Clinical review

Management of Crohn's disease

David S Rampton, reader in gastroenterology. 

Gastrointestinal Science Research Unit and Digestive Diseases Research Centre, St Bartholomew's and the Royal London School of Medicine and Dentistry, London E1 2AD

Correspondence to: Department of Gastroenterology, Royal London Hospital, London E1 1BB drampton{at}mds.qmw.ac.uk

	Introduction

Top Introduction Methods Aetiopathogenesis Assessment Treatment of active ileocaecal... Dietary therapy Surgery Treatment of other common... Maintenance of remission of... The future References

Over recent decades the incidence of Crohn's disease has increased in the United Kingdom and it now affects about 1 in 1500 people. Symptoms start at any age, with peaks in early and late adulthood. Although the disease is incurable its adverse effects on health and quality of life can be substantially reduced by appropriate treatment. This paper reviews the current management of adults with common presentations of Crohn's disease.

	Methods

Top Introduction Methods Aetiopathogenesis Assessment Treatment of active ileocaecal... Dietary therapy Surgery Treatment of other common... Maintenance of remission of... The future References

I searched Medline with the key terms Crohn's disease, drug therapy, dietary therapy, surgery, and therapy. Pharmacotherapeutic advances were derived from peer reviewed controlled clinical trials and meta-analyses published since 1993. Recent data were from the annual meeting of the American Gastroenterological Association. Citations about other aspects of Crohn's disease were mainly from review articles.

	Aetiopathogenesis

Top Introduction Methods Aetiopathogenesis Assessment Treatment of active ileocaecal... Dietary therapy Surgery Treatment of other common... Maintenance of remission of... The future References

The progressive elucidation of the pathogenesis, if not yet the cause, of Crohn's disease has improved our understanding of the possible modes of action of conventional treatment and has led to the development of new anti-inflammatory agents aimed at specific pathophysiological targets.

Epidemiological and genetic studies suggest that Crohn's disease is a polygenic disorder without any single Mendelian pattern of inheritance. Susceptibility loci for the disease have been reported recently on chromosomes 16, 3, 7, and 12; the latter three being shared with ulcerative colitis.¹ Several environmental factors have been implicated.¹ Claims for initiating roles for gut flora, food constituents, or specific infections such as mycobacterium paratuberculosis and measles have not yet been substantiated. The pathogenic significance of the strong association between cigarette smoking and Crohn's disease, and why smoking worsens the clinical course of the disease,² remains unclear.

Whatever the initiating factors in Crohn's disease, excessive activation of mucosal T cells leads to transmural inflammation, which is amplified and perpetuated by the release of proinflammatory cytokines and soluble mediators (fig 1).¹

View larger version (35K): [in this window] [in a new window]   Fig 1.   Aetiopathogenesis of Crohn's disease. Genetic and environmental factors activate mucosal T lymphocytes causing cytokine driven inflammation; increased epithelial permeability and granulomatous vasculitis, leading to focal intestinal microinfarction, may also contribute to the inflammatory process1

	Assessment

Top Introduction Methods Aetiopathogenesis Assessment Treatment of active ileocaecal... Dietary therapy Surgery Treatment of other common... Maintenance of remission of... The future References

Treatment of Crohn's disease depends not only on the site of the disease but also on the pathological process underlying the patient's presentation. ^{3 4} Inflammation, obstruction, abscess, and fistula need to be distinguished by appropriate investigation (table). Clinical evaluation and blood tests⁵ remain central to the assessment of symptomatic Crohn's disease, but recently there have been changes in the subsequent diagnostic approach.

Conventional radiology and colonoscopy
Plain abdominal radiography is still essential if intestinal obstruction is suspected: as in ulcerative colitis it helps to estimate the extent and severity of Crohn's colitis. For imaging the small intestine a barium follow through is more comfortable for patients, is less likely to miss proximal disease, and is safer than a small bowel enema (enteroclysis).⁶ Colonoscopy with ileoscopy, because it allows detection of superficial disease, biopsy and, when necessary, dilatation of strictures is now usually preferred to barium enema for investigation of the lower bowel (fig 2).⁶ Colonoscopy may also have a role, as in ulcerative colitis, in surveillance for colorectal cancer in patients with longstanding extensive Crohn's colitis.⁷

View larger version (139K): [in this window] [in a new window]   Fig 2.   Superficial aphthoid erosions in sigmoid colon in patient with ileocolonic Crohn's disease. Subtle lesions such as these are more readily seen at ileocolonoscopy than on barium enema

Newer imaging techniques
Scanning with radiolabelled leucocytes identifies sites of intestinal inflammation and intra-abdominal abscess non-invasively. Labelling with ⁹⁹technetium-hexamethyl propylene amine oxime is superior to ¹¹¹indium tropolonate in ease of use, availability, image quality, and radiation dose.⁶ Scintigraphic scanning with monoclonal antibodies to upregulated cellular adhesion molecules such as E selectin represents an ingenious application of improved understanding of the pathogenesis of Crohn's disease. ^{1 8}

	Treatment of active ileocaecal Crohn's disease

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General measures

Explanation, hospital care, and dietary advice
Patients need their illness fully explained, not least to enable them to participate in decisions about their therapy: discussion can be reinforced with information from support groups such as the National Association for Colitis and Crohn's disease. Hospital care is best undertaken by a team of medical and surgical gastroenterologists, dieticians, and nurse practitioners with a special interest in inflammatory bowel disease, nutrition, and stoma care. Undernourished patients need liquid protein supplements, whereas special nutritional measures are required for patients with short bowel syndrome due to extensive Crohn's disease or resection.¹⁰

Non-specific drugs
Codeine phosphate and loperamide remain useful antidiarrhoeal agents in Crohn's disease but may cause acute colonic dilatation in active colitis. By binding bile salts cholestyramine (4 g 1-3 times daily) reduces diarrhoea due to terminal ileal disease or resection. Haematinics, calcium, magnesium, zinc, and fat soluble vitamins may be needed for the replacement of particular deficiencies as may bisphosphonates, calcium, vitamin D, and hormone replacement therapy for osteoporosis. Sick inpatients may require intravenous fluid and electrolytes and blood transfusion, with subcutaneous heparin to reduce the risk of systemic venous thromboembolism.¹¹ Non-steroidal anti-inflammatory drugs may precipitate relapse of inflammatory bowel disease¹² and should be avoided.

Specific drug therapy
Clinical trials in Crohn's disease are bedevilled by difficulties in defining outcome measures, and by the heterogeneity, fluctuating course, and unpredictable placebo response of the disease.¹³ Nevertheless, several new treatments have been introduced recently as a result of well conducted controlled trials.

Corticosteroids
In active disease oral steroids still provide the quickest and most reliable response; about 70% of patients improve within 4 weeks. Conventionally, prednisolone (40-60 mg/day) is used, the dose being tapered by 5 mg every 7-10 days once improvement has begun. Very ill patients, or those with intestinal obstruction, need intravenous hydrocortisone or methylprednisolone initially.

Aminosalicylates
The newer oral 5-aminosalicylate formulations are better tolerated than sulphasalazine and can be used in higher doses. The pH dependent delayed release (Asacol, Salofalk) and, particularly, slow release (Pentasa) mesalazine preparations release 5-aminosalicylate more proximally in the gut than sulphasalazine making them useful in small bowel disease as well as colitis. High dose oral mesalazine (Pentasa 2 g twice daily, Asacol 1.2 g three times daily) given for up to 4 months induces remission in about 40% of patients with moderately active ileocaecal Crohn's disease.^16-18 However, even mesalazine may cause rash, headache, nausea, diarrhoea, pancreatitis, or blood dyscrasias in up to 5% of patients; interstitial nephritis occurs in around 1 in 500.¹⁹

Antibiotics
Metronidazole alone ^{3 4} or with ciprofloxacin²⁰ is moderately effective in active Crohn's disease. Treatment is given for up to 3 months but may be complicated by nausea, an unpleasant taste, alcohol intolerance, and a peripheral neuropathy, which can be irreversible. Preliminary reports have suggested possible therapeutic roles for ciprofloxacin, clarithromycin, rifabutin, and clofazimine, singly or in combination, ^{3 4} but conventional antituberculous triple therapy is ineffective.²¹

Immunosuppressive drugs
For patients refractory to, or dependent on, corticosteroids, who because of extensive disease or previous resection need to avoid surgery, adjunctive azathioprine (2-2.5 mg/kg/day) or 6-mercaptopurine (1-1.5 mg/kg/day) remain invaluable, the dose of steroids being tapered as improvement occurs.²² Response to the thiopurines may take up to 4 months, but hopes that intravenous azathioprine could be used to accelerate improvement have not been confirmed by a controlled trial.²³ Homozygous deficiency of 6-thiopurine methyltransferase, the enzyme responsible for the safe metabolic disposal of purine analogues, occurs in about 0.2% of people and may predispose to azathioprine's occasionally serious side effects (bone marrow depression,²⁴ acute pancreatitis, chronic hepatitis). Routine assay of 6-thiopurine methyltransferase is not yet available but in the future may help identify patients at particular risk. The British National Formulary recommends that patients starting a thiopurine require blood counts every week for the first 8 weeks of treatment and at least every 3 months thereafter. Existing data about the risk of malignancy in patients with Crohn's disease given thiopurines long term are reassuring.²⁵ It is not yet clear how long azathioprine or 6-mercaptopurine should be used in Crohn's disease. However, in patients maintained in remission on a thiopurine the risk of relapse after 4 years seems to be similar whether the drug is continued or stopped.²⁶

Antitumour necrosis factor  antibody
The first specific cytokine related therapy to reach clinical application in Crohn's disease is infliximab, a mouse-human chimeric antibody (cA2) to tumour necrosis factor ; this preparation was launched in the United States in late 1998 and in the United Kingdom in September 1999. ^{30 31}

Possible new treatments
The place of other new approaches specifically targeting steps in the inflammatory process awaits clarification. Possible treatments include bone marrow transplant, lymphapheresis, antiCD4 and cellular adhesion molecule antibodies, interleukin 10, interleukin 11, and antisense oligonucleotides to nuclear transcription factors.^34-37

	Dietary therapy

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In patients with a poor response to, or preference for avoiding, corticosteroids, and particularly in children, a liquid formula diet is a valuable option. Elemental (amino acid based), oligomeric (containing peptides), and polymeric (containing whole protein) feeds all approach the efficacy of corticosteroids if taken for 4-6 weeks as the sole nutritional source.³⁸ The usefulness of enteral therapy is unfortunately limited by its cost, the difficulty many patients have in adhering to it, the need often to give the feed by nasogastric tube or percutaneous gastrostomy, and the high relapse rate that follows its discontinuation. ^{10 38}

	Surgery

Surgery is usually indicated for patients whose ileocaecal disease fails to respond to drug or dietary therapy. Resection is not curative: there is a 50% chance of recurrence requiring further surgery at 10 years. Some patients prefer surgery at presentation to pharmacological or nutritional treatment of indefinite duration, but there are no controlled data to confirm the best approach. Although right hemicolectomy and stricturoplasty can both now be undertaken laparoscopically trials are required to compare open and laparoscopic surgery in this setting.³⁹

	Treatment of other common presentations of active Crohn's disease

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Obstructive small bowel disease
A raised platelet count, erythrocyte sedimentation rate, or C reactive protein concentration,⁵ and a positive radiolabelled leucocyte scan may distinguish active from fibrostenotic Crohn's disease, but usually a trial of intravenous corticosteroids is given. Parenteral nutrition is required if resumption of eating is unlikely within a week. Although patients not settling after 48-72 hours of conservative treatment usually need surgery, short upper jejunal, terminal ileal, or colonic strictures can now be treated by enteroscopic or colonoscopic balloon dilatation⁴⁰; the value of concomitant intralesional injection of triamcinolone is uncertain.⁴¹

Intra-abdominal abscess
Ultrasound and computed tomography are now used not only diagnostically but also to drain abscesses percutaneously. In patients whose abscesses have no enteric connection, this approach can obviate surgery.⁶

Intestinal fistula
Where there is no obstruction distal to the site of the fistula, enteral or parenteral nutrition, an oral thiopurine, or intravenous cyclosporin or antitumour necrosis factor  antibody cause some fistulae to heal. ^{3 22 31} Many patients, however, still require surgical resection of the fistula and involved intestine.

Perianal disease
Non-suppurative perianal Crohn's disease may respond to oral metronidazole or ciprofloxacin, or both, given for up to 3 months ^{3 4} and to long term thiopurine.²² Successful healing of perianal fistulae was reported in 62% of patients treated with three intravenous infusions over 6 weeks of antitumour necrosis factor  antibody compared with 26% of those given placebo.³¹ Although reopening of fistulae was common in the 3 months after treatment was stopped, antitumour necrosis factor  antibody may prove a useful advance in patients with refractory perianal disease. Patients with suppurating perianal Crohn's disease need surgery, minimised as far as possible: abscesses are drained and loose (seton) sutures inserted to facilitate the continued drainage of chronic fistulae.⁴²

Crohn's colitis
Medical treatment of active Crohn's colitis resembles that of active ulcerative colitis. Oral or, in ill patients, intravenous corticosteroids remain the mainstay of treatment. Colonic release formulations of budesonide are under development. Oral aminosalicylates, including sulphasalazine, are an alternative in patients not acutely ill. ^{3 4} In contrast with ulcerative colitis about 50% of patients with moderately active Crohn's colitis respond to oral metronidazole for up to 3 months,³ but there are no data about the efficacy of cyclosporin. Compliant patients with Crohn's colitis, like ileitis, may respond to a liquid formula diet.³⁸

	Maintenance of remission of Crohn's disease

Top Introduction Methods Aetiopathogenesis Assessment Treatment of active ileocaecal... Dietary therapy Surgery Treatment of other common... Maintenance of remission of... The future References

The most effective prophylactic measure in patients who smoke is to stop: the risk of relapse in non-smokers at 5 years is about 30% lower than in smokers.² The efficacy of drug prophylaxis is limited and depends on whether remission has been achieved by medical or surgical treatment.

Patients in remission after medical treatment
Meta-analysis shows that, unlike in ulcerative colitis, long term aminosalicylates have little or no prophylactic effect in this setting.⁴⁴ Prednisolone in safe doses has no routine prophylactic role. ^{3 4} Unfortunately long term budesonide (6 mg/day), although less likely to cause steroid related complications, delays time to relapse without increasing the remission rate at 1 year. ^{45 46} Thiopurines are of proved value in maintaining remission and reducing steroid requirements in the minority of patients dependent on long term corticosteroids in whom symptoms recur whenever their dose is reduced.²²

Patients in remission after surgical treatment
Long term aminosalicylates (at least 3 g/day mesalazine) reduce the risk of symptomatic relapse after resection by less than 15%.⁴⁴ Oral budesonide (6 mg/day) halves endoscopic, although not symptomatic, recurrence rate at 1 year after resection for active but not fibrostenotic Crohn's disease.⁴⁸ Oral metronidazole given for 3 months postoperatively reduces symptomatic as well as endoscopic recurrence rate at 1 year although not over a longer period⁴⁹: it may be a useful option in patients reluctant to take drugs long term.

	The future

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Advances in medical treatment are likely to take several directions. Efforts are being made to formulate corticosteroids, aminosalicylates, and azathioprine in ways that focus delivery more accurately to the site of the disease. Our improved understanding of the aetiopathogenesis of Crohn's disease will lead to the development of further drugs, of which antitumour necrosis factor  antibody has been the first to reach the bedside, that are selectively targeted at specific points in the inflammatory pathway. The choice of treatment will depend increasingly not only on the phenotypic expression of patients' disease but also on their genotype. Finally, gene therapy, for example, applied topically to inflamed gut mucosa is an imminent possibility.

In view of the increasing variety and complexity of therapeutic options it will be essential to ensure that the patient remains at the centre of the decision making process as the fully informed and final arbiter of the type of treatment he or she is to be given.

	Acknowledgments

The address of the National Association for Colitis and Crohn's Disease is 4 Beaumont House, Sutton Road, St Albans, Herts AL1 5HH.

	Footnotes

Competing interests: DSR has received grants from Astra, Ferring, GlaxoWellcome, Janssen-Cilag, Pharmacia-Upjohn, Roche, SmithKline Beecham, and Wyeth for recruiting patients to clinical trials (none relevant to this review), for self initiated pathophysiological studies, for giving non-promotional lectures, and for travel to international meetings.

	References

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1.	Fiocchi C. Inflammatory bowel disease: aetiology and pathogenesis. Gastroenterology 1998; 115: 182-205[Medline].
2.	Cosnes J, Carbonnel F, Beaugerie L, Le Quintrec Y, Gendre JP. Effects of cigarette smoking on the long-term course of Crohn's disease. Gastroenterology 1996; 110: 424-431[Medline].
3.	Hanauer SB, Meyers S. Management of Crohn's disease in adults. Am J Gastroenterol 1997; 92: 559-566[Medline].
4.	Hanauer SB. Inflammatory bowel disease. N Engl J Med 1996; 334: 841-848[Free Full Text].
5.	Hodgson HJF. Laboratory markers of inflammatory bowel disease. In: Allan RN, Rhodes JM, Hanauer SB, Keighley MF, Alexander-Williams J, Fazio VW, eds. Inflammatory bowel diseases. New York: Churchill Livingstone, 1997:329-334.
6.	Wills JS, Lobis IF, Denstman FJ. Crohn's disease: state of the art. Radiology 1997; 202: 597-610[Free Full Text].
7.	Sachar DB. Cancer in Crohn's disease: dispelling the myths. Gut 1994; 35: 1507-1508[Free Full Text].
8.	Bhatti M, Chapman P, Peters M, Haskard D, Hodgson HJF. Visualising E-selectin in the detection and evaluation of inflammatory bowel disease. Gut 1998; 43: 40-47[Abstract/Free Full Text].
9.	Haggett PJ, Moore NR, Shearman JD, Travis SPL, Jewell DP, Mortensen NJ. Pelvic and perineal complications of Crohn's disease: assessment using magnetic resonance imaging. Gut 1995; 36: 407-410[Abstract/Free Full Text].
10.	Lennard-Jones JE. Practical management of the short bowel. Aliment Pharmacol Therap 1994; 8: 563-579[Medline].
11.	Thromboembolism Risk Factors (THRIFT) Consensus Group. Risk of and prophylaxis for venous thromboembolism in hospital patients. BMJ 1992; 305: 567-574.
12.	Kaufmann HJ, Taubin HL. Non steroidal anti-inflammatory drugs activate quiescent inflammatory bowel disease. Ann Intern Med 1987; 107: 513-516.
13.	Feagan BG, McDonald JWD, Koval JJ. Therapeutics and inflammatory bowel disease: a guide to the interpretation of randomised controlled trials. Gastroenterology 1996; 110: 275-283[Medline].
14.	Rutgeerts P, Lofberg R, Malchow H, Lamers C, Olaison G, Jewell D, et al. A comparison of budesonide with prednisolone for active Crohn's disease. N Engl J Med 1994; 331: 842-845[Abstract/Free Full Text].
15.	Campieri M, Ferguson A, Doe W, Persson T, Nilsson LG. Oral budesonide is as effective as oral prednisolone in active Crohn's disease. Gut 1997; 41: 209-214[Abstract/Free Full Text].
16.	Thomsen OO, Cortot A, Jewell DP, Wright JP, Winter T, Veloso FT, et al. A comparison of budesonide and mesalamine for active Crohn's disease. N Engl J Med 1998; 339: 370-374[Abstract/Free Full Text].
17.	Singleton JW, Hanauer SB, Gitnick GL, Peppercorn MA, Robinson MG, Wruble LD, et al. Mesalamine capsules for the treatment of active Crohn's disease: results of a 16-week trial. Gastroenterology 1993; 104: 1293-1301[Medline].
18.	Tremaine WJ, Schroeder KW, Harrison JM, Zinsmeister AR. A randomised, 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: 278-282[Medline].
19.	World MJ, Stevens PE, Ashton MA, Rainford DJ. Mesalazine-associated interstitial nephritis. Nephrol Dialysis Transplant 1996; 11: 614-621[Abstract/Free Full Text].
20.	Prantera C, Zannoni F, Scribano ML, Berto E, Andreoli A, Kohn A, et al. An antibiotic regimen for the treatment of active Crohn's disease: a randomised, controlled clinical trial of metronidazole plus ciprofloxacin. Am J Gastroenterol 1996; 91: 328-332[Medline].
21.	Thomas GA, Swift GL, Green JT, Newcombe RG, Braniff-Mathews C, Rhodes J, et al. Controlled trial of anti-tuberculous chemotherapy in Crohn's disease: a five year follow up study. Gut 1998; 42: 497-500[Abstract/Free Full Text].
22.	Pearson DC, May GR, Fick GH, Sutherland LR. Azathioprine and 6-mercaptopurine in Crohn's disease: a meta-analysis. Ann Intern Med 1995; 122: 132-142.
23.	Sandborn WJ, Tremaine WJ, Wolf DC, Targan SR, Sninsky CA, Sutherland LR, et al. Lack of effect of intravenous administration on time to respond to azathioprine for steroid-treated Crohn's disease. Gastroenterology 1999; 117: 527-535[Medline].
24.	Connell WR, Kamm MA, Ritchie JK, Lennard-Jones JE. Bone marrow toxicity caused by azathioprine in inflammatory bowel disease: 27 years of experience. Gut 1993; 34: 1081-1085[Abstract/Free Full Text].
25.	Connell WR, Kamm MA, Dickson M, Balkwill AM, Ritchie JK, Lennard-Jones JE. Long term neoplasia risk after azathioprine treatment in inflammatory bowel disease. Lancet 1994; 343: 1249-1252[Medline].
26.	Bouhnik Y, Lémann NM, Mary JY, Scemama G, Tai R, Matuchansky C, et al. Long term follow up of patients with Crohn's disease treated with azathioprine or 6-mercaptopurine. Lancet 1996; 347: 215-219[Medline].
27.	Feagan BG, Rochon JR, Fedorak RN, Irvine EJ, Wild G, Sutherland L, et al. Methotrexate for the treatment of Crohn's disease. N Engl J Med 1995; 332: 292-297[Abstract/Free Full Text].
28.	Oren R, Moshkowitz M, Odes S, Becker S, Keter D, Pomeranz I, et al. Methotrexate in chronic active Crohn's disease: a double-blind, randomised, Israeli multi-centre trial. Am J Gastroenterol 1997; 92: 2203-2209[Medline].
29.	Neurath MF, Wanitschke R, Peters M, Krummenauer F, Meyer zum Büschenfelde K-H, Schlaak JF. Randomised trial of mycophenolate mofetil versus azathioprine for treatment of chronic active Crohn's disease. Gut 1999; 44: 625-628[Abstract/Free Full Text].
30.	Targan SR, Hanauer SB, van Deventer SJH, Mayer L, Present DH, Braakman T, et al. A short-term study of chimeric monoclonal antibody cA2 to tumour necrosis factor alpha for Crohn's disease. N Engl J Med 1997; 337: 1029-1035[Abstract/Free Full Text].
31.	Present DH, Rutgeerts P, Targan S, Hanauer SB, Mayer L, van Hogesand RA, et al. Infliximab for the treatment of fistulas in patients with Crohn's disease. N Engl J Med 1999; 340: 1398-1405[Abstract/Free Full Text].
32.	Rutgeerts P, D'Haens G, Targan S, Vasiliauskas E, Hanauer SB, Present DH, et al. Efficacy and safety of retreatment with anti-tumour necrosis factor antibody (Infliximab) to maintain remission in Crohn's disease. Gastroenterology 1999; 117: 761-769[Medline].
33.	Plevy SE, Taylor K, DeWoody KL, Schaible TF, Shealy D, Targan SR. Tumour necrosis factor micro-satellite haplotypes and perinuclear anti-neutrophil cytoplasmic antibody (pANCA) identify Crohn's disease patients with poor clinical responses to anti-TNF monoclonal antibody (cA2). Gastroenterology 1997; 112: A1062.
34.	Lopez-Cupero SO, Sullivan KM, McDonald GB. Course of Crohn's disease after allogeneic marrow transplantation. Gastroenterology 1998; 114: 433-440[Medline].
35.	Bickston SJ, Cominelli F. Inflammatory bowel disease: short- and long-term treatments. Adv Intern Med 1998; 43: 143-174[Medline].
36.	Van Deventer SJH, Elson CO, Fedorak RN. Multiple doses of intravenous interleukin-10 in steroid-refractory Crohn's disease. Gastroenterology 1997; 113: 383-389[Medline].
37.	Neurath MF, Pettersson S, Meyer zum Büschenfelde K-H, Strober W. Local administration of antisense phosphothiolate oligonucleotides to the p65 subunit of NF-kB abrogates established experimental colitis in mice. Nature Med 1996; 2: 998-1004[Medline].
38.	Griffiths AM, Ohlsson A, Sherman PM, Sutherland LR. Meta-analysis of enteral nutrition as a primary therapy of active Crohn's disease. Gastroenterology 1995; 108: 1056-1067[Medline].
39.	Ogunbiyi OA, Fleshman JW. Place of laparoscopic surgery in Crohn's disease. Baillière's Clin Gastroenterol 1998; 12: 157-165[Medline].
40.	Couckuyt H, Gevers AM, Coremans G, Hiele M, Rutgeerts P. Efficacy and safety of hydrostatic balloon dilatation of ileocolonic Crohn's strictures: a prospective longterm analysis. Gut 1995; 36: 577-580[Abstract/Free Full Text].
41.	Lavey A. Triamcinolone improves outcome in Crohn's disease strictures. Dis Colon Rectum 1997; 40: 184-186[Medline].
42.	Kodner IJ. Perianal Crohn's disease. In: Allan RN, Rhodes JM, Hanauer SB, Keighley MF, Alexander-Williams J, Fazio VW, eds. Inflammatory bowel diseases. New York: Churchill Livingstone, 1997:863-872.
43.	Panis Y, Poupard B, Nemeth J, Lavergne A, Hautefeuille P, Valleur P. Ileal pouch/anal anastomosis for Crohn's disease. Lancet 1996; 347: 854-857[Medline].
44.	Cammà C, Giunta M, Rosselli M, Cottone M. Mesalazine in the maintenance treatment of Crohn's disease: a meta-analysis adjusted for confounding variables. Gastroenterology 1997; 113: 1465-1473[Medline].
45.	Greenberg GR, Feagan BG, Martin F, Sutherland LR, Thomson ABR, Williams CN, et al. Oral budesonide as maintenance treatment for Crohn's disease: a placebo-controlled, dose-ranging study. Gastroenterology 1996; 110: 45-51[Medline].
46.	Lofberg R, Rutgeerts P, Malchow H, Lamers C, Danielsson Å, Olaison G, et al. Budesonide prolongs time to relapse in ileal and ileocaecal Crohn's disease. A placebo-controlled one year study. Gut 1996; 39: 82-86[Abstract/Free Full Text].
47.	Belluzi 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: 1557-1560[Abstract/Free Full Text].
48.	Hellers G, Cortot A, Jewell DP, Leijonmarck CE, Löfberg R, Malchow H, et al. Oral budesonide for prevention of post surgical recurrence in Crohn's disease. Gastroenterology 1999; 116: 294-300[Medline].
49.	Rutgeerts P, Hiele M, Geboes K, Peeters P, Penninckx F, Aerts R, et al. Controlled trial of metronidazole treatment for prevention of Crohn's recurrence after ileal resection. Gastroenterology 1995; 108: 1617-1621[Medline].