Hessels, A. (Arno) (2014) Role of thiopurine methyltransferase (TPMT) genotype and activity in the occurrence of relapse and adverse effects in ANCA-associated vasculitis patients treated with azathioprine. thesis, Medicine.
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Abstract
Background: ANCA-associated vasculitis (AAV) constitutes a group of primary vasculitides associated with the presence of antineutrophil cytoplasmic antibodies (ANCA). These include granulomatosis with polyangiitis (GPA; formerly Wegener’s granulomatosis), microscopic polyangiitis (MPA), renal limited vasculitis (RLV) and eosinophilic granulomatosis with polyangiitis (EGPA; formerly Churg-Strauss syndrome). Currently, azathioprine is the first choice treatment for maintaining remission in AAV, because it is most effective in preventing relapse, while risk of adverse effects does not significantly differ from other drugs used as maintenance treatment. However, some patients treated with azathioprine still experience relapse, while others experience serious adverse effects. It is important to determine factors that can predict the occurrence of relapse and adverse effects in patients treated with azathioprine, since this may contribute to individual optimization of therapy. The enzyme thiopurine methyltransferase (TPMT) is important in the metabolism of azathioprine. There are several polymorphisms for the gene encoding TPMT, each corresponding with a different level of enzyme activity. These polymorphisms may account for differences in occurrence of relapse and adverse effects between AAV patients treated with azathioprine. The goal of the present study was to investigate the relationship between both TPMT genotype and TPMT activity and the occurrence of relapse and adverse effects in AAV patients treated with azathioprine maintenance therapy after induction therapy with cyclophosphamide. Methods: 198 patients diagnosed and treated at the departments of Rheumatology & Clinical Immunology and Nephrology of the UMCG between July 1987 and August 2012 were included in the study. After diagnosis, all patients were treated with cyclophosphamide induction therapy, followed by azathioprine maintenance therapy. For all patients, relapses within 5 years after diagnosis, and occurrence of leukopenia (mild and moderate), infection, macrocytic anemia, liver toxicity (ASAT/ALAT>2x normal, or AF>1x normal), and intolerance to azathioprine were registered. These factors were compared between TPMT genotypes and tertiles of TPMT activity. Results: There was no significant difference in relapse free survival between TPMT genotypes (P=0.35). Relapse free survival was significantly higher in the lowest tertile of TPMT activity compared to the highest two tertiles (P=0.04), but this difference did not remain significant after correction for other factors associated with risk of relapse. There was no significant difference in occurrence of leukopenia, infection, macrocytic anemia, liver toxicity, or intolerance to azathioprine between different genotypes of TPMT and tertiles of TPMT activity. In logistic regression, leukocyte count at switch (i.e. at the end of cyclophosphamide induction therapy) was a strong predictor of leukopenia during azathioprine therapy (P<0.001). Conclusion: Based on the results of the present study, TPMT cannot be used to predict azathioprine-related adverse effects. Other factors, such as toxicity from cyclophosphamide, might be more useful for this purpose. A low TPMT activity (≤74.5 nmol/gHb/hr) might be associated with a lower risk of relapse.
| Item Type: | Thesis (Thesis) |
|---|---|
| Supervisor name: | Stegeman, Prof. Dr. C.A. |
| Faculty: | Medical Sciences |
| Date Deposited: | 25 Jun 2020 10:50 |
| Last Modified: | 25 Jun 2020 10:50 |
| URI: | https://umcg.studenttheses.ub.rug.nl/id/eprint/1133 |
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