DÄ internationalArchive8/2009The Diagnosis and Treatment of Crohn's Disease and Ulcerative Colitis

Review article

The Diagnosis and Treatment of Crohn's Disease and Ulcerative Colitis

Dtsch Arztebl Int 2009; 106(8): 123-33; DOI: 10.3238/arztebl.2009.0123

Baumgart, D C

Introduction: Crohn's disease and ulcerative colitis are chronic inflammatory diseases resulting from an inappropriate immune response, in genetically susceptible individuals, to microbial antigens of commensal microorganisms. This inappropriate response is promoted by certain environmental factors. Both diseases manifest themselves primarily in the gastrointestinal tract yet can, in principle, affect all of the organ systems of the body. The purpose of this review article is to heighten awareness of these diseases among physicians whose primary clinical activities lie outside gastroenterology.
Methods: This is not a systematic review nor a meta-analysis. It is mainly based on the guidelines of national (DGVS and DACED) and international (AGA, ACG, BSG, CCFA, ECCO) specialist societies and expert groups, as well as on important reviews and a limited number of pivotal randomized, double-blind, controlled, multicenter studies.
Results: More than 300 000 people in Germany suffer from chronic inflammatory bowel diseases. The incidence and prevalence of IBD have risen in the past 10 years, particularly for Crohn's disease. Every fifth IBD patient is a child or adolescent. A better understanding of key events in the inflammatory cascade, e.g., the activation and polarization of T cells by TNF-alpha, IFN-gamma and IL-12/18 through dendritic cells, has led in recent years to the development of many new immune-modulating and biological treatments. Advanced endoscopic techniques and contrast-enhanced tomographic imaging techniques have expanded diagnostic capabilities.
Conclusion: A cure is still not possible, yet the opportunities for diagnosis and treatment have improved significantly. Early diagnosis is important so that patients can be referred onward for further diagnostic evaluation and appropriate treatment without delay.

Dtsch Arztebl Int 2009; 106(8): 123–33
DOI: 10.3238/arztebl.2009.0123
LNSLNS Crohn’s disease and ulcerative colitis are the two main forms of chronic inflammatory bowel disease. The clinical features, diagnostic assessment, and treatment of these diseases are the topic of this review article (1, 2). Their complex epidemiology, pathogenesis, and pathophysiology are extensively discussed elsewhere (2, 3).

Very important factors in the epidemiology of these diseases include the following:

- Ethnic origin
- The presence of susceptibility regions on at least 12 chromosomes
- Geographical factors
- Lifestyle.

These factors can contribute singly or in combination to the occurrence of the disease. In summary, chronic inflammatory bowel diseases result from an inappropriate innate and acquired immune response to commensal microorganisms in genetically susceptible individuals.

Crohn’s disease is a transmural inflammatory disease of the mucosa with episodic progression. It can affect every part of the gastrointestinal (GI) tract from the mouth to the anus. Typical manifestations include discontinuous involvement of different segments of the GI tract (L1–L4) and the development of complications such as strictures, abscesses, and fistulae (B1–B3p) (46). The Montreal classification also takes the age at initial diagnosis into account (A1–A3) (box).

Ulcerative colitis is a nontransmural inflammatory disease with episodic progression that is restricted to the colon. Depending on the part of the colon that is involved, it can be designated according to the Montreal classification as proctitis (E1), left colitis (sigmoid and descending colon) (E2), or extensive colitis (pancolitis) (E3). In a few patients, inflammation of the terminal ileum ("backwash ileitis") can also develop, making it difficult to distinguish this form of ulcerative colitis from Crohn’s ileocolitis (5, 7, 8) (box).

Methods
This article is neither a systematic review nor a meta-analysis. Excellent meta-analyses are already available, e.g., in the library of the Cochrane Collaboration (www.cochrane.org/reviews/eu/topics/73.html). Rather, it is intended as a general, practice-oriented overview of the diagnosis and treatment of Crohn’s disease and ulcerative colitis. The guidelines of national (DGVS, DACED) and international (AGA, ACG, BSG, CCFA, ECCO) specialist societies and expert groups are emphasized, and important review articles are cited, along with only a few pivotal randomized, double-blind, multicenter studies. Recent international guidelines are given priority over national consensus statements in order to give the reader the most up-to-date information possible.

Therapeutic recommendations are based mainly on the ECCO Consensus (ECCO = European Crohn’s and Colitis Association) and the guidelines of the German Society for Digestive and Metabolic Diseases (Deutsche Gesellschaft für Verdauungs- und Stoffwechselkrankheiten, DGVS), which are discussed in the context of the author's own clinical experience and practice. The evidence levels (EL) and recommendation grades (RG) given here are based on the categories of the Oxford Centers for Evidence-Based Medicine (www.cebm.net/ levels_of_evidence.asp#refs); thus, 1 is the highest level of evidence and A is the strongest recommendation grade. In the DGVS guidelines, the recommendation grade is given as A, B, C, or D.

Clinical features
The clinical features of the disease depend on its

localization (box) and often include diarrhea, abdominal pain, fever, clinical signs of subileus or ileus, and/or the passage of blood and mucus per rectum. Patients with Crohn’s disease often do not have bloody diarrhea, but rather abdominal pain or nonspecific abdominal symptoms. Patients with left colitis or ulcerative proctitis generally have a milder disease course (box gif ppt, table 1 gif ppt).

Extra-intestinal manifestations
Patients with Crohn's disease and ulcerative colitis can develop extra-intestinal manifestations (table 2 gif ppt). The most common types affect the musculoskeletal system (figure 1 jpg ppt), the skin (figure 2 jpg ppt), the eyes, and the hepatobiliary system (9, 10). These extra-intestinal manifestations are to be distinguished from the so-called associated autoimmune diseases (table 2).

The occurrence and severity of extra-intestinal manifestations may be independent of the clinical course of the underlying illness, i.e., some patients may present with an extra-intestinal manifestation as their first symptom of the disease while they still have only mild gastrointestinal manifestations, or none at all. In such situations, the clinician should always look for evidence of Crohn's disease or ulcerative colitis. In case optimizing the pharmacological treatment of the underlying gastrointestinal disease fails to improve the extra-intestinal manifestations, these may need to be treated with expert consultation in the medical specialties dealing specifically with the affected organs.

Diagnosis and assessment of disease activity
The diagnoses of Crohn’s disease and ulcerative colitis are made on clinical grounds supplemented with objective findings of radiological, endoscopic, and histological examination. In some cases, the diagnostic evaluation must be repeated after a certain period of time has passed. There is no gold standard for diagnosis (ECCO EL5, RG5, DGVS D) (47). When establishing the diagnosis, one must exclude other inflammatory, toxic, vascular, neoplastic, and infectious etiologies of enteritis and/or colitis (11) (tables 1 and 3).

Ulcerative colitis—According to the ECCO Consensus and the Montreal classification, the degree of activity of ulcerative colitis can be classified as follows (4):

- Mild (S1) (up to 4 stools per day, possibly bloody; pulse, temperature, hemoglobin concentration, and erythrocyte sedimentation rate [ESR] normal)
- Moderate (S2) (4 to 6 bloody stools daily and no signs of systemic involvement)
- Severe (S3) (more than 6 bloody stools daily and
signs of systemic involvement, such as temperature above 37.5°C, heart rate above 90/min, hemoglobin concentration below 10.5 g/dL, or ESR above 30 mm/h).

A patient in clinical remission (S0) should have no more than 3 stools per day without any admixture of blood or increased urgency of defecation (5).

Crohn’s disease—The degree of activity of Crohn’s disease is classified as follows, according to the ECCO Consensus (4):

- Mild (the patient is able to walk and can tolerate oral nutrition; there are no signs of dehydration, systemic involvement, abdominal pain or mass, ileus, or loss of more than 10% of body weight; the C-reactive protein [CRP] is usually elevated)
- Moderate (the patient suffers from intermittent vomiting, loss of more than 10% of body weight, lack of response to drug therapy for mild Crohn’s disease, or a painful mass; there is no ileus, and the CRP is elevated)
- Severe (the patient is cachectic with a body-mass index [BMI] under 18 or else has ileus, an abscess, or persistent symptoms despite intensive treatment; the CRP is elevated).

Clinical remission is said to be present if the patient is asymptomatic and has no sign of active inflammation. This includes patients who have responded to pharmacological or surgical treatment without any residual evidence of disease activity.

In clinical studies, the degree of activity of the disease can be quantified with the aid of a number of different indices, which, however, play no role in everyday clinical practice (DGVS B) (12, 13). As no index, taken alone, can provide a complete picture of the disease, data obtained in clinical studies are often difficult to interpret. A basic diagnostic algorithm derived from our own outpatient practice in a university medical center is summarized in table 3 (gif ppt).

Treatment with pharmacological agents
Goals
The goals of treatment for both varieties of chronic inflammatory bowel disease are the rapid induction of a steroid-free remission and the prevention of complications of the disease itself and its treatment. As a rule, the treatment is chosen on the basis of the extent and degree of severity of the disease, its responsiveness to previous treatments, and the individual patient situation (tables 4 and 5).

Duration and choice of treatment
Long-term treatment to maintain the patient in a state of remission should be provided to all patients with Crohn’s disease (no applicable ECCO Consensus statement) and ulcerative colitis (ECCO EL 1a, RG A).
With respect to the choice of drugs and the timing of their use, some of the professional societies favor a stratified approach. The usefulness of a "treatment pyramid" of this type is currently debated, because there is evidence from other specialties that the early administration of highly potent drugs such as anti-TNF biological agents may prevent late complications. On the other hand, treatment with immune modulators and biologics confers a cumulative risk of infections, lymphoma, and other types of malignancy, particularly in adolescents (14). It remains to be seen whether early, aggressive treatment can be applied successfully in this area of gastroenterology (15).

There is also a lack of consensus with respect to the optimal duration of treatment and to certain types of combination therapy. For the purine analogs, for example, some professional societies recommend temporary cessation of treatment under certain conditions after 2 years of remission and a total of 4 years of treatment (DGVS), while the author and other experts recommend continued treatment.

Still greater uncertainty besets the newer types of biological therapy, because scientific data are lacking to date. Most experts would agree that treatment with TNF-blockers should be continued only if the patient has shown a response after the first two doses (i.e., induction). It is also clear that episodic therapy—in distinction to regular, uninterrupted treatment—is associated with a less favorable disease course and a higher risk of adverse effects (immunization, allergic reactions). It remains unclear, however, when biological therapy should be stopped. Most clinical trials were performed for no more than 52 weeks and therefore are of no help in answering this question. At present, long-term data are being gathered in treatment registries, so that well-founded conclusions on this subject ought to be possible in the future.

Crohn’s disease
All patients with Crohn’s disease should be urged not to smoke, because smoking predisposes to exacerbations and complications (ECCO EL 1b, RG B, DGVS A).

Mild and moderate Crohn’s disease restricted to the ileum and cecum
In mild Crohn’s disease restricted to the ileum and cecum, induction therapy with budesonide can be started (ECCO EL 2a, RG B, DGVS A). Budesonide interferes with bone metabolism less than conventional steroids. Its protracted use, however, impairs the hypothalamic-pituitary regulation of glucocorticoid metabolism. This and the fact that budesonide was found to be unable to sustain remission for more than 6 months in controlled studies limit its utility to the induction of remission.

Most of the studies of mesalazine that have been performed with adequate scientific methodology have shown this agent to be ineffective for the induction of remissions (DGVS A). Because some controversy on this topic remains, the ECCO Consensus formulated a statement that it possesses "limited effectiveness" (ECCO EL1a, RG B). The author and many other expert colleagues around the world no longer use mesalazine to treat Crohn’s disease.

Moderate and severe cases of Crohn’s disease can also be treated with systemic corticosteroids, given either by mouth or by the intravenous route (ECCO EL 1a, RG A, DGVS A). In parallel, remission maintenance therapy with azathioprine or 6-mercaptopurine should be begun (ECCO EL 1a, RG B; except for initial manifestations, DGVS A). These drugs have a long latency of effect and thus cannot be used to induce a remission in the acute phase. When the treatments mentioned fail or are contraindicated, infliximab (ECCO EL 1b, RG A, DGVS) or adalimumab (DGVS A) can also be used (table 4 gif ppt).

Involvement of the small intestine or the upper gastrointestinal tract
Patients with extensive small-bowel involvement with a moderate or severe course should be treated with systemic corticosteroids (ECCO EL 1a, RG B, DGVS A and B). In parallel, remission maintenance therapy with azathioprine/6-mercaptopurine should be started (ECCO EL 1a, RG B, DGVS A); in case of failure or intolerance, methotrexate can be used instead (ECCO EL 1b, RG B, DGVS A). The use of infliximab should be considered in cases of nonresponse to treatment (EL 1b, RG B, DGVS A). If the upper GI tract is affected, a proton pump blocker such as esomeprazole should also be given (EL5 RG D, DGVS C). If the esophagus is affected, systemic glucocorticoids are the first line treatment (DGVS B) (table 4).

Crohn’s ileocolitis
Mild Crohn’s ileocolitis can be treated with sulfasalazine (ECCO EL 1b, RG A, DGVS A) or with systemic corticosteroids (ECCO EL 1a, RG A, DGVS A). Remission maintenance therapy with azathioprine, 6-mercaptopurine, or methotrexate should be begun in parallel (ECCO EL 1a, RG B, except for initial manifestations). If the above treatment fails or is contraindicated, infliximab (ECCO EL 1b, RG B) or adalimumab can also be used (table 4).

Fistulating Crohn’s disease
Fistulating disease must be treated by gastroenterologists in collaboration with surgeons and, in some cases, with experts from other clinical disciplines such as gynecology and urology (DGVS D). Contrast-enhanced magnetic resonance imaging (MRI) of the pelvic floor is a particularly useful means of documenting the involvement of adjacent organs by complex fistulae (ECCO EL 2b, RG B). All patients with perianal fistulae should undergo proctoscopy (ECCO EL 2a, RG B, DGVS C). Abscesses must be adequately drained (DGVS B); this may require incision and the insertion of setons (ECCO EL3, RG D). Perianal fistulae are easier to treat than internal fistulae, which often require major surgery. Internal fistulae penetrating into adjacent organs usually require complex treatment that is best provided by specialists.

Simple perianal fistulae are often initially treated with antibiotics, e.g., ciprofloxacin or metronidazole (ECCO EL3, RG D). For complex perianal fistulae, azathioprine or 6-mercaptopurine should be given in parallel. Patients with perianal fistulae that respond inadequately to treatment with antibiotics, azathioprine, or 6-mercaptopurine can be treated with infliximab (ECCO EL 1b, RG B). Adalimumab is also effective in fistulating Crohn’s disease but is not currently licensed for this indication in Germany (table 4).

Ulcerative colitis
Proctitis
Mild to moderate proctitis should be treated topically at first, e.g., with 1000 mg of mesalazine per rectum per day as induction therapy (ECCO EL 1b, RG B). If the response is inadequate or totally lacking, then a combination with oral mesalazine preparations or topical corticosteroids is more effective than monotherapy (ECCO EL 1b, RG B). The topically effective corticosteroids include hydrocortisone, budesonide, and beclomethasone. Effective remission maintenance therapy is usually achieved with topical mesalazine in a dose of, e.g., 3000 mg per week in 3 divided doses (ECCO EL 5, RG D) and/or oral mesalazine in a dose of at least 1000 mg daily (ECCO EL 1a, RG A) (table 5 gif ppt).

Left colitis
The treatment of choice for patients with mild to moderate left-sided ulcerative colitis consists of topical 5-aminosalicylic acid (ASA) derivatives (ECCO EL 1b, RG B, DGVS A) in combination with oral mesalazine preparations in a dose above 2000 mg daily (ECCO EL 1a, RG A). A dose of 1500 to 2400 mg 5-ASA po qd is effective for most patients. Patients who fail to respond adequately to oral 5-ASA preparations and/or topical treatment should be treated with systemic corticosteroids (ECCO EL 1b, RG C, DGVS B).

Severe left colitis must be treated in the hospital with systemic medications (ECCO EL 1b, RG B). The medical treatment can also include infliximab. Patients with a steroid-dependent (EL 1a, RG A) or steroid-refractory course (ECCO EL 1a, RG B) should be treated with azathioprine or 6-mercaptopurine for remission maintenance. Patients who have required infliximab to induce a remission should receive continued, regular maintenance treatment with infliximab (ECCO EL 1b, RG A) (table 5).

Extensive ulcerative colitis—pancolitis
The initial treatment of extensive, mild to moderate ulcerative colitis consists of systemic mesalazine (in a dose above 2000 mg daily: ECCO EL 1a, RG A, DGVS A) as well as topical mesalazine (ECCO EL 1b, RG A). Patients who do not respond to such treatment, or who are already receiving effective remission maintenance therapy, should be treated with systemic corticosteroids (ECCO EL 1b, RG C, DGVS B). Severe left colitis must be treated in the hospital with systemic medications (ECCO EL 1b, RG B), including infliximab.

Patients with a steroid-dependent course (ECCO EL 1a, RG A) or a steroid-refractory course (ECCO EL 1a, RG B) should be treated with either azathioprine or 6-mercaptopurine for remission maintenance. Patients who have required infliximab to induce remission should receive regular maintenance therapy with infliximab (ECCO EL 1b, RG A) (table 5).

Severe ulcerative colitis
Patients with severe ulcerative colitis should be treated in the hospital (ECCO EL 5, RG D). Treatment with intravenous methylprednisolone at a dose of 60 mg per day, or an equivalent dose of another steroid, should be initiated (ECCO EL 1b, RG B, DGVS A). Monotherapy with intravenous ciclosporin is reserved for patients who do not tolerate intravenous corticosteroids (ECCO EL 1b, RG C).

The response to intravenous steroids on the third day after the initiation of treatment is of critical importance for the course and should be evaluated objectively (ECCO EL 2b, RG B). Alternative treatment options thereafter include ciclosporin (ECCO EL 1b, RG B, DGVS A), tacrolimus (ECCO EL 1b, RG B, DGVS B), and infliximab (ECCO EL 1b, RG B).

Such treatments should be initiated and monitored in an experienced center. If drug therapy fails, proctocolectomy is indicated (DGVS C) (table 5).

Surgical treatment
Emergency surgery is indicated for patients with life-threatening complications, such as intestinal perforation, refractory bleeding, or toxic megacolon, that do not respond to pharmacotherapy (16). Elective surgery is indicated for patients with dysplasia or malignancy, a refractory disease course, or intolerance to long-term immunosuppression or other pharmacological therapies (17, 18). The most common surgical technique used to treat ulcerative colitis is total proctocolectomy with an ileal J-pouch anal anastomosis (IPAA). Specific indications for surgery in Crohn’s disease include the formation of fibrotic strictures causing partial or total intestinal obstruction, internal complicated fistulae, abdominal abscesses, and enterovesical, enterovaginal, and enterocutaneous fistulae (17).

Neoplastic complications and screening
Patients with ulcerative colitis and Crohn’s ileocolitis have an elevated risk of developing colon cancer, while patients with Crohn’s disease and enteritis have an elevated risk of developing small-bowel cancer (9, 18). Screening colonoscopy should be performed for the first time 8 to 10 years after the onset of the illness (ECCO EL 5, RG D). Patients with primary sclerosing cholangitis (PSC) have an even higher risk of carcinoma (ECCO EL 1a, RG A) and should undergo annual screening colonoscopy as soon as the diagnoses of chronic inflammatory bowel disease and PSC are established (ECCO EL 3, RG B) (19).

Safety and monitoring of pharmacotherapy
Many pharmacological treatments for chronic inflammatory bowel disease, especially corticosteroids, immune modulators, and immune suppressants, are associated with major adverse effects (20) (table 6 gif ppt). Biological agents should be used only after a careful weighing of their risks and benefits, as they confer an elevated risk of infection, lymphoma, and malignancy (21).

Furthermore, patients should be tested for the presence of an active infection (particularly tuberculosis, hepatitis, infectious enteritis or colitis (including C. difficile and cytomegalovirus [CMV]), especially before an immune-modulating or biological therapy is to be initiated. Opportunistic infections may arise later during the course of treatment, especially if multiple immune-modulating, immunosuppressive, or biological agents are used in combination (22). Complex therapies and refractory courses should be managed by appropriately trained and experienced clinicians. Special rules also apply to the vaccination of immunosuppressed patients.

Conflict of interest statement
The author has received unrestricted research grants from the Abbott, Astellas (Fujisawa), Biocodex, and Protein Design Labs companies. He has received honoraria for serving on Advisory Boards for the following companies: Abbott, Astra Zeneca, Berlex, Bristol Meyers Squibb, Centocor, Elan, Biogen, Essex, Medac, Ocera, Protein Design Labs, Schering, Schering Plough, UCB. He has organized continuing medical education events that were supported by the following companies: Abbott, Astra Zeneca, Dr. Falk, Ferring, Essex, Otsuka, Shire, UCB. All of his activities and contracts are in conformity with the "FSA-Kodex Fachkreise" (voluntary self-monitoring code for expert consultants to the pharmaceutical industry), have been checked by the Medicolegal Department of the Charité Hospital, Berlin, and have been approved by the directorate of the Faculty of Medicine.

Manuscript received on 7 May 2008; revised version accepted on
14 November 2008.

Translated from the original German by Ethan Taub, M.D.


Corresponding author
PD Dr. med. Daniel C. Baumgart
Charité – Campus Virchow Klinikum
Medizinische Klinik mit Schwerpunkt
Gastroenterologie und Hepatologie
Augustenburger Platz 1
13353 Berlin, Germany
daniel.baumgart@charite.de
www.danielbaumgart.de
1.
Baumgart DC, Sandborn WJ: Inflammatory bowel disease: clinical aspects and established and evolving therapies. Lancet 2007; 369:1641–57. MEDLINE
2.
Baumgart DC, Carding SR: Inflammatory bowel disease: cause and immunobiology. Lancet 2007; 369: 1627–40. MEDLINE
3.
Xavier RJ, Podolsky DK: Unravelling the pathogenesis of inflammatory bowel disease. Nature 2007; 448: 427–34. MEDLINE
4.
Stange EF, Travis SP, Vermeire S, Beglinger C, Kupcinkas L, Geboes K, et al.: European evidence based consensus on the diagnosis and management of Crohn's disease: definitions and diagnosis. Gut 2006; 55 Suppl 1: i1–15. MEDLINE
5.
Silverberg MS, Satsangi J, Ahmad T, Arnott ID, Bernstein CN, Brant SR et al.: Toward an integrated clinical, molecular and serological classification of inflammatory bowel disease: Report of a Working Party of the 2005 Montreal World Congress of Gastroenterology. Can J Gastroenterol 2005; 19 Suppl A: 5–36. MEDLINE
6.
Hoffmann JC, Preiss JC, Autschbach F, Buhr HJ, Hauser W, Herrlinger K et al.: S3-Leitlinie „Diagnostik und Therapie des Morbus Crohn“. Z Gastroenterol 2008; 46: 1094–146. MEDLINE
7.
Stange EF, Travis SPL, Vermeire S, Reinisch W, Geboes K, Barakauskiene A et al.: European evidence-based Consensus on the diagnosis and management of ulcerative colitis: Definitions and diagnosis. J Crohn's Colitis 2008; 2: 1–23.
8.
Hoffmann JC, Zeitz M, Bischoff SC, Brambs HJ, Bruch HP, Buhr HJ et al.: Diagnostik und Therapie der Colitis ulcerosa: Ergebnisse einer evidenzbasierten Konsensuskonferenz der Deutschen Gesellschaft für Verdauungs- und Stoffwechselerkrankungen zusammen mit dem Kompetenznetz chronisch entzündliche Darm­er­krank­ungen. Leitlinien. Z Gastroenterol 2004; 42: 979–83. MEDLINE
9.
Biancone L, Michetti P, Travis S, Escher JC, Moser G, Forbes A et al.: European evidence-based Consensus on the management of ulcerative colitis: Special situations. J Crohn's Colitis 2008; 2: 63–92.
10.
Caprilli R, Gassull MA, Escher JC, Moser G, Munkholm P, Forbes A et al.: European evidence based consensus on the diagnosis and management of Crohn's disease: special situations. Gut 2006; 55 Suppl 1: i36–i58. MEDLINE
11.
Thielman NM, Guerrant RL: Clinical practice. Acute infectious diarrhea. N Engl J Med 2004; 350: 38–47. MEDLINE
12.
Sandborn WJ, Feagan BG, Hanauer SB, Lochs H, Lofberg R, Modigliani R et al.: A review of activity indices and efficacy endpoints for clinical trials of medical therapy in adults with Crohn's disease. Gastroenterology 2002; 122: 512–30. MEDLINE
13.
D'Haens G, Sandborn WJ, Feagan BG, Geboes K, Hanauer SB, Irvine EJ et al.: A review of activity indices and efficacy end points for clinical trials of medical therapy in adults with ulcerative colitis. Gastroenterology 2007; 132: 763–86. MEDLINE
14.
Bongartz T, Sutton AJ, Sweeting MJ, Buchan I, Matteson EL, Montori V: Anti-TNF antibody therapy in rheumatoid arthritis and the risk of serious infections and malignancies: systematic review and meta-analysis of rare harmful effects in randomized controlled trials. JAMA 2006; 295: 2275–85. MEDLINE
15.
D'Haens G, Baert F, Van AG, Caenepeel P, Vergauwe P, Tuynman H et al.: Early combined immunosuppression or conventional management in patients with newly diagnosed Crohn's disease: an open randomised trial. Lancet 2008; 371: 660–7. MEDLINE
16.
Berg DF, Bahadursingh AM, Kaminski DL, Longo WE: Acute surgical emergencies in inflammatory bowel disease. Am J Surg 2002; 184: 45–51. MEDLINE
17.
Larson DW, Pemberton JH: Current concepts and controversies in surgery for IBD. Gastroenterology 2004; 126: 1611–9. MEDLINE
18.
Itzkowitz SH, Present DH: Consensus conference: Colorectal cancer screening and surveillance in inflammatory bowel disease. Inflamm Bowel Dis 2005; 11: 314–21. MEDLINE
19.
Loftus EV, Jr., Harewood GC, Loftus CG, Tremaine WJ, Harmsen WS, Zinsmeister AR et al.: PSC-IBD: a unique form of inflammatory bowel disease associated with primary sclerosing cholangitis. Gut 2005; 54: 91–6. MEDLINE
20.
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: 940–87. MEDLINE
21.
Siegel CA, Hur C, Korzenik JR, Gazelle GS, Sands BE: Risks and benefits of infliximab for the treatment of Crohn's disease. Clin Gastroenterol Hepatol 2006; 4: 1017–24. MEDLINE
22.
Toruner M, Loftus EV, Jr., Harmsen WS, Zinsmeister AR, Orenstein R, Sandborn WJ et al.: Risk factors for opportunistic infections in patients with inflammatory bowel disease. Gastroenterology 2008; 134: 929–36. MEDLINE
23.
Travis SP, Stange EF, Lemann M, Oresland T, Chowers Y, Forbes A et al.: European evidence based consensus on the diagnosis and management of Crohn's disease: current management. Gut 2006; 55 Suppl 1: i16–i35. MEDLINE
24.
Travis SPL, Stange EF, Lemann M, Ïresland T, Bemelman WA, Chowers Y et al.: European evidence-based Consensus on the management of ulcerative colitis: Current management. J Crohn's Colitis 2008; 2: 24-62.
25.
Mahadevan U, Kane S: American gastroenterological association institute technical review on the use of gastrointestinal medications in pregnancy. Gastroenterology 2006; 131: 283–311. MEDLINE
Medizinische Klinik mit Schwerpunkt Gastroenterologie und Hepatologie, Charité, Campus Virchow Klinikum, Medizinische Fakultät der Humboldt Universität zu Berlin: PD Dr. med. Baumgart
1. Baumgart DC, Sandborn WJ: Inflammatory bowel disease: clinical aspects and established and evolving therapies. Lancet 2007; 369:1641–57. MEDLINE
2. Baumgart DC, Carding SR: Inflammatory bowel disease: cause and immunobiology. Lancet 2007; 369: 1627–40. MEDLINE
3. Xavier RJ, Podolsky DK: Unravelling the pathogenesis of inflammatory bowel disease. Nature 2007; 448: 427–34. MEDLINE
4. Stange EF, Travis SP, Vermeire S, Beglinger C, Kupcinkas L, Geboes K, et al.: European evidence based consensus on the diagnosis and management of Crohn's disease: definitions and diagnosis. Gut 2006; 55 Suppl 1: i1–15. MEDLINE
5. Silverberg MS, Satsangi J, Ahmad T, Arnott ID, Bernstein CN, Brant SR et al.: Toward an integrated clinical, molecular and serological classification of inflammatory bowel disease: Report of a Working Party of the 2005 Montreal World Congress of Gastroenterology. Can J Gastroenterol 2005; 19 Suppl A: 5–36. MEDLINE
6. Hoffmann JC, Preiss JC, Autschbach F, Buhr HJ, Hauser W, Herrlinger K et al.: S3-Leitlinie „Diagnostik und Therapie des Morbus Crohn“. Z Gastroenterol 2008; 46: 1094–146. MEDLINE
7. Stange EF, Travis SPL, Vermeire S, Reinisch W, Geboes K, Barakauskiene A et al.: European evidence-based Consensus on the diagnosis and management of ulcerative colitis: Definitions and diagnosis. J Crohn's Colitis 2008; 2: 1–23.
8. Hoffmann JC, Zeitz M, Bischoff SC, Brambs HJ, Bruch HP, Buhr HJ et al.: Diagnostik und Therapie der Colitis ulcerosa: Ergebnisse einer evidenzbasierten Konsensuskonferenz der Deutschen Gesellschaft für Verdauungs- und Stoffwechselerkrankungen zusammen mit dem Kompetenznetz chronisch entzündliche Darm­er­krank­ungen. Leitlinien. Z Gastroenterol 2004; 42: 979–83. MEDLINE
9. Biancone L, Michetti P, Travis S, Escher JC, Moser G, Forbes A et al.: European evidence-based Consensus on the management of ulcerative colitis: Special situations. J Crohn's Colitis 2008; 2: 63–92.
10. Caprilli R, Gassull MA, Escher JC, Moser G, Munkholm P, Forbes A et al.: European evidence based consensus on the diagnosis and management of Crohn's disease: special situations. Gut 2006; 55 Suppl 1: i36–i58. MEDLINE
11. Thielman NM, Guerrant RL: Clinical practice. Acute infectious diarrhea. N Engl J Med 2004; 350: 38–47. MEDLINE
12. Sandborn WJ, Feagan BG, Hanauer SB, Lochs H, Lofberg R, Modigliani R et al.: A review of activity indices and efficacy endpoints for clinical trials of medical therapy in adults with Crohn's disease. Gastroenterology 2002; 122: 512–30. MEDLINE
13. D'Haens G, Sandborn WJ, Feagan BG, Geboes K, Hanauer SB, Irvine EJ et al.: A review of activity indices and efficacy end points for clinical trials of medical therapy in adults with ulcerative colitis. Gastroenterology 2007; 132: 763–86. MEDLINE
14. Bongartz T, Sutton AJ, Sweeting MJ, Buchan I, Matteson EL, Montori V: Anti-TNF antibody therapy in rheumatoid arthritis and the risk of serious infections and malignancies: systematic review and meta-analysis of rare harmful effects in randomized controlled trials. JAMA 2006; 295: 2275–85. MEDLINE
15. D'Haens G, Baert F, Van AG, Caenepeel P, Vergauwe P, Tuynman H et al.: Early combined immunosuppression or conventional management in patients with newly diagnosed Crohn's disease: an open randomised trial. Lancet 2008; 371: 660–7. MEDLINE
16. Berg DF, Bahadursingh AM, Kaminski DL, Longo WE: Acute surgical emergencies in inflammatory bowel disease. Am J Surg 2002; 184: 45–51. MEDLINE
17. Larson DW, Pemberton JH: Current concepts and controversies in surgery for IBD. Gastroenterology 2004; 126: 1611–9. MEDLINE
18. Itzkowitz SH, Present DH: Consensus conference: Colorectal cancer screening and surveillance in inflammatory bowel disease. Inflamm Bowel Dis 2005; 11: 314–21. MEDLINE
19. Loftus EV, Jr., Harewood GC, Loftus CG, Tremaine WJ, Harmsen WS, Zinsmeister AR et al.: PSC-IBD: a unique form of inflammatory bowel disease associated with primary sclerosing cholangitis. Gut 2005; 54: 91–6. MEDLINE
20. 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: 940–87. MEDLINE
21. Siegel CA, Hur C, Korzenik JR, Gazelle GS, Sands BE: Risks and benefits of infliximab for the treatment of Crohn's disease. Clin Gastroenterol Hepatol 2006; 4: 1017–24. MEDLINE
22. Toruner M, Loftus EV, Jr., Harmsen WS, Zinsmeister AR, Orenstein R, Sandborn WJ et al.: Risk factors for opportunistic infections in patients with inflammatory bowel disease. Gastroenterology 2008; 134: 929–36. MEDLINE
23. Travis SP, Stange EF, Lemann M, Oresland T, Chowers Y, Forbes A et al.: European evidence based consensus on the diagnosis and management of Crohn's disease: current management. Gut 2006; 55 Suppl 1: i16–i35. MEDLINE
24. Travis SPL, Stange EF, Lemann M, Ïresland T, Bemelman WA, Chowers Y et al.: European evidence-based Consensus on the management of ulcerative colitis: Current management. J Crohn's Colitis 2008; 2: 24-62.
25. Mahadevan U, Kane S: American gastroenterological association institute technical review on the use of gastrointestinal medications in pregnancy. Gastroenterology 2006; 131: 283–311. MEDLINE