Julián Panés

Genome-wide meta-analysis increases to 71 the number of confirmed Crohn's disease susceptibility loci

We undertook a meta-analysis of six Crohns disease genome-wide association studies (GWAS) comprising 6,333 affected individuals (cases) and 15,056 controls and followed up the top association signals in 15,694 cases, 14,026 controls and 414 parent-offspring trios. We identified 30 new susceptibility loci meeting genome-wide significance (P < 5 × 10−8). A series of in silico analyses highlighted particular genes within these loci and, together with manual curation, implicated functionally interesting candidate genes including SMAD3, ERAP2, IL10, IL2RA, TYK2, FUT2, DNMT3A, DENND1B, BACH2 and TAGAP. Combined with previously confirmed loci, these results identify 71 distinct loci with genome-wide significant evidence for association with Crohns disease.

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 …

Magnetic resonance for assessment of disease activity and severity in ileocolonic Crohn’s disease

Objective: Assessment of disease extension and activity is crucial to guide treatment in Crohn’s disease. The objective of the current cross-sectional study was to determine the accuracy of MR for this assessment. Design: 50 patients with clinically active (n = 35) or inactive (n = 15) Crohn’s disease underwent ileocolonoscopy (reference standard) and MR. T2-weighted and precontrast and postcontrast-enhanced T1-weighted sequences were acquired. Endoscopic activity was evaluated by CDEIS (Crohn’s Disease Endoscopic Index of Severity); in addition endoscopic lesions were classified as absent, mild (inflammation without ulcers) or severe (presence of ulceration). Results: The comparison of intestinal segments with absent, mild and severe inflammation demonstrated a progressive and significant (p<0.001) increase in the following MR parameters: wall thickness, postcontrast wall signal intensity, relative contrast enhancement, presence of oedema, ulcers, pseudopolyps and lymph node enlargement. Independent predictors for CDEIS in a segment were wall thickness (p = 0.007), relative contrast enhancement (p = 0.01), presence of oedema (p = 0.02) and presence of ulcers at MR (p = 0.003). There was a significant correlation (r = 0.82, p<0.001) between the CDEIS of the segment and the MR index calculated according to the logistic regression analysis coefficients. The MR index had a high accuracy for the detection of disease activity (area under the receiver operating characteristic (ROC) curve 0.891, sensitivity 0.81, specificity 0.89) and for the detection of ulcerative lesions (area under the ROC curve 0.978, sensitivity 0.95, specificity 0.91) in the colon and terminal ileum. Conclusion: The accuracy of MR for detecting disease activity and assessing severity brings about the possibility of using MR as an alternative to endoscopy in the evaluation of ileocolonic Crohn’s disease.

Tofacitinib, an Oral Janus Kinase Inhibitor, in Active Ulcerative Colitis

BACKGROUND Ulcerative colitis is a chronic inflammatory disease of the colon for which current treatments are not universally effective. One additional treatment may be tofacitinib (CP-690,550), an oral inhibitor of Janus kinases 1, 2, and 3 with in vitro functional specificity for kinases 1 and 3 over kinase 2, which is expected to block signaling involving gamma chain-containing cytokines including interleukins 2, 4, 7, 9, 15, and 21. These cytokines are integral to lymphocyte activation, function, and proliferation. METHODS In a double-blind, placebo-controlled, phase 2 trial, we evaluated the efficacy of tofacitinib in 194 adults with moderately to severely active ulcerative colitis. Patients were randomly assigned to receive tofacitinib at a dose of 0.5 mg, 3 mg, 10 mg, or 15 mg or placebo twice daily for 8 weeks. The primary outcome was a clinical response at 8 weeks, defined as an absolute decrease from baseline in the score on the Mayo scoring system for assessment of ulcerative colitis activity (possible score, 0 to 12, with higher scores indicating more severe disease) of 3 or more and a relative decrease from baseline of 30% or more with an accompanying decrease in the rectal bleeding subscore of 1 point or more or an absolute rectal bleeding subscore of 0 or 1. RESULTS The primary outcome, clinical response at 8 weeks, occurred in 32%, 48%, 61%, and 78% of patients receiving tofacitinib at a dose of 0.5 mg (P=0.39), 3 mg (P=0.55), 10 mg (P=0.10), and 15 mg (P<0.001), respectively, as compared with 42% of patients receiving placebo. Clinical remission (defined as a Mayo score ≤2, with no subscore >1) at 8 weeks occurred in 13%, 33%, 48%, and 41% of patients receiving tofacitinib at a dose of 0.5 mg (P=0.76), 3 mg (P=0.01), 10 mg (P<0.001), and 15 mg (P<0.001), respectively, as compared with 10% of patients receiving placebo. There was a dose-dependent increase in both low-density and high-density lipoprotein cholesterol. Three patients treated with tofacitinib had an absolute neutrophil count of less than 1500. CONCLUSIONS Patients with moderately to severely active ulcerative colitis treated with tofacitinib were more likely to have clinical response and remission than those receiving placebo. (Funded by Pfizer; ClinicalTrials.gov number, NCT00787202.).

Loss of Response and Requirement of Infliximab Dose Intensification in Crohn's Disease: A Review

OBJECTIVES:To review the frequency with which infliximabloses its effect and dose “intensification” is required for Crohns disease treatment.METHODS:Bibliographical searches were performed in MEDLINE, and European (ECCO) and American (DDW) Congresses. Studies evaluating loss of efficacy and requirement of infliximab dose intensification—defined either as an increase of the infliximab dose (generally from 5 mg/kg to 10 mg/kg) or as a decrease in the frequency of infusion (to as often as every 4 weeks)—in Crohns disease patients were included.RESULTS:Sixteen studies evaluating the incidence of loss of response to infliximab in Crohns disease patients were found. A total of 2,236 patients were included (the majority of them receiving a three-dose induction regimen at weeks 0, 2, and 6, followed by maintenance therapy every 8 weeks), providing 6,284 patient-years of follow-up. The mean percentage of patients with loss of infliximab response was 37%. However, as the follow-up time varied markedly among studies, the risk of losing response to infliximab is better expressed as the incidence of this complication per patient-year of follow-up. Therefore, the annual risk for loss of infliximab response was calculated to be 13% per patient-year.CONCLUSIONS:A variable but relevant proportion of Crohns disease patients on long-term infliximab treatment lose response. This may be interpreted in two different but compatible ways: a positive view, highlighting that infliximab therapy is relatively durable, with the majority of patients predicted to continue infliximab treatment at least during the first year; or a negative view, interpreting that a significant proportion of Crohns disease patients—more than 10% per patient-year of infliximab treatment—on long term will lose response and will require an increase in dose and/or decrease in infusion interval.

Leukocyte-endothelial cell interactions: Molecular mechanisms and implications in gastrointestinal disease

Leukocyte-endothelial cell adhesion is now recognized to represent an early and rate-limiting step in the leukocyte infiltration and accompanying tissue injury that is associated with acute and chronic inflammatory diseases of the gastrointestinal tract. Adhesive interactions such as leukocyte rolling, adherence, and transendothelial migration are influenced by a variety of physical, chemical, and molecular factors that ultimately result in a net up-regulation or down-regulation of the inflammatory response. Coordination of this process is made possible by the mediator-specific, time-sensitive expression of adhesion glycoproteins on the surface of leukocytes and/or vascular endothelial cells. In this review, the different families of relevant adhesion molecules that participate in the coordinated recruitment of leukocytes into inflamed tissue are described and then discussed in terms of the pathophysiological alterations observed in selected experimental models of gastrointestinal disease. These include ischemia/reperfusion injury, radiation enteritis, inflammatory bowel disease, and the inflammatory responses to substances liberated by Helicobacter pylori and Clostridium difficile.

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)

Selecting Therapeutic Targets in Inflammatory Bowel Disease (STRIDE): Determining Therapeutic Goals for Treat-to-Target.

OBJECTIVES:The Selecting Therapeutic Targets in Inflammatory Bowel Disease (STRIDE) program was initiated by the International Organization for the Study of Inflammatory Bowel Diseases (IOIBD). It examined potential treatment targets for inflammatory bowel disease (IBD) to be used for a “treat-to-target” clinical management strategy using an evidence-based expert consensus process.METHODS:A Steering Committee of 28 IBD specialists developed recommendations based on a systematic literature review and expert opinion. Consensus was gained if ≥75% of participants scored the recommendation as 7–10 on a 10-point rating scale (where 10=agree completely).RESULTS:The group agreed upon 12 recommendations for ulcerative colitis (UC) and Crohn’s disease (CD). The agreed target for UC was clinical/patient-reported outcome (PRO) remission (defined as resolution of rectal bleeding and diarrhea/altered bowel habit) and endoscopic remission (defined as a Mayo endoscopic subscore of 0–1). Histological remission was considered as an adjunctive goal. Clinical/PRO remission was also agreed upon as a target for CD and defined as resolution of abdominal pain and diarrhea/altered bowel habit; and endoscopic remission, defined as resolution of ulceration at ileocolonoscopy, or resolution of findings of inflammation on cross-sectional imaging in patients who cannot be adequately assessed with ileocolonoscopy. Biomarker remission (normal C-reactive protein (CRP) and calprotectin) was considered as an adjunctive target.CONCLUSIONS:Evidence- and consensus-based recommendations for selecting the goals for treat-to-target strategies in patients with IBD are made available. Prospective studies are needed to determine how these targets will change disease course and patients’ quality of life.

Imaging techniques for assessment of inflammatory bowel disease: Joint ECCO and ESGAR evidence-based consensus guidelines

The management of patients with IBD requires evaluation with objective tools, both at the time of diagnosis and throughout the course of the disease, to determine the location, extension, activity and severity of inflammatory lesions, as well as, the potential existence of complications. Whereas endoscopy is a well-established and uniformly performed diagnostic examination, the implementation of radiologic techniques for assessment of IBD is still heterogeneous; variations in technical aspects and the degrees of experience and preferences exist across countries in Europe. ECCO and ESGAR scientific societies jointly elaborated a consensus to establish standards for imaging in IBD using magnetic resonance imaging, computed tomography, ultrasonography, and including also other radiologic procedures such as conventional radiology or nuclear medicine examinations for different clinical situations that include general principles, upper GI tract, colon and rectum, perineum, liver and biliary tract, emergency situation, and the postoperative setting. The statements and general recommendations of this consensus are based on the highest level of evidence available, but significant gaps remain in certain areas such as the comparison of diagnostic accuracy between different techniques, the value for therapeutic monitoring, and the prognostic implications of particular findings.

Second European evidence-based consensus on the diagnosis and management of ulcerative colitis part 3: special situations.

### 8.1 General Proctocolectomy with ileal pouch-anal anastomosis (IPAA) is the procedure of choice for most patients with ulcerative colitis (UC) requiring colectomy.1 Pouchitis is a non-specific inflammation of the ileal reservoir and the most common complication of IPAA in patients with UC.2–7 Its frequency is related to the duration of follow up, occurring in up to 50% of patients 10 years after IPAA in large series from major referral centres.1–9 The cumulative incidence of pouchitis in patients with an IPAA for familial adenomatous polyposis is much lower, ranging from 0 to 10%.10–12 Reasons for the higher frequency of pouchitis in UC remain unknown. Whether pouchitis more commonly develops within the first years after IPAA or whether the risk continues to increase with longer follow up remains undefined. ### Statement 8A The diagnosis of pouchitis requires the presence of symptoms, together with characteristic endoscopic and histological abnormalities [EL3a, RG B]. Extensive UC, extraintestinal manifestations (i.e. PSC), being a non-smoker, p-ANCA positive serology and NSAID use are possible risk factors for pouchitis [EL3b, RG D] #### 8.1.1 Symptoms After proctocolectomy with IPAA, median stool frequency is 4 to 8 bowel movements,1–4,13,14 with about 700 mL of semiformed/liquid stool per day,2,13,14 compared to a volume of 200 mL/day in healthy people. Symptoms related to pouchitis include increased stool frequency and liquidity, abdominal cramping, urgency, tenesmus and pelvic discomfort.2,15 Rectal bleeding, fever, or extraintestinal manifestations may occur. Rectal bleeding is more often related to inflammation of the rectal cuff (“cuffitis,” Section 1.4),16 than to pouchitis. Faecal incontinence may occur in the absence of pouchitis after IPAA, but is more common in patients with pouchitis. Symptoms of pouch dysfunction in patients with IPAA may be caused by conditions other than pouchitis, including Crohns disease of the pouch,17–19 cuffitis16 and an irritable pouch …