapy after the diagnosis of Crohn's disease leads to a better treatment outcome than gradual intensification of pharmacotherapy.
  • Thiopurine i.e. azathioprine or mercaptopurine is started usually alongside TNF-alpha inhibitors to maintain remission Azathioprine or 6-Mercaptopurine for Maintaining Remission in Crohn's Disease.
    • TPMT and NUDT15 genotype testing is recommended before starting treatment, as reduced activity of these genes predisposes to adverse effects of the drug.
    • Considering maintenance therapy other than thiopurine is recommended for Epstein-Barr virus antibodies negative patients and patients over 65 years of age.
    • For patients intolerant to thiopurines or unsuitable for treatment,methotrexate is considered.
  • Treatment response should be assessed (faecal calprotectin assay, endoscopy or imaging) 3-6 months after the start of immunomodulating treatment.
  • Supportive therapy must be taken care of, including sufficient intake of calcium and vitamin D, and, in patients with ileal disease or who have undergone ileal surgery, vitamin B12 replacement therapy.

Surgery Oral 5-Aminosalicylic Acid for Maintenance of Surgically-Induced Remission in Crohn's Disease

  • Indications for immediate surgery
    • Intestinal perforation and related peritonitis
    • Often abscesses
    • Major intestinal haemorrhage
    • Perianal abscesses (incision)
  • Indications for elective surgery
    • Symptomatic intestinal strictures
    • Intestinal fistulae
    • Continuous development of anaemia due to haemorrhage
    • Treatment of perianal fistulae (usually by placement of the so-called Seton drains)
    • Dysplastic changes, cancer
  • The aim of surgery is to conserve as much bowel as possible by removing the worst affected bowel section.
    • Strictures of the small bowel can also be treated by stricturoplasty.
  • Segmental resection in Crohn's disease that is limited to the large bowel is more beneficial than subtotal colectomy.
  • Crohn's disease is usually considered to be a contraindication to ileal pouch-anal anastomosis (IPAA).
  • Sometimes the treatment involves an end ostomy.

Endoscopic treatment of strictures

  • The strictures to be dilated must not be complicated or longer than 4 cm.
  • The dilatation is carried out with the aid of an elongated balloon.
  • Possible complications following endoscopic dilatation include bowel perforation, sepsis and haemorrhage.

Endoscopic follow-up

  • Patients with Crohn's disease affecting the large bowel should be regularly followed up by endoscopy due to the cancer risk caused by the inflammation (see Ulcerative Colitis).

    References

    • Noor NM, Lee JC, Bond S, et al. A biomarker-stratified comparison of top-down versus accelerated step-up treatment strategies for patients with newly diagnosed Crohn's disease (PROFILE): a multicentre, open-label randomised controlled trial. Lancet Gastroenterol Hepatol 2024;(): [PubMed]
    • Loftus EV Jr, Panés J, Lacerda AP, et al. Upadacitinib Induction and Maintenance Therapy for Crohn's Disease. N Engl J Med 2023;388(21):1966-1980 [PubMed]
    • D'Haens G, Panaccione R, Baert F, et al. Risankizumab as induction therapy for Crohn's disease: results from the phase 3 ADVANCE and MOTIVATE induction trials. Lancet 2022;399(10340):2015-2030 [PubMed]
    • Torres J, Bonovas S, Doherty G, et al. ECCO Guidelines on Therapeutics in Crohn's Disease: Medical Treatment. J Crohns Colitis 2020;14(1):4-22 [PubMed]
    • Maaser C, Sturm A, Vavricka SR, et al. ECCO-ESGAR Guideline for Diagnostic Assessment in IBD Part 1: Initial diagnosis, monitoring of known IBD, detection of complications. J Crohns Colitis 2019;13(2):144-164. [PubMed]
    • Lamb CA, Kennedy NA, Raine T, et al. British Society of Gastroenterology consensus guidelines on the management of inflammatory bowel disease in adults. Gut 2019;68(Suppl 3):s1-s106 [PubMed]
    • Sipponen T, Färkkilä M. [Inflammatory bowel diseases]. In: Färkkilä M, Isoniemi H, Heikkinen M, Puolakkainen P (eds.). [Gastroenterology and hepatology]. Duodecim Publishing Company Ltd 2018. Available in Finnish.
    • Lepistö A. [Surgical treatment of Crohn's disease]. In: Färkkilä M, Isoniemi H, Heikkinen M, Puolakkainen P (eds.). [Gastroenterology and hepatology]. Duodecim Publishing Company Ltd 2018. Available in Finnish.

Related Keywords ⬆

ATC Code:

L04AC05

A07EA06

L04AB04

L01BB02

C05AA04

L04AB02

L04AX03

L04AX01

Primary/Secondary Keywords