Clinical Review: Crohn's disease

Contributed by Dr Guy Chung-Faye, consultant gastroenterologist, and Jaroslava Tumova, IBD nurse specialist, King's College Hospital, London.

Severe CD: 'cobblestone' appearance seen on endoscopy
Severe CD: 'cobblestone' appearance seen on endoscopy

Section 1: Epidemiology and aetiology
Crohn's disease (CD) is an inflammatory bowel disease (IBD). It is a complex, chronic relapsing inflammatory disorder of the GI tract and is characterised by patchy, transmural inflammation that can affect any part of the GI tract from mouth to anus, although the terminal ileum and right colon are most commonly affected.

It can be defined by the Montreal classification, which includes the disease location (terminal ileal, ileocolonic, colonic, upper GI) and the disease behaviour (inflammatory, fistulising or stricturing).

Epidemiology
The incidence of CD in the UK is 6.7 cases per 100,000 and the prevalence is 140 cases per 100,000 annually, although the incidence has been increasing. CD is a disease of mainly young people and has a bimodal distribution, with a peak incidence between 15 to 30 years old and a second smaller peak between 60 to 80 years old, although it may affect people of any age.

Aetiology
The causes of CD are uncertain but it is likely to have a multi-factorial aetiology, consisting of the interaction between predisposing genetic and environmental factors, which initiate an inflammatory response, resulting in a chronic activation of the immune system, with T-cells playing a prominent role.

Genetic factors
Around 5 to 10 per cent of IBD patients have a positive family history. First degree relatives of IBD patients are 10 to 14 times more likely to develop IBD than the general population.

In identical twins, the concordance rate for CD is approximately 50 per cent. It is estimated that CD has a greater coefficient of heritability than asthma, hypertension and schizophrenia and is at least as high as type-1 diabetes.

However, CD is a complex polygenic disease and although several genes have been identified, including the NOD2/CARD15 gene, each individual gene only confers a small increased susceptibility to CD.

Environmental factors
Cigarette smoking increases susceptibility of developing CD by threeto four-fold and is also associated with a more aggressive disease course and a lack of response to therapy.

The role of diet in the aetio-pathogenesis of CD has been studied but no dietary agents have been identified, although some studies have showed a link with refined sugars.

Other factors, such as the use of NSAIDs and GI infections, have been shown to cause disease flares but no infectious agent has been shown to be the causative link. There is no evidence that the MMR vaccine increases the risk of CD.1

Section 2: Making the diagnosis
Clinical features

Common symptoms include intermittent diarrhoea with or without rectal bleeding, abdominal pain, fatigue and weight loss. Pain is a common symptom and may be caused by inflammation or, less commonly, a stricture.

However, about 20 per cent of CD patients in clinical remission will continue to have pain underlining the importance of psychological and emotional factors in the pathogenesis of chronic disease. Extra-intestinal symptoms, such as arthropathy, iritis, uveitis, erythema nodosum and pyoderma gangrenosum, may also occur.

Diagnosis
CD shares features with many other conditions, such as infectious colitis, IBS, coeliac disease and diverticulitis and the diagnosis can often be difficult.

A range of investigations is required to confirm the diagnosis (see table below) and is best performed under the supervision of a gastroenterologist.

Faecal calprotectin is a neutrophil-derived protein, which is elevated in patients with mucosal GI inflammation and is a useful non-invasive test for IBD.2

However, faecal calprotectin is not a specific test for IBD, as levels can be increased in other conditions. It should be used as a screening tool; negative calprotectins exclude IBD, whereas an elevated level requires further investigation.

However, in IBD patients, calprotectin is an important non-invasive test for monitoring disease activity and response to therapy.

Ileocolonoscopy with biopsies is central to the diagnosis of CD. The main features seen on endoscopy include loss of vascular pattern, granularity, friability, diffuse ulceration and bleeding, sometimes with the typical 'cobblestone appearance' - although in early, mild CD, the mucosa may appear normal or show multiple aphthoid ulcers only.

Ulceration in CD is often surrounded by normal mucosa ('skip' lesions). As the disease progresses, these ulcers may coalesce into larger and deeper ones and may become fistulas and abscesses. The main histological features are transmural inflammation, epithelioid granulomas, discontinuous crypt distortion and focal cryptitis.

Video capsule endoscopy is a wireless endoscopic procedure, allowing non-invasive visualisation of the small bowel not within reach of standard upper or lower endoscopy. The patient swallows a disposable video capsule, which transmits video images as it passes through the small bowel and is excreted naturally after 24 to 48 hours.

Presenting symptoms of Crohn's disease
Common symptoms Less common symptoms
Abdominal pain Rectal bleeding
Diarrhoea (intermittent) Perianal symptoms (fissures, abcesses)
Weight loss Fever
Fatigue Loss of appetite
  Extra-intestinal symptoms (arthropathy,
iritis, uveitis, erythema nodosum)

A plain abdominal X-ray is essential if intestinal obstruction is suspected. Small bowel radiology is less sensitive than video capsule endoscopy but is useful if a stricture is suspected.

Ultrasound offers a non-ionising method of identifying thickened bowel, abscesses and free fluid but is less sensitive than CT to evaluate deeper parts of the bowel. MRI is the investigation of choice for perianal disease with the advantage of lack of ionising radiation, particularly in young patients who may need multiple investigations.

Investigations
Initial assessment 

Physical examination, including height and
weight.

Past medical and family history.

Laboratory investigations Blood - FBC, CRP, ESR, biochemistry, LFTs
- coeliac disease screen.
Stool - culture, including Clostridium
difficile toxin - faecal calprotectin.
Endoscopy Ileocolonoscopy and biopsies.
Video capsule endoscopy +/enteroscopy.
Radiology X-ray abdomen (if obstruction suspected).
Barium enema/small bowel follow through.
CT and MRI.

Section 3: Managing the condition
Although symptom control and maintaining remission is important, mucosal healing is an important long-term goal, as it may alter the course of CD and reduce complications.

Lifestyle factors
Smoking cessation is a very effective intervention in CD.3 It is also important to assess the nutritional status of CD patients and provide supplementation when needed. Elemental or polymeric diets may be used to induce remission where corticosteroids are contraindicated (mainly in children).


In early mild CD the mucosa may show multiple aphtoid ulcers only

Drug treatment
The introduction of corticosteroid therapy significantly changed the management of patients with IBD and reduced mortality rates. However, long-term usage carries a high risk of side-effects.

5-Aminosalicylates (mesalazine) are well tolerated but generally are of limited benefit.

Antibiotics, such as metronidazole and ciprofloxacin, are helpful in the short to medium-term treatment of perianal CD.

In addition, metronidazole has shown benefit in preventing post-surgical recurrence.

Thiopurines, such as azathioprine (AZA) and 6-mercaptopurine, are the most widely used immunosuppressive agents in IBD. Thiopurines are now used much earlier and more widely for patients who require multiple courses of corticosteroids. They have been shown to be effective in up to 65 per cent of patients. However, discontinuation is required in up to 25 per cent of patients due to side-effects.4 There is an increased risk of infection and bone marrow suppression can occur.

Methotrexate is effective in achieving and maintaining remission in CD5 and is given intramuscularly or subcutaneously. Care should be taken in females of childbearing age as it is highly teratogenic.

Biological therapy with chimeric or humanised monoclonal antibodies (IgG) with anti-TNF activity, such as infliximab and adalimumab, has been a major therapeutic advance for the treatment of inflammatory conditions. Biologics are highly effective and are usually given after the failure of immunosuppressive therapy.

IV infliximab is effective in 58 per cent, although it is most efficacious as a regular infusion every eight weeks and has also been shown to induce mucosal healing and reduces hospitalisations.6 Furthermore, infliximab is effective in fistulising disease.7

Adalimumab has demonstrated its effectiveness in induction and maintenance of remission in patients with CD. Both infliximab and adalimumab have been approved for use in CD by NICE.

However, it is vital to consider the small increased risk of infections and malignancies with biological therapy, especially when used in combination with immunosupressants. Side-effects include infusion reactions (common), infections (including rare TB reactivations) and a slight increased risk in malignancies, including lymphomas (very rare).

Testing for latent TB is recommended prior to commencing biological therapy.

Fistulising and/or perianal disease affects up to 40 per cent of CD patients. Fistulas usually require a combination of antibiotics, immunosuppressive agents or surgery. Infliximab has also been shown to be effective for the treatment of fistulas.

Surgery
Fibrotic strictures are a complication in 18 per cent of CD patients and although surgical resection offers immediate relief, disease recurrence is the norm. Endoscopic balloon dilatation and surgical stricturoplasty are desirable alternatives to resection.

Surgery is rarely curative in CD and should only be undertaken for symptomatic, macroscopic disease, with close liaison between gastroenterologist and surgeon.

Section 4: Prognosis
Initially, CD presents with a predominantly inflammatory disease but progresses either to a fistulising (70 per cent) or stricturing (18 per cent) disease phenotype over 20 years.8 CD can have a major impact on patients' lives, affecting relationships, fertility, education and career. CD causes significant disability, with 15 per cent of patients unable to work after five to 10 years of disease.

Despite advances in the medical management of CD, most patients undergo bowel surgery at some point. Approximately 70 to 80 per cent will require surgery in their lifetime. There is a small increase in mortality in CD patients, compared with the general population.

Impact on sexual health
As CD predominantly affects young patients, body image is a concern and this may impact on their relationships and sexual health. Sexual activity can be affected by fatigue, infections, dyspareunia, diminished libido and medication side-effects, as well as complications, such as perianal disease.

Women may have concerns about their ability to conceive and reduced fertility is typically related to disease activity and is also a potential side-effect of pelvic surgery.

In males, sulfasalazine may cause a reversible oligospermia. However, most patients with inactive or well-controlled CD have an uneventful pregnancy. Active disease may cause slightly lower birth weight and an increase in premature births.

Patients with perianal disease should be considered for a caesarean section. During pregnancy, the risks and benefits of continuing treatment need to be discussed.

Malignancies
Patients with extensive colonic CD have a small increased risk of colorectal cancer and surveillance should be considered.Furthermore, CD patients on immunosuppressants and biologics have a small increased risk of skin cancers and lymphomas. However, a study has shown that patients treated with infliximab have similar rates of cancers and lymphomas as those not treated with infliximab.9

Section 5: Case study
A 25-year-old female presented to her GP with abdominal pain, diarrhoea but no weight loss. She worked as a teacher and found her job very stressful. She had no significant past medical or family history. Her FBC, biochemical profile, CRP and ESR were normal and she was diagnosed with irritable bowel syndrome and was treated with mebeverine.

Four months later, she returned complaining of increased stool frequency, abdominal pain and occasional rectal bleeding and she was referred to the gastroenterologist.

Gastroenterology clinic
Physical examination revealed tenderness in right iliac fossa, blood results showed a mild anemia (Hb 10.3g/dL), CRP of 7mg/L and normal biochemistry. Her coeliac screen and stool cultures were negative but her faecal calprotectin was 530 microgram/g (normal<60).

A colonoscopy showed patchy aphthous ulcers throughout the colon, with severe inflammation in the ileocaecal region, suggestive of CD.

The patient was treated with a reducing course of prednisolone for six weeks and she was also started on regular mesalazine. She improved on this regimen but relapsed one month after stopping the prednisolone. She required a further course of prednisolone and she was then started on AZA with regular FBC monitoring.

She was well for 18 months but then, despite optimising her AZA dose, she started having frequent relapses and was then started on infliximab, while she remained on AZA.

After the initial three infusions, she improved significantly and went on a maintenance regimen every eight weeks. She became symptom free and her CD went into complete remission, which was confirmed by normal faecal calprotectins.

Two years later, she became pregnant and after discussion with her gastroenterologist, she stopped the AZA but continued with the infliximab as it was maintaining her CD in remission. She had an uneventful pregnancy and gave birth to a healthy baby. She currently remains well on eight-weekly infliximab infusions.

  • Visit the GP Curriculum Centre for hundreds of articles linked to key topics in the RCGP curriculum.

Section 6: Evidence base

Clinical trials

  • ACCENT I (A CD clinical trial evaluating infliximab in a new long-term teatment regimen).6

The ACCENT I study compared episodic versus scheduled infliximab therapy.

This trial clearly demonstrated that scheduled treatment was more effective than episodic treatment in inducing and maintaining remission and mucosal healing.

It also provided useful evidence that clinical response can be achieved by increasing the infliximab dosage in patients who are no longer responding to standard infliximab therapy.

This study showed that infliximab was highly effective in fistulising CD, with a response rate of 68 per cent compared with 26 per cent in the placebo group.

This study randomised immunomodulator naive patients to receive AZA, infliximab or both.

The trial demonstrated that infliximab (monotherapy or combination with AZA) was more effective than AZA alone. It also demonstrated the benefit of initiating infliximab early in the treatment of CD.

The incidence of serious infections was not increased in patients receiving infliximab and AZA combination therapy.

Guidelines

  • British Society of Gastroenterology guidelines.

Mowat C, Cole A, Windsor A, et al. Guidelines for the management of inflammatory bowel disease in adults. Gut 2011; doi: 10.1136/gut. 2010.224154.

  • Dignass A, Van Assche G, Lindsay JO, et al.

The second European evidence-based consensus on the diagnosis and management of Crohn's disease: current management. J Crohns Colitis 2010: 4: 28-62.

The previous 2002 guidance was too restrictive, allowing the use of infliximab in patients with severe active CD but not in patients with fistulising disease alone.

The new 2010 NICE guidance suggests a scheduled course of treatment of one year is the most cost-effective therapy, after which a full reassessment of disease is required.

The guidance also allows for the use of infliximab for fistulising disease and in paediatric patients. The new guidance refers to the licensed indications which involve failure of steroids and/or immune suppressants, raising the option of using biologics earlier in the disease course.

Key text

  • Feldman M, Friedman LS, Brandt LJ. Sleisenger and Fordtran's Gastrointestinal and Liver Disease (9th edition). Philadelphia, Saunders, 2010. A comprehensive overview of CD.

Visit MIMS Learning for an updated version of this article

CPD IMPACT: EARN MORE CREDITS

These further action points may allow you to earn more credits by increasing the time spent and the impact achieved.

  • Review all of your patients with CD, check their smoking status and counsel them accordingly.
  • Review your shared care protocols for patients taking immunosuppressive therapies - are they up to date?
  • Investigate whether your laboratory performs faecal calprotectin tests and hold a clinical meeting to discuss its uses.

References

1. Seagroatt V. BMJ 2005; 330: 1120.

2. Bjarnason I, Sherwood R. J Pediatr Gastroenterol Nutr 2001; 33: 11-3.

3. Johnson GJ, Cosnes J, Mansfield JC. Aliment Pharmacol Ther 2005; 21: 921-31.

4. Pearson DC, May GR, Fick G, et al. Cochrane Database Syst Rev 2000; CD000067.

5. Feagan BG, Rochon J, Fedorak RN, et al. N Engl J Med 1995; 332: 292-7.

6. Hanauer SB, Feagan BG, Lichtenstein GR, et al. Lancet 2002; 359: 1541-9.

7. Present DH, Rutgeerts P, Targan S, et al. N Engl J Med 1999; 340: 1398-405.

8. Cosnes J, Cattan S, Blain A, et al. Inflamm Bowel Dis 2002; 8: 244-50.

9. Lichtenstein GR, Cohen RD, Feagan BG, et al. Gastroenterology 2010; 138: S475.

10. Colombel JF, Sandborn WJ, Reinisch W, et al. N Engl J Med 2010; 362: 1383-95.

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