T Kuhbacher, UR Fölsch, Department of Internal Medicine, University Hospital Schleswig-Holstein, Campus Kiel, Schitten-helmstr.12, Kiel 24105, Germany

Correspondence to: UR Fölsch, Department of Internal Medicine, University Hospital Schleswig-Holstein, Campus Kiel, Schittenhelmstr.12, 24105 Kiel, Germany. urföelsch@1med.uni-kiel.de

Telephone: +49-431-5971271    Fax: +49-431-5971271

Received: 2006-07-11               Accepted: 2006-12-28

Abstract

In recent years, great progress has been made regarding the treatment of inflammatory bowel disease (IBD), particularly in the field of biological therapies. Nevertheless, the ultimate treatment is not in sight. With the development of new medication, it has become clear that we need a new understanding of IBD. Therapy needs to fit the different subtypes of IBD; e.g. mild disease in comparison to severe chronic active disease or Crohn's disease with or without fistulation or stenosis. The following article gives a practical overview of actual treatments for IBD. The intention of this article is not to provide a complete review of all new scientific developments, but to give a practical guideline for therapy of IBD.

© 2007 The WJG Press. All rights reserved.

Key words: Inflammatory bowel disease; Ulcerative colitis; Crohn's disease; Immunomodulators; Anti-tumor necrosis factor

Kuhbacher T, Fölsch UR. Practical guidelines for the treatment of inflammatory bowel disease. World J Gastroenterol 2007; 13(8): 1149-1155

 http://www.wjgnet.com/1007-9327/13/1149.asp

INTRODUCTION

Crohn’s disease and ulcerative colitis are both defined as inflammatory bowel diseases (IBD), characterized by a chronic inflammation of the gut mucosa. The clinical course of both diseases can differ from a mild form, in which the patient reaches long-term remission without taking permanent medication, to a chronic active form, in which remission is only reached by permanently taking immunosuppressives and/or biologics or by taking them for a long period of time. Patients are not only burdened by the most common symptoms of IBDs; e.g. diarrhea, bowel pain, fever and complications such as fistulation, stenosis and abscesses in Crohn's disease and megacolon in ulcerative colitis, but are also burdened by the side-effects of the therapeutics, which the patients take to achieve a normal quality of life. Therefore, it is a great responsibility for a physician to consider treatment for an individual patient.

Recent discussions in the field of IBD are concerned with recommendations for a step-down or step-up therapy.  A step-down therapy means using the most effective biologic or immunosuppressive treatment on the market, even without prior use of therapeutics such as steroids, in order to reach an effective remission as soon as possible.  A step-up therapy means using a “classical” treatment by, for example, starting with aminosalicylates and ending up with an immunosuppressive and/or biological. Even if using a common step-up therapy treatment, the decision about which drug to use should be based on the individual patient, considering the clinical course and diagnosed complications according to current treatment guidelines.

This article provides a short overview of IBD and practical guidelines for the actual treatment of IBD (Figures 1 and 2). It is recognized that there is still an urgent medical need for improvement in the treatment in IBD and that treatments may not be sufficient for all patients, although great progress has been made in therapeutic approaches in the last decades (especially regarding biological therapeutics). The current guidelines for IBD therapy are distinguished by the course, place and severity of the clinical disease^[1-7]. In Crohn’s disease, a mild active form, a moderate or severe active form or a severe chronically active form can be differentiated. Patients can also be defined as steroid-dependent or steroid-refractory. The endoscopic and clinical pattern, the segments of the body that are involved (e.g. only small colon or small and large colon and/or stomach), the complications (such as fistulation and/or stenosis) as well as the duration of the inflammation and the response (or loss of response) to steroids are taken into account in the evaluation. In ulcerative colitis, differentiation is easier because inflammation only involves the large colon, starting from the rectum to the coecum. Therefore, treatment is determined by the clinical disease course and the involved segments of the colon, such as left-sided disease or pancolitis, as well as the response to steroids (steroid-dependent or steroid-refractory). In the following paragraphs the treatment of IBD will be discussed according to use of different therapeutic drugs.

5-Aminosalicylates (5-ASA)

5-ASA are bowel-specific drugs that are metabolized in the gut where the predominant actions occur. As a derivative of salicylic acid, 5-ASA is also an antioxidant that traps free radicals, which are potentially damaging by-products of metabolism. In the radical induction theory of ulcerative colitis, 5-ASA functions as a free radical trap as well as an anti-inflammatory drug. 5-ASA is considered to be the active moiety of sulphasalazine, which metabolizes to it. Oral and/or topical 5-ASA is recommended for mild to moderate ulcerative colitis to induce and maintain remission. The dosage of 5-ASA should be no less than 3 g/d. In practice, most patients do not like a topical treatment, but in left-sided disease, an enema with 4 g of 5-ASA 2 times per day or suppositories with 500 mg 5-ASA 3 times per day are most effective. Sometimes it is helpful for the patient to use the enema only in the evening and the suppositories in the morning. In Crohn’s disease, aminosalicylates should also be used in initial therapy for mild disease, although discussion about efficacy has increased recently. In contrast to ulcerative colitis, the use of aminosalicylates for the maintenance of remission is not recommended for Crohn’s disease because clinical studies have not shown success in remission maintenance^[8,9]. 5-ASA is a standard treatment for ulcerative colitis, but not for Crohn’s disease. In the last few years, new formulations have been on the market with varying clinical value. In some special cases; e.g. patients with an ileostoma, a formulation that sets metabolites free prior to the large bowel may be helpful. In patients with IBD and arthritis, sulphasalazine rather than 5-ASA formulations seems to be more effective regarding arthritis. In most patients, the side-effects are not very severe with headache as one of the most common side-effects. However, in some cases nephritis, pancreatitis and hair loss have been reported, which suggests regular monitoring of renal and liver enzymes at least once in three months.

Antibiotics

Antibiotics (e.g. metronidazole) play only a minor role in the additional treatment of fistulizing disease^[10]. Although metronidazole (for up to 3 mo in a dosage of 400 mg 2 times per day) is often used in post-operative management after an ileocecal resection or fistula/abscess operation for Crohn’s disease, this therapy is not based on study evidence. A side-effect of long-term treatment with metronidazole is polyneuropathy and monitoring is, therefore, required. Antibiotics are also used in the conservative treatment of small abscesses. Understanding the role of microbiota and antibiotics in IBD may become important in the future, but currently clinical studies have not provided support for this concern.

Corticosteroids

In patients with moderate to severe Crohn’s disease or ulcerative colitis, corticosteroids are effective for the induction of clinical response and remission^[11-16]. Dosages from 40-60 mg/d or 1 mg/kg per day orally are effective for the induction of remission. After the induction of remission, the steroid dose should be tapered (10 mg/wk until 40 mg; 5 mg/wk until 20 mg, followed by a tapering of 2.5 mg/wk). In severe disease, the application of parenteral glucocorticoids as soon as possible is useful for an anti-inflammatory response. Before the initiation of steroid treatment, the presence of an abscess should be excluded. In patients who have been on glucocorticoids for more than one month, an ACTH (Adrenocorticotropic hormone)-Test should be performed before beginning tapering of the steroid. The ACTH-test can detect deficient cortisol production in the body. If there is a deficiency, hydrocortisone should be used as a substitute.

Budesonide

The benefits of glucocorticoid therapy should be carefully balanced against possible side-effects. Budesonide can reduce typical steroid side effects by a 90% first-pass metabolism in the liver and erythrocytes. Due to a special structural formulation, budesonide achieves the best anti-inflammatory effect in ileocecal inflammation^[17-20]. Therefore, it is useful in therapy for Crohn’s disease with ileocecal inflammation only. However, neither budesonide nor any other glucocorticosteroid should be used for a maintenance therapy due to the side-effects (e.g. Cushing-syndrome, osteoporosis or cardiomyopathy^[21,22]). All patients treated with corticosteroids should additionally receive vitamin D and calcium substitution to avoid bone loss.

Immunosuppressives

The clinical course of 36% of IBD patients is defined as steroid-refractory and in 20% as steroid-dependent^[23]. Immunomodulators are, therefore, recommended for the treatment of chronic active IBD. Studies have shown an efficacy for immunosuppressives that is similar to azathioprine and its metabolite, 6-mercaptopurine (6-MP; 2-3 mg/kg per day, resp. 1-1.5 mg/kg per day), in the long-term use of chronic active disease. Immunomodulators have been shown to be efficient for the control of inflammation and remission maintenance. Only limited data exists on the efficacy of immunosuppressants in fistulizing Crohn’s disease and the prevention of post-operative recurrence^[24-30]. Evidence-based data is missing on the post-operative use of azathioprine and many IBD referral centers are using azathioprine for the prevention of post-operative recurrence. Prior to an initiation of treatment with azathioprine or 6-MP, patients should be thiopurine methyltransferase (TPMT) genotype assessed in order to detect for a homozygous deficiency in TPMT in an effort to avert AZA or 6-MP-induced potential adverse events. All patients on azathioprine or 6-MP should be monitored weekly in the first month and after that once a month regarding their white blood count and liver enzymes because a myelosuppression or an elevation of liver enzymes subsequent to the use of azathioprine or 6-MP can occur. In such cases, the dosage of azathioprine or 6-MP should be reduced or paused until lab values are normal. In patients with gastrointestinal side-effects after the intake of azathioprine, a change to 6-MP should be considered.

Methotrexate and cyclosporine

Methotrexate is another immunomodulatory agent that is used in long-term treatment of IBD. The dosage for induction of remission in chronic active disease is 25 mg i.m. per week for 16 wk, followed by a maintenance treatment of 15 mg i.m. per week. In contrast to azathioprine and 6-MP, the data on use of methotrexate is rather scarce^[31-33]. Cyclosporine is reserved for the treatment of severe steroid-refractory ulcerative colitis only. Intravenous cyclosporine (2-4 mg/kg) was able to prevent a decidered colectomy in two of three patients with severe ulcerative colitis. Due to its toxicity, use should be considered carefully; i.e. it should be used only in very severe active disease cases to avoid a colectomy. In Crohn’s disease, cyclosporine has been shown to be effective only in fistulizing, but not luminal disease^[34-37].

Tacrolimus

Only very inadequate data is available for tacrolimus. Improvement of fistula drainage, but not closure was demonstrated in a randomized, placebo-controlled trial with tacrolimus^[38,39].

Infliximab

Biological therapies, especially anti-TNF agents, play a pivotal role in the treatment of chronic active IBD and fistulizing disease^[40-43]. The first anti-TNF agent on the market, infliximab, is a chimeric IgG1 mouse/human monoclonal antibody. Randomised, placebo-controlled trials (ACCENTⅠand Ⅱ) demonstrated the efficacy of infliximab (5 mg/kg, i.v.) in the induction of clinical response and remission in patients with active Crohn´s disease. In fistulizing disease, complete fistula closure of at least 50% of the fistulas could be seen in 55% of the patients after three infusions of infliximab at wk 0, 2 and 6 (ACCENT Ⅱ). Given on a regular basis in intervals of 8-12 wk (5 mg/kg i.v.), infliximab is able to maintain remission^[44-50].

In ulcerative colitis, the recently completed ACTⅠand ACT Ⅱ randomised, placebo-controlled trials demonstrated the efficacy of infliximab treatment in induction of remission and mucosal healing in 61.2% of the infliximab treated patients versus 32.4% of placebo treated patients^[51,52].

Contraindications and side-effects should be taken into consideration carefully prior to infliximab therapy^[53].  Due to immunogenicity, infliximab can lead to the formation of human anti-chimeric antibodies (HACA) in 30% to 75% of the patients. Additional administration of immunosuppressants; e.g. azathioprine and/or pretreatment with intravenous prednisolone, can reduce the risks of HACA formation. The main reported side-effect is an infusion reaction, which can occur as an acute allergic/anaphylactic reaction or a delayed hypersensitivity reaction. In clinical trials, observations have included infections, drug-induced lupus, cardiac failure, non-Hodgkin's lymphoma and, in post-marketing surveillance, tuberculosis, pneumonia, histoplasmosis, listeriosis and aspergillosis. To avoid a potential tuberculosis reactivation, a purified protein derivative (PPD) skin test and a chest-X-ray should be performed prior to infliximab treatment^[54-67].

Patients with perianal or enterocutaneous fistulizing Crohn’s disease should be treated first with infliximab. The effect of infliximab is not as effective on entero-enteral or recto-vaginal fistulas. Patients with steroid-refractory or chronic active Crohn’s disease or ulcerative colitis who do not respond to immunosuppressive therapy alone should also be treated with infliximab. The recommended treatment regimen is an induction scheme with three infusions (5 mg/kg i.v.) at 0, 2 and 6 wk, followed by a maintenance treatment of infliximab every 8 wk (5 mg/kg i.v.). Additionally, immunosuppressive therapy with azathioprine, for example, is recommended. HACA testing is not recommended routinely for every patient on infliximab, but it is recommended if there is a delayed hypersensitivity reaction or if the last infliximab infusion was more than 12 wk previous.

Adalimumab

Other TNF agents also showed efficacy in Crohn’s disease. The human IgG1 antibody adalimumab, which is a therapeutic agent used for rheumatoid arthritis, was effective in open-label experience. A placebo-controlled, randomised trial was also conducted. One advantage, in comparison to infliximab, might be the completely human structure of the antibody, which leads to better tolerance and a subcutaneous route of administration. Data on adverse reactions in Crohn’s disease patients are still not available, but adalimumab is well-tolerated in patients with rheumatoid arthritis^[68-71].

CDP-870

Certolizumab pegol (CDP-870), which is a polyethylene-glycolated Fab-fragment of the anti-tumour necrosis factor, has been shown to be effective in the treatment of Crohn’s disease in a recent published, randomised, placebo-controlled trial. At week ten, 52.8% of the certolizumab (400 mg) treated patients showed a clinical response versus 30.1% in the placebo treated group (the high placebo response was seen in a large patient subgroup with low C-reactive protein levels; this might have been due to statistical separation between treatment and placebo group^[72]). The antibody was well tolerated. Ongoing trials, however, are necessary to establish efficacy in Crohn’s disease.

CDP-571

CDP-571, which is a humanized IgG4 monoclonal antibody against tumour necrosis factor alpha, initially showed an induction of clinical response in controlled trials, but failed in a phase Ⅲ trial which was discontinued^[73].

Onercept and eternacept

Onercept, which is a recombinant human p55 soluble receptor to TNF, and also eternacept, which is a recombinant human p75 soluble receptor to TNF, failed in a phase Ⅱ trial with Crohn’s disease and both trials were discontinued^[74-76].

Natalizumab

Adhesion molecule inhibiting agents, such as natalizumab, which is a humanized IgG4 antibody, demonstrated a clinical response in a clinical trial in Crohn’s disease, but all trials had to be stopped immediately after cases of progressive multifocal leucencephalopathy in patients receiving natalizumab for multiple sclerosis were reported^[77-79].

The antisense oligonucleotide of the adhesion molecule ICAM-1 (anti-ICAM-1) was ineffective in Crohn’s disease^[80].

A hopeful, novel approach for the treatment of Crohn’s disease is an anti-IL-12/IL-23p40 antibody that proved effective for induction of response and remission in a phase Ⅱ study^[81].

b-Interferon

The use of b-Interferon, which has been investigated in a small pilot study in ulcerative colitis with a subcutaneous administration, seems to be effective, but larger, randomised, placebo-controlled studies need to be performed to clarify the clinical efficacy^[82].

In conclusion, the only biological therapeutic today, which has been proven effective in IBD and is available on the market is infliximab. The market release of new TNF agents might happen in the near future.

Probiotics

A different group of therapeutic agents for therapy of IBD are probiotics. The use of probiotics has been advocated in colonic inflammatory disease for a long time. Only recently, two controlled trials demonstrated that E. coli nissle is as effective as 5-ASA for remission maintenance in ulcerative colitis^[83,84]. For remission maintenance and pouchitis, studies demonstrated the benefit of probiotics^[85,86]. Due to a better understanding of the molecular events and the pathophysiological processes of this disease, it is hoped that more probiotic agents will be developed in the near future.

5-ASA

A short, practical guideline would be incomplete without discussing IBD and pregnancy. 5-ASA is not harmful during pregnancy and there is very little placental transport. 5-ASA should be avoided during breast feeding because there are no studies on 5-ASA use during breast feeding^[87]. Acute disease or a flare up of IBD can be treated throughout an entire pregnancy with steroids. Glucocorticoids pass the placental barrier, but there has been no significant evidence of teratogenesis. There have been some observations of cleft lip and palate associated with the intake of steroids. In general, no increase in fetal complications have been found with use of 5-ASA compared to the general population^[88].

Azathioprine or 6-mercaptupurine

The use of azathioprine or 6-mercaptupurine should not be completed during pregnancy. Extensive experience with use of these substances during pregnancy exists with other autoimmune diseases and patients who received renal transplants. No teratogenic effects in humans have been reported so far. However, it is very important to discuss all the data and possible complications with the patient and it is essential that the decision to take the drug should be made by the patient^[89].

Methotrexate is contraindicated during pregnancy as it is mutagenic and teratogenic^[90]. Cyclosporine is not teratogenic, but due to its side-effects, it needs to be considered very carefully and should only be used to avoid a colectomy^[91]. Infliximab should not be given as maintenance therapy during pregnancy. In very severe disease, it can be considered as an emergency therapy^[92].Nutrition has not been discussed in this article so far. However, the balance of trace elements and vitamins is essential for successful therapy. Vitamin B12 and folinic acid, for example, should be monitored in Crohn’s disease patients with ileal inflammation to avoid a deficiency syndrome, which can lead to severe anemia. Also ferritin should be monitored and, if necessary, substituted orally or intravenously to avoid severe iron deficiency anemia. In severe cases of iron deficiency anemia, erythropoietin (10 000IE s.c. 3 times per week) plus iron i.v. (62.5 mg in 250 mL NaCl) is effective^[93]. In severe ulcerative colitis or Crohn’s disease, patients profit from short term parenteral or additional high calorie nutrition^[94].

All above treatment regimens attempt to avoid complications and inflammation in IBD. However, all conservative therapy sometimes fails or is not effective enough. Examples might be therapy for refractory ulcerative colitis, which can only be successfully treated by an operation (e.g. a colectomy with an ileoanal pouch anastomosis), non-inflammatory stricture in Crohn’s disease or severe fistulizing disease, in which a protective ileostoma can be very useful for supporting conservative treatment. In such cases, close collaboration with an experienced IBD surgeon is essential.

It can be summarized that although a number of new biological agents have been developed in the last decades for the treatment of IBD, there is still a great need for new pharmcotherapeutics, particularly for chronic refractory disease patients with multiple complications.

REFERENCES

1       Hanauer SB, Meyers S. Management of Crohn's disease in adults. Am J Gastroenterol 1997; 92: 559-566   PubMed

2       Stange EF, Schreiber S, Folsch UR, von Herbay A, Scholmerich J, Hoffmann J, Zeitz M, Fleig WE, Buhr HJ, Kroesen AJ,   Moser G, Matthes H, Adler G, Reinshagen M, Stein J. Z Gastroenterol 2003; 41: 19-20   PubMed

3       Hoffmann JC, Zeitz M, Bischoff SC, Brambs HJ, Bruch HP, Buhr HJ, Dignass A, Fischer I, Fleig W, Folsch UR, Herrlinger   K, Hohne W, Jantschek G, Kaltz B, Keller KM, Knebel U, Kroesen AJ, Kruis W, Matthes H, Moser G, Mundt S, Pox C,   Reinshagen M, Reissmann A, Riemann J, Rogler G, Schmiegel W, Scholmerich J, Schreiber S, Schwandner O,   Selbmann HK, Stange EF, Utzig M, Wittekind C. Z Gastroenterol 2004; 42: 979-983   PubMed

4       RRutgeerts PJ. Conventional treatment of Crohn's disease: objectives and outcomes. Inflamm Bowel Dis 2001; 7   Suppl 1: S2-S8   PubMed

5       Kuhbacher T, Schreiber S, Folsch UR. Ulcerative colitis: conservative management and long-term effects.   Langenbecks Arch Surg 2004; 389: 350-353   PubMed

6       Feagan BG. Maintenance therapy for inflammatory bowel disease. Am J Gastroenterol 2003; 98: S6-S17   PubMed

7       Hanauer SB, Present DH. The state of the art in the management of inflammatory bowel disease. Rev Gastroenterol   Disord 2003; 3: 81-92   PubMed

8       Camma C, Giunta M, Rosselli M, Cottone M. Mesalamine in the maintenance treatment of Crohn's disease: a meta-  analysis adjusted for confounding variables. Gastroenterology 1997; 113: 1465-1473   PubMed

9       Sutherland L, Roth D, Beck P, May G, Makiyama K. Oral 5-aminosalicylic acid for inducing remission in ulcerative   colitis. Cochrane Database Syst Rev 2000; : CD000543   PubMed

10      Thukral C, Travassos WJ, Peppercorn MA. The Role of Antibiotics in Inflammatory Bowel Disease. Curr Treat Options   Gastroenterol 2005; 8: 223-228   PubMed

11      Summers RW, Switz DM, Sessions JT Jr, Becktel JM, Best WR, Kern F Jr, Singleton JW. National Cooperative Crohn's    Disease Study: results of drug treatment. Gastroenterology 1979; 77: 847-869   PubMed

12      Malchow H, Ewe K, Brandes JW, Goebell H, Ehms H, Sommer H, Jesdinsky H. European Cooperative Crohn's Disease    Study (ECCDS): results of drug treatment. Gastroenterology 1984; 86: 249-266   PubMed

13      Truelove SC, Witts LJ. Cortisone in ulcerative colitis; final report on a therapeutic trial. Br Med J 1955; 2: 1041-1048     PubMed

14      Modigliani R, Mary JY, Simon JF, Cortot A, Soule JC, Gendre JP, Rene E. Clinical, biological, and endoscopic picture of    attacks of Crohn's disease. Evolution on prednisolone. Groupe d'Etude Therapeutique des Affections Inflammatoires    Digestives. Gastroenterology 1990; 98: 811-818   PubMed

15      Shepherd HA, Barr GD, Jewell DP. Use of an intravenous steroid regimen in the treatment of acute Crohn's disease. J   Clin Gastroenterol 1986; 8: 154-159   PubMed

16      Smith RC, Rhodes J, Heatley RV, Hughes LE, Crosby DL, Rees BI, Jones H, Evans KT, Lawrie BW. Low dose steroids    and clinical relapse in Crohn's disease: a controlled trial. Gut 1978; 19: 606-610   PubMed

17      Ferguson A, Campieri M, Doe W, Persson T, Nygard G. Oral budesonide as maintenance therapy in Crohn's disease--   results of a 12-month study. Global Budesonide Study Group. Aliment Pharmacol Ther 1998; 12: 175-183   PubMed

18      Thomsen OO, Cortot A, Jewell D, Wright JP, Winter T, Veloso FT, Vatn M, Persson T, Pettersson E. A comparison of    budesonide and mesalamine for active Crohn's disease. International Budesonide-Mesalamine Study Group. N Engl J    Med 1998; 339: 370-374   PubMed

19      Hellers G, Cortot A, Jewell D, Leijonmarck CE, Lofberg R, Malchow H, Nilsson LG, Pallone F, Pena S, Persson T,    Prantera C, Rutgeerts P. Oral budesonide for prevention of postsurgical recurrence in Crohn's disease. The IOIBD    Budesonide Study Group. Gastroenterology 1999; 116: 294-300   PubMed

20      Lofberg R, Rutgeerts P, Malchow H, Lamers C, Danielsson A, Olaison G, Jewell D, Ostergaard Thomsen O, Lorenz-  Meyer H, Goebell H, Hodgson H, Persson T, Seidegard C. Budesonide prolongs time to relapse in ileal and ileocaecal   Crohn's disease. A placebo controlled one year study. Gut 1996; 39: 82-86   PubMed

21      Lukert BP, Raisz LG. Glucocorticoid-induced osteoporosis: pathogenesis and management. Ann Intern Med 1990; 112:   352-364   PubMed

22      Chun A, Chadi RM, Korelitz BI, Colonna T, Felder JB, Jackson MH, Morgenstern EH, Rubin SD, Sacknoff AG, Gleim GM.   Intravenous corticotrophin vs. hydrocortisone in the treatment of hospitalized patients with Crohn's disease: a   randomized double-blind study and follow-up. Inflamm Bowel Dis 1998; 4: 177-181   PubMed

23      Munkholm P, Langholz E, Davidsen M, Binder V. Frequency of glucocorticoid resistance and dependency in Crohn's   disease. Gut 1994; 35: 360-362   PubMed

24      Candy S, Wright J, Gerber M, Adams G, Gerig M, Goodman R. A controlled double blind study of azathioprine in the   management of Crohn's disease. Gut 1995; 37: 674-678   PubMed

25      Hawthorne AB, Logan RF, Hawkey CJ, Foster PN, Axon AT, Swarbrick ET, Scott BB, Lennard-Jones JE. Randomised   controlled trial of azathioprine withdrawal in ulcerative colitis. BMJ 1992; 305: 20-22   PubMed

26      Pearson DC, May GR, Fick GH, Sutherland LR. Azathioprine and 6-mercaptopurine in Crohn disease. A meta-analysis.   Ann Intern Med 1995; 123: 132-142   PubMed

27      Pearson DC, May GR, Fick G, Sutherland LR. Azathioprine for maintaining remission of Crohn's disease. Cochrane   Database Syst Rev 2000; CD000067   PubMed

28      Sandborn W, Sutherland L, Pearson D, May G, Modigliani R, Prantera C. Azathioprine or 6-mercaptopurine for   inducing remission of Crohn's disease. Cochrane Database Syst Rev 2000; CD000545   PubMed

29      Hanauer SB, Korelitz BI, Rutgeerts P, Peppercorn MA, Thisted RA, Cohen RD, Present DH. Postoperative maintenance   of Crohn's disease remission with 6-mercaptopurine, mesalamine, or placebo: a 2-year trial. Gastroenterology 2004;   127: 723-729   PubMed

30      Korelitz BI, Adler DJ, Mendelsohn RA, Sacknoff AL. Long-term experience with 6-mercaptopurine in the treatment of   Crohn's disease. Am J Gastroenterol 1993; 88: 1198-1205   PubMed

31      Sandborn WJ. A review of immune modifier therapy for inflammatory bowel disease: azathioprine, 6-mercaptopurine,   cyclosporine, and methotrexate. Am J Gastroenterol 1996; 91: 423-433   PubMed

32      Kozarek RA, Patterson DJ, Gelfand MD, Botoman VA, Ball TJ, Wilske KR. Methotrexate induces clinical and histologic   remission in patients with refractory inflammatory bowel disease. Ann Intern Med 1989; 110: 353-356   PubMed

33      Feagan BG, Fedorak RN, Irvine EJ, Wild G, Sutherland L, Steinhart AH, Greenberg GR, Koval J, Wong CJ, Hopkins M,   Hanauer SB, McDonald JW. A comparison of methotrexate with placebo for the maintenance of remission in Crohn's   disease. North American Crohn's Study Group Investigators. N Engl J Med 2000; 342: 1627-1632   PubMed

34      Lichtiger S, Present DH, Kornbluth A, Gelernt I, Bauer J, Galler G, Michelassi F, Hanauer S. Cyclosporine in severe   ulcerative colitis refractory to steroid therapy. N Engl J Med 1994; 330: 1841-1845   PubMed

35      Van Assche G, D'Haens G, Noman M, Vermeire S, Hiele M, Asnong K, Arts J, D'Hoore A, Penninckx F, Rutgeerts P.   Randomized, double-blind comparison of 4 mg/kg versus 2 mg/kg intravenous cyclosporine in severe ulcerative colitis.   Gastroenterology 2003; 125: 1025-1031   PubMed

36      Egan LJ, Sandborn WJ, Tremaine WJ. Clinical outcome following treatment of refractory inflammatory and fistulizing   Crohn's disease with intravenous cyclosporine. Am J Gastroenterol 1998; 93: 442-448   PubMed

37      Lichtenstein GR, Abreu MT, Cohen R, Tremaine W. American Gastroenterological Association Institute technical   review on corticosteroids, immunomodulators, and infliximab in inflammatory bowel disease. Gastroenterology 2006;   130: 940-987   PubMed

38      Fellermann K, Ludwig D, Stahl M, David-Walek T, Stange EF. Steroid-unresponsive acute attacks of inflammatory   bowel disease: immunomodulation by tacrolimus (FK506). Am J Gastroenterol 1998; 93: 1860-1866   PubMed

39      Sandborn WJ, Present DH, Isaacs KL, Wolf DC, Greenberg E, Hanauer SB, Feagan BG, Mayer L, Johnson T, Galanko J,   Martin C, Sandler RS. Tacrolimus for the treatment of fistulas in patients with Crohn's disease: a randomized, placebo-  controlled trial. Gastroenterology 2003; 125: 380-388   PubMed

40      van Deventer SJ. Review article: targeting TNF alpha as a key cytokine in the inflammatory processes of Crohn's   disease--the mechanisms of action of infliximab. Aliment Pharmacol Ther 1999; 13 Suppl 4: 3-8; discussion 38     PubMed

41         Van Assche G, Vermeire S, Rutgeerts P. Medical treatment of inflammatory bowel diseases. Curr Opin Gastroenterol   2005; 21: 443-447   PubMed

42      Rutgeerts PJ. An historical overview of the treatment of Crohn's disease: why do we need biological therapies? Rev   Gastroenterol Disord 2004; 4 Suppl 3: S3-S9   PubMed

43      Targan SR, Hanauer SB, van Deventer SJ, Mayer L, Present DH, Braakman T, DeWoody KL, Schaible TF, Rutgeerts PJ.   A short-term study of chimeric monoclonal antibody cA2 to tumor necrosis factor alpha for Crohn's disease. Crohn's   Disease cA2 Study Group. N Engl J Med 1997; 337: 1029-1035   PubMed

44      Hanauer SB, Feagan BG, Lichtenstein GR, Mayer LF, Schreiber S, Colombel JF, Rachmilewitz D, Wolf DC, Olson A, Bao   W, Rutgeerts P. Maintenance infliximab for Crohn's disease: the ACCENT I randomised trial. Lancet 2002; 359: 1541-  1549   PubMed

45      Present DH, Rutgeerts P, Targan S, Hanauer SB, Mayer L, van Hogezand RA, Podolsky DK, Sands BE, Braakman T,   DeWoody KL, Schaible TF, van Deventer SJ. Infliximab for the treatment of fistulas in patients with Crohn's disease. N   Engl J Med 1999; 340: 1398-1405   PubMed

46      Hanauer SB. Efficacy and safety of tumor necrosis factor antagonists in Crohn's disease: overview of randomized   clinical studies. Rev Gastroenterol Disord 2004; 4 Suppl 3: S18-S24   PubMed

47      Sandborn WJ. New concepts in anti-tumor necrosis factor therapy for inflammatory bowel disease. Rev Gastroenterol   Disord 2005; 5: 10-18   PubMed

48    Travassos WJ, Cheifetz AS. Infliximab: Use in Inflammatory Bowel Disease. Curr Treat Options Gastroenterol   2005; 8: 187-196   PubMed

49      Rutgeerts P, Feagan BG, Lichtenstein GR, Mayer LF, Schreiber S, Colombel JF, Rachmilewitz D, Wolf DC, Olson A, Bao   W, Hanauer SB. Comparison of scheduled and episodic treatment strategies of infliximab in Crohn's disease.   Gastroenterology 2004; 126: 402-413   PubMed

50      Rutgeerts P, D'Haens G, Targan S, Vasiliauskas E, Hanauer SB, Present DH, Mayer L, Van Hogezand RA, Braakman T,   DeWoody KL, Schaible TF, Van Deventer SJ. Efficacy and safety of retreatment with anti-tumor necrosis factor antibody   (infliximab) to maintain remission in Crohn's disease. Gastroenterology 1999; 117: 761-769   PubMed

51      Rutgeerts P, Feagan BG, Olson A, Johanns J, Travers S, Present D, Sands BE, Sandborn W, Olson A. A Randomized   Placebo-Controlled Trial Of Infliximab Therapy for Active Ulcerative Colitis: the Act 1 Trial

52      Sandborn WJ, Rachmilewitz D, Hanauer SB, Lichtenstein GR, de Villiers WJ, Olson A,Joharms J, Traverse S, Colombel   JF. Infliximab Induction and Maintenance Therapy for Ulcerative Colitis: the Act 2 Trial

53      Schreiber S, Campieri M, Colombel JF, van Deventer SJ, Feagan B, Fedorak R, Forbes A, Gassull M, Gendre JP, van   Hogezand RA, Lofberg R, Modigliani R, Pallone F, Petritsch W, Prantera C, Rampton D, Seibold F, Vatn M, Zeitz M,   Rutgeerts P. Use of anti-tumour necrosis factor agents in inflammatory bowel disease. European guidelines for 2001-  2003. Int J Colorectal Dis 2001; 16: 1-11; discussion 12-13   PubMed

54      Hanauer SB, Wagner CL, Bala M, Mayer L, Travers S, Diamond RH, Olson A, Bao W, Rutgeerts P. Incidence and   importance of antibody responses to infliximab after maintenance or episodic treatment in Crohn's disease. Clin   Gastroenterol Hepatol 2004; 2: 542-553   PubMed

55      Baert F, Noman M, Vermeire S, Van Assche G, D' Haens G, Carbonez A, Rutgeerts P. Influence of immunogenicity on   the long-term efficacy of infliximab in Crohn's disease. N Engl J Med 2003; 348: 601-608   PubMed

56      Farrell RJ, Alsahli M, Jeen YT, Falchuk KR, Peppercorn MA, Michetti P. Intravenous hydrocortisone premedication   reduces antibodies to infliximab in Crohn's disease: a randomized controlled trial. Gastroenterology 2003; 124: 917-  924   PubMed

57      Cheifetz A, Smedley M, Martin S, Reiter M, Leone G, Mayer L, Plevy S. The incidence and management of infusion   reactions to infliximab: a large center experience. Am J Gastroenterol 2003; 98: 1315-1324   PubMed

58      Hanauer S, Rutgeerts P, Targan S, D’Haens G, Targan S, Kam L, Present D, Mayer L, Wagner C, LaSorda J, Sands B,   Livingston R. Delayed hypersensitivity to infliximab (Remicade) reinfusion after a 2-4 year interval without treatment.   Gastroenterology. 1999; 116: A731

59      Remicade [package insert]. Malvern. PA: Centocor, 2004

60      Vermeire S, Noman M, Van Assche G, Baert F, Van Steen K, Esters N, Joossens S, Bossuyt X, Rutgeerts P.   Autoimmunity associated with anti-tumor necrosis factor alpha treatment in Crohn's disease: a prospective cohort   study. Gastroenterology 2003; 125: 32-39   PubMed

61      Mohan N, Edwards ET, Cupps TR, Oliverio PJ, Sandberg G, Crayton H, Richert JR, Siegel JN. Demyelination occurring   during anti-tumor necrosis factor alpha therapy for inflammatory arthritides. Arthritis Rheum 2001; 44: 2862-2869     PubMed

62      Thomas CW Jr, Weinshenker BG, Sandborn WJ. Demyelination during anti-tumor necrosis factor alpha therapy with   infliximab for Crohn's disease. Inflamm Bowel Dis 2004; 10: 28-31   PubMed

63      Brown SL, Greene MH, Gershon SK, Edwards ET, Braun MM. Tumor necrosis factor antagonist therapy and lymphoma   development: twenty-six cases reported to the Food and Drug Administration. Arthritis Rheum 2002; 46: 3151-3158     PubMed

64      Kwon HJ, Cote TR, Cuffe MS, Kramer JM, Braun MM. Case reports of heart failure after therapy with a tumor necrosis   factor antagonist. Ann Intern Med 2003; 138: 807-811   PubMed

65      Keane J, Gershon S, Wise RP, Mirabile-Levens E, Kasznica J, Schwieterman WD, Siegel JN, Braun MM. Tuberculosis   associated with infliximab, a tumor necrosis factor alpha-neutralizing agent. N Engl J Med 2001; 345: 1098-1104     PubMed

66      Lee JH, Slifman NR, Gershon SK, Edwards ET, Schwieterman WD, Siegel JN, Wise RP, Brown SL, Udall JN Jr, Braun   MM. Life-threatening histoplasmosis complicating immunotherapy with tumor necrosis factor alpha antagonists   infliximab and etanercept. Arthritis Rheum 2002; 46: 2565-2570   PubMed

67      Velayos FS, Sandborn WJ. Pneumocystis carinii pneumonia during maintenance anti-tumor necrosis factor-alpha   therapy with infliximab for Crohn's disease. Inflamm Bowel Dis 2004; 10: 657-660   PubMed

68      Papadakis KA, Shaye OA, Vasiliauskas EA, Ippoliti A, Dubinsky MC, Birt J, Paavola J, Lee SK, Price J, Targan SR, Abreu   MT. Safety and efficacy of adalimumab (D2E7) in Crohn's disease patients with an attenuated response to infliximab.   Am J Gastroenterol 2005; 100: 75-79   PubMed

69      Sandborn WJ, Hanauer S, Loftus EV Jr, Tremaine WJ, Kane S, Cohen R, Hanson K, Johnson T, Schmitt D, Jeche R. An   open-label study of the human anti-TNF monoclonal antibody adalimumab in subjects with prior loss of response or   intolerance to infliximab for Crohn's disease. Am J Gastroenterol 2004; 99: 1984-1989   PubMed

70      Youdim A, Vasiliauskas EA, Targan SR, Papadakis KA, Ippoliti A, Dubinsky MC, Lechago J, Paavola J, Loane J, Lee SK,   Gaiennie J, Smith K, Do J, Abreu MT. A pilot study of adalimumab in infliximab-allergic patients. Inflamm Bowel Dis   2004; 10: 333-338   PubMed

71      Baker DE. Adalimumab: human recombinant immunoglobulin g1 anti-tumor necrosis factor monoclonal antibody. Rev   Gastroenterol Disord 2004; 4: 196-210   PubMed

72      Schreiber S, Rutgeerts P, Fedorak RN, Khaliq-Kareemi M, Kamm MA, Boivin M, Bernstein CN, Staun M, Thomsen OO,   Innes A. A randomized, placebo-controlled trial of certolizumab pegol (CDP870) for treatment of Crohn's disease.   Gastroenterology 2005; 129: 807-818   PubMed

73      Sandborn WJ, Feagan BG, Radford-Smith G, Kovacs A, Enns R, Innes A, Patel J. CDP571, a humanised monoclonal   antibody to tumour necrosis factor alpha, for moderate to severe Crohn's disease: a randomised, double blind, placebo   controlled trial. Gut 2004; 53: 1485-1493   PubMed

74      Sandborn WJ, Hanauer SB, Katz S, Safdi M, Wolf DG, Baerg RD, Tremaine WJ, Johnson T, Diehl NN, Zinsmeister AR.   Etanercept for active Crohn's disease: a randomized, double-blind, placebo-controlled trial. Gastroenterology 2001;   121: 1088-1094   PubMed

75      D'Haens G, Swijsen C, Noman M, Lemmens L, Ceuppens J, Agbahiwe H, Geboes K, Rutgeerts P. Etanercept in the   treatment of active refractory Crohn's disease: a single-center pilot trial. Am J Gastroenterol 2001; 96: 2564-2568     PubMed

76      Rutgeerts P, Lemmens L, Van Assche G, Noman M, Borghini-Fuhrer I, Goedkoop R. Treatment of active Crohn's   disease with onercept (recombinant human soluble p55 tumour necrosis factor receptor): results of a randomized,   open-label, pilot study. Aliment Pharmacol Ther 2003; 17: 185-192   PubMed

77      Sandborn WJ, Colombel JF, Enns R, Feagan BG, Hanauer SB, Lawrance IC, Panaccione R, Sanders M, Schreiber S,   Targan S, van Deventer S, Goldblum R, Despain D, Hogge GS, Rutgeerts P. Natalizumab induction and maintenance   therapy for Crohn's disease. N Engl J Med 2005; 353: 1912-1925   PubMed

78      Van Assche G, Van Ranst M, Sciot R, Dubois B, Vermeire S, Noman M, Verbeeck J, Geboes K, Robberecht W,   Rutgeerts P. Progressive multifocal leukoencephalopathy after natalizumab therapy for Crohn's disease. N Engl J Med   2005; 353: 362-368   PubMed

79      Kleinschmidt-DeMasters BK, Tyler KL. Progressive multifocal leukoencephalopathy complicating treatment with   natalizumab and interferon beta-1a for multiple sclerosis. N Engl J Med 2005; 353: 369-374   PubMed

80      Schreiber S, Nikolaus S, Malchow H, Kruis W, Lochs H, Raedler A, Hahn EG, Krummenerl T, Steinmann G. Absence of   efficacy of subcutaneous antisense ICAM-1 treatment of chronic active Crohn's disease. Gastroenterology 2001; 120:   1339-1346   PubMed

81      Mannon PJ, Fuss IJ, Mayer L, Elson CO, Sandborn WJ, Present D, Dolin B, Goodman N, Groden C, Hornung RL,   Quezado M, Yang Z, Neurath MF, Salfeld J, Veldman GM, Schwertschlag U, Strober W. Anti-interleukin-12 antibody for   active Crohn's disease. N Engl J Med 2004; 351: 2069-2079   PubMed

82      Nikolaus S, Rutgeerts P, Fedorak R, Steinhart AH, Wild GE, Theuer D, Mohrle J, Schreiber S. Interferon beta-1a in   ulcerative colitis: a placebo controlled, randomised, dose escalating study. Gut 2003; 52: 1286-1290   PubMed

83      Rembacken BJ, Snelling AM, Hawkey PM, Chalmers DM, Axon AT. Non-pathogenic Escherichia coli versus mesalazine   for the treatment of ulcerative colitis: a randomised trial. Lancet 1999; 354: 635-639   PubMed

84      Kruis W, Schutz E, Fric P, Fixa B, Judmaier G, Stolte M. Double-blind comparison of an oral Escherichia coli preparation   and mesalazine in maintaining remission of ulcerative colitis. Aliment Pharmacol Ther 1997; 11: 853-858   PubMed

85      Gionchetti P, Rizzello F, Helwig U, Venturi A, Lammers KM, Brigidi P, Vitali B, Poggioli G, Miglioli M, Campieri M.   Prophylaxis of pouchitis onset with probiotic therapy: a double-blind, placebo-controlled trial. Gastroenterology 2003;   124: 1202-1209   PubMed

86      Mimura T, Rizzello F, Helwig U, Poggioli G, Schreiber S, Talbot IC, Nicholls RJ, Gionchetti P, Campieri M, Kamm MA.   Once daily high dose probiotic therapy (VSL#3) for maintaining remission in recurrent or refractory pouchitis. Gut 2004;   53: 108-114   PubMed

87      Diav-Citrin O, Park YH, Veerasuntharam G, Polachek H, Bologa M, Pastuszak A, Koren G. The safety of mesalamine in   human pregnancy: a prospective controlled cohort study. Gastroenterology 1998; 114: 23-28   PubMed

88      Mogadam M, Dobbins WO 3rd, Korelitz BI, Ahmed SW. Pregnancy in inflammatory bowel disease: effect of   sulfasalazine and corticosteroids on fetal outcome. Gastroenterology 1981; 80: 72-76   PubMed

89      Alstead EM, Ritchie JK, Lennard-Jones JE, Farthing MJ, Clark ML. Safety of azathioprine in pregnancy in inflammatory   bowel disease. Gastroenterology 1990; 99: 443-446   PubMed

90      Donnenfeld AE, Pastuszak A, Noah JS, Schick B, Rose NC, Koren G. Methotrexate exposure prior to and during   pregnancy. Teratology 1994; 49: 79-81   PubMed

91      Radomski JS, Ahlswede BA, Jarrell BE, Mannion J, Cater J, Moritz MJ, Armenti VT. Outcomes of 500 pregnancies in   335 female kidney, liver, and heart transplant recipients. Transplant Proc 1995; 27: 1089-1090   PubMed

92      Aberra FN. To be or not to be: infliximab during pregnancy? Inflamm Bowel Dis 2006; 12: 76-78   PubMed

93      Schreiber S, Howaldt S, Schnoor M, Nikolaus S, Bauditz J, Gasche C, Lochs H, Raedler A. Recombinant erythropoietin   for the treatment of anemia in inflammatory bowel disease. N Engl J Med 1996; 334: 619-623   PubMed

94      O'Sullivan M, O'Morain C. Nutritional Treatments in Inflammatory Bowel Disease. Curr Treat Options Gastroenterol   2001; 4: 207-213   PubMed

                                                                                                  S- Editor  Liu Y    L- Editor  Zhu LH    E- Editor  Che YB

Reviews	Add
more>>