Crohn’s disease is an inflammatory bowel disease that can affect any part of the gastrointestinal tract. Inflammation can be focal or widespread. Abscesses, internal and external fistulas, and bowel obstruction may arise.

It mainly presents as abdominal pain, diarrhoea, fever, weight loss, or iron deficiency. Causes include bacteria, genetic (20-30% have a family history), lifestyle, environment, or random causes. Crohn’s disease affects the same number of females as it does males. The peak age of onset varies between 15-25 years of age. Incidence has doubled since the 1970’s (this is not just due to better recognition).

Crohn’s disease is diagnosed when typical features are seen in a combination of colonoscopy, histological and radiological investigations. Faecal biomarkers (calprotectin and lactoferrin) can help diagnose Crohn’s disease. This provides a non-invasive option, however faecal testing is not funded by Medicare so it is not commonly used. Patients may choose to pay the full cost for this test because it eliminates the need for a colonoscopy. It also has a potential role in detecting flares once diagnosis is established.

It has been shown that morbidity is increased with Crohn’s disease, however life expectancy is unchanged. That is why treatments aim to improve the quality of life, rather than quantity.

The severity of the disease and the site(s) of the affected bowel determine which drugs may be used and their route of administration or formulation. The aims of therapy are to induce and then maintain remission, and to prevent relapse. It is also important to prevent complications and nutritional deficiencies.

Mild to Moderate Crohn’s Disease

Oral or parenteral corticosteroids (e.g. prednisolone, hydrocortisone), are the most effective first-line drugs for treating active Crohn’s disease. Response rates in most clinical trials are about 60-70% at 12-16 weeks. Corticosteroids are effective for inducing remission in acute disease but ineffective as maintenance. Once in remission (which usually takes 7-14 days), the dose should be reduced gradually according to disease severity and patient response. Rectal corticosteroids are effective for distal colonic inflammation.

5-Aminosalicylates (5-ASAs) such as sulphasalazine and mesalazine are commonly used as first-line treatments. They are used to induce remission in mild-to-moderate disease. Efficacy in maintaining remission is controversial. However, they may have a limited effect on the rate of postoperative recurrence of small bowel disease.

Thiopurines (azathioprine, mercaptopurine) are used for inducing and maintaining remission, decreasing postoperative relapse in complex disease, and for their corticosteroid-sparing effect in patients with corticosteroid dependent or resistant disease. Although onset of action may be up to three months, they may be used as adjunctive treatment in active disease. There are no direct comparisons of azathioprine with mercaptopurine, but some patients who are unable to tolerate one agent may tolerate the other.

Methotrexate is effective for inducing remission and/or preventing relapse and is mainly used in patients refractory to, or intolerant of, thiopurines. Although oral dosing is more convenient, parenteral administration may be more effective.

In clinical trials metronidazole and ciprofloxacin, alone or in combination, have been shown to have a limited effect when used in active Crohn’s disease of the colon. These antibiotics are sometimes added to corticosteroids, or less commonly to 5-ASAs, although there is no evidence to support these combinations. Antibiotics are considered a first-line agent by some clinicians, or they may be reserved for patients not responding after 4-6 week of a 5-ASA. Their use is strictly empiric. With any of these drugs, 8-16 weeks of treatment may be required. Responders are converted to maintenance therapy.

Severe Crohn’s Disease

Initial therapy for severe Crohn’s disease includes intravenous corticosteroids. Fluid, electrolyte, or blood replacement may also be required. The optimal duration of intravenous corticosteroid therapy is not known, but it is generally given for 3-7 days. Oral corticosteroids should be substituted when disease activity has subsided. Patients not responding to corticosteroids, or those who cannot be tapered, should receive a thiopurine or methotrexate.

As the onset of action of thiopurines and methotrexate may be delayed, therapy should be continued with thiopurines for at least 3-6 months, and methotrexate for 2-3 months, before they are deemed to have failed. The benefits of thiopurines extend for at least three or four years of therapy and probably longer. There is less information about the duration of benefit of methotrexate.

Tumour Necrosis Factor (TNF)-alpha antagonists (infliximab, adalimumab) are preferred by some as second-line agents after corticosteroids but are contraindicated with active infection. They may be considered for moderate-to-severe disease (including fistulae) unresponsive to conventional therapy. The cost-to-benefit ratio limits the use of these agents. Clinical trials have shown response rates of 60-70% in patients with refractory active Crohn’s disease.

Broad-spectrum antibiotics (metronidazole and/or ciprofloxacin) are often given, especially if transmural complications (e.g. abscesses or fistulas) are suspected.

Maintenance Therapy for Crohn’s Disease

Most patients need ongoing therapy to maintain remission. 5-ASAs are first-line drugs for maintenance therapy. Patients who require only a 5-ASA to achieve remission can be maintained on this drug. There is good evidence that thiopurines are effective for maintenance, and should be used in patients who have frequent relapses, or are corticosteroid-dependent. If these therapies are not tolerated or are ineffective, methotrexate may be considered.

TNF-alpha antagonists have also been shown to be effective for maintaining remission in luminal and fistulising Crohn’s disease. Patients who respond to infliximab for acute disease but who are not well maintained on antimetabolites may stay in remission with repeat doses of infliximab at eight week intervals.

Surgery

Even though about 70% of patients ultimately require surgery, it is always performed reluctantly. It is best reserved for recurrent intestinal obstruction or intractable fistulas or abscesses. Resection of the bowel may alleviate symptoms but does not cure the disease, since Crohn’s disease is likely to recur even after resection of all clinically apparent disease.

Ultimately, further surgery is required in nearly 50% of cases. However, recurrence rates appear to be reduced by early postoperative prophylaxis with mercaptopurine, metronidazole or possibly a 5-ASA. When surgery is performed for appropriate indications, almost all patients experience an improved quality of life.

Future Trends in Therapy

Quality of life is now paramount. Earlier, intensive therapy is being considered by many clinicians. Early diagnosis and prognosis is important because complications accumulate overtime, therefore it is essential to start treating as soon as possible to prevent complications. A study which followed patients over an extensive period found that over 20 years, there was an 88% risk of developing stricturing (18%) or penetrating (70%) disease.

The ‘Top Down’ method of using third-line biologicals early on is becoming more attractive. This method tries to eliminate steroids (or perhaps just use short courses initially during flare ups) and recognises that thiopurines take 6-8 weeks to give any benefit, which may be too late. PBS restrictions currently pose a challenge for this method; however pressure is being applied to allow the use of these more expensive drugs in patients who have poor prognosis. Early surgery is another option being looked at.

There is also a stronger push for patients to see specialists earlier. Currently, most patients will see their general practitioner for ‘flare ups’ and after two or more flare ups, they are referred to the specialist. Seeing a specialist while in the remission phase (i.e. before the second flare up) allows more time to make treatment decisions and improve the patient’s quality of life.

References:

  1. Andrews J. Managing Inflammatory Bowel Disease in 2012 [DVD]. Pharmaceutical Society of Australia; 2012.
  2. Rossi S, editor. Australian Medicines Handbook 2011. Adelaide: Australian Medicines Handbook Pty Ltd; 2012.
  3. Porter RS, editor. The Merck Manual 19th ed., Whitehouse Station: Merck Sharp &
    Dohme Corp; 2012.
  4. Gastrointestinal Expert Group. Therapeutic guidelines: gastrointestinal. Version 5. Melbourne: Therapeutic Guidelines Limited; 2011.

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