Crohn's Disease

Synonyms: regional ileitis, terminal ileitis, regional enteritis or granulomatous enteritis

Crohn's disease is a chronic inflammatory bowel disease of unknown aetiology characterised by focal, asymmetrical, transmural and occasionally granulomatous inflammation.¹

• It may affect any part of the gastrointestinal tract, but particularly the terminal ileum and proximal colon.
• Disease is restricted to the small bowel in 30% of patients and the large bowel in 20% of patients.
• Fistulae and strictures may occur.
• Unlike ulcerative colitis, there may be unaffected bowel between areas of active disease (skip lesions).
• The clinical course is characterised by exacerbations and remission.

• The incidence is about 5-10 per 100,000 per year with a prevalence of 50-100 per 100,000.
• The onset of Crohn's disease has a bimodal distribution. The first and largest peak occurs between the ages of 15-30 years; the second much smaller peak is between 60-80 years.²

Risk factors

• There is a genetic element (15-20% will have an affected family member with IBD, 70% concordance in identical twins).
• Smoking increases risk 3-4 fold, and smokers tend to have more aggressive disease and an earlier postoperative relapse.
• Other exacerbating factors include intercurrent infections (e.g. URTI or enteric), and NSAIDs.

Symptoms

• Symptoms are variable, but often include diarrhoea (which may be bloody) for more than six weeks, abdominal pain, and/or weight loss.
• These symptoms should raise the suspicion of Crohn's disease, especially in patients of young age.
• Systemic symptoms of malaise, anorexia, or fever are common.
• The history should include enquiry about possible extraintestinal manifestations involving the mouth, skin, eye, joints, and episodes of perianal abscess or anal fissure.³
• Children may present with poor growth or delayed puberty.

Examination

• General ill-health with signs of weight loss, fluid depletion and anaemia
• There may be hypotension, tachycardia and pyrexia during acute exacerbations
• Abdominal tenderness or distension, palpable masses
• Anal and perianal lesions (pendulous skin tags, abscesses, fistulae) are characteristic
• Mouth ulcers

Extra-intestinal

• Clubbing, erythema nodosum, pyoderma gangrenosum
• Conjunctivitis, episcleritis, iritis
• Large joint arthritis, sacroiliitis (10-12%), ankylosing spondylitis
• Fatty liver, primary sclerosing cholangitis, cholangiocarcinoma (rare)
• Granulomata may occur (in 50-70% of patients) in skin, epiglottis, mouth, vocal cords, liver, nodes, mesentery, peritoneum, bones, joints, muscle or kidney
• Renal stones
• Osteomalacia
• Malnutrition
• Amyloidosis

• The diagnosis is confirmed by clinical evaluation and a combination of endoscopic, histological, radiological and biochemical investigations.³
• Initial laboratory investigations should include CRP (or ESR if CRP not available), full blood count, renal function and electrolytes, and liver function tests. Serum levels of CRP are useful for assessing a patient's risk of relapse. High CRP levels are indicative of active disease or a bacterial complication. CRP levels can be used to guide therapy and follow up.
• Microbiological testing for infectious diarrhoea including Clostridium difficile toxin is recommended. Additional stool tests may be needed for patients who have travelled abroad (see article on Traveller's Diarrhoea).
• For suspected Crohn's disease, ileocolonoscopy and biopsies from the terminal ileum as well as each colonic segment to look for microscopic evidence of Crohn's are first line procedures to establish the diagnosis.
• Ileocolonoscopy defines the presence and severity of morphologic recurrence and predicts the clinical course, so is recommended in all patients where recurrence is suspected.⁴
• In a patient with evidence of Crohn's, further investigations are recommended to examine the location and extent of disease in the small bowel, usually including small bowel follow through or small bowel enema, and less often abdominal ultrasound, CT and MRI.³
• Gastroduodenoscopy and biopsy is only recommended in patients with upper gastrointestinal symptoms.³
• For perianal disease:
  • Pelvic MRI should be the initial procedure because it is accurate and non-invasive, although it is not needed routinely in simple fistulae.⁴
  • Examination under anaesthetic is considered the gold standard but only in the hands of an experienced surgeon. It may permit concomitant surgery.
  • As the presence of concomitant rectosigmoid inflammation has prognostic and therapeutic relevance, proctosigmoidoscopy should be used routinely in the initial evaluation.⁴
• Laparoscopy may be necessary in selected patients, especially where the differential diagnosis of intestinal tuberculosis is being considered.

• Infectious gastroenteritis
• Tuberculosis
• Ulcerative colitis
• Actinomycosis
• Carcinoid
• Amyloidosis
• Intestinal lymphoma
• Behcet's disease
• Bowel carcinoma
• Ischaemic colitis
• Radiation or drug induced colitis (e.g. NSAIDs)
• Diverticulitis
• Coeliac disease
• Irritable bowel syndrome
• Acute ileitis may mimic acute appendicitis

• The first decision is whether the patient requires urgent hospital admission; urgent hospital admission is required if:⁵
  • Severe abdominal pain, especially if tenderness on palpation
  • Severe diarrhoea (frequency 8 or more times per day), with or without rectal bleeding
  • Bowel obstruction
  • Fever, systemically unwell
• If the patient doesn't require admission, assess disease activity by thorough history and examination and blood tests (full blood count, CRP, renal function and electrolytes, liver function tests).
• If mild disease severity, consider increasing current prophylactic treatment (usually mesalazine) and/or using topical mesalazine or steroid (if any concerns, discuss with local hospital team).
• If more severe consider oral steroids (non-enteric coated to ensure absorption); discuss with local hospital team.

Mild disease

• Mild ileocaecal disease:
  • Patients with mild symptoms may not require treatment.
  • Budesonide (9 mg/day for 8 to 10 weeks) is effective for the treatment of active Crohn's disease in the terminal ileum and/or ascending colon and is preferred to prednisolone for mildly active disease because it is associated with fewer side effects.⁶
• Colonic disease:
  • Topical mesalazine may be effective in left sided colonic Crohn's of mild to moderate activity.
  • May be treated with sulfasalazine if only mildly active.

Moderate disease

• Localised ileocaecal disease:
  • Treated with budesonide 9 mg per day or an alternative systemic corticosteroid.⁶
  • Antibiotics can be added if septic complications are suspected.
• Colonic disease:
  • Topical mesalazine may be effective in left sided colonic Crohn's of mild to moderate activity.

Severe disease

• Urgent hospital admission is required.
• Localised ileocaecal disease:
  • Can initially be treated with systemic corticosteroids.
  • For those who have relapsed, azathioprine or mercaptopurine should be added (or methotrexate if intolerant).
  • Infliximab should be considered in addition for corticosteroid or immunomodulator refractory disease or intolerance, although surgical options should also be considered and discussed.⁷
• Extensive small bowel disease:
  • Treated with systemic corticosteroids if moderate or severe.
  • Azathioprine or mercaptopurine is recommended (or methotrexate if intolerant), with adjunctive nutritional support.
  • Infliximab should be considered in addition if treatment fails, although surgical options should also be considered and discussed.
• Colonic disease:
  • Systemic corticosteroids.⁷
  • For those who have relapsed, azathioprine or mercaptopurine should be added (or methotrexate if intolerant).
  • Infliximab should be considered in addition for corticosteroid or immunomodulator refractory disease or intolerance.
  • Surgical options should also be considered and discussed.

Early relapse

• Any patient who has an early (less than 3 months) relapse is best treated with azathioprine, mercaptopurine, or methotrexate.

Maintenance of remission

• Smoking cessation is probably the most important factor in maintaining remission.
• Prophylactic treatment is recommended after small intestinal resection. The drug of choice is mesalazine in doses above 2 g daily.
• Metronidazole has been shown to be effective after ileocolic resection.
• Other drugs including azathioprine or 6-mercaptopurine should be considered as first line therapy in high risk patients.⁴
• Infliximab can be effective. It is best used as part of a treatment strategy including immunomodulation once other options, including surgery, have been discussed with the patient.
• Sulphasalazine and corticosteroids are not recommended.

Non-surgical treatments

• Sulfasalazine daily is effective for active colonic disease, but not first line therapy in view of a high incidence of side effects. It may be appropriate in selected patients, e.g. those with associated arthritis.
• Metronidazole is effective, but not first line therapy in view of the potential for side effects. It has a role in selected patients with colonic or treatment resistant disease, or those who wish to avoid steroids.
• Azathioprine or mercaptopurine may be used as adjunctive therapy and as a steroid sparing agent.
• Infliximab:
  • Is effective, but is best avoided in patients with obstructive symptoms.
  • NICE have recommended that infliximab be only used for the treatment of severe Crohn's disease (see Appendix E in NICE guideline for disease activity index),⁸ in patients who are refractory to treatment with immunomodulating drugs (e.g. azathioprine or 6-mercaptopurine, methotrexate) and corticosteroids (or who have been intolerant of these treatments) and for whom surgery is inappropriate (e.g. because of diffuse disease and/or a risk of short bowel syndrome).
  • Infliximab is not recommended for patients with fistulising disease who do not have the other criteria for severe active Crohn's disease.
• Natalizumab (a recombinant humanized IgG4 monoclonal antibody) appears to be effective for induction of clinical response and remission in some patients with moderately to severely active Crohn's disease.⁹
• Elemental or polymeric diets are less effective than corticosteroids, but may be used to induce remission in selected patients with active disease who are unable or unwilling to take corticosteroid therapy, or as an adjunctive therapy.¹⁰
• Total parenteral nutrition is appropriate adjunctive therapy in complex, fistulating disease.

Corticosteroid dependent disease

• Should be treated with azathioprine or mercaptopurine (or methotrexate if intolerant or ineffective).
• If this fails, addition of infliximab should be considered, although surgical options should also be considered and discussed.

Corticosteroid refractory disease

• Should be treated with azathioprine or mercaptopurine (or methotrexate if intolerant or ineffective).
• In the absence of septic complications the addition of infliximab is indicated if immunomodulators fail or if a rapid response is required, although surgical options should also be considered and discussed.

Surgery

• Should be considered for those who have failed medical therapy and may be appropriate as primary therapy in patients with limited ileal or ileo-caecal disease.
• In Crohn's, surgery is not curative and should only be undertaken for symptomatic rather than asymptomatic, radiologically identified disease. Crohn's usually recurs following surgery. Resections should be conservative and limited to macroscopic disease.
• The procedure of choice in acute fulminant Crohn's is a subtotal colectomy leaving a long rectal stump, to facilitate later rectal excision and minimise the risk of intraperitoneal dehiscence.

• May be best treated with a proton pump inhibitor as first line treatment, if necessary together with systemic corticosteroids and azathioprine or mercaptopurine, or, if intolerant, with methotrexate.
• Infliximab is an alternative for refractory disease.
• Dilatation or surgery are appropriate for obstructive symptoms.

• Active perianal disease or fistulae are often associated with active Crohn's elsewhere in the gastrointestinal tract. The initial aim is to treat active disease and sepsis.
• For more complex, fistulating disease, the approach involves defining the anatomy, supporting nutrition, and potential surgery.
• For asymptomatic simple perianal fistulas, nothing has to be done. If simple fistulas are symptomatic then non-cutting Seton or fistulotomy are recommended. High dose antibiotics (metronidazole or ciprofloxacin) should be added.⁴
• Complex perianal disease:
  • Antibiotics and/or azathioprine/6-mercaptopurine should be used as the first choice of therapy for complex perianal Crohn's disease in combination with surgical therapy.⁴
  • The presence of a perianal abscess should be ruled out and if present it should be drained. Infliximab should be used as a second line treatment.
  • Seton placement should be recommended. A diverting ostomy or proctectomy may be necessary for severe disease refractory to medical therapy.⁴

• Oral Crohn's disease: topical steroids, topical tacrolimus, intra-lesional steroid injections, enteral nutrition, and infliximab may have a role in management but there are no randomised controlled trials.
• Arthritis and arthropathy: there is some general support for use of sulfasalazine, simple analgesics, non-steroidal anti-inflammatory agents, local corticosteroid injections, and physiotherapy.⁴ In axial arthritis the arguments in favour of intensive physiotherapy, sulfasalazine, methotrexate or infliximab are somewhat stronger.
• Erythema nodosum: systemic corticosteroids are usually required.
• Pyoderma gangrenosum: topical and systemic corticosteroids, with the more toxic ciclosporin and tacrolimus reserved for resistant cases. Newer data support the use of infliximab.⁴
• Episcleritis: may not require specific treatment, but will usually respond to topical corticosteroids.
• Uveitis is treated with topical and/or systemic corticosteroids.
• Primary sclerosing cholangitis: responds to ursodeoxycholic acid and may reduce the risk of colonic cancer. ERCP may be used to treat dominant strictures by dilatation and/or stenting.
• Advanced liver disease may necessitate transplantation.

• Bowel:
  • Strictures causing subacute or acute obstruction.
  • Fistulae between loops of bowel and other bowel, bladder, vagina, or skin.
  • Perforation, acute dilatation and massive haemorrhage can occur.
  • Crohn's colitis is associated with an increased risk of colonic carcinoma.
• Osteoporosis (especially with steroid therapy):
  • Weight bearing, isotonic exercise, stopping smoking, avoiding alcohol excess, and maintaining adequate dietary calcium are beneficial.
  • Regular use of bisphosphonates, calcitonin and its derivatives, and raloxifene may reduce or prevent further bone loss.
• Renal disease (secondary to obstruction of the right ureter by ileocaecal disease).
• Iron, folate and B₁₂ deficiency.
• Gallstones and renal stones (usually oxalate) especially when there has been a previous right hemicolectomy.
• If Crohn's in a pregnant patient is in remission, there is no effect on the prognosis for pregnancy. Women with active disease are more likely to have complications such as spontaneous abortions, miscarriages, stillbirths, and exacerbation of the disease.¹¹

• At least 50% of patients require surgical treatment in the first 10 years of disease and approximately 80% will require surgery within their lifetime. Potential risk factors for recurrence after surgery include colonic location, extent of the disease, smoking and absence of prophylactic medical therapy.⁴
• The overall mortality of Crohn's is slightly higher than the normal population and is greatest in the 2 years after diagnosis or in those with upper gastrointestinal disease.
• 75% of patients are fully capable of work in the year after diagnosis and 15% of patients unable to work after 5-10 years of disease.