REVIEW

Advances in Drug Therapy for Inflammatory Bowel Disease Mark A. Peppercorn, M D

Purpose: To identify advances in drug therapy for inflammatory bowel disease, and to evaluate the effectiveness of the new agents in treating both ulcerative colitis and Crohn disease. Data Identification: Studies published from January 1980 through June 1989 were identified using MEDLINE and through extensive hand searching of bibliographies in identified articles. Study Selection: One hundred and ten articles directly related to the topic were found and analyzed. Another 42 articles were relevant to the material reviewed. Data Extraction: Articles were selected on the basis of study quality and their significance with regard to treatment of inflammatory bowel disease. Results of Data Analysis: The aminosalicylates are emerging as effective and safe therapy for inflammatory bowel disease. Corticotropin can be considered the drug of choice for certain patients with severe ulcerative colitis, and new rapidly metabolized topical steroids appear to be as effective as traditional forms and have fewer side effects. Immunosuppressive agents, including 6-mercaptopurine and azathioprine, may be useful in treating difficult-to-manage patients with either Crohn disease or ulcerative colitis, whereas cyclosporin appears promising but should be reserved for patients in whom other measures have failed. Patients with refractory perineal Crohn disease and those with Crohn colitis may benefit from metronidazole. Many other drugs including clonidine, cromoglycate, chloroquine, fish oil, methotrexate, antituberculous agents, interferon, and superoxide dismutase have shown enough promise in preliminary studies to warrant controlled clinical trials. Conclusions: Drug therapy for inflammatory bowel disease, limited for many years to sulfasalazine and some corticosteroids, has been extended to include the aminosalicylates, rapidly metabolized topical steroids, immunosuppressive agents, and metronidazole. Potentially useful newer drugs await further study.

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. F o r many years the drug therapy for inflammatory bowel disease was limited to sulfasalazine and either topical or systemic corticosteroids. Recently, immunosuppressive agents and metronidazole have assumed important roles in the treatment of Crohn disease, and corticotropin has been established as a key drug for treating certain critically ill patients with ulcerative colitis. Now the aminosalicylates are emerging as a treatment for both ulcerative colitis and Crohn disease, and new rapidly metabolized topical steroids may replace standard forms for treatment of distal colitis. Moreover, preliminary studies suggest the potential value of many additional unrelated drugs, any one of which may emerge as safe and efficacious for patients with inflammatory bowel disease. This review summarizes our current understanding of the new drugs being used in the treatment of patients with inflammatory bowel disease and updates the status of those drugs currently under further investigation. The Aminosalicylates In the late 1930s, Dr. Nana Svartz, a Scandinavian rheumatologist, was instrumental in developing sulfasalazine for the treatment of rheumatoid arthritis. Known to respond to aspirin, rheumatoid arthritis was thought to be of bacterial origin. It seemed sensible, therefore, to develop an agent that combined one of the first sulfonamides, sulfapyridine, with an aspirin analog, 5-aminosalicylate (5-ASA). Sulfasalazine proved to be reasonably efficacious in treating rheumatologic disorders. However^ when Svartz tried the drug in a group of patients with colitis, the results were even more impressive ( 1 ) . In the ensuing years, sulfasalazine became the most widely prescribed drug for patients with inflammatory bowel disease. Clinical trials have established its usefulness in treating patients with active ulcerative colitis and Crohn colitis and its important role in maintaining remissions in patients with ulcerative colitis (2-17). Despite its widespread acceptance, the usefulness of sulfasalazine has been limited by a high degree of intolerance and the frequent occurrence of adverse reactions (18-20). Information about the side effects of sulfasalazine, coupled with insight into the pharmacology of the drug, has led to the development of a new generation of agents based on the structure of sulfasalazine, the aminosalicylates. Sulfasalazine is partially absorbed intact in the proximal jejunum, and a small fraction of this absorbed portion is excreted unchanged in the urine. The remaining absorbed portion is returned to

the intestine unchanged in the bile where, with the unabsorbed drug, it traverses the intestine intact until it encounters bacterial flora in the distal ileum and colon (21, 22). The intestinal bacteria in these areas initiate the first step in the metabolism of sulfasalazine, cleaving the azo-bond that joins the sulfapyridine and 5-ASA moieties (23-25). The sulfa portion is largely absorbed and after achieving high blood levels is metabolized by the liver and excreted in the urine. Most of the intolerance associated with sulfasalazine can be attributed to serum sulfapyridine levels, whereas the allergic reactions seen are similar to those described with other sulfonamides (18). In contrast, the 5-ASA portion is largely unabsorbed and remains in contact with the colonic mucosa until it is excreted in the stool. If either sulfapyridine or 5-ASA is ingested separately, each is absorbed in the proximal small bowel, metabolized by the liver, and excreted in the urine; thus, they never achieve sufficient levels in the distal intestine (26). The metabolism and distribution studies suggested that the parent drug, sulfasalazine, may merely be a vehicle for delivery of the active component, 5-ASA, to distal disease sites. If the sulfa moiety is responsible for the toxicity of the drug, and the 5-ASA moiety for its therapeutic efficacy, then why not develop ways of delivering 5-ASA itself to areas of diseased bowel? Topical Agents Azad Khan and colleagues (27) seized on the pharmacologic observations and were the first to administer 5-ASA in enema form directly to patients with ulcerative colitis. They compared 5-ASA enemas (700 mg in 100 mL of saline) with sulfapyridine and sulfasalazine enemas and found that patients receiving either the 5-ASA or sulfasalazine enemas showed a 75% clinical and sigmoidoscopic improvement, compared with a 35% response rate in the sulfapyridine group. Campieri and colleagues (28, 29) have reported their results with 5-ASA enemas in doses ranging from 2 to 4 g. They achieved a clinical remission or improvement in 90% of nearly 150 patients and found the 5-ASA enema at the 4-g dosage to be superior to hydrocortisone enemas. Four additional controlled trials (30-33) have documented the efficacy of 5-ASA enemas in dosages ranging from 1 to 4 g in patients with distal ulcerative colitis. Suppository forms of 5-ASA have also proved to be effective for patients with ulcerative proctitis. The easy application of suppositories allows for the administration of several daily doses, and their formulation in a wax matrix has the advantage of stability and allows the topical delivery of high doses that remain localized in the most distal bowel. Several controlled trials (3437) have shown the effectiveness of 5-ASA suppositories in doses of 200 mg to 1 g given two to three times daily in patients with active proctitis or distal colitis. Whereas 5-ASA in suppository form is very stable, stability of the drug was problematic in enema formulations. Although these difficulties have largely been overcome, the initial problems with stability led to the

development of enemas using 4-aminosalicylate (4A S A ) , an isomer of 5-ASA that proved to be more stable in a saline solution. Several trials (38-41) have shown that 4-ASA enemas are as effective in treating distal ulcerative colitis as 5-ASA enemas and are superior to placebo. Because the early placebo-controlled trials of topical aminosalicylate preparations were most attractive to patients with distal colitis unresponsive to accepted therapies, many of the patients studied actually had refractory disease, not new-onset colitis. It has been gratifying to realize that up to 75% of such patients improve or go into remission when receiving topical 5ASA, although the response time may be months rather than days or weeks (42-46). Earlier studies of the role of sulfasalazine in maintaining remission showed that patients with ulcerative colitis did well on maintenance drug but could be expected to flare when therapy was discontinued. This experience has been duplicated in studies (47) of topical 5-ASA: Relapse rates approach 100% when therapy is discontinued for patients brought into remission on topical 5-ASA. Fortunately, topical 5-ASA therapy in both the enema and suppository forms appears to be very effective as a prophylactic agent for patients with distal colitis. Biddle and colleagues (48) showed that 1-g 5-ASA enemas given for a 12-month period to patients with left-sided colitis in remission kept 9 of 12 patients clinically free of disease, whereas 11 of the 13 patients who received placebo had a clinical recurrence. Oral Agents Although clearly useful in active and remitted distal ulcerative colitis and proctitis, topical 5-ASA preparations reach, at best, only the splenic flexure and therefore cannot be relied on for treating patients with ulcerative colitis proximal to the sigmoid colon or those with Crohn disease of the small bowel and the ascending and transverse colons (49). Moreover, for longterm prophylaxis, oral forms of therapy are preferable to enemas or suppositories. These findings have spurred interest in developing oral aminosalicylates that can be delivered to the distal small intestine and colon. Three forms of oral 5-ASA have been developed and studied clinically. Delayed-release forms coat 5ASA with an acrylic-based resin that dissolves at pH greater than 6, delivering the 5-ASA to the distal ileum and colon. A slow-release form encapsulates 5ASA in microspheres of ethylcellulose and gradually dissolves in the small intestine, also delivering the free 5-ASA to the distal intestine. In the United States, both free topical and oral forms of 5-ASA carry the generic name mesalamine, but the same agents are referred to as mesalazine in Europe. A second formulation, olsalazine, links 5-ASA to itself by an azo-bond that, as in sulfasalazine, requires bacterial cleavage for the release of free 5-ASA. The third form, balsalazide, joins 5-ASA to an unabsorbed inert vehicle, again by an azo-bond (50-54).

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In several controlled trials various controlled-release forms of 5-ASA, as well as the olsalazine formulation, have been efficacious in patients with mild to moderately active ulcerative colitis, compared with sulfasalazine or placebo. In a study (55) that compared one of the acrylic-coated forms of 5-ASA with sulfasalazine, 8 6 % of patients with active ulcerative colitis improved in both groups by 8 weeks, but 6 0 % of the group receiving 5-ASA had an endoscopic remission, compared with 5 3 % of the group receiving sulfasalazine. Other studies of slow-release agents confirm these findings, although response appears to be related to the dosage of drug administered (56). Similar dose-response results have been reported with olsalazine, which has been effective at 2 and 3 g daily but has not been consistently effective at lower doses (57, 58). Fortunately, oral 5-ASA agents appear to be as effective prophylactically for ulcerative colitis as topical 5-ASA and sulfasalazine. Several studies (59-61) have established that relapse rates during 6 to 12 months of therapy with slow-release forms of 5-ASA and olsalazine are similar to those for sulfasalazine and better than those for placebo. Studies (62, 63) of oral 5-ASA in patients with Crohn disease have lagged somewhat behind those in patients with ulcerative colitis. Nevertheless, the emerging data have been promising. There is much hope that at least one of the slow-release forms of 5ASA will be effective in treating Crohn disease of the ileum, where sulfasalazine has been of less benefit. In one study (64) comparing a delayed-release preparation with sulfasalazine, the Crohn disease activity index and sedimentation rate fell to similar levels in both groups, and 8 7 % of patients receiving 5-ASA improved compared with 8 0 % of those receiving sulfasalazine. Several open trials have suggested the efficacy of 5-ASA in treating patients with Crohn disease who are resistant to other forms of therapy, but results from further controlled trials now in progress are awaited. One of the mysteries and disappointments of therapy for inflammatory bowel disease has been the inability of sulfasalazine to show efficacy in maintaining remission in patients with Crohn disease, which is surprising given its demonstrated usefulness in remitted ulcerative colitis (65). Thus far, results that are very preliminary suggest that oral 5-ASA may be no better than sulfasalazine for maintaining remission in patients with Crohn disease. Adverse Effects Eliminating the sulfa moiety has resulted in the desired improved tolerance of patients to the aminosalicylate agents as compared with sulfasalazine. The adverse effects of topical 5-ASA in a large trial were fewer than those seen with placebo (32). Hair loss reported in early studies has not been verified in subsequent ones (66). Several patients, however, have had an exacerbation of colitis while receiving topical 5ASA, which may in some cases be related to a sensitivity to the sulfites contained as preservatives in the ene52

mas (67, 68). Patients allergic to aspirin should avoid 5-ASA. The most frequent complaint, although still an uncommon problem, is that of anal irritation or anal pruritus. Although more adverse effects have been reported with oral 5-ASA than with topical therapy, these side effects have been infrequent and fewer than those described with sulfasalazine. Nevertheless, both perimyocarditis and pancreatitis associated with 5-ASA have recently been reported (69-71). The most frequent and disturbing side effect has been watery diarrhea, which has been reported in 15% to 3 5 % of patients on olsalazine (57). The incidence of watery diarrhea depends on the dose of drug and the extent of the colitis. Patients with universal colitis appear especially susceptible, probably because of the decreased water absorption by the right colon characteristic of such patients. Lowering the dose of olsalazine may eliminate the diarrhea, which appears to result from ileal secretion related to anion secretagogue properties of olsalazine (72). Overall, 8 0 % to 9 0 % of patients intolerant or allergic to sulfasalazine are able to tolerate 5-ASA (73). However, 10% to 2 0 % of patients will experience a reaction to 5-ASA identical to that experienced while receiving sulfasalazine, which clearly implicates the 5-ASA moiety and not the sulfa portion as the offending agent in such cases. Care must therefore be taken in placing any patient allergic to sulfasalazine on a 5-ASA agent. Mechanism of Action Research of 5-ASA has led to a new understanding of the mode of action of sulfasalazine and 5-ASA and may provide insights into the pathogenesis of inflammatory bowel disease itself. Initial enthusiasm for the hypothesis that 5-ASA worked by interrupting the cyclooxygenase pathway of arachidonic acid metabolism has waned because of evidence that more potent prostaglandin synthesis inhibitors may exacerbate inflammatory bowel disease despite lowering local prostaglandin levels (74). Attention has turned instead to the alternate pathway of arachidonic acid metabolism that generates chemotactically active substances such as leukotrienes. 5-Aminosalicylate (as well as sulfasalazine) acts as an inhibitor of the initial enzyme in this pathway, lipoxygenase, and results in the lowering of leukotriene levels in patients with inflammatory bowel disease (75, 76). Controlled studies on specific inhibitors of lipoxygenase are needed to see whether the lowering of leukotriene levels correlates with clinical improvement. 5-Aminosalicylate may also act as a scavenger of oxygen-derived free radicals known to be toxic to cells (77) and as a possible inhibitor of antibodies that might be directed at colonic antigens and thus may promote intestinal cell disruption (78). Recommendations for Therapy Both oral and topical forms of 5-ASA have been commercially available in Europe for several years. Although not yet available in the United States, it is an-

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ticipated that one or more of the oral forms of 5-ASA will be approved for distribution. The ultimate role for the oral agents is not clear, although at the very least they should be useful therapeutic alternatives for the patient intolerant or allergic to sulfasalazine. The controlled-release forms, by achieving high levels in the distal ileum, may be especially useful in treating patients with Crohn disease of the small intestine. Topical 5-ASA enemas have been available in the United States since early 1988, and it is likely that the suppository form of 5-ASA and topical forms of 4ASA will soon be approved. Based on efficacy and safety studies, 5-ASA is an attractive treatment choice for all patients with distal colitis, but not all physicians will be eager to use the drug as the initial agent of choice for such patients. Both sulfasalazine and topical steroids have excellent previous records. Moreover, the cost of a course of therapy with topical 5-ASA is prohibitive for some patients, being at least twice the cost of currently available hydrocortisone enemas and many times that of sulfasalazine itself. When used, it is appropriate to give the enema every night until a clinical and sigmoidoscopic remission is achieved; the patient should then be maintained on an every-othernight or every-third-night regimen. Some patients will flare as the enemas are tapered and will require more frequent dosage to sustain a remission. The optimal dosage schedule for remission and the required doses needed to induce remission are subjects of current controlled trials. Other questions regarding the use of 5ASA remain. For example: Is there an adjunctive role for sulfasalazine and oral aminosalicylates with topical 5-ASA preparations? Can patients who achieve remission on topical 5-ASA be maintained as easily on oral agents as on continued topical therapy? Will oral 5ASA emerge as successful and safe as topical 5-ASA for patients with distal ulcerative colitis? Corticosteroids Corticotropin Corticosteroids have been mainstays of therapy for patients with inflammatory bowel disease since their introduction to clinical medicine in the mid-1940s (79-81). Topical corticosteroids have proved to be effective for patients with distal colitis, whereas oral prednisone is active against mild to moderate active ulcerative colitis and Crohn disease. These agents have not proved to be useful as maintenance therapy for disease in remission. It was recognized early on that parenteral corticoids could be life-saving in a patient with fulminant colitis. Standard corticosteroids, such as hydrocortisone and prednisolone, as well as corticotropin ( A C T H ) , have been used, but there has been controversy about the comparative effectiveness of these agents (82-85). A recent study by Meyers and colleagues (86) set out to correct some problems with the designs of earlier investigations. The study was restricted to patients with severe ulcerative colitis for uniformity, specific clinical criteria of disease activity for eligibility were established, both A C T H and hy-

drocortisone were administered intravenously over 24 hours, and an attempt was made to study a large group of patients. The investigators studied 66 patients. Overall, results were similar, with 14 of the 34 patients receiving hydrocortisone ( 4 1 % ) and 14 of the 32 patients receiving A C T H ( 4 4 % ) achieving remission. However, in those patients not receiving steroid therapy in the 30 days before admission A C T H was clearly superior to hydrocortisone; 6 of 8 ( 7 5 % ) patients receiving A C T H achieved remission compared with 2 of 9 ( 2 2 % ) patients receiving hydrocortisone. Conversely, in those patients who were receiving steroids before admission, hydrocortisone was more effective in inducing remission; 5 3 % of such patients achieved remission compared with 2 5 % of patients receiving A C T H . Despite attempts to achieve a large sample size, the investigators were able to study only a limited number of patients not previously receiving steroids. Nonetheless, they make a convincing argument for using A C T H in such patients. New Topical Corticosteroids As indicated, topical corticosteroids are widely used and clearly effective for patients with distal colitis (8790). Their long-term use, however, may be associated with the same chronic side effects seen with systemic corticosteroids. Considerable excitement, therefore, has been generated by studies of newer preparations that appear to possess the same anti-inflammatory action and clinical efficacy as conventional forms but are free of the adverse effects seen with the standard enemas. The absence of toxicity of these newer topical agents relates to their mode of metabolism. They undergo extensive first-pass metabolism in the blood by erythrocytes and in the liver, resulting in metabolites with little or no biologic activity. Previously used as an inhalant for asthma patients, beclomethasone dipropionate in enema form has been compared with prednisolone enemas in a double-blind, randomized controlled study of patients with distal ulcerative colitis. N o difference in the clinical sigmoidoscopic or histologic outcome was noted between the two drugs, but only the beclomethasone failed to affect fasting Cortisol levels (91). Other studies (92) have also shown the anti-inflammatory effects of beclomethasone in patients with distal colitis without producing hypothalamic-pituitary-adrenal suppression. Budesonide, like beclomethasone dipropionate, is topically active and undergoes extensive first-pass hepatic metabolism. In a study (93) of patients with active distal ulcerative colitis, budesonide proved to be superior to prednisolone enemas in all parameters examined. Endogenous Cortisol levels were significantly depressed in the prednisolone-treated patients but not in those receiving budesonide. Tixocortol pivalate is a nonglucocorticoid, nonmineralocorticoid derivative of Cortisol in which a 21-thiol group esterified with pivalic acid replaces a 21-hydroxyl group on ring D. Because of the rapid transformation of the rectally administered compound first within erythrocytes and then by the liver, the compound is

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devoid of systemic activity. Its anti-inflammatory activity when topically administered is its only steroidrelated property, and its local anti-inflammatory potency is equal to or greater than that of hydrocortisone. Although topical and oral forms of the drug have been tested in France for several years, tixocortol pivalate has only recently been studied in the United States. An initial multicenter trial compared the efficacy and safety of topical tixocortol pivalate and hydrocortisone in 108 patients with active distal ulcerative colitis. After 3 weeks, 5 0 % of tixocortol-treated patients and 4 0 % of the hydrocortisone group were in remission. Nausea, fluid retention, and effects on hematologic parameters were noted with hydrocortisone but not with tixocortol, but a few patients had anal irritation while receiving the latter drug. In a similar 3-week study (94) of patients with distal ulcerative colitis, tixocortol pivalate enemas were as effective as hydrocortisone enemas, and no detrimental effects on Cortisol levels or on the pituitary-adrenal function were observed in the tixocortol group. Finally, in an open trial (95) of the drug in patients with refractory distal colitis, a striking clinical and sigmoidoscope improvement was noted in those who were treated with nightly tixocortol enemas for 2 to 4 weeks; there were no adverse effects. Recommendations for Therapy For patients with new-onset severe or fulminant ulcerative colitis or similar patients not receiving recent steroid therapy, high-dose intravenous A C T H given continuously at 120 units per 24 hours is the drug of choice. Conversely, for such patients already receiving steroids, the treatment of choice is a conventional corticosteroid (for example, hydrocortisone or prednisolone) given in high doses parenterally (300 mg or 60 mg per 24 hours, respectively). There is no clinical evidence to support switching from one form of therapy to another. None of the newer topical steroid preparations is yet available in the United States. If ongoing placebo-controlled trials verify the efficacy of these agents, and long-term studies continue to show no significant adverse side effects, then one or more of these agents will probably replace the standard corticosteroid forms currently being used. Immunosuppressive Agents Azathioprine and 6-Mercaptopurine Early enthusiasm in the 1960s for using azathioprine and 6-mercaptopurine in treating inflammatory bowel disease diminished when placebo-controlled trials yielded conflicting results and failed to show convincing efficacy for the drugs when used individually (7, 96-102). Present and colleagues (103), encouraged by their results in individual patients, designed a doubleblind, controlled crossover trial of 6-mercaptopurine in patients with Crohn disease which differed in funda54

mental ways from the earlier trials. First, specific therapeutic goals were defined for each patient. Second, other drugs being taken by the patient before the study were not withdrawn, eliminating the deterioration often seen in trials in which steroid therapy for patients already ill was tapered before entry. And finally, the study was carried out for 2 years, thus distinguishing it from the short-term studies previously reported. Their results were impressive and have served as a cornerstone for the increasing use of 6-mercaptopurine as well as of azathioprine in treating Crohn disease in the past few years. Of the patients receiving 6-mercaptopurine, 6 7 % improved, compared with 8% receiving placebo. The 6-mercaptopurine allowed steroid discontinuation in 5 5 % of those patients receiving steroids at the start of the study and a reduction in dosage in another 2 0 % . This steroid-sparing property of immunosuppressive agents had been shown earlier both in patients with ulcerative colitis and in those with Crohn disease (99, 102). Moreover, 6 5 % of patients with fistula showed a favorable response to 6mercaptopurine (104). It was notable that the mean time to respond to the drug was 3.1 months, and several patients took up to 9 months to achieve the desired effect. Neither sulfasalazine nor corticosteroids are effective in maintaining remission in patients with Crohn disease. Both azathioprine and 6-mercaptopurine, in contrast, appear to be effective prophylactic agents in patients with Crohn disease who achieve remission with some therapy (105-107). These agents, when continued over at least a 1-year period, keep 8 0 % to 9 0 % of patients in remission, whereas the flare rate once immunosuppressive therapy is tapered and discontinued approaches 8 0 % in 1 year. In addition to their role in the treatment of patients with Crohn disease who are difficult to manage, immunosuppressive drugs may be beneficial for certain patients with ulcerative colitis (108). In a recently reported group of patients with ulcerative colitis refractory to steroids or sulfasalazine, or both, 25 of 34 patients ( 7 3 % ) responded to a course of therapy with 6-mercaptopurine, with diminution of the steroid dosage in 22 ( 6 8 % ) of the patients (109). Concern about potential adverse effects of the immunosuppressive agents has made many clinicians wary of using them. The development of lymphoma in patients who have had a renal transplant and the occurrence of life-threatening neutropenia in patients with hematologic malignancies and rheumatoid arthritis have been particular concerns (110, 111). A study (112) of the short- and long-term side effects of 6mercaptopurine in 396 patients with inflammatory bowel disease has done much to allay the anxieties provoked by toxicity concerns. Bone marrow depression occurred in only 2 % of patients, with no mortality, and appeared to be dose-related. The increasing use of these agents in lower doses appears to avoid leukopenia except in rare circumstances. Only one case of malignancy (cerebral lymphoma) could be attributed to the use of 6-mercaptopurine. Other adverse effects included pancreatitis in 3 . 3 % of patients and allergic

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reactions with fever and rash in 2 % ; hepatitis was seen in only one patient. The overall toxicity was 7.6%, with full reversal of those reactions that were thought to be either dose-related or allergic. Despite an apparently good safety profile, patients must be monitored closely with frequent blood counts and careful, thorough follow-up. Cyclosporine Cyclosporine, a suppressor of cell-mediated immunity, has had great success in patients undergoing organ transplantation. In addition, patients with various "autoimmune" disorders seem to respond to the drug. Limited studies in patients with inflammatory bowel disease suggest that the drug may have a role in treating selected patients. In an open trial (113) of patients with refractory Crohn disease, 10 of 15 patients improved while receiving cyclosporine, with a sustained benefit seen in 7 patients. The results of other open trials (114-116) involving a small number of patients with both ulcerative colitis and Crohn disease were encouraging enough to warrant a placebo-controlled trial. In this study (117) 22 of 37 patients ( 5 9 % ) treated with cyclosporine improved during a 3-month period compared with 11 of 34 patients ( 3 2 % ) receiving placebo. The improvement was maintained in 3 8 % of patients as the cyclosporine was tapered over the following 3 months. Although the relatively quick onset of action of cyclosporine makes it an attractive alternative to 6-mercaptopurine and azathioprine, the high incidence of side effects associated with the drug in other clinical settings may limit its use in patients with inflammatory bowel disease. Recommendations for Therapy Azathioprine or 6-mercaptopurine should be considered in the patient with Crohn disease refractory to therapy with other agents, such as sulfasalazine, corticosteroids, and metronidazole. Azathioprine and 6mercaptopurine may be especially useful in treating patients with fistulas, those who are steroid-dependent, and those who relapse quickly after a course of medical therapy or surgical resection. Their role in treating patients with ulcerative colitis remains unclear but needs to be considered in the patient with refractory disease who wishes to avoid colectomy. The safety margin for these agents is increased if the initial dose is 50 m g / d with subsequent increases, in those not responding, to a total dose not exceeding 1.5 m g / kg body weight daily. Nonetheless, frequent blood counts are mandatory. Although cyclosporine appears promising, its use should be limited to controlled trials except in critical situations where other modalities have failed. Metronidazole Initially marketed as the first effective therapy for Trichomonas species infection and subsequently used for its efficacy against anaerobic bacteria, metronidazole

has become in recent years an important addition to the treatment of Crohn disease involving the perineum and colon. A Scandinavian controlled trial (118) found that metronidazole, 400 mg twice daily, was as effective as sulfasalazine in patients with ileocolitis and colitis. Like sulfasalazine, the drug did not appear to be as beneficial for patients with ileitis alone. Recently, in a placebo-controlled trial (119) metronidazole was shown to be effective therapy for patients with Crohn disease in doses of 10 m g / k g body weight daily and 20 m g / k g body weight daily. Startling success with metronidazole has been reported in uncontrolled studies (120, 121) of patients with refractory chronic perineal manifestations of Crohn disease. More than 8 0 % of patients maintained on therapy for at least 2 months had healing of rectovaginal fistulas, complex abscesses, and proctectomy wounds. Effective doses ranged from 10 to 20 m g / k g body weight daily. The recurrence of active perineal disease after tapering or discontinuation of therapy is high, usually mandating maintenance therapy at some level. Unfortunately, metronidazole does not appear to be effective for treating ulcerative colitis. Efficacy could not be shown for either topical metronidazole in patients with chronic ulcerative proctitis or for oral metronidazole in patients with mild and moderate active ulcerative colitis (122, 123). Moreover, metronidazole was of no benefit as an adjunct to corticosteroids in the treatment of patients with severe ulcerative colitis (124). There have been no published studies to date on the possible role of metronidazole as an adjunct to other therapies for Crohn disease or in maintaining remission in patients with Crohn disease. Adverse effects of metronidazole can limit its use, and gastrointestinal upset as well as peripheral neuropathy are encountered, especially at high doses (125). Because of the positive in-vitro mutagenicity test, there has been concern about the long-term carcinogenic potential of metronidazole. To date there has been no proof of any increased risk for tumor in patients receiving the drug, but the safety of its longterm use in patients with inflammatory bowel disease has not been fully established (126, 127). Recommendations for Therapy For the patient with Crohn colitis or ileocolitis of mild to moderate severity who does not respond to or cannot tolerate sulfasalazine, metronidazole, 250 mg two to four times daily, should be considered. If no response is seen in 4 to 8 weeks, the drug should be withdrawn. If a response is seen, the drug can be continued safely for 3 to 4 months, at which point tapering can be attempted. In patients with refractory perineal disease, somewhat higher doses (exceeding 1 g daily) are often needed, and long-term maintenance therapy at reduced doses will often be necessary. Despite concerns about long-term risks, the use of metronidazole in such patients is justified by their otherwise desperate situation.

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Potential New Drug Therapies The promise of the new topical and oral aminosalicylates, the rapidly metabolized topical steroids, and cyclosporine; as well as the newly established roles for A C T H , 6-mercaptopurine, azathioprine, and metronidazole, have been described. Many other agents, differing in nature from those now in use, have been efficacious in preliminary trials involving patients with both ulcerative colitis and Crohn disease. Sodium Cromoglycate Sodium cromoglycate has been used to treat various disorders such as asthma associated with IgE-mediated hypersensitivity reactions. Because of the finding of increased eosinophils and mast cells in the rectal biopsy specimens from patients with ulcerative colitis, oral sodium cromoglycate was tried earlier in this clinical setting. However, no benefit of the drug was noted in either patients with active colitis or patients in remission (128, 129). Recently, the drug has been re-evaluated as a topical enema in patients with distal ulcerative colitis and proctitis (130). A group of patients were randomly assigned to receive either cromoglycate enemas or prednisolone enemas; both treatment groups did well, with cromoglycate being as effective as the steroid preparation. Further studies of this agent in topical form in patients with active and quiescent disease are anticipated. Sucralfate Sucralfate, a cytoprotective mucopolysaccharide used for treating peptic ulcers, improved acetic acid-induced colitis in animals; in an open trial it appeared to be effective when given topically in a 10% solution to patients with distal ulcerative colitis (131, 132). These observations prompted a controlled trial (133) comparing sucralfate enemas in a 10% solution with prednisolone enemas in active distal colitis. Although some patients receiving sucralfate had diminished rectal bleeding, decreased stool frequency, and an improved sigmoidoscopic appearance, 71 % of those treated with prednisolone went into remission, compared with 2 8 % of patients receiving sucralfate. In another study (134) of patients with distal colitis, patients were randomly assigned to receive placebo, sucralfate in a 4 % solution, or 5-ASA enemas. Patients receiving 5-ASA did well, whereas the sucralfate group did no better than the placebo group. These results have cast doubt on the usefulness of topical sucralfate in treating distal colitis. Clonidine Clonidine is a centrally acting alpha-2 agonist used as therapy for hypertension. In a 30-week study (135) of 45 patients with active ulcerative colitis, clonidine (0.3 mg three times daily) was compared with prednisone (20 mg three times daily) and sulfasalazine (1.5 g three times daily). Clonidine was as effective as pred56

nisone and more effective than sulfasalazine in improving symptoms and sigmoidoscopic appearance. Adverse effects included depression and dryness. The investigators suggested that clonidine acts centrally, with secondary effects on bowel motility. This intriguing study clearly needs the corroboration of other investigations. Chloroquine A defect in the ability of certain antigen-bearing epithelial cells in patients with inflammatory bowel disease to stimulate suppressor T cells has been described in in-vitro studies. Studies suggest that the defect might relate to abnormal processing of foreign proteins, a defect that could be reversed by administering chloroquine, which has the ability to slow antigen processing. Because of these basic observations, an open trial (136) involving 10 patients with active ulcerative colitis or Crohn disease was initiated using chloroquine therapy. After 8 weeks, eight of the ten patients with ulcerative colitis improved clinically and endoscopically. The patients with Crohn disease failed to show significant improvement. Side effects were limited to transient blurred vision and nasal congestion. Because of these encouraging early results, a placebocontrolled trial has been initiated. Lipoxygenase Inhibitors: Eicosapentaenoic Acid (Fish Oil) It has been noted that 5-aminosalicylate and sulfasalazine may work by inhibiting the lipoxygenase pathway of arachidonic acid metabolism, resulting in a decreased production of leukotrienes, the potent chemotactic agents that recruit polys to sites of inflammation. Eicosapentaenoic acid specifically affects neutrophil function by competitively inhibiting the formation of leukotriene B4. The clinical response and neutrophil function in six patients with ulcerative colitis receiving eicosapentaenoic acid were measured and compared with those of control patients (137). After 8 weeks of drug therapy, the patients with ulcerative colitis improved clinically and histologically and their neutrophil function was altered as expected. Further studies with this or similar specific inhibitors of arachidonic acid metabolism may not only provide new drugs for use in treatment but may offer further insights into the pathogenesis of inflammatory bowel disease. Methotrexate The anti-inflammatory properties of methotrexate, a folic acid antagonist, have accounted for the success of this drug in treating psoriasis and rheumatoid arthritis and have motivated preliminary studies in patients with primary biliary cirrhosis and sclerosing cholangitis (138, 139). These experiences led to its use in the treatment of inflammatory bowel disease. In an open trial (140), 14 patients with refractory Crohn disease and 7 with refractory ulcerative colitis were given

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methotrexate, 25 mg intramuscularly once weekly for 12 weeks. Eleven patients with Crohn disease and 5 of those with ulcerative colitis showed objective signs of improvement. Five of 7 patients with Crohn colitis but none of the patients with ulcerative colitis went into an endoscopic remission. Diarrhea, nausea, transient leukopenia, and mild reversible elevations in transaminase levels were noted in a few patients. Antituberculous Agents The similarities between intestinal tuberculosis and Crohn disease have long been appreciated and have led to speculation about a causative infectious agent in the latter. Several laboratories in recent years have isolated an atypical Mycobacterium species from the tissues of certain patients with Crohn disease (141, 142). These findings led to an open study (143) in which 6 patients with severe refractory Crohn disease were treated with streptomycin and rifabutin. After 4 months, all 6 patients had improved, with withdrawal of steroids, healing of fistula, and a diminution in the Crohn disease activity index. Similarly, 12 of 17 patients with active Crohn disease showed improvement on a four-drug regimen over a 6-month period (144). In a study (145) with a somewhat different design, a combination therapy with rifabutin and ethambutol had no effect on the endoscopic appearance of recurrent ileitis after resection and anastomosis. Moreover, a high rate of flu-like symptoms was noted with these drugs. As with the other new agents, randomized, controlled trials of antituberculous agents in patients with Crohn disease are needed before the routine use of such drugs can be recommended.

of cells by the scavenging of these free radicals. A known free radical scavanger, superoxide dismutase, has been used with success in several open trials involving patients with both Crohn disease and ulcerative colitis. Emerit and colleagues (148) showed the regression of pyoderma gangrenosum and vulvar ulcerations in 3 patients with Crohn disease who received superoxide dismutase packaged in liposomes. In another trial (149), 10 of 12 patients with active Crohn disease improved while receiving superoxide dismutase, whereas in a third study (150), 10 of 12 patients with active ulcerative colitis showed marked improvement while receiving the agent. D-Penicillamine, which may work by the same mechanism, has also been used successfully in a few patients with Crohn disease (151). Recommendations for Therapy Although promising, the results with these new agents are so preliminary that their routine administration to patients with inflammatory bowel disease is not advised. Nevertheless, clinicians will undoubtedly consider their use in individual patients with refractory disease and limited treatment alternatives. Whenever possible, however, their usefulness should be studied in randomized, placebo-controlled trials. The importance of such trials to establish the efficacy of potentially toxic drugs in inflammatory bowel disease is clear when the variable natural history of both ulcerative colitis and Crohn disease is appreciated (152). Requests for Reprints: Mark A. Peppercorn, M D , Beth Israel Hospital, Dana 501, 330 Brookline Avenue, Boston, MA 02215. Current Author Address: Dr. Peppercorn: Beth Israel Hospital, Dana 501, 330 Brookline Avenue, Boston, MA 02215.

Immune Adjuvants Agents that enhance cell-mediated immunity have been studied in patients with Crohn disease, stimulated by evidence of possible transmissible viral agents in the disorder. N o efficacy of transfer factor or Bacille Calmette-Guerin (BCG) has been found in previous trials. In contrast, a few patients with Crohn disease appear to have benefited from 6 weeks of treatment with interferon in an open-labeled study (146). Moreover, levamisole, an agent that enhances neutrophilic activity and has been used in treating rheumatologic disorders, may be beneficial for patients with Crohn disease who are in remission. Finally, a different approach to manipulation of the immune system, T lymphocyte apheresis, has been shown to be successful in treating patients with Crohn disease in preliminary trials (147). Oxygen-Derived Free Radical Scavengers Oxygen-derived free radicals, which are released during the oxidative burst of polymorphonuclear leukocytes in inflammatory processes, have been implicated as cytotoxic in various states, including inflammatory bowel disease. It was noted above that a possible mechanism of action of 5-ASA involves the protection

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Advances in drug therapy for inflammatory bowel disease.

To identify advances in drug therapy for inflammatory bowel disease, and to evaluate the effectiveness of the new agents in treating both ulcerative c...
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