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Precision Medicine With Leflunomide: Consideration of DHODH Haplotype and Plasma Teriflunomide Concentration Can Substantially Modify Outcomes in Patients With Rheumatoid Arthritis

Author

Arthritis Care Res (Hoboken). 2020 Apr 27. doi: 10.1002/acr.24236. Online ahead of print.

Michael D Wiese 1 2, Ashley M Hopkins 3, Catherine King 1 4, Mihir D Wechalekar 3 5, Anita Lee 6 7, Llewellyn Spargo 6, Robert Metcalf 6, Leah McWilliams 6, Catherine Hill 6 7 8, Leslie G Cleland 6, Susanna M Proudman 6 7

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Author Information

  • 1University of South Australia, UniSA: Clinical and Health Sciences, North Terrace, Adelaide, SA, 5000, Australia.
  • 2University of South Australia, Health and Biomedical Innovation, North Terrace, Adelaide, SA, 5000, Australia.
  • 3Flinders University of South Australia, College of Medicine and Public Health, Sturt Road, Bedford Park, SA, 5042, Australia.
  • 4University of South Australia, Australian Centre for Precision Health, University of South Australia Cancer Research Institute, North Terrace, Adelaide, SA, 5000, Australia.
  • 5Flinders Medical Centre, Department of Rheumatology, Flinders Drive, Bedford Park, SA, 5042, Australia.
  • 6Royal Adelaide Hospital, Department of Rheumatology, Port Road, Adelaide, SA, 5000, Australia.
  • 7The University of Adelaide, Adelaide Medical School, Corner of North Terrace and George Street, Adelaide, SA, 5000, Australia.
  • 8The Queen Elizabeth Hospital, Department of Rheumatology, Woodville Road, Woodville, SA, 5011, Australia.

Abstract

Objective: Leflunomide is a commonly used disease modifying drug in the treatment of Rheumatoid Arthritis (RA). Its effects are mediated via inhibition of dihydroorotate dehydrogenase (DHODH) by its active metabolite teriflunomide, and the pharmacokinetics of teriflunomide are highly variable. We examined the association between DHODH haplotype and plasma teriflunomide concentration with response to leflunomide in patients with RA where leflunomide was added to existing disease modifying drugs after failure to achieve an adequate response with conventional 'triple therapy'.

Methods: Patients with RA who were taking, or were about to initiate leflunomide were included. Participant characteristics including DHODH haplotype were determined. Up to five plasma samples were collected after leflunomide was initiated for assays of total and free teriflunomide concentration. Disease activity was determined via the 28-joint disease activity score (DAS28). The association between DAS28 and patient covariates was determined by linear mixed effect modelling.

Results: A total of 67 patients were included in the study. The DAS28 after initiation of leflunomide was associated with baseline DAS28 (β=0.70, p<0.001) and was higher in those who carried DHODH Haplotype 2 (β=0.56, p=0.01) and did not carry the shared epitope (β=0.56, p=0.013). As total and free plasma teriflunomide concentration increased, DAS28 was significantly lower (p<0.001 and p=0.001 respectively). When considering threshold concentrations, teriflunomide concentrations above 16 mg/L were associated with a DAS28 that was 0.33 lower, and when free teriflunomide concentration was above 35 µg/L, DAS28 was 0.32 lower.

Conclusion: Teriflunomide concentration and carriage of DHODH Haplotype 2 are associated with response to leflunomide in patients with RA, and a total plasma teriflunomide concentration of at least 16 mg/L is needed to maximise the likelihood of response.