Fig. 34.1 Factors associated with inflammatory bowel disease.
Investigations into the aetiology of inflammatory bowel disease have confirmed the multiplicity of factors that might be involved. The association of some events is strong while others are weak. Some changes may occur as a consequence of the disease rather than being involved in the cause. CD, Crohn’s disease; IBD, inflammatory bowel disease; IL, interleukin; TNFα, tumour necrosis factor α; UC, ulcerative colitis.
Treatment of both types of IBD is intended to induce and maintain remission. The drugs used for these two conditions are broadly similar, but Crohn’s disease is less responsive to some of the widely used drugs, especially when it involves the small intestine. Better understanding of the pathogenic mechanisms in IBD has resulted in advances in treatment, although much still needs to be learned.
Drugs for inflammatory bowel disease
Mechanism of action and effects
The active anti-inflammatory constituent of all the aminosalicylates is 5-aminosalicylic acid (5-ASA). The different aminosalicylate drugs are formulated in a variety of ways, but they are all designed to deliver 5-ASA to the lumen of the colon (see Pharmacokinetics). Sulfasalazine was the first aminosalicylate shown to be effective in treating IBD. Colonic bacteria cleave sulfasalazine into its constituent parts: 5-ASA and sulfapyridine. Sulfapyridine is responsible for many of the unwanted effects of this drug, but in contrast to its role in inflammatory arthritis (Ch. 30) it has no therapeutic value in IBD. The mechanisms of action of aminosalicylates are not clear, but they may involve inhibition of leucocyte chemotaxis by reducing cytokine formation, reduced free radical generation and inhibition of the production of lipid inflammatory mediators (such as prostanoids, leukotrienes and platelet-activating factor). Aminosalicylates are increasingly used as first-line prophylaxis of mild to moderate ulcerative colitis, and are highly effective for reducing relapse rates. Their efficacy in Crohn’s disease is less well established, particularly for non-colonic disease. They are less effective in treatment of acute exacerbations of IBD.
Pharmacokinetics
Sulfasalazine is partially absorbed from the gut intact, but most reaches the colon, where it undergoes reduction by gut bacteria to sulfapyridine and 5-ASA. Sulfapyridine and about 20% of the 5-ASA are absorbed from the colon, and then metabolised in the liver. Both have plasma half-lives of 5–20 h. There are several ways of delivering 5-ASA to the mucosa of the lower gut without also giving sulfapyridine. Mesalazine (the 5-ASA molecule itself) is given as an enteric-coated or modified-release formulation to limit absorption from the small bowel and deliver adequate drug to the colon. Olsalazine is a drug comprising two 5-ASA molecules joined by an azo bond. It is not absorbed from the upper gut and 5-ASA is released after reductive splitting of the azo bond by colonic flora. Balsalazide is a prodrug in which 5-ASA is linked to a carrier molecule (4-amino-benzoyl-β-alanine) by an azo bond, which is cleaved by bacterial reduction in the large bowel.
Mesalazine and sulfasalazine can be given rectally (by suppository or enema) to treat distal disease in the colon.
Corticosteroids
Corticosteroids (Ch. 44) are very effective for inducing remission in active IBD; however, there is little evidence that they prevent relapse when used at doses that do not produce significant unwanted effects. Newer corticosteroids formulated for topical use, such as budesonide (see also Ch. 44), have limited systemic unwanted effects and are useful alternatives to the older drugs. Topical treatment with liquid or foam enemas or suppositories is used for localised rectal disease, but oral or parenteral administration is needed for more severe or extensive disease.
Cytokine inhibitors (ANTI-TNFα antibodies)
Mechanisms and uses
Infliximab was the first monoclonal antibody to be approved for the treatment of Crohn’s disease. Adalimumab is effective when infliximab is poorly tolerated or for those who have become refractory to treatment. Inhibition of the binding of TNFα to its receptors reduces production of pro-inflammatory cytokines (e.g. IL-1 and IL-6), leucocyte migration and infiltration, and activation of neutrophils and eosinophils. Infliximab may also be useful for treatment of severe attacks of ulcerative colitis. Unwanted effects of TNFα antibodies are discussed in Chapter 30.
Immunosuppressants
Azathioprine and, less often, mercaptopurine are useful in some people with active IBD and may enable corticosteroid doses to be reduced. Mercaptopurine is more frequently used in North America; it may be a little less effective than azathioprine but perhaps with a lower rate of nausea. Maximal efficacy is not achieved with either drug for about 6–12 weeks. Nausea, vomiting, rashes and a hypersensitivity syndrome affect about 10% of people during the first 6 weeks of therapy. Pancreatitis and liver toxicity are rare but serious complications.
Methotrexate is useful in Crohn’s disease. It is given subcutaneously or intramuscularly and is only used when azathioprine has failed. Ciclosporin can induce remission in corticosteroid-resistant ulcerative colitis but has no long-term efficacy. More details of these drugs are found in Chapter 38.
Antibacterials
Metronidazole (Ch. 51) is moderately effective for treatment of some aspects of Crohn’s disease, particularly perianal disease, although the mechanism of action is uncertain. Ciprofloxacin probably has similar efficacy.
Management of inflammatory bowel disease
Treatment is determined by the extent and severity of disease. Non-steroidal anti-inflammatory drugs (NSAIDs) and also selective cyclo-oxygenase 2 (COX-2) inhibitors (Ch. 29) can exacerbate symptoms in severe colitis and should not be used. Opioids (Ch. 35) should be avoided in the treatment of diarrhoea in extensive colitis since they can precipitate the life-threatening complication toxic megacolon.
Rectal drug delivery is often successful if the disease is limited to the rectum or left side of the colon (distal colitis). For mild symptoms, topical mesalazine is more effective than topical corticosteroid. Foam enemas or suppositories will treat inflammation up to 12–20 cm from the anus, while liquid enemas are effective up to 30–60 cm (i.e. to the splenic flexure). Oral aminosalicylate can be combined with rectal administration to improve efficacy. For more severe disease an oral corticosteroid may be necessary to induce remission, with gradual dosage reduction to minimise unwanted effects once control is achieved.
More extensive colitis will settle with an oral aminosalicylate if symptoms are mild to moderate, but the response can take 6–8 weeks. Oral corticosteroids such as prednisolone induce remission more quickly. Severe colitis requires intensive fluid and electrolyte replacement; anaemia should be corrected by transfusion, and large doses of parenteral corticosteroid should be given. Infliximab can be used for severe refractory disease. Surgery is required in about 20% of people with ulcerative colitis.
Once symptoms are quiescent, maintenance treatment with topical mesalazine or an oral aminosalicylate should be life-long and reduces the relapse rate by two-thirds. It also reduces the risk of developing colorectal cancer by up to 75%.
The indications for immunosuppressants in the treatment of ulcerative colitis are the same as for Crohn’s disease (see below). Azathioprine is the only immunosuppressant agent with a good evidence base for long-term therapy of ulcerative colitis. Intravenous ciclosporin may induce remission in refractory cases.
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