Mojca Zajc Avramovič1,2, Vita Dolžan1,2, Nataša Toplak1,2, Meta Accetto1,2, Lara Lusa1,2, Tadej Avčin3,4. 1. From the Department of Allergology, Rheumatology and Clinical Immunology, Children's Hospital, University Medical Centre Ljubljana; Institute of Biochemistry, and Department of Pediatrics, and Institute for Biostatistics and Medical Informatics, Medical Faculty, University of Ljubljana, Ljubljana, Slovenia. 2. M. Zajc Avramovič, MD, Department of Allergology, Rheumatology and Clinical Immunology, Children's Hospital, University Medical Centre Ljubljana; V. Dolčan, MD, PhD, Institute of Biochemistry, Medical Faculty, University of Ljubljana; N. Toplak, MD, PhD, Department of Allergology, Rheumatology and Clinical Immunology, Children's Hospital, University Medical Centre Ljubljana, and Department of Pediatrics, Medical faculty, University of Ljubljana; M. Accetto, MD, Department of Allergology, Rheumatology and Clinical Immunology, Children's Hospital, University Medical Centre Ljubljana; L. Lusa, PhD, Institute for Biostatistics and Medical Informatics, Medical Faculty, University of Ljubljana; T. Avčin, MD, PhD, Department of Allergology, Rheumatology and Clinical Immunology, Children's Hospital, University Medical Centre Ljubljana, and Department of Pediatrics, Medical faculty, University of Ljubljana. 3. From the Department of Allergology, Rheumatology and Clinical Immunology, Children's Hospital, University Medical Centre Ljubljana; Institute of Biochemistry, and Department of Pediatrics, and Institute for Biostatistics and Medical Informatics, Medical Faculty, University of Ljubljana, Ljubljana, Slovenia. tadej.avcin@kclj.si. 4. M. Zajc Avramovič, MD, Department of Allergology, Rheumatology and Clinical Immunology, Children's Hospital, University Medical Centre Ljubljana; V. Dolčan, MD, PhD, Institute of Biochemistry, Medical Faculty, University of Ljubljana; N. Toplak, MD, PhD, Department of Allergology, Rheumatology and Clinical Immunology, Children's Hospital, University Medical Centre Ljubljana, and Department of Pediatrics, Medical faculty, University of Ljubljana; M. Accetto, MD, Department of Allergology, Rheumatology and Clinical Immunology, Children's Hospital, University Medical Centre Ljubljana; L. Lusa, PhD, Institute for Biostatistics and Medical Informatics, Medical Faculty, University of Ljubljana; T. Avčin, MD, PhD, Department of Allergology, Rheumatology and Clinical Immunology, Children's Hospital, University Medical Centre Ljubljana, and Department of Pediatrics, Medical faculty, University of Ljubljana. tadej.avcin@kclj.si.
Abstract
OBJECTIVE: To identify clinical and pharmacogenetic determinants of efficacy and toxicity of methotrexate (MTX) in juvenile idiopathic arthritis (JIA) over time. METHODS: A cohort of 119 consecutive patients with JIA treated with MTX was reviewed. The Juvenile Arthritis Disease Activity Score including 71 joints was used to measure disease activity. Nonresponders were patients who did not reach a minimum of 30% improvement after 6 months of treatment or were switched to biologic drugs in the first 6 months because of inefficacy. All adverse events (AE) were noted. Genotyping of single-nucleotide polymorphisms (SNP) in the genes coding for MTX transporters, folate pathway, and adenosine pathway was performed using real-time PCR methods. Univariate and multivariable penalized logistic and Cox regression were used to analyze data. RESULTS: Thirty patients (25.8%) were defined as nonresponders and 55 (47.2%) were switched to biologics during the followup. Sixty-five patients (54.5%) reported AE in a total of 405 patient-years, and 10 patients (8.4%) discontinued MTX because of AE. AMPD1 rs17602729 and MTHFD1 rs2236225 were associated with gastrointestinal AE while the latter together with MTRR rs1801394 also demonstrated associations with developing hepatoxicity. MTHFR rs1801131, ABCG2 rs2231137, wild-type of MTR rs1805087, and wild-type of ABCC2 rs2273697 were identified as potential markers for discontinuing MTX treatment because of AE. MTHFR rs1801133, MTRR rs1801394, and ABCC2 rs2273697 were associated with switching to biologics. CONCLUSION: SNP in different MTX metabolic pathways influence treatment with MTX. Genetic variability is a better marker for toxicity than efficacy.
OBJECTIVE: To identify clinical and pharmacogenetic determinants of efficacy and toxicity of methotrexate (MTX) in juvenile idiopathic arthritis (JIA) over time. METHODS: A cohort of 119 consecutive patients with JIA treated with MTX was reviewed. The Juvenile Arthritis Disease Activity Score including 71 joints was used to measure disease activity. Nonresponders were patients who did not reach a minimum of 30% improvement after 6 months of treatment or were switched to biologic drugs in the first 6 months because of inefficacy. All adverse events (AE) were noted. Genotyping of single-nucleotide polymorphisms (SNP) in the genes coding for MTX transporters, folate pathway, and adenosine pathway was performed using real-time PCR methods. Univariate and multivariable penalized logistic and Cox regression were used to analyze data. RESULTS: Thirty patients (25.8%) were defined as nonresponders and 55 (47.2%) were switched to biologics during the followup. Sixty-five patients (54.5%) reported AE in a total of 405 patient-years, and 10 patients (8.4%) discontinued MTX because of AE. AMPD1rs17602729 and MTHFD1rs2236225 were associated with gastrointestinal AE while the latter together with MTRRrs1801394 also demonstrated associations with developing hepatoxicity. MTHFRrs1801131, ABCG2rs2231137, wild-type of MTR rs1805087, and wild-type of ABCC2rs2273697 were identified as potential markers for discontinuing MTX treatment because of AE. MTHFRrs1801133, MTRRrs1801394, and ABCC2rs2273697 were associated with switching to biologics. CONCLUSION: SNP in different MTX metabolic pathways influence treatment with MTX. Genetic variability is a better marker for toxicity than efficacy.
Entities:
Keywords:
DRUG EFFICACY; DRUG TOXICITY; JUVENILE IDIOPATHIC ARTHRITIS; METHOTREXATE; PHARMACOGENETIC DETERMINANTS; SINGLE-NUCLEOTIDE POLYMORPHISMS
Authors: Rosario López-Rodríguez; Aida Ferreiro-Iglesias; Aurea Lima; Miguel Bernardes; Andrzej Pawlik; Agnieszka Paradowska-Gorycka; Jerzy Świerkot; Ryszard Slezak; Vita Dolžan; Isidoro González-Álvaro; Javier Narváez; Rafael Cáliz; Eva Pérez-Pampín; Antonio Mera-Varela; Laura Vidal-Bralo; José Gorgonio Acuña Ochoa; Carmen Conde; Juan J Gómez-Reino; Antonio González Journal: Sci Rep Date: 2018-05-09 Impact factor: 4.379