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Effect of NUDT15 polymorphisms on early hematological safety of low-dose azathioprine in Chinese patients with pemphigus vulgaris: A prospective cohort study.

ABSTRACT: Azathioprine (AZA) is the preferred immunosuppressant for treating pemphigus vulgaris (PV), with discontinuation mainly attributed to hematological adverse events (AE). Reportedly, nucleoside diphosphate-linked moiety X-type motif 15 (NUDT15) polymorphisms have been strongly associated with thiopurine-induced leukopenia. To investigate hematological AE of low-dose AZA based on NUDT15 genotypes among patients with PV, a prospective cohort study was conducted in patients with PV, followed-up for the first 8 weeks after AZA administration. All patients were divided into wild homozygous and heterozygous NUDT15 groups. Both groups initiated AZA at low dose (50 mg/day) and continued with different dose-escalating approaches. Bone marrow suppression was considered the principal outcome. Overall, 62 patients with PV were enrolled (48 in the wild homozygous NUDT15 group vs. 14 in the heterozygous NUDT15 group). Except for median maintenance doses of AZA, no statistically significant differences were observed between the two groups in terms of age, sex, white blood cells, neutrophil count, platelet count, hemoglobin level, median final doses of corticosteroids (mg prednisone equivalent), pemphigus disease area index, and anti-desmoglein 1/3 autoantibodies. In both groups, patients presented similar hematological AE and treatment responses after administration of different low-dose AZA treatment strategies. Low-dose AZA based on NUDT15 genotypes can reduce the risk of early hematological AE among patients with PV.

SUBMITTER: Zhou X

PROVIDER: S-EPMC9299774 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:To observe gene polymorphisms of TPMT and NUDT15, and compare their predictive value for azathioprine (AZA)-induced leukopenia in inflammatory bowel disease (IBD).This study enrolled 219 patients diagnosed with IBD in Xiangya Hospital, Central South University, Changsha, China from February 2016 to November 2017. Peripheral blood of all patients was collected to detect their genotypes of TPMT and NUDT15 by pyrosequencing at the Department of Clinical Pharmacology, Hunan Key Laboratory of Pharmacogenetics, Xiangya Hospital. Eighty patients were treated with AZA according to the disease condition. During the first month, patients who received AZA underwent routine blood tests and liver function tests once a week. The endpoint of the study was leukopenia induced by AZA. By analyzing patient characteristics, genotypes and leukopenia induced by drug use, we found the risk factors associated with AZA-induced leukopenia.There were 219 patients with IBD (160 men and 59 women), including 39 who were confirmed with ulcerative colitis (UC), 176 with Crohn's disease (CD) and 4 with undetermined IBD (UIBD). There were 44 patients (20.1%) with mutant genotype of NUDT15 (C/T); among them, 16 received AZA, and 8 (50%) developed leukopenia. There were 175 patients (79.7%) with wild genotype of NUDT15 (C/C); among them, 64 received AZA, and 11 (17.2%) developed leukopenia. A significant difference was found between NUDT15 C/T and its wild-type C/C (P = 0.004). There were only 3 patients with TPMT mutant genotype of A/G (1.4%) who participated in the research, and 1 of them was treated with AZA and developed leukopenia. The remaining 216 patients (98.6%) were found to bear the wild genotype of TPMT (A/A); among them, 79 patients received AZA, and 18 (22.8%) developed leukopenia, and there was no significant difference from those with A/G (P = 0.071). The frequency of TPMT mutation was 1.4%, and NUDT15 mutation rate was significantly higher and reached 20.1% (P = 0.000). Therefore, NUDT15 gene polymorphism was obviously a better biomarker than TPMT gene polymorphism in the prediction of AZA-induced leukopenia.Mutation rate of NUDT15 in Chinese IBD patients is higher than that of TPMT. NUDT15 polymorphism is a better predictor for AZA-induced leukopenia than TPMT polymorphism.

Project description:BACKGROUND: A number of autoimmune diseases have been clinically and pathologically characterized. In contrast, target antigens have been identified only in a few cases and, in these few cases, the knowledge of the exact epitopic antigenic sequence is still lacking. Thus the major objective of current work in the autoimmunity field is the identification of the epitopic sequences that are related to autoimmune reactions. Our labs propose that autoantigen peptide epitopes able to evoke humoral (auto)immune response are defined by the sequence similarity to the host proteome. The underlying scientific rationale is that antigen peptides acquire immunoreactivity in the context of their proteomic similarity level. Sequences uniquely owned by a protein will have high potential to evoke an immune reaction, whereas motifs with high proteomic redundancy should be immunogenically silenced by the tolerance phenomenon. The relationship between sequence redundancy and peptide immunoreactivity has been successfully validated in a number of experimental models. Here the hypothesis has been applied to pemphigus diseases and the corresponding desmoglein autoantigens. METHODS: Desmoglein 3 sequence similarity analysis to the human proteome followed by dot-blot/NMR immunoassays were carried out to identify and validate possible epitopic sequences. RESULTS: Computational analysis led to identifying a linear immunodominant desmoglein-3 epitope highly reactive with the sera from Pemphigus vulgaris as well as Pemphigus foliaceous. The epitopic peptide corresponded to the amino acid REWVKFAKPCRE sequence, was located in the extreme N-terminal region (residues 49 to 60), and had low redundancy to the human proteome. Sequence alignment showed that human desmoglein 1 and 3 share the REW-KFAK-RE sequence as a common motif with 75% residue identity. CONCLUSION: This study 1) validates sequence redundancy to autoproteome as a main factor in shaping desmoglein peptide immunogenicity; 2) offers a molecular mechanicistic basis in analyzing the commonality of autoimmune responses exhibited by the two forms of pemphigus; 3) indicates possible peptide-immunotherapeutical approaches for pemphigus diseases.

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Effect of NUDT15 polymorphisms on early hematological safety of low-dose azathioprine in Chinese patients with pemphigus vulgaris: A prospective cohort study.

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