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O'Shea M, Kuhn A, Creo AL, Kohorst M, Ferdjallah A. Profound Hypoglycemia and High Anion Gap Metabolic Acidosis in a Pediatric Leukemic Patient Receiving 6-Mercaptopurine. CHILDREN (BASEL, SWITZERLAND) 2024; 11:160. [PMID: 38397272 PMCID: PMC10886981 DOI: 10.3390/children11020160] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/14/2023] [Revised: 01/10/2024] [Accepted: 01/22/2024] [Indexed: 02/25/2024]
Abstract
A 13-year-old male undergoing maintenance chemotherapy with methotrexate and 6-mercaptopurine (6MP), for very high-risk B-cell acute lymphoblastic leukemia (ALL), presented with vomiting due to severe hypoglycemia with metabolic acidosis. While his laboratory values were concerning for a critically ill child, the patient was relatively well appearing. Hypoglycemia is a rare but serious side effect of 6MP with an unexpectedly variable presentation; therefore, a high index of suspicion is needed for its prompt detection and treatment. This patient also had severe metabolic acidosis, likely secondary to hypoglycemia, creating a serious clinical picture despite a well-appearing child. This example of incongruity between laboratory tests and clinical appearance adds nuance to the existing literature. Moreover, although 6MP-associated hypoglycemia is rare, it may be more prevalent than the literature suggests, as symptoms of hypoglycemia-nausea, vomiting, and somnolence-mirror common chemotherapy side effects. 6MP-induced hypoglycemia can be ameliorated with the addition of allopurinol to shunt metabolism in favor of the production of therapeutic metabolites over hepatotoxic metabolites. Additionally, a morning administration of 6MP and frequent snacks may also help to prevent hypoglycemia. Overall, this case adds to the literature of unusual reactions to 6MP including hypoglycemia in an older child without traditional risk factors.
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Affiliation(s)
- Molly O'Shea
- Mayo Clinic Alix School of Medicine, Rochester, MN 55905, USA
| | - Alexis Kuhn
- Pediatric Hematology and Oncology, Mayo Clinic, Rochester, MN 55905, USA
| | - Ana L Creo
- Pediatric Endocrinology, Mayo Clinic, Rochester, MN 55905, USA
| | - Mira Kohorst
- Pediatric Hematology and Oncology, Mayo Clinic, Rochester, MN 55905, USA
| | - Asmaa Ferdjallah
- Pediatric Hematology and Oncology, Mayo Clinic, Rochester, MN 55905, USA
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Yewale RV, Ramakrishna BS, Doraisamy BV, Basumani P, Venkataraman J, Jayaraman K, Murali A, Premkumar K, Kumar AS. Long-term safety and effectiveness of azathioprine in the management of inflammatory bowel disease: A real-world experience. JGH Open 2023; 7:599-609. [PMID: 37744710 PMCID: PMC10517446 DOI: 10.1002/jgh3.12955] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2023] [Revised: 06/15/2023] [Accepted: 07/22/2023] [Indexed: 09/26/2023]
Abstract
Background and Aim Azathioprine (AZA) forms the cornerstone for maintenance of sustained remission in inflammatory bowel disease (IBD). There is apprehension regarding the long-term effectiveness and safety of AZA in IBD. We present our experience with AZA use and outcomes in a cohort of IBD patients followed up over a long period of time. Methods Records of 507 IBD patients under treatment at a single, tertiary care center in south India between 2013 and 2022 were evaluated retrospectively. Long-term compliance, tolerance, clinical outcome at the point of last follow-up, type and duration to the onset of adverse events, and subsequent amendment to treatment with regard to AZA were analyzed. Results Of 507 patients with IBD, 320 patients (207 Crohn's disease [CD], 113 ulcerative colitis [UC]) who received AZA were included. The median follow-up was 41 months (interquartile range 15.5-77.5). Total duration of exposure was 1359 patient-years with median usage of 33 months. Of the patients, 26.9% received AZA for >5 years. Mean initiation and maximum doses of AZA were 0.97 and 1.72 mg/kg/day. Among the participants, 20.6% experienced side effects, including myelotoxicity (7.2%) and gastrointestinal intolerance (5.6%). Six patients developed malignancy. Among the side effects, 39.4% of side effects were dose-dependent. Among the patients, 38.1% had relapses requiring pulse corticosteroid therapy, and 16.2% had more than one relapse after commencement of AZA. AZA was continued till the last follow-up in 76.5%. Among the patients, 49.7% (UC 51.3, CD 48.8) attained durable remission without biologics, and 5.3% continued to have active disease. Conclusion AZA is safe and effective in the long-term in IBD. Effectiveness, tolerance, and compliance with AZA are well sustained beyond 5 years of usage and comparable between UC and CD.
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Affiliation(s)
- Rohan V Yewale
- Institute of Gastroenterology, SRM Institutes for Medical ScienceChennaiTamil NaduIndia
| | | | - Babu Vinish Doraisamy
- Institute of Gastroenterology, SRM Institutes for Medical ScienceChennaiTamil NaduIndia
| | - Pandurangan Basumani
- Department of GastroenterologyApollo Hospitals Greams RoadChennaiTamil NaduIndia
| | - Jayanthi Venkataraman
- Department of HepatologySri Ramachandra Institute of Higher Education and ResearchChennaiTamil NaduIndia
| | - Kayalvizhi Jayaraman
- Institute of Gastroenterology, SRM Institutes for Medical ScienceChennaiTamil NaduIndia
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Laube R, Selinger CP, Seow CH, Christensen B, Flanagan E, Kennedy D, Mountifield R, Seeho S, Shand A, Williams AJ, Leong RW. Australian inflammatory bowel disease consensus statements for preconception, pregnancy and breast feeding. Gut 2023; 72:1040-1053. [PMID: 36944479 DOI: 10.1136/gutjnl-2022-329304] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/13/2022] [Accepted: 02/21/2023] [Indexed: 03/23/2023]
Abstract
OBJECTIVE Because pregnancy outcomes tend to be worse in women with inflammatory bowel disease (IBD) than in those without, we aimed to update consensus statements that guide the clinical management of pregnancy in patients with IBD. DESIGN A multidisciplinary working group was established to formulate these consensus statements. A modified RAND/UCLA appropriateness method was used, consisting of a literature review, online voting, discussion meeting and a second round of voting. The overall agreement among the delegates and appropriateness of the statement are reported. RESULTS Agreement was reached for 38/39 statements which provide guidance on management of pregnancy in patients with IBD. Most medications can and should be continued throughout pregnancy, except for methotrexate, allopurinol and new small molecules, such as tofacitinib. Due to limited data, no conclusion was reached on the use of tioguanine during pregnancy. Achieving and maintaining IBD remission before conception and throughout pregnancy is crucial to optimise maternofetal outcomes. This requires a multidisciplinary approach to engage patients, allay anxieties and maximise adherence tomedication. Intestinal ultrasound can be used for disease monitoring during pregnancy, and flexible sigmoidoscopy or MRI where clinically necessary. CONCLUSION These consensus statements provide up-to-date, comprehensive recommendations for the management of pregnancy in patients with IBD. This will enable a high standard of care for patients with IBD across all clinical settings.
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Affiliation(s)
- Robyn Laube
- Faculty of Medicine and Health Sciences, Macquarie University, Sydney, New South Wales, Australia
- Department of Gastroenterology, Macquarie University Hospital, Sydney, New South Wales, Australia
| | | | - Cynthia H Seow
- Department of Medicine, University of Calgary, Calgary, Alberta, Canada
| | - Britt Christensen
- Gastroenterology Department, Royal Melbourne Hospital, Melbourne, Victoria, Australia
| | - Emma Flanagan
- Department of Gastroenterology, University of Melbourne, Melbourne, Victoria, Australia
| | - Debra Kennedy
- MotherSafe, Royal Hospital for Women, Sydney, New South Wales, Australia
| | - Reme Mountifield
- Department of Gastroenterology, Flinders Medical Centre, Adelaide, South Australia, Australia
| | - Sean Seeho
- Department of Obstetrics and Gynaecology, Royal North Shore Hospital, St Leonards, New South Wales, Australia
| | - Antonia Shand
- Department of Maternal Foetal Medicine, Royal Hospital for Women, Sydney, New South Wales, Australia
| | - Astrid-Jane Williams
- Department of Gastroenterology, Liverpool Hospital, Liverpool, New South Wales, Australia
| | - Rupert W Leong
- Faculty of Medicine and Health Sciences, Macquarie University, Sydney, New South Wales, Australia
- Department of Gastroenterology, Macquarie University Hospital, Sydney, New South Wales, Australia
- Gastroenterology and Liver Services, Concord Repatriation General Hospital, Concord, New South Wales, Australia
- The University of Sydney Faculty of Medicine and Health, Sydney, New South Wales, Australia
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Mallick B, Malik S. Use of Azathioprine in Ulcerative Colitis: A Comprehensive Review. Cureus 2022; 14:e24874. [PMID: 35698683 PMCID: PMC9184176 DOI: 10.7759/cureus.24874] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/09/2022] [Indexed: 01/10/2023] Open
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Cytotoxicity of Thiopurine Drugs in Patients with Inflammatory Bowel Disease. TOXICS 2022; 10:toxics10040151. [PMID: 35448412 PMCID: PMC9026123 DOI: 10.3390/toxics10040151] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/11/2022] [Revised: 03/11/2022] [Accepted: 03/17/2022] [Indexed: 02/04/2023]
Abstract
The effectiveness of thiopurine drugs in inflammatory bowel disease (IBD) was confirmed more than a half-century ago. It was proven that these can be essential immunomodulatory medications. Since then, they have been used routinely to maintain remission of Crohn’s disease (CD) and ulcerative colitis (UC). The cytotoxic properties of thiopurines and the numerous adverse effects of the treatment are controversial. However, the research subject of their pharmacology, therapy monitoring, and the search for predictive markers are still very relevant. In this article, we provide an overview of the current knowledge and findings in the field of thiopurines in IBD, focusing on the aspect of their cytotoxicity. Due to thiopurines’ benefits in IBD therapy, it is expected that they will still constitute an essential part of the CD and UC treatment algorithm. More studies are still required on the modulation of the action of thiopurines in combination therapy and their interaction with the gut microbiota.
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Deben DS, Wong DR, van Bodegraven AA. Current status and future perspectives on the use of therapeutic drug monitoring of thiopurine metabolites in patients with inflammatory bowel disease. Expert Opin Drug Metab Toxicol 2022; 17:1433-1444. [PMID: 35023443 DOI: 10.1080/17425255.2021.2029406] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
INTRODUCTION Despite new treatment options for inflammatory bowel disease (IBD), conventional thiopurines remain a common treatment option for maintaining remission, particularly in non-Westernized countries. Therapeutic drug monitoring (TDM) is advised in standard care for optimizing therapy strategies to improve effectiveness, reveal nonadherence and reduce toxicity. Still, the rationale of TDM is debated. AREAS COVERED Key insights on TDM of thiopurine metabolites are discussed. The pharmacology of thiopurines is described, emphasizing the interindividual differences in pharmacogenetics, pharmacokinetics and pharmacodynamics. Pharmacological differences between conventional thiopurines and tioguanine are outlined. Finally, several optimization strategies for thiopurine therapy in IBD are discussed. EXPERT OPINION TDM has been a useful, but limited, tool to individualize thiopurine therapy. Pharmacokinetic data on the active thiopurine metabolites, derived from measurements in erythrocytes, associated with clinical response only partially predict effectiveness and toxicity. An additional pharmacodynamic marker, such as Rac1/pSTAT3 expression in leukocytes, may improve applicability of TDM in the future.
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Affiliation(s)
- Debbie S Deben
- Dept. of Clinical Pharmacy, Clinical pharmacology and Toxicology, Zuyderland Medical Centre, Sittard-Geleen/Heerlen, The Netherlands
| | - Dennis R Wong
- Dept. of Clinical Pharmacy, Clinical pharmacology and Toxicology, Zuyderland Medical Centre, Sittard-Geleen/Heerlen, The Netherlands
| | - Adriaan A van Bodegraven
- Dept. of Gastroenterology, Geriatrics, Internal and Intensive Care Medicine (Co-MIK), Zuyderland Medical Centre Sittard-Geleen/Heerlen, The Netherlands.,Dept. of Gastroenterology and Hepatology, Amsterdam, The Netherlands
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Dickson AL, Daniel LL, Zanussi J, Dale Plummer W, Wei WQ, Liu G, Reese T, Anandi P, Birdwell KA, Kawai V, Cox NJ, Dupont WD, Hung AM, Feng Q, Stein CM, Chung CP. TPMT and NUDT15 Variants Predict Discontinuation of Azathioprine for Myelotoxicity in Patients with Inflammatory Disease: Real-World Clinical Results. Clin Pharmacol Ther 2022; 111:263-271. [PMID: 34582038 PMCID: PMC8678305 DOI: 10.1002/cpt.2428] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2021] [Accepted: 09/20/2021] [Indexed: 01/03/2023]
Abstract
Azathioprine is used frequently to treat several inflammatory conditions. However, treatment is limited by adverse events-in particular, myelotoxicity. Thiopurine-S-methyltransferase (TPMT) and nudix hydrolase-15 (NUDT15) are enzymes involved in azathioprine metabolism; variants in the genes encoding these enzymes increase the risk for azathioprine myelotoxicity. The Clinical Pharmacogenetics Implementation Consortium (CPIC) has recommended dose adjustments based on the results of TPMT and NUDT15 genotyping. However, little is known about the importance of this genetic information in routine clinical care. We hypothesized that in patients with inflammatory diseases, TPMT and NUDT15 genotype data predict the risk of discontinuing azathioprine due to myelotoxicity. This was a retrospective cohort study in 1,403 new adult azathioprine users for the management of inflammatory conditions for whom we had genetic information and clinical data. Among patients who discontinued azathioprine, we adjudicated the reason(s). Genotyping was performed using the Illumina Infinium Expanded Multi-Ethnic Genotyping Array plus custom content. We used CPIC guidelines to determine TPMT and NUDT15 metabolizer status; patients were grouped as either: (i) poor/intermediate, or (ii) normal/indeterminate metabolizers. We classified 110 patients as poor/intermediate, and 1,293 patients as normal/indeterminate metabolizers. Poor/intermediate status was associated with a higher risk for azathioprine discontinuation due to myelotoxicity compared to normal/indeterminate metabolizers (hazard ratio (HR) = 2.90, 95% confidence interval (CI): 1.58-5.31, P = 0.001). This association remained significant after adjustment for race, age at initiation, sex, primary indication, and initial daily dose of azathioprine (adjusted HR (aHR) = 2.67, 95% CI: 1.44-4.94, P = 0.002). In conclusion, TPMT and NUDT15 metabolizer status predicts discontinuation due to myelotoxicity for patients taking azathioprine for inflammatory conditions.
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Affiliation(s)
- Alyson L Dickson
- Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - Laura L Daniel
- Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - Jacy Zanussi
- Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - W Dale Plummer
- Department of Biostatistics, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - Wei-Qi Wei
- Department of Bioinformatics, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - Ge Liu
- Department of Bioinformatics, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - Tyler Reese
- Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - Prathima Anandi
- Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - Kelly A Birdwell
- Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - Vivian Kawai
- Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - Nancy J Cox
- Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA
- Vanderbilt Genetics Institute, Vanderbilt University School of Medicine, Nashville, Tennessee, USA
| | - William D Dupont
- Department of Biostatistics, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - Adriana M Hung
- Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA
- Tennessee Valley Healthcare System - Nashville Campus, Nashville, Tennessee, USA
| | - QiPing Feng
- Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - C Michael Stein
- Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA
- Department of Pharmacology, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - Cecilia P Chung
- Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA
- Vanderbilt Genetics Institute, Vanderbilt University School of Medicine, Nashville, Tennessee, USA
- Tennessee Valley Healthcare System - Nashville Campus, Nashville, Tennessee, USA
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Singh A, Mahajan R, Kedia S, Dutta AK, Anand A, Bernstein CN, Desai D, Pai CG, Makharia G, Tevethia HV, Mak JWY, Kaur K, Peddi K, Ranjan MK, Arkkila P, Kochhar R, Banerjee R, Sinha SK, Ng SC, Hanauer S, Verma S, Dutta U, Midha V, Mehta V, Ahuja V, Sood A. Use of thiopurines in inflammatory bowel disease: an update. Intest Res 2022; 20:11-30. [PMID: 33845546 PMCID: PMC8831775 DOI: 10.5217/ir.2020.00155] [Citation(s) in RCA: 61] [Impact Index Per Article: 20.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/04/2020] [Revised: 02/19/2021] [Accepted: 03/01/2021] [Indexed: 12/11/2022] Open
Abstract
Inflammatory bowel disease (IBD), once considered a disease of the Western hemisphere, has emerged as a global disease. As the disease prevalence is on a steady rise, management of IBD has come under the spotlight. 5-Aminosalicylates, corticosteroids, immunosuppressive agents and biologics are the backbone of treatment of IBD. With the advent of biologics and small molecules, the need for surgery and hospitalization has decreased. However, economic viability and acceptability is an important determinant of local prescription patterns. Nearly one-third of the patients in West receive biologics as the first/initial therapy. The scenario is different in developing countries where biologics are used only in a small proportion of patients with IBD. Increased risk of reactivation of tuberculosis and high cost of the therapy are limitations to their use. Thiopurines hence become critical for optimal management of patients with IBD in these regions. However, approximately one-third of patients are intolerant or develop adverse effects with their use. This has led to suboptimal use of thiopurines in clinical practice. This review article discusses the clinical aspects of thiopurine use in patients with IBD with the aim of optimizing their use to full therapeutic potential.
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Affiliation(s)
- Arshdeep Singh
- Department of Gastroenterology, Dayanand Medical College and Hospital, Ludhiana, India
| | - Ramit Mahajan
- Department of Gastroenterology, Dayanand Medical College and Hospital, Ludhiana, India
| | - Saurabh Kedia
- Department of Gastroenterology and Human Nutrition, All India Institute of Medical Sciences, New Delhi, India
| | - Amit Kumar Dutta
- Department of Gastroenterology, Christian Medical College, Vellore, India
| | - Abhinav Anand
- Department of Gastroenterology and Human Nutrition, All India Institute of Medical Sciences, New Delhi, India
| | - Charles N. Bernstein
- University of Manitoba IBD Clinical and Research Centre, Max Rady College of Medicine, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB, Canada
| | - Devendra Desai
- P. D. Hinduja Hospital and Medical Research Centre, Mumbai, India
| | - C. Ganesh Pai
- Department of Gastroenterology, Kasturba Medical College, Manipal, India
| | - Govind Makharia
- Department of Gastroenterology and Human Nutrition, All India Institute of Medical Sciences, New Delhi, India
| | | | - Joyce WY Mak
- Department of Medicine and Therapeutics, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, Hong Kong
| | - Kirandeep Kaur
- Department of Pharmacology, Dayanand Medical College and Hospital, Ludhiana, India
| | - Kiran Peddi
- Citizens Centre for Digestive Disorders, Hyderabad, India
| | - Mukesh Kumar Ranjan
- Department of Gastroenterology and Human Nutrition, All India Institute of Medical Sciences, New Delhi, India
| | - Perttu Arkkila
- Department of Gastroenterology, Helsinki University Central Hospital, Helsinki, Finland
| | - Rakesh Kochhar
- Department of Gastroenterology, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| | - Rupa Banerjee
- Asian Institute of Gastroenterology Hyderabad, Hyderabad, India
| | - Saroj Kant Sinha
- Department of Gastroenterology, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| | - Siew Chien Ng
- Department of Medicine and Therapeutics, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, Hong Kong
| | - Stephen Hanauer
- Department of Medicine, Northwestern University, Chicago, IL, USA
| | - Suhang Verma
- Department of Gastroenterology, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| | - Usha Dutta
- Department of Gastroenterology, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| | - Vandana Midha
- Department of Internal Medicine, Dayanand Medical College, Ludhiana, India
| | - Varun Mehta
- Department of Gastroenterology, Dayanand Medical College and Hospital, Ludhiana, India
| | - Vineet Ahuja
- Department of Gastroenterology and Human Nutrition, All India Institute of Medical Sciences, New Delhi, India
| | - Ajit Sood
- Department of Gastroenterology, Dayanand Medical College and Hospital, Ludhiana, India
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Belhocine M, Mourad A, Chapdelaine A, Mansour AM, Troyanov Y, Doré M. Optimizing Thiopurine Therapy with a Xanthine Oxidase Inhibitor in Patients with Systemic Autoimmune Diseases: A Single-Centre Experience. Can J Hosp Pharm 2021; 74:361-369. [PMID: 34602624 DOI: 10.4212/cjhp.v74i4.3199] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022]
Abstract
Background Thiopurines are a mainstay of therapy for autoimmune diseases. However, up to 20% to 30% of patients experience overproduction of the methylated metabolites, known as 6-MMP, to the detriment of the active metabolite, 6-thioguanine nucleotide (6-TGN). These patients, commonly referred to as "shunters", are predisposed to thiopurine resistance and hepatotoxicity. In patients with inflammatory bowel diseases, the combination of thiopurine with a xanthine oxidase inhibitor (XOI) is used to reverse this skewed metabolism and to prevent treatment failure or hepatotoxicity. Data on the use of this strategy for patients with other diseases are limited. Objectives To investigate and describe the use of thiopurine-XOI combination therapy in shunters with systemic autoimmune diseases. Methods Shunters treated in the study hospital between January 1, 2005, and December 31, 2015, were identified using the hospital's laboratory database, and clinical data were collected retrospectively. For each patient with optimization of thiopurine therapy, clinical and laboratory data were assessed over a 6-month period. Results Thirty-four patients were identified as shunters; for 14 of these patients, thiopurine therapy was optimized with an XOI. In these 14 patients, the median dose of azathioprine was reduced from 1.95 to 0.78 mg/kg with combination therapy. In addition, median 6-TGN level increased from 135 to 385 pmol/8 × 108 erythrocytes (p = 0.001); furthermore, 6-TGN levels rose to above 235 pmol/8 ×108 erythrocytes for 11 of the 14 patients. Conversely, the median 6-MMP level decreased from 6267 to 271 pmol/8 × 108 erythrocytes (p = 0.001). Except for a 12% increase in mean corpuscular volume, no clinically significant changes in blood count were recorded. Notable infections were reported in 3 patients, and 1 patient had to discontinue treatment because of cytopenia. After 6 months, median prednisone daily dose was reduced by 74%, from 16.7 mg to 4.4 mg (p = 0.005), and 4 patients had been weaned off corticosteroids. Of the 14 patients, 11 (79%) were in full remission, and 2 (14%) were in partial remission. Conclusion Optimizing thiopurine therapy with an XOI may be a safe and effective strategy for patients with systemic autoimmune diseases.
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Affiliation(s)
- Mériem Belhocine
- , MD, FRCPC, is an internal medicine specialist with Hôpital du Sacré-Coeur de Montréal, and a Clinical Professor of Medicine in the Faculty of Medicine, Université de Montréal, Montréal, Quebec
| | - Alissar Mourad
- , PharmD, MSc, was, at the time of this study, a PharmD student in the Faculty of Pharmacy, Université de Montréal, Montréal, Quebec. She has now graduated and is a pharmacist with the Centre intégré universitaire de santé et services sociaux du Centre-sud-de-l'Ile-de-Montréal, Montréal, Quebec
| | - Aurélie Chapdelaine
- , MD, FRCPC, is an internal medicine specialist with the Department of Medicine, Hôpital Notre-Dame, Montréal, Quebec
| | - Anne-Marie Mansour
- , MD, MSc, FRCPC, is an internal medicine specialist with the Department of Medicine, Hôpital du Sacré-Coeur de Montréal, and a Clinical Professor of Medicine with the Faculty of Medicine, Université de Montréal, Montréal, Quebec
| | - Yves Troyanov
- , MD, FRCPC, is a rheumatologist with the Department of Medicine, Hôpital du Sacré-Coeur de Montréal, and a Clinical Professor of Medicine with the Faculty of Medicine, Université de Montréal, Montréal, Quebec
| | - Maxime Doré
- , BSc, BPharm, MSc, is a Clinical Pharmacist with the Hôpital du Sacré-Coeur de Montréal, Montréal, Quebec
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10
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Nguyen ALH, Sparrow MP. Evolving Role of Thiopurines in Inflammatory Bowel Disease in the Era of Biologics and New Small Molecules. Dig Dis Sci 2021; 66:3250-3262. [PMID: 33073334 DOI: 10.1007/s10620-020-06662-z] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/13/2020] [Accepted: 10/06/2020] [Indexed: 12/09/2022]
Abstract
In recent years, with the increasing availability of biologic therapies and due to safety concerns, the role of thiopurines in the management of inflammatory bowel disease has been questioned. While acknowledging that the benefit/risk ratio of biologic therapies is very high, they are expensive and are not required by a majority of patients. Therefore, thiopurines do retain an important role as steroid-sparing and maintenance agents when used as monotherapy, and in combination therapy with biologics due to their clinical and pharmacokinetic optimization of anti-tumor necrosis factor agents in particular. Safety concerns with thiopurines are real but also relatively rare, and with careful pre-treatment screening and ongoing monitoring thiopurine benefits outweigh risks in the majority of appropriately selected patients. Measurement of newer pharmacogenomic markers such as nudix hydrolase 15 (NUDT15), when combined with knowledge of existing known mutations (e.g., thiopurine S-methyltransferase-TPMT), will hopefully minimize the risk of potentially life-threatening leukopenia by allowing for pre-treatment dosing stratification. Further optimization of thiopurine dosing via measurement of thiopurine metabolites should be performed routinely and is superior to weight-based dosing. The association of thiopurines with malignancies including lymphoproliferative disorders needs to be recognized in all patients and individualized in each patient. The decrease in lymphoma risk after thiopurine cessation provides an incentive for thiopurine de-escalation in appropriate patients after a period of prolonged deep remission. This review will summarize the current role of thiopurines in inflammatory bowel disease management and provide recommendations for commencing and monitoring therapy, and when to consider de-escalation.
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Affiliation(s)
- Anke L H Nguyen
- Department of Gastroenterology, Alfred Health, 55 Commercial Road, Melbourne, 3004, VIC, Australia.,Monash University, Melbourne, Australia
| | - Miles P Sparrow
- Department of Gastroenterology, Alfred Health, 55 Commercial Road, Melbourne, 3004, VIC, Australia. .,Monash University, Melbourne, Australia.
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Lu X, Ce Q, Jin L, Zheng J, Sun M, Tang X, Li D, Sun J. Deoiled sunflower seeds ameliorate depression by promoting the production of monoamine neurotransmitters and inhibiting oxidative stress. Food Funct 2020; 12:573-586. [PMID: 33367360 DOI: 10.1039/d0fo01978j] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/13/2023]
Abstract
We aimed to evaluate the antidepressant activity of deoiled sunflower seeds (SFS), which are rich in tryptophan, in our mouse model and explored a possible mechanism of action. Male C57BL/6J mice were subjected to chronic unpredictable mild stress (CUMS) and were administered a diet containing SFS as the main protein source. SFS alleviated CUMS-induced depression-like behaviors, compared to the effects of a whey protein-based diet. This effect was related to increases in the levels of serotonin, dopamine, norepinephrine, acetylcholine, and brain-derived neurotrophic factor in SFS-fed mice. These changes accompanied the amelioration of inflammatory abnormalities and oxidative stress. SFS increased the aromatic amino acid levels, and the ratio of tryptophan to neutral amino acids. Furthermore, the antidepressant-like effects of SFS were involved in lipid, nucleotide, and amino acid metabolism. In summary, SFS was found to attenuate depression-like symptoms in mice. These antidepressant effects may be related to the increase in the levels of aromatic amino acids and neurotransmitters, amelioration of oxidative stress and inflammation, and the regulation of the levels of abnormal metabolites to the normal levels.
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Affiliation(s)
- Xiaomeng Lu
- Institute of Nutrition and Health, School of Public Health, Qingdao University, Qingdao 266071, Shandong, China.
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12
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van Hoeve K, Vermeire S. Thiopurines in Pediatric Inflammatory Bowel Disease: Current and Future Place. Paediatr Drugs 2020; 22:449-461. [PMID: 32797366 DOI: 10.1007/s40272-020-00411-5] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/23/2022]
Abstract
Thiopurines have been widely used to maintain steroid-free remission in children with inflammatory bowel disease (IBD). However, within the expanding treatment armamentarium, the role of these non-selective immunomodulators has been questioned, especially in pediatric patients, who often present with a more aggressive disease course, which can impact growth and development. The less favorable safety but also inferior efficacy profile associated with thiopurines, in contrast to the newer biological therapies, has interfered with their use. The future place of thiopurines in the management of childhood IBD, therefore, needs revisiting. This review provides a practical overview on the historical and current use of thiopurines in pediatric IBD with specific attention for thiopurine S-methyltransferase testing and monitoring of thiopurine metabolite levels as an approach to improve outcomes. We also give a personal expert opinion on the future role of these drugs in childhood IBD.
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Affiliation(s)
- Karen van Hoeve
- Department of Pediatric Gastroenterology and Hepatology and Nutrition, University Hospitals Leuven, KU Leuven, Leuven, Belgium.,TARGID, Department of Chronic Diseases and Metabolism (CHROMETA), KU Leuven, Leuven, Belgium
| | - Séverine Vermeire
- TARGID, Department of Chronic Diseases and Metabolism (CHROMETA), KU Leuven, Leuven, Belgium. .,Department of Gastroenterology and Hepatology, University Hospitals Leuven, KU Leuven, Leuven, Belgium.
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13
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Anandi P, Dickson AL, Feng Q, Wei WQ, Dupont WD, Plummer D, Liu G, Octaria R, Barker KA, Kawai VK, Birdwell K, Cox NJ, Hung A, Stein CM, Chung CP. Combining clinical and candidate gene data into a risk score for azathioprine-associated leukopenia in routine clinical practice. THE PHARMACOGENOMICS JOURNAL 2020; 20:736-745. [PMID: 32054992 PMCID: PMC7426242 DOI: 10.1038/s41397-020-0163-4] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/04/2019] [Revised: 01/22/2020] [Accepted: 01/30/2020] [Indexed: 02/06/2023]
Abstract
Leukopenia is a serious, frequent side effect associated with azathioprine use. Currently, we use thiopurine methyltransferase (TPMT) testing to predict leukopenia in patients taking azathioprine. We hypothesized that a risk score incorporating additional clinical and genetic variables would improve the prediction of azathioprine-associated leukopenia. In the discovery phase, we developed four risk score models: (1) age, sex, and TPMT metabolizer status; (2) model 1 plus additional clinical variables; (3) sixty candidate single nucleotide polymorphisms; and (4) model 2 plus model 3. The area under the receiver-operating-characteristic curve (AUC) of the risk scores was 0.59 (95% CI: 0.54-0.64), 0.75 (0.71-0.80), 0.66 (0.61-0.71), and 0.78 (0.74-0.82) for models 1, 2, 3, and 4, respectively. During the replication phase, models 2 and 4 (AUC = 0.64, 95% CI: 0.59-0.70 and AUC = 0.63, 95% CI: 0.58-0.69, respectively) were significant in an independent group. Compared with TPMT testing alone, additional genetic and clinical variables improve the prediction of azathioprine-associated leukopenia.
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Affiliation(s)
- Prathima Anandi
- Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Alyson L Dickson
- Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA
| | - QiPing Feng
- Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Wei-Qi Wei
- Department of Biomedical Informatics, Vanderbilt University Medical Center, Nashville, TN, USA
| | - William D Dupont
- Department of Biostatistics, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Dale Plummer
- Department of Biostatistics, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Ge Liu
- Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Rany Octaria
- Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Katherine A Barker
- Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Vivian K Kawai
- Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Kelly Birdwell
- Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Nancy J Cox
- Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Adriana Hung
- Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA
| | - C Michael Stein
- Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Cecilia P Chung
- Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA.
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14
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Czaja AJ. Review article: opportunities to improve and expand thiopurine therapy for autoimmune hepatitis. Aliment Pharmacol Ther 2020; 51:1286-1304. [PMID: 32363674 DOI: 10.1111/apt.15743] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/16/2020] [Revised: 03/07/2020] [Accepted: 03/31/2020] [Indexed: 12/14/2022]
Abstract
BACKGROUND Thiopurines in combination with glucocorticoids are used as first-line, second-line and maintenance therapies in autoimmune hepatitis and opportunities exist to improve and expand their use. AIMS To describe the metabolic pathways and key factors implicated in the efficacy and toxicity of the thiopurine drugs and to indicate the opportunities to improve outcomes by monitoring and manipulating metabolic pathways, individualising dosage and strengthening the response. METHODS English abstracts were identified in PubMed by multiple search terms. Full-length articles were selected for review, and secondary and tertiary bibliographies were developed. RESULTS Thiopurine methyltransferase activity and 6-tioguanine (6-thioguanine) nucleotide levels influence drug efficacy and safety, and they can be manipulated to improve treatment response and prevent myelosuppression. Methylated thiopurine metabolites are associated with hepatotoxicity, drug intolerance and nonresponse and their production can be reduced or bypassed. Universal pre-treatment assessment of thiopurine methyltransferase activity and individualisation of dosage to manipulate metabolite thresholds could improve outcomes. Early detection of thiopurine resistance by metabolite testing, accurate estimations of drug onset and strength by surrogate markers and adjunctive use of allopurinol could improve the management of refractory disease. Dose-restricted tioguanine (thioguanine) could expand treatment options by reducing methylated metabolites, increasing the bioavailability of 6-tioguanine nucleotides and ameliorating thiopurine intolerance or resistance. CONCLUSIONS The efficacy and safety of thiopurines in autoimmune hepatitis can be improved by investigational efforts that establish monitoring strategies that allow individualisation of dosage and prediction of outcome, increase bioavailability of the active metabolites and demonstrate superiority to alternative agents.
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Affiliation(s)
- Albert J Czaja
- Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine and Science, Rochester, MN, USA
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16
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Pape S, Schramm C, Gevers TJG. Clinical management of autoimmune hepatitis. United European Gastroenterol J 2019; 7:1156-1163. [PMID: 31700628 PMCID: PMC6826525 DOI: 10.1177/2050640619872408] [Citation(s) in RCA: 55] [Impact Index Per Article: 9.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/27/2019] [Accepted: 07/31/2019] [Indexed: 02/06/2023] Open
Abstract
Autoimmune hepatitis is a rare and chronic liver disease that is characterised by increased serum transaminases and immunoglobulin G, inflammatory liver histology and presence of circulating autoantibodies. An autoimmune hepatitis diagnosis justifies life-long treatment in most patients in order to prevent development of cirrhosis and end-stage liver disease. The cornerstone of treatment is steroid induction therapy followed by maintenance therapy with azathioprine, which is effective in most cases. For patients who do not respond to standard treatment, second-line treatment with other immunosuppressants can be effective. Treatment should be aimed at biochemical remission of the disease, which is defined as normalization of transaminases and immunoglobulin G. Patients should be monitored intensively during the first months of treatment in order to monitor side-effects, assess symptoms and individualise treatment. Specialist consultation should be sought in difficult-to-treat patients. Future studies and networking initiatives should result in optimization of current treatment strategies in autoimmune hepatitis.
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Affiliation(s)
- Simon Pape
- Department of Gastroenterology and Hepatology, Radboud University Medical Center, Nijmegen, The Netherlands
- European Reference Network Hepatological Diseases (ERN RARE-LIVER), Hamburg, Germany
| | - Christoph Schramm
- European Reference Network Hepatological Diseases (ERN RARE-LIVER), Hamburg, Germany
- 1st Department of Internal Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
- Martin Zeitz Centre for Rare Diseases, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany
| | - Tom JG Gevers
- Department of Gastroenterology and Hepatology, Radboud University Medical Center, Nijmegen, The Netherlands
- European Reference Network Hepatological Diseases (ERN RARE-LIVER), Hamburg, Germany
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Chang JY, Cheon JH. Thiopurine Therapy in Patients With Inflammatory Bowel Disease: A Focus on Metabolism and Pharmacogenetics. Dig Dis Sci 2019; 64:2395-2403. [PMID: 31290039 DOI: 10.1007/s10620-019-05720-5] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/24/2019] [Accepted: 07/02/2019] [Indexed: 12/15/2022]
Abstract
Thiopurines have been widely used for the maintenance of remission or steroid sparing in patients with inflammatory bowel disease. However, potential drug-related adverse events frequently interfere with their use. Indeed, drug withdrawals associated with adverse reactions have been reported in approximately 25% of patients. To balance the efficacy, safety, and tolerability of thiopurines, regular monitoring of biomarkers (complete blood cell count, liver function test, and metabolic profiles), steady dose escalation, and pretreatment thiopurine S-methyltransferase (TPMT) genotype screening have been routinely recommended. However, the complex thiopurine metabolic pathway and individual differences attributed to pharmacogenetic diversity limit the effectiveness of these strategies in the optimization of thiopurine therapy. Recently, in an effort to facilitate more accurate and personalized prediction of thiopurine response or toxicity, novel genetic markers including NUDT15 and FTO genes were discovered. These discoveries are remarkable because TPMT screening has minimal efficacy for predicting myelosuppression especially in Asian populations, despite the fact that thee populations have a higher frequency of myelosuppression than Western populations. This review focuses on the current understanding of the metabolic pathway and the pharmacogenetics of thiopurines and suggests a personalized preventive strategy against potential adverse drug reactions to optimize their therapeutic application.
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Affiliation(s)
- Ji Young Chang
- Department of Internal Medicine, Institute of Gastroenterology, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun-gu, Seoul, 03722, Republic of Korea
- Department of Health Promotion Center, Ewha Womans University School of Medicine, Seoul, Korea
| | - Jae Hee Cheon
- Department of Internal Medicine, Institute of Gastroenterology, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun-gu, Seoul, 03722, Republic of Korea.
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18
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Vasudevan A, Gibson PR, Van Langenberg DR. Systematic Review: Cost-effective Strategies of Optimizing Anti-tumor Necrosis and Immunomodulators in Inflammatory Bowel Disease. Inflamm Bowel Dis 2019; 25:1462-1473. [PMID: 30689858 DOI: 10.1093/ibd/izy399] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/25/2018] [Revised: 12/02/2018] [Accepted: 12/20/2018] [Indexed: 12/23/2022]
Abstract
BACKGROUND Medication costs in inflammatory bowel disease (IBD) are now the principal driver of health care costs. Cost-effective strategies to optimize and rationalize treatment are therefore necessary. METHODS A systematic review until April 30, 2018, was performed to identify economic evaluations of strategies to optimize infliximab, adalimumab, and immunomodulators for the treatment of IBD in adults. A qualitative synthesis of the identified studies was performed. RESULTS Seventy articles were identified that met the inclusion criteria. Adalimumab seems cost-effective compared with infliximab as maintenance therapy for moderate to severe Crohn's disease (CD). Infusion costs are a significant additional treatment cost with infliximab. However, other studies found biosimilar infliximab more cost-effective than alternative biologics in fistulizing and moderate-severe luminal CD-although the latter did not reach a willingness-to-pay threshold of <$50,000. In moderate-severe ulcerative colitis, infliximab seems more cost-effective than adalimumab. Multiple tailored approaches to treatment based on objective markers of disease activity or efficacy have been shown to be cost-effective in CD, including following secondary loss of response to anti-TNF therapy for postoperative recurrence and in escalating treatment. For immunomodulator treatment, both thiopurine methyltransferase (TPMT) testing before commencing thiopurines and thiopurine metabolite testing for dose optimization seem cost-effective. CONCLUSION In a win-win for patients and payers, several potential avenues to achieve cost-effectiveness-but also therapeutic optimization of anti-TNF therapies-were elucidated in this review with comparatively sparse data for immunomodulators. Optimizing immunomodulator and anti-tumor necrosis factor alpha therapy to achieve objective disease control seems to be cost-effective at conventional willingness-to-pay thresholds in a number of clinical settings.
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Affiliation(s)
- Abhinav Vasudevan
- Department of Gastroenterology and Hepatology, Eastern Health, Monash University, Eastern Health Clinical School, Box Hill, Victoria, Australia
| | - Peter R Gibson
- Department of Gastroenterology, Alfred Health and Monash University, Victoria, Australia
| | - Daniel R Van Langenberg
- Department of Gastroenterology and Hepatology, Eastern Health, Monash University, Eastern Health Clinical School, Box Hill, Victoria, Australia
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19
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Ince MN, Elliott DE. Effective Use of the Laboratory in the Management of Patients with Inflammatory Bowel Diseases. Gastroenterol Clin North Am 2019; 48:237-258. [PMID: 31046973 DOI: 10.1016/j.gtc.2019.02.006] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Inflammatory bowel disease (IBD) comprises a group of chronic, intestinal inflammatory disorders, including ulcerative colitis and Crohn's disease. IBD is characterized by periods of relapse and remission. Long-term progressive intestinal inflammation can result in severe and devastating complications, such as intestinal strictures and/or fistulae. Immune suppressive medications with potent side effects are often used to control inflammation and limit disease activity. Laboratory tests guide various decisions in clinical management of IBD. We discuss tests used to diagnose IBD, assess for relapse or remission, monitor the effectiveness of therapeutic regimen, screen for the maintenance of health, and diagnose or prevent complications.
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Affiliation(s)
- M Nedim Ince
- Department of Internal Medicine, Division of Gastroenterology and Hepatology, University of Iowa, Carver College of Medicine, University of Iowa Hospitals and Clinics, 4546 JCP, 200 Hawkins Drive, Iowa City, IA 52242, USA.
| | - David E Elliott
- Department of Internal Medicine, Division of Gastroenterology and Hepatology, University of Iowa, Carver College of Medicine, University of Iowa Hospitals and Clinics, 4607 JCP, 200 Hawkins Drive, Iowa City, IA 52242, USA
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20
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Abstract
BACKGROUND Azathioprine (AZA) is the mainstay of maintenance therapy in pediatric autoimmune hepatitis (AIH). The use of thiopurines metabolites to individualize therapy and avoid toxicity has not, however, been clearly defined. METHODS Retrospective analysis of children ≤18 years diagnosed with AIH between January 2001 and 2016. Standard definitions were used for treatment response and disease flare. Thiopurine metabolite levels were correlated with the corresponding liver function test. RESULTS A total of 56 children (32 girls) were diagnosed with AIH at a median age of 11 years (interquartile range [IQR] 9). No difference in 6-thioguanine-nucleotide (6-TG) levels (271[IQR 251] pmol/8 × 10 red blood cell vs 224 [IQR 147] pmol/8 × 10 red blood cell, P = 0.06) was observed in children in remission when compared with those who were not in remission. No correlation was observed between the 6-TG and alanine aminotransferase levels (r = -0.179, P = 0.109) or between 6-methyl-mercaptopurine (6-MMP) and alanine aminotransferase levels (r = 0.139, P = 0.213). The 6-MMP/6-TG ratio was significantly lower in patients who were in remission (2[7] vs 5 (10), P = 0.04). Using a quartile analysis, we found that having a ratio of <4 was significantly associated with being in remission with OR 2.50 (95% confidence interval 1.02-6.10), P = 0.047. Use of allopurinol with low-dose AZA in 6 children with preferential 6-MMP production brought about remission in 5/6 (83.3%). CONCLUSIONS Thiopurine metabolite levels should be measured in patients with AIH who have experienced a loss of remission. A 6-MMP/6-TG ratio of <4 with the addition of allopurinol could be considered in these patients.
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21
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Lim SZ, Chua EW. Revisiting the Role of Thiopurines in Inflammatory Bowel Disease Through Pharmacogenomics and Use of Novel Methods for Therapeutic Drug Monitoring. Front Pharmacol 2018; 9:1107. [PMID: 30349479 PMCID: PMC6186994 DOI: 10.3389/fphar.2018.01107] [Citation(s) in RCA: 37] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2018] [Accepted: 09/10/2018] [Indexed: 12/12/2022] Open
Abstract
Azathioprine and 6-mercaptopurine, often referred to as thiopurine compounds, are commonly used in the management of inflammatory bowel disease. However, patients receiving these drugs are prone to developing adverse drug reactions or therapeutic resistance. Achieving predefined levels of two major thiopurine metabolites, 6-thioguanine nucleotides and 6-methylmercaptopurine, is a long-standing clinical practice in ensuring therapeutic efficacy; however, their correlation with treatment response is sometimes unclear. Various genetic markers have also been used to aid the identification of patients who are thiopurine-sensitive or refractory. The recent discovery of novel Asian-specific DNA variants, namely those in the NUDT15 gene, and their link to thiopurine toxicity, have led clinicians and scientists to revisit the utility of Caucasian biomarkers for Asian individuals with inflammatory bowel disease. In this review, we explore the limitations associated with the current methods used for therapeutic monitoring of thiopurine metabolites and how the recent discovery of ethnicity-specific genetic markers can complement thiopurine metabolites measurement in formulating a strategy for more accurate prediction of thiopurine response. We also discuss the challenges in thiopurine therapy, alongside the current strategies used in patients with reduced thiopurine response. The review is concluded with suggestions for future work aiming at using a more comprehensive approach to optimize the efficacy of thiopurine compounds in inflammatory bowel disease.
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Affiliation(s)
| | - Eng Wee Chua
- Faculty of Pharmacy, Universiti Kebangsaan Malaysia, Kuala Lumpur, Malaysia
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22
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de Boer NKH, Peyrin-Biroulet L, Jharap B, Sanderson JD, Meijer B, Atreya I, Barclay ML, Colombel JF, Lopez A, Beaugerie L, Marinaki AM, van Bodegraven AA, Neurath MF. Thiopurines in Inflammatory Bowel Disease: New Findings and Perspectives. J Crohns Colitis 2018; 12:610-620. [PMID: 29293971 DOI: 10.1093/ecco-jcc/jjx181] [Citation(s) in RCA: 57] [Impact Index Per Article: 8.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/20/2017] [Accepted: 12/20/2017] [Indexed: 02/08/2023]
Abstract
Thiopurines, available as azathioprine, mercaptopurine, and thioguanine, are immunomodulating agents primarily used to maintain corticosteroid-free remission in patients with inflammatory bowel disease. To provide a state-of-the-art overview of thiopurine treatment in inflammatory bowel disease, this clinical review critically summarises the available literature, as assessed by several experts in the field of thiopurine treatment and research in inflammatory bowel disease.
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Affiliation(s)
- Nanne K H de Boer
- Department of Gastroenterology and Hepatology, VU University Medical Centre, Amsterdam, The Netherlands
| | - Laurent Peyrin-Biroulet
- Department of Gastroenterology and Hepatology and Inserm U954, Nancy University Hospital, Lorraine University, Vandoeuvre-lès-Nancy, France
| | - Bindia Jharap
- Department of Gastroenterology, Meander Medical Centre, Amersfoort, The Netherlands
| | - Jeremy D Sanderson
- Department of Gastroenterology, Guy's and St Thomas' Hospitals, London, UK
| | - Berrie Meijer
- Department of Gastroenterology and Hepatology, VU University Medical Centre, Amsterdam, The Netherlands
| | - Imke Atreya
- Department of Gastroenterology, Pneumology and Endocrinology, Universitätsklinikum Erlangen, University of Erlangen-Nürnberg, Germany
| | - Murray L Barclay
- Department of Gastroenterology, Christchurch Hospital, Christchurch, New Zealand
| | | | - Anthony Lopez
- Department of Gastroenterology and Hepatology and Inserm U954, Nancy University Hospital, Lorraine University, Vandoeuvre-lès-Nancy, France
| | - Laurent Beaugerie
- Department of Gastroenterology, AP-HP, Hôpital Saint-Antoine,UPMC University, Paris, France
| | | | - Adriaan A van Bodegraven
- Department of Gastroenterology and Hepatology, VU University Medical Centre, Amsterdam, The Netherlands.,Department of Gastroenterology, Geriatrics, Internal and Intensive Care Medicine [Co-MIK], Zuyderland Medical Centre, Heerlen-Sittard-Geleen, The Netherlands
| | - Markus F Neurath
- Department of Gastroenterology, Pneumology and Endocrinology, Universitätsklinikum Erlangen, University of Erlangen-Nürnberg, Germany
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23
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Genomics and pharmacogenomics of pediatric acute lymphoblastic leukemia. Crit Rev Oncol Hematol 2018; 126:100-111. [PMID: 29759551 DOI: 10.1016/j.critrevonc.2018.04.002] [Citation(s) in RCA: 46] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2018] [Revised: 03/21/2018] [Accepted: 04/03/2018] [Indexed: 12/14/2022] Open
Abstract
Acute lymphoblastic leukaemia (ALL) is a prevalent form of pediatric cancer that accounts for 70-80% of all leukemias. Genome-based analysis, exome sequencing, transcriptomics and proteomics have provided insight into genetic classification of ALL and helped identify novel subtypes of the disease. B and T cell-based ALL are two well-characterized genomic subtypes, significantly marked by bone marrow disorders, along with mutations in trisomy 21 and T53. The other ALLs include Early T-cell precursor ALL, Philadelphia chromosome-like ALL, Down syndrome-associated ALL and Relapsed ALL. Chromosomal number forms a basis of classification, such as, hypodiploid ALL, near-haploid, low-hypodiploid, high-hypodiploid and hypodiploid-ALL. Advances in therapies targeting ALL have been noteworthy, with significant pre-clinical and clinical studies on drug pharmacokinetics and pharmacodynamics. Methotrexate and 6-mercaptopurine are leading drugs with best demonstrated efficacies against childhood ALL. The drugs in combination, following dose titration, have also been used for maintenance therapy. Methotrexate-polyglutamate is a key metabolite that specifically targets the disease pathogenesis, and 6-thioguanine nucleotides, derived from 6-mercaptopurine, impede replication and transcription processes, inducing cytotoxicity. Additionally, glucocorticoids, asparaginase, anthracycline, vincristine and cytarabine that trans-repress gene expression, deprives cells of asparagine, triggers cell cycle arrest, influences cytochrome-P450 polymorphism and inhibits DNA polymerase, respectively, have been used in chemotherapy in ALL patients. Overall, this review covers the progress in genome technology related to different sub-types of ALL and pharmacokinetics and pharmacodynamics of its medications. It also enlightens adverse effects of current drugs, and emphasizes the necessity of genome-wide association studies for restricting childhood ALL.
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24
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Bermejo F, Aguas M, Chaparro M, Domènech E, Echarri A, García-Planella E, Guerra I, Gisbert JP, López-Sanromán A. Recommendations of the Spanish Working Group on Crohn's Disease and Ulcerative Colitis (GETECCU) on the use of thiopurines in inflammatory bowel disease. GASTROENTEROLOGIA Y HEPATOLOGIA 2018; 41:205-221. [PMID: 29357999 DOI: 10.1016/j.gastrohep.2017.11.007] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/02/2017] [Accepted: 11/26/2017] [Indexed: 12/17/2022]
Abstract
Thiopurines (azathioprine and mercaptopurine) are widely used in patients with inflammatory bowel disease. In this paper, we review the main indications for their use, as well as practical aspects on efficacy, safety and method of administration. They are mainly used to maintain remission in steroid-dependent disease or with ciclosporin to control a severe ulcerative colitis flare-up, as well as to prevent postoperative Crohn's disease recurrence, and also in combination therapy with biologics. About 30-40% of patients will not respond to treatment and 10-20% will not tolerate it due to adverse effects. Before they are prescribed, immunisation status against certain infections should be checked. Determination of thiopurine methyltransferase activity (TPMT) is not mandatory but it increases initial safety. The appropriate dose is 2.5mg/kg/day for azathioprine and 1.5mg/kg/day for mercaptopurine. Some adverse effects are idiosyncratic (digestive intolerance, pancreatitis, fever, arthromyalgia, rash and some forms of hepatotoxicity). Others are dose-dependent (myelotoxicity and other types of hepatotoxicity), and their surveillance should never be interrupted during treatment. If therapy fails or adverse effects develop, management can include switching from one thiopurine to the other, reducing the dose, combining low doses of azathioprine with allopurinol and assessing metabolites, before their use is ruled out. Non-melanoma skin cancer, lymphomas and urinary tract tumours have been linked to thiopurine therapy. Thiopurine use is safe during conception, pregnancy and breastfeeding.
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Affiliation(s)
- Fernando Bermejo
- Servicio de Digestivo, Hospital Universitario de Fuenlabrada, Fuenlabrada, Madrid, España.
| | - Mariam Aguas
- Servicio de Digestivo, Hospital Universitari La Fe, Valencia, España; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), España
| | - María Chaparro
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), España; Servicios de Digestivo, Hospital Universitario de La Princesa, Instituto de Investigación Sanitaria Princesa (IIS-IP), Madrid, España
| | - Eugeni Domènech
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), España; Servicio de Digestivo, Hospital Universitari Germans Trias i Pujol, Badalona, España
| | - Ana Echarri
- Servicio de Digestivo, Complejo Hospitalario Universitario de Ferrol, Ferrol, España
| | | | - Iván Guerra
- Servicio de Digestivo, Hospital Universitario de Fuenlabrada, Fuenlabrada, Madrid, España
| | - Javier P Gisbert
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), España; Servicios de Digestivo, Hospital Universitario de La Princesa, Instituto de Investigación Sanitaria Princesa (IIS-IP), Madrid, España
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Archer R, Tappenden P, Ren S, Martyn-St James M, Harvey R, Basarir H, Stevens J, Carroll C, Cantrell A, Lobo A, Hoque S. Infliximab, adalimumab and golimumab for treating moderately to severely active ulcerative colitis after the failure of conventional therapy (including a review of TA140 and TA262): clinical effectiveness systematic review and economic model. Health Technol Assess 2018; 20:1-326. [PMID: 27220829 DOI: 10.3310/hta20390] [Citation(s) in RCA: 36] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Ulcerative colitis (UC) is the most common form of inflammatory bowel disease in the UK. UC can have a considerable impact on patients' quality of life. The burden for the NHS is substantial. OBJECTIVES To evaluate the clinical effectiveness and safety of interventions, to evaluate the incremental cost-effectiveness of all interventions and comparators (including medical and surgical options), to estimate the expected net budget impact of each intervention, and to identify key research priorities. DATA SOURCES Peer-reviewed publications, European Public Assessment Reports and manufacturers' submissions. The following databases were searched from inception to December 2013 for clinical effectiveness searches and from inception to January 2014 for cost-effectiveness searches for published and unpublished research evidence: MEDLINE, EMBASE, Cumulative Index to Nursing and Allied Health Literature, The Cochrane Library including the Cochrane Systematic Reviews Database, Cochrane Controlled Trials Register, Database of Abstracts of Reviews of Effects, the Health Technology Assessment database and NHS Economic Evaluation Database; ISI Web of Science, including Science Citation Index, and the Conference Proceedings Citation Index-Science and Bioscience Information Service Previews. The US Food and Drug Administration website and the European Medicines Agency website were also searched, as were research registers, conference proceedings and key journals. REVIEW METHODS A systematic review [including network meta-analysis (NMA)] was conducted to evaluate the clinical effectiveness and safety of named interventions. The health economic analysis included a review of published economic evaluations and the development of a de novo model. RESULTS Ten randomised controlled trials were included in the systematic review. The trials suggest that adult patients receiving infliximab (IFX) [Remicade(®), Merck Sharp & Dohme Ltd (MSD)], adalimumab (ADA) (Humira(®), AbbVie) or golimumab (GOL) (Simponi(®), MSD) were more likely to achieve clinical response and remission than those receiving placebo (PBO). Hospitalisation data were limited, but suggested more favourable outcomes for ADA- and IFX-treated patients. Data on the use of surgical intervention were sparse, with a potential benefit for intervention-treated patients. Data were available from one trial to support the use of IFX in paediatric patients. Safety issues identified included serious infections, malignancies and administration site reactions. Based on the NMA, in the induction phase, all biological treatments were associated with statistically significant beneficial effects relative to PBO, with the greatest effect associated with IFX. For patients in response following induction, all treatments except ADA and GOL 100 mg at 32-52 weeks were associated with beneficial effects when compared with PBO, although these were not significant. The greatest effects at 8-32 and 32-52 weeks were associated with 100 mg of GOL and 5 mg/kg of IFX, respectively. For patients in remission following induction, all treatments except ADA at 8-32 weeks and GOL 50 mg at 32-52 weeks were associated with beneficial effects when compared with PBO, although only the effect of ADA at 32-52 weeks was significant. The greatest effects were associated with GOL (at 8-32 weeks) and ADA (at 32-52 weeks). The economic analysis suggests that colectomy is expected to dominate drug therapies, but for some patients, colectomy may not be considered acceptable. In circumstances in which only drug options are considered, IFX and GOL are expected to be ruled out because of dominance, while the incremental cost-effectiveness ratio for ADA versus conventional treatment is approximately £50,300 per QALY gained. LIMITATIONS The health economic model is subject to several limitations: uncertainty associated with extrapolating trial data over a lifetime horizon, the model does not consider explicit sequential pathways of non-biological treatments, and evidence relating to complications of colectomy was identified through consideration of approaches used within previous models rather than a full systematic review. CONCLUSIONS Adult patients receiving IFX, ADA or GOL were more likely to achieve clinical response and remission than those receiving PBO. Further data are required to conclusively demonstrate the effect of interventions on hospitalisation and surgical outcomes. The economic analysis indicates that colectomy is expected to dominate medical treatments for moderate to severe UC. STUDY REGISTRATION This study is registered as PROSPERO CRD42013006883. FUNDING The National Institute for Health Research Health Technology Assessment programme.
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Affiliation(s)
- Rachel Archer
- Health Economics and Decision Science, School of Health and Related Research (ScHARR), University of Sheffield, Sheffield, UK
| | - Paul Tappenden
- Health Economics and Decision Science, School of Health and Related Research (ScHARR), University of Sheffield, Sheffield, UK
| | - Shijie Ren
- Health Economics and Decision Science, School of Health and Related Research (ScHARR), University of Sheffield, Sheffield, UK
| | - Marrissa Martyn-St James
- Health Economics and Decision Science, School of Health and Related Research (ScHARR), University of Sheffield, Sheffield, UK
| | - Rebecca Harvey
- Health Economics and Decision Science, School of Health and Related Research (ScHARR), University of Sheffield, Sheffield, UK
| | - Hasan Basarir
- Health Economics and Decision Science, School of Health and Related Research (ScHARR), University of Sheffield, Sheffield, UK
| | - John Stevens
- Health Economics and Decision Science, School of Health and Related Research (ScHARR), University of Sheffield, Sheffield, UK
| | - Christopher Carroll
- Health Economics and Decision Science, School of Health and Related Research (ScHARR), University of Sheffield, Sheffield, UK
| | - Anna Cantrell
- Health Economics and Decision Science, School of Health and Related Research (ScHARR), University of Sheffield, Sheffield, UK
| | - Alan Lobo
- Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, UK
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Warner B, Johnston E, Arenas-Hernandez M, Marinaki A, Irving P, Sanderson J. A practical guide to thiopurine prescribing and monitoring in IBD. Frontline Gastroenterol 2018; 9:10-15. [PMID: 29484155 PMCID: PMC5824765 DOI: 10.1136/flgastro-2016-100738] [Citation(s) in RCA: 52] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/27/2016] [Revised: 08/05/2016] [Accepted: 08/08/2016] [Indexed: 02/04/2023] Open
Abstract
Thiopurines are often the mainstay of treatment for many patients with inflammatory bowel disease. As such, a general understanding of the evidence behind their use and of their metabolism is extremely useful in clinical practice. This review gives a practical overview of thiopurine metabolism, the importance of thiopurine S-methyltransferase testing prior to the start of therapy and the monitoring of thioguanine nucleotide levels while on treatment, guiding a personalised approach to optimising thiopurine therapy.
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Affiliation(s)
- Ben Warner
- 1st Floor College House, St Thomas’ Hospital, London, UK
| | - Emma Johnston
- Department of Gastroenterology, Guy's and St Thomas’ NHS Foundation Trust, London, UK
| | | | | | - Peter Irving
- Department of Gastroenterology, Guy's and St Thomas’ NHS Foundation Trust, London, UK
| | - Jeremy Sanderson
- Department of Gastroenterology, Guy's and St Thomas’ NHS Foundation Trust, London, UK
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27
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Vasudevan A, Gibson PR, Langenberg DRV. Time to clinical response and remission for therapeutics in inflammatory bowel diseases: What should the clinician expect, what should patients be told? World J Gastroenterol 2017; 23:6385-6402. [PMID: 29085188 PMCID: PMC5643264 DOI: 10.3748/wjg.v23.i35.6385] [Citation(s) in RCA: 56] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/02/2017] [Revised: 07/03/2017] [Accepted: 08/15/2017] [Indexed: 02/06/2023] Open
Abstract
An awareness of the expected time for therapies to induce symptomatic improvement and remission is necessary for determining the timing of follow-up, disease (re)assessment, and the duration to persist with therapies, yet this is seldom reported as an outcome in clinical trials. In this review, we explore the time to clinical response and remission of current therapies for inflammatory bowel disease (IBD) as well as medication, patient and disease related factors that may influence the time to clinical response. It appears that the time to therapeutic response varies depending on the indication for therapy (Crohn's disease or ulcerative colitis). Agents with the most rapid time to clinical response included corticosteroids, calcineurin inhibitors, exclusive enteral nutrition, aminosalicylates and anti-tumor necrosis factor therapy which will work in most patients within the first 2 mo. Vedolizumab, methotrexate and thiopurines had a longer time to clinical response and can take several months to achieve maximal efficacy. Factors affecting the time to clinical response of therapies included use of concomitant therapy, disease duration, smoking status, disease phenotype and advanced age. There appears to be marked variation in time to clinical response for therapies used in IBD which is further influenced by disease and patient related factors. Understanding the expected time to therapeutic response is integral to inform further decision making, maintain a patient-centered approach and ensure treatment is given an appropriate timeframe to achieve maximal benefit prior to cessation.
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Affiliation(s)
- Abhinav Vasudevan
- Department of Gastroenterology and Hepatology, Eastern Health, Box Hill Hospital, Box Hill, Victoria 3128, Australia
- Monash University, Eastern Health Clinical School, Box Hill, Victoria 3128, Australia
| | - Peter R Gibson
- Department of Gastroenterology, Alfred Health and Monash University, Victoria 3004, Australia
| | - Daniel R van Langenberg
- Department of Gastroenterology and Hepatology, Eastern Health, Box Hill Hospital, Box Hill, Victoria 3128, Australia
- Monash University, Eastern Health Clinical School, Box Hill, Victoria 3128, Australia
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28
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Dart RJ, Irving PM. Optimising use of thiopurines in inflammatory bowel disease. Expert Rev Clin Immunol 2017; 13:877-888. [DOI: 10.1080/1744666x.2017.1351298] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Affiliation(s)
- Robin J. Dart
- IBD Centre, Department of Gastroenterology, St Thomas’ Hospital, London, UK
- Immunosurveillance Lab, Francis Crick Institute, London, UK
- Immunobiology, DIIID, King’s College London, Guy’s Hospital, London, UK
| | - Peter M. Irving
- IBD Centre, Department of Gastroenterology, St Thomas’ Hospital, London, UK
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29
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Tran-Minh ML, Sousa P, Maillet M, Allez M, Gornet JM. Hepatic complications induced by immunosuppressants and biologics in inflammatory bowel disease. World J Hepatol 2017; 9:613-626. [PMID: 28539989 PMCID: PMC5424291 DOI: 10.4254/wjh.v9.i13.613] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/03/2017] [Revised: 04/01/2017] [Accepted: 04/24/2017] [Indexed: 02/06/2023] Open
Abstract
The incidence of inflammatory bowel diseases (IBD) is rising worldwide. The therapeutic options for IBD are expanding, and the number of drugs with new targets will rapidly increase in coming years. A rapid step-up approach with close monitoring of intestinal inflammation is extensively used. The fear of side effects represents one the most limiting factor of their use. Despite a widespread use for years, drug induced liver injury (DILI) management remains a challenging situation with Azathioprine and Methotrexate. DILI seems less frequent with anti-tumor necrosis factor agents and new biologic therapies. The aim of this review is to report incidence, physiopathology and practical guidelines in case of DILI occurrence with the armamentarium of old and new drugs in the field of IBD.
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Axelrad JE, Roy A, Lawlor G, Korelitz B, Lichtiger S. Thiopurines and inflammatory bowel disease: Current evidence and a historical perspective. World J Gastroenterol 2016; 22:10103-10117. [PMID: 28028358 PMCID: PMC5155169 DOI: 10.3748/wjg.v22.i46.10103] [Citation(s) in RCA: 36] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/20/2016] [Revised: 11/10/2016] [Accepted: 11/28/2016] [Indexed: 02/06/2023] Open
Abstract
The use of thiopurines in inflammatory bowel disease (IBD) has been examined in numerous prospective, controlled trials, with a majority demonstrating a clinical benefit. We conducted this review to describe the historical and current evidence in the use of thiopurines in IBD. A systematic search was performed on MEDLINE between 1965 and 2016 to identify studies on thiopurines in IBD. The most robust evidence for thiopurines in IBD includes induction of remission in combination with anti-tumor necrosis factor (anti-TNF) agents, and maintenance of remission and post-operative maintenance in Crohn’s disease. Less evidence exists for thiopurine monotherapy in induction of remission, maintenance of ulcerative colitis, chemoprevention of colorectal cancer, and in preventing immunogenicity to anti-TNF. Evidence was often limited by trial design. Overall, thiopurines have demonstrated efficacy in a broad range of presentations of IBD. With more efficacious novel therapeutic agents, the positioning of thiopurines in the management of IBD will change and future studies will analyze the benefit of thiopurines alone and in conjunction with these new medications.
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31
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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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32
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Experts Opinion on the Practical Use of Azathioprine and 6-Mercaptopurine in Inflammatory Bowel Disease. Inflamm Bowel Dis 2016; 22:2733-2747. [PMID: 27760078 DOI: 10.1097/mib.0000000000000923] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
The relevance of azathioprine and 6-mercaptopurine therapy in inflammatory bowel disease, Crohn's disease, and ulcerative colitis, has been challenged in recent publications. In this article, a panel of experts gives advice, based on the relevant literature, on indications and practical use of azathioprine/6-mercaptopurine, prevention, and management of drug adverse reactions and special situations such as vaccination, pregnancy, and lactation.
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33
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González-Lama Y, Gisbert JP. Monitoring thiopurine metabolites in inflammatory bowel disease. Frontline Gastroenterol 2016; 7:301-307. [PMID: 28839871 PMCID: PMC5369498 DOI: 10.1136/flgastro-2015-100681] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/30/2015] [Revised: 03/09/2016] [Accepted: 03/16/2016] [Indexed: 02/04/2023] Open
Abstract
Thiopurines (azathioprine and mercaptopurine) are one of the immunosuppressive mainstays for the treatment of inflammatory bowel disease. In spite of its widespread use, thiopurine metabolism is still not fully understood, and a significant proportion of patients suffer toxicity or lack of efficacy. Different enzymatic pathways with individual variations constitute a pharmacogenetic model that seems to be suitable for monitoring and therapeutic intervention. This review is focused on current concepts and recent research that may help clinicians to rationally optimise thiopurine treatment in patients with inflammatory bowel disease.
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Affiliation(s)
- Yago González-Lama
- Gastroenterology and Hepatology Department, Puerta de Hierro University Hospital, Majadahonda, Madrid, Spain
| | - Javier P Gisbert
- Gastroenterology Unit, Hospital Universitario de La Princesa and Instituto de Investigación Sanitaria Princesa (IIS-IP), Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Madrid, Madrid, Spain
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Meijer B, Bouma G, de Boer NKH. Optimize Thiopurine Therapy in Autoimmune Hepatitis. Clin Gastroenterol Hepatol 2016; 14:1062-3. [PMID: 26872401 DOI: 10.1016/j.cgh.2016.02.006] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/19/2016] [Revised: 01/21/2016] [Accepted: 02/04/2016] [Indexed: 02/07/2023]
Affiliation(s)
- Berrie Meijer
- Department of Gastroenterology and Hepatology, VU University Medical Center, Amsterdam, The Netherlands
| | - Gerd Bouma
- Department of Gastroenterology and Hepatology, VU University Medical Center, Amsterdam, The Netherlands
| | - Nanne K H de Boer
- Department of Gastroenterology and Hepatology, VU University Medical Center, Amsterdam, The Netherlands
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Fong SCM, Blaker PA, Arenas-Hernandez M, Marinaki AM, Sanderson JD. Getting the best out of thiopurine therapy: thiopurine S-methyltransferase and beyond. Biomark Med 2015; 9:51-65. [PMID: 25605455 DOI: 10.2217/bmm.14.97] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023] Open
Abstract
Thiopurines are the cornerstone of treatment for a wide variety of medical disorders, ranging from pediatric leukemia to inflammatory bowel disease. Because of their complex metabolism and potential toxicities, the use of biomarkers to predict risk and response is paramount. Thiopurine S-methyltransferase and thiopurine metabolite levels have emerged as companion diagnostics with crucial roles in facilitating safe and effective treatment. This review serves to update the reader on how these tools are being developed and implemented in clinical practice. A useful paradigm in thiopurine therapeutic strategy is presented, along with fresh insights into the mechanisms underlying these approaches. We elaborate on potential future developments in the optimization of thiopurine therapy.
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Goldberg R, Irving PM. Toxicity and response to thiopurines in patients with inflammatory bowel disease. Expert Rev Gastroenterol Hepatol 2015; 9:891-900. [PMID: 25915575 DOI: 10.1586/17474124.2015.1039987] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
The use of thiopurines is well established in the management of inflammatory bowel disease. A wealth of data and experience, amassed over several decades, supporting their efficacy has recently been challenged by trials that failed to show a benefit in Crohn's disease when used early in the disease course, although other trials continue to support their role both as monotherapy and in combination with anti-TNF. Recent reports of previously unrecognized toxicity have also emerged. Fortunately, the absolute incidence of serious toxicity remains low, and an improved understanding of how best to minimize risk and the recognition of groups of patients at higher risk of toxicity from thiopurines means that they remain a relatively safe therapy in the majority of patients. In this paper, we review the literature evaluating the role of thiopurines in inflammatory bowel disease as well as their toxicity. We conclude that education regarding the spectrum of thiopurine side effects and optimal monitoring during therapy may help with optimizing safety and efficacy of these important medications.
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Affiliation(s)
- Rimma Goldberg
- Department of Gastroenterology, Guy's and St Thomas' NHS Foundation Trust, London, UK
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Konidari A, Anagnostopoulos A, Bonnett LJ, Pirmohamed M, El-Matary W. Thiopurine monitoring in children with inflammatory bowel disease: a systematic review. Br J Clin Pharmacol 2015; 78:467-76. [PMID: 24592889 DOI: 10.1111/bcp.12365] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2013] [Accepted: 02/14/2014] [Indexed: 12/13/2022] Open
Abstract
AIMS The aim was to systematically review the evidence on the clinical usefulness of thiopurine metabolite and white blood count (WBC) monitoring in the assessment of clinical outcomes in children with inflammatory bowel disease (IBD). METHODS Medline, Embase, Cochrane Central Register of controlled trials and http://www.clinicaltrials.gov were screened in adherence to the PRISMA statement by two independent reviewers for identification of eligible studies. Eligible studies were randomized controlled trials (RCTs), cohort studies and large case series of children with inflammatory bowel disease (IBD) (<18 years) who underwent monitoring of thiopurine metabolites and/or WBC. RESULTS Fifteen papers were identified (n = 1026). None of the eligible studies were RCTs. High 6-thioguanine nucleotide (6TGN) concentrations were not consistently associated with leucopenia. Leucopenia was not associated with achievement of clinical remission. A positive but not consistent correlation between 6TGN and clinical remission was reported. Haematological toxicity could not be reliably assessed with 6TGN measurements only. A number of studies supported the use of high 6-methylmercaptopurine ribonucleotides (6MMPR) as an indicator of hepatotoxicity. Low thiopurine metabolite concentration may be indicative of non-compliance. CONCLUSION Thiopurine metabolite testing does not safely predict clinical outcome, but may facilitate toxicity surveillance and treatment optimization in poor responders. Current evidence favours the combination of thiopurine metabolite/WBC monitoring and clinic follow-up for prompt identification of haematologic/hepatic toxicity safe dose adjustment, and treatment modification in cases of suboptimal clinical outcome or non-compliance. Well designed RCTs for the identification of robust surrogate markers of thiopurine efficacy and toxicity are required.
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Affiliation(s)
- Anastasia Konidari
- Department of Clinical and Molecular Pharmacology, Wolfson Centre for Personalised Medicine, Institute for Translational Medicine, University of Liverpool, Liverpool, UK
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Goel RM, Blaker P, Mentzer A, Fong SCM, Marinaki AM, Sanderson JD. Optimizing the use of thiopurines in inflammatory bowel disease. Ther Adv Chronic Dis 2015; 6:138-46. [PMID: 25954498 PMCID: PMC4416969 DOI: 10.1177/2040622315579063] [Citation(s) in RCA: 41] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Immunomodulator drugs, of which thiopurines can be considered the backbone, are widely used in the treatment of inflammatory bowel disease. They have been shown to be highly effective and safe; however, a significant proportion of patients are deemed to have a poor response or suffer adverse reactions. Knowing how to monitor and optimize thiopurine therapy in these scenarios is crucial to effective management. We discuss the metabolism of thiopurines, the use of enzyme/metabolite testing to guide treatment, as well as strategies to circumvent toxicity and side effects, such as allopurinol coprescription. The indications, use in pregnancy, safety profile and duration of thiopurine therapy are also discussed.
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Affiliation(s)
- Rishi M Goel
- Guy's & St Thomas' Hospitals - Gastroenterology, Westminster Bridge Road, London SE1 7EH, UK
| | - Paul Blaker
- Guy's & St Thomas' Hospitals - Gastroenterology, London, UK
| | - Alex Mentzer
- Guy's & St Thomas' Hospitals - Gastroenterology, London, UK
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Abstract
The prodrug azathioprine is primarily used for maintaining remission in inflammatory bowel disease, but approximately 30% of the patients suffer adverse side effects. The prodrug is activated by glutathione conjugation and release of 6-mercaptopurine, a reaction most efficiently catalyzed by glutathione transferase (GST) A2-2. Among five genotypes of GST A2-2, the variant A2*E has threefold-fourfold higher catalytic efficiency with azathioprine, suggesting that the expression of A2*E could boost 6-mercaptopurine release and adverse side effects in treated patients. Structure-activity studies of the GST A2-2 variants and homologous alpha class GSTs were made to delineate the determinants of high catalytic efficiency compared to other alpha class GSTs. Engineered chimeras identified GST peptide segments of importance, and replacing the corresponding regions in low-activity GSTs by these short segments produced chimeras with higher azathioprine activity. By contrast, H-site mutagenesis led to decreased azathioprine activity when active-site positions 208 and 213 in these favored segments were mutagenized. Alternative substitutions indicated that hydrophobic residues were favored. A pertinent question is whether variant A2*E represents the highest azathioprine activity achievable within the GST structural framework. This issue was addressed by mutagenesis of H-site residues assumed to interact with the substrate based on molecular modeling. The mutants with notably enhanced activities had small or polar residues in the mutated positions. The most active mutant L107G/L108D/F222H displayed a 70-fold enhanced catalytic efficiency with azathioprine. The determination of its structure by X-ray crystallography showed an expanded H-site, suggesting improved accommodation of the transition state for catalysis.
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Affiliation(s)
- Olof Modén
- Department of Chemistry-BMC, Uppsala University, Uppsala, Sweden
| | - Bengt Mannervik
- Department of Chemistry-BMC, Uppsala University, Uppsala, Sweden; Department of Neurochemistry, Stockholm University, Stockholm, Sweden.
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41
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Update 2014: advances to optimize 6-mercaptopurine and azathioprine to reduce toxicity and improve efficacy in the management of IBD. Inflamm Bowel Dis 2015; 21:445-52. [PMID: 25248004 DOI: 10.1097/mib.0000000000000197] [Citation(s) in RCA: 53] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
BACKGROUND The thiopurine drugs, 6-mercaptopurine (6-MP) and azathioprine (AZA), remain as a mainstay therapy in inflammatory bowel disease (IBD). Differences in metabolism of these drugs lead to individual variation in thiopurine metabolite levels that can determine its therapeutic efficacy and development of adverse reactions. In this update, we will review thiopurine metabolic pathway along with the up-to-date approaches in administering thiopurine medications based on the current literature. METHODS A search of the PubMed database by 2 independent reviewers identifying 98 articles evaluating thiopurine metabolism and IBD management. RESULTS Monitoring thiopurine metabolites can assist physicians in optimizing 6-MP and AZA therapy in treating patients with IBD. Of the dosing strategies reviewed, we found evidence for monitoring thiopurine metabolite level, use of allopurinol with thiopurine, use of mesalamine with thiopurine, combination therapy with thiopurine and anti-tumor necrosis factor agents, and split dosing of AZA or 6-MP to optimize thiopurine therapy and minimize adverse effects in IBD. CONCLUSIONS Based on the currently available literature, various dosing strategies to improve therapeutic response and reduce adverse reactions can be considered, including use of allopurinol with thiopurine, use of mesalamine with thiopurine, combination therapy with thiopurine and anti-tumor necrosis factor agents, and split dosing of thiopurine.
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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: 26] [Impact Index Per Article: 2.6] [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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Abstract
OBJECTIVES Thiopurines (azathioprine, 6-mercaptopurine) are a mainstay of treatment in Crohn disease (CD). Monitoring intracellular metabolite (6-thioguanine nucleotides [6-TGN] and 6-methylmercaptopurine [6-MMP]) levels can help optimize therapeutic efficacy and minimize potential toxicity. Determination of 6-MMP/6-TGN ratios may provide additional useful information, such as the identification of individuals with excessive thiopurine methyltransferase activity and disadvantageous 6-MMP overproduction. These patients are at increased risk of therapeutic failure and hepatotoxicity. The aim of the study was to evaluate the correlation of 6-MMP/6-TGN ratios with therapeutic efficacy and risk of hepatotoxicity in CD. METHODS The present study was a single-center cross-sectional study including pediatric patients with CD studied prospectively with clinical and laboratory assessments along with serial measurements of 6-MMP and 6-TGN. Clinical response was determined using established clinical indices. RESULTS The study included 238 pediatric patients with CD with a total of 1648 evaluation points. The patients were in steroid-free remission at 59.1% of the evaluation points. 6-MMP/6-TGN ratios of 4 to 24 were protective against relapse (odds ratio [OR] 0.52, 95% confidence interval [CI] -0.39 to 0.69, P = 0.001). Hepatotoxicity was associated with high 6-MMP levels (>3919 pmol/8 × 10 red blood cell count: OR 7.65, 95% CI 3.7-15.9, P = 0.001) and high 6-MMP/6-TGN ratios (>24: OR 5.35, 95% CI -3.43 to 8.43, P = 0.001). CONCLUSIONS We observed significant associations between 6-MMP/6-TGN ratios and clinical response, and risk of hepatotoxicity. Our results suggest that determination of thiopurine metabolite ratios is a valuable tool for identification of patients at increased risk of therapeutic failure and hepatotoxicity.
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Abstract
The antileukemic mechanisms of 6-mercaptopurine (6MP) and methotrexate (MTX) maintenance therapy are poorly understood, but the benefits of several years of myelosuppressive maintenance therapy for acute lymphoblastic leukemia are well proven. Currently, there is no international consensus on drug dosing. Because of significant interindividual and intraindividual variations in drug disposition and pharmacodynamics, vigorous dose adjustments are needed to obtain a target degree of myelosuppression. As the normal white blood cell counts vary by patients' ages and ethnicity, and also within age groups, identical white blood cell levels for 2 patients may not reflect the same treatment intensity. Measurements of intracellular levels of cytotoxic metabolites of 6MP and MTX can identify nonadherent patients, but therapeutic target levels remains to be established. A rise in serum aminotransferase levels during maintenance therapy is common and often related to high levels of methylated 6MP metabolites. However, except for episodes of hypoglycemia, serious liver dysfunction is rare, the risk of permanent liver damage is low, and aminotransferase levels usually normalize within a few weeks after discontinuation of therapy. 6MP and MTX dose increments should lead to either leukopenia or a rise in aminotransferases, and if neither is experienced, poor treatment adherence should be considered. The many genetic polymorphisms that determine 6MP and MTX disposition, efficacy, and toxicity have precluded implementation of pharmacogenomics into treatment, the sole exception being dramatic 6MP dose reductions in patients who are homozygous deficient for thiopurine methyltransferase, the enzyme that methylates 6MP and several of its metabolites. In conclusion, maintenance therapy is as important as the more intensive and toxic earlier treatment phases, and often more challenging. Ongoing research address the applicability of drug metabolite measurements for dose adjustments, extensive host genome profiling to understand diversity in treatment efficacy and toxicity, and alternative thiopurine dosing regimens to improve therapy for the individual patient.
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Ruemmele FM, Veres G, Kolho KL, Griffiths A, Levine A, Escher JC, Amil Dias J, Barabino A, Braegger CP, Bronsky J, Buderus S, Martín-de-Carpi J, De Ridder L, Fagerberg UL, Hugot JP, Kierkus J, Kolacek S, Koletzko S, Lionetti P, Miele E, Navas López VM, Paerregaard A, Russell RK, Serban DE, Shaoul R, Van Rheenen P, Veereman G, Weiss B, Wilson D, Dignass A, Eliakim A, Winter H, Turner D. Consensus guidelines of ECCO/ESPGHAN on the medical management of pediatric Crohn's disease. J Crohns Colitis 2014; 8:1179-1207. [PMID: 24909831 DOI: 10.1016/j.crohns.2014.04.005] [Citation(s) in RCA: 838] [Impact Index Per Article: 76.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/31/2014] [Revised: 04/14/2014] [Accepted: 04/14/2014] [Indexed: 02/07/2023]
Abstract
Children and adolescents with Crohn's disease (CD) present often with a more complicated disease course compared to adult patients. In addition, the potential impact of CD on growth, pubertal and emotional development of patients underlines the need for a specific management strategy of pediatric-onset CD. To develop the first evidenced based and consensus driven guidelines for pediatric-onset CD an expert panel of 33 IBD specialists was formed after an open call within the European Crohn's and Colitis Organisation and the European Society of Pediatric Gastroenterolog, Hepatology and Nutrition. The aim was to base on a thorough review of existing evidence a state of the art guidance on the medical treatment and long term management of children and adolescents with CD, with individualized treatment algorithms based on a benefit-risk analysis according to different clinical scenarios. In children and adolescents who did not have finished their growth, exclusive enteral nutrition (EEN) is the induction therapy of first choice due to its excellent safety profile, preferable over corticosteroids, which are equipotential to induce remission. The majority of patients with pediatric-onset CD require immunomodulator based maintenance therapy. The experts discuss several factors potentially predictive for poor disease outcome (such as severe perianal fistulizing disease, severe stricturing/penetrating disease, severe growth retardation, panenteric disease, persistent severe disease despite adequate induction therapy), which may incite to an anti-TNF-based top down approach. These guidelines are intended to give practical (whenever possible evidence-based) answers to (pediatric) gastroenterologists who take care of children and adolescents with CD; they are not meant to be a rule or legal standard, since many different clinical scenario exist requiring treatment strategies not covered by or different from these guidelines.
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Affiliation(s)
- F M Ruemmele
- Department of Paediatric Gastroenterology, APHP Hôpital Necker Enfants Malades, 149 Rue de Sèvres 75015 Paris, France; Université Paris Descartes, Sorbonne Paris Cité, 2 Rue de l'École de Médecine, 75006 Paris, France; INSERM U989, Institut IMAGINE, 24 Bd Montparnasse, 75015 Paris, France.
| | - G Veres
- Department of Paediatrics I, Semmelweis University, Bókay János str. 53, 1083 Budapest, Hungary
| | - K L Kolho
- Department of Gastroenterology, Helsinki University Hospital for Children and Adolescents, Stenbäckinkatu 11, P.O. Box 281, 00290 Helsinki, Finland
| | - A Griffiths
- Department of Paediatrics, Hospital for Sick Children, University of Toronto, 555 University Avenue, M5G 1X8 Toronto, ON, Canada
| | - A Levine
- Paediatric Gastroenterology and Nutrition Unit, Tel Aviv University, Edith Wolfson Medical Center, 62 HaLohamim Street, 58100 Holon, Israel
| | - J C Escher
- Department of Paediatric Gastroenterology, Erasmus Medical Center, Wytemaweg 80, 3015 CN Rotterdam, Netherlands
| | - J Amil Dias
- Unit of Paediatric Gastroenterology, Hospital S. João, A Hernani Monteiro, 4202-451, Porto, Portugal
| | - A Barabino
- Gastroenterology and Endoscopy Unit, Istituto G. Gaslini, Via G. Gaslini 5, 16148 Genoa, Italy
| | - C P Braegger
- Division of Gastroenterology and Nutrition, and Children's Research Center, University Children's Hospital Zurich, Steinwiesstrasse 75, 8032 Zurich, Switzerland
| | - J Bronsky
- Department of Pediatrics, University Hospital Motol, Uvalu 84, 150 06 Prague, Czech Republic
| | - S Buderus
- Department of Paediatrics, St. Marien Hospital, Robert-Koch-Str.1, 53115 Bonn, Germany
| | - J Martín-de-Carpi
- Department of Paediatric Gastroenterolgoy, Hepatology and Nutrition, Hospital Sant Joan de Déu, Paseo Sant Joan de Déu 2, 08950 Barcelona, Spain
| | - L De Ridder
- Department of Paediatric Gastroenterology, Erasmus Medical Center, Wytemaweg 80, 3015 CN Rotterdam, Netherlands
| | - U L Fagerberg
- Department of Pediatrics, Centre for Clinical Research, Entrance 29, Västmanland Hospital, 72189 Västerås/Karolinska Institutet, Stockholm, Sweden
| | - J P Hugot
- Department of Gastroenterology and Nutrition, Hopital Robert Debré, 48 Bd Sérurier, APHP, 75019 Paris, France; Université Paris-Diderot Sorbonne Paris-Cité, 75018 Paris France
| | - J Kierkus
- Department of Gastroenterology, Hepatology and Feeding Disorders, Instytut Pomnik Centrum Zdrowia Dziecka, Ul. Dzieci Polskich 20, 04-730 Warsaw, Poland
| | - S Kolacek
- Department of Paediatric Gastroenterology, Children's Hospital, University of Zagreb Medical School, Klaićeva 16, 10000 Zagreb, Croatia
| | - S Koletzko
- Department of Paediatric Gastroenterology, Dr. von Hauner Children's Hospital, Lindwurmstr. 4, 80337 Munich, Germany
| | - P Lionetti
- Department of Gastroenterology and Nutrition, Meyer Children's Hospital, Viale Gaetano Pieraccini 24, 50139 Florence, Italy
| | - E Miele
- Department of Translational Medical Science, Section of Paediatrics, University of Naples "Federico II", Via S. Pansini, 5, 80131 Naples, Italy
| | - V M Navas López
- Paediatric Gastroenterology and Nutrition Unit, Hospital Materno Infantil, Avda. Arroyo de los Ángeles s/n, 29009 Málaga, Spain
| | - A Paerregaard
- Department of Paediatrics 460, Hvidovre University Hospital, Kettegård Allé 30, 2650 Hvidovre, Denmark
| | - R K Russell
- Department of Paediatric Gastroenterology, Yorkhill Hospital, Dalnair Street, Glasgow G3 8SJ, United Kingdom
| | - D E Serban
- 2nd Department of Paediatrics, "Iuliu Hatieganu" University of Medicine and Pharmacy, Emergency Children's Hospital, Crisan nr. 5, 400177 Cluj-Napoca, Romania
| | - R Shaoul
- Department of Pediatric Gastroenterology and Nutrition, Rambam Health Care Campus Rappaport Faculty Of Medicine, 6 Ha'alya Street, P.O. Box 9602, 31096 Haifa, Israel
| | - P Van Rheenen
- Department of Paediatric Gastroenterology, Hepatology and Nutrition, University Medical Center Groningen, P.O. Box 30001, 9700 RB Groningen, Netherlands
| | - G Veereman
- Department of Paediatric Gastroenterology and Nutrition, Children's University Hospital, Laarbeeklaan 101, 1090 Brussels, Belgium
| | - B Weiss
- Paediatric Gastroenterology and Nutrition Unit, Edmond and Lily Safra Children's Hospital, Sheba Medical Center, 52625 Tel Hashomer, Israel
| | - D Wilson
- Child Life and Health, Paediatric Gastroenterology, Royal Hospital for Sick Children, 9 Sciennes Road, Edinburgh EH9 1LF, United Kingdom
| | - A Dignass
- Department of Medicine I, Agaplesion Markus Hospital, Wilhelm-Epstein-Str. 4, 60431 Frankfurt/Main, Gemany
| | - A Eliakim
- 33-Gastroenterology, Sheba Medical Center, 52621 Tel Hashomer, Israel
| | - H Winter
- Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Mass General Hospital for Children, 175 Cambridge Street, 02114 Boston, United States
| | - D Turner
- Pediatric Gastroenterology Unit, Shaare Zedek Medical Center, The Hebrew University of Jerusalem, Israel
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Melachuri S, Gandrud L, Bostrom B. The association between fasting hypoglycemia and methylated mercaptopurine metabolites in children with acute lymphoblastic leukemia. Pediatr Blood Cancer 2014; 61:1003-6. [PMID: 24415675 DOI: 10.1002/pbc.24928] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/05/2013] [Accepted: 12/12/2013] [Indexed: 11/11/2022]
Abstract
BACKGROUND Symptomatic fasting hypoglycemia has been reported as an unusual side effect in patients with acute lymphoblastic leukemia (ALL) on maintenance therapy. We evaluated the relation of the red cell 6-mercaptopurine (6-MP) metabolite 6-methyl-mercaptopurine (6MMP) with hypoglycemia. PROCEDURE We retrospectively reviewed charts of three patients with ALL and symptomatic hypoglycemia while fasting who were noted to have high levels of 6MMP. All patients had an empiric trial of switching from evening to morning 6-MP administration, and two patients were subsequently switched to twice daily dosing. Patients also received complex carbohydrates at bedtime. RESULTS Switching 6-MP from evening to morning administration reduced 6MMP levels yet preserved adequate levels of the active metabolite red cell 6-thioguanine nucleotide (6TGN). All patients had decreased hypoglycemic events when changed from evening to morning dosing. Two patients showed a rebound in 6MMP levels with return of hypoglycemic symptoms. Both were then switched to twice daily 6-MP dosing with one having a decrease in 6MMP and hypoglycemic symptoms. CONCLUSIONS High levels of 6MMP are associated with symptomatic hypoglycemia which may be mitigated by switching to morning or twice daily 6-MP dose administration.
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Affiliation(s)
- Samyuktha Melachuri
- Pediatric Hematology/Oncology, Children's Hospitals and Clinics of Minnesota, Minneapolis, Minnesota
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Abstract
Ulcerative colitis (UC) is a chronic inflammatory disorder of the gastrointestinal tract of unknown etiology that frequently presents in the pediatric population. The evaluation of pediatric UC involves excluding infection, and a colonoscopy that documents the clinical and histologic features of chronic colitis. Initial management of mild UC is typically with mesalamine therapy for induction and maintenance. Moderate UC is often initially treated with oral prednisone. Depending on disease severity and response to prednisone, maintenance options include mesalamine, mercaptopurine, azathioprine, infliximab, or adalimumab. Severe UC is typically treated with intravenous corticosteroids. Corticosteroid nonresponders should either undergo a colectomy or be treated with second-line medical rescue therapy (infliximab or calcineurin inhibitors). The severe UC patients who respond to medical rescue therapy can be maintained on infliximab or thiopurine, but 1-year remission rates for such patients are under 50 %. These medications are discussed in detail along with the initial work-up and a treatment algorithm.
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Affiliation(s)
- Brian P Regan
- Department of Gastroenterology, Inflammatory Bowel Disease Center, GI Division-Hunnewell Ground, Harvard Medical School, Boston Children's Hospital, 300 Longwood Avenue, Boston, MA, 02115, USA,
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Konidari A, Matary WE. Use of thiopurines in inflammatory bowel disease: Safety issues. World J Gastrointest Pharmacol Ther 2014; 5:63-76. [PMID: 24868487 PMCID: PMC4023326 DOI: 10.4292/wjgpt.v5.i2.63] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/22/2013] [Accepted: 02/19/2014] [Indexed: 02/06/2023] Open
Abstract
Thiopurines are widely used for maintenance treatment of inflammatory bowel disease. Inter-individual variability in clinical response to thiopurines may be attributed to several factors including genetic polymorphisms, severity and chronicity of disease, comorbidities, duration of administration, compliance issues and use of concomitant medication, environmental factors and clinician and patient preferences. The purpose of this review is to summarise the current evidence on thiopurine safety and toxicity, to describe adverse drug events and emphasise the significance of drug interactions, and to discuss the relative safety of thiopurine use in adults, elderly patients, children and pregnant women. Thiopurines are safe to use and well tolerated, however dose adjustment or discontinuation of treatment must be considered in cases of non-response, poor compliance or toxicity. Drug safety, clinical response to treatment and short to long term risks and benefits must be balanced throughout treatment duration for different categories of patients. Treatment should be individualised and stratified according to patient requirements. Enzymatic testing prior to treatment commencement is advised. Surveillance with regular clinic follow-up and monitoring of laboratory markers is important. Data on long term efficacy, safety of thiopurine use and interaction with other disease modifying drugs are lacking, especially in paediatric inflammatory bowel disease. High quality, collaborative clinical research is required so as to inform clinical practice in the future.
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Beswick L, Friedman AB, Sparrow MP. The role of thiopurine metabolite monitoring in inflammatory bowel disease. Expert Rev Gastroenterol Hepatol 2014; 8:383-92. [PMID: 24684593 DOI: 10.1586/17474124.2014.894878] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Thiopurines are the mainstay of medical management in inflammatory bowel disease (IBD), especially in the maintenance of disease remission. Given the limited IBD armamentarium it is important to optimize each therapy before switching to an alternative drug. Conventional weight based dosing of thiopurines in IBD leads to intolerance or inefficacy in many patients. More recently increased knowledge of their metabolism has allowed for dose optimization using thiopurine metabolite levels, namely 6-thioguanine nucleotides and 6-methylmercaptopurine, with the potential for improved outcomes in patients with IBD. This review will outline the current understanding of thiopurine metabolism and pharmacogenomics and will describe the clinical application of this knowledge in the optimization of thiopurines in individual patients.
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Affiliation(s)
- Lauren Beswick
- Department of Gastroenterology, Alfred Health and Monash University, Commercial Road, Melbourne, 3004 Victoria, Australia
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Yarur AJ, Abreu MT, Deshpande AR, Kerman DH, Sussman DA. Therapeutic drug monitoring in patients with inflammatory bowel disease. World J Gastroenterol 2014; 20:3475-84. [PMID: 24707130 PMCID: PMC3974514 DOI: 10.3748/wjg.v20.i13.3475] [Citation(s) in RCA: 45] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/30/2013] [Revised: 01/15/2014] [Accepted: 02/17/2014] [Indexed: 02/06/2023] Open
Abstract
Thiopurine analogs and anti-tumor necrosis factor (TNF) agents have dramatically changed the therapeutics of inflammatory bowel diseases (IBD), improving short and long-term outcomes. Unfortunately some patients do not respond to therapy and others lose response over time. The pharmacokinetic properties of these drugs are complex, with high inter-patient variability. Thiopurine analogs are metabolized through a series of pathways, which vary according to the patients' pharmacogenetic profile. This profile largely determines the ratios of metabolites, which are in turn associated with likelihoods of clinical efficacy and/or toxicity. Understanding these mechanisms allows for manipulation of drug dose, aiming to reduce the development of toxicity while improving the efficacy of treatment. The efficacy of anti-TNF drugs is influenced by many pharmacodynamic variables. Several factors may alter drug clearance, including the concomitant use of immunomodulators (thiopurine analogs and methotrexate), systemic inflammation, the presence of anti-drug antibodies, and body mass. The treatment of IBD has evolved with the understanding of the pharmacologic profiles of immunomodulating and TNF-inhibiting medications, with good evidence for improvement in patient outcomes observed when measuring metabolic pathway indices. The role of routine measurement of metabolite/drug levels and antibodies warrants further prospective studies as we enter the era of personalized IBD care.
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