Oral tacrolimus is an effective treatment for refractory ulcerative colitis (UC). However, tacrolimus is underutilized because of the difficulties in transitioning to subsequent maintenance therapy and concerns about adverse events.

We evaluated the clinical outcomes, adverse events, and accumulated medication costs in consecutive 72 UC patients treated with tacrolimus.

Fifty-five (76%) patients with pancolitis and 43 (60%) patients with acute severe disease were entered. Fifty-four (75%) achieved clinical remission 8 weeks after starting tacrolimus. At the last visit, 62 (86%) patients had colectomy-free remission, and 55 (76%) patients had corticosteroid-free remission. Eighteen (25%) patients maintained remission without additional treatment after tacrolimus discontinuation. Patients with continuous remission had a significantly lower history of thiopurine use and lower serum albumin levels at the induction of tacrolimus than patients with failure to induce or maintain remission. No severe adverse events due to tacrolimus treatment were observed. The accumulated medication costs over 3 years in patients with continuous remission after the start of tacrolimus were lower than those in patients with induction and maintenance of infliximab (p < 0.001).

Tacrolimus could have an irreplaceable role in the era of biologic therapies, especially for refractory UC patients with thiopurine-naïve and low serum albumin levels.

Thiopurines are a class of immunosuppressant and antineoplastic agents. They are widely used in the treatment of inflammatory bowel disease, haematological malignancies and autoimmune diseases, but can cause significant toxicity. Inherited gene mutations are now recognized as independent risk factors for severe adverse drug reactions to thiopurines even at 10-fold dose reductions. We present a case of thiopurine toxicity resulting in severe myelosuppression, hepatotoxicity and alopecia in an individual with homozygous *3/*3 loss-of-function alleles in the NUDT15 gene. Our case highlights important differences in gene mutation frequencies between races that can help guide pharmacogenomic testing.

Ceria-based nanoparticles are versatile in treating various inflammatory diseases, but their feasibility in clinical translation is undermined by safety concerns and a limited delivery system. Meanwhile, the idiopathic nature of inflammatory bowel disease (IBD) calls for a wider variety of therapeutics via moderation of the intestinal immune system. In this regard, the synthesis and oral formulation of iron-ceria nanoparticles (CF NPs) with enhanced nanozymic activity and lower toxicity risk than conventional ceria-based nanoparticles are reported. CF NPs are clustered in calcium phosphate (CaP) and coated with a pH-responsive polymer to provide the enteric formulation of iron-ceria nanotablets (CFNT). CFNT exhibits a marked alleviative efficacy in the dextran sodium sulfate (DSS)-induced enterocolitis model in vivo by modulating the pro-inflammatory behavior of innate immune cells including macrophages and neutrophils, promoting anti-inflammatory cytokine profiles, and downregulating key transcription factors of inflammatory pathways.

Nudix hydrolase 15 (NUDT15) deficiency is strongly associated with thiopurine-induced myelosuppression. Currently, testing for NUDT15 deficiency is based on the genotyping of the most frequent and clinically characterized no-function variants, that is, *2, *3 and *9. The Hispanic/Latino-predominant variant NUDT15 *4 (p.R139H) is classified as "uncertain function" by the Clinical Pharmacogenetics Implementation Consortium, because of insufficient data to ascertain its clinical actionability. In this study, we evaluated the association of NUDT15 *4 with mercaptopurine (6-MP) tolerance in a retrospective cohort of 1,399 patients with acute lymphoblastic leukemia (ALL) of diverse ancestries. All patients were wildtype for thiopurine methyltransferase gene. Patients were treated with 6-MP in the context of ALL frontline clinical trials. The tolerated dose of 6-MP was used to assess drug toxicity during the maintenance phase of ALL therapy. Patients with NUDT15 *1/*4 (n = 16, all of whom self-identified as Hispanic/Latino) tolerated a significantly lower dose of 6-MP than did those with NUDT15 *1/*1: median [interquartile range] of 39.0 [21.2-52.8] mg/m2, vs. 62.2 [47.9-71.6] mg/m2, P value < 0.001. No patient homozygous for *4 was detected. In a separate retrospective validation study, six patients were identified as having NUDT15 *1/*4 by routine clinical pharmacogenetics testing and tolerated a 6-MP median dose of 38.7 mg/m2 (IQR, 33.7-54.0), confirming the need for dose reduction attributed to the NUDT15 *4 variant. These results point to the need to include NUDT15 *4 in pharmacogenetics-guided thiopurine dosing algorithms.

Mesalazine and thiopurines are important therapeutic agents for pediatric patients with ulcerative colitis (UC). Mesalazine, which may be administered in different forms depending on delivery mechanisms, can affect thiopurine metabolism, leading to increased 6-thioguanine nucleotides (6-TGN) levels. Therefore, when using these two drugs simultaneously, their interactions must be considered. This study aimed to analyze 6-TGN according to mesalazine formulation in pediatric patients with UC.

We retrospectively reviewed the data of 236 pediatric patients with UC who visited a single health center between January 2021 and December 2023. Among the enrolled patients, 198 were administered thiopurines, and of these, 136 underwent testing for 6-TGN.

The mean dose of azathioprine (AZA) was 0.66 mg/kg, and the mean 6-TGN level was 211.64 pmol/8 × 10^8 red blood cells (RBCs). The mean 6-TGN level for the group concurrently using time-dependent mesalazine and AZA was 245.00 pmol/8 × 10^8 RBCs, while that for the group concurrently using multimatrix mesalazine (MMX) and AZA was 141.97 pmol/8 × 10^8 RBCs (P < 0.001). In the same patients, the mean 6-TGN level during time-dependent mesalazine treatment was 290.34 pmol/8 × 108 RBCs, whereas the mean 6-TGN level measured after switching to MMX was 148.54 pmol/8 × 108 RBCs (P = 0.016).

The group treated with MMX and AZA had a lower mean 6-TGN level than the group treated with time-dependent mesalazine and AZA. The mean 6-TGN level significantly decreased after switching from time-dependent mesalazine to MMX in the same patients. Therefore, when administering MMX, a higher dose of AZA is necessary to reach the target 6-TGN level, compared to the dose required when using time-dependent mesalazine.

Thiopurine S-methyltransferase (TPMT) and Nudix hydrolase (NUDT15) polymorphisms predispose to thiopurine-related leukopenia.

Retrospective evaluation of inflammatory bowel disease (IBD) patients harboring NUDT15 polymorphisms and exposed to thiopurines. We report the frequency of NUDT15 polymorphism, frequency of leukopenia, the tolerated dose of azathioprine, and the clinical efficacy of thiopurines.

Of 1440 patients, 118 (8.2%) had NUDT15 polymorphism. Among 51 with complete details, 46 were heterozygous (90.2%), and 5 homozygous (9.2%) for NUDT15. Twenty (43.5%) heterozygous and all homozygous patients developed leukopenia. Leukopenia was significantly more in NUDT15 heterozygous group compared to controls (43.45% vs 7.8%, Odds ratio: 9, 95% CI 3.57-22.9). The maximum tolerated dose of azathioprine was lower in NUDT15 heterozygous group (1.1 ± 0.4 mg per kg vs 1.7 ± 0.7 mg per kg, p = 0.002). The mean time to leukopenia was earlier in the heterozygous group vs controls (19 ± 56 weeks vs 70 ± 53 weeks, p-value 0.002). Seven (35%) of 20 heterozygous patients who developed leukopenia, could be maintained at a lower dose of thiopurine. Twenty-five maintained clinical remission while on thiopurines.

Thiopurines should be avoided in NUDT15 homozygous but can be used cautiously at lower dosages with frequent monitoring among heterozygous patients.

Kidney transplantation is currently the treatment of choice for patients with end-stage kidney diseases. Although significant advancements in kidney transplantation have been achieved over the past decades, the host's immune response remains the primary challenge, often leading to potential graft rejection. Effective management of the immune response is essential to ensure the long-term success of kidney transplantation. To address this issue, immunosuppressives have been developed and are now fully integrated into the clinical management of transplant recipients. However, the considerable inter- and intra-patient variability in pharmacokinetics (PK) and pharmacodynamics (PD) of these drugs represents the primary cause of graft rejection. This variability is primarily attributed to the polymorphic nature (genetic heterogeneity) of genes encoding xenobiotic-metabolizing enzymes, transport proteins, and, in some cases, drug targets. These genetic differences can influence drug metabolism and distribution, leading to either toxicity or reduced efficacy. The main objective of the present review is to report an historical overview of the pharmacogenetics of immunosuppressants, shedding light on the most recent findings and also suggesting how relevant is the research and investment in developing validated NGS-based commercial panels for pharmacogenetic profiling in kidney transplant recipients. These advancements will enable the implementation of precision medicine, optimizing immunosuppressive therapies to improve graft survival and kidney transplanted patient outcomes.

To share the experience of a US national reference laboratory, offering genotyping for TPMT and NUDT15, TPMT enzyme phenotyping and detection of thiopurine metabolites.

Retrospective review of archived datasets related to thiopurines drug therapy including patients' data that underwent TPMT and NUDT15 genotyping, and smaller data sets where genotyping was performed with TPMT enzyme levels (phenotyping) +/- therapeutic drug monitoring (TDM).

Thirteen percent of patients had variants in one or both genes tested. Testing for NUDT15 revealed 3.9% additional patients requiring thiopurines dosing recommendations. A correlation between TPMT enzyme activity and TPMT polymorphisms (odds ratio OD = 71.41, p-value <0.001) and between older age and higher enzyme levels (OD = 0.98, p-value = 0.002) was identified. No correlation between sex and TPMT enzyme levels, nor between TPMT genotyping and the level of thiopurine metabolites was found.

Adding NUDT15 to TPMT genotyping, identified additional 3.9% patients to benefit from thiopurine dose modifications. A significant correlation between genetic variants in TPMT and TPMT enzyme levels and between age and enzyme levels was established, while no correlation was identified between sex and enzyme levels nor between TPMT variation and thiopurine metabolites. Providers rely more significantly on genotyping only approach, rather than genotyping and phenotyping.

Thiopurine drugs are effective treatment options in inflammatory bowel disease and other conditions but discontinued in some patients due to toxicity.

We investigated thiopurine-induced toxicity in a pediatric inflammatory bowel disease cohort by utilizing exome sequencing data across a panel of 46 genes, including TPMT and NUDT15.

The cohort included 487 patients with a median age of 13.1 years. Of the 396 patients exposed to thiopurines, myelosuppression was observed in 11%, gastroenterological intolerance in 11%, hepatotoxicity in 4.5%, pancreatitis in 1.8%, and "other" adverse effects in 2.8%. TPMT (thiopurine S-methyltransferase) enzyme activity was normal in 87.4%, intermediate 12.3%, and deficient in 0.2%; 26% of patients with intermediate activity developed toxicity to thiopurines. Routinely genotyped TPMT alleles associated with defective enzyme activity were identified in 28 (7%) patients: TPMT*3A in 4.5%, *3B in 1%, and *3C in 1.5%. Of these, only 6 (21%) patients developed toxic responses. Three rare TPMT alleles (*3D, *39, and *40) not assessed on routine genotyping were identified in 3 patients, who all developed toxic responses. The missense variant p.R139C (NUDT15*3 allele) was identified in 4 patients (azathioprine 1.6 mg/kg/d), but only 1 developed toxicity. One patient with an in-frame deletion variant p.G13del in NUDT15 developed myelosuppression at low doses. Per-gene deleteriousness score GenePy identified a significant association for toxicity in the AOX1 and DHFR genes.

A significant association for toxicity was observed in the AOX1 and DHFR genes in individuals negative for the TPMT and NUDT15 variants. Patients harboring the NUDT15*3 allele, which is associated with myelosuppression, did not show an increased risk of toxicity.

Sunitinib exhibits considerable interindividual variability in exposure. While the target total plasma concentration of sunitinib and its active metabolite is 50-87.5 ng/mL for the intermittent dosing schedule, ~10-21% of patients experience higher exposures (>87.5 ng/mL), correlated with an increased risk for toxicity. Previous research identified single nucleotide variants (SNVs) in genes from the sunitinib pharmacokinetic pathway to be associated with efficacy and toxicity. However, significant interindividual variability in exposure remains unexplained. Our aim was to identify genetic variants associated with supratherapeutic exposure of sunitinib.

This was a genome-wide association study. Cases were identified during routine therapeutic drug monitoring and consisted of patients with dose-normalized sunitinib plasma concentrations >87.5 ng/mL (intermittent dosing) or >75 ng/mL (continuous dosing). Controls were sampled from the historical cohort EuroTARGET who tolerated the standard dose of 50 mg in an intermittent schedule. SNVs were tested for an association with sunitinib exposure. A P-value ≤5 × 10-8 was considered significant and a P-value between 5 × 10-8 and 5 × 10-6 was considered suggestive.

Sixty-nine cases and 345 controls were included for association analysis. One SNV (rs6923761), located on the gene glucagon-like peptide 1 receptor, was significantly associated with increased sunitinib exposure (P = 7.86 × 10-19). Twelve SNVs were suggestive for an association with sunitinib exposure (P ≤ 5 × 10-6).

While rs6923761 is associated with high sunitinib exposure, the underlying mechanism is not yet clarified and warrants further investigation. [Corrections made on 23 September 2024, after first online publication: In the preceding sentence, identifier rs6923671 has been changed to rs6923761 in this version.] We could not confirm the earlier found associations between SNVs in candidate genes involved in the pharmacokinetic pathway of sunitinib and its efficacy and toxicity.

The past 2 decades have witnessed extraordinary advances in our understanding of the genetic factors influencing inflammatory bowel disease (IBD), providing a foundation for the approaching era of genomic medicine. On behalf of the NIDDK IBD Genetics Consortium, we herein survey 11 grand challenges for the field as it embarks on the next 2 decades of research utilizing integrative genomic and systems biology approaches. These involve elucidation of the genetic architecture of IBD (how it compares across populations, the role of rare variants, and prospects of polygenic risk scores), in-depth cellular and molecular characterization (fine-mapping causal variants, cellular contributions to pathology, molecular pathways, interactions with environmental exposures, and advanced organoid models), and applications in personalized medicine (unmet medical needs, working toward molecular nosology, and precision therapeutics). We review recent advances in each of the 11 areas and pose challenges for the genetics and genomics communities of IBD researchers.

Precision cancer medicine is widely established, and numerous molecularly targeted drugs for various tumor entities are approved or are in development. Personalized pharmacotherapy in oncology has so far been based primarily on tumor characteristics, for example, somatic mutations. However, the response to drug treatment also depends on pharmacological processes summarized under the term ADME (absorption, distribution, metabolism, and excretion). Variations in ADME genes have been the subject of intensive research for >5 decades, considering individual patients' genetic makeup, referred to as pharmacogenomics (PGx). The combined impact of a patient's tumor and germline genome is only partially understood and often not adequately considered in cancer therapy. This may be attributed, in part, to the lack of methods for combined analysis of both data layers. Optimized personalized cancer therapies should, therefore, aim to integrate molecular information, which derives from both the tumor and the germline genome, and taking into account existing PGx guidelines for drug therapy. Moreover, such strategies should provide the opportunity to consider genetic variants of previously unknown functional significance. Bioinformatic analysis methods and corresponding algorithms for data interpretation need to be developed to integrate PGx data in cancer therapy with a special meaning for interdisciplinary molecular tumor boards, in which cancer patients are discussed to provide evidence-based recommendations for clinical management based on individual tumor profiles. SIGNIFICANCE STATEMENT: The era of personalized oncology has seen the emergence of drugs tailored to genetic variants associated with cancer biology. However, the full potential of targeted therapy remains untapped owing to the predominant focus on acquired tumor-specific alterations. Optimized cancer care must integrate tumor and patient genomes, guided by pharmacogenomic principles. An essential prerequisite for realizing truly personalized drug treatment of cancer patients is the development of bioinformatic tools for comprehensive analysis of all data layers generated in modern precision oncology programs.

Implementation of pharmacogenetic testing in clinical care has been slow and with few exceptions is hindered by the lack of real-world evidence on how to best target testing. In this retrospective register-based study, we analyzed a nationwide cohort of 1,425,000 patients discharged from internal medicine or surgical wards and a cohort of 2,178 university hospital patients for purchases and prescriptions of pharmacogenetically actionable drugs. Pharmacogenetic variants were obtained from whole genome genotype data for a subset (n = 930) of the university hospital patients. We investigated factors associated with receiving pharmacogenetically actionable drugs and developed a literature-based cost-benefit model for pre-emptive pharmacogenetic panel testing. In a 2-year follow-up, 60.4% of the patients in the nationwide cohort purchased at least one pharmacogenetically actionable drug, most commonly ibuprofen (25.0%) and codeine (19.4%). Of the genotyped subset, 98.8% carried at least one actionable pharmacogenetic genotype and 23.3% had at least one actionable gene-drug pair. Patients suffering from musculoskeletal or cardiovascular diseases were more prone to receive pharmacogenetically actionable drugs during inpatient episode. The cost-benefit model included frequently dispensed drugs in the university hospital cohort, comprising ondansetron (19.4%), simvastatin (7.4%), clopidogrel (5.0%), warfarin (5.1%), (es)citalopram (5.3%), and azathioprine (0.5%). For untargeted pre-emptive pharmacogenetic testing of all university hospital patients, the model indicated saving €17.49 in direct healthcare system costs per patient in 2 years without accounting for the cost of the test itself. Therefore, it might be reasonable to target pre-emptive pharmacogenetic testing to patient groups most likely to receive pharmacogenetically actionable drugs.

Cronkhite-Canada syndrome (CCS) is a rare non-hereditary chronic inflammatory disease characteristic of gastrointestinal polyps and ectodermal abnormalities. Corticosteroid therapy is the mainstay medication for CCS. Few studies indicated immunosuppressants might be the choices for patients with steroid refractory, steroid dependent or intolerant.

To examine the efficacy and safety of azathioprine (AZA) in CCS patients.

We retrospectively reviewed the records of 12 CCS patients treated with azathioprine between July 2014 and October 2023 and the clinical data including demographic characteristics, treatment regimen and adverse events were subsequently collected and analyzed. The genetic variants of TPMT and NUDT15 genes were also retrospectively assessed using sanger sequencing in 11 patients.

All patients were in active stage at baseline and 9 patients (75%) were in combination with corticosteroid. On account of the indication, 6 patients were steroid dependent or intolerant and another 6 patients needed augmentation therapy. The target dose of AZA was 1.0 to 1.5 mg/kg per day. Ten (83.3%) patients achieved clinical response, of whom 3 cases had endoscopic remission and 5 cases had endoscopic improvement respectively. Three (25%) patients suffered from pneumocystis carinii pneumonia, liver dysfunction and leukopenia, respectively, resulting in cessation of AZA in the initial 3 months. Four heterozygous missense variants of TPMT and NUDT15 were identified in four patients. One patient who had TPMT*6 and took AZA with the dose of 2.04 mg/kg per day suffered from severe leukopenia.

Azathioprine might be a good alternative medication in CCS patients who are steroid dependent or intolerant, or need augmentation therapy. The adverse events should be closely monitored especially myelosuppression and the tests of TPMT and NUDT15 genotypes before therapy may be helpful for medication guidance.

Thiopurines remain an important option in the treatment of IBD. However, the unpredictable and sometimes serious side effects and intolerance remain a major challenge. Pretreatment of extended genetic panel analysis, identification of novel variants, and monitoring of intermediate metabolites will help improve the overall outcome and reduce the toxicity.

Patients with inflammatory bowel disease (IBD) exhibit considerable interindividual variability in medication response, highlighting the need for precision medicine approaches to optimize and tailor treatment. Pharmacogenetics (PGx) offers the ability to individualize dosing by examining genetic factors underlying the metabolism of medications such as thiopurines. Pharmacogenetic testing can identify individuals who may be at risk for thiopurine dose-dependent adverse reactions including myelosuppression. We aimed to evaluate PGx variation in genes supported by clinical guidelines that inform dosing of thiopurines and characterize differences in the distribution of actionable PGx variation among diverse ancestral groups.

Pharmacogenetic variation in TPMT and NUDT15 was captured by genome-wide genotyping of 1083 pediatric IBD patients from a diverse Canadian cohort. Genetic ancestry was inferred using principal component analysis. The proportion of PGx variation and associated metabolizer status phenotypes was compared across 5 genetic ancestral groups within the cohort (Admixed American, African, East Asian, European, and South Asian) and to prior global estimates from corresponding populations.

Collectively, 11% of the cohort was categorized as intermediate or poor metabolizers of thiopurines, which would warrant a significant dose reduction or selection of alternate therapy. Clinically actionable variation in TPMT was more prevalent in participants of European and Admixed American/Latino ancestry (8.7% and 7.5%, respectively), whereas variation in NUDT15 was more prevalent in participants of East Asian and Admixed American/Latino ancestry (16% and 15% respectively).

These findings demonstrate the considerable interpopulation variability in PGx variation underlying thiopurine metabolism, which should be factored into testing diverse patient populations.

Thiopurine drugs are cornerstone treatment for patients with inflammatory bowel disease (IBD). The most common adverse drug reaction is thiopurine-induced myelosuppression (TIM), that may partly be explained by the genetic polymorphism NUDT15*3. The aim of this retrospective study was to determine the NUDT15*3 polymorphism frequency and its association with TIM in an IBD patient population in the Netherlands. DNA from patients previously genotyped for TPMT was genotyped for NUDT15*3. In IBD patients treated with thiopurines association tests with TIM were conducted. Out of 988 included patients, 13 (1.3%) were heterozygous for NUDT15*3. Of all patients, 606 had IBD and received thiopurine treatment. In these patients, 8/606 (1.3%) were heterozygous polymorphic for NUDT15*3 of which 50.0% developed TIM compared to 2.3% in the wild type patients (p < 0.001). The study results show a clinically relevant prevalence of NUDT15*3 in the Dutch patient population. Its strong association with TIM suggests pre-therapeutic genotyping potentially clinically utile.

Clinical trials conducted by the Intergroup Rhabdomyosarcoma (RMS) Study Group and the Children's Oncology Group have been pivotal to establishing current standards for diagnosis and therapy for RMS. Recent advancements in understanding the biology and clinical behavior of RMS have led to more nuanced approaches to diagnosis, risk stratification, and treatment. The complexities introduced by these advancements, coupled with the rarity of RMS, pose challenges to conducting large-scale phase 3 clinical trials to evaluate new treatment strategies for RMS. Given these challenges, systematic planning of future clinical trials in RMS is paramount to address pertinent questions regarding the therapeutic efficacy of drugs, biomarkers of response, treatment-related toxicity, and patient quality of life. Herein, the authors outline the proposed strategic approach of the Children's Oncology Group Soft Tissue Sarcoma Committee to the next generation of RMS clinical trials, focusing on five themes: improved novel agent identification and preclinical to clinical translation, more efficient trial development and implementation, expanded opportunities for knowledge generation during trials, therapeutic toxicity reduction and quality of life, and patient engagement.

Determining variant TPMT alleles to predict patient response to thiopurine therapy represents one of the first successful implementations of pharmacogenomics in clinical practice. However, despite the TPMT-adjusted thiopurine dosing, some TPMT wild-type patients still exhibit toxicity at standard doses. Over the past decade, the pharmacogene NUDT15 has emerged as a significant co-modulator of thiopurine therapy. Initially, NUDT15 was considered important predominantly in Asian populations, but recent studies have highlighted its relevance in European populations as well.To evaluate the pharmacogenetic significance of NUDT15 in the Slovenian population, we sequenced extended regions of exon 1 and exon 3 in 109 healthy individuals and 37 patients with acute lymphoblastic leukemia.We identified eight variants, including one with established clinical significance (allele *3) and one extremely rare variant (Chr13 at 48045861; GRCh38, NC_000013.11). The frequencies of most previously described variants in both the general population and in the ALL cohort were consistent with those reported in other European populations, except for rs45465203, which was less frequent in the Slovenian population. None of the variants, except for NUDT15*3, were associated with cumulative thiopurine doses in ALL patients. However, these variants warrant further investigation in larger ALL cohorts.

The therapeutic landscape for ulcerative colitis (UC) has recently broadened to include anti-TNFα, anti-integrin, and anti-IL-12/23p40 antibody agents. These biological agents are tailored to individual patient profiles. However, some patients cease biological treatment. This study investigates factors influencing the discontinuation of biological treatment in UC patients.

This retrospective single-cohort study encompasses UC patients who commenced treatment with biological agents like infliximab, adalimumab, golimumab, vedolizumab, and ustekinumab from April 2019 to March 2022. Patients were categorized into continuation and discontinuation groups based on their one-year treatment status. Baseline characteristics were compared between the groups.

Of the 116 UC patients, 102 were included in the study. Among these, 74 (72.5%) continued and 28 (27.5%) discontinued biological therapy. Discontinuation rates for infliximab, adalimumab, golimumab, vedolizumab, and ustekinumab were 33.3%, 25.0%, 50.0%, 30.2%, and 15.6%, respectively. The primary discontinuation reason was lack of efficacy (85.7%), followed by adverse events (7.1%), pregnancy (3.6%), and death (3.6%). The discontinuation group had a significantly lower rate of concomitant thiopurine compared to the continuation group (28.6% vs. 56.8%, p = 0.0132). Multivariable analysis revealed that concomitant thiopurine was independently associated with therapy continuation (p = 0.0075).

The study indicates that concomitant thiopurine significantly correlates with the continuation of biological therapies in UC patients, underscoring the importance of concomitant thiopurine in sustaining biological therapy. Further studies are warranted to assess the efficacy of combination therapy.

With the continuous development of genetics in healthcare, there has been a significant contribution to the development of precision medicine, which is ultimately aimed at improving the care of patients. Generally, drug treatments used in Oncology are characterized by a narrow therapeutic range and by their potential toxicity. Knowledge of pharmacogenomics and pharmacogenetics can be very useful in the area of Oncology, as they constitute additional tools that can help to individualize patients' treatment. This work includes a description of some genes that have been revealed to be useful in the field of Oncology, as they play a role in drug prescription and in the prediction of treatment response.

Immunomodulators are important for management of autoimmune diseases and hematological malignancies. Significant inter-individual variation in drug response/reactions exists due to genetic polymorphisms. We describe frequency of identified genetic polymorphisms among Sri Lankans.

Sri Lankan data were obtained from an anonymized database of 670 participants. Data on variants and global distribution of Minor Allele frequency (MAF) of other populations (South Asian, Ashkenazi-Jewish, East-Asian, European-Finnish, European-non-Finnish, Latino-American, African/African-American) were obtained from pharmGKB online database.

SLC19A1 (rs1051266) variant had a MAF (95% CI) of 63.3% (60.7-65.9). Other common variants included FCGR3A (rs396991), MTHFR (rs1801133), ITPA (rs1127354), CYP2C9*3 (rs1057910) and NUD15*3 (rs116855232), with MAFs of 35.3% (32.7-37.9), 12.2% (10.4-13.9), 10.9% (9.2-12.6), 9.8% (8.2-11.4), 8.3% (6.8-9.8) respectively. Less commonly present variants included CYP2C9*2 (rs1799853) (2.5%[1.7-3.4]), TPMT*3C (rs1142345) (1.9%[1.1-2.6]), TPMT*3B (rs1800460) (0.2%[0-0.5]), CYP3A5*6 (rs10264272) (0.2%[0-0.4]) and CYP3A4*18 (rs28371759) (0.1%[0-0.2]). The SLC19A1 (rs1051266), NUD15*3 (rs116855232), CYP2C9*3 (rs1057910), FCGR3A (rs396991), and ITPA (rs1127354) showed significantly higher frequencies in Sri Lankans compared to many other populations, exceptions include FCGR3A in Ashkenazi-Jewish and ITPA in East-Asians. Conversely, MTHFR (rs1801133), TPMT*3B (rs1800460), and CYP2C9*2 (rs1799853) were significantly less prevalent among Sri Lankans than in  many other populations. Sri Lankans exhibited lower prevalence of TPMT*3C (rs1142345) compared to European-non-Finnish, Latino-Americans, and African/African-Americans; CYP3A4*18 (rs28371759) compared to East-Asians; and CYP3A5*6 (rs10264272) compared to African/African-Americans and Latino-Americans.

Sri Lankans exhibit higher frequencies in variants reducing methotrexate efficacy (SLC19A1), increasing azathioprine myelotoxicity (NUDT15), and lower frequencies in variants linked to increased azathioprine toxicity (TPMT*3B, TPMT*3C), reduced tacrolimus efficacy (CYP3A4*18), and methotrexate toxicity risk (MTHFR). Beneficial variants enhancing rituximab efficacy (FCGR3A) are more prevalent, while those reducing tacrolimus dosage (CYP3A5*6) are less common. This highlights need for targeted medication strategies to improve treatment outcomes.

The analysis of haplotypes of variants is important for pharmacogenomics analysis and noninvasive prenatal testing for monogenic diseases. However, there is a lack of robust methods for targeted haplotyping.

We developed digital PCR haplotype sequencing (dHapSeq) for targeted haplotyping of variants, which is a method that compartmentalizes long DNA molecules into droplets. Within one droplet, 2 target regions are PCR amplified from one template molecule, and their amplicons are fused together. The fused products are then sequenced to determine the phase relationship of the single nucleotide polymorphism (SNP) alleles. The entire haplotype of 10s of SNPs can be deduced after the phase relationship of individual SNPs are determined in a pairwise manner. We applied dHapSeq to noninvasive prenatal testing in 4 families at risk for thalassemia and utilized it to detect NUDT15 diplotypes for predicting drug tolerance in pediatric acute lymphoblastic leukemia (72 cases and 506 controls).

For SNPs within 40 kb, phase relation can be determined with 100% accuracy. In 7 trio families, the haplotyping results for 97 SNPs spanning 185 kb determined by dHapSeq were concordant with the results deduced from the genotypes of both parents and the fetus. In 4 thalassemia families, a 19.3-kb Southeast Asian deletion was successfully phased with 97 downstream SNPs, enabling noninvasive determination of fetal inheritance using relative haplotype dosage analysis. In the NUDT15 analysis, the variant status and phase of the variants were successfully determined in all cases and controls.

The dHapSeq represents a robust and scalable haplotyping approach with numerous clinical and research applications.

Aims: This study aimed to investigate the impact of genetic polymorphisms of thiopurine methyltransferase (TPMT) and NUDT15 on pharmacokinetics profile of mercaptopurine in healthy adults in China. Methods: Blood samples were obtained from 45 healthy adult volunteers who were administered azathioprine. Genomic DNA was extracted and sequenced for TPMT and NUDT15. The plasma concentrations of 6-mercaptopurine (6-MP) were determined by ultra-performance liquid chromatography-tandem mass spectrometry. Finally, pharmacokinetic parameters were calculated based on the time-concentration curve. Results: Among the 45 healthy adult volunteers enrolled in the study, two TPMT allelic variants and three NUDT15 allelic variants were detected. In total, six genotypes were identified, including TPMT*1/*1&NUDT15*1/*1, TPMT*1/*1&NUDT15*1/*2, TPMT*1/*1&NUDT15*1/*9, TPMT*1/*1&NUDT15*2/*5, TPMT*1/*6&NUDT15*1/*2, and TPMT*1/*3&NUDT15*1/*2. The results indicated that Area Under Curve (AUC) of 6-MP in volunteers with TPMT*1/*3&NUDT15*1/*2 and TPMT*1/*6&NUDT15*1/*2 were 1.57-1.62-fold higher than in individuals carrying the wild type (TPMT*1/*1&NUDT15*1/*1). Compared with wild type, the half-life (T1/2) of TPMT*1/*6&NUDT15*1/*2 was extended by 1.98 times, whereas T1/2 of TPMT*1/*3&NUDT15*1/*2 decreased by 67%. The maximum concentration (Cmax) of TPMT*1/*3&NUDT15*1/*2 increased significantly by 2.15-fold, whereas the corresponding clearance (CL/F) decreased significantly by 58.75%. Conclusion: The findings of this study corroborate the notion that various genotypes of TPMT and NUDT15 can impact the pharmacokinetics of mercaptopurine, potentially offering foundational insights for personalized mercaptopurine therapy.

Inflammatory bowel diseases (IBD), with ulcerative colitis and Crohn's disease being their most common presentations, comprise a spectrum of diverse disease phenotypes, exhibiting variable behaviors ranging from an indolent course to aggressive phenotypes that impact quality of life of these patients. The last two decades have been marked by the development of new medications (biological therapy and novel small molecules) with diverse mechanisms of action, which have revolutionized the management of IBD, thereby enhancing the quality of life for these patients. This landscape of multiple therapeutic options underscores the need to define which medication will benefit each patient the most and at what speed it should be started. The objective of this review is to present personalized approaches for patients with IBD, thus contributing to therapeutic management.

Hematotoxicity is a life-threatening condition that has become the major cause of drug discontinuation in patients with acute lymphoblastic leukemia (ALL). The nudix hydrolase 15 (NUDT15) gene polymorphism (c.415C>T) is reported to have an association with the hematotoxicity of 6-mercaptopurine (6-MP) as maintenance therapy in patients with ALL. However, the prevalence of this genetic polymorphism in the Indonesian population is unknown. This study aimed to assess the frequency of NUDT15 polymorphism among Indonesian pediatric patients with ALL and its association with the hematotoxicity of 6-MP.

A total of 101 stored DNA samples from pediatric patients with ALL receiving 6-MP treatment were used for genetic testing. Direct sequencing was conducted to determine the NUDT15 c.415C>T genotype. Chi-square or Fisher's exact test were employed to examine the association between the NUDT15 c.415C>T genotype and hematotoxicity.

All (100%) of the DNA samples from patients with ALL treated with 6-MP exhibited a homozygous variant of the NUDT15 c.415C>T genotype, 70.3% of which showed hematotoxicity to some extent. We found no significant differences in NUDT15 gene polymorphism among patients with ALL with different states of hematotoxicity.

The observed high frequency of NUDT15 c.415C>T in our study population might explain the elevated prevalence of 6-MP-associated hematotoxicity in pediatric patients with ALL within the Indonesian population. Our study provides new insight regarding the NUDT15 gene polymorphism and its relation to hematotoxicity. Further studies are required to determine the necessity of adjusting the initial dose of 6-MP for Indonesian pediatric patients with ALL.

Acute lymphoblastic leukemia (ALL) is the most frequent pediatric cancer. 6-Mercaptopurine (6-MP) is a key component of ALL treatment. Its use, however, is also associated with adverse drug reactions, particularly myelosuppression. Thiopurine S-methyltransferase (TPMT) and, more recently, Nudix hydrolase 15 (NUDT15) deficiency, due to no-function variants in their respective genes, are well known for their role in the development of this toxicity. Two novel genetic variants, rs12199316 in TPMT and rs73189762 in the NUDT15 gene, were recently identified by targeted sequencing. The latter is particularly interesting because of its potential association with 6-MP intolerance. Here, we assessed the relationship of this variant with the risk of myelosuppression and 6-MP dose intensity in 275 patients treated with Dana Farber Cancer Institute ALL protocols at the Sainte Justine University Health Center. Carriers of the NUDT15 rs73189762 variant allele were at a higher risk of myelosuppression, as shown by absolute phagocyte count reduction during consolidation II and maintenance phases of therapy. Reduction in 6-MP dose intensity was observed in patients with both rs73189762 and known no-function variants in the NUDT15 and TPMT genes. This finding supports the initial observation and suggests that 6-MP dose reduction might be beneficial for individuals with this genotype combination.

Neuromyelitis optica spectrum disorder (NMOSD) is a rare autoimmune inflammatory disease that can affect multiple generations and cause complications with long-term prednisolone treatment. This study aimed to evaluate the efficacy and safety of mycophenolate mofetil (MMF) in preventing NMOSD relapse while reducing prednisolone dosage. The trial involved nine patients with NMOSD who received MMF along with prednisolone dose reduction. MMF was effective in achieving prednisolone dose reduction without relapse in 77.8% of patients, with a significant decrease in mean annualized relapse rate. All adverse events were mild. The findings suggest that MMF could be a viable treatment option for middle-aged and older patients who require steroid reduction.Clinical trial registration number: jRCT, jRCTs051180080. Registered February 27th, 2019-retrospectively registered, https://jrct.niph.go.jp/en-latest-detail/jRCTs051180080.

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.

Inflammatory bowel disease (IBD) is a chronic and relapsing immune-mediated disease of the gastrointestinal tract with a gradually increasing global incidence and prevalence. A prolonged course of IBD leads to a decline in patient quality of life and the creation of a substantial economic burden on society. Owing to the lack of specific diagnostic markers, the diagnosis of IBD still needs a gold standard based on a combination of clinical manifestations, imaging, laboratory, and endoscopic results. Accordingly, the current goals of IBD treatment are to alleviate clinical symptoms and reduce recurrence rates. Therefore, it is imperative to develop a standard set of procedures to diagnose and treat IBD. In this review, we summarize prominent and emerging studies, outline classical and contemporary approaches to diagnosing and managing IBD, and integrate multiple guidelines. Furthermore, we propose the possibility of establishing an early and comprehensive diagnostic workflow and personalized management strategy in the future. We aim to enhance the quality and standardization of diagnostic and treatment procedures for IBD.