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

Background NUDT15 polymorphisms are associated with leukopenia during treatment with thiopurines. However, data regarding its effect on treatment outcomes are scarce. Aims To investigate the outcomes between NUDT15 normal and intermediate metabolisers in paediatric patients with Crohn's disease (CD) treated with a combination therapy of infliximab (IFX) and azathioprine (AZA). Methods In this retrospective observational study, 143 patients categorised into the NUDT15 normal and intermediate metaboliser groups were compared based on clinical remission (CR), biochemical remission (BR), mucosal healing (MH) at 1 year treatment, IFX trough levels (TLs), antibodies to IFX (ATIs), 6-thioguanine nucleotide (6-TGN) levels, loss of response (LOR) and IFX durability. Results No significant differences were observed between the groups in CR, BR, MH at 1 year, whereas IFX TLs and ATIs and 6-TGN levels were comparable. However, LOR (6.5% vs 27.7%, P = 0.025) was significantly lower and IFX durability significantly higher (96.8% vs 80.4% P = 0.027) in the intermediate group. Multivariable Cox proportional hazard regression analysis showed that ATI positivity (hazard ratio (HR): 4.76, 95% CI: 2.25-10.07, P < 0.001) and the NUDT15 metaboliser group was associated with LOR (HR: 0.18, 95% CI: 0.04-0.76, P = 0.019). The Kaplan-Meier survival curves showed that the LOR-free survival rate was significantly lower in normal metabolisers (log-rank test P = 0.009). Conclusion NUDT15 intermediate metabolisers were associated with lower LOR in paediatric patients with CD treated with IFX and AZA combination therapy. This finding may partially explain the longer durability of IFX in Korean children than their counterparts in Western countries.