Prevention of thiopurine-induced early leukopenia in a Korean pediatric patient with Crohn’s disease who turned out to possess homozygous mutations in NUDT15 R139C

Abstract

Homozygous mutations in NUDT15 R139C are known as the major factor associated with thiopurine-induced early leukopenia, particularly in Asian patients. Therefore, NUDT15 genotyping is currently recommended before thiopurine treatment to identify patients who are NUDT15 poor metabolizers and consider the use of an alternative immunomodulatory therapy. We report a case of a 12-year-old Korean girl with Crohn’s disease (CD), in whom thiopurine-induced leukopenia was prevented by initiation of azathioprine (AZA) therapy at a low dose (0.5 mg/kg/day) and early detection of significant hair loss and white blood cell (WBC) count decrease at 17 days from the start of AZA treatment. The WBC count dropped from 8,970/μL to 3,370/μL in 2 weeks, and AZA treatment was stopped because of concerns of potential leukopenia in the near future. Her WBC count recovered to 5,120/μL after 3 weeks. Gene analysis later revealed that she had a homozygous mutation in NUDT15 R139C, resulting in a poor metabolizing activity of NUDT15. In situations when NUDT15 genotyping is unavailable, initiation of AZA therapy at 0.5 mg/kg/day with close observation of hair loss and WBC counts within 2 weeks may be an alternative way to prevent thiopurine-induced early leukopenia in Asian children with CD.

NUDT15 intermediate metabolisers are associated with lower loss of response in paediatric Crohn’s disease patients treated by combination treatment with infliximab and azathioprine

“…One of the important pharmacogenetic factors in thiopurine metabolism is associated with genetic polymorphisms of the nudix hydrolase 15 ( NUDT15 ) gene. Moriyama et al 13 observed that NUDT15 enzyme activity varied with the NUDT15 polymorphism, which is associated with leukopenia during treatment with thiopurines, particularly in Asians 14‐18 . However, data on the treatment outcomes of NUDT15 enzyme activities are scarce.…”

“…Moriyama et al 13 observed that NUDT15 enzyme activity varied with the NUDT15 polymorphism, which is associated with leukopenia during treatment with thiopurines, particularly in Asians. [14][15][16][17][18] However, data on the treatment outcomes of NUDT15 enzyme activities are scarce.…”

Identification of Candidate Genes for Min Pig Villi Hair Traits by Genome-Wide Association of Copy Number Variation

“…Another notable gene was Nudix hydrolase 15 ( NUDT15 ) which is located near CNV107 on chromosome 11. The gene of NUDT15 could encode an enzyme which is a negative regulator of thiopurine activation and toxicity [ 29 ], and a NUDT15 R139C mutation could cause thiopurine-induced early hair loss in Japanese and Korean patients [ 30 , 31 ]. Moreover, NUDT 15 c.415C > T polymorphism could also increase the risk of hair loss, as pointed out in the research of Wang et al [ 32 ].…”

KASL clinical practice guidelines for management of autoimmune hepatitis 2022

“…However, mutations for NUDT15 rather than TPMT should be considered in Asia [ 224 ]. Since most studies were conducted in patients with inflammatory bowel disease, further research is needed for pediatric patients with autoimmune diseases [ 269 ].…”

“…224 Since most studies were conducted in patients with inflammatory bowel disease, further research is needed for pediatric patients with autoimmune diseases. 269…”