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1
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Qu YT, Ding JY, Pan W, Liu FR, Dong AL. Perspectives in clinical research on Azathioprine for steroid-dependent ulcerative colitis. Front Med (Lausanne) 2025; 12:1551906. [PMID: 40201324 PMCID: PMC11975918 DOI: 10.3389/fmed.2025.1551906] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2024] [Accepted: 03/11/2025] [Indexed: 04/10/2025] Open
Abstract
This study explores the application of Azathioprine in the treatment of ulcerative colitis (UC) and the challenges associated with its long-term use. While short-term studies demonstrate the efficacy of Azathioprine in steroid-dependent UC, long-term data on its risks, including malignancies, infections, and chronic toxicity, remain insufficient. Furthermore, the impact of Azathioprine on patients' quality of life over extended periods is still unclear. The research highlights the importance of optimizing Azathioprine dosing based on genomic data, particularly through TPMT and NUDT15 genotyping, to minimize adverse effects. However, further research is needed to develop individualized treatment strategies that can improve efficacy and reduce toxicity. The identification of predictive biomarkers, through genomics and proteomics, is likely to play a crucial role in improving treatment precision by identifying patients who are most likely to benefit from Azathioprine therapy. Additionally, combining Azathioprine with biologic therapies (such as anti-TNF agents or integrin inhibitors) and interventions targeting the gut microbiome may enhance the drug's effectiveness while reducing reliance on steroids. Overall, large-scale clinical trials are urgently needed to evaluate the benefits and risks of these emerging therapies, ultimately supporting more personalized treatment approaches for steroid-dependent UC patients.
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Affiliation(s)
- Yuan-Ting Qu
- Department of Gastroenterology, Hongqi Hospital Affiliated to Mudanjiang Medical University, Mudanjiang, China
| | - Jia-Yuan Ding
- Department of Gastroenterology, Hongqi Hospital Affiliated to Mudanjiang Medical University, Mudanjiang, China
| | - Wei Pan
- Department of Gastroenterology, Hongqi Hospital Affiliated to Mudanjiang Medical University, Mudanjiang, China
| | - Fang-Rui Liu
- Department of Gastroenterology, Mudanjiang First People’s Hospital, Mudanjiang, China
| | - Ai-Lian Dong
- Department of Gastroenterology, Hongqi Hospital Affiliated to Mudanjiang Medical University, Mudanjiang, China
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Deenen MJ, van Noordenburg AJ, Bouwens-Bijsterveld J, van Dijk MA, Stapelbroek JM, Derijks LJJ, Gilissen LPL, Deiman BALM. Genetic association analysis and frequency of NUDT15*3 with thiopurine-induced myelosuppression in patients with inflammatory bowel disease in a large Dutch cohort. THE PHARMACOGENOMICS JOURNAL 2024; 24:39. [PMID: 39580429 DOI: 10.1038/s41397-024-00358-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/25/2024] [Revised: 10/29/2024] [Accepted: 11/13/2024] [Indexed: 11/25/2024]
Abstract
Thiopurine drugs are cornerstone treatment for patients with inflammatory bowel disease (IBD). The most common adverse drug reaction is thiopurine-induced myelosuppression (TIM), that may partly be explained by the genetic polymorphism NUDT15*3. The aim of this retrospective study was to determine the NUDT15*3 polymorphism frequency and its association with TIM in an IBD patient population in the Netherlands. DNA from patients previously genotyped for TPMT was genotyped for NUDT15*3. In IBD patients treated with thiopurines association tests with TIM were conducted. Out of 988 included patients, 13 (1.3%) were heterozygous for NUDT15*3. Of all patients, 606 had IBD and received thiopurine treatment. In these patients, 8/606 (1.3%) were heterozygous polymorphic for NUDT15*3 of which 50.0% developed TIM compared to 2.3% in the wild type patients (p < 0.001). The study results show a clinically relevant prevalence of NUDT15*3 in the Dutch patient population. Its strong association with TIM suggests pre-therapeutic genotyping potentially clinically utile.
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Affiliation(s)
- Maarten J Deenen
- Department of Clinical Pharmacy, Catharina Hospital, Eindhoven, the Netherlands.
- Department of Clinical Pharmacy & Toxicology, Leiden University Medical Centre, Leiden, the Netherlands.
| | | | | | - Maarten A van Dijk
- Department of Gastroenterology and Hepatology, Elkerliek Hospital, Helmond, the Netherlands
| | | | - Luc J J Derijks
- Department of Clinical Pharmacy, Máxima Medical Centre, Eindhoven, the Netherlands
- Department of Clinical Pharmacy & Toxicology, Maastricht University Medical Centre, Maastricht, the Netherlands
| | - Lennard P L Gilissen
- Department of Gastroenterology and Hepatology, Catharina Hospital, Eindhoven, the Netherlands
| | - Birgit A L M Deiman
- Department of Clinical Chemistry, Catharina Hospital, Eindhoven, the Netherlands
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Tatour M, Neeman Z, Aviv A, Hazzan R. Increased Risk of Non-Hodgkin Lymphoma in Autoimmune Hepatitis: A Large Retrospective Cohort Study. J Clin Med 2024; 13:6258. [PMID: 39458208 PMCID: PMC11508903 DOI: 10.3390/jcm13206258] [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: 07/26/2024] [Revised: 09/07/2024] [Accepted: 10/18/2024] [Indexed: 10/28/2024] Open
Abstract
Background/Objectives: Autoimmune hepatitis (AIH) is a chronic inflammatory liver disease caused by an autoimmune attack on hepatocytes. The first-line treatment for AIH comprises two core components: glucocorticoids and thiopurine analog inhibitors and mycophenolate mofetil (MMF). Numerous studies have suggested an increased risk for lymphoma among patients with either rheumatoid arthritis or inflammatory bowel disease (IBD) who are treated with azathioprine/6-mercaptopurine (6-MP). The relative risk of non-Hodgkin lymphoma (NHL) among autoimmune hepatitis patients treated with these immunosuppressive drugs remains unclear. We aimed at investigating the risk of NHL across a large retrospective AIH cohort after a long-term follow-up. Methods: This retrospective, population-based study comprised approximately 2.7 million adults over two decades. It included adult patients aged 20 years or older at the time of autoimmune hepatitis diagnosis who had initiated treatment with azathioprine, 6-MP, or MMF. The primary outcome was the development of non-Hodgkin lymphoma. Results: The study initially included 834 patients diagnosed with AIH. A total of 685 patients remained in the research cohort after matching the data to the local cancer registry. Compared to the predicted NHL rate in the general population, NHL incidence was considerably higher in AIH patients (Standardized Incidence Ratio, SIR = 36.5). Subgroup studies showed that lymphoma mainly affected patients 45 years of age and over and was detected primarily during the first seven years following the AIH diagnosis. No correlation was found between the incidence of NHL and the treatment drug used. Conclusions: Patients with AIH exhibit a markedly higher risk of NHL compared to the general population.
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Affiliation(s)
- Mifleh Tatour
- Clalit Health Services, Nof Hagalil 1710601, Israel;
- Department of Family Medicine, Clalit Health Services, Afula 1710601, Israel
| | - Ziv Neeman
- Imaging Institute & Nuclear Medicine, Emek Medical Center, Clalit Health Services, Afula 183411, Israel;
- Ruth and Bruce Rappaport, Faculty of Medicine, Technion—Institute of Technology, Haifa 3109601, Israel;
| | - Ariel Aviv
- Ruth and Bruce Rappaport, Faculty of Medicine, Technion—Institute of Technology, Haifa 3109601, Israel;
- Hematology Unit, HaEmek Medical Center, Afula 183411, Israel
| | - Rawi Hazzan
- Clalit Health Services, Nof Hagalil 1710601, Israel;
- Azrieli Faculty of Medicine, Bar-Ilan University, Safed 1311502, Israel
- Emek Medical Center, 21 Yitzhak Rabin Blvd, Afula 183411, Israel
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Crouwel F, Bayoumy AB, Mulder CJJ, Peters JHC, Boekema PJ, Derijks LJJ, de Boer SY, van de Meeberg PC, Ahmad I, Buiter HJC, de Boer NK. The Effectiveness and Safety of First-Line Thioguanine in Thiopurine-Naïve Inflammatory Bowel Disease Patients. Inflamm Bowel Dis 2024; 30:1492-1499. [PMID: 37658804 PMCID: PMC11369064 DOI: 10.1093/ibd/izad197] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/10/2023] [Indexed: 09/05/2023]
Abstract
BACKGROUND Currently thioguanine is solely used as treatment for inflammatory bowel disease after azathioprine and/or mercaptopurine failure. This study aimed to determine the safety, effectiveness, and 12-month drug survival of thioguanine in thiopurine-naïve patients with inflammatory bowel disease. METHODS A retrospective cohort study was performed in thiopurine-naïve patients with inflammatory bowel disease treated with thioguanine as first thiopurine derivate. Clinical effectiveness was defined as the continuation of thioguanine without the (re)initiation of concurrent biological therapy, systemic corticosteroids, or a surgical intervention. All adverse events were categorized by the Common Terminology Criteria for Adverse Events. RESULTS A total of 114 patients (male 39%, Crohn's disease 53%) were included with a median treatment duration of 25 months and a median thioguanine dosage of 20 mg/d. Clinical effectiveness at 12 months was observed in 53% of patients, and 78% of these responding patients remained responsive until the end of follow-up. During the entire follow-up period, 26 patients were primary nonresponders, 8 had a secondary loss of response, and 11 patients were unable to cease therapy with systemic corticosteroids within 6 months and were therefore classified as nonresponders. After 12 months, thioguanine was still used by 86% of patients. Fifty (44%) patients developed adverse events (grade 1 or 2) and 9 (8%) patients ceased therapy due to the occurrence of adverse events. An infection was documented in 3 patients, none of them requiring hospitalization and pancytopenia occurred in 2 other patients. No signs of nodular regenerative hyperplasia or portal hypertension were observed. CONCLUSIONS At 12 months, first-line thioguanine therapy was clinically effective in 53% of thiopurine-naïve inflammatory bowel disease patients with an acceptable safety profile.
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Affiliation(s)
- Femke Crouwel
- Department of Gastroenterology and Hepatology, Amsterdam Gastroenterology Endocrinology Metabolism Research Institute, Amsterdam University Medical Centre, Vrije Universiteit Amsterdam, Amsterdam, the Netherlands
| | - Ahmed B Bayoumy
- Department of Gastroenterology and Hepatology, Amsterdam Gastroenterology Endocrinology Metabolism Research Institute, Amsterdam University Medical Centre, Vrije Universiteit Amsterdam, Amsterdam, the Netherlands
| | - Chris J J Mulder
- Department of Gastroenterology and Hepatology, Amsterdam Gastroenterology Endocrinology Metabolism Research Institute, Amsterdam University Medical Centre, Vrije Universiteit Amsterdam, Amsterdam, the Netherlands
| | - Job H C Peters
- Department of Gastroenterology and Hepatology, Rode Kruis hospital, Beverwijk, the Netherlands
| | - Paul J Boekema
- Department of Gastroenterology and Hepatology, Máxima Medical Centre, Veldhoven, the Netherlands
| | - Luc J J Derijks
- Department of Clinical Pharmacy and Pharmacology, Máxima Medical Centre, Veldhoven, the Netherlands
| | - Sybrand Y de Boer
- Department of Gastroenterology and Hepatology, Slingeland Hospital, Doetinchem, the Netherlands
| | - Paul C van de Meeberg
- Department of Gastroenterology and Hepatology, Slingeland Hospital, Doetinchem, the Netherlands
| | - Ishfaq Ahmad
- Department of Gastroenterology and Hepatology, Streekziekenhuis Koningin Beatrix, Winterswijk, the Netherlands
| | - Hans J C Buiter
- Department of Radiology and Nuclear Medicine, Amsterdam University Medical Centre, Vrije Universiteit Amsterdam, Amsterdam, the Netherlands
| | - Nanne K de Boer
- Department of Gastroenterology and Hepatology, Amsterdam Gastroenterology Endocrinology Metabolism Research Institute, Amsterdam University Medical Centre, Vrije Universiteit Amsterdam, Amsterdam, the Netherlands
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Wewer MD, Letnar G, Andersen KK, Malham M, Wewer V, Seidelin JB, Bendtsen F, Burisch J. Thiopurines and the Risk of Cancer in Patients With Inflammatory Bowel Disease and Reference Individuals Without Inflammatory Bowel Disease - A Danish Nationwide Cohort Study (1996-2018). Clin Gastroenterol Hepatol 2024:S1542-3565(24)00772-9. [PMID: 39209201 DOI: 10.1016/j.cgh.2024.08.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/27/2024] [Revised: 08/14/2024] [Accepted: 08/15/2024] [Indexed: 09/04/2024]
Abstract
BACKGROUND & AIMS Thiopurine therapy is a cornerstone in the treatment of inflammatory bowel disease (IBD). We aimed to assess the effect of thiopurines on cancer risk in IBD according to drug exposure and age. METHODS Danish national registers were used to identify incident IBD patients, exposure to drugs, and status of cancers, in 1996 to 2018. Cox regressions were used to compare cancer risks in IBD and non-IBD individuals and to assess IBD patients' cumulative drug exposure and the association to first cancer, excluding non-melanoma skin cancer. RESULTS We followed 43,419 patients with IBD for a median of 8.2 years (interquartile range, 3.7-14.2 years) after IBD diagnosis. Cancer was reported in 3128 (7.2%) patients with IBD. The risk of cancer was increased in patients with IBD in all age categories compared with non-IBD individuals (<50 years: adjusted hazard ratio [aHR], 1.59; 95% confidence interval [CI], 1.43-1.77; 50-65 years: aHR, 1.31; 95% CI, 1.19-1.44; and >65 years: aHR, 1.14; 95% CI, 1.05-1.24). Monotherapy (aHR, 1.36; 95% CI, 1.17-1.57) and combination therapy (aHR, 2.49; 95% CI, 1.64-3.78) were associated with an increased risk of cancer compared to unexposed patients with IBD. Among elderly patients (>65 years), the aHR was 2.79 (95% CI, 1.24-6.28) in those receiving combination therapy. In patients discontinuing thiopurines, aHRs returned to the level of unexposed (aHR, 0.89; 95% CI, 0.78-1.01). The aHR was positively associated with cumulative thiopurine exposure and in patients with >5 years of exposure, reaching an aHR of 1.36 (95% CI, 1.15-1.61). CONCLUSIONS Thiopurines were associated with increased hazard of cancer, especially when used in combination therapy in the elderly. The hazard increased by 36% when patients were exposed to thiopurines for more than 5 years. Reassuringly, the hazard returned to baseline after discontinuation of thiopurines.
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Affiliation(s)
- Mads Damsgaard Wewer
- Gastro Unit, Medical Division, Hvidovre Hospital, University of Copenhagen, Hvidovre, Denmark; Copenhagen Center for Inflammatory Bowel Disease in Children, Adolescents and Adults, Hvidovre Hospital, Hvidovre, Denmark.
| | | | | | - Mikkel Malham
- Copenhagen Center for Inflammatory Bowel Disease in Children, Adolescents and Adults, Hvidovre Hospital, Hvidovre, Denmark; The Department of Paediatrics and Adolescent Medicine, Hvidovre Hospital, University of Copenhagen, Hvidovre, Denmark
| | - Vibeke Wewer
- Copenhagen Center for Inflammatory Bowel Disease in Children, Adolescents and Adults, Hvidovre Hospital, Hvidovre, Denmark; The Department of Paediatrics and Adolescent Medicine, Hvidovre Hospital, University of Copenhagen, Hvidovre, Denmark; Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Jakob Benedict Seidelin
- Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark; Department of Gastroenterology, Herlev Hospital, University of Copenhagen, Herlev, Denmark
| | - Flemming Bendtsen
- Gastro Unit, Medical Division, Hvidovre Hospital, University of Copenhagen, Hvidovre, Denmark; Copenhagen Center for Inflammatory Bowel Disease in Children, Adolescents and Adults, Hvidovre Hospital, Hvidovre, Denmark; Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Johan Burisch
- Gastro Unit, Medical Division, Hvidovre Hospital, University of Copenhagen, Hvidovre, Denmark; Copenhagen Center for Inflammatory Bowel Disease in Children, Adolescents and Adults, Hvidovre Hospital, Hvidovre, Denmark; Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
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6
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Gisbert JP, Chaparro M. Common Mistakes in Managing Patients with Inflammatory Bowel Disease. J Clin Med 2024; 13:4795. [PMID: 39200937 PMCID: PMC11355176 DOI: 10.3390/jcm13164795] [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: 08/05/2024] [Revised: 08/12/2024] [Accepted: 08/13/2024] [Indexed: 09/02/2024] Open
Abstract
Introduction: Errors are very common in medical practice and in particular, in the healthcare of patients with inflammatory bowel disease (IBD); however, most of these can be prevented. Aim: To address common errors in the management of IBD. Methods: Our approach to this problem consists in identifying mistakes frequently observed in clinical practice (according to our experience) in the management of patients with IBD, then reviewing the scientific evidence available on the subject, and finally proposing the most appropriate recommendation for each case. Results: The most common mistakes in the management of IBD include those related to diagnosis and differential diagnosis, prevention, nutrition and diet, treatment with different drugs (mainly 5-aminosalicylates, corticosteroids, thiopurines, and anti-TNF agents), extraintestinal manifestations, anemia, elderly patients, pregnancy, and surgery. Conclusions: Despite the availability of guidelines for both disease management and preventive aspects of IBD care, a considerable variation in clinical practice still remains. In this review, we have identified common mistakes in the management of patients with IBD in clinical practice. There is a clear need for a greater dissemination of clinical practice guidelines among gastroenterologists and for the implementation of ongoing training activities supported by scientific societies. Finally, it is desirable to follow IBD patients in specialized units, which would undoubtedly be associated with higher-quality healthcare and a lower likelihood of errors in managing these patients.
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Affiliation(s)
- Javier P. Gisbert
- Gastroenterology Unit, Hospital Universitario de La Princesa, Instituto de Investigación Sanitaria Princesa (IIS-Princesa), Universidad Autónoma de Madrid (UAM), Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), 28006 Madrid, Spain;
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Wang Y, Zhao X, Gao Y, Zhao C, Li J, Wang S, Xue B, Liu C, Ma X. 4-Octyl itaconate alleviates dextran sulfate sodium-induced ulcerative colitis in mice via activating the KEAP1-NRF2 pathway. Inflammopharmacology 2024; 32:2555-2574. [PMID: 38767761 DOI: 10.1007/s10787-024-01490-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2024] [Accepted: 04/23/2024] [Indexed: 05/22/2024]
Abstract
Ulcerative colitis (UC) is a chronic idiopathic inflammatory bowel disease with a relapsing-remitting course. Although its etiology remains unknown, excessive oxidative stress in colon is a major intermediate factor that can promote the progression of UC. In the present study, we investigated the effect and the underlying mechanisms of 4-Octyl itaconate (OI) on dextran sulfate sodium (DSS)-induced UC in mice. Our work identified that OI alleviated the colitis by reducing the oxidative stress and the apoptosis in colon tissue, then increasing the tight junction proteins expression and in turn enhancing the intestinal barrier function, thereby creating less severe inflammatory responses. Moreover, our results demonstrated that OI reduced the Kelch-like ECH-associated protein 1 (KEAP1) expression and subsequent upregulated nuclear factor E2-related factor (NRF2) expression and its nuclear translocation which in turn induced the expression of glutathione S-transferase (GST) and NAD(P)H: quinone oxidoreductase 1 (NQO1). In addition, ML385, a NRF2 antagonist, can inhibit the protective effects of OI on UC, indicating that the role of OI in this colitis model could be dependent on the activation of KEAP1-NRF2 pathway. Notably, OI co-administration significantly enhanced the therapeutic effects of mesalazine or 1400W on UC. Collectively, itaconate may have a great potential for use in the treatment of IBD.
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Affiliation(s)
- Yujin Wang
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Wenhuaxi Road 44#Shandong Province, Jinan, China
| | - Xue Zhao
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Wenhuaxi Road 44#Shandong Province, Jinan, China
| | - Yifei Gao
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Wenhuaxi Road 44#Shandong Province, Jinan, China
| | - Chenxi Zhao
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Wenhuaxi Road 44#Shandong Province, Jinan, China
| | - Jingxin Li
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Wenhuaxi Road 44#Shandong Province, Jinan, China
| | - Shuanglian Wang
- Medical Science and Technology Innovation Center, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, China
| | - Bing Xue
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Wenhuaxi Road 44#Shandong Province, Jinan, China
| | - Chuanyong Liu
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Wenhuaxi Road 44#Shandong Province, Jinan, China
| | - Xuelian Ma
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Wenhuaxi Road 44#Shandong Province, Jinan, China.
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Kucharzik T, Dignass A, Atreya R, Bokemeyer B, Esters P, Herrlinger K, Kannengiesser K, Kienle P, Langhorst J, Lügering A, Schreiber S, Stallmach A, Stein J, Sturm A, Teich N, Siegmund B. Aktualisierte S3-Leitlinie Colitis ulcerosa (Version 6.2). ZEITSCHRIFT FUR GASTROENTEROLOGIE 2024; 62:769-858. [PMID: 38718808 DOI: 10.1055/a-2271-0994] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 07/02/2024]
Affiliation(s)
- T Kucharzik
- Klinik für Allgemeine Innere Medizin und Gastroenterologie, Städtisches Klinikum Lüneburg, Lüneburg, Deutschland
| | - A Dignass
- Medizinische Klinik I, Agaplesion Markus Krankenhaus, Frankfurt, Deutschland
| | - R Atreya
- Medizinische Klinik 1 Gastroent., Pneumologie, Endokrin., Universitätsklinikum Erlangen, Erlangen, Deutschland
| | - B Bokemeyer
- Interdisziplinäres Crohn Colitis Centrum Minden - ICCCM, Minden, Deutschland
| | - P Esters
- Medizinische Klinik I, Agaplesion Markus Krankenhaus, Frankfurt, Deutschland
| | - K Herrlinger
- Innere Medizin I, Asklepios Klinik Nord, Hamburg, Deutschland
| | - K Kannengiesser
- Klinik für Allgemeine Innere Medizin und Gastroenterologie, Städtisches Klinikum Lüneburg, Lüneburg, Deutschland
| | - P Kienle
- Abteilung für Allgemein- und Viszeralchirurgie, Theresienkrankenhaus, Mannheim, Deutschland
| | - J Langhorst
- Klinik für Integrative Medizin und Naturheilkunde, Sozialstiftung Bamberg Klinikum am Bruderwald, Bamberg, Deutschland
| | - A Lügering
- Medizinisches Versorgungszentrum Portal 10, Münster, Deutschland
| | - S Schreiber
- Klinik für Innere Medizin I, Universitätsklinikum Schleswig Holstein, Kiel, Deutschland
| | - A Stallmach
- Klinik für Innere Medizin IV Gastroenterologie, Hepatologie, Infektiologie, Universitätsklinikum Jena, Jena, Deutschland
| | - J Stein
- Abteilung Innere Medizin mit Schwerpunkt Gastroenterologie, Krankenhaus Sachsenhausen, Frankfurt, Deutschland
| | - A Sturm
- Klinik für Innere Medizin mit Schwerpunkt Gastroenterologie, DRK Kliniken Berlin Westend, Berlin, Deutschland
| | - N Teich
- Internistische Gemeinschaftspraxis, Leipzig, Deutschland
| | - B Siegmund
- Medizinische Klinik für Gastroenterologie, Infektiologie und Rheumatologie, Charité Campus Benjamin Franklin - Universitätsmedizin Berlin, Berlin, Deutschland
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9
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Kim YY, Hur G, Jang HJ, Jeong S, Lee SW, Lee SJ, Rho MC, Kim SH, Lee S. Ferulic Acid Derivatives Ameliorate Intestine Barrier Destruction by Alleviating Inflammatory Responses in Dextran Sulfate Sodium-Induced Inflammatory Bowel Disease. TOXICS 2024; 12:268. [PMID: 38668491 PMCID: PMC11055104 DOI: 10.3390/toxics12040268] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/13/2024] [Revised: 03/29/2024] [Accepted: 04/02/2024] [Indexed: 04/29/2024]
Abstract
Inflammatory bowel disease (IBD), a chronic disorder affecting the colon and rectum, involves the overproduction of pro-inflammatory cytokines causing damage to tight junctions (TJ) in the intestinal epithelial cells and chronic inflammation. The current mainstay of treatment, sulfasalazine, often causes adverse effects, thereby necessitating the exploration of alternative herbal medicines with fewer side effects. Portulaca oleracea L. (P. oleracea), a traditional medicinal herb, contains feruloyl amide compounds. We synthesized new compounds by conjugating ferulic acid (FA) with (±)-octopamine. Our study focused on novel FA derivatives that demonstrate protective effects against the intestinal epithelial barrier and inflammatory responses. In lipopolysaccharide-induced cells, C1 and C1a inhibited the production of inflammatory mediators. In Caco-2 cells, these compounds maintained the TJ protein expression, thereby demonstrating their protective effects on the epithelial barrier. In a mouse model of dextran sulfate sodium-induced IBD, a treatment with these compounds ameliorated features including a body weight reduction, colon shortening, an increased disease activity index, and histopathological changes. Furthermore, C1a demonstrated greater efficacy than C1 at the same concentration. These findings suggest that the novel FA derivative (C1a) effectively alleviates clinical signs and inflammatory mediators in IBD, making these compounds potential candidates as natural medicines for the treatment of IBD.
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Affiliation(s)
- Yeon-Yong Kim
- Functional Biomaterials Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Jeongeup 56212, Republic of Korea; (Y.-Y.K.); (G.H.); (S.J.); (S.W.L.); (S.-J.L.); (M.-C.R.)
| | - Gayeong Hur
- Functional Biomaterials Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Jeongeup 56212, Republic of Korea; (Y.-Y.K.); (G.H.); (S.J.); (S.W.L.); (S.-J.L.); (M.-C.R.)
| | - Hyun-Jae Jang
- Natural Product Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Cheongju 28116, Republic of Korea;
| | - Seungwon Jeong
- Functional Biomaterials Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Jeongeup 56212, Republic of Korea; (Y.-Y.K.); (G.H.); (S.J.); (S.W.L.); (S.-J.L.); (M.-C.R.)
| | - Seung Woong Lee
- Functional Biomaterials Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Jeongeup 56212, Republic of Korea; (Y.-Y.K.); (G.H.); (S.J.); (S.W.L.); (S.-J.L.); (M.-C.R.)
| | - Seung-Jae Lee
- Functional Biomaterials Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Jeongeup 56212, Republic of Korea; (Y.-Y.K.); (G.H.); (S.J.); (S.W.L.); (S.-J.L.); (M.-C.R.)
| | - Mun-Chual Rho
- Functional Biomaterials Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Jeongeup 56212, Republic of Korea; (Y.-Y.K.); (G.H.); (S.J.); (S.W.L.); (S.-J.L.); (M.-C.R.)
| | - Sang-Hyun Kim
- Cell and Matrix Research Institute, Department of Pharmacology, School of Medicine, Kyungpook National University, Daegu 41944, Republic of Korea
| | - Soyoung Lee
- Functional Biomaterials Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Jeongeup 56212, Republic of Korea; (Y.-Y.K.); (G.H.); (S.J.); (S.W.L.); (S.-J.L.); (M.-C.R.)
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10
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Ranjan MK, Kumar P, Vuyyuru SK, Kante B, Mundhra SK, Golla R, Virmani S, Sharma R, Sahni P, Das P, Kalaivani M, Upadhyay AD, Makharia G, Kedia S, Ahuja V. Thiopurines Have Sustained Long-term Effectiveness in Patients with Inflammatory Bowel Disease, Which is Independent of Disease Duration at Initiation: A Propensity Score Matched Analysis. J Crohns Colitis 2024; 18:192-203. [PMID: 37584328 DOI: 10.1093/ecco-jcc/jjad135] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/21/2023] [Indexed: 08/17/2023]
Abstract
BACKGROUND AND AIMS Thiopurines are viable option for the treatment of inflammatory bowel disease [IBD] in resource-limited countries. However, data on the effect of disease duration at thiopurines initiation on long-term effectiveness are limited. METHOD We performed a propensity matched analysis of a retrospective cohort of patients with ulcerative colitis [UC] and Crohn's disease [CD]. Patients initiated on thiopurines early in the disease course [≤2 years] were compared with those started late [>2 years]. Effectiveness was defined as no requirement for hospitalisation, anti-tumour necrosis factor [TNF] agents, or surgery, and minimum steroid requirement [≤1 steroid course in 2 years] during follow-up. RESULTS A total of 988 [UC: 720, CD: 268] patients were included (male: 665 [60.8%], median age: 40 [32-51] years, median follow-up: 40 [19-81] months). Overall effectiveness at 5 and 10 years was 79% and 72% in UC, and 69% and 63% in CD, respectively. After propensity score matching, there was no difference in 5- and 10-year effectiveness between early and late thiopurine initiation groups either for UC [81% and 80% vs 82% and 74%; p = 0.92] or CD [76% and 66% vs 72% and 51%, p = 0.32]. Male sex for UC (negative: hazard ratio [HR]: 0.67, 95% confidence interval [CI): 0.45-0.97; p = 0.03), and ileal involvement [positive: HR: 3.03, 95% CI: 1.32-6.71; p = 0.008], steroid-dependent disease [positive: HR: 2.70, 95% CI: 1.26-5.68; p = 0.01] and adverse events [negative: HR: 0.47, 95% CI:0.27-0.80; p = 0.005] for CD were predictors of thiopurine effectiveness. CONCLUSION Thiopurines have sustained long-term effectiveness in both UC and CD. However, early thiopurine initiation had no better effect on long-term disease outcome compared with late initiation.
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Affiliation(s)
- Mukesh Kumar Ranjan
- Department of Gastroenterology and Human Nutrition, All India Institute of Medical Sciences, New Delhi, India
| | - Peeyush Kumar
- Department of Gastroenterology and Human Nutrition, All India Institute of Medical Sciences, New Delhi, India
| | - Sudheer Kumar Vuyyuru
- Department of Gastroenterology and Human Nutrition, All India Institute of Medical Sciences, New Delhi, India
| | - Bhaskar Kante
- Department of Gastroenterology and Human Nutrition, All India Institute of Medical Sciences, New Delhi, India
| | - Sandeep K Mundhra
- Department of Gastroenterology and Human Nutrition, All India Institute of Medical Sciences, New Delhi, India
| | - Rithvik Golla
- Department of Gastroenterology and Human Nutrition, All India Institute of Medical Sciences, New Delhi, India
| | - Shubi Virmani
- Department of Gastroenterology and Human Nutrition, All India Institute of Medical Sciences, New Delhi, India
| | - Raju Sharma
- Department of Radio Diagnosis, All India Institute of Medical Sciences, New Delhi, India
| | - Peush Sahni
- Department of Gastrointestinal Surgery, All India Institute of Medical Sciences, New Delhi, India
| | - Prasenjit Das
- Department of Pathology, All India Institute of Medical Sciences, New Delhi, India
| | - Mani Kalaivani
- Department of Biostatistics, All India Institute of Medical Sciences, New Delhi, India
| | - Ashish Datt Upadhyay
- Department of Biostatistics, All India Institute of Medical Sciences, New Delhi, India
| | - Govind Makharia
- Department of Gastroenterology and Human Nutrition, All India Institute of Medical Sciences, New Delhi, India
| | - Saurabh Kedia
- Department of Gastroenterology and Human Nutrition, All India Institute of Medical Sciences, New Delhi, India
| | - Vineet Ahuja
- Department of Gastroenterology and Human Nutrition, All India Institute of Medical Sciences, New Delhi, India
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11
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Vasudevan A, Con D, De Cruz P, Sparrow MP, Friedman AB, Garg M, Kashkooli S, Gibson PR, van Langenberg DR. Clinical trial: Combination allopurinol-thiopurine versus standard thiopurine in patients with IBD escalating to immunomodulators (the DECIDER study). Aliment Pharmacol Ther 2024; 59:504-514. [PMID: 38095246 DOI: 10.1111/apt.17831] [Citation(s) in RCA: 7] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/11/2023] [Revised: 09/29/2023] [Accepted: 11/29/2023] [Indexed: 01/23/2024]
Abstract
BACKGROUND Thiopurines are established treatments for inflammatory bowel disease (IBD), yet concerns remain regarding their safety. AIM To evaluate the use of thiopurine-allopurinol combination therapy compared to standard thiopurine therapy in IBD. METHODS We performed a multicentre, randomised, placebo-controlled trial to compare the efficacy and safety of thiopurine-allopurinol versus thiopurine with placebo for adults commencing a thiopurine for IBD. Patients had active disease at baseline; dosing of therapy was based on a pre-specified regimen and subsequent metabolites. The primary outcome was the proportion of patients achieving a composite of symptomatic disease activity remission (Harvey Bradshaw Index <5 for Crohn's disease, Simple Clinical Colitis Activity Index <4 for ulcerative colitis) and a faecal calprotectin <150 μg/g after 26 weeks of treatment. RESULTS The trial was terminated early due to slow recruitment. We randomised 102 participants (54 thiopurine-allopurinol, 48 thiopurine with placebo) with similar age (median 42 vs 48 years) and sex distribution (46% women per group). A higher proportion achieved the primary outcome in the thiopurine-allopurinol group (50% vs 35%, p = 0.14) and fewer participants stopped their allocated therapy due to adverse events (11% vs 29%, p = 0.02). Also, within the thiopurine-allopurinol group, thiopurine dose adjustments were less frequent (69% vs 92%, p = 0.03), a higher proportion achieved an early therapeutic 6-TGN level at week 6 (71% vs 53%, p = 0.19), and adverse events attributed to therapy were less frequent (15% vs 44%, p = 0.002). CONCLUSION Thiopurine-allopurinol therapy is safe and mitigates thiopurine adverse effects, thus enhancing tolerability without compromising efficacy (ACTRN12613001347752).
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Affiliation(s)
- Abhinav Vasudevan
- Department of Gastroenterology and Hepatology, Eastern Health, Box Hill, Victoria, Australia
- Monash University, Eastern Health Clinical School, Box Hill, Victoria, Australia
| | - Danny Con
- Department of Gastroenterology, The Austin Hospital, Melbourne, Victoria, Australia
| | - Peter De Cruz
- Department of Gastroenterology, The Austin Hospital, Melbourne, Victoria, Australia
- Department of Medicine, Austin Academic Centre, University of Melbourne, Melbourne, Victoria, Australia
| | - Miles P Sparrow
- Department of Gastroenterology, Central Clinical School, Monash University and Alfred Health, Melbourne, Victoria, Australia
| | - Antony B Friedman
- Department of Gastroenterology, Central Clinical School, Monash University and Alfred Health, Melbourne, Victoria, Australia
| | - Mayur Garg
- Department of Gastroenterology, Northern Health, Epping, Victoria, Australia
- Department of Medicine, Melbourne University, Melbourne, Australia
| | - Soleiman Kashkooli
- Department of Gastroenterology, Northern Health, Epping, Victoria, Australia
| | - Peter R Gibson
- Department of Gastroenterology, Central Clinical School, Monash University and Alfred Health, Melbourne, Victoria, Australia
| | - Daniel R van Langenberg
- Department of Gastroenterology and Hepatology, Eastern Health, Box Hill, Victoria, Australia
- Monash University, Eastern Health Clinical School, Box Hill, Victoria, Australia
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12
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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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13
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Kiyohara H, Yamazaki H, Moriya K, Akimoto N, Kawai S, Takenaka K, Fukuda T, Tominaga K, Umeno J, Shinzaki S, Honzawa Y, Takagi T, Ichikawa H, Endo T, Ozaki R, Andoh A, Matsuoka K, Hibi T, Kobayashi T. White Blood Cell Counts and Future Relapse in Ulcerative Colitis under Low-Dose Thiopurine Treatment in Real-World Practice: A 3-Year Japanese Multi-Center Retrospective Cohort Study. Inflamm Intest Dis 2024; 9:1-10. [PMID: 38298887 PMCID: PMC10830139 DOI: 10.1159/000535889] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/03/2023] [Accepted: 12/15/2023] [Indexed: 02/02/2024] Open
Abstract
Introduction Whether white blood cell (WBC) counts are predictors for the effectiveness of thiopurine treatment in ulcerative colitis (UC) has been inconclusive in previous studies with small sample sizes. We investigated the association between WBC counts and future relapses in UC patients in a large-scale multi-center study. Methods This retrospective cohort study enrolled a total of 723 UC patients in remission from 33 hospitals and followed up for 3 years. Relapse was defined as a need for treatment intensification. The risk of relapse was compared among patients with the baseline WBC counts <3,000/µL (N = 31), 3,000-4,000/µL (N = 167), 4,000-5,000/µL (N = 241), and ≥5,000/µL (N = 284) using a Cox regression model analysis. Moreover, exploratory analyses were conducted to identify other factors predicting relapse. Results During a median follow-up period of 1,095 (interquartile range, 1,032-1,119) days, relapse occurred in 17.2% (125/723). In a crude analysis, WBC counts were not associated with relapse; hazard ratios (HRs) (95% confidence interval [CI]) were 1.50 (0.74-3.06), 1.02 (0.66-1.59), and 0.67 (0.43-1.05) in WBC <3,000/µL, 3,000-4,000/µL, and 4,000-5,000/µL groups, respectively (WBC ≥5,000/µL group, as reference). Multivariable-adjusted analyses showed similar results; HRs (95% CI) were 1.21 (0.59-2.49), 1.08 (0.69-1.69), and 0.69 (0.44-1.07), in <3,000/µL, 3,000-4,000/µL, and 4,000-5,000/µL groups, respectively. In the exploratory analyses, thiopurine use <1 year and a mean corpuscular volume <90 fL were predictors for relapse. Discussion/Conclusion WBC counts were not predictors for future relapses in patients with UC treated with thiopurine as a maintenance therapy.
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Affiliation(s)
- Hiroki Kiyohara
- Center for Advanced IBD Research and Treatment, Kitasato University Kitasato Institute Hospital, Tokyo, Japan
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan
| | - Hajime Yamazaki
- Section of Clinical Epidemiology, Department of Community Medicine, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Kei Moriya
- Department of Gastroenterology and Hepatology, Nara Medical University, Nara, Japan
| | - Naohiko Akimoto
- Department of Gastroenterology, Nippon Medical School, Graduate School of Medicine, Tokyo, Japan
- Department of Gastroenterology, Nippon Medical School Chiba Hokusoh Hospital, Chiba, Japan
| | - Shoichiro Kawai
- Department of Gastroenterology and Hepatology, Osaka General Medical Center, Osaka, Japan
| | - Kento Takenaka
- Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, Tokyo, Japan
| | - Tomohiro Fukuda
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan
| | - Keiichi Tominaga
- Department of Gastroenterology, Dokkyo Medical University, Tochigi, Japan
| | - Junji Umeno
- Department of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Shinichiro Shinzaki
- Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Osaka, Japan
- Department of Gastroenterology, Hyogo Medical University, Hyogo, Japan
| | - Yusuke Honzawa
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Tomohisa Takagi
- Department of Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Hitoshi Ichikawa
- Department of Gastroenterology, Tokai University Hachioji Hospital, Tokyo, Japan
| | - Toshiyuki Endo
- Department of Gastroenterology, Showa University Fujigaoka Hospital, Kanagawa, Japan
| | - Ryo Ozaki
- Department of Gastroenterology and Hepatology, Kyorin University School of Medicine, Tokyo, Japan
| | - Akira Andoh
- Department of Gastroenterology, Shiga University of Medical Science, Shiga, Japan
| | - Katsuyoshi Matsuoka
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Toho University Sakura Medical Center, Chiba, Japan
| | - Toshifumi Hibi
- Center for Advanced IBD Research and Treatment, Kitasato University Kitasato Institute Hospital, Tokyo, Japan
| | - Taku Kobayashi
- Center for Advanced IBD Research and Treatment, Kitasato University Kitasato Institute Hospital, Tokyo, Japan
| | - IBD Terakoya Group
- Center for Advanced IBD Research and Treatment, Kitasato University Kitasato Institute Hospital, Tokyo, Japan
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan
- Section of Clinical Epidemiology, Department of Community Medicine, Graduate School of Medicine, Kyoto University, Kyoto, Japan
- Department of Gastroenterology and Hepatology, Nara Medical University, Nara, Japan
- Department of Gastroenterology, Nippon Medical School, Graduate School of Medicine, Tokyo, Japan
- Department of Gastroenterology, Nippon Medical School Chiba Hokusoh Hospital, Chiba, Japan
- Department of Gastroenterology and Hepatology, Osaka General Medical Center, Osaka, Japan
- Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, Tokyo, Japan
- Department of Gastroenterology, Dokkyo Medical University, Tochigi, Japan
- Department of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
- Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Osaka, Japan
- Department of Gastroenterology, Hyogo Medical University, Hyogo, Japan
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Kyoto University, Kyoto, Japan
- Department of Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine, Kyoto, Japan
- Department of Gastroenterology, Tokai University Hachioji Hospital, Tokyo, Japan
- Department of Gastroenterology, Showa University Fujigaoka Hospital, Kanagawa, Japan
- Department of Gastroenterology and Hepatology, Kyorin University School of Medicine, Tokyo, Japan
- Department of Gastroenterology, Shiga University of Medical Science, Shiga, Japan
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Toho University Sakura Medical Center, Chiba, Japan
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Yewale RV, Ramakrishna BS, Doraisamy BV, Basumani P, Venkataraman J, Jayaraman K, Murali A, Premkumar K, Kumar AS. Long-term safety and effectiveness of azathioprine in the management of inflammatory bowel disease: A real-world experience. JGH Open 2023; 7:599-609. [PMID: 37744710 PMCID: PMC10517446 DOI: 10.1002/jgh3.12955] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2023] [Revised: 06/15/2023] [Accepted: 07/22/2023] [Indexed: 09/26/2023]
Abstract
Background and Aim Azathioprine (AZA) forms the cornerstone for maintenance of sustained remission in inflammatory bowel disease (IBD). There is apprehension regarding the long-term effectiveness and safety of AZA in IBD. We present our experience with AZA use and outcomes in a cohort of IBD patients followed up over a long period of time. Methods Records of 507 IBD patients under treatment at a single, tertiary care center in south India between 2013 and 2022 were evaluated retrospectively. Long-term compliance, tolerance, clinical outcome at the point of last follow-up, type and duration to the onset of adverse events, and subsequent amendment to treatment with regard to AZA were analyzed. Results Of 507 patients with IBD, 320 patients (207 Crohn's disease [CD], 113 ulcerative colitis [UC]) who received AZA were included. The median follow-up was 41 months (interquartile range 15.5-77.5). Total duration of exposure was 1359 patient-years with median usage of 33 months. Of the patients, 26.9% received AZA for >5 years. Mean initiation and maximum doses of AZA were 0.97 and 1.72 mg/kg/day. Among the participants, 20.6% experienced side effects, including myelotoxicity (7.2%) and gastrointestinal intolerance (5.6%). Six patients developed malignancy. Among the side effects, 39.4% of side effects were dose-dependent. Among the patients, 38.1% had relapses requiring pulse corticosteroid therapy, and 16.2% had more than one relapse after commencement of AZA. AZA was continued till the last follow-up in 76.5%. Among the patients, 49.7% (UC 51.3, CD 48.8) attained durable remission without biologics, and 5.3% continued to have active disease. Conclusion AZA is safe and effective in the long-term in IBD. Effectiveness, tolerance, and compliance with AZA are well sustained beyond 5 years of usage and comparable between UC and CD.
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Affiliation(s)
- Rohan V Yewale
- Institute of Gastroenterology, SRM Institutes for Medical ScienceChennaiTamil NaduIndia
| | | | - Babu Vinish Doraisamy
- Institute of Gastroenterology, SRM Institutes for Medical ScienceChennaiTamil NaduIndia
| | - Pandurangan Basumani
- Department of GastroenterologyApollo Hospitals Greams RoadChennaiTamil NaduIndia
| | - Jayanthi Venkataraman
- Department of HepatologySri Ramachandra Institute of Higher Education and ResearchChennaiTamil NaduIndia
| | - Kayalvizhi Jayaraman
- Institute of Gastroenterology, SRM Institutes for Medical ScienceChennaiTamil NaduIndia
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15
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Yan Y, Wang Z, Zhou YL, Gao Z, Ning L, Zhao Y, Xuan B, Ma Y, Tong T, Huang X, Hu M, Fang JY, Cui Z, Chen H, Hong J. Commensal bacteria promote azathioprine therapy failure in inflammatory bowel disease via decreasing 6-mercaptopurine bioavailability. Cell Rep Med 2023; 4:101153. [PMID: 37586320 PMCID: PMC10439275 DOI: 10.1016/j.xcrm.2023.101153] [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: 11/28/2022] [Revised: 06/07/2023] [Accepted: 07/18/2023] [Indexed: 08/18/2023]
Abstract
Azathioprine (AZA) therapy failure, though not the primary cause, contributes to disease relapse and progression in inflammatory bowel disease (IBD). However, the role of gut microbiota in AZA therapy failure remains poorly understood. We found a high prevalence of Blautia wexlerae in patients with IBD with AZA therapy failure, associated with shorter disease flare survival time. Colonization of B. wexlerae increased inflammatory macrophages and compromised AZA's therapeutic efficacy in mice with intestinal colitis. B. wexlerae colonization reduced 6-mercaptopurine (6-MP) bioavailability by enhancing selenium-dependent xanthine dehydrogenase (sd-XDH) activity. The enzyme sd-XDH converts 6-MP into its inactive metabolite, 6-thioxanthine (6-TX), thereby impairing its ability to inhibit inflammation in mice. Supplementation with Bacillus (B.) subtilis enriched in hypoxanthine phosphoribosyltransferase (HPRT) effectively mitigated B. wexlerae-induced AZA treatment failure in mice with intestinal colitis. These findings emphasize the need for tailored management strategies based on B. wexlerae levels in patients with IBD.
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Affiliation(s)
- Yuqing Yan
- State Key Laboratory for Oncogenes and Related Genes, NHC Key Laboratory of Digestive Diseases, Division of Gastroenterology and Hepatology, Shanghai Institute of Digestive Disease, Shanghai Cancer Institute, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, 145 Middle Shandong Road, Shanghai 200001, China
| | - Zhenhua Wang
- State Key Laboratory for Oncogenes and Related Genes, NHC Key Laboratory of Digestive Diseases, Division of Gastroenterology and Hepatology, Shanghai Institute of Digestive Disease, Shanghai Cancer Institute, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, 145 Middle Shandong Road, Shanghai 200001, China
| | - Yi-Lu Zhou
- State Key Laboratory for Oncogenes and Related Genes, NHC Key Laboratory of Digestive Diseases, Division of Gastroenterology and Hepatology, Shanghai Institute of Digestive Disease, Shanghai Cancer Institute, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, 145 Middle Shandong Road, Shanghai 200001, China
| | - Ziyun Gao
- State Key Laboratory for Oncogenes and Related Genes, NHC Key Laboratory of Digestive Diseases, Division of Gastroenterology and Hepatology, Shanghai Institute of Digestive Disease, Shanghai Cancer Institute, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, 145 Middle Shandong Road, Shanghai 200001, China
| | - Lijun Ning
- State Key Laboratory for Oncogenes and Related Genes, NHC Key Laboratory of Digestive Diseases, Division of Gastroenterology and Hepatology, Shanghai Institute of Digestive Disease, Shanghai Cancer Institute, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, 145 Middle Shandong Road, Shanghai 200001, China
| | - Ying Zhao
- State Key Laboratory for Oncogenes and Related Genes, NHC Key Laboratory of Digestive Diseases, Division of Gastroenterology and Hepatology, Shanghai Institute of Digestive Disease, Shanghai Cancer Institute, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, 145 Middle Shandong Road, Shanghai 200001, China
| | - Baoqin Xuan
- State Key Laboratory for Oncogenes and Related Genes, NHC Key Laboratory of Digestive Diseases, Division of Gastroenterology and Hepatology, Shanghai Institute of Digestive Disease, Shanghai Cancer Institute, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, 145 Middle Shandong Road, Shanghai 200001, China
| | - Yanru Ma
- State Key Laboratory for Oncogenes and Related Genes, NHC Key Laboratory of Digestive Diseases, Division of Gastroenterology and Hepatology, Shanghai Institute of Digestive Disease, Shanghai Cancer Institute, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, 145 Middle Shandong Road, Shanghai 200001, China
| | - Tianying Tong
- State Key Laboratory for Oncogenes and Related Genes, NHC Key Laboratory of Digestive Diseases, Division of Gastroenterology and Hepatology, Shanghai Institute of Digestive Disease, Shanghai Cancer Institute, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, 145 Middle Shandong Road, Shanghai 200001, China
| | - Xiaowen Huang
- State Key Laboratory for Oncogenes and Related Genes, NHC Key Laboratory of Digestive Diseases, Division of Gastroenterology and Hepatology, Shanghai Institute of Digestive Disease, Shanghai Cancer Institute, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, 145 Middle Shandong Road, Shanghai 200001, China
| | - Muni Hu
- State Key Laboratory for Oncogenes and Related Genes, NHC Key Laboratory of Digestive Diseases, Division of Gastroenterology and Hepatology, Shanghai Institute of Digestive Disease, Shanghai Cancer Institute, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, 145 Middle Shandong Road, Shanghai 200001, China
| | - Jing-Yuan Fang
- State Key Laboratory for Oncogenes and Related Genes, NHC Key Laboratory of Digestive Diseases, Division of Gastroenterology and Hepatology, Shanghai Institute of Digestive Disease, Shanghai Cancer Institute, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, 145 Middle Shandong Road, Shanghai 200001, China
| | - Zhe Cui
- Department of Gastrointestinal Surgery, Renji Hospital, Shanghai Jiao Tong University School of Medicine, 145 Middle Shandong Road, Shanghai 200001, China.
| | - Haoyan Chen
- State Key Laboratory for Oncogenes and Related Genes, NHC Key Laboratory of Digestive Diseases, Division of Gastroenterology and Hepatology, Shanghai Institute of Digestive Disease, Shanghai Cancer Institute, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, 145 Middle Shandong Road, Shanghai 200001, China.
| | - Jie Hong
- State Key Laboratory for Oncogenes and Related Genes, NHC Key Laboratory of Digestive Diseases, Division of Gastroenterology and Hepatology, Shanghai Institute of Digestive Disease, Shanghai Cancer Institute, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, 145 Middle Shandong Road, Shanghai 200001, China.
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16
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Kucharzik T, Dignass A, Atreya R, Bokemeyer B, Esters P, Herrlinger K, Kannengiesser K, Kienle P, Langhorst J, Lügering A, Schreiber S, Stallmach A, Stein J, Sturm A, Teich N, Siegmund B. Aktualisierte S3-Leitlinie Colitis ulcerosa (Version 6.1) – Februar 2023 – AWMF-Registriernummer: 021-009. ZEITSCHRIFT FUR GASTROENTEROLOGIE 2023; 61:1046-1134. [PMID: 37579791 DOI: 10.1055/a-2060-0935] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 08/16/2023]
Affiliation(s)
- T Kucharzik
- Klinik für Allgemeine Innere Medizin und Gastroenterologie, Städtisches Klinikum Lüneburg, Lüneburg, Deutschland
| | - A Dignass
- Medizinische Klinik I, Agaplesion Markus Krankenhaus, Frankfurt, Deutschland
| | - R Atreya
- Medizinische Klinik 1 Gastroent., Pneumologie, Endokrin., Universitätsklinikum Erlangen, Erlangen, Deutschland
| | - B Bokemeyer
- Interdisziplinäres Crohn Colitis Centrum Minden - ICCCM, Minden, Deutschland
| | - P Esters
- Medizinische Klinik I, Agaplesion Markus Krankenhaus, Frankfurt, Deutschland
| | - K Herrlinger
- Innere Medizin I, Asklepios Klinik Nord, Hamburg, Deutschland
| | - K Kannengiesser
- Klinik für Allgemeine Innere Medizin und Gastroenterologie, Städtisches Klinikum Lüneburg, Lüneburg, Deutschland
| | - P Kienle
- Abteilung für Allgemein- und Viszeralchirurgie, Theresienkrankenhaus, Mannheim, Deutschland
| | - J Langhorst
- Klinik für Integrative Medizin und Naturheilkunde, Sozialstiftung Bamberg Klinikum am Bruderwald, Bamberg, Deutschland
| | - A Lügering
- Medizinisches Versorgungszentrum Portal 10, Münster, Deutschland
| | - S Schreiber
- Klinik für Innere Medizin I, Universitätsklinikum Schleswig Holstein, Kiel, Deutschland
| | - A Stallmach
- Klinik für Innere Medizin IV Gastroenterologie, Hepatologie, Infektiologie, Universitätsklinikum Jena, Jena, Deutschland
| | - J Stein
- Abteilung Innere Medizin mit Schwerpunkt Gastroenterologie, Krankenhaus Sachsenhausen, Frankfurt, Deutschland
| | - A Sturm
- Klinik für Innere Medizin mit Schwerpunkt Gastroenterologie, DRK Kliniken Berlin Westend, Berlin, Deutschland
| | - N Teich
- Internistische Gemeinschaftspraxis, Leipzig, Deutschland
| | - B Siegmund
- Medizinische Klinik für Gastroenterologie, Infektiologie und Rheumatologie, Charité Campus Benjamin Franklin - Universitätsmedizin Berlin, Berlin, Deutschland
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Yamashita N, Kawahara M, Imai T, Tatsumi G, Asai-Nishishita A, Andoh A. Loss of Nudt15 thiopurine detoxification increases direct DNA damage in hematopoietic stem cells. Sci Rep 2023; 13:11908. [PMID: 37488179 PMCID: PMC10366091 DOI: 10.1038/s41598-023-38952-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2022] [Accepted: 07/18/2023] [Indexed: 07/26/2023] Open
Abstract
Thiopurines, such as 6-mercaptopurine (6-MP), are widely used as cytotoxic agents and immunosuppressants for leukemia and autoimmune or inflammatory diseases. A nonsynonymous single nucleotide polymorphism (p.Arg139Cys; R139C) of the nucleoside diphosphate-linked moiety X-type motif 15 (NUDT15) gene causes the loss of thiopurine detoxification, inducing myelosuppression. To understand such hematotoxicity, we investigate the effects of NUDT15 R139C on hematopoietic stem cells (HSCs) upon thiopurine administration. Using previously established Nudt15R138C knock-in mice, which mimic myelosuppression in NUDT15R139C homozygous or heterozygous patients following thiopurine administration, we investigated the numerical changes of HSCs and hematopoietic progenitor cells following 6-MP administration using in vivo flowcytometry and ex vivo HSC expansion. Genes differentially expressed between Nudt15+/+ HSCs and Nudt15R138C/R138C HSCs were identified using RNA-sequencing before the emergence of 6-MP-induced HSC-damage. Gene Ontology (GO) and Transcriptional Regulatory Relationships Unraveled by Sentence-based Text Mining (TRRUST) analyses were performed to elucidate the molecular effects of 6-MP on HSCs. In Nudt15R138C/R138C mice, 6-MP induced exhaustion of HSCs faster than that of multipotent progenitors and as fast as that of myeloid-committed progenitors. Ex vivo-expanded Nudt15R138C/R138C HSCs were dose- and time-dependently damaged by 6-MP. GO analysis identified the DNA damage response and cell cycle process as the most strongly influenced processes in Nudt15R138C/R138C HSCs. TRRUST analysis revealed that the Trp53-regulated transcriptional regulatory network is influenced prior to HSC exhaustion in Nudt15R138C/R138C HSCs. The loss of NUDT15 thiopurine detoxification enhances thiopurine-mediated DNA damage via the Trp53 networks in HSCs. Therefore, caution is required in long-term thiopurine use in patients with NUDT15 R139C in view of its adverse effects on HSCs in the form of DNA damage.
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Affiliation(s)
- Noriaki Yamashita
- Division of Gastroenterology and Hematology, Department of Medicine, Shiga University of Medical Science, Seta-Tsukinowa, Otsu, Shiga, 520-2192, Japan
| | - Masahiro Kawahara
- Division of Gastroenterology and Hematology, Department of Medicine, Shiga University of Medical Science, Seta-Tsukinowa, Otsu, Shiga, 520-2192, Japan.
| | - Takayuki Imai
- Division of Gastroenterology and Hematology, Department of Medicine, Shiga University of Medical Science, Seta-Tsukinowa, Otsu, Shiga, 520-2192, Japan
| | - Goichi Tatsumi
- Division of Gastroenterology and Hematology, Department of Medicine, Shiga University of Medical Science, Seta-Tsukinowa, Otsu, Shiga, 520-2192, Japan
| | - Ai Asai-Nishishita
- Division of Gastroenterology and Hematology, Department of Medicine, Shiga University of Medical Science, Seta-Tsukinowa, Otsu, Shiga, 520-2192, Japan
| | - Akira Andoh
- Division of Gastroenterology and Hematology, Department of Medicine, Shiga University of Medical Science, Seta-Tsukinowa, Otsu, Shiga, 520-2192, Japan
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18
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Park J, Wu Y, Li Q, Choi J, Ju H, Cai Y, Lee J, Oh YK. Nanomaterials for antigen-specific immune tolerance therapy. Drug Deliv Transl Res 2023; 13:1859-1881. [PMID: 36094655 DOI: 10.1007/s13346-022-01233-3] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/25/2022] [Indexed: 11/26/2022]
Abstract
Impairment of immune tolerance might cause autologous tissue damage or overactive immune response against non-pathogenic molecules. Although autoimmune disease and allergy have complicated pathologies, the current strategies have mainly focused on symptom amelioration or systemic immunosuppression which can lead to fatal adverse events. The induction of antigen-specific immune tolerance may provide therapeutic benefits to autoimmune disease and allergic response, while reducing nonspecific immune adverse responses. Diverse nanomaterials have been studied to induce antigen-specific immune tolerance therapy. This review will cover the immunological background of antigen-specific tolerance, clinical importance of antigen-specific immune tolerance, and nanomaterials designed for autoimmune and allergic diseases. As nanomaterials for modulating immune tolerances, lipid-based nanoparticles, polymeric nanoparticles, and biological carriers have been covered. Strategies to provide antigen-specific immune tolerance have been addressed. Finally, current challenges and perspectives of nanomaterials for antigen-specific immune tolerance therapy will be discussed.
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Affiliation(s)
- Jinwon Park
- College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, 08826, Republic of Korea
| | - Yina Wu
- College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, 08826, Republic of Korea
| | - Qiaoyun Li
- College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, 08826, Republic of Korea
| | - Jaehyun Choi
- College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, 08826, Republic of Korea
| | - Hyemin Ju
- College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, 08826, Republic of Korea
| | - Yu Cai
- College of Pharmacy, Jinan University, Guangzhou, 510632, China
| | - Jaiwoo Lee
- College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, 08826, Republic of Korea
| | - Yu-Kyoung Oh
- College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, 08826, Republic of Korea.
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Li P, Chao K, Hu Z, Qin L, Yang T, Mao J, Zhu X, Hu P, Wang X, Gao X, Huang M. Plasma lipidomic profiling of thiopurine-induced leukopenia after NUDT15 genotype-guided dosing in Chinese IBD patients. Front Nutr 2023; 10:1138506. [PMID: 37441519 PMCID: PMC10333543 DOI: 10.3389/fnut.2023.1138506] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2023] [Accepted: 05/10/2023] [Indexed: 07/15/2023] Open
Abstract
Introduction Thiopurines, azathiopurine (AZA) and mercaptopurine (6-MP) have been regularly used in the treatment of inflammatory bowel disease (IBD). Despite optimized dosage adjustment based on the NUDT15 genotypes, some patients still discontinue or change treatment regimens due to thiopurine-induced leukopenia. Methods We proposed a prospective observational study of lipidomics to reveal the lipids perturbations associated with thiopurine-induced leukopenia. One hundred and twenty-seven IBD participants treated with thiopurine were enrolled, twenty-seven of which have developed thiopurine-induced leucopenia. Plasma lipid profiles were measured using Ultra-High-Performance Liquid Chromatography-Tandem Q-Exactive. Lipidomic alterations were validated with an independent validation cohort (leukopenia n = 26, non-leukopenia n = 74). Results Using univariate and multivariate analysis, there were 16 lipid species from four lipid classes, triglyceride (n = 11), sphingomyelin (n = 1), phosphatidylcholine (n = 1) and lactosylceramide (n = 3) identified. Based on machine learning feature reduction and variable screening strategies, the random forest algorithm established by six lipids showed an excellent performance to distinguish the leukopenia group from the normal group, with a model accuracy of 95.28% (discovery cohort), 79.00% (validation cohort) and an area under the receiver operating characteristic (ROC) curve (ROC-AUC) of 0.9989 (discovery cohort), 0.8098 (validation cohort). Discussion Our novel findings suggested that lipidomic provided unique insights into formulating individualized medication strategies for thiopurines in IBD patients.
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Affiliation(s)
- Pan Li
- Guangdong Provincial Key Laboratory of New Drug Design and Evaluation, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, China
| | - Kang Chao
- Department of Gastroenterology, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
- Guangdong Institute of Gastroenterology, Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, Supported by National Key Clinical Discipline, Guangzhou, China
| | - Zhanhua Hu
- Guangdong Provincial Key Laboratory of New Drug Design and Evaluation, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, China
| | - Lulu Qin
- School of Pharmaceutical Sciences, Guangdong Pharmaceutical University, Guangzhou, China
| | - Ting Yang
- Guangdong Provincial Key Laboratory of New Drug Design and Evaluation, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, China
| | - Jing Mao
- Guangdong Provincial Key Laboratory of New Drug Design and Evaluation, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, China
| | - Xia Zhu
- Guangdong Provincial Key Laboratory of New Drug Design and Evaluation, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, China
- Department of Gastroenterology, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
- Guangdong Institute of Gastroenterology, Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, Supported by National Key Clinical Discipline, Guangzhou, China
| | - Pinjin Hu
- Department of Gastroenterology, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
- Guangdong Institute of Gastroenterology, Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, Supported by National Key Clinical Discipline, Guangzhou, China
| | - Xueding Wang
- Guangdong Provincial Key Laboratory of New Drug Design and Evaluation, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, China
| | - Xiang Gao
- Department of Gastroenterology, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
- Guangdong Institute of Gastroenterology, Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, Supported by National Key Clinical Discipline, Guangzhou, China
| | - Min Huang
- Guangdong Provincial Key Laboratory of New Drug Design and Evaluation, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, China
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20
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Jansen FM, Smits LJT, Thomas PWA, de Jong DJ, Kreijne JE, van Dop WA, den Broeder N, Hoentjen F. Feasibility of Reduced Clinical Monitoring in Patients with Inflammatory Bowel Disease Treated with Thiopurine Therapy. Dig Dis Sci 2023:10.1007/s10620-023-07950-0. [PMID: 37131100 DOI: 10.1007/s10620-023-07950-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/16/2022] [Accepted: 04/06/2023] [Indexed: 05/04/2023]
Abstract
BACKGROUND Outpatient visits and laboratory assessments are routinely scheduled every 3 to 4 months in thiopurine-treated patients with inflammatory bowel disease (IBD) to timely detect thiopurine-related adverse events (AEs). AEs that require therapy adjustment beyond 12 months of treatment are rare. AIM AND METHODS This single-center prospective cohort study evaluated the safety of a reduced 6-monthly monitoring strategy in steroid-free patients with quiescent IBD on stable dose of azathioprine, mercaptopurine, or thioguanine monotherapy. The primary outcome was thiopurine-related AEs requiring therapy adjustments during a follow-up period of 24 months. Secondary outcomes included all AEs including laboratory toxicity, disease flares until 12 months, and the net monetary benefit from this strategy concerning IBD-related health care use. RESULTS We enrolled 85 patients with IBD (median age 42 years, 61% Crohn's disease, 62% female), with a median disease duration of 12.5 years and median thiopurine treatment duration of 6.7 years. During follow-up, 3 patients (4%) ceased thiopurines due to AEs: recurrent infections, non-melanoma skin cancer, and gastrointestinal complaints (nausea, vomiting). At 12 months, 25 laboratory toxicities were observed (including 13% myelotoxicity, 17% hepatotoxicity); none required therapy adjustments and all were transient. A reduced monitoring strategy had a net benefit of €136 per patient. CONCLUSION Three patients (4%) ceased thiopurine therapy due to thiopurine-related AEs, while no laboratory toxicity required therapy adjustments. Monitoring frequency of every 6 months seems feasible in patients with stable IBD on long-term (median duration > 6 years) maintenance thiopurine therapy and may contribute to reduced patient-burden and health care costs.
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Affiliation(s)
- Fenna M Jansen
- Department of Gastroenterology and Hepatology, Radboud University Medical Center, Nijmegen, The Netherlands.
| | - Lisa J T Smits
- Department of Gastroenterology and Hepatology, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Pepijn W A Thomas
- Department of Gastroenterology and Hepatology, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Dirk J de Jong
- Department of Gastroenterology and Hepatology, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Joany E Kreijne
- Department of Gastroenterology and Hepatology, Erasmus University Medical Center, Rotterdam, The Netherlands
| | - Willemijn A van Dop
- Department of Gastroenterology and Hepatology, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Nathan den Broeder
- Department of Gastroenterology and Hepatology, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Frank Hoentjen
- Department of Gastroenterology and Hepatology, Radboud University Medical Center, Nijmegen, The Netherlands
- Division of Gastroenterology, Department of Medicine, University of Alberta, Edmonton, Canada
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21
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Orfanoudaki E, Foteinogiannopoulou K, Theodoraki E, Koutroubakis IE. Recent Advances in the Optimization of Anti-TNF Treatment in Patients with Inflammatory Bowel Disease. J Clin Med 2023; 12:jcm12072452. [PMID: 37048536 PMCID: PMC10095227 DOI: 10.3390/jcm12072452] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2023] [Revised: 03/11/2023] [Accepted: 03/16/2023] [Indexed: 04/14/2023] Open
Abstract
Despite the evolution in inflammatory bowel disease (IBD) management during the last 20 years owing to the advent of new advanced therapies, anti-TNF agents still remain the cornerstone of therapy for both Crohn's disease and ulcerative colitis. However, this does not only secure favorable outcomes for patients considering the progressive disease character and the high likelihood of primary or secondary loss of response. Therefore, trying to reach a better treatment approach and maximize the benefits anti-TNF agents offer, optimization strategies should be examined. It has been indicated that optimizing treatment with anti-TNF enhances drug efficacy and has been associated with improved disease outcomes and a complication-free disease course. From this perspective, we aim to provide an overview of currently available data and recent advances in the practices of anti-TNF treatment optimization. Special focus has been given to the role of therapeutic drug monitoring (TDM), as well as the utility of combining anti-TNF with an immunomodulator and the treat-to-target approach.
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Affiliation(s)
- Eleni Orfanoudaki
- Department of Gastroenterology, University Hospital of Heraklion, Medical School, University of Crete, 71003 Heraklion, Greece
| | - Kalliopi Foteinogiannopoulou
- Department of Gastroenterology, University Hospital of Heraklion, Medical School, University of Crete, 71003 Heraklion, Greece
| | - Eirini Theodoraki
- Department of Gastroenterology, University Hospital of Heraklion, Medical School, University of Crete, 71003 Heraklion, Greece
| | - Ioannis E Koutroubakis
- Department of Gastroenterology, University Hospital of Heraklion, Medical School, University of Crete, 71003 Heraklion, Greece
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22
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Tešanović Perković D, Bukvić Mokos Z, Marinović B. Epidermolysis Bullosa Acquisita-Current and Emerging Treatments. J Clin Med 2023; 12:jcm12031139. [PMID: 36769788 PMCID: PMC9917799 DOI: 10.3390/jcm12031139] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2022] [Revised: 01/10/2023] [Accepted: 01/26/2023] [Indexed: 02/04/2023] Open
Abstract
Epidermolysis bullosa acquisita (EBA) is a rare chronic autoimmune subepidermal blistering disease of the skin and mucous membranes, usually beginning in adulthood. EBA is induced by autoantibodies to type VII collagen, a major component of anchoring fibrils in the dermal-epidermal junction (DEJ). The binding of autoantibodies to type-VII collagen subsequently leads to the detachment of the epidermis and the formation of mucocutaneous blisters. EBA has two major clinical subtypes: the mechanobullous and inflammatory variants. The classic mechanobullous variant presentation consists of skin fragility, bullae with minimal clinical or histological inflammation, erosions in acral distribution that heal with scarring, and milia formation. The inflammatory variant is challenging to differentiate from other autoimmune bullous diseases, most commonly bullous pemphigoid (BP) but also mucous membrane pemphigoid (MMP), Brunsting-Perry pemphigoid, and linear IgA dermatosis. Due to its recalcitrance conventional treatment of epidermolysis bullosa acquisita is shown to be demanding. Here we discuss novel therapeutic strategies that have emerged and which could potentially improve the quality of life in patients with EBA.
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Affiliation(s)
| | - Zrinka Bukvić Mokos
- Department of Dermatology and Venereology, School of Medicine, University Hospital Centre Zagreb, University of Zagreb, Kišpatićeva 12, 10000 Zagreb, Croatia
| | - Branka Marinović
- Department of Dermatology and Venereology, School of Medicine, University Hospital Centre Zagreb, University of Zagreb, Kišpatićeva 12, 10000 Zagreb, Croatia
- Correspondence:
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23
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Swanson GR, Biglin M, Raff H, Chouhan V, Jochum S, Shaikh M, Francey L, Bishehsari F, Hogenesch J, Keshavarzian A. Impact of Chronotherapy on 6-Mercaptopurine Metabolites in Inflammatory Bowel Disease: A Pilot Crossover Trial. Clin Transl Gastroenterol 2023; 14:e00549. [PMID: 36730289 PMCID: PMC9945554 DOI: 10.14309/ctg.0000000000000549] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/02/2022] [Accepted: 11/01/2022] [Indexed: 02/03/2023] Open
Abstract
INTRODUCTION Chronotherapy is the timing of medication according to biological rhythms of the host to optimize drug efficacy and minimize toxicity. Efficacy and myelosuppression of azathioprine/6-mercaptopurine (AZA/6-MP) are correlated with the metabolite 6-thioguanine, while the metabolite 6-methylmercaptopurine correlates with hepatotoxicity. METHODS This was a single-center, 10-week prospective crossover trial involving 26 participants with inactive inflammatory bowel disease (IBD) on a stable dose and time of AZA or 6-MP therapy. Participants were switched to the opposite delivery time (morning or evening) for 10 weeks, and metabolite measurements were at both time points. RESULTS In the morning vs evening dosing, 6-thioguanine levels were 225.7 ± 155.1 vs 175.0 ± 106.9 ( P < 0.01), and 6-methylmercaptopurine levels were 825.1 ± 1,023.3 vs 2,395.3 ± 2,880.3 ( P < 0.01), with 69% (18 out of 26) of participants had better metabolite profiles in the morning. Participants with optimal dosing in the morning had an earlier chronotype by corrected midpoint of sleep. DISCUSSION In the first study on a potential role of chronotherapy in IBD, we found (i) morning dosing of AZA or 6-MP resulted in more optimal metabolite profiles and (ii) host chronotype could help identify one-third of patients who would benefit from evening dosing. Circadian regulation of metabolic enzymes of AZA/6-MP activity in the liver is the likely cause of these differences. This pilot study confirms the need to incorporate chronotherapy in future multicenter clinical trials on IBD disease.
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Affiliation(s)
- Garth R. Swanson
- Center for Integrated Microbiome and Chronobiology Research, Rush University Medical Center, Chicago, Illinois, USA
- Rush University Medical Center, Department of Internal Medicine, Section of Digestive Diseases, Chicago, Illinois, USA;
| | - Mary Biglin
- Center for Integrated Microbiome and Chronobiology Research, Rush University Medical Center, Chicago, Illinois, USA
| | - Hannah Raff
- Center for Integrated Microbiome and Chronobiology Research, Rush University Medical Center, Chicago, Illinois, USA
| | - Vijit Chouhan
- Center for Integrated Microbiome and Chronobiology Research, Rush University Medical Center, Chicago, Illinois, USA
| | - Sarah Jochum
- Center for Integrated Microbiome and Chronobiology Research, Rush University Medical Center, Chicago, Illinois, USA
| | - Maliha Shaikh
- Center for Integrated Microbiome and Chronobiology Research, Rush University Medical Center, Chicago, Illinois, USA
- Rush University Medical Center, Department of Internal Medicine, Section of Digestive Diseases, Chicago, Illinois, USA;
| | - Lauren Francey
- Divisions of Human Genetics and Immunobiology, Center for Circadian Medicine, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.
| | - Faraz Bishehsari
- Center for Integrated Microbiome and Chronobiology Research, Rush University Medical Center, Chicago, Illinois, USA
- Rush University Medical Center, Department of Internal Medicine, Section of Digestive Diseases, Chicago, Illinois, USA;
| | - John Hogenesch
- Divisions of Human Genetics and Immunobiology, Center for Circadian Medicine, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.
| | - Ali Keshavarzian
- Center for Integrated Microbiome and Chronobiology Research, Rush University Medical Center, Chicago, Illinois, USA
- Rush University Medical Center, Department of Internal Medicine, Section of Digestive Diseases, Chicago, Illinois, USA;
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24
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Dailey J, Hyams JS. Natural History of Ulcerative Colitis in Children. PEDIATRIC INFLAMMATORY BOWEL DISEASE 2023:103-111. [DOI: 10.1007/978-3-031-14744-9_8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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25
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Vieujean S, Louis E. Precision medicine and drug optimization in adult inflammatory bowel disease patients. Therap Adv Gastroenterol 2023; 16:17562848231173331. [PMID: 37197397 PMCID: PMC10184262 DOI: 10.1177/17562848231173331] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/23/2022] [Accepted: 04/16/2023] [Indexed: 05/19/2023] Open
Abstract
Inflammatory bowel diseases (IBD) encompass two main entities including ulcerative colitis and Crohn's disease. Although having a common global pathophysiological mechanism, IBD patients are characterized by a significant interindividual heterogeneity and may differ by their disease type, disease locations, disease behaviours, disease manifestations, disease course as well as treatment needs. Indeed, although the therapeutic armamentarium for these diseases has expanded rapidly in recent years, a proportion of patients remains with a suboptimal response to medical treatment due to primary non-response, secondary loss of response or intolerance to currently available drugs. Identifying, prior to treatment initiation, which patients are likely to respond to a specific drug would improve the disease management, avoid unnecessary side effects and reduce the healthcare expenses. Precision medicine classifies individuals into subpopulations according to clinical and molecular characteristics with the objective to tailor preventative and therapeutic interventions to the characteristics of each patient. Interventions would thus be performed only on those who will benefit, sparing side effects and expense for those who will not. This review aims to summarize clinical factors, biomarkers (genetic, transcriptomic, proteomic, metabolic, radiomic or from the microbiota) and tools that could predict disease progression to guide towards a step-up or top-down strategy. Predictive factors of response or non-response to treatment will then be reviewed, followed by a discussion about the optimal dose of drug required for patients. The time at which these treatments should be administered (or rather can be stopped in case of a deep remission or in the aftermath of a surgery) will also be addressed. IBD remain biologically complex, with multifactorial etiopathology, clinical heterogeneity as well as temporal and therapeutic variabilities, which makes precision medicine especially challenging in this area. Although applied for many years in oncology, it remains an unmet medical need in IBD.
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Affiliation(s)
- Sophie Vieujean
- Hepato-Gastroenterology and Digestive Oncology, University Hospital CHU of Liège, Liège, Belgium
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26
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Yao J, Fekadu G, Ng SC, You JHS. Fecal microbiota transplantation for patients with active ulcerative colitis: A cost-effectiveness analysis. J Gastroenterol Hepatol 2023; 38:70-78. [PMID: 36181412 DOI: 10.1111/jgh.16015] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/14/2022] [Revised: 09/02/2022] [Accepted: 09/26/2022] [Indexed: 01/18/2023]
Abstract
BACKGROUND AND AIM Growing studies have demonstrated clinical benefits of fecal microbiota transplantation (FMT) therapy (administered by colonoscopy, enema, or both) for active ulcerative colitis (UC). This study aimed to evaluate the cost-effectiveness of standard treatment with and without FMT therapy for mild-to-moderate active UC from the perspective of US healthcare provider. METHODS A 10-year Markov model was developed to evaluate the costs and quality-adjusted life-years (QALYs) of standard treatment plus FMT therapy versus standard treatment alone. Model inputs were retrieved from publish data in literature. Base-case and sensitivity analyses were performed. RESULTS In the base-case analysis, standard treatment plus FMT therapy was more effective than standard treatment alone (by 0.068 QALYs). Comparing to standard treatment alone, standard treatment plus FMT therapy varied from cost-saving to incremental cost, subject to the number of FMT administrations. One-way sensitivity analysis identified the relative risk of achieving remission with FMT therapy to be the most influential factor on the incremental cost-effectiveness ratio of standard treatment plus FMT therapy. Monte-Carlo simulations showed that standard treatment plus FMT therapy with 3 and 6 administrations per FMT course was cost-effective (at willingness-to-pay threshold = 50 000 USD/QALY) in 90.77% and 67.03% of time, respectively. CONCLUSIONS Standard treatment plus FMT therapy appears to be more effective in gaining higher QALYs than standard therapy alone for patients with mild-to-moderate active UC. Cost-effectiveness of standard treatment plus FMT therapy is highly subject to the relative improvement in achieving remission with standard therapy plus FMT therapy and number of FMT administrations per FMT course.
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Affiliation(s)
- Jiaqi Yao
- School of Pharmacy, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong
| | - Ginenus Fekadu
- School of Pharmacy, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong
| | - Siew C Ng
- Microbiota I-Center, The Chinese University of Hong Kong, Hong Kong.,Department of Medicine and Therapeutics, LKS Institute of Health Science, State Key Laboratory of Digestive Disease, The Chinese University of Hong Kong, Hong Kong
| | - Joyce H S You
- School of Pharmacy, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong
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Bai H, Zhang X, Bush WS. Pharmacogenomic and Statistical Analysis. Methods Mol Biol 2023; 2629:305-330. [PMID: 36929083 DOI: 10.1007/978-1-0716-2986-4_14] [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] [Indexed: 03/18/2023]
Abstract
Genetic variants can alter response to drugs and other therapeutic interventions. The study of this phenomenon, called pharmacogenomics, is similar in many ways to other types of genetic studies but has distinct methodological and statistical considerations. Genetic variants involved in the processing of exogenous compounds exhibit great diversity and complexity, and the phenotypes studied in pharmacogenomics are also more complex than typical genetic studies. In this chapter, we review basic concepts in pharmacogenomic study designs, data generation techniques, statistical analysis approaches, and commonly used methods and briefly discuss the ultimate translation of findings to clinical care.
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Affiliation(s)
- Haimeng Bai
- Department of Population and Quantitative Health Sciences, Cleveland Institute for Computational Biology, Case Western Reserve University, Cleveland, OH, USA
- Department of Nutrition, Case Western Reserve University School of Medicine, Cleveland, OH, USA
| | - Xueyi Zhang
- Department of Population and Quantitative Health Sciences, Cleveland Institute for Computational Biology, Case Western Reserve University, Cleveland, OH, USA
| | - William S Bush
- Department of Population and Quantitative Health Sciences, Cleveland Institute for Computational Biology, Case Western Reserve University, Cleveland, OH, USA.
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Rezazadeh Ardabili A, Jeuring S, Mujagic Z, Oostenbrug L, Romberg‐Camps M, Jonkers D, van Bodegraven A, Pierik M. Classic drugs in the time of new drugs: real-world, long-term outcomes of thiopurine monotherapy in 1016 patients with inflammatory bowel disease. Aliment Pharmacol Ther 2022; 56:1030-1043. [PMID: 35794735 PMCID: PMC9544244 DOI: 10.1111/apt.17128] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/12/2022] [Revised: 05/01/2022] [Accepted: 06/24/2022] [Indexed: 12/11/2022]
Abstract
BACKGROUND Thiopurines remain recommended as maintenance therapy in patients with inflammatory bowel disease (IBD). Despite their widespread use, long-term effectiveness data are sparse and safety is an increasingly debated topic which thwarts proper delineation in the current IBD treatment algorithm. AIMS To document effectiveness and safety of thiopurine monotherapy in patients with IBD, using the population-based IBD South-Limburg (IBDSL) cohort METHODS: All patients starting thiopurine monotherapy as maintenance between 1991 and 2014 were included. Therapy was defined as effective if there was no escalation to biologicals, no course of corticosteroids, no surgery and no hospitalisation for active disease during treatment. Long-term effectiveness was assessed by adjusting for differences in follow-up using Kaplan-Meier analyses. Mid- to long-term safety regarding cancer incidence and clinically relevant liver disease was documented. RESULTS In total, 1016 patients (643 Crohn's disease [CD]; 373 ulcerative colitis [UC]) received thiopurine monotherapy at a median of 15.2 (Q1-Q3 4.2-48.5) months after diagnosis. During follow-up, effectiveness rates at 1, 5 and 10 years were 64%, 45%, 32%, respectively, in CD and and 66%, 41%, 36%, respectively in UC. No statistically significant differences in effectiveness were observed after stratification for era of initiation (pre-biological vs biological, CD: p = 0.56; UC: p = 0.43). Sixteen non-melanoma skin cancers (incidence rate [IR] 3.33/1000 PY), five lymphomas (IR 1.04/1000 PY) and one urinary tract cancer (IR 0.21/1000 PY) were recorded. Two cases of portal hypertension were identified. CONCLUSION In real-world practice, thiopurine monotherapy remains effective, safe and durable for patients with CD or UC, including in the era of biologics.
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Affiliation(s)
- Ashkan Rezazadeh Ardabili
- Department of Internal Medicine, Division of Gastroenterology and HepatologyMaastricht University Medical Centre+MaastrichtThe Netherlands
- School for Nutrition and Translational Research in Metabolism (NUTRIM)Maastricht University Medical Centre+MaastrichtThe Netherlands
| | - Steven Jeuring
- Department of Internal Medicine, Division of Gastroenterology and HepatologyMaastricht University Medical Centre+MaastrichtThe Netherlands
| | - Zlatan Mujagic
- Department of Internal Medicine, Division of Gastroenterology and HepatologyMaastricht University Medical Centre+MaastrichtThe Netherlands
- School for Nutrition and Translational Research in Metabolism (NUTRIM)Maastricht University Medical Centre+MaastrichtThe Netherlands
| | - Liekele Oostenbrug
- Department of Gastroenterology, Geriatrics, Internal and Intensive Care Medicine (Co‐MIK)Zuyderland Medical CentreSittard‐GeleenThe Netherlands
| | - Mariëlle Romberg‐Camps
- Department of Gastroenterology, Geriatrics, Internal and Intensive Care Medicine (Co‐MIK)Zuyderland Medical CentreSittard‐GeleenThe Netherlands
| | - Daisy Jonkers
- Department of Internal Medicine, Division of Gastroenterology and HepatologyMaastricht University Medical Centre+MaastrichtThe Netherlands
- School for Nutrition and Translational Research in Metabolism (NUTRIM)Maastricht University Medical Centre+MaastrichtThe Netherlands
| | - Adriaan van Bodegraven
- Department of Gastroenterology, Geriatrics, Internal and Intensive Care Medicine (Co‐MIK)Zuyderland Medical CentreSittard‐GeleenThe Netherlands
| | - Marieke Pierik
- Department of Internal Medicine, Division of Gastroenterology and HepatologyMaastricht University Medical Centre+MaastrichtThe Netherlands
- School for Nutrition and Translational Research in Metabolism (NUTRIM)Maastricht University Medical Centre+MaastrichtThe Netherlands
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Park J, Cheon JH. Updates on conventional therapies for inflammatory bowel diseases: 5-aminosalicylates, corticosteroids, immunomodulators, and anti-TNF-α. Korean J Intern Med 2022; 37:895-905. [PMID: 35882566 PMCID: PMC9449200 DOI: 10.3904/kjim.2022.132] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/04/2022] [Accepted: 05/13/2022] [Indexed: 12/03/2022] Open
Abstract
The incidence and prevalence of inflammatory bowel diseases (IBDs) are rapidly increasing worldwide. IBDs are considered an emerging problem not only in Western countries but also in developing counties. The relapses and complications of active IBD mandate various medications. Nevertheless, hospitalization, emergency room visits, or surgery may be required, resulting in a socioeconomic burden. Great advances have been made in the development of new therapeutic options for IBD to achieve induction and maintenance remission. Nevertheless, conventional therapy is still the mainstay in the treatment of IBD. This review article provides an update on recent advances in conventional therapies, including 5-aminosalicylates, corticosteroids, immunomodulators, and anti-tumor necrosis factor-α agents to treat IBD.
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Affiliation(s)
- Jihye Park
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul,
Korea
| | - Jae Hee Cheon
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul,
Korea
- Institute of Gastroenterology, Yonsei University College of Medicine, Seoul,
Korea
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Crouwel F, Buiter HJC, de Boer NK. The Thiopurine Tale: An Unexpected Journey. J Crohns Colitis 2022; 16:1177-1183. [PMID: 35024806 DOI: 10.1093/ecco-jcc/jjac004] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/03/2021] [Revised: 12/24/2021] [Accepted: 01/11/2022] [Indexed: 01/11/2023]
Abstract
Exactly 70 years ago [1951] mercaptopurine was discovered by Gertrude Elion as a novel treatment option for acute leukaemia. A total of three thiopurines (also thioguanine [1950] and azathioprine [1957]) were developed over time. These immunosuppressive drugs were also successfully introduced a few decades later to prevent rejection of transplanted organs and to treat several autoimmune diseases. For her discovery of thiopurines and other antimetabolite drugs, in 1988 Elion was rewarded, together with George Hitchings and James Black, with the Nobel Prize in Physiology or Medicine. Important steps have been made in recent years to unravel its metabolism, mode of action and pharmacogenetics. Today thiopurine [based] therapy remains an essential immunosuppressive approach in treating patients with inflammatory bowel disease.
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Affiliation(s)
- Femke Crouwel
- Department of Gastroenterology and Hepatology, Amsterdam Gastroenterology Endocrinology Metabolism Research Institute, Amsterdam University Medical Centre, Vrije Universiteit Amsterdam, Amsterdam, the Netherland
| | - Hans J C Buiter
- Department of Radiology and Nuclear Medicine, Amsterdam University Medical Centers, Vrije Universiteit Amsterdam, Amsterdam, the Netherlands
| | - Nanne K de Boer
- Department of Gastroenterology and Hepatology, Amsterdam Gastroenterology Endocrinology Metabolism Research Institute, Amsterdam University Medical Centre, Vrije Universiteit Amsterdam, Amsterdam, the Netherland
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Relapse rates after withdrawal of thiopurines in patients with inflammatory bowel disease. Int J Colorectal Dis 2022; 37:1817-1826. [PMID: 35835862 DOI: 10.1007/s00384-022-04216-5] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 07/08/2022] [Indexed: 02/04/2023]
Abstract
PURPOSE Withdrawal of thiopurines after remission is associated with an increased risk of relapse in patients with inflammatory bowel disease (IBD). However, long-term data on thiopurine withdrawal is limited, especially from developing countries where the cost of long-term therapy poses a significant burden on patients. METHODS Patients with IBD on thiopurine monotherapy for ≥ 4 months, who stopped thiopurines while in clinical remission and were not on any other immunomodulator or biologics at the time of withdrawal, were included in this retrospective analysis. RESULTS Among 1093 patients with IBD on thiopurine monotherapy, 461 patients stopped thiopurine due to various reasons. Among these, 218 (ulcerative colitis (UC) = 179; Crohn's disease (CD) = 39) patients were in clinical remission and were continued on mesalamine. Overall, 36.7% (n = 80) relapsed after a median duration of 20 months (IQR: 9-49). Relapse rate was higher in UC than CD (39.7% vs 23%, p = 0.055). Cumulative probabilities of relapse were 17%, 34%, and 44% at the end of 1, 3, and 5 years, respectively. The relapse rate at 5 years was significantly lower in patients who had stopped azathioprine after 4 years of therapy (31% vs 54%, p = 0.007). On multi-variate cox regression analysis, male sex [HR: 1.6(1.0-2.6), p = 0.02] and short duration of therapy with thiopurines [HR: 1.02 (1.01-1.02), p = 0.004] before withdrawal were associated with increased risk of relapse. CONCLUSION Approximately 50% patients with IBD in remission would relapse after 5 years of thiopurine withdrawal. Male sex and shorter treatment duration predict relapse. Treatment should be continued in patients who tolerate and maintain remission on long-term thiopurine.
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Ranjan MK, Kante B, Vuyyuru SK, Kumar P, Mundhra SK, Golla R, Sharma R, Sahni P, Das P, Makharia G, Kedia S, Ahuja V. Minimal risk of lymphoma and non-melanoma skin cancer despite long-term use of thiopurines in patients with inflammatory bowel disease: A longitudinal cohort analysis from northern India. J Gastroenterol Hepatol 2022; 37:1544-1553. [PMID: 35501287 DOI: 10.1111/jgh.15880] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/11/2022] [Revised: 04/05/2022] [Accepted: 04/18/2022] [Indexed: 12/09/2022]
Abstract
BACKGROUND AND AIM Thiopurines are widely used to maintain remission in both ulcerative colitis (UC) and Crohn's disease (CD). Reported effectiveness and tolerability rates have been variable across studies. There are only sparse data in Asian population regarding the long-term efficacy and safety of thiopurines. METHODS Records of 5351 patients followed up at inflammatory bowel disease (IBD) clinic, All India Institute of Medical Sciences, New Delhi from 2004 to 2020 were evaluated retrospectively. Safety was evaluated in terms of long-term adverse events and development of malignancy. RESULTS Of 5351 patients with IBD, 1093 who received thiopurine for > 3 months (UC = 788 [proctitis-1.9%, left-sided colitis-44.9%, & pancolitis-53.1%] & CD = 305 [inflammatory-42.6%, stricturing-46.9%, & fistulizing-10.5%]) were included (60.8%-male patients). Follow up and treatment duration on thiopurine were 7 (4-12) years and 39.4 ± 40.3 months, respectively, with 254 (23.2%) patients receiving thiopurines for more than 5 and 68 (6.2%) receiving for more than 10 years. Three hundred and fifty-nine (UC: 249 [31.6%]; CD: 110 [36.1%]; P = 0.1) patients developed adverse events; commonest was myelosuppression (23.4%) followed by gastrointestinal intolerance (3%), flu-like illness (1.7%), and arthralgia/myalgia (1.4%). Myelosuppression was the commonest cause of thiopurine withdrawal. No patient (including 254 patients on thiopurine for ≥ 5 years) developed lymphoma or non-melanoma skin cancer. The cumulative probability of staying free from adverse events in overall IBD cohort at 1, 2, and 5 years was 78.6%, 71.9%, and 68.4%, respectively, and this was comparable between UC and CD (P = 0.09). CONCLUSION Long-term follow up of patients with IBD from northern India on thiopurine monotherapy demonstrated minimal risk of development of lymphoma as well as non-melanoma skin cancer.
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Affiliation(s)
- Mukesh Kumar Ranjan
- Department of Gastroenterology and Human Nutrition, All India Institute of Medical Sciences, New Delhi, India
| | - Bhaskar Kante
- Department of Gastroenterology and Human Nutrition, All India Institute of Medical Sciences, New Delhi, India
| | - Sudheer Kumar Vuyyuru
- Department of Gastroenterology and Human Nutrition, All India Institute of Medical Sciences, New Delhi, India
| | - Peeyush Kumar
- Department of Gastroenterology and Human Nutrition, All India Institute of Medical Sciences, New Delhi, India
| | - Sandeep K Mundhra
- Department of Gastroenterology and Human Nutrition, All India Institute of Medical Sciences, New Delhi, India
| | - Rithvik Golla
- Department of Gastroenterology and Human Nutrition, All India Institute of Medical Sciences, New Delhi, India
| | - Raju Sharma
- Department of Radio Diagnosis, All India Institute of Medical Sciences, New Delhi, India
| | - Peush Sahni
- Department of Gastrointestinal Surgery, All India Institute of Medical Sciences, New Delhi, India
| | - Prasenjit Das
- Department of Pathology, All India Institute of Medical Sciences, New Delhi, India
| | - Govind Makharia
- Department of Gastroenterology and Human Nutrition, All India Institute of Medical Sciences, New Delhi, India
| | - Saurabh Kedia
- Department of Gastroenterology and Human Nutrition, All India Institute of Medical Sciences, New Delhi, India
| | - Vineet Ahuja
- Department of Gastroenterology and Human Nutrition, All India Institute of Medical Sciences, New Delhi, India
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Yeo JQ, Cheen HHM, Wong A, Lim TG, Chowbay B, Leong WF, Wang C, Salazar E, Chan WPW, Kong SC, Ong WC. Clinical utility of thiopurine metabolite monitoring in inflammatory bowel disease and its impact on healthcare utilization in Singapore. JGH Open 2022; 6:658-666. [PMID: 36262537 PMCID: PMC9575318 DOI: 10.1002/jgh3.12798] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2022] [Revised: 07/01/2022] [Accepted: 07/10/2022] [Indexed: 01/05/2023]
Abstract
Background and Aim Thiopurines are recommended for maintenance of steroid‐free remission (SFR) in inflammatory bowel disease (IBD). Thiopurine metabolite monitoring (MM) is increasingly used in the West but remains novel in Singapore, with limited information on its therapeutic and economic benefits. Hence, this study aims to investigate MM's clinical utility and its impact on healthcare resource utilization in Singaporean IBD patients. Methods A retrospective observational study was conducted at Singapore General Hospital outpatient IBD Centre. Patients with IBD, baseline MM during 2014–2017, and weight‐based thiopurine doses for ≥4 weeks were followed up for 1 year. Actions were taken to optimize therapy, and metabolite levels before and after the first action were documented. Outcomes assessed included SFR, no therapy escalation or surgery, healthcare resource utilization, and direct healthcare costs. Results Ninety IBD patients (50 Crohn's disease, 40 ulcerative colitis) were included. Among them, 40% had baseline metabolite levels within therapeutic range, 31.1% sub‐therapeutic, 21.1% supra‐therapeutic, and 7.8% shunters. Repeated MM with subsequent dose optimization helped 67.2% of patients achieve therapeutic levels after 1 year. Overall, 87.8% of patients achieved SFR and 90% had no therapy escalation or surgery. Despite greater outpatient visits and laboratory investigations with MM, the median total healthcare costs at 1 year only increased marginally (S$6407.66 [shunters] vs S$5215.20 [supra‐therapeutic] vs S$4970.80 [sub‐therapeutic] vs S$4370.48 [control (within therapeutic range)], P = 0.592). Conclusion MM guided timely therapy escalation for non‐responders, identification of non‐adherence, and reversal of shunting. Therefore, it is a useful clinical tool to optimize thiopurines without significantly increasing healthcare costs.
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Affiliation(s)
- Jia Qi Yeo
- National Healthcare Group Pharmacy Singapore
| | | | - Amanda Wong
- Department of Pharmacy Singapore General Hospital Singapore
| | - Teong Guan Lim
- Department of Pharmacy Singapore General Hospital Singapore
| | - Balram Chowbay
- Clinical Pharmacology Laboratory National Cancer Centre Singapore Singapore
- Centre for Clinician‐Scientist Development Duke‐NUS Medical School Singapore
- Singapore Immunology Network (SIgN) A*STAR (Agency for Science, Technology and Research), Biopolis Singapore
| | - Wai Fook Leong
- Singapore Immunology Network (SIgN) A*STAR (Agency for Science, Technology and Research), Biopolis Singapore
| | | | - Ennaliza Salazar
- Department of Gastroenterology and Hepatology Singapore General Hospital Singapore
| | - Webber Pak Wo Chan
- Department of Gastroenterology and Hepatology Singapore General Hospital Singapore
| | - San Choon Kong
- Department of Gastroenterology and Hepatology Sengkang General Hospital Singapore
| | - Wan Chee Ong
- Department of Pharmacy Singapore General Hospital Singapore
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Monotherapy with thiopurines in stricturing Crohn's disease: A real-life experience from low- and middle-income countries. Indian J Gastroenterol 2022; 41:343-351. [PMID: 35997952 DOI: 10.1007/s12664-022-01258-z] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/27/2021] [Accepted: 03/06/2022] [Indexed: 02/04/2023]
Abstract
BACKGROUND Stricturing Crohn's disease (CD) is difficult to manage medically with limited treatment options, anti-tumor necrosis factor (TNF) therapy being the first-line therapy. Although thiopurines are also recommended first-line treatment option for maintenance of remission in steroid-dependent CD, evidence on their use in stricturing CD is lacking. We evaluated the efficacy of azathioprine (AZA) in patients with stricturing CD. METHODS In this retrospective cohort study (January 2005 to July 2020), patients with stricturing CD who were managed with AZA as a primary therapy for at least 6 months, and had a follow-up of at least 6 months after AZA initiation were included. Disease characteristics, complications, long-term response, and adverse events were noted. RESULTS One hundred and fifteen patients were included (mean age 33.8±14 years, 67.8% males, median disease duration 98 months [IQR: 60-158], median follow-up duration 60 months [IQR: 50-96]). 46.1% (n=53) patients had significant anemia at presentation, and 73% (n=84) had isolated small bowel involvement. Median dose of AZA was 100 mg (equivalent to 1.5 mg/kg). Median therapy and follow-up duration (after AZA initiation) was 17 (IQR: 9-42) and 33 months (IQR 18-60), respectively. The cumulative probability of maintaining response without treatment failure at 1, 2, and 5 years was 73.1%, 40.7%, and 18.5%, respectively. Among patients with AZA failure, 15.6% received methotrexate, 13% received anti-TNFs, and 9.5% underwent surgery. Significant anemia (<10 g/dL) at presentation and steroid dependence predicted AZA failure. 31.3% patients experienced adverse events, commonest being leukopenia (n=29, 25.2%). CONCLUSION Azathioprine demonstrated good short-term and modest long-term response rates in patients with stricturing CD.
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Poly(curcumin β-amino ester)-Based Tablet Formulation for a Sustained Release of Curcumin. Gels 2022; 8:gels8060337. [PMID: 35735681 PMCID: PMC9222275 DOI: 10.3390/gels8060337] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2022] [Revised: 05/20/2022] [Accepted: 05/23/2022] [Indexed: 11/16/2022] Open
Abstract
Oral drug delivery remains the most common and well tolerated method for drug administration. However, its applicability is often limited due to low drug solubility and stability. One approach to overcome the solubility and stability limitations is the use of amorphous polymeric prodrug formulations, such as poly(β-amino ester) (PBAE). PBAE hydrogels, which are biodegradable and pH responsive, have shown promising results for the controlled release of drugs by improving the stability and increasing the solubility of these drugs. In this work, we have evaluated the potential use of PBAE prodrugs in an oral tablet formulation, studying their sustained drug release potential and storage stability. Curcumin, a low solubility, low stability antioxidant drug was used as a model compound. Poly(curcumin β-amino ester) (PCBAE), a crosslinked amorphous network, was synthesized by a previously published method using a commercial diacrylate and a primary diamine, in combination with acrylate-functionalized curcumin. PCBAE-based tablets were made and exhibited a sustained release for 16 h, following the hydrolytic degradation of PCBAE particles into native curcumin. In addition to the release studies, preliminary storage stability was assessed using standard and accelerated stability conditions. As PCBAE degradation is hydrolysis driven, tablet stability was found to be sensitive to moisture.
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Mallick B, Malik S. Use of Azathioprine in Ulcerative Colitis: A Comprehensive Review. Cureus 2022; 14:e24874. [PMID: 35698683 PMCID: PMC9184176 DOI: 10.7759/cureus.24874] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/09/2022] [Indexed: 01/10/2023] Open
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Disseminated cutaneous Actinomyces bovis infection in an immunocompromised host: case report and review of the literature. BMC Infect Dis 2022; 22:310. [PMID: 35351021 PMCID: PMC8962608 DOI: 10.1186/s12879-022-07282-w] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2021] [Accepted: 03/16/2022] [Indexed: 12/22/2022] Open
Abstract
Background Actinomycosis is an uncommon endogenous bacterial infection caused by Actinomyces species, characterized by the development of abscesses, tissue fibrosis, and fistulisation. It remains a diagnostic challenge, due to its similarities with diverse aetiologies’ presentation, such as neoplasms, tuberculosis, or fungal infections. Actinomyces bovis is a microorganism rarely reported as a cause of human disease. Cutaneous involvement is sporadic. In this case, Actinomyces bovis was responsible for disseminated cutaneous disease in an immunosuppressed patient. Case presentation We report the case of a 69-year-old female with multiple skin masses, under immunosuppressive therapy due to ulcerative colitis. Imaging exams were compatible with multiple cutaneous abscesses in the cervicofacial region and limbs. Actinomyces bovis was isolated in culture after abscess drainage. Antimicrobial therapy with parenteral penicillin G and oral amoxicillin was administered for 6 months, with complete resolution of cutaneous lesions and no relapse of the infection. Conclusions Considering actinomycosis as a possible diagnosis in the presence of subacute/chronic recurrent mass-like cutaneous lesions, especially in the setting of immunosuppression, may reduce the burden associated with delayed diagnosis and incorrect treatment and provide better outcomes and improvement of patient’s quality of life.
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Cytotoxicity of Thiopurine Drugs in Patients with Inflammatory Bowel Disease. TOXICS 2022; 10:toxics10040151. [PMID: 35448412 PMCID: PMC9026123 DOI: 10.3390/toxics10040151] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/11/2022] [Revised: 03/11/2022] [Accepted: 03/17/2022] [Indexed: 02/04/2023]
Abstract
The effectiveness of thiopurine drugs in inflammatory bowel disease (IBD) was confirmed more than a half-century ago. It was proven that these can be essential immunomodulatory medications. Since then, they have been used routinely to maintain remission of Crohn’s disease (CD) and ulcerative colitis (UC). The cytotoxic properties of thiopurines and the numerous adverse effects of the treatment are controversial. However, the research subject of their pharmacology, therapy monitoring, and the search for predictive markers are still very relevant. In this article, we provide an overview of the current knowledge and findings in the field of thiopurines in IBD, focusing on the aspect of their cytotoxicity. Due to thiopurines’ benefits in IBD therapy, it is expected that they will still constitute an essential part of the CD and UC treatment algorithm. More studies are still required on the modulation of the action of thiopurines in combination therapy and their interaction with the gut microbiota.
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Miao Z, Gu M, Yan J, Lu L, Xu Y, Ning L, Xu Y. Dual-targeted colon-based integrated micelle drug delivery system for treatment of ulcerative colitis. J Drug Target 2022; 30:657-672. [PMID: 35285362 DOI: 10.1080/1061186x.2022.2052887] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/18/2022]
Affiliation(s)
- Zhiwei Miao
- Department of Gastroenterology, Zhangjiagang TCM Hospital Affiliated to Nanjing University of Chinese Medicine, Zhangjiagang 215600, China
| | - Mingjia Gu
- Department of Nephrology, Changshu Hospital affiliated to Nanjing university of Chinese medicine, Changshu 215000, China
| | - Jing Yan
- Key Laboratory for Metabolic Diseases in Chinese Medicine, First Clinical Medical College, Nanjing University of Chinese Medicine, Nanjing 210000, China
| | - Lidan Lu
- Department of gynaecology, Changshu Hospital affiliated to Nanjing university of Chinese medicine, Changshu 215000, China.
| | - Yan Xu
- Department of Gastroenterology, Zhangjiagang TCM Hospital Affiliated to Nanjing University of Chinese Medicine, Zhangjiagang 215600, China
| | - Liqin Ning
- Department of Gastroenterology, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing 210029, China
| | - Yi Xu
- Department of Gastroenterology, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing 210029, China
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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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Fukuchi T, Kawashima K, Koga H, Utsunomiya R, Sugiyama K, Shimazu K, Eguchi T, Ishihara S. Induction of mucosal healing by intensive granulocyte/monocyte adsorptive apheresis (GMA) without use of corticosteroids in patients with ulcerative colitis: long-term remission maintenance after induction by GMA and efficacy of GMA re-treatment upon relapse. J Clin Biochem Nutr 2022; 70:197-204. [PMID: 35400813 PMCID: PMC8921725 DOI: 10.3164/jcbn.21-112] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2021] [Accepted: 10/20/2021] [Indexed: 12/15/2022] Open
Abstract
This study examined the long-term maintenance rate after inducing remission by intensive granulocyte/monocyte adsorptive apheresis (GMA) without use of corticosteroids (CS) and GMA re-treatment efficacy in the same patients upon relapse with ulcerative colitis. Patients who achieved clinical remission and mucosal healing (MH) by first-time intensive GMA (first GMA) without CS were enrolled. The cumulative non-relapse survival rate up to week 156 was calculated. Patients with relapse during the maintenance period underwent second-time intensive GMA (second GMA) without CS. Clinical remission and MH rates following second GMA were compared to those following first GMA in the same patients. Of the 84 patients enrolled, 78 were followed until week 156 and 34 demonstrated relapse. The cumulative non-relapse survival rate by week 156 was 56.4%. Clinical remission and MH rates after second GMA did not differ from those after first GMA in the same patients (week 6: clinical remission, 100% vs 88.4%, p = 0.134; MH, 100% vs 84.8%, p = 0.074). In conclusion, MH induction by intensive GMA without use of CS in ulcerative colitis patients contributes to subsequent long-term clinical remission maintenance. GMA re-treatment efficacy was comparable to that of first GMA in the same patients who had relapse.
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Affiliation(s)
- Takumi Fukuchi
- Department of Gastroenterology and Hepatology, Iseikai Hospital
| | - Kousaku Kawashima
- Department of Internal Medicine II, Shimane University Faculty of Medicine
| | - Hideaki Koga
- Department of Gastroenterology and Hepatology, Iseikai Hospital
| | - Ran Utsunomiya
- Department of Gastroenterology and Hepatology, Iseikai Hospital
| | - Kohei Sugiyama
- Department of Gastroenterology and Hepatology, Iseikai Hospital
| | - Keiji Shimazu
- Department of Nephrology, Saiseikai Nakatsu Hospital
| | - Takaaki Eguchi
- Department of Gastroenterology and Hepatology, Saiseikai Nakatsu Hospital
| | - Shunji Ishihara
- Department of Internal Medicine II, Shimane University Faculty of Medicine
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Chang JY, Cheon JH. Pharmacogenetics-based personalized treatment in patients with inflammatory bowel disease: A review. PRECISION AND FUTURE MEDICINE 2021. [DOI: 10.23838/pfm.2021.00128] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022] Open
Abstract
The development of treatment options has revolutionized the prognosis of inflammatory bowel disease (IBD). However, a particular group of patients still experience therapeutic failure or drug side effects. Although the high inter-patient variability in therapy is associated with clinical factors, including age, disease behavior, and disease duration, they attribute only a small proportion of inter-individual variability. Thus, pharmacogenetics evaluating associations between specific genetic variations and drug responses or side effects have focused on optimizing therapeutic efficacy and minimizing toxicity in IBD treatment. Thiopurine S-methyltransferase (TPMT) and nudix hydrolase 15 (NUDT15) are well-established predictive markers of thiopurine-induced myelosuppression. Low TPMT activity is related to increased 6-thioguanine nucleotide levels, subsequently leading to myelotoxicity. NUDT15 variants are strongly associated with thiopurine-induced early leukopenia in Asians, with a lower incidence of TPMT-deficient allele. The Korean Association for the Study of Intestinal Diseases guidelines recommend pretreatment determination of NUDT15 genotypes, especially in East Asians, and NUDT15 R139C measurement has been approved for clinical use since 2019. Several studies have attempted to identify powerful genetic markers for personalized medicine. In this article, we review the identified pharmacogenetics of currently available drugs, focusing on 5-aminosalicylic acid, glucocorticosteroids, thiopurines, and anti-tumor necrosis factor-alpha agents.
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Cifci S, Ekmen N. Prediction of Mucosal Health by NLR, CRP x NLR and MPV in Ulcerative Colitis: Can Their Availability Change According to Treatment Options? Cureus 2021; 13:e19942. [PMID: 34984116 PMCID: PMC8714053 DOI: 10.7759/cureus.19942] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/27/2021] [Indexed: 11/18/2022] Open
Abstract
Introduction Mucosal healing is the main treatment goal in ulcerative colitis (UC). Many noninvasive parameters have been used in clinical practice to assess mucosal healing. In this study, we aimed to evaluate the effectiveness of neutrophil-lymphocyte ratio (NLR), C-reactive protein (CRP) x NLR and mean platelet volume (MPV) in predicting mucosal health. Method This study was designed as a retrospective and single-center. A total of 165 patients, 126 active and 39 in remission, were included in this study. The patients were divided into two groups. The patients were divided into two groups. Group-1 consisted of newly diagnosed patients and patients using only mesalazine; Group-2 was including patients using CS and/or AZT plus mesalazine for at least one month. The relationship between Rachmilewitz endoscopic activity index (EAI) and erythrocyte sedimentation rate (ESR), CRP, NLR, CRP x NLR, MPV and platelet (PLT) was evaluated. Using receiver operating characteristic curves, cut-off values were determined for these parameters to predict active disease. Results A positive correlation was found between CRP, PLT and NLR and EAI (p<0.001). A negative correlation was found between MPV and EAI (p<0.001). The accuracy of CRP, NLR, CRP x NLR and PLT (2.65 mg/dl, 2.06, 4.29 and 278.5 x 109/L at the indicated cut-off values, respectively) in detecting disease activity was 77.0%, 65.1%, 77.0% and 72.2%, respectively. MPV was not statistically significant in predicting disease activation (p> 0.05). Conclusion CRP and CRP x NLR are significant non-invasive markers for detecting mucosal health in UC. In addition, these markers can be used to evaluate mucosal health regardless of treatment types.
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Yu J, Hyun HK, Park J, Kang EA, Park SJ, Park JJ, Kim TI, Kim WH, Cheon JH. Continued Postoperative Use of Tumor Necrosis Factor-α Inhibitors for the Prevention of Crohn's Disease Recurrence. Gut Liver 2021; 16:414-422. [PMID: 34420935 PMCID: PMC9099390 DOI: 10.5009/gnl210062] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/08/2021] [Revised: 06/12/2021] [Accepted: 06/14/2021] [Indexed: 11/29/2022] Open
Abstract
Background/Aims Many patients with Crohn’s disease (CD) undergo intestinal resection during the disease course. Despite surgery, postoperative recurrence (POR) commonly occurs. Although postoperative use of tumor necrosis factor α (TNF-α) inhibitors is known to be effective in preventing POR, few studies have evaluated the effectiveness of continuing the same TNF-α inhibitors postoperatively in patients who received TNF-ɑ inhibitors before surgery. Methods This retrospective observational study was performed in a single tertiary medical center. We retrospectively reviewed patients who had undergone the first intestinal resection due to CD and divided them into two groups TNF-α inhibitor users in both the preoperative and postoperative periods, and TNF-α inhibitor users in only the preoperative period. We compared the clinical outcomes between these two groups. Results In total, 45 patients who used TNF-α inhibitors preoperatively were recruited. Among them, TNF-α inhibitors were used postoperatively in 20 patients (44.4%). The baseline characteristics except age at diagnosis were similar in both groups. The rates of surgical and endoscopic recurrence were not different between the two groups, but the cumulative clinical recurrence rate was significantly lower in the postoperative TNF-α inhibitors group (log-rank p=0.003). In multivariate Cox regression analysis, postoperative TNF-α inhibitors use was significantly associated with a decreased risk of clinical recurrence (adjusted hazard ratio, 0.204; 95% confidence interval, 0.060 to 0.691; p=0.011). Conclusions Continuing TNF-α inhibitors postoperatively in patients who were receiving TNF-α inhibitors before surgery significantly reduced the rate of clinical recurrence. For patients with CD who received TNF-α inhibitors preoperatively, continuing their use after surgery could be recommended.
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Affiliation(s)
- Jongwook Yu
- Department of Internal Medicine and Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Korea
| | - Hye Kyung Hyun
- Department of Internal Medicine and Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Korea
| | - Jihye Park
- Department of Internal Medicine and Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Korea
| | - Eun Ae Kang
- Department of Internal Medicine and Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Korea
| | - Soo Jung Park
- Department of Internal Medicine and Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Korea
| | - Jae Jun Park
- Department of Internal Medicine and Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Korea
| | - Tae Il Kim
- Department of Internal Medicine and Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Korea
| | - Won Ho Kim
- Department of Internal Medicine and Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Korea
| | - Jae Hee Cheon
- Department of Internal Medicine and Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Korea
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Grover N, Bhatia P, Kumar A, Singh M, Lad D, Mandavdhare HS, Samanta J, Prasad KK, Dutta U, Sharma V. TPMT and NUDT15 polymorphisms in thiopurine induced leucopenia in inflammatory bowel disease: a prospective study from India. BMC Gastroenterol 2021; 21:327. [PMID: 34425754 PMCID: PMC8383411 DOI: 10.1186/s12876-021-01900-8] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/15/2020] [Accepted: 08/11/2021] [Indexed: 12/24/2022] Open
Abstract
BACKGROUND Polymorphisms in thiopurine methyltransferase (TPMT) and Nudix hydrolase-15 (NUDT15) have been implicated as the predominant cause of thiopurine induced leukopenia in the Western countries and East Asia respectively. Exact role of these polymorphisms in South Asian population with inflammatory bowel disease (IBD) is uncertain. METHODS We included consecutive patients with IBD who were initiated on thiopurines at a center in North India. The dosage of thiopurines was titrated using regular monitoring of hemogram and liver function tests. Three TPMT polymorphisms (c.238 G > C, c.460 G > A, and c.719A > G) and one NUDT15 polymorphism (c.415 C > T) were assessed. Comparison regarding incidence of leukopenia and maximum tolerated thiopurine dosage was performed between those with wild polymorphism and those with TPMT and NUDT15 polymorphisms, respectively. RESULTS Of the 119 patients (61 males, mean age 36.8 ± 13.5 years), 105 (88.2%) had ulcerative colitis and 14 (11.8%) had Crohn's disease. Leukopenia was noted in 33 (27.7%), gastrointestinal intolerance in 5 (4.2%) and pancreatitis in 2 (1.6%). TPMT polymorphisms were detected amongst five patients of whom 1 developed leukopenia. NUDT15 polymorphism was noted in 13 patients of whom 7 had leukopenia. The odds of developing leukopenia in TPMT polymorphism were non-significant (0.77, 95% CI:0.0822 to 7.2134, P = 0.819) but were significantly higher in those with NUDT15 polymorphism (3.5933, 1.1041 to 11.6951, P value: = 0.0336). CONCLUSION NUDT15 polymorphism was more frequent than TPMT polymorphisms and was associated with thiopurine induced leukopenia. However, the tested polymorphisms account for only 24.2% of the risk of thiopurine induced leukopenia.
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Affiliation(s)
- Narinder Grover
- Department of Internal Medicine, Pediatric Hemato-Oncology, Gastroenterology and Hematology, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| | - Prateek Bhatia
- Department of Internal Medicine, Pediatric Hemato-Oncology, Gastroenterology and Hematology, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| | - Antriksh Kumar
- Department of Internal Medicine, Pediatric Hemato-Oncology, Gastroenterology and Hematology, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| | - Minu Singh
- Department of Internal Medicine, Pediatric Hemato-Oncology, Gastroenterology and Hematology, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| | - Deepesh Lad
- Department of Internal Medicine, Pediatric Hemato-Oncology, Gastroenterology and Hematology, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| | - Harshal S. Mandavdhare
- Department of Internal Medicine, Pediatric Hemato-Oncology, Gastroenterology and Hematology, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| | - Jayanta Samanta
- Department of Internal Medicine, Pediatric Hemato-Oncology, Gastroenterology and Hematology, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| | - Kaushal K. Prasad
- Department of Internal Medicine, Pediatric Hemato-Oncology, Gastroenterology and Hematology, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| | - Usha Dutta
- Department of Internal Medicine, Pediatric Hemato-Oncology, Gastroenterology and Hematology, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| | - Vishal Sharma
- Department of Internal Medicine, Pediatric Hemato-Oncology, Gastroenterology and Hematology, Postgraduate Institute of Medical Education and Research, Chandigarh, India
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Sicilia B, García-López S, González-Lama Y, Zabana Y, Hinojosa J, Gomollón F. GETECCU 2020 guidelines for the treatment of ulcerative colitis. Developed using the GRADE approach. GASTROENTEROLOGIA Y HEPATOLOGIA 2021; 43 Suppl 1:1-57. [PMID: 32807301 DOI: 10.1016/j.gastrohep.2020.07.001] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/15/2020] [Accepted: 07/22/2020] [Indexed: 12/12/2022]
Abstract
INTRODUCTION Since the first edition of the Guidelines was published in 2013, much information has been generated around the treatment of ulcerative colitis, and new drugs and action protocols have been introduced. Clinical practice has changed substantially, warranting new approaches and a comprehensive review and update of the evidence. MATERIAL AND METHODS Once again, we used the GRADE approach, supported by an electronic tool (https://gradepro.org). The clinical scenarios are the same as in the previous version (induction and maintenance in severe and mild-moderate flare-ups), as are the variables and their evaluation. However, in the updated guidelines, three questions have been deleted, 14 added and 30 maintained, making a total of 44 clinical questions. After an exhaustive review of the evidence, the recommendations are now updated. RESULTS Of the 44 questions analysed, no recommendation could be established in two due to the very low quality of the evidence, while in the other 42, based on different degrees of quality of evidence, recommendations were made according to the GRADE system. In 25 of these questions the final recommendation is strongly in favour, in six strongly against, in seven weakly in favour and in four weakly against. According to the scenarios and recommendations, six algorithms are proposed as a simple guide for practical decision-making. CONCLUSIONS The aim of this update of the 2013 guidelines is to provide answers, based on the GRADE approach, to the different questions we ask ourselves daily when deciding the most appropriate treatment for our patients with ulcerative colitis in the different clinical scenarios.
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Affiliation(s)
- Beatriz Sicilia
- Unidad de Enfermedad Inflamatoria Intestinal, Servicio de Aparato Digestivo, Hospital Universitario de Burgos, España
| | - Santiago García-López
- Unidad de Enfermedad Inflamatoria Intestinal, Servicio de Aparato Digestivo, Hospital Universitario Miguel Servet, Instituto de Investigaciones Sanitarias de Aragón, Zaragoza, España.
| | - Yago González-Lama
- Unidad de Enfermedad Inflamatoria Intestinal, Servicio de Aparato Digestivo, Hospital Universitario Puerta de Hierro, Madrid, España
| | - Yamile Zabana
- Unidad de Enfermedad Inflamatoria Intestinal, Servicio de Aparato Digestivo Hospital Universitario Mútua Terrassa Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd)
| | - Joaquín Hinojosa
- Unidad de Enfermedad Inflamatoria Intestinal, Servicio de Aparato Digestivo, Hospital de Manises, Valencia, España
| | - Fernando Gomollón
- Unidad de Enfermedad Inflamatoria Intestinal, Servicio de Aparato Digestivo, Instituto de Investigaciones Sanitarias de Aragón, Hospital Clínico Universitario Lozano Blesa, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Zaragoza, España
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Yadav V, Mai Y, McCoubrey LE, Wada Y, Tomioka M, Kawata S, Charde S, Basit AW. 5-Aminolevulinic Acid as a Novel Therapeutic for Inflammatory Bowel Disease. Biomedicines 2021; 9:biomedicines9050578. [PMID: 34065300 PMCID: PMC8160866 DOI: 10.3390/biomedicines9050578] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2021] [Revised: 05/13/2021] [Accepted: 05/15/2021] [Indexed: 12/22/2022] Open
Abstract
5-Aminolevulinic acid (5-ALA) is a naturally occurring nonprotein amino acid licensed as an optical imaging agent for the treatment of gliomas. In recent years, 5-ALA has been shown to possess anti-inflammatory and immunoregulatory properties through upregulation of heme oxygenase-1 via enhancement of porphyrin, indicating that it may be beneficial for the treatment of inflammatory conditions. This study systematically examines 5-ALA for use in inflammatory bowel disease (IBD). Firstly, the ex vivo colonic stability and permeability of 5-ALA was assessed using human and mouse fluid and tissue. Secondly, the in vivo efficacy of 5-ALA, in the presence of sodium ferrous citrate, was investigated via the oral and intracolonic route in an acute DSS colitis mouse model of IBD. Results showed that 5-ALA was stable in mouse and human colon fluid, as well as in colon tissue. 5-ALA showed more tissue restricted pharmacokinetics when exposed to human colonic tissue. In vivo dosing demonstrated significantly improved colonic inflammation, increased local heme oxygenase-1 levels, and decreased concentrations of proinflammatory cytokines TNF-α, IL-6, and IL-1β in both plasma and colonic tissue. These effects were superior to that measured concurrently with established anti-inflammatory treatments, ciclosporin and 5-aminosalicylic acid (mesalazine). As such, 5-ALA represents a promising addition to the IBD armamentarium, with potential for targeted colonic delivery.
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Affiliation(s)
- Vipul Yadav
- Intract Pharma Limited, London Bioscience Innovation Centre, London NW1 0NH, UK
- Correspondence: (V.Y.); (A.W.B.)
| | - Yang Mai
- School of Pharmaceutical Sciences (Shenzen), Sun Yat-sen University, Guangzhou 510275, China;
| | - Laura E. McCoubrey
- Department of Pharmaceutics, UCL School of Pharmacy, University College, London WC1N 1AX, UK;
| | - Yasufumi Wada
- Neopharma Japan, Iidabashi Grand Bloom 4th Floor, 2-10-2 Fujimi, Chiyoda-ku, Tokyo 102-0071, Japan; (Y.W.); (M.T.); (S.K.); (S.C.)
| | - Motoyasu Tomioka
- Neopharma Japan, Iidabashi Grand Bloom 4th Floor, 2-10-2 Fujimi, Chiyoda-ku, Tokyo 102-0071, Japan; (Y.W.); (M.T.); (S.K.); (S.C.)
| | - Satofumi Kawata
- Neopharma Japan, Iidabashi Grand Bloom 4th Floor, 2-10-2 Fujimi, Chiyoda-ku, Tokyo 102-0071, Japan; (Y.W.); (M.T.); (S.K.); (S.C.)
| | - Shrikant Charde
- Neopharma Japan, Iidabashi Grand Bloom 4th Floor, 2-10-2 Fujimi, Chiyoda-ku, Tokyo 102-0071, Japan; (Y.W.); (M.T.); (S.K.); (S.C.)
| | - Abdul W. Basit
- Intract Pharma Limited, London Bioscience Innovation Centre, London NW1 0NH, UK
- Department of Pharmaceutics, UCL School of Pharmacy, University College, London WC1N 1AX, UK;
- Correspondence: (V.Y.); (A.W.B.)
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Wu Y, Tan Y, Ou D, Wang X, Wang Y. Azathioprine-induced toxoplasma gondii infection in a patient with Crohn's disease with NUDT15 variation: A case report. Medicine (Baltimore) 2021; 100:e25781. [PMID: 33950972 PMCID: PMC8104275 DOI: 10.1097/md.0000000000025781] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/11/2021] [Accepted: 04/15/2021] [Indexed: 01/04/2023] Open
Abstract
INTRODUCTION Azathioprine (AZA) has been widely used for the treatment of various immune-related diseases and has become a mainstay in the treatment of inflammatory bowel disease. However, patients with genetic mutations may experience severe adverse events when treated with azathioprine. Most of the previous literature focused on the TPMP gene-related adverse reactions, herein, we report a case of Crohn's disease patient with nucleoside diphosphate-linked moiety X motif 15 gene (NUDT15) variation and wild-type TPMP gene who developed toxoplasma gondii infection after azathioprine treatment. PATIENT CONCERNS A 56-year-old Crohn's disease patient developed toxoplasma gondii infection within 2 months after the administration of azathioprine; however, he had no relevant high-risk factors. DIAGNOSIS Subsequent genetic testing revealed that the patient was heterozygous for NUDT15. Therefore, it was reasonable to consider that the patient's genetic mutation resulted in reduced tolerance to azathioprine, leading to low immunity and eventually toxoplasma infection. INTERVENTIONS AZA was then discontinued; after anti-infection, antipyretic and other supportive treatments were administered, the patient's condition gradually improved. OUTCOMES The patient was followed up at 1, 3, and 6 months after discharge; fortunately, he was in good health. CONCLUSION We report a case of Crohn's disease in a patient who developed severe pneumonia caused by toxoplasma gondii infection due to the administration of AZA, with normal TPMP gene but NUDT15 gene mutation. This indicates that NUDT15 variation may contribute to severe adverse events in patients treated with azathioprine, and we suggest that NUDT15 genotype be detected before the use of azathioprine in order to provide personalized therapy and reduce side effects.
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Affiliation(s)
- Yanan Wu
- Department of Gastroenterology, The Second Xiangya Hospital
- Research Center of Digestive Disease, Central South University, Changsha, Hunan 410011, China
| | - Yuyong Tan
- Department of Gastroenterology, The Second Xiangya Hospital
- Research Center of Digestive Disease, Central South University, Changsha, Hunan 410011, China
| | - Dalian Ou
- Department of Gastroenterology, The Second Xiangya Hospital
- Research Center of Digestive Disease, Central South University, Changsha, Hunan 410011, China
| | - Xuehong Wang
- Department of Gastroenterology, The Second Xiangya Hospital
- Research Center of Digestive Disease, Central South University, Changsha, Hunan 410011, China
| | - Yongjun Wang
- Department of Gastroenterology, The Second Xiangya Hospital
- Research Center of Digestive Disease, Central South University, Changsha, Hunan 410011, China
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Poor Drug Sustainability in Inflammatory Bowel Disease Patients in Clinical Remission on Thiopurine Monotherapy. Dig Dis Sci 2021; 66:1650-1657. [PMID: 32591969 DOI: 10.1007/s10620-020-06427-8] [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: 04/14/2020] [Accepted: 06/16/2020] [Indexed: 12/12/2022]
Abstract
BACKGROUND Immunomodulator monotherapy is an important component in the treatment of inflammatory bowel disease (IBD). However, there is conflicting literature about thiopurines maintaining long-term remission in patients with active IBD. AIM To determine the durable clinical remission rate in adults with Crohn's disease (CD) or ulcerative colitis (UC) on thiopurine monotherapy over 5 years. METHODS We performed a retrospective analysis of adult patients identified at McGill University Health Centre from 2009 to 2012. We included IBD patients who initiated thiopurine monotherapy and were in remission for at least 3 months (Harvey-Bradshaw Index (HBI) < 5 points for CD and partial Mayo Score (pMS) < 2 points in UC). The primary endpoint was sustained clinical remission on thiopurines during a 5-year follow-up. This included patients who had not relapsed or discontinued the drug due to side effects. The secondary endpoint was clinical relapse over the follow-up period, which was defined as HBI > 5 in CD and pMS > 2 in UC. RESULTS There were 148 patients included in the study (100 CD; 48 UC). At 5 years, 23% (34/148) patients remained in clinical remission on thiopurine monotherapy (25 CD and 9 UC patients). Thirty-three percent (33/100) of CD and 46% (22/48) of UC patients relapsed while on thiopurines. There was no difference in relapse rates between CD and UC patients. Eighty-four percent (42/50) of patients with CD with side effects and all UC (17/17) patients who experienced side effects discontinued the drug. CONCLUSION This analysis demonstrates that there is poor sustainability of clinical remission in IBD patients on thiopurine monotherapy given that a high proportion of patients discontinue thiopurines due to either relapse or side effects.
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Ding L, Zhang FB, Liu H, Gao X, Bi HC, Huang L, Wang XD, Chen BL, Zhang Y, Lv C, Hu PJ, Huang M. Xanthine oxidase activity in thiopurine curative Chinese inflammatory bowel disease patients. Pharmacol Res Perspect 2021; 9:e00764. [PMID: 33929082 PMCID: PMC8085934 DOI: 10.1002/prp2.764] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2020] [Accepted: 03/14/2021] [Indexed: 11/21/2022] Open
Abstract
Xanthine oxidase (XO) competes with thiopurine S‐methyltransferase (TPMT) and hypoxanthine guanine phosphoribosyltransferase (HPRT) to metabolize azathioprine (AZA)/6‐mercaptopurine (6‐MP) in vivo. A retrospective investigation was performed to detect the activity of XO in thiopurine curative Chinese inflammatory bowel disease (IBD) patients. We also evaluated whether a relationship between XO activity and incidence of thiopurine‐induced adverse effects (AEs) existed. Clinical data and blood samples were collected from 140 IBD patients before receiving AZA/6‐MP therapy, and the erythrocyte XO activity was measured. The XO activities of all patients were 20.29 ± 4.43 U/g Hb. No sex difference in XO activity was observed (p = .728), and the XO activity showed no difference between the UC and CD patients (p = .082). AEs were observed in 41 (29.3%) patients including leukopenia (26, 18.57%), gastrointestinal intolerance (11, 7.86%), flu‐like symptom (5, 3.57%), alopecia (5, 3.57%), and hepatotoxicity (1, 0.71%). XO activity was significantly lower in the patients with AEs than in those without AEs (18.40 ± 3.73 vs. 21.07 ± 4.48 U/g Hb, p = .001), especially in the patients with leukopenia (18.29 ± 3.68 vs. 21.07 ± 4.48 U/g Hb, p = .004). However, no significant difference in XO activity was found between patients with and without other AEs. Decreased XO activity was observed in the patients who developed flu‐like symptoms (17.58 ± 3.50 U/g Hb) and alopecia (18.67 ± 2.91 U/g Hb) compared to those who did not, although the differences did not reach statistical significance. These findings suggested that patients with low XO expression might have a high risk of thiopurine‐induced toxicity.
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Affiliation(s)
- Liang Ding
- Clinical Trial and Research Center, People's Hospital of Baoan Shenzhen, Shenzhen, PR China
| | - Fang-Bin Zhang
- Department of Gastroenterology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, PR China
| | - Hui Liu
- Department of Pharmacy, The First Affiliated Hospital of Jinan University, Guangzhou, PR China
| | - Xiang Gao
- Department of Gastroenterology, The Sixth Affiliated Hospital of Sun Yat-sen University, Guangzhou, PR China
| | - Hui-Chang Bi
- Institute of Clinical Pharmacology, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, PR China
| | - Ling Huang
- Key Laboratory of Emergency and Trauma, Ministry of Education, College of Emergency and Trauma, Hainan Medical University, Haikou, China
| | - Xue-Ding Wang
- Institute of Clinical Pharmacology, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, PR China
| | - Bai-Li Chen
- Department of Gastroenterology, First Affiliated Hospital, Sun Yat-sen University, Guangzhou, PR China
| | - Yu Zhang
- Institute of Clinical Pharmacology, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, PR China
| | - Chuanzhu Lv
- Key Laboratory of Emergency and Trauma, Ministry of Education, College of Emergency and Trauma, Hainan Medical University, Haikou, China
| | - Pin-Jin Hu
- Department of Gastroenterology, The Sixth Affiliated Hospital of Sun Yat-sen University, Guangzhou, PR China
| | - Min Huang
- Institute of Clinical Pharmacology, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, PR China
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