Clinical Pharmacogenetic Models of Treatment Response to Methotrexate Monotherapy in Slovenian and Serbian Rheumatoid Arthritis Patients: Differences in Patient's Management May Preclude Generalization of the Models
Objectives: Methotrexate (MTX) is the first line treatment for rheumatoid arthritis (RA), but nevertheless 30% of patients experience MTX inefficacy. Our aim was to develop a clinical pharmacogenetic model to predict which RA patients will not respond to MTX monotherapy. We also assessed whether thi...
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doaj-c0d581df878a43da9deab8046b808ade2020-11-25T00:21:41ZengFrontiers Media S.A.Frontiers in Pharmacology1663-98122018-01-01910.3389/fphar.2018.00020290026Clinical Pharmacogenetic Models of Treatment Response to Methotrexate Monotherapy in Slovenian and Serbian Rheumatoid Arthritis Patients: Differences in Patient's Management May Preclude Generalization of the ModelsBarbara Jenko0Matija Tomšič1Matija Tomšič2Biljana Jekić3Vera Milić4Vita Dolžan5Sonja Praprotnik6Sonja Praprotnik7Pharmacogenetics Laboratory, Faculty of Medicine, Institute of Biochemistry, University of Ljubljana, Ljubljana, SloveniaDepartment of Rheumatology, University Medical Centre Ljubljana, Ljubljana, SloveniaFaculty of Medicine, University of Ljubljana, Ljubljana, SloveniaFaculty of Medicine, Institute of Human Genetics, University of Belgrade, Belgrade, SerbiaFaculty of Medicine, Institute of Rheumatology, University of Belgrade, Belgrade, SerbiaPharmacogenetics Laboratory, Faculty of Medicine, Institute of Biochemistry, University of Ljubljana, Ljubljana, SloveniaDepartment of Rheumatology, University Medical Centre Ljubljana, Ljubljana, SloveniaFaculty of Medicine, University of Ljubljana, Ljubljana, SloveniaObjectives: Methotrexate (MTX) is the first line treatment for rheumatoid arthritis (RA), but nevertheless 30% of patients experience MTX inefficacy. Our aim was to develop a clinical pharmacogenetic model to predict which RA patients will not respond to MTX monotherapy. We also assessed whether this model can be generalized to other populations by validating it on a group of Serbian RA patients.Methods: In 110 RA Slovenian patients, data on clinical factors and 34 polymorphisms in MTX pathway were analyzed by Least Absolute Shrinkage and Selection Operator (LASSO) penalized regression to select variables associated with the disease activity as measured by Disease Activity Score (DAS28) score after 6 months of MTX monotherapy. A clinical pharmacogenetic index was constructed from penalized regression coefficients with absolute value above 0.05. This index was cross-validated and also independently validated on 133 Serbian RA patients.Results: A clinical pharmacogenetic index for prediction of DAS28 after 6 months of MTX monotherapy in Slovenian RA patients consisted of DAS28 score at diagnosis, presence of erosions, MTX dose, Solute Carrier Family 19 Member 1 (SLC19A1) rs1051266, Solute Carrier Organic Anion Transporter Family Member 1B1 (SLCO1B1) rs2306283, Thymidylate Synthase (TYMS), and Adenosine Monophosphate Deaminase 1 (AMPD1) rs17602729. It correctly classified 69% of Slovenian patients as responders or nonresponders and explained 30% of variability in DAS28 after 6 months of MTX monotherapy. Testing for validity in another population showed that it classified correctly only 22.5% of Serbian RA patients.Conclusions: We developed a clinical pharmacogenetic model for DAS28 after 6 months of MTX monotherapy in Slovenian RA patients by combining clinical and genetic variables. The clinical pharmacogenetic index developed for Slovenian patients did not perform well on Serbian patients, presumably due to the differences in patients' characteristics and clinical management between the two groups.http://journal.frontiersin.org/article/10.3389/fphar.2018.00020/fullrheumatoid arthritispharmacogeneticsmethotrexatepolymorphismpredictive model |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Barbara Jenko Matija Tomšič Matija Tomšič Biljana Jekić Vera Milić Vita Dolžan Sonja Praprotnik Sonja Praprotnik |
spellingShingle |
Barbara Jenko Matija Tomšič Matija Tomšič Biljana Jekić Vera Milić Vita Dolžan Sonja Praprotnik Sonja Praprotnik Clinical Pharmacogenetic Models of Treatment Response to Methotrexate Monotherapy in Slovenian and Serbian Rheumatoid Arthritis Patients: Differences in Patient's Management May Preclude Generalization of the Models Frontiers in Pharmacology rheumatoid arthritis pharmacogenetics methotrexate polymorphism predictive model |
author_facet |
Barbara Jenko Matija Tomšič Matija Tomšič Biljana Jekić Vera Milić Vita Dolžan Sonja Praprotnik Sonja Praprotnik |
author_sort |
Barbara Jenko |
title |
Clinical Pharmacogenetic Models of Treatment Response to Methotrexate Monotherapy in Slovenian and Serbian Rheumatoid Arthritis Patients: Differences in Patient's Management May Preclude Generalization of the Models |
title_short |
Clinical Pharmacogenetic Models of Treatment Response to Methotrexate Monotherapy in Slovenian and Serbian Rheumatoid Arthritis Patients: Differences in Patient's Management May Preclude Generalization of the Models |
title_full |
Clinical Pharmacogenetic Models of Treatment Response to Methotrexate Monotherapy in Slovenian and Serbian Rheumatoid Arthritis Patients: Differences in Patient's Management May Preclude Generalization of the Models |
title_fullStr |
Clinical Pharmacogenetic Models of Treatment Response to Methotrexate Monotherapy in Slovenian and Serbian Rheumatoid Arthritis Patients: Differences in Patient's Management May Preclude Generalization of the Models |
title_full_unstemmed |
Clinical Pharmacogenetic Models of Treatment Response to Methotrexate Monotherapy in Slovenian and Serbian Rheumatoid Arthritis Patients: Differences in Patient's Management May Preclude Generalization of the Models |
title_sort |
clinical pharmacogenetic models of treatment response to methotrexate monotherapy in slovenian and serbian rheumatoid arthritis patients: differences in patient's management may preclude generalization of the models |
publisher |
Frontiers Media S.A. |
series |
Frontiers in Pharmacology |
issn |
1663-9812 |
publishDate |
2018-01-01 |
description |
Objectives: Methotrexate (MTX) is the first line treatment for rheumatoid arthritis (RA), but nevertheless 30% of patients experience MTX inefficacy. Our aim was to develop a clinical pharmacogenetic model to predict which RA patients will not respond to MTX monotherapy. We also assessed whether this model can be generalized to other populations by validating it on a group of Serbian RA patients.Methods: In 110 RA Slovenian patients, data on clinical factors and 34 polymorphisms in MTX pathway were analyzed by Least Absolute Shrinkage and Selection Operator (LASSO) penalized regression to select variables associated with the disease activity as measured by Disease Activity Score (DAS28) score after 6 months of MTX monotherapy. A clinical pharmacogenetic index was constructed from penalized regression coefficients with absolute value above 0.05. This index was cross-validated and also independently validated on 133 Serbian RA patients.Results: A clinical pharmacogenetic index for prediction of DAS28 after 6 months of MTX monotherapy in Slovenian RA patients consisted of DAS28 score at diagnosis, presence of erosions, MTX dose, Solute Carrier Family 19 Member 1 (SLC19A1) rs1051266, Solute Carrier Organic Anion Transporter Family Member 1B1 (SLCO1B1) rs2306283, Thymidylate Synthase (TYMS), and Adenosine Monophosphate Deaminase 1 (AMPD1) rs17602729. It correctly classified 69% of Slovenian patients as responders or nonresponders and explained 30% of variability in DAS28 after 6 months of MTX monotherapy. Testing for validity in another population showed that it classified correctly only 22.5% of Serbian RA patients.Conclusions: We developed a clinical pharmacogenetic model for DAS28 after 6 months of MTX monotherapy in Slovenian RA patients by combining clinical and genetic variables. The clinical pharmacogenetic index developed for Slovenian patients did not perform well on Serbian patients, presumably due to the differences in patients' characteristics and clinical management between the two groups. |
topic |
rheumatoid arthritis pharmacogenetics methotrexate polymorphism predictive model |
url |
http://journal.frontiersin.org/article/10.3389/fphar.2018.00020/full |
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