title: Clinical-pharmacogenetic predictive models for MTX discontinuation due to adverse events in rheumatoid arthritis.
abstract: We describe a novel approach to investigate and evaluate combined effect of a large number of clinical and pharmacogenetic factors on treatment outcome. We have used this approach to investigate predictors of methotrexate (MTX)-induced adverse events (AEs) leading to treatment discontinuation in rheumatoid arthritis (RA) patients. In total, 333 RA patients were genotyped for 34 polymorphisms in MTX transporters, folate and adenosine pathways. The effect of clinical and pharmacogenetic factors was assessed with penalized regression in the cause-specific Cox proportional hazards model. The predictive capacity was evaluated with the area under time-dependent receiver operating characteristic curve where cross-validation was applied. SLC19A1, ABCG2, ADORA3 and TYMS were associated with discontinuation because of AEs in clinical-pharmacogenetic model. Cross-validation showed that both clinical-pharmacogenetic model and nongenetic model had worthless predictive ability for MTX discontinuation because of AEs. These models could be further improved, either with additional polymorphisms or with epigenetic predictors.
authors.affiliation: Pharmacogenetics Laboratory, Institute of Biochemistry, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia.
authors.forename: B
authors.initials: B
authors.lastname: Jenko
authors.affiliation: Faculty of Medicine, Institute for Biostatistics and Medical Informatics, University of Ljubljana, Ljubljana, Slovenia.
authors.forename: L
authors.initials: L
authors.lastname: Lusa
authors.affiliation: Department of Rheumatology, University Medical Centre Ljubljana, Ljubljana, Slovenia.|Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia.
authors.forename: M
authors.initials: M
authors.lastname: Tomsic
authors.affiliation: Department of Rheumatology, University Medical Centre Ljubljana, Ljubljana, Slovenia.|Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia.
authors.forename: S
authors.initials: S
authors.lastname: Praprotnik
authors.affiliation: Pharmacogenetics Laboratory, Institute of Biochemistry, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia.
authors.forename: V
authors.initials: V
authors.lastname: Dolzan
mesh_terms: D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2 / Q000235:genetics; D000368:Aged; D018501:Antirheumatic Agents / Q000009:adverse effects* / Q000493:pharmacokinetics* / Q000627:therapeutic use; D001172:Arthritis, Rheumatoid / Q000188:drug therapy* / Q000235:genetics; D005260:Female; D005838:Genotype; D006801:Humans; D008297:Male; D008727:Methotrexate / Q000009:adverse effects* / Q000493:pharmacokinetics* / Q000627:therapeutic use; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000235:genetics; D033703:Nucleoside Transport Proteins / Q000235:genetics; D000071185:Pharmacogenomic Testing; D011110:Polymorphism, Genetic; D011237:Predictive Value of Tests; D016016:Proportional Hazards Models; D058978:Reduced Folate Carrier Protein / Q000235:genetics; D013940:Thymidylate Synthase / Q000235:genetics; D016896:Treatment Outcome
chemical_list: C116614:ABCG2 protein, human; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018501:Antirheumatic Agents; D009363:Neoplasm Proteins; D033703:Nucleoside Transport Proteins; D058978:Reduced Folate Carrier Protein; C548699:SLC19A1 protein, human; C444719:adenosine transporter; C000600377:TYMS protein, human; D013940:Thymidylate Synthase; D008727:Methotrexate