Alterations in the intestinal microbiome (dysbiosis) as a predictor of relapse after infliximab withdrawal in Crohn's disease.

BACKGROUND: Crohn's disease (CD)-associated dysbiosis could predispose patients to relapse. Gut microbiota composition of patients from the prospective cohort study designed to identify predictive factors of clinical relapse after infliximab discontinuation (STORI Study) was investigated to determine the impact of dysbiosis in CD relapse. METHODS: Fecal samples from 33 patients with CD in this cohort were collected at baseline, 2 months, 6 months, and at the end of the follow-up period (19 relapsers and 14 nonrelapsers). Healthy volunteers subjects (n = 29) were used as a control group. The fecal microbiota composition was assessed using quantitative PCR, and comparisons between the patient groups were made at different time points using the Wilcoxon test. The analysis of the time-to-relapse was performed according to the baseline median level of each bacterial signal. RESULTS: Dysbiosis was observed in patients with CD compared with healthy subjects, and it was characterized by low mean counts of Firmicutes (Clostridium coccoides [P = 0.0003], C. leptum [P < 0.0001], and Faecalibacterium prausnitzii [P = 0.003]). Lower rates of Firmicutes were seen in relapsers compared with nonrelapsers. Moreover, a low rate of F. prausnitzii (P = 0.014) and a low rate of Bacteroides (P = 0.030) predicted relapse independently from high C reactive protein level (P = 0.0001). CONCLUSIONS: In this work, we report that CD-associated dysbiosis, characterized by a decrease in Firmicutes, correlates with the time-to-relapse after infliximab withdrawal. A deficit in some bacterial groups or species, such as F. prausnitzii, may represent a predictive factor for relapse. Restoring normobiosis in CD could be a new goal for optimal CD management.

Small bowel capsule endoscopy for management of Crohn's disease: a retrospective tertiary care centre experience.

BACKGROUND: The role of small bowel capsule endoscopy in the management of established Crohn's disease is uncertain. METHODS: A retrospective study of small bowel capsule endoscopy tests performed in a referral centre from 2008 to 2011; 77 tests were performed in patients with known Crohn's disease. Six patients were excluded due to capsule test retention. Patients were classified into 4 indication groups: unexplained anaemia (G1, n = 6); discrepancy between clinical symptoms and morphology (G2, n = 25), full assessment of Crohn's disease location (G3, n = 37) and evaluation of mucosal healing (G4, n = 3). RESULTS: Twenty-seven (38%) patients had no lesions, 32 (45%) moderate and 12 (17%) severe lesions. Endoscopic lesions were found in 4/6 (67%) G1 patients, 11/25 (44%) G2 and 28/37 (76%) G3 (p < 0.03). Three months after endoscopy was performed, 38/71 patients experienced a change in their treatment that was significantly associated with the severity of endoscopic lesions and with test indications; in 60%, 20% and 58% of patients from G1, G2 and G3, respectively (p < 0.01). CONCLUSION: Small bowel capsule endoscopy resulted in management changes in the majority of patients with established Crohn's disease.

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.

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.

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.

Nutritional status and growth in pediatric Crohn's disease: a population-based study.

OBJECTIVES: Growth retardation and malnutrition are major features of pediatric Crohn's disease (CD). We examined nutritional and growth parameters from diagnosis to maximal follow-up in a population-based pediatric cohort, and we determined predictive factors. METHODS: A total of 261 patients (156 boys, 105 girls) with onset of CD before the age of 17 were identified from 1988 to 2004 through the EPIMAD registry (Registre des Maladies Inflammatoires Chroniques de l'Intestin) in northern France. Median age at diagnosis was 13 years (11.2-15.4) and median follow-up was 73 months (46-114). Z-scores of height/age, weight/age, and body mass index (BMI)/age were determined. Multivariate stepwise regression analysis identified predictive factors for malnutrition and growth retardation at maximal follow-up. RESULTS: At diagnosis, 25 children (9.5%) showed height less than -2 s.d., 70 (27%) weight less than -2 s.d., and 84 (32%) BMI less than -2 s.d. At maximal follow-up, growth retardation was present in 18 children (6.9%), whereas 40 (15%) had malnutrition. Nutritional status was more severely impaired in children with stricturing disease. Growth and nutritional retardation at diagnosis, young age, male gender, and extraintestinal manifestations at diagnosis were indicators of poor prognosis. A significant compensation was observed for weight and BMI in both genders and for height in girls. No treatment was associated with height, weight, or BMI at maximal follow-up. CONCLUSIONS: In our pediatric population-based study, growth retardation and severe malnutrition were still present at maximal follow-up in 6.9 and 15% of CD children, respectively. Young boys with substantial inflammatory manifestations of CD have a higher risk of subsequent growth failure, especially when growth retardation is present at diagnosis.

Mapping of inflammatory bowel disease in northern France: spatial variations and relation to affluence.

BACKGROUND: Geographic variations in the incidence of inflammatory bowel disease (IBD) may reflect variations in the distribution of environmental etiologic factors. We assessed spatial variation in the incidence of IBD in northern France and analyzed its association with a deprivation index. METHODS: All cases of IBD included in the EPIMAD registry between 1990 and 2003 were extracted. The standardized incidence ratio (SIR) was calculated for each canton in the region. The association between incidence and deprivation was assessed using the Townsend deprivation index. RESULTS: The mean annual incidence rates of Crohn's disease (CD) and ulcerative colitis (UC) were 6.2 x 10(-5) and 3.8 x 10(-5), respectively. The mean cumulative numbers of cases by canton were 18.4 (1-183) for CD and 11.3 (0-148) for UC. For both CD and UC, mapping depicted spatial heterogeneity in the SIR with spatial autocorrelation. A high relative risk (RR) of CD was observed in mainly rural and periurban cantons of the region. For UC, a high RR was found in cantons of the south and the center of Pas-de-Calais. No significant correlation was observed between spatial variations in IBD and deprivation. CONCLUSIONS: The incidence of IBD is associated with spatial heterogeneity in northern France. The noteworthy predominance of CD in agricultural areas warrants further investigations.

The natural history of pediatric ulcerative colitis: a population-based cohort study.

OBJECTIVES: The natural history of ulcerative colitis (UC) has been poorly described in children. METHODS: In a geographically derived incidence cohort diagnosed from 1988 to 2002, we identified 113 UC patients (age 0-17 years at diagnosis) with a follow-up of at least 2 years. The cumulative risk of colectomy was estimated by the Kaplan-Meier method. Risk factors for disease extension were assessed with logistic regression models, and risk factors for colectomy with Cox hazards proportional models. RESULTS: Median follow-up time was 77 months (46-125). At diagnosis, 28% of patients had proctitis, 35% left-sided colitis, and 37% extensive colitis. Disease course was characterized by disease extension in 49% of patients. A delay in diagnosis of more than 6 months and a family history of inflammatory bowel disease were associated with an increased risk of disease extension, with odds ratios of 5.0 (1.2-21.5) and 11.8 (1.3-111.3), respectively. The cumulative rate of colectomy was 8% at 1 year, 15% at 3 years, and 20% at 5 years. The presence of extra-intestinal manifestations (EIMS) at diagnosis was associated with an increased risk of colectomy (hazard ratio (HR)=3.5 (1.2-10.5)). Among the patients with limited disease at diagnosis, the risk of colectomy was higher in those who experienced disease extension than in those who did not (HR=13.3 1.7-101.7). CONCLUSIONS: Pediatric UC was characterized by widespread localization at diagnosis and a high rate of disease extension. Twenty percent of children had their colon removed after 5 years. The colectomy rate was influenced by disease extension and was associated with the presence of EIMS at diagnosis.

Effects of infliximab therapy on abdominal fat and metabolic profile in patients with Crohn's disease.

BACKGROUND: Tumor necrosis factor is an adipocytokine possessing a well-established lipolytic effect. In Crohn's disease (CD) patients, infliximab therapy may thus result in visceral fat accumulation, which is associated with an increased risk of metabolic syndrome. METHODS: A total of 132 CD patients were investigated. In a first prospective study, magnetic resonance imaging (MRI) quantification of subcutaneous and visceral abdominal fat was performed before and 8 weeks after initiation of infliximab induction therapy (5 mg/kg at weeks 0, 2, and 6) in 21 responding patients treated for perianal disease. In a second prospective study, fasting glycemia, glycated hemoglobin (HbA1c), HDL, LDL, and total cholesterol and triglyceride levels were assessed in 111 responding patients receiving infliximab infusions every 8 weeks, with a mean follow-up of 41 weeks. RESULTS: A significant homogeneous 18% increase in total abdominal fat was observed in the 21 CD patients after infliximab induction therapy (P = 0.027), independently of body mass index evolution. Infliximab maintenance therapy was associated with a decrease in glycemia (P < 0.0001) and HbA1c (P = 0.0005) concentrations, together with an increase in both total cholesterol (P = 0.02) and HDL cholesterol (P = 0.008) concentrations. All glycemic and lipid parameters remained within the normal range throughout the study. CONCLUSIONS: Infliximab induction therapy is associated with a significant increase in abdominal fat tissue in CD patients. Infliximab maintenance therapy has no deleterious effects on lipid profile and is accompanied by a decrease in glycemia and HbA1c concentrations, probably by reversing the impairment of tumor necrosis factor-induced insulin-mediated glucose uptake.

Natural history of pediatric Crohn's disease: a population-based cohort study.

BACKGROUND & AIMS: The natural history of pediatric Crohn's disease and risk factors necessitating surgery have not been thoroughly described. METHODS: In a geographically derived incidence cohort diagnosed from 1988 to 2002, we identified 404 Crohn's disease patients (ages, 0-17 years at diagnosis) with a follow-up time >or=2 years. RESULTS: Median follow-up time was 84 months (range, 52-124 months). The most frequent disease location at diagnosis was the terminal ileum/colon (63%). Follow-up was characterized by disease extension in 31% of children. Complicated behavior was observed in 29% of children at diagnosis and 59% at follow-up. Kaplan-Meier survival estimates of the cumulative incidence of surgery were 20% at 3 years and 34% at 5 years from diagnosis. Multivariate Cox models showed that both structuring behavior at diagnosis (hazard ratio [HR], 2.54; 95% confidence interval [CI]: 1.58-4.01) and treatment with corticosteroids (HR, 2.98; 95% CI: 1.64-5.41) were associated with increased risk for surgery, whereas treatment with azathioprine (HR, 0.51; 95% CI: 0.33-0.78) was associated with decreased risk. Azathioprine was introduced earlier in the course of disease in patients not undergoing surgery than in patients requiring surgery. CONCLUSIONS: Pediatric Crohn's disease was characterized by frequent occurrence, with time, of a severe phenotype with extensive, complicated disease. Immunosuppressive therapy may improve the natural history of this disease and decrease the need for performing surgery.

Multidrug resistance gene-1 polymorphisms and resistance to cyclosporine A in patients with steroid resistant ulcerative colitis.

BACKGROUND: Cyclosporine A (CsA) is inconstantly effective in inducing remission in acute attacks of ulcerative colitis (UC) not responding to steroids. This study aimed to establish whether multidrug resistance gene (MDR)1 polymorphisms would be associated with CsA failure. PATIENTS AND METHODS: The distribution of the different genotypes of single nucleotide polymorphisms (SNP) G2677T/A and C3435T of MDR1 exons 21 and 26, respectively, was studied in 154 patients (mean age, 44 yr) who had received CsA to treat severe attacks of steroid resistant UC in 11 centers in France and Belgium. Patients were classified as CsA failure (n = 50) when they needed colectomy within 30 days after CsA initiation. The SNPs were detected by use of a 5' nuclease allelic discrimination assay. RESULTS: There was a significant association between the G2677T/A polymorphism distribution (exon 21) and the risk for CsA failure (P = 0.0001). The TT genotype of exon 21 was significantly associated with the risk compared with the two other genotypes (odds ratio, 3.77; 95% confidence interval, 1.42-9.97, P = 0.007). There was no significant association between the genotype C3435T distribution (exon 26) and the risk of CsA failure (P = 0.23). CONCLUSION: The TT genotype of exon 21 MDR1 polymorphisms is associated with a higher risk of CsA failure in patients with steroid resistant UC. Further studies should be performed to establish whether other treatments could be more efficient to avoid surgery in this subset of patients.

[Epidemiology and risk factors of inflammatory bowel diseases]. / Epidémiologie et facteurs de risque des maladies inflammatoires chroniques de l'intestin.

Inflammatory bowel diseases (IBD) are a public health problem in industrialized countries, where 1 in 1000 people are affected Most patients are young adults. The incidence of IBD has increased considerably in western countries since the second world war but is beginning to level off. On the other hand, the incidence is still rising in low-incidence areas such as Eastern Europe, Asia and developing countries. Differences in incidence rates across age, time, and geographic areas suggest that environmental factors are involved in IBD, but only cigarette smoking and appendectomy have consistently been identified as risk factors. An important role of genetic factors in IBD was first suggested by epidemiological studies showing familial aggregation of IBD and by twin studies. In 2001, the first CD susceptibility gene, NOD2/CARD15 on chromosome 16, was characterized. Other susceptibility genes have since been located. Their identification should help to understand the complex interaction between the environment and the intestinal immune system.