Tuesday, March 17, 2009

Crohn's Disease

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.
Epidemiology
  • The incidence is 6.7 (range 1.6 to 14.6) cases per 100,000 annually and the prevalence is 140 (range 10-199) cases per 100,000.2
  • 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.3

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.
Presentation

Symptoms

  • Symptoms are variable, but often include diarrhoea (which may be bloody and become chronic - i.e. present for more than six weeks), abdominal pain, and/or weight loss.
    Such 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.4
  • 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 features

Investigations
  • The diagnosis is confirmed by clinical evaluation and a combination of endoscopic, histological, radiological and biochemical investigations.4
  • Initial investigations are full blood count, C reactive protein, urea and electrolytes, liver function tests, stool culture and microscopy.
    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 affected 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.5
  • 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.4
  • Gastroduodenoscopy and biopsy is only recommended in patients with upper gastrointestinal symptoms.4
  • 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.5
    • 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.5
  • Laparoscopy may be necessary in selected patients, especially where the differential diagnosis of intestinal tuberculosis is being considered.
Differential diagnosis

Grading of disease activity4
  • Mild:
    • Patient walking, eating and drinking
    • Less than 10% weight loss
    • No features of obstruction, fever, dehydration, abdominal mass, or tenderness
    • CRP usually increased above the upper limit of normal
  • Moderate:
    • Intermittent vomiting, or weight loss more than 10%
    • Treatment for mild disease ineffective, or tender mass
    • No overt obstruction
    • CRP raised above the upper limit of normal
  • Severe:
    • Cachexia (BMI <18 style="color: rgb(0, 0, 0); font-weight: 400; vertical-align: super; font-size: 0.75em; ">-2)
    • Evidence of obstruction or abscess
    • Persistent symptoms despite intensive treatment
    • CRP increased

Disease activity correlates with: degree of systemic illness, frequency of diarrhoea, raised white cell count, raised ESR and CRP, and reduced albumin.6

Management
  • Prompt referral is indicated for any patient with abdominal pain and diarrhoea associated with weight loss, iron deficiency, or raised inflammatory markers, especially if diarrhoea is nocturnal.2
  • Urgent hospital admission for patient known to have Crohn's disease is required if:6
    • 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 in a patient with Crohn's disease, consider increasing current prophylactic treatment (usually mesalazine) and/or using topical mesalazine or steroid (if any concerns, discuss with local hospital team). It is essential to be sure that there is no other cause for any clinical deterioration, e.g. infection.
  • If more severe consider oral steroids (non-enteric coated to ensure absorption); discuss with local hospital team.

Treatment options

  • Patients with mild disease may not need any maintenance therapy; smoking cessation is very important.
  • Mesalazine:
    • For mild or moderately active Crohn’s disease, mesalazine seems little better than placebo.2
    • However topical mesalazine may be effective in left sided colonic Crohn's of mild to moderate activity.
    • For maintenance, mesalazine seems to reduce the risk of relapse after surgery but not after medically induced remission.2
  • Corticosteroids:2
    • Corticosteroids effectively induce remission but do not prevent relapse.
    • Long term treatment with corticosteroids is inappropriate.
    • Corticosteroids with low systemic bioavailability, such as budesonide, are preferred for mild or moderately active Crohn’s disease.
    • 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.7
  • Antibiotics:
    • Antibiotics are appropriate for septic complications and perianal disease.2
  • Immunomodulators:
    • Immunomodulators such as azathioprine, mercaptopurine or methotrexate may be used as adjunctive therapy and as a steroid sparing agent to help maintain remission. These drugs are increasingly considered early in treatment, particularly for those likely to have aggressive disease.
    • Major side effects of azathioprine include myelosuppression, hepatitis, and pancreatitis; minor, often transient effects, include nausea, vomiting, and flu-like symptoms. Despite these side effects, thiopurines are tolerated by 75% of patients.2
  • Cytokine modulators:
    • Infliximab and adalimumab block the action of the cytokine tumour necrosis factor alpha (TNF alpha), which mediates inflammation in Crohn's disease.
    • Indications for anti-TNF alpha therapy include induction of response, remission, and maintenance for patients with moderate or severely active Crohn’s disease despite therapy with corticosteroids and/or immunomodulators. Patients with fistulas or extraintestinal manifestations may derive particular benefit.2
    • Infliximab and adalimumab have been shown to produce response rates up to 80% but steroid-free remission rates are much lower.
    • Initial treatment with infliximab and azathioprine ("top-down" therapy) has been shown to be more effective at achieving remission without steroids or surgery at six months than treatment with steroids and then azathioprine before infliximab ("step-up" therapy).2
    • Randomised controlled trials have shown few differences in efficacy between infliximab, adalimumab, and a third anti-TNF alpha drug, certolizumab pegol.2
    • Although maintenance therapy with infliximab has been associated with reduced admission to hospital over 12 months, maintenance therapy with infliximab is not currently recommended by NICE.
    • NICE have recommended that infliximab only be used for the treatment of severe Crohn's disease, in patients who are refractory to treatment with immunomodulating drugs 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).8
    • 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 humanised 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
    • The risk of serious infection from anti-TNF alpha agents is 2.8-4% but prednisolone has been associated with double the risk of serious infection and increased mortality.2
    • The use of anti-TNF alpha therapy in rheumatoid arthritis has shown an increased risk of malignancy.
  • 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.
  • Surgery:
    • Historically, up to 80% of patients with Crohn’s disease have surgery at some stage but rates of surgery may already be decreasing.
    • 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.
    • Laparoscopic resection is becoming the standard of care (particularly for ileocaecal resection).

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.11
  • 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.11
    • 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.

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.5
  • 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.

Corticosteroid dependent and steroid 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.

Oesophageal or gastroduodenal disease

  • 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.

Fistulating and perianal disease

  • 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.5
  • 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.5
    • 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.5

Treatment of extraintestinal manifestations

  • 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.5 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.5
  • 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. ERCP may be used to treat dominant strictures by dilatation and/or stenting.
  • Advanced liver disease may necessitate transplantation.
Complications
  • 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.12
Prognosis
  • Clinical indicators of a poor prognosis at diagnosis include perianal or stricturing disease, weight loss >5 kg, or the need for steroids.2
  • 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.5
  • 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 remain in work 10 years after diagnosis.2

Document references
  1. Crohn BB, Ginzburg L and Oppenheimer GD; Regional Ileitis: A Pathologic and Clinical Entity. JAMA 1932 (Oct 15) 99:1323-1329. (as PDF)
  2. Cummings JR, Keshav S, Travis SP; Medical management of Crohn's disease. BMJ. 2008 May 10;336(7652):1062-6.
  3. Rubin GP, Hungin AP, Kelly PJ, et al; Inflammatory bowel disease: epidemiology and management in an English general practice population. Aliment Pharmacol Ther. 2000 Dec;14(12):1553-9. [abstract]
  4. Stange EF, Travis SP, Vermeire S, et al; European evidence based consensus on the diagnosis and management of Crohn's disease: definitions and diagnosis. Gut. 2006 Mar;55 Suppl 1:i1-15.
  5. Caprilli R, Gassull MA, Escher JC, et al; European evidence based consensus on the diagnosis and management of Crohn's disease: special situations. Gut. 2006 Mar;55 Suppl 1:i36-58. [abstract]
  6. British Society of Gastroenterology; Guidelines for the management of inflammatory bowel disease in adults, Sept. 2004.
  7. Otley A, Steinhart AH; Budesonide for induction of remission in Crohn's disease. Cochrane Database Syst Rev. 2005 Oct 19;(4):CD000296. [abstract]
  8. Crohn's disease - infliximab, NICE Technology Appraisal (2002)
  9. MacDonald JK, McDonald JW; Natalizumab for induction of remission in Crohn's disease. Cochrane Database Syst Rev. 2007 Jan 24;(1):CD006097. [abstract]
  10. Teahon K, Bjarnason I, Pearson M, et al; Ten years' experience with an elemental diet in the management of Crohn's disease. Gut. 1990 Oct;31(10):1133-7. [abstract]
  11. SPL Travis; European evidence based consensus on the diagnosis and management of Crohn's disease: current management. Gut 2006;55;16-35.
  12. Rajapakse R, Korelitz BI; Inflammatory Bowel Disease During Pregnancy. Curr Treat Options Gastroenterol. 2001 Jun;4(3):245-251. [abstract]
Internet and further reading
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