Intest Res.  2022 Jan;20(1):90-100. 10.5217/ir.2020.00133.

Long-term efficacy and tolerability of dose-adjusted thiopurine treatment in maintaining remission in inflammatory bowel disease patients with NUDT15 heterozygosity

• Maeda T
• Sakuraba H
• Hiraga H
• Yoshida S
• Kakuta Y
• Kikuchi H
• Kawaguchi S
• Hasui K
• Tatsuta T
• Chinda D
• Mikami T
• Fukuda S

• KMID: 2525076
• DOI: http://doi.org/10.5217/ir.2020.00133

Abstract

Background/Aims
Thiopurines are key drugs for inflammatory bowel disease (IBD), including ulcerative colitis (UC) and Crohn’s disease (CD). Recently, NUDT15 polymorphism (R139C, c.415C > T) has been shown to be associated with thiopurineinduced adverse events in Asian populations. In patients with the C/T genotype, low-dose thiopurine treatment is recommended, but its long-term efficacy and tolerability remain unclear. This study aimed to uncover the long-term efficacy and appropriate dosage of thiopurine for IBD patients with the C/T genotype.
Methods
A total of 210 patients with IBD (103 UC and 107 CD) determined to have NUDT15 R139C variants were enrolled. Clinical data were retrospectively reviewed from medical records.
Results
Of 46 patients (21.9%) with the C/T genotype, 30 patients (65.2%) were treated with thiopurines. Three of whom (10.0%) discontinued thiopurine treatment due to adverse events and 27 of whom continued. The median maintenance dosage of 6-mercaptopurine was 0.25 mg/kg/day (range, 0.19–0.36 mg/kg/day), and 6-thioguanine nucleotides level was 230 (104–298) pmol/8 × 10⁸ red blood cells. Cumulative thiopurine continuation rates for 120 months for patients with the C/C and C/T genotypes were not significantly different (P= 0.895). Cumulative non-relapse rates in the patients with UC treated with thiopurine monotherapy and surgery-free rates in CD patients treated with combination therapy (thiopurines and anti-tumor necrosis factor-α agents) for maintenance remission were not significantly different at 60 months (C/C vs. C/T, P= 0.339 and P= 0.422, respectively).
Conclusions
Low-dose thiopurine treatment is an effective and acceptable treatment for patients with C/T genotype.

Keyword

heterozygosity; Inflammatory bowel disease; Thiopurine; Maintain remission

Figure

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  Fig. 1. Comparison of thiopurine dosage, time to adverse events (AEs), cumulative continuation rate according to NUDT15 genotypes. (A) Maintenance dosage of 6-mercaptopurine (6-MP) and serum 6-thioguanine nucleotides (6-TGN) levels in patients with C/C and C/T genotypes. (B) Dosage of 6-MP at the time when total AEs was developed are plotted. (C) Time to total AEs after starting thiopurine treatment is plotted in term of NUDT15 genotypes. (D) Cumulative continuation rate of thiopurine for 120 months in patients with C/C and C/T genotypes. Azathioprine doses were converted to a 6-MP dose using a conversion factor of 2.08. Data represents median (interquartile range). aP < 0.05. RBCs, red blood cells.

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  Fig. 2. Cumulative non-relapse rate for 60 months in ulcerative colitis patients with NUDT15 C/C and C/T genotypes. The patients were treated with thiopurine as maintenance remission.

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  Fig. 3. Cumulative surgery-free rate without change of therapy for 60 months in Crohn’s disease patients with NUDT15 C/C and C/T genotypes. The patients were treated with combination therapy (thiopurine+anti-tumor necrosis factor-α agent).

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  Fig. 4. Time-course of change in white blood cell (WBC) count (A, C, E) or mean corpuscular volume (MCV) (B, D, F) for 120 or 60 months in patients with NUDT15 C/C and C/T genotypes. Data represents median (interquartile range). aStatistically significant difference between the C/C and C/T genotypes (P < 0.05). Statistically significant difference from the start of thiopurine therapy (bC/C genotype; cC/T genotype, P < 0.05). UC, ulcerative colitis; CD, Crohn’s disease.

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