Edel McDermott

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.

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.

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.

Heightened Expression of CD39 by Regulatory T Lymphocytes Is Associated with Therapeutic Remission in Inflammatory Bowel Disease

Background:To evaluate whether changes in expression of CD39 by regulatory T lymphocytes (Treg) impact treatment response in inflammatory bowel disease. To then define the biological role of expression of CD39 on Treg in an animal model of colitis. Methods:A prospective study of consecutive patients commencing anti-tumor necrosis factor therapy with infliximab (IFX) or adalimumab (ADA), who were then followed for 12 months. Treatment responses were defined both symptomatically and by endoscopy showing mucosal healing. Peripheral blood Tregs were quantified by flow cytometry. Functional importance of CD39 expression by Treg was determined in an adoptive T-cell transfer model of colitis. Results:Forty-seven patients (ulcerative colitis, n = 22; Crohns disease, n = 25) were recruited; 16 patients were complete responders and 13 nonresponders to anti-tumor necrosis factor. CD39 expression by Treg was lower in active inflammatory bowel disease and increased significantly after treatment in responders (CD39+Treg/total Treg; 8% at baseline to 22.5% at late time point, P < 0.001). Responders were more likely to have therapeutic drug levels and in multivariate analysis therapeutic drug levels were associated with higher expression of CD39 by FoxP3+ Treg and lower frequencies of interleukin 17A expressing cells. Tregs with genetic deletion of CD39 exhibit decrements in potential to suppress intestinal inflammation in a murine (CD45RBhi) T-cell transfer model of colitis in vivo, when compared with wild-type Treg. Conclusions:Increased expression of CD39 by peripheral blood Treg is observed in the setting of clinical and endoscopic remission in inflammatory bowel disease. Deficiency of CD39 expression by Treg can be linked to inability to suppress experimental colitis.

Development, validation and clinical assessment of a short questionnaire to assess disease-related knowledge in inflammatory bowel disease patients

Abstract Objectives. Only two inflammatory bowel disease (IBD) knowledge scales are available, both primarily aimed at evaluating the effectiveness of clinical education programs. The aim of this study was to develop and validate a short knowledge questionnaire for clinical and academic research purposes. Material and methods. Following initial development, the questionnaire was tested on junior doctors, nurses and administrative staff to assess validity. The questionnaire was then assessed and compared with a previous questionnaire in 31 IBD patients. Three hundred and three further patients completed the questionnaire to establish reliability and determine factors independently associated with disease-related knowledge. Results. Doctors answered more questions correctly than nurses who scored better than administrative staff (p < 0.001). There was a fair correlation in scores between the short knowledge questionnaire and a previously validated long survey (r = 0.488; p = 0.005). The short knowledge questionnaire was quicker to complete (p < 0.001), was rated as less difficult to understand (p = 0.004) and induce less anxiety (p = 0.004). Both questionnaires were rated similarly with regard to relevance (p = 0.71). Internal consistency was demonstrated with a Cronbachs alpha of 0.73. In clinical testing on 301 patients, the final multivariate model identified young age, Crohns disease, higher educational status and the presence of a first-degree family member with IBD as being independently and significantly associated with disease-related knowledge. Conclusions. The short knowledge questionnaire is a simple, valid, reliable and easy to understand research instrument for rapidly assessing knowledge in IBD patients.

Determinants of short- and long-term survival from colorectal cancer in very elderly patients

PURPOSE Over 5100 colorectal cancers (CRCs) are diagnosed in the United Kingdom in 85 years and older age group per year but little is known of cancer progression in this group. We assessed clinical, pathological and molecular features of CRC with early and late mortality in such patients. METHODS Data were analysed in relation to early mortality and long-term survival in 90 consecutive patients with CRC aged 85 years or older in a single hospital. RESULTS Patients not undergoing operation, those with an ASA score of III or greater and those with advanced tumour stage were more likely to die within 30 days. Regression analysis showed that 30 day mortality was independently related to failure to undergo resection (odds ratio (O.R.), 10.0; 95% confidence interval [C.I.], 1.7-58.2; p=0.01) and an ASA score of III or greater (O.R. 13.0; 95% C.I., 1.4-12.6; p=0.03). All cause three and five year survival were 47% and 23% respectively for patients who are alive 30 days after diagnosis. Three and five year relative survivals were 64% and 54%, respectively. Long-term outcome was independently related to tumour stage (relative risk [R.R.], 2; 95% C.I., 1.3-3.1; p=0.001), presence of co-morbid diseases (R.R., 2.8; 95% C.I., 1.3-6.0; p=0.007) and lipid peroxidation status (R.R., 2.9; 95% C.I., 1.1-7.5; p=0.025). CONCLUSIONS An active multidisciplinary approach to the care of patients with CRC at the upper extreme of life is reasonable. It also seems sensible to individualise care based upon the extent of disease at diagnosis and the presence of co-morbid conditions. Further studies to examine the role of lipid peroxidation are warranted.

Clinical and Pathological Factors Associated with Colorectal Cancer at the Upper Extreme of Life

from the hospital infection control nurse that the patient had trichinosis. Immediately thoughts of pork, eosinophilia, muscle biopsies, other residents who may have eaten the same food, questions of incubation, our food services director, our kitchen, our meat distributors, the department of health, and the news media ran through my head. Luckily, seconds later I realized that a urinalysis and 2 g of metronidazole do not diagnose or treat trichinosis but rather trichomonas. The resident, fully alert and oriented, reported no sexual activity in years and no gynecology evaluation. Chlamydia and gonorrhea studies were determined to be negative. The patient remains asymptomatic of vaginal discharge and muscle pains. Guess what? Further investigation reveals she keeps kosher.

Sa1761 Anti-TNF Therapy Switches on CD39+ FoxP3 Tregs in Association With Symptomatic and Endoscopic Remission in IBD

BACKGROUND & AIMS: Interferon gamma (IFNγ) responses and distinct CD8+ T cell transcriptional signatures can be linked to clinical manifestations of inflammatory bowl disease (IBD). CD39 is an ectonucleotidase and is typically associated with CD4+ T regulatory memory cells, which have the capacity to generate immunosuppressive adenosine. However, immunomodulatory effects of CD39 expression on CD8+ T cells, as in IBD, remain unknown. METHODS:CD39+CD8+ T cells were purified from peripheral blood (PB) and lamina propria (LP) of patients with Crohns disease. Phenotypic features and functions of CD39+CD8+ T cells were assessed by flow cytometry and immunoblotting. RESULTS: CD39 expressing CD8+ T cells of patients with Crohns disease are IFNγ-producing cells, and exhibited type 1 CD8+ T cell (Tc1) properties. CD3 and CD28-mediated synergistic stimulation of CD8+ T cells augment CD39 expression, boost reactive oxygen species (ROS) generation, and increase IFNγ production. CD39+CD8+ T cells preferentially express CD28, and exhibit robust ROS-JNK/NFkB signals and IFNγ production. Decreases in ROSmediated by inhibitors of NADPH oxidases (NOX) or knockdown of gp91phox (NOX2) in CD8+ T cells abrogate effects of TCR ligation, and decrease both CD39 expression and IFNγ production. Curiously, CD39+CD8+ T cells inhibit IFNγ production by CD39-CD8+ T cells via generation of adenosine, which is operational via the paracrine expression of Adenosine 2A (ADORA2A) receptor. CONCLUSIONS: CD8+ Tc1 cells express CD39, which is further boosted by cell activation and ROS, which in turn limit IFNg responses by these cells. Strategies to regulate ROS signal cascades and adenosine-mediated effects might have therapeutic potential in the treatment of Crohns disease.

P652 Global DNA methylation in inflammatory bowel disease

P651 Identification of new genetic variants related to thiopurineinduced myelotoxicity in inflammatory bowel disease (IBD) patients with normal thiopurines-methyltransferase (TPMT): a genome-wide association study M. Chaparro1 *, A. Gonzalez-Neira2, M. Roman3, G. Pita2, T. Cabaleiro4, D. Herrero2, B. Herraez2, R. Alonso2, C. Taxonera5, P. Lopez-Serrano6, P. Martinez-Montiel7, I. Vera8, F. Bermejo9, A. Lopez-San Roman10, F. Abad-Santos4, J.P. Gisbert1. 1Hospital Universitario de La Princesa, IP and CIBERehd, Gastroenterology Unit, Madrid, Spain, 2Spanish Narional Cancer Research Institute, Madrid, Spain, 3Hospital Universitario de La Princesa and IP, Farmacy Unit, Madrid, Spain, 4Hospital Universitario de La Princesa and IP, Clinical Pharmacology Unit, Madrid, Spain, 5Hospital Clinico San Carlos, Gastroenterology Unit, Madrid, Spain, 6Hospital de Alcorcon, Gastroenterology Unit, Madrid, Spain, 7Hospital Doce de Octubre, Gastroenterology Unit, Madrid, Spain, 8Hospital Puerta de Hierro, Gastroenterology Unit, Madrid, Spain, 9Hospital de Fuenlabrada, Gastroenterology Unit, Madrid, Spain, 10Hospital Ramon y Cajal, Gastroenterology Unit, Madrid, Spain