Thiopurines are widely known as an effective treatment for patients with inflammatory bowel disease. However, a significant portion of these patients display individual variation in thiopurine metabolism resulting in an increased risk for adverse reactions and/or a sub-optimal therapeutic response.
Mayo Clinic Laboratories now offers end-to-end thiopurine testing services that will provide you with the support needed to optimize therapeutic outcomes.
Testing prior to initiation of therapy
Testing prior to the initiation of therapy enables clinicians to detect individuals with low thiopurine methyltransferase (TPMT) activity who are at risk for excessive myelosuppression or severe hematopoietic toxicity when taking thiopurine drugs.
Additionally, testing can also detect individuals with hyperactive TPMT activity who have therapeutic resistance to thiopurine drugs and may develop hepatotoxicity if treated with these drugs
A Test in Focus
Ann Moyer, M.D., Ph.D., gives an overview of TPMT testing. She discusses when this testing should be ordered, how this testing compares to previous testing approaches, and what clinical action can be taken due to the results of this testing.
Which Test Should I Order?
There are currently two types of testing that can be ordered to assess a patient’s risk prior to initiation of therapy, enzyme testing and genotype testing.
The current literature does not clearly demonstrate one of these tests to be superior over the other for TPMT testing. However, the enzyme test can detect individuals with increased metabolism and rare variants that are not included in the genotyping test. Recent research has shown that genetic variants in NUDT15 also affect thiopurine toxicity.1,2 NUDT15 can only be tested through the genotype test. Therefore, both the genotyping assay and the enzyme assay are considered complementary and are recommended.
Enzyme testing measures enzyme activity in a patient’s blood to determine how they metabolize thiopurines. If enzyme activity testing determines patients has a reduced ability to metabolize thiopurines, may adjust dosages or prescribe a different drug.
Our enzyme, or phenotyping, assay offers TPMT activity in three separate reactions, which do not interfere with one another and compete for TPMT. We designed our test this way for specificity, because measuring TPMT activity with only a single analyte frequently generates inconclusive results.
Additionally, the Mayo Clinic-developed multivariate pattern recognition software (CLIR) aids post-analytical interpretation to detect TPMT phenotype pattern differences, drive precise medicine, and reduce clinical uncertainty.
Genotype testing uses a patient’s genetic information to determine how they metabolize thiopurines. If patients have genetic variants that reduce their ability to metabolize thiopurines, clinicians may adjust dosages or prescribe a different drug.
In addition to testing for variants in TPMT, our testing also evaluates, Nudix hydrolase 15 (NUDT15), which can also have genetic variants that are strongly associated with thiopurine-related toxicity.
Including NUDT15 as part of testing is especially important to if clinicians are treating more diverse populations, as deficiency is most common among East Asian (22.6%), South Asian (13.6%), and Native American (12.5–21.2%) populations.
A Test in Focus
Ann Moyer, M.D., Ph.D., gives an overview of NUD15. She discusses when this testing should be ordered, how this testing compares to previous testing approaches, and what clinical action can be taken due to the results of this testing.
Why Test After Initiation of Therapy?
Testing after initiation of therapy enables clinicians to optimize therapy and identify elevated metabolite concentrations that may result in toxicity. Additionally, clinicians should order testing as needed for dose changes, flare-up, signs of toxicity, or suspicion of non-compliance, as well as in patients that do not respond to therapy as expected.
Recommended Time Points for Order:
- 4 weeks after starting treatment to ensure patient compliance and to look for early risk of toxicity
- 12-16 weeks (after TGN metabolites have reached steady-state)
1. Levine, et al. Inflamm Bowel Dis. 2011 Jun;17(6):1314-21.
2. Moriyama T, Nishii R, Perez-Andreu V, et al. NUDT15 polymorphisms alter thiopurine metabolism and hematopoietic toxicity. Nat Genet. 2016 Apr;48(4):367-73.
3. Goel RM, Blaker P, Mentzer, A, et al. Optimizing the use of thiopurines in inflammatory bowel disease. Ther. Adv. Chronic Dis. 2015;6(3):138-146