Corinne Gower-Rousseau

CARD15/NOD2 Mutational Analysis and Genotype-Phenotype Correlation in 612 Patients with Inflammatory Bowel Disease

CARD15/NOD2 encodes a protein involved in bacterial recognition by monocytes. Mutations in CARD15 have recently been found in patients with Crohn disease (CD), a chronic inflammatory condition of the digestive tract. Here, we report the mutational analyses of CARD15 in 453 patients with CD, including 166 sporadic and 287 familial cases, 159 patients with ulcerative colitis (UC), and 103 healthy control subjects. Of 67 sequence variations identified, 9 had an allele frequency >5% in patients with CD. Six of them were considered to be polymorphisms, and three (R702W, G908R, and 1007fs) were confirmed to be independently associated with susceptibility to CD. Also considered as potential disease-causing mutations (DCMs) were 27 rare additional mutations. The three main variants (R702W, G908R, and 1007fs) represented 32%, 18%, and 31%, respectively, of the total CD mutations, whereas the total of the 27 rare mutations represented 19% of DCMs. Altogether, 93% of the mutations were located in the distal third of the gene. No mutations were found to be associated with UC. In contrast, 50% of patients with CD carried at least one DCM, including 17% who had a double mutation. This observation confirmed the gene-dosage effect in CD. The patients with double-dose mutations were characterized by a younger age at onset (16.9 years vs. 19.8 years; P=.01), a more frequent stricturing phenotype (53% vs. 28%; P=.00003; odds ratio 2.92), and a less frequent colonic involvement (43% vs. 62%; P=.003; odds ratio 0.44) than were seen in those patients who had no mutation. The severity of the disease and extraintestinal manifestations were not different for any of the CARD15 genotypes. The proportion of familial and sporadic cases and the proportion of patients with smoking habits were similar in the groups of patients with CD with or without mutation. These findings provide tools for a DNA-based test of susceptibility and for genetic counseling in inflammatory bowel disease.

Incidence of inflammatory bowel disease in northern France (1988-1990).

There were no data concerning the incidence of inflammatory bowel disease (IBD) in France. The aim of this study was to investigate the incidence of Crohns disease and ulcerative colitis in northern France. This prospective population based study was realised through the gastroenterologists of the region Nord-Pas de Calais and the Somme Department. Each gastroenterologist referred patients consulting for the first time with clinical symptoms compatible with IBD. Data were collected by an interviewer practitioner present at the gastroenterologists consulting room. Two independent expert gastroenterologists assessed each case in a blind manner and made a final diagnosis of Crohns disease, ulcerative colitis, ulcerative proctitis, or unclassifiable chronic colitis. From 1988 to 1990, 1291 cases of IBD were recorded: 674 (52%) Crohns disease, 466 (36%) ulcerative colitis including 162 proctitis (35%), and 151 (12%) unclassifiable chronic colitis. The mean annual incidence was 4.9 per 100,000 for Crohns disease and 3.2 for ulcerative colitis. The sex ratio F/M was 1.3 for Crohns disease and 0.8 for ulcerative colitis. The highest age specific incidence rate for Crohns disease was between 20 and 29 years: 13.1 for women and 9.8 for men. The highest age specific incidence rate for ulcerative colitis was between 20 and 39 years: 5.5 for women and 6.5 for men. This first French prospective study has shown an incidence rate for Crohns disease comparable with that seen in north European studies but lower than that seen for ulcerative colitis. These results could be related to the different environmental factors or the genetic background of the population studied, or both.

Incidence, clinical presentation and location at diagnosis of pediatric inflammatory bowel disease: a prospective population-based study in northern France (1988-1999).

Objective: To assess the incidence and location at diagnosis of inflammatory bowel disease in children and adolescents in northern France between 1988 and 1999. Methods: A 12-year prospective population-based study was conducted by gastroenterologists and pediatric gastroenterologists of northern France (1,312,141 children <17 years of age). Results: From 1988 to 1999, 509 cases of childhood inflammatory bowel disease were recorded (7.2% of all inflammatory bowel disease cases in Northern France): 367 Crohn disease, 122 ulcerative colitis and 20 indeterminate colitis. The mean standardized incidence was 3.1/105 for inflammatory bowel disease as a whole (2.3 for Crohn disease, 0.8 for ulcerative colitis and 0.12 for indeterminate colitis). Crohn disease location at diagnosis was: small bowel and colon (71%), colon only (10%) and small bowel only (19%). Location of initial ulcerative colitis was: proctitis (11%), left colitis (57%) and pancolitis (32%). Although ulcerative colitis incidence remained stable (0.8), Crohn disease incidence increased from 2.1 in 1988 to 1990 to 2.6 in 1997 to 1999 (P = 0.2). Conclusions: The incidence of Crohn disease in the children of northern France showed an increasing trend (20%; not significant) during the 12-year period while the incidence of ulcerative colitis remained stable. In the entire population(children and adults)the incidence of Crohn disease increased significantly (+23%; P < 0.001), while the incidence of ulcerative colitis decreased (−17%; P < 0.0001).

Natural history of elderly-onset inflammatory bowel disease: a population-based cohort study

Data on the natural history of elderly-onset inflammatory bowel disease (IBD) are scarce. Methods In a French population-based cohort we identified 841 IBD patients >60 years of age at diagnosis from 1988 to 2006, including 367 Crohns disease (CD) and 472 ulcerative colitis (UC). Results Median age at diagnosis was similar for CD (70 years (IQR: 65–76)) and UC (69 years (64–74)). Median follow-up was 6 years (2–11) for both diseases. At diagnosis, in CD, pure colonic disease (65%) and inflammatory behaviour (78%) were the most frequent phenotype. At maximal follow-up digestive extension and complicated behaviour occurred in 8% and 9%, respectively. In UC, 29% of patients had proctitis, 45% left-sided and 26% extensive colitis without extension during follow-up in 84%. In CD cumulative probabilities of receiving corticosteroids (CSs), immunosuppressants (ISs) and anti tumor necrosis factor therapy were respectively 47%, 27% and 9% at 10 years. In UC cumulative probabilities of receiving CS and IS were 40% and 15%, respectively at 10 years. Cumulative probabilities of surgery at 1 year and 10 years were 18% and 32%, respectively in CD and 4% and 8%, respectively in UC. In CD complicated behaviour at diagnosis (HR: 2.6; 95% CI 1.5 to 4.6) was associated with an increased risk for surgery while CS was associated with a decreased risk (HR: 0.5; 0.3 to 0.8). In UC CS was associated with an increased risk (HR: 2.2; 1.1 to 4.6) for colectomy. Conclusions Clinical course is mild in elderly-onset IBD patients. This information would need to be taken into account by physicians when therapeutic strategies are established.

The changing pattern of Crohn’s disease incidence in northern France: a continuing increase in the 10‐ to 19‐year‐old age bracket (1988–2007)

Aliment Pharmacol Ther 2011; 33: 1133–1142

Candida albicans colonization and ASCA in familial Crohn's disease

OBJECTIVES:Anti-Saccharomyces cerevisiae antibodies (ASCAs) are present in 50–60% of patients with Crohns disease (CD) and in 20–25% of their healthy relatives (HRs). The yeast, Candida albicans, has been shown to generate ASCAs, but the presence of C. albicans in the digestive tract of CD patients and their HRs has never been investigated. Therefore, we studied C. albicans carriage in familial CD and its correlation with ASCAs.METHODS:Study groups consisted of 41 CD families composed of 129 patients and 113 HRs, and 14 control families composed of 76 individuals. Mouth swabs and stool specimens were collected for isolation, identification, and quantification of yeasts. Serum samples were collected for detection of ASCAs and anti-C. albicans mannan antibodies (ACMAs).RESULTS:C. albicans was isolated significantly more frequently from stool samples from CD patients (44%) and their HRs (38%) than from controls (22%) (P<0.05). The prevalence of ACMAs was similar between CD patients, their HRs, and controls (22, 19, and 21%, respectively, P=0.845), whereas the prevalence of ASCAs was significantly increased in CD families (72 and 34% in CD and HRs, respectively, in contrast to 4% in controls, P<0.0001). AMCA levels correlated with C. albicans colonization in all populations. ASCA levels correlated with C. albicans colonization in HRs but not in CD patients.CONCLUSIONS:CD patients and their first-degree HRs are more frequently and more heavily colonized by C. albicans than are controls. ASCAs correlate with C. albicans colonization in HRs but not in CD. In HRs, ASCAs could result from an altered immune response to C. albicans. In CD, a subsequent alteration in sensing C. albicans colonization could occur with disease onset.

Stressful Life Events as a Risk Factor for Inflammatory Bowel Disease Onset: A Population-Based Case–Control Study

BACKGROUND AND AIMS:Stress is often perceived by patients with inflammatory bowel disease (IBD) as the leading cause of their disease. The aim of this study was to assess whether stress, evaluated through life event (LE) occurrence, is associated with IBD onset.METHODS:Incident cases of IBD, including 167 patients with Crohns disease (CD) and 74 with ulcerative colitis (UC), were compared with two control groups, one of 69 patients with acute self-limited colitis (ASLC) and another of 255 blood donors (BDs). Stress was assessed using Paykels self-questionnaire of LEs. Only LEs occurring within 6 months before the onset of symptoms in IBD cases and ASLC controls and before blood donation in BD controls were registered. Anxiety and depression were assessed using Bates and Becks questionnaires, respectively.RESULTS:In univariate analysis, occurrence of LEs was more frequent in the 6-month period prior to diagnosis in CD cases than in UC cases or either control group. After adjustment for depression and anxiety scores as well as other characteristics such as smoking status and sociodemographic features, this association appeared no longer significant. No associations were noted between occurrence of LEs and onset of UC relative to controls.CONCLUSIONS:Despite its separate association with CD, LE occurrence does not appear to be an independent risk factor for IBD onset.

Epidemiology of inflammatory bowel diseases: New insights from a French population-based registry (EPIMAD)

Most data regarding the natural history of inflammatory bowel diseases and their therapeutic management are from tertiary referral-centres. However, the patients followed in these centres represent a selected sample and extrapolation of these data to the general population is disputable. The EPIMAD Registry covers a large area of Northern France with almost 6 million inhabitants representing 9.3% of the entire French population. From 1988 to 2008, 18,170 incident patients were recorded in the registry including 8071 incident Crohns disease, 5113 incident ulcerative colitis and 591 unclassified inflammatory bowel disease cases. The aim of this study was to review some of the most recent information obtained from this large population-based registry since its launch in 1988.

Biofeedback for the treatment of fecal incontinence

Biofeedback therapy has been proposed as a treatment for fecal incontinence with good, short-term results. PURPOSE: This study was designed to assess long-term clinical results of biofeedback therapy compared with medical therapy alone and to assess manometric results in patients treated with biofeedback. METHODS: Two groups of incontinent patients were studied. Group 1 consisted of 16 patients (3 males and 13 females; mean age, 59.9 years). Etiologies treated by biofeedback included descending perineum syndrome (7), postfistula or hemorroidectomy (4), and miscellaneous (5). Group 2 consisted of eight patients (two males, six females; mean age, 62.2 years). Etiologies treated with medical treatment alone (including enema and antidiarrheal therapy) included descending perineum syndrome (3), postfistula or hemorroidectomy (2), and miscellaneous (3). The incontinence score was initially 17.81±3.27 (standard deviation) in Group 1 and 17.0±2.77 in Group 2. Resting pressure of the upper and lower anal sphincter, maximum squeezing pressure, and duration of contraction were not initially different in Groups 1 and 2 but were significantly lower than in the control group of patients without incontinence (n=12; 8 males, 4 females; mean age, 66.4 years) (P<0.05). Follow-up duration was 30 months, with intermediate clinical score at 6 months for Group 1. RESULTS: After biofeedback therapy, the incontinence score at 30 months was lower in Group 1 (14.43±6.35vs.17.81 ±3.27;P<0.035) and unchanged in Group 2 (18.0±2.72vs.17.0±2.77). However, in Group 1 the score at 6 months was much lower than at 30 months (6.31±7.81vs.14.43±6.35;P<0.001). Only the amplitude of voluntary contraction and upper anal pressure (51.1 (range, 27–90)vs36.7 (range, 20–80) mmHg) were significantly increased (81.5 (range, 55–120)vs.62.1 (range, 30–90) mmHg;P<0.05). CONCLUSION: Biofeedback improved continence at 6 months and at 30 months. However, the score at 6 months was much better, suggesting that the initial good results may deteriorate over a long time. These data suggest that it could be useful to reinitiate biofeedback therapy in some patients.

IBD across the age spectrum[mdash]is it the same disease?

IBD is a chronic disorder with disease onset ranging from early childhood to beyond the sixth decade of life. The factors that determine the age of onset currently remain unexplained. Is timing of occurrence a random event or is it indicative of different pathophysiological pathways leading to different phenotypes across the age spectrum? Over the past decade, several studies have suggested that the characteristics and natural history of IBD seem to be different according to age of onset. This heterogeneity suggests that the respective contributions of genetics, host immune system and environment to the aetiology and phenotype of Crohns disease and ulcerative colitis are different across ages. Critical reviews that focus on differences characterizing IBD between age groups are scarce. Therefore, this Review updates the knowledge of the differences in epidemiology, clinical characteristics, and natural history of paediatric, adult and elderly-onset IBD. In addition, potential differences in host–gene–microbial interactions according to age are highlighted.