DNA-Thioguanine (DNA-TG) Is a Promising Novel Method to Predict Adverse Events to Thiopurine in Inflammatory Bowel Disease

To the Editor

We commend Sharip et al.¹ for their insightful paper on predicting adverse outcomes in thiopurine-treated inflammatory bowel disease (IBD) patients. In the past, several attempts have been made to innovate therapeutic drug monitoring (TDM) for thiopurines with methods such as measuring mono, di, and triphosphates separately² or RAC1 pharmacodynamic measurements.³ We would like to highlight a promising novel method for measuring thiopurine metabolites, known as DNA-Thioguanine (DNA-TG). This DNA-TG represents the end metabolite of thiopurine metabolism, where thioguanine is incorporated into DNA and measured in white blood cells, the primary target of thiopurine treatment, which possesses the enzymatic machinery to metabolize thiopurines. Unlike red blood cells, where 6-thioguanine nucleotides (6-TGNs) are measured and which lack these enzymes. Recent technological advancements have enabled the measurement of DNA-TG using liquid chromatography coupled with tandem mass spectrometry. Recently, we conducted a systematic review and meta-analysis on the utility of DNA-TG. Our findings indicated that DNA-TG is a significant predictor of leukopenia in IBD patients (leukopenia vs no leukopenia, DNA-TG level + 161.8 fmol TG/µg DNA [95% CI 126.2-197.3], P < 0.0001).⁴ One of the advantages of DNA-TG over 6-TGNs is its ability to identify patients with the Nudix hydrolase 15 (NUDT15) variant and predict side effects in these patients. Current methodologies using 6-TGNs, which measure the total of mono-, di-, and triphosphorylated nucleotides, cannot identify NUDT15 variants (Figure 1). Therefore, DNA-TG offers a more comprehensive and sensitive approach for TDM in patients with NUDT15 variants. The studies by Yang et al.⁵ and Zhu et al.,⁶ upon which our meta-analysis was based, demonstrated benefits not only for patients with NUDT15 variants but also showed that DNA-TG outperformed 6-TGNs in predicting leukopenia in wildtype and thiopurine methyltransferase (TPMT) variant patients. Yang et al.⁵ also developed an intriguing tool for predicting leukopenia using DNA-TG levels and other patient parameters in IBD. However, there are some centers that measure mono-, di-, and triphosphorylated nucleotides separately but these measurements have never been compared to DNA-TG in terms of predicting the risk of leukopenia in NUDT15 variant patients.²

Figure 1.

Fictional numbers of thiopurine metabolites illustrate that despite different values for TGTP, the total number of 6-TGNs can be similar between wildtype and NUDT15 variant patients using conventional 6-TGN assays. Toxic thiopurine levels can be detected using DNA-TG in NUDT15 variants, but not using 6-TGNs. 6-MMP, 6-methylmercaptopurine; TGMP, thioinosine monophosphate;TGDP, thioguanosine diphosphate; TGTP, thioguanosine triphosphate.

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Although the development of DNA-TG measurement is ongoing, they hold significant promise for the future in predicting side effects such as leukopenia in IBD patients. We believe that more clinical research on DNA-TG implementation is mandatory.

Funding

For this manuscript, no funding was received.

Conflicts of Interest

A.B. has nothing to declare. N.K.d.B. has served as a speaker for AbbVie and MSD and has served as a consultant and principal investigator for TEVA Pharma BV and Takeda. He has received a (unrestricted) research grant from Dr. Falk, TEVA Pharma BV, MLDS, and Takeda. L.D. has served as a speaker for AbbVie, Celltrion, Janssen-Cilag and Takeda and has developed continuing education materials for Ferring. All outside the submitted work.

Statement of Ethics

No permission from the Medical Ethical Review Committee was needed for this study.

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