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W1195 Safety of Thiopurines in a Population-Based Cohort of Inflammatory Bowel Disease
W1194 Impact of an Extensive Thiopurine Methyltransferase (TPMT) Genotyping in Inflammatory Bowel Disease Patients Who Experienced Myelosuppression During Antipurine Therapy Olivier Dewit, Tom G. Moreels, Filip J. Baert, Harald Peeters, Reenaers Catherine, Martine De Vos, Philippe P. Van Hootegem, Vinciane Muls, Gigi Veereman, Fazia Mana, Joannes Holvoet, Serge Naegels, Yves Horsmans, Jean-Luc Gala Background & Aims: Azathioprine (AZA) is an immunosuppresive drug that is widely used in IBD. Among its side effects, myelosuppression (MS) is of major concern. Patients with TPMT deficiency have a high risk of MS when exposed to standard dose of AZA. In a previous study *, only 27 % of Crohn's Disease Caucasian patients with MS had a mutant allele of the TPMT gene associated with enzyme deficiency. Since this study, a number of new TPMT mutations have been described and our aim was to investigate their clinical relevance. Secondary aim was to evaluate, in TPMT deficient and normal pts, the delay, the severity, the complications, the hospitalization and outcome of MS. Methods: Inclusion criteria were leukopenia (white blood cell count < 3000/mm3), and /or thrombocytopenia (platelets < 100000/mm3) while taking AZA therapy. Patients (n=61, CD: 48, UC:13) were included from 11 Belgian centers. The median treatment dose was 2 mg/kg (0.7-2.5). Data were collected about the onset of treatment, the onset of MS, concomitant medications at that time, complications and hospitalization. For each patient, 30 milliliters venous blood was drawn at distance of MS event, in EDTA-treated tubes and sent to a central laboratory for full TPMT cDNA sequence analysis (exon 4 to 10), specifically designed to avoid the co-amplification of the TPMT pseudo-gene. Results: forty-six out of 61 were homozygous for the wild-type TPMT genotype (High methylator, HM), 11/61 were heterozygous for at least 1 non functional mutation (intermediate methylator, IM) and 4 were homozygous for non functional mutation (low methylator, LM). In the spectrum of 22 known TPMT mutations, only TPMT 2*, 3B* and 3C* mutated alleles were identified. According to the expected methylator status, median delay between AZA initiation and MS was 2 months (5 weeks-5 months) in the LM pts, 2,75 months (4 weeks-6 years) in IM pts ; and 6 months (11 days7 years) in HM. Occurrence of infections was the most frequent complication and was found in TPMT deficient pts 6/15 (40%) as well as normal TPMT pts 15/46 (33 %). No death was reported. Hospitalization was necessary in 7/15 pts (47 %) with deficient TPMT genotype and in 12/46 (26 %) of the patients with normal TPMT genotype. The median duration of hospitalization was 15 days (range 2-42) and similar in both groups. Conclusions: In this series of Caucasian IBD patient, only 1/4 (25 %) of MS during AZA was associated with TPMT deficient genotype. However, a shorter median time to MS onset and a proportionally higher rate of hospitalization was recorded in TPMT deficient pts. * Colombel et al, Gastroenterology 2000; 118:1025-1030.
W1192 Evaluation of Quick View of Rapid® 5 Access for Examination of Video Capsule Endoscopies Akiko Shiotani, Ryuji Nishi, Keisuke Honda, Makiko Kawakami, Hiroshi Imamura, Hiroshi Matsumoto, Ken-ichi Tarumi, Tomoari Kamada, Jiro Hata, Ken Haruma Background: Reading recorded images of video capsule endoscopy (VCE) takes on average 40-60 min. Since it is very time-consuming, one possible cost-effective strategy could be the use of expert endoscopic assistant and available software to select images. The availability of Quick View of RAPID® reader, which is software to assist the reader, is not applicable for clinical use because of the low sensitivity for detection of lesions and clinical usefulness of any software has not been proved. Aim: To evaluate clinical utility of RAPID® 5 Access in VCE examinations and find the optimum setting mode for reading to increase of diagnosis yield in shorten reading time. Methods: Two well-trained doctors and one expert nurse read the previous recorded images in 10 volunteers with known mucosal injury induced by low dose aspirin and in 10 obscure GI bleeding (OGIB) patients known to have a variety of lesions. We compared the detection rate of the lesions using quick view between RAPID® Reader ver. 4.1 and RAPID® 5 Access. We also compared the detection rate of the lesions and reading time among 3 setting modes of RAPID® 5 Access (A, single auto mode view speed 12; B quad view manual speed 35; C, single manual quick view speed 6). Results: The sensitivities of denuded redness (74% vs. 55.6%), erosion (74% vs.59.2%), large erosion (96% vs. 96%), and ulcer (100% vs. 50%) in the comparison of the rate of detection of the images in aspirin study by RAPID® 5 Access were significantly higher than those by RAPID® Reader. Quick view of RAPID® 5 Access detected all main lesions in OGIB patients, while RAPID® Reader missed 7 lesions (ie, 3 ulcer lesions, 3 elevated lesions and 1 malignant lesion). Comparison among the 3 modes of RAPID® 5 Access showed that the mode with single manual quick view and speed 6 was superior in both detection rate and reading time compared to the other modes. Conclusions: The Quick View of RAPID® 5 Access may improve diagnostic yield reducing reading time.
W1195 W1193
Safety of Thiopurines in a Population-Based Cohort of Inflammatory Bowel Disease Laurent Peyrin Biroulet, Edward V. Loftus, William S. Harmsen, Alan R. Zinsmeister, William J. Sandborn
Safety of Thiopurine Therapy in Inflammatory Bowel Disease (IBD): LongTerm Follow-up Study of 3,900 Patients Maria Chaparro, Ingrid Ordas, Eduardo Cabre, Valle Garcia, Guillermo Bastida, Mireia Penalva, Fernando Gomollon, Esther Garcia-Planella, Olga Merino, Ana Gutiérrez, Maria Esteve, Montserrat Andreu, M. García-Sepulcre, Joaquín Hinojosa, Isabel Vera, Fernando Muñoz, Juan L. Mendoza, Jose Luis Cabriada, Miguel A. Montoro, Manuel Barreiro, Gloria Ceña, Cristina Saro, Xavier Aldeguer Mante, Jesus Barrio, Javier P. Gisbert
Background and Aims: Few data on the safety profile of thiopurines in a population-based cohort of inflammatory bowel disease (IBD) exist. Methods: Using the resources of the Rochester Epidemiology Project, we identified all patients (pts) who had received azathioprine (AZA) or 6-mercaptopurine (6MP) among incident cases of IBD from Olmsted County, Minnesota, diagnosed between 1970 and 2004 and followed through 2005. All clinical and biological data were reviewed. Results were expressed as number of adverse events (AEs) per 100 pt-years of exposure to thiopurines. Results: A total of 165 (108 Crohn's disease, 57 ulcerative colitis, UC) pts out of 688 with IBD (310 Crohn's disease, 378 UC) were treated with AZA and/or 6MP. Median duration of thiopurine use was 10.9 months (range, 2 days-11.1 years) in UC and 3.0 years (1 day-12.0 years) in Crohn's disease. Forty UC pts (70%) experienced a total of 109 AEs. AEs judged as probably related to thiopurine treatment (n=59) included liver toxicity (abnormal liver tests or liver injury) not leading to therapeutic intervention (n=22), leukopenia without infection but leading to therapeutic intervention (n= 13), digestive symptoms (n=8), leukopenia without infection and not leading to therapeutic intervention (n=3), flu-like symptoms (n=3), arthralgia (n=2), neutropenia without leukopenia (n=2), one pancreatitis, one B-cell non-Hodgkin lymphoma, and others (n=4). The incidence of AEs was 800 per 100 pt-years of thiopurine exposure (+/-1560) in UC. Ninetyfour Crohn's disease pts (87%) experienced a total of 318 AEs. AEs judged as probably related to thiopurine treatment (n=155) included liver toxicity not leading to therapeutic intervention (n=74), digestive symptoms (n=19), leukopenia without infection leading or not to therapeutic intervention (n=18 and 19, respectively), liver toxicity leading to therapeutic intervention (n=6), infection without leukopenia (n=4), neutropenia without leukopenia (n= 3), flu-like symptoms (n=3), cutaneous lesions (n=3), and others (=6). The incidence of AEs was 840 (+/-3710) per 100 pt-years of exposure to thiopurines in Crohn's diseases. The AEs occurred independently of thiopurine dosage in both Crohn's disease and UC. When examining the first course of thiopurine in each pt, 55 IBD pts (33%) discontinued due to an AE. Conclusion: In this population-based cohort, the incidence of AEs per 100 pt-years of exposure to thiopurines ranged from 800 to 840 in IBD. Stopping drug due to AEs was frequent. Leukopenias and abnormal liver tests occurred frequently during the course of IBD, underscoring the need to closely monitor patients on thiopurines. Only one lymphoma was observed.
Background:Azathioprine (AZA) and mercaptopurine (MP) have shown to be effective in inducing and maintaining remission in IBD patients.The occurrence of adverse events (AE) is a major drawback in the use of AZA/MP. Aims:To evaluate the cumulative incidence, incidence rates, distribution and chronology of AE in patients on thiopurine treatment.To identify predictive factors associated with the development of thiopurine-induced AE. Methods:Retrospective review of medical records of IBD patients on thiopurine therapy from a National Spanish database (ENEIDA). Long-term incidence of AE was estimated using the Kaplan-Meier analysis.Cox-regression analysis was performed to identify potential predictive factors of AE. Results:3,900 patients (mean age 40 years, 59%male, 30%ulcerative colitis, 70% Crohn's disease (CD)) were included. 95% were on azathioprine and 5% on mercaptopurine. The median follow-up with thiopurines was 44 months (range 0-420). AE occurred a median of 1 month after starting treatment. The cumulative incidence of AE was 26%, with an annual risk of 7% per patient-year of treatment. 51% of AE causing discontinuation of treatment occurred in the first month of treatment, 76% after 6 months and 80% after 12 months. Most frequent AE were nauseas(8%), hepatotoxicity(4%), myelotoxicity(4%) and pancreatitis(4%). Three patients had lymphoma. Female gender (OR=1.4;95%CI=1.1-1.8) and CD(OR=2.5; 2-3) increased the risk of having nauseas. The risk of hepatotoxicity was lower in females (OR=0.6; 0.4-0.9) and higher in CD (OR=3.3, 2.5-4.5). The risk of myelotoxicity was significantly higher in patients treated with MP (OR=5; 2.5-11) and in females (OR=3.6; 2-6). The risk of pancreatitis was higher in CD (OR=2.5; 2-3.4). Overall, 17% of patients discontinued the treatment with thiopurines due to AE. 37% of these patients started thiopurines again, and 40% of them had AE again (4% with the same drug, and 36% after switching to the other thiopurine). Conclusions: 1.As many as 1/4 patients on thiopurine therapy had AE during follow-up. 2.A high proportion of patients(17%) had to discontinue the treatment with thiopurines due to AE. 3.More than half of patients that re-started thiopurine treatment after its discontinuation due to AE tolerated it. 4.Several predictor factors for some AE have been identified.
W1196 One Hour Infliximab Infusion in Infammatory Bowel Disease is Save and Well Tolerated Thomas W. Lee, Sandra L. Beard, Richard N. Fedorak Background: Infliximab (IFX), administered by intravenous infusion, is a chimeric monoclonal antibody to tumour necrosis factor alpha with proven efficacy in inducing and maintaining remission of inflammatory Bowel Disease (IBD). A protocol used in the initial
S-671
AGA Abstracts
AGA Abstracts
test and Student's “t” test was used to statistically analyse the results. Results: 20 patients (4.0%) were diagnosed with small bowel tumors by CE; 9 were GIST (45.0%). It was observed that traditional endoscopic and radiological methods failed to diagnose GIST in all these cases. CE was false negative in only one case in which the diagnosis of GIST was made by angiography. All CE positive patients and the patient diagnosed by angiography underwent surgical treatment with normalization of the haemoglobin values at follow-up. Limitations: the small number of cases. Conclusions: CE diagnosed GIST in 9/10 patients establishing it as an effective and sensitivity diagnostic modality in comparison to traditional radiology and confirming an important role for CE in the algorithm for the diagnostic workup in suspected small bowel tumors.
W1192 Evaluation of Quick View of Rapid® 5 Access for Examination of Video Capsule Endoscopies Akiko Shiotani, Ryuji Nishi, Keisuke Honda, Makiko Kawakami, Hiroshi Imamura, Hiroshi Matsumoto, Ken-ichi Tarumi, Tomoari Kamada, Jiro Hata, Ken Haruma Background: Reading recorded images of video capsule endoscopy (VCE) takes on average 40-60 min. Since it is very time-consuming, one possible cost-effective strategy could be the use of expert endoscopic assistant and available software to select images. The availability of Quick View of RAPID® reader, which is software to assist the reader, is not applicable for clinical use because of the low sensitivity for detection of lesions and clinical usefulness of any software has not been proved. Aim: To evaluate clinical utility of RAPID® 5 Access in VCE examinations and find the optimum setting mode for reading to increase of diagnosis yield in shorten reading time. Methods: Two well-trained doctors and one expert nurse read the previous recorded images in 10 volunteers with known mucosal injury induced by low dose aspirin and in 10 obscure GI bleeding (OGIB) patients known to have a variety of lesions. We compared the detection rate of the lesions using quick view between RAPID® Reader ver. 4.1 and RAPID® 5 Access. We also compared the detection rate of the lesions and reading time among 3 setting modes of RAPID® 5 Access (A, single auto mode view speed 12; B quad view manual speed 35; C, single manual quick view speed 6). Results: The sensitivities of denuded redness (74% vs. 55.6%), erosion (74% vs.59.2%), large erosion (96% vs. 96%), and ulcer (100% vs. 50%) in the comparison of the rate of detection of the images in aspirin study by RAPID® 5 Access were significantly higher than those by RAPID® Reader. Quick view of RAPID® 5 Access detected all main lesions in OGIB patients, while RAPID® Reader missed 7 lesions (ie, 3 ulcer lesions, 3 elevated lesions and 1 malignant lesion). Comparison among the 3 modes of RAPID® 5 Access showed that the mode with single manual quick view and speed 6 was superior in both detection rate and reading time compared to the other modes. Conclusions: The Quick View of RAPID® 5 Access may improve diagnostic yield reducing reading time.
W1195 W1193
Safety of Thiopurines in a Population-Based Cohort of Inflammatory Bowel Disease Laurent Peyrin Biroulet, Edward V. Loftus, William S. Harmsen, Alan R. Zinsmeister, William J. Sandborn
Safety of Thiopurine Therapy in Inflammatory Bowel Disease (IBD): LongTerm Follow-up Study of 3,900 Patients Maria Chaparro, Ingrid Ordas, Eduardo Cabre, Valle Garcia, Guillermo Bastida, Mireia Penalva, Fernando Gomollon, Esther Garcia-Planella, Olga Merino, Ana Gutiérrez, Maria Esteve, Montserrat Andreu, M. García-Sepulcre, Joaquín Hinojosa, Isabel Vera, Fernando Muñoz, Juan L. Mendoza, Jose Luis Cabriada, Miguel A. Montoro, Manuel Barreiro, Gloria Ceña, Cristina Saro, Xavier Aldeguer Mante, Jesus Barrio, Javier P. Gisbert
Background and Aims: Few data on the safety profile of thiopurines in a population-based cohort of inflammatory bowel disease (IBD) exist. Methods: Using the resources of the Rochester Epidemiology Project, we identified all patients (pts) who had received azathioprine (AZA) or 6-mercaptopurine (6MP) among incident cases of IBD from Olmsted County, Minnesota, diagnosed between 1970 and 2004 and followed through 2005. All clinical and biological data were reviewed. Results were expressed as number of adverse events (AEs) per 100 pt-years of exposure to thiopurines. Results: A total of 165 (108 Crohn's disease, 57 ulcerative colitis, UC) pts out of 688 with IBD (310 Crohn's disease, 378 UC) were treated with AZA and/or 6MP. Median duration of thiopurine use was 10.9 months (range, 2 days-11.1 years) in UC and 3.0 years (1 day-12.0 years) in Crohn's disease. Forty UC pts (70%) experienced a total of 109 AEs. AEs judged as probably related to thiopurine treatment (n=59) included liver toxicity (abnormal liver tests or liver injury) not leading to therapeutic intervention (n=22), leukopenia without infection but leading to therapeutic intervention (n= 13), digestive symptoms (n=8), leukopenia without infection and not leading to therapeutic intervention (n=3), flu-like symptoms (n=3), arthralgia (n=2), neutropenia without leukopenia (n=2), one pancreatitis, one B-cell non-Hodgkin lymphoma, and others (n=4). The incidence of AEs was 800 per 100 pt-years of thiopurine exposure (+/-1560) in UC. Ninetyfour Crohn's disease pts (87%) experienced a total of 318 AEs. AEs judged as probably related to thiopurine treatment (n=155) included liver toxicity not leading to therapeutic intervention (n=74), digestive symptoms (n=19), leukopenia without infection leading or not to therapeutic intervention (n=18 and 19, respectively), liver toxicity leading to therapeutic intervention (n=6), infection without leukopenia (n=4), neutropenia without leukopenia (n= 3), flu-like symptoms (n=3), cutaneous lesions (n=3), and others (=6). The incidence of AEs was 840 (+/-3710) per 100 pt-years of exposure to thiopurines in Crohn's diseases. The AEs occurred independently of thiopurine dosage in both Crohn's disease and UC. When examining the first course of thiopurine in each pt, 55 IBD pts (33%) discontinued due to an AE. Conclusion: In this population-based cohort, the incidence of AEs per 100 pt-years of exposure to thiopurines ranged from 800 to 840 in IBD. Stopping drug due to AEs was frequent. Leukopenias and abnormal liver tests occurred frequently during the course of IBD, underscoring the need to closely monitor patients on thiopurines. Only one lymphoma was observed.
Background:Azathioprine (AZA) and mercaptopurine (MP) have shown to be effective in inducing and maintaining remission in IBD patients.The occurrence of adverse events (AE) is a major drawback in the use of AZA/MP. Aims:To evaluate the cumulative incidence, incidence rates, distribution and chronology of AE in patients on thiopurine treatment.To identify predictive factors associated with the development of thiopurine-induced AE. Methods:Retrospective review of medical records of IBD patients on thiopurine therapy from a National Spanish database (ENEIDA). Long-term incidence of AE was estimated using the Kaplan-Meier analysis.Cox-regression analysis was performed to identify potential predictive factors of AE. Results:3,900 patients (mean age 40 years, 59%male, 30%ulcerative colitis, 70% Crohn's disease (CD)) were included. 95% were on azathioprine and 5% on mercaptopurine. The median follow-up with thiopurines was 44 months (range 0-420). AE occurred a median of 1 month after starting treatment. The cumulative incidence of AE was 26%, with an annual risk of 7% per patient-year of treatment. 51% of AE causing discontinuation of treatment occurred in the first month of treatment, 76% after 6 months and 80% after 12 months. Most frequent AE were nauseas(8%), hepatotoxicity(4%), myelotoxicity(4%) and pancreatitis(4%). Three patients had lymphoma. Female gender (OR=1.4;95%CI=1.1-1.8) and CD(OR=2.5; 2-3) increased the risk of having nauseas. The risk of hepatotoxicity was lower in females (OR=0.6; 0.4-0.9) and higher in CD (OR=3.3, 2.5-4.5). The risk of myelotoxicity was significantly higher in patients treated with MP (OR=5; 2.5-11) and in females (OR=3.6; 2-6). The risk of pancreatitis was higher in CD (OR=2.5; 2-3.4). Overall, 17% of patients discontinued the treatment with thiopurines due to AE. 37% of these patients started thiopurines again, and 40% of them had AE again (4% with the same drug, and 36% after switching to the other thiopurine). Conclusions: 1.As many as 1/4 patients on thiopurine therapy had AE during follow-up. 2.A high proportion of patients(17%) had to discontinue the treatment with thiopurines due to AE. 3.More than half of patients that re-started thiopurine treatment after its discontinuation due to AE tolerated it. 4.Several predictor factors for some AE have been identified.
W1196 One Hour Infliximab Infusion in Infammatory Bowel Disease is Save and Well Tolerated Thomas W. Lee, Sandra L. Beard, Richard N. Fedorak Background: Infliximab (IFX), administered by intravenous infusion, is a chimeric monoclonal antibody to tumour necrosis factor alpha with proven efficacy in inducing and maintaining remission of inflammatory Bowel Disease (IBD). A protocol used in the initial
S-671
AGA Abstracts
AGA Abstracts
test and Student's “t” test was used to statistically analyse the results. Results: 20 patients (4.0%) were diagnosed with small bowel tumors by CE; 9 were GIST (45.0%). It was observed that traditional endoscopic and radiological methods failed to diagnose GIST in all these cases. CE was false negative in only one case in which the diagnosis of GIST was made by angiography. All CE positive patients and the patient diagnosed by angiography underwent surgical treatment with normalization of the haemoglobin values at follow-up. Limitations: the small number of cases. Conclusions: CE diagnosed GIST in 9/10 patients establishing it as an effective and sensitivity diagnostic modality in comparison to traditional radiology and confirming an important role for CE in the algorithm for the diagnostic workup in suspected small bowel tumors.