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190 Retrospective Study of the Natural Long-Term History of Untreated Celiac Disease
CONCLUSION: We showed that analyses of VOC in exhaled air could distinguish IBD patients from healthy controls. The test was especially fit to distinguish active disease from CD or UC in remission. We therefore conclude that VOCs are a non-invasive biomarker for the follow-up of IBD. Exhaled air, in contrast to stool samples for leucocyte markers, can always and easily be provided in the out patient clinic. A prospective study in a large cohort of IBD patients is presently ongoing. Furthermore the relation with mucosal healing will be assessed. 1. Van Berkel et al. J Chromatogr B Analyt Technol Biomed Life Sci. 2008;861:101-7 190 Retrospective Study of the Natural Long-Term History of Untreated Celiac Disease Debby Kryszak, Bushra N. Bhatti, Craig Sturgeon, Sandra Clipp, Kathy Helzlsouer, Alessio Fasano Background. Celiac disease (CD) is one of the most common lifelong disorders in the US. However the prevalence trend of untreated CD and its natural history over time are still unclear. We investigated a cohort first tested in 1974 and then followed up to 2007. Patients. The Odyssey cohort includes adults resident in Maryland that participated in both CLUE I (1974) and CLUE II (1989) studies and then followed on by periodical clinical questionnaire. We analyzed 3511 paired sera samples from Odyssey cohort. CD prevalence in 1974/1989 was compared with that observed in a sample of 2845 healthy adults screened in our laboratory between 1996 and 2001 by serological antiendomysial antibody (EMA) testing. Methods. Sera were first tested for IgA anti-transglutaminase (tTG) antibodies and those with elevated anti-tTG were subsequently tested for serum IgA EMA. CD was defined as cases in which both anti-tTG and EMA were positive. Results. Overall we analyzed samples from 7896 subjects, 4354 from CLUE I and 3542 from CLUE II. The CLUE I group had 9 positive Anti-tTG and EMA samples out of 4354 samples screened (1:484), while the CLUE II group had 14 positive Anti-tTG and EMA samples out of 3542 samples (1:253). The prevalence of CD in the Odyssey cohort was 0.21 % (95 % CI = 0.072 - 0.34) in 1974 and 0.45 % (95 % CI = 0.24 - 0.66) in 1989. In the year 2000 American sample the prevalence of CD was 0.95 % (95 % CI 0.59 - 1.3%) Compared to controls, untreated CD subjects showed higher incidence of osteoporosis and associated autoimmune disorders. Conclusions. There has been a significant increase of CD prevalence in the US during these last 3 decades, a trend that was associated to higher co-morbidity in undiagnosed patients.
188 Accuracy of Preoperative Serologic Testing in Patients Undergoing Intestinal Resection for Inflammatory Bowel Disease Nicolas M. Intagliata, Brian R. Swenson, Charles M. Friel, Eugene F. Foley, Brian W. Behm Background: In patients with inflammatory bowel disease (IBD) undergoing intestinal resection, preoperative determination of IBD subtype [e.g., Crohn's disease (CD), ulcerative colitis (UC), IBD unclassified (IBD-U)] is important for operative planning. The use of serologic testing to aid in the differentiation of IBD subtypes may be useful in this setting. Methods: A surgical database was used to identify patients that underwent intestinal resection for IBDrelated disease from 1997 to 2008 at the University of Virginia. An electronic chart review was performed to identify the subgroup of patients that had preoperative serologic testing performed. Preoperative clinical diagnoses, serology results, and pathology results were obtained for this subgroup using electronic medical records. The accuracy of preoperative clinical diagnosis and IBD First Step serologic diagnosis were obtained using surgical pathology diagnosis as the gold standard. We examined the ability to correctly predict UC preoperatively using sensitivity and specificity analysis and compared the Receiver Operating Characteristic Area Under the Curve (ROC-AUC) for clinical and serologic diagnoses. Results: We identified 485 patients who underwent intestinal resection for IBD-related disease. Fiftythree patients had preoperative serologic testing performed using the IBD First Step™ (Prometheus Laboratories, San Diego, California). In this group, surgical pathology diagnoses included 27 (50.9%) UC, 20 (37.7%) CD, and 6 (11.3%) IBD-U. Using surgical pathology as the gold standard, preoperative clinical diagnosis was accurate in 44 (83.0%) patients and IBD First Step diagnosis was accurate in 32 (60.4%) patients. Preoperative clinical diagnosis had a sensitivity of 96.3% and specificity of 69.2% of predicting UC (ROC-AUC = 0.93) while IBD First Step serology demonstrated a sensitivity of 64.0% and specificity of 57.7% of predicting UC (ROC-AUC = 0.67), p=0.0003. Conclusion: In this cohort of patients, the preoperative use of serologic testing was unable to accurately determine IBD subtypes in a significant proportion of patients undergoing intestinal resection for IBD-related disease. Preoperative clinical diagnosis performed significantly better than serology in this setting. Preoperative serologic testing lacked sensitivity and specificity for the detection of ulcerative colitis in this patient population.
191 ALV003, a Combination Oral Protease, Is Active, Safe and Tolerable in Healthy Volunteers and Subjects with Celiac Disease in Phase 1 Trials Mitchell Garber, Matthew Siegel, Vijaya Pratha, Andrew Spencer, Pawan Kumar, Wendy A. Botwick, Revati Shreeniwas BACKGROUND: Celiac disease (CD) is a hereditary inflammatory disorder resulting from dietary exposure to gluten proteins found in wheat, barley and rye. Since a gluten free diet (GFD) fails to normalize small bowel histology in up to half of adults with CD, new therapies are needed. ALV003 is a combination of two glutenases (ALV001 and ALV002) with complementary substrate specificity that efficiently degrades immunotoxic gluten peptides. STUDY DESIGN: The activity, safety, and tolerability of ALV003 were studied in two phase 1 clinical trials (ALV003-0811 [N=28] and ALV003-0812 [N=53]). Both were single dose, single blind, placebo controlled cross over trials. ALV003 (100, 300, 900, 1800 mg) was administered to fasted subjects in ALV003-0811 and together with a homogenized meal (meat, potatoes, butter, juice, ice cream, bread) in ALV003-0812. Subjects were healthy volunteers [N=76] and patients with well controlled CD (300 mg ALV003 [N=5]). ALV003 drug solution was administered via a nasogastric tube. Gastric samples were assessed for ALV003 glutenase activity and protein level. RESULTS: A dose dependent increase in ALV003 activity was observed in fasting gastric aspirates, and ALV003 proteins were detected as early as 5 minutes (min) and persisted up to 180 min post dose. Gastric aspirates collected 30 min following a meal showed that ALV003 (100 and 300 mg) consistently degraded 1 gram wheat bread gluten in the stomach of all 16 dosed subjects as determined by competitive ELISA (78% mean gluten elimination vs placebo; p<0.01, Wilcoxon signed-rank test). Drug was detected by western blot in meal aspirates. ALV003 activity and protein levels in the stomach of CD subjects were similar to healthy volunteers. All doses were well tolerated in the fed and fasted states with no serious adverse events (AEs) or dose limiting toxicities. Mild or moderate AEs, judged by the Investigator to be related to ALV003, were reported in 11 subjects in both studies (mainly gastrointestinal). Low levels of ALV001 were detected in the serum in 1/6 subjects (1800 mg) in ALV003-0811. Anti-ALV001 antibodies (ab) were detected in 8/81subjects (7 in ALV003-0811; 1 in ALV003-0812). Neither ALV002 nor anti-ALV002 ab were detected. There were no AEs associated with positive ab responses. SUMMARY: 1. ALV003 is a combination oral protease that efficiently degrades gluten in the stomach with minimal systemic exposure. 2. ALV003 is safe and tolerable at doses 18fold higher than levels that degrade gluten. 3. Most AEs were mild or moderate and selflimited. 4. ALV003 activity and safety in CD subjects were similar to healthy volunteers. *Authors contributed equally to this project
189 Analysis of Volatile Organic Compounds in Exhaled Air As a Non Invasive Biomarker for Inflammatory Bowel Disease (IBD) Alexander Bodelier, Marie J. Pierik, Jan W. Dallinga, Joep Van Berkel, Edwin Moonen, Wim Hameeteman, Daisy Jonkers, Ad Masclee, Frederik J. Van Schooten Crohn's disease (CD) and ulcerative colitis (UC) are chronic relapsing diseases of the gastrointestinal tract together referred to as IBD. The diagnosis, differential diagnosis and major therapeutic decisions are made after endoscopic assessment of mucosal inflammation. Mucosal healing is also an important end-point in clinical trials. Ileocoloscopy however is an invasive procedure with possible severe side effects. Inflammation is accompanied by the overproduction of reactive oxygen species which leads to local or systemic oxidative stress and subsequantly degradation of cell membranes by lipid peroxidation. During this process polyunsaturated fatty acids are converted to volatile organic compounds (VOCs) that are secreted via the lungs. Hundreds of different VOCs exist in human breath, and their relative concentrations alter in the presence of disease. Quantities of these VOCs can be measured by collection of exhaled breath and analysis on a gas chromatography time-of-flight mass spectrometer (GC-TOF-MS) (1). MATERIALS & METHODS: Exhaled air was collected in inert Tedlar bags of 20 patients with active CD, 18 CD patiënts in remission, 20 patients with active UC, 23 UC patients in remisson and 38 healthy controls. Remission was defined as a CDAI below 150 or a SCCAI below 2.5 for CD and UC respectively. Smokers and non smokers were equaly devided among groups. Quantities of VOCs were analysed on GCTOF-MS. RESULTS: We determined which compounds in the database were of interest with regard to the classification of active versus non-active disease by discriminant analyses with a leave one out method. The optimal subset of compounds able to correctly classify our dataset was selected. Six to 8 compounds could classify with 95-100% accuracy CD in remission vs. active CD and UC in remission vs. active UC. When comparing CD and UC with healthy controls the sensitivity to distinguish IBD patients from controls was 100%.
192 Prevalence of Celiac Disease and Gluten-Sensitivity in Subjects with Schizophrenia Debby Kryszak, Bushra N. Bhatti, Craig Sturgeon, William W. Eaton, Nicola G. Cascella, Patricia Gregory, Alessio Fasano Background: Celiac disease is an immune-mediated reaction to gluten, presenting with diarrhea, weight loss, abdominal complaints and a range of less common associated neurologic and psychiatric symptoms. Evidence of a link between schizophrenia and celiac disease dates back as far as 1961. A theory for this association presented by Dohan was that gluten serves as an environmental trigger in individuals predisposed to schizophrenia. This theory
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AGA Abstracts
AGA Abstracts
parameters, with or without endoscopy and histology. Calprotectin concentrations were determined using a commercially available monoclonal antibody-based ELISA (Immundiagnostik AG, Bensheim, Germany) and a one step semi-quantitative immunochromatographic office-based rapid strip test device (Prevent ID® Cal Detect, Preventis GmbH, Bensheim, Germany). RESULTS: Some of the symptomatic IBD patients during their follow up underwent repeated stool tests thus yielding a total of 1091 stool samples (690 in CD and 401 from UC) in 332 IBD patients. The mean age ±SD for all the patients were 43.6 years±14.8 with a range of 18-91 years.The performance characteristics of the of the new office-based assay are as shown in Table. CONCLUSION: This new office-based FC assay proved to be an accurate, simple (can be performed at physician's office by health care personnel/patients' themselves), rapid (needs about 10 minutes), convenient (unique non touch sample preparation), noncumbersome (without ELISA- reader), and nearly 10 times cheaper option for detecting FC than the routine ELISA-based assay. Performance characteristics of Calprotectin ELISA and Bedside test
188 Accuracy of Preoperative Serologic Testing in Patients Undergoing Intestinal Resection for Inflammatory Bowel Disease Nicolas M. Intagliata, Brian R. Swenson, Charles M. Friel, Eugene F. Foley, Brian W. Behm Background: In patients with inflammatory bowel disease (IBD) undergoing intestinal resection, preoperative determination of IBD subtype [e.g., Crohn's disease (CD), ulcerative colitis (UC), IBD unclassified (IBD-U)] is important for operative planning. The use of serologic testing to aid in the differentiation of IBD subtypes may be useful in this setting. Methods: A surgical database was used to identify patients that underwent intestinal resection for IBDrelated disease from 1997 to 2008 at the University of Virginia. An electronic chart review was performed to identify the subgroup of patients that had preoperative serologic testing performed. Preoperative clinical diagnoses, serology results, and pathology results were obtained for this subgroup using electronic medical records. The accuracy of preoperative clinical diagnosis and IBD First Step serologic diagnosis were obtained using surgical pathology diagnosis as the gold standard. We examined the ability to correctly predict UC preoperatively using sensitivity and specificity analysis and compared the Receiver Operating Characteristic Area Under the Curve (ROC-AUC) for clinical and serologic diagnoses. Results: We identified 485 patients who underwent intestinal resection for IBD-related disease. Fiftythree patients had preoperative serologic testing performed using the IBD First Step™ (Prometheus Laboratories, San Diego, California). In this group, surgical pathology diagnoses included 27 (50.9%) UC, 20 (37.7%) CD, and 6 (11.3%) IBD-U. Using surgical pathology as the gold standard, preoperative clinical diagnosis was accurate in 44 (83.0%) patients and IBD First Step diagnosis was accurate in 32 (60.4%) patients. Preoperative clinical diagnosis had a sensitivity of 96.3% and specificity of 69.2% of predicting UC (ROC-AUC = 0.93) while IBD First Step serology demonstrated a sensitivity of 64.0% and specificity of 57.7% of predicting UC (ROC-AUC = 0.67), p=0.0003. Conclusion: In this cohort of patients, the preoperative use of serologic testing was unable to accurately determine IBD subtypes in a significant proportion of patients undergoing intestinal resection for IBD-related disease. Preoperative clinical diagnosis performed significantly better than serology in this setting. Preoperative serologic testing lacked sensitivity and specificity for the detection of ulcerative colitis in this patient population.
191 ALV003, a Combination Oral Protease, Is Active, Safe and Tolerable in Healthy Volunteers and Subjects with Celiac Disease in Phase 1 Trials Mitchell Garber, Matthew Siegel, Vijaya Pratha, Andrew Spencer, Pawan Kumar, Wendy A. Botwick, Revati Shreeniwas BACKGROUND: Celiac disease (CD) is a hereditary inflammatory disorder resulting from dietary exposure to gluten proteins found in wheat, barley and rye. Since a gluten free diet (GFD) fails to normalize small bowel histology in up to half of adults with CD, new therapies are needed. ALV003 is a combination of two glutenases (ALV001 and ALV002) with complementary substrate specificity that efficiently degrades immunotoxic gluten peptides. STUDY DESIGN: The activity, safety, and tolerability of ALV003 were studied in two phase 1 clinical trials (ALV003-0811 [N=28] and ALV003-0812 [N=53]). Both were single dose, single blind, placebo controlled cross over trials. ALV003 (100, 300, 900, 1800 mg) was administered to fasted subjects in ALV003-0811 and together with a homogenized meal (meat, potatoes, butter, juice, ice cream, bread) in ALV003-0812. Subjects were healthy volunteers [N=76] and patients with well controlled CD (300 mg ALV003 [N=5]). ALV003 drug solution was administered via a nasogastric tube. Gastric samples were assessed for ALV003 glutenase activity and protein level. RESULTS: A dose dependent increase in ALV003 activity was observed in fasting gastric aspirates, and ALV003 proteins were detected as early as 5 minutes (min) and persisted up to 180 min post dose. Gastric aspirates collected 30 min following a meal showed that ALV003 (100 and 300 mg) consistently degraded 1 gram wheat bread gluten in the stomach of all 16 dosed subjects as determined by competitive ELISA (78% mean gluten elimination vs placebo; p<0.01, Wilcoxon signed-rank test). Drug was detected by western blot in meal aspirates. ALV003 activity and protein levels in the stomach of CD subjects were similar to healthy volunteers. All doses were well tolerated in the fed and fasted states with no serious adverse events (AEs) or dose limiting toxicities. Mild or moderate AEs, judged by the Investigator to be related to ALV003, were reported in 11 subjects in both studies (mainly gastrointestinal). Low levels of ALV001 were detected in the serum in 1/6 subjects (1800 mg) in ALV003-0811. Anti-ALV001 antibodies (ab) were detected in 8/81subjects (7 in ALV003-0811; 1 in ALV003-0812). Neither ALV002 nor anti-ALV002 ab were detected. There were no AEs associated with positive ab responses. SUMMARY: 1. ALV003 is a combination oral protease that efficiently degrades gluten in the stomach with minimal systemic exposure. 2. ALV003 is safe and tolerable at doses 18fold higher than levels that degrade gluten. 3. Most AEs were mild or moderate and selflimited. 4. ALV003 activity and safety in CD subjects were similar to healthy volunteers. *Authors contributed equally to this project
189 Analysis of Volatile Organic Compounds in Exhaled Air As a Non Invasive Biomarker for Inflammatory Bowel Disease (IBD) Alexander Bodelier, Marie J. Pierik, Jan W. Dallinga, Joep Van Berkel, Edwin Moonen, Wim Hameeteman, Daisy Jonkers, Ad Masclee, Frederik J. Van Schooten Crohn's disease (CD) and ulcerative colitis (UC) are chronic relapsing diseases of the gastrointestinal tract together referred to as IBD. The diagnosis, differential diagnosis and major therapeutic decisions are made after endoscopic assessment of mucosal inflammation. Mucosal healing is also an important end-point in clinical trials. Ileocoloscopy however is an invasive procedure with possible severe side effects. Inflammation is accompanied by the overproduction of reactive oxygen species which leads to local or systemic oxidative stress and subsequantly degradation of cell membranes by lipid peroxidation. During this process polyunsaturated fatty acids are converted to volatile organic compounds (VOCs) that are secreted via the lungs. Hundreds of different VOCs exist in human breath, and their relative concentrations alter in the presence of disease. Quantities of these VOCs can be measured by collection of exhaled breath and analysis on a gas chromatography time-of-flight mass spectrometer (GC-TOF-MS) (1). MATERIALS & METHODS: Exhaled air was collected in inert Tedlar bags of 20 patients with active CD, 18 CD patiënts in remission, 20 patients with active UC, 23 UC patients in remisson and 38 healthy controls. Remission was defined as a CDAI below 150 or a SCCAI below 2.5 for CD and UC respectively. Smokers and non smokers were equaly devided among groups. Quantities of VOCs were analysed on GCTOF-MS. RESULTS: We determined which compounds in the database were of interest with regard to the classification of active versus non-active disease by discriminant analyses with a leave one out method. The optimal subset of compounds able to correctly classify our dataset was selected. Six to 8 compounds could classify with 95-100% accuracy CD in remission vs. active CD and UC in remission vs. active UC. When comparing CD and UC with healthy controls the sensitivity to distinguish IBD patients from controls was 100%.
192 Prevalence of Celiac Disease and Gluten-Sensitivity in Subjects with Schizophrenia Debby Kryszak, Bushra N. Bhatti, Craig Sturgeon, William W. Eaton, Nicola G. Cascella, Patricia Gregory, Alessio Fasano Background: Celiac disease is an immune-mediated reaction to gluten, presenting with diarrhea, weight loss, abdominal complaints and a range of less common associated neurologic and psychiatric symptoms. Evidence of a link between schizophrenia and celiac disease dates back as far as 1961. A theory for this association presented by Dohan was that gluten serves as an environmental trigger in individuals predisposed to schizophrenia. This theory
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AGA Abstracts
AGA Abstracts
parameters, with or without endoscopy and histology. Calprotectin concentrations were determined using a commercially available monoclonal antibody-based ELISA (Immundiagnostik AG, Bensheim, Germany) and a one step semi-quantitative immunochromatographic office-based rapid strip test device (Prevent ID® Cal Detect, Preventis GmbH, Bensheim, Germany). RESULTS: Some of the symptomatic IBD patients during their follow up underwent repeated stool tests thus yielding a total of 1091 stool samples (690 in CD and 401 from UC) in 332 IBD patients. The mean age ±SD for all the patients were 43.6 years±14.8 with a range of 18-91 years.The performance characteristics of the of the new office-based assay are as shown in Table. CONCLUSION: This new office-based FC assay proved to be an accurate, simple (can be performed at physician's office by health care personnel/patients' themselves), rapid (needs about 10 minutes), convenient (unique non touch sample preparation), noncumbersome (without ELISA- reader), and nearly 10 times cheaper option for detecting FC than the routine ELISA-based assay. Performance characteristics of Calprotectin ELISA and Bedside test