UNASSIGNED: Thiopurines, azathiopurine (AZA) and mercaptopurine (6-MP) have been regularly used in the treatment of inflammatory bowel disease (IBD). Despite optimized dosage adjustment based on the NUDT15 genotypes, some patients still discontinue or change treatment regimens due to thiopurine-induced leukopenia.
UNASSIGNED: We proposed a prospective observational study of lipidomics to reveal the lipids perturbations associated with thiopurine-induced leukopenia. One hundred and twenty-seven IBD participants treated with thiopurine were enrolled, twenty-seven of which have developed thiopurine-induced leucopenia. Plasma lipid profiles were measured using Ultra-High-Performance Liquid Chromatography-Tandem Q-Exactive. Lipidomic alterations were validated with an independent validation cohort (leukopenia n = 26, non-leukopenia n = 74).
UNASSIGNED: Using univariate and multivariate analysis, there were 16 lipid species from four lipid classes, triglyceride (n = 11), sphingomyelin (n = 1), phosphatidylcholine (n = 1) and lactosylceramide (n = 3) identified. Based on machine learning feature reduction and variable screening strategies, the random forest algorithm established by six lipids showed an excellent performance to distinguish the leukopenia group from the normal group, with a model accuracy of 95.28% (discovery cohort), 79.00% (validation cohort) and an area under the receiver operating characteristic (ROC) curve (ROC-AUC) of 0.9989 (discovery cohort), 0.8098 (validation cohort).
UNASSIGNED: Our novel findings suggested that lipidomic provided unique insights into formulating individualized medication strategies for thiopurines in IBD patients.

UNASSIGNED: Thiopurines are believed to increase cancer risks, but data from Asian patients are sparse. We determined the risks of malignancies in thiopurine users with inflammatory bowel disease (IBD) or other indications from Hong Kong.
UNASSIGNED: All patients who had received thiopurines between 2005 and 2009 in Hong Kong were identified from local electronic healthcare database. Patients were followed from the start date of thiopurines until death or end of study in 2017. We excluded patients with baseline malignancy. Standardized incidence ratios (SIR) and the corresponding 95% confidence intervals (CI) of all malignancies were computed against matched local general population from the cancer registry. Patients in the same diagnosis category but not exposed to thiopurines were included as controls.
UNASSIGNED: There were 7452 thiopurines users (median age 47.0 years), including 595 IBD patients, with a median follow-up of 11.2 years. Of them, 684 (9.2%) developed malignancies with an overall SIR of 2.30 (95% CI 2.13-2.48). The SIR in IBD patients who used thiopurines was 2.37 (95% CI 1.71-3.18) as compared with non-users (SIR 1.35, 95% CI 1.05-1.72). Highest risk of malignancies was observed in post-transplant patients (SIR 3.83, 95% CI 3.34-4.35), and lower risks were seen in patients with rheumatological diseases (SIR 1.46, 95% CI 1.02-2.02).
UNASSIGNED: IBD patients in Hong Kong who used thiopurines had 2.37-fold increase in risk of malignancies than the general population, which was higher than non-users and different from thiopurine users for other indications.

Conflicting data exist regarding the influence of thiopurines exposure on adverse pregnancy outcomes in female patients with inflammatory bowel disease (IBD).
The aim of this study was to provide an up-to-date and comprehensive assessment of the safety of thiopurines in pregnant IBD women.
All relevant articles reporting pregnancy outcomes in women with IBD received thiopurines during pregnancy were identified from the databases (PubMed, Embase, Cochrane Library, and ClinicalTrials.gov) with the publication data up to April 2020. Data of included studies were extracted to calculate the relative risk (RR) of multiple pregnancy outcomes: congenital malformations, low birth weight (LBW), preterm birth, small for gestational age (SGA), and spontaneous abortion. The meta-analysis was performed using the random-effects model.
Eight studies matched with the inclusion criteria and a total of 1201 pregnant IBD women who used thiopurines and 4189 controls comprised of women with IBD received drugs other than thiopurines during pregnancy were included. Statistical analysis results demonstrated that the risk of preterm birth was significantly increased in the thiopurine-exposed group when compared to IBD controls (RR, 1.34; 95% CI, 1.00-1.79; p=0.049; I2 =41%), while no statistically significant difference was observed in the incidence of other adverse pregnancy outcomes.
Thiopurines used in women with IBD during pregnancy is not associated with congenital malformations, LBW, SGA, or spontaneous abortion, but appears to have an association with an increased risk of preterm birth.

OBJECTIVE: Although 5-aminosalicylates and thiopurines may have an antineoplastic effect on colorectal neoplasia in patients with inflammatory bowel disease (IBD), their impact on the progression of low-grade dysplasia (LGD) in IBD is uncertain. Therefore, we performed a systematic review and meta-analysis to evaluate whether 5-aminosalicylates or thiopurines can protect against the progression of LGD in patients with IBD.
METHODS: Systematic searches of PubMed, EMBASE, Cochrane Library databases, and major conference proceedings were conducted to identify all eligible studies through March 2020. Data were pooled using a random effects model. Study quality was assessed using the Newcastle-Ottawa Scale.
RESULTS: Five studies comprising 776 IBD patients with LGD were included. Overall, 5-aminosalicylates (Hazard ratio (HR) = 0.91, 95% confidence interval (CI) 0.55-1.51) and thiopurines (HR = 0.64, 95% CI 0.23-1.79) did not significantly reduce the risk of advanced colorectal neoplasia (high-grade dysplasia/cancer) in IBD patients with LGD. Moreover, the effects of 5-aminosalicylates or thiopurines on risk of advanced colorectal neoplasia in IBD patients with LGD were not significant by different primary sclerosing cholangitis status, study quality, sample size, and IBD type.
CONCLUSIONS: In this study, we did not find a significant protective effect of 5-aminosalicylates or thiopurines on the progression of LGD in patients with IBD.

Prospective testing for variants in the thiopurine S-methyltransferase (TPMT) is considered a key process in the development of thiopurine therapy. This testing is done to avoid toxicity and side effects in the management of diverse immunological and malignant conditions. Real-time fluorescent PCR techniques using duplex-crossed allele-specific primers in a single tube (DCAS-PCR) were developed in this study to genotype the common loss-of-function TPMT*3B c.460G > A (rs1800460) and TPMT*3C c.719A > G (rs1142345) usually occurring in individuals of Chinese ethnicity. In this method, several integrated strategies were used to completely eliminate the non-specific amplification that is commonly presented in traditional allele-specific (AS) PCR. These strategies include using AS-primers (ASP) that both are artificially mismatched in the penultimate positions and phosphorothioate modifications in the 5\'-termini positions. In the assay, an AS-blocker was used, locus-specific TaqMan (LST) probes were used and we used at least two fragments were simultaneously amplified in a single tube which satisfy the thermodynamic characteristics of DNA polymerase to eliminate non-specific amplification. In a group of 200 unselected subjects, the results showed that 8 samples were heterozygous of TPMT*3C, and all samples possessed wild-type TPMT*3B. There was no non-specific amplification, and the genotypes were 100% consistent with Sanger sequencing.

OBJECTIVE: The thiopurines are effective in the management of patients with inflammatory bowel disease (IBD), but the association between thiopurines use and the risk of skin cancer (including nonmelanoma skin cancer [NMSC] and melanoma skin cancer) has already been sufficiently reported. However, the results of these studies are inconsistent, and thus, the objective of our analysis was to explore whether thiopurines can lead to an excess risk of skin cancer in IBD patients.
METHODS: MEDLINE, EMBASE, and the Cochrane Library were searched to identify relevant studies that evaluated the risk of skin cancer in IBD patients treated with thiopurines. A random effects meta-analysis was conducted to calculate the pooled incidence rate ratios as well as risk ratios (RRs). Subgroup analysis was performed to explore the potential source of heterogeneity.
RESULTS: Thirteen studies comprising 149 198 participants were included. The result suggested that thiopurines significantly increased the risk of overall skin cancer in IBD patients (random effects: RR = 1.80, 95% confidence interval [CI] 1.14-2.87, P = 0.013), among which NMSC showed an excess risk associated with thiopurines use (random effects: RR = 1.88, 95% CI 1.48-2.38, P < 0.001) while no increased risk was observed with respect to melanoma skin cancer (random effects: RR = 1.22, 95% CI 0.90-1.65, P = 0.206). Subgroup analysis regarding sample size and geographic distribution in skin cancer and follow-up duration in NMSC reached statistical significance, while other subgroups showed no significance.
CONCLUSIONS: Exposition of thiopurines in patients with IBD is associated with a higher risk of skin cancer. Routine skin screening and daily skin protective practice are recommended for these patients.

OBJECTIVE: Measuring 6-thioguanine nucleotide (6-TGN) level is useful in optimizing dose of azathioprine (AZA) and monitoring for toxicity. Lower dose of AZA was suggested for maintenance of clinical remission in Asian patients than Caucasian patients with Crohn\'s disease (CD). However, the optimal 6-TGN threshold required in Asian patients is undetermined. Therefore, the aim of the current study is to explore the optimal 6-TGN threshold required in Asian patients with CD for maintenance of clinical remission.
METHODS: A retrospective cohort study in a tertiary referral center recruited 252 CD patients. The primary endpoint was disease relapse. The levels of 6-TGN and AZA dose were compared in remission group and relapse group. Remission rate was compared across the increased 6-TGN level and dose range.
RESULTS: Patients with 6-TGN range of 0-180.94 pmol/8 × 108 red blood cells (RBC) had lower remission rate compared with those with 180.94-255.50 pmol/8 × 108 RBC (P = 0.020). Quartile analysis showed that increasing 6-TGN level beyond 180 pmol/8 × 108 RBC produced negligible gain in rate of remission. Frequency of adverse events significantly increased in patients with 6-TGN level > 355 pmol/8 × 108 RBC (8.0% with 6-TGN > 355 pmol/8 × 108 RBC vs 2.7% with 6-TGN < 355 pmol/8 × 108 RBC, P = 0.035).
CONCLUSIONS: Our study suggested that optimal 6-TGN threshold required to maintain clinical remission in Chinese patients was 180-355 pmol/8 × 108 RBC.

OBJECTIVE: Thiopurines (TPs) are effective in reducing clinical and endoscopic recurrence in postoperative patients with Crohn\'s disease (CD). However, whether TPs could prevent surgical recurrence (SR) remains unknown. We aimed to explore whether TPs could prevent SR and identify risk factors associated with SR.
METHODS: This was a retrospective cohort study of 246 postoperative patients with CD. Cox proportional hazard model was used to identify risk factors for SR. Patients were stratified according to the presence of risk factors.
RESULTS: A total of 50 (20.3%) patients suffered SR after a mean follow up of 54.3±46.4 months. Multivariable analysis showed independent risk factors for SR were penetrating disease behavior (HR 8.628; 95% CI 1.573-47.341; P = 0.01), ileocolonic disease location (HR 2.597; 95% CI 1.047-6.445; P = 0.04) and isolated upper gastrointestinal disease (UGID) location (HR 5.082; 95% CI 1.496-17.267; P = 0.009). However, use of TPs after surgery significantly reduced the risk of SR (HR 0.120; 95% CI 0.063-0.231; P < 0.001). When stratifying patients according to risk factors, there was no statistical difference of SR between patients treated or not by TPs (P = 0.08) in low-risk group (n = 46). However, in high risk group (n = 200), patients with TPs use had a lower risk of SR than those without TPs (HR 0.093; 95% CI 0.048-0.178; P < 0.001).
CONCLUSIONS: Penetrating disease behavior and ileocolonic/isolated (UGID) location were associated with SR in CD patients. TPs use was beneficial in decreasing risk for SR in CD patients at high risk.

BACKGROUND: Thiopurines, commonly used to treat autoimmune conditions and cancer, can be limited by life-threatening leucopenia. However, whether NUDT15 (nucleoside diphosphate-linked moiety X-type motif 15) is associated with thiopurine-induced leucopenia in Asians is controversial.
METHODS: Relevant studies in English that were published until July 10, 2016 were identified through PubMed, EMbase, and other web knowledge databases. Study quality was assessed according to the Newcastle-Ottawa Scale (NOS) criteria. Summary risk ratio (RR) and 95% confidence intervals (CI) were estimated based on a fixed-effects model or a random-effects model, depending on the absence or presence of significant heterogeneity.
RESULTS: Seven studies of 1138 patients met our inclusion criteria. Random-effects model meta-analysis provided evidence that T carriers of NUDT15 c.415C>T were significantly correlated with high incidences of thiopurine-induced leukocytopenia [CT + TT vs. CC: RR = 3.79, 95%CI (2.64 ~ 5.44), P < 0.00001]. This correlation was especially strong in TT patients, where it was found to be significantly increased by 6.54-fold compared with CC patients [TT vs. CC: RR = 6.54, 95%CI (3.34 ~ 12.82), P < 0.00001]. We also found that the NUDT15 c.415C>T variant was common in Asians and Hispanics, but rare in Europeans and Africans; the frequency of the NUDT15 c.415C>T distribution varied substantially by race/ethnicity.
CONCLUSIONS: The results of this meta-analysis confirm that NUDT15 c.415C>T may be an important predictor of thiopurine-induced leukocytopenia in Asians. Genotype targeting of NUDT15 c.415C>T before initiating thiopurine treatment may be useful to limit leukocytopenia.

Patients with inflammatory bowel disease (IBD) are at risk of developing haemophagocytic lymphohistiocytosis (HLH) because of chronic systemic inflammation as well as exposure to immunosuppressive medications. The two main causes of HLH in IBD patients are infection with cytomegalovirus and Epstein-Barr virus. Patients with Crohn\'s disease are more susceptible to HLH than those with ulcerative colitis. The majority of cases are seen in people receiving an immunosuppressive regimen that included thiopurines.