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Inflammatory bowel disease
06 March,13
Category: Inflammatory

Inflammatory bowel disease covers chronic non-specific inflammatory conditions of the gastrointestinal tract, of which the two major forms are Crohn\'s disease and ulcerative colitis.

Crohn\'s disease is characterised by thickened areas of the gastrointestinal wall, with inflammation extending through all layers, deep ulceration and fissuring of the mucosa, and the presence of granulomas; affected areas may occur in any part of the gastrointestinal tract, interspersed with areas of relatively normal tissue; the terminal ileum is frequently involved. Symptoms depend on the site of disease but may include abdominal pain, diarrhoea, fever, weight loss, and rectal bleeding. Extra-intestinal manifestations may include joint inflammation, skin lesions, mouth ulcers, and liver disorders.

In ulcerative colitis, disease is confined to the colon and rectum, inflammation is superficial but continuous over the affected area, and granulomas are rare. In mild disease, the rectum alone may be affected (proctitis); in severe disease, ulceration is extensive and much of the mucosa may be lost, with an increased risk of toxic dilatation of the colon, a potentially life-threatening complication. Symptoms include diarrhoea and rectal bleeding. The extra-intestinal manifestations are similar to those of Crohn\'s disease.

Although there are important differences between Crohn\'s disease and ulcerative colitis which affect their management, the broad principles of treatment, and the drugs used, are similar. The aminosalicylate derivatives are generally the first choice in mild to moderate active disease, and are of particular value for maintenance treatment of ulcerative colitis; the role of maintenance treatment in Crohn\'s disease is less well established. Corticosteroids are also used in the initial treatment of active disease, dosage and route varying with disease site and severity. Immunosuppressant therapy may be helpful in chronic active disease. For Crohn\'s disease an elemental diet may have some value in active disease, but diet plays a lesser role in ulcerative colitis.

Active disease.
The major group of drugs used to induce remission in moderate to severe active ulcerative colitis and Crohn\'s disease (including ileal disease) is the corticosteroids. Oral prednisolone or prednisone is often used; in the most severe cases hydrocortisone or methylprednisolone may be given intravenously.

Dosage is high initially, and is reduced gradually as symptoms improve, but adverse effects remain a problem, hence the interest in poorly absorbed or rapidly metabolised corticosteroids such as beclometasone, budesonide, or tixocortol. Oral budesonide is effective in inducing remission in Crohn\'s disease, and is probably comparable in effect to conventional corticosteroids; although some suggest that it may be slightly less effective, adverse effects are reduced. It appears to be more effective than the 5-aminosalicylate mesalazine in inducing remission of Crohn\'s disease affecting the ileum and/or colon.

Oral sulfasalazine, a 5-aminosalicylate derivative (5-aminosalicylic acid linked to sulfapyridine), is of value in producing remission of mild ulcerative colitis and in Crohn\'s disease affecting the colon, but has produced equivocal results in Crohn\'s ileitis.

The discovery that 5-aminosalicylate was the active component of sulfasalazine led to the development of numerous derivatives, including mesalazine (5-aminosalicylic acid itself in slow-release or enteric-coated form), olsalazine (2 molecules of 5-aminosalicylic acid joined by an azo bond), and a variety of forms, such as balsalazide, in which the active moiety was joined to inert carriers.

All the above have been shown to be effective in active ulcerative colitis, and may be better tolerated than sulfasalazine, since many of the latter\'s adverse effects are due to its sulfonamide portion. In patients who can tolerate sulfasalazine, the newer drugs have no clinical advantage for remission induction. Nevertheless, the risk of adverse effects on starting sulfasalazine therapy has led to increasing use of the newer derivatives.

In patients with disease confined to the distal colon or rectum, local topical therapy may be appropriate. Choice of topical formulation depends on the location of inflammation, with suppositories suitable for proctitis (disease up to the recto-sigmoid junction), but foam or liquid enemas for proctocolitis (more proximal disease).

Topical corticosteroids are less effective than topical mesalazine and a combination of topical and oral aminosalicylate seems to be more effective than either alone. In UK guidelines, first-line treatment for distal ulcerative colitis consists of topical mesalazine combined with an oral aminosalicylate; in those intolerant of topical mesalazine a topical corticosteroid may be combined with the oral aminosalicylate. Oral corticosteroid therapy is reserved for patients who fail to improve on these combinations.

Other drugs used in active inflammatory bowel disease include immunosuppressants. The majority of studies have been with azathioprine, or its metabolite mercaptopurine. Because they have a slow onset of action (months) their use in acute disease is limited, but they are of benefit in remission induction in patients with chronically active disease, particularly corticosteroid-resistant or corticosteroid-dependent disease.

Low-dose intramuscular methotrexate also appears to be useful in active Crohn\'s disease (although evidence for the oral route is lacking), and is probably of value in ulcerative colitis. Conversely, ciclosporin has not generally proved useful in chronically active inflammatory bowel disease but may have some value in the short-term treatment of acute severe ulcerative colitis.

Other immunosuppressants that have been used with some success include tacrolimus and mycophenolate mofetil, although further studies are needed to evaluate the role of these drugs. Infliximab or adalimumab, monoclonal antibodies to tumour necrosis factor, are effective in active Crohn\'s disease; infliximab, which has also shown promising results in ulcerative colitis, may be particularly valuable in fistulising Crohn\'s disease. Thalidomide, a tumour necrosis factor inhibitor, has also been tried in Crohn\'s disease with some benefit, but another such inhibitor, pentoxifylline, was ineffective.

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