DNA-Thioguanine Nucleotides as a Marker for Thiopurine Induced Late Leukopenia after Dose Optimizing by NUDT15 C415T in Chinese Patients with IBD.

Thiopurine dose optimization by thiopurine-S-methyltransferase (TPMT) or nudix hydrolase-15 (NUDT15) significantly reduced early leucopenia in Asia. However, it fails to avoid the late incidence (> 2 months). Although laboratory monitoring of 6-thioguanine nucleotides (6TGN) to optimize thiopurine dose was suggested in White patients the exact association between leucopenia and 6TGN was controversial in Asian patients. In the present study, we aimed to explore whether DNA-thioguanine nucleotides (DNA-TGs) in leukocytes, compared with 6TGN in erythrocytes, can be a better biomarker for late leucopenia. This was a prospective, observational study. Patients with inflammatory bowel disease (IBD) prescribed thiopurine from February 2019 to December 2019 were recruited. Thiopurine dose was optimized by NUDT15 C415T (rs116855232). DNA-TG and 6TGN levels were determined at the time of late leucopenia or 2 months after the stable dose was obtained. A total of 308 patients were included. Thiopurine induced late leucopenia (white blood cells < 3.5 × 109 /L) were observed in 43 patients (14.0%), who had significantly higher DNA-TG concentration than those without leucopenia (P = 4.1 × 10-9 , 423.3 (~ 342.2 to 565.7) vs. 270.5 (~ 188.1 to 394.3) fmol/µg DNA). No difference in 6TGN concentrations between leucopenia and non-leucopenia was found. With a DNA-TG threshold of 340.1 fmol/µg DNA, 83.7% of leucopenia cases could be identified. Multivariate analysis showed that DNA-TG was an independent risk factor for late leucopenia. Quantification of DNA-TG, rather than 6TGN, can be applied to gauge thiopurine therapy after NUDT15 screening in Chinese patients with IBD.

Thiopurines are superior to mesalamine for preventing postoperative recurrence in patients with Crohn's disease and two or more risk factors.

OBJECTIVE: To confirm the hypothesis that thiopurines are better than mesalamine for preventing postoperative recurrence of Crohn's disease (CD) in patients with more than two risk factors. METHODS: In total 87 consecutive CD patients who underwent curative ileocolonic resection and ileocolic anastomosis were retrospectively recruited, including 43 prescribed with thiopurines and 44 with mesalamine after surgery. Four risk factors were predefined for subgroup analyses: smoking, penetrating disease, perianal disease and previous resection. End-points included clinical (Crohn's disease activity index >200) and endoscopic recurrence (Rutgeerts score ≥i2) within 52 weeks. RESULTS: There were no significant differences in clinical (37.2% vs 54.5%, P = 0.105) and endoscopic recurrence (55.8% vs 75.0%, P = 0.060) between the thiopurines and mesalamine groups by week 52. In the subgroup analysis of patients with two or more risk factors, clinical (35.7% vs 81.8%, P = 0.042) and endoscopic recurrence (64.3% vs 100%, P= 0.046) were less frequent in the thiopurine group than the mesalamine group. With one additional risk factor, the risk of endoscopic recurrence in the thiopurines group increased by 2.201-fold (95% confidence interval [CI] 1.178-4.115), adjusted for treatment intervention. While the risk of clinical and endoscopic recurrence in patients treated with mesalamine increased by 3.383-fold and 5.884-fold (95% CI 1.260-9.081 and 1.598-21.662). Three patients treated with thiopurines withdrew for adverse events. CONCLUSIONS: Thiopurines may be superior to mesalamine for preventing postoperative recurrence of CD in patients with two or more risk factors. Caution is needed in light of the adverse events caused by thiopurines.

High-risk human papilloma virus infection and cervical neoplasm in female inflammatory bowel disease patients: a cross-sectional study.

BACKGROUND AND AIM: This cross-sectional study investigated the prevalence and risk factors of high-risk human papilloma virus (HPV) infection, especially types 16 and 18, and cervical neoplasia in female Inflammatory bowel disease (IBD) patients. METHODS: From July 2014 to January 2017, sexually active, female, Chinese IBD patients (21-60 years) and age-matched controls underwent cervical ThinPrep cytology testing (TCT) and high-risk HPV-DNA detection, and completed questionnaires about awareness of cervical cancer and HPV. Cervical dysplasia was categorized as cervical intraepithelial neoplasia (CIN) 1, 2 and 3. RESULTS: Of 124 IBD patients (30 ulcerative colitis and 94 Crohn's disease), 17 (13.7%) had high-risk HPV among whom 9 (7.3%) had HPV 16/18 infection and 4 (3.2%) had cervical CIN (3 CIN 3, 1 CIN 1) by pathology. Among 372 controls, 33 (8.9%) had high-risk HPV and only 1 (0.3%) had HPV 16 infection. Cervical TCT detected atypical squamous cells of unknown significance in one control; no control had CIN. The HPV 16/18 infection rate and CIN prevalence were significantly higher in IBD patients than controls (both P < 0.001). The HPV-infection rate was higher in patients administered methotrexate [P = 0.005, odds ratio (95% confidence interval) 4.76 (1.471-15.402)] or more than two immunosuppressants [P = 0.013, odds ratio (95% confidence interval) 3.64 (1.255-10.562)]. Thiopurine, steroid, infliximab and disease behavior/location were not associated with HPV infection. Only 29.3% of patients had undergone cervical-cancer screening. Awareness of HPV infection and HPV-related cervical cancer was poor (28.2%). CONCLUSIONS: Female IBD patients are at increased risk of high-risk HPV infection and cervical neoplasia, which may be associated with immunosuppressants. Education and routine follow-up with HPV-DNA testing and TCT are recommended, especially in female Chinese IBD patients.

Plateletcrit: a sensitive biomarker for evaluating disease activity in Crohn's disease with low hs-CRP.

OBJECTIVE: This study aimed to investigate whether PLT indices could act as non-invasive biomarkers for active Crohn's disease (CD). METHODS: Altogether 130 CD patients and 130 age- and gender-matched healthy volunteers were retrospectively enrolled in the study. CD patients were further divided into patients with active disease (Crohn's disease activity index [CDAI] >150) and in remission. PLT indices including PLT count, mean platelet volume (MPV), platelet distribution width (PDW), platelet large cell ratio (P-LCR) and plateletcrit (PCT) were detected. High-sensitivity C-reactive protein (hs-CRP) and erythrocyte sedimentation rate (ESR) levels were also determined. RESULTS: In active CD, PLT and PCT levels were notably higher but P-LCR and PDW levels were lower than those in healthy controls and patients in remission. PLT, PDW, P-LCR and PCT were significantly correlated with CDAI (P < 0.05). The receiver operating characteristic (ROC) curve showed that with a cut-off value of 0.28%, PCT achieved a sensitivity of 67% and a specificity of 63% for detecting active CD, with the area under ROC curve (AUROC) of 0.67, which was inferior to hs-CRP and ESR. For patients with active disease who had hs-CRP levels lower than 10.0 mg/L, PCT turned out to be the best index for monitoring disease activity (sensitivity 71%, specificity 85%, AUROC 0.77, P = 0.02). CONCLUSION: PCT may act as a specific and sensitive biomarker for determining active CD, especially in patients with an hs-CRP level lower than 10.0 mg/L.

Contribution of MDR1 gene polymorphisms on IBD predisposition and response to glucocorticoids in IBD in a Chinese population.

OBJECTIVE: The cornerstone of conventional treatment for inflammatory bowel disease (IBD) is glucocorticoid (GC). Single nucleotide polymorphisms (SNPs) of genes such as multidrug resistance 1 (MDR1) are related to patient's response to GC, and MDR1 polymorphisms are associated with susceptibility to IBD in Caucasians. We aimed to investigate whether the polymorphisms of five genes including MDR1 influence the response to GC in Chinese patients and the relationship between MDR1 and IBD susceptibility. METHODS: SNPs were selected and genotyped in 156 IBD patients treated with GC and 223 healthy controls. Patients were evaluated and classified as GC-dependent, GC-resistant or responsive to GC after treatment. RESULTS: The CC genotypes of rs1128503 and rs1045642 in MDR1 gene were more frequent in Crohn's disease (CD) patients who were GC-dependent than in those responsive to GC (odds ratio [OR] 6.583, 95% confidence interval [CI] 1.760-24.628, P = 0.019 and OR 3.873, 95% CI 1.578-9.506, P = 0.009, respectively). The G allele of MDR1 rs2032582 was less frequent among CD patients than in controls (OR 0.668, 95% CI 0.484-0.921, P = 0.014). G allele carriers were also less likely to develop non-stricturing and non-penetrating CD (OR 0.661, 95% CI 0.462-0.946, P = 0.023) and ileocolonic CD (OR 0.669, 95% CI 0.472-0.948, P = 0.024). CONCLUSIONS: Polymorphisms of MDR1 are associated with patient's GC response and a predisposition to CD in Chinese population. Further studies are needed to elucidate the role of MDR1 polymorphisms in IBD and that as genetic markers for GC response.