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Sa1262 The Impact of Thiopurine Hypermethylation on Clinical Outcomes in Patients With Inflammatory Bowel Disease
AGA Abstracts
Sa1259
Sa1261
Prospective Study of Prevalence an Incidence of Vertebral Fractures in LongTerm Anti-TNF Alpha Maintenance Therapy Treatment for Inflammatory Bowel Disease Belen Maldonado-Perez, Maria Angeles Vázquez-Gámez, Luisa Castro-Laria, Maria Jose Montoya-Garcia, Ramon Perez-Cano, Juan M Herrerias
Normalized Wall Thickness At MRE Predicts Clinical Remission in Crohn's Disease After Infliximab Discontinuation: A 5 Years' Follow-Up Study Maria Laura Annunziata, Luigi Giovanni Papparella, Ilaria Sansoni, Paola Balestrieri, Michele Cicala
Background Osteoporosis is an extraintestinal complication of inflammatory bowel disease (IBD). A decrease in bone mineral density (BMD) is a common finding in this disease, as well as an increase in the risk of fracture, whose physiopathogenic mechanisms are not yet fully clarified. The evidence suggests that the TNF-alpha and TNF superfamily are fundamental in the bone remodelling. Methods We evaluated long term therapy effect with anti-TNF alpha on the prevalence an incidence of morphometric vertebral fractures, BMD and parameters of bone remodelling in patients with IBD after 8 years of follow up.We try to identify posible risk factors related to the occurrence of vertebral fractures and associated with changes in BMD. Observational, longitudinal, prospective 8 years follow-up study. We included 71 patients (38 with Crohn's disease, 32 with ulcerative colitis and 1 with indeterminate colitis); median age: 37.2 ± 11.9 years; range: 13-67 years, 27 women and 44 men, recruited from the IBD Unit of our Hospital. 23 of them were treated with anti-TNF, 48 patients who did not received treatment, were the reference group. All patients were performed a questionnaire data collection (affiliation, anthropometric,toxic habits and related disease). At the beginning and end of the study were made: A posteroanterior and lateral X-rays of the dorsal and lumbar spine (D7 to L5) to calculate the rate of vertebral deformity. We measured BMD by DEXA(QDR-1000 Hologic densitometer) of the lumbar spine (L2-L4) and proximal right femur. We also determinate biochemical parameters and bone remodeling. Results The incidence of vertebral fractures in our study population was 7%(from a 14,1% initial prevalence to 21% in 8 years follow up). The greatest number of fractures was observed in patients treated with anti-TNF (17.4%), although without statistical significance.Patients with biologic treatment significantly increased BMD in both lumbar spine (p = 0.01) and femoral neck (p =0.02).Anti-TNF in fractured patients, did not modify the behavior of BMD and parameters of bone remodeling. We found a statistically significant increase in alkaline phosphatase (p = 0.002),OC (p = 0.001)and PTH (p = 0.02)in the treated group compared to the reference group. We found a positive correlation between biological therapy and BMD in the fractured group of our patients (p = 0.01). No relationship between steroids treatment and new vertebral fractures was observed.In multivariate analysis, none of the measured parameters was predictor of fracture. Conclusions Anti-TNF-alpha therapy leads to a significant increase in BMD. Although this treatment did not decrease the risk of a new vertebral fracture, perhaps studies with more patients and longer term could modify these results.
BACKGROUND: Mucosal healing (MH) following withdrawal of anti-TNFα therapy has been associated with improved clinical outcomes in Crohn's disease (CD), although it cannot predict healing of the entire intestinal wall. Magnetic Resonance Enterography (MRE) has been demonstrated to correlate with clinical and endoscopic disease activity in CD. AIM: to investigate the role of MRE in predicting clinical outcome 5 years after following Infliximab (IFX) discontinuation in ileal CD patients. METHODS: Clinical data from 90 CD patients treated with IFX since June 2005 were retrospectively analyzed. Of these 90 patients, 16 ileal CD patients, treated with IFX until deep remission and C-reactive protein (CRP) <5 were obtained and who performed both ileo-colonoscopy and MRE examination at the time of anti-TNFα discontinuation, entered the study. Cumulative probability to be in clinical remission was estimated using the Kaplan-Meier method. Factors independently associated with clinical relapse (MH, wall thickness at MRE, smoke habits, gender, number of infusions) were evaluated in a multiple logistic regression analysis. RESULTS: All patients were treated for a mean number of 22 infusions (range 13-36). At the time of IFX discontinuation, 8 (50%) patients presented MH at colonoscopy, 6 (37.5%) presented normalized wall thickness (NWT) at MRE and 4 (25%) reached both MH and NWT. Median follow-up was 37 months (range 11-60). Ten (62.5%) out of 16 patients experienced clinical relapse during the 5year follow-up period. Median time to relapse was 36 and 25 months for patients with and without MH at colonoscopy at the time of IFX discontinuation, respectively (p = 0.8). Of the 10 patients with clinical relapse, 4 had achieved MH but not NWT at MRE and 4 patients with both MH and NWT at MRE were still in remission at 5 years after IFX discontinuation. Univariate analysis showed that patients who relapsed still presented wall thickening at MRE (9 vs 1, p = 0.015) although the logistic regression did not confirm this finding. None of the other risk factors was independently associated with clinical remission at 5 years in the multivariate model. The cumulative probability of relapse-free survival was 0.34, while the probability, in those patients with NWT at MRE, was 0.83 at 60 months. CONCLUSIONS: To our knowledge, this is the first study that specifically investigates the role of MRE as a potential tool in predicting clinical relapse after anti-TNFα discontinuation. In this retrospective analysis, normalization of WT was able to predict clinical remission after discontinuation of IFX therapy at the 5-year follow-up. Moreover, MH alone, without a concomitant normalization of WT at MRE, does not appear to correlate with improved clinical outcomes in the long term.
Sa1260
Sa1262
Practice Patterns in the Management of Patients With Inflammatory Bowel Disease: Results of a National Survey of Gastroenterologists Karen Lasch, Terry A. Glauser, Lyann Ursos, Jill Erickson, Patrick H. Nevins, Gregory Salinas
The Impact of Thiopurine Hypermethylation on Clinical Outcomes in Patients With Inflammatory Bowel Disease Paul A. Blaker, Steven C. Fong, Melissa A. Smith, Viraj C. Kariyawasam, Anthony M. Marinaki, Peter M. Irving, Jeremy D. Sanderson
BACKGROUND: As the prevalence and burden of inflammatory bowel disease (IBD) in the United States continue to increase, it is important to optimize IBD therapy, which is typically chronic. The aim of this survey was to investigate physician practice patterns and preferences in IBD management. METHODS: Two nominal group technique focus groups were conducted in March 2013 via web interface and teleconference to elicit barriers that gastroenterologists face in managing IBD. A review of literature published in/after 2005 on practice gaps and issues in IBD management also was conducted via MEDLINE, SearchMedica, and Internet searches. Focus group and literature review findings framed a 3-case vignette survey that was pilot tested and distributed to practicing US gastroenterologists in June 2013 (n=151). The survey assessed the following topics: patient management, evaluation and classification of treatment response, barriers and side effects, and information needs. Survey responses were summarized using descriptive statistics. RESULTS: Respondents (n=151) were mostly community-based gastroenterologists (82%) in group (72%) or private solo (15%) practices, seeing a mean of 11 patients with ulcerative colitis [UC] and 11 with Crohn's disease per week. When assessing therapy response in a UC patient, respondents viewed clinical remission (9.3 on 10-point scale), discontinuation of steroids (8.8), and endoscopic remission (8.0) as more important than histologic remission (7.2) or normalization of C-reactive protein (6.2). Consistent with the goal of limiting long-term steroid use, 61% of respondents identified the need for steroid-sparing therapy in an IBD patient whose symptoms responded to higher prednisone doses but returned when the dose was lowered. When presented with an IBD patient who had lost response to anti-tumor necrosis factor (TNF) therapy, 29% of respondents indicated they would check antibodies levels, 23% would check anti-TNF levels, 17% would add an extra infusion, 15% would increase anti-TNF dose, and 12% would switch anti-TNFs. Regarding anti-TNF therapy, physicians were most concerned about serious infection (5.8 on 10-point scale), infusion reaction (5.6), and reactivation of tuberculosis (5.5) but indicated their patients were most concerned about lymphomas (6.8), serious infection (6.6), and other malignancies (6.4). A total of 54% of respondents reported their patients proactively discuss treatment side effects (mostly lymphoma/cancer risk [23%]), 27% quality of life issues, and 14% psychological health issues. CONCLUSIONS: Survey data show practice patterns in IBD management consistent with evolving treatment paradigms, which acknowledge a role for remission beyond control of clinical symptoms, but also highlight inconsistencies in clinical approach (eg, next steps after anti-TNF secondary failure).
Introduction Approximately 15% of patients with inflammatory bowel disease (IBD) prescribed azathioprine (AZA)/mercaptopurine (MP) demonstrate a skewed drug metabolism with low levels of thioguanine nucleotides (TGN) and unexpectedly high levels of methylmercaptopurine (MeMP). This predicts a lack of treatment efficacy and excess adverse events; however studies on the effect of thiopurine hypermethylation (TH) in adult IBD patients are lacking. Importantly, where identified TH can be circumvented with the use of low dose AZA/MP and allopurinol. The aim of this study is to characterise the impact of TH in IBD patients and determine if thiopurine metabolite profiles at week 4 of treatment can predict its occurrence to allow early combination treatment. Methods 273 patients with IBD, who were anti-TNF-α therapy Naive and matched for red blood cell thiopurine-S-methyltransferase activity, were retrospectively identified from electronic records. Of these 181 patients demonstrated average MeMP:TGN ratios < 11 (at least 2 profiles between weeks 12 - 52) and were used as a control group that was compared to 92 patients with average MeMP:TGN ratios ≥ 11. Clinical outcomes were recorded for the first 12 months of therapy. A failure of AZA/MP as monotherapy was determined by 3 gastroenterologists with expertise in IBD. Thiopurine metabolite profiles were measured in 139 patients at week 4 of therapy and were compared to average metabolite profiles between 12 - 52 weeks of treatment to determine their predictive value. Results The average MeMP:TGN ratios in those with and without TH were 21.0 and 2.52 respectively (p = <0.0001, Mann-Whitney U-test). The normalised dose of thiopurine was higher in patients with TH (1.91 mg/ kg vs. 2.09 mg/ kg; p = < 0.0001; Mann-Whitney U-test). Patients with TH were more likely to fail AZA/ MP monotherapy as first line treatment during the first 12 months of therapy, in comparison with patients with normal methylation profiles (p = 0.0088, Gehan-Breslow-Wilcoxon Test). The difference in the number of treatment failures at 12 months was 15.7%. There was no difference in the occurrence of gastrointestinal intolerance, myelotoxicity or pancreatitis between groups, however there was an excess of hepatotoxicity with TH (p = 0.0006; OR 8.058; 95% CI 2.188 - 29.670; Fisher's exact). TH was demonstrated in 83.7% of cases by 12 weeks of therapy. A MeMP : TGN level > 6.17 at week 4 accurately predicted TH (ratio ≥ 11) after 12 weeks of therapy (AUC = 0.839; p = < 0.0001; sensitivity = 75.4%; specificity = 88.4%). Conclusion TH is associated with an excess of thiopurine treatment failures as monotherapy immunosuppression during the first 12 months of treatment. We also confirm its association with hepatotoxicity. A MeMP:TGN > 6.17 may be useful in early identification of patients likely to benefit from combination treatment.
AGA Abstracts
S-246
Sa1259
Sa1261
Prospective Study of Prevalence an Incidence of Vertebral Fractures in LongTerm Anti-TNF Alpha Maintenance Therapy Treatment for Inflammatory Bowel Disease Belen Maldonado-Perez, Maria Angeles Vázquez-Gámez, Luisa Castro-Laria, Maria Jose Montoya-Garcia, Ramon Perez-Cano, Juan M Herrerias
Normalized Wall Thickness At MRE Predicts Clinical Remission in Crohn's Disease After Infliximab Discontinuation: A 5 Years' Follow-Up Study Maria Laura Annunziata, Luigi Giovanni Papparella, Ilaria Sansoni, Paola Balestrieri, Michele Cicala
Background Osteoporosis is an extraintestinal complication of inflammatory bowel disease (IBD). A decrease in bone mineral density (BMD) is a common finding in this disease, as well as an increase in the risk of fracture, whose physiopathogenic mechanisms are not yet fully clarified. The evidence suggests that the TNF-alpha and TNF superfamily are fundamental in the bone remodelling. Methods We evaluated long term therapy effect with anti-TNF alpha on the prevalence an incidence of morphometric vertebral fractures, BMD and parameters of bone remodelling in patients with IBD after 8 years of follow up.We try to identify posible risk factors related to the occurrence of vertebral fractures and associated with changes in BMD. Observational, longitudinal, prospective 8 years follow-up study. We included 71 patients (38 with Crohn's disease, 32 with ulcerative colitis and 1 with indeterminate colitis); median age: 37.2 ± 11.9 years; range: 13-67 years, 27 women and 44 men, recruited from the IBD Unit of our Hospital. 23 of them were treated with anti-TNF, 48 patients who did not received treatment, were the reference group. All patients were performed a questionnaire data collection (affiliation, anthropometric,toxic habits and related disease). At the beginning and end of the study were made: A posteroanterior and lateral X-rays of the dorsal and lumbar spine (D7 to L5) to calculate the rate of vertebral deformity. We measured BMD by DEXA(QDR-1000 Hologic densitometer) of the lumbar spine (L2-L4) and proximal right femur. We also determinate biochemical parameters and bone remodeling. Results The incidence of vertebral fractures in our study population was 7%(from a 14,1% initial prevalence to 21% in 8 years follow up). The greatest number of fractures was observed in patients treated with anti-TNF (17.4%), although without statistical significance.Patients with biologic treatment significantly increased BMD in both lumbar spine (p = 0.01) and femoral neck (p =0.02).Anti-TNF in fractured patients, did not modify the behavior of BMD and parameters of bone remodeling. We found a statistically significant increase in alkaline phosphatase (p = 0.002),OC (p = 0.001)and PTH (p = 0.02)in the treated group compared to the reference group. We found a positive correlation between biological therapy and BMD in the fractured group of our patients (p = 0.01). No relationship between steroids treatment and new vertebral fractures was observed.In multivariate analysis, none of the measured parameters was predictor of fracture. Conclusions Anti-TNF-alpha therapy leads to a significant increase in BMD. Although this treatment did not decrease the risk of a new vertebral fracture, perhaps studies with more patients and longer term could modify these results.
BACKGROUND: Mucosal healing (MH) following withdrawal of anti-TNFα therapy has been associated with improved clinical outcomes in Crohn's disease (CD), although it cannot predict healing of the entire intestinal wall. Magnetic Resonance Enterography (MRE) has been demonstrated to correlate with clinical and endoscopic disease activity in CD. AIM: to investigate the role of MRE in predicting clinical outcome 5 years after following Infliximab (IFX) discontinuation in ileal CD patients. METHODS: Clinical data from 90 CD patients treated with IFX since June 2005 were retrospectively analyzed. Of these 90 patients, 16 ileal CD patients, treated with IFX until deep remission and C-reactive protein (CRP) <5 were obtained and who performed both ileo-colonoscopy and MRE examination at the time of anti-TNFα discontinuation, entered the study. Cumulative probability to be in clinical remission was estimated using the Kaplan-Meier method. Factors independently associated with clinical relapse (MH, wall thickness at MRE, smoke habits, gender, number of infusions) were evaluated in a multiple logistic regression analysis. RESULTS: All patients were treated for a mean number of 22 infusions (range 13-36). At the time of IFX discontinuation, 8 (50%) patients presented MH at colonoscopy, 6 (37.5%) presented normalized wall thickness (NWT) at MRE and 4 (25%) reached both MH and NWT. Median follow-up was 37 months (range 11-60). Ten (62.5%) out of 16 patients experienced clinical relapse during the 5year follow-up period. Median time to relapse was 36 and 25 months for patients with and without MH at colonoscopy at the time of IFX discontinuation, respectively (p = 0.8). Of the 10 patients with clinical relapse, 4 had achieved MH but not NWT at MRE and 4 patients with both MH and NWT at MRE were still in remission at 5 years after IFX discontinuation. Univariate analysis showed that patients who relapsed still presented wall thickening at MRE (9 vs 1, p = 0.015) although the logistic regression did not confirm this finding. None of the other risk factors was independently associated with clinical remission at 5 years in the multivariate model. The cumulative probability of relapse-free survival was 0.34, while the probability, in those patients with NWT at MRE, was 0.83 at 60 months. CONCLUSIONS: To our knowledge, this is the first study that specifically investigates the role of MRE as a potential tool in predicting clinical relapse after anti-TNFα discontinuation. In this retrospective analysis, normalization of WT was able to predict clinical remission after discontinuation of IFX therapy at the 5-year follow-up. Moreover, MH alone, without a concomitant normalization of WT at MRE, does not appear to correlate with improved clinical outcomes in the long term.
Sa1260
Sa1262
Practice Patterns in the Management of Patients With Inflammatory Bowel Disease: Results of a National Survey of Gastroenterologists Karen Lasch, Terry A. Glauser, Lyann Ursos, Jill Erickson, Patrick H. Nevins, Gregory Salinas
The Impact of Thiopurine Hypermethylation on Clinical Outcomes in Patients With Inflammatory Bowel Disease Paul A. Blaker, Steven C. Fong, Melissa A. Smith, Viraj C. Kariyawasam, Anthony M. Marinaki, Peter M. Irving, Jeremy D. Sanderson
BACKGROUND: As the prevalence and burden of inflammatory bowel disease (IBD) in the United States continue to increase, it is important to optimize IBD therapy, which is typically chronic. The aim of this survey was to investigate physician practice patterns and preferences in IBD management. METHODS: Two nominal group technique focus groups were conducted in March 2013 via web interface and teleconference to elicit barriers that gastroenterologists face in managing IBD. A review of literature published in/after 2005 on practice gaps and issues in IBD management also was conducted via MEDLINE, SearchMedica, and Internet searches. Focus group and literature review findings framed a 3-case vignette survey that was pilot tested and distributed to practicing US gastroenterologists in June 2013 (n=151). The survey assessed the following topics: patient management, evaluation and classification of treatment response, barriers and side effects, and information needs. Survey responses were summarized using descriptive statistics. RESULTS: Respondents (n=151) were mostly community-based gastroenterologists (82%) in group (72%) or private solo (15%) practices, seeing a mean of 11 patients with ulcerative colitis [UC] and 11 with Crohn's disease per week. When assessing therapy response in a UC patient, respondents viewed clinical remission (9.3 on 10-point scale), discontinuation of steroids (8.8), and endoscopic remission (8.0) as more important than histologic remission (7.2) or normalization of C-reactive protein (6.2). Consistent with the goal of limiting long-term steroid use, 61% of respondents identified the need for steroid-sparing therapy in an IBD patient whose symptoms responded to higher prednisone doses but returned when the dose was lowered. When presented with an IBD patient who had lost response to anti-tumor necrosis factor (TNF) therapy, 29% of respondents indicated they would check antibodies levels, 23% would check anti-TNF levels, 17% would add an extra infusion, 15% would increase anti-TNF dose, and 12% would switch anti-TNFs. Regarding anti-TNF therapy, physicians were most concerned about serious infection (5.8 on 10-point scale), infusion reaction (5.6), and reactivation of tuberculosis (5.5) but indicated their patients were most concerned about lymphomas (6.8), serious infection (6.6), and other malignancies (6.4). A total of 54% of respondents reported their patients proactively discuss treatment side effects (mostly lymphoma/cancer risk [23%]), 27% quality of life issues, and 14% psychological health issues. CONCLUSIONS: Survey data show practice patterns in IBD management consistent with evolving treatment paradigms, which acknowledge a role for remission beyond control of clinical symptoms, but also highlight inconsistencies in clinical approach (eg, next steps after anti-TNF secondary failure).
Introduction Approximately 15% of patients with inflammatory bowel disease (IBD) prescribed azathioprine (AZA)/mercaptopurine (MP) demonstrate a skewed drug metabolism with low levels of thioguanine nucleotides (TGN) and unexpectedly high levels of methylmercaptopurine (MeMP). This predicts a lack of treatment efficacy and excess adverse events; however studies on the effect of thiopurine hypermethylation (TH) in adult IBD patients are lacking. Importantly, where identified TH can be circumvented with the use of low dose AZA/MP and allopurinol. The aim of this study is to characterise the impact of TH in IBD patients and determine if thiopurine metabolite profiles at week 4 of treatment can predict its occurrence to allow early combination treatment. Methods 273 patients with IBD, who were anti-TNF-α therapy Naive and matched for red blood cell thiopurine-S-methyltransferase activity, were retrospectively identified from electronic records. Of these 181 patients demonstrated average MeMP:TGN ratios < 11 (at least 2 profiles between weeks 12 - 52) and were used as a control group that was compared to 92 patients with average MeMP:TGN ratios ≥ 11. Clinical outcomes were recorded for the first 12 months of therapy. A failure of AZA/MP as monotherapy was determined by 3 gastroenterologists with expertise in IBD. Thiopurine metabolite profiles were measured in 139 patients at week 4 of therapy and were compared to average metabolite profiles between 12 - 52 weeks of treatment to determine their predictive value. Results The average MeMP:TGN ratios in those with and without TH were 21.0 and 2.52 respectively (p = <0.0001, Mann-Whitney U-test). The normalised dose of thiopurine was higher in patients with TH (1.91 mg/ kg vs. 2.09 mg/ kg; p = < 0.0001; Mann-Whitney U-test). Patients with TH were more likely to fail AZA/ MP monotherapy as first line treatment during the first 12 months of therapy, in comparison with patients with normal methylation profiles (p = 0.0088, Gehan-Breslow-Wilcoxon Test). The difference in the number of treatment failures at 12 months was 15.7%. There was no difference in the occurrence of gastrointestinal intolerance, myelotoxicity or pancreatitis between groups, however there was an excess of hepatotoxicity with TH (p = 0.0006; OR 8.058; 95% CI 2.188 - 29.670; Fisher's exact). TH was demonstrated in 83.7% of cases by 12 weeks of therapy. A MeMP : TGN level > 6.17 at week 4 accurately predicted TH (ratio ≥ 11) after 12 weeks of therapy (AUC = 0.839; p = < 0.0001; sensitivity = 75.4%; specificity = 88.4%). Conclusion TH is associated with an excess of thiopurine treatment failures as monotherapy immunosuppression during the first 12 months of treatment. We also confirm its association with hepatotoxicity. A MeMP:TGN > 6.17 may be useful in early identification of patients likely to benefit from combination treatment.
AGA Abstracts
S-246