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Drugs

, Volume 47, Issue 1, pp 25–50 | Cite as

Methotrexate in Rheumatoid Arthritis

An Update
  • Bernard Bannwarth
  • Laurence Labat
  • Yola Moride
  • Thierry Schaeverbeke
Review Article

Summary

Methotrexate has been approved for the treatment of refractory rheumatoid arthritis by several regulatory agencies, including the Food and Drug Administration. The tendency is now to prescribe it at earlier stages of the disease.

Methotrexate is a well known antifolate. Its exact mechanism of action in rheumatoid arthritis remains uncertain. The polyglutamated derivatives of methotrexate are potent inhibitors of various enzymes, including dihydrofolate reductase and 5-aminoimidazole-4-carboxamide ribonucleotide transformylase. Inhibitory effects on cytokines, particularly interleukin-1, and on arachidonic acid metabolism, as well as effects on proteolytic enzymes, have been reported. Some of them may be linked to the antifolate properties of methotrexate. Overall, the drug appears to act in rheumatoid arthritis as an anti-inflammatory agent with subtle immunomodulating properties. Direct inhibitory effects on rapidly proliferating cells in the synovium have also been suggested.

Methotrexate is usually given orally. Marked interindividual variation in its bioavailability has been found. Food intake has no significant effect on the pharmacokinetics of oral methotrexate.

Methotrexate undergoes significant metabolism. The functionally important metabolites are the polyglutamated derivatives of methotrexate, which are selectively retained in the cells. Less than 10% of a dose of methotrexate is oxidised to 7-hydroxy-methotrexate, irrespective of the route of administration. This metabolite is extensively (91 to 93%) bound to plasma proteins, in contrast to the parent drug (35 to 50% bound). Methotrexate is mainly excreted by the kidneys. It undergoes tubular secretion and may thereby compete with various organic acid compounds.

Early placebo-controlled trials demonstrated that weekly low dosage methotrexate produced early symptomatic improvement in most rheumatoid arthritis patients. Two meta-analyses showed that methotrexate is among the most efficacious of slow-acting antirheumatic agents, together with parenteral gold (sodium aurothiomalate), penicillamine and sulfasalazine. Furthermore, in the short term context of clinical trials, methotrexate has one of the best efficacy/toxicity ratios.

There is little evidence that methotrexate, or any available slow-acting antirheumatic agent, is a true disease-modifying drug. However, the probability that a patient will continue methotrexate therapy over time appears quite favourable compared with any other slow-acting antirheumatic drug. Combination therapy with slow-acting drugs has been advised for the management of rheumatoid arthritis, but the evidence currently available does not support general use of combination therapy including methotrexate.

Almost all investigations indicated that toxic effects, rather than lack of response, were the major reason for discontinuing methotrexate therapy. An analysis of more than 3000 courses of therapy with 6 slow-acting drugs indicated that the overall toxicity of methotrexate was similar to that of penicillamine and azathioprine. Hydroxychloroquine was the least toxic, followed by sodium aurothiomalate, whereas auranofin was the most toxic.

Few predisposing factors to methotrexate toxicity have been clearly identified, and individual susceptibility plays a primary role in determining toxicity. Folate supplementation may decrease the incidence of common adverse effects, but whether it prevents more serious adverse reactions remains to be answered. Gastrointestinal symptoms, stomatitis, increased levels of liver enzymes and mild cytopenia are frequent adverse effects associated with methotrexate therapy. Furthermore, severe, and possibly life-threatening, complications have been reported. These include advanced liver fibrosis and cirrhosis, interstitial pneumonitis, severe neutropenia and pancytopenia, as well as opportunistic infections. Epstein-Barr virus-associated lymphomas have also been reported. Finally, a variety of other adverse events, such as central nervous system and cutaneous reactions, have been ascribed to methotrexate use.

Numerous drug interactions may occur in patients receiving low dosage methotrexate. Most are probably not clinically significant. Conversely, methotrexate toxicity may be precipitated by concurrent use of cotrimoxazole (trimethoprim/sulfamethoxazole), probenecid, and possibly non-steroidal anti-inflammatory drugs (NSAIDs).

On the basis of the available data, methotrexate should generally not be the first slow-acting antirheumatic drug to be used. However, unlike other cytotoxic agents, it should no longer be regarded as tertiary therapy for rheumatoid arthritis. Low dosage methotrexate may become one of the drugs considered earlier in the course of rheumatoid arthritis not controlled by NSAIDs alone.

Keywords

Rheumatoid Arthritis Methotrexate Rheumatoid Arthritis Patient Auranofin Methotrexate Therapy 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

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References

  1. Ahern M, Booth J, Loxton A, McCarthy P, Meffin P, et al. Methotrexate kinetics in rheumatoid arthritis: is there an interaction with nonsteroidal antiinflammatory drugs?. Journal of Rheumatology 15: 1356–1360, 1988PubMedGoogle Scholar
  2. Ahern MJ, Kevat S, Hill W, Hayball PJ, Harley H, et al. Hepatic methotrexate content and progression of hepatic fibrosis: preliminary findings. Annals of the Rheumatic Diseases 50: 477–480, 1991PubMedCrossRefGoogle Scholar
  3. Alarcon GS, Koopman WJ, McCarty MJ. Nonperipheral accelerated nodulosis in a methotrexate-treated rheumatoid arthritis patient. Arthritis and Rheumatism 36: 132–133, 1993PubMedCrossRefGoogle Scholar
  4. Alarcon GS, Lopez-Mendez A, Walter J, Boerbooms AMT, Russell AS, et al. Radiographic evidence of disease progression in methotrexate treated and nonmethotrexate disease modifying antirheumatic drug treated rheumatoid arthritis patients: a meta-analysis. Journal of Rheumatology 19: 1868–1873, 1992PubMedGoogle Scholar
  5. Alarcon GS, Tracy IC, Blackburn WD. Methotrexate in rheumatoid arthritis. Toxic effects as the major factor in limiting long-term treatment. Arthritis and Rheumatism 32: 671–676, 1989PubMedCrossRefGoogle Scholar
  6. Al-Awadhi A, Dale P, McKendry RJR. Pancytopenia associated with low dose methotrexate therapy. A regional survey. Journal of Rheumatology 20: 1121–1125, 1993PubMedGoogle Scholar
  7. Alexandre C, Chaffanjon C, Tavan P, Thomas T, Pallot-Prades B, et al. Aplasie médullaire dans une polyarthrite rhumatoïde traitée par le méthotrexate à faible dose. Revue du Rhumatisme et des Maladies Ostéo-Articulaires 57: 233–234, 1990PubMedGoogle Scholar
  8. Altz-Smith M, Kendall LG, Stamm AM. Cryptococcosis associated with low-dose methotrexate for arthritis. American Journal of Medicine 83: 179–181, 1987PubMedCrossRefGoogle Scholar
  9. Anaya JM, Jorgensen C, Daurès JP, Combe B, Sany J. Taux de maintenance thérapeutique du méthotrexate au cours de la polyarthrite rhumatoïde. Etude prospective de 191 cas. Revue du Rhumatisme et des Maladies Ostéo-Articulaires 59: 181–187, 1992PubMedGoogle Scholar
  10. Aponte J, Petrelli M. Histopathologic findings in the liver of rheumatoid arthritis patients treated with long-term bolus methotrexate. Arthritis and Rheumatism 31: 1457–1464, 1988PubMedCrossRefGoogle Scholar
  11. Arnold MH, O’Callaghan J, McCredie M, Beller EM, Kelly DE, et al. Comparative controlled trial of low-dose weekly methotrexate versus azathioprine in rheumatoid arthritis: 3-year prospective study. British Journal of Rheumatology 29: 120–125, 1990PubMedCrossRefGoogle Scholar
  12. Basin KS, Escalante A, Beardmore TD. Severe pancytopenia in a patient taking low dose methotrexate and probenecid. Journal of Rheumatology 18: 609–610, 1991PubMedGoogle Scholar
  13. Barrera P, Boerbooms AMT, Janssen EM, Sauerwein RW, Gallati H, et al. Circulating soluble tumor necrosis factor receptors, interleukin-2 receptors, tumor necrosis factor a, and interleukin-6 levels in rheumatoid arthritis. Longitudinal evaluation during methotrexate and azathioprine therapy. Arthritis and Rheumatism 36: 1070–1079, 1993PubMedCrossRefGoogle Scholar
  14. Bjorkman DJ, Hammond EH, Lee RG, Clegg DO, Tolman KG. Hepatic ultrastructure after methotrexate therapy for rheumatoid arthritis. Arthritis and Rheumatism 31: 1465–1472, 1988PubMedCrossRefGoogle Scholar
  15. Brick JE, Moreland LW, Al-Kawas F, Chang WWL, Layne RD, et al. Prospective analysis of liver biopsies before and after methotrexate therapy in rheumatoid patients. Seminars in Arthritis and Rheumatism 19: 31–44, 1989PubMedCrossRefGoogle Scholar
  16. Bridges SL, Lopez-Mendez A, Han KH, Tracy IC, Alarcon GS. Should methotrexate be discontinued before elective orthopedic surgery in patients with rheumatoid arthritis?. Journal of Rheumatology 18: 984–988, 1991PubMedGoogle Scholar
  17. Brooks PJ, Spruill WJ, Parish RC, Birchmore DA. Pharmacokinetics of methotrexate administered by intramuscular and subcutaneous injections in patients with rheumatoid arthritis. Arthritis and Rheumatism 33: 91–94, 1990PubMedCrossRefGoogle Scholar
  18. Bruyn GAW, Essed CA, Houtman PM, Willemse FW. Fatal cardiac nodules in a patient with rheumatoid arthritis treated with low dose methotrexate. Journal of Rheumatology 20: 912–914, 1993PubMedGoogle Scholar
  19. Buchbinder R, Hall S, Ryan PFJ, Littlejohn GO, Harkness AJL. Severe bone marrow failure due to low dose oral methotrexate. Journal of Rheumatology 15: 1586–1588, 1988PubMedGoogle Scholar
  20. Buchbinder R, Hall S, Sambrook PN, Champion GD, Harkness A, et al. Methotrexate therapy in rheumatoid arthritis: a life table review of 587 patients treated in community practice. Journal of Rheumatology 20: 639–644, 1993PubMedGoogle Scholar
  21. Buckley LM, Vacek PM, Cooper SM. Administration of folinic acid after low dose methotrexate in patients with rheumatoid arthritis. Journal of Rheumatology 17: 1158–1161, 1990PubMedGoogle Scholar
  22. Carson CW, Cannon GW, Egger MJ, Ward JR, Clegg BO. Pulmonary disease during the treatment of rheumatoid arthritis with low dose pulse methotrexate. Seminars in Arthritis and Rheumatism 16: 186–195, 1987PubMedCrossRefGoogle Scholar
  23. Chabner BA, Allegra CJ, Curt GA, Clendeninn NJ, Baram J, et al. Polyglutamation of methotrexate. Is methotrexate a prodrug?. Journal of Clinical Investigation 76: 907–912, 1985PubMedCrossRefGoogle Scholar
  24. Chang DM, Weinblatt ME, Schur PH. The effects of methotrexate on interleukin 1 in patients with rheumatoid arthritis. Journal of Rheumatology 19: 1678–1682, 1992PubMedGoogle Scholar
  25. Clegg DO, Furst DE, Tolman KG, Pogue R. Acute, reversible hepatic failure associated with methotrexate treatment of rheumatoid athritis. Journal of Rheumatology 16: 1123–1126, 1989PubMedGoogle Scholar
  26. Cobeta-Garcia JC, Ruiz-Jimeno MT, Fontova-Garrofé R. Non-Hodgkin’s lymphoma, rheumatoid arthritis and methotrexate. Journal of Rheumatology 20: 200–201, 1993PubMedGoogle Scholar
  27. Colburn KK, Cao JD. Thymoma associated with rheumatoid arthritis in a patient taking methotrexate. Journal of Rheumatology 13: 437–439, 1986PubMedGoogle Scholar
  28. Combe B, Guttierrez M, Anaya JM, Sany J. Possible efficacy of hydroxychloroquine on accelerated nodulosis during methotrexate therapy for rheumatoid arthritis. Journal of Rheumatology 20: 755–756, 1993PubMedGoogle Scholar
  29. Cronstein BN. Molecular mechanism of methotrexate action in inflammation. Inflammation 16: 150–162, 1992CrossRefGoogle Scholar
  30. Doolittle GC, Simpson KM, Lindsley HB. Methotrexate-associated, early-onset pancytopenia in rheumatoid arthritis. Archives of Internal Medicine 149: 1430–1431, 1989PubMedCrossRefGoogle Scholar
  31. Edmonds JP, Scott DL, Furst DE, Brooks P, Paulus HE. Antirheumatic drugs: a proposed new classification. Arthitis and Rheumatism 36: 336–339, 1993CrossRefGoogle Scholar
  32. Ellman MH, Hou S, Ginsberg D. Low-dose methotrexate and severe neutropenia in patients undergoing renal dialysis. Arthritis and Rheumatism 33: 1060–1061, 1990PubMedCrossRefGoogle Scholar
  33. Ellman MH, Hurwitz H, Thomas C, Kozloff M. Lymphoma developing in a patient with rheumatoid arthritis taking low dose weekly methotrexate. Journal of Rheumatology 18: 1741–1743, 1991PubMedGoogle Scholar
  34. Ellman MH, Telfer MC, Turner AF. Benefit of G-CSF for methotrexate-induced neutropenia in rheumatoid arthritis. American Journal of Medicine 92: 337–338, 1992PubMedCrossRefGoogle Scholar
  35. Elsasser S, Dalquen P, Soler M, Perruchoud AP. Methotrexate induced pneumonitis: appearance four weeks after discontinuation of treatment. American Review of Respiratory Disease 140: 1089–1092, 1989PubMedGoogle Scholar
  36. Fehlauer CS, Carson CW, Cannon GW, Ward JR, Samuelson CO, et al. Methotrexate therapy in rheumatoid arthritis: 2-year retrospective followup study. Journal of Rheumatology 16: 307–312, 1989PubMedGoogle Scholar
  37. Felson DT, Anderson JJ, Meenan RE The comparative efficacy and toxicity of second-line drugs in rheumatoid arthritis. Results of two metaanalyses. Arthritis and Rheumatism 33: 1449–1461, 1990PubMedCrossRefGoogle Scholar
  38. Felson DT, Anderson JJ, Meenan RF. Use of short-term efflcacy/toxicity tradeoffs to select second-line drugs in rheumatoid arthritis. A metaanalysis of published clinical trials. Arthritis and Rheumatism 35: 1117–1125, 1992PubMedCrossRefGoogle Scholar
  39. Frenia ML, Long KS. Methotrexate and nonsteroidal antiinflammatory drug interactions. Annals of Pharmacotherapy 26: 234–237, 1992PubMedGoogle Scholar
  40. Fries JF, Singh G, Lenert L, Furst DE. Aspirin, hydroxychloroquine and hepatic enzymes abnormalities with methotrexate in rheumatoid arthritis. Arthritis and Rheumatism 33: 1611–1619, 1990PubMedCrossRefGoogle Scholar
  41. Fries JF, Williams CA, Ramey D, Bloch DA. The relative toxicity of disease-modifying antirheumatic drugs. Arthritis and Rheumatism 36: 297–306, 1993PubMedCrossRefGoogle Scholar
  42. Furst DE. Proposition: methotrexate should not be the first secondline agent to be used in rheumatoid arthritis if NSAIDs fail. Seminars in Arthritis and Rheumatism 20: 69–75, 1990aPubMedCrossRefGoogle Scholar
  43. Furst DE. Rational use of disease-modifying antirheumatic drugs. Drugs 39: 19–37, 1990bPubMedCrossRefGoogle Scholar
  44. Furst DE, Erikson N, Clute L, Koehnke R, Burmeister LF, et al. Adverse experience with methotrexate during 176 weeks of a longterm prospective trial in patients with rheumatoid arthritis. Journal of Rheumatology 17: 1628–1635, 1990PubMedGoogle Scholar
  45. Furst DE, Koehnke R, Burmeister LF, Kohler J, Cargill I. Increasing methotrexate effect with increasing dose in the treatment of resistant rheumatoid arthritis. Journal of Rheumatology 16: 313–320, 1989PubMedGoogle Scholar
  46. Furst DE, Kremer JM. Methotrexate in rheumatoid arthritis. Arthritis and Rheumatism 31: 305–314, 1988PubMedCrossRefGoogle Scholar
  47. Furst DE, Weinblatt M. Methotrexate and rheumatoid arthritis. Annals of Internal Medicine 110: 89–90, 1989Google Scholar
  48. Gispen JG, Alarcon GS, Johnson JJ, Acton RT, Barger BO, et al. Toxicity to methotrexate in rheumatoid arthritis. Journal of Rheumatology 14: 74–79, 1987PubMedGoogle Scholar
  49. Gøtzche PC, Pødenphant J, Olesen M, Halberg PK Meta-analysis of second-line antirheumatic drugs: sample size bias and uncertain benefit. Journal of Clinical Epidemiology 45: 587–594, 1992CrossRefGoogle Scholar
  50. Govert JA, Patton S, Fine RL. Pancytopenia from using trimethoprim and methotrexate. Annals of Internal Medicine 117: 877–878, 1992PubMedGoogle Scholar
  51. Green L, Schattner A, Berkenstadt H. Severe reversible interstitial pneumonitis induced by low dose methotrexate: report of a case and review of the literature. Journal of Rheumatology 15: 110–112, 1988PubMedGoogle Scholar
  52. Hall P de la M, Ahern MJ, Jarvis LR, Stoll P, Jenner MA, et al. Two methods of assessment of methotrexate hepatotoxicity in patients with rheumatoid arthritis. Annals of the Rheumatic Diseases 50: 471–476, 1991PubMedCrossRefGoogle Scholar
  53. Hamdy H, McKendry RJR, Mierins E, Liver JA. Low-dose methotrexate compared with azathioprine in the treatment of rheumatoid arthritis. A twenty-four-week controlled clinical trial. Arthritis and Rheumatism 30: 361–368, 1987PubMedCrossRefGoogle Scholar
  54. Hanrahan PS, Russell AS. Concurrent use of folinic acid and methotrexate in rheumatoid arthritis. Journal of Rheumatology 15: 1078–1080, 1988PubMedGoogle Scholar
  55. Hanrahan PS, Scrivens GA, Russell AS. Prospective long term follow-up of methotrexate therapy in rheumatoid arthritis: toxicity, efficacy and radiological progression. British Journal of Rheumatology 28: 147–153, 1989PubMedCrossRefGoogle Scholar
  56. Haraoui B, Pelletier JP, Cloutier JM, Faure MP, Martel-Pelletier J. Synovial membrane histology and immunopathology in rheumatoid arthritis and osteoarthritis. In vivo effects of antirheumatic drugs. Arthritis and Rheumatism 34: 153–163, 1991PubMedCrossRefGoogle Scholar
  57. Harth M. Mechanisms of action of disease modifying antirheumatic drugs. Journal of Rheumatology 19 (Suppl. 32): 100–103, 1992Google Scholar
  58. Hawley DJ, Wolfe F. Are the results of controlled clinical trials and observational studies of second line therapy in rheumatoid arthritis valid and generalizable as measures of rheumatoid arthritis outcome: analysis of 122 studies. Journal of Rheumatology 18: 1008–1014, 1991PubMedGoogle Scholar
  59. He YL, Tanigawara Y, Yasuhara M, Hori R. Effect of folinic acid on tissue residence and excretion of methotrexate in rats. Drug Metabolism and Disposition 19: 729–734, 1991PubMedGoogle Scholar
  60. Health and Public Policy Committee, American College of Physicians. Methotrexate in rheumatoid arthritis. Annals of Internal Medicine 107: 418–419, 1987Google Scholar
  61. Hendel J, Nyfors A. Nonlinear renal elimination kinetics of methotrexate due to saturation of renal tubular reabsorption. European Journal of Clinical Pharmacology 26: 121–124, 1984PubMedCrossRefGoogle Scholar
  62. Herman RA, Veng-Pedersen P, Hoffman J, Koehnke R, Furst DE. Pharmacokinetics of low-dose methotrexate in rheumatoid arthritis patients. Journal of Pharmaceutical Sciences 78: 165–171, 1989PubMedCrossRefGoogle Scholar
  63. Hilliquin P, Laoussadi S, Menkes CJ. Traitement de la polyarthrite rhumatoïde par le méthotrexate. Revue du Rhumatisme et des Maladies Ostéo-Articulaires 58: 419–426, 1991PubMedGoogle Scholar
  64. Hirata S, Matsubara T, Saura R, Tateishi H, Hirohata K. Inhibition of in vitro vascular endothelial cell proliferation and in vivo neovascularization by low-dose methotrexate. Arthritis and Rheumatism 32: 1065–1073, 1989PubMedCrossRefGoogle Scholar
  65. Howland WL. Methotrexate-associated bone marrow suppression following surgery. Arthritis and Rheumatism 31: 1586–1587, 1988PubMedCrossRefGoogle Scholar
  66. Jeurissen ME, Boerbooms AM, Van De Putte LB. Pancytopenia and methotrexate with trimethoprim-sulfamethoxazole. Annals of Internal Medicine 111: 261, 1989PubMedGoogle Scholar
  67. Jeurissen ME, Boerbooms AMT, Van De Putte LBA, Doesburg WH, Lemmens AM. Influence of methotrexate and azathioprine on radiologic progression in rheumatoid arthritis. A randomized, double-blind study. Annals of Internal Medicine 114: 999–1004, 1991PubMedGoogle Scholar
  68. Joyce DA, Will RK, Hoffman DM, Laing B, Blackbourn SJ. Exacerbation of rheumatoid arthritis in patients treated with methotrexate after administration of folinic acid. Annals of the Rheumatic Diseases 50: 913–914, 1991PubMedCrossRefGoogle Scholar
  69. Kamel OW, Van De Rijn M, Weiss LM, Del Zoppo GJ, Hench PK, et al. Brief report: reversible lymphomas associated with Epstein-Barr virus occuring during methotrexate therapy for rheumatoid arthritis and dermatomyositis. New England Journal of Medicine 328: 1217–1321, 1993CrossRefGoogle Scholar
  70. Katz JN, Larson MG, Ginsburg KS. Reconsideration of the risk of post-arthroplasty infection in patients treated with methotrexate. Arthritis and Rheumatism 34: 1624, 1991PubMedCrossRefGoogle Scholar
  71. Kerstens PJSM, Boerbooms AMT, Jeurissen MEC, Fast JH, Assmann KJM, et al. Accelerated nodulosis during low dose methotrexate therapy for rheumatoid arthritis. An analysis of ten cases. Journal of Rheumatology 19: 867–871, 1992PubMedGoogle Scholar
  72. Kevat S, Ahern M, Hall P. Hepatotoxicity of methotrexate in rheumatic diseases. Medical Toxicology 3: 197–208, 1988aPubMedCrossRefGoogle Scholar
  73. Kevat SG, Hill WR, McCarthy PJ, Ahern MJ. Pancytopenia induced by low-dose methotrexate for rheumatoid arthritis. Australian and New Zealand Journal of Medicine 18: 697–700, 1988bPubMedCrossRefGoogle Scholar
  74. Kingsmore SF, Hall BD, Allen NB, Rice JR, Caldwell DS. Association of methotrexate, rheumatoid arthritis and lymphoma: report of 2 cases and literature review. Journal of Rheumatology 19: 1462–1465, 1992PubMedGoogle Scholar
  75. Klippel JH. Winning the battle, losing the war? Another editorial about rheumatoid arthritis. Journal of Rheumatology 17: 1118–1122, 1990PubMedGoogle Scholar
  76. Kozloski GD, De Vito JM, Kisicki JC, Johnson JB. The effect of food on the absorption of methotrexate sodium tablets in healthy volunteers. Arthritis and Rheumatism 35: 761–764, 1992PubMedCrossRefGoogle Scholar
  77. Kozlowski RD, Steinbrunner JV, MacKenzie AH, Clough JD, Wilke WS, et al. Outcome of first-trimester exposure to low dose methotrexate in eight patients with rheumatic disease. American Journal of Medicine 88: 589–592, 1990PubMedCrossRefGoogle Scholar
  78. Kraus A, Alarcon-Segovia D. Low dose methotrexate and NSAID induced ‘mild’ renal insufficiency and severe neutropenia. Journal of Rheumatology 18: 1274, 1991PubMedGoogle Scholar
  79. Kremer JM. Methotrexate 1989 — the evolving story. Journal of Rheumatology 16: 261–263, 1989PubMedGoogle Scholar
  80. Kremer JM. Liver biopsies in patients with rheumatoid arthritis receiving methotrexate: where are we going?. Journal of Rheumatology 19: 189–191, 1992PubMedGoogle Scholar
  81. Kremer JM, Galivan J, Streckfuss A, Kamen B. Methotrexate metabolism analysis in blood and liver of rheumatoid arthritis patients. Association with hepatic folate deficiency and formation of polyglutamates. Arthritis and Rheumatism 29: 832–834, 1986PubMedCrossRefGoogle Scholar
  82. Kremer JM, Kaye GI. Electron microscopic analysis of sequential liver biopsy samples from patients with rheumatoid arthritis. Correlation with light microscopic findings. Arthritis and Rheumatism 32: 1202–1213, 1989PubMedCrossRefGoogle Scholar
  83. Kremer JM, Lee JK. The safety and efficacy of the use of methotrexate in long-term therapy for rheumatoid arthritis. Arthritis and Rheumatism 29: 822–831, 1986PubMedCrossRefGoogle Scholar
  84. 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 and Rheumatism 32: 121–127, 1989PubMedCrossRefGoogle Scholar
  85. 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 and Rheumatism 35: 138–145, 1992PubMedCrossRefGoogle Scholar
  86. Kremer JM, Rynes RI, Bartholomew LE. Severe flare of rheumatoid arthritis after discontinuation of long-term methotrexate therapy. Double-blind study. American Journal of Medicine 82: 781–786, 1987PubMedCrossRefGoogle Scholar
  87. Kujala GA, Shamma’a JM, Chang WL, Brick JE. Hepatitis with bridging fibrosis and reversible hepatic insufficiency in a woman with rheumatoid arthritis taking methotrexate. Arthritis and Rheumatism 33: 1037–1041, 1990PubMedCrossRefGoogle Scholar
  88. Lafforgue P, Monjanel-Mouterde S, Durand A, Catalin J, Acquaviva PC. Is there an interaction between low doses of corticosteroids and methotrexate in patients with rheumatoid arthritis? A pharmacokinetic study in 33 patients. Journal of Rheumatology 20: 263–267, 1993PubMedGoogle Scholar
  89. Le Goff P, Fauquert P, Guillermit MN. Trois cas de pneumopathie au cours du traitement de la polyarthrite rhumatoïde par le méthotrexate. Revue du Rhumatisme et des Maladies Ostéo-Articulaires 56: 23–25, 1989PubMedGoogle Scholar
  90. Leroux JL, Damon M, Chavis C, Crastes de Paulet A, Blotman F. Effets du méthotrexate sur la synthèse de leucotriènes et de dérivés de la lipoxygénase par les polynucléaires au cours de la polyarthrite rhumatoïde. Revue du Rhumatisme et des Maladies Ostéo-Articulaires 59: 587–591, 1992PubMedGoogle Scholar
  91. L’Hirondel JL, Prevost JN, Galateau F, Loyau G. Pneumopathie aiguë au cours du traitement d’une polyarthrite rhumatoïde sévère par méthotrexate à faibles doses en administration orale fractionnée. Revue du Rhumatisme et des Maladies Ostéo-Articulaires 56: 419–424, 1989PubMedGoogle Scholar
  92. Lioté F, Pertuiset E, Cochand-Priollet B, Dombret H, Nemeth J, et al. Pseudo-lymphome B sous méthotrexate au cours de la polyarthrite rhumatoïde. Abstract. Revue du Rhumatisme et des Maladies Ostéo-Articulaires 59: 369, 1992Google Scholar
  93. Louie S, Lillington GA. Low dose methotrexate pneumonitis in rheumatoid arthritis. Thorax 41: 703–704, 1986PubMedCrossRefGoogle Scholar
  94. MacKinnon SK, Starkebaum G, Willkens RF. Pancytopenia associated with low dose pulse methotrexate in the treatment of rheumatoid arthritis. Seminars in Arthritis and Rheumatism 15: 119–126, 1985PubMedCrossRefGoogle Scholar
  95. Maricic M, Davis M, Gall EP. Megaloblastic pancytopenia in a patient receiving concurrent methotrexate and trimethoprim-sulfamethoxazole treatment. Arthritis and Rheumatism 29: 133–135, 1986PubMedCrossRefGoogle Scholar
  96. Mathers D, Russell AS. Methotrexate. In Dixon & Furst (Eds) Second line agents in the treatment of rheumatic diseases, pp. 287–310, Marcel Dekker, New York, 1992Google Scholar
  97. McCarty DJ. Suppress rheumatoid inflammation early and leave the pyramid to the Egyptians. Journal of Rheumatology 17: 1115–1118, 1990PubMedGoogle Scholar
  98. Meyer FA, Yaron I, Mashiah V, Yaron M. Methotrexate inhibits proliferation but not interleukin 1 stimulated secretory activities of cultured human fibroblasts. Journal of Rheumatology 20: 238–242, 1993PubMedGoogle Scholar
  99. Mielants H, Veys EM, Van Der Straeten C, Ackerman C, Goemaere S. The efficacy and toxicity of a constant low dose of methotrexate as a treatment of intractable rheumatoid arthritis: an open prospective study. Journal of Rheumatology 18: 978–983, 1991PubMedGoogle Scholar
  100. Morand EF, McCloud PI, Littlejohn GO. Life table analysis of 879 treatment episodes with slow acting antirheumatic drugs in community rheumatology practice. Journal of Rheumatology 19: 704–708, 1992PubMedGoogle Scholar
  101. Morassut P, Goldstein R, Cyr M, Karsh J, McKendry RJR. Gold sodium thiomalate compared to low dose methotrexate in the treatment of rheumatoid arthritis. A randomized, double blind 26-week trial. Journal of Rheumatology 16: 302–306, 1989PubMedGoogle Scholar
  102. Morgan SL, Alarcon GS, Krumdieck CL. Folic acid supplementation during methotrexate therapy: it makes sense. Journal of Rheumatology 20: 929–930, 1993PubMedGoogle Scholar
  103. Morgan SL, Baggott JE, Refsum H, Ueland PM. Homocysteine levels in patients with rheumatoid arthritis treated with low-dose methotrexate. Clinical Pharmacology and Therapeutics 50: 547–556, 1991PubMedCrossRefGoogle Scholar
  104. Morgan SL, Baggott JE, Vaughn WH, Young PK, Austin JV, et al. The effect of folic acid supplementation on the toxicity of low-dose methotrexate in patients with rheumatoid arthritis. Arthritis and Rheumatism 33: 9–18, 1990PubMedCrossRefGoogle Scholar
  105. Mulherin D, Cummiskey JM, Doyle GD, FitzGerald O. Methotrexate pneumonitis in rheumatoid arthritis. A dramatic response to treatment. British Journal of Rheumatology 31: 356–357, 1992PubMedCrossRefGoogle Scholar
  106. Nesher G, Moore TL, Dorner RW. In vitro effects of methotrexate on peripheral blood monocytes: modulation by folinic acid and S-adenosylmethionine. Annals of the Rheumatic Diseases 50: 637–641, 1991PubMedCrossRefGoogle Scholar
  107. Newman ED, Harrington TM. Fatal methotrexate pneumonitis in rheumatoid arthritis. Arthritis and Rheumatism 31: 1585–1586, 1988PubMedCrossRefGoogle Scholar
  108. Nordstrom DM, West SG, Andersen PA, Sharp JT. Pulse methotrexate therapy in rheumatoid arthritis. A controlled prospective roentgenographic study. Annals of Internal Medicine 107: 797–801, 1987PubMedGoogle Scholar
  109. Oguey D, Këlliker F, Gerber NJ, Reichen J. Effect of food on the bioavailability of low-dose methotrexate in patients with rheumatoid arthritis. Arthritis and Rheumatism 35: 611–614, 1992PubMedCrossRefGoogle Scholar
  110. Olsen NJ, Callaghan LF, Pincus T. Immunologie studies of rheumatoid arthritis patients treated with methotrexate. Arthritis and Rheumatism 30: 481–488, 1987PubMedCrossRefGoogle Scholar
  111. O’Neill T, Simpson J, Smyth SJ, Lovell C, Calin A. Porphyria cutanea tarda associated with methotrexate therapy. British Journal of Rheumatology 32: 411–412, 1993PubMedCrossRefGoogle Scholar
  112. Paulus HE. The use of combinations of disease-modifying antirheumatic agents in rheumatoid arthritis. Arthritis and Rheumatism 33: 113–120, 1990PubMedCrossRefGoogle Scholar
  113. Perhala RS, Wilke WS, Clough JD, Segal AM. Local infectious complications following large joint replacement in rheumatoid arthritis patients treated with methotrexate versus those not treated with methotrexate. Arthritis and Rheumatism 34: 146–152, 1991PubMedCrossRefGoogle Scholar
  114. Phillips CA, Cera PJ, Mangan TF, Newman ED. Clinical liver disease in patients with rheumatoid arthritis taking methotrexate. Journal of Rheumatology 19: 229–233, 1992PubMedGoogle Scholar
  115. Pincus T, Marcum SB, Callahan LF. Longterm drug therapy for rheumatoid arthritis in seven rheumatology private practices: II. Second line drugs and prednisone. Journal of Rheumatology 19: 1885–1894, 1992PubMedGoogle Scholar
  116. Pourel J, Guillemin F, Fener P, Webanck L, Béné MC, et al. Delayed methotrexate pneumonitis in rheumatoid arthritis. Journal of Rheumatology 18: 303–304, 1991PubMedGoogle Scholar
  117. Preston SJ, Diamond T, Scott A, Laurent MR. Methotrexate osteopathy in rheumatic disease. Annals of the Rheumatic Diseases 52: 582–585, 1993PubMedCrossRefGoogle Scholar
  118. Rau R, Herborn G, Karger T, Menninger H, Elhardt D et al. A double blind randomized parallel trial of intramuscular methotrexate and gold sodium thiomalate in early erosive rheumatoid arthritis. Journal of Rheumatology 18: 328–333, 1991aPubMedGoogle Scholar
  119. Rau R, Herborn G, Karger T, Werdier D. Retardation of radiologic progression in rheumatoid arthritis with methotrexate therapy. A controlled study. Arthritis and Rheumatism 34: 1236–1244, 1991bPubMedCrossRefGoogle Scholar
  120. Rau R, Wassenberg S, Herborn G. Can methotrexate reduce the renal toxicity of parenteral gold?. Journal of Rheumatology 20: 759–761, 1993PubMedGoogle Scholar
  121. Ridley MG, Wolfe CS, Mathews JA. Life threatening acute pneumonitis during low dose methotrexate treatment for rheumatoid arthritis: a case report and review of the literature. Annals of the Rheumatic Diseases 47: 784–788, 1988PubMedCrossRefGoogle Scholar
  122. Rooney TW, Furst DE. Methotrexate. In McCarty & Koopman (Eds) Arthritis and allied conditions. A textbook of rheumatology, 12th ed, Vol. 1, pp. 621–636, Lea and Febiger, Philadelphia, 1993Google Scholar
  123. Sany J, Anaya JM, Canovas F, Combe B, Jorgensen C, et al. Influence of methotrexate on the frequency of postoperative infectious complications in patients with rheumatoid arthritis. Journal of Rheumatology 20: 1129–1132, 1993PubMedGoogle Scholar
  124. Sany J, Kaliski S, Couret M, Cuchacovich M, Daures JR Radiologie progression during intramuscular methotrexate treatment of rheumatoid arthritis. Journal of Rheumatology 17: 1636–1641, 1990PubMedGoogle Scholar
  125. Searles G, McKendry RJR. Methotrexate pneumonitis in rheumatoid arthritis: potential risk factors. Four case reports and a review of the literature. Journal of Rheumatology 14: 1164–1171, 1987PubMedGoogle Scholar
  126. Segal R, Caspi D, Tishler M, Fishel B, Yaron M. Accelerated nodulosis and vasculitis during methotrexate therapy for rheumatoid arthritis. Arthritis and Rheumatism 31: 1182–1185, 1988PubMedCrossRefGoogle Scholar
  127. Segal R, Yaron M, Tartakovski B. Methotrexate: mechanism of action in rheumatoid arthritis. Seminars in Arthritis and Rheumatism 20: 190–200, 1990aPubMedCrossRefGoogle Scholar
  128. Segal R, Yaron M, Tartakovsky B. Rescue of interleukin-1 activity by leucovorin following inhibition by methotrexate in a murine in vitro system. Arthritis and Rheumatism 33: 1745–1748, 1990bPubMedCrossRefGoogle Scholar
  129. Seideman P. Methotrexate. The relationship between dose and clinical effect. British Journal of Rheumatology 32: 751–753, 1993PubMedCrossRefGoogle Scholar
  130. Seideman P, Beck O, Eksborg S, Wennberg M. The pharmacokinetics of methotrexate and its 7-hydroxy metabolite in patients with rheumatoid arthritis. British Journal of Clinical Pharmacology 35: 409–412, 1993PubMedCrossRefGoogle Scholar
  131. Seideman P, Müller-Suur R. Renal effects of aspirin and low dose methotrexate in rheumatoid arthritis. Annals of the Rheumatic Diseases 52: 613–615, 1993PubMedCrossRefGoogle Scholar
  132. Shergy WJ, Polisson RP, Caldwell DS, Rice JR, Pisetsky DS, et al. Methotrexate-associated hepatotoxicity: retrospective analysis of 210 patients with rheumatoid arthritis. American Journal of Medicine 85: 771–774, 1988PubMedCrossRefGoogle Scholar
  133. Shiroky JB, Frost A, Skelton JD, Haegert DG, Newkirk MM, et al. Complications of immunosuppression associated with weekly low dose methotrexate. Journal of Rheumatology 18: 1172–1175, 1991PubMedGoogle Scholar
  134. Shiroky JB, Neville C, Esdaile JM, Choquette D, Zummer M, et al. Low-dose methotrexate with leucovorin (folinic acid) in the management of rheumatoid arthritis, results of a multicenter, randomized, double-blind, placebo-controlled trial. Arthritis and Rheumatism 36: 795–803, 1993PubMedCrossRefGoogle Scholar
  135. Shiroky JB, Neville C, Skelton JD. High dose intravenous methotrexate for refractory rheumatoid arthritis. Journal of Rheumatology 19: 247–251, 1992PubMedGoogle Scholar
  136. Sinnett MJ, Groff GD, Raddatz DA, Franck WA, Bertino JS. Methotrexate pharmacokinetics in patients with rheumatoid arthritis. Journal of Rheumatology 16: 745–748, 1989PubMedGoogle Scholar
  137. Slørdal L, Sager G, Aarbakke J. Pharmacokinetic interactions with methotrexate: is 7-hydroxy-methotrexate the culprit?. Lancet 1: 591–592, 1988PubMedCrossRefGoogle Scholar
  138. Songsiridej N, Furst DE. Methotrexate — the rapidly acting drug. Baillière’s Clinical Rheumatology 4: 575–593, 1990PubMedCrossRefGoogle Scholar
  139. Sperling RI, Coblyn JS, Larkin JK, Benincaso AI, Austen KF, et al. Inhibition of leukotriene B4 synthesis in neutrophils from patients with rheumatoid arthritis by a single oral dose of methotrexate. Arthritis and Rheumatism 33: 1149–1155, 1990PubMedCrossRefGoogle Scholar
  140. Stenger AAME, Houtman PM, Bruyn GAW. Does folate supplementation make sense in patients with rheumatoid arthritis treated with methotrexate?. Annals of the Rheumatic Diseases 51: 1019–1920, 1992PubMedCrossRefGoogle Scholar
  141. Stewart CF, Evans WE. Drug-drug interactions with antirheumatic agents: review of selected clinically important interactions. Journal of Rheumatology 17 (Suppl. 22): 16–23, 1990Google Scholar
  142. Stewart CF, Fleming RA, Germain BF, Seleznick MJ, Evans WE. Aspirin alters methotrexate disposition in rheumatoid arthritis patients. Arthritis and Rheumatism 34: 1514–1520, 1991aPubMedCrossRefGoogle Scholar
  143. Stewart KA, Mackenzie AH, Wilke WS. Folate supplementation in methotrexate-treated rheumatoid arthritis patients. Seminars in Arthritis and Rheumatism 20: 332–338, 1991bPubMedCrossRefGoogle Scholar
  144. Suarez-Almazor ME, Fitzgerald A, Grace M, Russell AS. A randomized controlled trial of parenteral methotrexate compared with sodium aurothiomalate (Myochrysine®) in the treatment of rheumatoid arthritis. Journal of Rheumatology 15: 753–756, 1988PubMedGoogle Scholar
  145. Taillan B, Gamier G, Ferrari E, Castanet J, Pesce A, et al. Malignant lymphoma in a patient with rheumatoid arthritis treated with lowdose methotrexate. Revue du Rhumatisme et des Maladies Ostéo-Articulaires (English Edition) 60: 214–216, 1993Google Scholar
  146. Tan N, Grisanti MW, Grisanti JM. Oral methotrexate in the treatment of Felty’s syndrome. Journal of Rheumatology 20: 599–601, 1993PubMedGoogle Scholar
  147. Tanaka Y, Shiozawa K, Nishibayashi Y, Imura S. Methotrexate induced early onset pancytopenia in rheumatoid arthritis: drug allergy? idiosyncrasy?. Journal of Rheumatology 19: 1320–1321, 1992PubMedGoogle Scholar
  148. Thomas MH, Gutterman LA. Methotrexate toxicity in a patient receiving trimethoprim-sulfamethoxazole. Journal of Rheumatology 13: 440–441, 1986PubMedGoogle Scholar
  149. Tishler M, Caspi D, Fishel B, Yaron M. The effects of leucovorin (folinic acid) on methotrexate therapy in rheumatoid arthritis patients. Arthritis and Rheumatism 31: 906–908, 1988PubMedCrossRefGoogle Scholar
  150. Tishler M, Caspi D, Yaron M. Methotrexate treatment of rheumatoid arthritis: is a fortnightly maintenance schedule enough?. Annals of the Rheumatic Diseases 51: 1330–1331, 1992PubMedCrossRefGoogle Scholar
  151. Tracy TS, Krohn K, Jones DR, Bradley JD, Hall SD, et al. The effects of a salicylate, ibuprofen, and naproxen on the disposition of methotrexate in patients with rheumatoid arthritis. European Journal of Clinical Pharmacology 42: 121–125, 1992PubMedCrossRefGoogle Scholar
  152. Tugwell P, Bennett K, Bell M, Gent M. Methotrexate in rheumatoid arthritis. Feedback on American College of Physicians guidelines. Annals of Internal Medicine 110: 581–583, 1989PubMedGoogle Scholar
  153. Tugwell P, Bennett K, Gent M. Methotrexate in rheumatoid arthritis. Indications, contraindications, efficacy, and safety. Annals of Internal Medicine 107: 358–366, 1987PubMedGoogle Scholar
  154. Walker AM, Funch D, Dreyer NA, Tolman KG, Kremer JM, et al. Determinants of serious liver disease among patients receiving low-dose methotrexate for rheumatoid arthritis. Arthritis and Rheumatism 36: 329–335, 1993PubMedCrossRefGoogle Scholar
  155. Watson RGP, Smallwood RA. Low-dose methotrexate therapy and hepatotoxicity. The view of the hepatologist. Medical Journal of Australia 155: 428–430, 1991PubMedGoogle Scholar
  156. Weinblatt ME, Fraser P. Elevated mean corpuscular volume as a predictor of hematologic toxicity due to methotrexate therapy. Arthritis and Rheumatism 32: 1592–1596, 1989PubMedCrossRefGoogle Scholar
  157. Weinblatt ME, Kaplan H, Germain BF, Merriman RC, Solomon SD, et al. Low-dose methotrexate compared with auranofin in adult rheumatoid arthritis. A thirthy-six-week, double-blind trial. Arthritis and Rheumatism 33: 330–338, 1990PubMedCrossRefGoogle Scholar
  158. Weinblatt ME, Maier AL. Longterm experience with low dose weekly methotrexate in rheumatoid arthritis. Journal of Rheumatology 17 (Suppl. 22): 33–38, 1990Google Scholar
  159. 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. Journal of Rheumatology 20: 950–952, 1993aPubMedGoogle Scholar
  160. Weinblatt ME, Polisson R, Blotner SD, Sosman JL, Aliabadi P, et al. The effect of drug therapy on radiographic progression of rheumatoid arthritis. Results of a 36-week randomized trial comparing methotrexate and auranofln. Arthritis and Rheumatism 36: 613–619, 1993bPubMedCrossRefGoogle Scholar
  161. Weinblatt ME, Weissman BN, Holdsworth DE, Fraser PA, Maier AL, et al. Long-term prospective study of methotrexate in the treatment of rheumatoid arthritis. 84-month update. Arthritis and Rheumatism 35: 129–137, 1992PubMedCrossRefGoogle Scholar
  162. Welles WL, Silkworm J, Oronsky AL, Kerwar SS, Galivan J. Studies on the effect of low dose methotrexate on rat adjuvant arthritis. Journal of Rheumatology 12: 904–906, 1985PubMedGoogle Scholar
  163. Wernick R, Smith DL. Central nervous system toxicity associated with weekly low-dose methotrexate treatment. Arthritis and Rheumatism 32: 770–775, 1989PubMedCrossRefGoogle Scholar
  164. White DA, Rankin JA, Stover DE, Gellene RA, Gupta S. Methotrexate pneumonitis. Bronchoalveolar lavage findings suggest an immunologie disorder. American Review of Respiratory Disease 139: 18–21, 1989PubMedCrossRefGoogle Scholar
  165. Whiting-O’Keefe Q, Fye KH, Sack KD. Methotrexate and histologic abnormalities: a meta-analysis. American Journal of Medicine 90: 711–716, 1991PubMedGoogle Scholar
  166. Wijnands MJ, Van Riel PL, Gribnau FW, Van De Putte LB. Risk factors of second-line antirheumatic drugs in rheumatoid arthritis. Seminars in Arthritis and Rheumatism 19: 337–352, 1990PubMedCrossRefGoogle Scholar
  167. Wilke WS, Kremer JM, Mackenzie AM, Segal AM, Mazanec DJ, et al. Methotrexate and rheumatoid arthritis. Annals of Internal Medicine 110: 88–89, 1989Google Scholar
  168. Wilke WS, Mackenzie AH. Methotrexate therapy in rheumatoid arthritis. Drugs 32: 103–113, 1986PubMedCrossRefGoogle Scholar
  169. Willkens RF. New perspectives of secondary and tertiary therapy for rheumatoid arthritis. Drugs 37: 739–754, 1989PubMedCrossRefGoogle Scholar
  170. Willkens RF. Resolve: methotrexate is the drug of choice after NSAIDs in rheumatoid arthritis. Seminars in Arthritis and Rheumatism 20: 76–80, 1990PubMedCrossRefGoogle Scholar
  171. Willkens RF, Urowitz MB, Stablein DM, McKendry RJR, Berger RG, et al. Comparison of azathioprine, methotrexate, and the combination of both in the treatment of rheumatoid arthritis. A controlled clinical trial. Arthritis and Rheumatism 35: 849–856, 1992PubMedCrossRefGoogle Scholar
  172. Wolfe F, Cathey MA. The effect of age on methotrexate efficacy and toxicity. Journal of Rheumatology 18: 973–977, 1991PubMedGoogle Scholar
  173. Wolfe F, Hawley DJ, Cathey MA. Termination of slow acting antirheumatic therapy in rheumatoid arthritis: a 14-year prospective evaluation of 1017 consecutive starts. Journal of Rheumatology 17: 994–1002, 1990PubMedGoogle Scholar
  174. Zimmerman J. Methotrexate transport in the human intestine. Evidence for heterogeneity. Biochemical Pharmacology 43: 2377–2383, 1992CrossRefGoogle Scholar

Copyright information

© Adis International Limited 1994

Authors and Affiliations

  • Bernard Bannwarth
    • 1
  • Laurence Labat
    • 1
  • Yola Moride
    • 1
  • Thierry Schaeverbeke
    • 1
  1. 1.Departments of Clinical Pharmacology and RheumatologyGroupe Hospitalier Pellegrin and UniversitéBordeaux CedexFrance

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