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Methotrexate therapy in rheumatoid arthritis. A two year prospective follow-up

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One hundred and thirty seven rheumatoid arthritis (RA) patients refractory to D-penicillamine and some of them (15%) refractory to other slow active drugs were treated with oral methotrexate (MTX) (10–15mg weekly). After 12–24 months of treatment, 94 and 74 patients respectively showed a significant improvement as judged by duration of morning stiffness (p<0.0001), grip strength (p<0.0001), degree of joint swelling (p<0.01) and tenderness (p<0.0001) compared to pre-treatment values. This clinical improvement was also associated with a decrease of erythrocyte sedimentation rate (p<0.0001), decrease of C-reactive protein (p<0.0001) and with improvement of anaemia (p<0.05). No changes were seen in rheumatoid factor titres. Seventy-four of the patients were followed for up to 24 months. Thirty-one of them (23%) had complete remission and 43 (31%) had an excellent response. Adverse drug reaction during MTX therapy included: elevated liver enzymes in 34 patients, mucosal ulcers in 21, nausea and vomiting in 8, diarrhoea in 4, leukopenia in 2, interstitial pneumonitis in one, intestinal bleeding in one and finally septic arthritis in another patient. The majority of these side effects were resolved without sequelae. However, 15 patients (11%) with adverse drug reactions had to discontinue the treatment. Forty-one of our patients who received a cumulative mean dose of MTX of 1550.5±235.5 mg underwent a percutaneous liver biopsy. Ten patients had normal tissue, 12 had minimal changes, 13 nonspecific changes and 6 patients had mild fibrosis. We conclude that MTX therapy in refractory RA patients appears to be effective, but requires close monitoring for toxicity. Hepatotoxicity with fibrosis and cirrhosis due to long term MTX therapy may be relatively uncommon in RA patients.

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References

  1. Bleyer, W.A. The clinical pharmacology of methotrexate: new applications of an old drug. Cancer 1978, 41, 36–51.

    PubMed  Google Scholar 

  2. Nyfors, A. Methotrexate therapy of psoriasis. Dan Med Bull 1980, 27, 74–96.

    PubMed  Google Scholar 

  3. Black, R.L., O'Brien, W.M., Van Scott, E.J., Averbach, R., Eisen, A.Z., Bunim, J.J. Methotrexate therapy in psoriatic arthritis. JAMA 1964, 189, 743–747.

    PubMed  Google Scholar 

  4. Owen, E.T., Cohen, M.L. Methotrexate in Reiter's disease. Ann Rheum Dis 1979, 38, 48–50.

    Google Scholar 

  5. Bookbinder, S.A., Espinosa, L.R., Fenske, N.A., Germain, B.F., Vasey, F.B. Methotrexate: its use in the rheumatic diseases. Clin Exp Rheumatol 1984, 2, 185–193.

    PubMed  Google Scholar 

  6. Gubner, R., August, S., Ginsburg, V. Therapeutic suppression of tissue reactivity. II. Effect of aminopterin in rheumatoid arthritis and psoriasis. Am J Med Sci 1951, 221, 176–182.

    PubMed  Google Scholar 

  7. Willkens, R.F., Watson, M.A., Paxson, C.S. Low dose pulse methotrexate therapy in rheumatoid arthritis. J Rheumatol 1980, 7, 501–505.

    PubMed  Google Scholar 

  8. Steinsson, K., Weinstein, A., Korn, J., Abeles, M. Low dose methotrexate in rheumatoid arthritis. J Rheumatol 1982, 9, 860–866.

    PubMed  Google Scholar 

  9. Thompson, R.N., Watts, C., Edelman, J., Esdaile, J., Russell, A.S. A controlled two centre trial of parenteral methotrexate therapy for refractory rheumatoid arthritis. J Rheumatol 1984, 11, 760–763.

    PubMed  Google Scholar 

  10. Willkens, R.F. Short-term efficacy of methotrexate in the treatment of rheumatoid arthritis. J Rheumatol 1985, Suppl. 12, 21–24.

    Google Scholar 

  11. Weinblatt, M.E., Coblyn, J.S., Fox, D.A., Holdsworth, D.E., Glass, D.N., Tzentham, D.E. Efficacy of low dose methotrexate in rheumatoid arthritis. N Engl J Med 1985, 302, 818–822.

    Google Scholar 

  12. Williams, H.J., Willkens, R.F., Samuelson, C.O.Jr., et al. Comparison of low dose oral pulse methotrexate and placebo in the treatment of rheumatoid arthritis: a controlled clinical trial. Arthritis Rheum 1985, 28, 721–730.

    PubMed  Google Scholar 

  13. Hamdy, H., McKendry, R.J.R., Mierins, E., Liver, J.A. Low dose methotrexate compared with azathioprine in the treatment of rheumatoid arthritis. Arthritis Rheum 1987, 30, 361–368.

    PubMed  Google Scholar 

  14. Andersen, P.A., West, S.G., O'Dell, J.R., Via, C.S., Claypool, R.G., Kotzin, B.L. Weekly pulse methotrexate in rheumatoid arthritis. Ann Intern Med 1985, 103, 489–496.

    PubMed  Google Scholar 

  15. Boerbooms, A.M.Th., Jeurissen, M.E.C., Westgeest, A.A.A., Theunisse, H., Van de Putte, L.B.A. Methotrexate in refractory rheumatoid arthritis. Clin Rheumatol 1988, 7, 249–256.

    PubMed  Google Scholar 

  16. Weinstein, A., Marlowe, S., Korn, J., Farouhan, F. Low dose methotrexate treatment of rheumatoid arthritis. Long term observations. Am J Med 1985, 79, 331–337.

    PubMed  Google Scholar 

  17. Kremer, J.M. Long term methotrexate therapy in rheumatoid arthritis: A review. J Rheumatol 1985, Suppl. 12, 25–28.

    Google Scholar 

  18. Kremer, J.M., Lee, J.K. The safety and efficacy of the use of methotrexate in long-term therapy for rheumatoid arthritis. Arthritis Rheum 1986, 29, 822–831.

    PubMed  Google Scholar 

  19. Nordstrom, D.M., West, S.G., Andersen, P.A., Sharp, J.T. Pulse methotrexate therapy in rheumatoid arthritis. Ann Intern Med 1987, 107, 797–801.

    PubMed  Google Scholar 

  20. Tishler, M., Caspi, D., Rosenbach, T.O., et al. Methotrexate in rheumatoid arthritis: a prospective study in Israeli patients with immunogenetic correlations. Ann Rheum Dis 1988, 47, 654–659.

    PubMed  Google Scholar 

  21. Fehlauer, C.S., Carson, C.W., Cannon, G.W., et al. Methotrexate therapy in rheumatoid arthritis: 2-year retrospective follow-up study. J Rheumatol 1989, 16, 307–312.

    PubMed  Google Scholar 

  22. Aponte, J., Pertrelly, M. Histophathologic findings in the liver of rheumatoid arthritis patients treated with long-term bolus methotrexate. Arthritis Rheum 1988, 31, 1457–1464.

    PubMed  Google Scholar 

  23. Kremer, J.M., Lee, R.G., Tolman, K.G. Liver histology in rheumatoid arthritis patients receiving long-term methotrexate therapy. Arthritis Rheum 1989, 32, 121–127.

    PubMed  Google Scholar 

  24. Arnett, F.C., Edworthy, S.M., Bloch, D.A., McShane, D.J., Fries, J.F., Cooper, N.S., Healey, L.A., Kaplan, S.R., Liang, M.H., Luthra, H.S., Medsger, T.A.Jr., Mitchell, D.M., Neustadt, D.H., Pinals, R.S., Schaller, J.G., Sharp, J.T., Wilder, R.L., Hunder, G.G. The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis. Arthritis Rheum 1988, 31, 315–324.

    PubMed  Google Scholar 

  25. Pinals, R.S., Masi, A.T., Larsen, R.A. Preliminary criteria for clinical remission in rheumatoid arthritis. Arthritis Rheum 1981, 24, 1308–1315.

    PubMed  Google Scholar 

  26. Evans, W.E., Cristensen, M.L. Drug interactions with methotrexate. J Rheumatol 1985. Suppl. 12, 15–20.

    Google Scholar 

  27. Roenigk, H.H.Jr., Aurbach, R., Maibach, H.J., Weinstein, G.D. Methotrexate guidelines revised. J Am Acad Dermatol 1982, 6, 145–155.

    PubMed  Google Scholar 

  28. Steinbrocker, O., Traeger, C.H., Batterman, R.C. Therapeutic criteria in rheumatoid arthritis. JAMA 1949, 140, 651–662.

    Google Scholar 

  29. Andonopoulos, A.P., Drosos, A.A., Skopouli, F.N., Acritidis, N.C., Moutsopoulos, H.M. Secondary Sjögren's syndrome in rheumatoid arthritis. J Rheumatol 1987, 14, 1098–1103.

    PubMed  Google Scholar 

  30. Urowitz, M.B., Gordon, D.A., Smythe, H.A., Pruzanski, W., Ogryzlo, M.A. Azathioprine in rheumatoid arthritis: a double-blind cross-over study. Arthritis Rheum 1973, 16, 411–419.

    PubMed  Google Scholar 

  31. Berry, H., Liyanage, S.P., Durance, R.A., Barnes, C.G., Berger, L.A., Evans, S. Azathioprine and penicillamine in treatment of rheumatoid arthritis: a controlled trial. Br Med J 1976, 1, 1052–1054.

    PubMed  Google Scholar 

  32. Woodland, J., Chaput de Saintonge, D.M., Evans, S.J.W., Sharman, V.L., Currey, H.F. Azathioprine in rheumatoid arthritis: double-blind study of full versus half doses versus placebo. Ann Rheum Dis 1981, 40, 359–368.

    Google Scholar 

  33. Penn, I. Occurrence of cancer in immune deficiencies. Cancer 1974, 34, 858–866.

    PubMed  Google Scholar 

  34. Coban, C.D., Sheon, R.P., Kirsner, A.B. Immunosuppressive drugs and acute leukemia. Ann Intern Med 1973, 79, 131–132.

    Google Scholar 

  35. Cooperative Clinics Committee of the American Rheumatism Association: A controlled trial of cyclophosphamide in rheumatoid arthritis. N Engl J Med 1970, 283, 883–889.

    Google Scholar 

  36. Townes, A.S., Sowa, J.M., Shulman, L.E. Controlled trial of cyclophosphamide in rheumatoid arthritis. Arthritis Rheum 1976, 19, 563–573.

    PubMed  Google Scholar 

  37. Lidsky, M.D., Sharp, J.T., Billings, S. Double-blind study of cyclophosphamide in rheumatoid arthritis. Arthritis Rheum 1973, 16, 148–153.

    PubMed  Google Scholar 

  38. Wall, R.L., Clansen, K.P. Carcinoma of the urinary bladder in patients receiving cyclophosphamide. N Engl J Med 1975, 293, 271–273.

    PubMed  Google Scholar 

  39. Tannenbaum, H., Schur, P.H. Development of reticulum cell sarcoma during cyclophosphamide therapy. Arthritis Rheum 1974, 17, 15–18.

    PubMed  Google Scholar 

  40. Love, R.R., Sowa, J.M. Myelomonocytic leukemia following cyclophosphamide therapy of rheumatoid disease. Ann Intern Med 1977, 86, 199–204.

    PubMed  Google Scholar 

  41. Zachariae, H., Kragballe, K., Sogaard, H. Methotrexate-induced liver cirrhosis: studies including serial liver biopsies during continued treatment. Br J Dermatol 1980, 102, 407–412.

    PubMed  Google Scholar 

  42. Robinson, J.K., Baughman, R.D., Auerbach, R., Cimis, R.J. Methotrexate hepatotoxicity in psoriasis; consideration of liver biopsies at regular intervals. Arch Dermatol 1980, 116, 413–415.

    PubMed  Google Scholar 

  43. Weinblatt, M.E. Toxicity of low dose methotrexate in rheumatoid arthritis. J Rheumatol 1985, Suppl. 12, 35–39.

    Google Scholar 

  44. Gispen, J.S., Alarcon, G.S., Johnson, J.J., Acton, R.T., Barger, B.O., Koopman, W.J. Toxicity to methotrexate in rheumatoid arthritis. J Rheumatol 1987, 14, 74–79.

    PubMed  Google Scholar 

  45. Tolman, K.G., Clegg, D.O., Lee, R.G., Ward, J.R. Methotrexate and the liver. J Rheumatol 1985, Suppl. 12: 29–34.

    Google Scholar 

  46. Furst, D.E., Koehnke, R., Burmeister, L.F., Kohler, J., Cargill, I. Increasing methotrexate effect with increasing dose in the treatment of resistant rheumatoid arthritis. J Rheumatol 1989, 16, 313–320.

    PubMed  Google Scholar 

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Authors and Affiliations

  1. Department of Internal Medicine, Medical School, University of Ioannina, 451 10, Ioannina, Greece

    A. A. Drosos, D. Psychos, A. P. Andonopoulos, S. Stefanaki-Nikou, E. B. Tsianos & H. M. Moutsopoulos

  2. Department of Pathology, Medical School, University of Ioannina, Ioannina, Greece

    S. Stefanaki-Nikou

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  1. A. A. Drosos
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  2. D. Psychos
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  3. A. P. Andonopoulos
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  5. E. B. Tsianos
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  6. H. M. Moutsopoulos
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Drosos, A.A., Psychos, D., Andonopoulos, A.P. et al. Methotrexate therapy in rheumatoid arthritis. A two year prospective follow-up. Clin Rheumatol 9, 333–341 (1990). https://doi.org/10.1007/BF02114393

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