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Coelho T, Cheng G, Lewis S, Ashton JJ, Barakat F, Driscoll KCT, Sholeye-Bolaji AE, Batra A, Afzal NA, Beattie RM, Ennis S. Pharmacogenomic Assessment of Genes Implicated in Thiopurine Metabolism and Toxicity in a UK Cohort of Pediatric Patients With Inflammatory Bowel Disease. Inflamm Bowel Dis 2025; 31:362-375. [PMID: 39011784 DOI: 10.1093/ibd/izae126] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/07/2023] [Indexed: 07/17/2024]
Abstract
BACKGROUND Thiopurine drugs are effective treatment options in inflammatory bowel disease and other conditions but discontinued in some patients due to toxicity. METHODS We investigated thiopurine-induced toxicity in a pediatric inflammatory bowel disease cohort by utilizing exome sequencing data across a panel of 46 genes, including TPMT and NUDT15. RESULTS The cohort included 487 patients with a median age of 13.1 years. Of the 396 patients exposed to thiopurines, myelosuppression was observed in 11%, gastroenterological intolerance in 11%, hepatotoxicity in 4.5%, pancreatitis in 1.8%, and "other" adverse effects in 2.8%. TPMT (thiopurine S-methyltransferase) enzyme activity was normal in 87.4%, intermediate 12.3%, and deficient in 0.2%; 26% of patients with intermediate activity developed toxicity to thiopurines. Routinely genotyped TPMT alleles associated with defective enzyme activity were identified in 28 (7%) patients: TPMT*3A in 4.5%, *3B in 1%, and *3C in 1.5%. Of these, only 6 (21%) patients developed toxic responses. Three rare TPMT alleles (*3D, *39, and *40) not assessed on routine genotyping were identified in 3 patients, who all developed toxic responses. The missense variant p.R139C (NUDT15*3 allele) was identified in 4 patients (azathioprine 1.6 mg/kg/d), but only 1 developed toxicity. One patient with an in-frame deletion variant p.G13del in NUDT15 developed myelosuppression at low doses. Per-gene deleteriousness score GenePy identified a significant association for toxicity in the AOX1 and DHFR genes. CONCLUSIONS A significant association for toxicity was observed in the AOX1 and DHFR genes in individuals negative for the TPMT and NUDT15 variants. Patients harboring the NUDT15*3 allele, which is associated with myelosuppression, did not show an increased risk of toxicity.
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Affiliation(s)
- Tracy Coelho
- Department of Paediatric Gastroenterology, University Hospital Southampton, Southampton, United Kingdom
| | - Guo Cheng
- Human Genetics and Genomic Medicine, University of Southampton, Southampton, United Kingdom
| | - Sophie Lewis
- Department of Paediatric Gastroenterology, University Hospital Southampton, Southampton, United Kingdom
| | - James J Ashton
- Department of Paediatric Gastroenterology, University Hospital Southampton, Southampton, United Kingdom
- Human Genetics and Genomic Medicine, University of Southampton, Southampton, United Kingdom
| | - Farah Barakat
- Department of Paediatric Gastroenterology, University Hospital Southampton, Southampton, United Kingdom
| | - Kouros C T Driscoll
- Department of Paediatric Gastroenterology, University Hospital Southampton, Southampton, United Kingdom
| | - Adebola E Sholeye-Bolaji
- Department of Paediatric Gastroenterology, University Hospital Southampton, Southampton, United Kingdom
| | - Akshay Batra
- Department of Paediatric Gastroenterology, University Hospital Southampton, Southampton, United Kingdom
| | - Nadeem A Afzal
- Department of Paediatric Gastroenterology, University Hospital Southampton, Southampton, United Kingdom
| | - Robert M Beattie
- Department of Paediatric Gastroenterology, University Hospital Southampton, Southampton, United Kingdom
| | - Sarah Ennis
- Human Genetics and Genomic Medicine, University of Southampton, Southampton, United Kingdom
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Ueda H, Narumi K, Asano S, Saito Y, Furugen A, Kobayashi M. Comparative study on the occurrence of adverse effects in the concomitant use of azathioprine and aldehyde oxidase inhibitors. Expert Opin Drug Saf 2024; 23:89-97. [PMID: 38097359 DOI: 10.1080/14740338.2023.2295976] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2023] [Accepted: 11/28/2023] [Indexed: 12/19/2023]
Abstract
OBJECTIVES Aldehyde oxidase (AO) is a molybdenum-containing redox enzyme similar to xanthine oxidase that is involved in the thiopurine metabolism. This study investigated the effects of drug-drug interactions (DDIs) between azathioprine (AZA) and AO inhibitors on hematologic and hepatic disorders using the U.S. Food and Drug Administration Adverse Event Reporting System and the Japanese Adverse Drug Event Report database. METHODS The presence of DDI was assessed using the interaction signal scores (ISSs) calculated via the reporting odds ratios and 95% confidence intervals. The study used reports of 'azathioprine' as a suspect drug for adverse effects. AO inhibitors were selected based on previous in vitro reports. RESULTS Some drugs tested positive for ISSs in each database and type of adverse effect (hematologic or hepatic disorder) analysis. Among these drugs, chlorpromazine, clozapine, hydralazine, and quetiapine could inhibit AZA metabolism via AO, given the previously reported clinical blood concentration and inhibitory effects of each drug. CONCLUSION Concomitant use of AO inhibitors increased the signals for AZA-induced adverse effects. To date, no studies have evaluated the clinical importance of AO as a drug-metabolizing enzyme, and further in vitro and clinical research is needed to clarify the contribution of AO to the pharmacokinetics of thiopurines.
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Affiliation(s)
- Hinata Ueda
- Laboratory of Clinical Pharmaceutics & Therapeutics, Division of Pharmasciences, Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo, Japan
| | - Katsuya Narumi
- Laboratory of Clinical Pharmaceutics & Therapeutics, Division of Pharmasciences, Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo, Japan
- Education Research Center for Clinical Pharmacy, Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo, Japan
| | - Shuho Asano
- Laboratory of Clinical Pharmaceutics & Therapeutics, Division of Pharmasciences, Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo, Japan
| | - Yoshitaka Saito
- Department of Clinical Pharmaceutics & Therapeutics, Faculty of Pharmaceutical Sciences, Hokkaido University of Science, Sapporo, Japan
| | - Ayako Furugen
- Laboratory of Clinical Pharmaceutics & Therapeutics, Division of Pharmasciences, Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo, Japan
| | - Masaki Kobayashi
- Laboratory of Clinical Pharmaceutics & Therapeutics, Division of Pharmasciences, Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo, Japan
- Education Research Center for Clinical Pharmacy, Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo, Japan
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Moovara Cackamvalli P, Al Bakri FMA, Khanjar IAM. Azathioprine induced acute sialadenitis: A case report. Clin Case Rep 2023; 11:e7662. [PMID: 37434959 PMCID: PMC10332252 DOI: 10.1002/ccr3.7662] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2022] [Revised: 03/15/2023] [Accepted: 06/08/2023] [Indexed: 07/13/2023] Open
Abstract
Key clinical message Patients presenting with acute sialadenitis need careful review of their medications. Azathioprine is one of such drugs, which can rarely induce acute sialadenitis. Prompt discontinuation of the medication leads to reversal of the patient condition. Abstract Acute sialadenitis is one of the rare adverse effects of azathioprine. We report a case of acute submandibular sialadenitis following initiation of azathioprine which resolved upon discontinuation of the drug.
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Daniluk U, Krawiec P, Pac-Kożuchowska E, Dembiński Ł, Bukowski JS, Banaszkiewicz A, Woźniuk-Kaźmierczak A, Czkwianianc E, Brylak J, Walkowiak J, Borys-Iwanicka A, Kofla-Dłubacz A, Pytrus T, Zdanowicz K, Lebensztejn DM. Pancreatic Involvement in the Course of Inflammatory Bowel Disease in Children-A Multi-Center Study. J Clin Med 2023; 12:4174. [PMID: 37445210 DOI: 10.3390/jcm12134174] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2023] [Revised: 06/18/2023] [Accepted: 06/19/2023] [Indexed: 07/15/2023] Open
Abstract
The coexistence of inflammatory bowel disease (IBD) with pancreatic pathology is rare in children. A retrospective analysis of data from 1538 children diagnosed with IBD in 2014-2021 was conducted to determine the frequency and causes of pancreatitis and asymptomatic hyperlipasemia (HL) or hyperamylasemia (HA) in this group of patients. Among the 176 children (11.4%) with pancreatic involvement (PI), acute pancreatitis (AP) was diagnosed in 77 children (43.8%), and HA or HL was observed in 88 children (50.0%). Only a few patients were diagnosed with autoimmune or chronic pancreatitis (6.2%). PI was observed at the time of the IBD diagnosis in 26.1% of the cases. A total of 54.5% of the patients had moderate to severe IBD, and 96% had colonic involvement at the time of diagnosis of PI. Idiopathic PI was the most common (57%), followed by drug-induced PI (37%) and azathioprine (AZA). In patients with AZA-induced AP, the successful introduction of 6-mercaptopurine (6-MP) to therapy was noted in 62.5% of the children. Our results suggest that routine monitoring of pancreatic enzymes in patients with IBD should be performed, especially after the initiation of the AZA treatment. The presence of transient HA/HL in IBD does not necessarily indicate pancreatic pathology.
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Affiliation(s)
- Urszula Daniluk
- Department of Pediatrics, Gastroenterology, Hepatology, Nutrition, Allergology and Pulmonology, Medical University of Bialystok, 15-274 Bialystok, Poland
| | - Paulina Krawiec
- Department of Pediatrics and Gastroenterology, Medical University of Lublin, 20-059 Lublin, Poland
| | - Elżbieta Pac-Kożuchowska
- Department of Pediatrics and Gastroenterology, Medical University of Lublin, 20-059 Lublin, Poland
| | - Łukasz Dembiński
- Department of Pediatric Gastroenterology and Nutrition, Medical University of Warsaw, 02-091 Warsaw, Poland
| | - Jan Stanisław Bukowski
- Department of Pediatric Gastroenterology and Nutrition, Medical University of Warsaw, 02-091 Warsaw, Poland
| | - Aleksandra Banaszkiewicz
- Department of Pediatric Gastroenterology and Nutrition, Medical University of Warsaw, 02-091 Warsaw, Poland
| | - Anna Woźniuk-Kaźmierczak
- Department of Gastroenterology, Allergology and Pediatrics, Polish Mother's Memorial Hospital-Research Institute, 93-338 Lodz, Poland
| | - Elżbieta Czkwianianc
- Department of Gastroenterology, Allergology and Pediatrics, Polish Mother's Memorial Hospital-Research Institute, 93-338 Lodz, Poland
| | - Jan Brylak
- Department of Pediatric Gastroenterology and Metabolic Diseases, Poznan University of Medical Sciences, 60-572 Poznan, Poland
| | - Jarosław Walkowiak
- Department of Pediatric Gastroenterology and Metabolic Diseases, Poznan University of Medical Sciences, 60-572 Poznan, Poland
| | - Agnieszka Borys-Iwanicka
- 2nd Clinical Department of Pediatrics, Gastroenterology and Nutrition, Medical University of Wroclaw, 50-369 Wroclaw, Poland
| | - Anna Kofla-Dłubacz
- 2nd Clinical Department of Pediatrics, Gastroenterology and Nutrition, Medical University of Wroclaw, 50-369 Wroclaw, Poland
| | - Tomasz Pytrus
- 2nd Clinical Department of Pediatrics, Gastroenterology and Nutrition, Medical University of Wroclaw, 50-369 Wroclaw, Poland
| | - Katarzyna Zdanowicz
- Department of Pediatrics, Gastroenterology, Hepatology, Nutrition, Allergology and Pulmonology, Medical University of Bialystok, 15-274 Bialystok, Poland
| | - Dariusz Marek Lebensztejn
- Department of Pediatrics, Gastroenterology, Hepatology, Nutrition, Allergology and Pulmonology, Medical University of Bialystok, 15-274 Bialystok, Poland
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Lerchova T, Hradsky O, Kulich M, Veres G, Dias JA, Sładek M, Kolacek S, Van Biervliet S, Melek J, Serban DE, Winther K, de Meij T, Schwarz J, Kolho KL, Escher JC, Bronsky J. Prediction of thiopurine failure in pediatric Crohn's disease: pediatric IBD Porto group of ESPGHAN. Pediatr Res 2023; 93:1659-1666. [PMID: 36008595 DOI: 10.1038/s41390-022-02270-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/25/2022] [Revised: 07/26/2022] [Accepted: 08/05/2022] [Indexed: 11/08/2022]
Abstract
BACKGROUND Maintaining of remission early in the disease course of Crohn's disease (CD) is essential and has major impact on the future prognosis. This study aimed to identify baseline predictors to develop model allowing stratification of patients who will not benefit from long-term azathioprine (AZA) treatment and will require more intensive therapy. METHODS This study was designed to develop clinical prediction rule using retrospective data analysis of pediatric CD patients included in prospective inception cohort. Clinical relapse was defined as necessity of re-induction of remission. Sequence of Cox models was fitted to predict risk of relapse. RESULTS Out of 1190 CD patients from 13 European centers, 441 were included, 50.3% patients did not experience clinical relapse within 2 years of AZA treatment initiation. Median time to relapse was 2.11 (CI 1.59-2.46) years. Of all the tested parameters available at diagnosis, six were significant in multivariate analyses: C-reactive protein (p = 0.038), body mass index Z-score >0.8 SD (p = 0.002), abnormal sigmoid imaging (p = 0.039), abnormal esophageal endoscopy (p = 0.005), ileocolonic localization (p = 0.023), AZA dose in specific age category (p = 0.031). CONCLUSIONS Although the possibility of predicting relapse on AZA treatment appears limited, we developed predictive model based on six baseline parameters potentially helpful in clinical decision. IMPACT The possibility of predicting relapse on AZA treatment appears to be possible but limited. We identified six independent predictors available at diagnosis of early AZA/6-MP treatment failure in pediatric CD patients. Using combination of these factors, a model applicable to clinical practice was created. A web-based tool, allowing estimation of individual relapse risk in pediatric CD patients on a particular therapeutic regimen, has been developed.
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Affiliation(s)
- Tereza Lerchova
- Department of Pediatrics, 2nd Faculty of Medicine, Charles University and Motol University Hospital, Prague, Czech Republic.
| | - Ondrej Hradsky
- Department of Pediatrics, 2nd Faculty of Medicine, Charles University and Motol University Hospital, Prague, Czech Republic
| | - Michal Kulich
- Department of Probability and Mathematical Statistics, Faculty of Mathematics and Physics, Charles University, Prague, Czech Republic
| | - Gabor Veres
- Pediatric Institute-Clinic, University of Debrecen, Debrecen, Hungary
| | | | - Małgorzata Sładek
- Polish-American Children's Hospital, Jagiellonian University, Cracow, Poland
| | - Sanja Kolacek
- Children's Hospital Zagreb Faculty of Medicine, Zagreb, Croatia
| | | | - Jan Melek
- Department of Pediatrics, University Hospital, Charles University, Hradec Kralove, Czech Republic
| | - Daniela E Serban
- 2nd Clinic of Pediatrics, "Iuliu Hatieganu" University of Medicine and Pharmacy, Emergency Clinical Hospital for Children, Cluj-Napoca, Romania
| | | | - Tim de Meij
- Amsterdam UMC, location VUMC, Amsterdam, Netherlands
| | - Jan Schwarz
- Department of Pediatrics, Faculty of Medicine in Pilsen, Charles University, Prague, Czech Republic
| | | | | | - Jiri Bronsky
- Department of Pediatrics, 2nd Faculty of Medicine, Charles University and Motol University Hospital, Prague, Czech Republic
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Chambers EK, Stratulat E, Judge G, Shafique S, Ladel L. Stomach Pain Upon Stomach Pain: Medication-Induced Pancreatitis. Cureus 2023; 15:e35554. [PMID: 37007369 PMCID: PMC10060005 DOI: 10.7759/cureus.35554] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/27/2023] [Indexed: 03/02/2023] Open
Abstract
As a first-line immunosuppressant to maintain remission in Crohn's disease, 6-mercaptopurine (6-MP) has been commonly used. A rare, unpredictable, dose-independent and idiosyncratic reaction to this medication is acute pancreatitis. Unlike other side effects of this drug which have been well characterized and are often dose-dependent, acute pancreatitis is an uncommon adverse effect not frequently encountered in clinical practice. In this case report, we describe a 40-year-old man with Crohn's disease who developed acute pancreatitis within two weeks of starting 6-MP. Discontinuation of the drug followed by fluid resuscitation led to the overall improvement of symptoms within 72 hours. No complications were noted during the follow-up. It is our intention to raise awareness for this lesser-known side effect with this case report and to urge physicians to provide thorough counseling prior to starting on this medication, especially in patients with inflammatory bowel disease (IBD). Additionally, we hope to reinforce this disease entity as a differential for acute pancreatitis and aim to emphasize the importance of detailed medication reconciliations with this report, especially in the emergency department, to enable quick diagnoses and limit unnecessary treatments.
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Mateen B, Patel M, Akobeng A, Gordon M, Hayee B. Systematic review: The effectiveness of 6-thioguanine nucleotide-based dose optimisation of thiopurines in the treatment of inflammatory bowel disease. Wellcome Open Res 2023. [DOI: 10.12688/wellcomeopenres.18846.1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023] Open
Abstract
Introduction: Clinical guidelines highlight the potential utility of metabolite-based thiopurine dose optimisation strategies in inflammatory bowel disease (IBD). The aim of this review was to summarise the evidence of effectiveness and safety of a 6-thioguanine nucleotide (6-TGN) metabolite-based dosing strategy for maintenance of remission using azathioprine or mercaptopurine in Crohn's disease and ulcerative colitis. Methods: We searched the Cochrane central register of controlled trials, EMBASE, clinicaltrials.gov, the WHO international clinical trials registry platform, and relevant grey literature, up to 1 December 2021. Inclusion criteria were: all randomised (active comparator) controlled trials of azathioprine or mercaptopurine used for the purposes of maintenance of remission in Crohn's disease or ulcerative colitis where the dose in the intervention arm was optimised based on 6-TGN metabolite assay results. Studies of any duration were eligible for inclusion, and no age restrictions were applied. Results: No studies met the eligibility criteria for this review. Four randomised controlled studies (two of which are currently underway) were identified that assessed the effectiveness of metabolite-based dose optimisation for thiopurine therapy, but were not eligible either because they did not differentiate between induction and maintenance therapy or because of a lack of an appropriate active comparator. Conclusions: There is no RCT-based evidence for dose optimisation using a 6-TGN metabolite-based dosing strategy for maintenance of remission in Crohn's disease or ulcerative colitis. Where evidence is available from combination induction and maintenance trials, it suggests that such a strategy is no better than weight-based dosing. Cochrane protocol registration: CD014795
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Bayoumy AB, Jagt JZ, van Wering HM, de Ridder L, Hummel T, Wolters VM, Stapelbroek J, Benninga MA, Mulder CJ, de Boer NK, de Meij TG. Safety of Thioguanine in Pediatric Inflammatory Bowel Disease: A Multi-Center Case Series. J Pediatr Gastroenterol Nutr 2022; 75:e111-e115. [PMID: 36136124 PMCID: PMC9645549 DOI: 10.1097/mpg.0000000000003621] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/09/2022] [Accepted: 08/11/2022] [Indexed: 01/12/2023]
Abstract
OBJECTIVES Thioguanine (TG) has been shown as a safe alternative in adults with inflammatory bowel disease (IBD) who did not tolerate conventional thiopurines [azathioprine (AZA)/mercaptopurine]. However, data in pediatric IBD are scarce. Therefore, we aimed to assess the safety of TG as maintenance therapy. METHODS A retrospective, multicenter cohort study of children with IBD on TG was performed in the Netherlands. TG-related adverse events (AE) were assessed and listed according to the common terminology criteria for AE. RESULTS Thirty-six children with IBD (median age 14.5 years) on TG (median dose 15 mg/day) were included in 6 centers. Five AE occurred during follow-up [pancreatitis (grade 3), hepatotoxicity (grade 3) (n = 2), Clostridium difficile infection (grade 2), and abdominal pain (grade 2)]. All patients (n = 8) with a previously AZA-induced pancreatitis did not redevelop pancreatitis on TG. CONCLUSIONS In pediatric IBD, TG seems a safe alternative in case of AZA-induced pancreatitis. Further research assessing long-term TG-related safety and efficacy is needed.
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Affiliation(s)
- Ahmed B. Bayoumy
- From the Faculty of Medicine, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands
| | - Jasmijn Z. Jagt
- the Department of Pediatric Gastroenterology, Emma Children’s Hospital, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, the Netherlands
- the Amsterdam UMC, Vrije Universiteit Amsterdam, Paediatric Gastroenterology, Amsterdam Gastroenterology Endocrinology Metabolism, Amsterdam, the Netherlands
| | - Herbert M. van Wering
- the Department of Pediatric Gastroenterology, Amphia Hospital, Breda, the Netherlands
| | - Lissy de Ridder
- the Department of Pediatric Gastroenterology, Erasmus MC Sophia Children’s Hospital, Rotterdam, the Netherlands
| | - Thalia Hummel
- the Department of Pediatric Gastroenterology, Medisch Spectrum Twente, Enschede, the Netherlands
| | - Victorien M. Wolters
- the Department of Pediatric Gastroenterology, Wilhelmina Children’s Hospital, University Medical Center Utrecht, Utrecht, the Netherlands
| | - Janneke Stapelbroek
- the Department of Pediatric Gastroenterology, Catharina Hospital, Eindhoven, the Netherlands
| | - Marc A. Benninga
- the Department of Pediatric Gastroenterology and Nutrition, Emma Children’s Hospital, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, the Netherlands
| | - Chris J.J. Mulder
- the Department of Gastroenterology and Hepatology, Amsterdam Gastroenterology and Metabolism Research Institute, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, the Netherlands
| | - Nanne K.H. de Boer
- the Department of Gastroenterology and Hepatology, Amsterdam Gastroenterology and Metabolism Research Institute, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, the Netherlands
| | - Tim G.J. de Meij
- the Department of Pediatric Gastroenterology, Emma Children’s Hospital, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, the Netherlands
- the Department of Pediatric Gastroenterology and Nutrition, Emma Children’s Hospital, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, the Netherlands
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Prabha R, Mathew SK, Joseph AJ, Mathew BS. Exposure of Azathioprine Metabolites and Clinical Outcome in Indian Patients with Crohn’s Disease. J Pharmacol Pharmacother 2022. [DOI: 10.1177/0976500x221085804] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/18/2022] Open
Abstract
Aim: The aim of this study was to determine the concentration of 6-thioguanine nucleotide (6-TGN) and 6-methylmercaptopurine (6-MMP), the interpatient variability, and the relationship with disease activity in patients with Chron’s disease on long-term stable doses of azathioprine (AZA). Methods: This is a prospective, tertiary care single-center hospital study in adult Chron’s disease patients treated with AZA. The quantification of phenotypic thiopurine methyltransferase enzyme activity in red blood cells and the estimation of the concentration of 6-TGN and 6-MMP in whole blood was performed using the HPLC-UV detector method. A clinical response was categorized as remission (Harvey-Bradshaw Index [HBI] < 5) or improvement (drop from baseline of at least three points of HBI) based on HBI. Exposure to metabolite concentrations and the clinical response to AZA treatment was observed. Results: Study analysis included 30 patients who were initiated on AZA, and they were followed up with an estimation of metabolite concentrations to determine their clinical outcome. At six months, 93% of ( n = 28) patients continued to be on AZA and had clinical improvement. All the patients achieved remission of Chron’s disease. Only two patients developed adverse effects such as joint pain and thrombocytopenia. Conclusion: AZA is a safe and effective therapy in managing Chron’s disease when administered after determining thiopurine methyltransferase phenotype and with dose optimization performed using therapeutic drug monitoring of 6-TGN and 6-MMP.
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Affiliation(s)
- Ratna Prabha
- Clinical Pharmacology Unit, Christian Medical College, Vellore, Tamil Nadu, India
| | - Sumith K. Mathew
- Clinical Pharmacology Unit, Christian Medical College, Vellore, Tamil Nadu, India
| | - A. J. Joseph
- Department of Gastroenterology, Christian Medical College, Vellore, Tamil Nadu, India
| | - Binu Susan Mathew
- Clinical Pharmacology Unit, Christian Medical College, Vellore, Tamil Nadu, India
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Finding Predictors of Azathioprine-Induced Pancreatitis in Patients With Inflammatory Bowel Disease. Pancreas 2022; 51:288-294. [PMID: 35584388 DOI: 10.1097/mpa.0000000000002012] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/10/2022]
Abstract
OBJECTIVES Azathioprine (AZA)-induced pancreatitis (AIP) is a common, idiosyncratic adverse effect whose incidence and risk factors data in inflammatory bowel disease (IBD) patients are not fully clarified. We aimed to establish the incidence, clinical course and identify risk factors for AIP. METHODS A retrospective study including all IBD patients on AZA between January 2013 and July 2020 was conducted. Patients with AIP were considered. RESULTS Azathioprine-induced pancreatitis occurred in 33 patients (7.5%; 442 patients on AZA). The mean time receiving AZA until AIP was 25 days, with a mean dose of 88 mg. All patients had a mild course of disease, which resolved with suspension of AZA and with no complications. Smoking (P = 0.02), single daily dose of AZA (P < 0.001), and concomitant budesonide (P = 0.001) were risk factors for AIP. In multivariate analysis, concomitant treatment with budesonide (odds ratio, 5.3; P = 0.002) and single daily dose of AZA (odds ratio, 3.8; P = 0.002) were the only predictors of AIP. CONCLUSIONS Although AIP was a relatively common adverse effect, it presented a mild course in all patients. Smoking, concomitant use of budesonide, and single-dose regimen of AZA should be avoided in IBD patients treated with AZA.
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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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van Liere ELSA, Bayoumy AB, Mulder CJJ, Warner B, Hayee B, Mateen BA, Nolan JD, de Boer NKH, Anderson SHC, Ansari AR. Azathioprine with Allopurinol Is a Promising First-Line Therapy for Inflammatory Bowel Diseases. Dig Dis Sci 2022; 67:4008-4019. [PMID: 34729677 PMCID: PMC9287424 DOI: 10.1007/s10620-021-07273-y] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/29/2021] [Accepted: 10/01/2021] [Indexed: 12/13/2022]
Abstract
BACKGROUND Beneficial response to first-line immunosuppressive azathioprine in patients with inflammatory bowel disease (IBD) is low due to high rates of adverse events. Co-administrating allopurinol has been shown to improve tolerability. However, data on this co-therapy as first-line treatment are scarce. AIM Retrospective comparison of long-term effectiveness and safety of first-line low-dose azathioprine-allopurinol co-therapy (LDAA) with first-line azathioprine monotherapy (AZAm) in patients with IBD without metabolite monitoring. METHODS Clinical benefit was defined as ongoing therapy without initiation of steroids, biologics or surgery. Secondary outcomes included CRP, HBI/SCCAI, steroid withdrawal and adverse events. RESULTS In total, 166 LDAA and 118 AZAm patients (median follow-up 25 and 27 months) were evaluated. Clinical benefit was more frequently observed in LDAA patients at 6 months (74% vs. 53%, p = 0.0003), 12 months (54% vs. 37%, p = 0.01) and in the long-term (median 36 months; 37% vs. 24%, p = 0.04). Throughout follow-up, AZAm patients were 60% more likely to fail therapy, due to a higher intolerance rate (45% vs. 26%, p = 0.001). Only 73% of the effective AZA dose was tolerated in AZAm patients, while LDAA could be initiated and maintained at its target dose. Incidence of myelotoxicity and elevated liver enzymes was similar in both cohorts, and both conditions led to LDAA withdrawal in only 2%. Increasing allopurinol from 100 to 200-300 mg/day significantly lowered liver enzymes in 5/6 LDAA patients with hepatotoxicity. CONCLUSIONS Our poor AZAm outcomes emphasize that optimization of azathioprine is needed. We demonstrated a long-term safe and more effective profile of first-line LDAA. This co-therapy may therefore be considered standard first-line immunosuppressive.
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Affiliation(s)
- Elsa L. S. A. van Liere
- Faculty of Medicine, Amsterdam UMC, VU University Medical Centre, De Boelelaan 1118, 1081 HZ Amsterdam, The Netherlands ,Department of Gastroenterology and Hepatology, Surrey and Sussex NHS, Easy Surrey Hospital, Redhill, RH1 5RH UK
| | - Ahmed B. Bayoumy
- Faculty of Medicine, Amsterdam UMC, VU University Medical Centre, De Boelelaan 1118, 1081 HZ Amsterdam, The Netherlands
| | - Chris J. J. Mulder
- Department of Gastroenterology and Hepatology, AGEM Research Institute, Amsterdam UMC, VU University Medical Centre, 1081 HZ Amsterdam, The Netherlands
| | - Ben Warner
- Department of Gastroenterology and Hepatology, Guy’s and St Thomas’ NHS Foundation Trust, London, SE1 7EH UK
| | - Bu Hayee
- IBD Service, King’s College Hospital NHS Foundation Trust, London, SE5 9RS UK
| | - Bilal A. Mateen
- IBD Service, King’s College Hospital NHS Foundation Trust, London, SE5 9RS UK
| | - Jonathan D. Nolan
- Department of Gastroenterology and Hepatology, Surrey and Sussex NHS, Easy Surrey Hospital, Redhill, RH1 5RH UK
| | - Nanne K. H. de Boer
- Department of Gastroenterology and Hepatology, AGEM Research Institute, Amsterdam UMC, VU University Medical Centre, 1081 HZ Amsterdam, The Netherlands
| | - Simon H. C. Anderson
- Department of Gastroenterology and Hepatology, Guy’s and St Thomas’ NHS Foundation Trust, London, SE1 7EH UK
| | - Azhar R. Ansari
- Department of Gastroenterology and Hepatology, Surrey and Sussex NHS, Easy Surrey Hospital, Redhill, RH1 5RH UK
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Jagt JZ, Pothof CD, Buiter HJC, van Limbergen JE, van Wijk MP, Benninga MA, de Boer NKH, de Meij TGJ. Adverse Events of Thiopurine Therapy in Pediatric Inflammatory Bowel Disease and Correlations with Metabolites: A Cohort Study. Dig Dis Sci 2022; 67:241-251. [PMID: 33532972 PMCID: PMC8741678 DOI: 10.1007/s10620-021-06836-3] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/06/2020] [Accepted: 01/07/2021] [Indexed: 01/18/2023]
Abstract
BACKGROUND In the recent era of growing availability of biological agents, the role of thiopurines needs to be reassessed with the focus on toxicity. AIMS We assessed the incidence and predictive factors of thiopurine-induced adverse events (AE) resulting in therapy cessation in pediatric inflammatory bowel disease (IBD), related to thiopurine metabolites and biochemical abnormalities, and determined overall drug survival. METHODS We performed a retrospective, single-center study of children diagnosed with IBD between 2000 and 2019 and treated with thiopurine therapy. The incidence of AE and overall drug survival of thiopurines were evaluated using the Kaplan-Meier method. Correlations between thiopurine metabolites and biochemical tests were computed using Spearman's correlation coefficient. RESULTS Of 391 patients with IBD, 233 patients (162 Crohn's disease, 62 ulcerative colitis, and 9 IBD-unclassified) were prescribed thiopurines (230 azathioprine and 3 mercaptopurine), of whom 50 patients (22%) discontinued treatment, at least temporary, due to thiopurine-induced AE (median follow-up 20.7 months). Twenty-six patients (52%) were rechallenged and 18 of them (70%) tolerated this. Sixteen patients (6%) switched to a second thiopurine agent after azathioprine intolerance and 10 of them (63%) tolerated this. No predictive factors for development of AE could be identified. Concentrations of 6-thioguanine nucleotides (6-TGN) were significantly correlated with white blood cell and neutrophil count, 6-methylmercaptopurine (6-MMP) concentrations with alanine aminotransferase and gamma-glutamyltranspeptidase. CONCLUSIONS Approximately 20% of pediatric patients with IBD discontinued thiopurine treatment due to AE. A rechallenge or switch to mercaptopurine is an effective strategy after development of AE. Concentrations of 6-TGN and 6-MMP are associated with biochemical abnormalities.
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Affiliation(s)
- Jasmijn Z. Jagt
- grid.12380.380000 0004 1754 9227Department of Pediatric Gastroenterology, Emma Children’s Hospital, Amsterdam, UMC, Vrije Universiteit Amsterdam, 1105 AZ Amsterdam, The Netherlands
| | - Christine D. Pothof
- grid.12380.380000 0004 1754 9227Department of Pediatric Gastroenterology, Emma Children’s Hospital, Amsterdam, UMC, Vrije Universiteit Amsterdam, 1105 AZ Amsterdam, The Netherlands
| | - Hans J. C. Buiter
- grid.12380.380000 0004 1754 9227Department of Clinical Pharmacology and Pharmacy, Amsterdam, UMC, Vrije Universiteit Amsterdam, 1105 AZ Amsterdam, The Netherlands
| | - Johan E. van Limbergen
- grid.5650.60000000404654431Department of Pediatric Gastroenterology, UMC, Emma Children’s Hospital, Amsterdam, Academic Medical Centre, 1081 HV Amsterdam, The Netherlands
| | - Michiel P. van Wijk
- grid.12380.380000 0004 1754 9227Department of Pediatric Gastroenterology, Emma Children’s Hospital, Amsterdam, UMC, Vrije Universiteit Amsterdam, 1105 AZ Amsterdam, The Netherlands ,grid.5650.60000000404654431Department of Pediatric Gastroenterology, UMC, Emma Children’s Hospital, Amsterdam, Academic Medical Centre, 1081 HV Amsterdam, The Netherlands
| | - Marc A. Benninga
- grid.5650.60000000404654431Department of Pediatric Gastroenterology, UMC, Emma Children’s Hospital, Amsterdam, Academic Medical Centre, 1081 HV Amsterdam, The Netherlands
| | - Nanne K. H. de Boer
- grid.12380.380000 0004 1754 9227Department of Gastroenterology and Hepatology, Amsterdam Gastroenterology and Metabolism Research Institute, Amsterdam, UMC, Vrije Universiteit Amsterdam, 1081 HV Amsterdam, The Netherlands
| | - Tim G. J. de Meij
- grid.12380.380000 0004 1754 9227Department of Pediatric Gastroenterology, Emma Children’s Hospital, Amsterdam, UMC, Vrije Universiteit Amsterdam, 1105 AZ Amsterdam, The Netherlands ,grid.5650.60000000404654431Department of Pediatric Gastroenterology, UMC, Emma Children’s Hospital, Amsterdam, Academic Medical Centre, 1081 HV Amsterdam, The Netherlands
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Khaeso K, Udayachalerm S, Komvilaisak P, Chainansamit SO, Suwannaying K, Laoaroon N, Kuwatjanakul P, Nakkam N, Sukasem C, Puangpetch A, Tassaneeyakul W, Chaiyakunapruk N. Meta-Analysis of NUDT15 Genetic Polymorphism on Thiopurine-Induced Myelosuppression in Asian Populations. Front Pharmacol 2021; 12:784712. [PMID: 34925040 PMCID: PMC8675242 DOI: 10.3389/fphar.2021.784712] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2021] [Accepted: 11/16/2021] [Indexed: 12/20/2022] Open
Abstract
Backgound: The high incidence of thiopurine-induced myelosuppression in Asians is known to be attributable to genetic variation in thiopurine metabolism. A quantitative synthesis to summarize the genetic association with thiopurine-induced myelosuppression in Asians was therefore conducted. Methods: A Literature search was performed from January 2016 to May 2021 in the following databases: PubMed, Web of Science, and Embase and addition search included the studies from Zhang et al. Two reviewers independently extracted the following data: the author’s name, year of publication, ethnicity, drugs, diseases, genetic polymorphisms, onset, type of myelosuppression and results of Hardy-Weinberg equilibrium. The Newcastle-Ottawa Scale was used to assess the quality of the studies. The pooled odds ratios (OR) and 95% confidence intervals (CI) were calculated to evaluate the associations of NUDT15 and the risk of thiopurine-induced myelosuppression stratified by onset and type of myelosuppressive. Subgroup analysis by NUDT15 genetic polymorphisms was performed. Results: A total of 30 studies was included in this meta-analysis. The overall OR for the relationship between NUDT15 genetic polymorphisms and thiopurine-induced early onset of leukopenia and neutropenia in Asian populations were 11.43 (95% CI 7.11–18.35) and 16.35 (95% CI 10.20–26.22). Among NUDT15 polymorphisms, NUDT15*3 showed a significantly increased risk of early leukopenia (OR 15.31; 95% CI 9.65–24.27) and early neutropenia (OR 15.85; 95% CI 8.80–28.53). A significantly higher thiopurine-induced early neutropenic risk was also found for NUDT15*2 (OR 37.51; 95% CI 1.99–708.69). Whereas, NUDT15*5 and NUDT15*6 variants showed a lower risk of leukopenia. Conclusion: This study suggests that NUDT15*3 and NUDT15*2 are important genetic markers of thiopurine-induced early onset of myelotoxicity in Asians, therefore, early detection of these variants before initiating thiopurine therapy is necessary.
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Affiliation(s)
- Kanyarat Khaeso
- Department of Pharmacology, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand
| | - Sariya Udayachalerm
- Department of Pharmacotherapy, College of Pharmacy, University of Utah, Salt Lake City, UT, United States
| | - Patcharee Komvilaisak
- Department of Pediatrics, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand
| | | | - Kunanya Suwannaying
- Department of Pediatrics, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand
| | - Napat Laoaroon
- Department of Pediatrics, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand
| | | | - Nontaya Nakkam
- Department of Pharmacology, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand
| | - Chonlaphat Sukasem
- Division of Pharmacogenomics and Personalized Medicine, Department of Pathology, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand
- Laboratory for Pharmacogenomics, Somdech Phra Debaratana Medical Center (SDMC), Ramathibodi Hospital, Bangkok, Thailand
| | - Apichaya Puangpetch
- Division of Pharmacogenomics and Personalized Medicine, Department of Pathology, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand
- Laboratory for Pharmacogenomics, Somdech Phra Debaratana Medical Center (SDMC), Ramathibodi Hospital, Bangkok, Thailand
| | - Wichittra Tassaneeyakul
- Department of Pharmacology, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand
- *Correspondence: Wichittra Tassaneeyakul, ; Nathorn Chaiyakunapruk,
| | - Nathorn Chaiyakunapruk
- Department of Pharmacotherapy, College of Pharmacy, University of Utah, Salt Lake City, UT, United States
- *Correspondence: Wichittra Tassaneeyakul, ; Nathorn Chaiyakunapruk,
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15
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Rönnblom A, Ljunggren Ö, Karlbom U. Complications and adverse effects related to surgical and medical treatment in patients with inflammatory bowel disease in a prospectively recruited population-based cohort. Scand J Gastroenterol 2021; 56:1296-1303. [PMID: 34369245 DOI: 10.1080/00365521.2021.1961309] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
BACKGROUND Medical adverse effects and surgical complications have been reported during treatment of patients with inflammatory bowel diseases (IBDs). There is however a shortage of studies describing these in the same cohort of patients. AIM To describe medical adverse effects and surgical complications in a prospectively followed population-based cohort of patients followed for at least 10 years. METHODS All newly diagnosed patients with ulcerative colitis (UC) and Crohn's disease (CD) in the county of Uppsala between 2005 and 2009 were prospectively followed. At the end of 2019, the medical notes were scrutinised and all medical adverse effects and postoperative surgical complications were registered. RESULTS A total of 330 patients with UC and 153 patients with CD in all age groups were included in the cohort. Four hundred and forty-two of these (91.5%) could be followed for 10 years or until death. One hundred and twenty-two patients (26.9%) experienced one or more adverse effects during the pharmacological treatment, and 25 of these could be classified as serious. Fifty-seven malignancies were diagnosed during the observation time. Surgery was performed in 16/330 UC and 33/153 CD patients. Frequency of early postoperative complications was 31% for UC patients and 36% for CD patients. Most complications were minor but two patients were re-operated, two needed intensive care and one patient died postoperatively. CONCLUSIONS Adverse effects related to medical therapy were experienced by approximately every fourth patient, and by every third patient that was operated.
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Affiliation(s)
- Anders Rönnblom
- Section of Gastroenterology and Hepatology, Akademiska Hospital, Magtarmmottagningen, Uppsala, Sweden
| | - Östen Ljunggren
- Department of Medical Sciences, Uppsala University, Uppsala University Hospital, Uppsala, Sweden
| | - Urban Karlbom
- Department of Surgical Sciences, Uppsala University, University Hospital, Uppsala, Sweden
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16
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Mateen BA, Patel M, Akobeng AK, Gordon M, Hayee B. 6-thioguanine nucleotide monitoring in azathioprine and mercaptopurine monotherapy for the treatment of inflammatory bowel disease. Hippokratia 2021. [DOI: 10.1002/14651858.cd014795] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Affiliation(s)
- Bilal Akhter Mateen
- Department of Gastroenterology; Kings College Hospital NHS Foundation Trust; London UK
- School of Life Sciences & Medicine; Kings College London; London UK
| | - Mehul Patel
- School of Life Sciences & Medicine; Kings College London; London UK
| | | | - Morris Gordon
- School of Medicine; University of Central Lancashire; Preston UK
| | - Bu'Hussain Hayee
- Department of Gastroenterology; Kings College Hospital NHS Foundation Trust; London UK
- School of Life Sciences & Medicine; Kings College London; London UK
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17
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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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18
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Eskazan T, Bozcan S, Atay K, Yildirim S, Demir N, Celik S, Tuncer M, Hatemi I, Celik AF, Erzin Y. Frequency, Predisposing Factors, and Clinical Outcome of Azathioprine-Induced Pancreatitis Among Patients With Inflammatory Bowel Disease: Results From a Tertiary Referral Center. Pancreas 2021; 50:1274-1280. [PMID: 34860811 DOI: 10.1097/mpa.0000000000001914] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
OBJECTIVE The aim of the study was to identify the frequency of azathioprine-induced acute pancreatitis (AZA-AP) and related factors. METHODS Seven hundred eighty-seven inflammatory bowel disease (IBD) patients on AZA therapy were retrospectively analyzed. Azathioprine-induced AP was diagnosed with positive imaging and/or an at least 3-fold increased amylase level, in presence of typical abdominal pain. The AZA-AP group was compared with patients on AZA therapy with no history of pancreatitis and 4 numerical adjacent cases with the same diagnosis were selected (group B). RESULTS Fifty-four patients developed gastrointestinal symptoms (6.9%); however, only half of them (26 of 54) had pancreatitis, except 1, all within the first 2 months under AZA. When the AZA-AP group was compared with group B, only budesonide usage and active smoking were significantly more common in group A (46.2% vs 25%, P = 0.034, and 77% vs 51%, P = 0.017, respectively). Active smoking was the only independent risk factor for AZA-AP development (odds ratio, 3.208 [95% confidence interval, 1.192-8.632]). CONCLUSIONS All IBD patients developed AZA-AP nearly all within the first 2 months. Azathioprine intolerance may be a hidden diagnosis in at least half of the patients with AZA-AP symptoms. All smoker IBD patients should be monitored closely for AZA-AP development.
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Affiliation(s)
- Tugce Eskazan
- From the Division of Gastroenterology, Department of Internal Medicine, Cerrahpasa School of Medicine, Istanbul University-Cerrahpasa
| | - Selma Bozcan
- From the Division of Gastroenterology, Department of Internal Medicine, Cerrahpasa School of Medicine, Istanbul University-Cerrahpasa
| | - Kadri Atay
- From the Division of Gastroenterology, Department of Internal Medicine, Cerrahpasa School of Medicine, Istanbul University-Cerrahpasa
| | - Suleyman Yildirim
- From the Division of Gastroenterology, Department of Internal Medicine, Cerrahpasa School of Medicine, Istanbul University-Cerrahpasa
| | - Nurhan Demir
- From the Division of Gastroenterology, Department of Internal Medicine, Cerrahpasa School of Medicine, Istanbul University-Cerrahpasa
| | - Sinem Celik
- Acibadem University, Atasehir Acibadem Hospital, Istanbul, Turkey
| | - Murat Tuncer
- From the Division of Gastroenterology, Department of Internal Medicine, Cerrahpasa School of Medicine, Istanbul University-Cerrahpasa
| | - Ibrahim Hatemi
- From the Division of Gastroenterology, Department of Internal Medicine, Cerrahpasa School of Medicine, Istanbul University-Cerrahpasa
| | - Aykut Ferhat Celik
- From the Division of Gastroenterology, Department of Internal Medicine, Cerrahpasa School of Medicine, Istanbul University-Cerrahpasa
| | - Yusuf Erzin
- From the Division of Gastroenterology, Department of Internal Medicine, Cerrahpasa School of Medicine, Istanbul University-Cerrahpasa
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19
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Lian X, Li Y, Li L, U K, Wang W, Shi Y, Ma J, Wang H. A novel single-tube multiplex real-time PCR assay for genotyping of thiopurine intolerance-causing variant NUDT15 c.415C>T. Exp Biol Med (Maywood) 2021; 246:1961-1967. [PMID: 34192970 DOI: 10.1177/15353702211026579] [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: 12/04/2022] Open
Abstract
Thiopurines are commonly used in the treatment of acute lymphoblastic leukaemia and autoimmune conditions, can be limited by myelosuppression. The NUDT15 c.415C>T variant is strongly associated with thiopurine-induced myelosuppression, especially in Asians. The purpose of this study was to develop a fast and reliable genotyping method for NUDT15 c.415C>T and investigate the polymorphic distribution among different races in China. A single-tube multiplex real-time PCR assay for NUDT15 c.415C>T genotyping was established using allele-specific TaqMan probes. In 229 samples, the genotyping results obtained through the established method were completely concordant with those obtained by Sanger sequencing. The distributions of NUDT15 c.415C>T among 173 Han Chinese, 48 Miaos, 40 Kazakhs, and 40 Kirghiz were different, with allelic frequencies of 0.06, 0.02, 0.07, and 0, respectively. This method will provide a powerful tool for the implementation of the genotyping-based personalized prescription of thiopurines in clinical settings.
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Affiliation(s)
- Xiaoyun Lian
- Department of Hematology, Shaanxi Provincial Peoples' Hospital, Xi'an 710068, China
| | - Yanwei Li
- The National Engineering Research Center for Miniaturized Detection Systems, Northwest University, Xi'an 710069, China
| | - Lan Li
- Department of Hematology, Shaanxi Provincial Peoples' Hospital, Xi'an 710068, China
| | - Kaicheng U
- American Heritage School, Plantation, FL 33325, USA
| | - Wenxia Wang
- The National Engineering Research Center for Miniaturized Detection Systems, Northwest University, Xi'an 710069, China
| | - Yinmin Shi
- The National Engineering Research Center for Miniaturized Detection Systems, Northwest University, Xi'an 710069, China
| | - Jiying Ma
- The National Engineering Research Center for Miniaturized Detection Systems, Northwest University, Xi'an 710069, China
| | - Huijuan Wang
- The National Engineering Research Center for Miniaturized Detection Systems, Northwest University, Xi'an 710069, China
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20
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Pancreatic Disorders in Children with Inflammatory Bowel Disease. ACTA ACUST UNITED AC 2021; 57:medicina57050473. [PMID: 34064706 PMCID: PMC8151997 DOI: 10.3390/medicina57050473] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2021] [Revised: 04/26/2021] [Accepted: 05/09/2021] [Indexed: 02/06/2023]
Abstract
Background and Objectives: Inflammatory bowel disease (IBD) is a chronic condition and mainly affects the intestines, however, the involvement of the other organs of the gastrointestinal tract (upper part, pancreas, and liver) have been observed. The coexistence of IBD with pancreatic pathology is rare, however, it has been diagnosed more frequently during recent years in the pediatric population. This article reviews the current literature on the most common pancreatic diseases associated with IBD in the pediatric population and their relationship with IBD activity and treatment. Materials and Methods: We performed a systematic review of data from published studies on pancreatic disorders, also reported as extraintestinal manifestations (EIMs), among children with IBD. We searched PubMed and Web of Science to identify eligible studies published prior to 25 April 2020. Results: Forty-four papers were chosen for analysis after a detailed inspection, which aimed to keep only the research studies (case control studies and cohort studies) or case reports on children and only those which were written in English. The manifestations of IBD-associated pancreatic disorders range from asymptomatic increase in pancreatic enzymes activity to severe disease such as acute pancreatitis. Acute pancreatitis (AP) induced by drugs, mainly thiopurine, seems to be the most- often-reported pancreatic disease associated with IBD in children. AP associated with other than drug etiologies, and chronic pancreatitis (CP), are rarely observed in the course of pediatric IBD. The pancreatic involvement can be strictly related to the activity of IBD and can also precede the diagnosis of IBD in some pediatric patients. The course of AP is mild in most cases and may occasionally lead to the development of CP, mainly in cases with a genetic predisposition. Conclusions: The involvement of the pancreas in the course of IBD may be considered as an EIM or a separate co-morbid disease, but it can also be a side effect of IBD therapy, therefore a differential diagnosis should always be performed. As the number of IBD incidences with concomitant pancreatic diseases is constantly increasing in the pediatric population, it is important to include pancreatic enzymes level measurement in the workup of IBD.
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21
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Giraud EL, Thomas PWA, van Lint JA, van Puijenbroek EP, Römkens TEH, West RL, Russel MGVM, Jansen JM, Jessurun NT, Hoentjen F. Adverse Drug Reactions from Real-World Data in Inflammatory Bowel Disease Patients in the IBDREAM Registry. Drug Saf 2021; 44:581-588. [PMID: 33538994 PMCID: PMC8053178 DOI: 10.1007/s40264-021-01045-3] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/15/2021] [Indexed: 02/07/2023]
Abstract
Introduction Inflammatory bowel disease (IBD) frequently requires chronic immunosuppressive treatment and active involvement from patients during treatment decision making. Information about the risk of developing adverse drug reactions (ADRs) to IBD therapies is required in this process. Objective The aim of this study was to describe the ADRs reported in IBD patients from real-world data, using the Dutch nationwide IBDREAM registry, and compare the occurrence and cumulative incidences with the Summary of Product Characteristics (SmPC) of the associated drugs. Methods In this retrospective multicentre study, ADRs related to IBD medication were assessed. Only reports associated with the use of drugs used for the maintenance treatment of IBD were included. All ADRs were verified by healthcare professionals and coded by trained pharmacovigilance assessors. Results In total, 3080 ADRs were reported in 1179 patients. Twenty-three new drug–ADR associations related to the use of azathioprine, mercaptopurine, infliximab, oral mesalamine and thioguanine were reported in the IBDREAM registry that were not mentioned in the corresponding SmPCs. The most frequently reported new association was pyrexia for azathioprine (3.1%) and mercaptopurine (4.9%). In addition, there were seven ADRs with a higher cumulative incidence in IBDREAM compared with the SmPC, and included, among others, arthralgia during mercaptopurine use (2.5%), and diarrhoea (1.4%), alopecia (1.2%) and infections (1.6%) during azathioprine use. Conclusions Based on real-world data, ADR reporting demonstrated new ADRs and higher incidences of ADRs to IBD therapies. This information will contribute to drug safety by updating the SmPCs, allowing better risk assessment and communication towards patients. Supplementary Information The online version contains supplementary material available at 10.1007/s40264-021-01045-3.
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Affiliation(s)
- Eline L Giraud
- Netherlands Pharmacovigilance Centre Lareb, 's-Hertogenbosch, The Netherlands
| | - Pepijn W A Thomas
- Department of Gastroenterology and Hepatology, Radboud University Medical Centre, Nijmegen, The Netherlands.
| | - Jette A van Lint
- Netherlands Pharmacovigilance Centre Lareb, 's-Hertogenbosch, The Netherlands
| | | | - Tessa E H Römkens
- Department of Gastroenterology and Hepatology, Jeroen Bosch Ziekenhuis, 's-Hertogenbosch, The Netherlands
| | - Rachel L West
- Department of Gastroenterology and Hepatology, Franciscus Gasthuis en Vlietland, Rotterdam, The Netherlands
| | - Maurice G V M Russel
- Department of Gastroenterology and Hepatology, Medisch Spectrum Twente, Enschede, The Netherlands
| | - Jeroen M Jansen
- Department of Gastroenterology and Hepatology, Onze Lieve Vrouwe Gasthuis, Amsterdam, The Netherlands
| | - Naomi T Jessurun
- Netherlands Pharmacovigilance Centre Lareb, 's-Hertogenbosch, The Netherlands
| | - Frank Hoentjen
- Department of Gastroenterology and Hepatology, Radboud University Medical Centre, Nijmegen, The Netherlands
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Alves da Silva JI, Caetano C, Pedroto I. Azathioprine-Induced Acute Submandibular Sialadenitis in a Crohn's Disease Patient. GE PORTUGUESE JOURNAL OF GASTROENTEROLOGY 2020; 27:361-363. [PMID: 32999909 PMCID: PMC7506223 DOI: 10.1159/000505037] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/24/2019] [Revised: 11/12/2019] [Indexed: 04/30/2023]
Abstract
INTRODUCTION Azathioprine (AZA) is a widely used immunosuppressive drug in inflammatory bowel disease (IBD). The occurrence of adverse effects (AEs) is a major downside in the use of this drug, leading to treatment withdrawal in a variable proportion of patients. CASE PRESENTATION We report the case of a Crohn's disease patient who developed sialadenitis as an AE to AZA. DISCUSSION AND CONCLUSION To our knowledge this AE has been reported only once in the literature. Sialadenitis is a common disorder and refers to inflammation of a salivary gland. It has many causes, such as bacterial and viral infections, ductal obstruction, and drugs. There are several AEs related to this drug, categorized as dose-dependent and dose-independent. Their knowledge is essential for therapeutic management in IBD, which is already challenging, requiring an individualized approach.
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Affiliation(s)
- Joana Inês Alves da Silva
- Gastroenterology, Centro Hospitalar Universitário do Porto, Porto, Portugal
- *Joana Inês Alves da Silva, Gastroenterology, Centro Hospitalar Universitário do Porto, Largo do Prof. Abel Salazar, PT–4099-001 Porto (Portugal), E-Mail
| | - Cidalina Caetano
- Gastroenterology, Centro Hospitalar Universitário do Porto, Porto, Portugal
| | - Isabel Pedroto
- Gastroenterology, Centro Hospitalar Universitário do Porto, Porto, Portugal
- Instituto de Ciências Biomédicas Abel Salazar, Porto, Portugal
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Thiopurines' Metabolites and Drug Toxicity: A Meta-Analysis. J Clin Med 2020; 9:jcm9072216. [PMID: 32668748 PMCID: PMC7408995 DOI: 10.3390/jcm9072216] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2020] [Revised: 07/06/2020] [Accepted: 07/09/2020] [Indexed: 12/13/2022] Open
Abstract
Many questions remain unanswered regarding therapeutic drug monitoring (TDM) utility with thiopurines. This study aims to establish a relationship between thiopurines' metabolites and drug toxicity. We performed a systematic review with inclusion of studies evaluating the relationship between thiopurines' metabolites and drug toxicity. Meta-analysis of mean difference (MD), correlations and odds ratio (OR) was performed. We identified 21,240 records, 72 of which were eligible for meta-analysis. Levels of 6-thioguanine nucleotides (6-TGN) were higher in patients with leukopenia (MD 127.06 pmol/8 × 108 RBC) and gastrointestinal intolerance (MD 201.46 pmol/8 × 108 RBC), and lower in patients with hepatotoxicity (MD -40.6 pmol × 108 RBC). We established a significant correlation between 6-TGN and leukocytes (r = -0.21), neutrophils (r = -0.24) and alanine aminotransferase levels (r = -0.24). OR for leukopenia in patients with elevated 6-TGN was 4.63 (95%CI 2.24; 9.57). An optimal cut-off of 135 pmol/8 × 108 RBC for leukopenia was calculated (sensitivity 75.4%; specificity 46.4%). 6-methylmercaptopurine ribonucleotides (6-MMPR) were significantly associated with hepatotoxicity (MD 3241.2 pmol/8 × 108 RBC; OR 4.28; 95%CI 3.20; 5.71). Levels of 6-MMPR measured in the first 8 weeks of treatment were associated with leukopenia. We conclude that TDM could be used to prevent thiopurines' toxicity. As optimal metabolites level may vary according to indication, physicians may adapt posology to decrease toxicity without compromising efficacy.
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24
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Gordon M, Grafton-Clarke C, Akobeng A, Macdonald J, Chande N, Hanauer S, Arnott I. Pancreatitis associated with azathioprine and 6-mercaptopurine use in Crohn's disease: a systematic review. Frontline Gastroenterol 2020; 12:423-436. [PMID: 35401955 PMCID: PMC8989005 DOI: 10.1136/flgastro-2020-101405] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/07/2020] [Revised: 04/14/2020] [Accepted: 05/14/2020] [Indexed: 02/04/2023] Open
Abstract
Thiopurines are proven agents in the treatment of Crohn's disease. While pancreatitis is recognised as an adverse event associated with therapy, the effect size and morbidity of thiopurine-induced pancreatitis is not known. The aim of this systematic review and meta-analysis was to quantify the risk of pancreatitis with azathioprine and 6-mercaptopurine (6-MP) within Crohn's disease. We searched six electronic databases from inception to 29 October 2019. The primary outcomes measures were the occurrence of pancreatitis. We calculated pooled OR with corresponding 95% CIs for risk of pancreatitis. A number needed to harm analysis was performed. The search identified 4418 studies, of which 25 randomised controlled trials met the criteria for inclusion. The number of patients treated with azathioprine to cause an episode of pancreatitis was 36 (induction of remission) and 31 (maintenance of remission). The risk of pancreatitis in patients receiving azathioprine across all contexts was 3.80%, compared with a control risk of 0.2% (placebo) and 0.5% (5-aminosalicylic acid agents). There was no difference seen between 6-MP and placebo, although this was a low certainty result due to imprecision from very low event numbers and patient numbers. There is a probably increased occurrence of pancreatitis when azathioprine is used in Crohn's disease (moderate certainty), with incidence overall approximately 3.8%. Most cases are mild and resolve on cessation of therapy and no mortality was reported. There was no increased occurrence seen when using 6-MP, although this is a low certainty finding. PROSPERO prior to the study (CRD42019138065).
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Affiliation(s)
- Morris Gordon
- School of Medicine, University of Central Lancashire, Preston, UK
| | | | - Anthony Akobeng
- Evidence-Based Practice and Systematic Review Group, Sidra Medical and Research Center, Doha, Ad Dawhah, Qatar
| | | | - Nilesh Chande
- Division of Gastroenterology, Western University, London, Ontario, Canada
| | - Stephen Hanauer
- Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA
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25
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Biemans VBC, Savelkoul E, Gabriëls RY, Simsek M, Dijkstra G, Pierik MJ, West RL, de Boer NK, Hoentjen F. A comparative analysis of tioguanine versus low-dose thiopurines combined with allopurinol in inflammatory bowel disease patients. Aliment Pharmacol Ther 2020; 51:1076-1086. [PMID: 32339331 PMCID: PMC7318327 DOI: 10.1111/apt.15730] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/10/2020] [Revised: 03/02/2020] [Accepted: 03/25/2020] [Indexed: 12/20/2022]
Abstract
BACKGROUND Both tioguanine and low-dose thiopurines combined with allopurinol (LDTA) can be considered for the treatment of inflammatory bowel disease (IBD) when conventional thiopurines fail due to adverse events. AIM To compare the safety of tioguanine and LDTA in IBD patients. METHODS Inflammatory bowel disease patients who failed conventional thiopurines due to adverse events and initiated LDTA in standard care were identified in the prospective ICC Registry. IBD patients who failed conventional thiopurines due to adverse events and initiated tioguanine were enrolled in three university hospitals. Patients on concomitant biologicals were excluded. The primary outcome was discontinuation of therapy due to adverse events. Secondary outcomes included: safety outcomes and surgery-, biological- and corticosteroid-free clinical remission (physician global assessment = 0) after 104 weeks. Both multiple logistic regression and propensity score matching were used to correct for confounders. RESULTS In total, 182 IBD patients treated with tioguanine (n = 94) or LDTA (n = 88) were included with a median follow-up of 104 weeks (IQR 91-104). Of these, 19% (tioguanine: 20%, LDTA: 18%) of patients discontinued therapy due to adverse events. After adjusting for confounders, there were no differences in terms of discontinuation rate due to adverse events (OR 0.50, 95% CI 0.15-1.68, P = 0.26), adverse events (OR 0.89, 95% CI 0.44-1.81, P = 0.75), infections (OR 1.05, 95% CI 0.40-2.73, P = 0.93), hospitalisations (OR 2.00, 95% CI 0.64-6.23, P = 0.23) or clinical remission (OR 0.74, 95%CI 0.33-1.68, P = 0.48). All results are comparable with the propensity score matched cohort. CONCLUSION Nineteen percent of IBD patients with prior failure to conventional thiopurines due to adverse events discontinued therapy with tioguanine or LDTA due to adverse events. Either therapy may be considered before escalating to biological therapy.
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Affiliation(s)
- Vince B. C. Biemans
- Department of Gastroenterology and HepatologyRadboud University Medical CentreNijmegenThe Netherlands,Department of Gastroenterology and HepatologyMaastricht University Medical CentreMaastrichtThe Netherlands
| | - Edo Savelkoul
- Department of Gastroenterology and HepatologyRadboud University Medical CentreNijmegenThe Netherlands
| | | | - Melek Simsek
- Amsterdam University Medical CentreVrije UniversiteitAmsterdamThe Netherlands,Amsterdam Gastroenterology & Metabolism research instituteAmsterdamThe Netherlands
| | - Gerard Dijkstra
- University Medical Centre GroningenGroningenThe Netherlands,University of GroningenGroningenthe Netherlands
| | - Marieke J. Pierik
- Department of Gastroenterology and HepatologyMaastricht University Medical CentreMaastrichtThe Netherlands
| | | | - Nanne K.H. de Boer
- Amsterdam University Medical CentreVrije UniversiteitAmsterdamThe Netherlands,Amsterdam Gastroenterology & Metabolism research instituteAmsterdamThe Netherlands
| | - Frank Hoentjen
- Department of Gastroenterology and HepatologyRadboud University Medical CentreNijmegenThe Netherlands
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26
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Role of Thiopurines in Pediatric Inflammatory Bowel Diseases: A Real-Life Prospective Cohort Study. J Pediatr Gastroenterol Nutr 2020; 70:825-832. [PMID: 31764416 DOI: 10.1097/mpg.0000000000002566] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
OBJECTIVES Use of thiopurines for inflammatory bowel diseases (IBDs) is declining in some parts of the world. We aimed to explore outcomes of thiopurines and predictors of response in a real-world prospective cohort of children with dose optimization. METHODS Children with IBD treated with thiopurines without biologics were enrolled. Dosing was guided by thiopurine S-methyltransferase-activity at baseline and by clinical response and toxicity at 4 months; 1 year into the study, therapeutic drug monitoring at 4 months was also considered in the decision making. The primary outcome was steroid-free remission without treatment escalation by 12 months (SFR), using the intention-to-treat approach. RESULTS A total of 129 children were included (74% Crohn disease [CD] and 26% ulcerative colitis [UC]). SFR was achieved in 37 (39%) CD and 13 (39%) UC patients, and SFR with normal erythrocyte sedimentation rate/C-reactive protein in 20 (21%) and 9 (27%), respectively. At 4 months, mean corpuscular volume/white blood cell ratio and Δ absolute neutrophil count weakly correlated with 6-thioguanine (r = 0.33, P = 0.02 and r = 0.32, P = 0.02, respectively). In CD, SFR was associated with 4-month median weighted Pediatric Crohn Disease Activity Index (2.5 [IQR 0-7.5] in responders vs 5 in nonresponders [0-12.5], P = 0.048) and Δabsolute neutrophil count (1.7 [IQR 0.7-4.1] vs 0.05 [-2.3-0.9]; P = 0.03). Mild drug-related adverse events were recorded in 30 children (22%), 3 required stopping the drug. CONCLUSIONS In this real-life prospective cohort using dose optimization, thiopurines were safe and effective in 21% of CD and 27% of UC patients, including normalization of C-reactive protein and erythrocyte sedimentation rate. Thiopurines remain a viable option in the treatment algorithm of mild-moderate pediatric IBD, especially in girls whose risk for lymphoma is lower.
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27
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Kreijne JE, de Vries AC, de Veer RC, Bouma G, Dijkstra G, Voskuil MD, West R, van Moorsel SAW, de Jong DJ, de Boer NK, van der Woude CJ. Limited added value of laboratory monitoring in thiopurine maintenance monotherapy in inflammatory bowel disease patients. Aliment Pharmacol Ther 2020; 51:1353-1364. [PMID: 32342997 DOI: 10.1111/apt.15734] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/08/2019] [Revised: 08/13/2019] [Accepted: 03/25/2020] [Indexed: 12/11/2022]
Abstract
BACKGROUND To timely detect myelotoxicity and hepatotoxicity, laboratory monitoring at 3-month intervals is advised throughout thiopurine maintenance treatment for IBD. However, reported incidence rates of myelotoxicity and hepatotoxicity in maintenance treatment are low. AIM To assess incidence rates and clinical consequences of myelotoxicity and hepatotoxicity in thiopurine maintenance therapy after at least 1 year of thiopurine treatment. METHODS Retrospective analysis of therapy adjustment for laboratory toxicity in adult IBD patients after 12 consecutive months of azathioprine (AZA) or mercaptopurine monotherapy (ie baseline) between 2000 and 2016. Incidence rates of laboratory toxicity (ie myelotoxicity [leucocyte count <4.0 × 10e9/L, and/or platelet count <150 × 10e9/L] and/or hepatotoxicity (gamma-glutamyltransferase [GGT], alkaline phosphatase [AP], ALT and/or AST above ULN, excluding isolated increased AST/AP]) and associated diagnostic procedures and complications were assessed. RESULTS In total, 12,391 laboratory assessments were performed on 1132 patients (56% female, AZA 74%) during 3.3 years of median follow-up. Median monitoring frequency was 3.1 assessments/treatment year. Only 83/12,391 (0.7%) assessments resulted in therapy adjustment, dose reduction in 46 patients, cessation in 28 and allopurinol initiation in nine; risk of therapy adjustment was 1.9% per treatment year. Incidence rates of myelotoxicity were 7.1% (5.1% mild/1.8% moderate/0.1% severe) and hepatotoxicity 5.1% (3.8% mild/1.1% moderate/0.2% severe) per treatment year. Treatment-related complications with concurrent laboratory toxicity occurred in 12 patients (1.1%) and would not have been prevented by monitoring. CONCLUSION Severe laboratory toxicity is uncommon after 1 year of thiopurine monotherapy at 4-month monitoring intervals. Therapy adjustments are rare after detection of laboratory toxicity. After 1 year of thiopurine monotherapy, laboratory monitoring may be lowered to less than a 4-month interval.
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Affiliation(s)
- Joany E Kreijne
- Department of Gastroenterology and Hepatology, Erasmus MC University Medical Center, Rotterdam, The Netherlands
| | - Annemarie C de Vries
- Department of Gastroenterology and Hepatology, Erasmus MC University Medical Center, Rotterdam, The Netherlands
| | - Rozanne C de Veer
- Department of Gastroenterology and Hepatology, Erasmus MC University Medical Center, Rotterdam, The Netherlands
| | - Gerd Bouma
- Department of Gastroenterology and Hepatology, Amsterdam UMC, Vrije Universiteit Amsterdam, AG&M Research Institute, Amsterdam, The Netherlands
| | - Gerard Dijkstra
- Department of Gastroenterology and Hepatology, University of Groningen and University Medical Center Groningen, Groningen, The Netherlands
| | - Michiel D Voskuil
- Department of Gastroenterology and Hepatology, University of Groningen and University Medical Center Groningen, Groningen, The Netherlands
| | - Rachel West
- Department of Gastroenterology and Hepatology, Franciscus Gasthuis & Vlietland, Rotterdam, The Netherlands
| | - Sofia A W van Moorsel
- Department of Pharmacology, Zuyderland Medical Center, Heerlen-Sittard-Geleen, The Netherlands
| | - Dirk J de Jong
- Department of Gastroenterology and Hepatology, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Nanne K de Boer
- Department of Gastroenterology and Hepatology, Amsterdam UMC, Vrije Universiteit Amsterdam, AG&M Research Institute, Amsterdam, The Netherlands
| | - C Janneke van der Woude
- Department of Gastroenterology and Hepatology, Erasmus MC University Medical Center, Rotterdam, The Netherlands
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28
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Bayoumy AB, Simsek M, Seinen ML, Mulder CJJ, Ansari A, Peters GJ, De Boer NK. The continuous rediscovery and the benefit-risk ratio of thioguanine, a comprehensive review. Expert Opin Drug Metab Toxicol 2020; 16:111-123. [PMID: 32090622 DOI: 10.1080/17425255.2020.1719996] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Introduction: In the 1950s, thioguanine (TG), a thiopurine-derivative together with azathioprine (AZA) and mercaptopurine (MP), were developed for the treatment of childhood leukemia. Over the years, the use of TG was also explored for other, mainly immune-mediated and inflammatory, diseases such as in the field of dermatology and rheumatology (e.g. psoriasis, systemic lupus erythematosus (SLE)) and gastroenterology and hepatology (e.g. inflammatory bowel diseases (IBD), autoimmune hepatitis).Areas covered: This review provides a comprehensive overview of all the clinical uses of TG and describes its mechanism of action, pharmacokinetic/pharmacodynamic features, and toxicity.Expert opinion: Thioguanine has shown beneficial clinical effects in hematological (particularly leukemia) and several immune-inflammatory diseases including psoriasis, SLE, polycythemia vera, Churg-Strauss syndrome, IBD, collagenous sprue, refractory celiac disease, and autoimmune hepatitis. Thioguanine is not effective in treating solid-cancers. At relatively low dosages, i.e. 0.2- 0.3mg/kg/day or 20 mg/day, TG has a favorable risk-benefit ratio and is a safe and effective drug in the long-term treatment of amongst other IBD patients. Thioguanine toxicity, especially myelotoxicity, and hepatotoxicity, including nodular regenerative hyperplasia (NRH) of the liver, is limited when dosed adequately. The occurrence of NRH appears dose-dependent and has been especially described during high dose TG above 40 mg/day.
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Affiliation(s)
- Ahmed B Bayoumy
- Amsterdam UMC, Department of Gastroenterology and Hepatology, VU University Medical Center, Amsterdam, Netherlands
| | - Melek Simsek
- Amsterdam UMC, Department of Gastroenterology and Hepatology, VU University Medical Center, AG&M Research Institute, Amsterdam, Netherlands
| | - Margien L Seinen
- Amsterdam UMC, Department of Gastroenterology and Hepatology, VU University Medical Center, Amsterdam, Netherlands
| | - Chris J J Mulder
- Amsterdam UMC, Department of Gastroenterology and Hepatology, VU University Medical Center, Amsterdam, Netherlands
| | - Azhar Ansari
- Department of Gastroenterology, Surrey and Sussex NHS, Easy Surrey Hospital, Surrey, UK
| | - Godefridus J Peters
- Amsterdam UMC, VU University Medical Center, Laboratory Medical Oncology, Cancer Center Amsterdam, Amsterdam, Netherlands.,Department of Biochemistry, Medical University of Gdansk, Gdansk, Poland
| | - Nanne K De Boer
- Amsterdam UMC, Department of Gastroenterology and Hepatology, VU University Medical Center, AG&M Research Institute, Amsterdam, Netherlands
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29
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Challenges in Pediatric Inflammatory Bowel Disease. ARS MEDICA TOMITANA 2020. [DOI: 10.2478/arsm-2019-0027] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
Abstract
Abstract
Inflammatory bowel disease (IBD) is a chronic condition of the gastrointestinal tract comprising of two entities: Crohn disease (CD) and Ulcerative colitis (UC). Considered rare in children in the past, inflammatory bowel disease is nowadays more frequently found, raising diagnostic and treatment challenges.
In our study, we have taken into consideration all children diagnosed with inflammatory bowel disease, in the Department of Pediatrics of the Clinical Emergency County Hospital of Constanta, from 2016 to 2019.
14 children were diagnosed with inflammatory bowel disease during this timeframe, 8 with Crohn disease (57,14%) and 6 with Ulcerative colitis (42,86%). The mean age at onset was 8.2 years for Crohn disease patients, varying between 20 months to 15 years, and 12.8 years for Ulcerative colitis patients, varying between 8 to 14 years.
After a positive diagnosis, different types of induction therapy was implemented, depending on the activity and severity of the disease, as well as on the type of inflammatory bowel disease. 12 patients received iv corticosteroids for an average of five days, followed by oral corticosteroids for 4-8 weeks. Aminosalicylates (Mesalazine) was used as a sole induction treatment in children with UC, or in association with corticosteroids in severe cases (4 cases). Immunomodulatory treatment (Azathioprine) was used for maintaining remission in 5 children with Crohn disease for an average period of 6 months. In 3 cases of CD, antibiotics, such as Metronidazole, were used in the initial treatment.
Biological therapy, such as Adalimumab (ADA), was administered as an induction therapy in patients with refractory to conventional treatment forms, in 5 cases, with a favourable outcome.
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30
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Derijks LJJ, Wong DR, Hommes DW, van Bodegraven AA. Clinical Pharmacokinetic and Pharmacodynamic Considerations in the Treatment of Inflammatory Bowel Disease. Clin Pharmacokinet 2019; 57:1075-1106. [PMID: 29512050 DOI: 10.1007/s40262-018-0639-4] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
According to recent clinical consensus, pharmacotherapy of inflammatory bowel disease (IBD) is, or should be, personalized medicine. IBD treatment is complex, with highly different treatment classes and relatively few data on treatment strategy. Although thorough evidence-based international IBD guidelines currently exist, appropriate drug and dose choice remains challenging as many disease (disease type, location of disease, disease activity and course, extraintestinal manifestations, complications) and patient characteristics [(pharmaco-)genetic predisposition, response to previous medications, side-effect profile, necessary onset of response, convenience, concurrent therapy, adherence to (maintenance) therapy] are involved. Detailed pharmacological knowledge of the IBD drug arsenal is essential for choosing the right drug, in the right dose, in the right administration form, at the right time, for each individual patient. In this in-depth review, clinical pharmacodynamic and pharmacokinetic considerations are provided for tailoring treatment with the most common IBD drugs. Development (with consequent prospective validation) of easy-to-use treatment algorithms based on these considerations and new pharmacological data may facilitate optimal and effective IBD treatment, preferably corroborated by effectiveness and safety registries.
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Affiliation(s)
- Luc J J Derijks
- Department of Clinical Pharmacy and Pharmacology, Máxima Medical Center, PO Box 7777, 5500 MB, Veldhoven, The Netherlands.
| | - Dennis R Wong
- Department of Clinical Pharmacy, Pharmacology and Toxicology, Zuyderland Medical Center, Sittard-Geleen, The Netherlands
| | - Daniel W Hommes
- Center for Inflammatory Bowel Diseases, UCLA, Los Angeles, CA, USA
| | - Adriaan A van Bodegraven
- Department of Gastroenterology, Zuyderland Medical Center, Sittard-Geleen, The Netherlands
- Department of Gastroenterology, VU University Medical Center, Amsterdam, The Netherlands
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31
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van Gennep S, Konté K, Meijer B, Heymans MW, D'Haens GR, Löwenberg M, de Boer NKH. Systematic review with meta-analysis: risk factors for thiopurine-induced leukopenia in IBD. Aliment Pharmacol Ther 2019; 50:484-506. [PMID: 31342537 DOI: 10.1111/apt.15403] [Citation(s) in RCA: 26] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/31/2018] [Revised: 02/02/2019] [Accepted: 06/16/2019] [Indexed: 12/11/2022]
Abstract
BACKGROUND Thiopurine-induced leukopenia, a frequently observed and potentially life-threatening adverse event, complicates the clinical management of IBD patients. AIM To assess risk factors for thiopurine-induced leukopenia in IBD. METHODS MEDLINE, EMBASE, BIOSIS and Cochrane library were searched for studies reporting at least one risk factor for thiopurine-induced leukopenia. Pooled odds ratio (OR) was calculated for each potential risk factor using a random effects model. Studies that were not eligible for meta-analysis were described qualitatively. RESULTS Seventy articles were included, 34 (11 229 patients) were included in meta-analyses. A significantly higher thiopurine-induced leukopenia risk was found for TPMT (OR 3.9, 95% [CI] 2.5-6.1) and for NUDT15 R139C (OR 6.9, 95% CI 5.2-9.1), G52A (OR 3.2, 95% CI 1.3-7.9) and 36_37ins/delGGAGTC variant carriers (OR 5.6, 95% CI 2.8-11.4). A potential association between high 6-thioguanine nucleotides (6-TGN) or 6-methylmercaptopurine (6-MMP) levels and leukopenia was observed, since most studies reported higher metabolite levels in leukopenic patients (6-TGN: 204-308 (Lennard method) and 397 (Dervieux method), 6-MMP: 4020-10 450 pmol/8 x 108 RBC) compared to controls (6-TGN: 170-212 (Lennard method) and 269 (Dervieux method), 6-MMP: 1025-4550 pmol/8 x 108 RBC). CONCLUSIONS TPMT and NUDT15 variants predict thiopurine-induced leukopenia. High 6-TGN and 6-MMP levels might induce leukopenia, although exact cut-off values remain unclear. Potential preventive measures to reduce the risk of thiopurine-induced leukopenia include pre-treatment TPMT and NUDT15 genotyping. Routine thiopurine metabolite measurement might be efficient, yet cut-off levels must be validated in advance.
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Affiliation(s)
- Sara van Gennep
- Department of Gastroenterology and Hepatology, Amsterdam Gastroenterology and Metabolism Research Institute, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands
| | - Kadère Konté
- Department of Gastroenterology and Hepatology, Amsterdam Gastroenterology and Metabolism Research Institute, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands
| | - Berrie Meijer
- Department of Gastroenterology and Hepatology, Amsterdam Gastroenterology and Metabolism Research Institute, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands
| | - Martijn W Heymans
- Department of Clinical Epidemiology and Biostatistics, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands
| | - Geert R D'Haens
- Department of Gastroenterology and Hepatology, Amsterdam Gastroenterology and Metabolism Research Institute, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands
| | - Mark Löwenberg
- Department of Gastroenterology and Hepatology, Amsterdam Gastroenterology and Metabolism Research Institute, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands
| | - Nanne K H de Boer
- Department of Gastroenterology and Hepatology, Amsterdam Gastroenterology and Metabolism Research Institute, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands
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32
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Kreijne JE, de Veer RC, de Boer NK, Dijkstra G, West R, Moorsel SAW, de Jong DJ, van der Woude CJ, de Vries AC. Real-life study of safety of thiopurine-allopurinol combination therapy in inflammatory bowel disease: myelotoxicity and hepatotoxicity rarely affect maintenance treatment. Aliment Pharmacol Ther 2019; 50:407-415. [PMID: 31359480 DOI: 10.1111/apt.15402] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/22/2019] [Revised: 02/12/2019] [Accepted: 06/16/2019] [Indexed: 01/01/2023]
Abstract
BACKGROUND Low-dose thiopurine-allopurinol (LDTA) combination therapy is a commonly applied optimisation strategy in IBD patients with a skewed thiopurine metabolism. AIM To assess continued LDTA maintenance treatment at annual intervals and explore risk factors for treatment cessation METHODS: Adult IBD patients treated with LDTA between 2009 and 2016 were retrospectively included. Data on the incidence of clinical and laboratory adverse events (AEs), including hepatotoxicity and myelotoxicity resulting in imposing LDTA therapy cessation and associated risk factors were collected. RESULTS In total, 221 IBD patients (46% male, median age 42 years) were included. Maintenance LDTA treatment was continued in 78% of patients at 1 year (n = 145), 66% at 2 years (n = 83), 57% at 3 years (n = 52) and 52% at 4 years (n = 33). Treatment in patients receiving LDTA therapy for AEs during thiopurine monotherapy was more often continued than in patients initiating LDTA for other indications (eg, ineffectiveness of thiopurine monotherapy, routinely discovered skewed metabolism) (P = 0.016). Myelotoxicity during thiopurine monotherapy resolved in 87% and hepatotoxicity in 86% after median of 1.2 and 1.4 months after LDTA initiation. Cumulative incidence of AEs during LDTA resulting in therapy cessation within total follow-up of 449 treatment-years was 7% for clinical AEs, 4% for myelotoxicity and 1% for hepatotoxicity. CONCLUSION LDTA therapy is a safe and beneficial optimisation strategy in IBD patients. Continued maintenance LDTA treatment is 52% after 4 years of treatment and most commonly affected by ineffectiveness of LDTA rather than LDTA-attributed toxicity. LDTA optimisation strategy is most advantageous in patients failing thiopurine monotherapy due to AEs.
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Affiliation(s)
- Joany E Kreijne
- Department of Gastroenterology and Hepatology, Erasmus MC University Medical Center, Rotterdam, The Netherlands
| | - Rozanne C de Veer
- Department of Gastroenterology and Hepatology, Erasmus MC University Medical Center, Rotterdam, The Netherlands
| | - Nanne K de Boer
- Department of Gastroenterology and Hepatology, Amsterdam UMC, Vrije Universiteit Amsterdam, AG&M Research Institute, Amsterdam, The Netherlands
| | - Gerard Dijkstra
- Department of Gastroenterology and Hepatology, University Medical Center Groningen and University of Groningen, Groningen, The Netherlands
| | - Rachel West
- Department of Gastroenterology and Hepatology, Sint Franciscus Gasthuis & Vlietland, Rotterdam, The Netherlands
| | - Sofia A W Moorsel
- Department of Pharmacology, Zuyderland Medical Center, Heerlen-Sittard-Geleen, The Netherlands
| | - Dirk J de Jong
- Department of Gastroenterology and Hepatology, Radboud University Medical Center, Nijmegen, The Netherlands
| | - C Janneke van der Woude
- Department of Gastroenterology and Hepatology, Erasmus MC University Medical Center, Rotterdam, The Netherlands
| | - Annemarie C de Vries
- Department of Gastroenterology and Hepatology, Erasmus MC University Medical Center, Rotterdam, The Netherlands
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Ooi CJ, Hilmi I, Banerjee R, Chuah SW, Ng SC, Wei SC, Makharia GK, Pisespongsa P, Chen MH, Ran ZH, Ye BD, Park DI, Ling KL, Ong D, Ahuja V, Goh KL, Sollano J, Lim WC, Leung WK, Ali RAR, Wu DC, Ong E, Mustaffa N, Limsrivilai J, Hisamatsu T, Yang SK, Ouyang Q, Geary R, De Silva JH, Rerknimitr R, Simadibrata M, Abdullah M, Leong RWL. Best practices on immunomodulators and biologic agents for ulcerative colitis and Crohn's disease in Asia. J Gastroenterol Hepatol 2019; 34:1296-1315. [PMID: 30848854 DOI: 10.1111/jgh.14648] [Citation(s) in RCA: 34] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/13/2018] [Revised: 02/05/2019] [Accepted: 03/02/2019] [Indexed: 02/05/2023]
Abstract
The Asia-Pacific Working Group on Inflammatory Bowel Disease was established in Cebu, Philippines, under the auspices of the Asia-Pacific Association of Gastroenterology with the goal of improving inflammatory bowel disease care in Asia. This consensus is carried out in collaboration with Asian Organization for Crohn's and Colitis. With biologic agents and biosimilars becoming more established, it is necessary to conduct a review on existing literature and establish a consensus on when and how to introduce biologic agents and biosimilars in conjunction with conventional treatments for ulcerative colitis and Crohn's disease in Asia. These statements also address how pharmacogenetics influences the treatments of ulcerative colitis and Crohn's disease and provides guidance on response monitoring and strategies to restore loss of response. Finally, the review includes statements on how to manage treatment alongside possible hepatitis B and tuberculosis infections, both common in Asia. These statements have been prepared and voted upon by members of inflammatory bowel disease workgroup employing the modified Delphi process. These statements do not intend to be all-encompassing, and future revisions are likely as new data continue to emerge.
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Affiliation(s)
- Choon Jin Ooi
- Department of Gastroenterology and Hepatology, Singapore General Hospital, Singapore.,Duke-NUS Medical School, Singapore
| | - Ida Hilmi
- Faculty of Medicine, University Malaya Medical Centre, Kuala Lumpur, Malaysia
| | - Rupa Banerjee
- Asian Institute of Gastroenterology, New Delhi, India
| | | | - Siew Chien Ng
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong
| | - Shu Chen Wei
- Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
| | - Govind K Makharia
- Department of Gastroenterology and Human Nutrition, All India Institute of Medical Sciences, New Delhi, India
| | | | - Min Hu Chen
- Division of Gastroenterology, The First University Hospital, Sun Yat-sen University, Guangzhou, China
| | - Zhi Hua Ran
- Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Byong Duk Ye
- Department of Gastroenterology and IBD Center, University of Ulsan College of Medicine, Ulsan, Korea
| | - Dong Il Park
- Department of Internal Medicine, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Korea
| | | | - David Ong
- Division of Gastroenterology & Hepatology, University Medicine Cluster, National University Hospital of Singapore, Singapore
| | - Vineet Ahuja
- Department of Gastroenterology and Human Nutrition, All India Institute of Medical Sciences, New Delhi, India
| | - Khean Lee Goh
- University of Malaya Specialist Centre, Kuala Lumpur, Malaysia
| | - Jose Sollano
- Department of Medicine, University of Santo Tomas, Manila, Philippines
| | - Wee Chian Lim
- Department of Gastroenterology & Hepatology, Tan Tock Seng Hospital, Singapore
| | - Wai Keung Leung
- Division of Gastroenterology & Hepatology, Department of Medicine, University of Hong Kong, Hong Kong
| | | | - Deng Chyang Wu
- Department of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Evan Ong
- Department of Medicine, University of Santo Tomas, Manila, Philippines
| | - Nazri Mustaffa
- Department of Internal Medicine, School of Medical Sciences, Health Campus, Universiti Sains, George Town, Malaysia
| | - Julajak Limsrivilai
- Department of Medicine, Faculty of Medicine, Siriraj Hospital, Mahidol University, Bangkok, Thailand
| | - Tadakazu Hisamatsu
- The Third Department of Internal Medicine, Kyorin University School of Medicine, Mitaka, Japan
| | - Suk Kyun Yang
- Department of Gastroenterology, University of Ulsan College of Medicine, Ulsan, Korea
| | - Qin Ouyang
- Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu, China
| | - Richard Geary
- Department of Medicine, University of Otago, Christchurch, Christchurch, New Zealand
| | | | | | - Marcellus Simadibrata
- Department of Internal Medicine, Faculty of Medicine, Universitas Indonesia, Depok, Indonesia
| | - Murdani Abdullah
- Division of Gastroenterology, Department of Internal Medicine, Dr Cipto Mangankusumo National Hospital, Central Jakarta, Indonesia
| | - Rupert W L Leong
- Gastroenterology and Liver Services, Concord Hospital, Sydney, New South Wales, Australia
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34
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Ooi CJ, Hilmi I, Banerjee R, Chuah SW, Ng SC, Wei SC, Makharia GK, Pisespongsa P, Chen MH, Ran ZH, Ye BD, Park DI, Ling KL, Ong D, Ahuja V, Goh KL, Sollano J, Lim WC, Leung WK, Ali RAR, Wu DC, Ong E, Mustaffa N, Limsrivilai J, Hisamatsu T, Yang SK, Ouyang Q, Geary R, De Silva JH, Rerknimitr R, Simadibrata M, Abdullah M, Leong RW. Best practices on immunomodulators and biologic agents for ulcerative colitis and Crohn's disease in Asia. Intest Res 2019; 17:285-310. [PMID: 31146509 PMCID: PMC6667368 DOI: 10.5217/ir.2019.00026] [Citation(s) in RCA: 65] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/20/2019] [Accepted: 04/15/2019] [Indexed: 02/07/2023] Open
Abstract
The Asia-Pacific Working Group on inflammatory bowel disease (IBD) was established in Cebu, Philippines, under the auspices of the Asian Pacific Association of Gastroenterology with the goal of improving IBD care in Asia. This consensus is carried out in collaboration with Asian Organization for Crohn’s and Colitis. With biologic agents and biosimilars becoming more established, it is necessary to conduct a review on existing literature and establish a consensus on when and how to introduce biologic agents and biosimilars in the conjunction with conventional treatments for ulcerative colitis (UC) and Crohn’s disease (CD) in Asia. These statements also address how pharmacogenetics influence the treatments of UC and CD and provide guidance on response monitoring and strategies to restore loss of response. Finally, the review includes statements on how to manage treatment alongside possible hepatitis B and tuberculosis infections, both common in Asia. These statements have been prepared and voted upon by members of IBD workgroup employing the modified Delphi process. These statements do not intend to be all-encompassing and future revisions are likely as new data continue to emerge.
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Affiliation(s)
- Choon Jin Ooi
- Department of Gastroenterology and Hepatology, Singapore General Hospital, Singapore
| | | | - Rupa Banerjee
- Asian Institute of Gastroenterology, New Delhi, India
| | | | - Siew Chien Ng
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong
| | - Shu Chen Wei
- Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
| | - Govind K Makharia
- Department of Gastroenterology and Human Nutrition, All India Institute of Medical Sciences, New Delhi, India
| | - Pises Pisespongsa
- Gastroenterology and Hepatology, Bumrungrad International University, Bangkok, Thailand
| | - Min Hu Chen
- Division of Gastroenterology, The First University Hospital, Sun Yat-sen University, Guangzhou, China
| | - Zhi Hua Ran
- Department of Gastroenterology and Hepatology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Byong Duk Ye
- Department of Gastroenterology and IBD Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Dong Il Park
- Department of Internal Medicine, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Korea
| | | | - David Ong
- Division of Gastroenterology and Hepatology, National University Hospital of Singapore, University Medicine Cluster, Singapore
| | - Vineet Ahuja
- Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
| | - Khean Lee Goh
- University of Malaya Specialist Centre, Kuala Lumpur, Malaysia
| | - Jose Sollano
- Department of Medicine, University of Santo Tomas, Manila, Philippines
| | - Wee Chian Lim
- Department of Gastroenterology and Hepatology, Tan Tock Seng Hospital, Singapore
| | - Wai Keung Leung
- Division of Gastroenterology and Hepatology, Department of Medicine, University of Hong Kong, Hong Kong
| | - Raja Affendi Raja Ali
- Faculty of Medicine, UKM Medical and Specialist Centres, The National University of Malaysia, Kuala Lumpur, Malaysia
| | - Deng Chyang Wu
- Department of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Evan Ong
- Department of Medicine, University of Santo Tomas, Manila, Philippines
| | - Nazri Mustaffa
- Department of Internal Medicine, School of Medical Sciences, Health Campus, Sains University, Kubang Kerian, Malaysia
| | - Julajak Limsrivilai
- Department of Medicine, Faculty of Medicine, Siriraj Hospital, Mahidol University, Bangkok, Thailand
| | - Tadakazu Hisamatsu
- The Third Department of Internal Medicine, Kyorin University School of Medicine, Mitaka, Japan
| | - Suk Kyun Yang
- Department of Gastroenterology, University of Ulsan College of Medicine, Seoul, Korea
| | - Qin Ouyang
- Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu, China
| | - Richard Geary
- Department of Medicine, University of Otago, Christchurch, New Zealand
| | | | | | - Marcellus Simadibrata
- Department of Internal Medicine, Faculty of Medicine, University of Indonesia, Jakarta, Indonesia
| | - Murdani Abdullah
- Division of Gastroenterology, Department of Internal Medicine, Cipto Mangunkusumo National Hospital, Jakarta, Indonesia
| | - Rupert Wl Leong
- Gastroenterology and Liver Services, Concord Hospital, Sydney, Australia
| | -
- Department of Gastroenterology and Hepatology, Singapore General Hospital, Singapore
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35
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Eriksson C, Rundquist S, Cao Y, Montgomery S, Halfvarson J. Impact of thiopurines on the natural history and surgical outcome of ulcerative colitis: a cohort study. Gut 2019; 68:623-632. [PMID: 29618498 DOI: 10.1136/gutjnl-2017-315521] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/23/2017] [Revised: 03/14/2018] [Accepted: 03/20/2018] [Indexed: 12/20/2022]
Abstract
OBJECTIVE Thiopurines are used as maintenance therapy in ulcerative colitis (UC), but whether these drugs influence the natural history of the disease is unknown. We aimed to assess the effect of thiopurines in terms of colectomy, hospital admission, progression in disease extent and anti-tumour necrosis factor (TNF) therapy within 10 years from initiation. DESIGN Patients diagnosed with UC within the Örebro University Hospital catchment area, during 1963-2010, who initiated thiopurines (n=253) were included. To overcome the risk of confounding by indication, we compared patients who stopped treatment within 12 months because of an adverse reaction (n=76) with patients who continued therapy or discontinued due to other reasons (n=177) and assessed long-term outcomes using Cox regression with adjustment for potential confounding factors. RESULTS The cumulative probability of colectomy within 10 years was 19.5% in tolerant patients compared with 29.0% in intolerant (adjusted HR 0.49; 95% CI 0.21 to 0.73). The probability of hospital admission was 34.0% in tolerant versus 56.2% in intolerant patients (adjusted HR 0.36; 95% CI 0.23 to 0.56). The risk for progression in disease extent was 20.4% in tolerant patients compared with 48.8% in intolerant (adjusted HR 0.47; 95% CI 0.21 to 1.06). Within 10 years, 16.1% of tolerant and 27.5% of intolerant patients received anti-TNF therapy (adjusted HR 0.49; 95% CI 0.26 to 0.92). CONCLUSION Based on the novel approach of comparing patients tolerant and intolerant to thiopurines, we reveal that thiopurines have a profound beneficial impact of the natural history and long-term colectomy rates of UC.
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Affiliation(s)
- Carl Eriksson
- Department of Gastroenterology, Faculty of Medicine and Health, Örebro University, Örebro, Sweden
| | - Sara Rundquist
- Department of Gastroenterology, Faculty of Medicine and Health, Örebro University, Örebro, Sweden
| | - Yang Cao
- Clinical Epidemiology and Biostatistics, School of Medical Sciences, Örebro University, Örebro, Sweden.,Unit of Biostatistics, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden
| | - Scott Montgomery
- Clinical Epidemiology and Biostatistics, School of Medical Sciences, Örebro University, Örebro, Sweden.,Clinical Epidemiology Unit, Department of Medicine, Karolinska Institutet, Stockholm, Sweden.,Department of Epidemiology and Public Health, University College London, London, UK
| | - Jonas Halfvarson
- Department of Gastroenterology, Faculty of Medicine and Health, Örebro University, Örebro, Sweden
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36
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Aloi M, Cucchiara S. Acute pancreatitis and azathioprine in paediatric inflammatory bowel disease. THE LANCET. CHILD & ADOLESCENT HEALTH 2019; 3:131-132. [PMID: 30685365 DOI: 10.1016/s2352-4642(19)30019-7] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/15/2019] [Accepted: 01/16/2019] [Indexed: 06/09/2023]
Affiliation(s)
- Marina Aloi
- Pediatric Gastroenterology and Liver Unit, Department of Pediatrics, Sapienza University of Rome, Rome 00161, Italy.
| | - Salvatore Cucchiara
- Pediatric Gastroenterology and Liver Unit, Department of Pediatrics, Sapienza University of Rome, Rome 00161, Italy
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37
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Wintzell V, Svanström H, Olén O, Melbye M, Ludvigsson JF, Pasternak B. Association between use of azathioprine and risk of acute pancreatitis in children with inflammatory bowel disease: a Swedish-Danish nationwide cohort study. THE LANCET CHILD & ADOLESCENT HEALTH 2019; 3:158-165. [PMID: 30685366 DOI: 10.1016/s2352-4642(18)30401-2] [Citation(s) in RCA: 26] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Subscribe] [Scholar Register] [Received: 11/01/2018] [Revised: 11/27/2018] [Accepted: 11/29/2018] [Indexed: 01/16/2023]
Abstract
BACKGROUND Studies have shown an association between use of azathioprine and increased risk of acute pancreatitis in adult inflammatory bowel disease. However, whether an association exists among paediatric patients is not known. We aimed to investigate whether use of azathioprine is associated with the risk of acute pancreatitis in children with inflammatory bowel disease. METHODS We did a nationwide register-based cohort study in Sweden (2006-16) and Denmark (2000-16). All paediatric patients (<18 years of age) with inflammatory bowel disease during the study period were identified through hospital records. Episodes of incident azathioprine use and no use of any thiopurine were matched (1:1) using propensity scores, controlling for sociodemographic characteristics, comorbidities, previous treatment, indicators of disease severity, and health care use. Incident acute pancreatitis (physician-assigned diagnosis with ICD-10 code K85) occurring in the 90 days following treatment initiation were identified through outpatient and inpatient hospital records. FINDINGS We identified 3574 azathioprine episodes and 18 700 no-use episodes, which resulted in 3374 pairs after propensity score matching; baseline characteristics in the matched cohort were well balanced. Among the matched azathioprine episodes, mean age was 14·3 years (SD 3·1), 1854 (54·9%) were male, 1923 (57·0%) had Crohn's disease, and 1451 (43·0%) had ulcerative colitis or unclassified inflammatory bowel disease. Within the first 90 days following initiation of azathioprine, 40 acute pancreatitis events occurred (incidence rate 49·1 events per 1000 person-years) compared with six events in the no-use group (8·4 events per 1000 person-years). Azathioprine use was associated with an increased risk of acute pancreatitis (incidence rate ratio 5·82 [95% CI 2·47-13·72]; absolute difference 1·0 [95% CI 0·3-2·6] events per 100 patients) during the 90-day risk period. INTERPRETATION Use of azathioprine was associated with an increased risk of acute pancreatitis in children with inflammatory bowel disease during the first 90 days following treatment initiation, suggesting the need for regular and rigorous monitoring. The risk of acute pancreatitis needs to be considered when deciding on optimal treatment strategies. FUNDING Swedish Research Council, Frimurare Barnhuset Foundation, and the Åke Wiberg Foundation.
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Affiliation(s)
- Viktor Wintzell
- Clinical Epidemiology Division, Department of Medicine, Karolinska Institutet, Stockholm, Sweden.
| | - Henrik Svanström
- Clinical Epidemiology Division, Department of Medicine, Karolinska Institutet, Stockholm, Sweden; Department of Epidemiology Research, Statens Serum Institute, Copenhagen, Denmark
| | - Ola Olén
- Clinical Epidemiology Division, Department of Medicine, Karolinska Institutet, Stockholm, Sweden; Department of Clinical Science and Education, Stockholm South Hospital, Karolinska Institutet, Stockholm, Sweden; Department of Pediatric Gastroenterology and Nutrition, Sachs' Children and Youth Hospital, Stockholm, Sweden
| | - Mads Melbye
- Department of Epidemiology Research, Statens Serum Institute, Copenhagen, Denmark; Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark; Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA
| | - Jonas F Ludvigsson
- Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden; Department of Pediatrics, Örebro University Hospital, Örebro University, Örebro, Sweden; Division of Epidemiology and Public Health, School of Medicine, University of Nottingham, Nottingham, UK; Department of Medicine, Columbia University College of Physicians and Surgeons, New York, NY, USA
| | - Björn Pasternak
- Clinical Epidemiology Division, Department of Medicine, Karolinska Institutet, Stockholm, Sweden; Department of Epidemiology Research, Statens Serum Institute, Copenhagen, Denmark
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Fecal calprotectin is significantly linked to azathioprine metabolite concentrations in Crohn's disease. Eur J Gastroenterol Hepatol 2019; 31:99-108. [PMID: 30212402 DOI: 10.1097/meg.0000000000001262] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
BACKGROUND The value of therapeutic drug monitoring during azathioprine (AZA) therapy with respect to clinical outcomes has been convincingly demonstrated in recent meta-analyses. However, the association between AZA metabolites and the mucosal state in inflammatory bowel disease is largely unclear. AIMS We investigated the association between AZA's active metabolite 6-thioguanine nucleotides (6-TGN) and fecal calprotectin (FC) as a well-validated surrogate marker of mucosal inflammation in patients with Crohn's disease (CD) on AZA monotherapy. PATIENTS AND METHODS Of 443 6-TGN measurements, 140 values from 88 patients with CD on AZA monotherapy visiting the inflammatory bowel disease outpatient clinic between 2009 and 2016 were retrospectively analyzed. In a subcohort with serial 6-TGN measurements, longitudinal FC measurements in patients with versus without intervention (dose increase, allopurinol, and education) were assessed. RESULTS In patients with 6-TGN concentrations within a predefined range (250-450 pmol/8×10 red blood cells), FC was significantly lower (median: 119.5 vs. 327.2 mg/kg, P=0.003), and hemoglobin as well as serum protein concentrations were significantly higher than in patients with 6-TGN outside of this range. C-reactive protein and transferrin saturation were not different. In the longitudinal cohort, 6-TGN increased in the intervention group, but only a minority reached the defined range; no significant change in FC was observed. CONCLUSION This study is the first to show that in patients with CD receiving AZA monotherapy, 6-TGN concentrations within a defined range (250-450 pmol/8×10 red blood cells) are associated with significantly lower FC. A treat-to-target concept directed by 6-TGN to reach mucosal healing may thus be a promising approach (DRKS00013246).
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39
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Abstract
Crohn's disease and ulcerative colitis affect an increasing number of patients, and utilization of immune suppressant and biologic therapies is also increasing. These agents are linked to adverse events ranging from mild nuisance symptoms to potentially life-threatening complications including infections and malignancies. Areas covered: This review provides an updated discussion on adverse events associated with immunomodulator, anti-TNF-α, anti-integrin, and anti-IL 12/IL-23 antibody therapies. In addition, we review the risk profile of the currently widely available infliximab biosimilar medication. Expert commentary: Providers should engage in risk-benefit discussion with information specific to each medication discussed, and consider individualized risk factors when selecting therapeutic agents. Drug monitoring and shared decision-making results in more personalized medical management of inflammatory bowel disease.
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Affiliation(s)
- Sandra M Quezada
- a Department of Medicine, Division of Gastroenterology and Hepatology , University of Maryland School of Medicine , Baltimore , MD , USA
| | - Leon P McLean
- b Department of Medicine , Geisel School of Medicine at Dartmouth , Hanover , NH , USA.,c Granite State Gastrointestinal Consultants , Derry , NH , USA
| | - Raymond K Cross
- a Department of Medicine, Division of Gastroenterology and Hepatology , University of Maryland School of Medicine , Baltimore , MD , USA
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40
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Thiopurine Optimization Through Combination With Allopurinol in Children With Inflammatory Bowel Diseases. J Pediatr Gastroenterol Nutr 2018; 67:341-345. [PMID: 29601433 DOI: 10.1097/mpg.0000000000001986] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/10/2022]
Abstract
OBJECTIVES Thiopurines are commonly used in the maintenance of remission for children with inflammatory bowel diseases (IBDs). Variation in drug metabolism may affect hepatotoxicity or therapeutic effect. We aimed to describe our center's experience with thiopurine optimization through the use of reduced thiopurine dosing in combination with allopurinol upon hepatotoxicity, drug metabolite levels, and clinical outcomes in children with IBD. METHODS Patients aged 2 to 21 years with IBD treated with the combination of thiopurines/allopurinol between 2008 and 2015 were retrospectively reviewed. Patients previously treated with antitumor necrosis factor therapy were excluded. Demographic data, transaminase levels (aspartate transaminase, alanine transaminase), drug metabolites levels (6-thioguanine [6-TG], 6-methylmercaptopurine), physician global assessment, and corticosteroid use were recorded at baseline, 6, and 12 months. RESULTS Fifty-two patients (29 girls, 56%) met inclusion criteria. Thirty-two of 52 (62%) remained on the combination for 12 months. In those remaining on the thiopurine/allopurinol combination, median alanine transaminase and aspartate transaminase levels were reduced (P < 0.001) and median 6-TG levels were increased (P < 0.001) at both 6 and 12 months. Corticosteroid use was decreased at both 6 (P < 0.001) and 12 months (P < 0.001) compared to use at baseline. Remission rates also improved at both 6 (P = 0.013) and 12 months (P = 0.003). Twenty of the 52 patients (38%) had discontinued the thiopurine/allopurinol combination within 12 months of initiation with 17 of 52 (33%) initiating antitumor necrosis factor therapy. CONCLUSIONS Low-dose thiopurines in combination with allopurinol improved hepatotoxicity and increased 6-TG levels in children with IBD. Corticosteroid use was reduced and remission rates improved in those patients remaining on this combination for 1 year. However, approximately 40% of patients required a change in therapy within 12 months.
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Godat S, Fournier N, Safroneeva E, Juillerat P, Nydegger A, Straumann A, Vavricka S, Biedermann L, Greuter T, Fraga M, Abdelrahman K, Hahnloser D, Sauter B, Rogler G, Michetti P, Schoepfer AM. Frequency and type of drug-related side effects necessitating treatment discontinuation in the Swiss Inflammatory Bowel Disease Cohort. Eur J Gastroenterol Hepatol 2018; 30:612-620. [PMID: 29384798 DOI: 10.1097/meg.0000000000001078] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
BACKGROUND AND AIM Systematic analyses of inflammatory bowel disease (IBD) drug-related side effects necessitating treatment cessation in large cohorts of patients with IBD are scarce. We aimed to assess the frequency and type of drug-related side effects requiring drug cessation in patients included in the Swiss IBD Cohort. PATIENTS AND METHODS A retrospective review was performed of data from the Swiss IBD Cohort physician questionnaires documenting a treatment cessation for the following drug categories: aminosalicylates, topical and systemic steroids, thiopurines, methotrexate, tumor necrosis factor-antagonists, and calcineurin inhibitors (tacrolimus, cyclosporine). RESULTS A total of 3192 patients were analyzed, of whom 1792 (56.1%) had Crohn's disease, 1322 (41.4%) had ulcerative colitis, and 78 (2.5%) had IBD unclassified. Of 3138 patients treated with IBD drugs, 2129 (67.8%) presented with one or several drug-related side effects necessitating drug cessation. We found a significant positive correlation between the number of concomitantly administered IBD drugs and the occurrence of side effects requiring drug cessation (P<0.001). Logistic regression modeling identified Crohn's disease diagnosis [odds ratio (OR)=1.361, P=0.017], presence of extraintestinal manifestations (OR=2.262, P<0.001), IBD-related surgery (OR=1.419, P=0.006), and the increasing number of concomitantly used IBD drugs [OR=2.007 (P<0.001) for two concomitantly used IBD drugs; OR=3.225 (P<0.001) for at least three concomitantly used IBD drugs] to be associated significantly with the occurrence of IBD drug-related adverse events that necessitated treatment cessation. CONCLUSION Physicians should keep in mind that the number of concomitantly administered IBD drugs is the main risk factor for drug-related adverse events necessitating treatment cessation.
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Affiliation(s)
| | - Nicolas Fournier
- Institute of Social and Preventive Medicine (IUMSP), Lausanne University Hospital
| | | | - Pascal Juillerat
- Division of Gastroenterology and Hepatology, University Hospital Bern, Bern
| | | | - Alex Straumann
- Swiss EoE Center, Pediatrician Römerhof, Olten.,Division of Gastroenterology and Hepatology, University Hospital Zurich
| | - Stephan Vavricka
- Division of Gastroenterology and Hepatology, University Hospital Zurich.,Division of Gastroenterology and Hepatology, Triemli Hospital
| | - Luc Biedermann
- Division of Gastroenterology and Hepatology, University Hospital Zurich
| | - Thomas Greuter
- Division of Gastroenterology and Hepatology, University Hospital Zurich
| | | | | | - Dieter Hahnloser
- Division of Visceral Surgery, Lausanne University Hospital, University of Lausanne
| | | | - Gerhard Rogler
- Division of Gastroenterology and Hepatology, University Hospital Zurich
| | - Pierre Michetti
- Division of Gastroenterology and Hepatology.,Crohn and Colitis Center, Clinique La Source, Lausanne
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42
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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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43
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Friedman AB, Brown SJ, Bampton P, Barclay ML, Chung A, Macrae FA, McKenzie J, Reynolds J, Gibson PR, Hanauer SB, Sparrow MP. Randomised clinical trial: efficacy, safety and dosage of adjunctive allopurinol in azathioprine/mercaptopurine nonresponders (AAA Study). Aliment Pharmacol Ther 2018; 47:1092-1102. [PMID: 29468701 DOI: 10.1111/apt.14571] [Citation(s) in RCA: 37] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/30/2017] [Revised: 09/26/2017] [Accepted: 01/25/2018] [Indexed: 02/06/2023]
Abstract
BACKGROUND Thiopurine hypermethylation towards 6-methylmercaptopurine (6MMP) instead of 6-thioguanine nucleotides (6TGN) is associated with inefficacy in patients with IBD. Allopurinol reverses such hypermethylation. AIMS To prospectively determine efficacy of allopurinol-thiopurine combination and to compare 2 doses of allopurinol. DESIGN In a multicentre, double-blind trial, patients with clinically active or steroid-dependent IBD and thiopurine shunting were randomised to 50 or 100 mg/d allopurinol and 25% of their screening thiopurine dose, which was subsequently optimised, aiming for 6TGN of 260-500 pmol/8x108 RBCs. The primary endpoint was steroid-free clinical remission at 24 weeks. RESULTS Of 73 patients, 39 (53% [95% CI 42-65]) achieved steroid-free remission, (54% with 50 mg/d and 53% with 100 mg/d). 81% were able to discontinue steroids. Therapeutic 6TGN levels were achieved in both groups. Final thiopurine doses were lower with 100 mg/d allopurinol (P < 0.005). 6MMP: 6TGN ratio decreased from mean 64 to 4 (P < 0.001), being higher with 50 mg/d (6 ± 1.83) than for 100 mg/d ([1 ± 0.16], P = 0.003). Three patients on 50 mg/d failed to sustain low ratios at 24 weeks. Toxicity was minimal; three patients on 50 mg/d allopurinol developed transient leukopenia. Alanine aminotransferase concentrations decreased (P < 0.001) similarly in both arms. Faecal calprotectin levels at study end were lower in patients who achieved the primary endpoint (median 171 [85-541] vs 821[110-5892] ug/g, P = 0.03). CONCLUSIONS Low-dose allopurinol-thiopurine combination safely reverses shunting and optimises 6TGN with associated improvement in disease activity. 100 mg/d allopurinol is preferable due to greater metabolite profile stability and lower thiopurine dose without additional toxicity.
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Affiliation(s)
- A B Friedman
- Department of Gastroenterology, The Alfred Hospital and Monash University, Melbourne, Australia
| | - S J Brown
- St Vincent's Hospital, Melbourne, Australia
| | - P Bampton
- Flinders medical Centre, Adelaide, Australia
| | - M L Barclay
- Christchurch Hospital, Christchurch, New Zealand
| | - A Chung
- Eastern Health and Monash University, Melbourne, Australia
| | - F A Macrae
- Royal Melbourne Hospital, Melbourne, Australia
| | - J McKenzie
- The Alfred Hospital and Monash University, Melbourne, Australia
| | - J Reynolds
- The Alfred Hospital and Monash University, Melbourne, Australia
| | - P R Gibson
- The Alfred Hospital and Monash University, Melbourne, Australia
| | | | - M P Sparrow
- The Alfred Hospital and Monash University, Melbourne, Australia
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44
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Weitzel KW, Smith DM, Elsey AR, Duong BQ, Burkley B, Clare-Salzler M, Gong Y, Higgins TA, Kong B, Langaee T, McDonough CW, Staley BJ, Vo TT, Wake DT, Cavallari LH, Johnson JA. Implementation of Standardized Clinical Processes for TPMT Testing in a Diverse Multidisciplinary Population: Challenges and Lessons Learned. Clin Transl Sci 2018; 11:175-181. [PMID: 29351371 PMCID: PMC5867028 DOI: 10.1111/cts.12533] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2017] [Accepted: 12/03/2017] [Indexed: 01/11/2023] Open
Abstract
Although thiopurine S‐methyltransferase (TPMT) genotyping to guide thiopurine dosing is common in the pediatric cancer population, limited data exist on TPMT testing implementation in diverse, multidisciplinary settings. We established TPMT testing (genotype and enzyme) with clinical decision support, provider/patient education, and pharmacist consultations in a tertiary medical center and collected data over 3 years. During this time, 834 patients underwent 873 TPMT tests (147 (17%) genotype, 726 (83%) enzyme). TPMT tests were most commonly ordered for gastroenterology, rheumatology, dermatology, and hematology/oncology patients (661 of 834 patients (79.2%); 580 outpatient vs. 293 inpatient; P < 0.0001). Thirty‐nine patients had both genotype and enzyme tests (n = 2 discordant results). We observed significant differences between TPMT test use and characteristics in a diverse, multispecialty environment vs. a pediatric cancer setting, which led to unique implementation needs. As pharmacogenetic implementations expand, disseminating lessons learned in diverse, real‐world environments will be important to support routine adoption.
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Affiliation(s)
- Kristin W Weitzel
- University of Florida Health Personalized Medicine Program, Gainesville, Florida, USA.,University of Florida College of Pharmacy Center for Pharmacogenomics, Gainesville, Florida, USA
| | - D Max Smith
- University of Florida Health Personalized Medicine Program, Gainesville, Florida, USA.,University of Florida College of Pharmacy Center for Pharmacogenomics, Gainesville, Florida, USA
| | - Amanda R Elsey
- University of Florida Health Personalized Medicine Program, Gainesville, Florida, USA.,University of Florida College of Pharmacy Center for Pharmacogenomics, Gainesville, Florida, USA.,University of Florida Clinical and Translational Science Institute, Gainesville, Florida, USA
| | - Benjamin Q Duong
- University of Florida Health Personalized Medicine Program, Gainesville, Florida, USA.,University of Florida College of Pharmacy Center for Pharmacogenomics, Gainesville, Florida, USA
| | - Benjamin Burkley
- University of Florida College of Pharmacy Center for Pharmacogenomics, Gainesville, Florida, USA
| | - Michael Clare-Salzler
- UF Department of Immunology, Pathology, and Laboratory Medicine, Gainesville, Florida, USA.,UF Health Pathology Laboratories, Gainesville, Florida, USA
| | - Yan Gong
- University of Florida College of Pharmacy Center for Pharmacogenomics, Gainesville, Florida, USA
| | - Tara A Higgins
- UF Health Shands Hospital Department of Pharmacy, Gainesville, Florida, USA
| | - Benjamin Kong
- Oregon Health and Science University, Portland, Oregon, USA
| | - Taimour Langaee
- University of Florida College of Pharmacy Center for Pharmacogenomics, Gainesville, Florida, USA
| | - Caitrin W McDonough
- University of Florida College of Pharmacy Center for Pharmacogenomics, Gainesville, Florida, USA
| | - Benjamin J Staley
- UF Health Shands Hospital Department of Pharmacy, Gainesville, Florida, USA
| | - Teresa T Vo
- University of South Florida Health College of Pharmacy, Tampa, Florida, USA
| | - Dyson T Wake
- NorthShore University Health System, Evanston, Illinois, USA
| | - Larisa H Cavallari
- University of Florida Health Personalized Medicine Program, Gainesville, Florida, USA.,University of Florida College of Pharmacy Center for Pharmacogenomics, Gainesville, Florida, USA
| | - Julie A Johnson
- University of Florida Health Personalized Medicine Program, Gainesville, Florida, USA.,University of Florida College of Pharmacy Center for Pharmacogenomics, Gainesville, Florida, USA
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45
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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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46
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Clinical Value of Mercaptopurine After Failing Azathioprine Therapy in Patients With Inflammatory Bowel Disease. Ther Drug Monit 2017; 38:463-70. [PMID: 27158876 DOI: 10.1097/ftd.0000000000000312] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
BACKGROUND Thiopurines have been widely accepted as immunosuppressive therapy in inflammatory bowel disease. However, many patients have to discontinue thiopurines due to intolerance or ineffectiveness. A therapeutically beneficial effect of switching from azathioprine (AZA) to mercaptopurine (MP) after developing adverse events (AEs) has been reported. The authors assessed the clinical value of MP therapy after AZA discontinuation due to intolerance and, secondary, due to ineffectiveness. METHODS In this retrospective single-center study, the authors analyzed data from patients in whom AZA therapy had failed and who were subsequently treated with MP. RESULTS Thirty-eight patients initiated MP therapy after intolerance to AZA. Intolerance reoccurred in 22 (58%) patients and the remaining 16 (42%) tolerated MP. In 18 out of 48 patients (38%), the AEs that led to discontinuation of MP were similar to those of AZA. A longer duration of prior AZA use was more common in patients who were subsequently tolerant for MP (5.3 versus 1.2 months; P = 0.04). Twenty-two patients discontinued AZA due to ineffectiveness. Eight (36%) patients had clinical benefit from a switch to MP. Six out of these 8 (75%) patients used allopurinol alongside MP, due to ineffectiveness based on a skewed thiopurine metabolism. Patients were more likely to have clinical benefit if the interval between both thiopurines was longer (4.4 versus 0.01 months; P < 0.05). CONCLUSIONS The authors showed that a noteworthy number of patients benefitted therapeutically from a switch from AZA to MP when failing due to intolerance or ineffectiveness; however, the percentage was lower than previously reported in literature.
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47
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Broekman MMTJ, Coenen MJH, Wanten GJ, van Marrewijk CJ, Klungel OH, Verbeek ALM, Hooymans PM, Guchelaar H, Scheffer H, Derijks LJJ, Wong DR, de Jong DJ. Risk factors for thiopurine-induced myelosuppression and infections in inflammatory bowel disease patients with a normal TPMT genotype. Aliment Pharmacol Ther 2017; 46:953-963. [PMID: 28914446 PMCID: PMC5698717 DOI: 10.1111/apt.14323] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/13/2017] [Revised: 07/09/2017] [Accepted: 08/25/2017] [Indexed: 12/21/2022]
Abstract
BACKGROUND Leucopenia is a common side effect in patients treated with thiopurines. Variants in the thiopurine S-methyltransferase (TPMT) gene are the best-known risk factor, but only explain up to 25% of leucopenia cases. AIM To identify the clinical risk factors for thiopurine-induced leucopenia in patients without a common TPMT variant, and explore if these patients are at increased risk for infections. METHODS Post hoc analysis of the Thiopurine response Optimisation by Pharmacogenetic testing in Inflammatory bowel disease Clinics (TOPIC) trial. For this analysis, patients without a variant in TPMT (*2, *3A or*3C) were included. Uni- and multivariate Cox-proportional hazard models were used to identify risk factors for leucopenia and infections. Leucopenia was defined as a white blood cell (WBC) count <3.0 × 109 /L and infections were classified according to the Common Terminology Criteria for Adverse Events. RESULTS Sixty hundred and ninety-five patients (90.6%) included in the TOPIC-trial had no variant in TPMT, of which 45 (6.5%) developed leucopenia. Median time to leucopenia was 56 (29-112) days. Multivariate analysis showed that use of mercaptopurine compared to azathioprine was associated with leucopenia (hazard ratio [HR] 2.61 [95% CIs, 1.39-4.88; P < .01]) and a higher baseline WBC count was protective (HR 0.80 [95% CIs, 0.71-0.89; P < .01]). Risk factors for infections were older age (per 10 year; HR 2.07 [95% CIs, 1.18-3.63; P = .01]) and concomitant use of biologic drugs (HR 2.15 [95% CIs, 1.14-4.07; P = .02]). CONCLUSIONS Low baseline WBC count and mercaptopurine, due to a relatively higher dose, were risk factors for thiopurine-induced leucopenia in patients without a TPMT variant.
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Affiliation(s)
- M. M. T. J. Broekman
- Department of GastroenterologyRadboud Institute for Molecular Life SciencesRadboud University Medical CenterNijmegenThe Netherlands
| | - M. J. H. Coenen
- Department of Human GeneticsRadboud Institute for Health SciencesRadboud University Medical CenterNijmegenThe Netherlands
| | - G. J. Wanten
- Department of GastroenterologyRadboud Institute for Molecular Life SciencesRadboud University Medical CenterNijmegenThe Netherlands
| | - C. J. van Marrewijk
- Department of Human GeneticsRadboud Institute for Health SciencesRadboud University Medical CenterNijmegenThe Netherlands
| | - O. H. Klungel
- Department of Pharmacoepidemiology and PharmacotherapyUtrecht UniversityUtrechtThe Netherlands
| | - A. L. M. Verbeek
- Department for Health EvidenceRadboud University Medical CenterNijmegenThe Netherlands
| | - P. M. Hooymans
- Department of Clinical Pharmacy, Pharmacology and ToxicologyZuyderland Medical CenterSittard‐GeleenThe Netherlands
| | - H.‐J. Guchelaar
- Department of Clinical Pharmacy and ToxicologyLeiden University Medical CenterLeidenThe Netherlands
| | - H. Scheffer
- Department of Human GeneticsRadboud Institute for Health SciencesRadboud University Medical CenterNijmegenThe Netherlands
| | - L. J. J. Derijks
- Department of Clinical PharmacyMáxima Medical CenterVeldhovenThe Netherlands
| | - D. R. Wong
- Department of Clinical Pharmacy, Pharmacology and ToxicologyZuyderland Medical CenterSittard‐GeleenThe Netherlands
| | - D. J. de Jong
- Department of GastroenterologyRadboud Institute for Molecular Life SciencesRadboud University Medical CenterNijmegenThe Netherlands
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48
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Abstract
BACKGROUND There are substantial global differences in the preference for mercaptopurine (MP) or its prodrug azathioprine (AZA) as first-choice thiopurine to treat inflammatory bowel diseases. Studies comparing both agents are scarce. Our aim was to compare AZA and MP in thiopurine-naive patients with inflammatory bowel disease for the frequency of side effects and efficacy. METHODS Post hoc analysis of the "Thiopurine response Optimization by Pharmacogenetic testing in Inflammatory bowel disease Clinics" (TOPIC) trial, in which thiopurine-naive patients with inflammatory bowel disease with an indication for a thiopurine were randomized for a genotype-based dose versus standard of care. For this study, Cox proportional hazard ratios (HRs) were calculated to compare AZA and MP for discontinuation rates within 5 months, incidence of hepatotoxicity, leukopenia, and gastrointestinal side effects. Treatment efficacy was compared by logistic regression. RESULTS Patient characteristics were similar for patients treated with AZA (n = 494, 64.4%) and MP (n = 273, 35.6%), yet patients with MP were relatively higher dosed compared with those on AZA. Discontinuation rates within 5 months were not different, 39.3% (AZA) and 38.1% (MP), HR 0.92 (95% confidence interval, 0.72-1.17; P = 0.50); however, patients on MP were more often subjected to dose reductions (30% versus 14%, P < 0.01). Higher rates of hepatotoxicity, HR 1.93 (95% confidence interval, 1.35-2.76; P < 0.01) and leukopenia, HR 2.55 (95% confidence interval, 1.51-4.30; P < 0.01) were observed with MP, which annulled in a secondary analysis with adjustment for the higher dose and metabolite levels. CONCLUSIONS Patients treated with MP were relatively higher dosed, which resulted in more dose-dependent side effects and a higher rate of dose reductions.
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49
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Macaluso FS, Renna S, Maida M, Dimarco M, Sapienza C, Affronti M, Orlando E, Rizzuto G, Orlando R, Ventimiglia M, Cottone M, Orlando A. Tolerability profile of thiopurines in inflammatory bowel disease: a prospective experience. Scand J Gastroenterol 2017; 52:981-987. [PMID: 28554266 DOI: 10.1080/00365521.2017.1333626] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
OBJECTIVES The occurrence of thiopurine-related adverse events (AEs) may complicate the management of patients with inflammatory bowel disease (IBD). We aimed to evaluate the tolerability of thiopurines in a current IBD setting. MATERIALS AND METHODS All consecutive patients who started a treatment with azathioprine (AZA) from January 2010 to March 2016 were entered in a prospectively maintained database, and the AEs which led to the permanent discontinuation of the drug were reported. RESULTS Two hundred and fifty three patients were included. Median total follow-up was 32 months (range: 0.2-75 months). At the end of the study, AZA was discontinued in 160 patients (63.2%). The main reason leading to drug withdrawal was the occurrence of AEs (109/160 patients [68.1%]; cumulative incidence among the entire cohort: 43.1%). Overall, the most frequent AEs leading to treatment withdrawal were nausea (31/253 patients, 12.3%) and subjective symptoms, i.e., poorly defined side effects such as fatigue, headache and muscle pain (20/253 patients, 7.9%). Among the 109 AZA-intolerant patients, a switch to 6-mercaptopurine (6-MP) was performed in 44 cases (40.4%). At the end of follow-up, 6-MP was discontinued in 35/44 patients (79.5%), mostly due to AEs (29/35 patients, 82.8%). Azathioprine-induced hepatic and pancreatic toxicity was associated with male gender (p = .01 and p = .03, respectively), and occurrence of nausea with Crohn's disease (p = .04). CONCLUSIONS Our real-life prospective cohort showed the higher cumulative incidence of thiopurine withdrawal due to AEs reported to date. Switching from AZA to 6-MP was often ineffective.
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Affiliation(s)
- Fabio Salvatore Macaluso
- a Di.Bi.M.I.S., Division of Internal Medicine , "Villa Sofia-Cervello" Hospital, University of Palermo , Palermo , Italy
| | - Sara Renna
- a Di.Bi.M.I.S., Division of Internal Medicine , "Villa Sofia-Cervello" Hospital, University of Palermo , Palermo , Italy
| | - Marcello Maida
- b Gastroenterology and Endoscopy Unit , "Villa Sofia-Cervello" Hospital , Palermo , Italy
| | - Mariangela Dimarco
- a Di.Bi.M.I.S., Division of Internal Medicine , "Villa Sofia-Cervello" Hospital, University of Palermo , Palermo , Italy
| | - Chiara Sapienza
- a Di.Bi.M.I.S., Division of Internal Medicine , "Villa Sofia-Cervello" Hospital, University of Palermo , Palermo , Italy
| | - Marco Affronti
- a Di.Bi.M.I.S., Division of Internal Medicine , "Villa Sofia-Cervello" Hospital, University of Palermo , Palermo , Italy
| | - Emanuele Orlando
- a Di.Bi.M.I.S., Division of Internal Medicine , "Villa Sofia-Cervello" Hospital, University of Palermo , Palermo , Italy
| | - Giulia Rizzuto
- a Di.Bi.M.I.S., Division of Internal Medicine , "Villa Sofia-Cervello" Hospital, University of Palermo , Palermo , Italy
| | - Rosalba Orlando
- a Di.Bi.M.I.S., Division of Internal Medicine , "Villa Sofia-Cervello" Hospital, University of Palermo , Palermo , Italy
| | - Marco Ventimiglia
- a Di.Bi.M.I.S., Division of Internal Medicine , "Villa Sofia-Cervello" Hospital, University of Palermo , Palermo , Italy
| | - Mario Cottone
- a Di.Bi.M.I.S., Division of Internal Medicine , "Villa Sofia-Cervello" Hospital, University of Palermo , Palermo , Italy
| | - Ambrogio Orlando
- a Di.Bi.M.I.S., Division of Internal Medicine , "Villa Sofia-Cervello" Hospital, University of Palermo , Palermo , Italy
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50
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Abstract
BACKGROUND Hepatoxicity is a relative uncommon complication related with Azathioprine, however most studies were performed in inflammatory bowel diseases patients. The aim of this study is to report the clinical profile of patients with Azathioprine-induced hepatotoxicity. METHODS All medical records of patients received Azathioprine from 2010 to 2015 were retrospectively reviewed. Hepatotoxicity was defined as serum alanine aminotransferase (ALT) or aspatate aminotransferase (AST) or total bilirubin >2 times upper limit normal. Other causes of liver diseases were excluded. All subjects were followed until the resolution of liver injury. RESULTS Two-hundred and ninety-three patients receiving Azathioprine were retrospectively reviewed. Eight patients (2.7%) were diagnosed with Azathioprine-induced hepatotoxicity. The median age was 45 year with female preponderance. The latency to onset of liver injury ranged from 7 to 236 d, and 4 patients were symptomatic. Median peak levels were ALT 295 U/L, alkaline phosphatase 169 U/L, and total bilirubin 1 mg/dl. According to R-ratio, mixed pattern (50%) was more frequent than cholestatic (37.5%) and hepatocellular pattern (12.5%). Liver biopsies were performed in 2 patients, and showed hepatocellular and canalicular cholestasis with mild portal and peri-portal inflammation. All patients recovered fully with a median time of 41.3 days. Two patients developed prolonged cholestasis >2 months, hence none had liver failure or required liver transplantation. CONCLUSION Hepatotoxicity is relative uncommon in patients receiving Azathioprine, and predominantly is mixed hepatocellular and cholestatic in nature. Even though all patients recover fully after drug withdrawal, severe cholestasis can occur.
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Affiliation(s)
- Sith Siramolpiwat
- a Chulabhorn International College of Medicine , Thammasat University , Pathumthani , Thailand.,b Division of Gastroenterology, Department of Internal Medicine, Faculty of Medicine , Thammasat University , Pathumthani , Thailand
| | - Dussadee Sakonlaya
- c Department of Pathology, Faculty of Medicine , Thammasat University , Pathumthani , Thailand
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