Clinical Pharmacokinetics

, Volume 42, Issue 2, pp 139–151

Pharmacokinetics and Pharmacodynamics of Methotrexate in Non-Neoplastic Diseases

  • Jiří Grim
  • Jaroslav Chládek
  • Jiřina Martínková
Review Article Special Populations


Low dose pulse methotrexate (LDMTX) therapy has become effective in the treatment of autoimmune and lymphoproliferative diseases. The pharmacokinetics of LDMTX is individually highly variable, resulting in a different systemic exposure to the drug and a variable therapeutic/toxic effect in patients. The improvements and exacerbations of disease activity in relation to the introductions and discontinuations of LDMTX therapy suggest the possible immunosuppresive and anti-inflammatory properties of the drug. Because of a strong correlation between the drug pharmacokinetics and the therapeutic outcomes (pharmacodynamics), it seems to be possible to individualise the LDMTX therapy according to the results of pharmacokinetic/pharmacodynamic analysis. In the case of psoriasis, pharmacokinetic/pharmacodynamic analysis in our local study revealed a highly significant inverse relationship between PASI (expressed as a percent of the initial value) and a steady-state AUCMTX (area under the curve of methotrexate plasma concentrations; r8 = −0.65, p < 0.001). The considerable inter-individual variability and low intra-individual variability in MTX pharmacokinetics, supports a role for therapeutic monitoring and dose individualisation at the start of pharmacotherapy. The results of this study suggest that a steady-state AUCMTX value of 700 nmol · h/L and higher are associated with a significantly better success rate of antipsoriatic therapy than lower values. The preliminary results in our follow-up study suggest the statistically higher incidence of unwanted effects depending on maximum plasma concentration of the drug. Moreover, statistically significant correlation was found between the toxic effects and exposure to the drug regarding methotrexate plasma concentrations and intracellular storage in erythrocytes. However, the data are still in the process of being completed and are not yet published.


  1. 1.
    van Ede AE, Laan RF, Blom HJ, et al. Methotrexate in rheumatoid arthritis: an update with focus on mechanisms involved toxicity. Semin Arthritis Rheum 1998; 27: 277–92PubMedCrossRefGoogle Scholar
  2. 2.
    Weinblatt ME, Kaplan H, Germain BF, et al. Low-dose methotrexate compared with auranofin in adult rheumatoid arthritis: a thirty-six week, double-blind trial. Arthritis Rheum 1990; 33: 330–8PubMedCrossRefGoogle Scholar
  3. 3.
    Bannwarth B, Pehourcq F, Schaeverbeke T, et al. Clinical pharmacokinetics of low-dose methotrexate in rheumatoid arthritis. Clin Pharmacokinet 1996; 30: 194–210PubMedCrossRefGoogle Scholar
  4. 4.
    van de Putte LB, Boerbooms AM, Barrera P, et al. Methotrexate: anti-inflammatory or immunosuppressive? Clin Exp Rheumatol 1993; 11 Suppl. 8: S97–9PubMedGoogle Scholar
  5. 5.
    Bianchi ML, Cimaz R, Galbiati E, et al. Bone mass change during methotrexate treatment in patients with juvenile rheumatoid arthritis. Osteoporos Int 1999; 10: 20–5PubMedCrossRefGoogle Scholar
  6. 6.
    Kozarek RA, Patterson DJ, Gelfand MD, et al. Methotrexate induces clinical and histologic remission in patients with refractory inflammatory bowel disease. Ann Intern Med 1989; 110: 353–6PubMedGoogle Scholar
  7. 7.
    Oren R, Moshkowitz M, Odes S, et al. Methotrexate in chronic active Crohn’s disease: a double blind, randomized, Israeli multicenter trial. Am J Gastroenterol 1997; 92(12): 2203–9PubMedGoogle Scholar
  8. 8.
    Mack DR, Young R, Kaufman SS, et al. Methotrexate in patients with Crohn’s disease after 6-mercaptopurine. J Pediatr 1998; 132: 830–5PubMedCrossRefGoogle Scholar
  9. 9.
    Boehm IB, Boehm GA, Bauer R. Management of cutaneous lupus erythematosus with low-dose methotrexate: indication for modulation of inflammatory mechanisms. Rheumatol Int 1998; 18: 59–62PubMedCrossRefGoogle Scholar
  10. 10.
    Silverman DE, Lang B. An overview of the treatment of childhood SLE. Scand J Rheumatol 1997; 26: 241–6PubMedCrossRefGoogle Scholar
  11. 11.
    Sundeep D, Rex MM, Glenn JJ. Methotrexate treatment for sarcoid-associated panuveitis. Opthalmology 1999; 106: 111–8CrossRefGoogle Scholar
  12. 12.
    Furst DE, Koehnke R, Burmeister LF, et al. Increasing methotrexate effects with increasing dose in the treatment of resistant rheumatoid arthritis. J Rheumatol 1989; 16: 313–20PubMedGoogle Scholar
  13. 13.
    Chladek J, Grim J, Martinkova J, et al. Pharmacokinetics and pharmacodynamics of low-dose methotrexate the treatment of psoriasis. Br J Clin Pharmacol 2002; 54(2): 147–56PubMedCrossRefGoogle Scholar
  14. 14.
    Bologna C, Anaya JM, Bressolle F, et al. Correlation between methotrexate pharmacokinetic parameters, and clinical and biological status in rheumatoid arthritis patients. Clin Exp Rheumatol 1995; 13: 465–70PubMedGoogle Scholar
  15. 15.
    Chládek J, Martínková J, Simková M, et al. Pharmacokinetics of low doses of methotrexate in patients with psoriasis over the early period of treatment. Eur J Clin Pharmacol 1998; 53: 437–44PubMedCrossRefGoogle Scholar
  16. 16.
    Shen DD, Azarnoff DL. Clinical pharmacokinetics of methotrexate. Clin Pharmacokinet 1978; 3: 1–13PubMedCrossRefGoogle Scholar
  17. 17.
    Songsiridej N, Furst DE. Methotrexate: the rapidly acting drug. Baillieres Clin Rheumatol 1990; 4: 575–93PubMedCrossRefGoogle Scholar
  18. 18.
    Crom WR, Evans WE. Methotrexate: applied pharmacokinetics. In: Evans WE, Schentag JJ, Jusko WJ, editors. 10, Principle of therapeutic drug monitoring. Vancouver (BC): Applied Therapeutics, 1992: 1–42Google Scholar
  19. 19.
    Henderson ES, Adamson RH, Oliverio VT. The metabolic fate of tritiated methotrexate. II. absorption and excretion in man. Cancer Res 1965; 25: 1018–23PubMedGoogle Scholar
  20. 20.
    Hendel J, Nyfors A. Impact of methotrexate therapy on the folate status of psoriatic patients. Clin Exp Dermatol 1985; 10: 30–53PubMedCrossRefGoogle Scholar
  21. 21.
    Lebbe C, Beyeler C, Gerber NJ, et al. Intraindividual variability of the bioavailability of low dose methotrexate after oral administration in rheumatoid arthritis. Ann Rheum Dis 1994; 53: 475–7PubMedCrossRefGoogle Scholar
  22. 22.
    Ahern M, Booth J, Loxton A, et al. Methotrexate kinetics in rheumatoid arthritis: is there an interaction with nonsteroidal anti-inflammatory drugs? J Rheumatol 1988; 15: 1356–60PubMedGoogle Scholar
  23. 23.
    Herman RA, Veng-Pedersen P, Hoffman J, et al. Pharmacokinetics of low-dose methotrexate in rheumatoid arthritis patients. J Pharm Sci 1989; 78(2): 165–71PubMedCrossRefGoogle Scholar
  24. 24.
    Oguey D, Köllinker F, Gerber NJ, et al. Effect of food on the bioavailability of low-dose methotrexate in patients with rheumatoid arthritis. Arthritis Rheum 1992; 35: 611–4PubMedCrossRefGoogle Scholar
  25. 25.
    Bannwarth B, Labat L, Moride Y, et al. Methotrexate in rheumatoid arthritis: an update. Drugs 1994; 47: 25–50PubMedCrossRefGoogle Scholar
  26. 26.
    Anaya JM, Fabre D, Bressolle F, et al. Effect of etodolac on methotrexate pharmacokinetics in patients with rheumatoid arthritis. J Rheumatol 1994; 21: 203–8PubMedGoogle Scholar
  27. 27.
    Combe B, Edno L, Lafforgue P, et al. Total and free methotrexate pharmacokinetics, with and without piroxicam, in rheumatoid arthritis patients. Br J Rheumatol 1995; 34: 421–8PubMedCrossRefGoogle Scholar
  28. 28.
    Skeith KJ, Russell AS, Jamali F, et al. Lack of significant interaction between low dose methotrexate and ibuprofen or flurbiprofen in patients with arthritis. J Rheumatol 1990; 17: 1008–10PubMedGoogle Scholar
  29. 29.
    Seideman P, Beck O, Eksborg S, et al. The pharmacokinetics of methotrexate and 7-hydroxy metabolite in patients with rheumatoid arthritis. Br J Clin Pharmacol 1993; 35: 409–12PubMedCrossRefGoogle Scholar
  30. 30.
    Brooks PJ, Spruill WJ, Parish RC, et al. Pharmacokinetics of methotrexate administered by intramuscular and subcutaneous injections in patients with rheumatoid arthritis. Arthritis Rheum 1990; 33: 91–4PubMedCrossRefGoogle Scholar
  31. 31.
    Jundt JW, Browne BA, Fiocco GP, et al. A comparison of low-dose methotrexate bioavailability: oral solution, oral tablet, subcutaneous and intramuscular dosing. J Rheumatol 1993; 20: 1845–9PubMedGoogle Scholar
  32. 32.
    Wigginton SM, Chu BCF, Weisman MH, et al. Methotrexate pharmacokinetics after intraarticular injection in patients with rheumatoid arthritis. Arthritis Rheum 1980; 23: 119–22PubMedCrossRefGoogle Scholar
  33. 33.
    Bjerring P, Beck HI, Zachariae H, et al. Topical treatment of psoriatic skin with methotrexate cream: a clinical, pharmacokinetic, and histological study. Acta Derm Venereol 1986; 66(6): 515–9PubMedGoogle Scholar
  34. 34.
    Edno L, Bressolle F, Gomeni R, et al. Total and free methotrexate pharmacokinetics in rheumatoid arthritis patients. Ther Drug Monit 1996; 18: 128–34PubMedCrossRefGoogle Scholar
  35. 35.
    Furst DE, Erikson N, Clute L, et al. Adverse experience with methotrexate during 176 weeks of a long-term prospective trial in patients with rheumatoid arthritis. J Rheumatol 1990; 17: 1628–35PubMedGoogle Scholar
  36. 36.
    Tracy TS, Worster T, Bradley JD, et al. Methotrexate disposition following concomitant administration of ketoprofen, piroxicam and flurbiprofen in patients with rheumatoid arthritis. Br J Clin Pharmacol 1994; 37: 453–6PubMedCrossRefGoogle Scholar
  37. 37.
    Sprecher E, Bergman R, Sprecher H, et al. Reduced folate carrier (RFC-1) gene expression in normal and psoriatic skin. Arch Dermatol Res 1998; 290: 656–60PubMedCrossRefGoogle Scholar
  38. 38.
    Roenigk HH, Maibach HI. Methotrexate. In: Roenigk HH, Maibach HI, editors. Psoriasis. 3rd ed. New York: Marcel Dekker Inc, 1998: 609–29Google Scholar
  39. 39.
    Kremer JM, Galivan J, Streckfuss A, et al. Methotrexate metabolism analysis in blood and liver of rheumatoid arthritis patients: association with hepatic folate deficiency and formation of polyglutamates. Arthritis Rheum 1986; 29: 832–5PubMedCrossRefGoogle Scholar
  40. 40.
    Hendel J, Nyfors A. Pharmacokinetics of methotrexate in erythrocytes in psoriasis. Eur J Clin Pharm 1984; 27(5): 607–10CrossRefGoogle Scholar
  41. 41.
    Hendel J, Nyfors A. Non-linear renal elimination kinetics of methotrexate due to saturation of renal tubular reabsorption. Eur J Clin Pharmacol 1984; 26: 121–4PubMedCrossRefGoogle Scholar
  42. 42.
    Leeb B, Dunky A, Orgis E, et al. Hämatozelluläres Methotrexate bei Langzeittherapie entzündlich rheumatischer Ehrkrankungen. Acta Med Austriaca 1988; 15: 140–4PubMedGoogle Scholar
  43. 43.
    Bologna C, Endo L, Anaya JM, et al. Methotrexate concentrations in synovial membrane and trabecular and cortical bone in rheumatoid arthritis patients. Arthritis Rheum 1994; 37: 1770–3PubMedCrossRefGoogle Scholar
  44. 44.
    Genestier L, Paillot R, Fournel S, et al. Immunosuppressive properties of methotrexate: apoptosis and clonal deletion of activated peripheral T cells. J Clin Invest 1998; 102(2): 322–8PubMedCrossRefGoogle Scholar
  45. 45.
    Olsen EA. The pharmacology of methotrexate. J Am Acad Dermatol 1991; 25 (Pt 1): 306–18PubMedCrossRefGoogle Scholar
  46. 46.
    Bertino JR. Clinical pharmacology of methotrexate. Med Pediatr Oncol 1982; 10: 401–11PubMedCrossRefGoogle Scholar
  47. 47.
    Cronstein BN. The mechanism of action of methotrexate. Rheum Dis Clin North Am 1997; 23(4): 739–55PubMedCrossRefGoogle Scholar
  48. 48.
    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: 38–40PubMedGoogle Scholar
  49. 49.
    Furst DE. Practical clinical pharmacology and drug interactions of low-dose methotrexate therapy in rheumatoid arthritis. Br J Rheumatol 1995; 34: 20–5PubMedGoogle Scholar
  50. 50.
    Eksborg S, Albertoni F, Beck O, et al. Methotrexate in rheumatoid arthritis: a limited sampling strategy for estimation of the area under the plasma concentration versus time curve. Ther Drug Monit 1994; 16: 560–3PubMedCrossRefGoogle Scholar
  51. 51.
    Bressolle F, Bologna C, Edno L, et al. A limited sampling method to estimate methotrexate pharmacokinetics in patients with rheumatoid arthritis using a Bayesian approach and the population data modeling program P-PHARM. Eur J Clin Pharmacol 1996; 49(4): 285–92PubMedCrossRefGoogle Scholar
  52. 52.
    Bressolle F, Kinowski JM, Morel J, et al. Folic acid alters methotrexate availability in patients with rheumatoid arthritis. J Rheumatol 2000; 27(9): 2110–4PubMedGoogle Scholar
  53. 53.
    Bruce WR, Meeker BE, Valeriote FA. Comparison of the sensitivity of normal hematopoietic and transplanted lymphoma colony-forming cells to chemotherapeutic agents administered in vivo. J Natl Cancer Inst 1966; 37: 233–45PubMedGoogle Scholar
  54. 54.
    Koerber H, Gross WL, Iven H. Do steroids influence low dose methotrexate pharmacokinetics? J Rheumatol 1994; 21: 1170–1PubMedGoogle Scholar
  55. 55.
    Osswald H, Gleiter C, Muhlbauer B. Therapeutic use of theophylline to antagonize renal effects of adenosine [review]. Clin Nephrol 1995; 43 Suppl. 1: S33–7PubMedGoogle Scholar
  56. 56.
    Jeurissen ME, Boerbooms AM, van de Putte LB. Pancytopenia and methotrexate with trimethoprim-sulfamethoxazole [letter]. Ann Intern Med 1989; 111: 261PubMedGoogle Scholar
  57. 57.
    Furst DE. The rational use of methotrexate in rheumatoid arthritis and other rheumatic diseases. Br J Rheumatol 1997; 36: 1196–204PubMedCrossRefGoogle Scholar
  58. 58.
    Morabito L, Montesinos MC, Schreibman DM, et al. Methotrexate and sulphasalazine promote adenosine release by a mechanism that requires ecto-5 -nucleotidase-mediated conversion of adenine nucleotides. J Clin Invest 1998; 101: 295–300PubMedCrossRefGoogle Scholar
  59. 59.
    Dolhain RJ, Tak PP, Dijkmans BA, et al. Methotrexate reduces inflammatory cell numbers expression of monokines and adhesion molecules in synovial tissue of patients with rheumatoid arthritis. Br J Rheumatol 1998; 37(5): 502–8PubMedCrossRefGoogle Scholar
  60. 60.
    Bouma MG, van den Wildenberg FA, Buurman WA. Adenosine inhibits cytokine release and expression of adhesion molecules by activated human endothelial cells. Am J Physiol 1996; 39: 522–9Google Scholar
  61. 61.
    Sajjadi FG, Takabayashi K, Foster AC, et al. Inhibition of TNFα expression by adenosine: role of A3 adenosine receptors. J Immunol 1996; 156: 3435–42PubMedGoogle Scholar
  62. 62.
    Le Moine O, Stordeur P, Schandene L, et al. Adenosine enhances IL-10 secretion by human monocytes. J Immunol 1996; 156: 4408–14PubMedGoogle Scholar
  63. 63.
    Bernini JC, Fort DW, Greiner JC, et al. Aminophylline for methotrexate-induced neurotoxicity. Lancet 1995; 345: 544–7PubMedCrossRefGoogle Scholar
  64. 64.
    Pigatto D, Gibelli E, Ranza R, et al. Methotrexate in psoriatic polyarthritis. Acta Derm Venereol Suppl (Stockh) 1994; 186: 114–5Google Scholar
  65. 65.
    Weinblatt ME, Kremer JM, Bankhurst AD, et al. A trial of etanercept, a recombinant tumor necrosis factor: Fc fusion protein, in patients with rheumatoid arthritis receiving methotrexate. N Engl J Med 1999; 340(4): 253–9PubMedCrossRefGoogle Scholar
  66. 66.
    Health and Public Policy Committee, American College of Physicians. MTX in rheumatoid arthritis. Ann Intern Med 1987; 107: 418–9Google Scholar
  67. 67.
    Tishler M, Caspi D, Yaron M. Methotrexate treatment of rheumatoid arthritis: is a fortnightly maintenance schedule enough? Ann Rheum Dis 1992; 51: 1330–1PubMedCrossRefGoogle Scholar
  68. 68.
    Godfrey C, Sweeney K, Miller K, et al. The population pharmacokinetics of long-term methotrexate in rheumatoid arthritis. Br J Clin Pharmacol 1998; 46: 369–76PubMedCrossRefGoogle Scholar
  69. 69.
    Ravelli A, Di Fuccia G, Molinaro M, et al. Plasma levels after oral methotrexate in children with juvenile rheumatoid arthritis. J Rheumatol 1993; 20: 1573–7PubMedGoogle Scholar
  70. 70.
    Capone D, Spano A, Gentile A, et al. Are there differences in methotrexate kinetics between responding and nonresponding patients with rheumatoid arthritis? BioDrugs 2000; 13(5): 373–9PubMedCrossRefGoogle Scholar
  71. 71.
    Longo GS, Gorlick R, Tong WP, et al. γ-Glutamyl hydrolase and folylpolyglutamylsynthetase activities predict polyglutamylation of methotrexate in acute leukemias. Oncol Res 1997; 9: 259–63PubMedGoogle Scholar
  72. 72.
    Ortiz Z, Shea B, Suarez-Almazor M, et al. The efficacy of folic and folinic acid in reducing methotrexate gastrointestinal toxicity in rheumatoid arthritis: a metaanalysis of randomized controlled trials. J Rheum 1998; 25: 36–43PubMedGoogle Scholar
  73. 73.
    Roenigk HH, Auerbach R, Bergfeld WF, et al. A cooperative prospective study of the effects of chemotherapy of psoriasis on liver biopsies. In: Farber EM, Cox AJ, editors. Psoriasis: Proceedings of the Second International Symposium. New York: York Medical Books, 1976: 243–8Google Scholar
  74. 74.
    Nyfors A. Liver biopsies from psoriatics related to methotrexate therapy: 3. Findings in post-methotrexate liver biopsies from 160 patients. Acta Pathol Microbiol Scand [A] 1977; 85: 511–8Google Scholar
  75. 75.
    Mitchell D, Smith A, Rowan B, et al. Serum type III procollagen peptide, dynamic liver function tests and hepatic fibrosis in psoriatic patients receiving methotrexate. Br J Dermatol 1990; 122: 1–7PubMedCrossRefGoogle Scholar
  76. 76.
    Zachariae H, Grunnet E, Sogaard H. Liver biopsy in methotrexate-treated psoriatics -a re-evaluation. Acta Derm Venereol (Stockh) 1975; 55: 291–6Google Scholar
  77. 77.
    Robinson JK, Baughman RD, Auerbach R, et al. Methotrexate hepatotoxicity in psoriasis: consideration of liver biopsy at regular intervals. Arch Dermatol 1980; 116(4): 413–5PubMedCrossRefGoogle Scholar
  78. 78.
    Zachariae H, Kragballe K, Sogaard H. Methotrexate induced liver cirrhosis: studies including serial liver biopsies during continued treatment. Br J Dermatol 1980; 102: 407–12PubMedCrossRefGoogle Scholar
  79. 79.
    van de Kerkhof PC, Hoefnagels WH, van Haelst UJ, et al. Methotrexate maintenance therapy and liver damage in psoriasis. Clin Exp Dermatol 1985; 10: 194–200PubMedCrossRefGoogle Scholar
  80. 80.
    Themido R, Louriero M, Pecegueiro M, et al. Methotrexate hepatotoxicity in psoriatic patients submitted long-term therapy. Acta Derm Venereol (Stockh) 1992; 72: 361–4Google Scholar
  81. 81.
    van Dooren-Greebe RJ, Kuijpers AL, Mulder J, et al. Methotrexate revisited: effects of long-term treatment in psoriasis. Br J Dermatol 1994; 130: 204–10PubMedCrossRefGoogle Scholar
  82. 82.
    Haagsma CJ, Blom HJ, van Riel PLCM, et al. Influence of sulphasalazine, methotrexate, and the combination of both on plasma homocysteine concentrations in patients with rheumatoid arthritis. Ann Rheum Dis 1999; 58: 79–84PubMedCrossRefGoogle Scholar
  83. 83.
    Morgan SL, Baggott JE, Refsum H, et al. Homocysteine levels in patients with rheumatoid arthritis treated with low-dose methotrexate. Pharmacol Ther 1991; 50: 547–56CrossRefGoogle Scholar
  84. 84.
    van der Put NM, Steegers-Theunissen RP, Frosst P, et al. Mutated methylenetetrahydrofolate reductase as a risk factor for spina bifida. Lancet 1995; 346: 1070–1PubMedCrossRefGoogle Scholar
  85. 85.
    Van Ede AE, Laan RF, Bloom HJ, et al. Homocysteine and folate status in methotrexate-treated patients with rheumatoid arthritis. Rheumatology (Oxford) 2002; 41(6): 658–65CrossRefGoogle Scholar
  86. 86.
    Barrera P, Laan RF, van Riel PL, et al. Methotrexate-related pulmonary complications in rheumatoid arthritis. Ann Rheum Dis 1994; 53: 434–9PubMedCrossRefGoogle Scholar
  87. 87.
    Al-Awadhi A, Dale P, McKendry RJ. Pancytopenia associated with low dose methotrexate therapy: a regional survey. J Rheumatol 1993; 20: 1121–5PubMedGoogle Scholar
  88. 88.
    Basin KS, Escalante A, Beardmore TD. Severe pancytopenia in a patient taking low dose methotrexate and probenecid. J Rheumatol 1991; 18: 609–10PubMedGoogle Scholar
  89. 89.
    Thomas MH, Gutterman LA. Methotrexate toxicity in a patient receiving trimethoprim-sulfamethoxazole. J Rheumatol 1986; 13: 440–1PubMedGoogle Scholar
  90. 90.
    Groenendal H, Rampen FH. Methotrexate and trimethoprimsulfamethoxazole: a potentially hazardous combination. Clin Exp Dermatol 1990; 15: 358–60PubMedCrossRefGoogle Scholar
  91. 91.
    Stewart CF, Evans WE. Drug-drug interactions with antirheumatic agents: review of selected clinically important interactions. J Rheumatol 1990; 17 Suppl. 22: 16–23Google Scholar
  92. 92.
    Alarcon GS, Kremer JM, Macaluso M, et al. Risk factors for methotrexate-induced lung injury in patients with rheumatoid arthritis: a multicenter, case-control study. Methotrexate study group. Ann Intern Med 1997; 127: 356–64PubMedGoogle Scholar
  93. 93.
    Weinblatt ME, Kaplan H, Germain BF, et al. Methotrexate in rheumatoid arthritis: a five-year prospective study. Arthritis Rheum 1994; 37: 1492–8PubMedCrossRefGoogle Scholar
  94. 94.
    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: 138–45PubMedCrossRefGoogle Scholar
  95. 95.
    Weinblatt ME, Weissman BN, Holsworth DE, et al. Long-term prospective study of methotrexate in treatment of rheumatoid arthritis: 84 months update. Arthritis Rheum 1992; 35: 129–37PubMedCrossRefGoogle Scholar
  96. 96.
    Wallace CA, Bleyer WA, Sherry DD, et al. Toxicity and serum levels of methotrexate in children with juvenile rheumatoid arthritis. Arthritis Rheum 1989; 32: 677–81PubMedCrossRefGoogle Scholar
  97. 97.
    Wallace CA, Sherry DD. A practical approach to avoidance of methotrexate toxicity. J Rheumatol 1995; 22: 1009–12PubMedGoogle Scholar
  98. 98.
    Morgan SL, Baggott JE, Vaughn WH, et al. Supplementation with folic acid during methotrexate therapy for rheumatoid arthritis: a double-blind, placebo-controlled trial. Ann Intern Med 1994; 121: 833–41PubMedGoogle Scholar
  99. 99.
    Bologna C, Picot MC, Jorgnesen C, et al. Study of eight cases of cancer in 426 rheumatoid arthritis patients treated with methotrexate. Ann Rheum Dis 1997; 56: 97–102PubMedCrossRefGoogle Scholar
  100. 100.
    Beauparalant P, Papp K, Haraoui B. The incidence of cancer associated with the treatment of rheumatoid arthritis. Semin Arthritis Rheum 1999; 29(3): 148–58CrossRefGoogle Scholar
  101. 101.
    Morgan SL, Baggott JE, Vaughn WH, et al. The effect of folic acid supplementation on the toxicity of low-dose methotrexate in patients with rheumatoid arthritis. Arthritis Rheum 1990; 33(1): 9–18PubMedCrossRefGoogle Scholar
  102. 102.
    Morgan SL, Baggott JE, Lee JY, et al. Folic acid supplementation prevents deficient blood folate levels and hyper-homocysteinemia during longterm, low dose methotrexate therapy for rheumatoid arthritis: implications for cardiovascular disease prevention. J Rheumatol 1998; 25: 441–6PubMedGoogle Scholar
  103. 103.
    Weinblatt ME, Maier AL, Coblyn JS. Low dose leucovorin does not interfere with the efficacy of methotrexate in rheumatoid arthritis: an 8 week randomized placebo controlled trial. J Rheumatol 1993; 20: 950–2PubMedGoogle Scholar
  104. 104.
    Hunt PG, Rose CD, McIlvain-Simpson G, et al. The effects of daily intake of folic acid on the efficacy of methotrexate therapy in children with juvenile rheumatoid arthritis: a control study. J Rheumatol 1997; 24: 2230–4PubMedGoogle Scholar
  105. 105.
    Shiroky JB. The use of folates concomitantly with low-dose pulse methotrexate. Rheum Dis Clin North Am 1997; 23(4): 969–80PubMedCrossRefGoogle Scholar
  106. 106.
    Shiroky JB, Neville C, Esdaile J, et al. Low-dose methotrexate with leucovorin (folinic acid) in the management of rheumatoid arthritis. Arthritis Rheum 1993; 36(6): 795–803PubMedCrossRefGoogle Scholar

Copyright information

© Adis International Limited 2003

Authors and Affiliations

  • Jiří Grim
    • 1
  • Jaroslav Chládek
    • 1
  • Jiřina Martínková
    • 1
  1. 1.Department of PharmacologyCharles UniversityHradec KrálovéCzech Republic

Personalised recommendations