Crohn’s Disease

(Regional ileitis, terminal ileitis, regional enteritis or granulomatous enteritis)

Incidence

The onset of Crohn’s disease has two age peaks: the first and largest peak occurs between the ages of 15-30 years; the second much smaller peak is between 60-80 years.

Crohn’s disease is becoming increasingly recognised in children of all ages and 20-30% are diagnosed before the age of 20. One study recorded a rising incidence of all forms of IBD in Scotland.

The female:male ratio in adults is 1.8:1. In children, the ratio is reversed; the ratio of boys to girls is 1.6:1.

Hazards

There is a genetic element (15-20% will have an affected family member with IBD, 70% concordance in identical twins).

Smoking increases risk three- to four-fold and smokers tend to have more aggressive disease and an earlier postoperative relapse.

Other exacerbating factors include intercurrent infections (eg, upper respiratory tract infection (URTI) or enteric) and non-steroidal anti-inflammatory drugs (NSAIDs).

Appearance

Symptoms

Symptoms are variable but often include diarrhoea (which may be bloody and become chronic – ie 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.

Typically, there will be periods of acute exacerbation, interspersed with remissions or less active disease.

Systemic symptoms of malaise, anorexia, or fever are common. The history should include enquiry about possible extra-intestinal manifestations involving the mouth, skin, eyes, joints and episodes of perianal abscess or anal fissure.

Children may present with poor growth, delayed puberty, malnutrition and bone demineralisation.

Probes

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.

Extra-intestinal features

Clubbing, erythema nodosum, pyoderma gangrenosum, Conjunctivitis, episcleritis, Iritis

Large joint arthritis, sacroiliitis (10-12%), ankolysing spondylitis

Fatty liver, Primary sclerosing cholangitid, cholangiocarcinoma (rare).

Granulomata may occur (in 50-70% of patients) in the skin, epiglottis, mouth, vocal cords, liver, nodes, mesentery, peritoneum, bones, joints, muscle or kidney.

Renal stones, osteomalacia, malnutrition

Amyloidosis.

Tests

The diagnosis is confirmed by clinical evaluation and a combination of endoscopic, histological, radiological and biochemical investigations.

Initial investigations are FBC, CRP, U&Es, LFTs, 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.

Antibodies to the yeast Saccharomyces cerevisiae (ie anti-S. cerevisiae antibodies (ASCA)) are more common in Crohn’s disease than in ulcerative colitis. Perinuclear antineutrophil cytoplasmic antibody (p-ANCA), is more common in ulcerative colitis than in Crohn’s disease. These two tests are sometimes useful in differentiating the two conditions but they are not particularly specific and need to be combined with clinical assessment.

Microbiological testing for infectious diarrhoea including clostridium difficile toxin is recommended. Additional stool tests may be needed for patients who have travelled abroad.

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 disease, are first-line procedures to establish the diagnosis.

Ileocolonoscopy defines the presence and severity of morphological recurrence and predicts the clinical course, so is recommended in all patients where recurrence is suspected.

In a patient with evidence of Crohn’s disease, 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 scanning.

Radionucleotide scanning may be used for patients too ill to undergo colonoscopy or barium studies. Gastroduodenoscopy and biopsy are only recommended in patients with upper gastrointestinal symptoms.

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.

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.

Laparoscopy may be necessary in selected patients and research into its effectiveness compared to laparotomy is ongoing. It is especially useful where the differential diagnosis of intestinal tuberculosis is being considered, and is also frequently employed in paediatric patients.

Other causes with same symtomps

1. Infectious gastroentritis
2. Tuberculosis
3. Ulcerative colitis
4. Actinomycosis
5. Carcinoid.
6. Amyloidosis
7. Intestinal lymphoma
8. Bechet’s disease
9. Bowel carcinoma
10. Ischaemic colitis
11. Diverticulitis
12. Radiation or drug-induced colitis (eg, NSAIDs)
13. Coeliac disease
14. Irritable bowel syndrome
15. Acute ileitis may mimic acute appendicitis

Wellness Program

Patient with abdominal pain and diarrhoea associated with weight loss, iron deficiency, or raised inflammatory markers, especially if diarrhoea is nocturnal. Urgent hospital admission for a patient known to have Crohn’s disease is required if:

There is severe abdominal pain, especially if there is tenderness on palpation.

There is severe diarrhoes (>8 or more/day) with or without rectal bleeding.

There bowel obstruction

The patient has fever, and is systemically unwell.

If the patient does not require admission, assess disease activity by thorough history and examination and blood tests (FBC, CRP, renal function and electrolytes, LFTs).

If there is mild disease in a patient with Crohn’s disease, consider increasing current prophylactic treatment (usually mesalazine) and/or using topical mesalazine or steroid (if there are any concerns, discuss this with the local hospital team). It is essential to be sure that there is no other cause for any clinical deterioration – eg, infection.

If there is more severe disease, consider oral steroids (non-enteric coated to ensure absorption); discuss with the local hospital team.

Curing 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 symptoms are better controlled

However, topical mesalazine may be effective in left-sided colonic Crohn’s disease of mild-to-moderate activity.

For maintenance, mesalazine seems to reduce the risk of relapse after surgery but not after medically induced remission.

Corticosteroids:

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.

5-aminosalicylate (5-ASA) is a less effective alternative treatment, where corticosteroids are not tolerated or are contra-indicated. It should not be considered in severe disease.

Budesonide is effective for the treatment of active Crohn’s disease in the terminal ileum and/or ascending colon. Modified-release budesonide which is active along the entire length of the colon is now available. Budesonide has fewer side-effects than prednisolone but may be less effective.

Enteral nutrition may be considered as an alternative to corticosteroids to induce remission when there are particular concerns about growth in children and young people.

Antibiotics:

Antibiotics are appropriate for septic complications and perianal disease.

Anti-diarrhoeals such as loperamide are contra-indicated during episodes of active colitis, as they cause toxic megacolon; however, they can be prescribed for the control of chronic diarrhoea in patients with stable disease.

Bile acid sequestrants such as colestyramine and colestipol may be useful to control secretory diarrhoea in patients with terminal ileal disease.

Abdominal cramps may be controlled by antispasmodics such as propantheline, dicycloverine, or hyoscyamine, providing intestinal obstruction has been excluded.

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.

Thiopurine methyltransferase (TPMT) activity should be assessed before offering azathioprine or mercaptopurine.They should NOT be offered if TPMT activity is very low or absent.

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.

Cytokine modulators:

Infliximab and adalimumab block the action of the cytokine TNF-alpha, which mediates inflammation in Crohn’s disease.

Recommendation is to give infliximab for severe active or active fistulising Crohn’s disease until treatment failure (including surgery) or for 12 months, whichever is the shorter. Treatment should only be continued after that if there is evidence of active disease. Adalimumab can be used as an alternative.

One study reported the successful use of low-dose infliximab to prevent recurrence post-surgery.

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.

The use of anti-TNF alpha therapy in Crohn’s disease has shown an increased risk of non-Hodgkin’s lymphoma, but the absolute rate is low.

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.

Total parenteral nutrition is appropriate adjunctive therapy in complex, fistulating disease. Surgery:

Historically, between 50-80% of patients with Crohn’s disease have surgery at some stage. The use of infliximab has made little difference to the rates of surgery, which may be due to its use as a treatment for acute episodes rather than as maintenance therapy.

Onestudy suggested that a significant number of patients are having surgery earlier in their disease.

Surgery should be considered for those who have failed medical therapy and may be appropriate as primary therapy in patients with limited ileal or ileocaecal disease.

In Crohn’s disease, surgery is not curative and should only be undertaken for symptomatic rather than asymptomatic, radiologically identified disease. Crohn’s disease 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.

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.

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.

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.

Sulfasalazine 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 disease 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.

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.

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.

Treatment of extra-intestinal manifestations

Oral Crohn’s disease: topical steroids, topical tacrolimus, intralesional 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.

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.

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. Endoscopic retrograde cholangiopancreatography (ERCP) may be used to treat dominant strictures by dilatation and/or stenting.

Advanced liver disease may necessitate transplantation.

Complications

Bowel:

1. Strictures causing subacute or acute obstruction.
2. Fistulae between loops of bowel and other bowel, bladder, vagina, or skin.
3. Perforation, acute dilatation and massive haemorrhage can occur.
4. Crohn’s colitis is associated with an increased risk of colonic carcinoma. Colonoscopic surveillance should be offered.

Osteoporosis (especiallywith steroid therapy):

Weight bearing, isotonic exercise, stopping smoking, avoiding alcohol excess and maintaining adequate dietary calcium are beneficial.

Consider assessing for changes in bone mineral density in children who have low body mass index, unexpected fracture or high levels of corticosteroid use.

Regular use of bisphosphonates and raloxifene may reduce or prevent further bone loss.

Renal disease (secondary to obstruction of the right ureter by ileocaecal disease). Iron, folate and vitamin B12 deficiency.

Gallstones and renal stones (usually oxalate) especially when there has been a previous right hemicolectomy.

Crohn’s disease may cause a delay in growth and puberty in children.

If Crohn’s disease 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.Treatment of pregnant women with infliximab does not increase the incidence of adverse outcomes.

Long term outcomes

Clinical indicators of a poor prognosis at diagnosis include perianal or stricturing disease, weight loss >5 kg, or the need for steroids.

Genetic and serological prognostic markers are being developed.

At least 50% of patients require surgical treatment in the first ten 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.

Studies of overall mortality of Crohn’s disease are conflicting, with some reporting no increased risk compared to the general population whilst others report a five-times increase.

75% of patients remain in work ten years after diagnosis.

Crohn’s disease is a chronic inflammatory bowel disease (IBD) of unknown aetiology, characterised by focal, asymmetrical, transmural and occasionally granulomatous inflammation. Infectious agents such as

Mycobacterium paratuberculosis, Pseudomonas spp. and Listeria spp. have all been implicated. An increase in TNF-alpha, high-fat diets and genetic mutations have all been mooted as possible causes.

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 30% of patients. 40% of patients have involvement of the small and large bowel.

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.