Medical management of severe inflammatory disease of the rectum and distal colon: Non-nutritional aspects

1 Medical management of severe inflammatory disease of the rectum and distal colon: Nonnutritional aspects REX J. POLSON J. J. MISIEWICZ Inflammation of the rectum from whatever cause results in mucosal oedema and friability and usually presents with rectal bleeding and passage of mucus per rectum. Where the inflammation is confined to the rectum (proctitis) thereispassageoffreshbloodeitherstreakedontheoutsideofnormalstoolor separate from the faecal matter. This bleeding may wrongly be attributed to haemorrhoids by the patient or the doctor. In all patients with rectal bleeding, and particularly in those who also pass mucus, once carcinoma or polyps have been excluded, proctitis should be suspected and an adequate rectal examination must be performed. In those with localized haemorrhagic proctitis, symptoms often develop insidiously, with a bowel habit which is frequently normal or even constipated. Although the area of inflammation may be localized, it can cause extremely distressing symptoms, with pain, tenesmus and leakage of rectal contents. If the disease is more extensive (colitis), the blood becomes mixed with the stool, which also becomes more liquid, ultimately resulting in the passage of blood mixed with pus, mucus and faecal material. In addition to changes in stool consistency with rectal bleeding, extensive severe inflammation of the colonic mucosa leads to a disturbed bowel habit, with urgency of defecation and also occasionally abdominal pain, malaise, fever and weight loss. The management of severe ulcerative colitis with toxic megacolon is outside the scope of this chapter (Misiewicz et al, 1987).

INVESTIGATION

As rectal inflammation may have different causes (Table l), the initial investigation is aimed at establishing a diagnosis and the extent and severity of mucosal inflammation. Clinical history, as detailed later, may provide useful diagnostic information, such as gradual onset and a family history in ulcerative colitis and Bailli2re’s Clinical GastroenterologyVol. 6, No. 1, March 1992 ISBN 0-702G1622-5

1 Copyright 0 1992, by Baillikre Tindall All rights of reproduction in any form reserved

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Table 1. Differential rectal inflammation.

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diagnosis of

Ulcerative colitis Crohn’s disease Radiation proctitis Infective colitis: Campylobacter Shigella Salmonella Clostridium dijticile

Amoebiasis Sexually transmitted proctitis

Crohn’s disease, a history of radiotherapy in radiation colitis, or an abrupt onset and contact history in infective colitis. Physical examination will show the degree of systemic disturbance caused by the intestinal inflammation, reflecting the extent and severity of disease. Extraintestinal manifestations, such as clubbing, iritis, arthritis or erythema nodosum, may be present in ulcerative colitis or Crohn’s disease. Essential further assessment involves the examination of the distal colonic mucosa. This not only allows assessment of the severity of inflammation (Baron et al, 1964), but may also show an upper limit to the extent of the disease. There are three ways in which the unprepared distal large bowel can be examined. Proctoscopy is easy to do but allows examination of the anal canal and distal rectum only, making biopsies difficult to take. Rigid sigmoidoscopy is also easy and allows views of the colonic mucosa, which can be biopsied, up to 2.5 cm. Flexible sigmoidoscopy allows even more of the distal colon to be visualized and biopsied, but is technically more difficult, takes longer to do and requires a special light source. For routine use, rigid sigmoidoscopy is acceptable. A biopsy from the anterior wall of the rectum, S-10cm from the anal margin, should always be taken for histopathological examination during the initial assessment of a patient with proctitis. The histological degree of inflammation can be graded (Truelove and Richard, 1956). Bacteriological examination of the stools to exclude an infective cause is important in the first assessment of patients with bloody diarrhoea, and may also be needed in patients with a previous diagnosis of idiopathic inflammatory bowel disease as they too can acquire an infective colitis. In some patients the initial investigation may also include serological tests to confirm diagnoses such as amoebiasis, schistosomiasis or chlamydial lymphogranuloma venereum. A full blood count will confirm or exclude the presence of anaemia, while a leucocytosis, thrombocytosis or a raised erythrocyte sedimentation rate (ESR) and/or C-reactive protein concentration all indicate increasingly severe disease. Biochemical assessment is necessary to exclude electrolyte disturbances and associated hepatic dysfunction, or hypoalbuminaemia, which may occur in severe disease. In patients in whom the upper limit of inflammation cannot be seen using a sigmoidoscope, additional examinations of the bowel using fibreoptic

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colonoscopy or air contrast barium enema are needed to determine the extent and severity of the disease. Colonoscopy has the advantage over radiology of allowing histological confirmation of the disease. It must be stressed that all patients in whom the source of bleeding has not been confidently diagnosed at sigmoidoscopy must have the whole colon visualized endoscopically or radiologically.

ULCERATIVE

PROCTOCOLITIS

The incidence and prevalence of ulcerative colitis are variable, but are approximately S-8/100 000 and 70-90/100 000, respectively, in Western Europe (Rhodes and Mayberry, 1986). The disease usually starts in the rectum and may extend proximally in continuity into the colon, although only about 10% of patients with proctitis ultimately develop an extensive colitis (Ritchie et al, 1978). Proctitis is generally believed to be a variant of ulcerative colitis; the diagnostic, histopathological and management criteria are similar, although they are modulated in proctitis by the limited extent of the mucosal inflammation. In addition, the anatomical location of the inflammation poses some special problems. Pathology Ulcerative colitis is a chronic inflammatory disease of unknown aetiology in which a variable length of large bowel mucosa becomes diffusely inflamed and may ulcerate. Microscopically there is increased vascularity and oedema of the mucosa, with infiltration of the lamina propria by acute and chronic inflammatory cells. Neutrophils accumulate in the crypts to form ‘crypt abscesses’, while goblet cells discharge mucus and so apparently decrease in number. The surface epithelium flattens and glands are destroyed. Although the inflammatory and ulcerating process can be severe, it is confined to the mucosa and does not penetrate the muscularis mucosae, except rarely in association with perforation or acute dilatation of the colon. Management This is determined by the severity and extent of the colitis. Thus those patients with a gradual onset and limited disease can be managed as outpatients, but those patients with a severe acute attack who have extensive disease may need admission to hospital. Patients with limited disease

Patients with inflammation localized to the rectum, even if this is severe, usually do not have constitutional symptoms and so rarely, if ever, need to be admitted to hospital. Prolonged or excessive bleeding may occasionally result in anaemia, which may require blood transfusion.

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Patients with extensive disease Patients with severe rectal inflammation and systemic illness as part of more extensive disease may require hospital admission to allow correction of dehydration, electrolyte deficiencies such as hypokalaemia, anaemia and poor nutritional state. Inpatient care also allows parenteral treatment of the colitis and the careful regular assessments necessary to determine whether surgical intervention is indicated. Corticosteroids

These drugs can be given either rectally for localized inflammation of the rectum, or systemically when the disease is more extensive. Truelove and Witts (1955) were the first to establish the benefit of cortisone in the treatment of acute ulcerative colitis. Further work has confirmed that other corticosteroids are also effective and that these can be given rectally, orally or parenterally. In patients with localized severe inflammation of the rectum topical treatment is the most appropriate. Topical steroids. Retention enemas of prednisolone or hydrocortisone formulated in either an aqueous or foam vehicle are effective in healing active rectal disease, and generally have little in the way of systemic sideeffects. Thus hydrocortisone acetate foam enemas are effective (Somerville et al, 1985) with no apparent absorption of the active component (Neumann et al, 1989), whilst absorption of steroid from the rectum is considerable if prednisolone phosphate enemas are used (Powell-Tuck et al, 1976), but is decreased with betamethasone, or preferably prednisolone metasulphobenzoate, enemas (Lee et al, 1980). Corticosteroid suppositories are also effective in ulcerative proctitis. They are easier to use and may be a more suitable approach than enemas in some patients, especially those with mild symptoms. Enemas and suppositories are particularly beneficial if used at bedtime as they can then usually be retained for several hours. Morning enemas, or suppositories, should be used after initial morning evacuations, to which all patients with inflammatory bowel disease are prone. The efficacy of all topical treatments is governed, to some extent, by the duration of their retention in the lumen. If the treatment appears ineffective, it is useful to go over the technique and timing of administration with the patient, establish how long the enemas are retained and correct any technical errors. As steroid retention enemas and suppositories are largely free from unwanted effects, it is useful for patients with proctitis or ulcerative colitis to keep a small stock at home, to be used promptly if a relapse occurs. Generally enemas are given twice daily for a moderate to severe relapse, and the frequency of administration is then gradually decreased as symptoms improve, usually within 2 or 3 weeks. The extent of distribution proximally into the colon depends in part on the volume of the enema. If more extensive disease is being treated, the volume

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and the dose can be varied by supplying the patient with soluble prednisolone tablets, a 60 ml plastic syringe and a 12 French gauge catheter. Variable dose and volume enemas can be made up by the patient using tap water (Howe1 Jones et al, 1965). Oral steroids. In patients with rectal inflammation as part of a more extensive proctocolitis, oral or parenteral corticosteroid therapy may be needed. Oral prednisolone 20-60 mg daily is effective in a dose-related manner in patients with ulcerative colitis, although doses higher than 40 mg daily are associated with appreciable side-effects (Baron et al, 1962). A single morning dose of prednisolone is as effective as a divided dose regimen and has fewer side-effects (Powell-Tuck et al, 1978). The combination of oral and topical steroids is more effective than either alone (Truelove, 1960). There is no indication for using oral corticosteroids once a patient’s colitis is in remission, as cortisone (37.5 mg daily) and prednisolone (15 mg daily) have been shown to be ineffective in preventing relapses of ulcerative colitis (Truelove and Witts, 1959; Lennard-Jones et al, 1965). As soon as a patient treated with systemic steroids shows signs of improving, the dose should gradually be decreased to zero. Starting from 40mg daily, this is usually possible in 1 to 2 months, the rate of withdrawal being determined by the need to maintain the clinical response and also to allow endogenous corticosteroid production to return without precipitating adrenal insufficiency. Parenteralsteroids. In severe attacks of ulcerative colitis (more than six stools daily, with systemic disturbance such as fever, tachycardia or anaemia, or an ESR of 30 mm/h or more) (Truelove and Witts, 1955), intravenous hydrocortisone 100-200mg q.d.s. daily is the preferred treatment. Intramuscular adrenocorticotrophic hormone (ACTH) 40 units daily is equally effective (Kaplan et al, 1975)) and may be useful inpatients in whom intravenous access is difficult. Severely ill patients will also need additional intravenous fluid and electrolyte replacement and possibly parenteral nutritional support. If steroid treatment fails to give any improvement within 5-7 days then surgery must be seriously considered. Aminosalicylic

acid derivatives

These drugs can be given either rectally for localized inflammation rectum, or orally when the disease is more extensive.

of the

Sulphasalazine

Sulphasalazine consists of 5-aminosalicylic acid bound through an azo bond to sulphapyridine. Absorption of the drug in the small intestine is minimal, so that most of the dose reaches the colon. Here colonic bacteria split the azo bond and release the two compounds. The 5-aminosalicylic acid component of sulphasalazine is the active anti-inflammatory agent (Azad Khan et al,

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1977; Van Hees et al, 1980), with most of the side-effects caused by the sulphapyridine moiety and its derivatives. Topical. Sulphasalazine enemas are effective in inducing remission of active distal ulcerative colitis (Palmer et al, 1981). Oral. Placebo-controlled studies have shown that oral sulphasalazine is effective in treating active colitis, although it is not nearly as effective as corticosteroids (Truelove et al, 1962). The major use of oral sulphasalazine is, however, in long-term maintenance therapy, where it significantly decreases the frequency of relapses of ulcerative colitis (Misiewicz et al, 1965), an effect which operates over many years (Dissanayake and Truelove, 1973). A dose of 2.Og daily appears to give maximal clinical effect with least side-effects (Azad Khan et al, 1980). Thus sulphasalazine is often used for prolonged periods in maintaining patients with rectal inflammation who go into remission on treatment with topical or systemic corticosteroids. Sulphasalazine should be continued long-term in patients with recurrent ulcerative colitis, and given for at least 1 year after the first episode. It has recently been emphasized that sulphasalazine rather than 5aminosalicylic acid alone may have additional properties, such as effects on neutrophil, B lymphocyte and natural killer cell function, which could be important in its anti-inflammatory actions in ulcerative colitis. These need further investigation (Hayllar and Bjarnason, 1991). Side-effects. The side-effects of sulphasalazine have an incidence of 15-30%. They include dyspepsia, nausea, vomiting, diarrhoea and headache. As they may be dose related they can often be avoided by starting with sulphasalazine OSg daily and gradually increasing the dose until the limits of tolerance. Alternatively the dose may be decreased until the side-effect subsides or becomes tolerable. Non-dose-related side-effects, such as erythema nodosum or hypersensitivity rashes, are also likely to be due to the sulphapyridine and these too may be avoided by desensitization using a starting dose of 1 mg daily (Holdsworth, 1981). Rare side-effects include fever, agranulocytosis, Heinz body haemolytic anaemia, inflammatory reactions affecting lung, liver, myocardium and pancreas, and male infertility. The latter is due mainly to changes in sperm motility, but abnormal forms are often present and the total number may be decreased-changes that reverse within 2 or 3 months of stopping the drug (Toovey et al, 1981). The development of newer 5-aminosalicylic acid drugs has provided an alternative to dose modification in the management of sulphasalazine side-effects. Newer 5-aminosalicylic

acid derivatives

Pharmacology. As the main benefits of sulphasalazine are due to S-aminosalicylic acid with most of the side-effects due to sulphapyridine, various pharmacological methods have been developed to deliver 5-aminosalicylic acid to the colon. These include controlled release preparations or linking

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5-aminosalicylic acid to a carrier molecule other than sulphapyridine. Three products are at present licensed in the United Kingdom for the treatment of ulcerative colitis. Mesalazine (Asacol) is 5-aminosalicylic acid coated with a polyacrylic resin which disintegrates at a pH above 7, as in the large intestine. This can result in rapid local release of 5-aminosalicylic acid which can overload local acetylation mechanisms, resulting in absorption of nonacetylated 5-aminosalicylic acid. This compound is nephrotoxic in experimental animals, while acetylated 5-aminosalicylic acid is not (Calder et al, 1971). Although this drug has been used without problems in many patients, there has been some concern recently regarding nine reports of serious nephrotoxicity associated with the use of mesalazine (Committee on Safety of Medicines, 1990). This has led to the recommendation that mesalazine is best avoided in patients with established renal impairment. An alternative mesalazine preparation, Pentasa, is 5-aminosalicylic acid in the form of lmm granules coated with ethylcellulose, which gradually dissolves and releases the drug throughout the small and large intestine. This does not give a sudden large release of 5-aminosalicylic acid in the colon, and may diminish the amount of non-acetylated 5-aminosalicylic acid in the circulation. An alternative approach is provided by olsalazine, which consists of two 5-aminosalicylic acid molecules joined by an azo bond which, as in sulphasalazine, is cleaved by colonic bacteria in the proximal large bowel. The same principles as outlined for steroids apply, so that for localized rectal inflammation topical preparations can be used, whilst in patients with rectal involvement as part of a more generalized disease, oral treatment is more suitable. Mesalazine is poorly absorbed in the colon (Campieri et al, 1985), making it suitable for topical treatment in patients with localized disease. In a study of 47 patients with colonic inflammation distal to the splenic flexure which was not responsive to conventional therapy, daily 5-aminosalicylic acid enemas led to improvement within 3 months in 41 (87%)) with complete remission in 39 (83%) (McPhee et al, 1987). A similar study from Canada showed that 48 of 76 (63%) patients with colitis extending up to 50cm were ‘much improved’ after 6 weeks’ treatment with 5aminosalicylic acid 4g enemas compared with 22 of 77 (29%) patients on placebo (P = 0.001). Disease activity, based on symptoms and sigmoidoscopic appearance, decreased by 55% in patients on 5-aminosalicylic acid and 24% in those on placebo (P = 0.0001). Response was more likely in those with disease confined to 20-40 cm from the anus, was not affected by concurrent oral sulphasalazine, but was less likely in those needing concurrent oral steroids. Decreased rectal bleeding was often recorded within 3 days of starting treatment (Sutherland et al, 1987). The 5-aminosalicylic acid enemas were well tolerated in both studies. A randomized, double-blind trial in seven centres in Denmark compared the efficacy of 5-aminosalicylic acid 1 g with that of prednisolone 25 mg given daily rectally to outpatients with mild to moderate proctosigmoiditis. Improvement or remission was recorded in 77% of the 53 5-aminosalicylic acid-treated patients and in 72% of the 61 prednisolone-treated patients, Mesalazine.

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showing that 5-aminosalicylic acid is at least as effective as prednisolone for topical treatment (Danish 5-ASA Group, 1987). 5-aminosalicylic acid suppositories are also effective in patients with active colitis affecting the distal 20cm of the bowel. Thus 11 of 14 (79%) patients treated with 5-aminosalicylic acid 500mg suppositories t.d.s. for 6 weeks were in remission compared with none of 13 receiving placebo. Studies of technetium-99m labelled 5-aminosalicylic acid suppositories show that the drug was retained for 3 h with spread limited to the rectum (Williams et al, 1987). A more recent Italian randomized controlled trial has also shown a significant improvement in patients with proctitis (< 20 cm) treated with 5-aminosalicylic acid suppositories. Clinical remission occurred at 4 weeks in 7 of the 31(39%) patients receiving placebo, in 22 of the 32 (69%) patients receiving mesalazine 500 mg twice daily and in 23 of the 31 (74%) patients receiving mesalazine 500mg t.d.s. (Campieri et al, 1990). Treatment with 5-aminosalicylic acid suppositories, 400 mg twice daily, may also be effective in maintaining remission in patients with distal colitis. Thus in one small study with 1 year of follow-up the cumulative remission rate in patients treated with 5-aminosalicylic acid 400mg twice daily was 92% compared with 21% in the placebo group (P= 0.001). No side-effects were observed (D’Arienzo et al, 1990). These findings need to be confirmed by further larger studies. Thus in patients with ulcerative colitis limited to the rectum or rectosigmoid, 70-90% should respond to treatment with topical 5-aminosalicylic acid drugs, with most going into remission. Treatment is well tolerated and is comparable to that with topical corticosteroids, although at present is more expensive. However, the greater experience with using topical corticosteroids and the fact that they are cheaper makes them the preferred first line treatment at present. A recently reported international study involving 46 gastroenterology clinics in seven countries compared oral mesalazine 1.5 g daily with oral sulphasalazine 3.Og in patients with active, mild to moderate ulcerative colitis (Rachmilewitz, 1989). At 8 weeks, clinical remission was recorded in 74% patients on mesalazine and in 81% patients receiving sulphasalazine, with endoscopic remission in 49% and 47%, respectively. The two drugs thus appear to be equally effective, but side-effects occurred in only 14% of the mesalazine patients compared with 25% of those on sulphasalazine. In another study, however, there were equal withdrawal rates with both drugs (McManus, 1989). Olsaluzine. Clinical trials so far have been aimed at documenting the effects of oral olsalazine in patients with mild to moderate ulcerative colitis, with no studies directed at its effect in localized rectal inflammation. Two recent double-blind studies have compared oral olsalazine and sulphasalazine in mild to moderate ulcerative colitis. The first showed that in 37 patients presenting with their first attack of distal colitis, after 4 weeks’ treatment olsalazine 2g was as effective as sulphasalazine 3 g and was somewhat better tolerated (Rao et al, 1989). The second study compared olsalazine 3 g with sulphasalazine 3 g in 56 patients (36% in their first attack)

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and found that both were equally successful in decreasing diarrhoea and bleeding. The higher dose of olsalazine did not enhance the therapeutic response, suggesting there was perhaps a maximal effective delivery level of Saminosalicylic acid to the inflamed colonic mucosa (Willoughby et al, 1988). In one placebo-controlled double-blind trial on 105 patients with mild to moderate ulcerative colitis, olsalazine 2g daily, although inducing endoscopic improvement of the rectal inflammation after 4 weeks’ treatment, did not produce improvements in stool frequency, urgency, abdominal pain or biopsy appearances (Feurle et al, 1989). I-Aminosalicylic acid. Oral 4-aminosalicylic acid (para-aminosalicylic acidpreviously used in the treatment of tuberculosis) can cause clinically important renal toxicity with crystalluria, haematuria and nephritis. Its use in ulcerative colitis has therefore been restricted to topical treatment of distal disease. A recent trial compared 4-aminosalicylic acid 2g enemas with prednisolone 20mg enemas in 51 patients with acute distal colitis. After 6 weeks, clinical, sigmoidoscopic and histological improvement was similar on both treatments (O’Donnell et al, 1990). Immunosuppressive

agents

In patients with ulcerative colitis who have severe colonic inflammation or disease refractory to treatment with corticosteroids and Saminosalicylic acid drugs, treatment with alternative immunosuppressive agents may be beneficial. Azathioprine

There is no evidence that azathioprine is of benefit in active ulcerative colitis either when localized to the rectum or when more widespread, although it may be of some use in patients with established disease as long-term maintenance therapy in a dose of 1.5-2.0mg/kg (Jewel1 and Truelove, 1974). It should be reserved for those who have frequent relapses once steroids are tailed off. Azathioprine also has a useful steroid-sparing effect in those few patients who seem to benefit from long-term steroid therapy (Kirk and Lennard-Jones, 1982). 6Mercaptopurine

Azathioprine is largely converted to 6-mercaptopurine within the body and therefore their pharmacological effects are similar. There has been a reluctance to use 6-mercaptopurine for fear of long-term toxicity, although a recent review has shown that this might be less than expected (Present et al, 1989). In 396 patients with inflammatory bowel disease (120 ulcerative colitis, 276 Crohn’s disease) treated for a mean of 34 months and followed for a mean of 60 months, direct toxicity was recorded in 7.6% (pancreatitis 3.3%) allergic reactions 2%) marrow depression 2% and hepatitis 0.3%).

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There was no mortality and all patients recovered on discontinuing or decreasing the 6-mercaptopurine treatment. Infections were seen in 7.4%, but were only severe in 1.8% and no deaths resulted. With regard to the long-term risk of malignancy, although several tumours were seen, only a single histiocytic lymphoma of the brain was felt to be related to the 6-mercaptopurine. The authors conclude that the toxicity is not excessive, and that 6-mercaptopurine should be used in appropriate clinical situations. There are no controlled studies of 6-mercaptopurine in ulcerative colitis, but uncontrolled studies have shown it to be effective in 60-70% of patients who have failed to respond to steroids and 5-aminosalicylic acid drugs and so may provide an alternative to surgical intervention (Present et al, 1989). Methotrexate In an open trial, methotrexate 25mg i.m. weekly for 12 weeks with responders switched to oral therapy was given to seven patients with refractory ulcerative colitis. A positive response was recorded clinically in five, although endoscopic or histological remission did not occur, and three were subsequently withdrawn from treatment because of lack of sustained benefit (Kozarek et al, 1989). Methotrexate worked more quickly than azathioprine and 6-mercaptopurine and caused only minor side-effects, and further trials are justified in patients with intractable disease. There is no place as yet for the use of this drug in the routine treatment of ulcerative colitis. Cyclosporin Cyclosporin is widely used in organ transplantation and has a selective effect on T lymphocyte mediated immune responses (Cohen et al, 1984). Its effect on inflammatory bowel disease has recently been studied. Cyclosporin is available in topical, oral and parenteral forms. Topical. Two preliminary reports have shown cyclosporin enemas to be successful in left-sided colitis. In the first, eight outpatients who had colitis resistant to both topical corticosteroids and 5-aminosalicylic acid were given nightly cyclosporin 3.5 mg/kg retention enemas for 2 weeks (Brynskov et al, 1989a). Six improved clinically and sigmoidoscopically. Hydrophilic enemas were used and resulted in minimal to no detectable cyclosporin blood levels either during or for 2 weeks after the treatment. In the second study of six patients with chronic proctosigmoiditis unresponsive to conventional therapy, topical cyclosporin led to a response in three (Ranzi et al, 1989). Absorption of cyclosporin was insignificant and no toxicity was noted. These are all preliminary uncontrolled studies and, at present topical cyclosporin cannot be recommended for use outside a research setting. Oral. There are only anecdotal reports of the efficacy of oral cyclosporin in ulcerative colitis (Stange et al, 1989).

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Purenterul. Intravenous cyclosporin may be suitable for patients with severe ulcerative colitis, particularly those with widespread disease who are systemically unwell. Intravenous cyclosporin 4mg/kg daily given to 15 patients with severe active ulcerative colitis (14 had not responded to intravenous hydrocortisone 300 mg/day given for at least 10 days) (Lichtiger and Present, 1990), produced improvement in 11 (73%) with avoidance of colectomy; mean response time was 5.8 days. Responders were then maintained on oral cyclosporin 6-8mg/kg daily for 6 months. Nine of 11 responders (82%) remained in remission, with six able to discontinue their steroids. Two patients (18%) relapsed during oral therapy; one underwent elective colectomy, while the second patient refused colectomy but went into clinical remission after changing to 6-mercaptopurine treatment. Sideeffects were slight and self-limiting, with none necessitating withdrawal from the study. There are no controlled data in these studies of the effects of intravenous cyclosporin and, although only minor side-effects were reported in these studies, it is well recognized from the use of cyclosporin in organ transplantation that side-effects can be of major importance. These can be prevented to some extent by careful control of the blood concentration of cyclosporin, although decreased levels may impair clinical efficacy and not all side-effects are dose dependent. At present, systemic cyclosporin cannot be recommended for routine use in ulcerative colitis; it should ideally only be given in a research setting.

Other agents In spite of the benign nature of proctitis in most patients, intractability is a common problem (Biddle et al, 1988) and the resulting symptoms of pain, tenesmus and leakage of rectal contents can be extremely distressing. Thus other agents, both oral and topical, have been sought. Sodium cromoglycate

Despite promising results from early trials with sodium cromoglycate (cromolyn sodium USP), more recent placebo-controlled studies have shown no benefit, at least in doses up to 800 mg daily given orally or rectally (Hovdenak et al, 1986). Sucralfate

Sucralfate 4g enemas for 4 weeks were compared with prednisolone metasulphobenzoate 20mg enemas in a study of 44 patients with distal ulcerative colitis (Riley et al, 1989). Although the steroid was more effective, improvement was also seen in the sucralfate-treated group. This study did not include a placebo group and so it is not possible to conclude that sucralfate has therapeutic efficacy, but further trials are probably indicated, particularly as toxicity is likely to be low.

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Arsenicals

Although first reported to have some efficacy in the treatment of proctitis 25 years ago (Cormell et al, 1965), the toxicity of acetarsol has limited its usage (Bowen et al, 1961). A recent study has, however, suggested that acetarsol is effective in proctitis and may occasionally be useful for short-term use to try and induce remission in resistant cases (Forbes et al, 1989). Bismuth

A preliminary open study has shown some improvement in symptoms and sigmoidoscopic and histological appearances in nine out of 11 patients with active proctitis treated for 4 weeks with nightly tripotassium dicitrato bismuthate enemas (Srivastava et al, 1990). In future trials, blood bismuth levels should be measured as rectal absorption could lead to toxicity which would limit its use on a long-term basis. Similar results have been reported for bismuth salicylate enemas (Ryder et al, 1990). Placebo-controlled trials are needed to determine its short-term efficacy. Lignocaine

Preliminary studies with the use of topical lignocaine (lidocaine USP) to treat ulcerative proctitis suggest some efficacy and the need for larger, well-designed studies (Bjorck et al, 1988). Metronidazole

Given orally this has been shown to be of limited benefit in patients with chronic proctitis (Davies et al, 1977), and therefore should no longer be used. Summary of medical management patients with ulcerative colitis

of severe rectal inflammation

in

Localized severe inflammation of the rectum in patients with ulcerative colitis is usually amenable to topical treatment with corticosteroids, although these drugs should be given orally or parenterally in patients who are systemically unwell. Similarly those with more generalized colonic inflammation will also need systemic therapy. Additional treatment with 5aminosalicylic acid drugs, again either topically or orally, can be useful in the acute phase, but is more suitable for long-term use in maintaining remission of the disease. In those who fail to respond or have only limited improvement when treated with steroids and 5-aminosalicylic acid drugs, the other agents described in detail earlier can be tried, although this should be part of a controlled trial if possible.

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COLITIS

Crohn’s disease is predominantly a disorder of north-western Europe, North America, Australia, New Zealand and the white population of South Africa, with an incidence in these areas which has increased over the past few decades and is at present 4-51100 000, with a prevalence of 40-501100 000 (Allan, 1986). Pathology

Crohn’s disease is often discontinuous, giving rise to the characteristic skip lesions, and, unlike ulcerative colitis which affects only the large bowel, any part of the gastrointestinal tract can be involved. At presentation two-thirds of patients with Crohn’s disease will have disease of the distal ileum, with or without right colonic involvement. A further 5% will have diffuse small bowel disease (Gyde et al, 1980). A further 14% of patients will have extensive colonic disease, 5% have distal colonic involvement and 7% have large and small intestinal Crohn’s disease at presentation. Perianal disease is present in at least 65% of patients with Crohn’s disease, and is usually painless and asymptomatic (Buchmann et al, 1980). Occasionally, if there is local abscess formation with pus under pressure or an active anal fissure, perianal Crohn’s disease may become painful. Characteristic fleshy anal skin tags are often present. Further consideration of small intestinal Crohn’s disease is beyond the scope of this chapter (Misiewicz et al, 1987). Shallow aphthous ulcers usually surrounded by normal mucosa and giving rise to the typical cobblestone pattern are present in the early stages. More severe disease is characterized by deep fissuring ulcers, and can result in fistula formation with submucosal fibrosis, which may lead to strictures. Microscopically, the inflammation is transmural, with non-caseating granulomata present in 65% of patients, and especially in those with rectal and colonic disease. This has led to the synonym for Crohn’s colitis of granulomatous colitis. Management

This will be determined primarily by the extent and severity of the disease, with severe disease needing admission to hospital. As Crohn’s disease often affects the small intestine as well as the colon, nutritional deficiencies and electrolyte disturbances are more common than in ulcerative colitis, and may need specific treatment. As Crohn’s disease can affect the whole of the gastrointestinal tract and can recur after resection, surgical intervention is not as useful in Crohn’s disease as it is in patients with ulcerative colitis who fail to respond to medical therapy. In patients with severe Crohn’s disease it is often necessary to persevere with medical management, and a variety of drugs may have to be tried either alone or in combination in order to obtain remission. Drugs may be given topically to patients with distal localized disease, or systemically to those with more diffuse disease. As Crohn’s disease

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commonly affects areas of the bowel other than the rectum, oral treatment is often needed. Corticosteroids Topical steroids. Corticosteroid enemas, or suppositories, are useful in the treatment of localized inflammation of the rectum or rectosigmoid, and the comments made about their use in ulcerative colitis apply equally in Crohn’s disease. The response of perianal lesions can, however, be disappointing. Oral steroids. The American National Cooperative Crohn’s Disease Study (NCCDS) showed that oral prednisolone 0.25-0.75 mg/kg, to a maximum of 60 mg, given daily for 4 months (the dose being adjusted to the activity of the disease) was more effective than placebo (P < 0.0006). These results applied to those with ileal (P= 0.002) and ileocolic disease (I’= O.OOS), but the results in patients with colonic disease were not significant, perhaps because of the small size of the sample (Summers et al, 1979). The main role of steroids in Crohn’s colitis is to suppress the acute inflammation of the gut, and therefore it is important to ensure as far as possible that symptoms are due to inflammation rather than fibrosis or sepsis. Leucocytosis , thrombocythaemia and a raised ESR and/or Creactive protein concentration suggest the presence of inflammation, and this is supported by the finding of thickened bowel wall on ultrasound scans and barium studies. A positive radionuclide scan using indium-labelled white blood cells is useful, where available, in localizing the sites of active inflammation. However, it is often difficult to be sure that symptoms are mainly due to inflammation, as a combination of factors may be present, and it may be necessary to conduct a trial of treatment with careful observation of the overall clinical response. Symptoms usually improve after l-2 weeks of either oral prednisolone 20-40mg daily or, in more severe illness, intravenous hydrocortisone 300 mg. The steroids can then be tailed off, usually over l-2 months. Several studies have not shown any effect on the incidence of relapses from longterm steroids in those with inactive disease. Thus prednisolone 7.5 mg daily for up to 3 years had no effect on preventing disease relapse, recurrence or extension in 33 patients compared with 26 controls (Smith et al, 1978), nor did prednisolone 0.25 mg/kg (up to 20 mg) daily maintain remission in the NCCDS trial any better than placebo over l-2 years (Summers et al, 1979). Similarly, prednisolone (with sulphasalazine 3 g daily) at a starting dose of 15 mg daily and reducing to nil 33 weeks after operation failed to decrease the recurrence rate after surgical resection for Crohn’s disease over the first 3 postoperative years (Bergman and Krause, 1976). A more recent study, however, showed that in 18 patients with Crohn’s disease in clinical remission but who still had abnormal laboratory values (ESR, C-reactive protein, acid aI-glycoprotein and c-wl-antitrypsin concentrations), only one out of nine patients relapsed while taking methylprednisolone 0.25 mg/kg compared with seven out of nine taking placebo for 6 months (Brignola et al, 1988). This study emphasizes the difficulty in defining remission in patients

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with Crohn’s disease who may be clinically well, but who still have laboratory, endoscopic or radiological abnormalities. Conversely, some patients have symptomatic disease with little objective evidence of disease activity. Notwithstanding the results of available trials, clinical experience suggests that long-term symptom control can be achieved in patients with Crohn’s disease with low doses of oral steroids (prednisolone 15 mg daily or less), and that many patients seem very sensitive to even small variations of the dose. The aim should be to use the smallest dose of steroid compatible with keeping the patient reasonably well. Parenteral steroids. Patients with severe Crohn’s colitis usually respond to the same treatments given for ulcerative colitis, with hydrocortisone 100 mg t.d.s. intravenously or ACTH 40 units daily intramuscularly resulting in significant clinical improvement (Kaplan et al, 1975). Side-effects, particularly oedema, tend to be more common in those treated parenterally than with oral therapy and hence oral therapy is usually tried initially.

Aminosalicylic

acid derivatives

The mode of action and side-effects of these drugs in patients with Crohn’s disease are similar to those described above for ulcerative colitis. Sulphasalazine Oral. In the treatment of active Crohn’s disease, the American NCCDS trial showed sulphasalazine 1 g/15 kg body weight (up to 5 g) daily given over 4 months was no better than placebo in ileal disease, but was effective in ileocolic (P= 0.027) and colonic disease (P= 0.006) (Summers et al, 1979). Another smaller trial also showed no certain benefit in ileal Crohn’s disease, but a significant therapeutic effect in ileocolic and colonic disease (Anthonisen et al, 1974), whilst a third controlled double-blind study showed unequivocal significant benefit for sulphasalazine in a dose of 4-6 g daily over a period of 6 months in all Crohn’s disease patients, although the number with ileal disease was small (Van Hees et al, 1981). In inactive disease the NCCDS trial showed that sulphasalazine 0.5 gi 15 kg body weight (up to 2.5 g) did not decrease the relapse rate over l-2 years (Summers et al, 1979). This and other studies have also shown that sulphasalazine does not decrease the relapse rates after resection (Bergman and Krause, 1976; Lennard-Jones, 1977; Wenckert et al, 1978). The numbers of patients in these studies may have been too small to show a small beneficial effect of sulphasalazine (Wenckert et al, 1978). A multicentre study of 232 patients which examined the effect of radical versus non-radical resection combined with concomitant use of sulphasalazine (3 g) or placebo in preventing disease recurrence in Crohn’s disease suggested that recurrence was less frequent with limited resection, and that sulphasalazine prophylaxis was better than placebo-the recurrence rate at 1 year was 16%

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with sulphasalazine and 28% with placebo (P
J. J. MISIEWICZ

that the two

Sulphasalazine in combination with steroids. A trial of prednisolone with and without sulphasalazine did not show that the addition of sulphasalazine (1 g/15 kg up to 5 g daily) increased the remission rate in active disease, or decreased the relapses in patients with inactive disease, nor that sulphasalazine had a steroid-sparing effect in Crohn’s disease (Singleton et al, 1979). The results of trials of the efficacy of sulphasalazine and the newer 5-aminosalicylic acid agents used topically in patients with severe rectal inflammation due to Crohn’s disease are awaited, as are the results of studies of oral treatment of Crohn’s disease with the newer 5-aminosalicylic acid derivatives. Immunosuppressive

therapy

In patients with Crohn’s disease who have severe colonic inflammation or disease refractory to treatment with corticosteroids and 5-aminosalicylic acid drugs, treatment with alternative immunosuppressive agents may be beneficial. Azathioprine The NCCDS trial did not show a significant effect of azathioprine in active Crohn’s disease, though the results suggest a trend in favour of the drug (Summers et al, 1979). Two crossover studies also did not show that azathioprine was beneficial (Rhodes et al, 1971; Klein et al, 1974). There are, however, some difficulties interpreting these studies, such as recent steroid withdrawal, the role of azathioprine side-effects in compliance, and anatomical complications of Crohn’s disease which could not be expected to respond to treatment (Lennard-Jones, 1986). Studies have shown that azathioprine given with prednisolone will allow a greater decrease in the mean steroid dose than placebo (15.5 mg and 6.1 mg, P
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6-Mercaptopurine

6-Mercaptopurine has been shown to be effective in those patients with active Crohn’s disease who failed to respond to sulphasalazine and steroids, with 26 of 39 patients improving on 6-mercaptopurine and only three on placebo (P
In an open trial of methotrexate (25mg i.m. weekly for 12 weeks, then tapering oral doses) there was a dramatic endoscopic resolution of disease in five patients with refractory Crohn’s colitis, with four showing no histological evidence of microscopic disease (Kozarek et al, 1989). Methotrexate worked more quickly than azathioprine or 6-mercaptopurine and caused only minor side-effects, so that treatment would be justified in patients with intractable disease. Methotrexate may be used to try and induce remission in patients with active Crohn’s disease who have failed to respond to steroids, 5-aminosalicylic acid drugs and azathioprine or 6-mercaptopurine. Cyclosporin

There has been considerable interest recently in the role of cyclosporin in Crohn’s disease, with some early anecdotal reports showing that it can be successful, although these have been tempered by concern about the sideeffects of cyclosporin, particularly its nephrotoxicity. A placebo-controlled, double-blind, randomized trial of oral cyclosporin (5-7.5 mgikg daily) in 71 patients with active Crohn’s disease resistant to or intolerant of steroids (Brynskov et al, 1989b) showed that after 3 months’ treatment, 22 of the 37 patients (59%) on cyclosporin improved, compared with 11 of the 34 on placebo (32%) (P = 0.032). The improvement became evident in 19 of the 22 responders during the first 2 weeks of cyclosporin treatment. In the subsequent 3 months, during which treatment was gradually withdrawn, improvement continued in 14 of the 37 patients (38%) in the cyclosporin group and 5 of the 34 (15%) in the placebo group. This means that eight of 22 responders (36%) relapsed. In addition, nearly 30% of the patients had some malabsorption of the cyclosporin and, in spite of no serious adverse events being recorded in this study, the potential for short- and long-term

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toxicity (particularly nephrotoxicity) remains (Sachar, 1989). Clearly the results of further trials are needed. Although over half the patients in the above study had colonic involvement, there is no mention of whether severe rectal inflammation was present and so the role of oral cyclosporin in the treatment of this condition when due to Crohn’s disease remains unknown. Similarly there are no reports of the use of topical cyclosporin in such patients. At present cyclosporin cannot be recommended for routine use in Crohn’s disease. It may be of value in some patients with active disease resistant to steroids, 5aminosalicylic acid drugs and azathioprine or 6-mercaptopurine, and ideally should be used as part of a research study. Antibacterial

drugs

Antibacterial drugs can decrease secondary infection in patients with severe rectal inflammation due to Crohn’s disease, and may decrease the antigenic stimulus of enteric bacteria to the diseased mucosa. One uncontrolled study giving broad-spectrum antibiotics continuously in various combinations for up to 5 years suggested that this could result in improvement (Moss et al, 1978). At present, routine antibiotics are not advised in the management of Crohn’s disease unless there are specific indications. Metronidazole

Metronidazole is particularly active against anaerobic organisms such as Bacteroides species, and at 1 g daily for 2 months was shown to cause clinical and haematological improvement in six patients with colonic Crohn’s disease (P
therapy

There is still interest in the possible role of mycobacteria in the pathogenesis of Crohn’s disease, and there are occasional case reports of remission of Crohn’s disease with antimycobacterial therapy (Warren et al, 1986; Schultz et al, 1987). However, one small controlled study of two antimycobacterial drugs gave negative results (Shaffer et al, 1984), as did an uncontrolled study

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of five patients treated for several months with quadruple therapy, with transient improvement attributed to the general antibacterial activity of the drugs (Jarnerot et al, 1989). These drugs should not therefore be used in Crohn’s disease unless as part of a clinical trial. Sulphadoxine-pyrimethamine

A controlled trial in 51 patients with active chronic Crohn’s disease showed no benefit from this long-acting broad-spectrum antibiotic which has activity against some mycobacteria (Elliott et al, 1982). Dapsone

Dapsone was effective in four out of six patients with Crohn’s disease (Ward and McManus, 1975), and in a recent case report dapsone 75mg daily resulted in a dramatic improvement within 2 weeks (Prantera et al, 1988). Further controlled studies are needed to define a role for dapsone in the treatment of Crohn’s disease. Other agents

Controlled trials have failed to show any benefit from levamisole (Wesdorp et al, 1977; Swarbrick and O’Donoghue, 1978), transfer factor (Vicary et al, 1979), oral bacillus Calmette-G&in (BCG) (Burnham et al, 1979) and sodium cromoglycate (Binder et al, 1981) in Crohn’s disease generally, although their effects in colonic Crohn’s disease have not been specifically assessed. Medical treatment

of perianal Crohn’s disease

Perianal Crohn’s disease, which often has a distressing appearance, may cause little in the way of symptoms. Anal pain from an ulcer or chronic fissure may respond to topical treatment with corticosteroids and 5-aminosalicylic acid drugs, and these can also be applied to ulcers in the perianal skin, natal cleft or groin. Severe perianal disease without abscess formation often improves on treatment with oral metronidazole (up to 20 mg/kg), although relapse and drug side-effects limit long-term efficacy. In some patients control of the intestinal Crohn’s disease, using the topical and oral treatments outlined earlier, will result in improvement of the perianal disease, with fistulas closing or becoming dry and indolent. Pain resulting from anal fissures unresponsive to medical treatment or from perianal abscesses usually requires surgical treatment (Brooke, 1987). Similarly, perianal fistulas may need to be deroofed and, rarely, in some patients with intractable perianal disease panproctocolectomy is necessary. Sometimes the resulting surgical wounds fail to heal. In these patients meticulous wound toilet with topical steroids, and in severe instances even oral steroids with azathioprine, may be needed to promote healing.

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Summary of management of Crohn’s rectal inflammation Patients with inflammation limited to the rectum and sigmoid colon usually respond to topical treatment with steroids and/or 5aminosalicylic acid drugs given either as enemas or suppositories. If there is any evidence of sepsis or fistulas then metronidazole may be helpful. Patients with inflammation extending more proximally and those with severe disease require treatment with steroids given orally or parenterally, possibly with additional immunomodulating drugs such as azathioprine or cyclosporin. In addition, 5aminosalicylic acid drugs and/or metronidazole may also be beneficial. Once the disease is in remission these drugs and azathioprine can be continued, but the steroids and any other immunosuppressive drugs should be withdrawn if possible. RADIATION

COLITIS

Patients with radiation colitis will usually give a history of radiotherapy for a gynaecological malignancy. Although the colon and rectum are less radiosensitive than the small intestine, approximately 8% of patients treated with pelvic irradiation develop clinically important radiation colitis. Radiation suppresses cell proliferation in the crypts and leads to acute ulceration and bleeding, which usually settles within a week or two. This can result in rectal bleeding and diarrhoea and may also cause tenesmus and a mucous discharge. Sigmoidoscopically the rectal mucosa is oedematous and reddened and may even be friable and ulcerated. Subsequently fibrous stenosis and possibly further ulceration may develop secondary to ischaemia as a result of an obliterative vasculitis. Initial treatment is aimed at avoiding constipation, with steroid retention enemas in addition if necessary. The proctitis which can develop as a late complication will usually respond to treatment with topical steroid enemas, although it sometimes proves refractory to therapy and the other agents used in rectal inflammation due to ulcerative colitis have also been tried in this condition. In a recent prospective study of 37 patients with radiationinduced proclosigmoiditis (Kochhar et al, 1991), both 3.Og oral sulphasalazine with twice daily 20mg prednisolone enemas and 2.Og sucralfate enemas given with oral placebo resulted in significant clinical and endoscopic improvement. The sucralfate enemas gave a significantly better clinical response and were better tolerated, and as they are cheaper the authors concluded they should be the preferred mode of short-term treatment. High doses of 5aminosalicylic acid enemas have also been used with some success in this condition (Triantafillidis et al, 1990), and early reports suggest that sodium pentosan polysulphate may be an effective treatment in chronic radiation-induced proctitis. Strictures and fistulas will often require surgical treatment. INFECTIVE

COLITIS

In all patients with an abrupt onset of bloody diarrhoea an infective cause

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must be excluded. It may also be possible to identify the source of the infection and to find other cases. Stool cultures will usually allow organisms such as Campylobacter (commonly associated with severe cramping abdominal pain) Shigelfa and Salmonella to be detected. A history of antibiotic usage and a ‘membrane’ visible on sigmoidoscopy will suggest a diagnosis of pseudomembranous colitis, which can be confirmed by detection of the toxin of Clostridium di#iciZe in the stools. Amoebiasis can be diagnosed from stool specimens and rectal biopsies, with serological tests being positive in 70% of patients with invasive disease. Sexually transmitted proctitis due to organisms such as Neixseria gonorrhoeae, Chlamydia trachomatis or the herpes virus can easily be overlooked as a cause of severe rectal inflammation. Gonococcal proctitis is characteristically associated with large quantities of purulent exudate, whilst Chlamydia produces lymphogranuloma venereum with a proctitis macroscopically similar to ulcerative colitis but can cause rectal strictures and perianal fissures. Stool and rectal biopsy cultures may be best taken by a venereologist who will have the appropriate culture media available. It is quite possible for patients with idiopathic inflammatory bowel disease to contract an infective colitis, following which it may be unclear whether symptoms are solely due to the infection or whether the infection has triggered a relapse. Detailed discussion of the treatments available for these conditions is beyond the scope of this chapter, but in some cases specific antimicrobial therapy is needed. CONCLUSION

As the aetiology of ulcerative colitis and Crohn’s disease are at present unknown and indeed are likely to be multifactorial, our current treatment is merely symptomatic, aimed at reducing and preventing inflammation rather than correcting the underlying cause. The majority of patients with severe proctitis due to ulcerative colitis or Crohn’s disease respond well to acute treatment with steroids given either systemically or topically, with additional benefit both in the acute phase and during maintenance treatment being provided by the 5aminosalicylic acid drugs. Azathioprine is useful as a steroid-sparing agent, while metronidazole is helpful in Crohn’s disease patients, particularly those with perianal sepsis. For those patients who do not respond to these first line therapies and for those with frequent relapses, alternative therapies are required. The fact that so many different agents have been tried confirms that none is particularly successful, although in individual cases a good response may be obtained. Both ulcerative colitis and Crohn’s disease are chronic diseases characterized by relapses and long-term follow-up is essential, particularly as there is an increased risk of developing colonic carcinoma in these patients. Future research must be concentrated on trying to find and treat the

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underlying cause of the idiopathic inflammatory bowel diseases, as well as improving the delivery of our current drugs to lessen their side-effects. Severe rectal inflammation due to radiation proctitis responds to treatments in a similar way to the inflammation resulting from ulcerative colitis, and in both conditions surgical treatment may be required. An infective cause must be considered for all cases of severe rectal inflammation, and once the causative organism has been identified in the stool, on rectal biopsy or serologically, appropriate antimicrobial therapy should be administered.

SUMMARY

Rectal bleeding is the cardinal symptom in patients with inflammation of the rectum, and initial management must be directed at establishing an underlying diagnosis. In many patients in the Western World this will be idiopathic inflammatory bowel disease, although in all cases other causes such as infection must be excluded. Idiopathic proctitis is usually due to either ulcerative colitis or Crohn’s disease, and in both conditions corticosteroids, either systemic or topical, provide the mainstay of treatment. The 5 aminosalicylic acid drugs are helpful in both acute and maintenance treatment, again given either systemically or topically, while metronidazole is of value in patients with Crohn’s disease. In those with refractory proctitis alternative agents such as azathioprine, immunomodulating drugs and barrier agents may be useful. Severe inflammation of the rectum secondary to pelvic irradiation will also usually respond to topical steroid therapy, although sucralfate enemas may be equally successful; in resistant cases other treatments may be needed. Infective proctitis, when diagnosed, may require treatment with specific antimicrobial agents.

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