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.

Barbara Jenko,Matija Tomšič,Vera Milić,Sonja Praprotnik,Vita Dolžan,Biljana Jekić

doi:10.3389/fphar.2018.00020

Barbara Jenko, Matija Tomšič + Show 4 more

Open Access

https://doi.org/10.3389/fphar.2018.00020

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Abstract

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.

Highlights

Personalized medicine strives to prescribe the right drug for the right patient at the time of diagnosis
rheumatoid arthritis (RA) patients were considered eligible for inclusion if they were initially treated with MTX monotherapy for at least 6 months, were over 18 years old and were of Central Caucasian origin
The study group consisted of 110 Slovenian RA patients, while the validation group consisted of 133 Serbian RA patients

Summary

Introduction

Personalized medicine strives to prescribe the right drug for the right patient at the time of diagnosis. To prevent joint damage and erosions there is a need to identify patients with a higher risk to experience treatment inefficacy With this aim the clinical pharmacogenetic model for the prediction of non-response to MTX treatment was introduced (Wessels et al, 2007) and validated (Fransen et al, 2012) in Dutch patients with an early onset of RA. It included female gender, DAS at baseline, rheumatoid factor (RF), smoking and Methylenetetrahydrofolate Dehydrogenase 1 (MTHFD1), Adenosine Monophosphate Deaminase 1 (AMPD1), Inosine Triphosphatase (ITPA), and 5-Aminoimidazole-4-carboxamide ribonucleotide Formyltransferase/IMP Cyclohydrolase (ATIC) polymorphisms. It resulted in a good prediction of non-responders, it is not widely used in clinical practice outside the Netherlands (Wessels et al, 2007; Fransen et al, 2012)

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