Skip to main content

Pharmacogenetics in Rheumatoid Arthritis

  • Protocol
  • First Online:
Pharmacogenomics in Drug Discovery and Development

Part of the book series: Methods in Molecular Biology ((MIMB,volume 1175))

Abstract

Rheumatoid arthritis (RA) is a systemic inflammatory arthritis leading to severe joint damage and associated with high morbidity and mortality. Disease-modifying antirheumatic drugs (DMARDs) are the mainstay of treatment in RA. DMARDs not only relieve the clinical signs and symptoms of RA but also inhibit the radiographic progression of disease. In the last decade, a new class of disease-modifying medications, the biologic agents, has been added to the existing spectrum of DMARDs in RA. However, patients’ response to these agents is not uniform with considerable variability in both efficacy and toxicity. There are no reliable means of predicting an individual patient’s response to a given DMARD prior to initiation of therapy. In this chapter, the current published literature on the pharmacogenetics of traditional DMARDS and the newer biologic DMARDs in RA is highlighted. Pharmacogenetics may help individualize drug therapy in patients with RA in the near future.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Protocol
USD 49.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 89.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 119.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Pincus T, Callahan LF, Sale WG, Brooks AL, Payne LE, Vaughn WK (1984) Severe functional declines, work disability, and increased mortality in seventy-five rheumatoid arthritis patients studied over nine years. Arthritis Rheum 27(8):864–872

    CAS  PubMed  Google Scholar 

  2. Weinblatt ME, Coblyn JS, Fox DA, Fraser PA, Holdsworth DE, Glass DN et al (1985) Efficacy of low-dose methotrexate in rheumatoid arthritis. N Engl J Med 312(13):818–822

    CAS  PubMed  Google Scholar 

  3. Kremer JM, Phelps CT (1992) Long-term prospective study of the use of methotrexate in the treatment of rheumatoid arthritis. Update after a mean of 90 months. Arthritis Rheum 35(2):138–145

    CAS  PubMed  Google Scholar 

  4. Kremer JM (2001) Rational use of new and existing disease-modifying agents in rheumatoid arthritis. Ann Intern Med 134(8):695–706

    CAS  PubMed  Google Scholar 

  5. Strand V, Cohen S, Schiff M, Weaver A, Fleischmann R, Cannon G et al (1999) Treatment of active rheumatoid arthritis with leflunomide compared with placebo and methotrexate. Leflunomide Rheumatoid Arthritis Investigators Group. Arch Intern Med 159(21):2542–2550

    CAS  PubMed  Google Scholar 

  6. Bathon JM, Martin RW, Fleischmann RM, Tesser JR, Schiff MH, Keystone EC et al (2001) A comparison of etanercept and methotrexate in patients with early rheumatoid arthritis. N Engl J Med 343(22):1586–1593

    Google Scholar 

  7. Hooijberg JH, Broxterman HJ, Kool M, Assaraf YG, Peters GJ, Noordhuis P et al (1999) Antifolate resistance mediated by the multidrug resistance proteins MRP1 and MRP2. Cancer Res 59(11):2532–2535

    CAS  PubMed  Google Scholar 

  8. Longo GS, Gorlick R, Tong WP, Lin S, Steinherz P, Bertino JR (1997) Glutamyl hydrolase and folylpolyglutamate synthetase activities predict polyglutamylation of methotrexate in acute leukemias. Oncol Res 9:259–263

    CAS  PubMed  Google Scholar 

  9. Barredo JC, Synold TW, Laver J, Relling MV, Pui CH, Priest DG et al (1994) Differences in constitutive and post-methotrexate folylpolyglutamate synthetase activity in B-lineage and T-lineage leukemia. Blood 84:564–569

    CAS  PubMed  Google Scholar 

  10. Galpin AJ, Schuetz JD, Masson E, Yanishevski Y, Synold TW, Barredo JC et al (1997) Differences in folylpolyglutamate synthetase and dihydrofolate reductase expression in human B-lineage versus T-lineage leukemic lymphoblasts: mechanisms for lineage differences in methotrexate polyglutamylation and cytotoxicity. Mol Pharmacol 52:155–163

    CAS  PubMed  Google Scholar 

  11. Rots MG, Pieters R, Peters GJ, Noordhuis P, van Zantwijk CH, Kaspers GJ et al (1999) Role of folylpolyglutamate synthetase and folylpolyglutamate hydrolase in methotrexate accumulation and polyglutamylation in childhood leukemia. Blood 93:1677–1683

    CAS  PubMed  Google Scholar 

  12. Galivan J (1980) Evidence for the cytotoxic activity of polyglutamate derivatives of methotrexate. Mol Pharmacol 17(1):105–110

    CAS  PubMed  Google Scholar 

  13. van Ede AE, Laan RF, Blom HJ, De Abreu RA, van de Putte LB (1998) Methotrexate in rheumatoid arthritis: an update with focus on mechanisms involved in toxicity. Sem Arthritis Rheum 27(5):277–292

    Google Scholar 

  14. Szeto DW, Cheng YC, Rosowsky A, Yu CS, Modest EJ, Piper JR et al (1979) Human thymidylate synthetase–III. Effects of methotrexate and folate analogs. Biochem Pharmacol 28(17):2633–2637

    CAS  PubMed  Google Scholar 

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

    PubMed Central  PubMed  Google Scholar 

  16. Rothem L, Aronheim A, Assaraf YG (2003) Alterations in the expression of transcription factors and the reduced folate carrier as a novel mechanism of antifolate resistance in human leukemia cells. J Biol Chem 278:8935–8941

    CAS  PubMed  Google Scholar 

  17. Rothem L, Stark M, Kaufman Y, Mayo L, Assaraf YG (2004) Reduced folate carrier gene silencing in multiple antifolate-resistant tumor cell lines is due to a simultaneous loss of function of multiple transcription factors but not promoter methylation. J Biol Chem 279:374–384

    CAS  PubMed  Google Scholar 

  18. Whetstine JR, Witt TL, Matherly LH (2002) The human reduced folate carrier gene is regulated by the AP2 and sp1 transcription factor families and a functional 61-base pair polymorphism. J Biol Chem 277:43873–43880

    CAS  PubMed  Google Scholar 

  19. Lein DO, Dervieux T, Park G, Barham R, Smith K, Walsh M et al (2003) Single nucleotide polymorphisms in the folate/purine synthesis pathway predict methotrexate's effects in rheumatoid arthritis [abstract]. Arthritis Rheum 48:S438

    Google Scholar 

  20. Chave KJ, Ryan TJ, Chmura SE, Galivan J (2003) Identification of single nucleotide polymorphisms in the human gamma-glutamyl hydrolase gene and characterization of promoter polymorphisms. Gene 319:167–175

    CAS  PubMed  Google Scholar 

  21. Dervieux T, Kremer J, Lein DO, Capps R, Barham R, Meyer G, Smith K et al (2004) Contribution of common polymorphisms in reduced folate carrier and gamma-glutamylhydrolase to methotrexate polyglutamate levels in patients with rheumatoid arthritis. Pharmacogenetics 14:733–739

    CAS  PubMed  Google Scholar 

  22. Cheng Q, Wu B, Kager L, Panetta JC, Zheng J, Pui CH et al (2004) A substrate specific functional polymorphism of human gamma-glutamyl hydrolase alters catalytic activity and methotrexate polyglutamate accumulation in acute lymphoblastic leukaemia cells. Pharmacogenetics 14:557–567

    CAS  PubMed  Google Scholar 

  23. Hayashi H, Fujimaki C, Daimon T, Tsuboi S, Matsuyama T, Itoh K (2009) Genetic polymorphisms in folate pathway enzymes as a possible marker for predicting the outcome of methotrexate therapy in Japanese patients with rheumatoid arthritis. J Clin Pharm Ther 34:355–361

    CAS  PubMed  Google Scholar 

  24. Dervieux T, Furst D, Lein DO, Capps R, Smith K, Walsh M 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

    CAS  PubMed  Google Scholar 

  25. Hoffmeyer S, Burk O, von Richter O, Arnold HP, Brockmoller J, Johne A et al (2000) Functional polymorphisms of the human multidrug-resistance gene: multiple sequence variations and correlation of one allele with P-glycoprotein expression and activity in vivo. Proc Natl Acad Sci U S A 97:3473–3478

    CAS  PubMed Central  PubMed  Google Scholar 

  26. Kim RB, Leake BF, Choo EF, Dresser GK, Kubba SV, Schwarz UI et al (2001) Identification of functionally variant MDR1 alleles among European Americans and African Americans. Clin Pharmacol Ther 70:189–199

    CAS  PubMed  Google Scholar 

  27. Tanabe M, Ieiri I, Nagata N, Inoue K, Ito S, Kanamori Y et al (2001) Expression of P-glycoprotein in human placenta: relation to genetic polymorphism of the multidrug resistance (MDR)-1 gene. J Pharmacol Exp Ther 297:1137–1143

    CAS  PubMed  Google Scholar 

  28. Norris MD, De Graaf D, Haber M, Kavallaris M, Madafiglio J, Gilbert J et al (1996) Involvement of MDR1 P-glycoprotein in multifactorial resistance to methotrexate. Int J Cancer 65:613–619

    CAS  PubMed  Google Scholar 

  29. Mickisch GH, Merlino GT, Galski H, Gottesman MM, Pastan I (1991) Transgenic mice that express the human multidrug-resistance gene in bone marrow enable a rapid identification of agents that reverse drug resistance. Proc Natl Acad Sci U S A 88:547–551

    CAS  PubMed Central  PubMed  Google Scholar 

  30. Morgan C, Hider SL, Bell E, Bruce IN (2002) Methotrexate is not a substrate for P-glycoprotein in patients with rheumatoid arthritis. Ann Rheum Dis 61:199

    Google Scholar 

  31. Pawlik A, Wrzesniewska J, Fiedorowicz-Fabrycy I, Gawronska-Szklarz B (2004) The MDR1 3435 polymorphism in patients with rheumatoid arthritis. Int J Clin Pharmacol Ther 42:496–503

    CAS  PubMed  Google Scholar 

  32. Rozen R (1996) Molecular genetics of methylenetetrahydrofolate reductase deficiency. J Inherit Metab Dis 19(5):589–594

    CAS  PubMed  Google Scholar 

  33. Frosst P, Blom HJ, Milos R, Goyette P, Sheppard CA, Matthews RG et al (1995) A candidate genetic risk factor for vascular disease: a common mutation in methylenetetrahydrofolate reductase. Nat Genet 10(1):111–113

    CAS  PubMed  Google Scholar 

  34. van der Put NM, Gabreels F, Stevens EM, Smeitink JA, Trijbels FJ, Eskes TK et al (1998) A second common mutation in the methylenetetrahydrofolate reductase gene: an additional risk factor for neural-tube defects? Am J Hum Genet 62(5):1044–1051

    PubMed Central  PubMed  Google Scholar 

  35. Kang SS, Zhou J, Wong PW, Kowalisyn J, Strokosch G (1988) Intermediate homocysteinemia: a thermolabile variant of methylenetetrahydrofolate reductase. Am J Hum Genet 43(4):414–421

    CAS  PubMed Central  PubMed  Google Scholar 

  36. Haagsma CJ, Blom HJ, van Riel PL, Van’t Hof MA, Giesendorf BA, van Oppenraaij-Emmerzaal D et al (1999) Influence of sulphasalazine, methotrexate, and the combination of both on plasma homocysteine concentrations in patients with rheumatoid arthritis. Ann Rheum Dis 58(2):79–84

    CAS  PubMed Central  PubMed  Google Scholar 

  37. van Ede AE, Laan RF, Blom HJ, Huizinga TW, Haagsma CJ, Giesendorf BA et al (2001) 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 44(11):2525–2530

    PubMed  Google Scholar 

  38. Berkun Y, Levartovsky D, Rubinow A, Orbach H, Aamar S, Grenader T 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

    CAS  PubMed Central  PubMed  Google Scholar 

  39. Urano W, Taniguchi A, Yamanaka H, Tanaka E, Nakajima H, Matsuda Y 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

    CAS  PubMed  Google Scholar 

  40. Dervieux T, Greenstein N, Kremer J (2006) Pharmacogenomic and metabolic biomarkers in the folate pathway and their association with methotrexate effects during dosage escalation in rheumatoid arthritis. Arthritis Rheum 54:3095–3103

    CAS  PubMed  Google Scholar 

  41. Kurzawski M, Pawlik A, Safranow K, Herczynska M, Drozdzik M (2007) 677C>T and 1298A>C MTHFR polymorphisms affect methotrexate treatment outcome in rheumatoid arthritis. Pharmacogenomics 8:1551–1559

    CAS  PubMed  Google Scholar 

  42. Wessels JA, de Vries-Bouwstra JK, Heijmans BT, Slagboom PE, Goekoop-Ruiterman YP, Allaart CF et al (2006) Efficacy and toxicity of methotrexate in early rheumatoid arthritis are associated with single-nucleotide polymorphisms in genes coding for folate pathway enzymes. Arthritis Rheum 54:1087–1095

    CAS  PubMed  Google Scholar 

  43. Taniguchi A, Urano W, Tanaka E, Furihata S, Kamitsuji S, Inoue E et al (2007) Validation of the associations between single nucleotide polymorphisms or haplotypes and responses to disease-modifying antirheumatic drugs in patients with rheumatoid arthritis: a proposal for prospective pharmacogenomic study in clinical practice. Pharmacogenet Genomics 17:383–390

    CAS  PubMed  Google Scholar 

  44. Kim SK, Jun JB, El-Sohemy A, Bae SC (2006) Cost-effectiveness analysis of MTHFR polymorphism screening by polymerase chain reaction in Korean patients with rheumatoid arthritis receiving methotrexate. J Rheumatol 33:1266–1274

    CAS  PubMed  Google Scholar 

  45. Xiao H, Xu J, Zhou X, Stankovich J, Pan F, Zhang Z et al (2010) Associations between the genetic polymorphisms of MTHFR and outcomes of methotrexate treatment in rheumatoid arthritis. Clin Exp Rheumatol 28:728–733

    CAS  PubMed  Google Scholar 

  46. Weisman MH, Furst DE, Park GS, Kremer JM, Smith KM, Wallace DJ et al (2006) Risk genotypes in folate-dependent enzymes and their association with methotrexate-related side effects in rheumatoid arthritis. Arthritis Rheum 54:607–612

    CAS  PubMed  Google Scholar 

  47. Ranganathan P, Culverhouse R, Marsh S, Mody A, Scott-Horton TJ, Brasington R et al (2008) Methotrexate (MTX) pathway gene polymorphisms and their effects on MTX toxicity in Caucasian and African American patients with rheumatoid arthritis. J Rheumatol 35:572–579

    CAS  PubMed  Google Scholar 

  48. Caliz R, del Amo J, Balsa A, Blanco F, Silva L, Sanmarti R et al (2012) The C677T polymorphism in the MTHFR gene is associated with the toxicity of methotrexate in a Spanish rheumatoid arthritis population. Scand J Rheumatol 41:10–14

    CAS  PubMed  Google Scholar 

  49. Fisher MC, Cronstein BN (2009) Metaanalysis of methylenetetrahydrofolate reductase (MTHFR) polymorphisms affecting methotrexate toxicity. J Rheumatol 36:539–545

    PubMed Central  PubMed  Google Scholar 

  50. Lee YH, Song GG (2010) Associations between the C677T and A1298C polymorphisms of MTHFR and the efficacy and toxicity of methotrexate in rheumatoid arthritis: a meta-analysis. Clin Drug Investig 30:101–108

    CAS  PubMed  Google Scholar 

  51. Horie N, Aiba H, Oguro K, Hojo H, Takeishi K (1995) Functional analysis and DNA polymorphism of the tandemly repeated sequences in the 5′-terminal regulatory region of the human gene for thymidylate synthase. Cell Struct Funct 20:191–197

    CAS  PubMed  Google Scholar 

  52. Kawakami K, Omura K, Kanehira E, Watanabe Y (1999) Polymorphic tandem repeats in the thymidylate synthase gene is associated with its protein expression in human gastrointestinal cancers. Anticancer Res 19:3249–3252

    CAS  PubMed  Google Scholar 

  53. DiPaolo A, Chu E (2004) The role of thymidylate synthase as a molecular biomarker [comment]. Clin Cancer Res 10:411–412

    CAS  PubMed  Google Scholar 

  54. Pullarkat ST, Stoehlmacher J, Ghaderi V, Xiong YP, Ingles SA, Sherrod A et al (2001) Thymidylate synthase gene polymorphism determines response and toxicity of 5-FU chemotherapy. Pharmacogenomics J 1:65–70

    CAS  PubMed  Google Scholar 

  55. Kawakami K, Watanabe G (2003) Identification and functional analysis of single nucleotide polymorphism in the tandem repeat sequence of thymidylate synthase gene. Cancer Res 63:6004–6007

    CAS  PubMed  Google Scholar 

  56. Ulrich CM, Bigler J, Velicer CM, Greene EA, Farin FM, Potter JD (2000) Searching expressed sequence tag databases: discovery and confirmation of a common polymorphism in the thymidylate synthase gene. Cancer Epidemiol Biomarkers Prev 9(12):1381–1385

    CAS  PubMed  Google Scholar 

  57. Grzybowska EA, Wilczynska A, Siedlecki JA (2001) Regulatory functions of 3′UTRs. Biochem Biophys Res Commun 288:291–295

    CAS  PubMed  Google Scholar 

  58. Kumagai K, Hiyama K, Oyama T, Maeda H, Kohno N (2003) Polymorphisms in the thymidylate synthase and methylenetetrahydrofolate reductase genes and sensitivity to the low-dose methotrexate therapy in patients with rheumatoid arthritis. Int J Mol Med 11(5):593–600

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  60. Sherr CJ (1994) G1 phase progression: cycling on cue. Cell 79:551–555

    CAS  PubMed  Google Scholar 

  61. Betticher DC, Thatcher N, Altermatt HJ, Hoban P, Ryder WD, Heighway J (1995) Alternate splicing produces a novel cyclin D1 transcript. Oncogene 11:1005–1011

    CAS  PubMed  Google Scholar 

  62. Lu F, Gladden AB, Diehl JA (2003) An alternatively spliced cyclin D1 isoform, cyclin D1b, is a nuclear oncogene. Cancer Res 63:7056–7061

    CAS  PubMed  Google Scholar 

  63. Hochhauser D, Schnieders B, Ercikan-Abali E, Gorlick R, Muise-Helmericks R, Li WW et al (1996) Effect of cyclin D1 overexpression on drug sensitivity in a human fibrosarcoma cell line. J Natl Cancer Inst 88:1269–1275

    CAS  PubMed  Google Scholar 

  64. Jekic B, Lukovic L, Bunjevacki V, Milic V, Novakovic I, Damnjanovic T et al (2013) Association of the TYMS 3G/3G genotype with poor response and GGH 354GG genotype with the bone marrow toxicity of the methotrexate in RA patients. Eur J Clin Pharmacol 69:377–383

    CAS  PubMed  Google Scholar 

  65. Grabar PB, Rojko S, Logar D, Dolzan V (2010) Genetic determinants of methotrexate treatment in rheumatoid arthritis patients: a study of polymorphisms in the adenosine pathway. Ann Rheum Dis 69:931–932

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  67. Marinaki AM, Ansari A, Duley JA, Arenas M, Sumi S, Lewis CM et al (2004) Adverse drug reactions to azathioprine therapy are associated with polymorphism in the gene encoding inosine triphosphate pyrophosphatase (ITPase). Pharmacogenetics 14:181–187

    CAS  PubMed  Google Scholar 

  68. Krynetski EY, Tai HL, Yates CR, Fessing MY, Loennechen T, Schuetz JD et al (1996) Genetic polymorphism of thiopurine S-methyltransferase: clinical importance and molecular mechanisms. Pharmacogenetics 6:279–290

    CAS  PubMed  Google Scholar 

  69. Tai HL, Krynetski EY, Yates CR, Loennechen T, Fessing MY, Krynetskaia NF et al (1996) Thiopurine S-methyltransferase deficiency: two nucleotide transitions define the most prevalent mutant allele associated with loss of catalytic activity in Caucasians. Am J Hum Genet 58(4):694–702

    CAS  PubMed Central  PubMed  Google Scholar 

  70. Tai HL, Krynetski EY, Schuetz EG, Yanishevski Y, Evans WE (1997) Enhanced proteolysis of thiopurine S-methyltransferase (TPMT) encoded by mutant alleles in humans (TPMT*3A, TPMT*2): mechanisms for the genetic polymorphism of TPMT activity. Proc Natl Acad Sci U S A 94:6444–6449

    CAS  PubMed Central  PubMed  Google Scholar 

  71. Yates CR, Krynetski EY, Loennechen T, Fessing MY, Tai HL, Pui CH et al (1997) Molecular diagnosis of thiopurine S-methyltransferase deficiency: genetic basis for azathioprine and mercaptopurine intolerance.[see comment]. Ann Intern Med 126(8):608–614

    CAS  PubMed  Google Scholar 

  72. Ameyaw MM, Collie-Duguid ES, Powrie RH, Ofori-Adjei D, McLeod HL (1999) Thiopurine methyltransferase alleles in British and Ghanaian populations. Hum Mol Genet 8(2):367–370

    CAS  PubMed  Google Scholar 

  73. Hon YY, Fessing MY, Pui CH, Relling MV, Krynetski EY, Evans WE (1999) Polymorphism of the thiopurine S-methyltransferase gene in African-Americans. Hum Mol Genet 8:371–376

    CAS  PubMed  Google Scholar 

  74. Evans WE, Hon YY, Bomgaars L, Coutre S, Holdsworth M, Janco R et al (2001) Preponderance of thiopurine S-methyltransferase deficiency and heterozygosity among patients intolerant to mercaptopurine or azathioprine. J Clin Oncol 19(8):2293–2301

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  76. Corominas H, Domenech M, Laiz A, Gich I, Geli C, Diaz C et al (2003) Is thiopurine methyltransferase genetic polymorphism a major factor for withdrawal of azathioprine in rheumatoid arthritis patients? Rheumatology 42(1):40–45

    CAS  PubMed  Google Scholar 

  77. Boonsrirat U, Angsuthum S, Vannaprasaht S, Kongpunvijit J, Hirankarn N, Tassaneeyakul W et al (2008) Azathioprine-induced fatal myelosuppression in systemic lupus erythematosus patient carrying TPMT*3C polymorphism. Lupus 17:132–134

    CAS  PubMed  Google Scholar 

  78. Higgs JE, Payne K, Roberts C, Newman WG (2010) Are patients with intermediate TPMT activity at increased risk of myelosuppression when taking thiopurine medications? Pharmacogenomics 11:177–188

    CAS  PubMed  Google Scholar 

  79. von Ahsen N, Armstrong VW, Behrens C, von Tirpitz C, Stallmach A, Herfarth H et al (2005) Association of inosine triphosphatase 94C>A and thiopurine S-methyltransferase deficiency with adverse events and study drop-outs under azathioprine therapy in a prospective Crohn disease study. Clin Chem 51:2282–2288

    Google Scholar 

  80. Shipkova M, Franz J, Abe M, Klett C, Wieland E, Andus T (2011) Association between adverse effects under azathioprine therapy and inosine triphosphate pyrophosphatase activity in patients with chronic inflammatory bowel disease. Ther Drug Monit 33:321–328

    CAS  PubMed  Google Scholar 

  81. Gearry RB, Roberts RL, Barclay ML, Kennedy MA (2004) Lack of association between the ITPA 94C>A polymorphism and adverse effects from azathioprine. Pharmacogenetics 14:779–781

    CAS  PubMed  Google Scholar 

  82. Eklund BI, Moberg M, Bergquist J, Mannervik B (2006) Divergent activities of human glutathione transferases in the bioactivation of azathioprine. Mol Pharmacol 70:747–754

    CAS  PubMed  Google Scholar 

  83. Stocco G, Martelossi S, Barabino A, Decorti G, Bartoli F, Montico M et al (2004) Glutathione-S-transferase genotypes and the adverse effects of azathioprine in young patients with inflammatory bowel disease. Inflamm Bowel Dis 13:57–64

    Google Scholar 

  84. Stocco G, Cuzzoni E, De Iudicibus S, Franca R, Favretto D, Malusa N et al (2013) Deletion of glutathione-S-transferase M1 reduces azathioprine metabolite concentrations in young patients with inflammatory bowel disease. J Clin Gastroenterol 48(1):43–51

    Google Scholar 

  85. Kerstens PJ, Stolk JN, De Abreu RA, Lambooy LH, van de Putte LB, Boerbooms AA (1995) Azathioprine-related bone marrow toxicity and low activities of purine enzymes in patients with rheumatoid arthritis. Arthritis Rheum 38:142–145

    CAS  PubMed  Google Scholar 

  86. Das KM, Eastwood MA, McManus JP, Sircus W (1973) Adverse reactions during salicylazosulfapyridine therapy and the relation with drug metabolism and acetylator phenotype. N Engl J Med 289:491–495

    CAS  PubMed  Google Scholar 

  87. Pullar T, Capell HA (1986) Variables affecting efficacy and toxicity of sulphasalazine in rheumatoid arthritis. A review. Drugs 32(Suppl 1):54–57

    PubMed  Google Scholar 

  88. Wadelius M, Stjernberg E, Wiholm BE, Rane A (2000) Polymorphisms of NAT2 in relation to sulphasalazine-induced agranulocytosis. Pharmacogenetics 10(1):35–41

    CAS  PubMed  Google Scholar 

  89. Kuhn UD, Anschutz M, Schmucker K, Schug BS, Hippius M, Blume HH (2010) Phenotyping with sulfasalazine - time dependence and relation to NAT2 pharmacogenetics. Int J Clin Pharmacol Ther 48:1–10

    CAS  PubMed  Google Scholar 

  90. Genovese MC, Bathon JM, Martin RW, Fleischmann RM, Tesser JR, Schiff MH et al (2002) Etanercept versus methotrexate in patients with early rheumatoid arthritis: two-year radiographic and clinical outcomes. Arthritis Rheum 46:1443–1450

    CAS  PubMed  Google Scholar 

  91. Maini RN, Breedveld FC, Kalden JR, Smolen JS, Davis D, Macfarlane JD et al (1998) Therapeutic efficacy of multiple intravenous infusions of anti-tumor necrosis factor alpha monoclonal antibody combined with low-dose weekly methotrexate in rheumatoid arthritis. Arthritis Rheum 41:1552–1563

    CAS  PubMed  Google Scholar 

  92. Keystone EC, Kavanaugh AF, Sharp JT, Tannenbaum H, Hua Y, Teoh LS et al (2004) Radiographic, clinical, and functional outcomes of treatment with adalimumab (a human anti-tumor necrosis factor monoclonal antibody) in patients with active rheumatoid arthritis receiving concomitant methotrexate therapy: a randomized, placebo-controlled, 52-week trial. Arthritis Rheum 50:1400–1411

    CAS  PubMed  Google Scholar 

  93. Seitz M, Wirthmuller U, Moller B, Villiger PM (2007) The -308 tumour necrosis factor-alpha gene polymorphism predicts therapeutic response to TNFalpha-blockers in rheumatoid arthritis and spondyloarthritis patients. Rheumatology (Oxf) 46:93–96

    CAS  Google Scholar 

  94. Cuchacovich M, Ferreira L, Aliste M, Soto L, Cuenca J, Cruzat A et al (2004) Tumour necrosis factor-alpha (TNF-alpha) levels and influence of -308 TNF-alpha promoter polymorphism on the responsiveness to infliximab in patients with rheumatoid arthritis. Scand J Rheumatol 33:228–232

    CAS  PubMed  Google Scholar 

  95. Pavy S, Toonen EJ, Miceli-Richard C, Barrera P, van Riel PL, Criswell LA et al (2010) Tumour necrosis factor alpha -308G->A polymorphism is not associated with response to TNFalpha blockers in Caucasian patients with rheumatoid arthritis: systematic review and meta-analysis. Ann Rheum Dis 69:1022–1028

    CAS  PubMed  Google Scholar 

  96. Lee YH, Ji JD, Bae SC, Song GG (2010) Associations between tumor necrosis factor-alpha (TNF-alpha) -308 and -238 G/A polymorphisms and shared epitope status and responsiveness to TNF-alpha blockers in rheumatoid arthritis: a metaanalysis update. J Rheumatol 37:740–746

    CAS  PubMed  Google Scholar 

  97. Zeng Z, Duan Z, Zhang T, Wang S, Li G, Gao J et al (2013) Association between tumor necrosis factor-alpha (TNF-alpha) promoter -308 G/A and response to TNF-alpha blockers in rheumatoid arthritis: a meta-analysis. Modern Rheumatol/Jpn Rheum Assoc 23:489–495

    CAS  Google Scholar 

  98. Maxwell JR, Potter C, Hyrich KL, Barton A, Worthington J, Isaacs JD et al (2008) Association of the tumour necrosis factor-308 variant with differential response to anti-TNF agents in the treatment of rheumatoid arthritis. Hum Mol Genet 17:3532–3538

    CAS  PubMed  Google Scholar 

  99. Fabris M, Tolusso B, Di Poi E, Assaloni R, Sinigaglia L, Ferraccioli G (2002) Tumor necrosis factor-alpha receptor II polymorphism in patients from southern Europe with mild-moderate and severe rheumatoid arthritis. J Rheumatol 29:1847–1850

    CAS  PubMed  Google Scholar 

  100. Santee SM, Owen-Schaub LB (1996) Human tumor necrosis factor receptor p75/80 (CD120b) gene structure and promoter characterization. J Biol Chem 271:21151–21159

    CAS  PubMed  Google Scholar 

  101. Morita C, Horiuchi T, Tsukamoto H, Hatta N, Kikuchi Y, Arinobu Y et al (2001) Association of tumor necrosis factor receptor type II polymorphism 196R with Systemic lupus erythematosus in the Japanese: molecular and functional analysis. Arthritis Rheum 44:2819–2827

    CAS  PubMed  Google Scholar 

  102. Ongaro A, De Mattei M, Pellati A, Caruso A, Ferretti S, Masieri FF et al (2008) Can tumor necrosis factor receptor II gene 676T>G polymorphism predict the response grading to anti-TNFalpha therapy in rheumatoid arthritis? Rheumatol Int 28:901–908

    CAS  PubMed  Google Scholar 

  103. Vasilopoulos Y, Bagiatis V, Stamatopoulou D, Zisopoulos D, Alexiou I, Sarafidou T et al (2011) Association of anti-CCP positivity and carriage of TNFRII susceptibility variant with anti-TNF-alpha response in rheumatoid arthritis. Clin Exp Rheumatol 29:701–704

    CAS  PubMed  Google Scholar 

  104. Criswell LA, Lum RF, Turner KN, Woehl B, Zhu Y, Wang J 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

    CAS  PubMed  Google Scholar 

  105. Gregersen PK, Silver J, Winchester RJ (1987) The shared epitope hypothesis. An approach to understanding the molecular genetics of susceptibility to rheumatoid arthritis. Arthritis Rheum 30:1205–1213

    CAS  PubMed  Google Scholar 

  106. Waldron-Lynch F, Adams C, Amos C, Zhu DK, McDermott MF, Shanahan F et al (2001) Tumour necrosis factor 5′ promoter single nucleotide polymorphisms influence susceptibility to rheumatoid arthritis (RA) in immunogenetically defined multiplex RA families. Genes Immun 2:82–87

    CAS  PubMed  Google Scholar 

  107. Mulcahy B, Waldron-Lynch F, McDermott MF, Adams C, Amos CI, Zhu DK et al (1996) Genetic variability in the tumor necrosis factor-lymphotoxin region influences susceptibility to rheumatoid arthritis. Am J Hum Genet 59:676–683

    CAS  PubMed Central  PubMed  Google Scholar 

  108. Martinez A, Salido M, Bonilla G, Pascual-Salcedo D, Fernandez-Arquero M, de Miguel S et al (2004) Association of the major histocompatibility complex with response to infliximab therapy in rheumatoid arthritis patients. Arthritis Rheum 50:1077–1082

    CAS  PubMed  Google Scholar 

  109. Stahl EA, Raychaudhuri S, Remmers EF, Xie G, Eyre S, Thomson BP et al (2010) Genome-wide association study meta-analysis identifies seven new rheumatoid arthritis risk loci. Nat Genet 42:508–514

    CAS  PubMed  Google Scholar 

  110. Cui J, Saevarsdottir S, Thomson B, Padyukov L, van der Helm-van Mil AH, Nititham J et al (2010) Rheumatoid arthritis risk allele PTPRC is also associated with response to anti-tumor necrosis factor alpha therapy. Arthritis Rheum 62:1849–1861

    CAS  PubMed Central  PubMed  Google Scholar 

  111. Plant D, Prajapati R, Hyrich KL, Morgan AW, Wilson AG, Isaacs JD et al (2012) Replication of association of the PTPRC gene with response to anti-tumor necrosis factor therapy in a large UK cohort. Arthritis Rheum 64:665–670

    CAS  PubMed Central  PubMed  Google Scholar 

  112. Krintel SB, Palermo G, Johansen JS, Germer S, Essioux L, Benayed R et al (2012) Investigation of single nucleotide polymorphisms and biological pathways associated with response to TNFalpha inhibitors in patients with rheumatoid arthritis. Pharmacogenet Genomics 22:577–589

    CAS  PubMed  Google Scholar 

  113. Bowes JD, Potter C, Gibbons LJ, Hyrich K, Plant D, Morgan AW et al (2009) Investigation of genetic variants within candidate genes of the TNFRSF1B signalling pathway on the response to anti-TNF agents in a UK cohort of rheumatoid arthritis patients. Pharmacogenet Genomics 19:319–323

    CAS  PubMed  Google Scholar 

  114. Coulthard LR, Taylor JC, Eyre S, Robinson JI, Wilson AG, Isaacs JD et al (2011) Genetic variants within the MAP kinase signalling network and anti-TNF treatment response in rheumatoid arthritis patients. Ann Rheum Dis 70:98–103

    PubMed  Google Scholar 

  115. Barton A, Eyre S, Ke X, Hinks A, Bowes J, Flynn E et al (2009) Identification of AF4/FMR2 family, member 3 (AFF3) as a novel rheumatoid arthritis susceptibility locus and confirmation of two further pan-autoimmune susceptibility genes. Hum Mol Genet 18:2518–2522

    CAS  PubMed Central  PubMed  Google Scholar 

  116. Hafler JP, Maier LM, Cooper JD, Plagnol V, Hinks A, Simmonds MJ et al (2009) CD226 Gly307Ser association with multiple autoimmune diseases. Genes Immun 10:5–10

    CAS  PubMed Central  PubMed  Google Scholar 

  117. Tan RJ, Gibbons LJ, Potter C, Hyrich KL, Morgan AW, Wilson AG et al (2010) Investigation of rheumatoid arthritis susceptibility genes identifies association of AFF3 and CD226 variants with response to anti-tumour necrosis factor treatment. Ann Rheum Dis 69:1029–1035

    CAS  PubMed Central  PubMed  Google Scholar 

  118. Marotte H, Pallot-Prades B, Grange L, Tebib J, Gaudin P, Alexandre C et al (2006) The shared epitope is a marker of severity associated with selection for, but not with response to, infliximab in a large rheumatoid arthritis population. Ann Rheum Dis 65:342–347

    CAS  PubMed Central  PubMed  Google Scholar 

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

    CAS  PubMed Central  PubMed  Google Scholar 

  120. Schotte H, Schluter B, Drynda S, Willeke P, Tidow N, Assmann G 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

    CAS  PubMed Central  PubMed  Google Scholar 

  121. Jancic I, Arsenovic-Ranin N, Sefik-Bukilica M, Zivojinovic S, Damjanov N, Spasovski V et al (2013) 174G/C interleukin-6 gene promoter polymorphism predicts therapeutic response to etanercept in rheumatoid arthritis. Rheumatol Int 33:1481–1486

    CAS  PubMed  Google Scholar 

  122. Potter C, Cordell HJ, Barton A, Daly AK, Hyrich KL, Mann DA et al (2010) Association between anti-tumour necrosis factor treatment response and genetic variants within the TLR and NF{kappa}B signalling pathways. Ann Rheum Dis 69:1315–1320

    CAS  PubMed  Google Scholar 

  123. Tutuncu Z, Kavanaugh A, Zvaifler N, Corr M, Deutsch R, Boyle D (2005) Fcgamma receptor type IIIA polymorphisms influence treatment outcomes in patients with inflammatory arthritis treated with tumor necrosis factor alpha-blocking agents. Arthritis Rheum 52:2693–2696

    CAS  PubMed  Google Scholar 

  124. Canete JD, Suarez B, Hernandez MV, Sanmarti R, Rego I, Celis R et al (2009) Influence of variants of Fc gamma receptors IIA and IIIA on the American College of Rheumatology and European League against rheumatism responses to anti-tumour necrosis factor alpha therapy in rheumatoid arthritis. Ann Rheum Dis 68:1547–1552

    CAS  PubMed  Google Scholar 

  125. Tsukahara S, Ikari K, Sato E, Yamanaka H, Hara M, Tomatsu T et al (2008) A polymorphism in the gene encoding the Fcgamma IIIA receptor is a possible genetic marker to predict the primary response to infliximab in Japanese patients with rheumatoid arthritis. Ann Rheum Dis 67:1791–1792

    CAS  PubMed  Google Scholar 

  126. Kastbom A, Bratt J, Ernestam S, Lampa J, Padyukov L, Soderkvist P et al (2007) Fcgamma receptor type IIIA genotype and response to tumor necrosis factor alpha-blocking agents in patients with rheumatoid arthritis. Arthritis Rheum 56:448–452

    CAS  PubMed  Google Scholar 

  127. Liu C, Batliwalla F, Li W, Lee A, Roubenoff R, Beckman E et al (2008) Genome-wide association scan identifies candidate polymorphisms associated with differential response to anti-TNF treatment in rheumatoid arthritis. Mol Med (Camb) 14:575–581

    CAS  Google Scholar 

  128. Plant D, Bowes J, Potter C, Hyrich KL, Morgan AW, Wilson AG et al (2011) Genome-wide association study of genetic predictors of anti-tumor necrosis factor treatment efficacy in rheumatoid arthritis identifies associations with polymorphisms at seven loci. Arthritis Rheum 63:645–653

    CAS  PubMed Central  PubMed  Google Scholar 

  129. Umicevic Mirkov M, Cui J, Vermeulen SH, Stahl EA, Toonen EJ, Makkinje RR et al (2013) Genome-wide association analysis of anti-TNF drug response in patients with rheumatoid arthritis. Ann Rheum Dis 72:1375–1381

    PubMed  Google Scholar 

  130. Martin M, Romero X, de la Fuente MA, Tovar V, Zapater N, Esplugues E et al (2001) CD84 functions as a homophilic adhesion molecule and enhances IFN-gamma secretion: adhesion is mediated by Ig-like domain 1. J Immunol (Balt) 167:3668–3676

    CAS  Google Scholar 

  131. Tangye SG, Nichols KE, Hare NJ, van de Weerdt BC (2003) Functional requirements for interactions between CD84 and Src homology 2 domain-containing proteins and their contribution to human T cell activation. J Immunol (Balt) 171:2485–2495

    CAS  Google Scholar 

  132. Cui J, Stahl EA, Saevarsdottir S, Miceli C, Diogo D, Trynka G et al (2013) Genome-wide association study and gene expression analysis identifies CD84 as a predictor of response to etanercept therapy in rheumatoid arthritis. PLoS Genet 9:e1003394

    CAS  PubMed Central  PubMed  Google Scholar 

  133. Acosta-Colman I, Palau N, Tornero J, Fernandez-Nebro A, Blanco F, Gonzalez-Alvaro I et al (2013) GWAS replication study confirms the association of PDE3A-SLCO1C1 with anti-TNF therapy response in rheumatoid arthritis. Pharmacogenomics 14:727–734

    CAS  PubMed  Google Scholar 

  134. Daien CI, Fabre S, Rittore C, Soler S, Daien V, Tejedor G et al (2012) TGF beta1 polymorphisms are candidate predictors of the clinical response to rituximab in rheumatoid arthritis. Joint Bone Spine 79:471–475

    CAS  PubMed  Google Scholar 

  135. Coenen MJ, Gregersen PK (2009) Rheumatoid arthritis: a view of the current genetic landscape. Genes Immun 10:101–111

    CAS  PubMed Central  PubMed  Google Scholar 

  136. Boissier MC (2011) Cell and cytokine imbalances in rheumatoid synovitis. Joint Bone Spine 78:230–234

    CAS  PubMed  Google Scholar 

  137. Guo Z, Binswanger U, Knoflach A (2002) Role of codon 10 and codon 25 polymorphisms on TGF-beta 1 gene expression and protein synthesis in stable renal allograft recipients. Transplant Proc 34:2904–2906

    CAS  PubMed  Google Scholar 

  138. Ruyssen-Witrand A, Rouanet S, Combe B, Dougados M, Le Loet X, Sibilia J et al (2013) Association between -871C>T promoter polymorphism in the B-cell activating factor gene and the response to rituximab in rheumatoid arthritis patients. Rheumatology (Oxf) 52:636–641

    CAS  Google Scholar 

  139. Fabris M, Quartuccio L, Vital E, Pontarini E, Salvin S, Fabro C et al (2013) The TTTT B lymphocyte stimulator promoter haplotype is associated with good response to rituximab therapy in seropositive rheumatoid arthritis resistant to tumor necrosis factor blockers. Arthritis Rheum 65:88–97

    CAS  PubMed  Google Scholar 

  140. Ruyssen-Witrand A, Rouanet S, Combe B, Dougados M, Le Loet X, Sibilia J et al (2012) Fcgamma receptor type IIIA polymorphism influences treatment outcomes in patients with rheumatoid arthritis treated with rituximab. Ann Rheum Dis 71:875–877

    CAS  PubMed  Google Scholar 

  141. Quartuccio L, Fabris M, Pontarini E, Salvin S, Zabotti A, Benucci M et al (2013) The 158VV Fcgamma receptor 3A genotype is associated with response to rituximab in rheumatoid arthritis: results of an Italian multicentre study. Ann Rheum Dis 73(4):716–721

    PubMed  Google Scholar 

  142. Kastbom A, Coster L, Arlestig L, Chatzidionysiou A, van Vollenhoven RF, Padyukov L et al (2012) Influence of FCGR3A genotype on the therapeutic response to rituximab in rheumatoid arthritis: an observational cohort study. BMJ Open 2(5):pii: e001524

    Google Scholar 

  143. Sarsour K, Greenberg J, Johnston JA, Nelson DR, O'Brien LA, Oddoux C et al (2013) The role of the FcGRIIIa polymorphism in modifying the association between treatment and outcome in patients with rheumatoid arthritis treated with rituximab versus TNF-alpha antagonist therapies. Clin Exp Rheumatol 31:189–194

    PubMed  Google Scholar 

  144. Fabris M, Quartuccio L, Lombardi S, Saracco M, Atzeni F, Carletto A (2012) The CC homozygosis of the -174G>C IL-6 polymorphism predicts a lower efficacy of rituximab therapy in rheumatoid arthritis. Autoimmun Rev 11:315–320

    CAS  PubMed  Google Scholar 

  145. Wang J, Bansal AT, Martin M, Germer S, Benayed R, Essioux L et al (2013) Genome-wide association analysis implicates the involvement of eight loci with response to tocilizumab for the treatment of rheumatoid arthritis. Pharmacogenomics J 13:235–241

    PubMed  Google Scholar 

  146. Ranganathan P, Culverhouse R, Marsh S, Ahluwalia R, Shannow WD, Eisen S et al (2004) Simple nucleotide polymorphism profiling across the Methotrexate pathway in normal subjects and patients with rheumatoid arthritis. Pharmacogenomics 5(5):559–569

    Google Scholar 

  147. Veenstra DL, Higashi MK, Phillips KA (2000) Assessing the cost-effectiveness of pharmacogenomics. AAPS Pharmsci 2:E29

    CAS  PubMed  Google Scholar 

  148. Ranganathan P, Mcleod HL (2006) Methotrexate pharmacogenetics: first step toward individualized therapy in rheumatoid arthritis. Arthritis Rheum 54(5):1366–1377

    Google Scholar 

  149. Ranganathan P (2005) Pharmacogenomics of tumor necrosis factor antagonists in rheumatoid arthritis. Pharmacogenomics 2(4):279–282

    Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Prabha Ranganathan .

Editor information

Editors and Affiliations

Rights and permissions

Reprints and permissions

Copyright information

© 2014 Springer Science+Business Media New York

About this protocol

Cite this protocol

Sen, D., Paul, J.R., Ranganathan, P. (2014). Pharmacogenetics in Rheumatoid Arthritis. In: Yan, Q. (eds) Pharmacogenomics in Drug Discovery and Development. Methods in Molecular Biology, vol 1175. Humana Press, New York, NY. https://doi.org/10.1007/978-1-4939-0956-8_16

Download citation

  • DOI: https://doi.org/10.1007/978-1-4939-0956-8_16

  • Published:

  • Publisher Name: Humana Press, New York, NY

  • Print ISBN: 978-1-4939-0955-1

  • Online ISBN: 978-1-4939-0956-8

  • eBook Packages: Springer Protocols

Publish with us

Policies and ethics