Where Do We Stand on Drug Treatment for Ulcerative Colitis?

1 he best treatment for any disease process cannot be considered optimal without knowing the cause of the disease. This is certainly true of ulcerative colitis. Of the various modalities available for the treatment, some of which work some of the time, not one is effective in all cases. This is in keeping with the realization that the etiology of ulcerative colitis remains an enigma, despite the progress made in understanding the natural course, complications, surgical innovations, and overall management including drug therapy. Although ulcerative colitis is presumed to be an ancient disease, the first reports that convince us that it was recognized as a distinct entity came from Wilks and Moxon (1) in England during the second half of the nineteenth century. Evidently, no effective nonsurgical therapy existed at that time, thus encouraging the participation of surgeons who tried temporary colostomies, cecostomies, and appendicostomies. The debates of the day centered on which of these treatments was the most effective. Perhaps the intent was to create a vent for drainage or to completely or partially divert the fecal stream; however, these ostomies were also used to introduce various antiseptic solutions to bathe the more distal inflamed bowel. With very few exceptions, this early drug therapy was not successful; the failures, however, served to challenge the concept that ulcerative colitis was a bacillary dysentery and to broaden the etiologic considerations. Our current experience with trials of new drugs in the treatment of old diseases should help us to understand the use of sulfanilamides and related drugs as they became available in the 1930s. Rheumatoid arthritis, not colitis, dominated the interest of Dr. Nanna Svartz at the Karolinska Institute in Stockholm. She tried the newly created sulfasalazine, formulated by A.B. Pharmacia Company, on her patients with arthritis. One of these patients had ulcerative colitis (perhaps the arthritis was an extraintestinal manifestation of the colitis), and the colitis coincidently went into remission. Thus, serendipity accounted for the introduction of modernday drug therapy for ulcerative colitis. Subsequent studies by Dr. Svartz confirmed that the drug was effective for treating ulcerative colitis (2). Further, it was shown to have maintenance (prophylactic) value with strong evidence for continued drug therapy after remission was achieved (3). Even then, however, little understanding existed as to why sulfasalazine worked and whether the observed effect was due to the sulfapyridine, the 5-aminosalicylic acid (5-ASA) component, or both. Clinicians were slow to accept the idea that sulfasalazine differed from the other sulfonamide preparations 692

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being used to treat ulcerative colitis. Gradually, the drug was accepted as an effective treatment for patients with mild and moderate disease. The acceptance and establishment of the best way to use sulfasalazine in the treatment of ulcerative colitis were slowed in large part by the introduction of systemic corticosteroids and adrenocorticotropic hormone (ACTH) in the late 1940s. The uncontrolled trials of the early 1950s suggested that these drugs were extremely useful and relatively safe in the treatment of ulcerative colitis (3). Truelove and Witts (4) then documented the dramatic effectiveness of corticosteroids in a controlled trial of oral cortisone compared with placebo, and soon thereafter Lennard-Jones and colleagues (5) showed that oral prednisone (40 to 60 mg) was significantly more effective than placebo and sulfasalazine in achieving remissions. Clinicians were impressed with the dramatic response of ulcerative colitis to corticosteroid therapy and with the reduction in complications and mortality. Even if remission was not achieved, colectomy could now be done electively rather than urgently, and the prognosis was improved (6). It slowly became clear, however, that prolonged steroid use was associated with serious side effects and, further, that the drugs had no maintenance (prophylactic) value (7, 8). These realizations about steroids, along with the failure of therapy or patients' intolerance of sulfasalazine, provided new initiative in the search for therapeutic alternatives. The rationale for using immunosuppressive drugs to treat ulcerative colitis stemmed from the need for a new approach, from observations implicating autoimmune mechanisms, and from the success of azathioprine in preventing rejection of donor organs. The metabolic product of azathioprine, 6-mercaptopurine, was tried first (9). Uncontrolled trials of both drugs showed a response rate as high as 70% to 80%. Controlled trials, however, did not confirm the success. As shown later, the mean response time of Crohn disease to 6-mercaptopurine was 3.1 months and could be as long as a year. Therefore it was concluded that the controlled trials had not been long enough. Subsequently, 6-mercaptopurine has been shown to be effective in many patients with ulcerative colitis who have failed to respond to steroid therapy (3, 10). However, no new controlled trials have been conducted. The lack of universal enthusiasm for the use of immunosuppressive drugs to treat ulcerative colitis has resulted from the lack of controlled trials, the fear of toxicity, and the conviction that ulcerative colitis is a benign disease that can be cured by colectomy. The fear of toxicity has been reduced by long-term experi-

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ence with 6-mercaptopurine in both Crohn disease and ulcerative colitis (11). The advent of the ileo-pouch anal anastomosis, however, has caused many clinicians to favor colectomy over a trial of 6-mercaptopurine, despite the fact that the surgery has not produced consistently good results; some patients are crippled by its complications and some require later conversion to a conventional ileostomy. The exact mechanism of action of 6-mercaptopurine and azathioprine has not been clarified. Presumably, they inhibit the formation of new T cells, whereas the steroids lyse already existing clones, but they may also have an anti-inflammatory effect. A recent approach to the management of ulcerative colitis has centered on soluble mediators of inflammation, which presumably play a role in this disease as in others and which have been inhibited at some level by all the drugs used thus far. The mediators that have been studied most extensively are the arachidonic acid metabolites, prostaglandins, leukotrienes, and cytokines. Many others probably remain to be identified, as do all the cells of origin. Ongoing studies are attempting to define the effects of inflammatory mediators on the functional capabilities of various relevant cell types. The exact point in the pathway of inflammation at which the available therapeutic agents have their greatest effect has not yet been identified. In this issue of the journal, Stenson and associates (12) review the known pathways of inflammation: arachidonic acid via the cycloxygenase pathway to prostaglandins E 2 , and arachidonic acid via the 5-lipoxygenase pathway to leukotriene B 4 . Increased levels of both end products are found in patients with ulcerative colitis. Another polyunsaturated fatty acid, eicosapentaenoic acid, is found in abundance in fish oil and, like arachidonic acid, is metabolized through the cycloxygenase pathway to prostaglandins and through the 5-lipoxygenase pathway to leukotriene B 5 , a much less potent neutrophil chemotactic agent than leukotriene B 4 . They show us, in a double-blind crossover comparison with placebo, that fish oil supplementation, which should serve to increase production of B 5 and to decrease the levels of B 4 , did indeed reduce the contents of rectal dialysates of leukotrienes. The clinical improvement was modest. The steroid dose, however, could be reduced, and histologic improvement was impressive, even if the gross sigmoidoscopic improvement was not. Encouraging results have been reported by others (13, 14). Stenson and coworkers (12) conclude that dietary fish oil supplementation is not likely to serve as a primary treatment for ulcerative colitis but might have an adjunctive role. Based on multicenter trials, another 5-lipoxygenase inhibitor showing promise in the treatment of ulcerative colitis is zileuton (Abbott Laboratories, North Chicago, Illinois). This drug is now undergoing controlled trials. No other therapeutic approaches, despite initial enthusiasm, have shown lasting success. Parenteral nutrition has not been shown to be useful in treating ulcerative colitis, except perhaps in the preparation for surgery. Despite the absence of dilation of the colon, oral feedings have sometimes been eliminated in favor of parenteral nutrition; this is an error in management.

Cromoglycate, given orally or rectally, has not been effective against active disease or in maintenance of remission. Levamisole, clonidine, zinc, and sucralfate have also proved ineffective. Prostaglandins resulted in side effects that required discontinuation of treatment. Metronidazole, which has been effective in patients with perirectal Crohn disease, has been unsuccessful in the treatment of ulcerative colitis when given as a suppository or by an intravenous route and has produced unconvincing results when administered orally. Antibiotics have generally failed to produce favorable results in patients with ulcerative colitis despite having some role in the treatment of Crohn disease. Based on the epidemiologic studies showing the association between nonsmoking or discontinued smoking and ulcerative colitis, Lashner and colleagues (18) tried nicotine gum in a small placebo controlled trial and showed improvement in three of five patients. Meanwhile, three major groups of drug therapies are being refined, despite the lack of clear understanding of how they work or specifically where in the pathway of inflammation they interfere. Oral sulfasalazine is effective in patients with mild to moderate ulcerative colitis and in the maintenance of remission. Oral steroids are superior, but cannot be used as maintenance drugs. The 5-ASA split product of sulfasalazine is now available. The oral preparations seem to be as effective as the parent compound without most of its side effects or toxicity. The delivery systems of these preparations are different. Olsalazine (Dipentum, Kabi Pharmacia, Piscataway, New Jersey), which is now available by prescription, seems to be best for left-sided ulcerative colitis, but causes diarrhea in many patients; this poses problems in the treatment of a disease that has diarrhea among its symptoms. Asacol (Norwich Eaton Pharmaceuticals, Norwich, New York) and Pentasa (Marion Merrell Dow, Kansas City, Missouri), which release the 5-ASA in a pH-influenced, time-dependent manner, do not seem to cause diarrhea and might be equally effective for the treatment of ulcerative colitis; these show more promise than Dipentum for the treatment of Crohn disease where release of the drug occurs in the small bowel and contact may be extended due to the presence of strictures and delayed motility (15). Rectal preparations of 5-ASA (Rowasa, Solvay Pharmaceuticals, Marietta, Georgia) have been very effective in the treatment of ulcerative proctitis and often have a supplementary role in the treatment of left-sided colitis. The suppositories are better tolerated than the enemas by most patients and are probably better for treatment of limited proctitis from 1 to 5 cm. The enemas will probably prove to be more effective in cases of more extensive disease. In general, no reason exists to consider oral 5-ASA more effective than equivalent doses of its parent compound, sulfasalazine in the treatment of ulcerative colitis. Perhaps, because of its decreased toxicity, large doses of 5-ASA may be tolerated and may provide an advantage. Advances have also occurred in the use of ACTH and corticosteroids. Studies are in progress to determine which agent is the most effective and under what specific circumstances. In more severely ill patients, the

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disease should be brought under control using high-dose intravenous ACTH or corticosteroids to allow time for a chronic-phase drug to be effective. Rarely should steroids in any form be used as maintenance drugs. Rectal steroids do not seem to be more effective than rectal 5-ASA preparations. Cortenemas or cortifoam may work better in some cases, but consideration of their use as maintenance drugs warrants objections similar to those regarding oral preparations. Several poorly absorbed steroids have been investigated, including prednisolone metasulphobenzoate and beclomethasone dipropionate; others, with no glucocorticoid effect and no interference with the normal adrenal-pituitary-hypothalamus axis after absorption, have been tried, including tixocortol pivalate and budesonide. Based on their successes, poorly absorbed and low-glucocorticoid preparations are being tried orally as well; these include fluticasone, budesonide, and tixocortol. Theoretically, these drugs will all have an advantage over oral steroids, but are unlikely to prove successful for maintenance. The roles for immunosuppressive drugs remain promising; 6-mercaptopurine has had success in half of the patients with ulcerative colitis resistant to steroids and other drugs (10). Intravenous cyclosporine has seemed to reverse severe ulcerative colitis in patients who otherwise would have needed colectomy (16), but oral administration, perhaps because of poor absorption, has not shown promise for maintenance therapy. Methotrexate has an established role for patients with resistant Crohn disease but seemingly less so for those with ulcerative colitis (17). Chloroquine, however, which shows "dampening of the immune system," has been found by Mayer and Sachar to be more effective in patients with ulcerative colitis than in those with Crohn disease. These investigators are now conducting a double-blind trial with Plaquenil (Sanofi Winthrop Pharmaceuticals, New York, New York), a related antimalarial drug that has fewer side effects (unpublished data). A role may also exist for intravenous immunoglobulins. If response to ulcerative colitis is to follow the favorable results of immunosuppressive treatment of other diseases and treatment of patients after transplant surgery, we can look forward to trials of FK-506, a drug that shows promise of being more effective and safer than all the existing immunosuppressive drugs. The cause of ulcerative colitis still remains unknown. Any successful therapy should be encouraged and its mode of action should be investigated. Most progress


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has been the outcome of successful drug therapy, working backward to find out why in the search for etiology. Burton I. Korelitz, MD Lenox Hill Hospital New York, NY 10021 Requests for Reprints: Burton I. Korelitz, MD, Department of Medicine, Lenox Hill Hospital, 100 East 77th Street, New York, NY 10021. Annals

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References 1. Kirsner JB. Historical aspects of inflammatory bowel disease. J Clin Gastroenterol. 1988;10:286-97. 2. Svartz N. The treatment of 124 cases of ulcerative colitis with salazapyrine and attempts of desensitization in cases of hypersensitiveness to sulfa. Acta Med Scand. 1948;139(Suppl 206):465-72. 3. Margolin ML, Krumholz MP, Fochios SE, Korelitz BI. Clinical trials in ulcerative colitis: II. Historical review. Am J Gastroenterol. 1988;83:227-43. 4. Truelove SC, Witts LJ. Cortisone in ulcerative colitis. Final report on a therapeutic trial. Br Med J. 1955;2:104-8. 5. Lennard-Jones JE, Longmore AJ, Newell AC, Wilson CWE, Jones FA. An assessment of prednisone, salazapyrine and topical hydrocortisone hemisuccinate used as outpatient treatment for ulcerative colitis. Gut. 1960;1:217-27. 6. Korelitz BI, Lindner AE. The influence of corticotropin and adrenal steroids in the course of ulcerative colitis: comparison with presteroid era. Gastroenterology. 1964;46:671-9. 7. Kirsner JB, Palmer WL, Spencer JA, Bicks RD, Johnson CF. Corticotropin (ACTH) and the adrenal steroids in the management of ulcerative colitis: observations in 240 patients. Ann Intern Med. 1959;50:891-927. 8. Lennard-Jones JE, Misiewicz J J , Connell AM, Jones FA. Prednisone as maintenance treatment for ulcerative colitis in remission. Lancet. 1965;1:188-9. 9. Bean RH. The treatment of chronic ulcerative colitis with 6-mercaptopurine. Med J Aust. 1962;28:592-3. 10. Adler DJ, Korelitz BI. The therapeutic efficacy of 6-mercaptopurine in refractory ulcerative colitis. Am J Gastroenterol. 1990;85:717-22. 11. Present DH, Meltzer SJ, Krumholz WP, Wolke A, Korelitz BI. 6-Mercaptopurine in the management of inflammatory bowel disease: short term and long term toxicity. Ann Intern Med. 1989;111: 641-9. 12. Stenson WF, Cort D, Rodgers J, et al. Dietary supplementation with fish oil in ulcerative colitis. Ann Intern Med. 1992;116:609-14. 13. McCall TB, O'Leary D, Bloomfield J, O'Morain CA. Therapeutic potential of fish oil in the treatment of ulcerative colitis. Aliment Pharmacol Ther. 1989;3:415-24. 14. Salomon P, Kornbluth AA, Janowitz HD. Treatment of ulcerative colitis with fish oil in 3 omega fatty acid: an open trial. J Clin Gastroenterol. 1990;12:157-61. 15. Faber SM, Korelitz BI. Use of asacol in treatment of inflammatory bowel disease. In: Korelitz BI, Sohn N; eds. Management of Inflammatory Bowel Disease. St. Louis: Mosby Year Book; 1992. 16. Lichtiger S, Present DH. Cyclosporine in treatment of severe active ulcerative colitis. Preliminary report. Lancet. 1990;336:16-9. 17. Kozarek RA, Patterson DJ, Gelfand MD, Botoman VA, Ball TJ, Wilske KR. Methotrexate induces clinical and histologic remission in patients with refractory inflammatory bowel disease. Ann Intern Med. 1989;110:353-6. 18. Lashner BA, Hanauer SB, Silverstein MD. Testing nicotine gum for ulcerative colitis patients. Experience with single-patient trials. Dig Dis Sci. 1990;35:827-32. (g) 1992 American College of Physicians

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Where do we stand on drug treatment for ulcerative colitis?

EDITORIALS Where Do We Stand on Drug Treatment for Ulcerative Colitis? 1 he best treatment for any disease process cannot be considered optimal with...
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