Long-term outcome of enterocutaneous fistula in patients with Crohn's disease treated with anti-TNF therapy: a cohort study from the GETAID.

OBJECTIVES: Although anti-tumor necrosis factor (TNF) therapy is the treatment of choice for perianal fistulizing Crohn's disease (CD), the efficacy and safety of anti-TNF therapy in enterocutaneous fistula (ECF) remains unclear. METHODS: Between January 2008 and December 2009, we retrospectively reviewed the outcomes of all CD patients with ECF (excluding perianal fistula) treated with anti-TNF therapy followed up in Groupe d'Etude Thérapeutique des Affections Inflammatoires du tube Digestif (GETAID) centers. ECF closure and tolerance of anti-TNF therapy were studied using univariate and multivariate analyses. RESULTS: Forty-eight patients (twenty-six women; median age 34.6 (interquartile range=25.0-45.5) years) were included in this study. The median follow-up period was 3.0 (2.0-6.6) years. The fistula was located in the small bowel (n=38), duodenum (n=1), and colon (n=9). The fistula has been developed in ileocolonic anastomosis in 17 (35%) cases. Sixteen patients (33%) had complex fistulas with multiple tracts and eleven patients (23%) had a high ECF output (if wearing an ostomy bag). Complete ECF closure was achieved in 16 (33%) patients, of whom eight relapsed during the follow-up period. In multivariate analysis, complete ECF closure was associated with the absence of multiple ECF tracts and associated stenosis. An abdominal abscess developed in 15 (31%) patients. ECF resection was needed in 26 (54%) patients. One patient died after surgery owing to abdominal sepsis. CONCLUSIONS: In CD patients with ECF, anti-TNF therapy may be effective in up to one-third of patients, especially in the absence of stenosis and complex fistula. A careful selection of patients is mandatory to prevent treatment failure and improves the safety.

Analysis of single nucleotide polymorphisms in the region of CLDN2-MORC4 in relation to inflammatory bowel disease.

AIM: To investigate a possible genetic influence of claudin (CLDN)1, CLDN2 and CLDN4 in the etiology of inflammatory bowel disease. METHODS: Allelic association between genetic regions of CLDN1, CLDN2 or CLDN4 and patients with inflammatory bowel disease, Crohn's disease (CD) or ulcerative colitis were investigated using both a case-control study approach (one case randomly selected from each of 191 Swedish inflammatory bowel disease families and 333 controls) and a family-based study (463 non-Swedish European inflammatory bowel disease -families). A nonsynonymous coding single nucleotide polymorphism in MORC4, located on the same linkage block as CLDN2, was investigated for association, as were two novel CLDN2 single nucleotide polymorphism markers, identified by resequencing. RESULTS: A single nucleotide polymorphism marker (rs12014762) located in the genetic region of CLDN2 was significantly associated to CD (case-control allelic OR = 1.98, 95%CI: 1.17-3.35, P = 0.007). MORC4 was present on the same linkage block as this CD marker. Using the case-control approach, a significant association (case control allelic OR = 1.61, 95%CI: 1.08-2.41, P = 0.018) was found between CD and a nonsynonymous coding single nucleotide polymorphism (rs6622126) in MORC4. The association between the CLDN2 marker and CD was not replicated in the family-based study. Ulcerative colitis was not associated to any of the single nucleotide polymorphism markers. CONCLUSION: These findings suggest that a variant of the CLDN2-MORC4 region predisposes to CD in a Swedish population.

Endoscopic improvement of mucosal lesions in patients with moderate to severe ileocolonic Crohn's disease following treatment with certolizumab pegol.

OBJECTIVE: To evaluate the efficacy of certolizumab pegol (CZP) in improving endoscopic lesions in patients with active ileocolonic Crohn's disease (CD). METHODS: This phase IIIB multicentre open-label clinical trial enrolled 89 adult patients with active endoscopic disease (ulceration in ≥2 intestinal segments with a Crohn's Disease Endoscopic Index of Severity (CDEIS) score ≥8 points). Patients received subcutaneous CZP 400 mg at weeks 0, 2 and 4 and every 4 weeks up to week 52. Endoscopic evaluations were performed at weeks 0, 10 and 54. The primary outcome was mean change in CDEIS score at week 10; secondary outcome measures included endoscopic response (decrease in CDEIS score >5 points), remission (CDEIS score <6), complete remission (CDEIS score <3) and mucosal healing (no ulcer) at weeks 10 and 54. RESULTS: In the intention-to-treat population (n=89) the mean±SD CDEIS score was 14.5±5.3 at baseline; the mean decrease in CDEIS score at week 10 was 5.7 (95% CI 4.6 to 6.8, p<0.0001). Rates of endoscopic response, endoscopic remission, complete endoscopic remission and mucosal healing at week 10 were 54%, 37%, 10% and 4%, respectively. At week 54 the corresponding rates were 49%, 27%, 14% and 8%, respectively. The safety profile was consistent with that of previous CZP trials. CONCLUSIONS: Following CZP treatment in patients with active CD, endoscopic lesions were improved as shown by the decrease in mean CDEIS score and by endoscopic response and remission rates. These benefits were achieved as early as week 10 and were generally maintained through week 54. CLINICAL TRIAL REGISTRATION NUMBER: NCT00297648.

Ciclosporin versus infliximab in patients with severe ulcerative colitis refractory to intravenous steroids: a parallel, open-label randomised controlled trial.

BACKGROUND: Ciclosporin and infliximab are potential rescue treatments to avoid colectomy in patients with acute severe ulcerative colitis refractory to intravenous corticosteroids. We compared the efficacy and safety of these drugs for this indication. METHODS: In this parallel, open-label, randomised controlled trial, patients were aged at least 18 years, had an acute severe flare of ulcerative colitis defined by a Lichtiger score greater than 10 points, and had been given an unsuccessful course of high-dose intravenous steroids. None of the patients had previously received ciclosporin or infliximab. Between June 1, 2007, and Aug 31, 2010, patients at 27 European centres were randomly assigned (via computer-derived permutation tables; 1:1) to receive either intravenous ciclosporin (2 mg/kg per day for 1 week, followed by oral drug until day 98) or infliximab (5 mg/kg on days 0, 14, and 42). In both groups, azathioprine was started at day 7 in patients with a clinical response. Neither patients nor investigators were masked to study treatment. The primary efficacy outcome was treatment failure defined by absence of a clinical response at day 7, a relapse between day 7 and day 98, absence of steroid-free remission at day 98, a severe adverse event leading to treatment interruption, colectomy, or death. Analysis was by intention to treat. This trial is registered with EudraCT (2006-005299-42) and ClinicalTrials.gov (NCT00542152). FINDINGS: 115 patients were randomly assigned; 58 patients were allocated to receive ciclosporin and 57 to receive infliximab. Treatment failure occurred in 35 (60%) patients given ciclosporin and 31 (54%) given infliximab (absolute risk difference 6%; 95% CI -7 to 19; p=0·52). Nine (16%) patients in the ciclosporin group and 14 (25%) in the infliximab group had severe adverse events. INTERPRETATION: Ciclosporin was not more effective than infliximab in patients with acute severe ulcerative colitis refractory to intravenous steroids. In clinical practice, treatment choice should be guided by physician and centre experience. FUNDING: Association François Aupetit, Société Nationale Française de Gastroentérologie, and the International Organization for the study of Inflammatory Bowel Disease.

Challenges to the design, execution, and analysis of randomized controlled trials for inflammatory bowel disease.

Treatment of inflammatory bowel disease has greatly improved with the development of targeted, monoclonal antibody-based therapies. Tumor necrosis factor antagonists are frequently used to treat patients with Crohn's disease or ulcerative colitis, but they have side effects and their efficacy often decreases with use. New, more effective drugs are therefore needed and in development. However, many agents that appeared to be promising in preclinical studies have failed to show efficacy in clinical trials. We discuss possible reasons for the failures of these reagents in trials, which include the high rate of response to placebo, an inadequate range of doses, inappropriate timing of end point measurements, the changing therapeutic environment, and the competitive trial system. We also review regulatory guidelines for end points and trial design and recommend ways to improve trials.

Clinical predictors at diagnosis of disabling pediatric Crohn's disease.

BACKGROUND: Identification of children with Crohn's disease (CD) at high risk of disabling disease would be invaluable in guiding initial therapy. Our study aimed to identify predictors at diagnosis of a subsequent disabling course in a population-based cohort of patients with pediatric-onset CD. METHODS: Among 537 patients with pediatric CD diagnosed at <17 years of age, 309 (57%) with 5-year follow-up were included. Clinical and demographic factors associated with subsequent disabling CD were studied. Three definitions of disabling CD were used: Saint-Antoine and Liège Hospitals' definitions and a new pediatric definition based on the presence at maximal follow-up of: 1) growth delay defined by body mass index (BMI), weight or height lower than -2 SD Z score; and 2) at least one intestinal resection or two anal interventions. Predictors were determined using multivariate analyses and their accuracy using the kappa method considering a relevant value ≥ 0.6. RESULTS: According to the Saint-Antoine definition, the rate of disabling CD was 77% and predictors were complicated behavior and L1 location. According to the Liège definition, the rate was 37% and predictors included behavior, upper gastrointestinal disease, and extraintestinal manifestations. According to the pediatric definition, the rate of disabling CD was 15%, and predictors included complicated behavior, age <14, and growth delay at diagnosis. Kappa values for each combination of predictors were, respectively, 0.2, 0.3, and 0.2 and were nonrelevant. CONCLUSIONS: Clinical parameters at diagnosis are insufficient to predict a disabling course of pediatric CD. More complex models including serological and genetic biomarkers should be tested.

Developing an instrument to assess the endoscopic severity of ulcerative colitis: the Ulcerative Colitis Endoscopic Index of Severity (UCEIS).

BACKGROUND: Variability in endoscopic assessment necessitates rigorous investigation of descriptors for scoring severity of ulcerative colitis (UC). OBJECTIVE: To evaluate variation in the overall endoscopic assessment of severity, the intra- and interindividual variation of descriptive terms and to create an Ulcerative Colitis Endoscopic Index of Severity which could be validated. DESIGN: A two-phase study used a library of 670 video sigmoidoscopies from patients with Mayo Clinic scores 0-11, supplemented by 10 videos from five people without UC and five hospitalised patients with acute severe UC. In phase 1, each of 10 investigators viewed 16/24 videos to assess agreement on the Baron score with a central reader and agreed definitions of 10 endoscopic descriptors. In phase 2, each of 30 different investigators rated 25/60 different videos for the descriptors and assessed overall severity on a 0-100 visual analogue scale. κ Statistics tested inter- and intraobserver variability for each descriptor. A general linear mixed regression model based on logit link and ß distribution of variance was used to predict overall endoscopic severity from descriptors. RESULTS: There was 76% agreement for 'severe', but 27% agreement for 'normal' appearances between phase I investigators and the central reader. In phase 2, weighted κ values ranged from 0.34 to 0.65 and 0.30 to 0.45 within and between observers for the 10 descriptors. The final model incorporated vascular pattern, (normal/patchy/complete obliteration) bleeding (none/mucosal/luminal mild/luminal moderate or severe), erosions and ulcers (none/erosions/superficial/deep), each with precise definitions, which explained 90% of the variance (pR(2), Akaike Information Criterion) in the overall assessment of endoscopic severity, predictions varying from 4 to 93 on a 100-point scale (from normal to worst endoscopic severity). CONCLUSION: The Ulcerative Colitis Endoscopic Index of Severity accurately predicts overall assessment of endoscopic severity of UC. Validity and responsiveness need further testing before it can be applied as an outcome measure in clinical trials or clinical practice.

High frequency of fatal haemophagocytic lymphohistiocytosis syndrome in enteropathy-associated T cell lymphoma.

INTRODUCTION: Enteropathy-associated T-cell lymphoma is a rare form of T-cell lymphoma associated with a poor prognosis and the relative ineffectiveness of standard chemotherapy. The occurrence of haemophagocytic lymphohistiocytosis has been reported only once with this entity. PATIENTS AND METHODS: A retrospective study of 15 patients with enteropathy-associated T-cell lymphoma (type 1 in 12), followed-up in our units, since 1985. Two patients died before starting chemotherapy. The remaining 13 patients were treated with standard chemotherapy (n=7) and purine nucleotide analogues (n=6). RESULTS: Median follow-up was 8.7 (1-97) months. Surgery was required in 10 patients (66%) for intestinal complications (n=7) or elective small bowel resection (n=3). Survival probability was 40% and 20% at 1 and 5 years, respectively (Kaplan-Meier method). Survival was not significantly different between the two chemotherapy regimens. However, a slight decrease of febrile neutropenia was observed in the purine nucleotide analogues group (p=0.06). Haemophagocytic lymphohistiocytosis occurred in 6/15 (40%) cases. In these six patients, haemophagocytic lymphohistiocytosis was always fatal within 3 months. CONCLUSION: Enteropathy-associated T-cell lymphoma is associated with a poor outcome, independently of the chemotherapy regimens administered and frequent occurrence of haemophagocytic lymphohistiocytosis. The latter complication should be considered for urgent rescue therapy.

Recommendations for the treatment of Crohn's disease with tumor necrosis factor antagonists: an expert consensus report.

BACKGROUND: Symptom relief is the traditional treatment goal in Crohn's disease (CD). New goals including mucosal healing and bowel preservation are now achievable with tumor necrosis factor (TNF) antagonists. Infliximab and adalimumab are approved as second-line treatments for severe, active CD. Certolizumab pegol is approved only in the U.S. and Switzerland as second-line treatment for moderate-to-severe, active CD. Data from trials of infliximab suggest that high-risk patients and patients with active inflammation (CRP elevation and/or ileocolonic ulcers) may benefit from earlier use of this drug. METHODS: A Delphi survey was used to obtain consensus on issues surrounding bowel preservation and use of TNF antagonists. At the time of this survey, infliximab was the only TNF antagonist approved for the treatment of CD in Europe, Canada, and Australia. An expert panel of 12 gastroenterologists with substantial clinical experience using infliximab in clinical practice and trials in these areas participated. RESULTS: The experts agreed that bowel preservation and mucosal healing are relevant and achievable goals, and form a rationale for using TNF antagonists in CD patients. Control of inflammation and induction of mucosal healing were considered essential for bowel preservation. Consensus areas: 1) mucosal healing is predictive of improved long-term disease course and increases the likelihood of steroid-free remission; 2) infliximab induces sustained mucosal healing, promotes bowel preservation, and reduces hospitalizations and surgeries; 3) benefits of infliximab in relation to mucosal healing, bowel preservation, and clinical remission increase when therapy is initiated earlier. CONCLUSIONS: Treatment with TNF antagonists helps preserve the bowel in CD patients.

Maintenance of remission among patients with Crohn's disease on antimetabolite therapy after infliximab therapy is stopped.

BACKGROUND & AIMS: It is important to determine whether infliximab therapy can be safely interrupted in patients with Crohn's disease who have undergone a period of prolonged remission. We assessed the risk of relapse after infliximab therapy was discontinued in patients on combined maintenance therapy with antimetabolites and identified factors associated with relapse. METHODS: We performed a prospective study of 115 patients with Crohn's disease who were treated for at least 1 year with scheduled infliximab and an antimetabolite and had been in corticosteroid-free remission for at least 6 months. Infliximab was stopped, and patients were followed up for at least 1 year. We associated demographic, clinical, and biologic factors with time to relapse using a Cox model. RESULTS: After a median follow-up period of 28 months, 52 of the 115 patients experienced a relapse; the 1-year relapse rate was 43.9% ± 5.0%. Based on multivariable analysis, risk factors for relapse included male sex, the absence of surgical resection, leukocyte counts >6.0 × 10(9)/L, and levels of hemoglobin ≤145 g/L, C-reactive protein ≥5.0 mg/L, and fecal calprotectin ≥300 µg/g. Patients with no more than 2 of these risk factors (approximately 29% of the study population) had a 15% risk of relapse within 1 year. Re-treatment with infliximab was effective and well tolerated in 88% of patients who experienced a relapse. CONCLUSIONS: Approximately 50% of patients with Crohn's disease who were treated for at least 1 year with infliximab and an antimetabolite agent experienced a relapse within 1 year after discontinuation of infliximab. However, patients with a low risk of relapse can be identified using a combination of clinical and biologic markers.

Genotype/phenotype analyses for 53 Crohn's disease associated genetic polymorphisms.

BACKGROUND & AIMS: Recent studies reported a role for more than 70 genes or loci in the susceptibility to Crohn's disease (CD). However, the impact of these associations in clinical practice remains to be defined. The aim of the study was to analyse the relationship between genotypes and phenotypes for the main 53 CD-associated polymorphisms. METHOD: A cohort of 798 CD patients with a median follow up of 7 years was recruited by tertiary adult and paediatric gastroenterological centres. A detailed phenotypic description of the disease was recorded, including clinical presentation, response to treatments and complications. The participants were genotyped for 53 CD-associated variants previously reported in the literature and correlations with clinical sub-phenotypes were searched for. A replication cohort consisting of 722 CD patients was used to further explore the putative associations. RESULTS: The NOD2 rare variants were associated with an earlier age at diagnosis (p = 0.0001) and an ileal involvement (OR = 2.25[1.49-3.41] and 2.77 [1.71-4.50] for rs2066844 and rs2066847, respectively). Colonic lesions were positively associated with the risk alleles of IL23R rs11209026 (OR = 2.25 [1.13-4.51]) and 6q21 rs7746082 (OR = 1.60 [1.10-2.34] and negatively associated with the risk alleles of IRGM rs13361189 (OR = 0.29 [0.11-0.74]) and DEFB1 rs11362 (OR = 0.50 [0.30-0.80]). The ATG16L1 and IRGM variants were associated with a non-inflammatory behaviour (OR = 1.75 [1.22-2.53] and OR = 1.50 [1.04-2.16] respectively). However, these associations lost significance after multiple testing corrections. The protective effect of the IRGM risk allele on colonic lesions was the only association replicated in the second cohort (p = 0.03). CONCLUSIONS: It is not recommended to genotype the studied polymorphisms in routine practice.

Assessing patients' satisfaction with anti-TNFα treatment in Crohn's disease: qualitative steps of the development of a new questionnaire.

PURPOSE: To develop a self-administered questionnaire assessing patients' satisfaction with treatments in Crohn's disease for use in clinical research and epidemiological studies. PATIENTS AND METHODS: Semi-directive interviews (16) were conducted with patients with severe Crohn's disease treated with anti-tumor necrosis factor alpha (anti-TNFα). Transcripts were analyzed and concepts related to satisfaction with treatment were extracted and organized into a model. Items were generated using patients' words. The resulting test version was tested for relevance and comprehension with 7 patients and revised accordingly; the new version was tested with 5 other patients and revised to provide the pilot version. A clinician advisory board was involved at each milestone of the development. RESULTS: The test questionnaire assessed treatment satisfaction through 67 items, organized into 5 sections: treatment efficacy, side-effects, convenience and constraints, overall impact, and satisfaction. Conceptual content of the questionnaire includes comparison with prior state and with expectations, satisfaction, acceptability, and intentions. The questionnaire was generally well accepted and understood by patients; few modifications were made in the structure and item formulation. After the second round of comprehension tests, the pilot version contained 62 items; the questionnaire was named Satisfaction of PAtients in Crohn's diseasE (SPACE(©)). CONCLUSION: The questionnaire is a unique tool to assess treatment satisfaction in patients with Crohn's disease. A scoring and validation study is currently being performed to finalize and establish its scoring, as well as its psychometric properties.

TNF alpha antagonist therapy and safety monitoring.

OBJECTIVES: To develop and/or update fact sheets about TNFα antagonists treatments, in order to assist physicians in the management of patients with inflammatory joint disease. METHODS: 1. selection by a committee of rheumatology experts of the main topics of interest for which fact sheets were desirable; 2. identification and review of publications relevant to each topic; 3. development and/or update of fact sheets based on three levels of evidence: evidence-based medicine, official recommendations, and expert opinion. The experts were rheumatologists and invited specialists in other fields, and they had extensive experience with the management of chronic inflammatory diseases, such as rheumatoid. They were members of the CRI (Club Rhumatismes et Inflammation), a section of the Société Francaise de Rhumatologie. Each fact sheet was revised by several experts and the overall process was coordinated by three experts. RESULTS: Several topics of major interest were selected: contraindications of TNFα antagonists treatments, the management of adverse effects and concomitant diseases that may develop during these therapies, and the management of everyday situations such as pregnancy, surgery, and immunizations. After a review of the literature and discussions among experts, a consensus was developed about the content of the fact sheets presented here. These fact sheets focus on several points: 1. in RA and SpA, initiation and monitoring of TNFα antagonists treatments, management of patients with specific past histories, and specific clinical situations such as pregnancy; 2. diseases other than RA, such as juvenile idiopathic arthritis; 3. models of letters for informing the rheumatologist and general practitioner; 4. and patient information. CONCLUSION: These TNFα antagonists treatments fact sheets built on evidence-based medicine and expert opinion will serve as a practical tool for assisting physicians who manage patients on these therapies. They will be available continuously at www.cri-net.com and updated at appropriate intervals.

Increased risk for nonmelanoma skin cancers in patients who receive thiopurines for inflammatory bowel disease.

BACKGROUND & AIMS: Patients with inflammatory bowel disease (IBD) who have been exposed to thiopurines might have an increased risk of skin cancer. We assessed this risk among patients in France. METHODS: We performed a prospective observational cohort study of 19,486 patients with IBD, enrolled from May 2004 to June 2005, who were followed up until December 31, 2007. The incidence of nonmelanoma skin cancer (NMSC) in the general population, used for reference, was determined from the French Network of Cancer Registries. RESULTS: Before the age of 50 years, the crude incidence rates of NMSC among patients currently receiving or who previously received thiopurines were 0.66/1000 and 0.38/1000 patient-years, respectively; these values were 2.59/1000 and 1.96/1000 patient-years for the age group of 50 to 65 years and 4.04/1000 and 5.70/1000 patient-years for patients older than 65 years. Among patients who had never received thiopurines, the incidence of NMSC was zero before the age of 50 years, 0.60/1000 for the ages of 50 to 65 years, and 0.84/1000 for those older than 65 years. A multivariate Cox regression model stratified by propensity score quintiles showed that ongoing thiopurine treatment (hazard ratio [HR], 5.9; 95% confidence interval [CI], 2.1-16.4; P = .0006) and past thiopurine exposure (HR, 3.9; 95% CI, 1.3-12.1; P = .02) were risk factors for NMSC. They also identified age per 1-year increase as a risk factor for NMSC (HR, 1.08; 95% CI, 1.05-1.11; P < .0001). CONCLUSIONS: Ongoing and past exposure to thiopurines significantly increases the risk of NMSC in patients with IBD, even before the age of 50 years. These patients should be protected against UV radiation and receive lifelong dermatologic screening.

Activation of the receptor NKG2D leads to production of Th17 cytokines in CD4+ T cells of patients with Crohn's disease.

BACKGROUND & AIMS: The natural killer group 2 member D (NKG2D) is a stimulatory receptor expressed on a subset of mucosal and peripheral CD4+ T cells in patients with Crohn's disease (CD) and other inflammatory diseases. Ligand activation of NKG2D in patients induces CD4+ T cells to release T-helper (Th) 1 cytokines and become cytotoxic. We investigated the Th17 cytokines produced by T cells that express NKG2D in blood and intestinal mucosa samples from patients with CD. METHODS: We isolated CD4+ T cells from peripheral blood and lamina propria samples of patients with CD or ulcerative colitis (UC) and healthy individuals (controls). We analyzed the phenotype and functions of the CD4+NKG2D+ T cells and the cytokines they produce in response to NKG2D stimulation. RESULTS: In patients with CD, CD4+ T cells that express NKG2D produced high levels of interleukin (IL)-17 and IL-22 and expressed high levels of CCR6, the IL-23 receptor, CD161, and RORC (a transcription factor that regulates expression of Th17 cytokines). CD4+ T cells that produced IL-17 expressed high levels of NKG2D and CD161. Costimulation of NKG2D and the T-cell receptor (TCR) significantly increased production of IL-17 and tumor necrosis factor α by CD4+ T cells, compared with activation of only the TCR. CD4+NKG2D+ T cells also responded to Th17 polarization. CONCLUSIONS: NKG2D is a functional marker of CD4+ T cells that produce IL-17 in patients with CD, via costimulation of the TCR and NKG2D. Reagents developed to block NKG2D might reduce gastrointestinal inflammation in patients with CD.

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

Crohn's 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 Crohn's disease (IPNIC) group. This instrument, called the Crohn's 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 patient's 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.

Crohn's disease recurrence after total proctocolectomy with definitive ileostomy.

BACKGROUND: Total proctocolectomy with definitive ileostomy is the ultimate treatment for refractory colonic Crohn's disease (CD). Aim of the study was to report the outcome of Crohn's disease patients after total proctocolectomy with definitive ileostomy. PATIENTS AND METHODS: Between 1990 and 2005, 55 patients underwent total proctocolectomy with definitive ileostomy for Crohn's disease in our institution. None of them received preventive post-operative treatment. We studied clinical recurrence, need for immunosuppressants (IS), anti-TNF therapy and re-operation in this retrospective cohort. RESULTS: Median follow-up was 5.4 years. Probabilities of clinical Crohn's disease recurrence were 4%, 27% and 39% at 1, 5 and 8 years, respectively. In multivariate analysis, clinical recurrence rate was significantly higher for patients with penetrating disease behaviour (RR 1.7 IC95% [1.5-19], p=0.05) and absence of perianal disease (RR=1.6, IC95% [1.4-10]; p=0.01). Clinical recurrences were located in terminal ileum in all cases and treated medically in 9 of 16 patients including IS or anti TNF agents in 7 cases. Probabilities of treatment with immunosuppressants or anti-TNF therapy were 4%, 15% and 15% at 1, 5 and 8 years, respectively. Nearly one third of the patients (29%) underwent surgery for mechanical complications (N=11) and/or CD recurrence (N=7). Probabilities of reoperation for Crohn's disease recurrence were 0%, 10% and 18% at 1, 5 and 8 years, respectively. CONCLUSION: Recurrence after total proctocolectomy with definitive ileostomy for Crohn's disease is not uncommon, and in our series often required immunosuppressants or surgical procedure.

Long-term outcome of treatment with infliximab in pediatric-onset Crohn's disease: a population-based study.

BACKGROUND: We examined short- and long-term benefits and safety of infliximab (IFX) in a population-based cohort of Crohn's disease (CD) patients <17 years old at diagnosis. METHODS: The following parameters were assessed: short- and long-term efficacy of IFX, impact of drug efficacy, and mode of administration on rate of resection surgery, growth and nutritional catch-up, and adverse events (AEs). RESULTS: In all, 120 patients (69 female) required IFX with a median duration of 32 months (Q1 = 8-Q3 = 60). Median age at diagnosis was 14.5 years (12-16) and median interval between diagnosis and IFX initiation was 41 months (22-78). Median follow-up since CD diagnosis was 111 months (75-161). Fifty patients (42%) received episodic and 70 (58%) maintenance therapy. Sixty-five (54%) patients were in the "IFX efficacy" group: 38 (32%) still receiving IFX at the last visit and 27 (22%) stopping IFX while in remission. The "IFX failure" group included 55 (46%) patients: 17 (14%) who stopped IFX due to AEs and 38 (32%) nonresponders. The risk of surgery was reduced (P = 0.009) in the "IFX efficacy" group and lower (P = 0.03) in patients with scheduled versus episodic therapy. Patients in the "IFX efficacy" group had significant catch-up growth (P = 0.04), while those in the "IFX failure" group did not. Twenty-four patients presented AEs leading to cessation of IFX in 17 of them. CONCLUSIONS: In this population-based cohort of pediatric-onset CD, IFX treatment was effective in more than half of patients during a median follow-up of 32 months. Long-term IFX responders had a lower rate of surgery and improved catch-up in growth, especially when receiving scheduled IFX therapy.

Meta-analysis identifies 29 additional ulcerative colitis risk loci, increasing the number of confirmed associations to 47.

Genome-wide association studies and candidate gene studies in ulcerative colitis have identified 18 susceptibility loci. We conducted a meta-analysis of six ulcerative colitis genome-wide association study datasets, comprising 6,687 cases and 19,718 controls, and followed up the top association signals in 9,628 cases and 12,917 controls. We identified 29 additional risk loci (P < 5 × 10(-8)), increasing the number of ulcerative colitis-associated loci to 47. After annotating associated regions using GRAIL, expression quantitative trait loci data and correlations with non-synonymous SNPs, we identified many candidate genes that provide potentially important insights into disease pathogenesis, including IL1R2, IL8RA-IL8RB, IL7R, IL12B, DAP, PRDM1, JAK2, IRF5, GNA12 and LSP1. The total number of confirmed inflammatory bowel disease risk loci is now 99, including a minimum of 28 shared association signals between Crohn's disease and ulcerative colitis.

Resequencing of positional candidates identifies low frequency IL23R coding variants protecting against inflammatory bowel disease.

Genome-wide association studies (GWAS) have identified dozens of risk loci for many complex disorders, including Crohn's disease. However, common disease-associated SNPs explain at most ∼20% of the genetic variance for Crohn's disease. Several factors may account for this unexplained heritability, including rare risk variants not adequately tagged thus far in GWAS. That rare susceptibility variants indeed contribute to variation in multifactorial phenotypes has been demonstrated for colorectal cancer, plasma high-density lipoprotein cholesterol levels, blood pressure, type 1 diabetes, hypertriglyceridemia and, in the case of Crohn's disease, for NOD2 (refs. 14,15). Here we describe the use of high-throughput resequencing of DNA pools to search for rare coding variants influencing susceptibility to Crohn's disease in 63 GWAS-identified positional candidate genes. We identify low frequency coding variants conferring protection against inflammatory bowel disease in IL23R, but we conclude that rare coding variants in positional candidates do not make a large contribution to inherited predisposition to Crohn's disease.