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Genetic polymorphisms in metabolic pathways of leflunomide in the treatment of rheumatoid arthritis


1, 2, 3, 4, 5, 6

 

  1. Charles University in Prague, Medical Faculty and University Hospital in Hradec Kralove, 2nd Department of Internal Medicine-Gastroenterology, Prague, Czech Republic.
  2. Charles University in Prague, Faculty of Pharmacy in Hradec Kralove, Department of Social and Clinical Pharmacy, Prague, Czech Republic.
  3. Charles University in Prague, University Hospital in Hradec Kralove, Institute of Clinical Biochemistry and Diagnostics, Prague, Czech Republic.
  4. Charles University in Prague, Medical Faculty and University Hospital in Hradec Kralove, 2nd Department of Internal Medicine-Gastroenterology, Prague, Czech Republic.
  5. Charles University in Prague, Faculty of Pharmacy in Hradec Kralove, Department of Social and Clinical Pharmacy, Prague, Czech Republic.
  6. Charles University in Prague, Faculty of Pharmacy in Hradec Kralove, Department of Pharmacology and Toxicology, Prague, Czech Republic.

CER7628
2015 Vol.33, N°3
PI 0426, PF 0432
Review

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PMID: 25664505 [PubMed]

Received: 28/05/2014
Accepted : 16/09/2014
In Press: 29/01/2015
Published: 22/06/2015

Abstract

Leflunomide (LEF) is a disease-modifying anti-rheumatic drug used for treating rheumatoid arthritis (RA). More than 50% of patients are withdrawn from LEF treatment within one year, mainly due to AEs. Importantly, it is not possible to predict which patients will respond to LEF therapy nor if adverse outcome occurs. Pharmacogenetic studies indicate an impact of single nucleotid polymorphisms (SNPs) on the variability in LEF serum levels with potential relevance to effectiveness and tolerability in individual RA patients. In vitro studies have demonstrated that cytochromes P450 (CYPs), mainly CYP1A2, CYP2C19, and CYP3A4, are involved in LEF metabolite activation. It was shown that CYP1A2*1F allele may be associated with LEF toxicity in patients with RA. In case of dihydroorotate dehydrogenase (DHODH) gene SNP (rs3213422, 19C>A), it was shown that C allele may be associated with LEF toxicity and therapeutic effect. Finally, oestrogen receptor genes SNPs in females may be associated with LEF therapy efficacy. In summary, the results of the current studies suggest a possible diagnostic value of genotyping for patients with RA as biomarkers of LEF therapy efficacy or conversely as indicators of serious side effects. In the future, it will be necessary to corroborate these results in studies with larger numbers of patients and longer follow-up. Moreover, it would be appropriate to focus on CYP2C19, ATP5A1 and PKD1L3 genes.

Rheumatology Article