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Severe thiopurine‐induced leukocytopenia and hair loss in Japanese patients with defective NUDT 15 variant: Retrospective case–control study
Author(s) -
Kishibe Mari,
Nozaki Hiroyoshi,
Fujii Mizue,
Iinuma Shin,
Ohtsubo Sawa,
Igawa Satomi,
Kanno Kyoko,
Honma Masaru,
Kishibe Kan,
Okamoto Kensaku,
IshidaYamamoto Akemi
Publication year - 2018
Publication title -
the journal of dermatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.9
H-Index - 65
eISSN - 1346-8138
pISSN - 0385-2407
DOI - 10.1111/1346-8138.14588
Subject(s) - thiopurine methyltransferase , itpa , leukocytopenia , azathioprine , compound heterozygosity , medicine , adverse effect , retrospective cohort study , gastroenterology , biology , genotype , genetics , toxicity , gene , allele , disease , ribavirin
Azathioprine ( AZA )‐metabolizing enzyme gene polymorphism is strongly related to thiopurine‐induced leukocytopenia, which has not been well recognized in dermatological practice. We tried to see whether NUDT 15 gene polymorphism can be the most susceptible genetic factor for AZA toxicity and the gene screening is beneficial to avoid the adverse events of AZA for the treatment of skin diseases. A retrospective study was carried out on 15 adult Japanese patients who were treated with AZA . Gene polymorphism of thiopurine‐metabolizing enzymes NUDT 15 R139C, ITPA 94C>A, TPMT *2, TPMT *3B and TPMT *3C was analyzed. The single nucleotide polymorphisms were prospectively investigated in eight patients who were considered to have received AZA treatments. Two NUDT 15 R139C homozygous patients developed agranulocytosis, severe thrombocytopenia and massive hair loss. The gene screening prior to AZA treatment identified one heterozygote of NUDT 15 R139C and ITPA 94C>A, and three heterozygotes of ITPA 94C>A or TMPT *3C. Although this study was a retrospective single‐center case–control observational study that enrolled a small number of patients, NUDT 15 R139C homozygosity is a genetic risk of thiopurine‐induced potentially fetal hematological abnormalities. To avoid serious adverse events, gene screening of thiopurine‐metabolizing enzymes, at least NUDT 15 R139C, should be considered prior to administration in genetically predisposed populations, such as Japanese. We highlight that massive hair loss in the early period of the initiation of AZA would be a sign of impending severe myelotoxicity.