Azathioprine-induced severe myelosuppression accompanied by massive hair loss and painful oral ulcer in an autoimmune hepatitis patient with NUDT15 minor variant: A case report.
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ABSTRACT:
SUBMITTER: Takeuchi Y
PROVIDER: S-EPMC8385330 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:This study aimed to investigate the influence of TPMT*3C, ITPA, NUDT15, and 6-thioguanine nucleotides (6-TGN) on azathioprine (AZA)-induced myelosuppression in Southwest China patients with autoimmune hepatitis (AIH). A total of 113 Chinese patients with AIH receiving AZA maintenance treatment were evaluated. The relevant clinical data of the patients were collected from the hospital information system. Genotyping of TPMT*3C(rs1142345), ITPA (rs1127354) and NUDT15(rs116855232) was conducted using a TaqMan double fluorescent probe. The concentration of 6-TGN was determined using UPLC-MS/MS. Among AIH patients treated with AZA, 40 (35.4%) exhibited different degrees of myelosuppression. The NUDT15 variant was associated with leukopenia (P = 8.26 × 10-7; OR = 7.5; 95% CI 3.08-18.3) and neutropenia (P = 3.54 × 10-6; OR = 8.05; 95% CI 2.96-21.9); however, no significant association with myelosuppression was observed for TPMT*3C and ITPA variants (P > 0.05). There was no significant difference in 6-TGN concentration between AIH patients with or without myelosuppression (P = 0.556), nor was there a significant difference between patients with variant alleles of TPMT*3C, ITPA, or NUDT15 and wild-type patients (P > 0.05). Interestingly, it was found that patients with a lower BMI had higher adjusted 6-TGN levels and a higher incidence of myelosuppression (P = 0.026 and 0.003). This study confirmed that NUDT15 variants are a potential independent risk predictor for AZA-induced leukopenia and neutropenia. BMI may be a crucial non-genetic factor that affects the concentration of AZA metabolites and myelosuppression. In addition, the 6-TGN concentration in red blood cells does not reflect the toxicity of AZA treatment, and new biomarkers for AZA therapeutic drug monitoring need further research.
| S-EPMC8042108 | biostudies-literature
Project description:The aim of this study was to investigate the influence of NUDT15 R139C, thiopurine S-methyltransferase (TPMT), and 6-TGN on azathioprine (AZA) induced leukopenia in Chinese autoimmune patients. Among 87 enrolled patients, 23 (26.4%) had leukopenia. The NUDT15 R139C variant was associated with leukopenia (p = 1.86 × 10-7; OR: 7.59; 95% CI: 3.16-18.21). However, TPMT genotype was not shown to be correlated with the incidence of leukopenia (p = 0.95). There was no significant difference of 6-TGN concentration between patients with or without leukopenia (p = 0.15) and no association was found in patients with NUDT15 R139C variants alleles (p = 0.62). Finally, we found that the range of 6-TGN concentrations in autoimmune diseases was much lower than the established 6-TGN monitoring range for inflammatory bowel diseases. Therefore, the variant of NUDT15 R139C is strongly associated with AZA-induced leukopenia in Chinese patients with various autoimmune diseases such as systemic lupus erythematosus, Sjögren's syndrome, etc.
| S-EPMC5949564 | biostudies-literature
Project description:Azathioprine (AZA) is commonly used for many autoimmune disorders; however, the limitation of its clinical use is due to potential toxicities, including severe leukopenia. Recent studies have identified genetic NUDT15 variants strongly associated with AZA-induced leukopenia in Asian patients. This study aimed to investigate the strength of above genetic association and evaluate the usefulness of prospective screening of the NUDT15 variants to prevent AZA-induced leukopenia in Chinese patients. AZA-induced leukopenia in patients with autoimmune disorders were enrolled from multiple medical centers in Taiwan/China between 2012 and 2017 to determine the strength of genetic association of NUDT15 or TPMT variants by whole exome sequencing (WES). Furthermore, a prospective study was conducted between 2018 and 2021 to investigate the incidence of AZA-induced leukopenia with and without genetic screening. The WES result showed the genetic variants of NUDT15 R139C (rs116855232) (P = 3.7 × 10-25 , odds ratio (OR) = 21.7, 95% confidence interval (95% CI) = 12.1-38.8) and NUDT15 rs746071566 (P = 4.2 × 10-9 , OR = 7.1, 95% CI = 3.7-13.7), but not TPMT, were associated with AZA-induced leukopenia and NUDT15 R139C variant shows the highest sensitivity with 92.5%. Furthermore, the targeted screening of 1,013 participants for NUDT15 R139C enabled those identified as carriers to use alternative immunosuppressants. This strategy resulted in a significant decrease in the incidence of AZA-induced leukopenia compared with historical incidence (incidence rate = from 7.6% decreased to 0.4%; P = 9.3 × 10-20 ). In conclusion, the NUDT15 R139C variant was strongly associated with AZA-induced leukopenia in Chinese patients. The genetic screening of NUDT15 R139C followed by use of alternative immunosuppressants in identified carriers effectively decreased the incidence of AZA leukopenia for patients with autoimmune disorders.
| S-EPMC9804440 | biostudies-literature
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| S-EPMC5691095 | biostudies-literature
Project description: Not available
| S-EPMC2791984 | biostudies-literature
Project description:Backgound: The high incidence of thiopurine-induced myelosuppression in Asians is known to be attributable to genetic variation in thiopurine metabolism. A quantitative synthesis to summarize the genetic association with thiopurine-induced myelosuppression in Asians was therefore conducted. Methods: A Literature search was performed from January 2016 to May 2021 in the following databases: PubMed, Web of Science, and Embase and addition search included the studies from Zhang et al. Two reviewers independently extracted the following data: the author's name, year of publication, ethnicity, drugs, diseases, genetic polymorphisms, onset, type of myelosuppression and results of Hardy-Weinberg equilibrium. The Newcastle-Ottawa Scale was used to assess the quality of the studies. The pooled odds ratios (OR) and 95% confidence intervals (CI) were calculated to evaluate the associations of NUDT15 and the risk of thiopurine-induced myelosuppression stratified by onset and type of myelosuppressive. Subgroup analysis by NUDT15 genetic polymorphisms was performed. Results: A total of 30 studies was included in this meta-analysis. The overall OR for the relationship between NUDT15 genetic polymorphisms and thiopurine-induced early onset of leukopenia and neutropenia in Asian populations were 11.43 (95% CI 7.11-18.35) and 16.35 (95% CI 10.20-26.22). Among NUDT15 polymorphisms, NUDT15*3 showed a significantly increased risk of early leukopenia (OR 15.31; 95% CI 9.65-24.27) and early neutropenia (OR 15.85; 95% CI 8.80-28.53). A significantly higher thiopurine-induced early neutropenic risk was also found for NUDT15*2 (OR 37.51; 95% CI 1.99-708.69). Whereas, NUDT15*5 and NUDT15*6 variants showed a lower risk of leukopenia. Conclusion: This study suggests that NUDT15*3 and NUDT15*2 are important genetic markers of thiopurine-induced early onset of myelotoxicity in Asians, therefore, early detection of these variants before initiating thiopurine therapy is necessary.
| S-EPMC8675242 | biostudies-literature
Project description:ImportanceUse of thiopurines may be limited by myelosuppression. TPMT pharmacogenetic testing identifies only 25% of at-risk patients of European ancestry. Among patients of East Asian ancestry, NUDT15 variants are associated with thiopurine-induced myelosuppression (TIM).ObjectiveTo identify genetic variants associated with TIM among patients of European ancestry with inflammatory bowel disease (IBD).Design, setting, and participantsCase-control study of 491 patients affected by TIM and 679 thiopurine-tolerant unaffected patients who were recruited from 89 international sites between March 2012 and November 2015. Genome-wide association studies (GWAS) and exome-wide association studies (EWAS) were conducted in patients of European ancestry. The replication cohort comprised 73 patients affected by TIM and 840 thiopurine-tolerant unaffected patients.ExposuresGenetic variants associated with TIM.Main outcomes and measuresThiopurine-induced myelosuppression, defined as a decline in absolute white blood cell count to 2.5 × 109/L or less or a decline in absolute neutrophil cell count to 1.0 × 109/L or less leading to a dose reduction or drug withdrawal.ResultsAmong 1077 patients (398 affected and 679 unaffected; median age at IBD diagnosis, 31.0 years [interquartile range, 21.2 to 44.1 years]; 540 [50%] women; 602 [56%] diagnosed as having Crohn disease), 919 (311 affected and 608 unaffected) were included in the GWAS analysis and 961 (328 affected and 633 unaffected) in the EWAS analysis. The GWAS analysis confirmed association of TPMT (chromosome 6, rs11969064) with TIM (30.5% [95/311] affected vs 16.4% [100/608] unaffected patients; odds ratio [OR], 2.3 [95% CI, 1.7 to 3.1], P = 5.2 × 10-9). The EWAS analysis demonstrated an association with an in-frame deletion in NUDT15 (chromosome 13, rs746071566) and TIM (5.8% [19/328] affected vs 0.2% [1/633] unaffected patients; OR, 38.2 [95% CI, 5.1 to 286.1], P = 1.3 × 10-8), which was replicated in a different cohort (2.7% [2/73] affected vs 0.2% [2/840] unaffected patients; OR, 11.8 [95% CI, 1.6 to 85.0], P = .03). Carriage of any of 3 coding NUDT15 variants was associated with an increased risk (OR, 27.3 [95% CI, 9.3 to 116.7], P = 1.1 × 10-7) of TIM, independent of TPMT genotype and thiopurine dose.Conclusions and relevanceAmong patients of European ancestry with IBD, variants in NUDT15 were associated with increased risk of TIM. These findings suggest that NUDT15 genotyping may be considered prior to initiation of thiopurine therapy; however, further study including additional validation in independent cohorts is required.
| S-EPMC6439872 | biostudies-literature
Project description:BackgroundNUDT15 R139C is an Asian-prevalent genetic variant related to azathioprine (AZA) intolerance in patients with inflammatory bowel disease (IBD). However, it remains unclear how to utilize the genotyping results to improve the step-up dosing strategy with an already low starting dose in Asian practice.MethodsClinical data of eligible IBD patients who received AZA therapy and NUDT15 R139C testing were retrospectively collected. The relationship between NUDT15 genotype, AZA doses, and AZA-induced toxicity and efficacy were comprehensively analysed.ResultsA total of 159 patients were included for toxicity analysis. Compared with the wild genotype, patients heterozygous for R139C are more prone to developing myelotoxicity and alopecia (P = 0.007; P = 0.042). In particular, they had a 5.4-fold risk of developing myelotoxicity when AZA dosage was increased from 25 mg/d to 50 mg/d (P < 0.001). Regarding efficacy, 115 patients who had received AZA for >4 months and maintained clinical remission on AZA monotherapy were included for further analysis. R139C heterozygotes were finally titrated to a significantly lower dose than the wild genotype [median (interquartile range): 0.83 (0.75-0.96) vs 1.04 (0.89-1.33) mg/kg/d, P = 0.001], whereas the clinical remission rates did not differ between groups (P = 0.88).ConclusionsIBD patients with R139C heterozygote are highly susceptible to AZA-induced myelotoxicity at an escalated dose of 50 mg/d. Thus, they may require a smaller dose increase after a starting dose of 25 mg/d. The final target dose of these patients could be set lower than that of the wild genotypes without compromising efficacy.
| S-EPMC7793196 | biostudies-literature
Project description:IntroductionAzathioprine (AZA) has been widely used for the treatment of various immune-related diseases and has become a mainstay in the treatment of inflammatory bowel disease. However, patients with genetic mutations may experience severe adverse events when treated with azathioprine. Most of the previous literature focused on the TPMP gene-related adverse reactions, herein, we report a case of Crohn's disease patient with nucleoside diphosphate-linked moiety X motif 15 gene (NUDT15) variation and wild-type TPMP gene who developed toxoplasma gondii infection after azathioprine treatment.Patient concernsA 56-year-old Crohn's disease patient developed toxoplasma gondii infection within 2 months after the administration of azathioprine; however, he had no relevant high-risk factors.DiagnosisSubsequent genetic testing revealed that the patient was heterozygous for NUDT15. Therefore, it was reasonable to consider that the patient's genetic mutation resulted in reduced tolerance to azathioprine, leading to low immunity and eventually toxoplasma infection.InterventionsAZA was then discontinued; after anti-infection, antipyretic and other supportive treatments were administered, the patient's condition gradually improved.OutcomesThe patient was followed up at 1, 3, and 6 months after discharge; fortunately, he was in good health.ConclusionWe report a case of Crohn's disease in a patient who developed severe pneumonia caused by toxoplasma gondii infection due to the administration of AZA, with normal TPMP gene but NUDT15 gene mutation. This indicates that NUDT15 variation may contribute to severe adverse events in patients treated with azathioprine, and we suggest that NUDT15 genotype be detected before the use of azathioprine in order to provide personalized therapy and reduce side effects.
| S-EPMC8104275 | biostudies-literature
Project description:The aim of this study was to investigate the correlation between genetic polymorphisms of azathioprine-metabolizing enzymes and adverse reactions of myelosuppression. To this end, a retrospective analysis was performed on 1,419 Chinese patients involving 40 different diseases and 3 genes: ITPA (94C>A), TPMT*3 (T>C), and NUDT15 (415C>T). Strict inclusion and exclusion criteria were established to collect the relative cases, and the correlation between azathioprine and myelosuppression was evaluated by adverse drug reaction criteria. The mutation rates of the three genes were 29.32, 3.73, and 21.92% and grades I to IV myelosuppression occurred in 54 (9.28%) of the 582 patients who took azathioprine. The highest proportion of myelosuppression was observed in 5 of the 6 (83.33%) patients carrying the NUDT15 (415C>T) TT genotype and 12 of the 102 (11.76%) patients carrying the NUDT15 (415C>T) CT genotype. Only the NUDT15 (415C>T) polymorphism was found to be associated with the adverse effects of azathioprine-induced myelosuppression (odds ratio [OR], 51.818; 95% CI, 5.280-508.556; p = 0.001), which suggested that the NUDT15 (415C>T) polymorphism could be an influencing factor of azathioprine-induced myelosuppression in the Chinese population. Epistatic interactions between ITPA (94C>A) and NUDT15 (415C>T) affect the occurrence of myelosuppression. Thus, it is recommended that the genotype of NUDT15 (415C>T) and ITPA (94C>A) be checked before administration, and azathioprine should be avoided in patients carrying a homozygous NUDT15 (415C>T) mutation. This study is the first to investigate the association between genetic polymorphisms of these three azathioprine-metabolizing enzymes and myelosuppression in a large number of cases with a diverse range of diseases.
| S-EPMC8167793 | biostudies-literature