Optimizing therapeutic outcomes
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 suboptimal 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 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 a patient has a reduced ability to metabolize thiopurines, a clinician 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 have genetic variants that are strongly associated with thiopurine-related toxicity.
Including NUDT15 as part of testing is especially important when 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 NUDT15. 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, suspicion of noncompliance, as well as in patients who 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)
HLA-DQA1 typing provides additional data point for mono- vs. combo-therapy decision
A recent genome-wide association study* performed in a cohort of 1,610 anti–TNF-naïve patients with Crohn’s disease found that carriers of the HLA-DQA1*05 allele had almost double the risk of immunogenicity to anti-TNF therapies.
This data, while needing additional confirmatory research, was compelling enough that it is reasonable to begin checking the HLA marker as an additional data point to guide mono- vs. combo-therapy decisions for patients who are about to begin anti-TNF therapy.
Additionally, for patients who are already on anti-TNF therapy but there is suspicion that the patient is beginning to fail, checking the HLA marker could be another useful data point if, and when, the patient's therapy is changed.
*The Personalising Anti-TNF Therapy in Crohn’s Disease study (PANTS)
The Personalising Anti-TNF Therapy in Crohn’s Disease Study (PANTS) was a United Kingdom–wide, multicenter, prospective observational cohort reporting the treatment failure rates of the anti-TNF drugs infliximab and adalimumab in 1,610 anti–TNF-naïve patients with Crohn’s disease. The initial study with this cohort was aimed at identifying clinical and pharmacokinetic factors that predict primary non-response at week 14 after starting treatment, non-remission at week 54, and adverse events leading to drug withdrawal.
After the initial study, a spinoff, genome-wide association study was performed with this cohort, with the goal of identifying variants associated with time-to-development of anti-drug antibodies.
This spinoff study found that carriers of the HLA-DQA1*05 allele had almost double the risk of immunogenicity to anti-TNF therapies.
Learn more about how to order these evaluations at your institution.
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