Denise Keegan

Association of NOD2 with Crohn's disease in a homogenous Irish population.

Linkage of IBD to the pericentromeric region of chromosome 16 has been widely confirmed by analyses of multiple populations. The NOD2 gene is located in the peak region of linkage on chromosome 16 and thought to be involved in the activation of nuclear factor (NF) κB in response to bacterial components. Mutations in the NOD2 gene are found to be strongly associated with susceptibility to Crohns disease (CD). A total of 65 Irish CD families were genotyped to determine if NOD2 mutations conferred susceptibility to CD and the prevalence of these mutations in sporadic and familial forms of the disease. The Irish population is relatively homogenous and thus may provide advantages in genetic studies of complex diseases. We confirmed the IBD1 locus as a susceptibility locus for IBD within the Irish population by linkage analysis followed by linkage disequilibrium studies. No significant evidence of linkage was observed to the previously identified regions on chromosomes 1, 12 and 14. In all, 131 CD affected families were then genotyped for seven of the previously published NOD2 single-nucleotide polymorphisms (SNPs). Allelic transmission distortion was investigated using the pedigree disequilibrium test (PDT). SNP13 (3020insC) was found to be associated with CD (P=0.0186). Patients who possessed a rare allele of SNP8, 12 or 13 presented earlier when compared to patients without rare variants (mean age, 20.1 vs 24 years, P=0.011) and the rare allele of SNP13 was observed to be predominantly linked to ileal disease (P=0.02). This report confirms the importance of NOD2 as a susceptibility gene for CD within the Irish population.

Primary Sclerosing Cholangitis and Disease Distribution in Inflammatory Bowel Disease

BACKGROUND & AIMS The relationship between site of intestinal inflammation and primary sclerosing cholangitis (PSC) development in inflammatory bowel disease (IBD) has not been studied extensively, but may be important in understanding the pathogenesis of PSC. We aimed to determine patterns of disease distribution in IBD patients with and without PSC. METHODS We performed a 2-part study involving the following: (1) 2754 IBD patients and (2) 82 separate PSC patients attending the Irish National Liver Transplant Unit. RESULTS Fifty-nine of 2708 (2.2%) IBD patients had PSC. In ulcerative colitis patients, PSC incidence increased with increasing colonic involvement (P = .001) and was relatively rare in those without total colitis. Thirteen Crohns disease patients had PSC, none with isolated small-bowel disease had PSC (P = .03). In study 2, the majority of ulcerative colitis patients with PSC had total colitis, whereas the remainder had disease extending at least to the left colon. In addition, all 10 PSC patients with Crohns disease had colonic involvement. CONCLUSIONS An inflamed colon, but not small bowel, is important in PSC development and it is possible that bacterial translocation and subsequent portal bacteremia is important in PSC development in IBD.

Long-term clinical results of ileocecal resection for Crohn's disease.

Background: The efficacy of biologic agents in Crohns disease (CD) has led to proposals that they be introduced early in the disease (top‐down treatment) with the aim of reducing corticosteroid dependency and surgical resection. However, the long‐term use of biologic agents in limited CD may be difficult to justify. The aims were to assess outcomes for ileocecal resection in CD and evaluate its role in the current era. Methods: The study included 139 CD patients who underwent ileocecal resection between 1980 and 2000. Data were retrieved from a prospectively maintained database. Disease recurrence was defined as symptoms in addition to endoscopic or radiological evidence of disease activity. Severe disease recurrence was defined as a need for repeat resection surgery. Results: Seventy‐two (52%) patients developed disease recurrence. Median (interquartile range) time to recurrence was 7.1 (5–10.6) years. Forty‐nine (35%) patients required repeat resection surgery. Median (IQ range) time to repeat surgery was 7.2 (4.9–10.8) years. The presence of granulomas was associated with disease recurrence (P = 0.03) and repeat resection surgery (P = 0.01). Conclusions: Long‐term outcomes for ileocecal resection in CD are excellent with 48% of patients remaining symptom‐free and only 35% requiring repeat resection surgery at 10 years. This should be borne in mind when considering biologic therapy.

Efficacy of Adalimumab as a long term maintenance therapy in ulcerative colitis.

INTRODUCTION Adalimumab is a recombinant human IgG1 monoclonal antibody to TNF-alpha. There are limited data with regard to its efficacy in ulcerative colitis. We report experience of adalimumab in ulcerative colitis in a single centre with a focus on the ability of this agent to maintain response and avoid colectomy in the medium to long-term. METHODS Twenty-three ulcerative colitis patients (mean age 32 years; 7 female) who received adalimumab were identified from a prospectively maintained database of over 2700 IBD patients. The primary study endpoint was treatment failure defined as discontinuation of adalimumab due to lack of efficacy, as defined by requiring an alternative maintenance therapy or colectomy, or intolerance. Colectomy rate was recorded as a secondary endpoint. RESULTS Most patients (96%) had received immunosuppressants prior to adalimumab therapy (infliximab 20/23 87%). Sixteen of 23 patients (70%) discontinued adalimumab. Six primary failures, 8 secondary loss of response, one had unacceptable side effects and one discontinued treatment after 6 months but remains in remission. Overall estimated cumulative treatment failure rates at 6, 12 and 24 months were 50%, 65% and 72% respectively. Median follow-up in patients continuing adalimumab is 23 months (IQR 17-31 months). Treatment failure was unrelated to patient age, gender, disease extent, smoking status or CRP. Colectomy free survival was 59% at 2 years. No patient experienced a major adverse event. CONCLUSION Adalimumab shows some efficacy as a maintenance strategy in Ulcerative Colitis, but only a limited proportion of patients remain well on continued treatment at 2 years.

Prolonged avoidance of repeat surgery with endoscopic balloon dilatation of anastomotic strictures in Crohn's disease

BACKGROUND AND AIMS There is a high rate of stricturing post-operative recurrence in Crohns disease (CD) particularly at sites of surgical anastomosis, and over 50% of these patients will require a repeat resection. Endoscopic dilatation of anastomotic strictures is an alternative to surgical resection in selected patients. We aimed to evaluate the safety and long term efficacy of endoscopic balloon dilatation of symptomatic anastomotic strictures in CD. METHODS Retrospective analysis of a prospectively maintained inflammatory bowel disease database of patients attending a single academic centre (n=1244 patients with CD) who underwent dilatation. RESULTS Fifty-five dilatations were performed in 31 patients (mean age 43 ± SD 12, 47% female). Median follow-up period was 46 months (IQR 14-62). Ninety percent of patients had successful initial dilatation and no complications occurred. Six (21%) avoided further dilatations or surgery in the follow-up period. Stricture recurrence was detected in 22 patients; 15 (54%) patients had repeat dilatations and seven (25%) went straight to surgery. Eight (28%) patients were managed with repeat dilatations of the stricture (median dilatations=2 range 2-6) and seven (25%) required surgery despite repeat dilatations. Median time from first dilatation to repeat surgery was 14.5 months (IQR 3-28) and to repeat dilatation was 13.8 months (IQR 4-28). There was no difference in immunomodulator use, biologic use and smoking status between the groups requiring surgery versus dilatation only. CONCLUSION Endoscopic balloon dilatation of anastomotic strictures is safe and effective in providing symptomatic relief in CD patients. Forty-five percent of patients had a sustained response to single/serial balloon dilatation with avoidance of further surgical resection for a median interval of 46 months. Post-operative medical therapy and smoking status did not predict requirement for recurrent dilatation or surgery.

DNA methylation profiling in inflammatory bowel disease provides new insights into disease pathogenesis

BACKGROUND AND AIMS Inflammatory bowel diseases (IBDs) are heterogeneous disorders with complex aetiology. Quantitative genetic studies suggest that only a small proportion of the disease variance observed in IBD is accounted for by genetic variation, indicating a potential role for differential epigenetic regulation in disease aetiology. The aim of this study was to assess genome-wide DNA methylation changes specifically associated with ulcerative colitis (UC), Crohns disease (CD) and IBD activity. METHODS DNA methylation was quantified in peripheral blood mononuclear cells (PBMCs) from 149 IBD cases (61 UC, 88 CD) and 39 controls using the Infinium HumanMethylation450 BeadChip. Technical and functional validation was performed using pyrosequencing and the real-time polymerase chain reaction. Cross-tissue replication of the top differentially methylated positions (DMPs) was tested in colonic mucosa tissue samples obtained from paediatric IBD cases and controls. RESULTS A total of 3196 probes were differentially methylated between CD cases and controls, while 1481 probes were differentially methylated between UC cases and controls. There was considerable (45%) overlap between UC and CD DMPs. The top-ranked IBD-associated PBMC differentially methylated region (promoter region of TRIM39-RPP2) was also significantly hypomethylated in colonic mucosa from paediatric UC patients. In addition, we confirmed TRAF6 hypermethylation using pyrosequencing and found reduced TRAF6 gene expression in PBMCs of IBD patients. CONCLUSIONS Our data provide new insights into differential epigenetic regulation of genes and molecular pathways, which may contribute to the pathogenesis and activity of IBD.

Hereditary mixed polyposis syndrome due to a BMPR1A mutation

The conditions Juvenile Polyposis Syndrome (JPS) and Hereditary Mixed Polyposis Syndrome (HMPS) are associated with an increased risk of colorectal carcinoma. The genetic mechanisms which explain these conditions have until recently been poorly understood. Recent interest has focused on the transforming growth factor (TGF)‐β signalling pathway and, in particular, on mutations in the SMAD4 gene. However, not all cases of JPS and HMPS have mutations in SMAD4 and focus has now shifted to other components of the TGF‐β pathway to clarify the genetic mechanisms involved in these conditions. In this report, we describe the significance of a bone morphogenetic protein receptor type 1A gene mutation in an Irish family.

Body image dissatisfaction: clinical features, and psychosocial disability in inflammatory bowel disease.

Background:Body image refers to a persons sense of their physical appearance and body function. A negative body image self-evaluation may result in psychosocial dysfunction. Crohns disease and ulcerative colitis are associated with disabling features, and body image dissatisfaction is a concern for many patients with inflammatory bowel disease (IBD). However, no study has assessed body image and its comorbidities in patients with IBD using validated instruments. Our aim was to explore body image dissatisfaction in patients with IBD and assess its relationship with biological and psychosocial variables. Methods:We studied 330 patients (median age, 36 yr; range, 18–83; 169 men) using quantitative and qualitative methods. Patients completed a self-administered questionnaire that included a modified Hopwood Body Image Scale, the Cash Body Image Disturbance Questionnaire, and other validated instruments. Clinical and disease activity data were also collected. Results:Body image dissatisfaction was associated with disease activity (P < 0.001) and steroid treatment (P = 0.03) but not with immunotherapy (P = 0.57) or biological (P = 0.55) therapy. Body image dissatisfaction was also associated with low levels of general (P < 0.001) and IBD-specific (P < 0.001) quality of life, self-esteem (P < 0.001), and sexual satisfaction (P < 0.001), and with high levels of anxiety (P < 0.001) and depression (P < 0.001). Qualitative analysis indicated that patients were concerned about both physical and psychosocial consequences of body image dissatisfaction, including steroid side effects and impaired work and social activities. Conclusions:Body image dissatisfaction is common in patients with IBD, relates to specific clinical variables and is associated with significant psychological dysfunction. Its measurement is warranted as part of a comprehensive patient-centered IBD assessment.

The Short Health Scale: A valid and reliable measure of health related quality of life in English speaking inflammatory bowel disease patients

BACKGROUND Health related quality of life in inflammatory bowel disease is influenced both by disease activity as well as by the psychosocial characteristics of the individual patient. The Short Health Scale (SHS) is a four-part visual analogue scale questionnaire using open-ended questions that are designed to assess the impact of inflammatory bowel disease on a health related quality of life. The four dimensions include bowel symptoms, activities of daily life, worry and general wellbeing. It has previously been validated in Swedish and Norwegian speaking patients. AIM To evaluate the SHS in an English speaking inflammatory bowel disease population. METHODS Four hundred and ninety Crohns disease and ulcerative colitis patients completed the SHS. Individual SHS items were correlated with Inflammatory Bowel Disease Questionnaire (IBDQ) dimensions and with disease activity to assess validity. Test-retest reliability was assessed in 38 patients who completed the Short Health Scale two weeks apart. RESULTS All four items correlated with corresponding IBDQ dimensions with correlation coefficients ranging from -0.66 to -0.74 (all p values<0.001). In addition, total SHS scores correlated with total IBDQ scores in both Crohns disease (-0.836) and ulcerative colitis (0.797). There was a stepwise increase in Short Health Scale scores with increasing disease activity (all p values<0.001). Reliability was confirmed with test-retest correlations ranging from 0.70 to 0.89 (all p values<0.005). CONCLUSIONS The Short Health Scale is a valid and reliable measure of health related quality of life in English speaking inflammatory bowel disease patients.

Impact of magnetic resonance enterography in the management of small bowel Crohn's disease.

Introduction Magnetic resonance enterography (MRE) is a relatively new imaging modality that involves small bowel distension with orally administered fluid. Few studies have assessed its impact on patient management. Aim The aim of this study was to determine whether MRE influenced the management of patients with established small bowel Crohn’s disease (CD). Materials and methods From a prospectively maintained database of patients with inflammatory bowel disease, we identified patients with small bowel CD who underwent MRE between January 2007 and December 2010. The results of the MRE and subsequent changes in patient management within 1 month were evaluated. Results Thirty women and 27 men with CD were included. Seven patients (12%) had a normal MRE. Forty-two of 57 (74%) patients had a change in management, and 41/50 (82%) patients with an abnormal MRE had changes in management (P<0.0008). After MRE, 20/42 (47%) patients had surgery and 22/42 (53%) had changes in medical treatment. Patients with stricturing disease had more surgical intervention (P=0.02), and patients with active disease on MRE had more medical intervention (P=0.0001). Patients with two or more abnormalities on MRE had more surgery compared with medical therapy (P=0.02). Conclusion The majority of patients with small bowel CD had a change in management as a result of the MRE. Because of its high clinical impact on patient management, MRE should become one of the preferred methods of small bowel evaluation in CD. Specific MRE findings may help to stratify treatment options, however, further work is required to validate this.