BackgroundDespite NUDT15 variants showing significant association with thiopurine-induced adverse events (AEs) in Asians, it remains unclear which variants of NUDT15 or whether additional genetic variants should be tested to predict AEs. To clarify the best pharmacogenetic test to be used clinically, we performed association studies of NUDT15 variants and haplotypes with AEs, genome-wide association study (GWAS) to discover additional variants, and ROC analysis to select the model to predict severe AEs.MethodsOverall, 2630 patients with inflammatory bowel disease (IBD) were enrolled and genotyped for NUDT15 codon 139; 1291 patients were treated with thiopurines. diplotypes were analyzed in 970 patients, and GWASs of AEs were performed with 1221 patients using population-optimized genotyping array and imputation.ResultsWe confirmed the association of NUDT15 p.Arg139Cys with leukopenia and alopecia (p = 2.20E−63, 1.32E−69, OR = 6.59, 12.1, respectively), and found a novel association with digestive symptoms (p = 6.39E−04, OR = 1.89). Time to leukopenia was significantly shorter, and when leukopenia was diagnosed, thiopurine doses were significantly lower in Arg/Cys and Cys/Cys than in Arg/Arg. In GWASs, no additional variants were found to be associated with thiopurine-induced AEs. Despite strong correlation of leukopenia frequency with estimated enzyme activities based on the diplotypes (r2 = 0.926, p = 0.0087), there were no significant differences in the AUCs of diplotypes from those of codon 139 to predict severe AEs (AUC = 0.916, 0.921, for acute severe leukopenia, AUC = 0.990, 0.991, for severe alopecia, respectively).ConclusionsGenotyping of NUDT15 codon 139 was sufficient to predict acute severe leukopenia and alopecia in Japanese patients with IBD.Electronic supplementary materialThe online version of this article (10.1007/s00535-018-1486-7) contains supplementary material, which is available to authorized users.

An association between FCGR3A-158 V/F polymorphism and biological responses to infliximab has been reported in Crohn's disease (CD) in Western countries. However, little is known about the mechanism by which gene polymorphism affects the responses to infliximab. The aims of this study were to confirm the association in Japanese CD patients and to reveal the effect of gene polymorphism on biological responses to infliximab. Japanese CD patients were examined retrospectively at weeks 8 and 30. Clinical and biological responses were assessed by the Crohn's disease activity index and C-reactive protein levels, respectively. The infliximab-binding affinity of natural killer (NK) cells from FCGR3A-158 V/V, V/F and F/F donors was examined. Infliximab-mediated antibody-dependent cell-mediated cytotoxicity (ADCC) activities were also determined using transmembrane TNF-α-expressing Jurkat T cells as target cells and peripheral blood mononuclear cells (PBMCs) from V/V, V/F and F/F donors as effector cells. Biological responses at week 8 were statistically higher in V/V patients, whereas no significant differences were observed in either clinical responses at weeks 8 and 30 or biological responses at week 30 among the three genotypes. NK cells and PBMCs from V/V patients also showed higher infliximab-binding affinity and infliximab-mediated ADCC activity, respectively. Our results suggest that FCGR3A-158 polymorphism is a predicting factor of biological responses to infliximab in the early phases. FCGR3A-158 polymorphism was also found to affect the infliximab-binding affinity of NK cells and infliximab-mediated ADCC activity in vitro, suggesting that an effect on ADCC activity influences biological responses to infliximab in CD patients.

Background and study aims Intestinal stricture associated with Crohn’s disease (CD) is usually treated by endoscopic balloon dilation (EBD) or stricture plasty. Although EBD is effective and safe for such strictures, refractory stricture after EBD poses a problem. Hence, other novel approaches for these refractory strictures are required. On the other hand, the efficacy of radial incision and cutting (RIC) method for esophageal stricture after esophagogastric surgery is reported. In this pilot study, we adopted the RIC technique for five CD patients with refractory intestinal stricture to dilate their strictures. We conducted the RIC procedure using an electric needle knife with a ceramic tip on the top of the needle. Four cases were of anastomotic stricture after ileocecal resection and the remaining one case was of stricture due to mucosal healing. The RIC procedure was successful for all five patients. Average procedure time was 18.6 minutes. One patient developed delayed bleeding after RIC. There were no cases of perforation. RIC could be an alternative therapy for intestinal stricture associated with CD. Further studies should be conducted to clarify its efficacy and safety.

Background and Aim: Colorectal endoscopic submucosal dissection (ESD) is recommended to be carried out only by endoscopists with sufficient experience in gastric ESD. However, early gastric carcinoma is less common in Western countries than in Japan, and endoscopic maneuverability differs between the stomach and colorectum. We assessed the feasibility of colorectal ESD carried out by endoscopists with no or little experience in gastric ESD. Methods:We analyzed en bloc resection, R0 resection and perforation rates in 180 consecutive colorectal ESD carried out by three endoscopists who had no or <5 cases of experience in gastric ESD. We also identified factors associated with R0 resection failure.Results: Overall en bloc and R0 resection rates were 93.3% (168/180) and 82.2% (148/180), respectively. All 11 cases with perforation were treated endoscopically. Dividing 180 cases into three learning phases (early, middle, or late phases), the en bloc and R0 resection rates increased from 88.3% and 75.0% in the early phase to 98.3% and 88.3% in the late phase, respectively. Perforation rate also improved from 10.0% to 3.3%. Factors associated with R0 resection failure were location at junctions (odds ratio: 6.8, 95% CI: 1.9-27.5), preoperative factors reflecting fibrosis (5.8, 1.9-19.0), and late phase (0.2, 0.1-0.7). Conclusion: Endoscopists without experience in gastric ESDcarried out colorectal ESD safely. In the early and middle phases (≤40 cases), they should treat mainly rectal lesions but may also resect lesions in the colon avoiding flexures. Lesions located at junctions and those with preoperative factors reflecting fibrosis should be resected after completing 40 procedures.

Background Some patients with inflammatory bowel disease (IBD) who were under mesalamine treatment develop adverse reactions called “mesalamine allergy,” which includes high fever and worsening diarrhea. Currently, there is no method to predict mesalamine allergy. Pharmacogenomic approaches may help identify these patients. Here we analyzed the genetic background of mesalamine intolerance in the first genome-wide association study of Japanese patients with IBD. Methods Two independent pharmacogenetic IBD cohorts were analyzed: the MENDEL (n = 1523; as a discovery set) and the Tohoku (n = 788; as a replication set) cohorts. Genome-wide association studies were performed in each population, followed by a meta-analysis. In addition, we constructed a polygenic risk score model and combined genetic and clinical factors to model mesalamine intolerance. Results In the combined cohort, mesalamine-induced fever and/or diarrhea was significantly more frequent in ulcerative colitis vs Crohn’s disease. The genome-wide association studies and meta-analysis identified one significant association between rs144384547 (upstream of RGS17) and mesalamine-induced fever and diarrhea (P = 7.21e-09; odds ratio = 11.2). The estimated heritability of mesalamine allergy was 25.4%, suggesting a significant correlation with the genetic background. Furthermore, a polygenic risk score model was built to predict mesalamine allergy (P = 2.95e-2). The combined genetic/clinical prediction model yielded a higher area under the curve than did the polygenic risk score or clinical model alone (area under the curve, 0.89; sensitivity, 71.4%; specificity, 90.8%). Conclusions Mesalamine allergy was more common in ulcerative colitis than in Crohn’s disease. We identified a novel genetic association with and developed a combined clinical/genetic model for this adverse event.