Simon Travis

The second European evidence-based Consensus on the diagnosis and management of Crohn's disease: Definitions and diagnosis.

Crohns disease is a lifelong disease arising from an interaction between genetic and environmental factors, but observed predominantly in developed countries of the world. The precise aetiology is unknown and therefore a causal therapy is not yet available. Within Europe there is a distinct North–South gradient, but the incidence appears to have increased in Southern countries in recent years.1 Many patients live with a considerable symptom burden despite medical treatment in the hope that the aetiology of the disease will shortly be revealed and curative therapies emerge. Since it is uncertain that the precise pathogenesis of Crohns disease will be revealed anytime soon, clinicians have to advise patients on the basis of information available today rather than an unknown future. Despite a multiplicity of randomised trials there will always be many questions that can only be answered by the exercise of judgement and opinion. This leads to differences in practice between clinicians, which may be brought into sharp relief by differences in emphasis between countries. The Consensus endeavours to address these differences. The Consensus is not meant to supersede the guidelines of different countries (such as those from the UK,2 Germany,3 or France), which reach broadly the same conclusions since they are, after all, based on the same evidence. Rather, the aim of the Consensus is to promote a European perspective on the management of Crohns disease and its dilemmas. Since the development of guidelines is an expensive and time-consuming process, it may help to avoid duplication of effort in the future. A Consensus is also considered important because an increasing number of therapeutic trials are based in Europe, especially in eastern European countries where practice guidelines have yet to be published. This document is based on the European consensus on the diagnosis and management of Crohns …

The second European evidence-based Consensus on the diagnosis and management of Crohn's disease: Special situations.

Principal changes with respect to the 2004 ECCO guidelines Ileocolonoscopy is recommended within the first year after surgery where treatment decisions may be affected (Statement 8C). Thiopurines are more effective than mesalazine or imidazole antibiotics alone in post-operative prophylaxis (Statement 8F). ### 8.1 Epidemiology of post-operative Crohns disease In the natural history of CD, intestinal resection is almost unavoidable since about 80% of patients require surgery at some stage. Surgery is unfortunately not curative as the disease inexorably recurs in many patients. The post-operative recurrence rate varies according to the definition used: clinical, endoscopic, radiological, or surgical. It is lowest when the repeat resection rate is considered, intermediate when clinical indices are used and highest when endoscopy is employed as the diagnostic tool.1–10 Data from endoscopic follow-up of patients after resection of ileo-caecal disease have shown that in the absence of treatment, the post-operative recurrence rate is around 65–90% within 12 months and 80–100% within 3 years of the operation. The clinical recurrence without therapy is about 20–25%/year.1,10 It has been demonstrated that the post-operative clinical course of CD is best predicted by the severity of endoscopic lesions. Symptoms, in fact, appear only when severe lesions are present and it is not uncommon to observe patients with fairly advanced recurrent lesions at endoscopy who remain asymptomatic.1 For these reasons, clinical indices such as the CDAI have low sensitivity at discriminating between patients with or without post-operative recurrence.11 These data mandate strategies aimed at interrupting or delaying the natural course of post-operative recurrence. Several medications have been tried in an attempt to prevent post-operative recurrence, mostly with disappointing results. The aim of this Consensus was therefore critically to evaluate the optimal strategies for the management of post-operative recurrence in CD. Most, if not all, of the evidence available deals with …

Second European evidence-based consensus on the diagnosis and management of ulcerative colitis Part 2: Current management

### 5.1 General When deciding the appropriate treatment strategy for active ulcerative colitis one should consider the activity, distribution (proctitis, left-sided, extensive1), and pattern of disease. The disease pattern includes relapse frequency, course of disease, response to previous medications, side-effect profile of medication and extra-intestinal manifestations. The age at onset and disease duration may also be important factors. #### 5.1.1 Disease activity The principal disease activity scoring systems used in clinical trials are covered in Section 1.2 and have been comprehensively reviewed.2 However there are some practical points that are relevant for routine clinical use. For example, it is most important to distinguish patients with severe ulcerative colitis necessitating hospital admission from those with mild or moderately active disease who can generally be managed as outpatients. The simplest, best validated and most widely used index for identifying severe UC remains that of Truelove and Witts3: 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). Only one additional criterion in addition to the bloody stool frequency ≥ 6/day is needed to define a severe attack.4,5 It should be standard practice to confirm the presence of active colitis by sigmoidoscopy before starting treatment. Flexible sigmoidoscopy and biopsy may exclude unexpected causes of symptoms that mimic active disease such as cytomegalovirus colitis, rectal mucosal prolapse, Crohns disease, malignancy, or even irritable bowel syndrome and haemorrhoidal bleeding. There may be a significant overlap between other diseases that mimic ulcerative colitis and the broad spectrum of UC damage.6,7 In addition, all patients with active disease require stool cultures with Clostridium difficile toxin assay to exclude enteric infection. Patients with an appropriate …

Secukinumab, a human anti-IL-17A monoclonal antibody, for moderate to severe Crohn's disease: unexpected results of a randomised, double-blind placebo-controlled trial

Objective The authors tested whether the anti-interleukin (IL)-17A monoclonal antibody secukinumab was safe and effective for the treatment of active Crohns disease. Design In a double-blind, randomised, placebo-controlled proof-of-concept study, 59 patients with moderate to severe Crohns disease (Crohns Disease Activity Index (CDAI) ≥220 to ≤450) were assigned in a 2:1 ratio to 2×10 mg/kg intravenous secukinumab or placebo. The primary end point, addressed by Bayesian statistics augmented with historical placebo information, was the probability that secukinumab reduces the CDAI by ≥50 points more than placebo at week 6. Ancillary analyses explored associations of 35 candidate genetic polymorphisms and faecal calprotectin response. Results 59 patients (39 secukinumab, 20 placebo, mean baseline CDAI 307 and 301, respectively) were recruited. 18/59 (31%) patients discontinued prematurely (12/39 (31%) secukinumab, 6/20 (30%) placebo), 10/59 (17%) due to insufficient therapeutic effect (8/39 (21%) secukinumab, 2/20 (10%) placebo). Fourteen serious adverse events occurred in 10 patients (seven secukinumab, three placebo); 20 infections, including four local fungal infections, were seen on secukinumab versus none on placebo. Primary end point analysis estimated <0.1% probability (∆CDAI (SD) =33.9 (19.7), 95% credible interval −4.9 to 72.9) that secukinumab reduces CDAI by ≥50 points more than placebo. Secondary area under the curve analysis (weeks 4–10) showed a significant difference (mean ΔCDAI=49; 95% CI (2 to 96), p=0.043) in favour of placebo. Post hoc subgroup analysis showed that unfavourable responses on secukinumab were driven by patients with elevated inflammatory markers (CRP≥10 mg/l and/or faecal calprotectin≥200 ng/ml; mean ΔCDAI=62; 95% CI (−1 to 125), p=0.054 in favour of placebo). Absence of the minor allele of tumour necrosis factor-like ligand 1A was strongly associated with lack of response measured by baseline-adjusted changes in calprotectin at week 6 (p=0.00035 Bonferroni-corrected). Conclusions Blockade of IL-17A was ineffective and higher rates of adverse events were noted compared with placebo. Clinical trial registration This trial was registered at ClinicalTrial.gov with the number NCT01009281.

Second European evidence-based consensus on the diagnosis and management of ulcerative colitis Part 1: Definitions and diagnosis

### 1.1 Introduction Ulcerative colitis is a lifelong disease arising from an interaction between genetic and environmental factors, observed predominantly in the developed countries of the world. The precise aetiology is unknown and therefore medical therapy to cure the disease is not yet available. Within Europe there is a North–South gradient, but the incidence appears to have increased in Southern and Eastern countries in recent years.1,2 Patients may live with a considerable symptom burden despite medical treatment (66% describe interference with work and 73% with leisure activities3) in the hope that the aetiology of ulcerative colitis will shortly be revealed and a cure emerge. Although this is conceivable in the next decade, clinicians have to advise patients on the basis of information available today. Despite randomised trials there will always be many questions that can only be answered by the exercise of judgement and opinion. This leads to differences in practice between clinicians, which may be brought into sharp relief by differences in emphasis between countries. This Consensus endeavours to address these differences. The Consensus is not meant to supersede the guidelines of different countries (such as those from the UK,4 or Germany,5) which reach broadly the same conclusions since they are, after all, based on the same evidence. Rather, the aim of the Consensus is to promote a European perspective on the management of ulcerative colitis (UC) and its dilemmas. Since the development of guidelines is an expensive and time-consuming process, it may help to avoid duplication of effort in the future. A European Consensus is also considered important because an increasing number of therapeutic trials recruit from Central and Eastern European countries where practice guidelines have yet to be published. This document updates the previous European Consensus on the diagnosis and management of UC, and …

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

### 5.1 General The 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. #### 5.1.1 Disease activity The 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). #### 5.1.2 Approach Patients should be encouraged to participate actively in …

European evidence-based Consensus on the diagnosis and management of ulcerative colitis: Definitions and diagnosis

### 1.1 Introduction Ulcerative colitis is a life long disease arising from an interaction between genetic and environmental factors, but observed predominantly in the developed countries of the world. The precise aetiology is unknown and therefore medical therapy to cure the disease is not yet available. Within Europe there is a North–South gradient, but the incidence appears to have increased in Southern and developing countries in recent years.1,2 Patients may live with a considerable symptom burden despite medical treatment (66% describe interference with work and 73% with leisure activities3) in the hope that the aetiology of ulcerative colitis will shortly be revealed and a cure emerges. Although this is conceivable in the next decade, clinicians have to advise patients on the basis of information available today. Despite randomized trials there will always be many questions that can only be answered by the exercise of judgement and opinion. This leads to differences in practice between clinicians, which may be brought into sharp relief by differences in emphasis between countries. The Consensus endeavours to address these differences. The Consensus is not meant to supersede the guidelines of different countries (such as those from the UK,4 or Germany5), which reach broadly the same conclusions since they are, after all, based on the same evidence. Rather, the aim of the Consensus is to promote a European perspective on the management of ulcerative colitis (UC) and its dilemmas. Since the development of guidelines is an expensive and time-consuming process, it may help to avoid duplication of effort in the future. A European Consensus is also considered important because an increasing number of therapeutic trials recruit from Central and Eastern European countries where practice guidelines have yet to be published. This document sets out the current European Consensus on the diagnosis and management …

IL-23-responsive innate lymphoid cells are increased in inflammatory bowel disease.

Increased numbers of innate lymphoid cells in patients with inflammatory bowel disease.

Mucosal healing in inflammatory bowel diseases: a systematic review

Recent studies have identified mucosal healing on endoscopy as a key prognostic parameter in the management of inflammatory bowel diseases (IBD), thus highlighting the role of endoscopy for monitoring of disease activity in IBD. In fact, mucosal healing has emerged as a key treatment goal in IBD that predicts sustained clinical remission and resection-free survival of patients. The structural basis of mucosal healing is an intact barrier function of the gut epithelium that prevents translocation of commensal bacteria into the mucosa and submucosa with subsequent immune cell activation. Thus, mucosal healing should be considered as an initial event in the suppression of inflammation of deeper layers of the bowel wall, rather than as a sign of complete healing of gut inflammation. In this systematic review, the clinical studies on mucosal healing are summarised and the effects of anti-inflammatory or immunosuppressive drugs such as 5-aminosalicylates, corticosteroids, azathioprine, ciclosporin and anti-TNF antibodies (adalimumab, certolizumab pegol, infliximab) on mucosal healing are discussed. Finally, the implications of mucosal healing for subsequent clinical management in patients with IBD are highlighted.

Development of the Crohn's disease digestive damage score, the Lemann score.

Crohns disease (CD) is a chronic progressive destructive disease. Currently available instruments measure disease activity at a specific point in time. An instrument to measure cumulative structural damage to the bowel, which may predict long-term disability, is needed. The aim of this article is to outline the methods to develop an instrument that can measure cumulative bowel damage. The project is being conducted by the International Program to develop New Indexes in Crohns disease (IPNIC) group. This instrument, called the Crohns Disease Digestive Damage Score (the Lémann score), should take into account damage location, severity, extent, progression, and reversibility, as measured by diagnostic imaging modalities and the history of surgical resection. It should not be “diagnostic modality driven”: for each lesion and location, a modality appropriate for the anatomic site (for example: computed tomography or magnetic resonance imaging enterography, and colonoscopy) will be used. A total of 24 centers from 15 countries will be involved in a cross-sectional study, which will include up to 240 patients with stratification according to disease location and duration. At least 120 additional patients will be included in the study to validate the score. The Lémann score is expected to be able to portray a patients disease course on a double-axis graph, with time as the x-axis, bowel damage severity as the y-axis, and the slope of the line connecting data points as a measure of disease progression. This instrument could be used to assess the effect of various medical therapies on the progression of bowel damage. (Inflamm Bowel Dis 2011)