Review article: medical treatment of mild to moderately active Crohn s disease

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1 Aliment Pharmacol Ther 2003; 17 (Suppl. 2): Review article: medical treatment of mild to moderately active Crohn s disease R. LÖFBERG Karolinska Institutet, IBD-unit at HMQ Sophia Hospital, Stockholm, Sweden SUMMARY Crohn s disease is a chronic, debilitating subset of inflammatory bowel diseases, which may affect any part of the gastrointestinal tract. The most common sites of inflammation are the terminal ileum and/or the colon. Fistulous disease is present in up to 20% of patients, particularly in those having rectal involvement. The aetiology of Crohn s disease still remains obscure, therefore medical therapy is directed towards symptomatic relief in active disease and relapse prevention in the long-term setting. Contemporary Crohn s disease management comprises individual treatment depending mainly on Crohn s disease localization in the gastrointestinal tract and the disease severity. The mainstay of current medical treatment for mild to moderately active stages of Crohn s disease includes aminosalicylates, antibiotics, glucococorticosteroids and immunomodulators. Biologics such as anti TNF-compounds and anti-integrins are being introduced. INTRODUCTION Considerable progress has taken place in the field of medical treatment of inflammatory bowel disease during the last decade. The novel category of biological compounds has shown the most dramatic development, with several potent drugs being approved or in the process of being approved in Europe and North America. Still, the mainstay of therapy in Crohn s disease comprises the use of relatively old, conventional but well proven drugs including glucocorticosteroids and immunomodulators. 5-ASA derivatives and antibiotics are widely used despite evidence for their effectiveness being limited. This review aims at outlining the currently available medical treatment for the use in active Crohn s disease with respect to disease presentation and localization. Correspondence to: Prof. R. Löfberg, Associate Professor of Medicine, Karolinska Institutet, IBD-unit at HMQ Sophia Hospital, SE Stockholm, Sweden. ibd@sophiahemmet.se DRUGS FOR ILEAL AND ILEOCAECAL DISEASE Several drugs have been evaluated for the treatment of classical Crohn s disease, i.e. involvement of the terminal ileum and not infrequently also the caecum. The results from well-designed and conducted comparative trials have consistently shown that glucocorticosteroids are the most efficacious type of drugs for induction of symptomatic remission. 1, 2 Overall, more than 60% of the patients treated with a standardized course of oral prednisolone (doses ranging from 40 to 60 mg/day) with gradual tapering will respond favourably. Moreover, uncontrolled data indicate that higher doses of glucocorticosteroids (1 mg/kg bodyweight) may increase response and remission rates, 3 but the risk of inducing undesired glucocorticosteroid associated side-effects then also increases. Although prednisolone has been used as the standard compound in glucocorticosteroid therapy for a long time, the current drug of choice in active ileal and ileocaecal Crohn s disease has now become the oral formulations of budesonide. Given in a slow-release preparation this topically active glucocorticosteroid is as efficacious in inducing clinical remission as oral 18 Ó 2003 Copyright Blackwell Publishing Ltd

2 REVIEW: MEDICAL TREATMENT OF CROHN S DISEASE 19 prednisolone. Budesonide reduces the Crohn s Disease Activity Index (CDAI) score below the level of 150 in 55 69% of the patients, as shown in several randomized controlled trials. 4 6 The ratio between efficacy and glucocorticosteroid related side-effects and adverse events has significantly improved in comparison with standard oral prednisolone. 4, 6 Moreover, in comparison with a high dose 5-ASA regimen (4 g/day), oral budesonide is both safer and more efficacious for induction of remission in mild to moderately active ileocaecal Crohn s disease. 7 Aminosalicylates seem to have only a minor role to play in active ileocaecal Crohn s disease despite the theoretically attractive small bowel release profiles offered by some of the microgranulae and ph-dependent preparations. Antibiotics may have some effect in ileocaecal Crohn s disease but data so far is limited. Metronidazole has a moderate effect in milder disease. 8 Ciprofloxacin may also be efficacious, but results from larger, placebo-controlled randomized controlled trials are lacking. Clinical experience with other antibiotics, e.g. claritromycin, are encouraging but are based mostly on anecdotal reports. For patients with refractory or glucocorticosteroiddependent ileal and ileocaecal disease, not suitable for surgical resection, antimetabolites may be tried, i.e. azathioprine and 6-mercaptsopurine. The slow onset of action, however, hampers their use in the acute setting. 9 Some patients experience a rather fast response (1 2 weeks), but in most patients it takes up to 2 3 months 9 before the full beneficial effect is apparent. They are usually introduced together with glucocorticosteroids, and the dose of the latter is then gradually tapered. A recent meta-analysis 10 of several smaller studies clearly indicates that azathioprine and 6-mercaptsopurine are of value in active Crohn s disease. In case of intolerance to these compounds, methotrexate may sometimes be successful as a second line alternative for induction of remission, 11 but is attributed with more side-effects. Another, third line option in ileacaecal disease may be infliximab, 12 but experience from the use of this advanced and comparatively expensive anti-tnf-alpha chimeric monoclonal antibody therapy is still limited in this setting of ileocaecal Crohn s disease. COLONIC/COLORECTAL DISEASE Crohn s disease patients with colonic or colorectal involvement comprise a group that may be quite difficult to treat. Sulfasalazine has been one of the mainstays of medical therapy at least in moderately severe cases. 1, 2 The favourable release profile of 5-ASA in the colon and rectum makes sulfasalazine an ideal 5-ASA carrier, but problems with sulpha intolerance/allergy in up to 20% of the patients limits its use. Other oral 5-ASA preparations with a delayed release profile have also proven efficacy in active mild to moderate ileo-colonic/colonic/colorectal disease. 13 Metronidazole, an orphan drug for inflammatory bowel disease, has been evaluated in a few randomized controlled trials and seems be comparable to sulfasalazine in terms of overall efficacy in patients with colorectal involvement. 14 Antimicrobial as well as immunomodulatory effects of metronidazole may be of importance in Crohn s disease therapy. When introducing metronidazole, a gradual dose increase is advisable in order to minimize problems with nausea and metallic taste. Patients should also be informed of the antabuselike effects generating a decreased tolerance towards alcohol. Glucocorticosteroids are the most efficacious therapy for induction of remission also in colonic and colorectal Crohn s disease. 1, 2 Colonoscopic studies, however, have indicated that the clinical efficacy is not necessarily mirrored by healing of Crohn s disease lesions. 3 From clinical experience it is known that patients with colorectal and classical Crohn s disease involvement often will have a rapid clinical relapse following cessation of glucocorticosteroid treatment, and two studies have shown that the early introduction of azathioprine will confer a substantial benefit in 15, 16 the medium-term perspective. New insights into the complicated metabolism of azathioprine and 6- mercaptsopurine, and the availability of measurements of both thiopurine methyl transferase (TPMT)-enzyme activity and active azathioprine metabolites in blood, have helped to fine-tune this immunomodulatory treatment in individual Crohn s disease patients. For patients with chronic active, glucocorticosteroiddependent or refractory colonic Crohn s disease being intolerant/allergic to azathioprine/6-mercaptsopurine, mycophenolate has been suggested as an alternative, as has methotrexate. 11 The high frequency of side-effects, particularly from the gastrointestinal tract, caused by these two drugs often make them difficult to use over longer periods of time. Cyclosporin although being widely used in both North America and in Europe for severe, glucocorticosteroidrefractory attacks of ulcerative colitis, has not been found to be consistently effective in colonic Crohn s

3 20 R. LÖFBERG Table 1. Treatment options for induction and maintenance of remission in mild to moderate Crohn s disease First line options Active disease Ileal/ileocaecal Crohn s disease: budesonide Colonic/colorectal Crohn s disease: metronidazole/sulfasalazine Fistulizing disease: metronidazol/azathioprine or 6-mercaptsopurine Maintenance of remission Ileal/ileocaecal Crohn s disease: azathioprine/6-mercaptsopurine Colorectal Crohn s disease: metronidazol/sulfasalazine/ aazathioprine or 6-mercaptsopurine Fistulizing disease: metronidazole/azathioprine or 6-mercaptsopurine Second/third line options Active disease Ileal/ileocaecal Crohn s disease: antibiotics, conventional glucocorticosteroids, azathioprine or 6-mercaptsopurine, infliximab Colorectal Crohn s disease: antibiotics, conventional glucocorticosteroids, azathioprine or 6-mercaptsopurine, infliximab Fistulizing disease: infliximab Maintenance of remission Ileal/ileocaecal Crohn s disease: methotrextate, infliximab? Colorectal Crohn s disease: methotrextate, infliximab? Fistulizing disease: infliximab disease. Inadequate dosing may be one explanation for this, but nevertheless, the risk for an abundance of significant side-effects, including lethal opportunistic infections, has limited its use for Crohn s disease. 17 In patients that have tried but failed with conventional glucocorticosteroids, antibiotics and/or antimetabolites, treatment with an anti-tnf antibody is often a logical option. An infusion of infliximab (optimal dose: 5 mg/ kg) results in prompt resolution of symptoms in about 30 40% of the patients. 12 Furthermore, complete healing of endoscopic and histological inflammatory lesions has also been demonstrated in some patients. A further 20 30% of the patients treated with infliximab experience significant improvement, while one-third responds poorly or not at all. A response usually lasts for up to 8 12 weeks, but long-term remission may occur, particularly when infliximab is combined with adequate dosing of azathioprine/6-mercaptsopurine. The safety-profile has not yet been fully explored because the drug has only been in use for 2 3 years. Short-term safety has been shown to be satisfactory, but the risk for opportunistic lethal infections and increased risk for malignancy requires vigilance in long-term surveillance. Other types of anti-tnf-alpha biologics include the CDP 475 humanized antibody, which has been demonstrated to be efficacious in moderate to severe Crohn s disease. 18 It is still not known if this antibody may offer a superior safety profile. Interestingly, anti- TNF-alpha fusion proteins, such as etanercept, which is efficacious in rheumatoid arthritis, appears to have less effect on active Crohn s disease. Other biological compounds now in the final evaluation for use in Crohn s disease include a PEG-ulated anti-tnf-alpha AB (CDP870) and natalizumab, an alpha-4 anti-integrin that interferes with leucocyte homing. Both compounds have shown promising efficacy and encouraging safety profiles in Phase II trials. Another bilological drug proposed for use in active Crohn s disease was a recombinant Il-10 protein. Unfortunately, an extensive phase II III programme failed to show efficacy of this cytokine believed to exert anti-inflammatory action. FISTULIZING DISEASE A small but important sub-group that has a very bad quality of life. Most patients have perianal or perirectal disease, but up to 10% of the patients suffer from enteroenteric, recto-vesical or recto-vaginal fistulae. There are few studies showing any efficacy of the standard types of drugs for Crohn s disease. Based on clinical experience, however, the use of a combination of antibiotics (preferably metronidazole and ciprofloxacin) and antimetabolites (azathioprine or 6-mercaptsopurine) is of substantial benefit in the majority of patients. 19 Although not leading to a complete relief of symptoms and/or closure of fistulae, this combination is still a first line option in the light of the benign long-term toxicity profile. Therapy with infliximab has been convincingly shown to alleviate perianal fistulizing disease. A substantial improvement in the number of draining fistulae, or complete closure, after three treatments with intravenous infusions over a 6-week period has been reported. 20 It remains to be shown whether or not the entire fistula tract heals, or if it is just a temporary down-regulation of pus secretion and orifice closure that is achieved. If perianal/rectal fistulae are not provided with setons, the long-term response from infliximab is limited, and most fistulae recur. A combination of adequate drainage, antibiotic cover as well as antimetabolite therapy is the treatment of choice for this debilitating type of complication of Crohn s disease. High dose of intravenous cyclosporin has been shown to be efficacious in smaller series of patients, but is not

4 REVIEW: MEDICAL TREATMENT OF CROHN S DISEASE 21 generally recommended. 19 More complicated rectovaginal, recto-vesical or entero-enteric fistulae almost invariably require surgical treatment. EXTRAINTESTINAL MANIFESTATIONS Glucocorticosteroids are the most efficacious drugs for patients also experiencing extraintestinal manifestions and especially concomitant athralgia or arthritis. Sulfasalazine may have an advantage over standard 5-ASA preparations in this respect. Budesonide seems to offer similar effects as prednisolone, with about three-quarters of the patients getting symptomatic relief of joint pain in the acute setting of Crohn s disease. 21 Other complicated extraintestinal manifestations associated with Crohn s disease, such as glucocorticosteroidrefractory pyoderma gangrenosum, may respond favourably to ciclosporin or infliximab. CONCLUSIONS The new biologics for inflammatory bowel diseaseconditions have been directed primarily towards alleviating severe and moderately severe inflammatory activity in patients with symptomatic Crohn s disease, and most often they have been developed in parallel for several other chronic inflammatory disorders including rheumatoid arthritis or multiple sclerosis. Some of the new compounds, in particular the anti-tnf-alpha antibodies such as infliximab, seem to have broad potential in the setting of chronic inflammatory disorders, while others have impact only in certain conditions or subsets of patients. Although showing promising effects in animal models and subsets of inflammatory bowel disease patients, several new biologic compounds have failed when large phase III studies have been performed (e.g. IL-10, ISIS 2302) underscoring the difficulties involved in transforming biological cytokine/anticytokine concepts and other theories based on recent advances in molecular biology into clinical therapy. The prospects for the intermediate future still comprise an abundance of new candidate drugs, biologics as well as new conventional small molecules, for treatment of Crohn s disease. Albeit not having the full potential of definite cure, those new drugs will offer our patients alternative strategies for safer and more efficacious suppression of disease activity. In parallel, we will also enhance our ability to master the use of conventional drugs. Our improved armamentarium of medical therapy should have, and probably already has had an impact on the overall morbidity in Crohn s disease and a decreased rate of major surgery (i.e. colectomy and resections), but this has not yet been shown in larger, epidemiological studies. REFERENCES 1 Summers RW, Switz DN, Sessions JT, et al. National cooperative Crohn s disease study: results of drug treatment. Gastroenterology 1979; 77: Malchow H, Ewe K, Brandes JW, et al. European cooperative Crohn s disease study (ECCDS): results of drug treatment. Gastroenterology 1984; 86: Modigliani R, Mary JY, Simon JF, et al. Clinical, biological and endoscopic picture of attacks of Crohn s disease. Evolution of prednisolone. Gastroenterology 1990; 98: Rutgerts P, Löfberg R, Malchow H, et al. A comparison of budesonide with prednisolone for active Crohn s disease. N Eng J Med 1994; 331: Greenberg G, Feagan B, Martin F, et al. Oral budesonide for active Crohn s disease. N Eng J Med 1994; 331: Campieri M, Ferguson A, Doe W, et al. Oral budesonide is as effective as oral prednisolone in active Crohn s disease. Gut 1997; 41: Thomsen OO, Cortot A, Jewell D, et al. A comparison of budesonide and mesalamine for active Crohn s disease. N Eng J Med 1998; 339: Sutherland L, Singleton J, Sessions J, et al. Double blind, placebo controlled trial of metronidazole in Crohn s disease. Gut 1991; 32: Sandborn WJ, Tremaine WJ, Wolf DC, et al. Lack of effect of intravenous administration on time to respond to azathioprine for steroid treated Crohn s disease. Gastroenterology 1999; 117: Sandborn W, Sutherland L, Pearson D, et al. Azathioprine or 6-mercaptsopurine for inducing remission of active Crohn s disease. Cochrane Database Sust Rev 2000; 2: CD Feagan BG, Rochon J, Fedorak RN, et al. Methotrexate for the treatment of Crohn s disease. N Eng J Med 1995; 332: Targan SR, Hanauer SB, van Deventer SJH, et al. A short-term study of a chimeric monoclonal antibody ca2 to tumor necrosis factor alpha for Crohn s disease. N Eng J Med 1997; 337: Tremaine WJ, Schroeder KW, Harrrison JM, et al. A randomized, double-blind, placebo-controlled trial of the oral mesalamine (5-ASA) preparation Asacol in the treatment of symptomatic Crohn s colitis and ileocolitis. J Clin Gastroenterol 1994; 19: Ursing B, Alm T, Barany F, et al. A comparative study of metronidazole and sulfasalazine for active Crohn s disease. Gastroenterology 1982; 83: Ewe K, Presse AG, Singe CC, et al. Azathioprine combined with prednisolone or monotherapy with prednisolone in active Crohn s disease. Gastroenterology 1993; 105:

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