6-Thioguanine Nucleotide Levels Are Associated With Mucosal Healing in Patients With Crohn’s Disease

Mao, Ren; Guo, Jing; Luber, Raphael P.; Chen, Bai Li; He, Yao; Zeng, Zhi; Ben‐Horin, Shomron; Sparrow, Miles P.; Roblin, Xavier; Chen, Min Hu

doi:10.1093/ibd/izy173

Cited by 14 publications

(13 citation statements)

References 29 publications

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“…An upper limit of 6-TGN of 450 pmol/8 × 10 8 RBC, beyond which toxicity would outweigh clinical benefits, was suggested, although this has never been rigorously defined. More recent studies have shown that 6-TGN levels in the upper therapeutic range may be required to achieve mucosal healing [40]. A retrospective multi-center, international study demonstrated that patients with mucosal healing had higher 6-TGN levels compared to those without (359.0 vs 277.1 pmol/8 × 10 8 RBC; p = 0.017).…”

Section: Optimization Including Therapeutic Drug Monitoringmentioning

confidence: 99%

Evolving Role of Thiopurines in Inflammatory Bowel Disease in the Era of Biologics and New Small Molecules

Nguyen

Sparrow

2020

Dig Dis Sci

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In recent years, with the increasing availability of biologic therapies and due to safety concerns, the role of thiopurines in the management of inflammatory bowel disease has been questioned. While acknowledging that the benefit/risk ratio of biologic therapies is very high, they are expensive and are not required by a majority of patients. Therefore, thiopurines do retain an important role as steroid-sparing and maintenance agents when used as monotherapy, and in combination therapy with biologics due to their clinical and pharmacokinetic optimization of anti-tumor necrosis factor agents in particular. Safety concerns with thiopurines are real but also relatively rare, and with careful pre-treatment screening and ongoing monitoring thiopurine benefits outweigh risks in the majority of appropriately selected patients. Measurement of newer pharmacogenomic markers such as nudix hydrolase 15 (NUDT15), when combined with knowledge of existing known mutations (e.g., thiopurine S-methyltransferase-TPMT), will hopefully minimize the risk of potentially life-threatening leukopenia by allowing for pre-treatment dosing stratification. Further optimization of thiopurine dosing via measurement of thiopurine metabolites should be performed routinely and is superior to weight-based dosing. The association of thiopurines with malignancies including lymphoproliferative disorders needs to be recognized in all patients and individualized in each patient. The decrease in lymphoma risk after thiopurine cessation provides an incentive for thiopurine de-escalation in appropriate patients after a period of prolonged deep remission. This review will summarize the current role of thiopurines in inflammatory bowel disease management and provide recommendations for commencing and monitoring therapy, and when to consider de-escalation.

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Section: Optimization Including Therapeutic Drug Monitoringmentioning

confidence: 99%

Evolving Role of Thiopurines in Inflammatory Bowel Disease in the Era of Biologics and New Small Molecules

Nguyen

Sparrow

2020

Dig Dis Sci

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“…When TP are used as monotherapy, TGN levels above 230-235 pmol/8 × 10 8 RBC have been associated with clinical response, and more than 450 pmol/8 × 10 8 RBC have been associated with an increased risk of myelotoxicity (5,85). Regarding mucosal healing, a cutoff level of 397 pmol/8 × 10 8 RBC has been proposed with high specificity but low sensibility (86.7 and 35.3%, respectively) (86). In Chinese patients, a cutoff point between 180 and 355 pmol/8 × 10 8 RBC has been associated with remission (87).…”

Section: Adjusting Dose Of Tp Depending On Metabolitesmentioning

confidence: 99%

Thiopurines in Inflammatory Bowel Disease. How to Optimize Thiopurines in the Biologic Era?

2021

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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.

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“…While a threshold of 235 pmol/10 8 RBC may be sufficient for clinical remission, mucosal healing, increasingly recognized as a more robust, and potentially disease-modifying endpoint (73, 74), may require higher levels. A recent multicenter, international retrospective study showed that 6-TGN levels were associated with mucosal healing, and that a level of 397 pmol/10 8 RBC was 86.7% specific but only 35.3% sensitive for mucosal healing (75). However, higher 6-TGN levels are also associated with increased rates of early or late myelotoxicity (23), particularly above 450 pmol/8 × 10 8 RBC (76), and so a fine balance exists between response and toxicity.…”

Section: Predictors Of Response To Thiopurinesmentioning

confidence: 99%

“…However, higher 6-TGN levels are also associated with increased rates of early or late myelotoxicity (23), particularly above 450 pmol/8 × 10 8 RBC (76), and so a fine balance exists between response and toxicity. Interestingly, while a lower thiopurine dose may be sufficient for Asian patients, as discussed above, it is the 6-TGN and not the dose that was associated with mucosal healing in a cohort including a large proportion of Chinese patients (75).…”

Section: Predictors Of Response To Thiopurinesmentioning

confidence: 99%

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

et al. 2019

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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.

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6-Thioguanine Nucleotide Levels Are Associated With Mucosal Healing in Patients With Crohn’s Disease

Abstract: Higher 6-TGN levels are independently associated with a reduced rate of endoscopically active disease and a higher rate of mucosal healing in CD patients. Prospective studies of adequate sample size are required to confirm these findings.

Cited by 14 publications

References 29 publications

Evolving Role of Thiopurines in Inflammatory Bowel Disease in the Era of Biologics and New Small Molecules

Evolving Role of Thiopurines in Inflammatory Bowel Disease in the Era of Biologics and New Small Molecules

Thiopurines in Inflammatory Bowel Disease. How to Optimize Thiopurines in the Biologic Era?

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

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