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Vieujean S, Jairath V, Peyrin-Biroulet L, Dubinsky M, Iacucci M, Magro F, Danese S. Understanding the therapeutic toolkit for inflammatory bowel disease. Nat Rev Gastroenterol Hepatol 2025:10.1038/s41575-024-01035-7. [PMID: 39891014 DOI: 10.1038/s41575-024-01035-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 12/19/2024] [Indexed: 02/03/2025]
Abstract
Inflammatory bowel disease (IBD), encompassing ulcerative colitis and Crohn's disease, is a group of chronic, immune-mediated disorders of the gastrointestinal tract that present substantial clinical challenges owing to their complex pathophysiology and tendency to relapse. A treat-to-target approach is recommended, involving iterative treatment adjustments to achieve clinical response, reduce inflammatory markers and achieve long-term goals such as mucosal healing. Lifelong medication is often necessary to manage the disease, maintain remission and prevent complications. The therapeutic landscape for IBD has evolved substantially; however, a ceiling on therapeutic efficacy remains and surgery is sometimes required (owing to uncontrolled disease activity or complications). Effective IBD management involves comprehensive care, including medication adherence and a collaborative clinician-patient relationship. This Review discusses current therapeutic options for IBD, detailing mechanisms of action, efficacy, safety profiles and guidelines for use of each drug class. We also explore emerging therapies and the role of surgery. Additionally, the importance of a multidisciplinary team and personalized care in managing IBD is emphasized, advocating for patient empowerment and involvement in treatment decisions. By synthesizing current knowledge and emerging trends, this Review aims to equip healthcare professionals with a thorough understanding of therapeutic options for IBD, enhancing informed, evidence-based decisions in clinical practice.
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Affiliation(s)
- Sophie Vieujean
- Hepato-Gastroenterology and Digestive Oncology, University Hospital CHU of Liège, Liège, Belgium
- Department of Gastroenterology, INFINY Institute, CHRU Nancy, Vandœuvre-lès-Nancy, France
| | - Vipul Jairath
- Division of Gastroenterology, Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada
| | - Laurent Peyrin-Biroulet
- Department of Gastroenterology, INFINY Institute, CHRU Nancy, Vandœuvre-lès-Nancy, France
- Division of Gastroenterology and Hepatology, McGill University Health Centre, Montreal, Quebec, Canada
| | - Marla Dubinsky
- Department of Paediatrics, Susan and Leonard Feinstein IBD Center, Icahn School of Medicine, Mount Sinai, New York, NY, USA
| | - Marietta Iacucci
- APC Microbiome Ireland, College of Medicine and Health, University College of Cork, Cork, Ireland
| | - Fernando Magro
- CINTESIS@RISE, Faculty of Medicine, University of Porto, Porto, Portugal
| | - Silvio Danese
- Gastroenterology and Endoscopy, IRCCS Ospedale San Raffaele and University Vita-Salute San Raffaele, Milano, Italy.
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de Boer NKH, Simsek M, Meijer B, Neurath MF, van Bodegraven A, Mulder CJJ. Drug rediscovery in gastroenterology: from off-label to on-label use of thioguanine in inflammatory bowel disease. Gut 2023; 72:1985-1991. [PMID: 37380330 DOI: 10.1136/gutjnl-2023-329679] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/09/2023] [Accepted: 06/16/2023] [Indexed: 06/30/2023]
Abstract
Drug rediscovery refers to the principle of using 'old' drugs outside the indications mentioned in the summary of product characteristics. In the past decades, several drugs were rediscovered in a wide variety of medical fields. One of the most recent examples is the unconditional registration of thioguanine (TG), a thiopurine derivative, in patients with inflammatory bowel disease in the Netherlands. In this paper, we aim to visualise potential hurdles that hamper drug rediscovery in general, emphasise the global need for optimal use and development of potentially useful drugs, and provide an overview of the registration process for TG in the Netherlands. With this summary, we aim to guide drug rediscovery trajectories in the near future.
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Affiliation(s)
- Nanne K H de Boer
- Gastroenterology and Hepatology, Amsterdam University Medical Centres, Amsterdam, The Netherlands
- Research Institute, Amsterdam Gastroenterology Endocrinology Metabolism, Amsterdam, Noord-Holland, The Netherlands
| | - Melek Simsek
- Gastroenterology and Hepatology, Amsterdam University Medical Centres, Amsterdam, The Netherlands
- School of Medicine, VU University, Amsterdam, The Netherlands
| | - Berrie Meijer
- Gastroenterology and Hepatology, Amsterdam University Medical Centres, Amsterdam, The Netherlands
- School of Medicine, VU University, Amsterdam, The Netherlands
| | - Markus F Neurath
- First Department of Medicine, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany
| | - Ad van Bodegraven
- Department of Gastroenterology, Geriatrics, Internal and Intensive Care Medicine (Co-MIK), Zuyderland Medical Centre, Heerlen-Sittard-Geleen, The Netherlands
| | - Chris J J Mulder
- Gastroenterology and Hepatology, Amsterdam University Medical Centres, Amsterdam, The Netherlands
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Zhang X, Rosh JR. Safety Summary of Pediatric Inflammatory Bowel Disease Therapies. Gastroenterol Clin North Am 2023; 52:535-548. [PMID: 37543398 DOI: 10.1016/j.gtc.2023.05.007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/07/2023]
Abstract
Therapeutic options for the treatment of pediatric inflammatory bowel disease include aminosalicylates, enteral nutrition, corticosteroids, immunomodulators, biologics, and emerging small molecule agents. Infectious risk due to systemic immunosuppression should be mitigated by appropriate screening before therapy initiation. Rare but serious malignancies have been associated with thiopurine use alone and in combination with anti-tumor necrosis factor agents, often in the setting of a primary Epstein-Barr virus infection. Potential agent-specific adverse events such as cytopenias, hepatotoxicity, and nephrotoxicity warrant regular clinical and laboratory monitoring.
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Affiliation(s)
- Xiaoyi Zhang
- Pediatric Gastroenterology, Department of Pediatrics, Division of Gastroenterology, Hepatology and Nutrition, Indiana University, 705 Riley Hospital Drive, ROC 4210, Indianapolis, IN 46202, USA. https://twitter.com/xtzhang
| | - Joel R Rosh
- Pediatric Gastroenterology, Division of Pediatric Gastroenterology, Liver Disease, and Nutrition, Cohen Children's Medical Center of New York, 1991 Marcus Avenue, Suite M100, Lake Success, NY 11042, USA.
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Eltantawy N, El-Zayyadi IAEH, Elberry AA, Salah LM, Abdelrahim MEA, Kassem AB. Association of genetic polymorphism of NUDT15, TPMT and ITPA gene in the toxicity and efficacy of azathioprine-based regimen in Egyptian inflammatory bowel disease patients. BENI-SUEF UNIVERSITY JOURNAL OF BASIC AND APPLIED SCIENCES 2023. [DOI: 10.1186/s43088-023-00340-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/03/2023] Open
Abstract
Abstract
Background
Inflammatory Bowel disease (IBD) is a chronic progressive condition that prompts generous physical and mental morbidity. Choosing the best kind of management and medication dosage prevents new episodes of high disease activity during therapy because of adverse drug reactions (ADRs). This can lead to cessation or inefficacy of the treatment, or complete non-responsiveness to specific medications. Pharmacogenetics (PGx) is a well-established aspect in IBD. One of the exemplary instances of PGx is thiopurines, which are frequently utilized as IBD therapy. This study aimed to evaluate specific gene polymorphism involved in the toxicity and efficacy of Azathioprine (AZA) use in the management in Egyptian patients and to find the correlation between the polymorphism of Nudix Hydrolase15 (NUDT15) gene (rs116855232), The Thiopurine methyltransferase (TPMT) gene (rs1800460) and Inosine Triphosphatase (ITPA) gene (rs1127354) which are involved in the metabolism of the medications utilized in IBD management.
Methods
This prospective study was performed in 150 patients with IBD. All patients were treated with 2 mg/kg per day AZA (Imuran, GlaxoSmithKline®) for at least 3 months at therapeutic doses to induce remission. Subsequent treatment of AZA. The minimum follow-up period for those who did not experience ADR was one year. Among the studied patients, one hundred twenty-nine patients were treated with combination regimen of steroids (oral prednisone 1 mg/kg/day).
Also, treatment failure was considered among the patients who could not tolerate AZA side effects, or there was no improvement after dose modification.
Results
The most identifiable adverse effect among the studied population was anemia followed by leukopenia and myelosuppression. SNPs genotype TPMT (rs1800460) and ITPA gene (rs1127354) were significantly related to adverse effects among IBD patients receiving Azathioprine treatment. There was a lack of any variants in the NUDT15 genotype among the Egyptian population.
Conclusion
Further research is required in to clarify the relationship between NUDT15 PGx and AZA-ADRs. The effect of NUDT15 PGx on toxicity and ADRs as yet necessitates to be elucidated. Studies with a larger sample size and involving different ethnicities are also necessary.
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Dickson AL, Daniel LL, Jackson E, Zanussi J, Yang W, Plummer WD, Dupont WD, Wei WQ, Nepal P, Hung AM, Cox NJ, Van Driest SL, Feng Q, Yang JJ, Stein CM, Mosley JD, Chung CP. Race, Genotype, and Azathioprine Discontinuation : A Cohort Study. Ann Intern Med 2022; 175:1092-1099. [PMID: 35724382 PMCID: PMC9378477 DOI: 10.7326/m21-4675] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/03/2023] Open
Abstract
BACKGROUND Thiopurines are an important class of immunosuppressants despite their risk for hematopoietic toxicity and narrow therapeutic indices. Benign neutropenia related to an ACKR1 variant (rs2814778-CC) is common among persons of African ancestries. OBJECTIVE To test whether rs2814778-CC was associated with azathioprine discontinuation attributed to hematopoietic toxicity and lower thiopurine dosing. DESIGN Retrospective cohort study. SETTING Two tertiary care centers. PATIENTS Thiopurine users with White or Black race. MEASUREMENTS Azathioprine discontinuation attributed to hematopoietic toxicity. Secondary outcomes included weight-adjusted final dose, leukocyte count, and change in leukocyte count. RESULTS The rate of azathioprine discontinuation attributed to hematopoietic toxicity was 3.92 per 100 person-years among patients with the CC genotype (n = 101) and 1.34 per 100 person-years among those with the TT or TC genotype (n = 1365) (hazard ratio [HR] from competing-risk model, 2.92 [95% CI, 1.57 to 5.41]). The risk remained significant after adjustment for race (HR, 2.61 [CI, 1.01 to 6.71]). The risk associated with race alone (HR, 2.13 [CI, 1.21 to 3.75]) was abrogated by adjustment for genotype (HR, 1.13 [CI, 0.48 to 2.69]). Lower last leukocyte count and lower dosing were significant among patients with the CC genotype. Lower dosing was validated in an external cohort of 94 children of African ancestries prescribed the thiopurine 6-mercaptopurine (6-MP) for acute lymphoblastic leukemia. The CC genotype was independently associated with lower 6-MP dose intensity relative to the target daily dose of 75 mg/m2 (median, 0.83 [IQR, 0.70 to 0.94] for the CC genotype vs. 0.94 [IQR, 0.72 to 1.13] for the TT or TC genotype; P = 0.013). LIMITATIONS Unmeasured confounding; data limited to tertiary centers. CONCLUSION Patients with the CC genotype had higher risk for azathioprine discontinuation attributed to hematopoietic toxicity and lower thiopurine doses. Genotype was associated with those risks, even after adjustment for race. PRIMARY FUNDING SOURCE National Institutes of Health.
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Affiliation(s)
- Alyson L Dickson
- Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee (A.L.D., L.L.D., E.J., J.Z., P.N., A.M.H., N.J.C., Q.F., C.M.S., C.P.C.)
| | - Laura L Daniel
- Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee (A.L.D., L.L.D., E.J., J.Z., P.N., A.M.H., N.J.C., Q.F., C.M.S., C.P.C.)
| | - Elise Jackson
- Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee (A.L.D., L.L.D., E.J., J.Z., P.N., A.M.H., N.J.C., Q.F., C.M.S., C.P.C.)
| | - Jacy Zanussi
- Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee (A.L.D., L.L.D., E.J., J.Z., P.N., A.M.H., N.J.C., Q.F., C.M.S., C.P.C.)
| | - Wenjian Yang
- Pharmacy and Pharmaceutical Sciences Department, St. Jude Children's Research Hospital, Memphis, Tennessee (W.Y., J.J.Y.)
| | - W Dale Plummer
- Department of Biostatistics, Vanderbilt University Medical Center, Nashville, Tennessee (W.D.P., W.D.D.)
| | - William D Dupont
- Department of Biostatistics, Vanderbilt University Medical Center, Nashville, Tennessee (W.D.P., W.D.D.)
| | - Wei-Qi Wei
- Department of Biomedical Informatics, Vanderbilt University Medical Center, Nashville, Tennessee (W.W.)
| | - Puran Nepal
- Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee (A.L.D., L.L.D., E.J., J.Z., P.N., A.M.H., N.J.C., Q.F., C.M.S., C.P.C.)
| | - Adriana M Hung
- Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee (A.L.D., L.L.D., E.J., J.Z., P.N., A.M.H., N.J.C., Q.F., C.M.S., C.P.C.)
| | - Nancy J Cox
- Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee (A.L.D., L.L.D., E.J., J.Z., P.N., A.M.H., N.J.C., Q.F., C.M.S., C.P.C.)
| | - Sara L Van Driest
- Departments of Medicine and Pediatrics, Vanderbilt University Medical Center, Nashville, Tennessee (S.L.V.)
| | - QiPing Feng
- Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee (A.L.D., L.L.D., E.J., J.Z., P.N., A.M.H., N.J.C., Q.F., C.M.S., C.P.C.)
| | - Jun J Yang
- Pharmacy and Pharmaceutical Sciences Department, St. Jude Children's Research Hospital, Memphis, Tennessee (W.Y., J.J.Y.)
| | - C Michael Stein
- Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee (A.L.D., L.L.D., E.J., J.Z., P.N., A.M.H., N.J.C., Q.F., C.M.S., C.P.C.)
| | - Jonathan D Mosley
- Departments of Medicine and Biomedical Informatics, Vanderbilt University Medical Center, Nashville, Tennessee (J.D.M.)
| | - Cecilia P Chung
- Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee (A.L.D., L.L.D., E.J., J.Z., P.N., A.M.H., N.J.C., Q.F., C.M.S., C.P.C.)
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[Effect of genetic polymorphism of TPMT and NUDT15 on the tolerance of 6-mercaptopurine therapy in adult acute lymphoblastic leukemia]. ZHONGHUA XUE YE XUE ZA ZHI = ZHONGHUA XUEYEXUE ZAZHI 2021; 42:911-916. [PMID: 35045652 PMCID: PMC8763585 DOI: 10.3760/cma.j.issn.0253-2727.2021.11.005] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Abstract
Objective: To investigate the effect of genetic polymorphisms of TPMT*2 rs1800462, TPMT*3B rs1800460, TPMT*3C rs1142345, and NUDT15 rs116855232 on the tolerance of 6-mercaptopurine (6-MP) therapy in adult acute lymphoblastic leukemia (ALL) . Methods: A total of 216 adult patients who were diagnosed with ALL and treated with cyclophosphamide, cytarabine, and 6-MP [complementary and alternative medicine (CAM) regimen] from September 2015 to December 2019 were included. Polymorphisms were detected by TaqMan SNP Genotyping Assay. Combined with clinical data, the influence of genetic polymorphism on the tolerance of 6-MP in the treatment of ALL was analyzed. Results: Among the 216 patients, 185 (85.65%) patients had B-ALL and 31 (14.35%) patients had T-ALL. 216 (100%) patients had CC genotype for both TPMT*2 rs1800462 and TPMT*3B rs1800460. The number of TT and TC genotypes for TPMT*3C rs1142345 was 209 (96.76%) and 7 (3.24%) , respectively. The allele frequency was 1.62% for TPMT*3C rs1142345. The number of CC, CT, and TT genotypes for NUDT15 rs116855232 was 166 (76.85%) , 48 (22.22%) , and 2 (0.93%) , respectively. The allele frequency was 12.04% for NUDT15 rs116855232. The TPMT*3C rs1142345 mutant group (TC+CC genotype) had less transfusion volume of packed red blood cell than the wild group (CC genotype) (P=0.036) , and the mutant group (TC+CC genotype) had a higher risk to develop hepatotoxicity (increased aspartate aminotransferase) than the wild group (CC genotype) (OR=9.559, 95% CI 1.135-80.475, P=0.038) . The durations of white blood cells (WBC) <1×10(9)/L and absolute neutrophil count (ANC) <0.5×10(9)/L in the NUDT15 rs116855232 mutation group (CT+TT genotype) were longer than that in the wild group (CC genotype) (P=0.005, P=0.007) , and the transfusion volume of apheresis-derived platelets in the mutant group (CT+TT type) was greater than that in the wild group (CC genotype) (P=0.014) . Conclusion: Genetic polymorphism of TMPT and NUDT15 has an effect on the tolerance of 6-MP in the treatment of adult ALL. Detecting genotypes of patients with ALL before treatment helps to optimize the dosage of 6-MP, which may help shorten the bone marrow suppression duration and reduce blood transfusion volume.
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Bakulin IG, Skalinskaya MI, Maev IV, Skazyvaeva EV, Zhuravleva MS, Gaikovaya LB, Bakulina NV, Ermakov AI, Alekseenko ES, Ivanova KN, Solovev MV. Pharmacotherapy of inflammatory bowel diseases: efficacy performance and safety management. TERAPEVT ARKH 2021; 93:841-852. [DOI: 10.26442/00403660.2021.08.200982] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2021] [Accepted: 08/30/2021] [Indexed: 12/30/2022]
Abstract
Treatment of inflammatory bowel diseases IBD (Crohns disease, ulcerative colitis) is aimed at achieving clinical, endoscopic and histological remission, minimizing surgical complications, and ensuring a normal quality of life. However, the use of medical treatment is potentially associated with various adverse events, among which infectious complications, malignant neoplasms, as well as myelotoxicity, hepatotoxicity, skin lesions and others. The risk of side effects depends on the type of drug therapy (5-aminosalicylates, thiopurines, biologicals, etc.), the duration of treatment, the presence of extra-intestinal manifestations, etc. The article provides an overview of data on both the effectiveness and frequency of various side effects of the main classes of drugs in IBD, presents methods of investigation which can predict the effectiveness and development of side effects, the implementation of which can be considered as a variant of personalized therapy in IBD.
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Boonyawat B, Monsereenusorn C, Photia A, Lertvivatpong N, Kaewchaivijit V, Jindatanmanusan P, Rujkijyanont P. ITPA:c.94C>A and NUDT15:c.415C>T Polymorphisms and Their Relation to Mercaptopurine-Related Myelotoxicity in Childhood Leukemia in Thailand. APPLICATION OF CLINICAL GENETICS 2021; 14:341-351. [PMID: 34349542 PMCID: PMC8326781 DOI: 10.2147/tacg.s318912] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/06/2021] [Accepted: 07/19/2021] [Indexed: 11/30/2022]
Abstract
Background Mercaptopurine is a key agent in childhood leukemia treatment. Genetic polymorphism in the genes involving thiopurine metabolisms is related to 6-MP related toxicity. Objective This study aimed to determine the prevalence of ITPA:c.94C>A and NUDT15:c.415C>T polymorphisms among Thai children diagnosed with leukemia and their association with mercaptopurine-related myelotoxicity. Methods Patients and survivors with a diagnosis of leukemia treated with mercaptopurine-containing chemotherapy regimens were enrolled. Clinical data and laboratory parameters during treatment as well as ITPA:c.94C>A and NUDT15:c.415C>T genotypes were analyzed. Results In all, 99 patients with acute leukemia or survivors were enrolled in the study. The prevalences of ITPA:c.94C>A, NUDT15:c.415C>T, and co-occurrence of ITPA:c.94C>A and NUDT15:c.415C>T polymorphisms were 34, 17, and 4%, respectively. Numbers of absolute neutrophil count (ANC) and platelet count significantly decreased among patients carrying NUDT15:c.415C>T compared with NUDT15 wild type patients with p-values<0.001 and 0.019, respectively. The differences were not observed among patients carrying ITPA:c.94C>A compared with ITPA wild type patients. According to multivariate GEE, NUDT15:c.415C>T and co-occurrence of ITPA:c.94C>A and NUDT15:c.415C>T had a significant negative effect on ANC during treatment (coefficient: −463.81; CI: −778.53, −149.09; p-value=0.004 and coefficient: −527.56; CI: −1045.65, −9.48; p-value=0.046). No significant effect of ITPA:c.94C>A on ANC during treatment was observed. Conclusion ITPA:c.94C>A and NUDT15:c.415C>T polymorphisms are common among Thai children with leukemia. A strong association with mercaptopurine-related myelotoxicity was observed among patients carrying either NUDT15:c.415C>T alone or combined with ITPA:c.94C>A.
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Affiliation(s)
- Boonchai Boonyawat
- Division of Medical Genetics, Department of Pediatrics, Phramongkutklao College of Medicine and Phramongkutklao Hospital, Bangkok, Thailand
| | - Chalinee Monsereenusorn
- Division of Hematology-Oncology, Department of Pediatrics, Phramongkutklao College of Medicine and Phramongkutklao Hospital, Bangkok, Thailand
| | - Apichat Photia
- Division of Hematology-Oncology, Department of Pediatrics, Phramongkutklao College of Medicine and Phramongkutklao Hospital, Bangkok, Thailand
| | - Nawachai Lertvivatpong
- Division of Hematology-Oncology, Department of Pediatrics, Phramongkutklao College of Medicine and Phramongkutklao Hospital, Bangkok, Thailand
| | - Varissara Kaewchaivijit
- Department of Pediatrics, Phramongkutklao College of Medicine and Phramongkutklao Hospital, Bangkok, Thailand
| | - Punyanuch Jindatanmanusan
- Division of Hematology-Oncology, Department of Pediatrics, Phramongkutklao College of Medicine and Phramongkutklao Hospital, Bangkok, Thailand
| | - Piya Rujkijyanont
- Division of Hematology-Oncology, Department of Pediatrics, Phramongkutklao College of Medicine and Phramongkutklao Hospital, Bangkok, Thailand
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9
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Moyer AM. NUDT15: A bench to bedside success story. Clin Biochem 2021; 92:1-8. [PMID: 33675810 DOI: 10.1016/j.clinbiochem.2021.02.007] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2021] [Revised: 02/10/2021] [Accepted: 02/14/2021] [Indexed: 12/13/2022]
Abstract
Recently, the enzyme nudix hydrolase 15 (NUDT15) has been identified as an additional component of the thiopurine metabolism pathway. NUDT15 (also known as MTH2) catalyzes the dephosphorylation of 6-thioguanosine triphosphate (6-TGTP) and 6-thio-deoxyguanosine triphosphate (6-TdGTP), which is the active metabolite of thiopurine medications. Thiopurine compounds, which were first synthesized in the 1950s, are widely used in the treatment of childhood leukemia, inflammatory bowel disease, and autoimmune disorders. For many years, TPMT has been recognized as an enzyme that is involved in thiopurine metabolism, and interindividual variation in TPMT activity has been known to contribute to differences in risk of thiopurine toxicity. Genetic variation that leads to decreased NUDT15 activity has been recognized as an additional contributor, beyond TPMT, to thiopurine toxicity. In some populations, including Asian and Latino populations, NUDT15 genetic variants are more common than TPMT variants, making this a significant biomarker of toxicity. Clinical genetic testing is now available for a subset of NUDT15 variants, representing a remarkably fast translation from bench to bedside. This review will focus on NUDT15 - from discovery to clinical implementation.
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Affiliation(s)
- Ann M Moyer
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN 55905, United States.
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10
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Hegyi PJ, Szakács Z, Faluhelyi N, Németh BC, Bajor J, Hegyi P. Recurrent acute pancreatitis induced by 5-ASA and azathioprine in ulcerative colitis. Pancreatology 2020; 20:1656-1660. [PMID: 33250090 DOI: 10.1016/j.pan.2020.10.026] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/30/2020] [Revised: 10/04/2020] [Accepted: 10/05/2020] [Indexed: 12/11/2022]
Abstract
Drug-induced acute pancreatitis (DIAP) is an often-neglected entity where the disorder is the consequence of the toxic effects of various agents applied to treat potentially life-threatening conditions, such as inflammatory bowel disease. Here, we present the case of a male patient with ulcerative colitis with a history of two episodes of recurrent acute pancreatitis. After excluding other potential causes, we suspected DIAP since the patient received 5-aminosalycilate (5-ASA) prior to the first episode and, one year later, azathioprine (AZA) prior to the second episode. The causative effect of AZA was confirmed by performing a re-challenge with a reduced dose. While both episodes of DIAP had a mild disease course, they were associated with acute relapse of ulcerative colitis. Last seen, the patient was asymptomatic. With this case, we would like to highlight the importance and diagnostic difficulties of DIAP in the background of recurrent cases when common etiological factors of acute pancreatitis are excluded.
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Affiliation(s)
- Péter Jenő Hegyi
- Institute for Translational Medicine, Medical School, University of Pécs, Pécs, Hungary
| | - Zsolt Szakács
- Institute for Translational Medicine, Medical School, University of Pécs, Pécs, Hungary; Szentágothai Research Center, University of Pécs, Pécs, Hungary
| | - Nándor Faluhelyi
- Department of Diagnostic Imaging, University of Pécs, Pécs, Hungary
| | - Balázs Csaba Németh
- Centre for Translational Medicine, First Department of Medicine, Faculty of Medicine, University of Szeged, Szeged, Hungary
| | - Judit Bajor
- Division of Gastroenterology, First Department of Medicine, Medical School, University of Pécs, Pécs, Hungary
| | - Péter Hegyi
- Institute for Translational Medicine, Medical School, University of Pécs, Pécs, Hungary; Centre for Translational Medicine, First Department of Medicine, Faculty of Medicine, University of Szeged, Szeged, Hungary.
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Lin R, Lin W, Wang C, Dong J, Zheng W, Zeng D, Liu Y, Lin C, Jiao Z, Huang P. Population pharmacokinetics of azathioprine active metabolite in patients with inflammatory bowel disease and dosage regimens optimisation. Basic Clin Pharmacol Toxicol 2020; 128:482-492. [PMID: 33150655 DOI: 10.1111/bcpt.13530] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2020] [Revised: 10/12/2020] [Accepted: 11/02/2020] [Indexed: 12/25/2022]
Abstract
Azathioprine is a first-line drug used to maintain the remission of inflammatory bowel disease (IBD). As a prodrug, azathioprine is metabolised to produce active 6-thioguanine nucleotides (6-TGN). There are large individual variations in the pharmacokinetics/pharmacodynamics of 6-TGN in patients with IBD. Here, we aimed to develop a model to quantitatively investigate factors that affect 6-TGN pharmacokinetics to formulate a dosage guideline for azathioprine. Data were collected prospectively from 100 adult patients with IBD who were receiving azathioprine. Patients were genotyped for two single-nucleotide polymorphisms (TPMT*3C c.719A > G and NUDT15 c.415C > T). Using high-performance liquid chromatography, we measured 156 steady-state trough concentrations of 6-TGN within the range 0.09 to 1.16 mg/L (ie 133-1733 pmol per 8 × 108 RBC). The covariates analysed included sex, age, body-weight, laboratory tests and concomitant medications. A population pharmacokinetic model was established using "non-linear mixed-effects modelling" software and the "first-order conditional estimation method with interaction." Body-weight, TPMT*3C polymorphisms and co-therapy with mesalazine were found to be important factors influencing the clearance of 6-TGN. A dosage guideline for azathioprine was developed based on the PPK model that enables individualised azathioprine dosing in adult patients with different body-weights, TPMT*3C genotypes and co-administration with mesalazine.
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Affiliation(s)
- Rongfang Lin
- Department of Pharmacy, The First Affiliated Hospital, Fujian Medical University, Fuzhou, China
| | - Weiwei Lin
- Department of Pharmacy, The First Affiliated Hospital, Fujian Medical University, Fuzhou, China
| | - Changlian Wang
- Department of Pharmacy, The First Affiliated Hospital, Fujian Medical University, Fuzhou, China
| | - Jiashan Dong
- Department of Pharmacy, The First Affiliated Hospital, Fujian Medical University, Fuzhou, China
| | - Weiwei Zheng
- Department of Gastroenterology, The First Affiliated Hospital, Fujian Medical University, Fuzhou, China
| | - Dayong Zeng
- Department of Pharmacy, The First Affiliated Hospital, Fujian Medical University, Fuzhou, China
| | - Yiwei Liu
- Department of Pharmacy, The First Affiliated Hospital, Fujian Medical University, Fuzhou, China
| | - Cuihong Lin
- Department of Pharmacy, The First Affiliated Hospital, Fujian Medical University, Fuzhou, China
| | - Zheng Jiao
- Department of Pharmacy, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, China
| | - Pinfang Huang
- Department of Pharmacy, The First Affiliated Hospital, Fujian Medical University, Fuzhou, China
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12
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Anandi P, Dickson AL, Feng Q, Wei WQ, Dupont WD, Plummer D, Liu G, Octaria R, Barker KA, Kawai VK, Birdwell K, Cox NJ, Hung A, Stein CM, Chung CP. Combining clinical and candidate gene data into a risk score for azathioprine-associated leukopenia in routine clinical practice. THE PHARMACOGENOMICS JOURNAL 2020; 20:736-745. [PMID: 32054992 PMCID: PMC7426242 DOI: 10.1038/s41397-020-0163-4] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/04/2019] [Revised: 01/22/2020] [Accepted: 01/30/2020] [Indexed: 02/06/2023]
Abstract
Leukopenia is a serious, frequent side effect associated with azathioprine use. Currently, we use thiopurine methyltransferase (TPMT) testing to predict leukopenia in patients taking azathioprine. We hypothesized that a risk score incorporating additional clinical and genetic variables would improve the prediction of azathioprine-associated leukopenia. In the discovery phase, we developed four risk score models: (1) age, sex, and TPMT metabolizer status; (2) model 1 plus additional clinical variables; (3) sixty candidate single nucleotide polymorphisms; and (4) model 2 plus model 3. The area under the receiver-operating-characteristic curve (AUC) of the risk scores was 0.59 (95% CI: 0.54-0.64), 0.75 (0.71-0.80), 0.66 (0.61-0.71), and 0.78 (0.74-0.82) for models 1, 2, 3, and 4, respectively. During the replication phase, models 2 and 4 (AUC = 0.64, 95% CI: 0.59-0.70 and AUC = 0.63, 95% CI: 0.58-0.69, respectively) were significant in an independent group. Compared with TPMT testing alone, additional genetic and clinical variables improve the prediction of azathioprine-associated leukopenia.
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Affiliation(s)
- Prathima Anandi
- Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Alyson L Dickson
- Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA
| | - QiPing Feng
- Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Wei-Qi Wei
- Department of Biomedical Informatics, Vanderbilt University Medical Center, Nashville, TN, USA
| | - William D Dupont
- Department of Biostatistics, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Dale Plummer
- Department of Biostatistics, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Ge Liu
- Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Rany Octaria
- Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Katherine A Barker
- Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Vivian K Kawai
- Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Kelly Birdwell
- Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Nancy J Cox
- Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Adriana Hung
- Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA
| | - C Michael Stein
- Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Cecilia P Chung
- Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA.
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13
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Drug-Induced Neutropenia During Treatment of Non-Neoplastic Dermatologic Diseases: A Review. Clin Drug Investig 2020; 40:915-926. [PMID: 32691244 DOI: 10.1007/s40261-020-00956-w] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Idiosyncratic drug-induced neutropenia (DIN) is a rare, potentially fatal adverse reaction. A literature search was performed on Pubmed and Embase, targeting articles indicating neutropenia as a complication during the treatment of non-neoplastic dermatological disorders. In 66 identified articles, the common incriminated drugs included conventional oral immunomodulators, topical cytotoxic agents, antibacterials, antifungals, biologics and targeted synthetic disease-modifying antirheumatic drugs, non-steroidal anti-inflammatory drugs, and retinoids, with dapsone being reported most often. The duration of drug exposure before the diagnosis of neutropenia varied, but mostly ranged from days to weeks. The majority of patients recovered after drug discontinuation and supportive management including antibiotics and granulocyte colony-stimulating factor, but fatal cases were reported. The proposed pathogenesis of DIN consists of direct drug toxicity and immune-mediated reaction. Certain genetic variants, individual variability in enzyme efficiency, and concomitant use of other drugs may increase the risk of DIN. Being familiar with the most commonly implicated agents and risk factors helps early identification and prompt management of this potentially fatal complication.
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14
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Daniel LL, Dickson AL, Chung CP. Precision medicine for rheumatologists: lessons from the pharmacogenomics of azathioprine. Clin Rheumatol 2020; 40:65-73. [PMID: 32617765 DOI: 10.1007/s10067-020-05258-2] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2020] [Revised: 06/16/2020] [Accepted: 06/22/2020] [Indexed: 12/13/2022]
Abstract
Precision medicine aims to personalize treatment for both effectiveness and safety. As a critical component of this emerging initiative, pharmacogenomics seeks to guide drug treatment based on genetics. In this review article, we give an overview of pharmacogenomics in the setting of an immunosuppressant frequently prescribed by rheumatologists, azathioprine. Azathioprine has a narrow therapeutic index and a high risk of adverse events. By applying candidate gene analysis and unbiased approaches, researchers have identified multiple variants associated with an increased risk for adverse events associated with azathioprine, particularly bone marrow suppression. Variants in two genes, TPMT and NUDT15, are widely recognized, leading drug regulatory agencies and professional organizations to adopt recommendations for testing before initiation of azathioprine therapy. As more gene-drug interactions are discovered, our field will continue to face the challenge of balancing benefits and costs associated with genetic testing. However, novel approaches in genomics and the integration of clinical and genetic factors into risk scores offer unprecedented opportunities for the application of pharmacogenomics in routine practice. Key Points • Pharmacogenomics can help us understand how individuals' genetics may impact their response to medications. • Azathioprine is a success story for the clinical implementation of pharmacogenomics, particularly the effects of TPMT and NUDT15 variants on myelosuppression. • As our knowledge advances, testing and dosing recommendations will continue to evolve, with our field striving to balance costs and benefits to patients. • As we aim toward the goals of precision medicine, future research may integrate increasingly individualized traits-including clinical and genetic characteristics-to predict the safety and efficacy of particular medications for individual patients.
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Affiliation(s)
- Laura L Daniel
- Department of Medicine, Division of Rheumatology, Vanderbilt University Medical Center (LLD, ALD, CPC), Nashville, TN, 37232, USA
| | - Alyson L Dickson
- Department of Medicine, Division of Rheumatology, Vanderbilt University Medical Center (LLD, ALD, CPC), Nashville, TN, 37232, USA
| | - Cecilia P Chung
- Department of Medicine, Division of Rheumatology, Vanderbilt University Medical Center (LLD, ALD, CPC), Nashville, TN, 37232, USA. .,Tennessee Valley Healthcare System-Nashville Campus (CPC), Nashville, TN, USA. .,Vanderbilt Genetics Institute, Vanderbilt University School of Medicine (CPC), Nashville, TN, USA.
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Martín-Masot R, Ortiz Pérez MP, Ramos Rueda N, Serrano Nieto J, Blasco-Alonso J, Navas-López VM. Análisis de la determinación de niveles de tiopurínicos en pacientes pediátricos con enfermedad inflamatoria intestinal. An Pediatr (Barc) 2020; 93:34-40. [PMID: 31784325 DOI: 10.1016/j.anpedi.2019.10.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2019] [Revised: 10/04/2019] [Accepted: 10/11/2019] [Indexed: 02/07/2023] Open
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16
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Martín-Masot R, Ortiz Pérez MP, Ramos Rueda N, Serrano Nieto J, Blasco-Alonso J, Navas-López VM. Laboratory determination of thiopurine levels in paediatric patients with inflammatory bowel disease. ANALES DE PEDIATRÍA (ENGLISH EDITION) 2020. [DOI: 10.1016/j.anpede.2019.10.008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
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17
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Predicting, Preventing, and Managing Treatment-Related Complications in Patients With Inflammatory Bowel Diseases. Clin Gastroenterol Hepatol 2020; 18:1324-1335.e2. [PMID: 32059920 DOI: 10.1016/j.cgh.2020.02.009] [Citation(s) in RCA: 82] [Impact Index Per Article: 16.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/09/2019] [Revised: 01/17/2020] [Accepted: 02/03/2020] [Indexed: 02/07/2023]
Abstract
Risk of complications from specific classes of drugs for inflammatory bowel diseases (IBDs) can be kept low by respecting contraindications. Patients with IBD frequently develop serious infections resulting from the disease itself or its treatment. At the time of diagnosis, patients' vaccination calendars should be updated according to IBD guidelines-live vaccines should be postponed for patients receiving immunosuppressive drugs. Opportunistic infections should be detected and the vaccine against pneumococcus should be given before patients begin immunosuppressive therapy. Thiopurines promote serious viral infections in particular, whereas tumor necrosis factor (TNF) antagonists promote all types of serious and opportunistic infections. Severe forms of varicella can be prevented by vaccinating seronegative patients against varicella zoster virus. Detection and treatment of latent tuberculosis is mandatory before starting anti-TNF therapy and other new IBD drugs. Tofacitinib promotes herpes zoster infection in a dose- and age-dependent manner. Physicians should consider giving patients live vaccines against herpes zoster before they begin immunosuppressive therapy or a recombinant vaccine, when available, at any time point during treatment. The risk of thiopurine-induced lymphomas can be lowered by limiting the use of thiopurines in patients who are seronegative for Epstein-Barr virus (especially young men) and in older men. The risk of lymphoma related to monotherapy with anti-TNF agents is still unclear. There are no robust data on the carcinogenic effects of recently developed IBD drugs. For patients with previous cancer at substantial risk of recurrence, physicians should try to implement a pause in the use of immunosuppressive therapy (except in patients with severe disease and no therapeutic alternative) and prioritize use of IBD drugs with the lowest carcinogenic effects. Finally, sun protection and skin surveillance from the time of diagnosis are recommended.
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Huang PW, Tseng YH, Tsai TF. Predictive Value of NUDT15 Variants on Neutropenia Among Han Chinese Patients with Dermatologic Diseases: A Single-Center Observational Study. Dermatol Ther (Heidelb) 2020; 10:263-271. [PMID: 32062783 PMCID: PMC7090103 DOI: 10.1007/s13555-020-00360-4] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2020] [Indexed: 11/28/2022] Open
Abstract
Introduction Azathioprine is a synthetic purine analogue derived from 6-mercaptopurine which acts by disrupting nucleic acid synthesis and interfering with T cell activation. It is effective in dermatology diseases related to the immune system. However, its side effects, including severe neutropenia, kept patients from using it. Mutations in thiopurine methyltransferase (TPMT) and inosine triphosphate pyrophosphohydrolase (ITPA) genes account for the major genetic polymorphism markers for azathioprine adverse risk factors in Caucasians, but not in Asians. The predictive value of the nucleoside diphosphate-linked moiety X motif 15 gene (NUDT15) has been studied in various diseases among different populations. The aim of our study was to determine the contribution of NUDT15 mutations in azathioprine-induced neutropenia in Han Chinese patients with dermatologic diseases. Methods The study enrolled all consecutive patients, older than 13 years old, with dermatological diseases currently treated orally with azathioprine in our clinic. Samples were also collected from patients with documented leukopenia in our prior study that examined the association between TPMT, ITPA, and neutropenia after informed reconsent. Complete blood count, differential count, and hepatic and renal function were checked regularly. The DNA samples for NUDT15 genotype were obtained from the patients. Results In total, we enrolled 56 patients (39 male, 17 female). The NUDT15 genotypes are mostly C/C (N = 36, 64.29%). Heterozygous variant (C/T) accounts for 30.36% (N = 17) and homozygous variant (T/T) accounts for 5.36% (N = 3). Among these patients, 15 patients (26.79%) developed neutropenia, including all three patients carry homozygous variant (T/T). The age-, sex-, and dose-adjusted risk of heterozygous variant compared to wild type is 9.383 (95% CI 1.32–66.96). Conclusions Pretreatment screening of NUDT15 might reduce the chance of azathioprine-induced neutropenia in Han Chinese patients with dermatologic diseases.
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Affiliation(s)
- Po-Wei Huang
- Department of Dermatology, National Taiwan University Hospital and National Taiwan University College of Medicine, No. 7, Chung-Shan South Road, Taipei, Taiwan
| | - Yu-Hsian Tseng
- Department of Dermatology, National Taiwan University Hospital and National Taiwan University College of Medicine, No. 7, Chung-Shan South Road, Taipei, Taiwan
| | - Tsen-Fang Tsai
- Department of Dermatology, National Taiwan University Hospital and National Taiwan University College of Medicine, No. 7, Chung-Shan South Road, Taipei, Taiwan.
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19
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Qu XM, Zhao N, Mo QY, Yao P, Su N, Wei K, Wang L, Huang JF, Ren XD, Ren S, Fu WL, Huang Q. Development of duplex-crossed allele-specific PCR targeting of TPMT*3B and *3C using crossed allele-specific blockers to eliminate non-specific amplification. Anal Biochem 2019; 575:54-62. [PMID: 30935835 DOI: 10.1016/j.ab.2019.03.019] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2019] [Revised: 03/26/2019] [Accepted: 03/26/2019] [Indexed: 12/18/2022]
Abstract
Prospective testing for variants in the thiopurine S-methyltransferase (TPMT) is considered a key process in the development of thiopurine therapy. This testing is done to avoid toxicity and side effects in the management of diverse immunological and malignant conditions. Real-time fluorescent PCR techniques using duplex-crossed allele-specific primers in a single tube (DCAS-PCR) were developed in this study to genotype the common loss-of-function TPMT*3B c.460G > A (rs1800460) and TPMT*3C c.719A > G (rs1142345) usually occurring in individuals of Chinese ethnicity. In this method, several integrated strategies were used to completely eliminate the non-specific amplification that is commonly presented in traditional allele-specific (AS) PCR. These strategies include using AS-primers (ASP) that both are artificially mismatched in the penultimate positions and phosphorothioate modifications in the 5'-termini positions. In the assay, an AS-blocker was used, locus-specific TaqMan (LST) probes were used and we used at least two fragments were simultaneously amplified in a single tube which satisfy the thermodynamic characteristics of DNA polymerase to eliminate non-specific amplification. In a group of 200 unselected subjects, the results showed that 8 samples were heterozygous of TPMT*3C, and all samples possessed wild-type TPMT*3B. There was no non-specific amplification, and the genotypes were 100% consistent with Sanger sequencing.
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Affiliation(s)
- Xue-Mei Qu
- Department of Laboratory Medicine, Southwest Hospital, Third Military Medical University(Army Medical University), Chongqing, 400038, PR China; Department of Laboratory Medicine, Daping Hospital, Third Military Medical University(Army Medical University), Chongqing, 400042, PR China
| | - Na Zhao
- Department of Laboratory Medicine, Southwest Hospital, Third Military Medical University(Army Medical University), Chongqing, 400038, PR China
| | - Qin-Yun Mo
- Department of Transfusion Medicine, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing 400038, PR China
| | - Pu Yao
- Department of Laboratory Medicine, Southwest Hospital, Third Military Medical University(Army Medical University), Chongqing, 400038, PR China
| | - Ning Su
- Department of Laboratory Medicine, Southwest Hospital, Third Military Medical University(Army Medical University), Chongqing, 400038, PR China
| | - Kun Wei
- Department of Laboratory Medicine, Southwest Hospital, Third Military Medical University(Army Medical University), Chongqing, 400038, PR China
| | - Liu Wang
- Department of Laboratory Medicine, Daping Hospital, Third Military Medical University(Army Medical University), Chongqing, 400042, PR China
| | - Jun-Fu Huang
- Department of Laboratory Medicine, Southwest Hospital, Third Military Medical University(Army Medical University), Chongqing, 400038, PR China
| | - Xiao-Dong Ren
- Department of Laboratory Medicine, Daping Hospital, Third Military Medical University(Army Medical University), Chongqing, 400042, PR China
| | - Sai Ren
- Department of Laboratory Medicine, Daping Hospital, Third Military Medical University(Army Medical University), Chongqing, 400042, PR China
| | - Wei-Ling Fu
- Department of Laboratory Medicine, Southwest Hospital, Third Military Medical University(Army Medical University), Chongqing, 400038, PR China
| | - Qing Huang
- Department of Laboratory Medicine, Daping Hospital, Third Military Medical University(Army Medical University), Chongqing, 400042, PR China; Department of Laboratory Medicine, Southwest Hospital, Third Military Medical University(Army Medical University), Chongqing, 400038, PR China.
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20
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Vinayaga-Pavan M, Frampton M, Pontikos N, Levine AP, Smith PJ, Jonasson JG, Björnsson ES, Segal AW, Smith AM. Elevation in Cell Cycle and Protein Metabolism Gene Transcription in Inactive Colonic Tissue From Icelandic Patients With Ulcerative Colitis. Inflamm Bowel Dis 2019; 25:317-327. [PMID: 30452647 PMCID: PMC6327231 DOI: 10.1093/ibd/izy350] [Citation(s) in RCA: 3] [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: 07/09/2018] [Indexed: 02/06/2023]
Abstract
BACKGROUND A combination of genetic and environmental factors is thought to be involved in the pathogenesis of ulcerative colitis (UC). In Iceland, the incidence of UC is one of the highest in the world. The aim of this study was to characterize patients with UC and identify potential germline mutations and pathways that could be associated with UC in this population. METHODS Exome sequencing and genome-wide microarray analysis on macroscopically noninflamed colonic mucosa from patients and controls were performed. Exome sequence data were examined for very rare or novel mutations that were over-represented in the UC cohort. Combined matching of variant analysis and downstream influence on transcriptomic expression in the rectum were analyzed. RESULTS One thousand eight hundred thirty-eight genes were differentially expressed in rectal tissue from UC patients and identified an upregulation in genes associated with cell cycle control and protein processing in the endoplasmic reticulum (ER). Two missense mutations in thiopurine S-methyltransferase (TPMT) with a minor allele frequency of 0.22 in the UC patients compared with a reported 0.062 in the Icelandic population were identified. A predicted damaging mutation in the gene SLC26A3 is potentially associated with increased expression of DUOX2 and DUOXA2 in rectal tissue. CONCLUSIONS Colonic mucosa of UC patients demonstrates evidence of an elevation in genes involving cell proliferation and processing of proteins within the ER. Exome sequencing identified a possible increased prevalence of 2 damaging TPMT variants within the UC population, suggesting screening the UC population before initiation of thiopurine analogue therapy to avoid toxicity associated with these mutations.
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Affiliation(s)
| | | | - Nikolas Pontikos
- UCL Genetics Institute, University College London, London, United Kingdom
| | | | | | - Jon G Jonasson
- Department of Pathology, Landspitali University Hospital Reykjavik, Iceland,Faculty of Medicine, University of Iceland, Reykjavik, Iceland
| | - Einar S Björnsson
- Faculty of Medicine, University of Iceland, Reykjavik, Iceland,Department of Gastroenterology and Hepatology, Landspitali University Hospital, Reykjavik, Iceland
| | | | - Andrew M Smith
- Microbial Diseases, Eastman Dental Institute,Molecular Medicine, Division of Medicine,Address correspondence to: Andrew M. Smith, PhD, Microbial Diseases, Eastman Dental Institute, Rayne Building, 5 University Street, University College London, London WC1E 6JF, United Kingdom ()
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Lucafò M, Franca R, Selvestrel D, Curci D, Pugnetti L, Decorti G, Stocco G. Pharmacogenetics of treatments for inflammatory bowel disease. Expert Opin Drug Metab Toxicol 2018; 14:1209-1223. [PMID: 30465611 DOI: 10.1080/17425255.2018.1551876] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2018] [Accepted: 11/20/2018] [Indexed: 12/15/2022]
Abstract
Inflammatory bowel disease is a chronic inflammation of the gut whose pathogenesis is still unclear. Although no curative therapy is currently available, a number of drugs are used in induction and maintenance therapy; however, for most of these drugs, a high inter-individual variability in response is observed. Among the factors of this variability, genetics plays an important role. Areas covered: This review summarizes the results of pharmacogenetic studies, considering the most important drugs used and in particular aminosalycilates, glucocorticoids, thiopurines, monoclonal antibodies and thalidomide. Most studies used a candidate gene approach, even if significant breakthroughs have been obtained recently from applying genome-wide studies. When available, also investigations considering epigenetics and pharmacogenetic dosing guidelines have been included. Expert opinion: Only for thiopurines, genetic markers identified as predictors of efficacy or adverse events have allowed the development of dosing guidelines. For the other drugs, encouraging results are available and great expectations rely on the study of epigenetics and integration with pharmacokinetic information, especially useful for biologics. However, to improve therapy of IBD patients with these drugs, for implementation in the clinics of pharmacogenetics, informatic clinical decision support systems and training about pharmacogenetics of health providers are needed.
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Affiliation(s)
- Marianna Lucafò
- a Experimental and Clinical Pharmacology Unit , National Cancer Institute - Centro di Riferimento Oncologico , Aviano , Italy
- b Institute for Maternal and Child Health IRCCS Burlo Garofolo , Diagnostics Department Trieste , Italy
| | - Raffaella Franca
- b Institute for Maternal and Child Health IRCCS Burlo Garofolo , Diagnostics Department Trieste , Italy
- c Department of Medical, Surgical and Health Sciences , University of Trieste , Trieste , Italy
| | - Davide Selvestrel
- d PhD School in Science of Reproduction and Development , University of Trieste , Trieste , Italy
| | - Debora Curci
- d PhD School in Science of Reproduction and Development , University of Trieste , Trieste , Italy
| | - Letizia Pugnetti
- d PhD School in Science of Reproduction and Development , University of Trieste , Trieste , Italy
| | - Giuliana Decorti
- b Institute for Maternal and Child Health IRCCS Burlo Garofolo , Diagnostics Department Trieste , Italy
- c Department of Medical, Surgical and Health Sciences , University of Trieste , Trieste , Italy
| | - Gabriele Stocco
- e Department of Life Sciences , University of Trieste , Trieste , Italy
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Fei X, Shu Q, Zhu H, Hua B, Wang S, Guo L, Fang Y, Ge W. NUDT15 R139C Variants Increase the Risk of Azathioprine-Induced Leukopenia in Chinese Autoimmune Patients. Front Pharmacol 2018; 9:460. [PMID: 29867468 PMCID: PMC5949564 DOI: 10.3389/fphar.2018.00460] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2017] [Accepted: 04/19/2018] [Indexed: 12/16/2022] Open
Abstract
The aim of this study was to investigate the influence of NUDT15 R139C, thiopurine S-methyltransferase (TPMT), and 6-TGN on azathioprine (AZA) induced leukopenia in Chinese autoimmune patients. Among 87 enrolled patients, 23 (26.4%) had leukopenia. The NUDT15 R139C variant was associated with leukopenia (p = 1.86 × 10−7; OR: 7.59; 95% CI: 3.16–18.21). However, TPMT genotype was not shown to be correlated with the incidence of leukopenia (p = 0.95). There was no significant difference of 6-TGN concentration between patients with or without leukopenia (p = 0.15) and no association was found in patients with NUDT15 R139C variants alleles (p = 0.62). Finally, we found that the range of 6-TGN concentrations in autoimmune diseases was much lower than the established 6-TGN monitoring range for inflammatory bowel diseases. Therefore, the variant of NUDT15 R139C is strongly associated with AZA-induced leukopenia in Chinese patients with various autoimmune diseases such as systemic lupus erythematosus, Sjögren's syndrome, etc.
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Affiliation(s)
- Xiang Fei
- Department of Pharmacy, Nanjing Drum Tower Hospital, Nanjing, China.,School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, China
| | - Qing Shu
- Department of Pharmacy, Nanjing Drum Tower Hospital, Nanjing, China
| | - Huaijun Zhu
- Department of Pharmacy, Nanjing Drum Tower Hospital, Nanjing, China
| | - Bingzhu Hua
- Department of Rheumatology and Immunology, Nanjing Drum Tower Hospital, Nanjing, China
| | - Shiying Wang
- Department of Rheumatology and Immunology, Nanjing Drum Tower Hospital, Nanjing, China
| | - Ling Guo
- Nanjing Drum Tower Hospital, Clinical College of Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, China
| | - Yun Fang
- Department of Pharmacy, Nanjing Drum Tower Hospital, Nanjing, China
| | - Weihong Ge
- Department of Pharmacy, Nanjing Drum Tower Hospital, Nanjing, China
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Zhou H, Li L, Yang P, Yang L, Zheng JE, Zhou Y, Han Y. Optimal predictor for 6-mercaptopurine intolerance in Chinese children with acute lymphoblastic leukemia: NUDT15, TPMT, or ITPA genetic variants? BMC Cancer 2018; 18:516. [PMID: 29720126 PMCID: PMC5932771 DOI: 10.1186/s12885-018-4398-2] [Citation(s) in RCA: 49] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2017] [Accepted: 04/18/2018] [Indexed: 12/16/2022] Open
Abstract
Background 6-mercaptopurine (6-MP) contributes substantially to remarkable improvement in the survival of childhood acute lymphoblastic leukemia (ALL) patients. However, 6-MP also has dose-limiting toxicities, particularly life-threatening myelosuppression, due to genetic polymorphisms in enzymes that metabolize 6-MP. Promising biomarkers for predicting 6-MP-induced leukopenia is still unclear in Chinese population. Here, we evaluated the associations of NUDT15, TPMT and ITPA genotypes with 6-MP intolerance in our cohort of childhood ALL patients. Methods A total of 105 Chinese pediatric patients with a confirmed diagnosis of ALL were enrolled. We identified the NUDT15 coding variant rs116855232 (c.415C > T), a newly discovered 6-MP toxicity-related locus in Asians, and polymorphisms in TPMT rs1142345 and ITPA rs11273540. Associations between genotypes and 6-MP dose sensitivity, leukopenia, hepatotoxicity, and therapy interruption were evaluated. Results The minor allele frequencies (MAFs) of NUDT15 rs116855232, TPMT rs1142345 and ITPA rs11273540 were 15.7, 2.9, and 18.1%, respectively. NUDT15 and TPMT genetic variants were strongly associated with 6-MP dose intensity. Patients with NUDT15 homogenous genotype (TT) were highly sensitive to 6-MP (dose intensity of 60.27%) compared to these with heterozygous genotype (TC) or wild type (CC), who tolerated an average dose intensity of 83.83 and 94.24%, respectively. The NUDT15 variant was a predictor for leukopenia (OR: 3.62, 95% CI 1.377–9.501, P = 0.009) and early-onset leukopenia (OR: 9.63, 95% CI 2.764–33.514, P = 3.75 × 10− 4). No differences were found between 6-MP dose intensity and ITPA polymorphisms. Conclusion NUDT15 variant is an optimal predictor for 6-MP intolerance in Chinese pediatric ALL patients and may have greatly clinical implications for individualized therapy.
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Affiliation(s)
- Hong Zhou
- Department of Pharmacy, Union Hospital, Tongji Medical College, Huazhong, University of Science and Technology, No. 1277, Jie Fang Road, Wuhan, 430022, China
| | - Lei Li
- Department of Pediatrics, Union Hospital, Tongji Medical College, Huazhong, University of Science and Technology, Wuhan, 430022, China
| | - Peng Yang
- Department of Geriatrics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Lin Yang
- Department of Pharmacy, Fujian Cancer Hospital & Fujian Medical University Cancer Hospital, Fuzhou, 350014, China
| | - Jin E Zheng
- Center for Stem Cell Research and Application, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Ying Zhou
- Department of Pharmacy, Union Hospital, Tongji Medical College, Huazhong, University of Science and Technology, No. 1277, Jie Fang Road, Wuhan, 430022, China
| | - Yong Han
- Department of Pharmacy, Union Hospital, Tongji Medical College, Huazhong, University of Science and Technology, No. 1277, Jie Fang Road, Wuhan, 430022, China.
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de Boer NKH, Peyrin-Biroulet L, Jharap B, Sanderson JD, Meijer B, Atreya I, Barclay ML, Colombel JF, Lopez A, Beaugerie L, Marinaki AM, van Bodegraven AA, Neurath MF. Thiopurines in Inflammatory Bowel Disease: New Findings and Perspectives. J Crohns Colitis 2018; 12:610-620. [PMID: 29293971 DOI: 10.1093/ecco-jcc/jjx181] [Citation(s) in RCA: 57] [Impact Index Per Article: 8.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/20/2017] [Accepted: 12/20/2017] [Indexed: 02/08/2023]
Abstract
Thiopurines, available as azathioprine, mercaptopurine, and thioguanine, are immunomodulating agents primarily used to maintain corticosteroid-free remission in patients with inflammatory bowel disease. To provide a state-of-the-art overview of thiopurine treatment in inflammatory bowel disease, this clinical review critically summarises the available literature, as assessed by several experts in the field of thiopurine treatment and research in inflammatory bowel disease.
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Affiliation(s)
- Nanne K H de Boer
- Department of Gastroenterology and Hepatology, VU University Medical Centre, Amsterdam, The Netherlands
| | - Laurent Peyrin-Biroulet
- Department of Gastroenterology and Hepatology and Inserm U954, Nancy University Hospital, Lorraine University, Vandoeuvre-lès-Nancy, France
| | - Bindia Jharap
- Department of Gastroenterology, Meander Medical Centre, Amersfoort, The Netherlands
| | - Jeremy D Sanderson
- Department of Gastroenterology, Guy's and St Thomas' Hospitals, London, UK
| | - Berrie Meijer
- Department of Gastroenterology and Hepatology, VU University Medical Centre, Amsterdam, The Netherlands
| | - Imke Atreya
- Department of Gastroenterology, Pneumology and Endocrinology, Universitätsklinikum Erlangen, University of Erlangen-Nürnberg, Germany
| | - Murray L Barclay
- Department of Gastroenterology, Christchurch Hospital, Christchurch, New Zealand
| | | | - Anthony Lopez
- Department of Gastroenterology and Hepatology and Inserm U954, Nancy University Hospital, Lorraine University, Vandoeuvre-lès-Nancy, France
| | - Laurent Beaugerie
- Department of Gastroenterology, AP-HP, Hôpital Saint-Antoine,UPMC University, Paris, France
| | | | - Adriaan A van Bodegraven
- Department of Gastroenterology and Hepatology, VU University Medical Centre, Amsterdam, The Netherlands.,Department of Gastroenterology, Geriatrics, Internal and Intensive Care Medicine [Co-MIK], Zuyderland Medical Centre, Heerlen-Sittard-Geleen, The Netherlands
| | - Markus F Neurath
- Department of Gastroenterology, Pneumology and Endocrinology, Universitätsklinikum Erlangen, University of Erlangen-Nürnberg, Germany
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25
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Saida K, Kamei K, Ogura M, Matsumura S, Kano Y, Sato M, Andoh A, Ishikura K. Azathioprine-induced Agranulocytosis and Severe Alopecia After Kidney Transplantation Associated With a NUDT15 Polymorphism: A Case Report. Transplant Proc 2018; 50:3925-3927. [PMID: 30577288 DOI: 10.1016/j.transproceed.2018.04.039] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2018] [Accepted: 04/12/2018] [Indexed: 01/17/2023]
Abstract
BACKGROUND Azathioprine (AZA) is the drug recommended for the continuation of immunosuppressive treatment after renal transplant in women during pregnancy. CASE REPORT A 37-year-old Japanese female developed agranulocytosis and severe alopecia after initiation of AZA (50 mg), used as an alternative to mycophenolate mofetil (MMF, 1000 mg) therapy in anticipation of a planned pregnancy. Within 4 days of the initiation of AZA therapy, the patient developed a high fever, leucopenia, and cranial alopecia. Genetic testing revealed a homozygous polymorphism of NUDT15 (rs116855232, NM_018283.3:c.415C>T: p.Arg139Cys), which has previously been identified as a risk factor for AZA-related complications in patients with inflammatory bowel disease. CONCLUSION Genetic screening for NUDT15 could contribute to the prevention of serious adverse reactions to AZA and provide the opportunity for personalized medicine. Identification of a safe alternative to MMF during pregnancy after a renal transplant is a problem to be resolved in the future.
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Affiliation(s)
- K Saida
- Division of Nephrology and Rheumatology, National Center for Child Health and Development, Tokyo, Japan
| | - K Kamei
- Division of Nephrology and Rheumatology, National Center for Child Health and Development, Tokyo, Japan
| | - M Ogura
- Division of Nephrology and Rheumatology, National Center for Child Health and Development, Tokyo, Japan
| | - S Matsumura
- Division of Nephrology and Rheumatology, National Center for Child Health and Development, Tokyo, Japan
| | - Y Kano
- Division of Nephrology and Rheumatology, National Center for Child Health and Development, Tokyo, Japan
| | - M Sato
- Division of Nephrology and Rheumatology, National Center for Child Health and Development, Tokyo, Japan
| | - A Andoh
- Department of Medicine, Shiga University of Medical Science, Shiga, Japan
| | - K Ishikura
- Division of Nephrology and Rheumatology, National Center for Child Health and Development, Tokyo, Japan.
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26
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Munnig-Schmidt E, Zhang M, Mulder CJ, Barclay ML. Late-onset Rise of 6-MMP Metabolites in IBD Patients on Azathioprine or Mercaptopurine. Inflamm Bowel Dis 2018. [PMID: 29522107 DOI: 10.1093/ibd/izx081] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/24/2023]
Abstract
BACKGROUND The thiopurines azathioprine and mercaptopurine remain pivotal maintenance treatments in inflammatory bowel disease (IBD); however, up to 15%-20% of patients preferentially produce the hepatotoxic metabolite 6-methylmercaptopurine (6MMP) at the expense of the therapeutic 6-thioguanine nucleotides (6TGN). This metabolic shunting usually begins within 3 months of therapy. We noted patients developing shunting many months or years after starting treatment and aimed to determine how often this late shunting occurs and whether this could be explained by patient factors or concomitant medications. METHODS The New Zealand database of thiopurine metabolite results from 2002 to 2016 (19085 6TGN/6MMP pairs from 7130 patients) was interrogated to identify patients developing a 6MMP/6TGN ratio >20 after at least 4 months treatment. Dosing history, concomitant therapy, and comorbidity data were assessed. RESULTS Fifteen percent of database patients developed preferential 6-MMP production, and of these, 29 patients had late-onset shunting with sufficient data available for validation. This extrapolates to 90 patients in total, representing 1.7% of IBD patients on thiopurines, or 10% of all those with preferential 6-MMP production. Time from starting therapy to shunting was 5 months to 10.4 years (median, 21 months). Eleven patients had abnormal liver function when shunting was recognized, all with 6MMP >5900 pmol/8 × 108 red blood cells. No common factors were found to explain the late onset. CONCLUSIONS Some IBD patients develop preferential 6MMP production many months or years after commencing therapy. This is important when considering frequency of metabolite monitoring, failure of therapy, or abnormal liver function. 10.1093/ibd/izx081_video1izx081.video15746667546001.
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Affiliation(s)
- Erik Munnig-Schmidt
- Department of Gastroenterology, VU Medical Centre, Amsterdam, the Netherlands
| | - Mei Zhang
- Department of Medicine, University of Otago Christchurch, Christchurch, New Zealand
| | - Chris J Mulder
- Department of Gastroenterology, VU Medical Centre, Amsterdam, the Netherlands
| | - Murray L Barclay
- Department of Medicine, University of Otago Christchurch, Christchurch, New Zealand.,Departments of Gastroenterology and Clinical Pharmacology, Christchurch Hospital, Christchurch, New Zealand
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27
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Guillotin V, Galli G, Viallard JF. [Usefulness of thiopurine methyltransferase polymorphism study and metabolites measurement for patients treated by azathioprine]. Rev Med Interne 2018; 39:421-426. [PMID: 29370945 DOI: 10.1016/j.revmed.2017.12.007] [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: 07/01/2017] [Revised: 12/18/2017] [Accepted: 12/28/2017] [Indexed: 11/18/2022]
Abstract
Azathioprine is widely used in internal medicine and frequently implicated in occurrence of adverse events. Among these adverse events the bone marrow suppression, a dose-related one, is the most serious because of is potential morbidity and mortality. Severe myelosuppression, associated with abnormal AZA metabolism, is linked to the thiopurine methyltransferase (TPMT) genetic polymorphism that results in a high variability of its activity with 89% of patients with a normal activity, 11% with an intermediate activity, and 0.3% with very low activity leading to a very high risk of bonne marrow suppression. TPMT status can be assessed prior to AZA treatment by measuring enzyme activity or genotyping techniques to identify patients for which the standard dose is not advisable. Furthermore, azathioprine metabolites monitoring is helpful for the follow up of patients, especially in therapeutic failure, to distinguish non-compliant patients from under-dosed, "shunters" or resistant patients.
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Affiliation(s)
- V Guillotin
- Laboratoire d'immunologie de l'hôpital Pellegrin, place Amélié-Raba-Léon, 33000 Bordeaux, France.
| | - G Galli
- Service de médecine interne et immunologie clinique, Hôpital Saint-André, rue Jean-Burguet, 33000 Bordeaux, France
| | - J-F Viallard
- Service de médecine interne, hôpital du Haut-Lévêque, avenue Magellan, 33604 Pessac, France
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28
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Meijer B, van Everdingen CK, Ramsoekh D, Stedman C, Frampton CMA, Mulder CJJ, Bouma G, de Boer NKH, Gearry RB. Transient elastography to assess liver stiffness in patients with inflammatory bowel disease. Dig Liver Dis 2018; 50:48-53. [PMID: 29050997 DOI: 10.1016/j.dld.2017.09.128] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/03/2017] [Revised: 09/26/2017] [Accepted: 09/27/2017] [Indexed: 12/11/2022]
Abstract
BACKGROUND Liver injury during inflammatory bowel disease (IBD) is primarily diagnosed by liver biopsy, which has a small but serious risk of severe complications. The aim of this study was to assess liver stiffness, and subsequently the prevalence and associations of liver fibrosis in IBD patients with thiopurine therapy and other clinical factors, by using transient elastography (TE). METHODS In this prospective, international two-center study, included IBD-patients underwent TE measurements. Laboratory results and medication reports, radiology results and historical liver biopsy results were extracted from the patient charts. RESULTS Transient elastography results of 168 patients were presented. Moderate and severe fibrosis were detected in 4% (7/168) and 1% (1/168) of the cohort, respectively. Factors contributing to lower liver stiffness were female gender and (historical) exposure to azathioprine. Further, there was a statistical trend towards lower liver stiffness in patients using thiopurines overall (4.7 vs. 5.2kPa, p=0.07). Liver stiffness correlated positively with waist circumference, liver enzyme tests, hemoglobin and 6-methylmercaptopurine concentration and negatively with platelet count. CONCLUSION Exposure to thiopurine therapy was not associated with higher liver stiffness, although no clinical difference in severity of fibrosis was detected. Further research should robustly determine the accuracy of TE as an evaluation of liver fibrosis in IBD patients.
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Affiliation(s)
- Berrie Meijer
- VU University Medical Center, Department of Gastroenterology and Hepatology, Amsterdam, The Netherlands.
| | - Charlotte K van Everdingen
- VU University Medical Center, Department of Gastroenterology and Hepatology, Amsterdam, The Netherlands; University of Otago, Department of Medicine, Christchurch, New Zealand
| | - Dewkoemar Ramsoekh
- VU University Medical Center, Department of Gastroenterology and Hepatology, Amsterdam, The Netherlands
| | - Catherine Stedman
- University of Otago, Department of Medicine, Christchurch, New Zealand; Christchurch Hospital, Department of Gastroenterology, Christchurch, New Zealand
| | | | - Chris J J Mulder
- VU University Medical Center, Department of Gastroenterology and Hepatology, Amsterdam, The Netherlands
| | - Gerd Bouma
- VU University Medical Center, Department of Gastroenterology and Hepatology, Amsterdam, The Netherlands
| | - Nanne K H de Boer
- VU University Medical Center, Department of Gastroenterology and Hepatology, Amsterdam, The Netherlands
| | - Richard B Gearry
- University of Otago, Department of Medicine, Christchurch, New Zealand; Christchurch Hospital, Department of Gastroenterology, Christchurch, New Zealand
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29
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Ho CC, Fong WY, Lee YH, Poon WT. Novel Tetra-Primer ARMS-PCR Assays for Thiopurine Intolerance Susceptibility Mutations NUDT15 c.415C>T and TPMT c.719A>G (TPMT*3C) in East Asians. Genes (Basel) 2017; 8:genes8100285. [PMID: 29065511 PMCID: PMC5664135 DOI: 10.3390/genes8100285] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2017] [Revised: 10/18/2017] [Accepted: 10/18/2017] [Indexed: 01/20/2023] Open
Abstract
Thiopurines are clinically useful in the management of diverse immunological and malignant conditions. Nevertheless, these purine analogues can cause lethal myelosuppression, which may be prevented by prospective testing for variants in the thiopurine S-methyltransferase (TPMT) and, in East Asians, Nudix hydrolase 15 (NUDT15) genes. Two single-tube, tetra-primer amplification refractory mutation system polymerase chain reaction (ARMS-PCR) assays were developed to genotype the common loss-of-function variants NUDT15 c.415C>T (rs116855232) and TPMT*3C c.719A>G (rs1142345). In a group of 60 unselected patients, one and seven were found to be homozygous and heterozygous, respectively, for NUDT15 c.415C>T; one was found to be heterozygous for TPMT*3C c.719A>G. There was no non-specific amplification, and the genotypes were 100% concordant with Sanger sequencing. Limit-of-detection for both assays was below 1 ng of heterozygous template per reaction. Time- and cost-effective ARMS-PCR assays, suitable for genotyping East-Asian patients for thiopurine intolerance, were successfully developed and validated.
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Affiliation(s)
- Chi-Chun Ho
- Department of Clinical Pathology, Pamela Youde Nethersole Eastern Hospital, Chai Wan, Hong Kong, China.
| | - Wai-Ying Fong
- Department of Clinical Pathology, Pamela Youde Nethersole Eastern Hospital, Chai Wan, Hong Kong, China.
| | - Yuen-Hon Lee
- Department of Clinical Pathology, Pamela Youde Nethersole Eastern Hospital, Chai Wan, Hong Kong, China.
| | - Wing-Tat Poon
- Department of Clinical Pathology, Pamela Youde Nethersole Eastern Hospital, Chai Wan, Hong Kong, China.
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30
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Yin D, Xia X, Zhang J, Zhang S, Liao F, Zhang G, Zhang Y, Hou Q, Yang X, Wang H, Ma Z, Wang H, Zhu Y, Zhang W, Wang Y, Liu B, Wang L, Xu H, Shu Y. Impact of NUDT15 polymorphisms on thiopurines-induced myelotoxicity and thiopurines tolerance dose. Oncotarget 2017; 8:13575-13585. [PMID: 28088792 PMCID: PMC5355121 DOI: 10.18632/oncotarget.14594] [Citation(s) in RCA: 35] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2016] [Accepted: 01/04/2017] [Indexed: 02/05/2023] Open
Abstract
Thiopurines are widely used as anticancer and immunosuppressive agents. However, life-threatening myelotoxicity has been noticed and largely explained by genetic variations, including NUDT15 polymorphisms (e.g., rs116855232). In this study, we conduct a meta-analysis to investigate the impact of rs116855232 on thiopurines-induced myelotoxicity susceptibility (1752 patients from 7 independent cohorts), as well as on thiopurines intolerance dose (2745 patients from 13 cohorts). Variant allele of rs116855232 contributes 7.86-fold (P < 0.00001, 95% CI: 6.13–10.08) higher risk to develop leucopenia with high specificity (91.74%) and sensitivity (43.19%), and lower thiopurines intolerance dose (P < 0.00001). Through bioinformatics prediction, amino acid changes induced by genetic variants are considered to reduce the stability, and break an α helix of NUDT15, which is part of the thiopurine binding pocket. Additionally, we conduct an expression quantitative trait loci (eQTL) analysis for NUDT15, and find a promoter-located eQTL signal (rs554405994), which may act as a potential marker to predict thiopurines-induced myelotoxicity. In conclusion, genetic polymorphisms in NUDT15 are strongly associated with adverse drug reaction (ADR) of thiopurines, although more evidences are needed to determine values of all functional NUDT15 polymorphisms for clinical regimen, rs116855232 should be considered as a highly credible pharmacogenetic indicator for thiopurines using espcially is Asians.
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Affiliation(s)
- Dandan Yin
- Department of Laboratory Medicine, National Key Laboratory of Biotherapy/Collaborative Innovation Center of Biotherapy and Precision Medicine Key Laboratory of Sichuan Province, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Xuyang Xia
- Department of Laboratory Medicine, National Key Laboratory of Biotherapy/Collaborative Innovation Center of Biotherapy and Precision Medicine Key Laboratory of Sichuan Province, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Junlong Zhang
- Department of Laboratory Medicine/Research Center of Clinical Laboratory Medicine, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Shouyue Zhang
- Department of Laboratory Medicine, National Key Laboratory of Biotherapy/Collaborative Innovation Center of Biotherapy and Precision Medicine Key Laboratory of Sichuan Province, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Fei Liao
- Department of Laboratory Medicine, National Key Laboratory of Biotherapy/Collaborative Innovation Center of Biotherapy and Precision Medicine Key Laboratory of Sichuan Province, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Ge Zhang
- Department of Pediatric Hematology/Oncology, West China Second Hospital Sichuan University, Chengdu, Sichuan, China
| | - Yan Zhang
- Department of Thoracic Oncology, Cancer Center, National Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Qianqian Hou
- Department of Laboratory Medicine, National Key Laboratory of Biotherapy/Collaborative Innovation Center of Biotherapy and Precision Medicine Key Laboratory of Sichuan Province, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Xue Yang
- Integrated Biomedical Sciences Program, University of Tennessee Health Science Center, Memphis, TN, USA
| | - Hong Wang
- Integrated Biomedical Sciences Program, University of Tennessee Health Science Center, Memphis, TN, USA
| | - Zhigui Ma
- Department of Pediatric Hematology/Oncology, West China Second Hospital Sichuan University, Chengdu, Sichuan, China
| | - Heyao Wang
- Department of Precision Medicine, China-Japan Friendship Hospital, Beijing, China
| | - Yiping Zhu
- Department of Pediatric Hematology/Oncology, West China Second Hospital Sichuan University, Chengdu, Sichuan, China
| | - Wei Zhang
- Department of Clinical Pharmacology, Hunan Key Laboratory of Pharmacogenetics, Xiangya Hospital, Central South University, Changsha, China
| | - Yuelan Wang
- Department of Laboratory Medicine, National Key Laboratory of Biotherapy/Collaborative Innovation Center of Biotherapy and Precision Medicine Key Laboratory of Sichuan Province, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Bo Liu
- Department of Laboratory Medicine, National Key Laboratory of Biotherapy/Collaborative Innovation Center of Biotherapy and Precision Medicine Key Laboratory of Sichuan Province, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Lanlan Wang
- Department of Laboratory Medicine/Research Center of Clinical Laboratory Medicine, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Heng Xu
- Department of Laboratory Medicine, National Key Laboratory of Biotherapy/Collaborative Innovation Center of Biotherapy and Precision Medicine Key Laboratory of Sichuan Province, West China Hospital, Sichuan University, Chengdu, Sichuan, China.,Department of Laboratory Medicine/Research Center of Clinical Laboratory Medicine, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Yang Shu
- Department of Laboratory Medicine, National Key Laboratory of Biotherapy/Collaborative Innovation Center of Biotherapy and Precision Medicine Key Laboratory of Sichuan Province, West China Hospital, Sichuan University, Chengdu, Sichuan, China
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31
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Chen XX, Shen SH. [Research advances in pharmacogenomics of mercaptopurine]. ZHONGGUO DANG DAI ER KE ZA ZHI = CHINESE JOURNAL OF CONTEMPORARY PEDIATRICS 2017; 19:1027-1033. [PMID: 28899477 PMCID: PMC7403070 DOI: 10.7499/j.issn.1008-8830.2017.09.019] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Subscribe] [Scholar Register] [Received: 03/16/2017] [Accepted: 05/07/2017] [Indexed: 06/07/2023]
Abstract
Mercaptopurine is a common chemotherapeutic drug and immunosuppressive agent and plays an important role in the treatment of acute lymphoblastic leukemia and inflammatory bowel disease. It may cause severe adverse effects such as myelosuppression, which may result in the interruption of treatment or complications including infection or even threaten patients' lives. However, the adverse effects of mercaptopurine show significant racial and individual differences, which reveal the important role of genetic diversity. Recent research advances in pharmacogenomics have gradually revealed the genetic nature of such differences. This article reviews the recent research advances in the pharmacogenomics and individualized application of mercaptopurine.
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Affiliation(s)
- Xiao-Xiao Chen
- Department of Hematology and Oncology, Shanghai Children's Medical Center, Medical School of Shanghai Jiaotong University, Shanghai 200127, China.
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32
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Guariso G, Gasparetto M. Treating children with inflammatory bowel disease: Current and new perspectives. World J Gastroenterol 2017; 23:5469-5485. [PMID: 28852307 PMCID: PMC5558111 DOI: 10.3748/wjg.v23.i30.5469] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/26/2017] [Revised: 06/02/2017] [Accepted: 07/24/2017] [Indexed: 02/06/2023] Open
Abstract
Inflammatory bowel disease (IBD) is a chronic inflammatory condition of the gut characterised by alternating periods of remission and relapse. Whilst the mechanism underlying this disease is yet to be fully understood, old and newer generation treatments can only target selected pathways of this complex inflammatory process. This narrative review aims to provide an update on the most recent advances in treatment of paediatric IBD. A MEDLINE search was conducted using “paediatric inflammatory bowel disease”, “paediatric Crohn’s disease”, “paediatric ulcerative colitis”, “treatment”, “therapy”, “immunosuppressant”, “biologic”, “monitoring” and “biomarkers” as key words. Clinical trials, systematic reviews, and meta-analyses published between 2014 and 2016 were selected. Studies referring to earlier periods were also considered in case the data was relevant to our scope. Major advances have been achieved in monitoring the individual metabolism, toxicity and response to relevant medications in IBD including thiopurines and biologics. New biologics acting on novel mechanisms such as selective interference with lymphocyte trafficking are emerging treatment options. Current research is investing in the development of reliable prognostic biomarkers, aiming to move towards personalised treatments targeted to individual patients.
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33
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Sato T, Takagawa T, Kakuta Y, Nishio A, Kawai M, Kamikozuru K, Yokoyama Y, Kita Y, Miyazaki T, Iimuro M, Hida N, Hori K, Ikeuchi H, Nakamura S. NUDT15, FTO, and RUNX1 genetic variants and thiopurine intolerance among Japanese patients with inflammatory bowel diseases. Intest Res 2017; 15:328-337. [PMID: 28670229 PMCID: PMC5478757 DOI: 10.5217/ir.2017.15.3.328] [Citation(s) in RCA: 38] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/27/2016] [Revised: 02/15/2017] [Accepted: 02/24/2017] [Indexed: 11/26/2022] Open
Abstract
Background/Aims Recent genome-wide analyses have provided strong evidence concerning adverse events caused by thiopurine drugs such as azathioprine (AZA) and 6-mercaptopurine. The strong associations identified between NUDT15 p.Arg139Cys and thiopurine-induced leukopenia and severe hair loss have been studied and confirmed over the last 2 years. However, other coding variants, including NUDT15 p.Val18_Val19insGlyVal, NUDT15 p.Val18Ile, and FTO p.Ala134Thr, and a noncoding variation in RUNX1 (rs2834826) remain to be examined in detail in this respect. Therefore, we investigated the correlation between these adverse events and the 5 recently identified variants mentioned above among Japanese patients with inflammatory bowel diseases (IBD). Methods One hundred sixty thiopurine-treated patients with IBD were enrolled. Genotyping was performed using TaqMan SNP Genotyping Assays or Sanger sequencing. Results None of the 5 variants were associated with gastrointestinal intolerance to AZA. However, NUDT15 p.Arg139Cys was significantly associated with the interval between initiation and discontinuation of AZA among patients with gastrointestinal intolerance. This variant was strongly associated with early (<8 weeks) and late (≥8 weeks) leukopenia and severe hair loss. Moreover, it correlated with the interval between initiation of thiopurine therapy and leukopenia occurrence, and average thiopurine dose. NUDT15 p.Val18_Val19insGlyVal, NUDT15 p.Val18Ile, FTO p.Ala134Thr, and RUNX1 rs2834826 exhibited no significant relationship with the adverse events examined. Conclusions Of the 5 variants investigated, NUDT15 p.Arg139Cys had the strongest impact on thiopurine-induced leukopenia and severe hair loss; therefore, its genotyping should be prioritized over that of other variants in efforts to predict these adverse events in Japanese patients with IBD.
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Affiliation(s)
- Toshiyuki Sato
- Division of Internal Medicine, Department of Inflammatory Bowel Disease, Hyogo College of Medicine, Nishinomiya, Japan
| | - Tetsuya Takagawa
- Division of Internal Medicine, Department of Inflammatory Bowel Disease, Hyogo College of Medicine, Nishinomiya, Japan.,Department of Intestinal Inflammation Research, Hyogo College of Medicine, Nishinomiya, Japan
| | - Yoichi Kakuta
- Division of Gastroenterology, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Akihiro Nishio
- Division of Internal Medicine, Department of Inflammatory Bowel Disease, Hyogo College of Medicine, Nishinomiya, Japan
| | - Mikio Kawai
- Division of Internal Medicine, Department of Inflammatory Bowel Disease, Hyogo College of Medicine, Nishinomiya, Japan
| | - Koji Kamikozuru
- Division of Internal Medicine, Department of Inflammatory Bowel Disease, Hyogo College of Medicine, Nishinomiya, Japan
| | - Yoko Yokoyama
- Division of Internal Medicine, Department of Inflammatory Bowel Disease, Hyogo College of Medicine, Nishinomiya, Japan
| | - Yuko Kita
- Division of Internal Medicine, Department of Inflammatory Bowel Disease, Hyogo College of Medicine, Nishinomiya, Japan
| | - Takako Miyazaki
- Division of Internal Medicine, Department of Inflammatory Bowel Disease, Hyogo College of Medicine, Nishinomiya, Japan
| | - Masaki Iimuro
- Division of Internal Medicine, Department of Inflammatory Bowel Disease, Hyogo College of Medicine, Nishinomiya, Japan
| | - Nobuyuki Hida
- Division of Internal Medicine, Department of Inflammatory Bowel Disease, Hyogo College of Medicine, Nishinomiya, Japan
| | - Kazutoshi Hori
- Division of Internal Medicine, Department of Inflammatory Bowel Disease, Hyogo College of Medicine, Nishinomiya, Japan.,Department of Intestinal Inflammation Research, Hyogo College of Medicine, Nishinomiya, Japan
| | - Hiroki Ikeuchi
- Department of Inflammatory Bowel Disease Surgery, Hyogo College of Medicine, Nishinomiya, Japan
| | - Shiro Nakamura
- Division of Internal Medicine, Department of Inflammatory Bowel Disease, Hyogo College of Medicine, Nishinomiya, Japan.,Department of Intestinal Inflammation Research, Hyogo College of Medicine, Nishinomiya, Japan
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Thiel J, Rizzi M, Engesser M, Dufner AK, Troilo A, Lorenzetti R, Voll RE, Venhoff N. B cell repopulation kinetics after rituximab treatment in ANCA-associated vasculitides compared to rheumatoid arthritis, and connective tissue diseases: a longitudinal observational study on 120 patients. Arthritis Res Ther 2017; 19:101. [PMID: 28521808 PMCID: PMC5437549 DOI: 10.1186/s13075-017-1306-0] [Citation(s) in RCA: 80] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2016] [Accepted: 05/02/2017] [Indexed: 01/24/2023] Open
Abstract
Background B cell depletion with rituximab (RTX) is approved for treatment of rheumatoid arthritis (RA) and ANCA-associated vasculitides (AAV). Recently, RTX has been shown to be effective in AAV maintenance therapy, but an optimal RTX treatment schedule is unknown and the time to B cell repopulation after RTX has not been studied. Methods Retrospective single-center analysis of B cell repopulation in patients with AAV, RA or connective tissue disease (CTD) treated with RTX. Results Beginning B cell repopulation within the first year after RTX treatment was observed in 93% of RA and 88% of CTD patients. Only 10% of patients with granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA) and no patient with eosinophilic granulomatosis with polyangiitis (EGPA) showed B cell repopulation within this time. Median time of B cell depletion was 26 months in GPA/MPA, and 21 months in EGPA compared to 9 months in RA, and 8 months in CTD (p < 0.0001). In 25 AAV-patients B cell depletion lasted for at least 44 months. There was a significant decline in serum immunoglobulin concentrations in GPA/MPA patients, but not in patients with RA or CTD. Significantly more GPA/MPA patients developed hygogammaglobulinemia (IgG <7 g/L) compared to patients with RA or CTD. Conclusions In contrast to RA and CTD, in AAV RTX induces long-lasting depletion of B cells that is associated with decreased antibody production. This observation points toward potential defects in the B cell compartment in AAV that are unmasked by immunosuppressive treatment and has important implications for the design of maintenance treatment schedules using RTX.
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Affiliation(s)
- Jens Thiel
- Department of Rheumatology and Clinical Immunology, Medical Center - University of Freiburg, Faculty of Medicine, Hugstetterstrasse 55, 79106, Freiburg, Germany
| | - Marta Rizzi
- Department of Rheumatology and Clinical Immunology, Medical Center - University of Freiburg, Faculty of Medicine, Hugstetterstrasse 55, 79106, Freiburg, Germany
| | - Marie Engesser
- Department of Rheumatology and Clinical Immunology, Medical Center - University of Freiburg, Faculty of Medicine, Hugstetterstrasse 55, 79106, Freiburg, Germany
| | - Ann-Kathrin Dufner
- Department of Rheumatology and Clinical Immunology, Medical Center - University of Freiburg, Faculty of Medicine, Hugstetterstrasse 55, 79106, Freiburg, Germany
| | - Arianna Troilo
- Department of Rheumatology and Clinical Immunology, Medical Center - University of Freiburg, Faculty of Medicine, Hugstetterstrasse 55, 79106, Freiburg, Germany
| | - Raquel Lorenzetti
- Department of Rheumatology and Clinical Immunology, Medical Center - University of Freiburg, Faculty of Medicine, Hugstetterstrasse 55, 79106, Freiburg, Germany
| | - Reinhard E Voll
- Department of Rheumatology and Clinical Immunology, Medical Center - University of Freiburg, Faculty of Medicine, Hugstetterstrasse 55, 79106, Freiburg, Germany
| | - Nils Venhoff
- Department of Rheumatology and Clinical Immunology, Medical Center - University of Freiburg, Faculty of Medicine, Hugstetterstrasse 55, 79106, Freiburg, Germany.
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Zhang AL, Yang J, Wang H, Lu JL, Tang S, Zhang XJ. Association of NUDT15 c.415C>T allele and thiopurine-induced leukocytopenia in Asians: a systematic review and meta-analysis. Ir J Med Sci 2017; 187:145-153. [PMID: 28470355 DOI: 10.1007/s11845-017-1608-x] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2016] [Accepted: 03/25/2017] [Indexed: 12/11/2022]
Abstract
BACKGROUND Thiopurines, commonly used to treat autoimmune conditions and cancer, can be limited by life-threatening leucopenia. However, whether NUDT15 (nucleoside diphosphate-linked moiety X-type motif 15) is associated with thiopurine-induced leucopenia in Asians is controversial. METHODS Relevant studies in English that were published until July 10, 2016 were identified through PubMed, EMbase, and other web knowledge databases. Study quality was assessed according to the Newcastle-Ottawa Scale (NOS) criteria. Summary risk ratio (RR) and 95% confidence intervals (CI) were estimated based on a fixed-effects model or a random-effects model, depending on the absence or presence of significant heterogeneity. RESULTS Seven studies of 1138 patients met our inclusion criteria. Random-effects model meta-analysis provided evidence that T carriers of NUDT15 c.415C>T were significantly correlated with high incidences of thiopurine-induced leukocytopenia [CT + TT vs. CC: RR = 3.79, 95%CI (2.64 ~ 5.44), P < 0.00001]. This correlation was especially strong in TT patients, where it was found to be significantly increased by 6.54-fold compared with CC patients [TT vs. CC: RR = 6.54, 95%CI (3.34 ~ 12.82), P < 0.00001]. We also found that the NUDT15 c.415C>T variant was common in Asians and Hispanics, but rare in Europeans and Africans; the frequency of the NUDT15 c.415C>T distribution varied substantially by race/ethnicity. CONCLUSION The results of this meta-analysis confirm that NUDT15 c.415C>T may be an important predictor of thiopurine-induced leukocytopenia in Asians. Genotype targeting of NUDT15 c.415C>T before initiating thiopurine treatment may be useful to limit leukocytopenia.
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Affiliation(s)
- A L Zhang
- Department of Pharmacy, The First Affiliated Hospital of Zhengzhou University, NO.1 Jianshe Road, Erqi District, 450052, Zhengzhou, People's Republic of China
| | - J Yang
- Department of Pharmacy, The First Affiliated Hospital of Zhengzhou University, NO.1 Jianshe Road, Erqi District, 450052, Zhengzhou, People's Republic of China
| | - H Wang
- Department of Pharmacy, The First Affiliated Hospital of Zhengzhou University, NO.1 Jianshe Road, Erqi District, 450052, Zhengzhou, People's Republic of China
| | - J L Lu
- Department of Pharmacy, The First Affiliated Hospital of Zhengzhou University, NO.1 Jianshe Road, Erqi District, 450052, Zhengzhou, People's Republic of China
| | - S Tang
- Department of Pharmacy, The First Affiliated Hospital of Zhengzhou University, NO.1 Jianshe Road, Erqi District, 450052, Zhengzhou, People's Republic of China
| | - X J Zhang
- Department of Pharmacy, The First Affiliated Hospital of Zhengzhou University, NO.1 Jianshe Road, Erqi District, 450052, Zhengzhou, People's Republic of China.
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Mantzaris GJ. Thiopurines and Methotrexate Use in IBD Patients in a Biologic Era. ACTA ACUST UNITED AC 2017; 15:84-104. [DOI: 10.1007/s11938-017-0128-0] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
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Affiliation(s)
- G. Moroni
- Nephrological Unit, Divisione di Nefrologia e Dialisi, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan, Italy
| | - C. Ponticelli
- Nephrological Unit, Humanitas Clinical and Research Center, Rozzano (Milano), Italy
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38
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Liu Q, Wang Y, Mei Q, Han W, Hu J, Hu N. Measurement of red blood cell 6-thioguanine nucleotide is beneficial in azathioprine maintenance therapy of Chinese Crohn's disease patients. Scand J Gastroenterol 2016; 51:1093-9. [PMID: 27152547 DOI: 10.3109/00365521.2016.1161068] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
OBJECTIVE It remains controversial whether 6-thioguanine nucleotide (6-TGN)-based dose adjusting can be beneficial in azathioprine (AZA) therapy. This study is designed to assess the role of 6-TGN concentrations in maintaining clinical remission in Chinese patients with Crohn's disease (CD). MATERIAL AND METHOD We performed a prospective observational study and collected data of CD patients in the First Affiliated Hospital of Anhui Medical University from June 2013 to April 2014. Demographic material, CD activity index, 6-TGN concentration, and laboratory tests were recorded at baseline and at each visit. In addition, 6-TGN was measured when drug adverse effects occurred. All patients achieved maintenance stage were administered a stable AZA dose at least 3 months before enrollment and were followed up at least 12 months. Thiopurine S-methyltransferase (TPMT) genotype was measured before AZA treatment. RESULTS Sixty-nine patients receiving maintenance therapy were analyzed. A positive correlation was found between 6-TGN levels and AZA dose (r = 0.258, p = 0.032). The mean 6-TGN concentration was 302.06 ± 115.84 in the remission group vs. 264.94 ± 164.53 pmol/8 × 10(8) RBC in those with active disease (t = 0.847, p = 0.40), and 197.74 ± 66.54 pmol/8 × 10(8) RBC in patients who relapsed vs. 310.26 ± 122.38 pmol/8 × 10(8) RBC for those in sustained remission (t= -2.541, p = 0.013). In the leukopenia group, the 6-TGN concentration was 469.11 ± 115.53 pmol/8 × 10(8) RBC vs. 257.31 ± 83.74 pmol/8 × 10(8) RBC in the non-leukopenia group (t = 7.622, p < 0.001). There was a significant negative correlation between leukocyte count and 6-TGN concentration (r= -0.326, p = 0.006). CONCLUSIONS 6-TGN measurement is a helpful method of preventing disease relapse and avoiding leukopenia in individual azathioprine maintenance therapy.
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Affiliation(s)
- Qiuyuan Liu
- a Department of Gastroenterology , The First Affiliated Hospital of Anhui Medical University , Hefei , Anhui , People's Republic of China
| | - Yanyan Wang
- b Department of Pharmacy , The First Affiliated Hospital of Anhui Medical University , Hefei , Anhui , People's Republic of China
| | - Qiao Mei
- a Department of Gastroenterology , The First Affiliated Hospital of Anhui Medical University , Hefei , Anhui , People's Republic of China
| | - Wei Han
- a Department of Gastroenterology , The First Affiliated Hospital of Anhui Medical University , Hefei , Anhui , People's Republic of China
| | - Jing Hu
- a Department of Gastroenterology , The First Affiliated Hospital of Anhui Medical University , Hefei , Anhui , People's Republic of China
| | - Naizhong Hu
- a Department of Gastroenterology , The First Affiliated Hospital of Anhui Medical University , Hefei , Anhui , People's Republic of China
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Valerie NCK, Hagenkort A, Page BDG, Masuyer G, Rehling D, Carter M, Bevc L, Herr P, Homan E, Sheppard NG, Stenmark P, Jemth AS, Helleday T. NUDT15 Hydrolyzes 6-Thio-DeoxyGTP to Mediate the Anticancer Efficacy of 6-Thioguanine. Cancer Res 2016; 76:5501-11. [PMID: 27530327 DOI: 10.1158/0008-5472.can-16-0584] [Citation(s) in RCA: 83] [Impact Index Per Article: 9.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2016] [Accepted: 07/04/2016] [Indexed: 12/22/2022]
Abstract
Thiopurines are a standard treatment for childhood leukemia, but like all chemotherapeutics, their use is limited by inherent or acquired resistance in patients. Recently, the nucleoside diphosphate hydrolase NUDT15 has received attention on the basis of its ability to hydrolyze the thiopurine effector metabolites 6-thio-deoxyGTP (6-thio-dGTP) and 6-thio-GTP, thereby limiting the efficacy of thiopurines. In particular, increasing evidence suggests an association between the NUDT15 missense variant, R139C, and thiopurine sensitivity. In this study, we elucidated the role of NUDT15 and NUDT15 R139C in thiopurine metabolism. In vitro and cellular results argued that 6-thio-dGTP and 6-thio-GTP are favored substrates for NUDT15, a finding supported by a crystallographic determination of NUDT15 in complex with 6-thio-GMP. We found that NUDT15 R139C mutation did not affect enzymatic activity but instead negatively influenced protein stability, likely due to a loss of supportive intramolecular bonds that caused rapid proteasomal degradation in cells. Mechanistic investigations in cells indicated that NUDT15 ablation potentiated induction of the DNA damage checkpoint and cancer cell death by 6-thioguanine. Taken together, our results defined how NUDT15 limits thiopurine efficacy and how genetic ablation via the R139C missense mutation confers sensitivity to thiopurine treatment in patients. Cancer Res; 76(18); 5501-11. ©2016 AACR.
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Affiliation(s)
- Nicholas C K Valerie
- Science for Life Laboratory, Division of Translational Medicine and Chemical Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden
| | - Anna Hagenkort
- Science for Life Laboratory, Division of Translational Medicine and Chemical Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden
| | - Brent D G Page
- Science for Life Laboratory, Division of Translational Medicine and Chemical Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden
| | - Geoffrey Masuyer
- Department of Biochemistry and Biophysics, Stockholm University, Stockholm, Sweden
| | - Daniel Rehling
- Department of Biochemistry and Biophysics, Stockholm University, Stockholm, Sweden
| | - Megan Carter
- Department of Biochemistry and Biophysics, Stockholm University, Stockholm, Sweden
| | - Luka Bevc
- Science for Life Laboratory, Division of Translational Medicine and Chemical Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden
| | - Patrick Herr
- Science for Life Laboratory, Division of Translational Medicine and Chemical Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden
| | - Evert Homan
- Science for Life Laboratory, Division of Translational Medicine and Chemical Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden
| | - Nina G Sheppard
- Science for Life Laboratory, Division of Translational Medicine and Chemical Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden
| | - Pål Stenmark
- Department of Biochemistry and Biophysics, Stockholm University, Stockholm, Sweden.
| | - Ann-Sofie Jemth
- Science for Life Laboratory, Division of Translational Medicine and Chemical Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden.
| | - Thomas Helleday
- Science for Life Laboratory, Division of Translational Medicine and Chemical Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden.
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