Inflammatory Bowel Disease: Medical Therapy Revisited J . E. LENNARD-JONES Dept. of Gastroenterology, St. Mark’s Hospital, London, U.K.
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Lennard-Jones JE. Inflammatory bowel disease: medical therapy revisited. Scand J Gastroenterol 1992;27 Suppl 192:llO-116. The chronic or recurrent immunologic and inflammatory response in ulcerative colitis and Crohn’s disease may be initiated from the gut lumen. Deviation of gut contents away from the inflamed area, bowel rest, or the use of liquid diets appears to benefit Crohn’s disease. The relative effects of complete bowel rest, or an elemental, hydrolysed, or polymeric liquid diet have not yet been established. Measures to alter the lumenal bacterial flora, including antibiotics, require further study. The use of corticosteroid drugs can be improved by the use of poorly absorbed or rapidly metabolized compounds. Arninosalicylates are effective in ulcerative colitis but require further study in Crohn’s disease. Immunosuppressive drugs are valuable not only for a steroid sparing effect but also for control of chronic inflammation. New treatments designed to reduce inflammation are promising but will need to have high potency and an effect at the earliest stages of inflammation before a large number of different inflammatory mediators are released.
Key words: Aminosalicylates; antibacterial drugs; corticosteroids; Crohn’s disease; diet; immunosuppressives; ulcerative colitis
J. E. Lennard-Jones, M . D . , 55 The Pryors, East Heath Road, London, U . K . hW3 1BP
This article is didactic, provocative, and meant to stimulate research. It is not a review, and references are not given for many of the well-known trials on which statements are based. Citations are limited to recent work or to publications that may be unfamiliar to the reader. Conceptually, it seems likely that the chronic or recurrent inflammation of ulcerative colitis and Crohn’s disease begins with an interaction between a factor in the gut lumen and the epithelial barrier between the gut contents and the vulnerable tissues of the mucosa. Chemical compounds or bacteria enter the lamina propria and initiate a complex immunologic and inflammatory response. Many types of cytokine and chemical mediator are released which recruit polymorphs, macrophages, and lymphocytes to the mucosa. Tissue and vascular damage result, which in turn contribute to self-perpetuating or relapsing inflammation. Factors acting from the lumen may be nutrients, other components of food or drinking water, bacteria, or compounds produced by the action of bacteria on nutrients. A consideration of treatment must therefore begin with food and drink, which may contain an aggravating factor or, alternatively, be deficient in a substance needed to maintain mucosal integrity or diminish inflammation. Bacteria may be important because of their metabolic activities, such as the production of fatty acids from carbohydrate residues. Certain bacteria can degrade colonic mucus, can adhere to the epithelium and affect its function, can produce toxins that damage the epithelium, or can invade the tissues of the gut. Insufficient attention has been given to the role of intestinal bacteria, or viruses, as a trigger factor in inflam-
matory bowel disease (IBD). Treatments designed to alter the bacterial flora of the gut may therefore be important. Once initiated, the inflammatory cascade can be reduced by measures that interfere with the synthesis of chemical mediators, which block their action, which reduce the clonal expansion of activated lymphocytes, or which antagonize the effect of toxic inflammatory products such as free oxygen radicals. These mechanisms appear to be the mode of action of the three classes of drug, all shown to have a beneficial effect in IBD: corticosteroids, aminosalicylates, and immunosuppressive drugs. Other potential therapeutic agents, so far the subject of anecdotal reports or small controlled trials, such as topical application of an organic arsenical or bismuth salicylate to the rectal mucosa, or the use of chloroquine, probably act by an effect on one of the mechanisms discussed. DEVELOPING EXPERIENCE IN THE CONDUCT O F CONTROLLED THERAPEUTIC TRIALS Early controlled trials were easier to interpret and required fewer patients to obtain decisive effects than modern trials because it was then possible to compare possible active treatments with placebo. In such trials it is possible to distinguish clearly between active and inactive treatments. For ethical reasons, modern trials usually have to compare a potential new treatment with an established active treatment. If the new treatment is effective, no difference in outcome may be apparent or it may be slight; very large trials are needed to detect small differences. In this circumstance,
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IBD: Medical Therapy
newer methods of analysis, such as confidence limits, must be applied to show the probability that one treatment is better than another, and to what degree. Such confidence intervals can often be estimated from relatively small trials, which may show whether a large multicentre trial is likely to produce a clear result (1). Furthermore, other factors such as frequency of adverse effects, acceptability by patients, and cost also enter into the choice of treatment. A small trial may show whether an improved therapeutic result is likely to be so great as to offset increased side effects or cost, or whether the established remedy may still be the treatment of choice. Therapeutic questions are posed for particular clinical problems. For example, does one treatment succeed when another fails? Modern trials seek to find an answer to a specific question in a defined group of patients, and this means that often such trials have to be based on many centres with all the problems this entails. Methods of diagnosis and assessment thus have to be widely applicable in many hospitals and yet yield defined end-points. Various indices that embrace symptoms, physical findings, and often laboratory variables have therefore been developed. The author prefers to see the results of a trial expressed separately for symptoms, clinical events, clinical measurements (for example, endoscopic findings, stool weight, body temperature, body weight), laboratory measurements, and any special investigations such as radiolabelled leucocyte excretion. In this manner the effect of a treatment on symptoms can be distinguished from its effect (or lack of effect) on inflammation or clinical course. A good example of this distinction is a recent study of Crohn’s disease in which steroids reduced symptoms but had little or no demonstrable effect on ulceration (2). DIETARY MODIFICATION Background In health, proteins, polysaccharides, and fat are mostly digested and absorbed in the upper small intestine. There is, therefore, no theoretical reason why diets composed solely of amino acids, glucose, and minimal fat should differ in their effect from a liquid diet containing a hydrolysate or, indeed, whole protein, polysaccharides, and fat, when a therapeutic effect is required in the distal small bowel or colon. If such diets are an effective treatment, it seems most likely that the effect is due to the absence of indigestible food residues, which act as a substrate for bacterial action. In this context it is interesting that severe colitis is associated with very high levels of lactic acid and a moderate increase of volatile fatty acids such as butyric and acetic acids in the stools (3,4). For this reason a low-carbohydrate diet has been recommended (3). An increase in fatty acids in the stool could be due to increased fermentation or to decreased uptake by the colonic mucosa. It has been shown that colonocytes utilize as an energy substrate, lumenal fatty
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acids. A deficiency of fatty acids, or inhibition of their metabolism, has been suggested as a cause of colitis. There is suggestive evidence that diversion of lumenal contents away from inflamed, or potentially inflamed, gut leads to healing or protection of normal mucosa in Crohn’s disease (5). The reason for this is not known. Dietary modification could remove an aggravating factor or supply a nutrient that improves the integrity of the epithelium or reduces inflammation. Thus, addition of omega3 fatty acids reduces the level of arachidonic acid in cell membranes, which in turn reduces the synthesis of potentially damaging eicosanoids. Established therapeutic facts 1. A high-fibre diet does not reduce the relapse rate in quiescent ulcerative colitis (6). 2. A diet low in sugar and unrefined carbohydrate but high in unrefined carbohydrate does not prevent relapse in quiescent Crohn’s disease (7). 3. A diet low in fruit and fibre does not benefit Crohn’s disease (8). 4. A liquid diet composed of a protein hydrolysate, little fat, and carbohydrate was less effective than a drug regimen using a corticosteroid and sulphasalazine in the treatment of active Crohn’s disease (9). 5. A liquid diet composed of amino acids, glucose, and little fat was as effective as corticosteroids in small controlled trials in active Crohn’s disease (10, 11). 6. Taking no food by mouth (maintaining nutrition by intravenous feeding) did not improve the results of corticosteroid treatment in acute ulcerative colitis (12, 13). Uncertain or controversial issues Controlled trials of dietary modification in IBD are difficult because patient compliance is often poor, numbers in the trial tend to be small, it is often difficult to distinguish the effects of the diet from simultaneous drug treatments, and some of the effect may depend on whether the nutrients are given as a liquid or as solids. For example, there is still uncertainty as to whether withholding nutrients by mouth, and substituting parenteral nutrition, benefits Crohn’s disease more than a liquid balanced formula diet, or more than drug therapy. Two interesting trials have attempted to dissociate the possible benefits of improved nutrition from the factor of bowel rest by comparing results in two groups of patients, one given parenteral nutrition alone and the other parenteral nutrition plus a liquid, or mainly liquid, diet. The results of the two treatments were similar, but in one trial 5 of 20 patients required surgical treatment during the trial, and 3 other patients at its conclusion (14); in the other, which included 32 patients, prednisone was continued at a dose of about 20mg daily (15). There is a tendency among published results for parenteral nutrition and nothing by mouth to give better results than liquid diets (16). Other trials have given conflicting results as to whether an elemen-
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tal diet and a polymeric diet give the same or different results in the treatment of active Crohn’s disease (17,18). There is uncertainty as to whether excluding specific foodstuffs benefits Crohn’s disease. A problem in this work is that individual patients vary so greatly in the foods that appear to make their disease worse (19). Trials of adding a supplement of omega-3 fatty acids to the diet have so far given equivocal results. Trials needed 1. The excellent multicentre trial in Crohn’s disease in which a hydrolysed liquid diet was given as an enteral tube feed for 1 month (9) now needs to be repeated to give a comparison between an elemental, a hydrolysed, and a polymeric diet. Measures of inflammatory activity, at least levels of acute-phase reactants in the blood, should be incorporated in the design. It is essential both therapeutically and for its importance in understanding dietary treatment that we know with certainty whether an elemental diet is better than the other two. If not, more palatable and cheaper liquid diets can replace elemental diets. If it is more effective, studies of adding specific nutrients to the elemental diet, such as a defined peptide or an indigestible carbohydrate, can be made to define the factors on which its success depends. 2. To date there has been no formal controlled trial of an elemental diet in ulcerative colitis, and this matter should be settled. 3. Further trials of diets containing essential fatty acids designed to reduce synthesis of inflammatory mediators may be needed.
MICROBIOLOGY Background The colon contains a predominance of anaerobic bacteria. Treatment with a drug combination such as metronidazole and co-trimoxazole (20) leads to a reversal of the normal ratio between anaerobes and aerobes, although the total bacterial count remains constant. During attacks of ulcerative colitis there is an increase in the gut flora of Escherichia coli with adhesive properties and an increase in the proportion of E. coli that produce haemolysin and enterotoxin. Acute attacks of ulcerative colitis are associated with detectable endotoxin levels in the blood. The blood of patients with Crohn’s disease contains antibodies to more strains of E. coli than patients with ulcerative colitis, and many more strains than healthy subjects. The lamina propria contains large quanties of IgG that reacts with enteric bacteria. Mycobacterium paratuberculosis has been cultured from the mucosa of a few patients with Crohn’s disease, and unidentified spheroplasts with acid-fast properties can be isolated from a larger proportion of patients. An insertional sequence characteristic of M. paratuberculosis can be detected by the polymerase chain reaction in the bowel
wall of about two-thirds of patients with Crohn’s disease, a proportion significantly greater than in tissue removed for ulcerative colitis or other disorders. Positive results of therapeutic trials 1. A comparative trial in Crohn’s disease has shown that metronidazole has approximately the same therapeutic benefit as sulphasalazine (21). Since sulphasalazine is less effective than corticosteroids (see below), metronidazole is only a moderately effective treatment. 2. Metronidazole in large doses, given over a prolonged period, suppresses inflammation of Crohn’s perianal lesions, but the lesions tend to give trouble again when the drug is stopped (22). 3. Metronidazole given intravenously to patients with severe acute colitis does not improve the results of treatment with prednisolone (23). 4. Tobramycin given by mouth to patients with active ulcerative colitis improves the results of treatment with prednisolone (24). Uncertain or controversial issues There is a surprising dearth of observations on treatments designed to alter the bacterial flora of the gut in IBD. Such measures do not necessarily imply the use of antibacterial drugs, since seeding the gut with known strains of nonpathogeneic bacteria can displace pathogenic strains. It may also be possible to develop vaccines against enteropathogenic E. coli. Administration of a monoclonal antibody to endotoxin may be one line of treatment in severe acute colitis. Lavage of the gastrointestinal tract with saline, combined with temporary peripheral intravenous feeding, could result in benefit as a treatment for acute ulcerative colitis or Crohn’s disease. Controlled trials needed 1. Controlled trials of antibacterial drugs active against aerobic bacteria are needed in both acute ulcerative colitis and active Crohn’s disease. 2. Controlled trials of drugs active against mycobacteria have so far given negative results. M . paratuberculosis is resistant to most currently available drugs; controlled trials of drugs to which this organism is sensitive will be needed.
CORTICOSTEROIDS Background Corticosteroids have multiple actions in reducing the inflammatory cascade. Among other actions, they inhibit release of free arachidonic acid from cell membranes and thus reduce the substrate available for synthesis of eicosanoids, including leukotriene B4, and also reduce lymphoid proliferation. Experimentally, corticosteroids in pharmacologic doses reduce immunologic reactions most effectively when given just before, or at the time of, exposure to
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antigen. There has been a long-running controversy as to whether corticosteroids applied locally to the inflamed mucosa of distal colitis act locally or after systemic absorption. The effectiveness of poorly absorbed steroids, or steroids metabolized on first passage through the mucosa or liver, has shown that these steroids have a local effect on inflammation. Established facts 1. Systemic corticosteroids reduce inflammation in a proportion of patients with acute ulcerative colitis; the proportion who improve is inversely related to the severity of the attack. 2. Systemic corticosteroids reduce inflammation in a proportion of patients with active Crohn’s disease. 3. Corticosteroids administered topically reduce the inflammation in about two-thirds of patients with active distal ulcerative colitis. This effect is similar whether or not the steroid is absorbed to give potentially therapeutic blood levels. 4. Systemic corticosteroids given in doses low enough to avoid systemic side effects do not reduce the relapse rate in quiescent ulcerative colitis or Crohn’s disease. Uncertain or controversial aspects of treatment There is only one trial showing a dose-response effect of a corticosteroid given by mouth in the treatment of mild/ moderate acute ulcerative colitis (25). The optimum dose and duration of treatment require further study. There are no trials comparing the effect of different doses of corticosteroid given intravenously in severe acute colitis. Most clinicians have settled for a dose equivalent to prednisolone, 60 mg daily, which is a compromise between clinical effectiveness and liability to adverse effects. There is one trial of a larger dose, which showed no obvious increase in efficacy (26). All clinicians see patients whose ulcerative colitis or Crohn’s disease remains under control while they take a corticosteroid in a dose equivalent to 10-15 mg prednisolone daily but in whom disease activity increases if the dose is reduced. The use of corticosteroids in the long term has been subject to little study. The incidence of side effects with long-term treatment using a minimally effective dose could be less than is currently believed, particularly in Crohn’s disease, in which absorption of orally administered steroids is less than normal (27). No attempt has been made in IBD to avoid osteoporosis by synchronous administration of calcitonin or other measures to reduce bone loss. The use of a targeted oral preparation of a poorly absorbed or rapidly metabolized corticosteroid has not been studied. Wellabsorbed corticosteroids given in one dose on alternate days require further study (28). The results of a large trial in which patients with Crohn’s disease, whose disease had been brought into remission with conventional doses of methyl prednisolone, were treated over a 2-year period with 8 mg
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methyl prednisolone daily support this approach (29). It is possible that such continuous treatment could be limited to symptomless patients in whom investigation shows continued disease activity (30). Trials needed 1. Comparative trials of dose and duration of oral steroids in moderate acute colitis. Does a high dose given for a few days give the same results as a lower dose given for a longer period with respect to disease remission and side effects? 2. A comparative trial of steroids given daily in the minimum effective dose, on alternate days in twice the daily minimum dose, and a placebo in the management of chronic active Crohn’s disease. 3. A trial against placebo of a poorly absorbed or rapidly metabolized corticosteroid in the long-term treatment of chronic active small-bowel Crohn’s disease. A similar trial of one of these steroids given in a delayed-release capsule could be undertaken in Crohn’s ileocolitis or colitis, and ulcerative colitis.
AMINOSALICY LATES Sulphasalazine, mesalazine, and para-aminosalicylic acid Sulphasalazine (SASP) is a moderately effective treatment in both mild/moderate acute ulcerative colitis and in quiescent colitis for maintaining remission. Pharmacokinetic studies showed that the drug is split by colonic bacteria into sulphapyridine and 5-aminosalicylic acid (5-ASA). The classic experiment of testing these constituents by administration as a retention enema in active colitis showed that the whole molecule (SASP) and 5-ASA, but not sulphapyridine, reduced inflammation. Subsequently, 4-aminosalicylic acid (4-ASA), better known as para-aminosalicylic acid (PAS), has been shown to be similarly effective. Much work has resulted in the development of two compounds with an azolink (olsalazine and colazide), and various formulations of 5-ASA designed to bring the drug into contact with the whole length of the gut, the distal ileal and colonic mucosa, or the mucosa of the whole colon. Much experimental work has shown that these drugs reduce the levels of eicosanoids in the inflamed mucosa and bowel lumen, and some act as scavengers of free oxygen radicals. It is not known whether the action of aminosalicylates in decreasing relapse in quiescent ulcerative colitis is the same as that in the reduction of inflammation in active colitis. Results of therapeutic trials 1. Sulphasalazine and mesalazine (in pH-sensitive capsules) are effective treatments in mild/moderate acute ulcerative colitis. 2. Sulphasalazine, olsalazine, colazide, and mesalazine (in delayed or positioned release forms) decrease the relapse rate in quiescent ulcerative colitis. This effect is dose-related for sulphasalazine and colazide.
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3. Sulphasalazine, 5-ASA, and 4-ASA are all effective when applied topically to the inflamed mucosa in distal ulcerative colitis. 4. Sulphasalazine given by mouth is more effective than placebo, but less effective than a corticosteroid, in the treatment of active Crohn’s disease, particularly Crohn’s colitis. 5. A preparation of mesalazine designed to release the drug in the distal ileum or right colon decreases the clinical relapse rate in quiescent Crohn’s disease (31,32). Uncertain or controversial issues It is not yet certain that the best oral preparation for delivering 5-ASA to the distal ileum and colon has been found. Olsalazine causes secretory small-intestinal diarrhoea in a small proportion of patients. Delayed-release preparations of 5-ASA lead to higher blood levels and urinary excretion of 5-ASA (mostly as the acetyl ester) than sulphasalazine or olsalazine. Occasional cases of renal damage may result. Sulphasalazine is associated with side effects related to the sulphapyridine moiety. Colazide appears at present to be free of these disadvantages. 4-ASA is a well-established drug that is chemically more stable than 5-ASA. There is little doubt about its effectiveness as a topical preparation in distal ulcerative colitis. Investigation is needed into its effectiveness when given by mouth, perhaps in a delayed-release preparation or pHsensitive capsule. Trials needed 1. Is it necessary to given aminosalicylates continuously to reduce the relapse rate in ulcerative colitis; could these drugs be given intermittently whenever the first symptom recurs? 2. Since recurrent colitis often begins as a proctitis, are 5 ASA or 4-ASA suppositories given daily over long periods as effective as oral treatments in diminishing the relapse rate in quiescent colitis? 3. Are the aminosalicylates helpful in the treatment of chronic active ulcerative colitis or Crohn’s disease? This issue could be settled by a double-blind withdrawal trial. 4. Are aminosalicylates given topically effective when distal ulcerative colitis is resistant to topical corticosteroids, and vice versa? 5. Do aminosalicytes lead to endoscopic healing in ileocolitis, including the earliest changes of recurrent disease after resection?
IMMUNOSUPPRESSIVE DRUGS Background The immunologic response in IBD requires activation of lymphocytes followed by clonal amplification. Azathioprine used in ulcerative colitis leads to a reduction in the number of plasma cells in the lamina propria, and the cellularity slowly increases when the drug is stopped. A progressive
fall in circulating K-cells was observed over a year during treatment of ulcerative colitis. Cyclosporin acts primarily by inhibiting the release of interleukin-2 from activated T cells, which prevents T-cell recruitment and amplification and inhibits the release of gamma-interferon. Azathioprine and the closely related 6-mercaptopurine act slowly over months. Cyclosporin appears to act rapidly, and there tends to be rapid relapse when it is stopped. Methotrexate has been used with apparent benefit in active Crohn’s colitis and ulcerative colitis, but its mode of action is unknown. These drugs are associated with adverse effects in some patients, and their use has thus to be monitored carefully and restricted to patients in whom the balance of risk and benefit justifies their use. Results of therapeutic trials 1. Azathioprine and 6-mercaptopurine exert a steroidsparing effect in chronic active ulcerative colitis and Crohn’s disease. 2. 6-Mercaptopurine has an antiinflammatory effect in chronic active Crohn’s disease when given with other drugs. 3. Azathioprine reduces inflammation in some patients with chronic active Crohn’s disease, and clinical activity tends to recur when the drug is withdrawn. 4. Azathioprine maintains quiescence in some patients with ulcerative colitis, and the disease relapses more frequently when the drug is withdrawn than when it is continued (33). 5. Cyclosporin benefited a small proportion of patients with active steroid-dependent Crohn’s disease in one trial. Uncertain and controversial issues The pharmacokinetics of azathioprine and 6-mercaptopurine have been little studied in IBD. It is not known if clinical response is related to drug absorption or other factors. There are anectotal reports of benefit from cyclosporin used intravenously in severe acute colitis unresponsive to intravenous steroids, as a treatment for enterocutaneous fistulae associated with active Crohn’s disease, and as a retention enema in distal colitis. Anecdotal reports of benefit from methotrexate need confirmation. Trials needed 1. Further trials of cyclosporin in chronic active Crohn’s disease. 2. Controlled trials of intravenous cyclosporin as an adjuvant to corticosteroids in acute ulcerative colitis. 3. Controlled trials of cyclosporin retention enemas in distal colitis. 4. Controlled trials of methotrexate as an adjuvant treatment in severe chronic active Crohn’s disease and ulcerative colitis.
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5. Controlled trials of azathioprine of 6-mercaptopurine, and cyclosporin in the treatment of enterocutaneous fistulae in active Crohn’s disease. 6. A multicentre withdrawal trial of azathioprine or 6mercaptopurine in Crohn’s disease performed after treatment for 2-3 years and 5 years or more, to ascertain whether the effect of the drug diminishes with time, and to correlate continued remission or relapse with laboratory and endoscopic markers of chronic disease activity. At present there is no knowledge about the optimum duration of treatment over several years. 5-LIPOXYGENASE INHIBITOR There is a correlation between the activity of inflammation in ulcerative colitis and the levels of leukotriene-B4 (LTB4) in the mucosa and the colonic lumen. This substance acts as a chemoattractant of leucocytes and has other actions as an inflammatory mediator. Inhibition of the enzyme which leads to synthesis of LTB4can be achieved by several experimental compounds. A drug suitatle for testing in man, Zileuton@, when given by mouth to patients with active ulcerative colitis, reduces LTB4 levels in rectal dialysis bags by about 70% and leads to clinical improvement in controlled trials in patients not taking an aminosalicylate (34,35). It seems likely that further and more effective inhibitors of 5lipoxygenase will become available and may offer a new type of treatment for IBD. MISCELLANEOUS Acetarsol Acetarsol, an organic arsenical used originally for the treatment of trichomonas vaginitis, has been used as a suppository for the treatment of proctitis for over 50 years. In a double-blind controlled trial it proved to be as effective as suppositories containing a corticosteroid. A recent study has again suggested that the drug is beneficial in proctitis but demonstrated potentially hazardous levels of inorganic arsenic in the blood, although clinical side effects are extremely rare (36). The mechanism of action of this compound is unknown and deserves further study. Bismuth subsalicylate Bismuth has many chemical and biologic properties in common with arsenic. Bismuth subsalicylate retention enemas appeared to benefit a group of patients with distal refractory colitis (37) without producing detectable levels of bismuth in the blood. A formal trial, against placebo, or against 5-ASA or corticosteroid enemas, appears to be indicated. Lidocaine On the basis of the rationale that the enteric nervous system may be involved in the pathophysiology of ulcerative
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colitis, an uncontrolled study of lidocaine gel used topically in the rectum has suggested that it reduces inflammation (38). A controlled study is needed. Sucralfate Sucralfate administered rectally in distal colitis has given encouraging results in two uncontrolled studies, but this impression has not been supported in two controlled trials (39,40). It seems more important to test other remedies with promise than to conduct further trials of sucralfate. Chloroquine Chloroquine shows evidence in vitro of affecting epithelial cell function in relation to the handling of foreign proteins. A pilot trial of chloroquine in ulcerative colitis gave encouraging results, and a controlled trial is in progress (41). Cromoglycate When antigen unites with IgE antibody fixed to mast cell membranes, the cells liberate mediators of inflammation including histamine. It is possible that an antigen entering the mucosa from the gut lumen causes an immediate-type sensitivity reaction in colitis. Cromoglycate, which is largely unabsorbed by the gut, has been given with the aim of reducing the release of histamine, which is known to occur in colitis. Controlled trials of cromoglycate given by mouth have mainly given negative results. A comparative trial of disodium cromoglycate with a corticosteroid, both given as a retention enema, gave equivalent results (42). Since other active compounds are available, it does not seem worth continuing to study this compound except perhaps in distal colitis refractory to other drugs.
CONCLUSION There is much still to be learnt about the optimum use of known active drugs. Further controlled trials of old and new drugs are needed, many of which will need organisation on a multicentre basis. A look back to revisit old treatments is a stimulus to renewed investigation. Progress has been slow but steady over the past 37 years since the results of the first controlled trials in colitis were published. Will there be a leap forward in the next decade? REFERENCES 1 . Powell-Tuck J , MacRae KD, Healy MJR, Lennard-Jones JE, Parkins RA. A defence of the small clinical trial: evaluation of three gastroenterological studies. Br Med J 1986;292:599-602. 2. Olaison G , Sjodahl R, Tagesson C. Glucocorticoid treatment in ileal Crohn’s disease: relief of symptoms but not of endoscopically viewed inflammation. Gut 1990;31:325-8. 3 . Frazer AC, Hood C, Davies AG, et al. J Carbohydrate intolerance in ulcerative colitis. Lancet 1966;1:503-5. 4. Burke DA, Godwin PGR, Axon TR. Faecal short chain fatty acids (SFA) in ulcerative colitis (UC) and controls. Gut 1987;28:A1387. 5. Rutgeerts P, Geboes K, Peeters M, et al. Effect of faecal stream
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M. Nutritional assistance (NA) and acute attacks of Crohn’s disease (CD): efficacy of total parenteral nutrition (TPN), as compared with elemental (EEN) and polymeric (PEN) enteral nutrition. Gastroenterology 1989;96A416. 17. Giaffer MH, North G, Holdsworth CD. Controlled trial of polymeric versus elemental diet in treatment of active Crohn’s disease. Lancet 1990;1:816-8. 18. Rigaud D, Cosnes J , Le Quintrec Y, RenC E, Gendre JP, Mignon M. Controlled trial comparing two types of enteral nutrition in treatment of active Crohn’s disease: elemental v polymeric diet. Gut 1991;32:1492-7. 19. Jones VA, Dickinson RJ, Workman E, Wilson AJ, Freeman AH, Hunter JO. Crohn’s disease: maintenance of remission by diet. Lancet 1985;2:177-80. 20. Hudson MJ, Hill MJ, Elliott PR, Berghouse LM, Burnham WR, Lennard-Jones JE. The microbial Rora of the rectal mucosa and faeces of patients with Crohn’s disease before and during antimicrobial chemotherapy. J Med Microbiol 1984;18:335-45. 21. Ursing B, Alm T, Barany F, Bergelin I, et al. A comparative study of metronidazole and sulfasalazine for active Crohn’s disease: the Cooperative Crohn’s Disease Study in Sweden. Gastroenterology 1982;83:550-62. 22. Brandt LJ, Bernstein LH, Boley SJ, Frank MS. Metronidazole therapy for perineal Crohn’s disease: a follow-up study. Gastroenterology 1982;83:383-7.
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venous metronidazole as an adjunct to corticosteroids in severe ulcerative colitis. Gut 1986;27:121&2. 24. Burke DA, Axon ATR, Clayden SA, Dixon MF, Johnston D , Lacey RW. The efficacy of tobramycin in the treatment of ulcerative colitis. Aliment Pharmacol Ther 1990;4: 123-9. 25. Baron JH, Connell AM, Kanaghinis TG, Lennard-Jones JE, Jones Avery F. Out-patient treatment of ulcerative colitis: comparison between three doses of oral prednisone. Br Med J 1962;2:441-3. 26. Ireland A, Rosenberg W , Jewell DP. High dose methyl-
prednisolone in the treatment of active ulcerative colitis. Gut 1988;29:A1466. 27. Shaffer JA, Williams SE, Turnberg LA, Houston JB, Rowland
M. Absorption of prednisolone in patients with Crohn’s disease. Gut 1983 ;24:182-6. 28. Bello C, Goldstein F, Thornton J J . Alternate-day prednisone treatment and treatment maintenance in Crohn’s disease. Am J Gastroenterol 1991;86:46&6. 29. Malchow H, Ewe K, Brandes JW, et al. European Cooperative Crohn’s Disease Study (ECCDS): results of drug treatment. Gastroenterology 1984;86:249-66. 30. Brignola C, Campieri M, Farruggia P, et al. The possible utility of steroids in the prevention of relapses of Crohn’s disease in remission. J Clin Gastroenterol 1988;10:631-4. 31. International Mesalazine Study Group. Coated oral 5-aminosalacylic acid versus placebo in maintaining remission of inactive Crohn’s disease. Aliment Pharmacol Ther 1990;4:55-64. 32. Prantera C, Pallone F, Brunetti G , et al. Oral 5-ASA in the maintenance treatment of Crohn’s disease. Results of a randomized placebo controlled trial with Asacol. Gastroenterology 1992. In press. 33. Hawthorne AB, Logan R F A , Hawkey CJ, et al. Randomized controlled trial of azathioprine withdrawal in ulcerative colitis. Br Med J 1992;305:20-2. 34. Bukhave K, Laursen LS, Lauritsen K, et al. 5-lipoxygenase inhibition in double-blind trial with zileuton: how much is sufficient in active ulcerative colitis? Gastroenterology 1991; 100:A200. 35. Stenson WF, Lauritsen K, Laursen LS, et al. A clinical trial of
zileuton, a specific inhibitor of 5-lipoxygenase, in ulcerative colitis. Gastroenterology 1991;100:A253. 36. Forbes A, Britton TC, House IM, Gazzard BG. Safety and efficacy of acetarsol suppositories in unresponsive proctitis. Aliment Pharmacol Ther 1989;3:553-6. 37. Ryder SD, Walker RJ, Jones H , Rhodes JM. Rectal bismuth subsalicylate as therapy for ulcerative colitis. Aliment Pharmacol Ther 1990;4:33>8. 38. Bjorck S, Dahlstrom A , Ahlman H. Topical treatment of ulcerative proctitis with lidocaine. Scand J Gastroenterol 1989; 24: 1061-72. 39. Campieri M, Gionchetti P, Belluzzi A , et al. 5-aminosalicylic
acid, sucralphate and placebo enemas in the treatment of distal ulcerative colitis. Gastroenterology 1988;94:A58. 40. Riley SA, Gupta I, Mani V. A comparison of sucralfate and prednisolone enemas in the treatment of active distal ulcerative colitis. Scand J Gastroenterol 1989;24:1014-8. 41. Mayer L, Sachar DB. Efficacy of chloroquine in the treatment of inflammatory bowel disease. Gastroenterology 1988;94:A293. 42. Grace RH, Gent AE, Hellier MD. Comparative trial of sodium cromoglycate enemas with prednisolone enemas in the treatment of ulcerative colitis. Gut 1987;28:88-92.
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Lennard-Jones JE. Inflammatory bowel disease: medical therapy revisited. Scand J Gastroenterol 1992;27 Suppl 192:llO-116. The chronic or recurrent immunologic and inflammatory response in ulcerative colitis and Crohn’s disease may be initiated from the gut lumen. Deviation of gut contents away from the inflamed area, bowel rest, or the use of liquid diets appears to benefit Crohn’s disease. The relative effects of complete bowel rest, or an elemental, hydrolysed, or polymeric liquid diet have not yet been established. Measures to alter the lumenal bacterial flora, including antibiotics, require further study. The use of corticosteroid drugs can be improved by the use of poorly absorbed or rapidly metabolized compounds. Arninosalicylates are effective in ulcerative colitis but require further study in Crohn’s disease. Immunosuppressive drugs are valuable not only for a steroid sparing effect but also for control of chronic inflammation. New treatments designed to reduce inflammation are promising but will need to have high potency and an effect at the earliest stages of inflammation before a large number of different inflammatory mediators are released.
Key words: Aminosalicylates; antibacterial drugs; corticosteroids; Crohn’s disease; diet; immunosuppressives; ulcerative colitis
J. E. Lennard-Jones, M . D . , 55 The Pryors, East Heath Road, London, U . K . hW3 1BP
This article is didactic, provocative, and meant to stimulate research. It is not a review, and references are not given for many of the well-known trials on which statements are based. Citations are limited to recent work or to publications that may be unfamiliar to the reader. Conceptually, it seems likely that the chronic or recurrent inflammation of ulcerative colitis and Crohn’s disease begins with an interaction between a factor in the gut lumen and the epithelial barrier between the gut contents and the vulnerable tissues of the mucosa. Chemical compounds or bacteria enter the lamina propria and initiate a complex immunologic and inflammatory response. Many types of cytokine and chemical mediator are released which recruit polymorphs, macrophages, and lymphocytes to the mucosa. Tissue and vascular damage result, which in turn contribute to self-perpetuating or relapsing inflammation. Factors acting from the lumen may be nutrients, other components of food or drinking water, bacteria, or compounds produced by the action of bacteria on nutrients. A consideration of treatment must therefore begin with food and drink, which may contain an aggravating factor or, alternatively, be deficient in a substance needed to maintain mucosal integrity or diminish inflammation. Bacteria may be important because of their metabolic activities, such as the production of fatty acids from carbohydrate residues. Certain bacteria can degrade colonic mucus, can adhere to the epithelium and affect its function, can produce toxins that damage the epithelium, or can invade the tissues of the gut. Insufficient attention has been given to the role of intestinal bacteria, or viruses, as a trigger factor in inflam-
matory bowel disease (IBD). Treatments designed to alter the bacterial flora of the gut may therefore be important. Once initiated, the inflammatory cascade can be reduced by measures that interfere with the synthesis of chemical mediators, which block their action, which reduce the clonal expansion of activated lymphocytes, or which antagonize the effect of toxic inflammatory products such as free oxygen radicals. These mechanisms appear to be the mode of action of the three classes of drug, all shown to have a beneficial effect in IBD: corticosteroids, aminosalicylates, and immunosuppressive drugs. Other potential therapeutic agents, so far the subject of anecdotal reports or small controlled trials, such as topical application of an organic arsenical or bismuth salicylate to the rectal mucosa, or the use of chloroquine, probably act by an effect on one of the mechanisms discussed. DEVELOPING EXPERIENCE IN THE CONDUCT O F CONTROLLED THERAPEUTIC TRIALS Early controlled trials were easier to interpret and required fewer patients to obtain decisive effects than modern trials because it was then possible to compare possible active treatments with placebo. In such trials it is possible to distinguish clearly between active and inactive treatments. For ethical reasons, modern trials usually have to compare a potential new treatment with an established active treatment. If the new treatment is effective, no difference in outcome may be apparent or it may be slight; very large trials are needed to detect small differences. In this circumstance,
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newer methods of analysis, such as confidence limits, must be applied to show the probability that one treatment is better than another, and to what degree. Such confidence intervals can often be estimated from relatively small trials, which may show whether a large multicentre trial is likely to produce a clear result (1). Furthermore, other factors such as frequency of adverse effects, acceptability by patients, and cost also enter into the choice of treatment. A small trial may show whether an improved therapeutic result is likely to be so great as to offset increased side effects or cost, or whether the established remedy may still be the treatment of choice. Therapeutic questions are posed for particular clinical problems. For example, does one treatment succeed when another fails? Modern trials seek to find an answer to a specific question in a defined group of patients, and this means that often such trials have to be based on many centres with all the problems this entails. Methods of diagnosis and assessment thus have to be widely applicable in many hospitals and yet yield defined end-points. Various indices that embrace symptoms, physical findings, and often laboratory variables have therefore been developed. The author prefers to see the results of a trial expressed separately for symptoms, clinical events, clinical measurements (for example, endoscopic findings, stool weight, body temperature, body weight), laboratory measurements, and any special investigations such as radiolabelled leucocyte excretion. In this manner the effect of a treatment on symptoms can be distinguished from its effect (or lack of effect) on inflammation or clinical course. A good example of this distinction is a recent study of Crohn’s disease in which steroids reduced symptoms but had little or no demonstrable effect on ulceration (2). DIETARY MODIFICATION Background In health, proteins, polysaccharides, and fat are mostly digested and absorbed in the upper small intestine. There is, therefore, no theoretical reason why diets composed solely of amino acids, glucose, and minimal fat should differ in their effect from a liquid diet containing a hydrolysate or, indeed, whole protein, polysaccharides, and fat, when a therapeutic effect is required in the distal small bowel or colon. If such diets are an effective treatment, it seems most likely that the effect is due to the absence of indigestible food residues, which act as a substrate for bacterial action. In this context it is interesting that severe colitis is associated with very high levels of lactic acid and a moderate increase of volatile fatty acids such as butyric and acetic acids in the stools (3,4). For this reason a low-carbohydrate diet has been recommended (3). An increase in fatty acids in the stool could be due to increased fermentation or to decreased uptake by the colonic mucosa. It has been shown that colonocytes utilize as an energy substrate, lumenal fatty
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acids. A deficiency of fatty acids, or inhibition of their metabolism, has been suggested as a cause of colitis. There is suggestive evidence that diversion of lumenal contents away from inflamed, or potentially inflamed, gut leads to healing or protection of normal mucosa in Crohn’s disease (5). The reason for this is not known. Dietary modification could remove an aggravating factor or supply a nutrient that improves the integrity of the epithelium or reduces inflammation. Thus, addition of omega3 fatty acids reduces the level of arachidonic acid in cell membranes, which in turn reduces the synthesis of potentially damaging eicosanoids. Established therapeutic facts 1. A high-fibre diet does not reduce the relapse rate in quiescent ulcerative colitis (6). 2. A diet low in sugar and unrefined carbohydrate but high in unrefined carbohydrate does not prevent relapse in quiescent Crohn’s disease (7). 3. A diet low in fruit and fibre does not benefit Crohn’s disease (8). 4. A liquid diet composed of a protein hydrolysate, little fat, and carbohydrate was less effective than a drug regimen using a corticosteroid and sulphasalazine in the treatment of active Crohn’s disease (9). 5. A liquid diet composed of amino acids, glucose, and little fat was as effective as corticosteroids in small controlled trials in active Crohn’s disease (10, 11). 6. Taking no food by mouth (maintaining nutrition by intravenous feeding) did not improve the results of corticosteroid treatment in acute ulcerative colitis (12, 13). Uncertain or controversial issues Controlled trials of dietary modification in IBD are difficult because patient compliance is often poor, numbers in the trial tend to be small, it is often difficult to distinguish the effects of the diet from simultaneous drug treatments, and some of the effect may depend on whether the nutrients are given as a liquid or as solids. For example, there is still uncertainty as to whether withholding nutrients by mouth, and substituting parenteral nutrition, benefits Crohn’s disease more than a liquid balanced formula diet, or more than drug therapy. Two interesting trials have attempted to dissociate the possible benefits of improved nutrition from the factor of bowel rest by comparing results in two groups of patients, one given parenteral nutrition alone and the other parenteral nutrition plus a liquid, or mainly liquid, diet. The results of the two treatments were similar, but in one trial 5 of 20 patients required surgical treatment during the trial, and 3 other patients at its conclusion (14); in the other, which included 32 patients, prednisone was continued at a dose of about 20mg daily (15). There is a tendency among published results for parenteral nutrition and nothing by mouth to give better results than liquid diets (16). Other trials have given conflicting results as to whether an elemen-
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tal diet and a polymeric diet give the same or different results in the treatment of active Crohn’s disease (17,18). There is uncertainty as to whether excluding specific foodstuffs benefits Crohn’s disease. A problem in this work is that individual patients vary so greatly in the foods that appear to make their disease worse (19). Trials of adding a supplement of omega-3 fatty acids to the diet have so far given equivocal results. Trials needed 1. The excellent multicentre trial in Crohn’s disease in which a hydrolysed liquid diet was given as an enteral tube feed for 1 month (9) now needs to be repeated to give a comparison between an elemental, a hydrolysed, and a polymeric diet. Measures of inflammatory activity, at least levels of acute-phase reactants in the blood, should be incorporated in the design. It is essential both therapeutically and for its importance in understanding dietary treatment that we know with certainty whether an elemental diet is better than the other two. If not, more palatable and cheaper liquid diets can replace elemental diets. If it is more effective, studies of adding specific nutrients to the elemental diet, such as a defined peptide or an indigestible carbohydrate, can be made to define the factors on which its success depends. 2. To date there has been no formal controlled trial of an elemental diet in ulcerative colitis, and this matter should be settled. 3. Further trials of diets containing essential fatty acids designed to reduce synthesis of inflammatory mediators may be needed.
MICROBIOLOGY Background The colon contains a predominance of anaerobic bacteria. Treatment with a drug combination such as metronidazole and co-trimoxazole (20) leads to a reversal of the normal ratio between anaerobes and aerobes, although the total bacterial count remains constant. During attacks of ulcerative colitis there is an increase in the gut flora of Escherichia coli with adhesive properties and an increase in the proportion of E. coli that produce haemolysin and enterotoxin. Acute attacks of ulcerative colitis are associated with detectable endotoxin levels in the blood. The blood of patients with Crohn’s disease contains antibodies to more strains of E. coli than patients with ulcerative colitis, and many more strains than healthy subjects. The lamina propria contains large quanties of IgG that reacts with enteric bacteria. Mycobacterium paratuberculosis has been cultured from the mucosa of a few patients with Crohn’s disease, and unidentified spheroplasts with acid-fast properties can be isolated from a larger proportion of patients. An insertional sequence characteristic of M. paratuberculosis can be detected by the polymerase chain reaction in the bowel
wall of about two-thirds of patients with Crohn’s disease, a proportion significantly greater than in tissue removed for ulcerative colitis or other disorders. Positive results of therapeutic trials 1. A comparative trial in Crohn’s disease has shown that metronidazole has approximately the same therapeutic benefit as sulphasalazine (21). Since sulphasalazine is less effective than corticosteroids (see below), metronidazole is only a moderately effective treatment. 2. Metronidazole in large doses, given over a prolonged period, suppresses inflammation of Crohn’s perianal lesions, but the lesions tend to give trouble again when the drug is stopped (22). 3. Metronidazole given intravenously to patients with severe acute colitis does not improve the results of treatment with prednisolone (23). 4. Tobramycin given by mouth to patients with active ulcerative colitis improves the results of treatment with prednisolone (24). Uncertain or controversial issues There is a surprising dearth of observations on treatments designed to alter the bacterial flora of the gut in IBD. Such measures do not necessarily imply the use of antibacterial drugs, since seeding the gut with known strains of nonpathogeneic bacteria can displace pathogenic strains. It may also be possible to develop vaccines against enteropathogenic E. coli. Administration of a monoclonal antibody to endotoxin may be one line of treatment in severe acute colitis. Lavage of the gastrointestinal tract with saline, combined with temporary peripheral intravenous feeding, could result in benefit as a treatment for acute ulcerative colitis or Crohn’s disease. Controlled trials needed 1. Controlled trials of antibacterial drugs active against aerobic bacteria are needed in both acute ulcerative colitis and active Crohn’s disease. 2. Controlled trials of drugs active against mycobacteria have so far given negative results. M . paratuberculosis is resistant to most currently available drugs; controlled trials of drugs to which this organism is sensitive will be needed.
CORTICOSTEROIDS Background Corticosteroids have multiple actions in reducing the inflammatory cascade. Among other actions, they inhibit release of free arachidonic acid from cell membranes and thus reduce the substrate available for synthesis of eicosanoids, including leukotriene B4, and also reduce lymphoid proliferation. Experimentally, corticosteroids in pharmacologic doses reduce immunologic reactions most effectively when given just before, or at the time of, exposure to
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antigen. There has been a long-running controversy as to whether corticosteroids applied locally to the inflamed mucosa of distal colitis act locally or after systemic absorption. The effectiveness of poorly absorbed steroids, or steroids metabolized on first passage through the mucosa or liver, has shown that these steroids have a local effect on inflammation. Established facts 1. Systemic corticosteroids reduce inflammation in a proportion of patients with acute ulcerative colitis; the proportion who improve is inversely related to the severity of the attack. 2. Systemic corticosteroids reduce inflammation in a proportion of patients with active Crohn’s disease. 3. Corticosteroids administered topically reduce the inflammation in about two-thirds of patients with active distal ulcerative colitis. This effect is similar whether or not the steroid is absorbed to give potentially therapeutic blood levels. 4. Systemic corticosteroids given in doses low enough to avoid systemic side effects do not reduce the relapse rate in quiescent ulcerative colitis or Crohn’s disease. Uncertain or controversial aspects of treatment There is only one trial showing a dose-response effect of a corticosteroid given by mouth in the treatment of mild/ moderate acute ulcerative colitis (25). The optimum dose and duration of treatment require further study. There are no trials comparing the effect of different doses of corticosteroid given intravenously in severe acute colitis. Most clinicians have settled for a dose equivalent to prednisolone, 60 mg daily, which is a compromise between clinical effectiveness and liability to adverse effects. There is one trial of a larger dose, which showed no obvious increase in efficacy (26). All clinicians see patients whose ulcerative colitis or Crohn’s disease remains under control while they take a corticosteroid in a dose equivalent to 10-15 mg prednisolone daily but in whom disease activity increases if the dose is reduced. The use of corticosteroids in the long term has been subject to little study. The incidence of side effects with long-term treatment using a minimally effective dose could be less than is currently believed, particularly in Crohn’s disease, in which absorption of orally administered steroids is less than normal (27). No attempt has been made in IBD to avoid osteoporosis by synchronous administration of calcitonin or other measures to reduce bone loss. The use of a targeted oral preparation of a poorly absorbed or rapidly metabolized corticosteroid has not been studied. Wellabsorbed corticosteroids given in one dose on alternate days require further study (28). The results of a large trial in which patients with Crohn’s disease, whose disease had been brought into remission with conventional doses of methyl prednisolone, were treated over a 2-year period with 8 mg
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methyl prednisolone daily support this approach (29). It is possible that such continuous treatment could be limited to symptomless patients in whom investigation shows continued disease activity (30). Trials needed 1. Comparative trials of dose and duration of oral steroids in moderate acute colitis. Does a high dose given for a few days give the same results as a lower dose given for a longer period with respect to disease remission and side effects? 2. A comparative trial of steroids given daily in the minimum effective dose, on alternate days in twice the daily minimum dose, and a placebo in the management of chronic active Crohn’s disease. 3. A trial against placebo of a poorly absorbed or rapidly metabolized corticosteroid in the long-term treatment of chronic active small-bowel Crohn’s disease. A similar trial of one of these steroids given in a delayed-release capsule could be undertaken in Crohn’s ileocolitis or colitis, and ulcerative colitis.
AMINOSALICY LATES Sulphasalazine, mesalazine, and para-aminosalicylic acid Sulphasalazine (SASP) is a moderately effective treatment in both mild/moderate acute ulcerative colitis and in quiescent colitis for maintaining remission. Pharmacokinetic studies showed that the drug is split by colonic bacteria into sulphapyridine and 5-aminosalicylic acid (5-ASA). The classic experiment of testing these constituents by administration as a retention enema in active colitis showed that the whole molecule (SASP) and 5-ASA, but not sulphapyridine, reduced inflammation. Subsequently, 4-aminosalicylic acid (4-ASA), better known as para-aminosalicylic acid (PAS), has been shown to be similarly effective. Much work has resulted in the development of two compounds with an azolink (olsalazine and colazide), and various formulations of 5-ASA designed to bring the drug into contact with the whole length of the gut, the distal ileal and colonic mucosa, or the mucosa of the whole colon. Much experimental work has shown that these drugs reduce the levels of eicosanoids in the inflamed mucosa and bowel lumen, and some act as scavengers of free oxygen radicals. It is not known whether the action of aminosalicylates in decreasing relapse in quiescent ulcerative colitis is the same as that in the reduction of inflammation in active colitis. Results of therapeutic trials 1. Sulphasalazine and mesalazine (in pH-sensitive capsules) are effective treatments in mild/moderate acute ulcerative colitis. 2. Sulphasalazine, olsalazine, colazide, and mesalazine (in delayed or positioned release forms) decrease the relapse rate in quiescent ulcerative colitis. This effect is dose-related for sulphasalazine and colazide.
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3. Sulphasalazine, 5-ASA, and 4-ASA are all effective when applied topically to the inflamed mucosa in distal ulcerative colitis. 4. Sulphasalazine given by mouth is more effective than placebo, but less effective than a corticosteroid, in the treatment of active Crohn’s disease, particularly Crohn’s colitis. 5. A preparation of mesalazine designed to release the drug in the distal ileum or right colon decreases the clinical relapse rate in quiescent Crohn’s disease (31,32). Uncertain or controversial issues It is not yet certain that the best oral preparation for delivering 5-ASA to the distal ileum and colon has been found. Olsalazine causes secretory small-intestinal diarrhoea in a small proportion of patients. Delayed-release preparations of 5-ASA lead to higher blood levels and urinary excretion of 5-ASA (mostly as the acetyl ester) than sulphasalazine or olsalazine. Occasional cases of renal damage may result. Sulphasalazine is associated with side effects related to the sulphapyridine moiety. Colazide appears at present to be free of these disadvantages. 4-ASA is a well-established drug that is chemically more stable than 5-ASA. There is little doubt about its effectiveness as a topical preparation in distal ulcerative colitis. Investigation is needed into its effectiveness when given by mouth, perhaps in a delayed-release preparation or pHsensitive capsule. Trials needed 1. Is it necessary to given aminosalicylates continuously to reduce the relapse rate in ulcerative colitis; could these drugs be given intermittently whenever the first symptom recurs? 2. Since recurrent colitis often begins as a proctitis, are 5 ASA or 4-ASA suppositories given daily over long periods as effective as oral treatments in diminishing the relapse rate in quiescent colitis? 3. Are the aminosalicylates helpful in the treatment of chronic active ulcerative colitis or Crohn’s disease? This issue could be settled by a double-blind withdrawal trial. 4. Are aminosalicylates given topically effective when distal ulcerative colitis is resistant to topical corticosteroids, and vice versa? 5. Do aminosalicytes lead to endoscopic healing in ileocolitis, including the earliest changes of recurrent disease after resection?
IMMUNOSUPPRESSIVE DRUGS Background The immunologic response in IBD requires activation of lymphocytes followed by clonal amplification. Azathioprine used in ulcerative colitis leads to a reduction in the number of plasma cells in the lamina propria, and the cellularity slowly increases when the drug is stopped. A progressive
fall in circulating K-cells was observed over a year during treatment of ulcerative colitis. Cyclosporin acts primarily by inhibiting the release of interleukin-2 from activated T cells, which prevents T-cell recruitment and amplification and inhibits the release of gamma-interferon. Azathioprine and the closely related 6-mercaptopurine act slowly over months. Cyclosporin appears to act rapidly, and there tends to be rapid relapse when it is stopped. Methotrexate has been used with apparent benefit in active Crohn’s colitis and ulcerative colitis, but its mode of action is unknown. These drugs are associated with adverse effects in some patients, and their use has thus to be monitored carefully and restricted to patients in whom the balance of risk and benefit justifies their use. Results of therapeutic trials 1. Azathioprine and 6-mercaptopurine exert a steroidsparing effect in chronic active ulcerative colitis and Crohn’s disease. 2. 6-Mercaptopurine has an antiinflammatory effect in chronic active Crohn’s disease when given with other drugs. 3. Azathioprine reduces inflammation in some patients with chronic active Crohn’s disease, and clinical activity tends to recur when the drug is withdrawn. 4. Azathioprine maintains quiescence in some patients with ulcerative colitis, and the disease relapses more frequently when the drug is withdrawn than when it is continued (33). 5. Cyclosporin benefited a small proportion of patients with active steroid-dependent Crohn’s disease in one trial. Uncertain and controversial issues The pharmacokinetics of azathioprine and 6-mercaptopurine have been little studied in IBD. It is not known if clinical response is related to drug absorption or other factors. There are anectotal reports of benefit from cyclosporin used intravenously in severe acute colitis unresponsive to intravenous steroids, as a treatment for enterocutaneous fistulae associated with active Crohn’s disease, and as a retention enema in distal colitis. Anecdotal reports of benefit from methotrexate need confirmation. Trials needed 1. Further trials of cyclosporin in chronic active Crohn’s disease. 2. Controlled trials of intravenous cyclosporin as an adjuvant to corticosteroids in acute ulcerative colitis. 3. Controlled trials of cyclosporin retention enemas in distal colitis. 4. Controlled trials of methotrexate as an adjuvant treatment in severe chronic active Crohn’s disease and ulcerative colitis.
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5. Controlled trials of azathioprine of 6-mercaptopurine, and cyclosporin in the treatment of enterocutaneous fistulae in active Crohn’s disease. 6. A multicentre withdrawal trial of azathioprine or 6mercaptopurine in Crohn’s disease performed after treatment for 2-3 years and 5 years or more, to ascertain whether the effect of the drug diminishes with time, and to correlate continued remission or relapse with laboratory and endoscopic markers of chronic disease activity. At present there is no knowledge about the optimum duration of treatment over several years. 5-LIPOXYGENASE INHIBITOR There is a correlation between the activity of inflammation in ulcerative colitis and the levels of leukotriene-B4 (LTB4) in the mucosa and the colonic lumen. This substance acts as a chemoattractant of leucocytes and has other actions as an inflammatory mediator. Inhibition of the enzyme which leads to synthesis of LTB4can be achieved by several experimental compounds. A drug suitatle for testing in man, Zileuton@, when given by mouth to patients with active ulcerative colitis, reduces LTB4 levels in rectal dialysis bags by about 70% and leads to clinical improvement in controlled trials in patients not taking an aminosalicylate (34,35). It seems likely that further and more effective inhibitors of 5lipoxygenase will become available and may offer a new type of treatment for IBD. MISCELLANEOUS Acetarsol Acetarsol, an organic arsenical used originally for the treatment of trichomonas vaginitis, has been used as a suppository for the treatment of proctitis for over 50 years. In a double-blind controlled trial it proved to be as effective as suppositories containing a corticosteroid. A recent study has again suggested that the drug is beneficial in proctitis but demonstrated potentially hazardous levels of inorganic arsenic in the blood, although clinical side effects are extremely rare (36). The mechanism of action of this compound is unknown and deserves further study. Bismuth subsalicylate Bismuth has many chemical and biologic properties in common with arsenic. Bismuth subsalicylate retention enemas appeared to benefit a group of patients with distal refractory colitis (37) without producing detectable levels of bismuth in the blood. A formal trial, against placebo, or against 5-ASA or corticosteroid enemas, appears to be indicated. Lidocaine On the basis of the rationale that the enteric nervous system may be involved in the pathophysiology of ulcerative
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colitis, an uncontrolled study of lidocaine gel used topically in the rectum has suggested that it reduces inflammation (38). A controlled study is needed. Sucralfate Sucralfate administered rectally in distal colitis has given encouraging results in two uncontrolled studies, but this impression has not been supported in two controlled trials (39,40). It seems more important to test other remedies with promise than to conduct further trials of sucralfate. Chloroquine Chloroquine shows evidence in vitro of affecting epithelial cell function in relation to the handling of foreign proteins. A pilot trial of chloroquine in ulcerative colitis gave encouraging results, and a controlled trial is in progress (41). Cromoglycate When antigen unites with IgE antibody fixed to mast cell membranes, the cells liberate mediators of inflammation including histamine. It is possible that an antigen entering the mucosa from the gut lumen causes an immediate-type sensitivity reaction in colitis. Cromoglycate, which is largely unabsorbed by the gut, has been given with the aim of reducing the release of histamine, which is known to occur in colitis. Controlled trials of cromoglycate given by mouth have mainly given negative results. A comparative trial of disodium cromoglycate with a corticosteroid, both given as a retention enema, gave equivalent results (42). Since other active compounds are available, it does not seem worth continuing to study this compound except perhaps in distal colitis refractory to other drugs.
CONCLUSION There is much still to be learnt about the optimum use of known active drugs. Further controlled trials of old and new drugs are needed, many of which will need organisation on a multicentre basis. A look back to revisit old treatments is a stimulus to renewed investigation. Progress has been slow but steady over the past 37 years since the results of the first controlled trials in colitis were published. Will there be a leap forward in the next decade? REFERENCES 1 . Powell-Tuck J , MacRae KD, Healy MJR, Lennard-Jones JE, Parkins RA. A defence of the small clinical trial: evaluation of three gastroenterological studies. Br Med J 1986;292:599-602. 2. Olaison G , Sjodahl R, Tagesson C. Glucocorticoid treatment in ileal Crohn’s disease: relief of symptoms but not of endoscopically viewed inflammation. Gut 1990;31:325-8. 3 . Frazer AC, Hood C, Davies AG, et al. J Carbohydrate intolerance in ulcerative colitis. Lancet 1966;1:503-5. 4. Burke DA, Godwin PGR, Axon TR. Faecal short chain fatty acids (SFA) in ulcerative colitis (UC) and controls. Gut 1987;28:A1387. 5. Rutgeerts P, Geboes K, Peeters M, et al. Effect of faecal stream
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diversion on recurrence of Crohn’s disease in the neoterminal ileum. Lancet 1991;338:771-4. 6. Davies PS, Rhodes J. Maintenance of remission in ulcerative colitis with sulphasalazine or a high-fibre diet: a clinical trial. Br Med J 1978;1:1524-5. 7. Ritchie JK, Wadsworth J , Lennard-Jones JE, Rogers E. Controlled multicentre therapeutic trial of an unrefined carbohydrate, fibre rich diet in Crohn’s disease. Br Med J
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