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The association between the 6-thioguanine nucleotide (6-TGN) level and clinical remission in Crohn’s disease (CD) remains controversial. Thiopurine-induced leukopenia is a life-threatening complication of CD in Asians that was recently shown to strongly correlate with  NUDT15  genetic variants. This study aimed to determine the relationship between thiopurine metabolite levels and therapeutic response, and to investigate the association of  NUDT15 ,  TPMT , and thiopurine metabolites with leukopenia in patients with CD. We enrolled 165 adult patients with CD undergoing thiopurine treatment. Clinical evaluation and laboratory examinations were carried out every 2–3 months. We measured thiopurine metabolites levels and genotyped  NUDT15  and  TPMT . During the median 12-month observational period, 95 (67.9%) patients exhibited clinical response and 45 (32.1%) did not respond to the treatment. The median 6-TGN level was significantly higher in responders than in non-responders ( P  < 0.001). The odds ratio of patients with a 6-TGN level ≥230 pmol/8 × 10 8  red blood cells for showing a clinical response was 4.63 (95% CI 1.62–11.9).  NUDT15  variant types were strongly associated with developing leukopenia. Patients with  NUDT15  homozygous variant genotype developed severe early leukopenia with an average reduction of 88.2% (range, 84–94%) from the baseline white blood cell count at 4 weeks. Our findings support the role of therapeutic drug monitoring in thiopurine maintenance treatment to optimize thiopurine therapy, especially, for non-responding CD patients. Thiopurine treatment should not be recommended to patients with  NUDT15  homozygous variant genotype due to severe early leukopenia.

Measurements of 6-thioguanine nucleotide levels with TPMT and NUDT15 genotyping in patients with Crohn’s disease