AB0014 GENETIC MARKERS OF METHOTREXATE HEPATOTOXICITY IN PATIENTS WITH RHEUMATOID ARTHRITIS
Authors: N. Martusevich, E. Aksenova, K. Gudkevich
Journal: Annals of the Rheumatic Diseases (2020)

Background: Methotrexate (MT) is a first-line drug in the treatment of rheumatoid arthritis (RA). The effectiveness and tolerability of the use of MT largely determines the prognosis of the course of the disease, the speed of achieving remission The development of hepatotoxicity (HT) is the most common adverse reaction, it is noted in 5-12.5% of cases and often requires the abolition of MT. In this regard, predicting the development of HT seems to be an important area of research. Objectives: to study genetic predictors of HT development in patients with RA using MT. Methods: 44 patients with a reliable diagnosis of RA were included in study. All of the patients used MT at a dose of 15.0 (12.5-17.5) mg/week in combination with folic acid 3-5 mg / day outside of MT. The average age was 46.7 ± 12.3 years; females- 81.8% (n = 36); mail 18.2% (n = 8). The duration of RA is 5.3 ± 2.2 months. All patients were divided into two groups: the first study group (n = 17) included patients with RA who developed a HT reaction to MT, which required the abolition of MT; in the second- (n = 27) - comparison group - patients with good efficacy and tolerability of MT. Genotypes for polymorphic alleles were analyzed in all patients: C677T (rs1801133) and A1298C (rs1801131) of the methylenetetrahydrofolate reductase gene (MTHFR); 347C&gt; G single-nucleotide polymorphism of the gene of aminoimidazole-carboxamidoriboside transformylase / inosine monophosphate cyclohydrolase (ATIC); c.80G&gt; A locus of the SLC19A1 gene encoding the folate transporter membrane carrier protein.Groups were compared according to possible inheritance models: dominant, recessive, codominant. Statistical data processing was carried out using the SATISTICA 10.0 software package using descriptive and nonparametric statistics methods. Results: The frequency of occurrence of various mutations in genes that affect the metabolism of MT among patients with RA in the study and comparison groups are presented in table 1 Table 1. The frequency of occurrence of various mutations in genes that affect the metabolism of MT Genetic option Study group ГТ+, n=17 Comparison group ГТ &lt;&lt;-&gt;&gt;, n=27 MTHFR-A1298C CC 5 6 CA 2 8 AA 10 13 MTHFR -C677T CC 7 9 CT 8 17 TT 2 1 347C&gt;G ATIC CC 9 6 CG 6 19 GG 2 2 SLC19A1c80A&gt;G AA 11 22 AG 6 4 GG 0 0 ГТ- hepatotoxicity When analyzing inheritance models, it was found that differences in hepatotoxicity for comparing genotypes (MTHFR-A1298C, MTHFR-C677T, SLC19A1c80A&gt; G) were not statistically significant. A statistically significant increase in the risk of hepatotoxicity was found for dominant (2.18 (1.06-4.47), x2 = 4.38, p = 0.03) and codominant (0.42 (0.19-0.92), x2 = 5.23, p = 0.02) models for the 347C&gt; G ATIC gene. Conclusion: Thus, an increase in the risk of hepatotoxicity for the dominant and codominant models for the 347C&gt;G ATIC gene allows recommending genotyping of the alleles of this gene before MT administration in order to reduce the risk of hepatotoxic reactions. Disclosure of Interests: Natalia Martusevich Shareholder of: k, E. Aksenova: None declared, Katsiarina Gudkevich: None declared