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The Montreal classification of inflammatory bowel disease: controversies, consensus, and implications

In recent years, investigators have readdressed the complex issues involved in the classification of inflammatory bowel diseases. In 2003, a Working Party of investigators with an interest in the issues involved in disease subclassification was formed with the aim of summarising recent developments in disease classification and establishing an integrated clinical, molecular, and serological classification of inflammatory bowel disease. The results of the Working Party were reported at the 2005 Montreal World Congress of Gastroenterology. Here we highlight the key issues that have emerged from discussions of the Montreal Working Party and the relevance to clinical practice and research activities.

Second European evidence-based consensus on the prevention, diagnosis and management of opportunistic infections in inflammatory bowel disease

The treatment of inflammatory bowel disease (IBD) has been revolutionised over the past decade by the increasing use of immunomodulators, mainly azathioprine (AZA)/6-mercaptopurine (6-MP) and methotrexate (MTX), together with the advent of biological therapy. Immunomodulators are being used more often and earlier in the course of the disease.1 The introduction of biologic agents, especially inhibitors of the key proinflammatory cytokine, tumor necrosis factor alpha (TNF-α) initiated a new therapeutic era, whose use has grown continuously since their introduction in 1998.2 With such immunomodulation, the potential for opportunistic infection is a key safety concern for patients with IBD.nnOpportunistic infections pose particular problems for the clinician: they are often difficult to recognise and are associated with appreciable morbidity or mortality, because they are potentially serious and hard to treat effectively. Enhancing awareness and improving the knowledge of gastroenterologists about opportunistic infections are important elements to optimise patient outcomes through the development of preventive or early diagnostic strategies.nnA long list of opportunistic infections has been described in patients with IBD. Many questions remain unanswered, not only concerning the need for screening, preventive measures or the best diagnostic approach, but also on appropriate treatment and management of immunomodulator therapy once infection occurs. This led the European Crohns and Colitis Organisation (ECCO) to establish a Consensus meeting on opportunistic infections in IBD. The formal process of a Consensus meeting has been described,3 but the purpose is to quantify expert opinion in the context of a systematic review of existing evidence. To organise the work, infections were classified into six major topics (see plan). Specific questions were asked for each infectious agent. The different topics were distributed to working groups that comprised junior and senior gastroenterologists with infectious disease experts. Each group performed a systematic review of the literature and answered …

European evidence based consensus on the diagnosis and management of Crohn's disease: current management.

This second section of the European Crohn’s and Colitis Organisation (ECCO) Consensus on the management of Crohn’s disease concerns treatment of active disease, maintenance of medically induced remission, and surgery. The first section on definitions and diagnosis includes the aims and methods of the consensus, as well as sections on diagnosis, pathology, and classification of Crohn’s disease. The third section on special situations in Crohn’s disease includes postoperative recurrence, fistulating disease, paediatrics, pregnancy, psychosomatics, extraintestinal manifestations, and alternative therapy for Crohn’s disease.

European evidence-based Consensus on the management of ulcerative colitis: Current management

### 5.1 GeneralnnThe general principles for treating active ulcerative colitis are to consider the activity, distribution (proctitis, left-sided, extensive,1 and pattern of disease (relapse frequency, course of disease, response to previous medications, side-effect profile of medication, extra-intestinal manifestation), before treatment decisions are made in conjunction with the patient.nn#### 5.1.1 Disease activitynnThe principal scoring systems used for clinical trials are covered in Section 5.1.2 and have been comprehensively reviewed.2 Some additional points are clinically relevant. In clinical practice it matters most to distinguish severe ulcerative colitis necessitating hospital admission from those with mild or moderate disease who can generally be treated as outpatients. The simplest, best validated and most widely used index for identifying acute severe UC remains that of Truelove & Wi_tts 3: any patient who has a bloody stool frequency ≥ 6/day and a tachycardia (> 90 bpm), or temperature > 37.8 °C, or anaemia (haemoglobin 30 mm/h) has severe ulcerative colitis (Table 1.3). This index has been used in 20/32 studies of intensive intravenous treatment for severe UC.4 Only one additional criterion in addition to the bloody stool frequency ≥ 6/day is needed to define a severe attack.5 While these criteria have the major limitation of being unresponsive and cannot track the course of disease, they do distinguish the severe from the moderate or mild and have value in everyday practice because they are easy to use, which no other index achieves. It should be standard practice to confirm active colitis by sigmoidoscopy or proctoscopy before starting treatment. Rectal mucosal biopsy helps exclude unexpected causes of symptoms similar to active disease (such as cytomegalovirus, amoebic, or other infection, rectal mucosal prolapse, Crohns disease, or even irritable bowel syndrome and haemorrhoidal bleeding).nn#### 5.1.2 ApproachnnPatients should be encouraged to participate actively in …

Dysbiosis in inflammatory bowel disease

Abundant data have incriminated intestinal bacteria in the initiation and amplification stages of inflammatory bowel diseases. However, the precise role of intestinal bacteria remains elusive. One theory has suggested a breakdown in the balance between putative species of “protective” versus “harmful” intestinal bacteria—this concept has been termed “dysbiosis”. Arguments in support of this concept are discussed.

Activated eosinophils and interleukin 5 expression in early recurrence of Crohn's disease.

Endoscopic recurrences after radical surgery for Crohns disease are useful for studying the pathogenesis of initial lesions of Crohns disease. Factors predisposing to recurrence are poorly understood, but it has been shown that eosinophilic infiltration of the neoileum may occur within a few weeks of resection. The aim of this study was to compare, in nine patients having an ileocolectomy, the infiltration of eosinophils and their activation state in normal and diseased areas of the neoileum, three months after surgery. Tissue eosinophils were studied by histochemical methods and electron microscopy. Mucosal expression of interleukin 5 (IL 5), an important eosinophil activating factor was studied using in situ hybridisation. Sixty per cent of patients had endoscopic recurrence at three months. Eosinophil infiltration was more pronounced in diseased than in endoscopically normal areas and was associated with a high expression of IL 5 mRNA. Ultrastructural analysis showed features of eosinophil activation, but no cytotoxic lesions of surrounding inflammatory or epithelial cells. This study suggests that local synthesis of IL 5 associated with eosinophil activation in the tissues could participate in early mucosal damage in Crohns disease.

Switch from systemic steroids to budesonide in steroid dependent patients with inactive Crohn's disease

BACKGROUND Steroid dependent patients with Crohns disease are at high risk of developing glucocorticosteroid induced side effects. AIMS We evaluated the possibility of switching from systemic steroids to budesonide (Entocort) in prednisolone/prednisone dependent patients with inactive Crohns disease affecting the ileum and/or ascending colon. PATIENTS Steroid dependent patients with a Crohns disease activity index ⩽200 were included. METHODS In a double blind multicentre trial, 120 patients were randomly assigned to receive budesonide 6 mg once daily or placebo. Prednisolone was tapered to zero during the first 4–10 weeks and budesonide or placebo was given concomitantly and for a further 12 weeks. Relapse was defined as an index >200 and an increase of 60 points from baseline or withdrawal due to disease deterioration. RESULTS After one and 13 weeks without prednisolone, relapse rates were 17% and 32%, respectively, in the budesonide group, and 41% and 65% in the placebo group (95% confidence intervals for the difference in percentages −41%, −8% and −51%, −16%; p=0.004 and p<0.001, respectively). The number of glucocorticosteroid side effects was reduced by 50% by switching from prednisolone and was similar in the budesonide and placebo groups. Basal plasma cortisol increased in both groups. CONCLUSIONS The majority of patients with steroid dependent ileocaecal Crohns disease may be switched to budesonide controlled ileal release capsules 6 mg without relapse, resulting in a sharp decrease in glucocorticosteroid side effects similar to placebo, and with an increase in plasma cortisol levels.

CARD4/NOD1 is not involved in inflammatory bowel disease

Background and aims: Inflammatory bowel diseases (IBD), including Crohn’s disease (CD) and ulcerative colitis (UC), are complex genetic disorders. CARD15/NOD2, a member of the Ced4 superfamily which includes Apaf-1 and CARD4/NOD1, has recently been associated with genetic predisposition to CD but additional genetic factors remain to be identified. Because CARD4/NOD1 shares many structural and functional similarities with CARD15, we tested its putative role in IBD. Patients and methods: The 11 exons of CARD4 were screened for the presence of variants in 63 unrelated IBD patients. The only non-private genetic variation encoding for a substitution in the peptidic chain was genotyped in 381 IBD families (235 CD, 58 UC, 81 mixed, and seven indeterminate colitis families) using a polymerase chain reaction-restriction fragment length polymorphism procedure. Genotyping data were analysed by the transmission disequilibrium test. Results: Five of nine sequence variations identified in the coding sequence of the gene encoded for non-conservative changes (E266K, D372N, R705Q, T787M, and T787K). Four were present in only one family. The remaining variant (E266K), which exhibited an allele frequency of 0.28, was not associated with CD, UC, or IBD. Furthermore, IBD patients carrying sequence variations in their CARD4 gene had a similar phenotype to those with a normal sequence. Conclusion: Our results suggest that CARD4 does not play a major role in genetic susceptibility to IBD.

Enhanced production of IL‐8 in chronic but not in early ileal lesions of Crohn's disease (CD)

Distinct Th1/Th2 patterns have been observed during the evolution of CD. The aim of this study was to compare neutrophil involvement and IL‐8 mRNA and protein expression during early recurrent lesions and chronic phases of CD. Twenty‐nine patients with CD having ileocolonic resection with anastomosis were studied. Biopsies were obtained during surgery from the non‐inflamed ileal mucosa and from chronic ileal lesions. Endoscopic ileal biopsies were also taken from early recurrent ileal lesions occurring 3u2003months after surgery. Neutrophil counts were performed and mucosal IL‐8 levels were evaluated by competitive reverse transcriptase‐polymerase chain reaction and immunohistochemistry. Early recurrent ileal lesions were characterized by low neutrophil counts and IL‐8 production at the mRNA and protein levels compared with the ileal chronic lesions. The main cellular sources of IL‐8 in the early recurrent lesions were neutrophils, while in chronic lesions the majority of IL‐8‐stained cells were CD3+ T cells and macrophages. These results confirmed that the nature of the inflammatory infiltrate and the expression of cytokine profiles may differ between the acute and chronic phases of CD.

Secretion of Immunoglobulins and Plasma-proteins From the Colonic Mucosa - An In-vivo Study in Man

There are no available data on immunoglobulins and albumin outputs into the normal human colon. We thus measured the intracolonic secretion rates of IgA, IgG, IgM, secretory component (SC) and plasma proteins (albumin (Alb), orosomucoid (Oro), transferrin (Transf) and α2‐macroglobulin (α2‐M)). Using a pancolonic perfusion technique in 10 healthy volunteers (six females, four males, mean age 24 years), concentrations and outputs of Alb, immunoglobulins, SC, Oro, Transf and α2‐M were measured in the rectal effluents by immunoradiometric assay. Monomeric (m) and polymeric (p) IgA distribution was analysed by sucrose density ultra‐centrifugation. The secretion of polymeric IgA (p‐IgA) was 153 μg/min, i.e. 220 mg/day, exceeding that of other immunoglobulins (m‐IgA 8·5 μg/min; IgG 33·5 μg/min; IgM 17μg/min) and of non‐immunoglobulin proteins (Alb 104 μg/min; Oro 9 μg/min; Transf 7 μg/min; α2‐M 4·5 μg/min), p‐IgA was entirely linked to SC (secretory IgA) and 12% of SC was in free form. About 62% of total IgA was IgA2. For each protein, a relative coefficient of excretion (RCE) was calculated (colon to serum concentration ratio expressed relative to that of Alb). The p‐IgA, IgM and m‐IgA RCE were 277, 6 and 2·2 times higher than the values predicted from their molecular weight. RCE of non‐immunoglobulin proteins also exceeded the values expected from a passive seepage from the vascular compartment. The intracolonic clearance of Alb extrapolated to 24 h was only 3·7 ml/day. These results show the high local production and/or the facilitated transport to the colonic lumen of p‐IgA, and are in very good agreement with the distribution of plasma cells in the colonic mucosa.