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Swallowed Budesonide for Treatment of Eosinophilic Esophagitis: Results From a Randomized, Open-Label, Clinical Trial
AGA Abstracts
gastric model by assessing leak pressures In Vitro. Material and Method KUMC suture device was created by using needle and beads. Whole thirty stomachs were harvested from pigs weighing 30 to 50kg. Standard gastrotomy was made by knife incision and dilation with a 18-mm controlled radial expansion (CRE) balloon. This novel device was compared with two other closure techniques; endoscopic clips and hand-sewn. Ten stomachs were tested per each study group. After closure, each stomach was inflated by an automated pressure gauge. The pressures to achieve air leakage and liquid leakage were recorded. Result In the vitro model, the burst pressure according to groups were mean 88.3 mmHg in the hand sewn group, 64.4 mmHg in the KUMC closure device group, 45.2 mmHg in the endoscopic clip group. Using one way ANOVA analysis, the KUMC closure device was statistically significant compared with either the hand-sewn closure or the endoscopic clip closure in the ex vivo model. (P<0.001) Post hoc paired comparison using Tukey HSD revealed that KUMC suture model is superior than endoscopic clip. (P=0.027) Conclusion KUMC closure device produce superior closures in comparison with endoscopic clips and inferior closure in comparison with hand sewn. Our new suture device competently produced a tight and reliable closure In Vitro study.
Figure); the MDQ scores were 10 ± 12 and 16 ± 17 (p=0.31; see Figure); and the EGD findings were improved in 45% and 91% (p=0.02), respectively. Overall, 27% of NEB and 64% of OVB had complete normalization of their esophageal biopsies (p=0.09). On followup EGD, 3 patients (14%; 1 in NEB and 2 in OVB) had candidal esophagitis. No patients had adrenal insufficiency post-treatment by cortisol stimulation testing. Conclusions: Orallyadministered viscous budesonide was more effective than nebulized/swallowed budesonide for improving esophageal eosinophil counts and endoscopic findings. Symptoms of dysphagia improved in both groups. Consideration of alternate formulations of topical corticosteroid preparations is warranted in EoE. This research was conducted with support from the InvestigatorSponsored Study Program of AstraZenca LP.
1032 Fixed Rings and Strictures in Eosinophilic Esophagitis Develop Due to Continuing Inflammation Over Time Alain Schoepfer, Ekaterina Safroneeva, Christian Bussmann, Peter Netzer, Susanne Portmann, Alex Straumann Background: Two distinct endoscopic phenotypes of Eosinophilic Esophagitis (EoE) have been identified: the inflammatory (IP) and the stenosing (SP) phenotype. The IP is characterized by the presence of florid inflammation (e.g. whitish exudates and edema), whereas the SP is characterized by the appearance of signs associated with remodeling, such as fixed rings and/or strictures. It is not known whether these EoE-associated phenotypes are reflective of different phases that this chronic disease undergoes during its lifetime course. Aim: To assess the phenotype at initial EoE presentation and diagnosis and to evaluate whether SP increases over time. Methods: Retrospective analysis of the Swiss EoE Database (SEED) extended by a review of patients charts, endoscopy and pathology records. Strictures and rings were assessed endoscopically and defined as a stenosis of the esophageal lumen with a diameter of 12 mm and less and a length of ≥10 mm and <10 mm, respectively. Index visit was defined as the time-point when EoE was diagnosed, and diagnostic delay was defined as period from initial EoE symptom presentation to diagnosis. Parametric data are described as mean ± SD, non-parametric data as median plus interquartile range (IQR). Results: Forty-four EoE patients were analyzed (33 males, mean age at index visit 41 ± 14 years, all Caucasians). Median follow-up time was 3.1 years (IQR 1-4, range 1-18 years). Median diagnostic delay was 5 years (IQR 2-16, range 0-34 years). At first diagnosis, 32% (14/44) of EoE patients had already presented with a stenosis, characterized by a single esophageal narrowing in 93% (13/14) of patients. The mean diameter of the stenoses was 10 ± 2 mm, and the mean length was 2.8 ± 2.9 cm. Twenty-nine percent (4/14) had fixed rings while 71% (10/14) had strictures. Twenty-nine percent of stenoses were located in the proximal esophagus and 71% in the distal esophagus. Peak eosinophil count did not change over time (48 ± 39 eos/HPF at index visit vs. 59 ± 41 eos/HPF at end of follow-up, n=44). The risk of the presence of a stenosis at index visit was 0% for a disease duration of 0-4 years, 37% for a disease duration between 5-10 years and 67% for a disease duration >10 years (p = 0.0035, trend test). Conclusions: The frequency of esophageal stenoses is proportional to the disease duration, whereas the inflammatory activity does not significantly change over time. Although stenoses may affect each segment of the esophagus, these are more commonly found in the distal esophagus. Our results suggest that inflammation (IP) is a hallmark of initial clinical manifestation of EoE and that SP develops over time as disease progresses. These findings underscore the necessity to reduce diagnostic delay in EoE and to control the underlying inflammatory processes to prevent further esophageal remodeling.
1034 Mucosal Contact Time Determines Histologic Effectiveness of Oral Budesonide Preparations in Eosinophilic Esophagitis: A Randomized Trial Using Scintigraphy Evan S. Dellon, Arif Sheikh, Ann Whitlow, Marija Ivanovic, Allen Chau, Kimberly Woodward, Olga Speck, Jessica Hores, John T. Woosley, Ryan D. Madanick, Roy C. Orlando, Nicholas J. Shaheen Background: Swallowed corticosteroids are used to treat eosinophilic esophagitis (EoE), but the optimal mode of delivery is unknown. Aim: To assess mucosal medication contact time, esophageal distribution, and eosinophil counts after treatment with either nebulized/ swallowed (NEB) or viscous/swallowed (OVB) budesonide for EoE. Methods: In this singlecenter, randomized, open-label clinical trial (NCT 00961233), subjects aged 18 or older with an incident diagnosis of EoE as per 2007 guidelines (≥15 eos/hpf [hpf area=0.24mm2] after 8 weeks of BID PPI) were randomized to receive 1 mg BID of budesonide for 8 weeks in 1 of 2 forms: nebulized (1 mg/2 mL solution over 5 mins, with instructions to swallow the mist), or orally (viscous slurry with 1 mg/2 mL solution mixed with 5g of sucralose). Nuclear scintigraphy was performed by mixing Tc99-DPTA with budesonide pre- administration. Esophageal emptying was recorded at baseline and post-treatment, and the mean area under the emptying curve (AUC) was calculated for the entire esophagus and by segment (prox, mid, and distal); higher AUCs indicated increased esophageal mucosal contact. Biopsies from the prox, mid, and distal esophagus were obtained at baseline and post-treatment. The change in eosinophil count was correlated with the AUC using nonparametric methods. Results: 22 patients completed the protocol (mean age 35 yrs; 59% male; 86% Caucasian). In the NEB group, the mean post-treatment eosinophil count changed from 79 to 57, 41 to 55, and 54 to 69 eos/hpf in the prox, mid, and distal esophagus (p=ns for all). In the OVB group, the counts decreased from 54 to 5, 59 to 8, and 53 to 11 (p<0.05 for all). Esophageal emptying AUCs were higher for OVB than NEB in the entire (59000 vs 28000; p=0.005), mid (9500 vs 4900; p=0.01), and distal esophagus (24500 vs 5900 counts; p= 0.001). AUC inversely correlated with the percent change in eosinophil count regardless of treatment type, with R=-0.67 (p=0.001) for the entire esophagus (see Figure), and R=-0.44 (p=0.05), R=-0.49 (p=0.05), and R=-0.55 (p=0.009) for the prox, mid, and distal esophagus. Patients with a complete histiologic response (<1 eos/hpf) also tended to have a higher AUC in all segments of the esophagus, regardless of treatment type. Conclusions: Orallyadministered viscous budesonide resulted in a larger decrease in esophageal eosinophils than nebulized/swallowed budesonide and yielded significantly higher esophageal medication exposure. A higher intensity of mucosal exposure correlated with lower eosinophil counts in all segments of the esophagus regardless of treatment type, implying that the effect of budesonide is local rather than systemic. Novel delivery systems to optimize mucosal contact time for topical steroids are needed in EoE. This research was conducted with support from the Investigator-Sponsored Study Program of AstraZeneca LP.
1033 Nebulized/Swallowed vs Viscous/Swallowed Budesonide for Treatment of Eosinophilic Esophagitis: Results From a Randomized, Open-Label, Clinical Trial Evan S. Dellon, Arif Sheikh, Olga Speck, Kimberly Woodward, Ann Whitlow, Jessica Hores, Marija Ivanovic, Allen Chau, John T. Woosley, Ryan D. Madanick, Roy C. Orlando, Nicholas J. Shaheen Background: Corticosteroids administered by swallowing inhaled or nebulized preparations are a mainstay of therapy for eosinophilic esophagitis (EoE). However, there are few data addressing the comparative efficacy of different topical corticosteroid preparations. Aim: To compare two topical budesonide preparations, nebulized/swallowed (NEB) and viscous/ swallowed (OVB), for treatment of EoE. Methods: We conducted a single-center, randomized, prospective, open-label clinical trial of nebulized then swallowed vs viscous budesonide (NCT00961233). Subjects were age 18 or older with an incident diagnosis of EoE as per 2007 guidelines; all had persistent dysphagia and ≥15 eosinophils in one high-power microscopy field (hpf area=0.24 mm2) after 8 weeks of BID PPI. They were randomized to receive 1 mg BID of budesonide for 8 weeks, given in one of two forms: nebulized (1 mg/ 2 mL solution over 5 minutes, with instructions to swallow the mist), or orally (viscous slurry with 1 mg/2 mL solution mixed with 5g of sucralose). The primary outcomes were levels of esophageal eosinophilia (maximum eosinophil count) on week 8 endoscopy, and symptoms of dysphagia measured by the Mayo Dysphagia Questionnaire-30 Day (MDQ). Symptom, endoscopic, and histologic data were collected at baseline and follow-up. Pathologists were masked to treatment allocation. Data analysis was by intention-to-treat. Results: Of the 25 patients enrolled (mean age 35 yrs; 60% male; 88% Caucasian), 22 completed the study protocol (2 lost-to-follow-up; 1 did not tolerate nebulizer treatments). At baseline for the NEB and OVB groups, the maximum eosinophil counts were 101 ± 85 and 83 ± 89 (p=0.62), and the MDQ scores were 34 ± 21 and 25 ± 18 (p=0.30), respectively. Baseline endoscopy was abnormal for all patients in the NEB and OVB groups, with rings in 85% and 100%, furrows in 85% and 92%, and plaques in 38% and 42%. After treatment with NEB or OVB, the maximum eosinophil counts were 89 ± 94 and 11 ± 23 (p=0.02; see
AGA Abstracts
1035 Longitudinal Assessment of Children With Eosinophilic Esophagitis (EoE) Identified Decreased Symptoms and Increased Quality of Life (QOL) Mary D. Klinnert, Rachel Harris, Lori Silveira, Wendy Moore, Dan Atkins, David M. Fleischer, Seema Aceves, Jonathan M. Spergel, Glenn Furuta Improved treatment approaches for pediatric EoE appear effective for individual patients. However, the effectiveness of treatment on QoL over time for pediatric patients with EoE has not been systematically assessed. We hypothesized that multidisciplinary treatment provided in tertiary care centers would improve symptoms and QoL over time, regardless of specific treatment approach. Methods: Children with confirmed EoE diagnoses who were treated in 3 tertiary care centers were enrolled in an ongoing longitudinal study. Children received individualized treatments that included diet modifications and/or topical steroids as directed by the center multidisciplinary team. Assessments occurred at the time of patients' first evaluation (baseline) and at 2- and 6-month follow-up with web-based questionnaires. Presence and severity of 8 EoE symptoms were queried; summed severity scores were analyzed. Quality of life was measured with the PedsQL™ parent (PR) and child self-report (CR) scales (100-point scales, high scores indicate better QoL). Statistical analysis used
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gastric model by assessing leak pressures In Vitro. Material and Method KUMC suture device was created by using needle and beads. Whole thirty stomachs were harvested from pigs weighing 30 to 50kg. Standard gastrotomy was made by knife incision and dilation with a 18-mm controlled radial expansion (CRE) balloon. This novel device was compared with two other closure techniques; endoscopic clips and hand-sewn. Ten stomachs were tested per each study group. After closure, each stomach was inflated by an automated pressure gauge. The pressures to achieve air leakage and liquid leakage were recorded. Result In the vitro model, the burst pressure according to groups were mean 88.3 mmHg in the hand sewn group, 64.4 mmHg in the KUMC closure device group, 45.2 mmHg in the endoscopic clip group. Using one way ANOVA analysis, the KUMC closure device was statistically significant compared with either the hand-sewn closure or the endoscopic clip closure in the ex vivo model. (P<0.001) Post hoc paired comparison using Tukey HSD revealed that KUMC suture model is superior than endoscopic clip. (P=0.027) Conclusion KUMC closure device produce superior closures in comparison with endoscopic clips and inferior closure in comparison with hand sewn. Our new suture device competently produced a tight and reliable closure In Vitro study.
Figure); the MDQ scores were 10 ± 12 and 16 ± 17 (p=0.31; see Figure); and the EGD findings were improved in 45% and 91% (p=0.02), respectively. Overall, 27% of NEB and 64% of OVB had complete normalization of their esophageal biopsies (p=0.09). On followup EGD, 3 patients (14%; 1 in NEB and 2 in OVB) had candidal esophagitis. No patients had adrenal insufficiency post-treatment by cortisol stimulation testing. Conclusions: Orallyadministered viscous budesonide was more effective than nebulized/swallowed budesonide for improving esophageal eosinophil counts and endoscopic findings. Symptoms of dysphagia improved in both groups. Consideration of alternate formulations of topical corticosteroid preparations is warranted in EoE. This research was conducted with support from the InvestigatorSponsored Study Program of AstraZenca LP.
1032 Fixed Rings and Strictures in Eosinophilic Esophagitis Develop Due to Continuing Inflammation Over Time Alain Schoepfer, Ekaterina Safroneeva, Christian Bussmann, Peter Netzer, Susanne Portmann, Alex Straumann Background: Two distinct endoscopic phenotypes of Eosinophilic Esophagitis (EoE) have been identified: the inflammatory (IP) and the stenosing (SP) phenotype. The IP is characterized by the presence of florid inflammation (e.g. whitish exudates and edema), whereas the SP is characterized by the appearance of signs associated with remodeling, such as fixed rings and/or strictures. It is not known whether these EoE-associated phenotypes are reflective of different phases that this chronic disease undergoes during its lifetime course. Aim: To assess the phenotype at initial EoE presentation and diagnosis and to evaluate whether SP increases over time. Methods: Retrospective analysis of the Swiss EoE Database (SEED) extended by a review of patients charts, endoscopy and pathology records. Strictures and rings were assessed endoscopically and defined as a stenosis of the esophageal lumen with a diameter of 12 mm and less and a length of ≥10 mm and <10 mm, respectively. Index visit was defined as the time-point when EoE was diagnosed, and diagnostic delay was defined as period from initial EoE symptom presentation to diagnosis. Parametric data are described as mean ± SD, non-parametric data as median plus interquartile range (IQR). Results: Forty-four EoE patients were analyzed (33 males, mean age at index visit 41 ± 14 years, all Caucasians). Median follow-up time was 3.1 years (IQR 1-4, range 1-18 years). Median diagnostic delay was 5 years (IQR 2-16, range 0-34 years). At first diagnosis, 32% (14/44) of EoE patients had already presented with a stenosis, characterized by a single esophageal narrowing in 93% (13/14) of patients. The mean diameter of the stenoses was 10 ± 2 mm, and the mean length was 2.8 ± 2.9 cm. Twenty-nine percent (4/14) had fixed rings while 71% (10/14) had strictures. Twenty-nine percent of stenoses were located in the proximal esophagus and 71% in the distal esophagus. Peak eosinophil count did not change over time (48 ± 39 eos/HPF at index visit vs. 59 ± 41 eos/HPF at end of follow-up, n=44). The risk of the presence of a stenosis at index visit was 0% for a disease duration of 0-4 years, 37% for a disease duration between 5-10 years and 67% for a disease duration >10 years (p = 0.0035, trend test). Conclusions: The frequency of esophageal stenoses is proportional to the disease duration, whereas the inflammatory activity does not significantly change over time. Although stenoses may affect each segment of the esophagus, these are more commonly found in the distal esophagus. Our results suggest that inflammation (IP) is a hallmark of initial clinical manifestation of EoE and that SP develops over time as disease progresses. These findings underscore the necessity to reduce diagnostic delay in EoE and to control the underlying inflammatory processes to prevent further esophageal remodeling.
1034 Mucosal Contact Time Determines Histologic Effectiveness of Oral Budesonide Preparations in Eosinophilic Esophagitis: A Randomized Trial Using Scintigraphy Evan S. Dellon, Arif Sheikh, Ann Whitlow, Marija Ivanovic, Allen Chau, Kimberly Woodward, Olga Speck, Jessica Hores, John T. Woosley, Ryan D. Madanick, Roy C. Orlando, Nicholas J. Shaheen Background: Swallowed corticosteroids are used to treat eosinophilic esophagitis (EoE), but the optimal mode of delivery is unknown. Aim: To assess mucosal medication contact time, esophageal distribution, and eosinophil counts after treatment with either nebulized/ swallowed (NEB) or viscous/swallowed (OVB) budesonide for EoE. Methods: In this singlecenter, randomized, open-label clinical trial (NCT 00961233), subjects aged 18 or older with an incident diagnosis of EoE as per 2007 guidelines (≥15 eos/hpf [hpf area=0.24mm2] after 8 weeks of BID PPI) were randomized to receive 1 mg BID of budesonide for 8 weeks in 1 of 2 forms: nebulized (1 mg/2 mL solution over 5 mins, with instructions to swallow the mist), or orally (viscous slurry with 1 mg/2 mL solution mixed with 5g of sucralose). Nuclear scintigraphy was performed by mixing Tc99-DPTA with budesonide pre- administration. Esophageal emptying was recorded at baseline and post-treatment, and the mean area under the emptying curve (AUC) was calculated for the entire esophagus and by segment (prox, mid, and distal); higher AUCs indicated increased esophageal mucosal contact. Biopsies from the prox, mid, and distal esophagus were obtained at baseline and post-treatment. The change in eosinophil count was correlated with the AUC using nonparametric methods. Results: 22 patients completed the protocol (mean age 35 yrs; 59% male; 86% Caucasian). In the NEB group, the mean post-treatment eosinophil count changed from 79 to 57, 41 to 55, and 54 to 69 eos/hpf in the prox, mid, and distal esophagus (p=ns for all). In the OVB group, the counts decreased from 54 to 5, 59 to 8, and 53 to 11 (p<0.05 for all). Esophageal emptying AUCs were higher for OVB than NEB in the entire (59000 vs 28000; p=0.005), mid (9500 vs 4900; p=0.01), and distal esophagus (24500 vs 5900 counts; p= 0.001). AUC inversely correlated with the percent change in eosinophil count regardless of treatment type, with R=-0.67 (p=0.001) for the entire esophagus (see Figure), and R=-0.44 (p=0.05), R=-0.49 (p=0.05), and R=-0.55 (p=0.009) for the prox, mid, and distal esophagus. Patients with a complete histiologic response (<1 eos/hpf) also tended to have a higher AUC in all segments of the esophagus, regardless of treatment type. Conclusions: Orallyadministered viscous budesonide resulted in a larger decrease in esophageal eosinophils than nebulized/swallowed budesonide and yielded significantly higher esophageal medication exposure. A higher intensity of mucosal exposure correlated with lower eosinophil counts in all segments of the esophagus regardless of treatment type, implying that the effect of budesonide is local rather than systemic. Novel delivery systems to optimize mucosal contact time for topical steroids are needed in EoE. This research was conducted with support from the Investigator-Sponsored Study Program of AstraZeneca LP.
1033 Nebulized/Swallowed vs Viscous/Swallowed Budesonide for Treatment of Eosinophilic Esophagitis: Results From a Randomized, Open-Label, Clinical Trial Evan S. Dellon, Arif Sheikh, Olga Speck, Kimberly Woodward, Ann Whitlow, Jessica Hores, Marija Ivanovic, Allen Chau, John T. Woosley, Ryan D. Madanick, Roy C. Orlando, Nicholas J. Shaheen Background: Corticosteroids administered by swallowing inhaled or nebulized preparations are a mainstay of therapy for eosinophilic esophagitis (EoE). However, there are few data addressing the comparative efficacy of different topical corticosteroid preparations. Aim: To compare two topical budesonide preparations, nebulized/swallowed (NEB) and viscous/ swallowed (OVB), for treatment of EoE. Methods: We conducted a single-center, randomized, prospective, open-label clinical trial of nebulized then swallowed vs viscous budesonide (NCT00961233). Subjects were age 18 or older with an incident diagnosis of EoE as per 2007 guidelines; all had persistent dysphagia and ≥15 eosinophils in one high-power microscopy field (hpf area=0.24 mm2) after 8 weeks of BID PPI. They were randomized to receive 1 mg BID of budesonide for 8 weeks, given in one of two forms: nebulized (1 mg/ 2 mL solution over 5 minutes, with instructions to swallow the mist), or orally (viscous slurry with 1 mg/2 mL solution mixed with 5g of sucralose). The primary outcomes were levels of esophageal eosinophilia (maximum eosinophil count) on week 8 endoscopy, and symptoms of dysphagia measured by the Mayo Dysphagia Questionnaire-30 Day (MDQ). Symptom, endoscopic, and histologic data were collected at baseline and follow-up. Pathologists were masked to treatment allocation. Data analysis was by intention-to-treat. Results: Of the 25 patients enrolled (mean age 35 yrs; 60% male; 88% Caucasian), 22 completed the study protocol (2 lost-to-follow-up; 1 did not tolerate nebulizer treatments). At baseline for the NEB and OVB groups, the maximum eosinophil counts were 101 ± 85 and 83 ± 89 (p=0.62), and the MDQ scores were 34 ± 21 and 25 ± 18 (p=0.30), respectively. Baseline endoscopy was abnormal for all patients in the NEB and OVB groups, with rings in 85% and 100%, furrows in 85% and 92%, and plaques in 38% and 42%. After treatment with NEB or OVB, the maximum eosinophil counts were 89 ± 94 and 11 ± 23 (p=0.02; see
AGA Abstracts
1035 Longitudinal Assessment of Children With Eosinophilic Esophagitis (EoE) Identified Decreased Symptoms and Increased Quality of Life (QOL) Mary D. Klinnert, Rachel Harris, Lori Silveira, Wendy Moore, Dan Atkins, David M. Fleischer, Seema Aceves, Jonathan M. Spergel, Glenn Furuta Improved treatment approaches for pediatric EoE appear effective for individual patients. However, the effectiveness of treatment on QoL over time for pediatric patients with EoE has not been systematically assessed. We hypothesized that multidisciplinary treatment provided in tertiary care centers would improve symptoms and QoL over time, regardless of specific treatment approach. Methods: Children with confirmed EoE diagnoses who were treated in 3 tertiary care centers were enrolled in an ongoing longitudinal study. Children received individualized treatments that included diet modifications and/or topical steroids as directed by the center multidisciplinary team. Assessments occurred at the time of patients' first evaluation (baseline) and at 2- and 6-month follow-up with web-based questionnaires. Presence and severity of 8 EoE symptoms were queried; summed severity scores were analyzed. Quality of life was measured with the PedsQL™ parent (PR) and child self-report (CR) scales (100-point scales, high scores indicate better QoL). Statistical analysis used
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