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  • Review Article
  • Published:

Pharmacogenetics: implications for therapy in rheumatic diseases

A Corrigendum to this article was published on 10 March 2015

This article has been updated

Abstract

DMARDs not only improve the joint pain and swelling associated with rheumatoid arthritis (RA), but also slow down the joint damage associated with the disease. The efficacy of biologic therapies, introduced in the past decade for the treatment of RA, has been unequivocally established. Similarly, in addition to traditional drugs such as hydroxychloroquine, new biologic agents such as rituximab have been introduced for systemic lupus erythematosus in recent years. However, considerable variability occurs in the responses of patients to these therapies. Pharmacogenetics, the study of variations in genes encoding drug transporters, drug-metabolizing enzymes and drug targets, and their translation to differential responses to drugs, is a rapidly progressing field in rheumatology. Pharmacogenetic applications, particularly to the old vanguard DMARD, methotrexate, and the newer, more expensive biologic agents, might make personalized therapy in rheumatic diseases possible. The pharmacogenetics of commonly used DMARDs and of biologic therapies are described in this Review.

Key Points

  • Responses to therapies used in rheumatic diseases vary considerably between individual patients

  • Pharmacogenetics—how drug efficacy and toxicity are affected by variations in genes encoding drug metabolizing enzymes, transporters and targets—is a nascent, promising area of research in rheumatology

  • Pharmacogenetic applications, both for traditional agents such as methotrexate, and for biologic agents, might facilitate individualized therapy in rheumatoid arthritis and systemic lupus erythematosus

  • The importance of a few genetic variants has been established by reproducibility, notably 677C>T polymorphism of methylene tetrahydrofolate reductase, and thiopurine S-methyltransferase allelic variants—markers of methotrexate and azathioprine toxicity, respectively

  • Although more research is needed to replicate preliminary findings, and to formally validate established markers, several exploratory, promising new markers are showing the future potential of this exciting field

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Figure 1: Cellular pathway of methotrexate—transport, conversion to polyglutamate forms, and downstream effects.
Figure 2: Metabolism of azathioprine.
Figure 3: Metabolism of sulfasalazine.
Figure 4: Metabolism of hydroxychloroquine.
Figure 5: Metabolism of leflunomide.
Figure 6: Metabolism of cyclophosphamide.
Figure 7: The TNF locus, with some of the polymorphic sites that are thought to influence the outcome of anti-TNF therapy.

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Change history

  • 10 March 2015

    There are two errors in Table 5 on page 546 of this article. The reported clinical effects of variant -308 G>A from Seitz et al. (2007) and Cuchacovich et al. (2006) should both read 'Associated with decreased efficacy' not 'Associated with increased efficacy' as originally printed. The error has been corrected for the HTML and PDF versions of the article.

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Correspondence to Prabha Ranganathan.

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Davila, L., Ranganathan, P. Pharmacogenetics: implications for therapy in rheumatic diseases. Nat Rev Rheumatol 7, 537–550 (2011). https://doi.org/10.1038/nrrheum.2011.117

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