EDITOR'S COLUMN

Azathioprine and the treatment of chronic inflammatory bowel disease A major flaw in the evaluation of therapeutic agents for inflammatory bowel disease is the assumption that their pharmacologic actions specifically influence the nature and course of the disease. 1 The unpredictability of responses to therapy for complex illnesses such as IBD is emphasized by the mysteriously beneficial effects of a placebo. In Crohn disease the inflammatory process involves deeper layers of the bowel, and the healing process tends to proceed more slowly than in ulcerative colitis. Consequently, antiinflammatory therapy, including the use of steroids, is required for longer periods in CD than in UC. Moreover, the tendency for CD to recur after surgical resection and bowel reanastomosis makes surgery a less permanent cure than in UC, in which total colectomy removes the target organ. 1 The causes of CD are unknown; this chronic granulomatous disease affects the small and large intestines, with a tendency to cause strictures, fistulas, and abscesses. It has a peak incidence in the second and third decades. In pediatrics, CD involves extraintestinal sites in up to 25% of patients. Surgical resection is not performed at the high adult rate of 75% to 90% but is needed for a significant percentage of pediatric patients. Disease activity fluctuates greatly, making assessment of short-term therapy particularly difficult. To date, only adrenal steroids relieve the symptoms consistently; no agent alters the natural history of the disease. 2 Unfortunately, the treatment required to suppress symptoms with steroids often involves high doses for prolonged periods and is associated with unacceptable side effects. More than 20 years ago, trials of other antiinflammatory agents were carried out to determine whether steroids might be replaced or dependence on them reduced. Earlier reports of these trials indicated that azathioprine, through its metabolite 6-mercaptopurine, might suppress the enteric symptoms of CD, allay the nonintestinal manifestations, and promote the healing of fistulas), 4 In 1970 the National Cooperative Crohn's Disease Study 5 employed a randomized, double-blind technique and assessed clinical activity by a scoring system, called an activity index, 6 to evaluate whether prednisone, azathioprine, or sulfasalazine administered individually had any advantage over placebo. This study showed that prednisone was 9/21/24954 732

effective in allaying the symptoms of active disease but could not maintain remission. However, azathioprine was statistically no better than placebo in terms of either effectiveness against symptoms or ability to maintain remission. Present et al., 7 encouraged by the results of treatment in individual patients, designed a double-blind, controlled, crossover trial of 6-MP in patients with CD that differed in fundamental ways from the earlier trials. First, specific therapeutic goals were defined for each patient. Second, other drugs being taken by the patient before the study were not withdrawn, eliminating the deterioration often seen in trials in which the steroid dosage was tapered before entry. Finally, the study was carried out for 2 years, distinguishing it from the short-term studies previously reported. The results obtained by Present et al. were impressive and have served as a cornerstone for the increasing use of 6-MP, as well as azathioprine, to treat CD in the past few years. PreCD IBD 6-MP UC

Crohn disease Inflammatory bowel disease 6-Mercaptopurine Ulcerative colitis

See related article, p. 809. sumably these results also stimulated the authors of the study reported in this issue, 8 who had similar therapeutic goals and did not withdraw other medications. Verhave et al.,8 using clearly defined criteria for patient selection, treated 21 patients (12 with CD, 9 with UC) with azathioprine, 2 mg/kg/day, for a median follow-up of 2 years. Response to therapy was evaluated by clinical measurements (control of symptoms and growth); laboratory measurements of hematocrit, erythrocyte sedimentation rate, and albumin; and the ability to tolerate a reduction of steroid dosage. Improvement in these measures was scored and defined as degree of response, partial response, or nonresponse. The authors' results are remarkably similar to those obtained in the adult studies; 16 (76%) of 21 patients responded, although 25% of these had only partial response. Patients with CD appeared to respond better than those with UC. The authors demonstrated three other important points: (1) the extended period required to obtain a response

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to azathioprine, usually more than 3 months, (2) the ability to increase the dosage to 2 m g / k g / d a y without significant side effects, and (3) the ability to reduce the steroid dosage in responding patients. Unfortunately, some of this initial enthusiasm must be tempered by several reservations. First, in contrast to the study of Present et al.,7 the trial reported here was not placebo controlled. Second, the low incidence of side effects requires reservation. Concern about the potential adverse effects of immunosuppressive agents have made many clinicians wary of using them. 9 Of particular concern are the development of lymphoma in patients who have had a renal transplant and the occurrence of life-threatening neutropenia in patients w{th hematologic malignancy or rheumatoid arthritis. Bone marrow depression has occurred in 2% of patients and is dose related; so far, one case of malignancy (cerebral lymphoma) has been attributed to the use of 6-MP. Pancreatitis has occurred in 3.3% of patients, and estimates of a complication rate of 7.6% to 10% have been quoted.7, 9 Moreover, the possibility of malignancy as a result of long-term drug therapy may be greater in children and adolescents than in adults. Reliance on drugs alone--that is, on steroids a l o n e - without attention to the general health needs of the patient, is an inadequate therapeutic approach. 1 The medical management of IBD should be comprehensive, individualized, and maintained in some form for long periods, probably for years. An effective program includes emotional support and the restoration of nutritional balance, with consideration of oral supplementation, 1~ nasogastric supplementation with an elemental diet, and parenteral alimentation for serious undernutrition. Some investigators believe that CD consists of two main components: an underlying predisposition to ulceration of the gut, and a secondary immunologic reaction to the passage of large amounts of foreign protein through the damaged gut wall. 11 A controlled trial in which exacerbations of CD were treated with either prednisone or an elemental diet (Vivonex) showed that patients given the elemental diet improved as much as, or by some criteria more than, those given steroids. 11 A randomized, controlled trial in which children were treated showed similar results, 12 with the elemental diet being as effective as the high-dose steroid regimen in inducing an improvement in disease activity index, 13 erythrocyte sedimentation rate, C-reactive protein value, albumin concentration, and body weight. Linear growth, assessed by height velocity for 6 months, was significantly greater in the children receiving an elemental diet. Moreover, it appears that there is a significant advantage to the use of elemental rather than nonelemental food supplements in this disease. 14A controlled trial of bowel rest and nutritional support showed that the majority of drugresistant patients with CD underwent remission with or

Editor's column

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without bowel rest, thereby contradicting one of the most hallowed traditions of gastroenterologists. 15 Explanations could include improved cell immunity as a result of nutritional repletion from a state of protein calorie malnutrition, an alteration in the bacterial flora of the intestine, a reduction in antigen absorption, and the provision of essential nutrients that influence the metabolism and differentiation of epithelial tissue and enhance repair of diseased m u c o s a . 16

Another agent used by some of these patients that further complicated evaluation was metronidazole. Significant success with metronidazole has been reported in uncontrolled studies of patients with chronic perianal manifestions of CD. 9 A Scandinavian controlled trial found that metronidazole, 400 mg twice daily, was as effective as sulfasalazine in the treatment of patients with ileocolitis an d colitis.17 There have been no published studies of the possible role of metronidazole as an adjunct to other therapies for CD or as maintenance therapy for CD patients in remission. Adverse effects of metronidazole may limit its long-term use, and there has been concern about the long-term carcinogenic potential of this drug. 9 In general, steroids are not always administered skillfully in the management of IBD; doses are sometimes too large or too small, given for injudiciously short periods, poorly supervised in terms of electrolyte and protein imbalance, discontinued too abruptly, or continued at excessive dosage levels for unduly long periods.l In view of all these problems, a variety of new approaches to treatment are being investigated. Patients with a toxic reaction to steroid therapy may be converted from a daily to an alternate-day schedule, 18 but because this process is not always easy, it must be gradual and adapted to the individual clinical situation. New topical steroids that are nonglucocorticoid, nonmineralocorticoid derivatives of cortisol are currently undergoing trial. 9 A number of new therapies for IBD have been tried recently. 5-Acetylsalicylic acid is the active component of sulfasalazine, which can now be given as topical therapy in both enema and suppository forms, and appears to be effective as a prophylactic agent for patients with distal colitis. Various oral forms of 5-acetylsalicylic acid have been developed and studied clinically; they feature "delayed release," "slow release," or binding of the drug to azo bonds that require bacterial cleavage for release of free 5-acetylsalicylic acid. These agents are still undergoing trial in the treatment of both adult and pediatric patients with IBD. 9 The use of cyclosporine, 19 methotrexate, sodium cromoglycate, sulcralfate, or clonidine is associated with variable, unsubstantiated results. Unfortunately, many of these drugs have potentially severe side effects. Provocative new approaches to the treatment of inflam-

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mation in IBD involve short-chain fatty acids and their role as the preferred metabolic substrate of colonic epithelium. Diversion colitis can be clinically ameliorated and histologically improved by intermittent exposure of the inflamed mucosa to a mixture of acetate, propionate, and tributyrate. 2~ The question of whether local nutritional deficiency leads to an inflammatory state is currently being investigated in patients with IBD. Unfortunately, it seems unlikely that we shall be able to sort out ways to evaluate these therapies without understanding the basic cause of the disease. Moreover, some of the information obtained in our scoring systems may be unreliable. Ileocolonoscopy is an essential diagnostic procedure routinely used to assess drug therapy for CD. Whereas the endoscopic healing rate is the gold standard for assessing drug efficacy in most digestive diseases that can be detected by endoscopy, therapeutic trials in CD have relied on clinicobiologic indexes. Recently the clinical, biologic, and endoscopic aspects of attacks of CD were assessed in a multicenter prospective study that included data collection on 28 clinical, biologic, and endoscopic items. 21 No correlation was found between the clinical activity index and any of the endoscopic data. Ninety-two percent of patients were in clinically determined remission within 7 weeks of treatment with oral prednisone. Only 38 of these 131 patients were also in endoscopically verified remission. Similar findings were shown in children in whom there were no correlations among the clinical, radiologic, and histologic data. 22 Health status is determined not only by disease activity but also by psychologic state, cultural influences, degree of social support, and effects of complications, previous surgery, and medication. 23 In an attempt to discover ways to reach more specific conclusions about new drug therapies, a number of different scoring systems have been devised, 6, 23 some specifically for the pediatric age group.13, 24 The multicenter pediatric CD study group of the European Society for Pediatric Gastroenterology and Nutrition was formed to conduct multicenter investigations and treatment trials. In April 1990 the National Foundation for Ileitis and Colitis sponsored a pediatric research forum on IBD; when protocols are completed, they will be reported to the pediatric gastroenterology collaborative research groups for implementation. Otherwise, our history of the treatment of IBD in the pediatric age group may compare with what has happened in cystic fibrosis, for which few of the clinical trials of therapy have been conducted in an acceptable format.2s John D. Lloyd-Still, MD Children's Memorial Hospital Northwestern University Chicago, IL 60614

The Journal of Pediatrics November 1990 REFERENCES

1. Kirsner JB. Observations of the medical treatment of inflammatory bowel disease. JAMA1980;243:557-64. 2. Sleisenger MH. How should we treat Crohn's disease? N Engl J Med 1980;302:1024-6. 3. Brooke BN, Javett SL, Davison OW. Further experience with azathioprine for Crohn's disease. Lancet 1970;2:1050-3. 4. Drucker WR, Jeejeebhoy KN. Azathioprine: an adjunct to surgical therapy of granulomatous enteritis. Ann Surg 1970; 172:618-25. 5. National Cooperative Crohn's Disease Study. Gastroenterology 1979;77:825-944. 6. Best WR, Becktel JM, Singleton JW, Kern F. Development of a Crohn's disease activity index. Gastroenterology 1976;70: 439-44. 7. Present DH, Korelitz BI, Wisch N, Glass JL, Sachar DB, Pasternack BS. Treatment of Crohn's disease with 6-mercaptopurine. N Engl J Med 1980;302:981-7. 8. Verhave M, Winter HS, Grand RJ. Azathioprine in the treatment of children with inflammatory bowel disease. J PEDIATR 1990;117:809-14. 9. Peppercorn MA. Advances in drug therapy for inflammatory bowel disease. Ann Intern Med 1990;112:50-60. 10. Kirschner BS, Klich JR, Kalman SS, Defavaro MV, Rosenberg IH. Reversal of growth retardation in Crohn's disease with therapy emphasizing oral nutritional restitution. Gastroenterology 1981;80:10-5. 11. Morain CO, Segal AW, Levi AJ. Elemental diet as primary treatment of acute Crohn's disease: a controlled trial. Br Med J 1984;288:1859-62. 12. Sanderson IR, Udeen S, Davis PSW, Savage MO, WalkerSmith JA. Remission induced by an elemental diet in small bowel Crohn's disease. Arch Dis Child 1987;61:123-7. 13. Lloyd-Still JD, Green OC. A clinical scoring system for chronic inflammatory bowel disease in children. Dig Dis Sci 1979;24:620-4. 14. Giaffer MH, North G, Holdsworth CD. Controlled trial of polymeric versus elemental diet in treatment of active Crohn's disease. Lancet 1990;1:816-9. 15. Greenberg GR, Fleming CR, Jeejeebhoy KN, Rosenberg IH, Sales D, Tremaine WJ. Controlled trial of bowel rest and nutritional support in the management of Crohn's disease. Gut 1988;29:1309-15. 16. Spector MH, Taylor J, Young EA, Wiser E. Stimulator of mucosal growth by gastric and ileal infusion of single amino acids in parenterally nourished rats. Digestion 1981;21 : 33-40. 17. Ursing B, Alm T, Barany F. 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. 18. Whittington PF, Barnes HV, Bayless TM. Medical management of Crohn's disease in adolescence. Gastroenterology 1977;72:1338-44. 19. Brynskov J, Freund L, Rasmussen SN, et al. A placebo-controlled, double-blind, randomized trial of cyclosporine therapy in active chronic Crohn's disease. N Engl J Med 1989;321:84550. 20. Harig JM, Soergel KH, Komorowski RA, Wood CM. Treatment of diversion co!itis with short-chain fatty acid irrigation. N Engl J Med 1989;320:23-8. 21. Modigliani R, Mary J, Simon J, et al. Clinical, biological, and

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endoscopic picture of attacks of Crohn's disease: evolution of prednisolone. Gastroenterology 1990;98:8tl-8. 22. Mashako MNL, Cezard JP, Navarro J, et al. Crohn's disease lesions in the upper gastrointestinal tract: correlation between clinical, radiological, endoscopic, and histological features in adolescents and children. J Pediatr Gastroenterol Nutr 1989; 8:442-6. 23. Garrett JW, Drossman DA. Health status in inflammatory bowel disease. Gastroenterology 1990;99:90-6.

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24. Holmquist L, Ahren C, Fallstrom SP. Relationship between results of laboratory tests and inflammatory activity assessed by colonoscopy in children and adolescents with ulcerative colitis and Crohn's colitis. J Pediatr Gastroenterol Nutr 1989; 9:187-93. 25. Pattishall EN. Negative clinical trials in cystic fibrosis research. Pediatrics 1990;85:277-8 i,

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Azathioprine and the treatment of chronic inflammatory bowel disease.

EDITOR'S COLUMN Azathioprine and the treatment of chronic inflammatory bowel disease A major flaw in the evaluation of therapeutic agents for inflamm...
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