60-second summary

Why read this article? Patients with ulcerative colitis and Crohn’s disease require medical management of their condition, and often surgery. This Update looks at drugs used in treatment, their comparative effectiveness and place in therapy, and surgical options that may be considered.

What drugs are used in ulcerative colitis?Many UC patients can be successfully controlled on moderate doses of aminosalicylates. Sulfasalazine is a cheap option but is not well tolerated by some patients, in which case the newer variations and formulations should be used. For distal or rectal disease, local steroid therapy with foam or enemas will be helpful. Some more resistant patients may require an infliximab injection every eight weeks.

What drugs are used in Crohn’s disease?Modified release mesalazine may be tried in ileitis. Oral steroid maintenance therapy should be avoided. Immunomodulators may be required to maintain remission, with methotrexate the recommended treatment. A minority of patients may require infliximab maintenance.

The general aims of management in inflammatory bowel disease (IBD) are to treat acute exacerbations promptly, and control the disease long term. For most patients with ulcerative colitis (UC), medical treatment is sufficient to achieve these goals. Patients with Crohn’s disease often require surgery. However, while a colectomy (surgical removal of the colon) can be regarded as definitive in patients with UC, a patient with Crohn’s is never regarded as cured.

The auto-immune and chronic inflammatory nature of IBD means the principal drugs used are anti-inflammatory and immunomodulatory. Currently there is no definitive set of official guidelines covering all aspects of management and experience is continually informing practice; the management of Crohn’s is tailored to each patient by a specialist, based on the severity of the disease, lesion site(s), complications and previous response to therapy.

1. Aminosalicylates

The aminosalicylates are the traditional mainstay drugs for IBD. Sulfasalazine was one of the first targeted therapy drugs explicitly designed for any disease, as the aetiology of UC was originally thought to involve colonic infection. 

Unfortunately, it turns out that infection is not an essential component of UC. Furthermore, sulfipyridine is responsible for far more adverse effects than the salicylate component, and it is now being replaced by modern agents containing only salicylate. Enteric coating is used to minimise the upper GI side-effects of sulfasalazine, but toxicity from absorbed sulphonamide can still occur, causing skin reactions and liver problems.

Mesalazine is 5-aminosalicylic acid, and available as a range of (non-interchangeable) modified release oral preparations with different release characteristics, as well as rectal foams, suppositories and enemas for distal colonic disease. Other drugs used include the pro-drug balsalazide (inert carrier) and the dimer olsalazine (split in the colon).

Aminosalicylates have a role in both the induction and maintenance of remission in UC, but are not generally useful in Crohn’s disease. The choice of drug depends initially on patient tolerance, with the site of the lesions dictating the optimal formulation. In general, local therapy with rectal preparations is only useful for rectal or distal colonic disease.

The most common adverse effect is GI disturbance (including possible diarrhoea with temporary exacerbation of colitis), but blood dyscrasias and renal impairment may also occur, and sulfasalazine can cause oligospermia and subfertility in men.

Aminosalicylates should be avoided in patients with salicylate/aspirin sensitivity.

2. Steroids

Corticosteroids offer both a substantial potential benefit and considerable risk in many severe inflammatory conditions. Short courses of systemic steroids can be life-saving in severe acute exacerbations of IBD (which can make patients seriously dehydrated, malnourished and debilitated). However, they should be reduced as soon as possible to avoid the long-term side effects of treatment. These include immunosuppression, hypertension, diabetes, weight gain, pituitary suppression and osteoporosis.

Unfortunately, some patients become steroid-dependent, with their condition relapsing when steroids are stopped. In such cases other immunosuppressants are combined for a steroid-sparing effect, to try to bring the oral steroid dose down to the equivalent of 8mg daily of prednisolone or less. At this dose, which is approximately equivalent to natural daily corticosteroid secretion levels, side effects are greatly reduced.

As with aminosalicylates, many steroid formulations are available, including intravenous, oral and rectal preparations. Rectal application not only allows high local drug levels, but reduces the total absorbed dose, helping to minimise side effects.

As modified-release budesonide achieves its maximum levels in the distal ileum and ascending colon, it is suitable for treating Crohn’s. It also has the additional benefit of extensive first-pass metabolism once absorbed, reducing systemic side effects.

3. Non-specific immunomodulators

Traditional cytotoxic immunosuppressants such as azathioprine, mercaptopurine and methorexate are non-specific and quite toxic. They reduce the proliferation of various leucocyte immune cells, but the same action in the bone marrow depresses the production of platelets, neutrophils and, in the long term, red blood cells. Therefore potentially dangerous side effects include bleeding disorders, susceptibility to infection and anaemia.

Azathioprine is metabolized by TPMT (thiopurine methyltransferase). Some patients are deficient in this, resulting in severe bone marrow depression at normal doses. Therefore TPMT status should be checked before starting therapy.These agents act synergistically with both aminosalicylates and steroids, although doses should be carefully monitored with regular full blood counts. They are used to supplement aminosalicylates when maximal doses are not sufficiently effective, and to allow reduced doses in steroid-dependent disease. They are used in induction and maintenance, in both UC and Crohn’s disease.

The more specific ciclosporin and tacrolimus are sometimes indicated for short periods.

4. Specific immunomodulators

The development of cytokine tumour necrosis factor inhibitors (antiTNFs) has substantially improved the management and prognosis of IBD, especially in Crohn’s disease. TNF plays a major role in the damaging inflammatory process and these agents have been extremely successful at inducing remission where other agents have failed. Adalimumab is only licensed in Crohn’s disease, while infliximab is licensed in both Crohn’s and UC. The main drawbacks are the cost of therapy and the need for injection (intravenous for infliximab, subcutaneous for adalimumab), but doses are infrequent.

The principal side effect is a predisposition to infection, especially tuberculosis reactivation. They are also antigenic, and may cause hypersensitivity reactions.

5. Antibiotics

Acute gastrointestinal complications such as fistulas, abscesses, perforation and megacolon can cause peritonitis and septicaemia, requiring antimicrobials. Metronidazole is favoured because anaerobic organisms are usually involved. Ciprofloxacin is also used.

6. Surgery

Surgery may result in temporary or permanent solutions. Short sections of diseased gut above the rectum may be excised (resection) and the ends rejoined (anastomosis), thereby preserving rectal/anal function. However, relapse at other sites usually follows surgery in Crohn’s disease, so surgery is delayed as long as possible to prevent repeated operations with their attendant risks.

In some patients who undergo resection, a pouch may be constructed above the rectum as a sort of reservoir to reduce faecal urgency and enable a close approximation to normal bowel function. Sometimes a temporary stoma may be made, with anastomosis performed later once the bowel has recovered. However, it will not always be possible to avoid constructing a permanent stoma.

Other therapies

Other important therapeutic considerations are nutrition and fluid and electrolyte balance. During an acute attack of IBD with severe prolonged diarrhoea, the patient is likely to be dehydrated and hypokalaemic, and possibly acidotic (because of bicarbonate loss). This may require intravenous fluid and electrolytes, and possibly total parenteral nutrition and blood transfusion followed by low residue oral nutrition when tolerated. It is unclear whether low or high residue diets significantly help in maintenance.

Care must be taken with antidiarrhoeal, antimotility and antispasmodic therapy. While they may be used in the very short term for convenience, they must be avoided in acute attacks as they may cause paralytic ileus, retention of toxins and possibly megacolon.

Russell Greene MRPharmS is a pharmaceutical writer and consultant, and former senior lecturer in clinical pharmacy, King’s College, London

Need to know: treatment plans for tackling ulcerative colitis and Crohn’s disease

Acute treatment

Mild attacks of UC may be managed conservatively, with judicious use of short-term anti-diarrhoeals and fluid replacement. Disease restricted to the distal colon or rectum may be treated with local aminosalicylates and/or steroids.

More severe attacks and those in the proximal colon require oral therapy with aminosalicylates, possibly supplemented with short-term steroids (eg budesonide), although the efficacy of the latter is uncertain.

Oral steroids, if needed, should be given as high-dose pulse therapy, eg up to 60mg prednisolone daily for five days, tailing off over four to eight weeks.

In Crohn’s, aminosalicylates are less effective and steroids are required, with the dose form determined by the site and severity of the disease; Crohn’s will usually require systemic therapy. Attention to patients’ nutrition and monitoring for possible anaemia is essential.

Resistant cases of either UC or Crohn’s require hospitalisation. Intravenous steroids, eg 100mg hydrocortisone six-hourly, are essential. If control is not achieved, or the disease is chronically active, immunomodulators may be added. The BNF recommends ciclosporin as the next step for UC and cytotoxics (eg azathioprine) for Crohn’s.

If all else fails, TNF inhibitors are required, given by injection at intervals of several weeks. Infliximab is also recommended, along with antibiotics, in fistulating Crohn’s disease not controlled by other drugs.

Maintenance therapy

In UC, long-term maintenance therapy is usually necessary for the majority of patients. They should be cared for under the guidance of specialist gastroenterology teams, although once stabilised treatment can be delegated to their GP. General health, nutrition, monitoring for anaemia and possibly stoma care also need to be considered.

Many UC patients can be successfully controlled on moderate doses of aminosalicylates. Sulfasalazine is a cheap option but is not well tolerated by some patients, in which case the newer variations and formulations should be used.

Gastrointestinal upsets are potentially confusing side effects. Renal function should be checked before long-term therapy, and patients should be warned to watch for signs of bone marrow suppression (eg bruising, sore throat).

Oral steroids should be avoided because of long-term side effects, although some patients nevertheless become steroid dependent. However, for distal or rectal disease, local steroid therapy with foam or enemas will be helpful. Other drugs may need to be added to achieve control, following the sequence used in acute disease. Some more resistant patients may require an infliximab injection every eight weeks.

In Crohn’s, aminosalicylates are less effective for maintenance, although modified release mesalazine may be tried in ileitis because it is released in the distal small bowel. Once again, oral steroid maintenance therapy should be avoided. Immunomodulators may be required to maintain remission, or as steroid-sparing agents in steroid-dependent patients, with methotrexate the recommended treatment. A minority of patients may require infliximab maintenance. Patients with Crohn’s disease who smoke should be encouraged to stop.

Reflect

What are the side effects of sulfasalazine? Which antibiotics are used to treat acute GI complications? Why should anti-diarrhoeal and antispasmodic therapy be used with care in IBD?

Plan

This article describes the management of IBD including treatment of acute attacks and maintenance of remission. It includes information about the drugs used such as aminosalicylates, steroids, immunosuppressants and TNF inhibitors.

Act

• Revise your knowledge of the drugs used to treat IBD including doses and side effects from Section 1.5 Chronic bowel disorders in the BNF and the NHS Choices website at http://tinyurl.com/colitis03. 
• Read the MUR tips on ulcerative colitis on the C+D website at http://tinyurl.com/colitis04.
• Find out more about special diets and IBD and foods that can cause bloating from the Life and IBD website at  http://tinyurl.com/colitis05.
• Read the information leaflets about coping with diarrhoea and wind on the National Association for Colitis and Crohn’s website at http://tinyurl.com/ colitis06 and http://tinyurl.com/colitis07. Print out any information that might be useful for your patients.

Evaluate

Are you now familiar with the drugs used in the treatment of acute exacerbations and maintenance of remission in IBD? Could you advise patients with IBD about their treatment?

<a href="http://www.chemistanddruggist.co.uk/c/portal/layout?p_l_id=259751&CMPI_SHARED_articleId=4344394&CMPI_SHARED_ImageArticleId=4344394&CMPI_SHARED_articleIdRelated=4344394&CMPI_SHARED_ToolsArticleId=4344394&CMPI_SHARED_CommentArticleId=4344394&articleTitle=Update%20Module%201546:%20Inflammatory%20bowel%20disease%20pt2tag:news.google.com,2005:cluster=http://www.chemistanddruggist.co.uk/c/portal/layout?p_l_id=259751″>Update Module 1546: Inflammatory bowel disease pt2 – Chemist + Druggist

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