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Hubert MO, Mayerle J, Sirtl S. [Pancreatitis from drugs-Drugs for treatment of pancreatitis]. INNERE MEDIZIN (HEIDELBERG, GERMANY) 2025; 66:524-532. [PMID: 40298970 DOI: 10.1007/s00108-025-01888-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Accepted: 03/04/2025] [Indexed: 04/30/2025]
Abstract
BACKGROUND Drugs are a rare but important cause of acute pancreatitis (AP) due to potential therapeutic consequences, accounting for up to 5% of all cases of AP. The diagnosis of drug-induced AP is challenging due to mostly weak evidence and complex diagnostic criteria. OBJECTIVE This review article defines drug-induced AP, summarizes the evidence for drugs associated with AP and highlights the challenges in the diagnosis of this condition. The second part of the article focuses on the main pillars of AP treatment. CURRENT DATA The association of most drugs associated with AP is based on case reports and case series but there are no high-quality studies. There is sufficient evidence of a causal relationship for only 40 of more than 500 drugs associated with AP and for almost none of the drugs the causal mechanism has been definitively clarified. Several classification systems and criteria have been proposed to assess whether a drug causally triggers AP, with criteria including the temporal association, the exclusion of other causes and recurrence of AP after re-exposure. CONCLUSION The diagnosis of drug-induced AP remains a challenge, with many common drugs being incorrectly associated with AP. There is an urgent need for the development of biomarkers to facilitate the diagnosis of drug-induced AP. Drug treatment for AP is still primarily a needs-based fluid management and efficient analgesia. New and causal therapeutic approaches need clinical validation.
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Affiliation(s)
- Max Ole Hubert
- Medizinische Klinik und Poliklinik II, LMU Klinikum München, Marchioninistr. 15, 81377, München, Deutschland
| | - Julia Mayerle
- Medizinische Klinik und Poliklinik II, LMU Klinikum München, Marchioninistr. 15, 81377, München, Deutschland.
| | - Simon Sirtl
- Medizinische Klinik und Poliklinik II, LMU Klinikum München, Marchioninistr. 15, 81377, München, Deutschland
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Anafy A, Mirkin Y, Galai T, Ben-Tov A, Moran-Lev H, Yerushalmy-Feler A, Cohen S, Amir AZ. Acute pancreatitis in children with inflammatory bowel disease: Risk factors, clinical course, and prognosis. J Pediatr Gastroenterol Nutr 2024; 79:325-334. [PMID: 38837432 DOI: 10.1002/jpn3.12279] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/21/2024] [Revised: 04/17/2024] [Accepted: 05/25/2024] [Indexed: 06/07/2024]
Abstract
OBJECTIVES To characterize the clinical course of acute pancreatitis (AP) in pediatric inflammatory bowel disease (IBD) patients compared to children with AP without IBD and to identify risk factors associated with AP among IBD patients. METHODS This retrospective, single-center study compared clinical characteristics of children (<19 years) with AP with and without concomitant IBD who were hospitalized 2005-2019. We also conducted a risk factor analysis of AP development in pediatric IBD. RESULTS Sixty-eight (54% males) patients with 120 episodes of AP were admitted at a median age of 15.3 years. Thirteen patients (14 episodes) had a co-diagnosis of IBD, representing 4% of our IBD patient population. The AP-IBD patients presented with lower amylase levels compared to the non-IBD patients (160 [interquartile range, IQR: 83-231] vs. 418 [IQR: 176-874] U/L, p > 0.01), all had a mild pancreatitis, and none required invasive intervention. The presumed etiology for AP in all IBD patients was IBD-related: IBD flare-up in five, side effects of medications in two, and undetermined in seven. The only risk factor for AP development among IBD patients was IBD-associated arthritis (23% vs. 3% for IBD-non-AP, p = 0.04), while extracolonic Crohn's disease and induction therapy with nutrition were negative risk factors (15% vs. 51%, p = 0.05, and 8% vs. 44%, p = 0.04, respectively). Other parameters, including disease type and medications, were nonsignificant. CONCLUSION The clinical course of AP in pediatric IBD patients is mild. Only IBD-associated arthritis emerged as a risk factor for the development of AP, while, unexpectedly, IBD medication did not.
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Affiliation(s)
- Adi Anafy
- The Pediatric Gastroenterology Institute, Dana-Dwek Children's Hospital, Tel Aviv Sourasky Medical Center, Tel-Aviv, Israel
- Tel Aviv University, The Faculty of Medical & Health Sciences, Tel-Aviv, Israel
| | - Yehoshua Mirkin
- Tel Aviv University, The Faculty of Medical & Health Sciences, Tel-Aviv, Israel
| | - Tut Galai
- The Pediatric Gastroenterology Institute, Dana-Dwek Children's Hospital, Tel Aviv Sourasky Medical Center, Tel-Aviv, Israel
- Tel Aviv University, The Faculty of Medical & Health Sciences, Tel-Aviv, Israel
| | - Amir Ben-Tov
- The Pediatric Gastroenterology Institute, Dana-Dwek Children's Hospital, Tel Aviv Sourasky Medical Center, Tel-Aviv, Israel
- Tel Aviv University, The Faculty of Medical & Health Sciences, Tel-Aviv, Israel
| | - Hadar Moran-Lev
- The Pediatric Gastroenterology Institute, Dana-Dwek Children's Hospital, Tel Aviv Sourasky Medical Center, Tel-Aviv, Israel
- Tel Aviv University, The Faculty of Medical & Health Sciences, Tel-Aviv, Israel
| | - Anat Yerushalmy-Feler
- The Pediatric Gastroenterology Institute, Dana-Dwek Children's Hospital, Tel Aviv Sourasky Medical Center, Tel-Aviv, Israel
- Tel Aviv University, The Faculty of Medical & Health Sciences, Tel-Aviv, Israel
| | - Shlomi Cohen
- The Pediatric Gastroenterology Institute, Dana-Dwek Children's Hospital, Tel Aviv Sourasky Medical Center, Tel-Aviv, Israel
- Tel Aviv University, The Faculty of Medical & Health Sciences, Tel-Aviv, Israel
| | - Achiya Z Amir
- The Pediatric Gastroenterology Institute, Dana-Dwek Children's Hospital, Tel Aviv Sourasky Medical Center, Tel-Aviv, Israel
- Tel Aviv University, The Faculty of Medical & Health Sciences, Tel-Aviv, Israel
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Lee D, Hua M, Wang D, Song L, Zhang T, Hua X, Yu K, Yang XR, Chanock SJ, Shi J, Landi MT, Zhu B. Pan-cancer mutational signature analysis of 111,711 targeted sequenced tumors using SATS. MEDRXIV : THE PREPRINT SERVER FOR HEALTH SCIENCES 2024:2023.05.18.23290188. [PMID: 37425683 PMCID: PMC10327246 DOI: 10.1101/2023.05.18.23290188] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 07/11/2023]
Abstract
Tumor mutational signatures are informative for cancer diagnosis and treatment. However, targeted sequencing, commonly used in clinical settings, lacks specialized analytical tools and a dedicated catalogue of mutational signatures. Here, we introduce SATS, a scalable mutational signature analyzer for targeted sequencing data. SATS leverages tumor mutational burdens to identify and quantify signatures in individual tumors, overcoming the challenges of sparse mutations and variable gene panels. Validations across simulated data, pseudo-targeted sequencing data, and matched whole-genome and targeted sequencing samples show that SATS can accurately detect common mutational signatures and estimate their burdens. Applying SATS to 111,711 tumors from the AACR Project GENIE, we created a pan-cancer mutational signature catalogue specific to targeted sequencing. We further validated signatures in lung, breast and colorectal cancers using an additional 16,774 independent samples. This signature catalogue is a valuable resource for estimating signature burdens in individual targeted sequenced tumors, facilitating the integration of mutational signatures with clinical data.
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Yang H, An Z, Zhao Y, Lu H. Tacrolimus Related Acute Pancreatitis: An Observational, Retrospective, Pharmacovigilance Study. Clin Ther 2024; 46:524-528. [PMID: 38729808 DOI: 10.1016/j.clinthera.2024.04.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2024] [Revised: 02/29/2024] [Accepted: 04/10/2024] [Indexed: 05/12/2024]
Abstract
PURPOSE Recent case reports have drawn attention to the emergence of acute pancreatitis, a potentially life-threatening complication associated with tacrolimus. This study uses the Food and Drug Administration Adverse Event Reporting System (FAERS) to investigate the risk signal of acute pancreatitis associated with calcineurin inhibitors (CNIs), with a focus on tacrolimus. METHODS We conducted an observational retrospective pharmacovigilance study utilizing the FAERS database, encompassing data from its inception to the third quarter of 2023. The assessment of the association between CNIs and acute pancreatitis was carried out using the Information Component (IC) and Reporting Odds Ratio (ROR). Logistic regression analysis was employed to elucidate factors contributing to fatal outcomes. All analyses were performed using R version 3.2.5. FINDING We identified 221 cases of acute pancreatitis linked to CNIs. The median age of individuals experiencing acute pancreatitis induced by tacrolimus was 43, with a predominant occurrence among male patients. Our study showed a significant association between CNIs and acute pancreatitis (ROR 1.82 [1.60-2.08], IC 0.85 [3.66-3.92]). Comparing tacrolimus and cyclosporine, the signal for tacrolimus seemed to be higher. Further analysis revealed that, with the exception of patients aged 60 and above, the signal for tacrolimus remained stable. Contrastingly, the signal for cyclosporine was unstable and limited to the male group and individuals aged less than 20 years. In cases of CNIs-related acute pancreatitis, the mortality rate was 31.67% (70/221 cases). Logistic regression analysis indicated that a younger age acts as a protective factor for death due to CNIs-related acute pancreatitis (OR 0.943, 95% CI 0.915-0.972, P = 0.000). IMPLICATIONS Our study has identified a safety signal for tacrolimus in relation to acute pancreatitis. Additionally, we observed advanced age as a significant risk factor for tacrolimus-related acute pancreatitis, leading to mortality. Given the widespread use of tacrolimus, it is crucial for healthcare providers to be vigilant and informed about the potential association with acute pancreatitis.
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Affiliation(s)
- Hui Yang
- Key Laboratory of Organ Regeneration and Reconstruction, State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China; University of Chinese Academy of Sciences, Beijing, China; Department of Pharmacy, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, China
| | - Zhuoling An
- Department of Pharmacy, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, China
| | - Yong Zhao
- Key Laboratory of Organ Regeneration and Reconstruction, State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China; University of Chinese Academy of Sciences, Beijing, China; Faculty of Synthetic Biology, Shenzhen University of Advanced Technology, Shenzhen, China; CAS Key Laboratory of Quantitative Engineering Biology, Shenzhen Institute of Synthetic Biology, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China
| | - Hezhe Lu
- Key Laboratory of Organ Regeneration and Reconstruction, State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China; University of Chinese Academy of Sciences, Beijing, China.
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Guerra I, Barros F, Chaparro M, Benítez JM, Martín-Arranz MD, de Francisco R, Piqueras M, de Castro L, Carbajo AY, Bermejo F, Mínguez M, Gutiérrez A, Mesonero F, Cañete F, González-Muñoza C, Calvo M, Sicilia B, Alfambra E, Rivero M, Lucendo AJ, Tardillo CA, Almela P, Bujanda L, van Domselaar M, Ramos L, Fernández Sánchez M, Hinojosa E, Verdejo C, Gimenez A, Rodríguez-Lago I, Manceñido N, Pérez Calle JL, Moreno MDP, Delgado-Guillena PG, Antolín B, Ramírez de la Piscina P, Casanova MJ, Soto Escribano P, Martín Arranz E, Pérez-Martínez I, Mena R, García Morales N, Granja A, Boscá Watts MM, Francés R, Fernández C, Calafat M, Roig-Ramos C, Vera MI, Carracedo Á, Domènech E, Gisbert JP. Evaluation of Genetic Variants Associated with the Risk of Thiopurine-Related Pancreatitis: A Case Control Study from ENEIDA Registry. Dig Dis 2024; 42:257-264. [PMID: 38452742 DOI: 10.1159/000537782] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/13/2023] [Accepted: 01/08/2024] [Indexed: 03/09/2024]
Abstract
INTRODUCTION Risk factors for developing pancreatitis due to thiopurines in patients with inflammatory bowel disease (IBD) are not clearly identified. Our aim was to evaluate the predictive pharmacogenetic risk of pancreatitis in IBD patients treated with thiopurines. METHODS We conducted an observational pharmacogenetic study of acute pancreatitis events in a cohort study of IBD patients treated with thiopurines from the prospectively maintained ENEIDA registry biobank of GETECCU. Samples were obtained and the CASR, CEL, CFTR, CDLN2, CTRC, SPINK1, CPA1, and PRSS1 genes, selected based on their known association with pancreatitis, were fully sequenced. RESULTS Ninety-five cases and 105 controls were enrolled; a total of 57% were women. Median age at pancreatitis diagnosis was 39 years. We identified 81 benign variants (50 in cases and 67 in controls) and a total of 35 distinct rare pathogenic and unknown significance variants (10 in CEL, 21 in CFTR, 1 in CDLN2, and 3 in CPA1). None of the cases or controls carried pancreatitis-predisposing variants within the CASR, CPA1, PRSS1, and SPINK1 genes, nor a pathogenic CFTR mutation. Four different variants of unknown significance were detected in the CDLN and CPA1 genes; one of them was in the CDLN gene in a single patient with pancreatitis and 3 in the CPA1 gene in 5 controls. After the analysis of the variants detected, no significant differences were observed between cases and controls. CONCLUSION In patients with IBD, genes known to cause pancreatitis seem not to be involved in thiopurine-related pancreatitis onset.
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Affiliation(s)
- Iván Guerra
- Hospital Universitario de Fuenlabrada, Madrid, Spain
| | - Francisco Barros
- Fundación Pública Galega de Medicina Xenómica (SERGAS)- Instituto de Investigación Sanitaria de Santiago (IDIS) and Grupo de Medicina Xenómica - Centro de Investigación en Red de Enfermedades Raras (CIBERER-ISCIII), CIMUS, Universidade de Santiago de Compostela, Santiago de Compostela, Spain
| | - María Chaparro
- Hospital Universitario de La Princesa, Instituto de Investigación Sanitaria Princesa (IIS-Princesa), Universidad Autónoma de Madrid (UAM), Madrid, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Madrid, Spain
| | - José M Benítez
- Hospital Universitario Reina Sofía e Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC), Córdoba, Spain
| | - María Dolores Martín-Arranz
- Department of Gastroenterology of La Paz University Hospital, School of Medicine. Universidad Autónoma de Madrid, Hospital La Paz Institute for Health Research, La Paz Hospital, Madrid, Spain
| | - Ruth de Francisco
- Hospital Universitario Central de Asturias, Instituto de Investigación Sanitaria del Principado de Asturias (ISPA), Oviedo, Spain
| | | | - Luisa de Castro
- Hospital Álvaro Cunqueiro-Complexo Hospitalario Universitario de Vigo, Instituto de Investigación Biomédica Galicia Sur, Vigo, Spain
| | - Ana Y Carbajo
- Hospital Universitario Rio Hortega, Valladolid, Spain
| | | | - Miguel Mínguez
- Hospital Clínico Universitario de Valencia, Valencia, Spain
| | - Ana Gutiérrez
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Madrid, Spain
- Hospital General Universitario Dr. Balmis de Alicante, ISABIAL, Alicante, Spain
| | | | - Fiorella Cañete
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Madrid, Spain
- Hospital Universitari Germans Trias i Pujol, Badalona, Spain
| | | | - Marta Calvo
- Hospital Universitario Puerta de Hierro-Majadahonda, Madrid, Spain
| | | | - Erika Alfambra
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Madrid, Spain
- Hospital Clínico Universitario "Lozano Blesa" e Instituto de Investigación Sanitaria de Aragón (IIS Aragón), Zaragoza, Spain
| | - Montserrat Rivero
- Hospital Universitario Marqués de Valdecilla e IDIVAL, Santander, Spain
| | - Alfredo J Lucendo
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Madrid, Spain
- Hospital General de Tomelloso, Ciudad Real, Spain
| | - Carlos A Tardillo
- Hospital Universitario Nuestra Señora Candelaria, Santa Cruz de Tenerife, Spain
| | - Pedro Almela
- Hospital General Universitari de Castelló, Castellón, Spain
| | - Luis Bujanda
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Madrid, Spain
- Hospital Donostia/Instituto Biodonostia, Universidad del País Vasco UPV/EHU, Donostia-San Sebastián, Spain
| | - Manuel van Domselaar
- Hospital Universitario de Torrejón y Universidad Francisco de Vitoria, Madrid, Spain
| | - Laura Ramos
- Hospital Universitario de Canarias, Santa Cruz de Tenerife, Spain
| | | | | | - Cristina Verdejo
- Hospital General Universitario de Ciudad Real, Ciudad Real, Spain
| | - Anna Gimenez
- Hospital Sant Joan de Déu-Althaia, Manresa, Spain
| | | | - Noemí Manceñido
- Hospital Universitario Infanta Sofía, San Sebastián de Los Reyes, Madrid, Spain
| | | | | | | | - Beatriz Antolín
- Hospital Clínico Universitario de Valladolid, Valladolid, Spain
| | | | - María José Casanova
- Hospital Universitario de La Princesa, Instituto de Investigación Sanitaria Princesa (IIS-Princesa), Universidad Autónoma de Madrid (UAM), Madrid, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Madrid, Spain
| | - Pilar Soto Escribano
- Hospital Universitario Reina Sofía e Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC), Córdoba, Spain
| | - Eduardo Martín Arranz
- Department of Gastroenterology of La Paz University Hospital, School of Medicine. Universidad Autónoma de Madrid, Hospital La Paz Institute for Health Research, La Paz Hospital, Madrid, Spain
| | - Isabel Pérez-Martínez
- Hospital Universitario Central de Asturias, Instituto de Investigación Sanitaria del Principado de Asturias (ISPA), Oviedo, Spain
| | | | - Natalia García Morales
- Hospital Álvaro Cunqueiro-Complexo Hospitalario Universitario de Vigo, Instituto de Investigación Biomédica Galicia Sur, Vigo, Spain
| | - Alicia Granja
- Hospital Universitario de Fuenlabrada, Madrid, Spain
| | | | - Rubén Francés
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Madrid, Spain
- Grupo de Inmunobiología hepática e intestinal, Universidad Miguel Hernández, San Juan de Alicante, Hospital General Universitario Dr. Balmis, ISABIAL, Alicante, Spain
| | | | - Margalida Calafat
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Madrid, Spain
- Hospital Universitari Germans Trias i Pujol, Badalona, Spain
| | | | | | - Ángel Carracedo
- Fundación Pública Galega de Medicina Xenómica (SERGAS)- Instituto de Investigación Sanitaria de Santiago (IDIS) and Grupo de Medicina Xenómica - Centro de Investigación en Red de Enfermedades Raras (CIBERER-ISCIII), CIMUS, Universidade de Santiago de Compostela, Santiago de Compostela, Spain
| | - Eugeni Domènech
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Madrid, Spain
- Hospital Universitari Germans Trias i Pujol, Badalona, Spain
- Departament de Medicina, Universitat Autònoma de Barcelona, Bellaterra, Spain
| | - Javier P Gisbert
- Hospital Universitario de La Princesa, Instituto de Investigación Sanitaria Princesa (IIS-Princesa), Universidad Autónoma de Madrid (UAM), Madrid, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Madrid, Spain
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Pădureanu V, Drăgoescu AN, Pădureanu R, Rośu MM, Rădulescu D, Dop D, For£ofoiu MC. Treatment approaches in autoimmune pancreatitis (Review). Biomed Rep 2024; 20:26. [PMID: 38259589 PMCID: PMC10801350 DOI: 10.3892/br.2023.1714] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2023] [Accepted: 12/11/2023] [Indexed: 01/24/2024] Open
Abstract
Autoimmune pancreatitis (AIP) is a rare disease. There are two distinct types of AIP: AIP type 1 (AIP-1), a pancreatic manifestation of a multi-organ disease linked to immunoglobulin (Ig)G4, and AIP type 2 (AIP-2), a pancreas-specific disease unrelated to IgG4. The usual course of treatment for AIP is oral corticosteroid medication. Rituximab has also been recommended for recurrent AIP-1 in order to initiate remission and provide ongoing treatment. Immunomodulators such as azathioprine are used to keep certain patients in remission. Evaluation also takes into account a number of pharmacological alternatives, including biologic drugs like anti-tumor necrosis factor therapy, a safe and efficient second-line treatment for AIP-2 relapse or steroid dependence. Corticosteroids and immunosuppressants, which are poorly tolerated due to considerable side effects, are being replaced by other biologic drugs, which may offer a beneficial therapeutic alternative.
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Affiliation(s)
- Vlad Pădureanu
- Department of Internal Medicine, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania
| | - Alice Nicoleta Drăgoescu
- Department of Anaesthesiology and Intensive Care, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania
| | - Rodica Pădureanu
- Department of Internal Medicine, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania
| | - Maria Magdalena Rośu
- Department of Diabetes, Nutrition and Metabolic Diseases, County Clinical Emergency Hospital of Craiova, Craiova 200642, Romania
| | - Dumitru Rădulescu
- Department of Pediatrics, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania
| | - Dalia Dop
- Department of Surgery, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania
| | - Mircea Cătălin For£ofoiu
- Department of Internal Medicine, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania
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Dohos D, Farkas N, Váradi A, Erőss B, Párniczky A, Szentesi A, Hegyi P, Sarlós P. Inflammatory bowel disease does not alter the clinical features and the management of acute pancreatitis: A prospective, multicentre, exact-matched cohort analysis. Pancreatology 2022; 22:1071-1078. [PMID: 36202731 DOI: 10.1016/j.pan.2022.09.241] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/06/2022] [Revised: 08/30/2022] [Accepted: 09/17/2022] [Indexed: 12/11/2022]
Abstract
OBJECTIVE AND AIMS Acute pancreatitis in inflammatory bowel disease occurs mainly as an extraintestinal manifestation or a side effect of medications. We aimed to investigate the prognostic factors and severity indicators of acute pancreatitis and the treatment of patients with both diseases. DESIGN We performed a matched case-control registry analysis of a multicentre, prospective, international acute pancreatitis registry. Patients with both diseases were matched to patients with acute pancreatitis only in a 1:3 ratio by age and gender. Subgroup analyses were also carried out based on disease type, activity, and treatment of inflammatory bowel disease. RESULTS No difference in prognostic factors (laboratory parameters, bedside index of severity in acute pancreatitis, imaging results) and outcomes of acute pancreatitis (length of hospitalization, severity, and local or systemic complications) were detected between groups. Significantly lower analgesic use was observed in the inflammatory bowel disease population. Antibiotic use during acute pancreatitis was significantly more common in the immunosuppressed group than in the non-immunosuppressed group (p = 0.017). However, none of the prognostic parameters or the severity indicators showed a significant difference between any subgroup of patients with inflammatory bowel disease. CONCLUSION No significant differences in the prognosis and severity of acute pancreatitis could be detected between patients with both diseases and with pancreatitis only. The need for different acute pancreatitis management is not justified in the coexistence of inflammatory bowel disease, and antibiotic overuse should be avoided.
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Affiliation(s)
- Dóra Dohos
- Institute for Translational Medicine, Medical School, University of Pécs, Pécs, Hungary; Szentágothai Research Centre, University of Pécs, Pécs, Hungary; Heim Pál National Institute of Pediatrics, Budapest, Hungary
| | - Nelli Farkas
- Institute for Translational Medicine, Medical School, University of Pécs, Pécs, Hungary
| | - Alex Váradi
- Institute for Translational Medicine, Medical School, University of Pécs, Pécs, Hungary
| | - Bálint Erőss
- Institute for Translational Medicine, Medical School, University of Pécs, Pécs, Hungary; Centre for Translational Medicine, Semmelweis University, Budapest, Hungary; Division of Pancreatic Diseases, Heart and Vascular Center, Semmelweis University, Budapest, Hungary
| | - Andrea Párniczky
- Institute for Translational Medicine, Medical School, University of Pécs, Pécs, Hungary; Heim Pál National Institute of Pediatrics, Budapest, Hungary
| | - Andrea Szentesi
- Institute for Translational Medicine, Medical School, University of Pécs, Pécs, Hungary
| | - Péter Hegyi
- Institute for Translational Medicine, Medical School, University of Pécs, Pécs, Hungary; Szentágothai Research Centre, University of Pécs, Pécs, Hungary; Centre for Translational Medicine, Semmelweis University, Budapest, Hungary; Division of Pancreatic Diseases, Heart and Vascular Center, Semmelweis University, Budapest, Hungary
| | - Patrícia Sarlós
- Division of Gastroenterology, First Department of Medicine, Medical School, University of Pécs, Hungary.
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Association of ITPA gene polymorphisms with adverse effects of AZA/6-MP administration: a systematic review and meta-analysis. THE PHARMACOGENOMICS JOURNAL 2022; 22:39-54. [PMID: 35034963 DOI: 10.1038/s41397-021-00255-3] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/10/2020] [Revised: 08/24/2021] [Accepted: 09/20/2021] [Indexed: 02/07/2023]
Abstract
Azathioprine (AZA) and its metabolite, mercaptopurine (6-MP), are widely used immunosuppressant drugs. Polymorphisms in genes implicated in AZA/6-MP metabolism, reportedly, could account in part for their potential toxicity. In the present study we performed a systematic review and a meta-analysis, comprising 30 studies and 3582 individuals, to investigate the putative genetic association of two inosine triphosphatase (ITPA) polymorphisms with adverse effects in patients treated with AZA/6-MP. We found that rs1127354 is associated with neutropenia in general populations and in children (OR: 2.39, 95%CI: 1.97-2.90, and OR: 2.43, 95%CI: 2.12-2.79, respectively), and with all adverse effects tested herein in adult populations (OR: 2.12, 95%CI: 1.22-3.69). We also found that rs7270101 is associated with neutropenia and leucopenia in all-ages populations (OR: 2.93, 95%CI: 2.36-3.63, and OR: 2.82, 95%CI: 1.76-4.50, respectively) and with all adverse effects tested herein in children (OR: 1.74, 95%CI: 1.06-2.87). Stratification according to background disease, in combination with multiple comparisons corrections, verified neutropenia to be associated with both polymorphisms, in acute lymphoblastic leukemia (ALL) patients. These findings suggest that ITPA polymorphisms could be used as predictive biomarkers for adverse effects of thiopurine drugs to eliminate intolerance in ALL patients and clarify dosing in patients with different ITPA variants.
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Koskensalo V, Aronen P, Färkkilä M, Kylänpää L, Lindström O, Rainio M, Udd M, Jokelainen K, Tenca A. Use of thiopurines is not a risk factor for post-ERC pancreatitis in patients with primary sclerosing cholangitis. Dig Liver Dis 2021; 53:1020-1027. [PMID: 34116970 DOI: 10.1016/j.dld.2021.05.009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/05/2021] [Revised: 05/04/2021] [Accepted: 05/11/2021] [Indexed: 12/11/2022]
Abstract
INTRODUCTION Risk of post-ERC pancreatitis (PEP) in patients with primary sclerosing cholangitis (PSC) is 1-7.8%. PSC is often associated with inflammatory bowel disease and autoimmune hepatitis, which are usually treated with thiopurines. The role of thiopurines in PEP risk is still unclear. AIMS AND METHODS We evaluated the thiopurine use in PEP. The data of 354 PSC patients who underwent 985 ERCs between 2009 and 2018 were collected. 177 patients treated with thiopurines (study group, SG) and 177 controls (CG) were matched with a propensity score (PSM). Odds ratios (ORs) with 95% confidence interval (95% CI) were calculated. Multivariable logistic regression analysis and generalized linear mixed model were performed. The P-value <0.05 was significant. RESULTS In matched data, 472 ERCs were performed in SG and 513 in CG. Thiopurines were used in 373/472 (79.0%) ERCs in SG. The PEP rate was 5.3% in SG and 5.7% in CG (p = 0.889). Unintentional pancreatic duct cannulation (OR 1.28, 95%CI 1.07-1.51, p = 0.004), and periampullary diverticulum (OR 4.87, 95%CI 1.72-11.98, p = 0.001) increased the risk of PEP. CONCLUSION Prior or present thiopurine use did not increase the risk of PEP.
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Affiliation(s)
- Vilja Koskensalo
- Department of Gastrointestinal Surgery, Helsinki University Hospital and University of Helsinki, Helsinki, Finland.
| | - Pasi Aronen
- Biostatistics Consulting Unit, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
| | - Martti Färkkilä
- Department of Gastroenterology, Helsinki University Hospital and University of Helsinki, Helsinki, Finland
| | - Leena Kylänpää
- Department of Gastrointestinal Surgery, Helsinki University Hospital and University of Helsinki, Helsinki, Finland
| | - Outi Lindström
- Department of Gastrointestinal Surgery, Helsinki University Hospital and University of Helsinki, Helsinki, Finland
| | - Mia Rainio
- Department of Gastrointestinal Surgery, Helsinki University Hospital and University of Helsinki, Helsinki, Finland
| | - Marianne Udd
- Department of Gastrointestinal Surgery, Helsinki University Hospital and University of Helsinki, Helsinki, Finland
| | - Kalle Jokelainen
- Department of Gastroenterology, Helsinki University Hospital and University of Helsinki, Helsinki, Finland
| | - Andrea Tenca
- Department of Gastroenterology, Helsinki University Hospital and University of Helsinki, Helsinki, Finland
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10
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Xu J, Xu L, Wei X, Li X, Cai M. A case report: acute pancreatitis associated with tacrolimus in kidney transplantation. BMC Nephrol 2019; 20:209. [PMID: 31174507 PMCID: PMC6555724 DOI: 10.1186/s12882-019-1395-x] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2018] [Accepted: 05/24/2019] [Indexed: 11/28/2022] Open
Abstract
Background Tacrolimus has been widely used for immunosuppressive therapy in solid organ transplantation (SOT) and allo-geneic stem cell transplantation (allo-SCT) over the past 2 decades. Pancreatitis caused by tacrolimus was rarely reported in kidney transplantation previously. Case presentation Here we presented a case of a 45-year-old male who underwent kidney transplantation and received immunosuppressive therapy of tacrolimus, on day + 67 after transplantation he developed acute pancreatitis with extremely high blood concentration of tacrolimus. We excluded other possible causes and speculated tacrolimus was the probable inducer of pancreatitis. After tacrolimus was discontinued and alternated with cyclosporine, he gradually recovered and was discharged home with no relapse. Conclusion Tacrolimus can be a probable cause of pancreatitis after kidney transplantation. We recommended clinicians to be aware of the possibility of tacrolimus-induced pancreatitis during tacrolimus treatment.
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Affiliation(s)
- Junnan Xu
- Organ Transplant Institute of People's Liberation Army, the 309th Hospital of People's Liberation Army, Beijing, China.,Beijing Key Laboratory of Immunology Regulatory and Organ Transplantation, Beijing, China.,Medical School of Chinese PLA, the Chinese PLA General Hospital, Beijing, China
| | - Liang Xu
- Organ Transplant Institute of People's Liberation Army, the 309th Hospital of People's Liberation Army, Beijing, China.,Beijing Key Laboratory of Immunology Regulatory and Organ Transplantation, Beijing, China.,Medical School of Chinese PLA, the Chinese PLA General Hospital, Beijing, China
| | - Xing Wei
- Organ Transplant Institute of People's Liberation Army, the 309th Hospital of People's Liberation Army, Beijing, China.,Beijing Key Laboratory of Immunology Regulatory and Organ Transplantation, Beijing, China
| | - Xiang Li
- Organ Transplant Institute of People's Liberation Army, the 309th Hospital of People's Liberation Army, Beijing, China.,Beijing Key Laboratory of Immunology Regulatory and Organ Transplantation, Beijing, China
| | - Ming Cai
- Organ Transplant Institute of People's Liberation Army, the 309th Hospital of People's Liberation Army, Beijing, China. .,Beijing Key Laboratory of Immunology Regulatory and Organ Transplantation, Beijing, China. .,Medical School of Chinese PLA, the Chinese PLA General Hospital, Beijing, China.
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11
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Ponticelli C, Glassock RJ. Prevention of complications from use of conventional immunosuppressants: a critical review. J Nephrol 2019; 32:851-870. [PMID: 30927190 DOI: 10.1007/s40620-019-00602-5] [Citation(s) in RCA: 61] [Impact Index Per Article: 10.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2019] [Accepted: 03/21/2019] [Indexed: 01/08/2023]
Abstract
Synthetic immunosuppressive drugs are largely used in immune-related renal diseases and in kidney transplantation. Most of these drugs have a low therapeutic index (the ratio that compares the blood concentration at which a drug becomes toxic and the concentration at which the drug is effective), which means that the drug should be dosed carefully and the patient monitored frequently. In this review, we consider the categories of synthetic immunosuppressive agents more frequently and conventionally used in clinical nephrology: glucocorticoids, Aalkylating agents (cyclophosphamide, chlorambucil), purine synthesis inhibitors (azathioprine, mycophenolate salts) and calcineurin inhibitors (cyclosporine, tacrolimus). For each category the possible side effects will be reviewed, the general and specific measures to prevent or treat the adverse events will be suggested, and the more common mistakes that may increase the risk of toxicity will be described. However, the efficacy and safety of immunosuppressive agents depend not only on the pharmacologic characteristics of single drugs but can be influenced also by the clinical condition and genetic characteristics of the patient, by the typology and severity of the underlying disease and by the interaction with other concomitantly used drugs.
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Affiliation(s)
- Claudio Ponticelli
- Division of Nephrology, Istituto Scientifico Ospedale Maggiore, Milan, Italy.
- , Via Ampere 126, 20131, Milan, Italy.
| | - Richard J Glassock
- The David Geffen School of Medicine, University of California, Los Angeles, CA, USA
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12
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Wintzell V, Svanström H, Olén O, Melbye M, Ludvigsson JF, Pasternak B. Association between use of azathioprine and risk of acute pancreatitis in children with inflammatory bowel disease: a Swedish-Danish nationwide cohort study. THE LANCET CHILD & ADOLESCENT HEALTH 2019; 3:158-165. [PMID: 30685366 DOI: 10.1016/s2352-4642(18)30401-2] [Citation(s) in RCA: 26] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Subscribe] [Scholar Register] [Received: 11/01/2018] [Revised: 11/27/2018] [Accepted: 11/29/2018] [Indexed: 01/16/2023]
Abstract
BACKGROUND Studies have shown an association between use of azathioprine and increased risk of acute pancreatitis in adult inflammatory bowel disease. However, whether an association exists among paediatric patients is not known. We aimed to investigate whether use of azathioprine is associated with the risk of acute pancreatitis in children with inflammatory bowel disease. METHODS We did a nationwide register-based cohort study in Sweden (2006-16) and Denmark (2000-16). All paediatric patients (<18 years of age) with inflammatory bowel disease during the study period were identified through hospital records. Episodes of incident azathioprine use and no use of any thiopurine were matched (1:1) using propensity scores, controlling for sociodemographic characteristics, comorbidities, previous treatment, indicators of disease severity, and health care use. Incident acute pancreatitis (physician-assigned diagnosis with ICD-10 code K85) occurring in the 90 days following treatment initiation were identified through outpatient and inpatient hospital records. FINDINGS We identified 3574 azathioprine episodes and 18 700 no-use episodes, which resulted in 3374 pairs after propensity score matching; baseline characteristics in the matched cohort were well balanced. Among the matched azathioprine episodes, mean age was 14·3 years (SD 3·1), 1854 (54·9%) were male, 1923 (57·0%) had Crohn's disease, and 1451 (43·0%) had ulcerative colitis or unclassified inflammatory bowel disease. Within the first 90 days following initiation of azathioprine, 40 acute pancreatitis events occurred (incidence rate 49·1 events per 1000 person-years) compared with six events in the no-use group (8·4 events per 1000 person-years). Azathioprine use was associated with an increased risk of acute pancreatitis (incidence rate ratio 5·82 [95% CI 2·47-13·72]; absolute difference 1·0 [95% CI 0·3-2·6] events per 100 patients) during the 90-day risk period. INTERPRETATION Use of azathioprine was associated with an increased risk of acute pancreatitis in children with inflammatory bowel disease during the first 90 days following treatment initiation, suggesting the need for regular and rigorous monitoring. The risk of acute pancreatitis needs to be considered when deciding on optimal treatment strategies. FUNDING Swedish Research Council, Frimurare Barnhuset Foundation, and the Åke Wiberg Foundation.
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Affiliation(s)
- Viktor Wintzell
- Clinical Epidemiology Division, Department of Medicine, Karolinska Institutet, Stockholm, Sweden.
| | - Henrik Svanström
- Clinical Epidemiology Division, Department of Medicine, Karolinska Institutet, Stockholm, Sweden; Department of Epidemiology Research, Statens Serum Institute, Copenhagen, Denmark
| | - Ola Olén
- Clinical Epidemiology Division, Department of Medicine, Karolinska Institutet, Stockholm, Sweden; Department of Clinical Science and Education, Stockholm South Hospital, Karolinska Institutet, Stockholm, Sweden; Department of Pediatric Gastroenterology and Nutrition, Sachs' Children and Youth Hospital, Stockholm, Sweden
| | - Mads Melbye
- Department of Epidemiology Research, Statens Serum Institute, Copenhagen, Denmark; Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark; Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA
| | - Jonas F Ludvigsson
- Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden; Department of Pediatrics, Örebro University Hospital, Örebro University, Örebro, Sweden; Division of Epidemiology and Public Health, School of Medicine, University of Nottingham, Nottingham, UK; Department of Medicine, Columbia University College of Physicians and Surgeons, New York, NY, USA
| | - Björn Pasternak
- Clinical Epidemiology Division, Department of Medicine, Karolinska Institutet, Stockholm, Sweden; Department of Epidemiology Research, Statens Serum Institute, Copenhagen, Denmark
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13
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Abstract
Drug-induced acute pancreatitis (DIAP) is a rare entity that is often challenging for clinicians. The aim of our study was to provide updated DIAP classes considering the updated definition of acute pancreatitis (AP) and in light of new medications and new case reports. A MEDLINE search (1950-2018) of the English language literature was performed looking for all adult (≥17 years old) human case reports with medication/drug induced as the cause of AP. The included case reports were required to provide the name of the drug, and diagnosis of AP must have been strictly established based on the revised Atlanta Classification criteria. A total of 183 medications were found to be implicated in 577 DIAP cases. A total of 78 cases were excluded because of minimal details or lack of definite diagnosis of AP. Drug-induced AP is rare, and most drugs cause mild DIAP. Only 2 drugs are well described in the literature to explain causation rather than association (azathioprine and didanosine). Larger case-control studies and a formal standardized DIAP reporting system are essential to study the true potential of the DIAP-implicated drugs described in this review.
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Affiliation(s)
- C Roberto Simons-Linares
- From the Digestive Disease Institute, Gastroenterology and Hepatology Department, Cleveland Clinic, Cleveland, OH
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14
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The Use of International Classification of Diseases Codes to Identify Patients with Pancreatitis: A Systematic Review and Meta-analysis of Diagnostic Accuracy Studies. Clin Transl Gastroenterol 2018; 9:191. [PMID: 30287807 PMCID: PMC6172207 DOI: 10.1038/s41424-018-0060-1] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/19/2018] [Accepted: 09/06/2018] [Indexed: 02/06/2023] Open
Abstract
Background Hospital discharge codes are increasingly used in gastroenterology research, but their accuracy in the setting of acute pancreatitis (AP) and chronic pancreatitis (CP), one of the most frequent digestive diseases, has never been assessed systematically. The aim was to conduct a systematic literature review and determine accuracy of diagnostic codes for AP and CP, as well as the effect of covariates. Methods Three databases (Pubmed, EMBASE and Scopus) were searched by two independent reviewers for relevant studies that used International Classification of Disease (ICD) codes. Summary estimates of sensitivity, specificity and positive predictive value were obtained from bivariate random-effects regression models. Sensitivity and subgroup analyses according to recurrence of AP and age of the study population were performed. Results A total of 24 cohorts encompassing 18,106 patients were included. The pooled estimates of sensitivity and specificity of ICD codes for AP were 0.85 and 0.96, respectively. The pooled estimates of sensitivity and specificity of ICD codes for CP were 0.75 and 0.94, respectively. The positive predictive value of ICD codes was 0.71 for either AP or CP. It increased to 0.78 when applied to incident episode of AP only. The positive predictive value decreased to 0.68 when the ICD codes were applied to paediatric patients. Conclusion Nearly three out of ten patients are misidentified as having either AP or CP with the indiscriminate use of ICD codes. Limiting the use of ICD codes to adult patients with incident episode of AP may improve identification of patients with pancreatitis in administrative databases.
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15
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Drug-Induced Gastrointestinal and Hepatic Disease Associated with Biologics and Nonbiologic Disease-Modifying Antirheumatic Drugs. Rheum Dis Clin North Am 2018; 44:29-43. [DOI: 10.1016/j.rdc.2017.09.003] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
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16
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Affiliation(s)
- Matthew Hum
- Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Alberta, Canada
| | - Muhammad N. Mahmood
- Department of Laboratory Medicine and Pathology, University of Alberta, Edmonton, Alberta, Canada
| | - Vivian Huang
- Division of Gastroenterology, University of Alberta, Edmonton, Alberta, Canada
| | - Marlene Dytoc
- Division of Dermatology, University of Alberta, Edmonton, Alberta, Canada
- Correspondence to: Marlene Dytoc, MD, PhD, FRCPC, Division of Dermatology, Faculty of Medicine and Dentistry, University of Alberta, 8 Floor, Clinical Sciences Building, 11350-83 Avenue, NW, Edmonton, T6G 2G3, Alberta, Canada.Division of DermatologyFaculty of Medicine and DentistryUniversity of Alberta8 Floor, Clinical Sciences Building, 11350-83 Avenue, NWEdmontonAlbertaT6G 2G3Canada
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17
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Coskun M, Steenholdt C, de Boer NK, Nielsen OH. Pharmacology and Optimization of Thiopurines and Methotrexate in Inflammatory Bowel Disease. Clin Pharmacokinet 2016; 55:257-74. [PMID: 26255287 DOI: 10.1007/s40262-015-0316-9] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Improving the efficacy and reducing the toxicity of thiopurines and methotrexate (MTX) have been areas of intense basic and clinical research. An increased knowledge on pharmacodynamics and pharmacokinetics of these immunomodulators has optimized treatment strategies in inflammatory bowel disease (IBD). This review focuses on the metabolism and mode of action of thiopurines and MTX, and provides an updated overview of individualized treatment strategies in which efficacy in IBD can be increased without compromising safety. The patient-based monitoring instruments adapted into clinical practice include pretreatment thiopurine S-methyltransferase testing, thiopurine metabolite monitoring, and blood count measurements that may help guiding the dosage to improve clinical outcome. Other approaches for optimizing thiopurine therapy in IBD include combination therapy with allopurinol, 5-aminosalicylates, and/or biologics. Similar strategies are yet to be proven effective in improving the outcome of MTX therapy. Important challenges for the management of IBD in the future relate to individualized dosing of immunomodulators for maximal efficacy with minimal risk of side effects. As low-cost conventional immunomodulators still remain a mainstay in pharmacotherapy of IBD, more research remains warranted, especially to substantiate these tailored management strategies in controlled clinical trials.
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Affiliation(s)
- Mehmet Coskun
- Department of Gastroenterology, Herlev Hospital, University of Copenhagen, Herlev, Denmark. .,Department of Biology and Biotech Research and Innovation Centre (BRIC), The Bioinformatics Centre, University of Copenhagen, Copenhagen, Denmark.
| | - Casper Steenholdt
- Department of Gastroenterology, Herlev Hospital, University of Copenhagen, Herlev, Denmark
| | - Nanne K de Boer
- Department of Gastroenterology and Hepatology, VU University Medical Center, Amsterdam, The Netherlands
| | - Ole Haagen Nielsen
- Department of Gastroenterology, Herlev Hospital, University of Copenhagen, Herlev, Denmark
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18
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Flaig T, Douros A, Bronder E, Klimpel A, Kreutz R, Garbe E. Tocilizumab-induced pancreatitis: case report and review of data from the FDA Adverse Event Reporting System. J Clin Pharm Ther 2016; 41:718-721. [PMID: 27670839 DOI: 10.1111/jcpt.12456] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2016] [Accepted: 08/26/2016] [Indexed: 12/13/2022]
Abstract
WHAT IS KNOWN AND OBJECTIVE Tocilizumab (TCZ) is a humanized monoclonal antibody acting against the IL-6 receptor. It is a drug used in the treatment of rheumatoid arthritis and can be either given intravenously every 4 weeks or subcutaneously once a week. Known adverse events (AE) associated with TCZ include: infections of the upper respiratory tract, arterial hypertension, hypercholesterolaemia and hypertriglyceridaemia. Here, we present the first well-documented case of TCZ-induced acute pancreatitis (AP) and a systematic review of the literature including data from the Food and Drug Administration Adverse Event Reporting System (FAERS) database. METHODS Patient data collection was performed within the Berlin Case-Control Surveillance Study. A literature search for TCZ-induced AP was conducted. Analysis of the FAERS database concerning TCZ-associated pancreatic AE from the period of 2009 until the first quarter of 2013 was conducted. RESULTS AND DISCUSSION A 40-year-old man presented with a 2-day history of progressive upper abdominal pain with elevated serum lipase and triglyceride levels. Biliary pancreatitis was ruled out by abdominal sonography and CT scan. Cessation of intravenously administered TCZ resulted in improvement of the patient's condition and a decline in elevated laboratory values, suggesting a probable relationship between TCZ intake and AP. Analysis of the FAERS database retrieved 52 cases of TCZ-associated AP that accounted for 70% of all pancreatic AE in association with TCZ use. Further literature search detected three additional cases in which TCZ use was associated with AP. WHAT IS NEW AND CONCLUSION Physicians should be aware of the probable association between TCZ use and AP. Targeted post-authorization studies are needed to confirm and quantify the risk of TCZ-induced AP.
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Affiliation(s)
- T Flaig
- Department of Clinical Pharmacology and Toxicology, Charité-Universitätsmedizin Berlin, Berlin, Germany
| | - A Douros
- Department of Clinical Pharmacology and Toxicology, Charité-Universitätsmedizin Berlin, Berlin, Germany
| | - E Bronder
- Department of Clinical Pharmacology and Toxicology, Charité-Universitätsmedizin Berlin, Berlin, Germany
| | - A Klimpel
- Department of Clinical Pharmacology and Toxicology, Charité-Universitätsmedizin Berlin, Berlin, Germany
| | - R Kreutz
- Department of Clinical Pharmacology and Toxicology, Charité-Universitätsmedizin Berlin, Berlin, Germany
| | - E Garbe
- Leibniz Institute for Prevention Research and Epidemiology BIPS, Bremen, Germany. .,Faculty of Human and Health Sciences, University of Bremen, Bremen, Germany.
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19
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Antonini F, Pezzilli R, Angelelli L, Macarri G. Pancreatic disorders in inflammatory bowel disease. World J Gastrointest Pathophysiol 2016; 7:276-282. [PMID: 27574565 PMCID: PMC4981767 DOI: 10.4291/wjgp.v7.i3.276] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/24/2016] [Revised: 07/08/2016] [Accepted: 07/20/2016] [Indexed: 02/06/2023] Open
Abstract
An increased incidence of pancreatic disorders either acute pancreatitis or chronic pancreatitis has been recorded in patients with inflammatory bowel disease (IBD) compared to the general population. Although most of the pancreatitis in patients with IBD seem to be related to biliary lithiasis or drug induced, in some cases pancreatitis were defined as idiopathic, suggesting a direct pancreatic damage in IBD. Pancreatitis and IBD may have similar presentation therefore a pancreatic disease could not be recognized in patients with Crohn's disease and ulcerative colitis. This review will discuss the most common pancreatic diseases seen in patients with IBD.
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20
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Shimizu S, Naitoh I, Nakazawa T, Hayashi K, Miyabe K, Kondo H, Nishi Y, Yoshida M, Umemura S, Hori Y, Kato A, Okumura F, Sano H, Hirata Y, Takada H, Ohara H, Joh T. Correlation between long-term outcome and steroid therapy in type 1 autoimmune pancreatitis: relapse, malignancy and side effect of steroid. Scand J Gastroenterol 2016; 50:1411-8. [PMID: 26061806 DOI: 10.3109/00365521.2015.1054424] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
OBJECTIVES Autoimmune pancreatitis (AIP) responds well to corticosteroid therapy (CST), and CST is essential to induce remission. However, the correlation between long-term outcome and CST has not been evaluated. We aimed to clarify the correlation between long-term outcome of AIP and CST. MATERIAL AND METHODS We retrospectively evaluated relapse, risk of malignancy and side effects of CST by focusing on the correlation with CST in 84 patients with type 1 AIP. RESULTS The incidence of relapse was 23.8%. The frequency of relapse after CST administration was significantly lower in patients taking CST for >6 months than in those who did not (22% versus 67%; p = 0.036). The incidence of malignancy was 10.7%. The standardized incidence ratio of malignancy was 2.14 [95% confidence interval 0.74-3.54]. There were no significant correlations between development of malignancy and CST. The incidences of total and serious side effects due to CST were 75% and 19.1%, respectively. Relapse was the only significant independent predictive risk factor for serious side effects in a multivariate analysis (odds ratio 4.065; 95% confidence interval 1.125-14.706; p = 0.032). The cumulative dose of corticosteroid was significantly higher in patients with serious side effects than in those without (12,645 mg versus 7322 mg; p = 0.041). CONCLUSIONS CST reduces relapse of AIP. However, CST causes serious side effects, particularly in relapsing patients. Alternative maintenance therapy to prevent relapse is needed.
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Affiliation(s)
- Shuya Shimizu
- Department of Gastroenterology and Metabolism , Nagoya City University Graduate School of Medical Sciences , Nagoya , Japan
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21
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Abstract
Inflammatory bowel disease (IBD) has been increasingly diagnosed in children and adults. Similarly, acute and chronic pancreatitis are increasingly prevalent conditions with potentially devastating consequences. There is a growing body of literature linking these 2 conditions. The purpose of this review is to provide a comprehensive outline of the association between IBD and pancreatitis and to explore their putative pathophysiology. Based on the collective reports, 2 outstanding reasons for pancreatitis in patients with IBD are medications and IBD complications.
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22
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Lee YK, Lim K, Hwang SH, Ahn YH, Shin GT, Kim H, Park IW. Metformin induced acute pancreatitis and lactic acidosis in a patient on hemodialysis. Yeungnam Univ J Med 2016. [DOI: 10.12701/yujm.2016.33.1.33] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022] Open
Affiliation(s)
- Yeon-Kyung Lee
- Department of Nephrology, Ajou University School of Medicine, Suwon, Korea
| | - Kihyun Lim
- Department of Nephrology, Ajou University School of Medicine, Suwon, Korea
| | - Su-Hyun Hwang
- Department of Nephrology, Ajou University School of Medicine, Suwon, Korea
| | - Young-Hwan Ahn
- Department of Nephrology, Ajou University School of Medicine, Suwon, Korea
| | - Gyu-Tae Shin
- Department of Nephrology, Ajou University School of Medicine, Suwon, Korea
| | - Heungsoo Kim
- Department of Nephrology, Ajou University School of Medicine, Suwon, Korea
| | - In-Whee Park
- Department of Nephrology, Ajou University School of Medicine, Suwon, Korea
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23
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Nielsen OH, Coskun M, Steenholdt C, Rogler G. The role and advances of immunomodulator therapy for inflammatory bowel disease. Expert Rev Gastroenterol Hepatol 2015; 9:177-89. [PMID: 25101818 DOI: 10.1586/17474124.2014.945914] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Immune modulating drugs such as thiopurines (azathioprine and 6-mercaptopurine) and methotrexate has been a mainstay for treatment of inflammatory bowel disease (IBD) for decades. However, despite widely used in IBD, questions still remain concerning the most rational treatment regimens of these agents. Results from a range of recent studies necessitate increased awareness on how to best use these potent drugs in the clinic. As controversy still remains regarding the most appropriate use of immunomodulators, this review is based on scrutinizing the current literature, with emphasis on randomized controlled trials and Cochrane reviews, focusing on aspects that can lead to optimal and evidence-based thiopurine and methotrexate treatment strategies in IBD.
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Affiliation(s)
- Ole Haagen Nielsen
- Department of Gastroenterology, Medical Section D112M, Herlev Hospital, University of Copenhagen, Herlev Ringvej 75, DK-2730 Herlev, Denmark
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24
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Tenner S. Drug induced acute pancreatitis: Does it exist? World J Gastroenterol 2014; 20:16529-16534. [PMID: 25469020 PMCID: PMC4248195 DOI: 10.3748/wjg.v20.i44.16529] [Citation(s) in RCA: 38] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/10/2014] [Revised: 05/08/2014] [Accepted: 07/16/2014] [Indexed: 02/06/2023] Open
Abstract
As the incidence of acute pancreatitis continues to rise, establishing the etiology in order to prevent recurrence is important. Although the etiology of acute pancreatitis is not difficult in the majority of patients, almost a quarter of patients are initially labeled as having idiopathic acute pancreatitis. When confronted with a patient with acute pancreatitis and no clear etiology defined as an absence alcoholism, gallstones (ultrasound and/or MRI), a normal triglyceride level, and absence of tumor, it often appears reasonable to consider a drug as the cause of acute pancreatitis. Over 100 drugs have been implicated by case reports as causing acute pancreatitis. While some of these case reports are well written, many case reports represent poorly written experiences of the clinician simply implicating a drug without a careful evaluation. Over-reliance on case reports while ignoring randomized clinical trials and large pharmacoepidemiologic surveys has led to confusion about drug induced acute pancreatitis. This review will explain that drug induced acute pancreatitis does occur, but it is rare, and over diagnosis leads to misconceptions about the disease resulting in inappropriate patient care, increased litigation and a failure to address the true entity: idiopathic acute pancreatitis.
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25
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Stobaugh DJ, Deepak P. Effect of tumor necrosis factor-α inhibitors on drug-induced pancreatitis in inflammatory bowel disease. Ann Pharmacother 2014; 48:1282-7. [PMID: 24982311 DOI: 10.1177/1060028014540869] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/17/2023] Open
Abstract
BACKGROUND Mesalamine and thiopurines (6-mercaptopurine and azathioprine) have been shown to increase the risk of developing acute pancreatitis in inflammatory bowel disease (IBD) patients. Tumor necrosis factor-α (TNF-α) inhibitors have been shown to protect against pancreatitis in animal models. OBJECTIVE To determine the risk of pancreatitis when comparing thiopurine monotherapy, mesalamine monotherapy, and thiopurine and mesalamine dual therapy to identical treatments but with the addition of a TNF-α inhibitor. METHODS Using a case-control design, the Food and Drug Administration Adverse Event Reporting System was queried for cases of pancreatitis and control reactions in IBD patients on a thiopurine or mesalamine. The proportional reporting ratio method was used to compare the different therapy regimens with the same regimen combined with a TNF-α inhibitor. RESULTS In all, 549 cases and controls were identified. When comparing thiopurine monotherapy with thiopurines combined with a TNF-α inhibitor, the odds of pancreatitis were lower in those on combination therapy (odds ratio [OR] = 0.04; 95% CI = 0.01-0.12). A similar trend was seen when comparing mesalamine monotherapy to mesalamine combined with a TNF-α inhibitor (OR = 0.08; 95% CI = 0.04-0.14) and when comparing those on both a thiopurine and mesalamine with those on all 3 therapies (OR = 0.04; 95% CI = 0.01-0.16). CONCLUSIONS Combination therapy with TNF-α inhibitors appears to be associated with a lower risk of pancreatitis in IBD patients on mesalamine, thiopurines, or a combination of both. Physicians should consider using TNF-α inhibitors in those with the greatest risk of pancreatitis, although prospective studies are needed.
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Douros A, Bronder E, Andersohn F, Klimpel A, Thomae M, Ockenga J, Kreutz R, Garbe E. Drug-induced acute pancreatitis: results from the hospital-based Berlin case-control surveillance study of 102 cases. Aliment Pharmacol Ther 2013; 38:825-34. [PMID: 23957710 DOI: 10.1111/apt.12461] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/12/2013] [Revised: 05/03/2013] [Accepted: 07/31/2013] [Indexed: 12/22/2022]
Abstract
BACKGROUND Drug toxicity is a well-known cause of acute pancreatitis (AP). Although many drugs have been associated with AP, the magnitude of the risk of most of them remains largely unknown. AIM To determine the pancreatotoxic risk of a wide range of drugs. METHODS The hospital-based Berlin case-control surveillance study, including all 51 Berlin hospitals in a hospital network, ascertained 102 cases with idiopathic AP (IAP) and 750 controls between 2002 and 2011. Patients with IAP were thoroughly validated using anamnestic, clinical or laboratory data. Drug exposure was obtained in a face-to-face interview. Possible drug aetiology was assessed in individual patients through a standardised causality assessment applying the criteria of the World Health Organization. Drug risks were further quantified [odds ratios (OR) with 95% confidence intervals (CI)] in a case-control design with unconditional logistic regression analysis. RESULTS The pancreatotoxic risk of several drugs, including azathioprine (OR 5.1; 95% CI 1.9-13.5), fenofibrate (OR 12.2; 95% CI 2.3-69.1), mesalazine (OR 3.3; 95% CI 1.1-9.5) or angiotensin-converting enzyme inhibitors, was corroborated by case-control analysis and causality assessment. Causality assessment suggested a pancreatotoxic potential, among others, for mercaptopurine or the seldom reported leflunomide, and alluded to a novel risk for tocilizumab. Case-control analysis showed an increased risk for two phytotherapeutics: harpagophytum and valerian radix. CONCLUSIONS Our study quantified the pancreatotoxic risk of different drugs and phytotherapeutics. The findings corroborate previous results from the literature but also indicate risks for substances not previously reported, highlighting the need for further controlled studies on pancreatic toxicity.
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Affiliation(s)
- A Douros
- Department of Clinical Pharmacology and Toxicology, Charité-Universitätsmedizin Berlin, Berlin, Germany
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Abstract
GOALS To determine the prevalence of ulcerative colitis (UC) in autoimmune pancreatitis (AIP) patients in a tertiary referral hospital and to compare the clinical and pathologic characteristics and outcomes of UC associated with AIP (AIP-UC) and UC patients. BACKGROUND Recently, it was suggested that UC is associated with AIP. However, the prevalence of UC in AIP, together with the clinical characteristics and outcomes of AIP-UC are not clear. STUDY We retrospectively reviewed the medical records of AIP patients diagnosed at the Asan Medical Center. RESULTS Of the 104 patients with AIP, 6 (5.8%) were also diagnosed with UC. Serum immunoglobulin G (IgG) and IgG4 were elevated in 1 patient (16.7%), respectively, and 4 (66.7%) showed idiopathic duct-centric pancreatitis (type 2 AIP). Compared with 24 matched patients with UC only, AIP-UC patients had a lower body mass index (P=0.003), higher C-reactive protein levels (P=0.048), and higher Mayo scores (P=0.006) at diagnosis of UC. Two AIP-UC patients (33.3%), but none with UC only showed increased infiltration of IgG4-positive cells into the colonic tissues (P=0.006). During follow-up, 2 AIP-UC patients (33.3%) underwent colectomy and 1 (16.7%) died, but no colectomies or deaths occurred in the UC only group. CONCLUSIONS AIP patients seem to have a higher risk of UC compared with the general population. The increased IgG4-positive cellular infiltration in the colonic tissue suggests that UC may be an extrapancreatic manifestation of AIP.
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Abstract
Drugs are thought to be a rare cause for acute pancreatitis; however 525 different drugs are listed in the World Health Organization (WHO) database suspected to cause acute pancreatitis as a side effect. Many of them are widely used to treat highly prevalent diseases. The true incidence is not entirely clear since only few systematic population based studies exist. The majority of the available data are derived from case reports or case control studies. Furthermore, the causality for many of these drugs remains elusive and for only 31 of these 525 dugs a definite causality was established. Definite proof for causality is defined by the WHO classification if symptoms reoccur upon rechallenge.In the actual algorithm the diagnosis is confirmed if no other cause of acute pancreatitis can be detected, and the patient is taking one of the suspected drugs.
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Comparison of steroid pulse therapy and conventional oral steroid therapy as initial treatment for autoimmune pancreatitis. J Gastroenterol 2011; 46:696-704. [PMID: 21188426 DOI: 10.1007/s00535-010-0361-y] [Citation(s) in RCA: 45] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/02/2010] [Accepted: 12/02/2010] [Indexed: 02/04/2023]
Abstract
BACKGROUND The efficacy of oral steroid therapy for autoimmune pancreatitis (AIP) is well known, and oral prednisolone treatment is most usually commenced at 30-40 mg/day, but there have been few reports about comparative studies of oral steroid therapy and steroid pulse therapy as the initial treatment for AIP. We studied the clinical course and image findings to estimate the utility of steroid pulse therapy for AIP, comparing it with oral steroid therapy. METHODS Laboratory and image findings were assessed retrospectively in 11 patients who received steroid pulse therapy, and the findings were compared to those in 10 patients who received conventional oral steroid therapy. RESULTS Change in pancreatic size showed no significant difference between the therapies after 2 weeks of treatment. Significant improvement of lower bile duct strictures after 2 weeks of treatment and that of immunoglobulin values within 6 months were shown with both therapies. However, steroid pulse therapy showed significant improvement of γ-guanosine triphosphate (GTP) in 2 weeks and of alanine aminotransferase (ALT) in 2 and 8 weeks, compared with oral steroid therapy. Moreover, there was one patient in whom the lower bile duct stricture was not improved by oral steroid therapy, but it did show improvement with steroid pulse therapy. CONCLUSIONS Initial steroid pulse therapy is a beneficial alternative to oral steroid therapy for the improvement of bile duct lesions. In future, the accumulation of a larger number of patients receiving steroid pulse therapy is needed, and prospective studies will be required.
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Pancreatitis aguda secundaria a azatioprina versus pancreatitis autoinmune en un paciente con colitis ulcerosa. FARMACIA HOSPITALARIA 2010; 34:310-2. [DOI: 10.1016/j.farma.2009.12.008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2009] [Revised: 12/03/2009] [Accepted: 12/10/2009] [Indexed: 11/15/2022] Open
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Abstract
Crohn's disease and ulcerative colitis, together popularly known as inflammatory bowel disease (IBD), are characterized by a number of extraintestinal manifestations. Although infrequent, acute pancreatitis, and less often chronic pancreatitis, may occur as a result of the disease itself or secondary to the medications used in the treatment. The increased incidence of acute pancreatitis in Crohn's disease can be explained based on the high predisposition to cholesterol as well as pigment stones as a result of ileal disease, anatomic abnormalities of the duodenum, immunologic disturbances associated with IBD, and, above all, to the side effects of many medications used in the treatment. Sulfasalazine, 5-aminosalicylic acid, azathioprine, and 6-mercaptopurine are well known to cause acute pancreatitis as a result of a possible idiosyncratic mechanism. Crohn's disease and ulcerative colitis share many clinical manifestations and treatment modalities. Nonspecific elevations of serum pancreatic enzymes in IBD make it difficult to avoid over diagnosis of acute pancreatitis, particularly in patients with Crohn's disease who suffer from abdominal pain often. The IBD-pancreas association is further reflected in many reports of exocrine as well as endocrine pancreatic insufficiency.
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Nitsche CJ, Jamieson N, Lerch MM, Mayerle JV. Drug induced pancreatitis. Best Pract Res Clin Gastroenterol 2010; 24:143-55. [PMID: 20227028 DOI: 10.1016/j.bpg.2010.02.002] [Citation(s) in RCA: 112] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/15/2009] [Revised: 01/26/2010] [Accepted: 02/05/2010] [Indexed: 01/31/2023]
Abstract
525 different drugs that can, as an adverse reaction, induce acute pancreatitis are listed in a WHO database. Compared to other causes drugs represent a relatively rare cause of pancreatitis. They should be considered as a triggering event in patients with no other identifiable cause of the disease, who takes medications that have been shown to induce pancreatitis. The prevalence of drug-induced pancreatitis is still unclear because most incidences have been documented only as isolated case reports. The overall incidence probably ranges from between 0.1 and 2% of pancreatitis cases. For only very few substances evidence from controlled trials has been obtained. Epidemiologic data suggest the risk of pancreatitis is highest for mesalazine (HR 3.5,) azathioprine (HR 2,5) and simvastatine (HR 1,8). Even when a definite association has been demonstrated it is often impossible to determine whether the drug, or the underlying condition for which the drug was taken has conferred the risk of pancreatitis (e.g. azathioprine and Crohns disease or pentamidine and HIV). Knowledge about the underlying pathophysiologic mechanisms as well as evidence for a direct causality often remains sparse. For only 31 drugs a definite causality has been established. The most frequently reported are mesalazine (nine cases in total, three cases with re-exposure), azathioprine (five cases in total, two cases with re-exposure) and simvastatin (one case in total, this one with re-exposure). As cause-effect relationship is generally accepted when symptoms re-occur upon re-challenge. Available data from case control studies suggest that even drugs with solid evidence for an association with pancreatitis only rarely cause the disease. Even when pancreatitis is induced as an adverse drug event the disease course is usually mild or even subclinical.
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Affiliation(s)
- Claudia J Nitsche
- Department of Medicine A, Ernst-Moritz-Arndt-University Greifswald, Friedrich-Loeffler-Strasse 23a, Greifswald 17475, Germany
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Larsen S, Bendtzen K, Nielsen OH. Extraintestinal manifestations of inflammatory bowel disease: epidemiology, diagnosis, and management. Ann Med 2010; 42:97-114. [PMID: 20166813 DOI: 10.3109/07853890903559724] [Citation(s) in RCA: 201] [Impact Index Per Article: 13.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Abstract Extraintestinal manifestations occur rather frequently in inflammatory bowel disease (IBD), e.g. ulcerative colitis (UC) and Crohn's disease (CD). The present paper provides an overview of the epidemiology, clinical characteristics, diagnostic process, and management of rheumatic, metabolic, dermatologic (mucocutaneous), ophthalmologic, hepatobiliary, hematologic, thromboembolic, urinary tract, pulmonary, and pancreatic extraintestinal manifestations related to IBD. Articles were identified through search of the PubMed and Embase databases, the Cochrane Library, and the web sites of the European Agency for the Evaluation of Medicinal Products (EMEA) and the US Food and Drug Administration (FDA) (cut-off date October 2009). The search terms 'Crohn's disease', 'inflammatory bowel disease', or 'ulcerative colitis' were combined with the terms 'adalimumab', 'anemia', 'arthritis', 'bronchiectasis', 'bronchitis', 'cutaneous manifestations', 'erythema nodosum', 'extraintestinal manifestations', 'hyperhomocysteinemia', 'infliximab', 'iridocyclitis', 'lung disease', 'ocular manifestations', 'osteomalacia', 'pancreatitis', 'primary sclerosing cholangitis', 'renal stones', 'sulfasalazine', 'thromboembolism', and 'treatment'. The search was performed on English-language reviews, practical guidelines, letters, and editorials. Articles were selected based on their relevance, and additional papers were retrieved from their reference lists. Since some of the diseases discussed are uncommon, valid evidence of treatment was difficult to obtain, and epidemiologic data on the rarer forms of extraintestinal manifestations are scarce. However, updates on the pathophysiology and treatment regimens are given for each of these disorders. This paper offers a current review of original research papers and randomized clinical trials, if any, within the field and makes an attempt to point out practical guidelines for the diagnosis and treatment of various extraintestinal manifestations related to IBD.
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Affiliation(s)
- Signe Larsen
- Department of Gastroenterology, Medical Section, Herlev Hospital, University of Copenhagen, Denmark
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Posalski JD, Ishimori ML, Wallace DJ, Weisman MH. Does mycophenolate mofetil prevent extra-renal flares in systemic lupus erythematosus? Results from an observational study of patients in a single practice treated for up to 5 years. Lupus 2009; 18:516-21. [PMID: 19395453 DOI: 10.1177/0961203308099471] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
In this study, the clinical course and change in extra-renal manifestations of patients with SLE taking mycophenolate mofetil (MMF) were evaluated. The charts of 75 consecutively identified patients on MMF from a single practice were reviewed for demographics, dates of SLE diagnosis, initiation, indication or discontinuation of MMF and other medications. British Isles Lupus Assessment Group (BILAG) organ system data were identified for 3 months prior to MMF and then for the subsequent 5 years. BILAG scores for each organ system and an overall score were calculated for intervals of 6 months. The mean age of 75 subjects was 35.8 years with SLE mean disease duration of 99.2 months. Indications for starting MMF were renal (70.7%), musculoskeletal (10.6%), mucocutaneous (9.3%), cardiorespiratory (5.3%), haematologic (4%), vasculitic (2.7%), neurologic (1.3%) and other (18.7%). The mean duration of treatment was 3.3 years; 22 discontinuations occurred. Overall, there was a >50% improvement in composite BILAG scores for 49.3% (37/75) of patients in the first year of treatment and in 20% (15/75) of patients who were still on MMF at >or=5 years. Most flares occurred at second and third year of treatment. The general and renal systems have the most improvement and clinical remissions; the musculoskeletal, mucocutaneous and haematological systems have the most recurrences. Approximately, 50% and 20% of patients taking MMF showed improvement in overall lupus disease activity at both 1 and 5 years, respectively. When evaluating organ system subsets separately, MMF improved disease activity in the first year, but had little effect in preventing new organ-specific flares, with most flares taking place in second and third year of treatment.
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Affiliation(s)
- J D Posalski
- Cedars Sinai Medical Center, Los Angeles, CA, USA
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Ahern TP, Lash TL, Sørensen HT, Pedersen L. Digoxin treatment is associated with an increased incidence of breast cancer: a population-based case-control study. Breast Cancer Res 2008; 10:R102. [PMID: 19055760 PMCID: PMC2656898 DOI: 10.1186/bcr2205] [Citation(s) in RCA: 56] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2008] [Revised: 11/12/2008] [Accepted: 12/03/2008] [Indexed: 11/26/2022] Open
Abstract
INTRODUCTION Laboratory and epidemiologic studies have suggested a modifying effect of cardiac glycosides (for example, digoxin and digitoxin) on cancer risk. We explored the association between digoxin treatment and invasive breast cancer incidence among postmenopausal Danish women. METHODS We used Danish registries to identify 5,565 postmenopausal women diagnosed with incident invasive breast carcinoma between 1 January 1991 and 31 December 2007, and 55,650 matched population controls. Cardiac glycoside prescriptions were ascertained from county prescription registries. All subjects had at least 2 years of recorded prescription drug and medical history data. We estimated the odds ratio associating digoxin use with breast cancer in conditional logistic regression models adjusted for age, county of residence, and use of anticoagulants, non-steroidal anti-inflammatory drugs (NSAIDs), aspirin, and hormone replacement therapy. We also explored the impact of confounding by indication and detection bias. RESULTS Digoxin was the sole cardiac glycoside prescribed to subjects during the study period. There were 324 breast cancer cases (5.8%) and 2,546 controls (4.6%) with a history of digoxin use at least 1 year before their index date (adjusted odds ratio (OR): 1.30; 95% confidence interval: 1.14 to 1.48). The breast cancer OR increased modestly with increasing duration of digoxin exposure (adjusted OR for 7 to 18 years of digoxin use: 1.39; 95% confidence interval: 1.10 to 1.74). The association was robust to adjustment for age, receipt of hormone replacement therapy, coprescribed drugs, and confounding by indication. A comparison of screening mammography rates between cases and controls showed no evidence of detection bias. CONCLUSIONS Our results suggest that digoxin treatment increases the risk of invasive breast cancer among postmenopausal women.
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Affiliation(s)
- Thomas P Ahern
- Department of Clinical Epidemiology, Aarhus University Hospital, Olof Palmes Alle 43-45, 8200 Aarhus N, Denmark
- Department of Epidemiology, Boston University School of Public Health, 715 Albany Street T3E, Boston, MA 02118, USA
| | - Timothy L Lash
- Department of Clinical Epidemiology, Aarhus University Hospital, Olof Palmes Alle 43-45, 8200 Aarhus N, Denmark
- Department of Epidemiology, Boston University School of Public Health, 715 Albany Street T3E, Boston, MA 02118, USA
| | - Henrik T Sørensen
- Department of Clinical Epidemiology, Aarhus University Hospital, Olof Palmes Alle 43-45, 8200 Aarhus N, Denmark
- Department of Epidemiology, Boston University School of Public Health, 715 Albany Street T3E, Boston, MA 02118, USA
| | - Lars Pedersen
- Department of Epidemiology, Boston University School of Public Health, 715 Albany Street T3E, Boston, MA 02118, USA
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Bermejo F, Lopez-Sanroman A, Taxonera C, Gisbert JP, Pérez-Calle JL, Vera I, Menchén L, Martín-Arranz MD, Opio V, Carneros JA, Van-Domselaar M, Mendoza JL, Luna M, López P, Calvo M, Algaba A. Acute pancreatitis in inflammatory bowel disease, with special reference to azathioprine-induced pancreatitis. Aliment Pharmacol Ther 2008; 28:623-8. [PMID: 18513380 DOI: 10.1111/j.1365-2036.2008.03746.x] [Citation(s) in RCA: 98] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
BACKGROUND Pancreatitis is a potentially severe condition. Patients with inflammatory bowel disease (IBD) seem to be at increased risk for acute pancreatitis. AIM To describe the incidence, main causes and possible predictive factors of acute pancreatitis in inflammatory bowel disease. METHODS Information was retrospectively extracted from the clinical records of patients followed in the IBD Units of nine hospitals in Madrid (n = 5073). RESULTS A total of 82 acute pancreatitis episodes were diagnosed (cumulative incidence, 1.6%); 98% of them were mild. Recurrent acute pancreatitis developed in 13% of patients. Most cases of acute pancreatitis (63.4%) were attributed to drug exposure [azathioprine/mercaptopurine (AZA/MP) n = 46, mesalazine (mesalamine) n = 6]; 20.7% were idiopathic, and 12.2% were biliary. Incidence of acute pancreatitis in patients treated with AZA/MP was 3.1%. In patients with acute pancreatitis, female gender (OR 3.4 95% CI: 1.3-9.3; P = 0.012) and Crohn's disease (CD) (OR 5.8 95% CI: 1.6-20.6; P = 0.007) were risk factors for AZA/MP-associated acute pancreatitis, the latter also when analysed only in patients treated with AZA/MP (n = 1477) (OR 5.2 95% CI: 1.8-14; P = 0.002). CONCLUSIONS The incidence of acute pancreatitis in our IBD patients (1.6%) is similar to that previously described. Drugs, mainly AZA/MP, are the leading cause. AZA-induced acute pancreatitis is always mild. Patients with CD are at a higher risk for AZA/MP-associated acute pancreatitis. The frequency of idiopathic acute pancreatitis is higher than expected, suggesting that part of these cases could be extraintestinal manifestations of IBD.
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Affiliation(s)
- F Bermejo
- Department of Gastroenterology, Hospital Universitario de Fuenlabrada, Community of Madrid, Madrid, Spain.
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Matsushita M, Ikeura T, Fukui T, Uchida K, Okazaki K. Refractory autoimmune pancreatitis: azathioprine or steroid pulse therapy? Am J Gastroenterol 2008; 103:1834; author reply 1834-5. [PMID: 18691195 DOI: 10.1111/j.1572-0241.2008.01959_1.x] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
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Gasse C, Jacobsen J, Pedersen L, Mortensen PB, Nørgaard M, Sørensen HT, Johnsen SP. Risk of Hospitalization for Acute Pancreatitis Associated with Conventional and Atypical Antipsychotics: A Population-Based Case-Control Study. Pharmacotherapy 2008; 28:27-34. [DOI: 10.1592/phco.28.1.27] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
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Affiliation(s)
- Anil R Balani
- Division of Gastroenterology, Hepatology and Nutrition, Winthrop University Hospital, Mineola, New York 11501, USA
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Van Dieren JM, Hansen BE, Kuipers EJ, Nieuwenhuis EES, Van der Woude CJ. Meta-analysis: Inosine triphosphate pyrophosphatase polymorphisms and thiopurine toxicity in the treatment of inflammatory bowel disease. Aliment Pharmacol Ther 2007; 26:643-52. [PMID: 17697198 DOI: 10.1111/j.1365-2036.2007.03412.x] [Citation(s) in RCA: 64] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
BACKGROUND Thiopurines are widely used for the treatment of inflammatory bowel disease, but are associated with the development of side effects. It has been suggested that the enzyme inosine triphosphate pyrophosphatase (ITPA) plays a role in the digestion of thiopurines and that defective activity resulting from polymorphisms in the inosine triphosphate pyrophosphatase encoding genes may be associated with thiopurine-induced side effects. Current studies are controversial regarding this hypothesis. AIM To perform a meta-analysis and gain more insight into a possible correlation between thiopurine-induced side effects and ITPA polymorphisms. METHODS We explored Medline for articles on ITPA polymorphisms and thiopurine toxicity. Studies that compared ITPA polymorphism frequencies among thiopurine-tolerant and -intolerant adult inflammatory bowel disease patients were included in this meta-analysis. RESULTS Nine published studies investigated associations between ITPA polymorphisms and thiopurine toxicity. Six studies (with 751 patients included) met our inclusion criteria and were processed in the meta-analysis. This analysis demonstrates that the ITPA 94C-->A polymorphism, is not significantly associated with any of the studied side effect parameters. CONCLUSIONS This meta-analysis does not prove a correlation between the development of thiopurine toxicity and the ITPA 94C-->A polymorphism. This implies that there is no clinical relevance to determine ITPA polymorphisms in thiopurine-treated patients.
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Affiliation(s)
- J M Van Dieren
- Department of Gastroenterology and Hepatology, Erasmus MC University Medical Center Rotterdam, Rotterdam, The Netherlands.
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Gisbert JP, Gomollón F. [Common errors in the management of the seriously ill patient with inflammatory bowel disease]. GASTROENTEROLOGIA Y HEPATOLOGIA 2007; 30:294-314. [PMID: 17493441 DOI: 10.1157/13101982] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Affiliation(s)
- Javier P Gisbert
- Servicio de Aparato Digestivo, Hospital Universitario de La Princesa, Universidad Autónoma, Madrid, Spain.
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Stocco G, Martelossi S, Barabino A, Decorti G, Bartoli F, Montico M, Gotti A, Ventura A. Glutathione-S-transferase genotypes and the adverse effects of azathioprine in young patients with inflammatory bowel disease. Inflamm Bowel Dis 2007; 13:57-64. [PMID: 17206640 DOI: 10.1002/ibd.20004] [Citation(s) in RCA: 55] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
BACKGROUND Adverse drug reactions to azathioprine, the prodrug of 6-mercaptopurine, occur in 15%-38% of patients and the majority are not explained by thiopurine-S-methyltransferase (TPMT) deficiency. Azathioprine is known to induce glutathione depletion and consumption of glutathione is greater in cells with high glutathione-S-transferase (GST) activity compared with those with low activity; moreover, some reports indicate that GST might play a direct role in the reaction of glutathione with azathioprine. The association between polymorphisms of GST-M1, GST-P1, GST-T1, and TPMT genes and the adverse effects of azathioprine was therefore investigated. METHODS Seventy patients with inflammatory bowel disease (IBD), treated with azathioprine, were enrolled and clinical data were retrospectively determined. TPMT and GST genotyping were performed by polymerase chain reaction (PCR) assays on DNA extracted from blood samples. RESULTS Fifteen patients developed adverse effects (21.4%); there was a significant underrepresentation of the GST-M1 null genotype among patients developing adverse drug reactions to azathioprine (odds ratio [OR] = 0.18, 95% confidence interval [CI] = 0.037-0.72, P = 0.0072) compared with patients who did not develop adverse effects. Patients heterozygous for TPMT mutations presented a marginally significant increased probability of developing adverse effects (OR = 6.38, 95% CI = 0.66-84.1, P = 0.062). Moreover, among the 55 patients who did not develop adverse effects, there was a significant underrepresentation of the GST-M1 null genotype among patients who displayed lymphopenia as compared with those that did not display this effect of azathioprine (OR = 0.15, 95% CI = 0.013-1.08, P = 0.032). CONCLUSION Patients with IBD with a wildtype GST-M1 genotype present increased probability of developing adverse effects and increased incidence of lymphopenia during azathioprine treatment.
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Affiliation(s)
- Gabriele Stocco
- Department of Biomedical Sciences, University of Trieste, Trieste, Italy.
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Sørensen HT, Jacobsen J, Nørgaard M, Pedersen L, Johnsen SP, Baron JA. Newer cyclo-oxygenase-2 selective inhibitors, other non-steroidal anti-inflammatory drugs and the risk of acute pancreatitis. Aliment Pharmacol Ther 2006; 24:111-6. [PMID: 16803609 DOI: 10.1111/j.1365-2036.2006.02959.x] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
BACKGROUND Case reports have suggested that the use of newer cyclo-oxygenase-2 selective inhibitors may cause acute pancreatitis, but there has been no formal study of the association. AIM To assess the relationship between the use of cyclo-oxygenase-2 inhibitors and other non-steroidal anti-inflammatory drugs, and risk of acute pancreatitis. METHODS A population-based case-control study was conducted using hospital discharge and prescription data from Denmark. Using conditional logistic regression with adjustment for multiple covariates, we estimated the relative risk of acute pancreatitis for use of the cyclo-oxygenase-2 inhibitors celecoxib and rofecoxib and for other non-steroidal anti-inflammatory drugs. RESULTS A total of 3083 cases of acute pancreatitis and 30 830 population controls were identified. For current use the relative risk estimate for celecoxib was 1.4 (95% CI: 0.8-2.3) and for rofecoxib was 1.3 (95% CI: 0.7-2.3). The overall relative risk for other non-steroidal anti-inflammatory drugs was 2.7 (95% CI: 2.4-3.0) with a substantial variation in risk between the individual drugs. The highest relative risk was for diclofenac (odds ratio 5.0, 95% CI: 4.2-5.9) and the lowest for naproxen (odds ratio 1.1, 95% CI: 0.7-1.7). CONCLUSION Cyclo-oxygenase-2 selective inhibitors are associated with a lower risk of acute pancreatitis than most other non-steroidal anti-inflammatory drugs.
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Affiliation(s)
- H T Sørensen
- Department of Clinical Epidemiology, Aarhus University Hospital, Aarhus C, Denmark.
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Sekimoto M, Takada T, Kawarada Y, Hirata K, Mayumi T, Yoshida M, Hirota M, Kimura Y, Takeda K, Isaji S, Koizumi M, Otsuki M, Matsuno S. JPN Guidelines for the management of acute pancreatitis: epidemiology, etiology, natural history, and outcome predictors in acute pancreatitis. JOURNAL OF HEPATO-BILIARY-PANCREATIC SURGERY 2006; 13:10-24. [PMID: 16463207 PMCID: PMC2779368 DOI: 10.1007/s00534-005-1047-3] [Citation(s) in RCA: 157] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Acute pancreatitis is a common disease with an annual incidence of between 5 and 80 people per 100,000 of the population. The two major etiological factors responsible for acute pancreatitis are alcohol and cholelithiasis (gallstones). The proportion of patients with pancreatitis caused by alcohol or gallstones varies markedly in different countries and regions. The incidence of acute alcoholic pancreatitis is considered to be associated with high alcohol consumption. Although the incidence of alcoholic pancreatitis is much higher in men than in women, there is no difference in sexes in the risk involved after adjusting for alcohol intake. Other risk factors include endoscopic retrograde cholangiopancreatography, surgery, therapeutic drugs, HIV infection, hyperlipidemia, and biliary tract anomalies. Idiopathic acute pancreatitis is defined as acute pancreatitis in which the etiological factor cannot be specified. However, several studies have suggested that this entity includes cases caused by other specific disorders such as microlithiasis. Acute pancreatitis is a potentially fatal disease with an overall mortality of 2.1%-7.8%. The outcome of acute pancreatitis is determined by two factors that reflect the severity of the illness: organ failure and pancreatic necrosis. About half of the deaths in patients with acute pancreatitis occur within the first 1-2 weeks and are mainly attributable to multiple organ dysfunction syndrome (MODS). Depending on patient selection, necrotizing pancreatitis develops in approximately 10%-20% of patients and the mortality is high, ranging from 14% to 25% of these patients. Infected pancreatic necrosis develops in 30%-40% of patients with necrotizing pancreatitis and the incidence of MODS in such patients is high. The recurrence rate of acute pancreatitis is relatively high: almost half the patients with acute alcoholic pancreatitis experience a recurrence. When the gallstones are not treated, the risk of recurrence in gallstone pancreatitis ranges from 32% to 61%. After recovering from acute pancreatitis, about one-third to one-half of acute pancreatitis patients develop functional disorders, such as diabetes mellitus and fatty stool; the incidence of chronic pancreatitis after acute pancreatitis ranges from 3% to 13%. Nevertheless, many reports have shown that most patients who recover from acute pancreatitis regain good general health and return to their usual daily routine. Some authors have emphasized that endocrine function disorders are a common complication after severe acute pancreatitis has been treated by pancreatic resection.
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Affiliation(s)
- Miho Sekimoto
- Department of Healthcare Economics and Quality Management, Kyoto University Graduate School of Medicine, Sakyo-ku, Kyoto 606-8501, Japan
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Moolsintong P, Loftus EV, Chari ST, Egan LJ, Tremaine WJ, Sandborn WJ. Acute pancreatitis in patients with Crohn's disease: clinical features and outcomes. Inflamm Bowel Dis 2005; 11:1080-4. [PMID: 16306770 DOI: 10.1097/01.mib.0000186485.30623.ad] [Citation(s) in RCA: 39] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
BACKGROUND Acute pancreatitis has occasionally been associated with Crohn's disease (CD), but whether a causal association exists remains unclear. We sought to determine the frequency of etiologies in a consecutive series of patients with CD with acute pancreatitis. METHODS A centralized diagnostic index was used to identify all patients with CD with acute pancreatitis that were evaluated at Mayo Clinic Rochester between 1976 and 2001. Both diagnoses were made or confirmed at our institution. Records were abstracted for demographics, presenting symptoms, diagnostic tests, risk factors of pancreatitis, treatment, and follow-up. RESULTS Forty-eight patients with CD with pancreatitis were identified. The median age at diagnosis of acute pancreatitis was 47 years (range, 31-91 yr). Forty-six (96%) met biochemical criteria for acute pancreatitis. The most sensitive radiographic tests were abdominal computed tomography (70%) and abdominal ultrasound (46%). The etiology of pancreatitis was considered to be gallstones (21%), significant alcohol intake (15%), use of purine analogs (13%), duodenal Crohn's involvement (12%), postendoscopic retrograde cholangiopancreatography complications (10%), postoperative complications (12%), use of other medications (4%) and idiopathic (8%). The median length of hospitalization was 7 days (range, 0-40 d). Ten patients (21%) had recurrence of acute pancreatitis. Three patients (6%) were subsequently diagnosed with pancreatic cancer. CONCLUSIONS A definite etiology could be identified in most patients with CD with acute pancreatitis. Gallstones and alcohol accounted for more than one third of cases, whereas CD, either because of duodenal involvement or medications used for its treatment, accounted for more than one quarter of the cases. A small proportion of patients remained idiopathic.
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Affiliation(s)
- Picha Moolsintong
- Department of Internal Medicine and Division of Gastroenterology and Hepatology, Mayo Clinic and Foundation, Rochester, MN 55905, USA
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Abstract
BACKGROUND AND AIMS Many frequently prescribed drugs are suspected to cause acute pancreatitis (AP). The goal of this paper is to bring to light the often occult but real problem of drug-induced pancreatitis (DIP). METHODS We searched the National Library of Medicine/Pubmed for reported cases of DIP from 1966 to April 30, 2004. Medications implicated in AP are classified based on the strength of evidence into one of three classes of drugs associated with pancreatitis. We reviewed the top 100 prescription medications in the United States for their association with AP. RESULTS Class I medications (medications implicated in greater than 20 reported cases of acute pancreatitis with at least one documented case following reexposure): didanosine, asparaginase, azathioprine, valproic acid, pentavalent antimonials, pentamidine, mercaptopurine, mesalamine, estrogen preparations, opiates, tetracycline, cytarabine, steroids, trimethoprim/sulfamethoxazole, sulfasalazine, furosemide, and sulindac. Class II medications (medications implicated in more than 10 cases of acute pancreatitis): rifampin, lamivudine, octreotide, carbamazepine, acetaminophen, phenformin, interferon alfa-2b, enalapril, hydrochlorothiazide, cisplatin, erythromycin, and cyclopenthiazide. Class III medications (all medications reported to be associated with pancreatitis). Of the top 100 most frequently prescribed medications in the United States, 44 have been implicated in AP, 14 of them fall into either Class I or II of medications associated with AP. CONCLUSIONS Among adverse drug reactions, pancreatitis is often-ignored because of the difficulty in implicating a drug as its cause. The physician should have a high index of suspicion for DIP, especially in specific subpopulations such as geriatric patients who may be on multiple medications, HIV+ patients, cancer patients, and patients receiving immunomodulating agents.
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Affiliation(s)
- Chirag D Trivedi
- Department of Medicine, Robert Wood Johnson Medical School, and Division of Gastroenterology, Hepatology and Clinical Nutrition, St. Peter's University Hospital, New Brunswick, NJ 08901, USA
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Sørensen HT, Skriver MV, Friis S, McLaughlin JK, Blot WJ, Baron JA. Use of antibiotics and risk of breast cancer: a population-based case-control study. Br J Cancer 2005; 92:594-6. [PMID: 15611791 PMCID: PMC2362073 DOI: 10.1038/sj.bjc.6602313] [Citation(s) in RCA: 33] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023] Open
Abstract
We examined the use of antibiotics among 2728 women with a first diagnosis of breast cancer during 1994–2003, and 27 280 population controls in North Jutland County, Denmark, based on hospital discharge diagnoses, prescription use from 1989 to 2002, and population registry data. We found no increased relative risk of breast cancer associated with use compared with nonuse. The odds ratio for breast cancer associated with more than 10 prescriptions for antibiotics was 1.00 (95% CI 0.86 –1.15). Relative risks were similar for different classes of antibiotics. A subanalysis based on cases and controls younger than 70 years of age, with data on first birth and number of children, showed similar risk estimates even after adjustment for age at first birth and parity. In our study, use of antibiotics was not associated with an increased risk of breast cancer.
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Affiliation(s)
- H T Sørensen
- Department of Clinical Epidemiology, Aarhus University Hospital, Vennelyst Boulevard 6, Building 260, DK-8000 Aarhus C, Denmark.
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Weersma RK, Peters FTM, Oostenbrug LE, van den Berg AP, van Haastert M, Ploeg RJ, Posthumus MD, Homan van der Heide JJ, Jansen PLM, van Dullemen HM. Increased incidence of azathioprine-induced pancreatitis in Crohn's disease compared with other diseases. Aliment Pharmacol Ther 2004; 20:843-50. [PMID: 15479355 DOI: 10.1111/j.1365-2036.2004.02197.x] [Citation(s) in RCA: 78] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
BACKGROUND Azathioprine is widely used in Crohn's disease. A major drawback is the occurrence of side-effects, especially acute pancreatitis. Acute pancreatitis is rarely seen when azathioprine is used for other diseases than Crohn's disease. AIM To survey side-effects of azathioprine after liver or renal transplantation, for systemic lupus erythematosis, Wegener's granulomatosis, autoimmune hepatitis, rheumatoid arthritis, ulcerative colitis or Crohn's disease. METHODS A computerized search using the term 'azathioprine' or 'imuran' was performed on the Hospital Information System of the university hospital Groningen, resulting in 1564 patients matching our criteria. RESULTS Eleven of 224 patients with Crohn's disease experienced acute pancreatitis (4.9%) compared with two of 129 (1.5%) with autoimmune hepatitis, two of 388 (0.5%) after renal transplantation, one of 254 (0.4%) after liver transplantation. Acute pancreatitis was more prevalent in Crohn's disease compared with any other disease. Azathioprine-toxicity necessitating withdrawal occurred significantly (P < 0,05) more in rheumatoid arthritis (78 of 317), ulcerative colitis (20 of 94) and Crohn's disease (52 of 224) compared with systemic lupus erythematosis (five of 73), Wegener's granulomatosis (six of 85), autoimmune hepatitis (eight of 129), after liver transplantation (17 of 254) and after renal transplantation (22 of 388). CONCLUSIONS Acute pancreatitis is strongly associated with Crohn's disease and rarely occurs with other underlying conditions. Overall azathioprine-induced toxicity and the necessity of withdrawal is more common in inflammatory bowel disease and rheumatoid arthritis compared with other diseases.
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Affiliation(s)
- R K Weersma
- Department of Gastroenterology and Hepatology, University Hospital Groningen, Groningen, The Netherlands.
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Munk EM, Pedersen L, Floyd A, Nørgård B, Rasmussen HH, Sørensen HT. Inflammatory bowel diseases, 5-aminosalicylic acid and sulfasalazine treatment and risk of acute pancreatitis: a population-based case-control study. Am J Gastroenterol 2004; 99:884-8. [PMID: 15128355 DOI: 10.1111/j.1572-0241.2004.04123.x] [Citation(s) in RCA: 38] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
OBJECTIVES Patients with inflammatory bowel diseases are suggested to have an increased risk of acute pancreatitis. Although azathioprine and glucocorticoids are risk factors for acute pancreatitis, the relation is poorly understood, in particular the role of 5-aminosalicylic acid and sulfasalazine treatment. To clarify these relations, we conducted a population-based case-control study. METHODS We identified 1,590 incident cases of acute pancreatitis from the Hospital Discharge Registry of the North Jutland County of Denmark from 1991 to 2002, and selected 10 controls per case (N = 15,913) from the Central Personal Registry, matched by age and gender. Among cases and controls, we identified patients with inflammatory bowel diseases. Data on drug use were extracted from a Pharmaco-epidemiological Prescription Database. RESULTS Adjusted odds ratios for acute pancreatitis in patients with Crohn's disease and ulcerative colitis were 3.7 (95% confidence interval (CI), 1.9-7.6) and 1.5 (95% CI, 0.7-3.6), respectively. In all patients treated with 5-aminosalicylic acid and sulfasalazine the adjusted odds ratios for acute pancreatitis were 0.7 (95% CI, 0.4-2.2) and 1.5 (95% CI, 0.4-5.2), respectively. Restricted to patients with inflammatory bowel diseases only, the adjusted odds ratios for acute pancreatitis in patients exposed to 5-aminosalicylic acid and sulfasalazine were 0.7 (95% CI, 0.1-3.8) and 0.6 (95% CI, 0.1-6.7), respectively. CONCLUSION We found a nearly four-fold increased risk of acute pancreatitis in patients with Crohn's disease and a 1.5-fold increased risk for ulcerative colitis. In patients with inflammatory bowel diseases, the use of 5-aminosalicylic acid or sulfasalazine was not associated with increased risk of acute pancreatitis.
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Affiliation(s)
- Estrid Muff Munk
- Department of Clinical Epidemiology, Aarhus University Hospital, DK-8000 Aarhus C, Denmark
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Pharmacoepidemiology and drug safety. Pharmacoepidemiol Drug Saf 2004; 12:699-714. [PMID: 14762987 DOI: 10.1002/pds.933] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/19/2023]
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