Laurent Beaugerie

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 …

Long-Term Evolution of Disease Behavior of Crohn's Disease

BackgroundThe Vienna classification of Crohns disease (CD) distinguishes three patient subgroups according to disease behavior: stricturing, penetrating, and inflammatory. Our aim was to assess the long-term evolution of the disease behavior of CD and to determine the predictive factors and prognostic implications of this evolution. MethodsOccurrence and predictive factors of a stricturing and/or a penetrating complication were searched for in 2,002 patients with CD studied retrospectively. In addition, the 1995–2000 disease course was assessed prospectively in a cohort of 646 patients with disease duration >5 years, classified according to their previous disease behavior. Results1,199 patients (60%) developed a stricturing (n = 254) or a penetrating (n = 945) complication. Twenty-year actuarial rates of inflammatory, stricturing, and penetrating disease were 12, 18, and 70%, respectively. The initial location of lesions was the main determinant of the time and type of the complication. In the cohort study, year-by-year activity and therapeutic requirements did not show significant sustained differences between behavioral subgroups. ConclusionMost patients with CD will eventually one day develop a stricturing or a perforating complication. Initial location determines the type of the complication. Classification of patients into a behavioral group from previous history has no impact upon activity during the following years.

Low Counts of Faecalibacterium prausnitzii in Colitis Microbiota

Background: The intestinal microbiota is suspected to play a role in colitis and particularly in inflammatory bowel disease (IBD) pathogenesis. The aim was to compare the fecal microbiota composition of patients with colitis to that of healthy subjects (HS). Methods: fecal samples from 22 active Crohns disease (A‐CD) patients, 10 CD patients in remission (R‐CD), 13 active ulcerative colitis (A‐UC) patients, 4 UC patients in remission (R‐UC), 8 infectious colitis (IC) patients, and 27 HS were analyzed by quantitative real‐time polymerase chain reaction (PCR) targeting the 16S rRNA gene. Bacterial counts were transformed to logarithms (Log10 CFU) for statistical analysis. Results: Bacteria of the phylum Firmicutes (Clostridium leptum and Clostridium coccoides groups) were less represented in A‐IBD patients (9.7; P = 0.004) and IC (9.4; P = 0.02), compared to HS (10.8). Faecalibacterium prausnitzii species (a major representative of the C. leptum group) had lower counts in A‐IBD and IC patients compared to HS (8.8 and 8.3 versus 10.4; P = 0.0004 and P = 0.003). The Firmicutes/Bacteroidetes ratio was lower in A‐IBD (1.3; P = 0.0001) and IC patients (0.4; P = 0.002). Compared to HS, Bifidobacteria were less represented in A‐IBD and IC (7.9 and 7.7 versus 9.2; P = 0.001 and P = 0.01). Conclusions: The fecal microbiota of patients with IBD differs from that of HS. The phylum Firmicutes and particularly the species F. prausnitzii, are underrepresented in A‐IBD patients as well as in IC patients. These bacteria could be crucial to gut homeostasis since lower counts of F. prausnitzii are consistently associated with a reduced protection of the gut mucosa. (Inflamm Bowel Dis 2009)

Lymphoproliferative disorders in patients receiving thiopurines for inflammatory bowel disease: a prospective observational cohort study

BACKGROUND Reports of an increased risk of lymphoproliferative disorders in patients receiving thiopurines for inflammatory bowel disease are controversial. We assessed this risk in a prospective observational cohort study. METHODS 19,486 patients with inflammatory bowel disease, of whom 11,759 (60.3%) had Crohns disease and 7727 (39.7%) had ulcerative colitis or unclassified inflammatory bowel disease, were enrolled in a nationwide French cohort by 680 gastroenterologists, who reported details of immunosuppressive therapy during the observation period, cases of cancer, and deaths. The risk of lymphoproliferative disorder was assessed according to thiopurine exposure. Median follow-up was 35 months (IQR 29-40). FINDINGS At baseline, 5867 (30.1%) of patients were receiving, 2809 (14.4%) had discontinued, and 10,810 (55.5%) had never received thiopurines. 23 new cases of lymphoproliferative disorder were diagnosed, consisting of one case of Hodgkins lymphoma and 22 cases of non-Hodgkin lymphoproliferative disorder. The incidence rates of lymphoproliferative disorder were 0.90 per 1000 (95% CI 0.50-1.49) patient-years in those receiving, 0.20/1000 (0.02-0.72) patient-years in those who had discontinued, and 0.26/1000 (0.10-0.57) patient-years in those who had never received thiopurines (p=0.0054). The multivariate-adjusted hazard ratio of lymphoproliferative disorder between patients receiving thiopurines and those who had never received the drugs was 5.28 (2.01-13.9, p=0.0007). Most cases associated with thiopurine exposure matched the pathological range of post-transplant disease. INTERPRETATION Patients receiving thiopurines for inflammatory bowel disease have an increased risk of developing lymphoproliferative disorders. FUNDING Programme Hospitalier de Recherche Clinique National (AOM05157), Association François Aupetit, Délégation Inter-régionale de la Recherche clinique Ile de France-Assistance Publique Hôpitaux de Paris (AP-HP), Ligue contre le Cancer, and Fonds de Recherche de la Société Nationale Française de Gastro-entérologie.

Impact of the increasing use of immunosuppressants in Crohn’s disease on the need for intestinal surgery

Background/Aim: Immunosuppressants are now used much earlier in the course of Crohn’s disease; however their effect on the natural history of the disease, especially on the need for surgery, is not known. The aim of this study was to assess the evolution of the need for surgery in Crohn’s disease during the last 25 years. Patients and Methods: The medical charts of 2573 patients were reviewed retrospectively. The use of immunosuppressants (azathioprine or methotrexate), the need for intestinal resection, and the occurrence of intestinal complications were assessed using Kaplan-Meier analysis in five consecutive cohorts of patients defined by the date of diagnosis of Crohn’s disease (1978–82; 1983–87; 1988–92; 1993–97; 1998–2002). Results: In 565 patients seen in the authors’ unit within the first three months after diagnosis, characteristics of Crohn’s disease at diagnosis did not differ from one cohort to another. The five year cumulative probability to receive immunosuppressants increased from 0 in the 1978–82 cohort to 0.13, 0.25, 0.25, and 0.56 in the 1983–87, 1988–92, 1993–97, and 1998–2002 cohorts, respectively (p<0.001). Concomitantly, the cumulative risk of intestinal resection remained unchanged (from 0.35 to 0.34 at five years; p = 0.81). The cumulative risk of developing a stricturing or a penetrating intestinal complication remained also unchanged. Similar results were obtained in the 2008 patients seen during the same period who were referred to us more than three months after diagnosis. Conclusion: Although immunosuppressants have been used more frequently over the last 25 years, there was no significant decrease of the need for surgery, or of intestinal complications of Crohn’s disease.

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.

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 …

Connecting dysbiosis, bile-acid dysmetabolism and gut inflammation in inflammatory bowel diseases

Objective Gut microbiota metabolises bile acids (BA). As dysbiosis has been reported in inflammatory bowel diseases (IBD), we aim to investigate the impact of IBD-associated dysbiosis on BA metabolism and its influence on the epithelial cell inflammation response. Design Faecal and serum BA rates, expressed as a proportion of total BA, were assessed by high-performance liquid chromatography tandem mass spectrometry in colonic IBD patients (42) and healthy subjects (29). The faecal microbiota composition was assessed by quantitative real-time PCR. Using BA profiles and microbiota composition, cluster formation between groups was generated by ranking models. The faecal BA profiles in germ-free and conventional mice were compared. Direct enzymatic activities of BA biotransformation were measured in faeces. The impact of BA on the inflammatory response was investigated in vitro using Caco-2 cells stimulated by IL-1β. Results IBD-associated dysbiosis was characterised by a decrease in the ratio between Faecalibacterium prausntizii and Escherichia coli. Faecal-conjugated BA rates were significantly higher in active IBD, whereas, secondary BA rates were significantly lower. Interestingly, active IBD patients exhibited higher levels of faecal 3-OH-sulphated BA. The deconjugation, transformation and desulphation activities of the microbiota were impaired in IBD patients. In vitro, secondary BA exerted anti-inflammatory effects, but sulphation of secondary BAs abolished their anti-inflammatory properties. Conclusions Impaired microbiota enzymatic activity observed in IBD-associated dysbiosis leads to modifications in the luminal BA pool composition. Altered BA transformation in the gut lumen can erase the anti-inflammatory effects of some BA species on gut epithelial cells and could participate in the chronic inflammation loop of IBD.

The role of anatomic factors in nutritional autonomy after extensive small bowel resection

BACKGROUND It is difficult to predict which patients with a postsurgical short bowel will require long-term parenteral nutrition. METHODS We performed a retrospective prognostic study for the time to home parenteral nutrition or death from malnutrition (nonautonomy), on the basis of 103 patients with a residual short bowel of 17 to 150 cm. The influence of anatomic variables was summarized through the use of Cox regression model. RESULTS Of the 103 patients included, 24 lost nutritional autonomy. Three anatomic variables were identified as having independent predictive information; remaining small bowel length (measured on small bowel x-rays; p = .0001), and jejunoileal anastomosis (p = .01) promoted autonomy, whereas end jejunostomy (p = .002) increased the risk of losing nutritional autonomy. CONCLUSIONS On the basis of these results and on the relative weight of these variables, high-risk patients for loss of nutritional autonomy were defined as those with jejunoileal anastomosis and a remaining small bowel length < 35 cm, patients with jejunocolic anastomosis and remaining small bowel length < 60 cm, and patients with an end jejunostomy and remaining small bowel length < 115 cm. This classification was thereafter validated on a prospective series of 32 patients.

CARD9 impacts colitis by altering gut microbiota metabolism of tryptophan into aryl hydrocarbon receptor ligands

Complex interactions between the host and the gut microbiota govern intestinal homeostasis but remain poorly understood. Here we reveal a relationship between gut microbiota and caspase recruitment domain family member 9 (CARD9), a susceptibility gene for inflammatory bowel disease (IBD) that functions in the immune response against microorganisms. CARD9 promotes recovery from colitis by promoting interleukin (IL)-22 production, and Card9−/− mice are more susceptible to colitis. The microbiota is altered in Card9−/− mice, and transfer of the microbiota from Card9−/− to wild-type, germ-free recipients increases their susceptibility to colitis. The microbiota from Card9−/− mice fails to metabolize tryptophan into metabolites that act as aryl hydrocarbon receptor (AHR) ligands. Intestinal inflammation is attenuated after inoculation of mice with three Lactobacillus strains capable of metabolizing tryptophan or by treatment with an AHR agonist. Reduced production of AHR ligands is also observed in the microbiota from individuals with IBD, particularly in those with CARD9 risk alleles associated with IBD. Our findings reveal that host genes affect the composition and function of the gut microbiota, altering the production of microbial metabolites and intestinal inflammation.