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Su1136 Factors Influencing the Treatment of Inflammatory Bowel Disease in Patients With Cancer Recurrence: Pilot Study
Su1135
AGA Abstracts
High Vitamin D Diet Leads to a Paradoxical Decrease of Bone Mineral Density in Adoptive T-Cell Transfer Colitis Claire B. Larmonier, Rita-Marie T. Woodford, Faihza M. Hill, Rupert Schreiner, Rajalakshmy Ramalingam, David G. Besselsen, Fayez K. Ghishan, Pawel R. Kiela Background: Inflammatory Bowel Disease is not only characterized by an aberrant immune response against commensal intestinal bacterial flora and mucosal damage but can also affect bone metabolism and bone mineral density (BMD) with osteopenia and osteoporosis as the two major extra-intestinal symptoms of IBD. Low BMD along with 25(OH) vitamin D3 deficiency have been reported in both Ulcerative colitis and Crohn's Disease and is associated with an increased risk of fracture. In IBD patients, inflammation-associated pro-inflammatory mediators, poor nutritional status and malabsortion affecting vitamin D3 and Ca2+ homeostasis, have been postulated to be the cause of altered bone morphology and metabolism. Moreover, immunomodulatory role of vitamin D3 has been reported in both innate and adaptive immune system. Therefore, vitamin D3 supplementation has been considered as a viable adjunctive therapeutic strategy in IBD. Vitamin D3 plays a pleiotropic role in bone modeling and regulates the balance of bone formation and bone resorption depending of the physiological environment. Moreover, a significant fraction of adult and pediatric IBD patients with low BMD have elevated levels of circulating 1,25(OH)2 D3. We hypothesized that vitamin D3 supplementation in active IBD may lead to a paradoxical loss in BMD. Methods: We evaluated the effect of vitamin D3 supplementation in adoptive IL-10-/-CD4+ T cell transfer model of chronic colitis. In this model, we evaluated the effect of vitamin D3 supplementation (switch from human equivalent dose of 730 IU to 3,648 IU daily) on established colitis and on BMD (μCT), bone metabolism and turnover. Results: 12-day highdose vitamin D3 supplementation during established disease had negligible effects on mucosal inflammation. Plasma level of vitamin D3 metabolites correlated with diet, but not with the disease status. Colitis reduced BMD. High vitamin D3 supplementation did not affect cortical bone structure but led to a further deterioration of trabecular bone morphology. High D3 diet negatively affected bone formation markers; osteocalcin and bone alkaline phosphatase, and increased bone resorption markers; RANKL/OPG transcript ratio, plasma OPG level and osteoclast activation marker ACp5. Consistently, expression of bone vitamin D receptor (VDR) was increased in mice with chronic colitis, especially in mice fed high vitamin D3 diet. Conclusion: Our data collectively suggests that vitamin D3 in a dose which does not improve inflammation, adversely affects BMD and bone turnover. The data provided by this study should be taken into consideration in the planning of further clinical studies with high vitamin D3 supplementation in IBD patients with active disease.
Su1137 Intestinal Fibrosis and Wound Healing in Experimental Crohn's Disease: Effect of Pegylated Murinized Rabbit Anti-Mouse TNF Laura J. Reingold, Andrew S. Kimball, Phyllissa Schmiedlin-Ren, Scott R. Owens, Ellen Zimmermann Debate exists about the effect of perioperative anti-TNF on wound healing and postoperative complications in patients with Crohn's disease (CD). Our aim was to determine if anti-TNF affects wound healing or tissue factors that influence wound integrity in a CD model. Methods: Peptidoglycan-polysaccharide (PGPS) or human serum albumin (HSA, control) was injected into the bowel wall of Lewis rats at laparotomy. PGPS and HSA injected rats were given pegylated murinized rabbit anti-mouse TNF or vehicle SC 3 times a week beginning d1 post-op. Animals were sacrificed on d28 (n=12). Incisions were collected. Gross abdominal score (sum of adhesions, mesenteric thickening, cecal wall thickening, cecal granulomas, and liver granulomas on 0-4 scales) was determined. Quantitative realtime PCR for proinflammatory and profibrotic factors was performed on cecal and incisional tissue. Histologic sections were stained and scored. Results: PGPS rats had higher gross abdominal scores, histologic scores, and relevant mRNA levels than HSA rats (previously shown). As expected, HSA-injected, vehicle treated rats (HSA/Veh) had no hernias or incisional abscesses (0%). All PGPS-injected, vehicle-treated rats (PGPS/Veh) developed abdominal hernias (100%). PGPS/Tx rats had a decreased rate of hernia formation (33%). Interestingly, hernias and subcutaneous abscesses were seen starting at d14 in all HSA-injected, anti-TNF treated rats (HSA/Tx, 100%). In cecal tissue, procollagen I, procollagen III and the profibrotic factors IGF-I and TGF β1 mRNAs were increased in PGPS/Veh compared to HSA/Veh (previously shown). Treatment with anti-TNF decreased these mRNAs (procollagen I 4.6±2.7 v 17.2±4.3, p=0.02; procollagen III 0.8±0.4 v 4.9±2.8, p=0.01; TGF β1 2.3±0.1 v 3.3±0.3, p=0.03; IGF-I 1.9±0.1 v 5.1±1.2, p=0.03). Decreased histologic tissue inflammation and fibrosis were also observed. In incisional tissue, animals with CD had higher levels of procollagen I and III, TGF1, IGF-I, PDGF-B, bFGF, and VEGF than control rats (PGPS/ Veh v HSA/Veh). Treatment with anti-TNF normalized these mRNAs to levels in HSA/Veh rats. Interestingly, mRNA levels in HSA/Tx were higher than HSA/Veh (fold HSA/Veh: collagen I 2.47, p=0.02; collagen III 2.6, p=0.01; TGF β 3.1, p=0.03; IGF-I 1.9, p=0.03; PDGF-B 1.4, p=0.08; bFGF 1.3, p=0.02; VEGF2.0, p=0.08). Histologic changes in incisions were associated with changes in mRNAs. Conclusion: Experimental Crohn's disease causes wound defects including hernias and abscesses independent of anti-TNF treatment. Rats with CD treated with anti-TNF had normalization of the incisional factors and improved wound integrity. Normal animals treated with anti-TNF demonstrated incisional hernias and associated changes in relevant mRNAs. Anti-TNF α therapy changes expression of key growth factors that could improve or adversely affect wound healing depending on the context.
Su1136 Factors Influencing the Treatment of Inflammatory Bowel Disease in Patients With Cancer Recurrence: Pilot Study Lourdes G. Bahamonde, Fernando S. Velayos, Seymour Katz, Seth Lipka, Iuliana Shapira, Keith Sultan AUTHORS/INSTITUTIONS: L.G. Bahamonde, S. Lipka, L. Rosen, K. Sultan, F. Velayos, I. Shapira, S. Katz. Department of Gastroenterology, North Shore-LIJ Health System, Manhasset, NY; Nassau University Medical Center, Hempstead, NY; University of California San Francisco, San Francisco, CA. Purpose: Physicians and patients are concerned with use of immunosuppressive medication for the treatment of IBD after a diagnosis of malignancy. There is no evidence to support discontinuing these therapies in the presence of malignancy, but these recommendations are also not evidence based. We performed a pilot study to determine the prevalence of IBD medication use before and after a diagnosis of a solid tumor malignancy. Methods: A retrospective pilot study in a sample of patients with IBD from a private practice (n=2287) was performed. Of 248 cases reviewed, a small cohort with solid tumor malignancy was identified (n=34). This pilot is to be followed by a larger study combining practice and university patients. Relevant factors identified in the pilot will be explored in greater detail in the larger (n=248) cohort. Relevant medication exposure prior to and after cancer diagnosis; cancer characteristics; and type of IBD were obtained from chart review. Results: Twenty-six patients had Crohn's disease and 8 had ulcerative colitis. The average age of IBD diagnosis was 41 years (± 20.50) and the average age of malignancy diagnosis was 57 years (± 17.23). Cancers diagnosed included rectal (n=3), colon (n=2), small bowel (n=3), breast (n=5), lymphoma (n=2), thyroid (n=3), prostate (n=4), endometrial (n=2), basal cell (n=2), melanoma (n=2), renal cell (n=2), appendiceal (n=1), bladder (n= 1), lung (n=1) and gastric (n=1). Three patients were diagnosed with malignancy recurrence, 67% of which were on immunomodulating treatment before and after the recurrence diagnosis. Five subjects (14.71%) remained on biologics after the primary malignancy diagnosis. The maximum number of follow-up years after a malignancy diagnosis was 28 years (median: 4.50 years). There were 3 subjects that experienced a recurrence (8.82%, 95% CI: 1.86%, 23.68%). Recurrences for these subjects occurred 3, 4 and 8 years after the malignancy diagnosis. Notable was a trend toward less use of mesalamine, steroids, and antibiotics and greater use of immunomodulator agents and anti-TNF biologic agents (see Table 1). Conclusion: We found more, rather than less use of immunomodulator and anti-TNF use after a diagnosis of a solid tumor malignancy. We plan to confirm these findings in the larger cohort and explore if this observation is due to exacerbation of disease related to treatment of cancer or greater desire to keep disease controlled. We will further investigate the role of immunosuppressive medication and risk of recurrence of cancer. Table 1
AGA Abstracts
Su1138 Do All Thiopurines Increase the Risk of Lymphoma to the Same Extent? A Nationwide Retrospective Cohort From the Veterans' Affairs Healthcare System Nabeel Khan, Yordanka N. Koleva, Ali Abbas Background: Thiopurine treatment is associated with increased risk of lymphoma. It is unknown whether this increment differs between azathioprine (AZA) and 6-mercaptopurine (6MP). Our aim was to identify incidence of lymphoma among thiopurines users stratified by medication type. Methods: Ulcerative colitis (UC) patients followed in the Veterans Affairs (VA) healthcare system from 2001 to 2011 were identified using ICD9 codes. We performed retrospective cohort study. Patients were followed from the index date of UC diagnosis in the VA system to the date of lymphoma diagnosis or October, 1st, 2011. Lymphoma cases were firstly identified by ICD9 codes then by manual chart review to confirm the diagnoses and the dates. Exposure to AZA or 6MP was assessed using pharmacy data. Person-years of follow-up were calculated and the incidence rate of lymphoma was calculated while on AZA, on MP and while off thiopurines. Multivariate Cox regression analysis was used to estimate the independent effect of AZA and MP. Thiopurine exposure was included in the model as time dependent variable. Patients contributed follow-up to any of the three groups of exposure based on the start and the stop dates of the medication. Results: We included 36891 patients in the analysis with median of follow-up of 6.7 years. Total person-year of follow-up analyzed was 224,770.6. Majority were white males (white 75%, male 93%) with median age at inclusion of 60 years old. Among the included patients, 4734 used thiopurines with median duration of 1 year. Numbers of lymphoma cases identified were 124, 10 and 8 while off thiopurines, on 6MP and on AZA respectively. Incidence rates of lymphoma were 0.57, 3.4, and 1.8 while off thiopurines, on 6MP, and on AZA respectively. Age, sex and race adjusted hazard ratio of lymphoma was 3.4 while on AZA and 6.4 while on 6MP compared to off thiopurines (Table). Conclusion In this nationwide cohort of UC patients,
S-408
AGA Abstracts
High Vitamin D Diet Leads to a Paradoxical Decrease of Bone Mineral Density in Adoptive T-Cell Transfer Colitis Claire B. Larmonier, Rita-Marie T. Woodford, Faihza M. Hill, Rupert Schreiner, Rajalakshmy Ramalingam, David G. Besselsen, Fayez K. Ghishan, Pawel R. Kiela Background: Inflammatory Bowel Disease is not only characterized by an aberrant immune response against commensal intestinal bacterial flora and mucosal damage but can also affect bone metabolism and bone mineral density (BMD) with osteopenia and osteoporosis as the two major extra-intestinal symptoms of IBD. Low BMD along with 25(OH) vitamin D3 deficiency have been reported in both Ulcerative colitis and Crohn's Disease and is associated with an increased risk of fracture. In IBD patients, inflammation-associated pro-inflammatory mediators, poor nutritional status and malabsortion affecting vitamin D3 and Ca2+ homeostasis, have been postulated to be the cause of altered bone morphology and metabolism. Moreover, immunomodulatory role of vitamin D3 has been reported in both innate and adaptive immune system. Therefore, vitamin D3 supplementation has been considered as a viable adjunctive therapeutic strategy in IBD. Vitamin D3 plays a pleiotropic role in bone modeling and regulates the balance of bone formation and bone resorption depending of the physiological environment. Moreover, a significant fraction of adult and pediatric IBD patients with low BMD have elevated levels of circulating 1,25(OH)2 D3. We hypothesized that vitamin D3 supplementation in active IBD may lead to a paradoxical loss in BMD. Methods: We evaluated the effect of vitamin D3 supplementation in adoptive IL-10-/-CD4+ T cell transfer model of chronic colitis. In this model, we evaluated the effect of vitamin D3 supplementation (switch from human equivalent dose of 730 IU to 3,648 IU daily) on established colitis and on BMD (μCT), bone metabolism and turnover. Results: 12-day highdose vitamin D3 supplementation during established disease had negligible effects on mucosal inflammation. Plasma level of vitamin D3 metabolites correlated with diet, but not with the disease status. Colitis reduced BMD. High vitamin D3 supplementation did not affect cortical bone structure but led to a further deterioration of trabecular bone morphology. High D3 diet negatively affected bone formation markers; osteocalcin and bone alkaline phosphatase, and increased bone resorption markers; RANKL/OPG transcript ratio, plasma OPG level and osteoclast activation marker ACp5. Consistently, expression of bone vitamin D receptor (VDR) was increased in mice with chronic colitis, especially in mice fed high vitamin D3 diet. Conclusion: Our data collectively suggests that vitamin D3 in a dose which does not improve inflammation, adversely affects BMD and bone turnover. The data provided by this study should be taken into consideration in the planning of further clinical studies with high vitamin D3 supplementation in IBD patients with active disease.
Su1137 Intestinal Fibrosis and Wound Healing in Experimental Crohn's Disease: Effect of Pegylated Murinized Rabbit Anti-Mouse TNF Laura J. Reingold, Andrew S. Kimball, Phyllissa Schmiedlin-Ren, Scott R. Owens, Ellen Zimmermann Debate exists about the effect of perioperative anti-TNF on wound healing and postoperative complications in patients with Crohn's disease (CD). Our aim was to determine if anti-TNF affects wound healing or tissue factors that influence wound integrity in a CD model. Methods: Peptidoglycan-polysaccharide (PGPS) or human serum albumin (HSA, control) was injected into the bowel wall of Lewis rats at laparotomy. PGPS and HSA injected rats were given pegylated murinized rabbit anti-mouse TNF or vehicle SC 3 times a week beginning d1 post-op. Animals were sacrificed on d28 (n=12). Incisions were collected. Gross abdominal score (sum of adhesions, mesenteric thickening, cecal wall thickening, cecal granulomas, and liver granulomas on 0-4 scales) was determined. Quantitative realtime PCR for proinflammatory and profibrotic factors was performed on cecal and incisional tissue. Histologic sections were stained and scored. Results: PGPS rats had higher gross abdominal scores, histologic scores, and relevant mRNA levels than HSA rats (previously shown). As expected, HSA-injected, vehicle treated rats (HSA/Veh) had no hernias or incisional abscesses (0%). All PGPS-injected, vehicle-treated rats (PGPS/Veh) developed abdominal hernias (100%). PGPS/Tx rats had a decreased rate of hernia formation (33%). Interestingly, hernias and subcutaneous abscesses were seen starting at d14 in all HSA-injected, anti-TNF treated rats (HSA/Tx, 100%). In cecal tissue, procollagen I, procollagen III and the profibrotic factors IGF-I and TGF β1 mRNAs were increased in PGPS/Veh compared to HSA/Veh (previously shown). Treatment with anti-TNF decreased these mRNAs (procollagen I 4.6±2.7 v 17.2±4.3, p=0.02; procollagen III 0.8±0.4 v 4.9±2.8, p=0.01; TGF β1 2.3±0.1 v 3.3±0.3, p=0.03; IGF-I 1.9±0.1 v 5.1±1.2, p=0.03). Decreased histologic tissue inflammation and fibrosis were also observed. In incisional tissue, animals with CD had higher levels of procollagen I and III, TGF1, IGF-I, PDGF-B, bFGF, and VEGF than control rats (PGPS/ Veh v HSA/Veh). Treatment with anti-TNF normalized these mRNAs to levels in HSA/Veh rats. Interestingly, mRNA levels in HSA/Tx were higher than HSA/Veh (fold HSA/Veh: collagen I 2.47, p=0.02; collagen III 2.6, p=0.01; TGF β 3.1, p=0.03; IGF-I 1.9, p=0.03; PDGF-B 1.4, p=0.08; bFGF 1.3, p=0.02; VEGF2.0, p=0.08). Histologic changes in incisions were associated with changes in mRNAs. Conclusion: Experimental Crohn's disease causes wound defects including hernias and abscesses independent of anti-TNF treatment. Rats with CD treated with anti-TNF had normalization of the incisional factors and improved wound integrity. Normal animals treated with anti-TNF demonstrated incisional hernias and associated changes in relevant mRNAs. Anti-TNF α therapy changes expression of key growth factors that could improve or adversely affect wound healing depending on the context.
Su1136 Factors Influencing the Treatment of Inflammatory Bowel Disease in Patients With Cancer Recurrence: Pilot Study Lourdes G. Bahamonde, Fernando S. Velayos, Seymour Katz, Seth Lipka, Iuliana Shapira, Keith Sultan AUTHORS/INSTITUTIONS: L.G. Bahamonde, S. Lipka, L. Rosen, K. Sultan, F. Velayos, I. Shapira, S. Katz. Department of Gastroenterology, North Shore-LIJ Health System, Manhasset, NY; Nassau University Medical Center, Hempstead, NY; University of California San Francisco, San Francisco, CA. Purpose: Physicians and patients are concerned with use of immunosuppressive medication for the treatment of IBD after a diagnosis of malignancy. There is no evidence to support discontinuing these therapies in the presence of malignancy, but these recommendations are also not evidence based. We performed a pilot study to determine the prevalence of IBD medication use before and after a diagnosis of a solid tumor malignancy. Methods: A retrospective pilot study in a sample of patients with IBD from a private practice (n=2287) was performed. Of 248 cases reviewed, a small cohort with solid tumor malignancy was identified (n=34). This pilot is to be followed by a larger study combining practice and university patients. Relevant factors identified in the pilot will be explored in greater detail in the larger (n=248) cohort. Relevant medication exposure prior to and after cancer diagnosis; cancer characteristics; and type of IBD were obtained from chart review. Results: Twenty-six patients had Crohn's disease and 8 had ulcerative colitis. The average age of IBD diagnosis was 41 years (± 20.50) and the average age of malignancy diagnosis was 57 years (± 17.23). Cancers diagnosed included rectal (n=3), colon (n=2), small bowel (n=3), breast (n=5), lymphoma (n=2), thyroid (n=3), prostate (n=4), endometrial (n=2), basal cell (n=2), melanoma (n=2), renal cell (n=2), appendiceal (n=1), bladder (n= 1), lung (n=1) and gastric (n=1). Three patients were diagnosed with malignancy recurrence, 67% of which were on immunomodulating treatment before and after the recurrence diagnosis. Five subjects (14.71%) remained on biologics after the primary malignancy diagnosis. The maximum number of follow-up years after a malignancy diagnosis was 28 years (median: 4.50 years). There were 3 subjects that experienced a recurrence (8.82%, 95% CI: 1.86%, 23.68%). Recurrences for these subjects occurred 3, 4 and 8 years after the malignancy diagnosis. Notable was a trend toward less use of mesalamine, steroids, and antibiotics and greater use of immunomodulator agents and anti-TNF biologic agents (see Table 1). Conclusion: We found more, rather than less use of immunomodulator and anti-TNF use after a diagnosis of a solid tumor malignancy. We plan to confirm these findings in the larger cohort and explore if this observation is due to exacerbation of disease related to treatment of cancer or greater desire to keep disease controlled. We will further investigate the role of immunosuppressive medication and risk of recurrence of cancer. Table 1
AGA Abstracts
Su1138 Do All Thiopurines Increase the Risk of Lymphoma to the Same Extent? A Nationwide Retrospective Cohort From the Veterans' Affairs Healthcare System Nabeel Khan, Yordanka N. Koleva, Ali Abbas Background: Thiopurine treatment is associated with increased risk of lymphoma. It is unknown whether this increment differs between azathioprine (AZA) and 6-mercaptopurine (6MP). Our aim was to identify incidence of lymphoma among thiopurines users stratified by medication type. Methods: Ulcerative colitis (UC) patients followed in the Veterans Affairs (VA) healthcare system from 2001 to 2011 were identified using ICD9 codes. We performed retrospective cohort study. Patients were followed from the index date of UC diagnosis in the VA system to the date of lymphoma diagnosis or October, 1st, 2011. Lymphoma cases were firstly identified by ICD9 codes then by manual chart review to confirm the diagnoses and the dates. Exposure to AZA or 6MP was assessed using pharmacy data. Person-years of follow-up were calculated and the incidence rate of lymphoma was calculated while on AZA, on MP and while off thiopurines. Multivariate Cox regression analysis was used to estimate the independent effect of AZA and MP. Thiopurine exposure was included in the model as time dependent variable. Patients contributed follow-up to any of the three groups of exposure based on the start and the stop dates of the medication. Results: We included 36891 patients in the analysis with median of follow-up of 6.7 years. Total person-year of follow-up analyzed was 224,770.6. Majority were white males (white 75%, male 93%) with median age at inclusion of 60 years old. Among the included patients, 4734 used thiopurines with median duration of 1 year. Numbers of lymphoma cases identified were 124, 10 and 8 while off thiopurines, on 6MP and on AZA respectively. Incidence rates of lymphoma were 0.57, 3.4, and 1.8 while off thiopurines, on 6MP, and on AZA respectively. Age, sex and race adjusted hazard ratio of lymphoma was 3.4 while on AZA and 6.4 while on 6MP compared to off thiopurines (Table). Conclusion In this nationwide cohort of UC patients,
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