Symposium on Gastroenterology for Internists
Immunotherapy in Inflammatory Bowel Disease David B. Sachar, M.D., * and Daniel H. Present, M.D. **
Whenever medical science is pitted against a disabling chronic disease of unknown etiology, obscure pathogenesis, and unsatisfactory response to treatment, it is almost inevitable that efforts will be made to find some role for immunologic therapy. This has been the case, for example, in several chronic kidney, liver, and pulmonary diseases, in a variety of neoplastic conditions, in certain resistant infections, in chronic granulomatous diseases such as sarcoidosis, and in most of the so-called connective tissue disorders. The inflammatory bowel diseases, ulcerative colitis and Crohn's disease, have proven to be no exception to this rule. An immunologic approach to the treatment of ileitis and colitis is not altogether lacking in rationale. These diseases are very often associated with aberrations of the immune system, both humoral and cellmediated,62,64 so it may well be logical to try to modulate their course by immunoregulatory therapy. Unfortunately, however, it is very difficult to assess the track record of this form of treatment. Published reports are sketchy, many clinical experiences are uncontrolled, and the natural courses of the diseases themselves have a bewildering tendency to spontaneous fluctuations and vicissitudes. In this review, we will summarize the current state of knowledge concerning the efficacy ofimmunotherapy in inflammatory bowel disease. While corticosteroids are generally recognized as having immunosuppressive effects, 18, 74 and while an immunosuppressive action has even been suggested for sulfasalazine (Azulfidine),65 we will limit our consideration here to antimetabolites, alkylating drugs, disodium cromoglycate, metronidazole, and immunostimulatory agents.
*Associate Professor of Medicine,
.*
Mount Sinai School of Medicine of the City University of New York, and Associate Attending Physician, Mount Sinai Hospital Associate Clinical Professor of Medicine, Mount Sinai School of Medicine of the City University of New York, and Associate Attending Physician, Mount Sinai Hospital
Medical Clinics of North America-Vol. 62, No. 1, January 1978
173
174
DAVID
B.
SACHAR AND DANIEL
H.
PRESENT
ULCERATIVE COLITIS Antimetabolites The first trial of antimetabolite therapy for inflammatory bowel disease was performed 15 years ago in AustraliabyR. H. D. Beanofthe Repatriation General Hospital in Heidelberg, Victoria. Noting the recent introduction of antimetabolite therapy for certain "autoimmune" diseases, and reasoning that ulcerative colitis was an "autoimmune" disease because of Broberger and Perlmann's demonstration of circulating anticoIon antibodies in this condition,l1 Bean treated one of his patients who had ulcerative colitis with 6-mercaptopurine (Purinethol), * initially 300 mg per day and later 50 to 100 mg on alternate days. The patient promply went into a dramatic reJ;Ilission, and he remained well throughout a 2-year treatment period an~ for months thereafter. Bean published an enthusiastic report of his case in the Medical Journal of Australia in 1962,6 with an equally favorable follow-up report of 7 cases in 1966,7 and the era of antimetabolite trials for inflammatory bowel disease was born. Several notes of caution were sounded in 1966. Avery Jones et al. 5 in England described their tragic experience with a 19 year old girl with ulcerative colitis who became leukopenic and died a rapid septic death within a few weeks of beginning treatment with azathioprine (Imuran). t Simultaneously, the University of Chicago group reported on 10 patients treated with azathioprine. lo Eight patients improved, with one of them unburdened of steroid-dependency for the first time in 3 years, and another relieved not only of colitis but also of associated arthritis and pyoderma gangrenosum. On the other hand, there was a substantial incidence ofleukopenia, thrombocytopenia, and alopecia on the very high doses of azathioprine administered (4 to 6 mg per kg per day for 2 to 3 weeks, followed by 2 to 3 mg per kg per day). Moreover, a follow-up report indicated that within the next 2 years, 9 of the 10 patients had required colectomy.9 Despite these and other cautionary notes, the past decade has seen almost unbridled enthusiasm in the published reports of antimetabolite therapy for ulcerative colitis. Mackay et al. 43.44 reported from Melbourne, Australia, on what they considered very encouraging results of azathioprine treatment in 12 patients. A number of their patients improved only when azathioprine was administered simultaneously with ACTH and 1 experienced a remission only after a diverting ileostomy; one patient died of post-colectomy septicemia and another suffered a sudden fatal bowel perforation. Nonetheless, a few ofthe remissions were impressive and the authors' attitude to the drug was highly favorable. Other optimistic reports of azathioprine or 6-mercaptopurine therapy came from England,30 Germany,58 France,68 India,39 Israel,66 ltaly,15.16 Cleveland,14 Boston,53. 63 and New York. 35. 37. 73 In a few of these reports, the series of patients with ulcerative colitis were partially "contaminated" *6-Mercaptopurine is a synthetic purine analogue which blocks the incorporation of natural purines into DNA and thereby interferes with cell metabolism. t Azathioprine is an apparently somewhat less toxic imidazolyl derivative and metabolic precursor of 6-mercaptopurine.
INFLAMMATORY BOWEL DISEASE
175
by cases which in retrospect were obviously Crohn's disease, but this was not a major problem. More important, in all of these papers interpretation of the responses to antimetabolite therapy was open to some confusion because of other treatments that were administered concomitantly; but even allowing for this problem, a considerable number of therapeutic responses could clearly not have been attributed to any change in treatment except for the introduction of the antimetabolite. By far the most serious difficulty with these studies, however, was that none of them was controlled. There was no correction for the effects of placebo response, observer bias, or spontaneous fluctuation in the course of disease. Still, in justice to these uncontrolled studies, occasional responses to the antimetabolite treatment were so unmistakable that in at least a certain subpopulation of patients the drug must have been having some beneficial effect. For example, in even the most pessimistic of series, which reported treatment failure and drug toxicity in almost every one of 7 patients treated with azathioprine, Bicks included one girl with a 9 year history of ulcerative colitis whose response to 1 year of antimetabolite therapy was unabashedly described as "magnificent."9 Finally, in 1972,10 years after Bean's initial enthusiastic case report, there appeared the first published report of a controlled clinical trial of azathioprine in ulcerative colitis. 28 In this study, 11 of 20 azathioprinetreated patients remained symptom-free for one year, versus 5 of 20 placebo-treated patients; of the only 3 outright treatment failures, all 3 were in the group receiving placebo. These results almost but not quite achieved statistical significance at the 95 per cent confidence level, and the authors concluded that "the clinical results with azathioprine can be judged to be encouraging but not definitely proved." Subsequently, however, the final report of this trial failed to demonstrate any significant benefit from azathioprine either as an adjunct to corticosteroids in treatment of an acute attack or as maintenance therapy for periods up to 1 year, although there was still a suggestion of possible benefit in a subgroup of patients suffering from relapses of established disease. 29 Meanwhile, two other double-blind controlled trials of azathioprine in ulcerative colitis have appeared. One trial comprised 30 steroiddependent patients, comparing a group of 16 treated with azathioprine 1.5 mg per kg per day to a group of 14 given placebo over a 6 month period. 57 It concluded that while the clinical course of the disease was not measurably different between the two groups, the drug did permit significant reduction of steroid dosage. The second trial included 20 patients not receiving steroids; 10weretreated with azathioprine, 2.5mgperkg, while the other 10 received sulfasalazine (Azulfidine), 65 mg per kg per day, for 3 months.17 A measurable objective improvement occurred with azathioprine treatment, although the degree of benefit was not significantly different from that achieved with sulfasalazine alone. What practical conclusions can we draw from all this? Antimetabolites may be able to exert certain beneficial effects in some patients with ulcerative colitis. Their therapeutic effects are not clearly correlated with their immunosuppressive effects,63 and whether anti-inflammatory or other properties are playing a role is still not known. But these are dangerous drugs, with potent myelotoxic activity; a number of patients in the
176
DAVID
B.
SACHAR AND DANIEL
H.
PRESENT
most "favorable" reports died following leukopenic episodes. Also, despite reports of their successful use even in children,36, 58 antimetabolites carry suspected albeit not firmly proven teratogenic and possibly even carcinogenic potential. 59 Moreover, there is no absolute necessity for their use in ulcerative colitis, since a safe and permanent cure is already available for this disease in the form of colectomy. Finally, prolonged nonoperative management of extensive ulcerative colitis may not prove to be a favor to the patient anyhow, in view of the certain increase in cancer risk after 10 years of disease. In fact, one of the "successfully" treated patients in the Boston series who ultimately came to colectomy was found to have an unsuspected small carcinoma with one of 28 lymph nodes already positive. 53 We may well conclude, therefore, that antimetabolite therapy is unsafe in acute fulminating colitis, inadvisable for permanent maintenance therapy, but conceivably useful as a short-term measure in certain patients unresponsive or intolerant to acceptable doses of steroids and sulfasalazine, and unwilling or unable to undergo curative surgery.
Cytotoxic Agents There are only a handful of reports on the use of alkylating or other cytotoxic agents in the treatment of ulcerative colitis. Busulfan (Myleran) was tested by Bean,7 who declared it "very useful" for long-term maintenance of remission (at the astronomical and presumably erroneous dose of 100 mg per day), but he offered no data in support of this conclusion, which has never been subsequently confirmed. Other cytotoxic agents that have been tried sporadically in some cases of ulcerative colitis are chlorambucil (Leukeran) and antilymphocyte serum. Reports from a group in Strasbourg suggested favorable results with these drugs,22, 51 but the cases were few, the studies uncontrolled, and the side effects considerable. Still another cytotoxic agent that has been studied is the nitrogen mustard, mechlorethamine (Mustargen), which was given in intravenous doses totalling 18 to 21 mg over a 6 day period (approximately 0.4 mg per kg per day) to 14 patients with "ulcerative colitis. "72 Some of these patients clearly had granulomatous rather than ulcerative colitis, but in any event a number of them appeared to have a dramatically beneficial response. On the other hand, the mechlorethamine was administered in every case together with 30 U per day of ACTH "to decrease nausea," so the influence of the mustard alone is difficult to determine. Moreover, one of the unfortunate nonresponders died of perforating enteritis postcolectomy, so the treatment seems quite hazardous. Long-term maintenance with oral mustard (Uracil) in this same series was reportedly not beneficial,14 and a controlled randomized trial described at the time as being "underway" was not subsequently reported. Therefore, while an occasional and sporadic good effect may have been observed (and while we have personally seen one chronically bleeding and acutely toxic patient respond dramatically to chlorambucil 2 mg a day and enter an uninterrupted 2 year remission thereafter), a review of the whole published experience with cytotoxic drugs leaves one unable to find any substantial indications for their use in ulcerative colitis.
INFLAMMATORY BOWEL DISEASE
177
Disodium Cromoglycate This drug (also called cromolyn sodium, or Aarane) is used forinhalation therapy of asthma, since it inhibits mast cell degranulation and thereby suppresses immediate hypersensitivity reactions in the bronchial mucosa. In an effort to capitalize on this same mast cell stabilizing property in the rectal mucosa of patients with chronic ulcerative proctitis, Heatley et al. conducted an 8-week double-blind placebo-matched crossover trial of disodium cromoglycate, 200 mg by enema twice daily, plus 100 mg orally 3 times a day.26 Of26 patients who completed the trial, 14 responded to cromolyn, 2 improved with placebo, and 10 failed to respond well to either treatment. Since these results appeared to favor the cromolyn therapy, another double-blind trial with 12 patients with more extensive though mild colitis was launched soon therafter. 45 It showed modest but significant subjective and objective benefit from 6 months of oral cromolyn (2 gm per day) compared to placebo. Others have described favorable results in 3 patients treated in an uncontrolled fashion. 20 This may ultimately prove to be a promising approach to therapy, but since the reported benefits so far have been undramatic, and since moreover the only form of disodium cromoglycate commercially available in the United States today is a 20 mg capsule labeled "For inhalation only," one might conclude that the terribly expensive, inconvenient, and unsanctioned oral administration of 100 capsules of cromolyn a day is a venture that might be better postponed until still further studies are available. 47 CROHN'S DISEASE If the availability of a permanent surgical cure somewhat dampens our enthusiasm for immunosuppressive therapy in ulcerative colitis, no such prospect exists to suppress our eagerness for any new or unconventional therapy that may help patients afflicted with debilitating and mutilating forms of Crohn's disease.
Antimetabolites While nitrogen mustard had been tested in regional enteritis as early as 1965,22 the first trial of antimetabolite therapy for Crohn's disease was reported from London by Brooke et al,12 in 1969. Six patients were treated with azathioprine and all 6 got better during a 6 month follow-up period. While it took 4 years before others picked up Bean's lead in the antimetabolite therapy of ulcerative colitis, there was no such delay in the rush to try azathioprine for Crohn's disease. A spate of uncontrolled reports followed quickly. * The pattern of these reports closely paralleled that of the early trials ofimmunosuppressive drugs for ulcerative colitis. Their approach was anecdotal, their series were often small and their follow-up intervals usually short, their interpretation was frequently complicated by other concomitant therapy, and in none of these reports were control *References 1, 2, 4, 13, 14, 21, 23, 30-32, 38, 52, 53, 68, 69.
178
DAVID
B.
SACHAR AND DANIEL
H.
PRESENT
patients studied. In at least one case, azathioprine was given for an attack of acute ileitis, a benign self-limited condition, and its use was mistakenly credited for the spontaneous abatement of the inflammation and for the failure of "Crohn's disease" to recur.27 Nonetheless, there were some sporadic responses of intractable Crohn's disease to the administration of antimetabolites, usually azathioprine, that appeared almost miraculous. Two particularly noteworthy phenomena that were occasionally observed in these uncontrolled studies were striking decreases in steroiddependency and dramatic healing of fistulae. The need for randomized double-blind controlled trials was clearly inescapable. In the past 4 years, there have been 7 randomized controlled trials of azathioprine or 6-mercaptopurine in the treatment of Crohn's disease. The first of these trials, by Willoughby et al.71 at St. Bartholomew's Hospital in London, studied 22 patients in a 24 week double-blind program, and demonstrated unequivocal benefit from azathioprine. Ten of the 11 patients on azathioprine remained in remission for the full 24 weeks, whereas 80fthe 11 placebo-treated patients relapsed and had to be withdrawn from the study. The next controlled trial of azathioprine was reported by Rhodes et al. 55 from Cardiff, but it was unable to demonstrate any advantage oftbe drug over placebo on account of the study design. 55 The trial period was only 2 months long, even though it had long been recognized that it usually requires at least 3 to 9 weeks and sometimes as long as four months before even an initial response to azathioprine in inflammatory bowel disease, with peak response not usually occurring for 3 to 9 months. 10. 21. 69 Nonetheless, even in this excessively brief trial, the only 2 patients among the 15 studied who manifested "definite" or "considerable" improvement were both on azathioprine at the time. Another controlled trial, from Ontario, could not demonstrate any significant objective benefit from azathioprine in 11 patients over a 1 year period, but all patients were in apparent remission anyhow-an unspecified number of them postoperatively-at the beginning of treatment. 70 Even so, the patients reported more subjective improvement on azathioprine as compared to placebo therapy, with the difference statistically significant at the 99 per cent confidence level. The fourth controlled trial was reported from Yale. 34 While this study did not demonstrate any consistent advantage of azathioprine treatment over placebo, the 4 month treatment period was probably too short to allow definitive conclusions. Moreover, these authors qualified even their negative findings by observing that among the 27 patients studied, the only ones who required surgery were four not receiving azathioprine, and also that the "dramatic" response of some patients to azathioprine "suggests that some 'subset' [of azathioprine-responsive patients] needs to be detected." The next controlled study, performed at the University of Chicago, indicated a significant benefit from 26 weeks of treatment with azathioprine in contrast to placebo, in permitting reduction or discontinuation of the dosage of steroid without wor:;ening of symptoms among the 10
INFLAMMATORY BOWEL DISEASE
179
patients with Crohn's disease who received the active drug. 56 The group receiving azathioprine experienced only 2 relapses versus 7 in the placebo group. As in the Yale study, azathioprine-responsiveness was not a consistent phenomenon, and the existence of "an azathioprine-responsive subgroup" was once again postulated. The most widely publicized controlled trial undertaken to date is the 234-patient series of the National Cooperative Crohn's Disease Study.60 Unfortunately, the design of this trial was so heavily biased against azathioprine-treatment that any possible benefits of the antimetabolite would be almost impossible to detect. By establishing only a 4 month treatment period, by requiring all other therapy (steroid and sulfasalazine) to be completely withdrawn within a few weeks of initiating study drugs, and by classifying the many early relapses that inevitably ensued as unqualified treatment failures, the National Cooperative Study was intrinsically biased against any therapeutic agent whose onset of action is slow or whose effectiveness is optimal when combined with other medications. Since a delayed onset of action and a gradual steroid-sparing effect are both characteristic properties of immunosuppressive treatment, the National Cooperative Study would be expected to lack the ability to detect any benefit from azathioprine, and this has indeed proven to be the case: "No significant difference was observed between response to azathioprine and that to placebo. "60 An altogether different conclusion emerges, however, from the Mount Sinai-Lenox Hill study of6-mercaptopurine in Crohn's disease. This is the most recently reported controlled trial and also the largest in terms of patient-years of follow-up. 54 Over a 7 year period, 83 patients with intractable Crohn's disease were entered into this randomized double-blind 2 year crossover study of6-mercaptopurine versus placebo. Overall clinical improvement, reduction of steroid requirements, and closure of fistulae occurred significantly more often among the patients treated with 6-mercaptopurine than in the group receiving placebo. Indeed, nearly two thirds of patients treated with 6-mercaptopurine in this study manifested objective drug-related improvement, while approximately 30 per cent experienced healing of external fistulae. Delayed onset of action (up to 4 to 6 months) was noted, once again emphasizing the indispensibility of at least 6 month, and preferably 1 year, periods of treatment for meaningful controlled trials. In contrast to their apparent efficacy in active disease, neither immunosuppressive treatment, steroids, nor sulfasalazine has been effective in reducing the postoperative recurrence rate of Crohn's disease, according to the latest report of the National Cooperative Study.61 In most of the reported series, controlled or not, the most common complications of antimetabolite therapy have been bone marrow depression, nausea, and allergic fevers or rashes, while other undesirable side effects have included intra-abdominal abscesses 50 and occasional instances of pancreatitis. 33, 49, 54, 60 The potential toxicity of this type of treatment is therefore considerable, but the best-designed longest-term controlled trials do suggest potential benefits as well, particularly in patients with steroid intolerance and/or chronic fistulous complications.
180
DAVID
B.
SACHAR AND DANIEL
H.
PRESENT
Other Immunosuppressive Agents While a number of alkylating agents have been tested in ulcerative colitis, only one such study, using nitrogen mustard, has been reported in Crohn's disease. 72 Paralleling their experience in ulcerative colitis, Winkelman and Brown described, in an uncontrolled series, dramatic responses to this drug (including the closure offistulae in four patients) and disastrous complications as well (including three bowel perforations, two of them fatal). Even antimetabolites, with all their potential hazards, seem a good deal safer than nitrogen mustard in inflammatory bowel disease. Another drug with reported immunosuppressive and even granuloma-inhibiting properties 25 that has been claimed to be effective in the treatment of Crohn's disease is metronidazole (Flagyl). Ursing and Kamme reported from Sweden that 13 out of 17 patients treated with metronidazole, 20 to 40 mg per kg per day, manifested striking clinical improvement. 67 Follow-up controlled studies have not yet been reported as of this date. Immunostimulation Since it is becoming increasingly clear that many patients with Crohn's disease manifest defects in their cellular immune systems,46.62 it is reasonable that attempts have been made to treat this condition with immunostimulating agents. Preliminary reports of un controlled studies have described favorable responses to BCG19.24 and transfer factor.3 N g and Vicary have published further evidence for the ability of transfer factor to restore depressed T-cell function in patients with Crohn's disease,48 although clinical response to the agent was not commented upon. One brief report from Ireland noted the failure of "immunostimulation therapy" in a few patients, but the nature ofthe therapy was not described. 42 There is also one report from France of "good" or "dramatic" results in a small handful of Crohn's disease patients treated with levamisole,8 an immunopotentiating imidazole drug long used in Europe as an antihelminthic and more recently undergoing intensive worldwide study in the therapy of rheumatoid arthritis, chronic infections, and cancer.41 This agent is currently the subject of a randomized double-blind controlled clinical trial for the treatment of Crohn's disease at the Mount Sinai Hospital in New York. CONCLUSIONS Immunosuppressive drugs are potentially dangerous. Their routine use in ulcerative colitis, a premalignant and surgically curable disease, is not advisable except as a short-term measure in patients intolerant of steroids or sulfasalazine and unwilling or unable to accept colectomy. They have a better-defined role in Crohn's disease, on the other hand, since this condition is incurable and potentially more mutilating. Here they have been reliably shown to have a steroid-sparing effect, to be at least as beneficial as sulfasalazine, and in some cases to produce healing
INFLAMMATORY BOWEL DISEASE
181
of chronic enterocutaneous and perianal fistulae. However, the accurate prediction of which patients will benefit from azathioprine and which patients will not remains an as yet unfulfilled challenge for the future.
REFERENCES 1. Arden Jones, R: Immunosuppressive therapy in Crohn's disease. Proc. Roy. Soc. Med., 64:171-173,1971. 2. Arden Jones, R: Larger doses of immunosuppressive drugs (letter). Lancet, 2:107,1974. 3. Asquith, P., Mallas, E., Ross, 1., et al.: Transfer factor in the treatment of Crohn's disease (abstract). Gut, 16:832, 1975. 4. Avery Jones, F., Brown, P., Lennard-Jones, J. E., et al.: Azathioprine for Crohn's disease (letter). Lancet, 2: 795, 1969. 5. Avery Jones, F., Lennard-Jones, J. E., Hinton, J. M., Reeves, W. G.: Dangers of immunosuppressive drugs in ulcerative colitis (letter). Brit. Med. J., 1 :1418, 1966. 6. Bean, R H. D.: The treatment of chronic ulcerative colitis with 6-mercaptopurine. Med. J. Austr., 2:592-593, 1962. 7. Bean, R H. D.: Treatment of ulcerative colitis with antimetabolites. Brit. Med. J., 1 :1081-1084, 1966. 8. Bertrand, J., Renoux, G., Renoux, M., et al.: Maladiede Crohnetlevamisole. Nouv. Presse med., 3:2265,1974. 9. Bicks, R 0.: Experimental therapeutic concepts in gastroenterology: Immunology. N.Y. State Med. J., 70:1207-1212,1970. 10. Bowen, G. E., Irons, G. V., Jr., Rhodes, J. B., et al.: Early experiences with azathioprine in ulcerative colitis: a note of caution. J .A.M.A., 195 :460-464, 1966. 11. Broberger, 0., Perlmann, P.: Autoantibodies in human ulcerative colitis. J. Exper. Med., 110:657-674, 1959. 12. Brooke, B. N., Hoffmann, D. C., and Swarbrick, E. T.: Azathioprine for Crohn's disease. Lancet, 2:612-614,1975. 13. Brooke, B. N., Javett, S. L., and Davison, O. W.: Further experience with azathioprine for Crohn's disease. Lancet, 2:1050-1053,1973. 14. Brown, C. H., and Achkar, E.: Azathioprine therapy for inflammatory bowel disease: a preliminary report. Amer. J. Gastroent., 54:363-377, 1970. 15. Caprilli, R: La terapia immunosoppressiva della colite ulcerosa. Atti XVIII Congr. N az. Soc. Ital. Gastroenterol., Siena, 1971, pp. 201-212. 16. Caprilli, R, Baldamenti, G., and De Santis, R: Rilievi su la terapia della proctocolite idiopatica con farmaci immunodepressivi. Policlinico Med., 73 :349-360, 1966. 17. Caprilli, R, Carratu, R, and Babbini, M.: A double-blind comparison of the effectiveness of azathioprine and sulfasalazine in idiopathic proctocolitis: preliminary report. Amer. J. Dig. Dis., 20:115-120,1975. 18. Claman, H. N.: Corticosteroids and lymphoid cells. New Eng. J. Med., 287 :388-397, 1972. 19. Crismer (1970), cited in GefIroy, Y., Colin, R, and Hecketsweiler, P.: Aspects nouveaux du traitement de la maladie de Crohn. Rev. Prat., 21 :2599-2612, 1971. 20. Della Cella, G., Garabaldi, L. R., and Durand, P.: Ulcerative colitis and disodium cromoglycate (letter). Lancet, 1: 1129, 1976. 21. Drucker, W. R, and Jeejeebhoy, K. N.: Azathioprine: an adjunct to surgical therapy of granulomatous enteritis. Ann. Surg., 172:618-625, 1970. 22. Eisenbeth, R, and Oberling, F.: Le traitement par les immunosuppresseurs de certaines rectocolites hemorrhagiques et purulentes: le role eventuel des lymphocytes. Presse Med., 77:2141-2142,1969. 23. Fausa, 0., and Gjone, E.: Azathioprine (Imurel) therapy in Crohn's disease. Acta Med. Scand., 190:211-212, 1971. 24. Geffroy, Y., Colin, R, Hecketsmeiler, P., et al.: Traitement de la maladie de Crohn par le B.C.G.: etude clinique, radiologique, evolutive. Arch. Mal. Appl. Dig.,60:293-298, 1971. 25. Grove, D. 1., Mahmoud, A. A. F., and Warren, K. S.: Suppression of cell-mediated immunity by metronidazole (abstract). Clin. Res., 24:286A, 1976. 26. Heatley, RV., Calcraft, B. J., Rhodes, J., et al.: Disodium cromoglycate in the treatment of chronic proctitis. Gut, 16:559-563, 1975. 27. Javett, S. L., and Hoffmann, V. J.: Azathioprine in acute Crohn's disease (letter). South Afr. Med. J., 46:1369, 1972. 28. Jewell, D. P., and Truelove, S. C.: Azathioprine in ulcerative colitis: an interim report on a controlled therapeutic trial. Brit. Med. J., 1 :709-712, 1972. 29. Jewell, D. P., and Truelove, S. C.: Azathioprine in ulcerative colitis: final report on controlled therapeutic trial. Brit. Med. J., 4:627-630, 1974.
182
DAVID
B.
SACHAR AND DANIEL
H.
PRESENT
30. Jones, R. A.: Immunosuppressive therapy in ulcerative colitis. Proc. Roy. Soc. Med., 62:499-501, 1969. 31. Karayannoupoulos, S., Chazan, B. I., Hancock, D. M., et al.: Anorectal Crohn's disease. Brit. J. elin. Pract., 26:377-379, 1!,j{:i. 32. Kasper, H., Zimmerman, H.-D., and Nagele, E.: Treatment of regional ileitis (Crohn's disease) with azathioprine. Germ. Med. Monthly, 15:521-523, 1970. 33. Kawanishi, H., Rudolph, E., and Bull, F. E.: Azathioprine-induced acute pancreatitis. New Eng. J. Med., 289:357, 1973. 34. Klein. M., Binder. .T. H., Mitchell, M., et al.: Treatment of Crohn's disease with azathioprine: a controlled evaluation. Gastroenterology, 66:916-922, 1974. 35. Korelitz, B. I., Glass, J. L., and Wisch, N.: Long-term immunosuppressive therapy of ulcerative colitis: continuation of a personal series. Amer. J. Dig. Dis., 18: 31 7-322, 1973. 36. Korelitz, B. I., Glass, J. L., and Wisch, N.: Long term observations of children with ulcerative colitis treated with an immunosuppressive (6-mercaptopurine) (abstract). Gastroenterology, 72:1083,1977. 37. Korelitz, B. I., and Wisch, N.: Long term therapy of ulcerative colitis with 6-mercaptopurine: a personal series. Amer. J. Dig. Dis., 17:111-118, 19.72. 38. Kyle, J.: The management of chronic Crohn's disease. Ulster Med. J., 40:59-63, 1971. 39. Lal, H. B., Caroli, R K., and Sengupta, D.: Treatment of ulcerative colitis with antimetabolite 6-mercaptopurine. J. Assoc. Phys. India, 15:129-136,1967. 40. Lennard-Jones, J. E., and Williams, C. B.: Azathioprine in the treatment of Crohn's disease. Proc. Roy. Soc. Med .. 65 :291-293. 1972. 41. Levamisole (editorial). Lancet, 1: 151-152, 1975. 42. McFadden, E. B., Thomes, D. R, and Fielding, J. F.: Immunostimulation therapy in Crohn's disease. Irish J. Med. ScL, 145:267, 1976. 43. Mackay, I. R, Wall, A. J.: Letter to the editor. Amer. J. Dig. Dis., 13:850-851, 1968. 44. Mackay, I. R, Wall, A. J., and Goldstein, G.: Response to azathioprine in ulcerative colitis: report of 7 cases. Amer J. Dig. Dis., 11 :536-545, 1966. 45. Mani, V., Lloyd, G., Green, F. H. Y., et al.: Treatment of ulcerative colitis with oral disodium cromoglycate: a double-blind controlled trial. Lancet, 1 :439-441, 1976. 46. Meyers, S., Sachar, D. B., Taub, R. N., et al.: Anergy to dinitrochlorobenzene and depression ofT-lymphocytes in Crohn's disease and ulcerative colitis. Gut, 17:911-915,1976. 47. New treatment for ulcerative colitis? (editorial) Brit. Med. J., 1 :2, 1976. 48. Ng, R. P., and Vicary, F. R: Cell-mediated immunity and transfer factor in Crohn's disease. Brit. Med. J., 2:87-88, 1976. 49. Nogueira, J. R, and Freedman, M. A.: Acute pancreatitis as a complication of Imuran therapy in regional enteritis. Gastroenterology, 62:1040-1041,1972. 50. Northfield, T. C., and Roberts, C. I.: Intra-abdominal abscesses due to azathioprine for Crohn's disease. Gut, 13:124-125,1972. 51. Oberling, F., and Hiebel, G.: Intravenous ALS in the treatment of severe rectocolitis (letter). New Eng. J. Med., 285:409-410, 1971. 52. Papp, J. P., Watson, D. W., and Bull, F. E.: Azathioprine treatment in Crohn's disease. Amer. J. Gastroent., 61 :136-142, 1974. 53. Patterson, J. F., Norton, R A., and Schwartz, R S.: Azathioprine treatment of ulcerative colitis, granulomatous colitis and regional enteritis. Amer. J. Dig. Dis., 16:327-332, 1971. 54. Present, D. H., Wisch, N., Glass, J. L., et al.: The efficacy of immunosuppressive therapy in Crohn's disease: arandomized long term double blind study (abstract). Gastroenterology, 72:1114, 1977. 55. Rhodes, J., Bainton, D., Beck, P., et aI.: Controlled trial of azathioprine in Crohn's disease. Lancet, 2:1273-1276, 1971. 56. Rosenberg, J. L., Levin, B., Wall, A. J., et aI.: A controlled trial of azathioprine in Crohn's disease. Amer. J. Dig. Dis., 20:721-726,1975. 57. Rosenberg, J. L., Wall, A. J., Levin, B., et aI.: A controlled trial of azathioprine in the management of chronic ulcerative colitis. Gastroenterology, 69:96-99, 1975. 58. Schafer, K. H., and Blaker, F.: Azathioprine in the treatment of ulcerative colitis (abstract). Acta Paediatr. Scand., 60:376-377, 1971. 59. Scharf, J., N ahir, M., Eidelman, S., et al.: Carcinoma of the bladder with azathioprine therapy. J.A.M.A., 237:152, 1977. 60. Singleton, J. W.: National Cooperative Crohn's Disease Study (NCCDS): preliminary results of Part I (abstract). Gastroenterology, 70:938, 1976. 61. Singleton, J. W.: National Cooperative Crohn's Disease Study (NCCDS): Results of drug treatment. A cooperative study. (abstract). Gastroenterology, 72:1133, 1977. 62. Strickland, R G., and Sachar, D. B.: The immunology of inflammatory bowel disease. In Glass, G. B. J., ed.: Progress in Gastroenterology, Vo13. New York, Grune and Stratton, 1977, in press.
INFLAMMATORY BOWEL DISEASE
183
63. Swanson, M. A., and Schwartz, R. S.: Immunosuppressive therapy: the relation between clinical response and immunologic competence. New Eng. J. Med., 277: 163-170, 1967. 64. Thayer, W. R., Jr.: The immunopathology of intestinal granulomatous disease. In Reis, L. V., ed.: Frontiers of Gastrointestinal Research: Immune Disorders. New York, S. Karger, 1975, pp. 74-124. 65. Thayer, W. R., Jr., Charland, C., and Field, C.: Salazopyrin and its effect on lymphocyte subpopulations and function (abstract). Gastroenterology, 70:942, 1975. 66. Theodor, E., Gilon, E., and Waks, U.: Treatment of ulcerative colitis with azathioprine. Brit. Med. J., 4:741-743, 1968. 67. Ursing, B., and Kamme, C.: Metronidazaole for Crohn's disease. Lancet, 1 :775-777, 1975. 68. Vachon, A., Tete, R., Barthe, J., et al.: Nouveaux resultats du traitement par l'azathioprine de la recto-colite hemorrhagique et de la maladie de Crohn colique. Arch. Mal. App. Dig., 61 :625-640, 1972. 69. Wallenstein, S., and Persson, S.: Azathioprine therapy for Crohn's disease Acta Chir. Scand., 138:521-526, 1972. 70. Watson, W. C., and Bukowsky, M.: Azathioprine in management of Crohn's disease: a randomized cross-over study (abstract). Gastroenterology, 66:796, 1974. 71. Willoughby, J. M. T., Kumar, P. J., Beckett, J., et al.: Controlled trial of azathioprine in Crohn's disease. Lancet, 2:944-947, 1971. 72. Winkelman, E. 1., and Brown, C. H.: Nitrogen mustard in the treatment of chronic ulcerative colitis and regional enteritis: a preliminary report. Cleveland Clin. Quart., 32: 165174, 1965. 73. Wisch, N., and Korelitz, B. 1.: Immunosuppressive therapy of ulcerative colitis, ileitis, and granulomatous colitis. Surg. Clin. N. Amer., 52:961-969, 1972. 74. Yu, D. T. Y., Clements, P. J., Paulus, H. E., et al.: Human lymphocyte subpopulations: effect of corticosteroids. J. Clin. Invest., 53:565-571, 1974. Mount Sinai School of Medicine of the City University of New York Fifth Avenue and 100th Street New York, New York 10029
Immunotherapy in Inflammatory Bowel Disease David B. Sachar, M.D., * and Daniel H. Present, M.D. **
Whenever medical science is pitted against a disabling chronic disease of unknown etiology, obscure pathogenesis, and unsatisfactory response to treatment, it is almost inevitable that efforts will be made to find some role for immunologic therapy. This has been the case, for example, in several chronic kidney, liver, and pulmonary diseases, in a variety of neoplastic conditions, in certain resistant infections, in chronic granulomatous diseases such as sarcoidosis, and in most of the so-called connective tissue disorders. The inflammatory bowel diseases, ulcerative colitis and Crohn's disease, have proven to be no exception to this rule. An immunologic approach to the treatment of ileitis and colitis is not altogether lacking in rationale. These diseases are very often associated with aberrations of the immune system, both humoral and cellmediated,62,64 so it may well be logical to try to modulate their course by immunoregulatory therapy. Unfortunately, however, it is very difficult to assess the track record of this form of treatment. Published reports are sketchy, many clinical experiences are uncontrolled, and the natural courses of the diseases themselves have a bewildering tendency to spontaneous fluctuations and vicissitudes. In this review, we will summarize the current state of knowledge concerning the efficacy ofimmunotherapy in inflammatory bowel disease. While corticosteroids are generally recognized as having immunosuppressive effects, 18, 74 and while an immunosuppressive action has even been suggested for sulfasalazine (Azulfidine),65 we will limit our consideration here to antimetabolites, alkylating drugs, disodium cromoglycate, metronidazole, and immunostimulatory agents.
*Associate Professor of Medicine,
.*
Mount Sinai School of Medicine of the City University of New York, and Associate Attending Physician, Mount Sinai Hospital Associate Clinical Professor of Medicine, Mount Sinai School of Medicine of the City University of New York, and Associate Attending Physician, Mount Sinai Hospital
Medical Clinics of North America-Vol. 62, No. 1, January 1978
173
174
DAVID
B.
SACHAR AND DANIEL
H.
PRESENT
ULCERATIVE COLITIS Antimetabolites The first trial of antimetabolite therapy for inflammatory bowel disease was performed 15 years ago in AustraliabyR. H. D. Beanofthe Repatriation General Hospital in Heidelberg, Victoria. Noting the recent introduction of antimetabolite therapy for certain "autoimmune" diseases, and reasoning that ulcerative colitis was an "autoimmune" disease because of Broberger and Perlmann's demonstration of circulating anticoIon antibodies in this condition,l1 Bean treated one of his patients who had ulcerative colitis with 6-mercaptopurine (Purinethol), * initially 300 mg per day and later 50 to 100 mg on alternate days. The patient promply went into a dramatic reJ;Ilission, and he remained well throughout a 2-year treatment period an~ for months thereafter. Bean published an enthusiastic report of his case in the Medical Journal of Australia in 1962,6 with an equally favorable follow-up report of 7 cases in 1966,7 and the era of antimetabolite trials for inflammatory bowel disease was born. Several notes of caution were sounded in 1966. Avery Jones et al. 5 in England described their tragic experience with a 19 year old girl with ulcerative colitis who became leukopenic and died a rapid septic death within a few weeks of beginning treatment with azathioprine (Imuran). t Simultaneously, the University of Chicago group reported on 10 patients treated with azathioprine. lo Eight patients improved, with one of them unburdened of steroid-dependency for the first time in 3 years, and another relieved not only of colitis but also of associated arthritis and pyoderma gangrenosum. On the other hand, there was a substantial incidence ofleukopenia, thrombocytopenia, and alopecia on the very high doses of azathioprine administered (4 to 6 mg per kg per day for 2 to 3 weeks, followed by 2 to 3 mg per kg per day). Moreover, a follow-up report indicated that within the next 2 years, 9 of the 10 patients had required colectomy.9 Despite these and other cautionary notes, the past decade has seen almost unbridled enthusiasm in the published reports of antimetabolite therapy for ulcerative colitis. Mackay et al. 43.44 reported from Melbourne, Australia, on what they considered very encouraging results of azathioprine treatment in 12 patients. A number of their patients improved only when azathioprine was administered simultaneously with ACTH and 1 experienced a remission only after a diverting ileostomy; one patient died of post-colectomy septicemia and another suffered a sudden fatal bowel perforation. Nonetheless, a few ofthe remissions were impressive and the authors' attitude to the drug was highly favorable. Other optimistic reports of azathioprine or 6-mercaptopurine therapy came from England,30 Germany,58 France,68 India,39 Israel,66 ltaly,15.16 Cleveland,14 Boston,53. 63 and New York. 35. 37. 73 In a few of these reports, the series of patients with ulcerative colitis were partially "contaminated" *6-Mercaptopurine is a synthetic purine analogue which blocks the incorporation of natural purines into DNA and thereby interferes with cell metabolism. t Azathioprine is an apparently somewhat less toxic imidazolyl derivative and metabolic precursor of 6-mercaptopurine.
INFLAMMATORY BOWEL DISEASE
175
by cases which in retrospect were obviously Crohn's disease, but this was not a major problem. More important, in all of these papers interpretation of the responses to antimetabolite therapy was open to some confusion because of other treatments that were administered concomitantly; but even allowing for this problem, a considerable number of therapeutic responses could clearly not have been attributed to any change in treatment except for the introduction of the antimetabolite. By far the most serious difficulty with these studies, however, was that none of them was controlled. There was no correction for the effects of placebo response, observer bias, or spontaneous fluctuation in the course of disease. Still, in justice to these uncontrolled studies, occasional responses to the antimetabolite treatment were so unmistakable that in at least a certain subpopulation of patients the drug must have been having some beneficial effect. For example, in even the most pessimistic of series, which reported treatment failure and drug toxicity in almost every one of 7 patients treated with azathioprine, Bicks included one girl with a 9 year history of ulcerative colitis whose response to 1 year of antimetabolite therapy was unabashedly described as "magnificent."9 Finally, in 1972,10 years after Bean's initial enthusiastic case report, there appeared the first published report of a controlled clinical trial of azathioprine in ulcerative colitis. 28 In this study, 11 of 20 azathioprinetreated patients remained symptom-free for one year, versus 5 of 20 placebo-treated patients; of the only 3 outright treatment failures, all 3 were in the group receiving placebo. These results almost but not quite achieved statistical significance at the 95 per cent confidence level, and the authors concluded that "the clinical results with azathioprine can be judged to be encouraging but not definitely proved." Subsequently, however, the final report of this trial failed to demonstrate any significant benefit from azathioprine either as an adjunct to corticosteroids in treatment of an acute attack or as maintenance therapy for periods up to 1 year, although there was still a suggestion of possible benefit in a subgroup of patients suffering from relapses of established disease. 29 Meanwhile, two other double-blind controlled trials of azathioprine in ulcerative colitis have appeared. One trial comprised 30 steroiddependent patients, comparing a group of 16 treated with azathioprine 1.5 mg per kg per day to a group of 14 given placebo over a 6 month period. 57 It concluded that while the clinical course of the disease was not measurably different between the two groups, the drug did permit significant reduction of steroid dosage. The second trial included 20 patients not receiving steroids; 10weretreated with azathioprine, 2.5mgperkg, while the other 10 received sulfasalazine (Azulfidine), 65 mg per kg per day, for 3 months.17 A measurable objective improvement occurred with azathioprine treatment, although the degree of benefit was not significantly different from that achieved with sulfasalazine alone. What practical conclusions can we draw from all this? Antimetabolites may be able to exert certain beneficial effects in some patients with ulcerative colitis. Their therapeutic effects are not clearly correlated with their immunosuppressive effects,63 and whether anti-inflammatory or other properties are playing a role is still not known. But these are dangerous drugs, with potent myelotoxic activity; a number of patients in the
176
DAVID
B.
SACHAR AND DANIEL
H.
PRESENT
most "favorable" reports died following leukopenic episodes. Also, despite reports of their successful use even in children,36, 58 antimetabolites carry suspected albeit not firmly proven teratogenic and possibly even carcinogenic potential. 59 Moreover, there is no absolute necessity for their use in ulcerative colitis, since a safe and permanent cure is already available for this disease in the form of colectomy. Finally, prolonged nonoperative management of extensive ulcerative colitis may not prove to be a favor to the patient anyhow, in view of the certain increase in cancer risk after 10 years of disease. In fact, one of the "successfully" treated patients in the Boston series who ultimately came to colectomy was found to have an unsuspected small carcinoma with one of 28 lymph nodes already positive. 53 We may well conclude, therefore, that antimetabolite therapy is unsafe in acute fulminating colitis, inadvisable for permanent maintenance therapy, but conceivably useful as a short-term measure in certain patients unresponsive or intolerant to acceptable doses of steroids and sulfasalazine, and unwilling or unable to undergo curative surgery.
Cytotoxic Agents There are only a handful of reports on the use of alkylating or other cytotoxic agents in the treatment of ulcerative colitis. Busulfan (Myleran) was tested by Bean,7 who declared it "very useful" for long-term maintenance of remission (at the astronomical and presumably erroneous dose of 100 mg per day), but he offered no data in support of this conclusion, which has never been subsequently confirmed. Other cytotoxic agents that have been tried sporadically in some cases of ulcerative colitis are chlorambucil (Leukeran) and antilymphocyte serum. Reports from a group in Strasbourg suggested favorable results with these drugs,22, 51 but the cases were few, the studies uncontrolled, and the side effects considerable. Still another cytotoxic agent that has been studied is the nitrogen mustard, mechlorethamine (Mustargen), which was given in intravenous doses totalling 18 to 21 mg over a 6 day period (approximately 0.4 mg per kg per day) to 14 patients with "ulcerative colitis. "72 Some of these patients clearly had granulomatous rather than ulcerative colitis, but in any event a number of them appeared to have a dramatically beneficial response. On the other hand, the mechlorethamine was administered in every case together with 30 U per day of ACTH "to decrease nausea," so the influence of the mustard alone is difficult to determine. Moreover, one of the unfortunate nonresponders died of perforating enteritis postcolectomy, so the treatment seems quite hazardous. Long-term maintenance with oral mustard (Uracil) in this same series was reportedly not beneficial,14 and a controlled randomized trial described at the time as being "underway" was not subsequently reported. Therefore, while an occasional and sporadic good effect may have been observed (and while we have personally seen one chronically bleeding and acutely toxic patient respond dramatically to chlorambucil 2 mg a day and enter an uninterrupted 2 year remission thereafter), a review of the whole published experience with cytotoxic drugs leaves one unable to find any substantial indications for their use in ulcerative colitis.
INFLAMMATORY BOWEL DISEASE
177
Disodium Cromoglycate This drug (also called cromolyn sodium, or Aarane) is used forinhalation therapy of asthma, since it inhibits mast cell degranulation and thereby suppresses immediate hypersensitivity reactions in the bronchial mucosa. In an effort to capitalize on this same mast cell stabilizing property in the rectal mucosa of patients with chronic ulcerative proctitis, Heatley et al. conducted an 8-week double-blind placebo-matched crossover trial of disodium cromoglycate, 200 mg by enema twice daily, plus 100 mg orally 3 times a day.26 Of26 patients who completed the trial, 14 responded to cromolyn, 2 improved with placebo, and 10 failed to respond well to either treatment. Since these results appeared to favor the cromolyn therapy, another double-blind trial with 12 patients with more extensive though mild colitis was launched soon therafter. 45 It showed modest but significant subjective and objective benefit from 6 months of oral cromolyn (2 gm per day) compared to placebo. Others have described favorable results in 3 patients treated in an uncontrolled fashion. 20 This may ultimately prove to be a promising approach to therapy, but since the reported benefits so far have been undramatic, and since moreover the only form of disodium cromoglycate commercially available in the United States today is a 20 mg capsule labeled "For inhalation only," one might conclude that the terribly expensive, inconvenient, and unsanctioned oral administration of 100 capsules of cromolyn a day is a venture that might be better postponed until still further studies are available. 47 CROHN'S DISEASE If the availability of a permanent surgical cure somewhat dampens our enthusiasm for immunosuppressive therapy in ulcerative colitis, no such prospect exists to suppress our eagerness for any new or unconventional therapy that may help patients afflicted with debilitating and mutilating forms of Crohn's disease.
Antimetabolites While nitrogen mustard had been tested in regional enteritis as early as 1965,22 the first trial of antimetabolite therapy for Crohn's disease was reported from London by Brooke et al,12 in 1969. Six patients were treated with azathioprine and all 6 got better during a 6 month follow-up period. While it took 4 years before others picked up Bean's lead in the antimetabolite therapy of ulcerative colitis, there was no such delay in the rush to try azathioprine for Crohn's disease. A spate of uncontrolled reports followed quickly. * The pattern of these reports closely paralleled that of the early trials ofimmunosuppressive drugs for ulcerative colitis. Their approach was anecdotal, their series were often small and their follow-up intervals usually short, their interpretation was frequently complicated by other concomitant therapy, and in none of these reports were control *References 1, 2, 4, 13, 14, 21, 23, 30-32, 38, 52, 53, 68, 69.
178
DAVID
B.
SACHAR AND DANIEL
H.
PRESENT
patients studied. In at least one case, azathioprine was given for an attack of acute ileitis, a benign self-limited condition, and its use was mistakenly credited for the spontaneous abatement of the inflammation and for the failure of "Crohn's disease" to recur.27 Nonetheless, there were some sporadic responses of intractable Crohn's disease to the administration of antimetabolites, usually azathioprine, that appeared almost miraculous. Two particularly noteworthy phenomena that were occasionally observed in these uncontrolled studies were striking decreases in steroiddependency and dramatic healing of fistulae. The need for randomized double-blind controlled trials was clearly inescapable. In the past 4 years, there have been 7 randomized controlled trials of azathioprine or 6-mercaptopurine in the treatment of Crohn's disease. The first of these trials, by Willoughby et al.71 at St. Bartholomew's Hospital in London, studied 22 patients in a 24 week double-blind program, and demonstrated unequivocal benefit from azathioprine. Ten of the 11 patients on azathioprine remained in remission for the full 24 weeks, whereas 80fthe 11 placebo-treated patients relapsed and had to be withdrawn from the study. The next controlled trial of azathioprine was reported by Rhodes et al. 55 from Cardiff, but it was unable to demonstrate any advantage oftbe drug over placebo on account of the study design. 55 The trial period was only 2 months long, even though it had long been recognized that it usually requires at least 3 to 9 weeks and sometimes as long as four months before even an initial response to azathioprine in inflammatory bowel disease, with peak response not usually occurring for 3 to 9 months. 10. 21. 69 Nonetheless, even in this excessively brief trial, the only 2 patients among the 15 studied who manifested "definite" or "considerable" improvement were both on azathioprine at the time. Another controlled trial, from Ontario, could not demonstrate any significant objective benefit from azathioprine in 11 patients over a 1 year period, but all patients were in apparent remission anyhow-an unspecified number of them postoperatively-at the beginning of treatment. 70 Even so, the patients reported more subjective improvement on azathioprine as compared to placebo therapy, with the difference statistically significant at the 99 per cent confidence level. The fourth controlled trial was reported from Yale. 34 While this study did not demonstrate any consistent advantage of azathioprine treatment over placebo, the 4 month treatment period was probably too short to allow definitive conclusions. Moreover, these authors qualified even their negative findings by observing that among the 27 patients studied, the only ones who required surgery were four not receiving azathioprine, and also that the "dramatic" response of some patients to azathioprine "suggests that some 'subset' [of azathioprine-responsive patients] needs to be detected." The next controlled study, performed at the University of Chicago, indicated a significant benefit from 26 weeks of treatment with azathioprine in contrast to placebo, in permitting reduction or discontinuation of the dosage of steroid without wor:;ening of symptoms among the 10
INFLAMMATORY BOWEL DISEASE
179
patients with Crohn's disease who received the active drug. 56 The group receiving azathioprine experienced only 2 relapses versus 7 in the placebo group. As in the Yale study, azathioprine-responsiveness was not a consistent phenomenon, and the existence of "an azathioprine-responsive subgroup" was once again postulated. The most widely publicized controlled trial undertaken to date is the 234-patient series of the National Cooperative Crohn's Disease Study.60 Unfortunately, the design of this trial was so heavily biased against azathioprine-treatment that any possible benefits of the antimetabolite would be almost impossible to detect. By establishing only a 4 month treatment period, by requiring all other therapy (steroid and sulfasalazine) to be completely withdrawn within a few weeks of initiating study drugs, and by classifying the many early relapses that inevitably ensued as unqualified treatment failures, the National Cooperative Study was intrinsically biased against any therapeutic agent whose onset of action is slow or whose effectiveness is optimal when combined with other medications. Since a delayed onset of action and a gradual steroid-sparing effect are both characteristic properties of immunosuppressive treatment, the National Cooperative Study would be expected to lack the ability to detect any benefit from azathioprine, and this has indeed proven to be the case: "No significant difference was observed between response to azathioprine and that to placebo. "60 An altogether different conclusion emerges, however, from the Mount Sinai-Lenox Hill study of6-mercaptopurine in Crohn's disease. This is the most recently reported controlled trial and also the largest in terms of patient-years of follow-up. 54 Over a 7 year period, 83 patients with intractable Crohn's disease were entered into this randomized double-blind 2 year crossover study of6-mercaptopurine versus placebo. Overall clinical improvement, reduction of steroid requirements, and closure of fistulae occurred significantly more often among the patients treated with 6-mercaptopurine than in the group receiving placebo. Indeed, nearly two thirds of patients treated with 6-mercaptopurine in this study manifested objective drug-related improvement, while approximately 30 per cent experienced healing of external fistulae. Delayed onset of action (up to 4 to 6 months) was noted, once again emphasizing the indispensibility of at least 6 month, and preferably 1 year, periods of treatment for meaningful controlled trials. In contrast to their apparent efficacy in active disease, neither immunosuppressive treatment, steroids, nor sulfasalazine has been effective in reducing the postoperative recurrence rate of Crohn's disease, according to the latest report of the National Cooperative Study.61 In most of the reported series, controlled or not, the most common complications of antimetabolite therapy have been bone marrow depression, nausea, and allergic fevers or rashes, while other undesirable side effects have included intra-abdominal abscesses 50 and occasional instances of pancreatitis. 33, 49, 54, 60 The potential toxicity of this type of treatment is therefore considerable, but the best-designed longest-term controlled trials do suggest potential benefits as well, particularly in patients with steroid intolerance and/or chronic fistulous complications.
180
DAVID
B.
SACHAR AND DANIEL
H.
PRESENT
Other Immunosuppressive Agents While a number of alkylating agents have been tested in ulcerative colitis, only one such study, using nitrogen mustard, has been reported in Crohn's disease. 72 Paralleling their experience in ulcerative colitis, Winkelman and Brown described, in an uncontrolled series, dramatic responses to this drug (including the closure offistulae in four patients) and disastrous complications as well (including three bowel perforations, two of them fatal). Even antimetabolites, with all their potential hazards, seem a good deal safer than nitrogen mustard in inflammatory bowel disease. Another drug with reported immunosuppressive and even granuloma-inhibiting properties 25 that has been claimed to be effective in the treatment of Crohn's disease is metronidazole (Flagyl). Ursing and Kamme reported from Sweden that 13 out of 17 patients treated with metronidazole, 20 to 40 mg per kg per day, manifested striking clinical improvement. 67 Follow-up controlled studies have not yet been reported as of this date. Immunostimulation Since it is becoming increasingly clear that many patients with Crohn's disease manifest defects in their cellular immune systems,46.62 it is reasonable that attempts have been made to treat this condition with immunostimulating agents. Preliminary reports of un controlled studies have described favorable responses to BCG19.24 and transfer factor.3 N g and Vicary have published further evidence for the ability of transfer factor to restore depressed T-cell function in patients with Crohn's disease,48 although clinical response to the agent was not commented upon. One brief report from Ireland noted the failure of "immunostimulation therapy" in a few patients, but the nature ofthe therapy was not described. 42 There is also one report from France of "good" or "dramatic" results in a small handful of Crohn's disease patients treated with levamisole,8 an immunopotentiating imidazole drug long used in Europe as an antihelminthic and more recently undergoing intensive worldwide study in the therapy of rheumatoid arthritis, chronic infections, and cancer.41 This agent is currently the subject of a randomized double-blind controlled clinical trial for the treatment of Crohn's disease at the Mount Sinai Hospital in New York. CONCLUSIONS Immunosuppressive drugs are potentially dangerous. Their routine use in ulcerative colitis, a premalignant and surgically curable disease, is not advisable except as a short-term measure in patients intolerant of steroids or sulfasalazine and unwilling or unable to accept colectomy. They have a better-defined role in Crohn's disease, on the other hand, since this condition is incurable and potentially more mutilating. Here they have been reliably shown to have a steroid-sparing effect, to be at least as beneficial as sulfasalazine, and in some cases to produce healing
INFLAMMATORY BOWEL DISEASE
181
of chronic enterocutaneous and perianal fistulae. However, the accurate prediction of which patients will benefit from azathioprine and which patients will not remains an as yet unfulfilled challenge for the future.
REFERENCES 1. Arden Jones, R: Immunosuppressive therapy in Crohn's disease. Proc. Roy. Soc. Med., 64:171-173,1971. 2. Arden Jones, R: Larger doses of immunosuppressive drugs (letter). Lancet, 2:107,1974. 3. Asquith, P., Mallas, E., Ross, 1., et al.: Transfer factor in the treatment of Crohn's disease (abstract). Gut, 16:832, 1975. 4. Avery Jones, F., Brown, P., Lennard-Jones, J. E., et al.: Azathioprine for Crohn's disease (letter). Lancet, 2: 795, 1969. 5. Avery Jones, F., Lennard-Jones, J. E., Hinton, J. M., Reeves, W. G.: Dangers of immunosuppressive drugs in ulcerative colitis (letter). Brit. Med. J., 1 :1418, 1966. 6. Bean, R H. D.: The treatment of chronic ulcerative colitis with 6-mercaptopurine. Med. J. Austr., 2:592-593, 1962. 7. Bean, R H. D.: Treatment of ulcerative colitis with antimetabolites. Brit. Med. J., 1 :1081-1084, 1966. 8. Bertrand, J., Renoux, G., Renoux, M., et al.: Maladiede Crohnetlevamisole. Nouv. Presse med., 3:2265,1974. 9. Bicks, R 0.: Experimental therapeutic concepts in gastroenterology: Immunology. N.Y. State Med. J., 70:1207-1212,1970. 10. Bowen, G. E., Irons, G. V., Jr., Rhodes, J. B., et al.: Early experiences with azathioprine in ulcerative colitis: a note of caution. J .A.M.A., 195 :460-464, 1966. 11. Broberger, 0., Perlmann, P.: Autoantibodies in human ulcerative colitis. J. Exper. Med., 110:657-674, 1959. 12. Brooke, B. N., Hoffmann, D. C., and Swarbrick, E. T.: Azathioprine for Crohn's disease. Lancet, 2:612-614,1975. 13. Brooke, B. N., Javett, S. L., and Davison, O. W.: Further experience with azathioprine for Crohn's disease. Lancet, 2:1050-1053,1973. 14. Brown, C. H., and Achkar, E.: Azathioprine therapy for inflammatory bowel disease: a preliminary report. Amer. J. Gastroent., 54:363-377, 1970. 15. Caprilli, R: La terapia immunosoppressiva della colite ulcerosa. Atti XVIII Congr. N az. Soc. Ital. Gastroenterol., Siena, 1971, pp. 201-212. 16. Caprilli, R, Baldamenti, G., and De Santis, R: Rilievi su la terapia della proctocolite idiopatica con farmaci immunodepressivi. Policlinico Med., 73 :349-360, 1966. 17. Caprilli, R, Carratu, R, and Babbini, M.: A double-blind comparison of the effectiveness of azathioprine and sulfasalazine in idiopathic proctocolitis: preliminary report. Amer. J. Dig. Dis., 20:115-120,1975. 18. Claman, H. N.: Corticosteroids and lymphoid cells. New Eng. J. Med., 287 :388-397, 1972. 19. Crismer (1970), cited in GefIroy, Y., Colin, R, and Hecketsweiler, P.: Aspects nouveaux du traitement de la maladie de Crohn. Rev. Prat., 21 :2599-2612, 1971. 20. Della Cella, G., Garabaldi, L. R., and Durand, P.: Ulcerative colitis and disodium cromoglycate (letter). Lancet, 1: 1129, 1976. 21. Drucker, W. R, and Jeejeebhoy, K. N.: Azathioprine: an adjunct to surgical therapy of granulomatous enteritis. Ann. Surg., 172:618-625, 1970. 22. Eisenbeth, R, and Oberling, F.: Le traitement par les immunosuppresseurs de certaines rectocolites hemorrhagiques et purulentes: le role eventuel des lymphocytes. Presse Med., 77:2141-2142,1969. 23. Fausa, 0., and Gjone, E.: Azathioprine (Imurel) therapy in Crohn's disease. Acta Med. Scand., 190:211-212, 1971. 24. Geffroy, Y., Colin, R, Hecketsmeiler, P., et al.: Traitement de la maladie de Crohn par le B.C.G.: etude clinique, radiologique, evolutive. Arch. Mal. Appl. Dig.,60:293-298, 1971. 25. Grove, D. 1., Mahmoud, A. A. F., and Warren, K. S.: Suppression of cell-mediated immunity by metronidazole (abstract). Clin. Res., 24:286A, 1976. 26. Heatley, RV., Calcraft, B. J., Rhodes, J., et al.: Disodium cromoglycate in the treatment of chronic proctitis. Gut, 16:559-563, 1975. 27. Javett, S. L., and Hoffmann, V. J.: Azathioprine in acute Crohn's disease (letter). South Afr. Med. J., 46:1369, 1972. 28. Jewell, D. P., and Truelove, S. C.: Azathioprine in ulcerative colitis: an interim report on a controlled therapeutic trial. Brit. Med. J., 1 :709-712, 1972. 29. Jewell, D. P., and Truelove, S. C.: Azathioprine in ulcerative colitis: final report on controlled therapeutic trial. Brit. Med. J., 4:627-630, 1974.
182
DAVID
B.
SACHAR AND DANIEL
H.
PRESENT
30. Jones, R. A.: Immunosuppressive therapy in ulcerative colitis. Proc. Roy. Soc. Med., 62:499-501, 1969. 31. Karayannoupoulos, S., Chazan, B. I., Hancock, D. M., et al.: Anorectal Crohn's disease. Brit. J. elin. Pract., 26:377-379, 1!,j{:i. 32. Kasper, H., Zimmerman, H.-D., and Nagele, E.: Treatment of regional ileitis (Crohn's disease) with azathioprine. Germ. Med. Monthly, 15:521-523, 1970. 33. Kawanishi, H., Rudolph, E., and Bull, F. E.: Azathioprine-induced acute pancreatitis. New Eng. J. Med., 289:357, 1973. 34. Klein. M., Binder. .T. H., Mitchell, M., et al.: Treatment of Crohn's disease with azathioprine: a controlled evaluation. Gastroenterology, 66:916-922, 1974. 35. Korelitz, B. I., Glass, J. L., and Wisch, N.: Long-term immunosuppressive therapy of ulcerative colitis: continuation of a personal series. Amer. J. Dig. Dis., 18: 31 7-322, 1973. 36. Korelitz, B. I., Glass, J. L., and Wisch, N.: Long term observations of children with ulcerative colitis treated with an immunosuppressive (6-mercaptopurine) (abstract). Gastroenterology, 72:1083,1977. 37. Korelitz, B. I., and Wisch, N.: Long term therapy of ulcerative colitis with 6-mercaptopurine: a personal series. Amer. J. Dig. Dis., 17:111-118, 19.72. 38. Kyle, J.: The management of chronic Crohn's disease. Ulster Med. J., 40:59-63, 1971. 39. Lal, H. B., Caroli, R K., and Sengupta, D.: Treatment of ulcerative colitis with antimetabolite 6-mercaptopurine. J. Assoc. Phys. India, 15:129-136,1967. 40. Lennard-Jones, J. E., and Williams, C. B.: Azathioprine in the treatment of Crohn's disease. Proc. Roy. Soc. Med .. 65 :291-293. 1972. 41. Levamisole (editorial). Lancet, 1: 151-152, 1975. 42. McFadden, E. B., Thomes, D. R, and Fielding, J. F.: Immunostimulation therapy in Crohn's disease. Irish J. Med. ScL, 145:267, 1976. 43. Mackay, I. R, Wall, A. J.: Letter to the editor. Amer. J. Dig. Dis., 13:850-851, 1968. 44. Mackay, I. R, Wall, A. J., and Goldstein, G.: Response to azathioprine in ulcerative colitis: report of 7 cases. Amer J. Dig. Dis., 11 :536-545, 1966. 45. Mani, V., Lloyd, G., Green, F. H. Y., et al.: Treatment of ulcerative colitis with oral disodium cromoglycate: a double-blind controlled trial. Lancet, 1 :439-441, 1976. 46. Meyers, S., Sachar, D. B., Taub, R. N., et al.: Anergy to dinitrochlorobenzene and depression ofT-lymphocytes in Crohn's disease and ulcerative colitis. Gut, 17:911-915,1976. 47. New treatment for ulcerative colitis? (editorial) Brit. Med. J., 1 :2, 1976. 48. Ng, R. P., and Vicary, F. R: Cell-mediated immunity and transfer factor in Crohn's disease. Brit. Med. J., 2:87-88, 1976. 49. Nogueira, J. R, and Freedman, M. A.: Acute pancreatitis as a complication of Imuran therapy in regional enteritis. Gastroenterology, 62:1040-1041,1972. 50. Northfield, T. C., and Roberts, C. I.: Intra-abdominal abscesses due to azathioprine for Crohn's disease. Gut, 13:124-125,1972. 51. Oberling, F., and Hiebel, G.: Intravenous ALS in the treatment of severe rectocolitis (letter). New Eng. J. Med., 285:409-410, 1971. 52. Papp, J. P., Watson, D. W., and Bull, F. E.: Azathioprine treatment in Crohn's disease. Amer. J. Gastroent., 61 :136-142, 1974. 53. Patterson, J. F., Norton, R A., and Schwartz, R S.: Azathioprine treatment of ulcerative colitis, granulomatous colitis and regional enteritis. Amer. J. Dig. Dis., 16:327-332, 1971. 54. Present, D. H., Wisch, N., Glass, J. L., et al.: The efficacy of immunosuppressive therapy in Crohn's disease: arandomized long term double blind study (abstract). Gastroenterology, 72:1114, 1977. 55. Rhodes, J., Bainton, D., Beck, P., et aI.: Controlled trial of azathioprine in Crohn's disease. Lancet, 2:1273-1276, 1971. 56. Rosenberg, J. L., Levin, B., Wall, A. J., et aI.: A controlled trial of azathioprine in Crohn's disease. Amer. J. Dig. Dis., 20:721-726,1975. 57. Rosenberg, J. L., Wall, A. J., Levin, B., et aI.: A controlled trial of azathioprine in the management of chronic ulcerative colitis. Gastroenterology, 69:96-99, 1975. 58. Schafer, K. H., and Blaker, F.: Azathioprine in the treatment of ulcerative colitis (abstract). Acta Paediatr. Scand., 60:376-377, 1971. 59. Scharf, J., N ahir, M., Eidelman, S., et al.: Carcinoma of the bladder with azathioprine therapy. J.A.M.A., 237:152, 1977. 60. Singleton, J. W.: National Cooperative Crohn's Disease Study (NCCDS): preliminary results of Part I (abstract). Gastroenterology, 70:938, 1976. 61. Singleton, J. W.: National Cooperative Crohn's Disease Study (NCCDS): Results of drug treatment. A cooperative study. (abstract). Gastroenterology, 72:1133, 1977. 62. Strickland, R G., and Sachar, D. B.: The immunology of inflammatory bowel disease. In Glass, G. B. J., ed.: Progress in Gastroenterology, Vo13. New York, Grune and Stratton, 1977, in press.
INFLAMMATORY BOWEL DISEASE
183
63. Swanson, M. A., and Schwartz, R. S.: Immunosuppressive therapy: the relation between clinical response and immunologic competence. New Eng. J. Med., 277: 163-170, 1967. 64. Thayer, W. R., Jr.: The immunopathology of intestinal granulomatous disease. In Reis, L. V., ed.: Frontiers of Gastrointestinal Research: Immune Disorders. New York, S. Karger, 1975, pp. 74-124. 65. Thayer, W. R., Jr., Charland, C., and Field, C.: Salazopyrin and its effect on lymphocyte subpopulations and function (abstract). Gastroenterology, 70:942, 1975. 66. Theodor, E., Gilon, E., and Waks, U.: Treatment of ulcerative colitis with azathioprine. Brit. Med. J., 4:741-743, 1968. 67. Ursing, B., and Kamme, C.: Metronidazaole for Crohn's disease. Lancet, 1 :775-777, 1975. 68. Vachon, A., Tete, R., Barthe, J., et al.: Nouveaux resultats du traitement par l'azathioprine de la recto-colite hemorrhagique et de la maladie de Crohn colique. Arch. Mal. App. Dig., 61 :625-640, 1972. 69. Wallenstein, S., and Persson, S.: Azathioprine therapy for Crohn's disease Acta Chir. Scand., 138:521-526, 1972. 70. Watson, W. C., and Bukowsky, M.: Azathioprine in management of Crohn's disease: a randomized cross-over study (abstract). Gastroenterology, 66:796, 1974. 71. Willoughby, J. M. T., Kumar, P. J., Beckett, J., et al.: Controlled trial of azathioprine in Crohn's disease. Lancet, 2:944-947, 1971. 72. Winkelman, E. 1., and Brown, C. H.: Nitrogen mustard in the treatment of chronic ulcerative colitis and regional enteritis: a preliminary report. Cleveland Clin. Quart., 32: 165174, 1965. 73. Wisch, N., and Korelitz, B. 1.: Immunosuppressive therapy of ulcerative colitis, ileitis, and granulomatous colitis. Surg. Clin. N. Amer., 52:961-969, 1972. 74. Yu, D. T. Y., Clements, P. J., Paulus, H. E., et al.: Human lymphocyte subpopulations: effect of corticosteroids. J. Clin. Invest., 53:565-571, 1974. Mount Sinai School of Medicine of the City University of New York Fifth Avenue and 100th Street New York, New York 10029
