Dataset Information

Can We Predict the Toxicity and Response to Thiopurines in Inflammatory Bowel Diseases?

ABSTRACT: Thiopurines are a cheap, effective treatment option in the management of inflammatory bowel disease (IBD). However, with the growing choice of targeted therapies available, as well as the well-documented toxicities of thiopurines, the role of thiopurines has been questioned. Nevertheless, given their inexpense in an era of spiraling healthcare costs, thiopurines remain an attractive option in the right patients. In the age of personalized medicine, being able to predict patients who will respond as well as those that will develop toxicity to a treatment is vital to tailoring therapy. This review will summarize the available literature with respect to predictors of response and toxicity to thiopurines in order to guide management in IBD. Specifically, toxicities addressed will include myelotoxicity, hepatotoxicity, pancreatitis, alopecia, gastrointestinal and flu-like symptoms, and complications associated with Epstein-Barr virus. While more work needs to be done to further our ability to predict both response to and side effects from therapies, pharmacogenomic research shows significant promise in its ability to personalize our use of thiopurines.

SUBMITTER: Luber RP

PROVIDER: S-EPMC6892750 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Can We Predict the Toxicity and Response to Thiopurines in Inflammatory Bowel Diseases?

Luber Raphael P RP Honap Sailish S Cunningham Georgina G Irving Peter M PM

Frontiers in medicine 20191128

Thiopurines are a cheap, effective treatment option in the management of inflammatory bowel disease (IBD). However, with the growing choice of targeted therapies available, as well as the well-documented toxicities of thiopurines, the role of thiopurines has been questioned. Nevertheless, given their inexpense in an era of spiraling healthcare costs, thiopurines remain an attractive option in the right patients. In the age of personalized medicine, being able to predict patients who will respond ...[more]

PMID: 31850357

Similar Datasets

Project description:Thiopurines have been a cornerstone in the treatment of inflammatory bowel disease (IBD). Although they have been used for more than 50 years, there are still some unsolved issues about their efficacy and, also, some safety concerns, mainly the risk of myelosuppression and life-threatening lymphoproliferative disorders. Furthermore, the development of biological therapy raises the question whether there is still a role for thiopurines in the IBD treatment algorithm. On the other hand, limited cost and wide availability make thiopurines a reasonable option in settings of limited resources and increasing prevalence of IBD. In fact, there is a growing interest in optimizing thiopurine therapy, since pharmacogenomic findings suggest that a personalized approach based on the genotyping of some molecules involved in its metabolism could be useful to prevent side effects. Polymorphisms of thiopurine methyltransferase enzyme (TPMT) that result in low enzymatic activity have been associated with an increased risk of myelotoxicity, especially in Caucasians; however, in Asians it is assumed that the variants of nudix hydrolase 15 (NUDT15) are more relevant in the development of toxicity. Age is also important, since in elderly patients the risk of complications seems to be increased. Moreover, the primo-infection of Epstein Barr virus and cytomegalovirus under thiopurine treatment has been associated with severe lymphoproliferative disorders. In addition to assessing individual characteristics that may influence thiopurines treatment outcomes, this review also discusses other strategies to optimize the therapy. Low-dose thiopurines combined with allopurinol can be used in hypermethylators and in thiopurine-related hepatotoxicity. The measurement of metabolites could be useful to assess compliance, identify patients at risk of adverse events and also facilitating the management of refractory patients. Thioguanine is also a rescue therapy in patients with toxicity related to conventional thiopurine therapy. Finally, the current indications for thiopurines in monotherapy or in combination with biologics, as well as the optimal duration of treatment, are also reviewed.

Project description:In this review, we provide an update on genome-wide association studies (GWAS) in inflammatory bowel disease (IBD). In addition, we summarize progress in defining the functional consequences of associated alleles for coding and noncoding genetic variation. In the small minority of loci where major association signals correspond to nonsynonymous variation, we summarize studies defining their functional effects and implications for therapeutic targeting. Importantly, the large majority of GWAS-associated loci involve noncoding variation, many of which modulate levels of gene expression. Recent expression quantitative trait loci (eQTL) studies have established that the expression of most human genes is regulated by noncoding genetic variations. Significant advances in defining the epigenetic landscape have demonstrated that IBD GWAS signals are highly enriched within cell-specific active enhancer marks. Studies in European ancestry populations have dominated the landscape of IBD genetics studies, but increasingly, studies in Asian and African-American populations are being reported. Common variation accounts for only a modest fraction of the predicted heritability and the role of rare genetic variation of higher effects (ie, odds ratios markedly deviating from 1) is increasingly being identified through sequencing efforts. These sequencing studies have been particularly productive in more severe very early onset cases. A major challenge in IBD genetics will be harnessing the vast array of genetic discovery for clinical utility through emerging precision medical initiatives. In this article, we discuss the rapidly evolving area of direct-to-consumer genetic testing and the current utility of clinical exome sequencing, especially in very early onset, severe IBD cases. We summarize recent progress in the pharmacogenetics of IBD with respect to partitioning patient responses to anti-TNF and thiopurine therapies. Highly collaborative studies across research centers and across subspecialties and disciplines will be required to fully realize the promise of genetic discovery in IBD.

Project description:Background & aimsA subset of patients with inflammatory bowel diseases (IBD) have continuously active inflammation, leading to a high number of complications and high direct health care costs (diagnostic tests, medications, and surgeries) and indirect costs (reduced employment and productivity and fewer opportunities for activities). Identifying these high-risk patients and providing effective interventions could produce better outcomes and reduce costs. We used prior year data to create IBD risk models to predict IBD-related hospitalizations, emergency department visits, and high treatment charges (>$30,000/year) in the subsequent year.MethodsWe performed a retrospective study of medical records from all patients with IBD treated at the University of Michigan Hospital from fiscal years 2013-2015. We selected clinical variables from the prior year and tested their abilities to predict 3 adverse outcomes (IBD-related hospitalizations, emergency department visits, and treatment charges >$30,000/year) in the subsequent year. Individual patients were only included once in the data set. We created a multivariate model that was based on a 70% randomly selected cohort (1005 patients) and validated the model on the other 30% (425 patients). Logistic regression was used for bivariate and multivariate analyses.ResultsFactors that predicted high-cost outcomes included the presence of psychiatric illness, use of corticosteroids, use of narcotics, low levels of hemoglobin, and high numbers of IBD-related hospitalizations. In the validation cohort, the model predicted IBD-related hospitalizations, emergency department visits, and high charges in the following year with receiver operating characteristic curve values of 0.751, 0.738, and 0.744, respectively.ConclusionsWe identified 5 factors that can effectively identify patients with IBD at high risk for hospitalization, emergency department visits, and high treatment charges in the next year. These patients should be closely monitored and aggressively managed.

Dataset Information

Can We Predict the Toxicity and Response to Thiopurines in Inflammatory Bowel Diseases?

Publications

Can We Predict the Toxicity and Response to Thiopurines in Inflammatory Bowel Diseases?

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets