NUDT15 R139C variation increases the risk of azathioprine-induced toxicity in Chinese subjects Case report and literature review
Azathioprine (AZA) is widely used as an immunosuppressive agent, and its efficacy has been recommended by many clinical studies. However, leukopenia, the most common toxicity, still restricts its clinical applications. Recent studies found that NUDT15 R139C polymorphism is strongly associated with A...
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| Abstract | Azathioprine (AZA) is widely used as an immunosuppressive agent, and its efficacy has been recommended by many clinical studies. However, leukopenia, the most common toxicity, still restricts its clinical applications. Recent studies found that NUDT15 R139C polymorphism is strongly associated with AZA-induced leukopenia in Koreans. However, the follow-up studies available are all limited to inflammatory bowel disease (IBD). Here, we report a case of a Chinese patient with Sjögren syndrome (SS) with wild-type TPMT*3C who was diagnosed with AZA-induced severe toxicity due to NUDT15 mutation based on clinical and laboratory characteristics.
A 22-year-old Chinese woman with SS developed severe leukopenia after AZA administration for 21 days. Detection of 6-thioguanine nucleotides (6-TGN) showed that the erythrocyte concentration had beyond the monitoring range, indicating that severe leukopenia might be caused by AZA. Furthermore, gene sequencing showed that NUDT15 R139C (poor metabolizer) homozygosity might explain this adverse event. Based on the evidence, AZA administration was immediately stopped and supportive treatments provided, and the patient eventually recovered.
In this report, we first provide detailed clinical and laboratory characteristics of AZA-induced leukopenia in a patient with SS with a mutant NUDT15 R139C genotype (TT allele) and normal TPMT activity. This case indicates that NUDT15 R139C and TPMT*3C genotypes, and more importantly, 6-TGN levels, should be routinely monitored for those administered with AZA to predict and prevent AZA-induced toxicity. |
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| AbstractList | Azathioprine (AZA) is widely used as an immunosuppressive agent, and its efficacy has been recommended by many clinical studies. However, leukopenia, the most common toxicity, still restricts its clinical applications. Recent studies found that NUDT15 R139C polymorphism is strongly associated with AZA-induced leukopenia in Koreans. However, the follow-up studies available are all limited to inflammatory bowel disease (IBD). Here, we report a case of a Chinese patient with Sjögren syndrome (SS) with wild-type TPMT*3C who was diagnosed with AZA-induced severe toxicity due to NUDT15 mutation based on clinical and laboratory characteristics.INTRODUCTIONAzathioprine (AZA) is widely used as an immunosuppressive agent, and its efficacy has been recommended by many clinical studies. However, leukopenia, the most common toxicity, still restricts its clinical applications. Recent studies found that NUDT15 R139C polymorphism is strongly associated with AZA-induced leukopenia in Koreans. However, the follow-up studies available are all limited to inflammatory bowel disease (IBD). Here, we report a case of a Chinese patient with Sjögren syndrome (SS) with wild-type TPMT*3C who was diagnosed with AZA-induced severe toxicity due to NUDT15 mutation based on clinical and laboratory characteristics.A 22-year-old Chinese woman with SS developed severe leukopenia after AZA administration for 21 days. Detection of 6-thioguanine nucleotides (6-TGN) showed that the erythrocyte concentration had beyond the monitoring range, indicating that severe leukopenia might be caused by AZA. Furthermore, gene sequencing showed that NUDT15 R139C (poor metabolizer) homozygosity might explain this adverse event. Based on the evidence, AZA administration was immediately stopped and supportive treatments provided, and the patient eventually recovered.CASE PRESENTATIONA 22-year-old Chinese woman with SS developed severe leukopenia after AZA administration for 21 days. Detection of 6-thioguanine nucleotides (6-TGN) showed that the erythrocyte concentration had beyond the monitoring range, indicating that severe leukopenia might be caused by AZA. Furthermore, gene sequencing showed that NUDT15 R139C (poor metabolizer) homozygosity might explain this adverse event. Based on the evidence, AZA administration was immediately stopped and supportive treatments provided, and the patient eventually recovered.In this report, we first provide detailed clinical and laboratory characteristics of AZA-induced leukopenia in a patient with SS with a mutant NUDT15 R139C genotype (TT allele) and normal TPMT activity. This case indicates that NUDT15 R139C and TPMT*3C genotypes, and more importantly, 6-TGN levels, should be routinely monitored for those administered with AZA to predict and prevent AZA-induced toxicity.CONCLUSIONIn this report, we first provide detailed clinical and laboratory characteristics of AZA-induced leukopenia in a patient with SS with a mutant NUDT15 R139C genotype (TT allele) and normal TPMT activity. This case indicates that NUDT15 R139C and TPMT*3C genotypes, and more importantly, 6-TGN levels, should be routinely monitored for those administered with AZA to predict and prevent AZA-induced toxicity. Azathioprine (AZA) is widely used as an immunosuppressive agent, and its efficacy has been recommended by many clinical studies. However, leukopenia, the most common toxicity, still restricts its clinical applications. Recent studies found that NUDT15 R139C polymorphism is strongly associated with AZA-induced leukopenia in Koreans. However, the follow-up studies available are all limited to inflammatory bowel disease (IBD). Here, we report a case of a Chinese patient with Sjögren syndrome (SS) with wild-type TPMT*3C who was diagnosed with AZA-induced severe toxicity due to NUDT15 mutation based on clinical and laboratory characteristics. A 22-year-old Chinese woman with SS developed severe leukopenia after AZA administration for 21 days. Detection of 6-thioguanine nucleotides (6-TGN) showed that the erythrocyte concentration had beyond the monitoring range, indicating that severe leukopenia might be caused by AZA. Furthermore, gene sequencing showed that NUDT15 R139C (poor metabolizer) homozygosity might explain this adverse event. Based on the evidence, AZA administration was immediately stopped and supportive treatments provided, and the patient eventually recovered. In this report, we first provide detailed clinical and laboratory characteristics of AZA-induced leukopenia in a patient with SS with a mutant NUDT15 R139C genotype (TT allele) and normal TPMT activity. This case indicates that NUDT15 R139C and TPMT*3C genotypes, and more importantly, 6-TGN levels, should be routinely monitored for those administered with AZA to predict and prevent AZA-induced toxicity. |
| Author | Hua, Bing-zhu Chen, Zhi-yong Shu, Qing Ge, Wei-hong Fei, Xiang Wang, Shi-ying Fang, Yun |
| AuthorAffiliation | a Department of Pharmacy, The Affiliated Drum Tower Hospital, Nanjing University Medical School c Department of Rheumatology and Immunology, The Affiliated Drum Tower Hospital, Nanjing University Medical School, Nanjing, China b School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University |
| AuthorAffiliation_xml | – name: b School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University – name: c Department of Rheumatology and Immunology, The Affiliated Drum Tower Hospital, Nanjing University Medical School, Nanjing, China – name: a Department of Pharmacy, The Affiliated Drum Tower Hospital, Nanjing University Medical School |
| Author_xml | – sequence: 1 givenname: Xiang surname: Fei fullname: Fei, Xiang – sequence: 2 givenname: Qing surname: Shu fullname: Shu, Qing – sequence: 3 givenname: Bing-zhu surname: Hua fullname: Hua, Bing-zhu – sequence: 4 givenname: Shi-ying surname: Wang fullname: Wang, Shi-ying – sequence: 5 givenname: Zhi-yong surname: Chen fullname: Chen, Zhi-yong – sequence: 6 givenname: Wei-hong surname: Ge fullname: Ge, Wei-hong – sequence: 7 givenname: Yun surname: Fang fullname: Fang, Yun |
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| Cites_doi | 10.7326/0003-4819-129-9-199811010-00007 10.1007/s00535-015-1142-4 10.1001/jama.2010.1014 10.1097/MEG.0000000000000564 10.1111/jcpt.12420 10.1016/S0016-5085(00)70140-5 10.1016/j.spen.2014.12.008 10.1111/bjh.13518 10.1097/00008571-199902000-00006 10.1002/pbc.26189 10.1053/j.gastro.2006.01.046 10.1111/apt.13559 10.1111/apt.13796 10.1002/pds.926 10.1136/gut.34.8.1081 10.1111/jgh.13494 10.2165/00063030-199809010-00004 10.1200/JCO.2014.59.4671 10.1038/jhg.2016.55 10.1136/gut.39.3.401 10.1002/acr.21591 10.1038/ng.3060 10.1136/bmj.e3821 10.1016/j.berh.2013.07.008 10.2217/pgs.14.32 10.1074/jbc.271.41.25059 |
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| Subtitle | Case report and literature review |
| Title | NUDT15 R139C variation increases the risk of azathioprine-induced toxicity in Chinese subjects |
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