What are the auxiliary tests for prescribing thiopurines?
Imuran and Purinethol are medications that regulate the activity of the immune system, thus reducing excessive immune response in the intestines. These medications start to take effect only after 2-4 months of administration, primarily being effective in maintaining remission rather than inducing it. The drugs break down in the body into two main substances: 6TG is the active compound, but at elevated levels, it could lead to decreased blood cell counts; and 6MMP, an inactive compound that may contribute to liver function elevation. The levels of these compounds are determined, among other factors, by the enzyme TPMT. After starting the medication, frequent blood tests are needed to ensure treatment safety. It's important to highlight that in most cases, the effectiveness of the treatment in controlling the disease outweighs the potential side effects.
The activity of the TPMT enzyme can be tested before treatment initiation, allowing for prediction of a portion of the risk for side effects. The enzyme can be tested both genetically and through enzymatic activity assays. Genetic markers can be tested at several medical centers (such as Beilinson, Rambam, Ichilov, and Shaare Zedek), though it has been found that among Jewish individuals, only a third of those with low activity will test positive for genetic markers. In the gastroenterology laboratory at Shaare Zedek Medical Center, there's the option to assess the enzymatic activity in addition to genetics, providing a more precise identification of populations at a higher risk for side effects. Furthermore, enzymatic activity testing (in contrast to genetics) allows the identification of patients with overly high enzyme activity, thereby predicting cases where the medication might not be effective and could even cause liver function elevation. After starting treatment, the levels of two breakdown products of the medications (6TG and 6MMP) can be tested in the blood, determining whether dosage adjustments are needed, whether dosage reduction is required, or if the medication is appropriate for the patient. The tests are conducted, among others, at medical centers such as Tel Hashomer, Shaare Zedek, Ichilov, and Rambam.
When is it advisable to undergo these tests?
In the United States, TPMT testing is routine and in many countries, it's even mandatory before starting treatment with Imuran or Purinethol. In European countries, TPMT testing is common and growing. At the Gastroenterology Institute for Children and Nutrition, most patients are referred for the testing, and sometimes, the results aid in determining dosage, making optimal treatment decisions, and setting the frequency of blood tests after treatment initiation. However, the test is not covered by the health system and is not always funded by the healthcare provider. Regarding the testing of drug levels (6TG and 6MMP levels), it can certainly be helpful in cases where there's suspicion of side effects (such as unclear liver function elevation, reduced blood cell counts, and various clinical symptoms like hair loss) or when the clinical impact of the medication is partial and direct assessment of the active compound's levels in the body is desired. Routine testing of drug levels is not necessary for everyone.
Are the tests reliable?
Genetic TPMT testing is reliable when positive, but not when negative (as only a third of cases with reduced enzyme activity are linked to a positive genetic response). The advantage of genetic testing is that it's not influenced by medication and can be performed even while taking Imuran and Purinethol (in contrast to enzymatic testing). On the other hand, enzymatic testing for enzyme activity identifies additional populations at risk and allows for the detection of excessively high activity. However, a normal result doesn't entirely negate the risk of side effects, and close medical and laboratory monitoring is essential. Measurement of drug levels (6TG and 6MMP levels) is reliable in cases where an abnormal result is obtained, differing significantly from the normal range. In such cases, the result can certainly be relied upon for treatment planning.
Click here to read the guidelines for TPMT enzyme activity testing.
Click here to read the guidelines for testing the metabolite levels of Imuran and Purinethol in the blood.