ACR Meeting Abstracts

ACR Meeting Abstracts

Abstract Number: 2520

Patient, Genetic and Disease Factors Influence the Response to the Disease Modifying Anti-Rheumatic Drug Leflunomide

Michael D. Wiese1, Ashley Hopkins2, Llew Spargo3, Leah McWilliams3, Catherine O'Doherty2, Leslie G. Cleland3 and Susanna Proudman4, 1Division of Health Sciences, School of Pharmacy, University of South Australia, Adelaide, Australia, 2School of Pharmacy and Medical Sciences, University of South Australia, Adelaide, Australia, 3Rheumatology Unit, Royal Adelaide Hospital, Adelaide, Australia, 4Department of Rheumatology, Royal Adelaide Hospital, SA, Australia

Meeting: 2014 ACR/ARHP Annual Meeting

Keywords: ,

Session Information

Title: Rheumatoid Arthritis - Small Molecules, Biologics and Gene Therapy: Therapeutic Strategies, Biomarkers and Predictors of Outcomes in Rheumatoid Arthritis

Session Type: Abstract Submissions (ACR)

Background/Purpose . Leflunomide is a disease modifying anti-rheumatic drug that is used in the treatment of rheumatoid arthritis (RA). Leflunomide is converted to teriflunomide by the Cytochrome P450 enzymes 1A2, 2C19 and 3A4, which is cleared via secretion into the gastro-intestinal tract by the transporter ABCG2. The primary mechanism of action is inhibition of di-hydroorotate dehydrogenase (DHODH) by teriflunomide. It is very effective in some patients, but treatment can be limited by intolerance and/or lack of efficacy. This study aimed to determine steady state teriflunomide concentration in a group of patients with RA and correlate steady state concentrations with response to leflunomide.

Methods . Patients with RA taking a stable dose of leflunomide according to a treat-to-target strategy were recruited from the Royal Adelaide Hospital Early Arthritis Clinic. Blood samples were taken for determination of free teriflunomide concentration and genetic differences in CYP1A2, CYP2C19, ABCG2 and DHODH. Disease activity was assessed by the 28-joint disease activity scores (DAS28). Factors associated with teriflunomide concentration and DAS28 were assessed by multivariate linear regression.

Results . 55 patients were included. The average leflunomide dose was 16.1mg/day, and the free teriflunomide concentration was 0.062mg/L – there was a 150-fold difference between maximum and minimum concentration. Leflunomide dose accounted for 10% of the variability in free teriflunomide concentration, and this increased to 38% when CYP1A2 and ABCG2 genotype were considered. 25 patients took leflunomide for at least 9 months (no other agents were added for treatment failure) and 76% of the variability in DAS28 was accounted for by considering baseline DAS28, shared epitope carriage, DHODH haplotype and free teriflunomide concentration.

Conclusion . Pharmacokinetic and pharmacogenomic variables appear to be associated with response to leflunomide in a group of RA patients treated according to a treat-to-target strategy, but this should be assessed in a prospectively recruited cohort.

Disclosure:

M. D. Wiese,
None;

A. Hopkins,
None;

L. Spargo,
None;

L. McWilliams,
None;

C. O’Doherty,
None;

L. G. Cleland,
None;

S. Proudman,
None.

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