BACKGROUND: Azathioprine (AZA) is a widely used immunosuppressant drug. Leukopenia is a serious adverse effect of the drug which often necessitates dose reduction or drug withdrawal. Predictors of leukopenia include genetic and nongenetic factors. Genetic polymorphism of AZA-metabolizing enzyme, thiopurine S-methyltransferase (TPMT) is well established. There is inconclusive evidence about the role of Nudix hydrolase (NUDT15) gene polymorphism. This case-control study assessed the association of genetic polymorphisms of NUDT15 and TPMT with leukopenia induced by AZA.
METHODS: Cases were patients on AZA who developed leukopenia (white blood cell count <4000/μl) within 1 year of treatment initiation that necessitated dose reduction or drug withdrawal. Age and gender-matched patients without leukopenia within 1 year of treatment with AZA served as controls. TPMT (3 loci: c238G to C, c460G to A, c719A to G) and NUDT15 (c 415C to T, rs116855232) genotyping were done using TPMT strip assay and polymerase chain reaction-restriction fragment length polymorphism, respectively. Genotype frequencies were noted, and the odds ratio was calculated to determine the association between genotypes and leukopenia.
RESULTS: Twenty-nine subjects (15 cases and 14 controls) were enrolled. Statistically significant differences were not observed in the TPMT genotype (*1/*1 and *1/*3C) (P = 0.23) between cases and controls. NUDT15 genotypes (*1/*1 and *1/*3) (P = 0.65) also showed no statistically significant difference between cases and controls.
CONCLUSIONS: The above genotypes do not appear to be associated with AZA-induced leukopenia in an eastern Indian population.

The STING (stimulator of interferon genes) pathway is one of the pathways that regulate innate immunity, and the extracellular hydrolytic enzyme ecto-nucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1) has been identified as its dominant negative regulator. Since activation of the innate immune system is a promising strategy for the treatment of various infectious diseases and cancers, ENPP1 inhibitors have attracted great attention as candidate drugs. We have previously identified small-molecule ENPP1 inhibitors having a [1,2,4]triazolo[1,5-a]pyrimidine scaffold by means of chemical screening using a fluorescence probe, TG-mAMP. In this study, we evaluated the structure-activity relationships of the hit and lead compounds in detail, and succeeded in developing compounds that strongly and selectively inhibit ENPP1 not only in vitro, but also in cellular systems.

BACKGROUND: Peri-implantitis (PI) is a frequent inflammatory disorder characterised by progressive loss of the supporting bone. Not all patients with recognised risk factors develop PI. The aim of this study is to evaluate the presence of single nucleotide polymorphisms (SNP) of inflammatory and bone metabolism related proteins in a population treated with dental implants from the Basque Country (Spain).
METHODS: We included 80 patients with diagnosis of PI and 81 patients without PI, 91 women and 70 men, with a mean age of 60.90 years. SNPs of BMP-4, BRINP3, CD14, FGF-3, FGF-10, GBP-1, IL-1α, IL-1β, IL-10, LTF, OPG and RANKL proteins were selected. We performed a univariate and bivariate analysis using IBM SPSS® v.28 statistical software.
RESULTS: Presence of SNPs GBP1 rs7911 (p = 0.041) and BRINP3 rs1935881 (p = 0.012) was significantly more common in patients with PI. Patients with PI who smoked (> 10 cig/day) showed a higher presence of OPG rs2073617 SNP (p = 0.034). Also, BMP-4 rs17563 (p = 0.018) and FGF-3 rs1893047 (p = 0.014) SNPs were more frequent in patients with PI and Type II diabetes mellitus.
CONCLUSIONS: Our findings suggest that PI could be favoured by an alteration in the osseointegration of dental implants, based on an abnormal immunological response to peri-implant infection in patients from the Basque Country (Spain).

This study evaluated the effectiveness of NUDT15 codon 139 genotyping in optimizing thiopurine treatment for inflammatory bowel disease (IBD) in Japan, using real-world data, and aimed to establish genotype-based treatment strategies.
A retrospective analysis of 4628 IBD patients who underwent NUDT15 codon 139 genotyping was conducted. This study assessed the purpose of the genotyping test and subsequent prescriptions following the obtained results. Outcomes were compared between the Genotyping group (thiopurine with genotyping test) and Non-genotyping group (thiopurine without genotyping test). Risk factors for adverse events (AEs) were analyzed by genotype and prior genotyping status.
Genotyping test for medical purposes showed no significant difference in thiopurine induction rates between Arg/Arg and Arg/Cys genotypes, but nine Arg/Cys patients opted out of thiopurine treatment. In the Genotyping group, Arg/Arg patients received higher initial doses than the Non-genotyping group, while Arg/Cys patients received lower ones (median 25 mg/day). Fewer AEs occurred in the Genotyping group because of their lower incidence in Arg/Cys cases. Starting with < 25 mg/day of AZA reduced AEs in Arg/Cys patients, while Arg/Arg patients had better retention rates when maintaining ≥ 75 mg AZA. Nausea and liver injury correlated with thiopurine formulation but not dosage. pH-dependent mesalamine reduced leukopenia risk in mesalamine users.
NUDT15 codon 139 genotyping effectively reduces thiopurine-induced AEs and improves treatment retention rates in IBD patients after genotype-based dose adjustments. This study provides data-driven treatment strategies based on genotype and identifies risk factors for specific AEs, contributing to a refined thiopurine treatment approach.

To investigate associations between inosine triphosphatase (ITPA) gene polymorphisms and long-term outcomes among chronic hepatitis C (CHC) patients in Northeast China treated with Peg-interferon (IFN)/ribavirin (RBV). CHC patients who received Peg-IFN-2a/RBV treatment during between 2011 and 2013 at 5 hepatitis centers in Northeast China were enrolled. ITPA single nucleotide polymorphisms rs1127354 and rs7270101 from all patients were detected and their associations with 5-year outcomes were analyzed. A total of 635 patients, including 421 infected with hepatitis C virus (HCV) genotype 1 and 214 infected with non-genotype 1 were included. No significant differences were observed in the distribution frequencies of ITPA rs1127354 variants and ITPase activity between patients with HCV genotype 1 and non-genotype 1. In patients who received more than 80% of the planned RBV dose, the 5-year virological response rate and the improvement in liver fibrosis were higher in those with ITPA rs1127354 non-CC with ITPase activity <25% compared with these outcomes in patients with ITPA rs1127354 CC with 100% ITPase activity. Multiple regression analysis revealed that HCV genotype non-1, low baseline HCV ribose nucleic acid (RNA) levels (≤4 × 105 IU/mL), interleukin-28B rs12979860 CC genotype, low baseline liver fibrosis (Fibroscan 0-2), and ITPA rs1127354 non-CC genotype were independent predictors for a high long-term virological response rate, whereas interleukin-28B rs12979860 CC genotype, ITPA rs1127354 non-CC genotype, and low baseline liver fibrosis were independent predictors for improvement of liver fibrosis. ITPA rs1127354 polymorphisms is predictors of long-term outcomes in CHC patients treated with Peg-IFN/RBV.

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The aim of the study was to correlate the immunohistochemical expression of cartilage intermediate layer protein 2 (CILP-2) and discoidin domain receptor 2 (DDR2), and the ultrastructural changes in the cartilage with the degree of articular cartilage damage in osteoarthritis (OA) patients. Cartilage samples were obtained from twenty patients aged from 46 to 68 years undergoing total knee arthroplasty. In each patient, medial and lateral tibial plateau samples were analysed applying OARSI histopathology grading. Positive correlation was noted between the extent of CILP-2 staining intensity and OARSI grades. Abundant staining for CILP-2 was found in the superficial and middle layers and in the pericellular matrix (PCM) of the deep zone. Transmission electron microscopy studies demonstrated strong damage of chondrocytes, the organelles were often diminished or focally aggregated. As a characteristic finding, PCM was frequently expanded, which may reflect a pathogenic step in OA progression. In conclusion, CILP-2 may potentially be a relevant marker of OA progression as its expression correlated better with cartilage damage than the known marker of articular cartilage damage, DDR2.

Thiopurine S-methyltransferase (TPTM) is a well known biomarker for thiopurine-induced leucopenia, which has limited value in Asia. Instead, NUDT15 C415T is a promising predictor in Asia.
To explore whether an optimised strategy based on NUDT15 C415T genotypes affects thiopurine-induced leucopenia, as well as efficacy in Chinese patients with Crohn\'s disease.
Patients with Crohn\'s disease and indications for thiopurines were included from two hospitals in China. They were randomly assigned to either the intervention or the control group. In the intervention group, those with genotype CC received a standard dose (control group), those with CT genotype received 50% of the standard dose, those with TT genotype received alternative drugs. The primary endpoint was thiopurine-induced leucopenia (<3.5 × 109 /L). Secondary outcomes were the incidence of other adverse events and the efficacy for maintaining steroid-free remission at week 36.
The rate of thiopurine-induced leucopenia was lower in the intervention group (n = 52) than in the control group (n = 66) (23.7% vs 32.4%, P = 0.049, RR = 0.73, 95% CI 0.53-1.00). In CT subgroup, the incidence of leucopenia in the intervention group (n = 10) was significantly lower than in the control group (n = 28) (31.3% vs 65.1%, RR = 0.48, 95% CI 0.28-0.84). Neither other adverse events nor treatment efficacy was significantly different between the two groups during follow-up.
Among Chinese patients with Crohn\'s disease, dose optimisation by NUDT15 C415T reduced the rate of thiopurine-induced leucopenia, without significant influence on efficacy. Using 50% dose reduction for heterozygotes, and alternative drugs for homozygotes, are practicable strategies. Clinical trial number: NCT02929706.

BACKGROUND: Polymorphisms in thiopurine methyltransferase (TPMT) and Nudix hydrolase-15 (NUDT15) have been implicated as the predominant cause of thiopurine induced leukopenia in the Western countries and East Asia respectively. Exact role of these polymorphisms in South Asian population with inflammatory bowel disease (IBD) is uncertain.
METHODS: We included consecutive patients with IBD who were initiated on thiopurines at a center in North India. The dosage of thiopurines was titrated using regular monitoring of hemogram and liver function tests. Three TPMT polymorphisms (c.238 G > C, c.460 G > A, and c.719A > G) and one NUDT15 polymorphism (c.415 C > T) were assessed. Comparison regarding incidence of leukopenia and maximum tolerated thiopurine dosage was performed between those with wild polymorphism and those with TPMT and NUDT15 polymorphisms, respectively.
RESULTS: Of the 119 patients (61 males, mean age 36.8 ± 13.5 years), 105 (88.2%) had ulcerative colitis and 14 (11.8%) had Crohn\'s disease. Leukopenia was noted in 33 (27.7%), gastrointestinal intolerance in 5 (4.2%) and pancreatitis in 2 (1.6%). TPMT polymorphisms were detected amongst five patients of whom 1 developed leukopenia. NUDT15 polymorphism was noted in 13 patients of whom 7 had leukopenia. The odds of developing leukopenia in TPMT polymorphism were non-significant (0.77, 95% CI:0.0822 to 7.2134, P = 0.819) but were significantly higher in those with NUDT15 polymorphism (3.5933, 1.1041 to 11.6951, P value: = 0.0336).
CONCLUSIONS: NUDT15 polymorphism was more frequent than TPMT polymorphisms and was associated with thiopurine induced leukopenia. However, the tested polymorphisms account for only 24.2% of the risk of thiopurine induced leukopenia.

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