Azathioprine Therapy in AAV Patients Not Affected by TPMT Enzyme Activity, Study Shows

Compared to patients with inflammatory bowel disorders, the safety and efficacy of azathioprine treatment in ANCA-associated vasculitis (AAV) patients is not affected by lower TPMT protein activity, researchers found.

The study, “Thiopurine methyltransferase genotype and activity cannot predict outcomes of azathioprine maintenance therapy for antineutrophil cytoplasmic antibody associated vasculitis: A retrospective cohort study,” was published in Plos One.

Azathioprine is an immunosuppressive drug widely used in autoimmune disorders to lower the activity level of the immune system. Its action depends on several metabolic  reactions that break azathioprine into 6-thioguanine nucleotides (6-TGN).

But while 6-TGN is responsible for azathioprine’s immunosuppressive effects, it also causes severe toxicity, reducing the amount of white blood cells and putting patients at risk for infections.

The TMPT (thiopurine methyltransferase) enzyme works to reduce the amount of 6-TGN formed. But some patients have variants of the TMPT gene that cause the enzyme to have lower activity. In several patient populations, mainly in inflammatory bowel diseases, lower TMPT has been linked to a higher azathioprine-related toxicity to the bone marrow.

This raised the hypothesis that patients with autoimmune disorders could benefit from tailored azathioprine treatment based on their TPMT levels and activity.

Researchers at the University of Groningen in the Netherlands investigated the impact of TPMT activity in patients with ANCA-associated vasculitis (AAV).

The study included 207 patients, diagnosed with either granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA), or renal limited vasculitis (RLV), between 1984 and 2013. All participants had received azathioprine as maintenance therapy after achieving remission with cyclophosphamide and prednisolone.

Researchers examined patients for variants of the TPMT gene and found that only 19 patients had TPMT gene variants associated with decreased enzyme activity. In these patients, TPMT enzyme activity was nearly twice as low as normal TPMT.

But over five years of follow-up, patients with TPMT variants had similar relapse rates compared to those with the normal gene version – 32% vs. 45%. There was a trend for higher enzyme activity to be correlated with higher rates of disease relapse, although this was not statistically significant. Both genetics and enzyme activity did not contribute significantly to the risk of disease relapse, researchers said.

During the duration of the study, 16% of patients were intolerant to azathioprine, 8% had gastrointestinal complaints, 8% had a febrile hypersensitivity reaction, and 1% had a rash. None of these adverse effects were associated with TPMT genetics or enzyme activity.

Also, no correlation was found between TPMT and lower levels of white blood cells or liver toxicity.

The effect of cyclophosphamide (Cytoxan) was shown to have a significant impact on patients’ response to azathioprine. Patients with higher white blood cell counts at the time of the treatment switch were 17% more likely to relapse during azathioprine therapy.

These findings suggest that TPMT genetics or activity cannot predict relapse of frequency and severity of adverse effects related to azathioprine maintenance therapy.

“Leukocyte counts after cyclophosphamide induction were related to both outcomes, implying a greater influence” of this therapy rather than azathioprine or TPMT in these AAV patients, researchers wrote. Additional studies are needed to confirm these new findings.