|
1
|
Ridley B, Nonino F, Baldin E, Casetta I, Iuliano G, Filippini G. Azathioprine for people with multiple sclerosis. Cochrane Database Syst Rev 2024; 12:CD015005. [PMID: 39651635 PMCID: PMC11626701 DOI: 10.1002/14651858.cd015005.pub2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2024]
Abstract
BACKGROUND Multiple sclerosis (MS) is an immune-mediated, chronic, inflammatory demyelinating disease of the central nervous system, impacting around 2.8 million people worldwide. Characterised by recurrent relapses or progression, or both, it represents a substantial global health burden, affecting people, predominantly women, at a young age (the mean age of diagnosis is 32 years). Azathioprine is used to treat chronic inflammatory and autoimmune diseases, and it is used in clinical practice as an off-label intervention for MS, especially where access to on-label disease-modifying treatments (DMTs) for MS is limited. Given this, a review of azathioprine's benefits and harms would be timely and valuable to inform shared healthcare decisions. OBJECTIVES To evaluate the benefits and harms of azathioprine (AZA) for relapsing and progressive multiple sclerosis (MS), compared to other disease-modifying treatments (DMTs), placebo or no treatment. Specifically, we will assess the following comparisons. AZA compared with other DMTs or placebo as first-choice treatment for relapsing forms of multiple sclerosis AZA compared with other DMTs or placebo for relapsing forms of MS when switching from another DMT AZA compared with other DMTs or placebo as first-choice treatment for progressive forms of MS AZA compared with other DMTs or placebo for progressive forms of MS when switching from another DMT SEARCH METHODS: We conducted an extensive search for relevant literature using standard Cochrane search methods. The most recent search date was 9 August 2023. SELECTION CRITERIA We included randomised controlled trials (RCTs) lasting 12 months or more that compared azathioprine versus DMTs, placebo or no intervention in adults with MS. We considered evidence from non-randomised studies of interventions (NRSIs) as these studies may provide additional evidence not available from RCTS. We excluded cluster-randomised trials, cross-over trials, interrupted time series, case reports and studies of within-group design with no control group. DATA COLLECTION AND ANALYSIS We followed standard Cochrane methodology. There were three outcomes we considered to be critical: disability, relapse and serious adverse events (SAEs, as defined in the studies). We were also interested in other important outcomes: quality-of-life (QoL) impairment (mental score), short-term adverse events (gastrointestinal disorders), long-term adverse events (neoplasms) and mortality. MAIN RESULTS We included 14 studies: eight RCTs (1076 participants included in meta-analyses) and six NRSIs (1029 participants). These studies involved people with relapsing and progressive MS. Most studies included more women (57 to 83%) than men, with participants' average age at the onset of MS being between 29.4 and 33.4 years. Five RCTs and all six NRSIs were conducted in Europe (1793 participants); two RCTs were conducted in the USA (126 participants) and one in Iran (94 participants). The RCTs lasted two to three years, while NRSIs looked back up to 10 years. Four studies received some funding or support from commercial interests and five were funded by government or philanthropy; the other five provided no information about funding. There are three ongoing studies. Comparison groups included other DMTs (interferon beta and cyclosporine A), placebo or no treatment. Below, we report on azathioprine as a 'first choice' treatment compared to interferon beta for people with relapsing MS. None of the studies reported on any critical or important outcome for this comparison for progressive MS. No study was retrieved comparing azathioprine to placebo or other DMTs for either relapsing or progressive MS. Furthermore, the NRSIs did not provide information not already covered in the RCTs. Azathioprine as a first-choice treatment compared to other DMTs (specifically, interferon beta) for relapsing MS - The evidence is very uncertain about the effect of azathioprine on the number of people with disability progression over two years compared to interferon beta (risk ratio (RR) 0.19, 95% confidence interval (CI) 0.02 to 1.58; 1 RCT, 148 participants; very low certainty evidence). - Azathioprine may decrease the number of people with relapses over a one- to two-year follow-up compared to interferon beta (RR 0.61, 95% CI 0.43 to 0.86; 2 RCTs, 242 participants; low-certainty evidence). - Azathioprine may result in a possible increase in the number of people with SAEs over two years in comparison with interferon beta (RR 6.64, 95% CI 0.35 to 126.27; 1 RCT, 148 participants; low-certainty evidence). - The evidence is very uncertain about the effect of azathioprine on the number of people with the short-term adverse event of gastrointestinal disorders over two years compared to interferon beta (RR 5.30, 95% CI 0.15 to 185.57; 2 RCTs, 242 participants; very low certainty evidence). We found no evidence comparing azathioprine to other DMTs for QoL impairment (mental score), long-term adverse events (neoplasms) or mortality. AUTHORS' CONCLUSIONS Azathioprine has been proposed as an alternative treatment for MS when access to approved, on-label DMTs is limited, especially in resource-limited settings. The limited evidence available suggests that azathioprine may result in a modest benefit in terms of relapse frequency, with a possible increase in SAEs, when compared to interferon beta-1b, for people with relapsing-remitting multiple sclerosis. The evidence for the effect on disability progression and short-term adverse events is very uncertain. Caution is required in interpreting the conclusions of this review since our certainty in the available evidence on the benefits and harms of azathioprine in multiple sclerosis is low to very low, implying that further evidence is likely to change our conclusions. An important limitation we noted in the available evidence is the lack of long-term comparison with other treatments and the failure of most studies to measure outcomes that are important to people with multiple sclerosis, such as quality of life and cognitive decline. This is especially the case in the evidence relevant to people with progressive forms of multiple sclerosis.
Collapse
Affiliation(s)
- Ben Ridley
- IRCCS Istituto delle Scienze Neurologiche di Bologna, Bologna, Italy
| | - Francesco Nonino
- IRCCS Istituto delle Scienze Neurologiche di Bologna, Bologna, Italy
| | - Elisa Baldin
- IRCCS Istituto delle Scienze Neurologiche di Bologna, Bologna, Italy
| | | | | | - Graziella Filippini
- Scientific Director's Office, Carlo Besta Foundation and Neurological Institute, Milan, Italy
| |
Collapse
|
|
2
|
Bayoumy AB, Ansari AR, Mulder CJJ, Schmiegelow K, Florin T, De Boer NKH. Innovating Thiopurine Therapeutic Drug Monitoring: A Systematic Review and Meta-Analysis on DNA-Thioguanine Nucleotides (DNA-TG) as an Inclusive Biomarker in Thiopurine Therapy. Clin Pharmacokinet 2024; 63:1089-1109. [PMID: 39031224 PMCID: PMC11343975 DOI: 10.1007/s40262-024-01393-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/03/2024] [Indexed: 07/22/2024]
Abstract
BACKGROUND AND OBJECTIVE Thioguanine (TG), azathioprine (AZA), and mercaptopurine (MP) are thiopurine prodrugs commonly used to treat diseases, such as leukemia and inflammatory bowel disease (IBD). 6-thioguanine nucleotides (6-TGNs) have been commonly used for monitoring treatment. High levels of 6-TGNs in red blood cells (RBCs) have been associated with leukopenia, the cutoff levels that predict this side effect remain uncertain. Thiopurines are metabolized and incorporated into leukocyte DNA. Measuring levels of DNA-incorporated thioguanine (DNA-TG) may be a more suitable method for predicting clinical response and toxicities such as leukopenia. Unfortunately, most methodologies to assay 6-TGNs are unable to identify the impact of NUDT15 variants, effecting mostly ethnic populations (e.g., Chinese, Indian, Malay, Japanese, and Hispanics). DNA-TG tackles this problem by directly measuring thioguanine in the DNA, which can be influenced by both TPMT and NUDT15 variants. While RBC 6-TGN concentrations have traditionally been used to optimize thiopurine therapy due to their ease and affordability of measurement, recent developments in liquid chromatography-tandem mass spectrometry (LC-MS/MS) techniques have made measuring DNA-TG concentrations in lymphocytes accurate, reproducible, and affordable. The objective of this systematic review was to assess the current evidence of DNA-TG levels as marker for thiopurine therapy, especially with regards to NUDT15 variants. METHODS A systematic review and meta-analysis were performed on the current evidence for DNA-TG as a marker for monitoring thiopurine therapy, including methods for measurement and the illustrative relationship between DNA-TG and various gene variants (such as TPMT, NUDT15, ITPA, NT5C2, and MRP4). PubMed and Embase were systematically searched up to April 2024 for published studies, using the keyword "DNA-TG" with MeSH terms and synonyms. The electronic search strategy was augmented by a manual examination of references cited in articles, recent reviews, editorials, and meta-analyses. A meta-analysis was performed using R studio 4.1.3. to investigate the difference between the coefficients (Fisher's z-transformed correlation coefficient) of DNA-TG and 6-TGNs levels. A meta-analysis was performed using RevMan version 5.4 to investigate the difference in DNA-TG levels between patients with or without leukopenia using randomized effect size model. The risk of bias was assessed using the Newcastle-Ottowa quality assessment scale. RESULTS In this systematic review, 21 studies were included that measured DNA-TG levels in white blood cells for either patients with ALL (n = 16) or IBD (n = 5). In our meta-analysis, the overall mean difference between patients with leukopenia (ALL + IBD) versus no leukopenia was 134.15 fmol TG/µg DNA [95% confidence interval (CI) (83.78-184.35), P < 0.00001; heterogeneity chi squared of 5.62, I2 of 47%]. There was a significant difference in DNA-TG levels for patients with IBD with and without leukopenia [161.76 fmol TG/µg DNA; 95% CI (126.23-197.29), P < 0.00001; heterogeneity chi squared of 0.20, I2 of 0%]. No significant difference was found in DNA-TG level between patients with ALL with or without leukopenia (57.71 fmol TG/µg DNA [95% CI (- 22.93 to 138.35), P < 0.80]). DNA-TG monitoring was found to be a promising method for predicting relapse rates in patients with ALL, and DNA-TG levels are likely a better predictor for leukopenia in patients with IBD than RBC 6-TGNs levels. DNA-TG levels have been shown to correlate with various gene variants (TPMT, NUDT15, ITPA, and MRP4) in various studies, points to its potential as a more informative marker for guiding thiopurine therapy across diverse genetic backgrounds. CONCLUSIONS This systematic review strongly supports the further investigation of DNA-TG as a marker for monitoring thiopurine therapy. Its correlation with treatment outcomes, such as relapse-free survival in ALL and the risk of leukopenia in IBD, underscores its role in enhancing personalized treatment approaches. DNA-TG effectively identifies NUDT15 variants and predicts late leukopenia in patients with IBD, regardless of their NUDT15 variant status. The recommended threshold for late leukopenia prediction in patients with IBD with DNA-TG is suggested to be between 320 and 340 fmol/µg DNA. More clinical research on DNA-TG implementation is mandatory to improve patient care and to improve inclusivity in thiopurine treatment.
Collapse
Affiliation(s)
- Ahmed B Bayoumy
- Department of Internal Medicine, Amsterdam University Medical Centers, Location Academic Medical Center, Amsterdam, The Netherlands.
| | - A R Ansari
- Department of Gastroenterology and Hepatology, London Bridge Hospital, London, UK
| | - C J J Mulder
- Department of Gastroenterology and Hepatology, AGEM Research Institute, Amsterdam University Medical Center, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands
| | - K Schmiegelow
- Department of Pediatrics and Adolescent Medicine, The Juliane Marie Centre, The University Hospital Rigshospitalet, Copenhagen, Denmark
- Institute of Clinical Medicine, The Faculty of Health Sciences, The University of Copenhagen, Copenhagen, Denmark
| | - Timothy Florin
- Mater Research, University of Queensland, Translational Research Institute, Woolloongabba, QLD, 4102, Australia
| | - N K H De Boer
- Department of Gastroenterology and Hepatology, AGEM Research Institute, Amsterdam University Medical Center, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands
| |
Collapse
|
|
3
|
Jun YK, Ji E, Yang HR, Choi Y, Shin CM, Park YS, Kim N, Lee DH, Yoon H. Differences in the risk of clinical failure between thiopurine and methotrexate in bio-naïve patients with Crohn's disease: a Korean nationwide population-based study. Therap Adv Gastroenterol 2024; 17:17562848241248321. [PMID: 38741927 PMCID: PMC11089848 DOI: 10.1177/17562848241248321] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/11/2023] [Accepted: 03/31/2024] [Indexed: 05/16/2024] Open
Abstract
Background Although immunomodulators are widely prescribed in patients with Crohn's disease (CD), it is unclear whether there is a difference in treatment outcomes between thiopurines and methotrexate (MTX). Objective To compare the risk of clinical failure between thiopurines and MTX in bio-naïve patients with CD. Design Nationwide, population-based study. Methods We used claims data from the Korean National Health Insurance Service. After inverse probability of treatment weighting, logistic regression and Cox proportional hazard analyses were used to evaluate the risk of clinical failure in bio-naïve patients with CD treated with thiopurine (thiopurine group) or MTX (MTX group). Results Overall, 10,296 adult and pediatric patients with CD [9912 (96.3%) and 384 (3.7%) in the thiopurine and MTX groups, respectively] were included. The odds ratios (ORs) of failure to induce remission were significantly higher in the MTX group than in the thiopurine group [adjusted OR (aOR), 1.115; 95% confidence interval (CI), 1.045-1.190; p = 0.001]. However, the opposite result was observed only in patients without concomitant steroid use: the MTX group had a lower risk of induction failure than the thiopurine group (aOR, 0.740; 95% CI, 0.673-0.813; p < 0.001). The risk of overall maintenance failure was higher in the MTX group than in the thiopurine group [adjusted hazard ratio (aHR), 1.117; 95% CI, 1.047-1.191; p = 0.001]. The risk of overall maintenance failure was higher in the standard-dose MTX group than in the low-dose MTX group (aHR, 1.296; 95% CI, 1.134-1.480; p < 0.001). There was no significant difference in the risk of maintenance failure according to the administration route of MTX. Conclusion Thiopurine is more effective than MTX in inducing and maintaining remission in bio-naïve patients with CD; however, the concomitant use of steroids influences inducing remission.
Collapse
Affiliation(s)
- Yu Kyung Jun
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, South Korea
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, South Korea
| | - Eunjeong Ji
- Medical Research Collaborating Center, Seoul National University Bundang Hospital, Seongnam, South Korea
| | - Hye Ran Yang
- Department of Pediatrics, Seoul National University Bundang Hospital, Seongnam, South Korea
| | - Yonghoon Choi
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, South Korea
| | - Cheol Min Shin
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, South Korea
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, South Korea
| | - Young Soo Park
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, South Korea
| | - Nayoung Kim
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, South Korea
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, South Korea
| | - Dong Ho Lee
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, South Korea
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, South Korea
| | - Hyuk Yoon
- Department of Internal Medicine, Seoul National University Bundang Hospital, 173-82, Gumi-ro, Bundang-gu, Seongnam, Gyeonggi-do 463-707, South Korea
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, South Korea
| |
Collapse
|
|
4
|
Kim YZ, Kang B, Kim ES, Kwon Y, Choe YH, Kim MJ. Efficacy of Combined Initial Treatment of Methotrexate with Infliximab in Pediatric Crohn's Disease: A Pilot Study. Biomedicines 2023; 11:2575. [PMID: 37761016 PMCID: PMC10526834 DOI: 10.3390/biomedicines11092575] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2023] [Revised: 09/18/2023] [Accepted: 09/18/2023] [Indexed: 09/29/2023] Open
Abstract
BACKGROUND The combination of antitumor necrosis factor-alpha (TNF-α) agents with immunomodulators (IMMs) is a common treatment for pediatric Crohn's disease (CD). Although methotrexate (MTX) can be a first-line medication as an IMM, most clinicians in real-life practice, especially in South Korea, are more familiar with thiopurines. This study aimed to compare the efficacy and immunogenicity of MTX and azathioprine (AZA) as concurrent therapies for pediatric CD. METHODS In this pilot study, 29 newly diagnosed pediatric patients with moderate-to-severe CD were randomized to receive either MTX (n = 15) (15 mg/body surface area (BSA) per week) or oral AZA (n = 14) (0.5 mg/kg per day) in combination with Infliximab (IFX). The primary outcomes were the proportion of patients in endoscopic, biochemical, and transmural remission after 14 and 54 weeks of IFX therapy. The trough levels (TLs) of IFX and anti-drug antibody (ADA) levels were also compared. RESULTS Among the 29 patients, there were no significant differences in the biochemical (p = 1.0 at week 14, p = 0.45 at week 54), endoscopic (p = 0.968 at week 14, p = 0.05 at week 54), or transmural (p = 0.103 at week 54) remission rates between the two medications during the concurrent therapy. Additionally, the trends in the IFX trough and ADA levels over time during the treatments were similar for both medications, with no significant differences (p = 0.686, p = 0.389, respectively). CONCLUSION The MTX showed comparable efficacy to the AZA in pediatric CD patients with moderate-to-severe disease. This effectively maintained adequate IFX levels and reduced ADA production. Therefore, although additional large-scale clinical trials are needed, this study demonstrated that either MTX or AZA can be selected as IMMs in the concurrent treatment of pediatric CD, depending on individual medical institutions' circumstances.
Collapse
Affiliation(s)
- Yoon-Zi Kim
- Department of Pediatrics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351, Republic of Korea
| | - Ben Kang
- Department of Pediatrics, School of Medicine, Kyungpook National University Chilgok Hospital, Daegu 41944, Republic of Korea
| | - Eun-Sil Kim
- Department of Pediatrics, Kangbuk Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 03181, Republic of Korea
| | - Yiyoung Kwon
- Department of Pediatrics, Inha University Hospital, Inha University School of Medicine, Incheon 22188, Republic of Korea;
| | - Yon-Ho Choe
- Department of Pediatrics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351, Republic of Korea
| | - Mi-Jin Kim
- Department of Pediatrics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351, Republic of Korea
| |
Collapse
|
|
5
|
Desai D, Jena A, Sharma V, Hibi T. Time to incorporate preemptive NUDT15 testing before starting thiopurines in inflammatory bowel disease in Asia and beyond: a review. Expert Rev Clin Pharmacol 2023; 16:643-653. [PMID: 37387532 DOI: 10.1080/17512433.2023.2232300] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2023] [Accepted: 06/29/2023] [Indexed: 07/01/2023]
Abstract
INTRODUCTION Thiopurine toxicity is related to genetic polymorphism. Thiopurine methyltransferase (TPMT) variants do not explain thiopurine toxicity in more than half of patients. Asians, despite the low prevalence of TPMT variants, are more susceptible to thiopurine toxicity. Since 2014, studies from many Asian countries have shown a strong association between nucleoside diphosphate-linked moiety X-type motif (NUDT) 15 polymorphism and thiopurine-induced myelotoxicity. AREAS COVERED An English language literature search was performed for TPMT and NUDT15 genetic variants in inflammatory bowel disease and other diseases. This article discusses the merits of preemptive NUDT15 and TPMT testing in Asian and non-Asian IBD populations. EXPERT OPINION The NUDT polymorphism occurs in up to 27% of the Asian and Hispanic population. Hematological toxicity occurs in up to one-third of patients with this genetic variant. Given this, preemptive testing for NUDT15 variant is worthwhile and is probably more cost-effective than TPMT testing in these groups. Prevalence of NUDT15 variants is low in non-Finnish European population, but NUDT15 variants have been linked to myelotoxicity along with TPMT genetic variants. NUDT15 preemptive testing should be considered in the migrant Asian population in Europe and North America and in Caucasian populations who develop myelotoxicity.
Collapse
Affiliation(s)
- Devendra Desai
- Division of Gastroenterology, P D Hinduja Hospital, Mumbai, India
| | - Anuraag Jena
- Department of Gastroenterology, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| | - Vishal Sharma
- Department of Gastroenterology, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| | - Toshifumi Hibi
- Center for Advanced IBD Research and Treatment, Kitasato Institute Hospital, Kitasato University, Tokyo, Japan
| |
Collapse
|
|
6
|
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.
Collapse
|
|
7
|
Ranjan MK, Kante B, Vuyyuru SK, Kumar P, Mundhra SK, Golla R, Sharma R, Sahni P, Das P, Makharia G, Kedia S, Ahuja V. Minimal risk of lymphoma and non-melanoma skin cancer despite long-term use of thiopurines in patients with inflammatory bowel disease: A longitudinal cohort analysis from northern India. J Gastroenterol Hepatol 2022; 37:1544-1553. [PMID: 35501287 DOI: 10.1111/jgh.15880] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/11/2022] [Revised: 04/05/2022] [Accepted: 04/18/2022] [Indexed: 12/09/2022]
Abstract
BACKGROUND AND AIM Thiopurines are widely used to maintain remission in both ulcerative colitis (UC) and Crohn's disease (CD). Reported effectiveness and tolerability rates have been variable across studies. There are only sparse data in Asian population regarding the long-term efficacy and safety of thiopurines. METHODS Records of 5351 patients followed up at inflammatory bowel disease (IBD) clinic, All India Institute of Medical Sciences, New Delhi from 2004 to 2020 were evaluated retrospectively. Safety was evaluated in terms of long-term adverse events and development of malignancy. RESULTS Of 5351 patients with IBD, 1093 who received thiopurine for > 3 months (UC = 788 [proctitis-1.9%, left-sided colitis-44.9%, & pancolitis-53.1%] & CD = 305 [inflammatory-42.6%, stricturing-46.9%, & fistulizing-10.5%]) were included (60.8%-male patients). Follow up and treatment duration on thiopurine were 7 (4-12) years and 39.4 ± 40.3 months, respectively, with 254 (23.2%) patients receiving thiopurines for more than 5 and 68 (6.2%) receiving for more than 10 years. Three hundred and fifty-nine (UC: 249 [31.6%]; CD: 110 [36.1%]; P = 0.1) patients developed adverse events; commonest was myelosuppression (23.4%) followed by gastrointestinal intolerance (3%), flu-like illness (1.7%), and arthralgia/myalgia (1.4%). Myelosuppression was the commonest cause of thiopurine withdrawal. No patient (including 254 patients on thiopurine for ≥ 5 years) developed lymphoma or non-melanoma skin cancer. The cumulative probability of staying free from adverse events in overall IBD cohort at 1, 2, and 5 years was 78.6%, 71.9%, and 68.4%, respectively, and this was comparable between UC and CD (P = 0.09). CONCLUSION Long-term follow up of patients with IBD from northern India on thiopurine monotherapy demonstrated minimal risk of development of lymphoma as well as non-melanoma skin cancer.
Collapse
Affiliation(s)
- Mukesh Kumar Ranjan
- Department of Gastroenterology and Human Nutrition, All India Institute of Medical Sciences, New Delhi, India
| | - Bhaskar Kante
- Department of Gastroenterology and Human Nutrition, All India Institute of Medical Sciences, New Delhi, India
| | - Sudheer Kumar Vuyyuru
- Department of Gastroenterology and Human Nutrition, All India Institute of Medical Sciences, New Delhi, India
| | - Peeyush Kumar
- Department of Gastroenterology and Human Nutrition, All India Institute of Medical Sciences, New Delhi, India
| | - Sandeep K Mundhra
- Department of Gastroenterology and Human Nutrition, All India Institute of Medical Sciences, New Delhi, India
| | - Rithvik Golla
- Department of Gastroenterology and Human Nutrition, All India Institute of Medical Sciences, New Delhi, India
| | - Raju Sharma
- Department of Radio Diagnosis, All India Institute of Medical Sciences, New Delhi, India
| | - Peush Sahni
- Department of Gastrointestinal Surgery, All India Institute of Medical Sciences, New Delhi, India
| | - Prasenjit Das
- Department of Pathology, All India Institute of Medical Sciences, New Delhi, India
| | - Govind Makharia
- Department of Gastroenterology and Human Nutrition, All India Institute of Medical Sciences, New Delhi, India
| | - Saurabh Kedia
- Department of Gastroenterology and Human Nutrition, All India Institute of Medical Sciences, New Delhi, India
| | - Vineet Ahuja
- Department of Gastroenterology and Human Nutrition, All India Institute of Medical Sciences, New Delhi, India
| |
Collapse
|
|
8
|
Huang W, Wang L, Xia J, Li W, Wang M, Yu J, Li Q, Wang B, Pan J, Du L, Ma J, Tan H, Chang X, Lu C, Zhao C, Lu J, Zhou L, ZhangBao J, Quan C. Efficacy and safety of azathioprine, mycophenolate mofetil and reduced dose of rituximab in neuromyelitis optica spectrum disorder. Eur J Neurol 2022; 29:2343-2354. [PMID: 35398950 DOI: 10.1111/ene.15355] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2022] [Accepted: 04/05/2022] [Indexed: 12/01/2022]
Affiliation(s)
- Wenjuan Huang
- Department of Neurology Huashan Hospital Shanghai Medical College Fudan University Shanghai China
- National Center for Neurological Disorders (NCND) Shanghai China
- Huashan Rare Disease Center Huashan Hospital Shanghai Medical College Fudan University Shanghai China
| | - Liang Wang
- Department of Neurology Huashan Hospital Shanghai Medical College Fudan University Shanghai China
- National Center for Neurological Disorders (NCND) Shanghai China
- Huashan Rare Disease Center Huashan Hospital Shanghai Medical College Fudan University Shanghai China
| | - Junhui Xia
- Department of Neurology The First Affiliated Hospital of Wenzhou Medical University Wenzhou Zhejiang Province China
| | - Wenyu Li
- Department of Neurology Sir Run Run Shaw Hospital School of Medicine Zhejiang University Hangzhou Zhejiang Province China
| | - Min Wang
- Department of Ophthalmology and Vision Science, Eye and ENT Hospital Fudan University Shanghai China
| | - Jian Yu
- Department of Ophthalmology and Vision Science, Eye and ENT Hospital Fudan University Shanghai China
| | - Qinying Li
- Department of Rehabilitation Medicine Jing’an District Centre Hospital of Shanghai Fudan University Shanghai 200040 China
| | - Bei Wang
- Department of Neurology Jing’an District Centre Hospital of Shanghai Fudan University Shanghai 200040 China
| | - Juyuan Pan
- Department of Neurology The First Affiliated Hospital of Wenzhou Medical University Wenzhou Zhejiang Province China
| | - Lei Du
- Department of Neurology The First Affiliated Hospital of Xinjiang Medical University Urumqi Xinjiang Uygur Autonomous Region China
| | - Jianhua Ma
- Department of Neurology The First Affiliated Hospital of Xinjiang Medical University Urumqi Xinjiang Uygur Autonomous Region China
| | - Hongmei Tan
- Department of Neurology Huashan Hospital Shanghai Medical College Fudan University Shanghai China
- National Center for Neurological Disorders (NCND) Shanghai China
- Huashan Rare Disease Center Huashan Hospital Shanghai Medical College Fudan University Shanghai China
| | - Xuechun Chang
- Department of Neurology Huashan Hospital Shanghai Medical College Fudan University Shanghai China
- National Center for Neurological Disorders (NCND) Shanghai China
- Huashan Rare Disease Center Huashan Hospital Shanghai Medical College Fudan University Shanghai China
| | - Chuanzhen Lu
- Department of Neurology Huashan Hospital Shanghai Medical College Fudan University Shanghai China
- National Center for Neurological Disorders (NCND) Shanghai China
- Huashan Rare Disease Center Huashan Hospital Shanghai Medical College Fudan University Shanghai China
| | - Chongbo Zhao
- Department of Neurology Huashan Hospital Shanghai Medical College Fudan University Shanghai China
- National Center for Neurological Disorders (NCND) Shanghai China
- Huashan Rare Disease Center Huashan Hospital Shanghai Medical College Fudan University Shanghai China
| | - Jiahong Lu
- Department of Neurology Huashan Hospital Shanghai Medical College Fudan University Shanghai China
- National Center for Neurological Disorders (NCND) Shanghai China
- Huashan Rare Disease Center Huashan Hospital Shanghai Medical College Fudan University Shanghai China
| | - Lei Zhou
- Department of Neurology Huashan Hospital Shanghai Medical College Fudan University Shanghai China
- National Center for Neurological Disorders (NCND) Shanghai China
- Huashan Rare Disease Center Huashan Hospital Shanghai Medical College Fudan University Shanghai China
| | - Jingzi ZhangBao
- Department of Neurology Huashan Hospital Shanghai Medical College Fudan University Shanghai China
- National Center for Neurological Disorders (NCND) Shanghai China
- Huashan Rare Disease Center Huashan Hospital Shanghai Medical College Fudan University Shanghai China
| | - Chao Quan
- Department of Neurology Huashan Hospital Shanghai Medical College Fudan University Shanghai China
- National Center for Neurological Disorders (NCND) Shanghai China
- Huashan Rare Disease Center Huashan Hospital Shanghai Medical College Fudan University Shanghai China
| | | |
Collapse
|
|
9
|
Singh A, Mahajan R, Kedia S, Dutta AK, Anand A, Bernstein CN, Desai D, Pai CG, Makharia G, Tevethia HV, Mak JWY, Kaur K, Peddi K, Ranjan MK, Arkkila P, Kochhar R, Banerjee R, Sinha SK, Ng SC, Hanauer S, Verma S, Dutta U, Midha V, Mehta V, Ahuja V, Sood A. Use of thiopurines in inflammatory bowel disease: an update. Intest Res 2022; 20:11-30. [PMID: 33845546 PMCID: PMC8831775 DOI: 10.5217/ir.2020.00155] [Citation(s) in RCA: 57] [Impact Index Per Article: 19.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/04/2020] [Revised: 02/19/2021] [Accepted: 03/01/2021] [Indexed: 12/11/2022] Open
Abstract
Inflammatory bowel disease (IBD), once considered a disease of the Western hemisphere, has emerged as a global disease. As the disease prevalence is on a steady rise, management of IBD has come under the spotlight. 5-Aminosalicylates, corticosteroids, immunosuppressive agents and biologics are the backbone of treatment of IBD. With the advent of biologics and small molecules, the need for surgery and hospitalization has decreased. However, economic viability and acceptability is an important determinant of local prescription patterns. Nearly one-third of the patients in West receive biologics as the first/initial therapy. The scenario is different in developing countries where biologics are used only in a small proportion of patients with IBD. Increased risk of reactivation of tuberculosis and high cost of the therapy are limitations to their use. Thiopurines hence become critical for optimal management of patients with IBD in these regions. However, approximately one-third of patients are intolerant or develop adverse effects with their use. This has led to suboptimal use of thiopurines in clinical practice. This review article discusses the clinical aspects of thiopurine use in patients with IBD with the aim of optimizing their use to full therapeutic potential.
Collapse
Affiliation(s)
- Arshdeep Singh
- Department of Gastroenterology, Dayanand Medical College and Hospital, Ludhiana, India
| | - Ramit Mahajan
- Department of Gastroenterology, Dayanand Medical College and Hospital, Ludhiana, India
| | - Saurabh Kedia
- Department of Gastroenterology and Human Nutrition, All India Institute of Medical Sciences, New Delhi, India
| | - Amit Kumar Dutta
- Department of Gastroenterology, Christian Medical College, Vellore, India
| | - Abhinav Anand
- Department of Gastroenterology and Human Nutrition, All India Institute of Medical Sciences, New Delhi, India
| | - Charles N. Bernstein
- University of Manitoba IBD Clinical and Research Centre, Max Rady College of Medicine, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB, Canada
| | - Devendra Desai
- P. D. Hinduja Hospital and Medical Research Centre, Mumbai, India
| | - C. Ganesh Pai
- Department of Gastroenterology, Kasturba Medical College, Manipal, India
| | - Govind Makharia
- Department of Gastroenterology and Human Nutrition, All India Institute of Medical Sciences, New Delhi, India
| | | | - Joyce WY Mak
- Department of Medicine and Therapeutics, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, Hong Kong
| | - Kirandeep Kaur
- Department of Pharmacology, Dayanand Medical College and Hospital, Ludhiana, India
| | - Kiran Peddi
- Citizens Centre for Digestive Disorders, Hyderabad, India
| | - Mukesh Kumar Ranjan
- Department of Gastroenterology and Human Nutrition, All India Institute of Medical Sciences, New Delhi, India
| | - Perttu Arkkila
- Department of Gastroenterology, Helsinki University Central Hospital, Helsinki, Finland
| | - Rakesh Kochhar
- Department of Gastroenterology, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| | - Rupa Banerjee
- Asian Institute of Gastroenterology Hyderabad, Hyderabad, India
| | - Saroj Kant Sinha
- Department of Gastroenterology, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| | - Siew Chien Ng
- Department of Medicine and Therapeutics, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, Hong Kong
| | - Stephen Hanauer
- Department of Medicine, Northwestern University, Chicago, IL, USA
| | - Suhang Verma
- Department of Gastroenterology, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| | - Usha Dutta
- Department of Gastroenterology, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| | - Vandana Midha
- Department of Internal Medicine, Dayanand Medical College, Ludhiana, India
| | - Varun Mehta
- Department of Gastroenterology, Dayanand Medical College and Hospital, Ludhiana, India
| | - Vineet Ahuja
- Department of Gastroenterology and Human Nutrition, All India Institute of Medical Sciences, New Delhi, India
| | - Ajit Sood
- Department of Gastroenterology, Dayanand Medical College and Hospital, Ludhiana, India
| |
Collapse
|
|
10
|
Chang JY, Cheon JH. Pharmacogenetics-based personalized treatment in patients with inflammatory bowel disease: A review. PRECISION AND FUTURE MEDICINE 2021. [DOI: 10.23838/pfm.2021.00128] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022] Open
Abstract
The development of treatment options has revolutionized the prognosis of inflammatory bowel disease (IBD). However, a particular group of patients still experience therapeutic failure or drug side effects. Although the high inter-patient variability in therapy is associated with clinical factors, including age, disease behavior, and disease duration, they attribute only a small proportion of inter-individual variability. Thus, pharmacogenetics evaluating associations between specific genetic variations and drug responses or side effects have focused on optimizing therapeutic efficacy and minimizing toxicity in IBD treatment. Thiopurine S-methyltransferase (TPMT) and nudix hydrolase 15 (NUDT15) are well-established predictive markers of thiopurine-induced myelosuppression. Low TPMT activity is related to increased 6-thioguanine nucleotide levels, subsequently leading to myelotoxicity. NUDT15 variants are strongly associated with thiopurine-induced early leukopenia in Asians, with a lower incidence of TPMT-deficient allele. The Korean Association for the Study of Intestinal Diseases guidelines recommend pretreatment determination of NUDT15 genotypes, especially in East Asians, and NUDT15 R139C measurement has been approved for clinical use since 2019. Several studies have attempted to identify powerful genetic markers for personalized medicine. In this article, we review the identified pharmacogenetics of currently available drugs, focusing on 5-aminosalicylic acid, glucocorticosteroids, thiopurines, and anti-tumor necrosis factor-alpha agents.
Collapse
|
|
11
|
Zhou X, Cheng L, Wang Y, Gou H, Ju K, Lan T, Zhan T, Li G, Gu Y, Sun Y, Xu Y, Sun Y, Zhou Y, Li W. Effect of NUDT15 polymorphisms on early hematological safety of low-dose azathioprine in Chinese patients with pemphigus vulgaris: A prospective cohort study. J Dermatol 2021; 49:402-410. [PMID: 34866237 PMCID: PMC9299774 DOI: 10.1111/1346-8138.16265] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2021] [Revised: 11/18/2021] [Accepted: 11/19/2021] [Indexed: 02/05/2023]
Abstract
Azathioprine (AZA) is the preferred immunosuppressant for treating pemphigus vulgaris (PV), with discontinuation mainly attributed to hematological adverse events (AE). Reportedly, nucleoside diphosphate‐linked moiety X‐type motif 15 (NUDT15) polymorphisms have been strongly associated with thiopurine‐induced leukopenia. To investigate hematological AE of low‐dose AZA based on NUDT15 genotypes among patients with PV, a prospective cohort study was conducted in patients with PV, followed‐up for the first 8 weeks after AZA administration. All patients were divided into wild homozygous and heterozygous NUDT15 groups. Both groups initiated AZA at low dose (50 mg/day) and continued with different dose‐escalating approaches. Bone marrow suppression was considered the principal outcome. Overall, 62 patients with PV were enrolled (48 in the wild homozygous NUDT15 group vs. 14 in the heterozygous NUDT15 group). Except for median maintenance doses of AZA, no statistically significant differences were observed between the two groups in terms of age, sex, white blood cells, neutrophil count, platelet count, hemoglobin level, median final doses of corticosteroids (mg prednisone equivalent), pemphigus disease area index, and anti‐desmoglein 1/3 autoantibodies. In both groups, patients presented similar hematological AE and treatment responses after administration of different low‐dose AZA treatment strategies. Low‐dose AZA based on NUDT15 genotypes can reduce the risk of early hematological AE among patients with PV.
Collapse
Affiliation(s)
- Xingli Zhou
- Department of Dermatology, Rare Diseases Center, West China Hospital, Sichuan University, Chengdu, China
| | - Liangliang Cheng
- School of Public Health, Sun Yat-Sen University, Guangzhou, China
| | - Yiyi Wang
- Department of Dermatology, Rare Diseases Center, West China Hospital, Sichuan University, Chengdu, China
| | - Hui Gou
- Department of Dermatology, Rare Diseases Center, West China Hospital, Sichuan University, Chengdu, China
| | - Ke Ju
- School of Public Health and Preventive Medicine, Monash University, Melbourne, Victoria, Australia.,West China School of Public Health and West China Fourth Hospital, Sichuan University, Chengdu, China
| | - TianJiao Lan
- West China School of Public Health and West China Fourth Hospital, Sichuan University, Chengdu, China
| | - Tongying Zhan
- Department of Dermatology, Rare Diseases Center, West China Hospital, Sichuan University, Chengdu, China
| | - GaoJie Li
- Department of Dermatology, Rare Diseases Center, West China Hospital, Sichuan University, Chengdu, China
| | - Yuanxia Gu
- Department of Dermatology, Rare Diseases Center, West China Hospital, Sichuan University, Chengdu, China
| | - Yeting Sun
- West China School of Medicine, West China Hospital, Sichuan University, Chengdu, China
| | - Yan Xu
- West China School of Medicine, West China Hospital, Sichuan University, Chengdu, China
| | - Yukun Sun
- West China School of Medicine, West China Hospital, Sichuan University, Chengdu, China
| | - Yanhong Zhou
- Department of Laboratory Medicine, West China Hospital, Sichuan University, Chengdu, China
| | - Wei Li
- Department of Dermatology, Rare Diseases Center, West China Hospital, Sichuan University, Chengdu, China
| |
Collapse
|
|
12
|
Khaeso K, Udayachalerm S, Komvilaisak P, Chainansamit SO, Suwannaying K, Laoaroon N, Kuwatjanakul P, Nakkam N, Sukasem C, Puangpetch A, Tassaneeyakul W, Chaiyakunapruk N. Meta-Analysis of NUDT15 Genetic Polymorphism on Thiopurine-Induced Myelosuppression in Asian Populations. Front Pharmacol 2021; 12:784712. [PMID: 34925040 PMCID: PMC8675242 DOI: 10.3389/fphar.2021.784712] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2021] [Accepted: 11/16/2021] [Indexed: 12/20/2022] Open
Abstract
Backgound: The high incidence of thiopurine-induced myelosuppression in Asians is known to be attributable to genetic variation in thiopurine metabolism. A quantitative synthesis to summarize the genetic association with thiopurine-induced myelosuppression in Asians was therefore conducted. Methods: A Literature search was performed from January 2016 to May 2021 in the following databases: PubMed, Web of Science, and Embase and addition search included the studies from Zhang et al. Two reviewers independently extracted the following data: the author’s name, year of publication, ethnicity, drugs, diseases, genetic polymorphisms, onset, type of myelosuppression and results of Hardy-Weinberg equilibrium. The Newcastle-Ottawa Scale was used to assess the quality of the studies. The pooled odds ratios (OR) and 95% confidence intervals (CI) were calculated to evaluate the associations of NUDT15 and the risk of thiopurine-induced myelosuppression stratified by onset and type of myelosuppressive. Subgroup analysis by NUDT15 genetic polymorphisms was performed. Results: A total of 30 studies was included in this meta-analysis. The overall OR for the relationship between NUDT15 genetic polymorphisms and thiopurine-induced early onset of leukopenia and neutropenia in Asian populations were 11.43 (95% CI 7.11–18.35) and 16.35 (95% CI 10.20–26.22). Among NUDT15 polymorphisms, NUDT15*3 showed a significantly increased risk of early leukopenia (OR 15.31; 95% CI 9.65–24.27) and early neutropenia (OR 15.85; 95% CI 8.80–28.53). A significantly higher thiopurine-induced early neutropenic risk was also found for NUDT15*2 (OR 37.51; 95% CI 1.99–708.69). Whereas, NUDT15*5 and NUDT15*6 variants showed a lower risk of leukopenia. Conclusion: This study suggests that NUDT15*3 and NUDT15*2 are important genetic markers of thiopurine-induced early onset of myelotoxicity in Asians, therefore, early detection of these variants before initiating thiopurine therapy is necessary.
Collapse
Affiliation(s)
- Kanyarat Khaeso
- Department of Pharmacology, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand
| | - Sariya Udayachalerm
- Department of Pharmacotherapy, College of Pharmacy, University of Utah, Salt Lake City, UT, United States
| | - Patcharee Komvilaisak
- Department of Pediatrics, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand
| | | | - Kunanya Suwannaying
- Department of Pediatrics, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand
| | - Napat Laoaroon
- Department of Pediatrics, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand
| | | | - Nontaya Nakkam
- Department of Pharmacology, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand
| | - Chonlaphat Sukasem
- Division of Pharmacogenomics and Personalized Medicine, Department of Pathology, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand
- Laboratory for Pharmacogenomics, Somdech Phra Debaratana Medical Center (SDMC), Ramathibodi Hospital, Bangkok, Thailand
| | - Apichaya Puangpetch
- Division of Pharmacogenomics and Personalized Medicine, Department of Pathology, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand
- Laboratory for Pharmacogenomics, Somdech Phra Debaratana Medical Center (SDMC), Ramathibodi Hospital, Bangkok, Thailand
| | - Wichittra Tassaneeyakul
- Department of Pharmacology, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand
- *Correspondence: Wichittra Tassaneeyakul, ; Nathorn Chaiyakunapruk,
| | - Nathorn Chaiyakunapruk
- Department of Pharmacotherapy, College of Pharmacy, University of Utah, Salt Lake City, UT, United States
- *Correspondence: Wichittra Tassaneeyakul, ; Nathorn Chaiyakunapruk,
| |
Collapse
|
|
13
|
Chao K, Huang Y, Zhu X, Tang J, Wang X, Lin L, Guo H, Zhang C, Li M, Yang Q, Huang J, Ye L, Hu P, Huang M, Cao Q, Gao X. Randomised clinical trial: dose optimising strategy by NUDT15 genotyping reduces leucopenia during thiopurine treatment of Crohn's disease. Aliment Pharmacol Ther 2021; 54:1124-1133. [PMID: 34563096 DOI: 10.1111/apt.16600] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/23/2021] [Revised: 05/22/2021] [Accepted: 08/27/2021] [Indexed: 12/14/2022]
Abstract
INTRODUCTION Thiopurine S-methyltransferase (TPTM) is a well known biomarker for thiopurine-induced leucopenia, which has limited value in Asia. Instead, NUDT15 C415T is a promising predictor in Asia. AIMS To explore whether an optimised strategy based on NUDT15 C415T genotypes affects thiopurine-induced leucopenia, as well as efficacy in Chinese patients with Crohn's disease. METHODS Patients with Crohn's disease and indications for thiopurines were included from two hospitals in China. They were randomly assigned to either the intervention or the control group. In the intervention group, those with genotype CC received a standard dose (control group), those with CT genotype received 50% of the standard dose, those with TT genotype received alternative drugs. The primary endpoint was thiopurine-induced leucopenia (<3.5 × 109 /L). Secondary outcomes were the incidence of other adverse events and the efficacy for maintaining steroid-free remission at week 36. RESULTS The rate of thiopurine-induced leucopenia was lower in the intervention group (n = 52) than in the control group (n = 66) (23.7% vs 32.4%, P = 0.049, RR = 0.73, 95% CI 0.53-1.00). In CT subgroup, the incidence of leucopenia in the intervention group (n = 10) was significantly lower than in the control group (n = 28) (31.3% vs 65.1%, RR = 0.48, 95% CI 0.28-0.84). Neither other adverse events nor treatment efficacy was significantly different between the two groups during follow-up. CONCLUSIONS Among Chinese patients with Crohn's disease, dose optimisation by NUDT15 C415T reduced the rate of thiopurine-induced leucopenia, without significant influence on efficacy. Using 50% dose reduction for heterozygotes, and alternative drugs for homozygotes, are practicable strategies. Clinical trial number: NCT02929706.
Collapse
Affiliation(s)
- Kang Chao
- Department of Gastroenterology, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.,Guangdong Institute of Gastroenterology, Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, Supported by National Key Clinical Discipline, Guangzhou, China
| | - Yibiao Huang
- Department of Gastroenterology, School of Medicine, Sir Run Run Shaw Hospital, Zhejiang University, Hangzhou, China
| | - Xia Zhu
- Department of Gastroenterology, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.,Guangdong Provincial Key Laboratory of New Drug Design and Evaluation, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, China.,Guangdong Institute of Gastroenterology, Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, Supported by National Key Clinical Discipline, Guangzhou, China
| | - Jian Tang
- Department of Gastroenterology, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.,Guangdong Institute of Gastroenterology, Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, Supported by National Key Clinical Discipline, Guangzhou, China
| | - Xueding Wang
- Guangdong Provincial Key Laboratory of New Drug Design and Evaluation, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, China
| | - Lang Lin
- Department of Gastroenterology, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.,Guangdong Institute of Gastroenterology, Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, Supported by National Key Clinical Discipline, Guangzhou, China
| | - Huili Guo
- Department of Gastroenterology, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.,Guangdong Institute of Gastroenterology, Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, Supported by National Key Clinical Discipline, Guangzhou, China
| | - Caibin Zhang
- Guangdong Provincial Key Laboratory of New Drug Design and Evaluation, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, China
| | - Miao Li
- Department of Gastroenterology, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.,Guangdong Institute of Gastroenterology, Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, Supported by National Key Clinical Discipline, Guangzhou, China
| | - Qingfan Yang
- Department of Gastroenterology, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.,Guangdong Institute of Gastroenterology, Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, Supported by National Key Clinical Discipline, Guangzhou, China
| | - Jie Huang
- Department of Gastroenterology, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.,Guangdong Institute of Gastroenterology, Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, Supported by National Key Clinical Discipline, Guangzhou, China
| | - Lingna Ye
- Department of Gastroenterology, School of Medicine, Sir Run Run Shaw Hospital, Zhejiang University, Hangzhou, China
| | - Pinjin Hu
- Department of Gastroenterology, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.,Guangdong Institute of Gastroenterology, Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, Supported by National Key Clinical Discipline, Guangzhou, China
| | - Min Huang
- Guangdong Provincial Key Laboratory of New Drug Design and Evaluation, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, China
| | - Qian Cao
- Department of Gastroenterology, School of Medicine, Sir Run Run Shaw Hospital, Zhejiang University, Hangzhou, China
| | - Xiang Gao
- Department of Gastroenterology, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.,Guangdong Institute of Gastroenterology, Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, Supported by National Key Clinical Discipline, Guangzhou, China
| |
Collapse
|
|
14
|
Kim YS. Treatment of inflammatory bowel diseases: focusing on 5-aminosalicylates and immunomodulators. JOURNAL OF THE KOREAN MEDICAL ASSOCIATION 2021. [DOI: 10.5124/jkma.2021.64.9.596] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022] Open
Abstract
Background: Recently, the incidence and prevalence rates of inflammatory bowel disease (IBD) have increased worldwide, including in Korea. Although there has been considerable progress in the management of IBD following the discovery of biologic agents, 5-aminosalicylate (5-ASA) and immunomodulators are still considered cornerstones in the management of mild to moderate IBD.Current Concepts: 5-ASA plays a key role in inducing remission in patients with mild to moderate ulcerative colitis. High doses of 5-ASA are more effective in inducing remission in patients with moderate ulcerative colitis, and combination therapy of oral 5-ASA and topical 5-ASA agents is recommended. Although the effect of 5-ASA in patients with Crohn disease is limited, high doses of 5-ASA can be effective for patients with mild disease, inflammatory behavior, and colonic involvement. Maintaining remission is essential for patients with IBD. Good doctor-patient relationships and encouraging drug adherence are recommended. Regarding drug adherence, a once-daily regimen is preferred for patients’ satisfaction. Thiopurines, the most important immunomodulators, show therapeutic benefits, such as steroid-sparing effects and remission maintenance in ulcerative colitis and Crohn disease after induction therapy. However, several side effects, including severe leukopenia, can induce the discontinuation of thiopurines. Close monitoring and management decisions should be individualized according to the risk of relapse and adverse events.Discussion and Conclusion: In conclusion, 5-ASA and immunomodulators are cornerstones in the management of IBD. As such, clinicians should have knowledge of these drugs and patients’ characteristics for proper prescription.
Collapse
|
|
15
|
Zeng D, Huang X, Lin S, Lin R, Weng X, Huang P. Cost-effectiveness analysis of genotype screening and therapeutic drug monitoring in patients with inflammatory bowel disease treated with azathioprine therapy: a Chinese healthcare perspective using real-world data. ANNALS OF TRANSLATIONAL MEDICINE 2021; 9:1138. [PMID: 34430579 PMCID: PMC8350671 DOI: 10.21037/atm-21-1980] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/22/2021] [Accepted: 07/07/2021] [Indexed: 11/15/2022]
Abstract
Background This study aimed to analyze the cost-effectiveness of combining screening for thiopurine methyl transferase (TPMT) and nucleotide triphosphate diphosphatase (NUDT15) defective alleles with therapeutic drug monitoring (TDM) in Chinese patients with inflammatory bowel disease (IBD) treated with azathioprine (AZA). Methods We evaluated the cost-effectiveness of combining screening for NUDT15 and TPMT deficiency with TDM in patients receiving AZA treatment over a 1-year horizon by developing a decision tree model. Real-world data and published literature were used to derive model inputs. The model’s primary outcomes included quality-adjusted life-years (QALYs) and incremental cost-effectiveness ratios (ICERs). One-way and probabilistic sensitivity analyses were used to address uncertainty. Results Compared to NUDT15 genotyping, the combined TPMT/NUDT15 genotyping strategy cost an additional $13.83, yielding an ICER of $3,929.54/QALY, which was under the willingness-to-pay level of $30,425 per QALY in China. Compared to strategies with singular TPMT genotyping or no genotyping, the combined TPMT/NUDT15 genotyping strategy gained 0.00406 and 0.00782 QALYs and reduced the cost by $25.15 and $99.06, respectively. Additionally, incorporating TDM of AZA was more effective and less expensive than strategies without TDM. One-way sensitivity analysis revealed the expense attached to severe myelotoxicity to be the factor with the greatest influence in the present research. The application of the combined genotype screening strategy with TDM of AZA treatment was found to have a 91.7% chance of being cost-effective. Conclusions For Chinese patients with IBD who receive an AZA regimen, a strategy involving combined NUDT15/TPMT genotype screening prior to treatment initiation and incorporating TDM for treatment management is cost-effective compared to strategies involving genotyping of NUDT15 or TPMT alone or genotyping without TDM.
Collapse
Affiliation(s)
- Dayong Zeng
- Department of Pharmacy, The First Affiliated Hospital of Fujian Medical University, Fuzhou, China
| | - Xiaoting Huang
- Department of Pharmacy, The First Affiliated Hospital of Fujian Medical University, Fuzhou, China
| | - Shen Lin
- Department of Pharmacy, The First Affiliated Hospital of Fujian Medical University, Fuzhou, China
| | - Rongfang Lin
- Department of Pharmacy, The First Affiliated Hospital of Fujian Medical University, Fuzhou, China
| | - Xiuhua Weng
- Department of Pharmacy, The First Affiliated Hospital of Fujian Medical University, Fuzhou, China
| | - Pinfang Huang
- Department of Pharmacy, The First Affiliated Hospital of Fujian Medical University, Fuzhou, China
| |
Collapse
|
|
16
|
Miao Q, Yan L, Zhou Y, Li Y, Zou Y, Wang L, Bai Y, Zhang J. Association of genetic variants in TPMT, ITPA, and NUDT15 with azathioprine-induced myelosuppression in southwest china patients with autoimmune hepatitis. Sci Rep 2021; 11:7984. [PMID: 33846471 PMCID: PMC8042108 DOI: 10.1038/s41598-021-87095-0] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2020] [Accepted: 03/23/2021] [Indexed: 02/05/2023] Open
Abstract
This study aimed to investigate the influence of TPMT*3C, ITPA, NUDT15, and 6-thioguanine nucleotides (6-TGN) on azathioprine (AZA)-induced myelosuppression in Southwest China patients with autoimmune hepatitis (AIH). A total of 113 Chinese patients with AIH receiving AZA maintenance treatment were evaluated. The relevant clinical data of the patients were collected from the hospital information system. Genotyping of TPMT*3C(rs1142345), ITPA (rs1127354) and NUDT15(rs116855232) was conducted using a TaqMan double fluorescent probe. The concentration of 6-TGN was determined using UPLC-MS/MS. Among AIH patients treated with AZA, 40 (35.4%) exhibited different degrees of myelosuppression. The NUDT15 variant was associated with leukopenia (P = 8.26 × 10–7; OR = 7.5; 95% CI 3.08–18.3) and neutropenia (P = 3.54 × 10–6; OR = 8.05; 95% CI 2.96–21.9); however, no significant association with myelosuppression was observed for TPMT*3C and ITPA variants (P > 0.05). There was no significant difference in 6-TGN concentration between AIH patients with or without myelosuppression (P = 0.556), nor was there a significant difference between patients with variant alleles of TPMT*3C, ITPA, or NUDT15 and wild-type patients (P > 0.05). Interestingly, it was found that patients with a lower BMI had higher adjusted 6-TGN levels and a higher incidence of myelosuppression (P = 0.026 and 0.003). This study confirmed that NUDT15 variants are a potential independent risk predictor for AZA-induced leukopenia and neutropenia. BMI may be a crucial non-genetic factor that affects the concentration of AZA metabolites and myelosuppression. In addition, the 6-TGN concentration in red blood cells does not reflect the toxicity of AZA treatment, and new biomarkers for AZA therapeutic drug monitoring need further research.
Collapse
Affiliation(s)
- Qiang Miao
- Department of Laboratory Medicine/Research Center of Clinical Laboratory Medicine, West China Hospital of Sichuan University, No.37, Guoxue Xiang, Wuhou District, Chengdu, 610041, China
| | - Lin Yan
- Department of Laboratory Medicine/Research Center of Clinical Laboratory Medicine, West China Hospital of Sichuan University, No.37, Guoxue Xiang, Wuhou District, Chengdu, 610041, China
| | - Yanhong Zhou
- Department of Laboratory Medicine/Research Center of Clinical Laboratory Medicine, West China Hospital of Sichuan University, No.37, Guoxue Xiang, Wuhou District, Chengdu, 610041, China
| | - Yi Li
- Department of Laboratory Medicine/Research Center of Clinical Laboratory Medicine, West China Hospital of Sichuan University, No.37, Guoxue Xiang, Wuhou District, Chengdu, 610041, China
| | - Yuangao Zou
- Department of Laboratory Medicine/Research Center of Clinical Laboratory Medicine, West China Hospital of Sichuan University, No.37, Guoxue Xiang, Wuhou District, Chengdu, 610041, China
| | - Lanlan Wang
- Department of Laboratory Medicine/Research Center of Clinical Laboratory Medicine, West China Hospital of Sichuan University, No.37, Guoxue Xiang, Wuhou District, Chengdu, 610041, China
| | - Yangjuan Bai
- Department of Laboratory Medicine/Research Center of Clinical Laboratory Medicine, West China Hospital of Sichuan University, No.37, Guoxue Xiang, Wuhou District, Chengdu, 610041, China.
| | - Junlong Zhang
- Department of Laboratory Medicine/Research Center of Clinical Laboratory Medicine, West China Hospital of Sichuan University, No.37, Guoxue Xiang, Wuhou District, Chengdu, 610041, China.
| |
Collapse
|
|
17
|
Xu Y, Qiao YQ, Li HY, Zhou M, Cai CW, Shen J, Ran ZH. NUDT15 genotyping during azathioprine treatment in patients with inflammatory bowel disease: implications for a dose-optimization strategy. Gastroenterol Rep (Oxf) 2021; 8:437-444. [PMID: 33442476 PMCID: PMC7793196 DOI: 10.1093/gastro/goaa021] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/10/2019] [Revised: 10/28/2019] [Accepted: 01/08/2020] [Indexed: 12/17/2022] Open
Abstract
Background NUDT15 R139C is an Asian-prevalent genetic variant related to azathioprine (AZA) intolerance in patients with inflammatory bowel disease (IBD). However, it remains unclear how to utilize the genotyping results to improve the step-up dosing strategy with an already low starting dose in Asian practice. Methods Clinical data of eligible IBD patients who received AZA therapy and NUDT15 R139C testing were retrospectively collected. The relationship between NUDT15 genotype, AZA doses, and AZA-induced toxicity and efficacy were comprehensively analysed. Results A total of 159 patients were included for toxicity analysis. Compared with the wild genotype, patients heterozygous for R139C are more prone to developing myelotoxicity and alopecia (P = 0.007; P = 0.042). In particular, they had a 5.4-fold risk of developing myelotoxicity when AZA dosage was increased from 25 mg/d to 50 mg/d (P < 0.001). Regarding efficacy, 115 patients who had received AZA for >4 months and maintained clinical remission on AZA monotherapy were included for further analysis. R139C heterozygotes were finally titrated to a significantly lower dose than the wild genotype [median (interquartile range): 0.83 (0.75-0.96) vs 1.04 (0.89-1.33) mg/kg/d, P = 0.001], whereas the clinical remission rates did not differ between groups (P = 0.88). Conclusions IBD patients with R139C heterozygote are highly susceptible to AZA-induced myelotoxicity at an escalated dose of 50 mg/d. Thus, they may require a smaller dose increase after a starting dose of 25 mg/d. The final target dose of these patients could be set lower than that of the wild genotypes without compromising efficacy.
Collapse
Affiliation(s)
- Ye Xu
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, Inflammatory Bowel Disease Research Center, Shanghai Institute of Digestive Disease, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Yu-Qi Qiao
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, Inflammatory Bowel Disease Research Center, Shanghai Institute of Digestive Disease, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Han-Yang Li
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, Inflammatory Bowel Disease Research Center, Shanghai Institute of Digestive Disease, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Mi Zhou
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, Inflammatory Bowel Disease Research Center, Shanghai Institute of Digestive Disease, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Chen-Wen Cai
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, Inflammatory Bowel Disease Research Center, Shanghai Institute of Digestive Disease, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Jun Shen
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, Inflammatory Bowel Disease Research Center, Shanghai Institute of Digestive Disease, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Zhi-Hua Ran
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, Inflammatory Bowel Disease Research Center, Shanghai Institute of Digestive Disease, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| |
Collapse
|
|
18
|
Nakase H. Optimizing the Use of Current Treatments and Emerging Therapeutic Approaches to Achieve Therapeutic Success in Patients with Inflammatory Bowel Disease. Gut Liver 2020; 14:7-19. [PMID: 30919602 PMCID: PMC6974326 DOI: 10.5009/gnl18203] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/08/2018] [Revised: 10/06/2018] [Accepted: 10/12/2018] [Indexed: 12/18/2022] Open
Abstract
The current goal of inflammatory bowel disease (IBD) treatment is a symptom-free everyday life accompanied by mucosal healing with minimal use of corticosteroids. Recent therapeutic advances, particularly, the emergence of anti-tumor necrosis factor (anti-TNF) antibodies, have changed the natural history of IBD. Additionally, these advances also led to the emergence of the therapeutic concept of the “treat to target” strategy. With the development of new drugs and clinical trials, not only biologics but also small molecules have been applied to clinical practice to better individualize and optimize therapy. However, if newer drugs, including anti-TNF therapies, are recommended for all patients diagnosed with IBD, a significant number of patients will be overtreated. The basic goal of IBD treatment is still to make the best use of conventional treatments based on IBD pathophysiology. Thus, physicians should be familiar with the modes of action of the available drugs. In this review, the author discusses the existing data for many approved drugs and provide insights for optimizing current treatments for the management of patients with IBD in the era of biologics.
Collapse
Affiliation(s)
- Hiroshi Nakase
- Department of Gastroenterology and Hepatology, Sapporo Medical University School of Medicine, Sapporo, Japan
| |
Collapse
|
|
19
|
Bae J, Choe BH, Kang B. Prevention of thiopurine-induced early leukopenia in a Korean pediatric patient with Crohn's disease who turned out to possess homozygous mutations in NUDT15 R139C. Yeungnam Univ J Med 2020; 37:332-336. [PMID: 32438538 PMCID: PMC7606952 DOI: 10.12701/yujm.2020.00178] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2020] [Revised: 04/30/2020] [Accepted: 05/07/2020] [Indexed: 11/15/2022] Open
Abstract
Homozygous mutations in NUDT15 R139C are known as the major factor associated with thiopurine-induced early leukopenia, particularly in Asian patients. Therefore, NUDT15 genotyping is currently recommended before thiopurine treatment to identify patients who are NUDT15 poor metabolizers and consider the use of an alternative immunomodulatory therapy. We report a case of a 12-year-old Korean girl with Crohn's disease (CD), in whom thiopurine-induced leukopenia was prevented by initiation of azathioprine (AZA) therapy at a low dose (0.5 mg/kg/day) and early detection of significant hair loss and white blood cell (WBC) count decrease at 17 days from the start of AZA treatment. The WBC count dropped from 8,970/μL to 3,370/μL in 2 weeks, and AZA treatment was stopped because of concerns of potential leukopenia in the near future. Her WBC count recovered to 5,120/μL after 3 weeks. Gene analysis later revealed that she had a homozygous mutation in NUDT15 R139C, resulting in a poor metabolizing activity of NUDT15. In situations when NUDT15 genotyping is unavailable, initiation of AZA therapy at 0.5 mg/kg/day with close observation of hair loss and WBC counts within 2 weeks may be an alternative way to prevent thiopurine-induced early leukopenia in Asian children with CD.
Collapse
Affiliation(s)
- Jaewoan Bae
- Department of Pediatrics, School of Medicine, Kyungpook National University, Daegu, Korea
| | - Byung-Ho Choe
- Department of Pediatrics, School of Medicine, Kyungpook National University, Daegu, Korea
- Crohn's and Colitis Association in Daegu-Gyeongbuk (CCAiD), Daegu, Korea
| | - Ben Kang
- Department of Pediatrics, School of Medicine, Kyungpook National University, Daegu, Korea
- Crohn's and Colitis Association in Daegu-Gyeongbuk (CCAiD), Daegu, Korea
| |
Collapse
|
|
20
|
Zhou XL, Zhan TY, Zhou YH, Shrestha K, Lan TJ, Li W. Complete remission of refractory pemphigus vulgaris in a Chinese patient with mutated NUDT15 by combination of minimal doses of azathioprine and prednisone. Dermatol Ther 2020; 33:e14079. [PMID: 32713039 DOI: 10.1111/dth.14079] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2020] [Revised: 07/22/2020] [Accepted: 07/24/2020] [Indexed: 02/05/2023]
Abstract
Although azathioprine (AZA) combined with corticosteroids remains the first-line therapy to treat patients with pemphigus vulgaris (PV), there are increasing reports of AZA-induced leukopenia, which provides the rationale for monitoring the blood cell count and testing the genotypes at the thiopurine methyltransferase (TPMT) and the nucleoside diphosphate-linked moiety X-type motif 15 (NUDT15) genes. Here, we reported a case of persistent refractory PV in a Chinese patient with three runs of AZA-corticosteroids treatment. In the first two runs he received AZA-corticosteroids at standard or slightly reduced doses and developed leukopenia. In the third run of treatment, he was found to have NUDT15 mutation (rs116855232) and wild-type homozygous TPMT*3C (rs1142345), treatment with minimal doses of AZA and prednisone resulted in a complete remission of PV without any side effects including leukopenia. Our observations not only highlight the benefits of testing the TPMT and NUDT15 genotypes and monitoring the dynamic changes of the white blood cell count in guiding the AZA therapy, but also suggest the potential of using the AZA-corticosteroids combination at very low doses in the treatment of refractory PV.
Collapse
Affiliation(s)
- Xing-Li Zhou
- Department of Dermatology, Rare Diseases Center, West China Hospital, Sichuan University, Chengdu, China
| | - Tong-Ying Zhan
- Department of Dermatology, Rare Diseases Center, West China Hospital, Sichuan University, Chengdu, China
| | - Yan-Hong Zhou
- Department of Laboratory Medicine, West China Hospital, Sichuan University, Chengdu, China
| | - Krista Shrestha
- Department of Dermatology, Rare Diseases Center, West China Hospital, Sichuan University, Chengdu, China
| | - Tian-Jiao Lan
- West China School of Public Health and West China Fourth Hospital, Sichuan University, Chengdu, China
| | - Wei Li
- Department of Dermatology, Rare Diseases Center, West China Hospital, Sichuan University, Chengdu, China
| |
Collapse
|
|
21
|
Chang JY, Park SJ, Jung ES, Jung SA, Moon CM, Chun J, Park JJ, Kim ES, Park Y, Kim TI, Kim WH, Cheon JH. Genotype-based Treatment With Thiopurine Reduces Incidence of Myelosuppression in Patients With Inflammatory Bowel Diseases. Clin Gastroenterol Hepatol 2020; 18:2010-2018.e2. [PMID: 31446180 DOI: 10.1016/j.cgh.2019.08.034] [Citation(s) in RCA: 33] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/21/2019] [Revised: 08/12/2019] [Accepted: 08/16/2019] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS Thiopurine-related myelosuppression (most frequently leukopenia) interferes with thiopurine therapy for patients with inflammatory bowel diseases (IBD). We investigated whether pretreatment analyses genetic variants associated with thiopurine-induced leukopenia could be used to effectively identify patients who required dose adjustments. METHODS We performed a multicenter, prospective study of patients with IBD at 5 tertiary medical centers in Korea, from January 2016 through September 2018. Seventy-two patients were randomly assigned to a group that underwent genotype analysis for the NUDT15 variant (rs116855232) and FTO variant (rs79206939) and 3 common TPMT variants (rs1800460, rs1800462, rs1142345) associated with myelosuppression and 92 patients were assigned to a group that did not undergo genotype analysis (non-genotyping group). Patients heterozygous for any variant received 50 mg azathioprine equivalents, whereas those who were homozygous for any variant received alternative drugs. Patients who did not carry any of the genetic variants and patients in the non-genotyping group received 50 mg azathioprine equivalents followed by dose escalation up to 2-2.5 mg/kg. Myelosuppression was defined as white blood cell counts below 3000/μL, levels of hemoglobin 10 g/dL, or platelet counts below 100 K/μL. RESULTS Twelve patients (16.7%) in the genotype analysis group and 33 patients (35.9%) in the non-genotyping group developed myelosuppression (P=.005). A multivariate analysis revealed that body mass indices above 21 kg/m2 (hazard ratio [HR], 0.43; 95% CI, 0.22-0.81; P = .009), pretreatment genotype analysis (HR, 0.37; 95% CI, 0.18-0.77; P = .008), and the maximum dose of thiopurines (HR, 0.34; 95% CI, 0.19-0.59; P < .001) independently decreased risk of myelosuppression. Pretreatment genotype analysis reduced numbers of outpatient clinic visit and numbers of patients with drug discontinuation or dose reductions. CONCLUSIONS In a randomized controlled study of patients undergoing thiopurine therapy for IBD, we found that selection of therapy based on genetic variants associated with thiopurine-induced leukopenia significantly reduced the proportion of patients with myelosuppression during treatment. ClinicalTrials.gov no: NCT03719118.
Collapse
Affiliation(s)
- Ji Young Chang
- Department of Internal Medicine and Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Soo Jung Park
- Department of Internal Medicine and Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Eun Suk Jung
- Department of Internal Medicine and Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Sung-Ae Jung
- Department of Internal Medicine, College of Medicine, Ewha Womans University, Ewha Medical Research Institute, Seoul, Republic of Korea
| | - Chang Mo Moon
- Department of Internal Medicine, College of Medicine, Ewha Womans University, Ewha Medical Research Institute, Seoul, Republic of Korea
| | - Jaeyoung Chun
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Jae Jun Park
- Department of Internal Medicine, Yonsei University College of Medicine, Gangnam Severance Hospital, Seoul, Republic of Korea
| | - Eun Sun Kim
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Korea University College of Medicine, Seoul, Republic of Korea
| | - Yehyun Park
- Department of Internal Medicine and Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Tae-Il Kim
- Department of Internal Medicine and Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Won Ho Kim
- Department of Internal Medicine and Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Republic of Korea.
| | - Jae Hee Cheon
- Department of Internal Medicine and Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Republic of Korea.
| |
Collapse
|
|
22
|
Kang B, Kim TJ, Choi J, Baek SY, Ahn S, Choi R, Lee SY, Choe YH. Adjustment of azathioprine dose should be based on a lower 6-TGN target level to avoid leucopenia in NUDT15 intermediate metabolisers. Aliment Pharmacol Ther 2020; 52:459-470. [PMID: 32598049 DOI: 10.1111/apt.15810] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/20/2020] [Revised: 04/13/2020] [Accepted: 05/03/2020] [Indexed: 12/16/2022]
Abstract
BACKGROUND The association between NUDT15 polymorphisms and thiopurine-induced leucopenia is well known. AIM To investigate the association between NUDT15 polymorphisms and time-to-leucopenia in paediatric patients with inflammatory bowel disease (IBD) receiving azathioprine and to determine the relationship between NUDT15 polymorphisms and 6-thioguanine nucleotide (6-TGN) levels. METHODS This retrospective observational study included Korean paediatric patients with IBD who were treated with azathioprine and underwent NUDT15 and TPMT genotyping. Azathioprine doses were adjusted by regular thiopurine metabolite monitoring. Factors associated with time-to-leucopenia and the relationship between NUDT15 polymorphisms and 6-TGN levels were analysed. RESULTS Among the 167 patients included, leucopenia was observed in 16% (19/119), 44% (20/45) and 100% (3/3) of the NUDT15 normal, intermediate and poor metabolisers respectively (P < 0.001). NUDT15 polymorphism was significantly associated with time-to-leucopenia (HR = 5.26, 95% CI = 2.74-10.09, P < 0.001). There was a positive association between 6-TGN levels and leucopenia among the NUDT15 intermediate/TPMT normal metabolisers (median 361.3 vs 263.8 pmol/8 × 108 RBC, P = 0.013). The most accurate 6-TGN cut-off level associated with leucopenia was 308.2 pmol/8 × 108 RBC (AUC = 0.742, 95% CI = 0.569-0.915, sensitivity 80.0%, specificity 72.7%, P < 0.001) in this subgroup. When the specificity was set to <15%, the 6-TGN cut-off level was 167.1 pmol/8 × 108 RBC (sensitivity 93.3%, specificity 13.6%). CONCLUSIONS NUDT15 polymorphisms were associated with time-to-leucopenia during azathioprine treatment in Korean paediatric patients with IBD. In order to reduce the development of thiopurine-induced leucopenia (<15%) in NUDT15 intermediate metabolisers, adjustment of azathioprine doses should be based on a lower 6-TGN target level (<167.1 pmol/8 × 108 RBC).
Collapse
Affiliation(s)
- Ben Kang
- Department of Pediatrics, School of Medicine, Kyungpook National University, Daegu, Korea
| | - Tae Jun Kim
- Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Jaeyoung Choi
- Department of Pediatrics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Sun-Young Baek
- Statistics and Data Center, Research Institute for Future Medicine, Samsung Medical Center, Seoul, Korea
| | - Soohyun Ahn
- Department of Mathematics, Ajou University, Suwon, Korea
| | - Rihwa Choi
- Department of Laboratory Medicine and Genetics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
- Department of Laboratory Medicine, Green Cross Laboratories, Yongin, Korea
| | - Soo-Youn Lee
- Department of Laboratory Medicine and Genetics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Yon Ho Choe
- Department of Pediatrics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| |
Collapse
|
|
23
|
Zhu X, Chao K, Li M, Xie W, Zheng H, Zhang JX, Hu PJ, Huang M, Gao X, Wang XD. Nucleoside diphosphate-linked moiety X-type motif 15 R139C genotypes impact 6-thioguanine nucleotide cut-off levels to predict thiopurine-induced leukopenia in Crohn’s disease patients. World J Gastroenterol 2019; 25:5850-5861. [PMID: 31636477 PMCID: PMC6801191 DOI: 10.3748/wjg.v25.i38.5850] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/24/2019] [Revised: 09/05/2019] [Accepted: 09/10/2019] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Thiopurine-induced leukopenia (TIL) is a life-threatening toxicity and occurs with a high frequency in the Asian population. Although nucleoside diphosphate-linked moiety X-type motif 15 (NUDT15) variants significantly improve the predictive sensitivity of TIL, more than 50% of cases of this toxicity cannot be predicted by this mutation. The potential use of the 6-thioguanine nucleotide (6TGN) level to predict TIL has been explored, but no decisive conclusion has been reached. Can we increase the predictive sensitivity based on 6TGN by subgrouping patients according to their NUDT15 R139C genotypes?
AIM To determine the 6TGN cut-off levels after dividing patients into subgroups according to their NUDT15 R139C genotypes.
METHODS Patients’ clinical and epidemiological characteristics were collected from medical records from July 2014 to February 2017. NUDT15 R139C, thiopurine S-methyltransferase, and 6TGN concentrations were measured.
RESULTS A total of 411 Crohn’s disease patients were included. TIL was observed in 72 individuals with a median 6TGN level of 323.4 pmol/8 × 108 red blood cells (RBC), which was not different from that of patients without TIL (P = 0.071). Then, we compared the 6TGN levels based on NUDT15 R139C. For CC (n = 342) and CT (n = 65) genotypes, the median 6TGN level in patients with TIL was significantly higher than that in patients without (474.8 vs 306.0 pmol/8 × 108 RBC, P = 9.4 × 10-5; 291.7 vs 217.6 pmol/8 × 108 RBC, P = 0.039, respectively). The four TT carriers developed TIL, with a median 6TGN concentration of 135.8 pmol/8 × 108 RBC. The 6TGN cut-off levels were 411.5 and 319.2 pmol/8 × 108 RBC for the CC and CT groups, respectively.
CONCLUSION The predictive sensitivity of TIL based on 6TGN is dramatically increased after subgrouping according to NUDT15 R139C genotypes. Applying 6TGN cut-off levels to adjust thiopurine therapies based on NUDT15 is strongly recommended.
Collapse
Affiliation(s)
- Xia Zhu
- Institute of Clinical Pharmacology, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510000, Guangdong Province, China
| | - Kang Chao
- Department of Gastroenterology, the Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou 510000, Guangdong Province, China
| | - Miao Li
- Department of Gastroenterology, the Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou 510000, Guangdong Province, China
| | - Wen Xie
- Center for Pharmacogenetics and Department of Pharmaceutical Sciences, University of Pittsburgh, Pittsburgh, PA 15261, United States
| | - Hong Zheng
- Institute of Clinical Pharmacology, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510000, Guangdong Province, China
| | - Jin-Xin Zhang
- School of Public Health, Sun Yat-sen University, Guangzhou 510000, Guangdong Province, China
| | - Pin-Jin Hu
- Department of Gastroenterology, the Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou 510000, Guangdong Province, China
| | - Min Huang
- Institute of Clinical Pharmacology, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510000, Guangdong Province, China
| | - Xiang Gao
- Department of Gastroenterology, the Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou 510000, Guangdong Province, China
| | - Xue-Ding Wang
- Institute of Clinical Pharmacology, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510000, Guangdong Province, China
| |
Collapse
|
|
24
|
Chang JY, Cheon JH. Thiopurine Therapy in Patients With Inflammatory Bowel Disease: A Focus on Metabolism and Pharmacogenetics. Dig Dis Sci 2019; 64:2395-2403. [PMID: 31290039 DOI: 10.1007/s10620-019-05720-5] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/24/2019] [Accepted: 07/02/2019] [Indexed: 12/15/2022]
Abstract
Thiopurines have been widely used for the maintenance of remission or steroid sparing in patients with inflammatory bowel disease. However, potential drug-related adverse events frequently interfere with their use. Indeed, drug withdrawals associated with adverse reactions have been reported in approximately 25% of patients. To balance the efficacy, safety, and tolerability of thiopurines, regular monitoring of biomarkers (complete blood cell count, liver function test, and metabolic profiles), steady dose escalation, and pretreatment thiopurine S-methyltransferase (TPMT) genotype screening have been routinely recommended. However, the complex thiopurine metabolic pathway and individual differences attributed to pharmacogenetic diversity limit the effectiveness of these strategies in the optimization of thiopurine therapy. Recently, in an effort to facilitate more accurate and personalized prediction of thiopurine response or toxicity, novel genetic markers including NUDT15 and FTO genes were discovered. These discoveries are remarkable because TPMT screening has minimal efficacy for predicting myelosuppression especially in Asian populations, despite the fact that thee populations have a higher frequency of myelosuppression than Western populations. This review focuses on the current understanding of the metabolic pathway and the pharmacogenetics of thiopurines and suggests a personalized preventive strategy against potential adverse drug reactions to optimize their therapeutic application.
Collapse
Affiliation(s)
- Ji Young Chang
- Department of Internal Medicine, Institute of Gastroenterology, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun-gu, Seoul, 03722, Republic of Korea
- Department of Health Promotion Center, Ewha Womans University School of Medicine, Seoul, Korea
| | - Jae Hee Cheon
- Department of Internal Medicine, Institute of Gastroenterology, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun-gu, Seoul, 03722, Republic of Korea.
| |
Collapse
|
|
25
|
Fan X, Yin D, Men R, Xu H, Yang L. NUDT15 Polymorphism Confer Increased Susceptibility to Thiopurine-Induced Leukopenia in Patients With Autoimmune Hepatitis and Related Cirrhosis. Front Pharmacol 2019; 10:346. [PMID: 31024313 PMCID: PMC6465603 DOI: 10.3389/fphar.2019.00346] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2018] [Accepted: 03/20/2019] [Indexed: 02/05/2023] Open
Abstract
The aim of this study was to investigate the influence of NUDT15 R139C and thiopurine S-methyltransferase (TPMT) on azathioprine (AZA) induced leukopenia in patients with autoimmune hepatitis (AIH) and related cirrhosis. A total of 149 Chinese AIH patients with a history of AZA treatment were retrospectively evaluated. The clinical and epidemiological characteristics of the patients were obtained from an electronic database and reviewed. NUDT15 (rs116855232) and TPMT∗3C (rs1142345) SNPs were genotyped using a PCR method. Twelve patients developed leukopenia, and this adverse drug reaction was significantly associated with the T risk allele in NUDT15 [P < 0.00001, odds ratio = 20.41; 95% confidence interval (CI) (7.84, 53.13)], with the sensitivity and specificity of 91.67 and 89.05%, respectively. The median maintenance dosages for patients with the rs116855232 CC and CT genotypes were 1.23 (0.95, 1.53) mg ⋅ kg−1 ⋅ d−1 and 0.96 (0.83, 1.19) mg ⋅ kg−1 ⋅ d−1, respectively (P = 0.028). In contrast, no significant association was observed for TPMT∗3C genotypes. Notably, subgroup analysis of the 13 patients with leukopenia before therapy, these white blood cell (WBC) counts did not show further reduction after AZA treatment and maintenance dosage was 1.13 (0.94, 1.60) mg ⋅ kg−1 ⋅ d−1. Therefore, NUDT15 polymorphism is significantly associated with thiopurine-induced leukopenia in Chinese patients with AIH and related cirrhosis. Adjusting the AZA dosage should be considered in patients according to the NUDT15 R139C genotypes.
Collapse
Affiliation(s)
- Xiaoli Fan
- Department of Gastroenterology and Hepatology, West China Hospital, Sichuan University, Chengdu, China
| | - Dandan Yin
- Department of Laboratory Medicine, National Key Laboratory of Biotherapy/Collaborative Innovation Center for Biotherapy and Precision Medicine Key Laboratory of Sichuan Province, West China Hospital, Sichuan University, Chengdu, China
| | - Ruoting Men
- Department of Gastroenterology and Hepatology, West China Hospital, Sichuan University, Chengdu, China
| | - Heng Xu
- Department of Laboratory Medicine, National Key Laboratory of Biotherapy/Collaborative Innovation Center for Biotherapy and Precision Medicine Key Laboratory of Sichuan Province, West China Hospital, Sichuan University, Chengdu, China
| | - Li Yang
- Department of Gastroenterology and Hepatology, West China Hospital, Sichuan University, Chengdu, China
| |
Collapse
|
|
26
|
Park YE, Kim TO. Sexual Dysfunction and Fertility Problems in Men with Inflammatory Bowel Disease. World J Mens Health 2019; 38:285-297. [PMID: 30929327 PMCID: PMC7308231 DOI: 10.5534/wjmh.190007] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2019] [Revised: 01/29/2019] [Accepted: 02/10/2019] [Indexed: 12/14/2022] Open
Abstract
Inflammatory bowel disease (IBD) is a chronic inflammatory disorder of the gastrointestinal tract that is usually diagnosed in young individuals. Crohn's disease and ulcerative colitis are the 2 principal forms of IBD. Patients with IBD demonstrate varying degrees of disease activity and sometimes need to undergo bowel surgery such as proctocolectomy with ileal pouch-anal anastomosis that involves removal of the entire colon and rectum with consequent sexual dysfunction. Several studies have shown that sulfasalazine, affects male fertility. Additionally, many men with IBD are unable to control their smoking, drinking, and eating habits, which can cause worsening of disease activity and fertility. Therefore, infertility and sexual dysfunction are important issues in young patients diagnosed with IBD because they are related to optimal management of the disease and patients' quality of life. Only a few studies have reported sexual dysfunction and infertility in men with IBD. Therefore, this study reviewed the current literature describing male sexual dysfunction scales and evaluated the causes of sexual dysfunction and infertility in men with IBD.
Collapse
Affiliation(s)
- Yong Eun Park
- Division of Gastroenterology, Department of Internal Medicine, Haeundae Paik Hospital, Inje University College of Medicine, Busan, Korea
| | - Tae Oh Kim
- Division of Gastroenterology, Department of Internal Medicine, Haeundae Paik Hospital, Inje University College of Medicine, Busan, Korea.
| |
Collapse
|
|
27
|
Özgenç F, Karakoyun M, Ecevit Ç, Hekimci H, Kıran Taşçı E, Erdemir G. Efficacy and safety of long-term thiopurine maintenance treatment for ulcerative colitis in Turkey: A single-center experience. TURKISH JOURNAL OF GASTROENTEROLOGY 2019; 29:650-654. [PMID: 30381272 DOI: 10.5152/tjg.2018.17151] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
BACKGROUND/AIMS Thiopurines are widely used in the treatment of inflammatory bowel disease, but data are limited. Or aim was to determine the outcome of thiopurine application in children diagnosed with ulcerative colitis (UC). MATERIALS AND METHODS Forty-eight patients with UC, diagnosed at our center between 2005 and 2016 and applied azathiopurine (AZA), were included in the study. Data were collected retrospectively. The diagnosis of UC was based on the conventional clinical, radiological, histological, and endoscopic assessment. All patients with UC at this intercept were analyzed at the 4- and 6-week and 3-month intervals after remission to determine patient characteristics, thiopurine properties, and its efficacy and toxicity. Determination of remission, relapse, and steroid refractoriness/dependency were guided according to the European Crohn's and Colitis Organisation consensus. RESULTS Azathiopurine was started at the median 1 month (0-12 months), and it was applied thereafter for maintenance (n=43). Response to remission induction was obtained in 40 (93.7%) patients. The median duration of the AZA treatment was 24 months (5-63). In 34 (85%) of the 40 children, it was well tolerated until the last visit. During the follow-up, adverse events occurred in 6 patients. These are leucopenia, neutropenia, vomiting, diarrhea, and skin rush. CONCLUSION Thiopurine is an appropriate treatment option for remission in patients with UC. For a long-term follow-up, it is very important to identify patients with UC who have clinical remission with side effects and with thiopurine application.
Collapse
Affiliation(s)
- Funda Özgenç
- Department of Pediatric Gastroenterology, Hepatology and Nutrition, Ege University School of Medicine, İzmir, Turkey
| | - Miray Karakoyun
- Department of Pediatric Gastroenterology, Hepatology and Nutrition, Tepecik Training and Research Hospital, İzmir, Turkey
| | - Çiğdem Ecevit
- Department of Pediatric Gastroenterology, Hepatology and Nutrition, Dr. Behçet Uz Children Hospital, İzmir, Turkey
| | - Hamiyet Hekimci
- Department of Pediatric Hematology, Ege University School of Medicine, İzmir, Turkey
| | - Ezgi Kıran Taşçı
- Department of Pediatric Gastroenterology, Hepatology and Nutrition, Ege University School of Medicine, İzmir, Turkey
| | - Gülin Erdemir
- Department of Pediatric Gastroenterology, Hepatology and Nutrition, Dr. Behçet Uz Children Hospital, İzmir, Turkey
| |
Collapse
|
|
28
|
Ahmad H, Kumar VL. Pharmacotherapy of ulcerative colitis - current status and emerging trends. J Basic Clin Physiol Pharmacol 2019; 29:581-592. [PMID: 30089097 DOI: 10.1515/jbcpp-2016-0014] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2016] [Accepted: 05/04/2018] [Indexed: 12/23/2022]
Abstract
Ulcerative colitis (UC) is a chronic mucosal inflammation of the large intestine restricted to the rectum and colon. Its clinical course follows an intermittent pattern with episodes of relapse, followed by remission and eventually resulting in mucosal damage. Although there is no permanent cure for UC, the currently available pharmacotherapy aims to induce and maintain clinical remission, promote the healing of colonic mucosa and avert any surgical intervention. The conventional drug therapy comprising of 5-aminosalicylates, thiopurines and corticosteroids has advanced recently in terms of formulations and dosing schedule, resulting in improved efficacy, safety and compliance. Calcineurin inhibitors, such as cyclosporin and tacrolimus, have emerged as steroid sparing agents. The treatment paradigm of UC patients who are refractory to conventional drugs has changed in view of the availability of biologics. Currently, there are four biologics approved by the US FDA for the treatment of UC, namely, infliximab, adalimumab, golimumab and vedolizumab, and several others are undergoing clinical trial. In this comprehensive review, the advantages and limitations of the medical therapy of UC are elaborated with an emphasis on the pharmacokinetic and pharmacodynamic aspects of the drugs.
Collapse
Affiliation(s)
- Hilal Ahmad
- Department of Pharmacology, All India Institute of Medical Sciences, Ansari Nagar, New Delhi, India
| | - Vijay L Kumar
- Department of Pharmacology, All India Institute of Medical Sciences, Ansari Nagar, New Delhi, India
| |
Collapse
|
|
29
|
Ye BD, Travis S. Improving the quality of care for inflammatory bowel disease. Intest Res 2019; 17:45-53. [PMID: 30449081 PMCID: PMC6361018 DOI: 10.5217/ir.2018.00113] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/05/2018] [Revised: 10/05/2018] [Accepted: 10/05/2018] [Indexed: 02/06/2023] Open
Abstract
Great strides have been achieved in the development of quality-of-care measures and standards for inflammatory bowel disease (IBD) over the last decade. The central structural component of care in IBD revolves around the multidisciplinary team, which should be equipped with the necessary resources to operate and implement decisions. Process measures have been defined by interest groups and can be adapted into process tools for the delivery of care for various patient subgroups and clinical scenarios. The emerging treat-to-target approach to IBD management may be used to achieve optimal long-term and holistic patient-centred outcomes, such as survival, control of inflammation and disease progression, symptomatic remission, quality of life and complications. Other important quality-of-care outcome measures for IBD include disutility of care, healthcare utilization and other patient-reported outcomes such as nutritional status and impact of fistulae. The current challenge for healthcare providers and health systems is the integration of quality-of-care structures and processes into clinical practice, and the consistent delivery of updated evidence-based quality IBD care to various patient populations by individual health care providers. Finally, the awareness and appreciation for quality of care in IBD is increasing in Asia, and Asian healthcare institutions should be encouraged to take the lead in improving the quality of care in IBD.
Collapse
Affiliation(s)
- Byong Duk Ye
- Department of Gastroenterology and Inflammatory Bowel Disease Center, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Simon Travis
- Translational Gastroenterology Unit, Oxford University Hospitals, Oxford, UK
| |
Collapse
|
|
30
|
Lim SZ, Chua EW. Revisiting the Role of Thiopurines in Inflammatory Bowel Disease Through Pharmacogenomics and Use of Novel Methods for Therapeutic Drug Monitoring. Front Pharmacol 2018; 9:1107. [PMID: 30349479 PMCID: PMC6186994 DOI: 10.3389/fphar.2018.01107] [Citation(s) in RCA: 37] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2018] [Accepted: 09/10/2018] [Indexed: 12/12/2022] Open
Abstract
Azathioprine and 6-mercaptopurine, often referred to as thiopurine compounds, are commonly used in the management of inflammatory bowel disease. However, patients receiving these drugs are prone to developing adverse drug reactions or therapeutic resistance. Achieving predefined levels of two major thiopurine metabolites, 6-thioguanine nucleotides and 6-methylmercaptopurine, is a long-standing clinical practice in ensuring therapeutic efficacy; however, their correlation with treatment response is sometimes unclear. Various genetic markers have also been used to aid the identification of patients who are thiopurine-sensitive or refractory. The recent discovery of novel Asian-specific DNA variants, namely those in the NUDT15 gene, and their link to thiopurine toxicity, have led clinicians and scientists to revisit the utility of Caucasian biomarkers for Asian individuals with inflammatory bowel disease. In this review, we explore the limitations associated with the current methods used for therapeutic monitoring of thiopurine metabolites and how the recent discovery of ethnicity-specific genetic markers can complement thiopurine metabolites measurement in formulating a strategy for more accurate prediction of thiopurine response. We also discuss the challenges in thiopurine therapy, alongside the current strategies used in patients with reduced thiopurine response. The review is concluded with suggestions for future work aiming at using a more comprehensive approach to optimize the efficacy of thiopurine compounds in inflammatory bowel disease.
Collapse
Affiliation(s)
| | - Eng Wee Chua
- Faculty of Pharmacy, Universiti Kebangsaan Malaysia, Kuala Lumpur, Malaysia
| |
Collapse
|
|
31
|
Cargnin S, Genazzani AA, Canonico PL, Terrazzino S. Diagnostic accuracy of NUDT15 gene variants for thiopurine-induced leukopenia: a systematic review and meta-analysis. Pharmacol Res 2018; 135:102-111. [DOI: 10.1016/j.phrs.2018.07.021] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/18/2018] [Revised: 07/19/2018] [Accepted: 07/19/2018] [Indexed: 02/07/2023]
|
|
32
|
Abstract
Autoimmune bullous diseases (AIBD), including pemphigus, bullous pemphigoid, epidermolysis bullosa acquisita, mucous membrane pemphigoid, and pemphigoid gestationis, pose significant therapeutic challenges, especially in pregnant and post-partum breastfeeding patients or those planning to conceive. Data on the safety and efficacy of therapeutic interventions during the perinatal period are lacking because randomized controlled trials are typically not performed in this setting. However, many of the treatments for AIBD are also used in other diseases, so data can be extrapolated from studies or case reports in these other patient populations. It appears that many of the treatments for AIBD can adversely affect the fetus or neonate, and alterations in immune status caused by pregnancy-associated hormonal changes can negatively impact disease control. This article summarizes and weighs the risks and benefits of the various agents used to treat AIBD during pregnancy. We also present the available information on lactation as well as effects on male fertility.
Collapse
Affiliation(s)
- Carolyn J Kushner
- Corporal Michael J. Crescenz VAMC, Philadelphia, PA, USA
- Department of Dermatology, Hospital of the University of Pennsylvania, Perelman School of Medicine at the University of Pennsylvania, 2 East Gates, Room 2075, 3400 Spruce Street, Philadelphia, PA, 19104, USA
| | - Josef Symon S Concha
- Corporal Michael J. Crescenz VAMC, Philadelphia, PA, USA
- Department of Dermatology, Hospital of the University of Pennsylvania, Perelman School of Medicine at the University of Pennsylvania, 2 East Gates, Room 2075, 3400 Spruce Street, Philadelphia, PA, 19104, USA
- Section of Dermatology, Department of Medicine, University of the Philippines-Philippine General Hospital, Manila, Philippines
| | - Victoria P Werth
- Corporal Michael J. Crescenz VAMC, Philadelphia, PA, USA.
- Department of Dermatology, Hospital of the University of Pennsylvania, Perelman School of Medicine at the University of Pennsylvania, 2 East Gates, Room 2075, 3400 Spruce Street, Philadelphia, PA, 19104, USA.
| |
Collapse
|
|
33
|
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.
Collapse
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
| |
Collapse
|
|
34
|
Song KH, Kim ES, Lee YJ, Jang BI, Kim KO, Kwak SG, Lee HS. Characteristics and management of patients with inflammatory bowel disease between a secondary and tertiary hospitals: a propensity score analysis. Intest Res 2018; 16:216-222. [PMID: 29743834 PMCID: PMC5934594 DOI: 10.5217/ir.2018.16.2.216] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/02/2017] [Revised: 08/13/2017] [Accepted: 08/14/2017] [Indexed: 01/28/2023] Open
Abstract
Background/Aims This study aimed to compare the clinical characteristics and management patterns of inflammatory bowel disease (IBD) patients in a secondary hospital (SH) with those in tertiary referral centers (TRC). Methods Data from IBD patients in SH and 2 TRCs were retrospectively reviewed. The cumulative thiopurine use rate was compared between hospitals after controlling for different baseline characteristics using propensity score matching. Results Among the total of 447 patients with IBD, 178 Crohn's disease (CD) and 269 ulcerative colitis (UC) patients were included. Regarding initial CD symptoms, patients from SH were more likely to show perianal symptoms, such as anal pain or discharge (56.6% vs. 34.3%, P=0.003), whereas those from TRCs more often had luminal symptoms, such as abdominal pain (54.9% vs. 17.1%, P<0.001), diarrhea (44.1% vs. 18.4%, P<0.001), and body weight loss (9.8% vs. 1.3%, P=0.025). Complicating behaviors, such as stricturing and penetrating, were significantly higher in TRCs, while perianal disease was more common in SH. Ileal location was more frequently observed in TRCs. For UC, SH had a more limited extent of disease (proctitis 58.8% vs. 21.2%, P<0.001). The cumulative azathioprine use rate in SH was significantly lower than that in TRCs in both CD and UC patients after controlling for disease behavior, location, and perianal disease of CD and extent of UC. Conclusions The clinical characteristics and management of the IBD patients in SH were substantially different from those in TRCs. Thiopurine treatment was less commonly used for SH patients.
Collapse
Affiliation(s)
- Ki Hwan Song
- Department of Surgery, Goo Hospital, Daegu, Korea
| | - Eun Soo Kim
- Department of Internal Medicine, School of Medicine, Kyungpook National University, Daegu, Korea
| | - Yoo Jin Lee
- Department of Internal Medicine, Keimyung University School of Medicine, Daegu, Korea
| | - Byung Ik Jang
- Department of Internal Medicine, Yeungnam University College of Medicine, Daegu, Korea
| | - Kyeong Ok Kim
- Department of Internal Medicine, Yeungnam University College of Medicine, Daegu, Korea
| | - Sang Gyu Kwak
- Department of Medical Statistics, Catholic University of Daegu School of Medicine, Daegu, Korea
| | - Hyun Seok Lee
- Department of Internal Medicine, School of Medicine, Kyungpook National University, Daegu, Korea
| | | |
Collapse
|
|
35
|
Lee JM, Lee KM, Kim JS, Kim YS, Cheon JH, Ye BD, Kim YH, Han DS, Lee CK, Park HJ. Postoperative course of Crohn disease according to timing of bowel resection: Results from the CONNECT Study. Medicine (Baltimore) 2018; 97:e0459. [PMID: 29668618 PMCID: PMC5916650 DOI: 10.1097/md.0000000000010459] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/30/2017] [Revised: 03/06/2018] [Accepted: 03/26/2018] [Indexed: 12/12/2022] Open
Abstract
Previous studies have demonstrated that early surgery in Crohn disease (CD) can result in a better clinical course than late surgery. The aim of this study was to compare the clinical course of CD following bowel resection performed at the time of diagnosis (early surgery) and during the course of the disease (late surgery).We reviewed medical records from a hospital-based cohort database that includes Korean CD patients diagnosed before 2009. Patients who underwent bowel resection were included. Age, sex, disease phenotype, time of surgery, medication history including use of corticosteroids, immunomodulators, and biologics, and further surgical history were assessed.In all, 243 CD patients who had undergone bowel resection were included, and 120 patients underwent surgery at the time of diagnosis, while 123 underwent surgery after diagnosis (median 105 months, range 2-277). The use of biologics was significantly higher in the late surgery group than in the early surgery group (P = .020). The use of immunomodulators and reoperation rates did not differ between the groups. Early surgery was associated with less use of biologics (Kaplan-Meier curve analysis P = .015). Multivariate analysis indicated that early surgery and old age at surgery were independent variables associated with less use of biologics.CD patients who underwent bowel resection at the time of diagnosis have a more favorable disease course, represented by less use of biologics. Early surgery might be a treatment option in a subset of CD patients.
Collapse
Affiliation(s)
- Ji Min Lee
- Department of Internal Medicine, St. Vincent's Hospital, The Catholic University of Korea, Suwon, Gyeonggi-do
| | - Kang-Moon Lee
- Department of Internal Medicine, St. Vincent's Hospital, The Catholic University of Korea, Suwon, Gyeonggi-do
| | - Joo Sung Kim
- Department of Internal Medicine, Seoul National University
| | - You Sun Kim
- Department of Internal Medicine, Inje University, Seoul Paik Hospital
| | - Jae Hee Cheon
- Department of Internal Medicine, Yonsei University College of Medicine
| | - Byong Duk Ye
- Department of Internal Medicine, University of Ulsan College of Medicine, Asan Medical Center
| | - Young-Ho Kim
- Department of Internal Medicine, Sungkyunkwan University School of Medicine, Seoul
| | - Dong Soo Han
- Department of Internal Medicine, Hanyang University Guri Hospital, Gyeonggi-do
| | | | - Hyun-Ju Park
- Department of Internal Medicine, Daehang Hospital, Seoul, Korea
| |
Collapse
|
|
36
|
Wang HH, He Y, Wang HX, Liao CL, Peng Y, Tao LJ, Zhang W, Yang HX. Comparison of TPMT and NUDT15 polymorphisms in Chinese patients with inflammatory bowel disease. World J Gastroenterol 2018; 24:941-948. [PMID: 29491687 PMCID: PMC5829157 DOI: 10.3748/wjg.v24.i8.941] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/24/2017] [Revised: 01/15/2018] [Accepted: 01/18/2018] [Indexed: 02/06/2023] Open
Abstract
AIM To observe gene polymorphisms of TPMT and NUDT15, and compare their predictive value for azathioprine (AZA)-induced leukopenia in inflammatory bowel disease (IBD).
METHODS This study enrolled 219 patients diagnosed with IBD in Xiangya Hospital, Central South University, Changsha, China from February 2016 to November 2017. Peripheral blood of all patients was collected to detect their genotypes of TPMT and NUDT15 by pyrosequencing at the Department of Clinical Pharmacology, Hunan Key Laboratory of Pharmacogenetics, Xiangya Hospital. Eighty patients were treated with AZA according to the disease condition. During the first month, patients who received AZA underwent routine blood tests and liver function tests once a week. The endpoint of the study was leukopenia induced by AZA. By analyzing patient characteristics, genotypes and leukopenia induced by drug use, we found the risk factors associated with AZA-induced leukopenia.
RESULTS There were 219 patients with IBD (160 men and 59 women), including 39 who were confirmed with ulcerative colitis (UC), 176 with Crohn’s disease (CD) and 4 with undetermined IBD (UIBD). There were 44 patients (20.1%) with mutant genotype of NUDT15 (C/T); among them, 16 received AZA, and 8 (50%) developed leukopenia. There were 175 patients (79.7%) with wild genotype of NUDT15 (C/C); among them, 64 received AZA, and 11 (17.2%) developed leukopenia. A significant difference was found between NUDT15 C/T and its wild-type C/C (P = 0.004). There were only 3 patients with TPMT mutant genotype of A/G (1.4%) who participated in the research, and 1 of them was treated with AZA and developed leukopenia. The remaining 216 patients (98.6%) were found to bear the wild genotype of TPMT (A/A); among them, 79 patients received AZA, and 18 (22.8%) developed leukopenia, and there was no significant difference from those with A/G (P = 0.071). The frequency of TPMT mutation was 1.4%, and NUDT15 mutation rate was significantly higher and reached 20.1% (P = 0.000). Therefore, NUDT15 gene polymorphism was obviously a better biomarker than TPMT gene polymorphism in the prediction of AZA-induced leukopenia.
CONCLUSION Mutation rate of NUDT15 in Chinese IBD patients is higher than that of TPMT. NUDT15 polymorphism is a better predictor for AZA-induced leukopenia than TPMT polymorphism.
Collapse
Affiliation(s)
- Hong-Hui Wang
- Department of Gastroenterology, Xiangya Hospital, Central South University, Changsha 410008, Hunan Province, China
| | - Ying He
- Department of Gastroenterology, Xiangya Hospital, Central South University, Changsha 410008, Hunan Province, China
| | - Hong-Xian Wang
- Department of Anesthesiology, Kunming Angel Women’s & Children’s Hospital, Kunming 650000, Yunnan Province, China
| | - Cheng-Ling Liao
- Department of Clinical Pharmacology, Hunan Key Laboratory of Pharmacogenetics, Xiangya Hospital, Central South University, Changsha 410008, Hunan Province, China
| | - Yu Peng
- Department of Gastroenterology, Xiangya Hospital, Central South University, Changsha 410008, Hunan Province, China
| | - Li-Jian Tao
- Department of Nephrology, Xiangya Hospital, Central South University, Changsha 410008, Hunan Province, China
| | - Wei Zhang
- Department of Clinical Pharmacology, Hunan Key Laboratory of Pharmacogenetics, Xiangya Hospital, Central South University, Changsha 410008, Hunan Province, China
| | - Hui-Xiang Yang
- Department of Gastroenterology, Xiangya Hospital, Central South University, Changsha 410008, Hunan Province, China
| |
Collapse
|
|
37
|
Kim YS. [How to Optimally Use Currently Available Drugs in a Therapeutic Algorithm?]. THE KOREAN JOURNAL OF GASTROENTEROLOGY 2018; 71:74-80. [PMID: 29471604 DOI: 10.4166/kjg.2018.71.2.74] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/03/2022]
Abstract
Recently, the incidence and prevalence of inflammatory bowel disease (IBD) have been increasing in worldwide, especially in Asian area. IBD is a chronic and progressive disease eventually causing bowel damage. The advance in the treatment of IBD over the past several decades has been achieved with the development of biologics. Furthermore, goals for management of IBD have been evolving from symptom-based management to mucosal healing, which can reduce the surgery rate and hospitalization. To treat the patients with IBD properly, identification of risk factors of patients should be preceded. In addition, the knowledge of several drugs, which are available in current situation is essential. In this review, optimal therapeutic approach with drugs including 5-aminosalicylate, steroid, immunomodulators and anti-TNF antagonists is discussed.
Collapse
Affiliation(s)
- You Sun Kim
- Department of Internal Medicine, Seoul Paik Hospital, Inje University College of Medicine, Seoul, Korea
| |
Collapse
|
|
38
|
Park DI, Hisamatsu T, Chen M, Ng SC, Ooi CJ, Wei SC, Banerjee R, Hilmi IN, Jeen YT, Han DS, Kim HJ, Ran Z, Wu K, Qian J, Hu PJ, Matsuoka K, Andoh A, Suzuki Y, Sugano K, Watanabe M, Hibi T, Puri AS, Yang SK. Asian Organization for Crohn's and Colitis and Asia Pacific Association of Gastroenterology consensus on tuberculosis infection in patients with inflammatory bowel disease receiving anti-tumor necrosis factor treatment. Part 1: risk assessment. Intest Res 2018; 16:4-16. [PMID: 29422793 PMCID: PMC5797269 DOI: 10.5217/ir.2018.16.1.4] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/08/2017] [Revised: 10/12/2017] [Accepted: 10/13/2017] [Indexed: 01/18/2023] Open
Abstract
Because anti-tumor necrosis factor (anti-TNF) therapy has become increasingly popular in many Asian countries, the risk of developing active tuberculosis (TB) among anti-TNF users may raise serious health problems in this region. Thus, the Asian Organization for Crohn's and Colitis and the Asia Pacific Association of Gastroenterology have developed a set of consensus statements about risk assessment, detection and prevention of latent TB infection, and management of active TB infection in patients with inflammatory bowel disease (IBD) receiving anti-TNF treatment. Twenty-three consensus statements were initially drafted and then discussed by the committee members. The quality of evidence and the strength of recommendations were assessed by using the Grading of Recommendations Assessment, Development, and Evaluation methodology. Web-based consensus voting was performed by 211 IBD specialists from 9 Asian countries concerning each statement. A consensus statement was accepted if at least 75% of the participants agreed. Part 1 of the statements comprised 2 parts: risk of TB infection Recommendaduring anti-TNF therapy, and screening for TB infection prior to commencing anti-TNF therapy. These consensus statements will help clinicians optimize patient outcomes by reducing the morbidity and mortality related to TB infections in patients with IBD receiving anti-TNF treatment.
Collapse
Affiliation(s)
- Dong Il Park
- Department of Internal Medicine, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Tadakazu Hisamatsu
- The Third Department of Internal Medicine, Kyorin University School of Medicine, Tokyo, Japan
| | - Minhu Chen
- Department of Gastroenterology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Siew Chien Ng
- Department of Medicine and Therapeutics, Institute of Digestive Disease, LKS Institute of Health Science, State Key Laboratory of Digestive Disease, The Chinese University of Hong Kong, Hong Kong, China
| | - Choon Jin Ooi
- Gleneagles Medical Centre and Duke-NUS Medical School, Singapore, Singapore
| | - Shu Chen Wei
- Department of Internal Medicine, National Taiwan University Hospital, National Taiwan University College of Medicine, Taipei, Taiwan
| | - Rupa Banerjee
- Department of Medical Gastroenterology, Asian Institute of Gastroenterology, Hyderabad, India
| | - Ida Normiha Hilmi
- Department of Medicine, University of Malaya, Kuala Lumpur, Malaysia
| | - Yoon Tae Jeen
- Department of Internal Medicine, Korea University College of Medicine, Seoul, Korea
| | - Dong Soo Han
- Department of Internal Medicine, Hanyang University Guri Hospital, Guri, Korea
| | - Hyo Jong Kim
- Department of Internal Medicine, Kyung Hee University School of Medicine, Seoul, Korea
| | - Zhihua Ran
- Department of Gastroenterology, Shanghai Jiao Tong University, Shanghai, China
| | - Kaichun Wu
- Department of Gastroenterology, Fourth Military Medical University, Xi'an, China
| | - Jiaming Qian
- Department of Gastroenterology, Peking Union Medical College, Beijing, China
| | - Pin-Jin Hu
- Department of Gastroenterology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Katsuyoshi Matsuoka
- Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, Tokyo, Japan
| | - Akira Andoh
- Department of Gastroenterology, Shiga University, Otsu, Japan
| | - Yasuo Suzuki
- Department of Internal Medicine, Toho University, Sakura, Japan
| | - Kentaro Sugano
- Department of Medicine, Jichi Medical University, Shimotsuke, Japan
| | - Mamoru Watanabe
- Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, Tokyo, Japan
| | - Toshifumi Hibi
- Center for Advanced IBD Research and Treatment, Kitasato University, Tokyo, Japan
| | - Amarender S Puri
- Department of Gastroenterology, Govind Ballabh Pant Institute of Postgraduate Medical Education and Research, New Delhi, India
| | - Suk-Kyun Yang
- Department of Gastroenterology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| |
Collapse
|
|
39
|
Im JP, Ye BD, Kim YS, Kim JS. Changing treatment paradigms for the management of inflammatory bowel disease. Korean J Intern Med 2018; 33:28-35. [PMID: 29334728 PMCID: PMC5768555 DOI: 10.3904/kjim.2017.400] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/04/2017] [Accepted: 12/12/2017] [Indexed: 02/07/2023] Open
Abstract
Inflammatory bowel disease (IBD) is a chronic and progressive inf lammatory condition of the gastrointestinal tract causing bowel damage, hospitalizations, surgeries, and disability. Although there has been much progress in the management of IBD with established and evolving therapies, most current approaches have failed to change the natural course. Therefore, the treatment approach and follow-up of patients with IBD have undergone a significant change. Usage of immunosuppressants and/or biologics early during the course of the disease, known as top-down or accelerated step-up approach, was shown to be superior to conventional management in patients who had been recently diagnosed with IBD. This approach can be applied to selected groups based on prognostic factors to control disease activity and prevent progressive disease. Therapeutic targets have been shifted from clinical remission mainly based on symptoms to objective parameters such as endoscopic healing due to the discrepancies observed between symptoms, objectively evaluated inf lammatory activity, and intestinal damage. The concept of treat-to-target in IBD has been supported by population-based cohort studies, post hoc analysis of clinical trials, and meta-analysis, but more evidence is needed to support this concept to be applied to the clinical practice. In addition, individualized approach with tight monitoring of non-invasive biomarker such as C-reactive protein and fecal calprotectin and drug concentration has shown to improve clinical and endoscopic outcomes. An appropriate de-escalation strategy is considered based on patient demographics, disease features, current disease status, and patients' preferences.
Collapse
Affiliation(s)
- Jong Pil Im
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Korea
| | - Byong Duk Ye
- Department of Gastroenterology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - You Sun Kim
- Department of Internal Medicine, Inje University Seoul Paik Hospital, Seoul, Korea
| | - Joo Sung Kim
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Korea
- Correspondence to Joo Sung Kim, M.D. Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, 101 Daehak-ro, Jongno-gu, Seoul 03080, Korea Tel: +82-2-740-8112 Fax: +82-2-742-8601 E-mail:
| |
Collapse
|
|
40
|
Park DI, Hisamatsu T, Chen M, Ng SC, Ooi CJ, Wei SC, Banerjee R, Hilmi IN, Jeen YT, Han DS, Kim HJ, Ran Z, Wu K, Qian J, Hu PJ, Matsuoka K, Andoh A, Suzuki Y, Sugano K, Watanabe M, Hibi T, Puri AS, Yang SK. Asian Organization for Crohn's and Colitis and Asian Pacific Association of Gastroenterology consensus on tuberculosis infection in patients with inflammatory bowel disease receiving anti-tumor necrosis factor treatment. Part 1: Risk assessment. J Gastroenterol Hepatol 2018; 33:20-29. [PMID: 29023903 DOI: 10.1111/jgh.14019] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/03/2017] [Accepted: 10/05/2017] [Indexed: 12/12/2022]
Abstract
Because anti-tumor necrosis factor (anti-TNF) therapy has become increasingly popular in many Asian countries, the risk of developing active tuberculosis (TB) among anti-TNF users may raise serious health problems in this region. Thus, the Asian Organization for Crohn's and Colitis and the Asian Pacific Association of Gastroenterology have developed a set of consensus statements about risk assessment, detection, and prevention of latent TB infection and management of active TB infection in patients with inflammatory bowel disease (IBD) receiving anti-TNF treatment. Twenty-three consensus statements were initially drafted and then discussed by the committee members. The quality of evidence and the strength of recommendations were assessed by using the Grading of Recommendations Assessment, Development, and Evaluation methodology. Web-based consensus voting was performed by 211 IBD specialists from nine Asian countries concerning each statement. A consensus statement was accepted if at least 75% of the participants agreed. Part 1 of the statements comprised two parts: (i) risk of TB infection during anti-TNF therapy and (ii) screening for TB infection prior to commencing anti-TNF therapy. These consensus statements will help clinicians optimize patient outcomes by reducing the morbidity and mortality related to TB infections in patients with IBD receiving anti-TNF treatment.
Collapse
Affiliation(s)
- Dong Ii Park
- Department of Internal Medicine, Kangbuk Samsung Hospital, Sungkyunkwan University, Seoul, Korea
| | - Tadakazu Hisamatsu
- The Third Department of Internal Medicine, Kyorin University School of Medicine, Tokyo, Japan
| | - Minhu Chen
- Department of Gastroenterology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Siew Chien Ng
- Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Institute of Digestive Disease, LKS Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong
| | - Choon Jin Ooi
- Gleneagles Medical Centre and Duke-NUS Medical School, Singapore
| | - Shu Chen Wei
- Department of Internal Medicine, College of Medicine, National Taiwan University Hospital, Taipei, Taiwan
| | - Rupa Banerjee
- Department of Medical Gastroenterology, Asian Institute of Gastroenterology, Hyderabad, India
| | - Ida Normiha Hilmi
- Department of Medicine, University of Malaya, Kuala Lumpur, Malaysia
| | - Yoon Tae Jeen
- Department of Internal Medicine, Korea University, Seoul, Korea
| | - Dong Soo Han
- Department of Internal Medicine, Hanyang University Guri Hospital, Gyunggi, Korea
| | - Hyo Jong Kim
- Department of Internal Medicine, Kyung Hee University, Seoul, Korea
| | - Zhihua Ran
- Department of Gastroenterology, Shanghai Jiao Tong University, Shanghai, China
| | - Kaichun Wu
- Department of Gastroenterology, Fourth Military Medical University, Xi'an, China
| | - Jiaming Qian
- Department of Gastroenterology, Peking Union Medical College, Beijing, China
| | - Pin-Jin Hu
- Department of Gastroenterology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Katsuyoshi Matsuoka
- Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, Tokyo, Japan
| | - Akira Andoh
- Department of Gastroenterology, Shiga University, Otsu, Japan
| | - Yasuo Suzuki
- Department of Internal Medicine, Toho University, Tokyo, Japan
| | - Kentaro Sugano
- Department of Medicine, Jichi Medical University, Shimotsuke, Japan
| | - Mamoru Watanabe
- Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, Tokyo, Japan
| | - Toshifumi Hibi
- Center for Advanced IBD Research and Treatment, Kitasato University, Tokyo, Japan
| | - Amarender S Puri
- Department of Gastroenterology, GB Pant Institute of Postgraduate Medical Education and Research, New Delhi, India
| | - Suk-Kyun Yang
- Department of Gastroenterology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Korea
| |
Collapse
|
|
41
|
Eun CS. Is the Therapeutic Drug Monitoring of Anti-TNF Agents Necessary in Korean Inflammatory Bowel Disease Patients? Gut Liver 2017; 11:3-4. [PMID: 28053295 PMCID: PMC5221852 DOI: 10.5009/gnl16574] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/20/2023] Open
Affiliation(s)
- Chang Soo Eun
- Department of Internal Medicine, Hanyang University Guri Hospital, Guri, Korea
| |
Collapse
|
|
42
|
Vasudevan A, Gibson PR, Langenberg DRV. Time to clinical response and remission for therapeutics in inflammatory bowel diseases: What should the clinician expect, what should patients be told? World J Gastroenterol 2017; 23:6385-6402. [PMID: 29085188 PMCID: PMC5643264 DOI: 10.3748/wjg.v23.i35.6385] [Citation(s) in RCA: 56] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/02/2017] [Revised: 07/03/2017] [Accepted: 08/15/2017] [Indexed: 02/06/2023] Open
Abstract
An awareness of the expected time for therapies to induce symptomatic improvement and remission is necessary for determining the timing of follow-up, disease (re)assessment, and the duration to persist with therapies, yet this is seldom reported as an outcome in clinical trials. In this review, we explore the time to clinical response and remission of current therapies for inflammatory bowel disease (IBD) as well as medication, patient and disease related factors that may influence the time to clinical response. It appears that the time to therapeutic response varies depending on the indication for therapy (Crohn's disease or ulcerative colitis). Agents with the most rapid time to clinical response included corticosteroids, calcineurin inhibitors, exclusive enteral nutrition, aminosalicylates and anti-tumor necrosis factor therapy which will work in most patients within the first 2 mo. Vedolizumab, methotrexate and thiopurines had a longer time to clinical response and can take several months to achieve maximal efficacy. Factors affecting the time to clinical response of therapies included use of concomitant therapy, disease duration, smoking status, disease phenotype and advanced age. There appears to be marked variation in time to clinical response for therapies used in IBD which is further influenced by disease and patient related factors. Understanding the expected time to therapeutic response is integral to inform further decision making, maintain a patient-centered approach and ensure treatment is given an appropriate timeframe to achieve maximal benefit prior to cessation.
Collapse
Affiliation(s)
- Abhinav Vasudevan
- Department of Gastroenterology and Hepatology, Eastern Health, Box Hill Hospital, Box Hill, Victoria 3128, Australia
- Monash University, Eastern Health Clinical School, Box Hill, Victoria 3128, Australia
| | - Peter R Gibson
- Department of Gastroenterology, Alfred Health and Monash University, Victoria 3004, Australia
| | - Daniel R van Langenberg
- Department of Gastroenterology and Hepatology, Eastern Health, Box Hill Hospital, Box Hill, Victoria 3128, Australia
- Monash University, Eastern Health Clinical School, Box Hill, Victoria 3128, Australia
| |
Collapse
|
|
43
|
Combined Detection of NUDT15 Variants Could Highly Predict Thiopurine-induced Leukopenia in Chinese Patients with Inflammatory Bowel Disease: A Multicenter Analysis. Inflamm Bowel Dis 2017; 23:1592-1599. [PMID: 28570428 DOI: 10.1097/mib.0000000000001148] [Citation(s) in RCA: 50] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
BACKGROUND NUDT15 c.415C>T was a novel genetic marker confirmed in our center for thiopurine-induced leukopenia in Chinese inflammatory bowel disease (IBD). For validation, a large cohort study is needed. Meanwhile, the newly discovered NUDT15 coding variants (c.36_37insGGAGTC and c.52 G>A) have not been studied in patients with IBD. We aimed to further confirm the influence of 3 NUDT15 variants (c.415C>T, c.36_37insGGAGTC, and c.52G>A) on thiopurine-induced leukopenia in Chinese patients with IBD. METHODS Patients prescribed on thiopurines for at least 2 weeks were recruited from 4 tertiary hospitals. Clinical data were collected. NUDT15 genotypes were determined with polymerase chain reaction-RFLP and sequencing. The interactions between variants and leukopenia were analyzed. RESULTS A total of 732 patients were included, 177 (24.3%) of whom developed leukopenia. There were strong associations of NUDT15 c.415C>T, c.36_37insGGAGTC, and c.52G>A with thiopurine-induced leukopenia (P = 1.81 × 10, P = 4.74 × 10 and P = 0.04, respectively), whereas there was no relevance for thiopurine S-methyltransferase genotypes (P = 0.25). The predictive sensitivity of NUDT15 c.415C>T was 49.2%, whereas it increased to 55.4% when combined analysis with c.36_37insGGAGTC and c.52G>A. Notably, not only the homozygotes with NUDT15 c.415C>T but also the heterozygotes both carrying c.415C>T and c.52G>A developed early leukopenia. The median dosage for NUDT15 c.415C>T carriers was significantly lower than that for wild-type (P < 0.001). CONCLUSIONS We confirmed that NUDT15 c.415C>T, c.36_37insGGAGTC, and c.52G>A variants were risk factors for thiopurine-induced leukopenia. Combined detection of the 3 variants could increase the predictive sensitivity of thiopurine-induced leukopenia and help to distinguish early leukopenia in heterozygote of c.415C>T in Chinese patients with IBD. Treatment monitoring by NUDT15 variants may be promising in individualized therapy.
Collapse
|
|
44
|
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.
Collapse
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
| |
Collapse
|
|
45
|
Park JJ, Yang SK, Ye BD, Kim JW, Park DI, Yoon H, Im JP, Lee KM, Yoon SN, Lee H. [Second Korean Guidelines for the Management of Crohn's Disease]. THE KOREAN JOURNAL OF GASTROENTEROLOGY 2017; 69:29-54. [PMID: 28135790 DOI: 10.4166/kjg.2017.69.1.29] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Crohn's disease (CD) is a chronic, progressive, and disabling inflammatory bowel disease (IBD) with an uncertain etiopathogenesis. CD can involve any site of the gastrointestinal tract from the mouth to the anus, and is associated with serious complications, such as bowel strictures, perforations, and fistula formation. The incidence and prevalence rates of CD in Korea are still lower compared with those in Western countries, but they have been rapidly increasing during the recent decades. Although there are no definitive curative modalities for CD, various medical and surgical therapies have been applied for the treatment of this disease. Concerning CD management, there have been substantial discrepancies among clinicians according to their personal experience and preference. To suggest recommendable approaches to the diverse problems of CD and to minimize the variations in treatment among physicians, guidelines for the management of CD were first published in 2012 by the IBD Study Group of the Korean Association for the Study of the Intestinal Diseases. These are the revised guidelines based on updated evidence, accumulated since 2012. These guidelines were developed by using mainly adaptation methods, and encompass induction and maintenance treatment of CD, treatment based on disease location, treatment of CD complications, including stricture and fistula, surgical treatment, and prevention of postoperative recurrence. These are the second Korean guidelines for the management of CD and will be continuously revised as new evidence is collected.
Collapse
Affiliation(s)
- Jae Jun Park
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea
| | - Suk Kyun Yang
- Department of Internal Medicine, University of Ulsan College of Medicine, Seoul, Korea
| | - Byong Duk Ye
- Department of Internal Medicine, University of Ulsan College of Medicine, Seoul, Korea
| | - Jong Wook Kim
- Department of Internal Medicine, Inje University College of Medicine Ilsan Paik Hospital, Goyang, Korea
| | - Dong Il Park
- Department of Internal Medicine, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Hyuk Yoon
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Korea
| | - Jong Pil Im
- Department of Internal Medicine, Seoul National University Hospital, Seoul, Korea
| | - Kang Moon Lee
- Department of Internal Medicine, The Catholic University of Korea College of Medicine, Suwon, Korea
| | - Sang Nam Yoon
- Department of Surgery, Hallym University College of Medicine, Chuncheon, Korea
| | - Heeyoung Lee
- Center for Preventive Medicine and Public Health, Seoul National University Bundang Hospital, Seongnam, Korea
| | | |
Collapse
|
|
46
|
Im JP. Adalimumab or infliximab: which is better for perianal fistula in Crohn's disease? Intest Res 2017; 15:147-148. [PMID: 28522942 PMCID: PMC5430004 DOI: 10.5217/ir.2017.15.2.147] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/27/2017] [Revised: 03/27/2017] [Accepted: 03/27/2017] [Indexed: 12/18/2022] Open
Affiliation(s)
- Jong Pil Im
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Korea
| |
Collapse
|
|
47
|
Park JJ, Yang SK, Ye BD, Kim JW, Park DI, Yoon H, Im JP, Lee KM, Yoon SN, Lee H. Second Korean guidelines for the management of Crohn's disease. Intest Res 2017; 15:38-67. [PMID: 28239314 PMCID: PMC5323307 DOI: 10.5217/ir.2017.15.1.38] [Citation(s) in RCA: 41] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/13/2017] [Revised: 01/15/2017] [Accepted: 01/16/2017] [Indexed: 02/07/2023] Open
Abstract
Crohn's disease (CD) is a chronic, progressive, and disabling inflammatory bowel disease (IBD) with an uncertain etiopathogenesis. CD can involve any site of the gastrointestinal tract from the mouth to the anus, and is associated with serious complications, such as bowel strictures, perforations, and fistula formation. The incidence and prevalence rates of CD in Korea are still lower compared with those in Western countries, but they have been rapidly increasing during the recent decades. Although there are no definitive curative modalities for CD, various medical and surgical therapies have been applied for the treatment of this disease. Concerning CD management, there have been substantial discrepancies among clinicians according to their personal experience and preference. To suggest recommendable approaches to the diverse problems of CD and to minimize the variations in treatment among physicians, guidelines for the management of CD were first published in 2012 by the IBD Study Group of the Korean Association for the Study of Intestinal Diseases. These are the revised guidelines based on updated evidence, accumulated since 2012. These guidelines were developed by using mainly adaptation methods, and encompass induction and maintenance treatment of CD, treatment based on disease location, treatment of CD complications, including stricture and fistula, surgical treatment, and prevention of postoperative recurrence. These are the second Korean guidelines for the management of CD and will be continuously revised as new evidence is collected.
Collapse
Affiliation(s)
- Jae Jun Park
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea
| | - Suk-Kyun Yang
- Department of Internal Medicine, University of Ulsan College of Medicine, Seoul, Korea
| | - Byong Duk Ye
- Department of Internal Medicine, University of Ulsan College of Medicine, Seoul, Korea
| | - Jong Wook Kim
- Department of Internal Medicine, Inje University College of Medicine Ilsan Paik Hospital, Goyang, Korea
| | - Dong Il Park
- Department of Internal Medicine, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Hyuk Yoon
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Korea
| | - Jong Pil Im
- Department of Internal Medicine, Seoul National University Hospital, Seoul, Korea
| | - Kang Moon Lee
- Department of Internal Medicine, The Catholic University of Korea College of Medicine, Suwon, Korea
| | - Sang Nam Yoon
- Department of Surgery, Hallym University College of Medicine, Chuncheon, Korea
| | - Heeyoung Lee
- Center for Preventive Medicine and Public Health, Seoul National University Bundang Hospital, Seongnam, Korea
| | | |
Collapse
|
|
48
|
Choi CH, Moon W, Kim YS, Kim ES, Lee BI, Jung Y, Yoon YS, Lee H, Park DI, Han DS. [Second Korean Guideline for the Management of Ulcerative Colitis]. THE KOREAN JOURNAL OF GASTROENTEROLOGY = TAEHAN SOHWAGI HAKHOE CHI 2017; 69:1-28. [PMID: 28135789 DOI: 10.4166/kjg.2017.69.1.1] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/17/2025]
Abstract
Ulcerative colitis (UC) is a chronic inflammatory bowel disorder characterized by a relapsing and remitting course. The direct and indirect costs of the treatment of UC are high, and the quality of life of patients is reduced, especially during exacerbation of the disease. The incidence and prevalence of UC in Korea are still lower than those of Western countries, but have been rapidly increasing during the past decades. Various medical and surgical therapies, including biologics, are currently used for the management of UC. However, many challenging issues exist, which sometimes lead to differences in practice between clinicians. Therefore, the Inflammatory Bowel Disease Study Group of the Korean Association for the Study of Intestinal Diseases established the first Korean guideline for the management of UC in 2012. This is an update of the first guideline. It was generally made by the adaptation of several foreign guidelines as was the first edition, and encompasses treatment of active colitis, maintenance of remission, and indication of surgery for UC. The specific recommendations are presented with the quality of evidence and classification of recommendations.
Collapse
Affiliation(s)
- Chang Hwan Choi
- Department of Internal Medicine, Chung-Ang University College of Medicine, Seoul, Korea
| | - Won Moon
- Department of Internal Medicine, Kosin University College of Medicine, Busan, Korea
| | - You Sun Kim
- Department of Internal Medicine, Seoul Paik Hospital, Inje University College of Medicine, Seoul, Korea
| | - Eun Soo Kim
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Kyungpook National University School of Medicine, Daegu, Korea
| | - Bo In Lee
- Division of Gastroenterology, Department of Internal Medicine, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Yunho Jung
- Division of Gastroenterology, Department of Medicine, Soonchunhyang University College of Medicine, Cheonan, Korea
| | - Yong Sik Yoon
- Division of Colon and Rectal Surgery, Department of Surgery, University of Ulsan College of Medicine and Asan Medical Center, Seoul, Korea
| | - Heeyoung Lee
- Center for Preventive Medicine and Public Health, Seoul National University Bundang Hospital, Seongnam, Korea
| | - Dong Il Park
- Department of Internal Medicine, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Dong Soo Han
- Department of Internal Medicine, Hanyang University College of Medicine, Guri, Korea
| |
Collapse
|
|
49
|
Choi CH, Moon W, Kim YS, Kim ES, Lee BI, Jung Y, Yoon YS, Lee H, Park DI, Han DS. Second Korean guidelines for the management of ulcerative colitis. Intest Res 2017; 15:7-37. [PMID: 28239313 PMCID: PMC5323310 DOI: 10.5217/ir.2017.15.1.7] [Citation(s) in RCA: 53] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/05/2017] [Revised: 01/10/2017] [Accepted: 01/11/2017] [Indexed: 12/12/2022] Open
Abstract
Ulcerative colitis (UC) is a chronic inflammatory bowel disease characterized by a relapsing and remitting course. The direct and indirect costs of the treatment of UC are high, and the quality of life of patients is reduced, especially during exacerbation of the disease. The incidence and prevalence of UC in Korea are still lower than those of Western countries, but have been rapidly increasing during the past decades. Various medical and surgical therapies, including biologics, are currently used for the management of UC. However, many challenging issues exist, which sometimes lead to differences in practice between clinicians. Therefore, the IBD study group of the Korean Association for the Study of Intestinal Diseases established the first Korean guidelines for the management of UC in 2012. This is an update of the first guidelines. It was generally made by the adaptation of several foreign guidelines as was the first edition, and encompasses treatment of active colitis, maintenance of remission, and indication of surgery for UC. The specific recommendations are presented with the quality of evidence and classification of recommendations.
Collapse
Affiliation(s)
- Chang Hwan Choi
- Department of Internal Medicine, Chung-Ang University College of Medicine, Seoul, Korea
| | - Won Moon
- Department of Internal Medicine, Kosin University College of Medicine, Busan, Korea
| | - You Sun Kim
- Department of Internal Medicine, Seoul Paik Hospital, Inje University College of Medicine, Seoul, Korea
| | - Eun Soo Kim
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Kyungpook National University School of Medicine, Daegu, Korea
| | - Bo-In Lee
- Division of Gastroenterology, Department of Internal Medicine, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Yunho Jung
- Division of Gastroenterology, Department of Medicine, Soonchunhyang University College of Medicine, Cheonan, Korea
| | - Yong Sik Yoon
- Division of Colon and Rectal Surgery, Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Heeyoung Lee
- Center for Preventive Medicine and Public Health, Seoul National University Bundang Hospital, Seongnam, Korea
| | - Dong Il Park
- Department of Internal Medicine, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Dong Soo Han
- Department of Internal Medicine, Hanyang University Guri Hospital, Guri, Korea
| | | |
Collapse
|
|
50
|
Park SK, Hong M, Ye BD, Kim KJ, Park SH, Yang DH, Hwang SW, Kwak MS, Lee HS, Song K, Yang SK. Influences of XDH genotype by gene-gene interactions with SUCLA2 for thiopurine-induced leukopenia in Korean patients with Crohn's disease. Scand J Gastroenterol 2016; 51:684-91. [PMID: 26863601 DOI: 10.3109/00365521.2015.1133698] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
BACKGROUND The impact of genetic variation in the thiopurine S-methyltransferase (TPMT) gene on thiopurine-induced leukopenia has been well demonstrated. Although xanthine dehydrogenase (XDH) is the second major contributor to azathioprine breakdown, polymorphisms in XDH have rarely been studied in IBD patients. We aim to access association between XDH variants and thiopurine-induced leukopenia by gene-gene interaction in a Crohn's disease (CD) population. STUDY A total of 964 CD patients treated with thiopurines were recruited from a tertiary referral center. The association between four XDH variants (p.Gly172Arg, p.Asn1109Thr, p.Arg149Cys, and p.Thr910Lys) and thiopurine-induced leukopenia was analyzed in cases with early leukopenia (n = 66), late leukopenia (n = 264), and in controls without leukopenia (n = 632). Three non-synonymous SNPs, which we previously reported association with thiopurine-induced leukopenia, NUDT15 (p.Arg139Cys), SUCLA2 (p.Ser199Thr), and TPMT *3C were selected for epistasis analysis with the XDH variants. RESULTS There was no significant association for two variants of XDH and thiopurine-induced leukopenia. In the epistasis analysis, only XDH (p.Asn1109Thr) * SUCLA2 (p.Ser199Thr) showed a statistically significant association with early leukopenia [odds ratio (OR) = 0.16; p = 0.03]. After genotype stratification, a positive association on the background of SUCLA2 wild-type (199Ser) between the XDH (p.Asn1109Thr) and early leukopenia (OR = 4.39; p = 0.01) was detected. CONCLUSION Genes associated with thiopurine-induced leukopenia can act in a complex interactive manner. Further studies are warranted to explore the mechanisms underlying the effects of the combination of XDH (p.Asn1109Thr) and SUCLA2 (199Ser) on thiopurine-induced leukopenia.
Collapse
Affiliation(s)
- Soo-Kyung Park
- a Department of Internal Medicine , Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine , Seoul , Korea
| | - Myunghee Hong
- b Department of Biochemistry and Molecular Biology , University of Ulsan College of Medicine , Seoul , Korea
| | - Byong Duk Ye
- c Department of Gastroenterology, Asan Medical Center , University of Ulsan College of Medicine , Seoul , Korea
| | - Kyung-Jo Kim
- c Department of Gastroenterology, Asan Medical Center , University of Ulsan College of Medicine , Seoul , Korea
| | - Sang Hyoung Park
- c Department of Gastroenterology, Asan Medical Center , University of Ulsan College of Medicine , Seoul , Korea
| | - Dong-Hoon Yang
- c Department of Gastroenterology, Asan Medical Center , University of Ulsan College of Medicine , Seoul , Korea
| | - Sung-Wook Hwang
- c Department of Gastroenterology, Asan Medical Center , University of Ulsan College of Medicine , Seoul , Korea
| | - Min Seob Kwak
- c Department of Gastroenterology, Asan Medical Center , University of Ulsan College of Medicine , Seoul , Korea
| | - Ho-Su Lee
- d Health Screening and Promotion Center, University of Ulsan College of Medicine , Seoul , Korea
| | - Kyuyoung Song
- b Department of Biochemistry and Molecular Biology , University of Ulsan College of Medicine , Seoul , Korea
| | - Suk-Kyun Yang
- c Department of Gastroenterology, Asan Medical Center , University of Ulsan College of Medicine , Seoul , Korea
| |
Collapse
|