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Pharmacogenetics in the rheumatic diseases, from prêt-à-porter to haute couture

Nature Clinical Practice Rheumatology volume 2, pages 2–3 (2006)Cite this article

Whether designed by Chanel or Armani, ready-to-wear, or prêt-à-porter, clothing is meant to be worn by many different people with many different body shapes. These same fashion design houses also offer made-to-order, or haute-couture, clothing that is designed with the needs and body shape of a specific individual in mind. Similarly, the goal of modern therapeutics is to develop 'haute-couture' therapeutic regimens fitted specifically to the needs and sensitivities of the individual patient, unlike the 'prêt-à-porter' agent that will work well for most people but is a poor fit for some. Although rheumatologists' suits and frocks have improved in recent years, therapies for rheumatic diseases remain prêt-à-porter; clinicians are able to predict toxicities of some antirheumatic drugs that might affect some patients, but predicting with any degree of certainty how an individual patient will respond to a variety of different drugs is not yet possible. Pharmacogenetics, the study of the genetic characteristics that dictate drug response and toxicity, is a rapidly advancing field that might improve the clinician's ability to match a patient with the right drug or drugs for their disease.

Along with nonsteroidal anti-inflammatory agents and corticosteroids, methotrexate is one of the most commonly used drugs in rheumatology today. The metabolic pathways affected by methotrexate are well known and the mechanism of action that methotrexate utilizes in the treatment of inflammatory diseases is at least partially understood.1 Common genetic polymorphisms have been found in the enzyme methylene tetrahydrofolate reductase, which lead to altered enzyme activity and are associated with an enhanced risk of methotrexate toxicity.2 Although genetic polymorphisms in methylene tetrahydrofolate reductase have been associated with methotrexate efficacy,3 these studies are not very convincing because of the small numbers of patients studied, the nonstandard definition of patient response and nonresponse to treatment, and the inability of other studies to detect a similar association.2 Another study by Dervieux and colleagues reports that polymorphisms in multiple proteins involved in methotrexate uptake, and in purine and pyrimidine synthesis (for example, reduced folate carrier 1, AICAR transformylase and thymidylate synthase) lead to enhanced methotrexate efficacy.4 Future studies should include larger numbers of patients and use standard outcome measures in order for these markers of efficacy to be established with confidence. Nonetheless, this study provides a model for future studies of genetic determinants of methotrexate efficacy since it is unlikely, based on current evidence, that polymorphisms in a single gene will be responsible for an individual patient's response to treatment with methotrexate.

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References

  1. Cronstein BN (2005) Low-dose methotrexate: a mainstay in the treatment of rheumatoid arthritis. Pharmacol Rev 57: 163–172

    Article  CAS  Google Scholar 

  2. Berkun Y et al. (2004) Methotrexate related adverse effects in patients with rheumatoid arthritis are associated with the A1298C polymorphism of the MTHFR gene. Ann Rheum Dis 63: 1227–1231

    Article  CAS  Google Scholar 

  3. Urano W et al. (2002) Polymorphisms in the methylenetetrahydrofolate reductase gene were associated with both the efficacy and the toxicity of methotrexate used for the treatment of rheumatoid arthritis, as evidenced by single locus and haplotype analyses. Pharmacogenetics 12: 183–190

    Article  CAS  Google Scholar 

  4. Dervieux T et al. (2004) Polyglutamation of methotrexate with common polymorphisms in reduced folate carrier, aminoimidazole carboxamide ribonucleotide transformylase, and thymidylate synthase are associated with methotrexate effects in rheumatoid arthritis. Arthritis Rheum 50: 2766–2774

    Article  CAS  Google Scholar 

  5. Clunie GP and Lennard L (2004) Relevance of thiopurine methyltransferase status in rheumatology patients receiving azathioprine. Rheumatology 43: 13–18

    Article  CAS  Google Scholar 

  6. Martinez A et al. (2004) Association of the major histocompatibility complex with response to infliximab therapy in rheumatoid arthritis patients. Arthritis Rheum 50: 1077–1082

    Article  CAS  Google Scholar 

  7. Mugnier B et al. (2003) Polymorphism at position -308 of the tumor necrosis factor α gene influences outcome of infliximab therapy in rheumatoid arthritis. Arthritis Rheum 48: 1849–1852

    Article  CAS  Google Scholar 

  8. Kang CP et al. (2005) The influence of a polymorphism at position -857 of the tumour necrosis factor α gene on clinical response to etanercept therapy in rheumatoid arthritis. Rheumatology 44: 547–552

    Article  CAS  Google Scholar 

  9. Criswell LA et al. (2004) The influence of genetic variation in the HLA-DRB1 and LTA-TNF regions on the response to treatment of early rheumatoid arthritis with methotrexate or etanercept. Arthritis Rheum 50: 2750–2756

    Article  CAS  Google Scholar 

  10. Schotte H et al. (2005) Interleukin 10 promoter microsatellite polymorphisms are associated with response to long term treatment with etanercept in patients with rheumatoid arthritis. Ann Rheum Dis 64: 575–581

    Article  CAS  Google Scholar 

  11. Padyukov L et al. (2003) Genetic markers for the efficacy of tumour necrosis factor blocking therapy in rheumatoid arthritis. Ann Rheum Dis 62: 526–529

    Article  CAS  Google Scholar 

Download references

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Authors and Affiliations

  1. Professor of Medicine in Pathology and Pharmacology in the Divisions of Clinical Pharmacology and Rheumatology at the Department of Medicine, New York University School of Medicine, New York, NY, USA

    Bruce N Cronstein

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Correspondence to Bruce N Cronstein.

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Competing interests

Dr Cronstein has served as a consultant to King Pharmaceuticals, Tap Pharmaceuticals, Bristol-Myers, Squibb Pharmaceuticals, Prometheus Laboratories and Regeneron. He receives research funding from the National Institutes of Health, King Pharmaceuticals and the General Clinical Research Center.

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Cronstein, B. Pharmacogenetics in the rheumatic diseases, from prêt-à-porter to haute couture. Nat Rev Rheumatol 2, 2–3 (2006). https://doi.org/10.1038/ncprheum0072

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