Three decades of low-dose methotrexate in rheumatoid arthritis: Can we predict toxicity?

Immunologic Research

Volumn 60, Issue 2-3, 2014, Pages 289-310

  Romão, Vasco C ^a,b   Lima, Aurea ^c,d,e   Bernardes, Miguel ^f,g   Canhão, Helena ^a,b   Fonseca, João Eurico ^a,b  

^a INSTITUTO DE MEDICINA MOLECULAR   (Portugal)

^b HOSPITAL DE SANTA MARIA   (Portugal)

^c UNIVERSITY INSTITUTE OF HEALTH SCIENCES IUCS   (Portugal)

^d PORTUGUESE ONCOLOGY INSTITUTE   (Portugal)

^e UNIVERSITY OF PORTO   (Portugal)

^f University of Porto   (Portugal)

^g HOSPITAL DE SÃO JOÃO   (Portugal)

Author keywords

Adverse drug reactions; Methotrexate; Predictors; Rheumatoid arthritis; Toxicity

Indexed keywords

5,10 METHYLENETETRAHYDROFOLATE REDUCTASE (FADH2); ADENOSINE MONOPHOSPHATE DEAMINASE; ADENOSINE MONOPHOSPHATE DEAMINASE 1; ADENOSINE RECEPTOR; ADENOSINE RECEPTOR SUBTYPE A2A; BREAST CANCER RESISTANCE PROTEIN; DIHYDROFOLATE REDUCTASE; FOLIC ACID; FOLYLPOLYGLUTAMATE SYNTHASE; GAMMA GLUTAMYL HYDROLASE; GLYCINE HYDROXYMETHYLTRANSFERASE; METHIONINE SYNTHASE REDUCTASE; METHOTREXATE; METHYLTRANSFERASE; MULTIDRUG RESISTANCE ASSOCIATED PROTEIN 1; MULTIDRUG RESISTANCE ASSOCIATED PROTEIN 2; MULTIDRUG RESISTANCE PROTEIN 1; REDUCED FOLATE CARRIER; SERINE HYDROXYMETHYLTRANSFERASE 1; THYMIDYLATE SYNTHASE; UNCLASSIFIED DRUG; ANTIRHEUMATIC AGENT; CARRIER PROTEIN;

BLOOD TOXICITY; DIZZINESS; FATIGUE; GASTROINTESTINAL TOXICITY; GENETIC ASSOCIATION; HEADACHE; HUMAN; LIVER TOXICITY; LOW DRUG DOSE; LUNG TOXICITY; META ANALYSIS (TOPIC); MOOD CHANGE; MOOD DISORDER; MUCOSAL DISEASE; MUCOSAL TOXICITY; PATIENT CARE; PRIORITY JOURNAL; PROPHYLAXIS; RANDOMIZED CONTROLLED TRIAL (TOPIC); REVIEW; RHEUMATOID ARTHRITIS; SKIN TOXICITY; SYSTEMATIC REVIEW (TOPIC); VERTIGO; VITAMIN SUPPLEMENTATION; ARTHRITIS, RHEUMATOID; DIET SUPPLEMENTATION; DRUG-RELATED SIDE EFFECTS AND ADVERSE REACTIONS; GENETICS; METABOLISM; PHARMACOGENETICS; PROGNOSIS; SIGNAL TRANSDUCTION;

ANTIRHEUMATIC AGENTS; ARTHRITIS, RHEUMATOID; CARRIER PROTEINS; DIETARY SUPPLEMENTS; DRUG-RELATED SIDE EFFECTS AND ADVERSE REACTIONS; FOLIC ACID; HUMANS; METHOTREXATE; PHARMACOGENETICS; PROGNOSIS; SIGNAL TRANSDUCTION;

EID: 84922076493     PISSN: 0257277X     EISSN: 15590755     Source Type: Journal    
DOI: 10.1007/s12026-014-8564-6     Document Type: Review

References (168)

1. Smolen JS, Landewé R, Breedveld FC, Buch M, Burmester G, Dougados M, et al. EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2013 update. Ann Rheum Dis. 2014;73:492–509.
2. Visser K, Katchamart W, Loza E, Martinez-Lopez JA, Salliot C, Trudeau J, et al. Multinational evidence-based recommendations for the use of methotrexate in rheumatic disorders with a focus on rheumatoid arthritis: integrating systematic literature research and expert opinion of a broad international panel of rheumatologists in the 3E. Ann Rheum Dis. 2009;68:1086–93.
3. Saevarsdottir S, Wallin H, Seddighzadeh M, Ernestam S, Geborek P, Petersson IF, et al. Predictors of response to methotrexate in early DMARD naive rheumatoid arthritis: results from the initial open-label phase of the SWEFOT trial. Ann Rheum Dis. 2011;70:469–75.
4. Hider SL, Buckley C, Silman AJ, Symmons DPM, Bruce IN. Factors influencing response to disease modifying antirheumatic drugs in patients with rheumatoid arthritis. J Rheumatol. 2005;32:11–6.
5. Maetzel A, Wong A, Strand V, Tugwell P, Wells G, Bombardier C. Meta-analysis of treatment termination rates among rheumatoid arthritis patients receiving disease-modifying anti-rheumatic drugs. Rheumatology. 2000;39:975–81.
6. Kremer JM, Phelps CT. Long-term prospective study of the use of methotrexate in the treatment of rheumatoid arthritis. Update after a mean of 90 months. Arthritis Rheum. 1992;35:138–45.
7. Van Jaarsveld CH, Jahangier ZN, Jacobs JW, Blaauw AA, van Albada-Kuipers GA, ter Borg EJ, et al. Toxicity of anti-rheumatic drugs in a randomized clinical trial of early rheumatoid arthritis. Rheumatology (Oxford). 2000;39:1374–82.
8. Alarcon GS, Tracy IC, Blackburn WD Jr. Methotrexate in rheumatoid arthritis. Toxic effects as the major factor in limiting long-term treatment. Arthritis Rheum. 1989;32:671–6.
9. Bologna C, Viu P, Picot MC, Jorgensen C, Sany J. Long-term follow-up of 453 rheumatoid arthritis patients treated with methotrexate: an open, retrospective, observational study. Br J Rheumatol. 1997;36:535–40.
10. Salliot C, van der Heijde D. Long-term safety of methotrexate monotherapy in patients with rheumatoid arthritis: a systematic literature research. Ann Rheum Dis. 2009;68:1100–4.
11. Rau R, Herborn G. Benefit and risk of methotrexate treatment in rheumatoid arthritis. Clin Exp Rheumatol. 2004;22:S83–94.
12. Albrecht K, Müller-Ladner U. Side effects and management of side effects of methotrexate in rheumatoid arthritis. Clin Exp Rheumatol. 2010;28:S95–101.
13. Yazici Y, Sokka T, Kautiainen H, Swearingen C, Kulman I, Pincus T. Long term safety of methotrexate in routine clinical care: discontinuation is unusual and rarely the result of laboratory abnormalities. Ann Rheum Dis. 2005;64:207–11.
14. Ohosone Y, Okano Y, Kameda H, Fujii T, Hama N, Hirakata M, et al. Clinical characteristics of patients with rheumatoid arthritis and methotrexate induced pneumonitis. J Rheumatol. 1997;24:2299–303.
15. Walker AM, Funch D, Dreyer NA, Tolman KG, Kremer JM, Alarcón GS, et al. Determinants of serious liver disease among patients receiving low-dose methotrexate for rheumatoid arthritis. Arthritis Rheum. 1993;36:329–35.
16. Gutierrez-Ureña S, Molina JF, García CO, Cuéllar ML, Espinoza LR. Pancytopenia secondary to methotrexate therapy in rheumatoid arthritis. Arthritis Rheum. 1996;39:272–6.
17. Lima A, Bernardes M, Sousa H, Azevedo R, Costa L, Ventura F, et al. SLC19A1 80G allele as a biomarker of methotrexate-related gastrointestinal toxicity in Portuguese rheumatoid arthritis patients. Pharmacogenomics. 2014;15:807–20.
18. Kent PD, Luthra HS, Michet C. Risk factors for methotrexate-induced abnormal laboratory monitoring results in patients with rheumatoid arthritis. J Rheumatol. 2004;31:1727–31.
19. Felson DT, Anderson JJ, Meenan RF. Use of short-term efficacy/toxicity tradeoffs to select second-line drugs in rheumatoid arthritis. A metaanalysis of published clinical trials. Arthritis Rheum. 1992;35:1117–25.
20. Romao VC, Canhao H, Fonseca JE. Old drugs, old problems: where do we stand in prediction of rheumatoid arthritis responsiveness to methotrexate and other synthetic DMARDs? BMC Med. 2013;11:17.
21. Hider SL, Silman AJ, Thomson W, Lunt M, Bunn D, Symmons DPM. Can clinical factors at presentation be used to predict outcome of treatment with methotrexate in patients with early inflammatory polyarthritis? Ann Rheum Dis. 2009;68:57–62.
22. Lima A, Monteiro J, Bernardes M, Sousa H, Azevedo R, Seabra V, et al. Prediction of methotrexate clinical response in Portuguese rheumatoid arthritis patients: implication of MTHFR rs1801133 and ATIC rs4673993 polymorphisms. Biomed Res Int. 2014;2014:368681.
23. Inoue K, Yuasa H. Molecular basis for pharmacokinetics and pharmacodynamics of methotrexate in rheumatoid arthritis therapy. Drug Metab Pharmacokinet. 2014;29:12–9.
24. Aletaha D, Kapral T, Smolen JS. Toxicity profiles of traditional disease modifying antirheumatic drugs for rheumatoid arthritis. Ann Rheum Dis. 2003;62:482–6.
25. Buhroo AM, Ortho MS. Adverse effects of low-dose methotrexate in patients with rheumatoid arthritis. Indian J Phys Med Rehabil. 2006;17:21–5.
26. Verstappen SMM, Bakker MF, Heurkens AHM, van der Veen MJ, Kruize AA, Geurts MAW, et al. Adverse events and factors associated with toxicity in patients with early rheumatoid arthritis treated with methotrexate tight control therapy: the CAMERA study. Ann Rheum Dis. 2010;69:1044–8.
27. Dalkilic E, Sahbazlar M, Gullulu M, Yavuz M, Dilek K, Ersoy A, et al. The time course of gastric methotrexate intolerance in patients with rheumatoid arthritis and psoriatic arthritis. Mod Rheumatol. 2013;23:525–8.
28. Ujfalussy I, Koó E, Seszták M, Gergely P. Termination of disease-modifying antirheumatic drugs in rheumatoid arthritis and in psoriatic arthritis. A comparative study of 270 cases. Z Rheumatol. 2003;62:155–60.
29. Visser K, van der Heijde DMFM. Risk and management of liver toxicity during methotrexate treatment in rheumatoid and psoriatic arthritis: a systematic review of the literature. Clin Exp Rheumatol. 2009;27:1017–1025.
30. Rau R, Karger T, Herborn G, Frenzel H. Liver biopsy findings in patients with rheumatoid arthritis undergoing longterm treatment with methotrexate. J Rheumatol. 1989;16:489–93.
31. Rau R, Schleusser B, Herborn G, Karger T. Long-term treatment of destructive rheumatoid arthritis with methotrexate. J Rheumatol. 1997;24:1881–9.
32. Kalantzis A, Marshman Z, Falconer DT, Morgan PR, Odell EW. Oral effects of low-dose methotrexate treatment. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2005;100:52–62.
33. Kerstens PJ, Boerbooms AM, Jeurissen ME, Fast JH, Assmann KJ, van de Putte LB. Accelerated nodulosis during low dose methotrexate therapy for rheumatoid arthritis. An analysis of ten cases. J Rheumatol. 1992;19:867–71.
34. Weinblatt ME, Trentham DE, Fraser PA, Holdsworth DE, Falchuk KR, Weissman BN, et al. Long-term prospective trial of low-dose methotrexate in rheumatoid arthritis. Arthritis Rheum. 1988;31:167–75.
35. Kremer JM, Alarcón GS, Weinblatt ME, Kaymakcian MV, Macaluso M, Cannon GW, et al. Clinical, laboratory, radiographic, and histopathologic features of methotrexate-associated lung injury in patients with rheumatoid arthritis: a multicenter study with literature review. Arthritis Rheum. 1997;40:1829–37.
36. Golden MR, Katz RS, Balk RA, Golden HE. The relationship of preexisting lung disease to the development of methotrexate pneumonitis in patients with rheumatoid arthritis. J Rheumatol. 1995;22:1043–7.
37. Willkens RF, Urowitz MB, Stablein DM, McKendry RJ, Berger RG, Box JH, et al. Comparison of azathioprine, methotrexate, and the combination of both in the treatment of rheumatoid arthritis. A controlled clinical trial. Arthritis Rheum. 1992;35:849–56.
38. Conway R, Low C, Coughlan RJ, O’Donnell MJ, Carey JJ. Methotrexate and lung disease in rheumatoid arthritis: a meta-analysis of randomized controlled trials. Arthritis Rheumatol (Hoboken, NJ). 2014;66:803–12.
39. Wolfe F, Caplan L, Michaud K. Treatment for rheumatoid arthritis and the risk of hospitalization for pneumonia: associations with prednisone, disease-modifying antirheumatic drugs, and anti-tumor necrosis factor therapy. Arthritis Rheum. 2006;54:628–34.
40. Kremer JM, Petrillo GF, Hamilton RA. Pharmacokinetics and renal function in patients with rheumatoid arthritis receiving a standard dose of oral weekly methotrexate: association with significant decreases in creatinine clearance and renal clearance of the drug after 6 months of therapy. J Rheumatol. 1995;22:38–40.
41. Seideman P, Müller-Suur R, Ekman E. Renal effects of low dose methotrexate in rheumatoid arthritis. J Rheumatol. 1993;20:1126–8.
42. The effect of age and renal function on the efficacy and toxicity of methotrexate in rheumatoid arthritis. Rheumatoid Arthritis Clinical Trial Archive Group. J Rheumatol 1995;22:218–23.
43. Kamel OW, van de Rijn M, LeBrun DP, Weiss LM, Warnke RA, Dorfman RF. Lymphoid neoplasms in patients with rheumatoid arthritis and dermatomyositis: frequency of Epstein-Barr virus and other features associated with immunosuppression. Hum Pathol. 1994;25:638–43.
44. Van der Veen MJ, van der Heide A, Kruize AA, Bijlsma JW. Infection rate and use of antibiotics in patients with rheumatoid arthritis treated with methotrexate. Ann Rheum Dis. 1994;53:224–8.
45. Singh G, Fries JF, Williams CA, Zatarain E, Spitz P, Bloch DA. Toxicity profiles of disease modifying antirheumatic drugs in rheumatoid arthritis. J Rheumatol. 1991;18:188–94.
46. Bernatsky S, Hudson M, Suissa S. Anti-rheumatic drug use and risk of serious infections in rheumatoid arthritis. Rheumatology (Oxford). 2007;46:1157–60.
47. Doran MF, Crowson CS, Pond GR, O’Fallon WM, Gabriel SE. Predictors of infection in rheumatoid arthritis. Arthritis Rheum. 2002;46:2294–300.
48. Smitten AL, Choi HK, Hochberg MC, Suissa S, Simon TA, Testa MA, et al. The risk of hospitalized infection in patients with rheumatoid arthritis. J Rheumatol. 2008;35:387–93.
49. McLean-Tooke A, Aldridge C, Waugh S, Spickett GP, Kay L. Methotrexate, rheumatoid arthritis and infection risk: what is the evidence? Rheumatology (Oxford). 2009;48:867–71.
50. Grennan DM, Gray J, Loudon J, Fear S. Methotrexate and early postoperative complications in patients with rheumatoid arthritis undergoing elective orthopaedic surgery. Ann Rheum Dis. 2001;60:214–7.
51. Beauparlant P, Papp K, Haraoui B. The incidence of cancer associated with the treatment of rheumatoid arthritis. Semin Arthritis Rheum. 1999;29:148–58.
52. Wolfe F, Michaud K. Lymphoma in rheumatoid arthritis: the effect of methotrexate and anti-tumor necrosis factor therapy in 18,572 patients. Arthritis Rheum. 2004;50:1740–51.
53. Moder KG, Tefferi A, Cohen MD, Menke DM, Luthra HS. Hematologic malignancies and the use of methotrexate in rheumatoid arthritis: a retrospective study. Am J Med. 1995;99:276–81.
54. Askling J, Fored CM, Brandt L, Baecklund E, Bertilsson L, Feltelius N, et al. Risks of solid cancers in patients with rheumatoid arthritis and after treatment with tumour necrosis factor antagonists. Ann Rheum Dis. 2005;64:1421–6.
55. Chakravarty EF, Michaud K, Wolfe F. Skin cancer, rheumatoid arthritis, and tumor necrosis factor inhibitors. J Rheumatol. 2005;32:2130–5.
56. Choi HK, Hernán MA, Seeger JD, Robins JM, Wolfe F. Methotrexate and mortality in patients with rheumatoid arthritis: a prospective study. Lancet. 2002;359:1173–7.
57. Van Halm VP, Nurmohamed MT, Twisk JWR, Dijkmans BAC, Voskuyl AE. Disease-modifying antirheumatic drugs are associated with a reduced risk for cardiovascular disease in patients with rheumatoid arthritis: a case control study. Arthritis Res Ther. 2006;8:R151.
58. Leeb BF, Witzmann G, Ogris E, Studnicka-Benke A, Andel I, Schweitzer H, et al. Folic acid and cyanocobalamin levels in serum and erythrocytes during low-dose methotrexate therapy of rheumatoid arthritis and psoriatic arthritis patients. Clin Exp Rheumatol. 1995;13:459–63.
59. Morgan SL, Baggott JE. Folate supplementation during methotrexate therapy for rheumatoid arthritis. Clin Exp Rheumatol. 2010;28:S102–9.
60. Shea B, Swinden MV, Tanjong Ghogomu E, Ortiz Z, Katchamart W, Rader T, et al. Folic acid and folinic acid for reducing side effects in patients receiving methotrexate for rheumatoid arthritis. Cochrane Database Syst Rev 2013. http://onlinelibrary.wiley.com/doi/10.1002/14651858.CD000951.pub2/abstract;jsessionid=196C939CA995673A7AF5D4F1E0BB978F.f04t01.
61. Whittle SL, Hughes RA. Folate supplementation and methotrexate treatment in rheumatoid arthritis: a review. 2004;43:267–71.
62. Ortiz Z, Shea B, Suarez-Almazor M, Moher D, Wells GA, Tugwell P. Folic acid and folinic acid for reducing side effects in patients receiving methotrexate for rheumatoid arthritis. Cochrane Database Syst Rev. 1999. http://onlinelibrary.wiley.com/doi/10.1002/14651858.CD000951/otherversions.
63. Griffith SM, Fisher J, Clarke S, Montgomery B, Jones PW, Saklatvala J, et al. Do patients with rheumatoid arthritis established on methotrexate and folic acid 5 mg daily need to continue folic acid supplements long term? Rheumatology (Oxford). 2000;39:1102–9.
64. Prey S, Paul C. Effect of folic or folinic acid supplementation on methotrexate-associated safety and efficacy in inflammatory disease: a systematic review. Br J Dermatol. 2009;160:622–8.
65. 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;50:913–4.
66. Hoekstra M, van de Laar MAFJ, Bernelot Moens HJ, Kruijsen MWM, Haagsma CJ. Longterm observational study of methotrexate use in a Dutch cohort of 1022 patients with rheumatoid arthritis. J Rheumatol. 2003;30:2325–9.
67. Bologna C, Viu P, Jorgensen C, Sany J. Effect of age on the efficacy and tolerance of methotrexate in rheumatoid arthritis. Br J Rheumatol. 1996;35:453–7.
68. Wolfe F, Cathey MA. The effect of age on methotrexate efficacy and toxicity. J Rheumatol. 1991;18:973–7.
69. Hoekstra M, van Ede AE, Haagsma CJ, van de Laar MAFJ, Huizinga TWJ, Kruijsen MWM, et al. Factors associated with toxicity, final dose, and efficacy of methotrexate in patients with rheumatoid arthritis. Ann Rheum Dis. 2003;62:423–6.
70. McKendry RJ, Dale P. Adverse effects of low dose methotrexate therapy in rheumatoid arthritis. J Rheumatol. 1993;20:1850–6.
71. Suzuki Y, Uehara R, Tajima C, Noguchi A, Ide M, Ichikawa Y, et al. Elevation of serum hepatic aminotransferases during treatment of rheumatoid arthritis with low-dose methotrexate. Risk factors and response to folic acid. Scand J Rheumatol. 1999;28:273–81.
72. Kremer JM, Lee RG, Tolman KG. Liver histology in rheumatoid arthritis patients receiving long-term methotrexate therapy. A prospective study with baseline and sequential biopsy samples. Arthritis Rheum. 1989;32:121–7.
73. Phillips CA, Cera PJ, Mangan TF, Newman ED. Clinical liver disease in patients with rheumatoid arthritis taking methotrexate. J Rheumatol. 1992;19:229–33.
74. Schmajuk G, Miao Y, Yazdany J, Boscardin WJ, Daikh DI, Steinman MA. Identification of risk factors for elevated transaminases in methotrexate users through an electronic health record. Arthritis Care Res (Hoboken). 2014;66:1159–66.
75. Bourré-Tessier J, Haraoui B. Methotrexate drug interactions in the treatment of rheumatoid arthritis: a systematic review. J Rheumatol. 2010;37:1416–21.
76. Franck H, Rau R, Herborn G. Thrombocytopenia in patients with rheumatoid arthritis on long-term treatment with low dose methotrexate. Clin Rheumatol. 1996;15:266–70.
77. Morgan SL, Baggott JE, Vaughn WH, Young PK, Austin JV, Krumdieck CL, et al. The effect of folic acid supplementation on the toxicity of low-dose methotrexate in patients with rheumatoid arthritis. Arthritis Rheum. 1990;33:9–18.
78. Morgan SL, Baggott JE, Vaughn WH, Austin JS, Veitch TA, Lee JY, et al. Supplementation with folic acid during methotrexate therapy for rheumatoid arthritis. A double-blind, placebo-controlled trial. Ann Intern Med. 1994;121:833–41.
79. Weinblatt ME, Fraser P. Elevated mean corpuscular volume as a predictor of hematologic toxicity due to methotrexate therapy. Arthritis Rheum. 1989;32:1592–6.
80. Preet Singh Y, Aggarwal A, Misra R, Agarwal V. Low-dose methotrexate-induced pancytopenia. Clin Rheumatol. 2007;26:84–7.
81. White DHN, Chapman PT, O’Donnell JL, James J, Frampton C, Stamp LK. Lack of association between elevated mean red cell volume and haematological toxicity in patients receiving long-term methotrexate for rheumatoid arthritis. Intern Med J. 2010;40:561–5.
82. Stewart KA, Mackenzie AH, Clough JD, Wilke WS. Folate supplementation in methotrexate-treated rheumatoid arthritis patients. Semin Arthritis Rheum. 1991;20:332–8.
83. Wernick R, Smith DL. Central nervous system toxicity associated with weekly low-dose methotrexate treatment. Arthritis Rheum. 1989;32:770–5.
84. Visser K, van der Heijde D. Optimal dosage and route of administration of methotrexate in rheumatoid arthritis: a systematic review of the literature. Ann Rheum Dis. 2009;68:1094–9.
85. Choy EHS, Smith C, Doré CJ, Scott DL. A meta-analysis of the efficacy and toxicity of combining disease-modifying anti-rheumatic drugs in rheumatoid arthritis based on patient withdrawal. Rheumatology (Oxford). 2005;44:1414–21.
86. Katchamart W, Trudeau J, Phumethum V, Bombardier C. Methotrexate monotherapy versus methotrexate combination therapy with non-biologic disease modifying anti-rheumatic drugs for rheumatoid arthritis. Cochrane Database Syst Rev. 2010. http://onlinelibrary.wiley.com/doi/10.1002/14651858.CD008495/full.
87. National Center for Biotechnology Information. dbSNP—Short Genetic Variations. http://www.ncbi.nlm.nih.gov/SNP/.
88. Hinken M, Halwachs S, Kneuer C, Honscha W. Subcellular localization and distribution of the reduced folate carrier in normal rat tissues. Eur J Histochem. 2011;55:e3.
89. Lynch M, Scofield DG, Hong X. The evolution of transcription-initiation sites. Mol Biol Evol. 2005;22:1137–46.
90. Owen SA, Hider SL, Martin P, Bruce IN, Barton A, Thomson W. Genetic polymorphisms in key methotrexate pathway genes are associated with response to treatment in rheumatoid arthritis patients. Pharmacogenomics J. 2013;13:227–34.
91. Chango A, Emery-Fillon N, de Courcy GP, Lambert D, Pfister M, Rosenblatt DS, et al. A polymorphism (80G->A) in the reduced folate carrier gene and its associations with folate status and homocysteinemia. Mol Genet Metab. 2000;70:310–5.
92. Baslund B, Gregers J, Nielsen CH. Reduced folate carrier polymorphism determines methotrexate uptake by B cells and CD4+T cells. Rheumatol. 2008;47:451–3.
93. Dervieux T, Kremer J, Lein DO, Capps R, Barham R, Meyer G, et al. Contribution of common polymorphisms in reduced folate carrier and gamma-glutamylhydrolase to methotrexate polyglutamate levels in patients with rheumatoid arthritis. Pharmacogenetics. 2004;14:733–9.
94. Bohanec Grabar P, Logar D, Lestan B, Dolzan V. Genetic determinants of methotrexate toxicity in rheumatoid arthritis patients: a study of polymorphisms affecting methotrexate transport and folate metabolism. Eur J Clin Pharmacol. 2008;64:1057–68.
95. Bohanec Grabar P, Leandro-Garcia LJ, Inglada-Perez L, Logar D, Rodriguez-Antona C, Dolzan V. Genetic variation in the SLC19A1 gene and methotrexate toxicity in rheumatoid arthritis patients. Pharmacogenomics. 2012;13:1583–94.
96. Dervieux T, Greenstein N, Kremer J. Pharmacogenomic and metabolic biomarkers in the folate pathway and their association with methotrexate effects during dosage escalation in rheumatoid arthritis. Arthritis Rheum. 2006;54:3095–103.
97. Takatori R, Takahashi KA, Tokunaga D, Hojo T, Fujioka M, Asano T, et al. ABCB1 C3435T polymorphism influences methotrexate sensitivity in rheumatoid arthritis patients. Clin Exp Rheumatol. 2006;24:546–54.
98. Wessels JAM, de Vries-Bouwstra JK, Heijmans BT, Slagboom PE, Goekoop-Ruiterman YPM, Allaart CF, et al. Efficacy and toxicity of methotrexate in early rheumatoid arthritis are associated with single-nucleotide polymorphisms in genes coding for folate pathway enzymes. Arthritis Rheum. 2006;54:1087–95.
99. Chatzikyriakidou A, Georgiou I, Voulgari PV, Papadopoulos CG, Tzavaras T, Drosos AA. Transcription regulatory polymorphism -43T>C in the 5′-flanking region of SLC19A1 gene could affect rheumatoid arthritis patient response to methotrexate therapy. Rheumatol Int. 2007;27:1057–61.
100. Drozdzik M, Rudas T, Pawlik A, Gornik W, Kurzawski M, Herczynska M. Reduced folate carrier-1 80G>A polymorphism affects methotrexate treatment outcome in rheumatoid arthritis. Pharmacogenomics J. 2007;7:404–7.
101. Stamp LK, Chapman PT, O’Donnell JL, Zhang M, James J, Frampton C, et al. Polymorphisms within the folate pathway predict folate concentrations but are not associated with disease activity in rheumatoid arthritis patients on methotrexate. Pharmacogenet Genomics. 2010;20:367–76.
102. Plaza-Plaza JC, Aguilera M, Cañadas-Garre M, Chemello C, González-Utrilla A, Faus Dader MJ, et al. Pharmacogenetic polymorphisms contributing to toxicity induced by methotrexate in the southern Spanish population with rheumatoid arthritis. OMICS. 2012;6:589–95.
103. Wang GS, Cooper TA. Splicing in disease: disruption of the splicing code and the decoding machinery. Nat Rev Genet. 2007;8:749–61.
104. Takano M, Yumoto R, Murakami T. Expression and function of efflux drug transporters in the intestine. Pharmacol Ther. 2006;109:137–61.
105. Llorente L, Richaud-Patin Y, Diaz-Borjon A, Alvarado de la Barrera C, Jakez-Ocampo J, de la Fuente H, et al. Multidrug resistance-1 (MDR-1) in rheumatic autoimmune disorders. Part I: Increased P-glycoprotein activity in lymphocytes from rheumatoid arthritis patients might influence disease outcome. Joint Bone Spine 2000;67:30–39.
106. Kim RB. Drugs as P-glycoprotein substrates, inhibitors, and inducers. Drug Metab Rev. 2002;34:47–54.
107. Wang D, Johnson AD, Papp AC, Kroetz DL, Sadee W. Multidrug resistance polypeptide 1 (MDR1, ABCB1) variant 3435C>T affects mRNA stability. Pharmacogenet Genomics. 2005;15:693–704.
108. Kooloos WM, Wessels JA, van der Straaten T, Allaart CF, Huizinga TW, Guchelaar H-J. Functional polymorphisms and methotrexate treatment outcome in recent-onset rheumatoid arthritis. Pharmacogenomics. 2010;11:163–75.
109. Ranganathan P, Culverhouse R, Marsh S, Mody A, Scott-Horton TJ, Brasington R, et al. Methotrexate (MTX) pathway gene polymorphisms and their effects on MTX toxicity in Caucasian and African American patients with rheumatoid arthritis. J Rheumatol. 2008;35:572–9.
110. Fung KL, Gottesman MM. A synonymous polymorphism in a common MDR1 (ABCB1) haplotype shapes protein function. Biochim Biophys Acta. 2009;1794:860–71.
111. Tanabe M, Ieiri I, Nagata N, Inoue K, Ito S, Kanamori Y, et al. Expression of P-glycoprotein in human placenta: relation to genetic polymorphism of the multidrug resistance (MDR)-1 gene. J Pharmacol Exp Ther. 2001;297:1137–43.
112. Berggren S, Gall C, Wollnitz N, Ekelund M, Karlbom U, Hoogstraate J, et al. Gene and protein expression of P-glycoprotein, MRP1, MRP2, and CYP3A4 in the small and large human intestine. Mol Pharm. 2007;4:252–7.
113. Van der Heijden JW, Oerlemans R, Tak PP, Assaraf YG, Kraan MC, Scheffer GL, et al. Involvement of breast cancer resistance protein expression on rheumatoid arthritis synovial tissue macrophages in resistance to methotrexate and leflunomide. Arthritis Rheum. 2009;60:669–77.
114. Breuninger LM, Paul S, Gaughan K, Miki T, Chan A, Aaronson SA, et al. Expression of multidrug resistance-associated protein in NIH/3T3 cells confers multidrug resistance associated with increased drug efflux and altered intracellular drug distribution. Cancer Res. 1995;55:5342–7.
115. Lee SH, Lee MS, Lee JH, Kim SW, Kang RH, Choi MJ, et al. MRP1 polymorphisms associated with citalopram response in patients with major depression. J Clin Psychopharmacol. 2010;30:116–25.
116. Van Aubel RA, Smeets PH, Peters JG, Bindels RJ, Russel FG. The MRP4/ABCC4 gene encodes a novel apical organic anion transporter in human kidney proximal tubules: putative efflux pump for urinary cAMP and cGMP. J Am Soc Nephrol. 2002;13:595–603.
117. Vlaming ML, Pala Z, van Esch A, Wagenaar E, de Waart DR, van de Wetering K, et al. Functionally overlapping roles of Abcg2 (Bcrp1) and Abcc2 (Mrp2) in the elimination of methotrexate and its main toxic metabolite 7-hydroxymethotrexate in vivo. Clin Cancer Res. 2009;15:3084–93.
118. Fromm MF, Kauffmann HM, Fritz P, Burk O, Kroemer HK, Warzok RW, et al. The effect of rifampin treatment on intestinal expression of human MRP transporters. Am J Pathol. 2000;157:1575–80.
119. Deo AK, Prasad B, Balogh L, Lai Y, Unadkat JD. Interindividual variability in hepatic expression of the multidrug resistance-associated protein 2 (MRP2/ABCC2): quantification by liquid chromatography/tandem mass spectrometry. Drug Metab Dispos. 2012;40:852–5.
120. Volk EL, Schneider E. Wild-type breast cancer resistance protein (BCRP/ABCG2) is a methotrexate polyglutamate transporter. Cancer Res. 2003;63:5538–43.
121. Zhang L, Spencer KL, Voruganti VS, Jorgensen NW, Fornage M, Best LG, et al. Association of Functional Polymorphism rs2231142 (Q141K) in the ABCG2 Gene With Serum Uric Acid and Gout in 4 US Populations: The PAGE Study. Am J Epidemiol. 2013;177:923–32.
122. Tian H, Cronstein BN. Understanding the mechanisms of action of methotrexate: implications for the treatment of rheumatoid arthritis. Bull NYU Hosp Jt Dis. 2007;65:168–73.
123. Owen SA, Lunt M, Bowes J, Hider SL, Bruce IN, Thomson W, et al. MTHFR gene polymorphisms and outcome of methotrexate treatment in patients with rheumatoid arthritis: analysis of key polymorphisms and meta-analysis of C677T and A1298C polymorphisms. Pharmacogenomics J. 2013;13:137–47.
124. Davis LA, Polk B, Mann A, Wolff RK, Kerr GS, Reimold AM, et al. Folic acid pathway single nucleotide polymorphisms associated with methotrexate significant adverse events in United States veterans with rheumatoid arthritis. Clin Exp Rheumatol. 2014;32:324–32.
125. Van der Straaten RJHM, Wessels JAM, de Vries-Bouwstra JK, Goekoop-Ruiterman YPM, Allaart CF, Bogaartz J, et al. Exploratory analysis of four polymorphisms in human GGH and FPGS genes and their effect in methotrexate-treated rheumatoid arthritis patients. Pharmacogenomics. 2007;8:141–50.
126. Chave KJ, Ryan TJ, Chmura SE, Galivan J. Identification of single nucleotide polymorphisms in the human gamma-glutamyl hydrolase gene and characterization of promoter polymorphisms. Gene. 2003;319:167–75.
127. Jekic B, Lukovic L, Bunjevacki V, Milic V, Novakovic I, Damnjanovic T, et al. 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. 2013;69:377–83.
128. Swierkot J, Szechinski J. Methotrexate in rheumatoid arthritis. Pharmacol Rep. 2006;58:473–92.
129. Stamp LK, Roberts RL. Effect of genetic polymorphisms in the folate pathway on methotrexate therapy in rheumatic diseases. Pharmacogenomics. 2011;12:1449–63.
130. Milic V, Jekic B, Lukovic L, Bunjevacki V, Milasin J, Novakovic I, et al. Association of dihydrofolate reductase (DHFR) -317AA genotype with poor response to methotrexate in patients with rheumatoid arthritis. Clin Exp Rheumatol. 2012;30:178–83.
131. Grabar PB, Rojko S, Logar D, Dolzan V. Genetic determinants of methotrexate treatment in rheumatoid arthritis patients: a study of polymorphisms in the adenosine pathway. Ann Rheum Dis. 2010;69:931–2.
132. Van Ede AE, Laan RF, Blom HJ, De Abreu RA, van de Putte LB. Methotrexate in rheumatoid arthritis: an update with focus on mechanisms involved in toxicity. Semin Arthritis Rheum. 1998;27:277–92.
133. 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;10:111–3.
134. Kim SK, Jun JB, El-Sohemy A, Bae SC. Cost-effectiveness analysis of MTHFR polymorphism screening by polymerase chain reaction in Korean patients with rheumatoid arthritis receiving methotrexate. J Rheumatol. 2006;33:1266–74.
135. Weisman MH, Furst DE, Park GS, Kremer JM, Smith KM, Wallace DJ, et al. Risk genotypes in folate-dependent enzymes and their association with methotrexate-related side effects in rheumatoid arthritis. Arthritis Rheum. 2006;54:607–12.
136. Xiao H, Xu J, Zhou X, Stankovich J, Pan F, Zhang Z, et al. Associations between the genetic polymorphisms of MTHFR and outcomes of methotrexate treatment in rheumatoid arthritis. Clin Exp Rheumatol. 2010;28:728–33.
137. Caliz R, del Amo J, Balsa A, Blanco F, Silva L, Sanmarti R, et al. The C677T polymorphism in the MTHFR gene is associated with the toxicity of methotrexate in a Spanish rheumatoid arthritis population. Scand J Rheumatol. 2012;41:10–4.
138. Aggarwal P, Naik S, Mishra KP, Aggarwal A, Misra R. Correlation between methotrexate efficacy and toxicity with C677T polymorphism of the methylenetetrahydrofolate gene in rheumatoid arthritis patients on folate supplementation. Indian J Med Res. 2006;124:521–6.
139. Taraborelli M, Andreoli L, Archetti S, Ferrari M, Cattaneo R, Tincani A. Methylenetetrahydrofolate reductase polymorphisms and methotrexate: no association with response to therapy nor with drug-related adverse events in an Italian population of rheumatic patients. Clin Exp Rheumatol. 2009;27:499–502.
140. Mena JP, Salazar-Paramo M, Gonzalez-Lopez L, Gamez-Nava JI, Sandoval-Ramirez L, Sanchez JD, et al. Polymorphisms C677T and A1298C in the MTHFR gene in Mexican patients with rheumatoid arthritis treated with methotrexate: implication with elevation of transaminases. Pharmacogenomics J. 2011;11:287–91.
141. Choe J-Y, Lee H, Jung H-Y, Park S-H, Bae S-C, Kim S-K. Methylenetetrahydrofolate reductase polymorphisms, C677T and A1298C, are associated with methotrexate-related toxicities in Korean patients with rheumatoid arthritis. Rheumatol Int. 2012;32:1837–42.
142. Van der Put NM, Gabreels F, Stevens EM, Smeitink JA, Trijbels FJ, Eskes TK, et al. A second common mutation in the methylenetetrahydrofolate reductase gene: an additional risk factor for neural-tube defects? Am J Hum Genet. 1998;62:1044–51.
143. Cáliz R, del Amo J, Balsa A, Blanco F, Silva L, Sanmarti R, et al. The C677T polymorphism in the MTHFR gene is associated with the toxicity of methotrexate in a Spanish rheumatoid arthritis population. Scand J Rheumatol. 2012;41:10–4.
144. Fenech M. The role of folic acid and Vitamin B12 in genomic stability of human cells. Mutat Res. 2001;475:57–67.
145. Matsuo K, Suzuki R, Hamajima N, Ogura M, Kagami Y, Taji H, et al. Association between polymorphisms of folate- and methionine-metabolizing enzymes and susceptibility to malignant lymphoma. Blood. 2001;97:3205–9.
146. Berkun Y, Abou Atta I, Rubinow A, Orbach H, Levartovsky D, Aamar S, et al. 2756GG genotype of methionine synthase reductase gene is more prevalent in rheumatoid arthritis patients treated with methotrexate and is associated with methotrexate-induced nodulosis. J Rheumatol. 2007;34:1664–9.
147. Wessels JAM, Kooloos WM, De Jonge R, De Vries-Bouwstra JK, Allaart CF, Linssen A, et al. Relationship between genetic variants in the adenosine pathway and outcome of methotrexate treatment in patients with recent-onset rheumatoid arthritis. Arthritis Rheum. 2006;54:2830–9.
148. Wettergren Y, Odin E, Carlsson G, Gustavsson B. MTHFR, MTR, and MTRR polymorphisms in relation to p16INK4A hypermethylation in mucosa of patients with colorectal cancer. Mol Med. 2010;16:425–32.
149. Olteanu H, Munson T, Banerjee R. Differences in the efficiency of reductive activation of methionine synthase and exogenous electron acceptors between the common polymorphic variants of human methionine synthase reductase. Biochemistry. 2002;41:13378–85.
150. 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;44:2525–30.
151. Heil SG, Van der Put NM, Waas ET, den Heijer M, Trijbels FJ, Blom HJ. Is mutated serine hydroxymethyltransferase (SHMT) involved in the etiology of neural tube defects? Mol Genet Metab. 2001;73:164–72.
152. Krajinovic M, Costea I, Primeau M, Dulucq S, Moghrabi A. Combining several polymorphisms of thymidylate synthase gene for pharmacogenetic analysis. Pharmacogenomics J. 2005;5:374–80.
153. Touroutoglou N, Pazdur R. Thymidylate synthase inhibitors. Clin Cancer Res. 1996;2:227–43.
154. Lima A, Seabra V, Martins S, Coelho A, Araujo A, Medeiros R. Thymidylate synthase polymorphisms are associated to therapeutic outcome of advanced non-small cell lung cancer patients treated with platinum-based chemotherapy. Mol Biol Rep. 2014;41:3349–57.
155. Marsh S, McKay JA, Cassidy J, McLeod HL. Polymorphism in the thymidylate synthase promoter enhancer region in colorectal cancer. Int J Oncol. 2001;19:383–6.
156. Corre S, Galibert MD. Upstream stimulating factors: highly versatile stress-responsive transcription factors. Pigment Cell Res. 2005;18:337–48.
157. Mandola MV, Stoehlmacher J, Muller-Weeks S, Cesarone G, Yu MC, Lenz HJ, et al. A novel single nucleotide polymorphism within the 5′ tandem repeat polymorphism of the thymidylate synthase gene abolishes USF-1 binding and alters transcriptional activity. Cancer Res. 2003;63:2898–904.
158. Marsh S. Thymidylate synthase pharmacogenetics. Investig New Drugs. 2005;23:533–7.
159. Kumagai K, Hiyama K, Oyama T, Maeda H, Kohno N. 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. 2003;11:593–600.
160. Pullmann R Jr, Abdelmohsen K, Lal A, Martindale JL, Ladner RD, Gorospe M. Differential stability of thymidylate synthase 3′-untranslated region polymorphic variants regulated by AUF1. J Biol Chem. 2006;281:23456–63.
161. Zhang Z, Shi Q, Sturgis EM, Spitz MR, Hong WK, Wei Q. Thymidylate synthase 5′- and 3′-untranslated region polymorphisms associated with risk and progression of squamous cell carcinoma of the head and neck. Clin Cancer Res. 2004;10:7903–10.
162. Mandola MV, Stoehlmacher J, Zhang W, Groshen S, Yu MC, Iqbal S, et al. A 6 bp polymorphism in the thymidylate synthase gene causes message instability and is associated with decreased intratumoral TS mRNA levels. Pharmacogenetics. 2004;14:319–27.
163. Dervieux T, Furst D, Lein DO, Capps R, Smith K, Walsh M, et al. 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. 2004;50:2766–74.
164. Dervieux T, Wessels JA, van der Straaten T, Penrod N, Moore JH, Guchelaar HJ, et al. Gene-gene interactions in folate and adenosine biosynthesis pathways affect methotrexate efficacy and tolerability in rheumatoid arthritis. Pharmacogenet Genomics. 2009;19:935–44.
165. Chan ES, Cronstein BN. Molecular action of methotrexate in inflammatory diseases. Arthritis Res. 2002;4:266–73.
166. Kremer JM. Toward a better understanding of methotrexate. Arthritis Rheum. 2004;50:1370–82.
167. Hider SL, Thomson W, Mack LF, Armstrong DJ, Shadforth M, Bruce IN. Polymorphisms within the adenosine receptor 2a gene are associated with adverse events in RA patients treated with MTX. Rheumatology. 2008;47:1156–9.
168. Morisaki T, Gross M, Morisaki H, Pongratz D, Zollner N, Holmes EW. Molecular basis of AMP deaminase deficiency in skeletal muscle. Proc Natl Acad Sci USA. 1992;89:6457–61.