TY - JOUR
AU1 - Burakoff, Robert
AB - Introduction In this part of the symposium a review of not often and sporadically used therapies will be discussed. There are several therapies for ulcerative colitis (UC) and Crohn's disease (CD) that have been evaluated in controlled trials but have never achieved popularity with the practicing GI community. This overview will evalu ate the current literature on these not-often-used therapies with an attempt to find their appropriate place in the continuum of medical care for CD and UC. Fish Oil Eicosapentanoic acid (EPA), which is present in fish oil, is metabolized through the cycloxygenase pathway to prostaglandins and by the neutrophil 5-lipoxygenase pathway to leukotriene B5, which is 30 times less potent than leukotrience B4 as a neutrophil chemotactic agent. Fish oil supplementation has been shown to be beneficial in rheumatoid arthritis. Since 1989 there have been several studies using fish oil supplementation in the treatment of active colitis and UC. Ulcerative Colitis In the first trial conducted with fish oil by Lorenz et al. (1) in 1989 with 10 patients with UC receiving approximately 2 g of EPA in a 7-month, double-blind, crossover trial, a trend towards clinical improvement was observed but did not quite reach statistical significance. In 1990, an open trial of 10 patients with mildmoderate UC received 15 max-EPA capsules providing 2.7 g of EPA. Seven of 10 patients improved, and the steroid dose was reduced in 4 of 5 patients on prednisone over an 8-week period (2). In 1992, several double-blind placebo-controlled trials were undertaken to determine the potential efficacy of fish oil supplementation in active UC. In a study by Stenson et al. (3), 18 patients completed a 4-month multicentered, randomized, double-blind, placebo-controlled crossover trial with a 1-month washout period. The patients had mild-to-moderate active UC and remained on sulfasalazine and prednisone. The patients received 18 max-EPA tablets/day equivalent to 3.24 g of eicosapentanoic acid. Fish oil supplementation resulted in improvement in histologic findings, weight gain, and reduction in rectal dialysate leukotriene B4 levels. Of the seven patients on prednisone, the mean prednisone dose decreased by 50% (13 mg/d to 6 mg/d) during fish oil treatment. The conclusion of the study was that fish oil provided a modest beneficial effect and that treatment with fish is probably most useful as adjunctive medical therapy as opposed to primary medical therapy. In a study by Aslan and Triadafilopoulos (4), 11 patients with mild-moderate UC were studied in an 8- month, double-blind placebo-controlled crossover trial of dietary supplementation with fish oil receiving approximately 4.2 g of omega-3 fatty acids per day. Mean disease activity index declined 56% in the fish oil group vs. 4% in the placebo group (p = <0.05). Antiinflammatory drugs were reduced or eliminated in eight patients (72%) while on fish oil. In the largest study to date by Hawthorne et al. (5), 87 patients received either 4.5 g of EPA acid or olive oil placebo daily for 1 yr. For patients entering the trial in relapse (N = 53), there was a significant reduction in corticosteroid requirement after 1 and 2 months of treatment. There was also a trend toward remission in the fish oil group defined by complete withdrawal of steroids but the difference was not statistically significant. For patients in remission, fish oil was no better than placebo in preventing relapse. In conclusion, in four trials using dietary supplementation with fish oil in UC administering 2.7 g or more of EPA, all four trials demonstrated moderate clinical benefit as adjunctive therapy and all four trials demonstrated a significant decrease in corticosteroid usage. Crohn's Disease There are very few studies on the use of fish oil supplementation for the treatment of CD. In the section on Maintenance Therapy by Dr. Bill Tremaine, he summarizes the study by Belluzi et al. in the New England Journal of Medicine in 1996 (6) demonstrating that 2.7 g of omega-3 fatty acids in fish oil capsules was effective in reducing the rate of relapse in CD in remission. Finally, from Belluzzi et al. (7), preliminary data in abstract form demonstrated that 2.7 g of omega-3 fatty acids in fish oil was significantly more effective vs. placebo in preventing CD relapse after ileal resection and ileo-colonic anastomosis. Future studies will need to be undertaken to determine if fish oil supplementation is as effective as mesalamine in preventing postsurgical relapse of CD. Nicotine for Ulcerative Colitis The majority of patients with UC are nonsmokers, and several studies have demonstrated that patients with a history of smoking have the onset of UC within a few years of stopping smoking. The first significant randomized, double-blind study with transdermal nicotine patches was reported by Pullan et al. in 1994 (8). Seventy-two patients with active UC were randomized to 15 to 25 mg/day of nicotine as tolerated vs. placebo for 6 weeks. All the patients were on mesalamine and 12 patients were on low-dose glucocorticoids. Seventeen out of 35 patients in the nicotine group achieved complete remission, as compared with 9 out 37 patients in the placebo group (p = 0.03). Side effects were common and included headache, lightheadedness, nausea, and sleep disturbance. The most recent randomized double-blind, placebocontrolled trial performed at the Mayo Clinic with 64 nonsmoking patients with mild-to-moderate active UC were randomized to transdermal nicotine (= 22 mg after the 1st week) vs. placebo while patients remained on concomitant medical therapy (9). After 4 weeks, 12 of 31 patients (39%) who received nicotine were clinically improved vs. 3 of 33 patients (9%) on placebo. These results demonstrated efficacy for transdermal nicotine in mild-moderate UC, but the results were not as dramatic as in the study by Pullan (8). Thomas et al. (10) performed a study comparing transdermal nicotine patches with prednisolone in active UC. Six out of 19 patients (31%) achieved full sigmoidoscopic remission on an average of 20 mg daily of nicotine (range, 15-25 mg daily) vs. 14 of 24 patients (58%) on 15 mg of prednisone (p = 0.08) in this 6-week study. These results were not as impressive as the previous studies, but in this study all patients were withdrawn from mesalamine at day 10 of the study. Therefore, nicotine may be most useful as adjunctive therapy with mesalamine. Transdermal nicotine does not seem to be effective in maintaining a remission in UC. In another study by Thomas et al., they performed a randomized, doubleblind study with 80 patients with UC, 40 patients received placebo and 40 patients received an average of 15 mg of nicotine over 16 hours over 6 months (11). All patients had been on mesalamine, which was withdrawn when the maintenance dose of nicotine was reached. At the end of 6 months, 14 of 40 patients relapsed in the nicotine group and 17 of 40 patients relapsed in the placebo group. In an attempt to avoid the side effects of nicotine and to determine the effectiveness of nicotine in left-sided UC, two open protocol pilot studies were undertaken to determine the safety and efficacy of nicotine enemas. In the first study by Sandborn et al. (12), 10 nonsmoking patients with mild-to-moderate left-sided UC unresponsive to 5-aminosalicylates were treated with nicotine tartrate liquid enemas 3 mg/100 ml during week 1 then 6 mg/100 ml for the next 3 weeks. Five out of seven patients (71%) demonstrated clinical and sigmoidoscopic improvement. Three patients could not retain the enemas. The second study by Green et al. (13) treated 22 nonsmoking patients with active colitis in an open study with 6 mg/100 ml of nicotine nightly for 4 weeks. Pretreatment medications including mesalazine (16) and prednisolone (8) were kept at a constant dose 1 month before the trial and during the study. Sixteen out of 17 patients who completed the study had improvement in the clinical score, and sigmoidoscopic and histological scores improved in 10 out of 17 patients. Three of 17 patients experienced a full remission. No serious side effects were observed. In summary, approximately 85% (21 out of 24) of the patients completing the two studies had clinical improvement. Topical nicotine therapy should undergo controlled trials and may prove to be an important adjunctive therapy for left-sided UC. Topical Short-Chain Fatty Acids for Ulcerative Colitis Short-chain fatty acids (SCFA), a by-product of anaerobic fermentation of undigested carbohydrates in the colon, are an important energy source for colonocytes. The SCFA butyrate is considered to be the best energy source for the colon and has been shown to stimulate sodium and water absorption. It has been demonstrated that colonocytes in UC, particularly in the left colon, have reduced SCFA oxidation relative to normal controls. Therefore, it has been postulated that supraphysiologic luminal SCFA concentrates may be able to overcome the presumed partial metabolic abnormality of colonocytes to oxidize SCFA. The most recent study by Breuer et al. (19) is the largest randomized, double-blind placebo-controlled multicenter trial in the United States, involving 103 patients with distal UC of at least 3 months' duration. The patients were randomized to either twice daily SCFA enemas (80 mM sodium acetate, 30 mM sodium propionate, and 40 mM sodium butyrate) or placebo for 6 weeks. Patients had to be on stable oral medication for at least 6 weeks (oral 5-amino salicylic acid [5-ASA] or corticosteroid and off corticosteroid enemas for > 1 month and off 5-ASA enemas > 1 week.) Ninety-one patients completed the trial, with the SCFA group having complete remissions and/or much improved in 33% vs. 20% in the placebo group, but this difference was not statistically significant (p = 0.14). However, in patients with a current episode of colitis, i.e., < 6 months' duration, the SCFA group had a statistically significant clinical improvement compared with the placebo group (48% vs. 18%, p = 0.03). In this trial, the patients had more severe disease compared with the other trials with 20% of patients on 30 mg of prednisone/day. In summary, SCFA enemas appear to be beneficial as either primary or adjunctive therapy in the treatment of mild-tomoderate left-sided UC in patients with activation of disease of relatively short duration. Unfortunately, the enemas are not commercially available, and most pharmacists are not willing to prepare this rather malodorous enema solution. Antibiotics for the Treatment of IBD It has become well accepted that bacteria play an important role in the pathogenesis of CD. Surgery for CD with subsequent diversion of proximal ileal contents results in mucosal healing and delay of recurrence of disease. Animal knockout models of intestinal inflammation will not develop enteric inflammation in a germ-free environment. Combined with the above clinical and basic science data, and with anecdotal experience by practicing gastroenterologists using antibiotics, antibiotics have found their way into the spectrum of medical therapy for some patients with CD. Is there adequate data to support the use of antibiotics in CD? The study by Brandt et al. in 1982 (20) focused attention on the value of metronidazole in healing perineal CD. This study was followed by the publication of the study by Ursing et al. (21) in 1982, demonstrating the comparable effectiveness of metronidazole and sulfasalazine in treating CD and describing a group of patients who did not respond to sulfasalazine but did respond to metronidazole. Since 1982 there have been several controlled trials with antibiotics in the treatment of CD. In a trial comparing metronidazole, metronidaxole, and sulfatrimethaprim or placebo (22), antibiotics were found to be superior to placebo at 2 weeks but not at 4 and 6 weeks. This study is difficult to evaluate because 50% of the patients receiving placebo had colonic involvement vs. 28% of patients in the metronidazole group. In a double-blind placebo-controlled trial of metronidazole (10 mg/kg/day and 20 mg/dg/day) vs. placebo in colonic CD both high- and low-dose metronidazole was more effective in decreasing activity of disease as measured by the Crohn's Disease Activity Index (23). In a randomized, controlled clinical trial comparing metronidazole and ciprofloxacin vs. methyprednisolone for active CD, the remission rate for antibiotic (metronidazole 250 mg q.i.d. and cipro 500 mg b.i.d.) therapy after 12 weeks was similar to the remission rate with methylprednisolone (46% vs. 63%, p = ns) (24). In a recent abstract by Colombel et al. (25), results were reported of a controlled trial comparing ciprofloxacin vs. mesalamine for active CD. Both were equally efficacious for healing active CD. A few observations are appropriate based on the results of the studies available to date. First, there is no evidence that antibiotic therapy is effective for isolated small bowel CD. Second, ciprofloxacin and metronidazole seem to be effective in treating mild-to-moderate CD and should be considered in patients not responding to 5-ASA prior to initiation of cortisone therapy. Third, if antibiotics other than metronidazole are used for CD, the patient should be carefully observed for exacerbation of diarrhea resulting from unmasking of Clostridium difficile colitis. Finally, placebo-controlled multicentered trials with site specific disease are desperately needed to determine if there is a permanent place for the use of antibiotics in treating active CD. There are no well-controlled randomized trials with antibiotics as a primary therapy for UC. Chloroquine and Hydroxychloroquine (Plaquenil) for Ulcerative Colitis Chloroquine and hydroxychloroquine have been used successfully in chronic inflammatory disorders such as systemic lupus erythematosus and rheumatoid arthritis because of their ability to inhibit the processing of antigen by antigen-presenting cells. Furthermore, these drugs have antiinflammatory properties including inhibition of polymorphonuclear leukocyte migration, inhibition of cytokine production by macrophages, and as partial inhibitors of the cycloxygenase pathway. Therefore, these drugs seem to have great potential in treating CD but initial studies with Plaquenil in CD were not successful. In a small pilot study (18 patients) in UC, there was a high response to Plaquenil (26). In a larger study by the same group with 93 patients in a placebo-controlled trial vs. hydroxychloroquine (400 mg/daily), no efficacy was noted in a 4-week period (27), although 15% of patients in the Plaquenil group went into remission. Unfortunately, there were no specific parameters that defined this subpopulation. In the most recent study by Goenka et al., summarized by Mayer (28), a randomized, controlled-blinded trial was performed in 40 patients with mild-to-moderate UC. The majority of patients were newly diagnosed and early in an exacerbation of the disease (<45 days). The patients were randomized to chloroquine phosphate (500 mg/day) or sulfasalazine (3 g/day). In the chloroquine group 60% of the patients had a complete remission (12 patients) and in the sulfasalazine group 55% (11 patients) had a complete remission by 4 weeks. There was no significant difference in the response to the two drugs. There were no significant side effects with chloroquine. In summary, the preliminary data with these drugs indicate a potential for their use in mild-to-moderate, new-onset UC. Multicentered controlled trials will be needed to determine whether they can be used as primary or adjunctive therapy for treating UC. Enteral Nutrition for the Treatment of Crohn's Disease Nutritional support as primary therapy for CD remains unsettled and has never been well accepted as a first line treatment for adults with active CD. However, several controlled trials have demonstrated the benefit of an elemental diet and oligopeptide and polymeric diets. The mechanism(s) by which these diets can induce a remission of CD has not been fully elucidated but several theoretical benefits occur with the ingestion of an elemental diet. These include: (a) bowel rest, (b) reduction of antigenic load to the small bowel, (c) changes in intestinal permeability, (d) the intestinal exposure to trophic amino acids, (e) modification of gut flora, and (f) the provision of calories in the form of simplified protein, carbohydrate, and fat. Elemental diet contains free amino acids, glucose, and short-chain triglycerides. There have been five controlled trials comparing elemental diet vs. corticosteroids for the treatment of active CD (29). In the five studies, a total of 120 patients received either elemental diet or steroids for an average duration of 4 weeks. The remission rate of approximately 80% was similar in each group. There have been four studies with oligopeptide diet as primary therapy for CD (29). Oligopeptide diets (or semielemental) contain a nitrogen source of di- and tripeptides. They have a lower osmolality and taste better than elemental diets. In the largest controlled trial by Lochs et al. (30) with 107 patients, 53% of the oligopeptide group achieved remission vs. 79% in the steroid group. Other smaller studies demonstrated a remission rate similar for steroids and elemental diet (75-80% for oligopeptide diets vs. 84-92% for steroids or elemental diet.) There have been five controlled trials comparing polymeric diets (whole protein diet) vs. elemental diet (4) or steroids (1) as primary therapy (29). Although there were significant differences in these trials, overall polymeric and elemental diets had similar efficacy in inducing a remission in CD (65% for polymeric diet vs. 62% for elemental diet). In the one controlled trial comparing polymeric diet to corticosteroids, there was no difference between the two treatments in remission rates or relapse rate at 1 year (31). However, three meta-analyses of enteral nutrition conclude corticosteroid therapy is better than enteral diets in treating active CD (32,33,34). However, when elemental diet and polymeric diet are compared to corticosteroids, the results are not conclusive. Why don't gastroenterologists in the U.S. use enteral diets more frequently? Primarily because they do not taste very good and reimbursement as a primary medical therapy may be problematic. However, the newer enteral diets are flavored and taste better, and now insurance companies are beginning to pay for enteral diets as primary therapy for chronic inflammatory disease of the gut. In conclusion, enteral diets certainly should be tried as primary therapy for active CD in patients who do not want corticosteroids and those who cannot tolerate the side effects of corticosteroids. Conclusion In this review one can see that there are several rather infrequently used or off-beat therapies that have been submitted to controlled clinical trials. All of these therapies have been demonstrated to have had partial, not outstanding, results in many of these controlled trials. Since there is no one safe, superb therapy for all forms of UC and CD, these various therapies need to be considered as potential beneficial adjunctive or, at times, primary therapy for mild-moderately active IBD. In the roundtable discussion to follow, we will attempt to debate the proper place for these not-often-used therapies. References 1. Lorenz R, Weber PC, Szimnau P. Heldwein W, Strasser T, Loeschke K. Supplementation with n-3 fatty acids from fish oil in chronic inflammatory bowel disease—a randomized, placebo-controlled, double-blind crossover trial. J Intern Med 1989;225(Suppl. 2):225-32. 2. Salmon P, Kornbluth AA, Janowitz HD. Treatment of ulcerative colitis with fish oil n-3-omega-fatty acid: an open trial. J Clin Gastroenterol 1990;12:157-61. 3. Stenson WF, Cort D, Rodgers J, Burakoff R, DeSchryver-Keeskemeti K, Gmamlich T, Beeken W. Dietary supplementation with fish oil in ulcerative colitis. Ann Int Med 1992;116:609-14. 4. Aslan A. Tridafilopoulos G. Fish oil fatty acid supplementation in active ulcerative colitis: a double-blind, placebo-controlled, crossover study. Am J Gastroenterol 1992;87:432-7. 5. Hawthorne AB, Daneshmend TK, Hawkey CJ, et al. Treatment of ulcerative colitis with fish oil supplementation: a prospective 12 month randomised controlled trial. Gut 1992;33:922-8. 6. Belluzzi A. Brignola C, Campieri M, Pera A, Boschi S, Miglioli M. Effect of an enteric-coated fish-oil preparation on relapses in Crohn's disease. N Engl J Med 1996;334:1557-60. 7. Belluzzi A, Brignola C. Belloli C, et al. A new enteric coated preparation of omega-3 fatty acids for preventing postsurgical recurrence in Crohn's disease. Gastroenterology 1997;112:A930. 8. Pullan RD, Rhodes J, et al. Transdermal nicotine for active ulcerative colitis. N Engl J Med 1994; 330;811-15. 9. Sandbom WJ, Tremaine WJ, Offord KP, et al. Transdermal nicotine for mildly to moderately active ulcerative colitis. A randomized, double-blind, placebo-controlled trial. Ann Int Med 1997; 126: 364-71. 10. Thomas GA, Rhodes J, Ragunath K, et al. Transdermal nicotine compared with oral prednisolone therapy for active ulcerative colitis. Eur J Gastroenterol Hepatol 1996;8(8):769-76. 11. Thomas GA, Rhodes J, Mani V, et al. Transdermal nicotine as maintenance therapy for ulcerative colitis. N Engl J Med 1995; 332:988-92. 12. Sandborn WJ, Tremaine WJ, Leighton JA, et al. Nicotine tartrate liquid enemas for mildly to moderately active left-sided ulcerative colitis unresponsive to first-line therapy: a pilot study. Aliment Pharmacol Ther 1997;11:663-71. 13. Green JT, Thomas GA, Rhodes J. et al. Nicotine enemas for active ulcerative colitis—a pilot study. Aliment Pharmacol Ther 1997;11 (5):859-63. 14. Scheppach W, Sommer H, Kirchner T, et al. Effect of butyrate enemas on the colonic mucosa in distal ulcerative colitis. Gastroenterology 1992;103:51-6. 15. Senagore AJ, Mackeigan JM, Scheider M, Ebrom S. Short-chain fatty acid enemas: a cost effective alternative in the treatment of nonspecific proctosigmoiditis. Dis Colon Rectum 1992;35:923-7. 16. Venia P, Marcheggiano A, Caprilli R, et al. Short-chain fatty acid topic treatment in distal ulcerative colitis. Aliment Pharmacol Ther 1995;9:309-13. 17. Steinhart AH, Hiruki T, Brczezinski A, Baker JP. Treatment of left-sided ulcerative colitis with butyrate enemas: a controlled trial. Aliment Pharmacol Ther 1996:10:729-36. 18. Scheppach W, German-Austrian SCFA Study Group. Treatment of distal ulcerative colitis with short-chain fatty acid enemas: a placebo-controlled trial. Dig Dis Sci 1996;41:2254-9. 19. Breuer RI, Soergel KH, Lashner BA, et al. Short-chain fatty acid rectal irrigation for left-sided ulcerative colitis: a randomized, placebo-controlled trial. Gut 1997;40:485-91. 20. Brandt LJ, Bernstein LH, Boley SJ, Frank MS. Metronidazole therapy for perineal Crohn's disease: a follow-up study. Gastroenterology 1982;83:383-7. 21. Ursing B, Alm T. Barany F, et al. A comparative study of metronidazole and sulfasalazine for active Crohn's disease: the cooperative Crohn's disease study in Sweden. Gastroenterology 1982:83:550-62. 22. Ambrose NS, Allan RN, Keighley MR, et al. Antibiotic therapy for treatment in relapse of intestinal Crohn's disease. Dis Colon Rectum 1985;28:81-5. 23. Sutherland LR, Singleton J. Sessions J, et al. Double-blind placebo-controlled trial of metronidazole in Crohn's disease. Gut 1991;32:1071-5. 24. Prantera C, Zannoni F, Scribano ML. et al. An antibiotic regimen for the treatment of active Crohn's disease: a randomized controlled clinical trial of metronidazole plus ciprofloxacin. Am J Gastroenterol 1996;91:328-32. 25. Colombel JF, Lemann M, Cassagnon M, et al., and GETAID. A controlled trial compaing ciprofloxacin with mesalazine for the treatment of active Crohn's disease. Gastroenterology 1997;112: A951. 26. Sachar D. Inflammatory Bowel Disease: Back to the Future. Am J Gastroenterol 1990;85:373-6. 27. Mayer L, et al. Effect of hydroxychloroquine in the treatment of active ulcerative colitis: results of the open label phase of the controlled trial. Gastroenterology 1990;100:A230. 28. Mayer L. What do malaria, rheumatoid arthritis, systemic lupus erythematosus and ulcerative colitis have in common? Inflammatory Bowel Diseases 1997;3:244-5. 29. O'Sullivan MA, O'Morain CA. Nutritional therapy in Crohn's disease. Inflammatory Bowel Diseases 1998;4:45-53. 30. Lochs H. Steinhatdt JH, Klaus-Wentz B, et al. Comparison of enteral nutrition and drug treatment in active Crohn's disease: results of the European Co-operative Crohns Disease Study IV. Gastroenterology 1991;101:881-8. 31. Gonzalez-Huix F, de Leon R, Fernandez-Banares F, et al. Polymeric enteral diets as primary treatment of active Crohn's disease: a prospective steroid-controlled trial. Gut 1993;34:778-82. 32. Fernandez-Banares F, Cabrc E, Esteve M, Gassull MA. How effective is enteral nutrition in inducing clinical remission in active Crohn's disease? A meta-analysis of the randomised controlled trials. J Parenter Enteral Nutr 1995;19:356-64. 33. Griffiths AM, Ohlsson A, Sherman PM, Sutherland LR. Metaanalysis of enteral nutrition as a primary treatment of active Crohn's disease. Gastroenterology 1995;108:1056-67. 34. Messori A, Trallori G, D'Albasio G, et al. Defined-formula diets versus steroids in the treatment of active Crohn's disease: a meta analysis. Stand J Gastroenterol 1996;31:267-72. Questions and Answers Fish Oil in IBD Robert Burakoff: My experience with fish oil has been as a rescue treatment for mild active ulcerative colitis, when patients are intolerant of mesalamine or sulfasalazine and I don't want to administer corticosteroids. William Tremaine: We have not been convinced by the data on fish oil. More and more, in patients who either are intolerant of 5-ASA or don't respond to highdose 5-ASA, we would probably try an immunomodulator such as azathioprine. We often bypass using corticosteroids if the patient has mild symptoms but enough symptoms to warrant additional treatment. Richard MacDermott: Many IBD patients prefer natural products instead of drug therapy. Fish oil offers patients an opportunity to use a natural product that has been shown in clinical trials to be of potential benefit. Daniel Present: For patients who want a natural treatment, fish oil might work, but I would go to an immunomodulator. I might be more inclined to try nicotine patches, which have produced some response. Robert Burakoff: We should note that a number of younger patients do not want to be on immunomodulatory therapy for a long period of time. The effect of fish oil in Crohn's disease patients after ileal resection was studied by Belluzzi and coworkers (Belluzzi A, Brignola C, Campieri M, et al. N Engl J Med 1996;334:1557-60). The remission rate in patients receiving 2.7 g of omega-3 fatty acids was 23/39 (59%), compared with 10/39 (26%) in the placebo group. Could fish oil be an alternative in patients who have mesalamine-associated diarrhea, who cannot tolerate sulfasalazine, or who do not want to be on immunomodulatory therapy? Richard MacDermott: The Belluzzi study used a mixture of fatty acids that we don't have in this country. The reason for rearranging the ratio of the naturally occurring fatty acids in fish oil was to make the product more palatable and easier for patients to take in large amounts. However, I have not seen follow-up studies by either Belluzzi or other groups. Furthermore, 1 am not certain that the results obtained with the mixture used by Belluzzi can be directly extrapolated to the commercial fish oil preparations currently available in this country. Robert Burakoff: I would agree that therapy with fish oil requires much stronger data than are currently available, given that patients have to take a lot of tablets and may potentially experience an upset stomach. The question remains whether the addition of a small dose of eicosapentanoic acid to other therapies such as mesalamine will be beneficial in patients who do not want to go on steroids and are not using immunomodulatory therapy. Daniel Present: The Belluzzi study identified a particular subgroup of patients who were clinically well, yet had abnormal laboratory parameters. This is a unique group. As Dr. MacDermott noted, though, their results have not been confirmed by themselves or by another group. Nicotine William Tremaine: We have two well-designed, placebo-controlled trials demonstrating efficacy of nicotine patches in the treatment of active ulcerative colitis (Sandborn WJ, Tremaine WJ, Offord KP, et al. Ann Intern Med 1997;126:364-71; Thomas GA, Rhodes J, Mani V, et al. N Engl J Med 1995;332:988-92). Who are the patients most likely to benefit from this therapy? In general, we have used nicotine therapy in patients who have had continued symptoms despite 5-ASA products or 5-ASA products plus corticosteroids. We often think of nicotine patches as a therapy to control a flare of symptoms and then to be tapered. After remission, the patient would continue on maintenance therapy with another agent, such as 5-ASA. Nevertheless, some patients have used nicotine for 6-12 months at a time. We have an abstract at the 1998 American Gastroenterologic Association annual meeting about the safety of longer-term use of nicotine (Sandborn WJ, Tremaine WJ, Hart RD. Gastroenterology 1998;114:A1074). Adverse reactions are a limiting factor with nicotine therapy. Nonsmokers often get side effects and even previous smokers can get dermatologic side effects from the patches. To avoid such side effects, nicotine enemas have been used in a couple of trials; they have shown efficacy in left-sided disease. There may be other opportunities for delivery of nicotine that will produce a higher benefit-to-risk ratio, such as with enteric-coated nicotine tablets. Robert Burakoff: Can practicing physicians obtain these nicotine enemas? Can a pharmacist make them? William Tremaine: Nicotine enemas should be reserved for use in clinical trials until we have more information about them. Richard MacDermott: We've used nicotine patches primarily for a subgroup of ulcerative proctosigmoiditis patients who were former smokers and who, after stopping smoking, had a recurrence or exacerbation of their disease. Nicotine patches have been effective in a few of these patients. Patients who were not former smokers have experienced significant side effects, such as headaches, and they've not wanted to continue to take nicotine patches. In my opinion, the issue with nicotine is helping patients with Crohn's disease to stop smoking. It is well established that the one major risk factor for development of Crohn's disease is smoking. Data have shown that stopping a patient from smoking will help prevent postsurgical recurrence of Crohn's disease, help to maintain medically induced remission, and improve the efficacy of the medications Crohn's disease patients are taking. I believe that stopping our Crohn's disease patients and their family members from smoking should be an essential part of our prevention and treatment strategies. Daniel Present: I think that nicotine produces some response, but it's not a great drug thus far in the way it's been used. Hopefully, newer modalities of administration will work. I remind physicians to read papers carefully. For example, in the Thomas study cited, the investigators took all patients off mesalamine. That's an absolutely wrong thing to do, because you're making patients worse before you make them better. This part of the study design clouds the results. If a patient is active on mesalamine, I would like to know whether nicotine would help that patient, because that's the true clinical situation. I'm going to take a radical stance for a certain subgroup of patients with chronic ulcerative colitis: These patients have stopped smoking. They have active disease, and various medications, including steroids, have been tried. They are candidates for a colectomy. What I do is I have these patients resume smoking. In my experience, most have dramatic responses and they go back into remission. Then I'm dealing with a different patient: I'm now trying to maintain them in remission, and hopefully if I can get them on a maintenance regimen, I will have them stop smoking later. I think that smoking for another 6 months is probably less deleterious in terms of morbidity and outcome than performing a colectomy. Robert Burakoff: Unfortunately I find that the reverse is true. Most of my patients figure out that they can resume smoking, even if I tell them not to, and not have to take the patch. They'll see me after an absence of 3-4 months and say, I went back to smoking. I feel fine. It becomes extremely difficult to convince them to stop smoking. So, from a public health point of view, I've avoided encouraging patients to smoke, but there's absolutely no question these individuals have a dramatic response to smoking. Short-Chain Fatty Acids in IBD William Tremaine: I think that short-chain fatty acids (SCFA) work well in diversion colitis. There are intriguing, small, uncontrolled trials suggesting benefit in inflammatory bowel disease, but I'm convinced by Richard Breuer's most recent study that it just doesn't work in ulcerative colitis. We do not use it as part of our treatment for ulcerative colitis or IBD. Richard MacDermott: The data with SCFA or butyrate enemas in diversion colitis are impressive. The data with SCFA or butyrate enemas in ulcerative colitis are not as impressive and we have much better enemas to use, such as Cortenema and Rowasa. We should recognize, however, that butyrate in and of itself has very important effects on intestinal epithelial cell function. Butyrate is a product of bacteria as they metabolize food products into SCFA. Switching from a full diet to enteral alimentation may lead to a decrease in butyrate concentrations in the small bowel, which in turn may downregulate mucosal enterocyte as well as lamina propria granulocyte and macrophage production of chemokines and proinflammatory cytokines. Daniel Present: Butyrate is the fuel source of the colonocyte, and ulcerative colitis is considered by some to be a disease of starvation of butyrate. When patients with severe colitis enter the hospital, are made NPO, and placed on total parenteral nutrition for long periods of time, not only are there no controlled data to suggest that this improves them in any way, it may even make them worse by denying them the butyrate they require. In this situation I always feed patients with ulcerative colitis who are ill in the hospital; however, I have no experience with the topical medicine. Robert Burakoff: The reasonably sized randomized trial by Richard Breuer did not show a significant response. The issue would be whether a subgroup of patients might benefit from this therapy. From a practical point of view, patients with fairly resistant proctitis or left-sided colitis who do not respond to other medications might be candidates for SCFA. However, we have been unable to get pharmacies to make this malodorous solution. Antibiotics for Crohn's Disease Robert Burakoff: What is the role of antibiotics in the treatment of Crohn's disease? Does site of disease matter? How long should we treat patients with antibiotics? When do we taper the dosage and how do we use it in combination? William Tremaine: We don't have documented benefit of antibiotics in ulcerative colitis, nor are there placebocontrolled trials that show the efficacy of metronidazole or any other antibiotic in Crohn's disease, but it's been our clinical experience that in some patients metronidazole can be helpful. Benefit with metronidazole often takes up to 6-8 weeks if we're treating perianal disease. Studies by Ursing and the Scandinavian Cooperative Crohn's Disease Study group (Ursing B, Alm T, Barany F, et al. Gastroenterology 1982;83:550-62) showed equivalent benefits with sulfasalazine over 4 months, with greater benefit in those unresponsive to sulfasalazine. In general, metronidazole can be used as we might use sulfasalazine, particularly in a sulfasalazineintolerant patient with Crohn's disease. After a patient has responded, my goal is dose reduction to avoid toxicity. Doses of 250 mg twice daily and sometimes once daily are sufficient to maintain benefit and to avoid symptoms of peripheral neuropathy. Some patients have taken low-dose metronidazole for longer than 12 months, with apparent continued benefit and no toxicity. We have even less data that ciprofloxacin is beneficial. Metronidazole has the advantages of being generic and inexpensive, while ciprofloxacin is extremely expensive. I' m less enthusiastic about using ciprofloxacin if metronidazole works. For the patient who does not tolerate metronidazole, ciprofloxacin is worth a try, but the scientific basis for this is not strong. Richard MacDermott: The traditional way of using antibiotics is to identify a bacterium that is pathogenic, treat with specific antibiotics, and then demonstrate eradication of the bacterium. In contrast, in patients with Crohn's disease, we're using antibiotics without demonstration of a specific pathogen. We need to carefully define the patient subgroups for whom antibiotics are appropriate. Well-described indications for the use of antibiotics in Crohn's disease include perirectal disease, fistulas, and abscesses. The use of antibiotics is more controversial in active Crohn's disease patients who are on steroids but are steroid refractory or steroid dependent. In these patients, I give a trial therapy lasting 1-2 months using either metronidazole or ciprofloxacin in low doses. If there is no response after 4-8 weeks of single-agent treatment, I give a 1- to 2-month trial therapy with the other antibiotic. If patients have moderately severe disease, I use ciprofloxacin and metronidazole in combination. If an antibiotic helps to improve symptoms, I try to see if the steroid dose can be gradually lowered. I also try to see if the patient can be switched to a medication that will maintain better control of their Crohn's disease over the long term, such as 6-mercaptopurine (6-MP) or azathioprine. Low-dose ciprofloxacin and/or metronidazole in combination with 6-MP or azathioprine and/or an oral 5-ASA product are important long-term treatment options necessary to help keep our Crohn's disease patients off steroids. Daniel Present: I would agree that low-dose metronidazole is a very effective drug without much toxicity, and I have no reservations about long-term therapy with metronidazole, being alert to the possibility of peripheral neuropathy. I use antibiotics as first-line therapy for Crohn's activity with mild to moderate flareups, especially with fistula. In lieu of steroids, I prefer antibiotics, which work with less efficacy but much less toxicity. In the initial studies by Moss (Moss AA, Carbone JV, Kressel HY. Am J Roentgenol 1978;131:787-90), less expensive antibiotics such as ampicillin or cephalosporins seemed to work. A subset of patients do respond to these antibiotics, and I try and identify them early in the course of the disease. As for efficacy in ulcerative colitis, Mark Peppercorn has written anecdotally of a dramatic response to ciprofloxacin in seven patients. I have also observed this response, and wonder whether these are really Crohn's patients who have not been diagnosed appropriately. For patients with fulminant colitis, I think there is a role, prior to colectomy, for a short trial of ciprofloxacin. But we need so much more data in this area! Robert Burakoff: It's easy to use these drugs on a short-term basis and assess whether patients get better, but what do we do long term? Are these drugs to be taken for 3 or 6 months or a year? These questions haven't been answered yet. Until multicenter trials are conducted, we really won't know if we're treating specific patients appropriately. Chloroquine and Hydroxychloroquine for Ulcerative Colitis William Tremaine: The number of patients in the Goenka study (Goenka MK, Kochhar R, Tandia B, Mehta SK. Am J Gastroenterol 1996;91:917-21) was small, but I'm struck by the new-onset patients in whom the sulfasalazine response was modest. Based on the results of most trials, we'd expect a higher remission rate than the 55% reported. These data need to be confirmed. I think practicing gastroenterologists should not be using chloroquine until additional trials have shown benefit. Daniel Present: Having been involved in the original trial in New York, I can provide some unpublished information. After we were well into the study, experts in the use of hydroxychloroquine (Plaquenil) for rheumatoid arthritis told us that the dose we used was too low. Upon completion of the study, we added higher doses of hydroxychloroquine to nonresponders, and we saw further responses with dosages of 600-800 mg/day. Clinicians in practice should not be using this drug, but I think that a study using a higher dose of hydroxychloroquine is indicated to determine whether this drug works. I have a few patients—perhaps 10 in all—who are maintained on hydroxychloroquine in complete remission, and attempts at withdrawal have resulted in exacerbation. Ophthalmologic adverse reactions have not been a problem, although we do refer patients to an ophthalmologist every 3-4 months. One patient developed myocarditis, which I was not aware of as an adverse reaction, but there are several cases in the literature. Robert Burakoff: We too have used hydroxychloroquine at lower doses in several patients with ulcerative colitis and found no response. From an immunologic point of view, hydroxychloroquine has been a reasonable adjunctive therapy for rheumatoid arthritis. Maybe we should be evaluating hydroxychloroquine as a potential adjunctive treatment with 5-ASA drugs. Enteral Nutrition for Crohn's Disease Robert Burakoff: If we assume a reasonable degree of tolerability and compliance, is elemental diet an alternative for patients with active Crohn's disease? With the flavor packs now available, I feel patients will accept elemental or semielemental diets. A number of patients will go into remission after taking 2 weeks of elemental diet for exacerbation of disease. As of 1997, reimbursement for nutritional therapy has been approved in New York State for chronic inflammatory diseases. In my opinion, elemental and semielemental diets are alternative therapies for patients with exacerbation of small-bowel Crohn's disease who do not respond to 5-ASA therapy and do not want to be or shouldn't be on steroids. William Tremaine: We view elemental diets as not having a role in the management of ulcerative colitis. For Crohn's disease, elemental diets make good sense and are an important part of therapy for the malnourished adult and for children to prevent growth failure. Use in other patient groups is problematic because of the expense. In the Midwest, nutritional therapy is not covered by insurance; 1 month of nutritional therapy is a much higher-priced treatment path than alternative approaches. In most U.S. studies, compliance has been a problem. Thus, for most adult patients, we are convinced by the data that there's no added benefit to elemental diets. Richard MacDermott: The initial studies with elemental diets were conducted in children with severe Crohn's disease. For many of these children, the elemental diets were important not only for inducing remission but also for reversing growth retardation. In adult patients with Crohn's disease who are malnourished and have multiple nutritional deficiencies, elemental diets have been very helpful. An intriguing question is how elemental diets induce clinical remission in a patient with Crohn's disease. Our understanding of the role of nutritional factors in modulating the mucosal immune system and intestinal inflammation is limited. As we learn more about how bacteria metabolize food to not only SCFA but other products as well, we may better understand some of the initiating and perpetuating factors in Crohn's disease that are related to dietary factors. Daniel Present: A recent survey reported that about 50% of patients with inflammatory bowel disease are now seeking alternative therapies. 1 think alternative therapies are successful because of the enthusiasm of the people practicing it, not because of any positive data. If there were as much enthusiasm for elemental diets, we'd have many patients who would fare better and be off steroids. But enthusiasm for elemental diets, at least for me, is difficult to generate. To use this treatment modality, one has to spend a lot of time, energy, and money. When the result is diminished compliance, as it often is, the overall experience can be frustrating. Perhaps having access to some centers dedicated to this modality is the best answer for those who want to try it. Robert Burakoff: There are patients for whom the taste of an elemental diet is not a problem and compliance is not an issue. In this small subset of patients, elemental diets are appropriate. However, the cost of enteric nutritional treatment averages $500-$1,000 a month, if we consider an adequate number of calories for the averagesized adult. Clearly, elemental diets should not be used in unenthusiastic patients because compliance will affect the outcome. Concluding Remarks Robert Burakoff: I think the clinical network of the Crohn's & Colitis Foundation of America will play a major role in answering many of these questions that have arisen concerning the best treatment for our patients. If the network's efforts are successful, when we meet in a few years, we should have some answers so that practicing gastroenterologists can better help their patients. Hans Fromm: I'd like to thank the panel for the excellent discussions. These sessions have helped us to focus on the issues that are really of interest to the practicing physician. © 1998 Crohn's & Colitis Foundation of America, Inc.
TI - Less Commonly Used Therapies for IBD or Treatments on the Fringe
JF - Inflammatory Bowel Diseases
DO - 10.1097/00054725-199811000-00009
DA - 1998-11-01
UR - https://www.deepdyve.com/lp/oxford-university-press/less-commonly-used-therapies-for-ibd-or-treatments-on-the-fringe-apsD1i66g0
SP - 308
EP - 317
VL - 4
IS - 4
DP - DeepDyve
ER -