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Su1436 Olmesartan-Associated Sprue: A French National Study
Su1438
Olmesartan-Associated Sprue: A French National Study Lysiane Marthey, Guillaume Cadiot, Philippe Seksik, Philippe Pouderoux, Joel Lacroute, Florence Skinazi, Bruno Mesnard, Jean Alain Chayvialle, Eric Lerebours, Anne Druez, David Parlier, Vered Abitbol, Michel Gompel, Matthieu Eoche, Eric Poncin, Roland Bobichon, Philippe Colardelle, Pauline Wils, Nadine Cerf Bensussan, Georgia Malamut, Franck Carbonnel
Risk of Cutaneous Malignant Melanoma in Celiac Disease: A Population-Based Study Benjamin Lebwohl, Hanna Eriksson, Johan Hansson, Peter H. Green, Jonas Ludvigsson Background: Celiac disease (CD) is associated with an increased risk of several malignancies, including cancers of the gastrointestinal tract and hematologic malignancies. Cutaneous malignant melanoma (CMM) risk is affected by the immune status of the host, and therefore may be associated with CD. Ipilimumab, a drug used to treat CMM, has been reported to unmask or trigger CD. Estimates on the risk of CMM in CD patients have yielded contradictory results. We therefore aimed to test for an association between CD and the subsequent development of CMM in a population-based setting in Sweden. Methods: We queried all (n= 28) pathology departments in Sweden and identified patients with small intestinal histology consistent with CD (Marsh 3). Each patient was matched to up to five controls, by the following matching parameters: age, gender, calendar period, and region. We then excluded all patients who had any diagnosis of CMM (invasive or in situ, identified through a population-based cancer registry) prior to the diagnosis of CD or the date of inclusion as a control. Using Cox proportional hazards, adjusting for degree of educational attainment, we tested for an association between CD and the subsequent diagnosis of CMM. We tested whether this association was modified by age or gender, and we subsequently performed separate analyses for the outcomes of in situ CMM and invasive CMM. Results: Among patients with CD (n=29,028) and matched controls (n=144,056) who were free of CMM at the start of follow-up, 62% were female and 41% were under the age of 20. Among 78 patients with CD who subsequently developed CMM (0.3%), the median time elapsed between CD diagnosis and CMM diagnosis was 7.7 (range 0.3-24.9) years. Overall, compared to controls there was no significant association between CD and risk of CMM (HR 0.94; 95%CI 0.73-1.20). This null association was similar for men (HR 0.99; 95%CI 0.68-1.44) and women (HR 0.89; 95%CI 0.64-1.24), and in all age strata. This did not vary over time after diagnosis or inclusion as a control (<1 year: HR 0.57; 95%CI 0.20-1.62; 1-5 years: HR 0.88; 95%CI 0.54-1.42; >5 years: HR 1.01; 95%CI 0.75-1.36). Neither the risk of in situ melanoma (HR 0.89; 95%CI 0.55-1.44) nor invasive melanoma (HR 0.93; 95%CI 0.701.25) was increased in patients with CD. Conclusions: In this population-based study we found no association between CD and the subsequent diagnosis of CMM. This null association was stable over time, in both genders, and across age groups. Prior studies showing a positive association between these two entities may have been due to referral bias.
Introduction. Diagnosis of non celiac sprue has long been difficult. There have been advances during the past 20 years: definition of refractory sprue, autoimmune enteropathy, low grade T cell lymphoma, et.c… More recently, a new cause has been discovered: olmesartanassociated sprue (Mayo Clinic Proc 2012; 87:732). The association has been questioned because in the ROADMAP phase 3-trial, the rate of diarrhea was similar in the olmesartan (olm) and the placebo arm (Mayo Clinic Proc 2012; 87:1230). The aim of our study was to report the French cases of olm sprue, to describe further this new entity, and to confirm or refute the causality by the study of olm interruptions and reintroductions. Patients and methods. In July 2013, we sent a mail to French gastroenterologists and invited them to notify the cases of olm-associated sprue. Clinical, biological and histological data were collected anonymously by internet. Quantitative variables are expressed as median [range]. Results. 31 patients (19 female), 70 year-old [46-91] were notified. Time between olm prescription (40mg/j [10-60]) and symptoms was 20 months [0-68]. 8/31 patients had a past history of auto-immune or inflammatory disease. Patients had diarrhea (31/31), vomiting (18/31), renal failure (19/31) and hypokalemia (25/31). Body weight loss was 20% [0-48]. Serum albumin level was 27g/l [13-43]. 28 patients were hospitalized (30 days [8-460]), 5 patients required intensive care. No death occurred. 9/17 patients were HLA DQ2 or DQ8. Anti-transglutaminase and anti-enterocyte antibodies were negative (29/30 and 15/15 respectively). Anti-nuclear antibodies were positive (9/10). Histological analysis of endoscopic biopsies showed duodenal villus atrophy (28/30), mostly subtotal or total (23/26), intraepithelial lymphocytosis (15/29), collagen sprue (2/26) and microscopic colitis (6/30). Gluten-free diet was efficient in 6/20 patients. 9/14 patients responded to steroids. 4/5 and 6/ 7 patients had remission with thiopurines and anti-TNF, respectively. 13 patients had 25 olm interruptions followed by reintroductions. Among them, 11/25 occurred before the start of steroids and immunosuppressives. Olm interruption was followed by remission (10/ 11), reintroduction was followed by relapse (9/10). 27/29 patients are in remission since olm interruption, 24 without immunosuppressives. Conclusion. Olm is associated with severe sprue and villus atrophy without intestinal markers of autoimmunity and with positive anti-nuclear antibodies. Olm sprue responds to thiopurines and/or anti-TNF as well as olm withdrawal. The study of cases with interruption and reintroduction of olm suggests a causality association between olm and sprue.
Su1439 Impaired Bone Microstructure Improves After One-Year on Gluten-Free Diet. A Prospective Longitudinal Study in Women With Active Celiac Disease Maria B. Zanchetta, Ana F. Costa, Vanesa Longobardi, Gabriela I. Longarini, Ma. de la Paz Temprano, Horacio Vázquez, Sonia I. Niveloni, Edgardo Smecuol, María Laura Moreno, Hwang Hui Jer, Roberto M. Mazure, Andrea F. Gonzalez, Eduardo Mauriño, Julio C. Bai
Su1437 Mucosal Healing and Risk of Ischemic Heart Disease in Celiac Disease: A Population-Based Cohort Study Benjamin Lebwohl, Louise Emilsson, Ole Fröbert, Andrew J. Einstein, Peter H. Green, Jonas Ludvigsson
Background: We have recently identified a significant deterioration of trabecular and cortical microarchitecture in peripheral bones of patients with undiagnosed celiac disease (CD) by using high resolution-peripheral quantitative computed tomography (HR-pQCT). Such finding may underlie bone fragility and lead to fractures in these patients. Up to now, the effect of the gluten-free diet (GFD) on microstructural parameters of peripheral bones has not been assessed. Aim: To explore one-year changes of bone microstructure associated with the GFD in a prospective cohort of premenopausal women with newly diagnosed CD. Materials: We prospectively enrolled 31 consecutive females with newly diagnosed CD. Up to now, 25 patients have been reassessed one-year after diagnosis. Clinical and biochemical status, CD specific serology, assessment of the degree of compliance with the GFD, bone densitometry and microstructural determinations (HR-pQCT) were performed at both time points. HR-pQCT bone volumetric and structural measurements were determined at the distal non-dominant radius and tibia. Parameters of patients were also compared with those of 22 healthy women of similar age and body mass index. Results: Compared with the baseline z-score, the one-year bone mineral density measured by dual energy x-ray absorptiometry (DXA) improved significantly at the distal radius (mean±SD) (-1.94±1.27 vs. -1.43±1.06; p<0.02) but not at the lumbar spine level. The microstructure of the trabecular compartment in the distal radius was significantly improved (trabecular/bone volume fraction, trabecular density and trabecular thickness: p<0.0001) at the one-year time point. At the level of tibia, treatment was associated with significant increment of the total volumetric density (p<0.01), cortical density (p<0.002), trabecular density (p<0.0001), trabecular/bone volume fraction (p<0.0001) and trabecular thickness (p<0.002). In contrast, the cortical thickness decreased significantly in both sites (p<0.001). Compare to the control group there were no statistical significant differences in most trabecular parameters measured by HR-pQCT. Conclusions: This is the first study exploring the effect of a one-year GFD on microstructural parameters measured by HR-pQCT in patients with newly diagnosed CD. Our study shows that trabecular parameters impaired at the time of diagnosis improved significantly by treatment reaching values comparable to those in healthy controls. We postulate that bone microarchitecture improvement underlie the decreased risk of fractures observed after treatment with a GFD.
Background: Patients with celiac disease (CD) have an increased risk of ischemic heart disease (IHD), a risk that persists for years after commencing the gluten-free diet. Patients with CD who have persistent villous atrophy (VA) on follow-up biopsy have an increased risk of lymphoproliferative malignancy, but it is unknown whether persistent VA affects the risk of IHD. Methods: We identified patients with histologic evidence of CD diagnosed at all 28 pathology departments in Sweden from the years 1969-2008. Among patients who underwent a follow-up small intestinal biopsy between 6 months and 5 years after their initial diagnosis of CD, we compared patients with persistent VA (Marsh 3) to those who showed histologic improvement. We assessed these two groups with regard to their risk of subsequent diagnosis of IHD, including angina pectoris or myocardial infarction. We used Cox proportional hazards, adjusting for age, gender, duration of CD, calendar period, and socioeconomic status. On sensitivity analysis, we further adjusted for concomitant diabetes mellitus. Results: Of 7,648 patients with CD who underwent a follow-up biopsy during the specified time-frame, 208 were excluded due to a diagnosis of IHD prior to their followup biopsy. Among the remaining patients (n=7,440), the median age at follow-up biopsy was 25 years, with 1,063 (14%) patients who were ≥60 years at the time of follow-up biopsy. 4,750 (64%) were female and 260 patients (3.5%) had a diagnosis of diabetes at the time of follow-up biopsy. Persistent VA was present in 3,198 (43%) patients. IHD occurred in 196 (2.6%) patients, with an overall incidence of 257 per 100,000 person-years (PY). While the unadjusted analysis showed a trend for a greater risk of IHD was among those with persistent VA (HR 1.30; 95%CI 0.97-1.73, p=0.08), after adjusting for the above covariates, there was no significant effect of persistent VA on IHD (HR 0.97; 95%CI 0.731.30). This null relationship was similar in both genders (males: HR 0.94; 95%CI 0.631.41; females: HR 1.07; 95%CI 0.71-1.64). Adjusting for diabetes had a negligible effect (HR 0.98; 95%CI 0.73-1.31). When restricted to individuals ≥60 years, the null association between persistent VA and IHD persisted (HR 0.94; 95%CI 0.64-1.36). When separately analyzing the outcomes of angina and myocardial infarction, the relationships were similarly null (angina: HR 0.94; 95%CI 0.64-1.38; myocardial infarction: HR 1.03; 95%CI 0.761.40). Conclusions: In this population-based study of patients with CD, persistent VA on follow-up biopsy was not associated with an increased risk of IHD. While increased age is associated with both persistent VA and IHD, failure to heal does not influence the risk of cardiac events.
Su1440 Histopathologic Outcomes in Olmesartan Related Enteropathy Akash Goel, Benjamin Lebwohl, Christina A. Tennyson, Suzanne K. Lewis, Carolina Arguelles-Grande, Peter H. Green, Stephen M. Lagana Introduction: Recently, the common antihypertensive drug olmesartan has been linked to a severe sprue-like enteropathy which can be mistaken clinically and pathologically for seronegative refractory celiac disease. We examined histopathologic parameters in duodenal biopsies during exposure and after cessation of olmesartan exposure in a cohort of these patients. Methods: Pathology records and slides were reviewed for 9 patients who presented with a severe sprue-like illness who were had negative celiac serologies and had olmesartan
S-469
AGA Abstracts
AGA Abstracts
Su1436
Olmesartan-Associated Sprue: A French National Study Lysiane Marthey, Guillaume Cadiot, Philippe Seksik, Philippe Pouderoux, Joel Lacroute, Florence Skinazi, Bruno Mesnard, Jean Alain Chayvialle, Eric Lerebours, Anne Druez, David Parlier, Vered Abitbol, Michel Gompel, Matthieu Eoche, Eric Poncin, Roland Bobichon, Philippe Colardelle, Pauline Wils, Nadine Cerf Bensussan, Georgia Malamut, Franck Carbonnel
Risk of Cutaneous Malignant Melanoma in Celiac Disease: A Population-Based Study Benjamin Lebwohl, Hanna Eriksson, Johan Hansson, Peter H. Green, Jonas Ludvigsson Background: Celiac disease (CD) is associated with an increased risk of several malignancies, including cancers of the gastrointestinal tract and hematologic malignancies. Cutaneous malignant melanoma (CMM) risk is affected by the immune status of the host, and therefore may be associated with CD. Ipilimumab, a drug used to treat CMM, has been reported to unmask or trigger CD. Estimates on the risk of CMM in CD patients have yielded contradictory results. We therefore aimed to test for an association between CD and the subsequent development of CMM in a population-based setting in Sweden. Methods: We queried all (n= 28) pathology departments in Sweden and identified patients with small intestinal histology consistent with CD (Marsh 3). Each patient was matched to up to five controls, by the following matching parameters: age, gender, calendar period, and region. We then excluded all patients who had any diagnosis of CMM (invasive or in situ, identified through a population-based cancer registry) prior to the diagnosis of CD or the date of inclusion as a control. Using Cox proportional hazards, adjusting for degree of educational attainment, we tested for an association between CD and the subsequent diagnosis of CMM. We tested whether this association was modified by age or gender, and we subsequently performed separate analyses for the outcomes of in situ CMM and invasive CMM. Results: Among patients with CD (n=29,028) and matched controls (n=144,056) who were free of CMM at the start of follow-up, 62% were female and 41% were under the age of 20. Among 78 patients with CD who subsequently developed CMM (0.3%), the median time elapsed between CD diagnosis and CMM diagnosis was 7.7 (range 0.3-24.9) years. Overall, compared to controls there was no significant association between CD and risk of CMM (HR 0.94; 95%CI 0.73-1.20). This null association was similar for men (HR 0.99; 95%CI 0.68-1.44) and women (HR 0.89; 95%CI 0.64-1.24), and in all age strata. This did not vary over time after diagnosis or inclusion as a control (<1 year: HR 0.57; 95%CI 0.20-1.62; 1-5 years: HR 0.88; 95%CI 0.54-1.42; >5 years: HR 1.01; 95%CI 0.75-1.36). Neither the risk of in situ melanoma (HR 0.89; 95%CI 0.55-1.44) nor invasive melanoma (HR 0.93; 95%CI 0.701.25) was increased in patients with CD. Conclusions: In this population-based study we found no association between CD and the subsequent diagnosis of CMM. This null association was stable over time, in both genders, and across age groups. Prior studies showing a positive association between these two entities may have been due to referral bias.
Introduction. Diagnosis of non celiac sprue has long been difficult. There have been advances during the past 20 years: definition of refractory sprue, autoimmune enteropathy, low grade T cell lymphoma, et.c… More recently, a new cause has been discovered: olmesartanassociated sprue (Mayo Clinic Proc 2012; 87:732). The association has been questioned because in the ROADMAP phase 3-trial, the rate of diarrhea was similar in the olmesartan (olm) and the placebo arm (Mayo Clinic Proc 2012; 87:1230). The aim of our study was to report the French cases of olm sprue, to describe further this new entity, and to confirm or refute the causality by the study of olm interruptions and reintroductions. Patients and methods. In July 2013, we sent a mail to French gastroenterologists and invited them to notify the cases of olm-associated sprue. Clinical, biological and histological data were collected anonymously by internet. Quantitative variables are expressed as median [range]. Results. 31 patients (19 female), 70 year-old [46-91] were notified. Time between olm prescription (40mg/j [10-60]) and symptoms was 20 months [0-68]. 8/31 patients had a past history of auto-immune or inflammatory disease. Patients had diarrhea (31/31), vomiting (18/31), renal failure (19/31) and hypokalemia (25/31). Body weight loss was 20% [0-48]. Serum albumin level was 27g/l [13-43]. 28 patients were hospitalized (30 days [8-460]), 5 patients required intensive care. No death occurred. 9/17 patients were HLA DQ2 or DQ8. Anti-transglutaminase and anti-enterocyte antibodies were negative (29/30 and 15/15 respectively). Anti-nuclear antibodies were positive (9/10). Histological analysis of endoscopic biopsies showed duodenal villus atrophy (28/30), mostly subtotal or total (23/26), intraepithelial lymphocytosis (15/29), collagen sprue (2/26) and microscopic colitis (6/30). Gluten-free diet was efficient in 6/20 patients. 9/14 patients responded to steroids. 4/5 and 6/ 7 patients had remission with thiopurines and anti-TNF, respectively. 13 patients had 25 olm interruptions followed by reintroductions. Among them, 11/25 occurred before the start of steroids and immunosuppressives. Olm interruption was followed by remission (10/ 11), reintroduction was followed by relapse (9/10). 27/29 patients are in remission since olm interruption, 24 without immunosuppressives. Conclusion. Olm is associated with severe sprue and villus atrophy without intestinal markers of autoimmunity and with positive anti-nuclear antibodies. Olm sprue responds to thiopurines and/or anti-TNF as well as olm withdrawal. The study of cases with interruption and reintroduction of olm suggests a causality association between olm and sprue.
Su1439 Impaired Bone Microstructure Improves After One-Year on Gluten-Free Diet. A Prospective Longitudinal Study in Women With Active Celiac Disease Maria B. Zanchetta, Ana F. Costa, Vanesa Longobardi, Gabriela I. Longarini, Ma. de la Paz Temprano, Horacio Vázquez, Sonia I. Niveloni, Edgardo Smecuol, María Laura Moreno, Hwang Hui Jer, Roberto M. Mazure, Andrea F. Gonzalez, Eduardo Mauriño, Julio C. Bai
Su1437 Mucosal Healing and Risk of Ischemic Heart Disease in Celiac Disease: A Population-Based Cohort Study Benjamin Lebwohl, Louise Emilsson, Ole Fröbert, Andrew J. Einstein, Peter H. Green, Jonas Ludvigsson
Background: We have recently identified a significant deterioration of trabecular and cortical microarchitecture in peripheral bones of patients with undiagnosed celiac disease (CD) by using high resolution-peripheral quantitative computed tomography (HR-pQCT). Such finding may underlie bone fragility and lead to fractures in these patients. Up to now, the effect of the gluten-free diet (GFD) on microstructural parameters of peripheral bones has not been assessed. Aim: To explore one-year changes of bone microstructure associated with the GFD in a prospective cohort of premenopausal women with newly diagnosed CD. Materials: We prospectively enrolled 31 consecutive females with newly diagnosed CD. Up to now, 25 patients have been reassessed one-year after diagnosis. Clinical and biochemical status, CD specific serology, assessment of the degree of compliance with the GFD, bone densitometry and microstructural determinations (HR-pQCT) were performed at both time points. HR-pQCT bone volumetric and structural measurements were determined at the distal non-dominant radius and tibia. Parameters of patients were also compared with those of 22 healthy women of similar age and body mass index. Results: Compared with the baseline z-score, the one-year bone mineral density measured by dual energy x-ray absorptiometry (DXA) improved significantly at the distal radius (mean±SD) (-1.94±1.27 vs. -1.43±1.06; p<0.02) but not at the lumbar spine level. The microstructure of the trabecular compartment in the distal radius was significantly improved (trabecular/bone volume fraction, trabecular density and trabecular thickness: p<0.0001) at the one-year time point. At the level of tibia, treatment was associated with significant increment of the total volumetric density (p<0.01), cortical density (p<0.002), trabecular density (p<0.0001), trabecular/bone volume fraction (p<0.0001) and trabecular thickness (p<0.002). In contrast, the cortical thickness decreased significantly in both sites (p<0.001). Compare to the control group there were no statistical significant differences in most trabecular parameters measured by HR-pQCT. Conclusions: This is the first study exploring the effect of a one-year GFD on microstructural parameters measured by HR-pQCT in patients with newly diagnosed CD. Our study shows that trabecular parameters impaired at the time of diagnosis improved significantly by treatment reaching values comparable to those in healthy controls. We postulate that bone microarchitecture improvement underlie the decreased risk of fractures observed after treatment with a GFD.
Background: Patients with celiac disease (CD) have an increased risk of ischemic heart disease (IHD), a risk that persists for years after commencing the gluten-free diet. Patients with CD who have persistent villous atrophy (VA) on follow-up biopsy have an increased risk of lymphoproliferative malignancy, but it is unknown whether persistent VA affects the risk of IHD. Methods: We identified patients with histologic evidence of CD diagnosed at all 28 pathology departments in Sweden from the years 1969-2008. Among patients who underwent a follow-up small intestinal biopsy between 6 months and 5 years after their initial diagnosis of CD, we compared patients with persistent VA (Marsh 3) to those who showed histologic improvement. We assessed these two groups with regard to their risk of subsequent diagnosis of IHD, including angina pectoris or myocardial infarction. We used Cox proportional hazards, adjusting for age, gender, duration of CD, calendar period, and socioeconomic status. On sensitivity analysis, we further adjusted for concomitant diabetes mellitus. Results: Of 7,648 patients with CD who underwent a follow-up biopsy during the specified time-frame, 208 were excluded due to a diagnosis of IHD prior to their followup biopsy. Among the remaining patients (n=7,440), the median age at follow-up biopsy was 25 years, with 1,063 (14%) patients who were ≥60 years at the time of follow-up biopsy. 4,750 (64%) were female and 260 patients (3.5%) had a diagnosis of diabetes at the time of follow-up biopsy. Persistent VA was present in 3,198 (43%) patients. IHD occurred in 196 (2.6%) patients, with an overall incidence of 257 per 100,000 person-years (PY). While the unadjusted analysis showed a trend for a greater risk of IHD was among those with persistent VA (HR 1.30; 95%CI 0.97-1.73, p=0.08), after adjusting for the above covariates, there was no significant effect of persistent VA on IHD (HR 0.97; 95%CI 0.731.30). This null relationship was similar in both genders (males: HR 0.94; 95%CI 0.631.41; females: HR 1.07; 95%CI 0.71-1.64). Adjusting for diabetes had a negligible effect (HR 0.98; 95%CI 0.73-1.31). When restricted to individuals ≥60 years, the null association between persistent VA and IHD persisted (HR 0.94; 95%CI 0.64-1.36). When separately analyzing the outcomes of angina and myocardial infarction, the relationships were similarly null (angina: HR 0.94; 95%CI 0.64-1.38; myocardial infarction: HR 1.03; 95%CI 0.761.40). Conclusions: In this population-based study of patients with CD, persistent VA on follow-up biopsy was not associated with an increased risk of IHD. While increased age is associated with both persistent VA and IHD, failure to heal does not influence the risk of cardiac events.
Su1440 Histopathologic Outcomes in Olmesartan Related Enteropathy Akash Goel, Benjamin Lebwohl, Christina A. Tennyson, Suzanne K. Lewis, Carolina Arguelles-Grande, Peter H. Green, Stephen M. Lagana Introduction: Recently, the common antihypertensive drug olmesartan has been linked to a severe sprue-like enteropathy which can be mistaken clinically and pathologically for seronegative refractory celiac disease. We examined histopathologic parameters in duodenal biopsies during exposure and after cessation of olmesartan exposure in a cohort of these patients. Methods: Pathology records and slides were reviewed for 9 patients who presented with a severe sprue-like illness who were had negative celiac serologies and had olmesartan
S-469
AGA Abstracts
AGA Abstracts
Su1436