- Email: [email protected]
S2019 Long-Term Efficacy of Infliximab Treatment in Pediatric Crohn's Disease in the Netherlands
AGA Abstracts
antibodies (gASCA) by ELISA (Glycominds Ltd., Lod, Israel) in a blinded fashion. Demographic and clinical data were analyzed. RESULTS: Serum levels of all markers, but AMCA and ACCA, were significantly higher in CD patients compared to UC and/or controls (p<0.02). 68% of CD patients were positive for at least one of the serological markers and CD patients were positive for a higher number of markers compared to UC and controls. gASCA was most accurate for the diagnosis of CD. All markers had a high specificity for CD vs. UC (85.2 - 100%). After correcting for age, sex, BMI, disease duration and disease location, respectively, multivariate logistic regression analysis of the CD subjects using each marker separately identified independent variables for marker positivity of gASCA IgG (p=0.015), gASCA IgA (p=0.012) and AMCA (P=0.005) for complicated disease behavior. gASCA IgG (p=0.006) was independently linked to small bowel disease location. None of the markers was associated with early disease onset, defined as disease diagnosis at an age of less than 10 years. In pediatric CD patients positivity for at least one marker out of the whole panel versus no marker positive was independently associated with fibrostenotic or fistulizing disease behavior (p=0.036) and ileal disease location (p=0.014). CONCLUSION: Serum anti-glycan antibodies can contribute to differential diagnosis of pediatric CD and are associated with complicated disease behavior and ileal disease location.
S2018a Associations Between DNA Variants in the TLR5 Gene and Pediatric-Onset Crohn's Disease Jared Sheridan, David R. Mack, Devendra K. Amre, Kenneth Morgan, David M. Israel, Ernest G. Seidman, Colette Deslandres, Philippe Lambrette, Alfreda Krupoves, Irina C. Costea, Houda H. Feguery, Jinsong Dong, Emile Levy, Theodore S. Steiner Background: The TLR5 (Toll-like receptor 5) gene is fundamental to the regulation of innate immune responses and inflammation. It recognizes bacterial flagellin, a component of bacterial flagella that lead to downstream events such as mobilization of NF-kB and production of TNF-α. Although In Vitro and In Vivo studies have demonstrated a key role for the TLR5 gene in Crohn's disease (CD), genetic studies have been equivocal. We investigated whether variants across the TLR5 gene were associated with CD in children. Methods: A case-control study was carried out at 3 pediatric gastroenterology clinics across Canada. Cases were children diagnosed with CD using standard criteria prior to age 20. Controls were recruited from different sources to represent population allele frequencies. Blood or saliva was acquired as a source of DNA. High frequency (>10%), tag-SNPs (single nucleotide polymorphisms) across the gene were identified and genotyped. Allelic, genotype and haplotype association analysis was carried out. TLR5 constructs of selected alleles were expressed in HEK 293T cells and NF-kB activation and IL-8 release in response to flagellin were measured. Results: A total of 478 cases and 400 controls were studied. The mean (±SD) age at diagnosis was 12.3 (±3.3) and most patients were male (56%). The majority of the patients had ileo-colonic disease (52%) and inflammatory behavior (87%) at diagnosis. Five tag-SNPs were investigated, all of which were in Hardy-Weinberg Equilibrium (HWE) in the controls. Of these SNPs, SNPs rs5744174, a non-synonymous coding SNP (OR=0.80, 95% CI=0.66-0.97, p=0.02) and an intronic SNP rs851139 (OR=0.81, 95% CI=0.67-0.99, p=0.04) were significantly associated with CD. Haplotype analysis revealed that two specific haplotypes comprising these two SNPs were significantly associated with CD. In Vitro analysis in HEK 293T cells showed that the C allele (protective allele in our data) of SNP rs5744174 was associated with reduced NF-kB activation and IL-8 release in response to bacterial flagellin. Linkage disequilibrium (LD) analysis showed that the two SNPs (rs851192, rs851193) nominally associated with CD in the WTCCC data were in complete LD (r2= 1.0) with SNP rs5744174. Conclusions: Findings from our genetic association and In Vitro studies suggest that the TLR5 gene may be associated with CD in children. A non-synonymous coding SNP that influences inflammatory responses to flagellin may be implicated.
S2017 Assessing Successful Transitioning in Adolescent IBD Patients to Adult Care Maureen Kelly, Maria E. Ferris, Carol A. Ford, J. B. Layton, Kristi Bickford, Sandra C. Kim Background: Inflammatory bowel diseases (IBD) significantly impact the well-being of adolescent patients. Therefore, successful transitioning is crucial to maintain the continuum from pediatric to adult GI care. Specific aim: Measure medical self-management preparedness in adolescent IBD patients using a validated scale. Methods: Patients managed in our pediatric IBD clinic were administered the TRXANSITION Scale™, a scoring system previously validated in chronic renal disease patients. This scale encompasses 10 global skills (33 questions) young adults need to acquire before transitioning to adult health providers. Reliability and reproducibility were enforced by having A. one research coordinator enroll and digitally record patients, and b. two independent, blinded researchers score 35 of the TRXANSITION Scale™ recordings. Participant's answers were scored based on their knowledge in each area (0 = none; 0.5 = some knowledge; 1 = adequate knowledge). Sub-section and total scores were used as outcome variables in separate regression models with age as a predictor. Differences between mean scores by other demographic factors were compared with ANOVA, and differences in distribution of categorical measures were calculated with chi-square tests. Results: 94 patients (12.2-20.8 yrs, mean: 15.2 ±1.9 yrs; 45% male, 55% female) completed the study. 70% were Caucasian, 23% were African-American, and 5% were in other groups. 76% had Crohn's disease, 23% had ulcerative colitis (UC), and 1% had indeterminate colitis. 26% had public insurance (Medicaid), 72% had private insurance and 2% were self-pay. Inter-rater reliability revealed a weighted Kappa statistic of 0.65 (95%CI: 0.61, 0.70). The mean TRXANSITION Scale™ score for all patients was 6.18±1.35 out of 10 (Range: 5.19.0; median: 6.31). Lowest scores were in self-management and reproduction issues. Highest scores were in knowledge of medications, illness type, adherence, nutrition, and ongoing support. Transition scores did not differ by gender, race, number of caregivers, or number of daily oral medications. Patients with private insurance had a significantly greater TRXANSITION score vs. patients with public insurance/self-pay (Private insurance: 6.4±1.3; Public/ self-pay: 5.5±1.3; p=0.003). Conclusion: Assessing the areas where adolescents need help in transition, and addressing these gaps in knowledge, are critical to prevent complications of IBD and to ensure comprehensive care once these adolescents reach adulthood. The deficits identified in adolescent IBD patients' medical self-management preparedness will be addressed through focused educational tools and active intervention.
S2019 Long-Term Efficacy of Infliximab Treatment in Pediatric Crohn's Disease in the Netherlands Charlotte de Bie, Thalia Hummel, Angelika Kindermann, Freddy Kokke, Gerard Damen, Corneille M. Kneepkens, Patrick van Rheenen, Joachim Schweizer, Hans Hoekstra, Obbe Norbruis, W. Tjon A Ten, Anita Vreugdenhil, Judith M. Deckers-Kocken, Carolien F. Gijsbers, Johanna C. Escher, Lissy de Ridder Introduction: Infliximab (IFX) is effective for induction and maintenance of remission in children with moderately to severely active Crohn's disease (CD). Little is known about the efficacy of IFX after more than three years of treatment. The primary aim of this study was therefore to assess the long-term efficacy of IFX treatment in pediatric CD. Methods: In this retrospective, multicenter study, all Dutch pediatric CD patients treated with IFX from October 1992 to October 2009 and with a minimal follow-up (FU) of three months since start of IFX, were studied. Patients were categorized according to duration of FU: 3 - 12 mo (n=34), 1 - 3 yr (n=74), 3 - 5 yr (n=36) and ≥ 5 yr (n=37). Treatment outcome was considered successful when good clinical response was maintained minimally 90 days after IFX stopped or when repeated IFX infusions were needed to maintain clinical response. Results: 181 CD patients (101M/80F) were treated with IFX by pediatric gastroenterologists in 13 hospitals. Mean age at start of IFX treatment was 14.5 years (range, 5.9 - 18.9 years) after a mean disease duration of 2.3 years (range, 0 - 10.1 years). A total of 2811 infusions was administered (mean, 15.5 infusions). Success of treatment was seen in respectively, 30/ 34 (88.2%), 45/74 (60.8%), 25/36 (69.4%) and 14/37 (37.8%) of patients in the FU categories 3 - 12 mo, 1 - 3 yr, 3 - 5 yr and ≥ 5 yr. Adjustments in treatment schedule (dosage increase to 10 mg/kg and/or shortening of the interval between two infusions) were needed in respectively, 26.7%, 44.4%, 63.6% and 50.0% of patients on maintenance treatment in the FU categories 3 - 12 mo, 1 - 3 yr, 3 - 5 yr and ≥ 5 yr. In total, 67 patients were (eventually) unsuccessfully treated with IFX. The majority of these patients underwent surgery (65.7%), followed by treatment with adalimumab (40.3%), corticosteroids (16.4%) and/or restart of IFX (14.9%; unsuccessful in seven patients). Conclusions: IFX is effective in refractory pediatric CD. However, the therapeutic effect decreases over time with lost response to IFX treatment in approximately 60% of patients after five years. In addition, the number of patients that requires adjustment in treatment schedule to maintain clinical response increases to more than 60% after three to five years of treatment. These data emphasize the need for developing an effective, long-term treatment strategy for pediatric CD.
S2018 The Processed Blood Volume Per Leukocytapheresis Session in Patients With Ulcerative Colitis Koji Kamikozuru, Ken Fukunaga, Yoko Yokoyama, Hiroto Miwa, Takayuki Matsumoto BACKGROUND: In Japan and parts of the EU, leukocytapheresis with a polyester leukocyte removal filter (LCA; Cellsorba) has been accepted as a non-drug based therapy in patients with active ulcerative colitis (UC), mostly patients who are refractory to conventional medications with pharmacologics. The primary aim of LCA could be recognized to settle autoimmune inflammation by eliminating the extra load of circulating activated leukocytes from patients' circulation, directly. Thus, proceeding volume (PV) of each LCA session should be an important parameter to regulate its clinical efficiency. In the present study, we have conducted a prospective trial of LCA for active UC under a variable PV, which was decided from patient's body weight (BW), and compared with conventional 3liter LCA. METHODS: Fourteen active UC were enrolled. Patients were treated with 5 weekly LCA with a calculated PV, which obtained from the equation of: PV (ml/session) =30 x BW (kg). Their average partial Mayo score and BW at entry were 5.7±1.0 points and 57.5 kg, respectively. The dosage of concomitant steroid was permitted only to decrease. Primary endpoint of the study was the partial Mayo score at 2 weeks after their last LCA. RESULTS: The average PV (ml) was 1726.1, range 1020-2460. And, the mean partial Mayo scores at the primary endpoint were proven to decrease significantly (2.0±1.2 points; P<0.05). The level of improvement was similar to that seen with patients treated with conventional 3liter LCA. CONCLUSIONS: The outcomes of this investigation showed that the clinical response to LCA based on BW with lower processed blood volume is similar to the routinely used 3liter per session. In Japan, there are those who say that the white blood cell level reaches a low level after processing just 1500mL and beyond this, an over-shoot phenomenon is likely. Based on this thinking, the mean processed blood volume in this study was close to 1500mL per one LCA session. Therefore, the obtained results could be indicated that gross amount of the removing leukocytes, which should be followed by PV, had have to regulate the clinical effect of LCA.
AGA Abstracts
S2020 Sigmoidoscopy Both Delays Time to Diagnosis and Has Poor Diagnostic Utility Compared to Full GI Endoscopic Assessment for Paediatric-Onset IBD Robin Dart, Richard K. Russell, Pamela Rogers, Peter M. Gillett, David C. Wilson Introduction: A significant proportion of Inflammatory Bowel Disease (IBD) presents in childhood and adolescence, a critical time for growth and development, so timely diagnosis is desirable to ensure patients achieve their growth potential. Our aim was to delineate factors including referral pathway and endoscopic investigation that may delay diagnosis in paediatric-onset IBD (PIBD). Methods: We performed a retrospective case note review in a tertiary PIBD centre from 1996-09. Symptom onset was defined as the length of history of presenting complaint; date of presentation was defined as the first presentation, often to primary care. Date of each referral, to whom, and the investigations carried out by each discipline before either diagnosis or onward referral were recorded. Date of diagnosis is
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antibodies (gASCA) by ELISA (Glycominds Ltd., Lod, Israel) in a blinded fashion. Demographic and clinical data were analyzed. RESULTS: Serum levels of all markers, but AMCA and ACCA, were significantly higher in CD patients compared to UC and/or controls (p<0.02). 68% of CD patients were positive for at least one of the serological markers and CD patients were positive for a higher number of markers compared to UC and controls. gASCA was most accurate for the diagnosis of CD. All markers had a high specificity for CD vs. UC (85.2 - 100%). After correcting for age, sex, BMI, disease duration and disease location, respectively, multivariate logistic regression analysis of the CD subjects using each marker separately identified independent variables for marker positivity of gASCA IgG (p=0.015), gASCA IgA (p=0.012) and AMCA (P=0.005) for complicated disease behavior. gASCA IgG (p=0.006) was independently linked to small bowel disease location. None of the markers was associated with early disease onset, defined as disease diagnosis at an age of less than 10 years. In pediatric CD patients positivity for at least one marker out of the whole panel versus no marker positive was independently associated with fibrostenotic or fistulizing disease behavior (p=0.036) and ileal disease location (p=0.014). CONCLUSION: Serum anti-glycan antibodies can contribute to differential diagnosis of pediatric CD and are associated with complicated disease behavior and ileal disease location.
S2018a Associations Between DNA Variants in the TLR5 Gene and Pediatric-Onset Crohn's Disease Jared Sheridan, David R. Mack, Devendra K. Amre, Kenneth Morgan, David M. Israel, Ernest G. Seidman, Colette Deslandres, Philippe Lambrette, Alfreda Krupoves, Irina C. Costea, Houda H. Feguery, Jinsong Dong, Emile Levy, Theodore S. Steiner Background: The TLR5 (Toll-like receptor 5) gene is fundamental to the regulation of innate immune responses and inflammation. It recognizes bacterial flagellin, a component of bacterial flagella that lead to downstream events such as mobilization of NF-kB and production of TNF-α. Although In Vitro and In Vivo studies have demonstrated a key role for the TLR5 gene in Crohn's disease (CD), genetic studies have been equivocal. We investigated whether variants across the TLR5 gene were associated with CD in children. Methods: A case-control study was carried out at 3 pediatric gastroenterology clinics across Canada. Cases were children diagnosed with CD using standard criteria prior to age 20. Controls were recruited from different sources to represent population allele frequencies. Blood or saliva was acquired as a source of DNA. High frequency (>10%), tag-SNPs (single nucleotide polymorphisms) across the gene were identified and genotyped. Allelic, genotype and haplotype association analysis was carried out. TLR5 constructs of selected alleles were expressed in HEK 293T cells and NF-kB activation and IL-8 release in response to flagellin were measured. Results: A total of 478 cases and 400 controls were studied. The mean (±SD) age at diagnosis was 12.3 (±3.3) and most patients were male (56%). The majority of the patients had ileo-colonic disease (52%) and inflammatory behavior (87%) at diagnosis. Five tag-SNPs were investigated, all of which were in Hardy-Weinberg Equilibrium (HWE) in the controls. Of these SNPs, SNPs rs5744174, a non-synonymous coding SNP (OR=0.80, 95% CI=0.66-0.97, p=0.02) and an intronic SNP rs851139 (OR=0.81, 95% CI=0.67-0.99, p=0.04) were significantly associated with CD. Haplotype analysis revealed that two specific haplotypes comprising these two SNPs were significantly associated with CD. In Vitro analysis in HEK 293T cells showed that the C allele (protective allele in our data) of SNP rs5744174 was associated with reduced NF-kB activation and IL-8 release in response to bacterial flagellin. Linkage disequilibrium (LD) analysis showed that the two SNPs (rs851192, rs851193) nominally associated with CD in the WTCCC data were in complete LD (r2= 1.0) with SNP rs5744174. Conclusions: Findings from our genetic association and In Vitro studies suggest that the TLR5 gene may be associated with CD in children. A non-synonymous coding SNP that influences inflammatory responses to flagellin may be implicated.
S2017 Assessing Successful Transitioning in Adolescent IBD Patients to Adult Care Maureen Kelly, Maria E. Ferris, Carol A. Ford, J. B. Layton, Kristi Bickford, Sandra C. Kim Background: Inflammatory bowel diseases (IBD) significantly impact the well-being of adolescent patients. Therefore, successful transitioning is crucial to maintain the continuum from pediatric to adult GI care. Specific aim: Measure medical self-management preparedness in adolescent IBD patients using a validated scale. Methods: Patients managed in our pediatric IBD clinic were administered the TRXANSITION Scale™, a scoring system previously validated in chronic renal disease patients. This scale encompasses 10 global skills (33 questions) young adults need to acquire before transitioning to adult health providers. Reliability and reproducibility were enforced by having A. one research coordinator enroll and digitally record patients, and b. two independent, blinded researchers score 35 of the TRXANSITION Scale™ recordings. Participant's answers were scored based on their knowledge in each area (0 = none; 0.5 = some knowledge; 1 = adequate knowledge). Sub-section and total scores were used as outcome variables in separate regression models with age as a predictor. Differences between mean scores by other demographic factors were compared with ANOVA, and differences in distribution of categorical measures were calculated with chi-square tests. Results: 94 patients (12.2-20.8 yrs, mean: 15.2 ±1.9 yrs; 45% male, 55% female) completed the study. 70% were Caucasian, 23% were African-American, and 5% were in other groups. 76% had Crohn's disease, 23% had ulcerative colitis (UC), and 1% had indeterminate colitis. 26% had public insurance (Medicaid), 72% had private insurance and 2% were self-pay. Inter-rater reliability revealed a weighted Kappa statistic of 0.65 (95%CI: 0.61, 0.70). The mean TRXANSITION Scale™ score for all patients was 6.18±1.35 out of 10 (Range: 5.19.0; median: 6.31). Lowest scores were in self-management and reproduction issues. Highest scores were in knowledge of medications, illness type, adherence, nutrition, and ongoing support. Transition scores did not differ by gender, race, number of caregivers, or number of daily oral medications. Patients with private insurance had a significantly greater TRXANSITION score vs. patients with public insurance/self-pay (Private insurance: 6.4±1.3; Public/ self-pay: 5.5±1.3; p=0.003). Conclusion: Assessing the areas where adolescents need help in transition, and addressing these gaps in knowledge, are critical to prevent complications of IBD and to ensure comprehensive care once these adolescents reach adulthood. The deficits identified in adolescent IBD patients' medical self-management preparedness will be addressed through focused educational tools and active intervention.
S2019 Long-Term Efficacy of Infliximab Treatment in Pediatric Crohn's Disease in the Netherlands Charlotte de Bie, Thalia Hummel, Angelika Kindermann, Freddy Kokke, Gerard Damen, Corneille M. Kneepkens, Patrick van Rheenen, Joachim Schweizer, Hans Hoekstra, Obbe Norbruis, W. Tjon A Ten, Anita Vreugdenhil, Judith M. Deckers-Kocken, Carolien F. Gijsbers, Johanna C. Escher, Lissy de Ridder Introduction: Infliximab (IFX) is effective for induction and maintenance of remission in children with moderately to severely active Crohn's disease (CD). Little is known about the efficacy of IFX after more than three years of treatment. The primary aim of this study was therefore to assess the long-term efficacy of IFX treatment in pediatric CD. Methods: In this retrospective, multicenter study, all Dutch pediatric CD patients treated with IFX from October 1992 to October 2009 and with a minimal follow-up (FU) of three months since start of IFX, were studied. Patients were categorized according to duration of FU: 3 - 12 mo (n=34), 1 - 3 yr (n=74), 3 - 5 yr (n=36) and ≥ 5 yr (n=37). Treatment outcome was considered successful when good clinical response was maintained minimally 90 days after IFX stopped or when repeated IFX infusions were needed to maintain clinical response. Results: 181 CD patients (101M/80F) were treated with IFX by pediatric gastroenterologists in 13 hospitals. Mean age at start of IFX treatment was 14.5 years (range, 5.9 - 18.9 years) after a mean disease duration of 2.3 years (range, 0 - 10.1 years). A total of 2811 infusions was administered (mean, 15.5 infusions). Success of treatment was seen in respectively, 30/ 34 (88.2%), 45/74 (60.8%), 25/36 (69.4%) and 14/37 (37.8%) of patients in the FU categories 3 - 12 mo, 1 - 3 yr, 3 - 5 yr and ≥ 5 yr. Adjustments in treatment schedule (dosage increase to 10 mg/kg and/or shortening of the interval between two infusions) were needed in respectively, 26.7%, 44.4%, 63.6% and 50.0% of patients on maintenance treatment in the FU categories 3 - 12 mo, 1 - 3 yr, 3 - 5 yr and ≥ 5 yr. In total, 67 patients were (eventually) unsuccessfully treated with IFX. The majority of these patients underwent surgery (65.7%), followed by treatment with adalimumab (40.3%), corticosteroids (16.4%) and/or restart of IFX (14.9%; unsuccessful in seven patients). Conclusions: IFX is effective in refractory pediatric CD. However, the therapeutic effect decreases over time with lost response to IFX treatment in approximately 60% of patients after five years. In addition, the number of patients that requires adjustment in treatment schedule to maintain clinical response increases to more than 60% after three to five years of treatment. These data emphasize the need for developing an effective, long-term treatment strategy for pediatric CD.
S2018 The Processed Blood Volume Per Leukocytapheresis Session in Patients With Ulcerative Colitis Koji Kamikozuru, Ken Fukunaga, Yoko Yokoyama, Hiroto Miwa, Takayuki Matsumoto BACKGROUND: In Japan and parts of the EU, leukocytapheresis with a polyester leukocyte removal filter (LCA; Cellsorba) has been accepted as a non-drug based therapy in patients with active ulcerative colitis (UC), mostly patients who are refractory to conventional medications with pharmacologics. The primary aim of LCA could be recognized to settle autoimmune inflammation by eliminating the extra load of circulating activated leukocytes from patients' circulation, directly. Thus, proceeding volume (PV) of each LCA session should be an important parameter to regulate its clinical efficiency. In the present study, we have conducted a prospective trial of LCA for active UC under a variable PV, which was decided from patient's body weight (BW), and compared with conventional 3liter LCA. METHODS: Fourteen active UC were enrolled. Patients were treated with 5 weekly LCA with a calculated PV, which obtained from the equation of: PV (ml/session) =30 x BW (kg). Their average partial Mayo score and BW at entry were 5.7±1.0 points and 57.5 kg, respectively. The dosage of concomitant steroid was permitted only to decrease. Primary endpoint of the study was the partial Mayo score at 2 weeks after their last LCA. RESULTS: The average PV (ml) was 1726.1, range 1020-2460. And, the mean partial Mayo scores at the primary endpoint were proven to decrease significantly (2.0±1.2 points; P<0.05). The level of improvement was similar to that seen with patients treated with conventional 3liter LCA. CONCLUSIONS: The outcomes of this investigation showed that the clinical response to LCA based on BW with lower processed blood volume is similar to the routinely used 3liter per session. In Japan, there are those who say that the white blood cell level reaches a low level after processing just 1500mL and beyond this, an over-shoot phenomenon is likely. Based on this thinking, the mean processed blood volume in this study was close to 1500mL per one LCA session. Therefore, the obtained results could be indicated that gross amount of the removing leukocytes, which should be followed by PV, had have to regulate the clinical effect of LCA.
AGA Abstracts
S2020 Sigmoidoscopy Both Delays Time to Diagnosis and Has Poor Diagnostic Utility Compared to Full GI Endoscopic Assessment for Paediatric-Onset IBD Robin Dart, Richard K. Russell, Pamela Rogers, Peter M. Gillett, David C. Wilson Introduction: A significant proportion of Inflammatory Bowel Disease (IBD) presents in childhood and adolescence, a critical time for growth and development, so timely diagnosis is desirable to ensure patients achieve their growth potential. Our aim was to delineate factors including referral pathway and endoscopic investigation that may delay diagnosis in paediatric-onset IBD (PIBD). Methods: We performed a retrospective case note review in a tertiary PIBD centre from 1996-09. Symptom onset was defined as the length of history of presenting complaint; date of presentation was defined as the first presentation, often to primary care. Date of each referral, to whom, and the investigations carried out by each discipline before either diagnosis or onward referral were recorded. Date of diagnosis is
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