Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Clinical Implications
  • Published:

Clinical Implication

Pharmacogenetic approaches to rheumatoid arthritis

The Pharmacogenomics Journal volume 4, pages 350–353 (2004)Cite this article

Rheumatoid arthritis (RA) is a chronic, systemic inflammatory disease that affects 0.5–1.0% of the general population.1 As the disease progresses, the inflammatory process of the synovium of the joints destroys articular architecture irreversibly. In the late stage, the disease causes a significant disability and high medical costs. About half of RA patients are unable to work at some time in the disease. Lifetime costs for RA were reported to be comparable to those for coronary artery disease or stroke.2 Moreover, life expectancy is shorter than the general population. Unfortunately, the cause of RA is still unknown. However, as the understanding of the pathophysiology of RA progresses, new therapeutic strategies and agents have been developed. The efficacy of early and aggressive treatment with disease-modifying antirheumatic drugs (DMARDs) is widely accepted. DMARDs, such as methotrexate (MTX), sulfasalazine (SSZ) and leflunomide, have documented prevention of the structural damage of the joints.3, 4 Recently, biologic response modifiers targeting specific cytokines, such as tumor necrosis factor-α (TNF-α) or interleukin-1, have been introduced, and the results indicated the effective suppression of the RA activity. However, the outcome of the treatment with DMARDs in RA patients is known to vary among patients. The difference in the response has been reported in biologic response modifiers.5, 6 Moreover, the use of these agents is limited by the development of unpredictable toxicities that are sometimes severe. Previously, it was described that the activities of some drug-metabolizing enzymes for DMARDs, such as N-acetyltransferase 2 (NAT2) for SSZ7 and thiopurine methyltransferase (TPMT) for azathioprine (AZA),8 are different among individuals. Recent advances in genetics have clarified that these individual differences are based on genetic polymorphisms, and this knowledge has encouraged the application of phamacogenetics to the treatment of RA.

MTX is one of the most widely used DMARDs for the treatment of RA. The principal pharmacological mechanism is thought to be the inhibition of dihydrofolate reductase, a key enzyme in the generation of bioactive folate compounds. Although precise mechanisms of action of MTX in RA remain controversial, it is widely accepted that the in vivo action of MTX is tightly related to the inhibition of the folate metabolism.9, 10, 11 Several well-controlled trials revealed the efficacy of MTX in RA. Nevertheless, the response rate to MTX has been reported to be only 463 to 65%,12 and the dose of MTX required to suppress effectively RA activity differs widely between patients. Toxicities of MTX can occur in some patients but not in others.13 Thus, the variabilities in both efficacy and toxicity indeed exist in the treatment of RA with MTX. As MTX was suggested to exert its efficacy and at least part of its toxicity through the inhibition of folate metabolism, it is possible that genetic polymorphisms in enzymes involved in folate metabolism may be related to these differential effects. The enzyme 5,10-methylenetetrahydrofolate reductase (MTHFR) is central to folate metabolism. Among more than 10 polymorphisms of MTHFR gene, C677T and A1298C are important because these polymorphisms are associated with reduced enzyme activities.14, 15 The reduction in the activities of this enzyme is likely to influence the development of efficacy or toxicity of MTX.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

References

  1. O’Dell JR . Rheumatoid arthritis: the clinical picture. In: Koopman WJ (ed). Arthritis and Allied Conditions. Lippincott Raven Publishers, Williams & Wilkins: Philadelphia 2001; pp 1153–1186.

    Google Scholar 

  2. Stone CE . The lifetime economic costs of rheumatoid arthritis. J Rheumatol 1984; 11: 819–827.

    CAS  PubMed  Google Scholar 

  3. Strand V, Cohen S, Schiff M, Weaver A, Fleischmann R, Cannon G et al. Treatment of active rheumatoid arthritis with leflunomide compared with placebo and methotrexate. Leflunomide Rheumatoid Arthritis Investigators Group. Arch Intern Med 1999; 159: 2542–2550.

    Article  CAS  Google Scholar 

  4. Smolen JS, Kalden JR, Scott DL, Rozman B, Kvien TK, Larsen A et al. Efficacy and safety of leflunomide compared with placebo and sulphasalazine in active rheumatoid arthritis: a double-blind, randomised, multicentre trial. European Leflunomide Study Group. Lancet 1999; 353: 259–266.

    Article  CAS  Google Scholar 

  5. Moreland LW, Koopman WJ . Biologic response modifiers for treating musculoskeletal disorders. In: Koopman WJ (ed). Arthritis and Allied Conditions. Lippincott Raven Publishers, Williams & Wilkins: Philadelphia 2001; pp 877–920.

    Google Scholar 

  6. Padyukov L, Lampa J, Heimburger M, Ernestam S, Cederholm T, Lundkvist I et al. Genetic markers for the efficacy of tumour necrosis factor blocking therapy in rheumatoid arthritis. Ann Rheum Dis 2003; 62: 526–529.

    Article  CAS  Google Scholar 

  7. Pullar T, Hunter JA, Capell HA . Effect of acetylator phenotype on efficacy and toxicity of sulphasalazine in rheumatoid arthritis. Ann Rheum Dis 1985; 44: 831–837.

    Article  CAS  Google Scholar 

  8. Stolk JN, Boerbooms AM, de Abreu RA, de Koning DG, van Beusekom HJ, Muller WH et al. Reduced thiopurine methyltransferase activity and development of side effects of azathioprine treatment in patients with rheumatoid arthritis. Arthritis Rheum 1998; 41: 1858–1866.

    Article  CAS  Google Scholar 

  9. Tishler M, Caspi D, Fishel B, Yaron M . The effects of leucovorin (folinic acid) on methotrexate therapy in rheumatoid arthritis patients. Arthritis Rheum 1988; 31: 906–908.

    Article  CAS  Google Scholar 

  10. Joyce DA, Will RK, Hoffman DM, Laing B, Blackbourn SJ . Exacerbation of rheumatoid arthritis in patients treated with methotrexate after administration of folinic acid. Ann Rheum Dis 1991; 50: 913–914.

    Article  CAS  Google Scholar 

  11. Ortiz Z, Shea B, Suarez-Almazor ME, Moher D, Wells GA, Tugwell P . The efficacy of folic acid and folinic acid in reducing methotrexate gastrointestinal toxicity in rheumatoid arthritis. A metaanalysis of randomized controlled trials. J Rheumatol 1998; 25: 36–43.

    CAS  PubMed  Google Scholar 

  12. Bathon JM, Martin RW, Fleischmann RM, Tesser JR, Schiff MH, Keystone EC et al. A comparison of etanercept and methotrexate in patients with early rheumatoid arthritis. N Engl J Med 2000; 343: 1586–1593.

    Article  CAS  Google Scholar 

  13. Weinblatt ME . Methotrexate. In: Kelley WN, Harris Jr ED, Ruddy S, Sledge CB (eds). Textbook of Rheumatology. WB Saunders: Philadelphia 1997; pp 771–786.

    Google Scholar 

  14. Frosst P, Blom HJ, Milos R, Goyette P, Sheppard CA, Matthews RG et al. A candidate genetic risk factor for vascular disease: a common mutation in methylenetetrahydrofolate reductase. Nat Genet 1995; 10: 111–113.

    Article  CAS  Google Scholar 

  15. Weisberg I, Tran P, Christensen B, Sibani S, Rozen R . A second genetic polymorphism in methylenetetrahydrofolate reductase (MTHFR) associated with decreased enzyme activity. Mol Genet Metab 1998; 64: 169–172.

    Article  CAS  Google Scholar 

  16. van Ede AE, Laan RF, Blom HJ, Huizinga TW, Haagsma CJ, Giesendorf BA et al. The C677T mutation in the methylenetetrahydrofolate reductase gene: a genetic risk factor for methotrexate-related elevation of liver enzymes in rheumatoid arthritis patients. Arthritis Rheum 2001; 44: 2525–2530.

    Article  CAS  Google Scholar 

  17. Urano W, Taniguchi A, Yamanaka H, Tanaka E, Nakajima H, Matsuda Y et al. 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 2002; 12: 183–190.

    Article  CAS  Google Scholar 

  18. Chan ES, Cronstein BN . Molecular action of methotrexate in inflammatory diseases. Arthritis Res 2002; 4: 266–273.

    Article  Google Scholar 

  19. Felson DT, Anderson JJ, Meenan RF . The comparative efficacy and toxicity of second-line drugs in rheumatoid arthritis. Results of two metaanalyses. Arthritis Rheum 1990; 33: 1449–1461.

    Article  CAS  Google Scholar 

  20. Donovan S, Hawley S, MacCarthy J, Scott DL . Tolerability of enteric-coated sulphasalazine in rheumatoid arthritis: results of a co-operating clinics study. Br J Rheumatol 1990; 29: 201–204.

    Article  CAS  Google Scholar 

  21. Jackson CG, Clegg DO . Sulfasalazine and minocycline. In: Koopman WJ (ed). Arthritis and Allied Conditions. Lippincott Raven Publishers, Williams & Wilkins: Philadelphia 2001; pp 767–782.

    Google Scholar 

  22. Blum M, Demierre A, Grant DM, Heim M, Meyer UA . Molecular mechanism of slow acetylation of drugs and carcinogens in humans. Proc Natl Acad Sci USA 1991; 88: 5237–5241.

    Article  CAS  Google Scholar 

  23. Bell DA, Taylor JA, Butler MA, Stephens EA, Wiest J, Brubaker LH et al. Genotype/phenotype discordance for human arylamine N-acetyltransferase (NAT2) reveals a new slow-acetylator allele common in African-Americans. Carcinogenesis 1993; 14: 1689–1692.

    Article  CAS  Google Scholar 

  24. Hickman D, Sim E . N-acetyltransferase polymorphism. Comparison of phenotype and genotype in humans. Biochem Pharmacol 1991; 42: 1007–1014.

    Article  CAS  Google Scholar 

  25. Tanaka E, Taniguchi A, Urano W, Nakajima H, Matsuda Y, Kitamura Y et al. Toxicities of sulfasalazine in patients with rheumatoid arthritis are associated with diplotype configuration at the N-acetyltransferase 2 gene. J Rheumatol 2002; 29: 2492–2499.

    CAS  PubMed  Google Scholar 

  26. McLeod HL, Siva C . The thiopurine S-methyltransferase gene locus—implications for clinical pharmacogenomics. Pharmacogenomics 2002; 3: 89–98.

    Article  CAS  Google Scholar 

  27. Yates CR, Krynetski EY, Loennechen T, Fessing MY, Tai HL, Pui CH et al. Molecular diagnosis of thiopurine S-methyltransferase deficiency: genetic basis for azathioprine and mercaptopurine intolerance. Ann Intern Med 1997; 126: 608–614.

    Article  CAS  Google Scholar 

  28. Black AJ, McLeod HL, Capell HA, Powrie RH, Matowe LK, Pritchard SC et al. Thiopurine methyltransferase genotype predicts therapy-limiting severe toxicity from azathioprine. Ann Intern Med 1998; 129: 716–718.

    Article  CAS  Google Scholar 

  29. Corominas H, Domenech M, Laiz A, Gich I, Geli C, Diaz C et al. Is thiopurine methyltransferase genetic polymorphism a major factor for withdrawal of azathioprine in rheumatoid arthritis patients? Rheumatology 2003; 42: 40–45.

    Article  CAS  Google Scholar 

  30. Marra CA, Esdaile JM, Anis AH . Practical pharmacogenetics: the cost effectiveness of screening for thiopurine S-methyltransferase polymorphisms in patients with rheumatological conditions treated with azathioprine. J Rheumatol 2002; 29: 2507–2512.

    PubMed  Google Scholar 

  31. Oh KT, Anis AH, Bae SC . Pharmacoeconomic analysis of thiopurine methyltransferase polymorphism screening by polymerase chain reaction for treatment with azathioprine in Korea. Rheumatology 2004; 43: 156–163.

    Article  CAS  Google Scholar 

  32. Kroeger KM, Carville KS, Abraham LJ . The −308 tumor necrosis factor-alpha promoter polymorphism effects transcription. Mol Immunol 1997; 34: 391–399.

    Article  CAS  Google Scholar 

  33. Wilson AG, Symons JA, McDowell TL, McDevitt HO, Duff GW . Effects of a polymorphism in the human tumor necrosis factor alpha promoter on transcriptional activation. Proc Natl Acad Sci USA 1997; 94: 3195–3199.

    Article  CAS  Google Scholar 

  34. Mugnier B, Balandraud N, Darque A, Roudier C, Roudier J, Reviron D . Polymorphism at position −308 of the tumor necrosis factor alpha gene influences outcome of infliximab therapy in rheumatoid arthritis. Arthritis Rheum 2003; 48: 1849–1852.

    Article  CAS  Google Scholar 

  35. Goldstein DB, Tate SK, Sisodiya SM . Pharmacogenetics goes genomic. Nat Rev Genet 2003; 4: 937–947.

    Article  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Institute of Rheumatology, Tokyo Women's Medical University, Tokyo, Japan

    A Taniguchi & N Kamatani

  2. Division of Statistical Genetics, Institute of Rheumatology, Tokyo Women's Medical University, Shinjuku-ku, Tokyo, Japan

    N Kamatani

Authors
  1. A Taniguchi
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. N Kamatani
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to A Taniguchi.

Additional information

DUALITY OF INTEREST

None declared.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Taniguchi, A., Kamatani, N. Pharmacogenetic approaches to rheumatoid arthritis. Pharmacogenomics J 4, 350–353 (2004). https://doi.org/10.1038/sj.tpj.6500263

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.tpj.6500263

Search

Advanced search

Quick links