Summary
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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Bleyer, W.A. The clinical pharmacology of methotrexate: new applications of an old drug. Cancer 1978, 41, 36–51.
Nyfors, A. Methotrexate therapy of psoriasis. Dan Med Bull 1980, 27, 74–96.
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.
Owen, E.T., Cohen, M.L. Methotrexate in Reiter's disease. Ann Rheum Dis 1979, 38, 48–50.
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.
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.
Willkens, R.F., Watson, M.A., Paxson, C.S. Low dose pulse methotrexate therapy in rheumatoid arthritis. J Rheumatol 1980, 7, 501–505.
Steinsson, K., Weinstein, A., Korn, J., Abeles, M. Low dose methotrexate in rheumatoid arthritis. J Rheumatol 1982, 9, 860–866.
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.
Willkens, R.F. Short-term efficacy of methotrexate in the treatment of rheumatoid arthritis. J Rheumatol 1985, Suppl. 12, 21–24.
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.
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.
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.
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.
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.
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.
Kremer, J.M. Long term methotrexate therapy in rheumatoid arthritis: A review. J Rheumatol 1985, Suppl. 12, 25–28.
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.
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.
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.
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.
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.
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.
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.
Pinals, R.S., Masi, A.T., Larsen, R.A. Preliminary criteria for clinical remission in rheumatoid arthritis. Arthritis Rheum 1981, 24, 1308–1315.
Evans, W.E., Cristensen, M.L. Drug interactions with methotrexate. J Rheumatol 1985. Suppl. 12, 15–20.
Roenigk, H.H.Jr., Aurbach, R., Maibach, H.J., Weinstein, G.D. Methotrexate guidelines revised. J Am Acad Dermatol 1982, 6, 145–155.
Steinbrocker, O., Traeger, C.H., Batterman, R.C. Therapeutic criteria in rheumatoid arthritis. JAMA 1949, 140, 651–662.
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.
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.
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.
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.
Penn, I. Occurrence of cancer in immune deficiencies. Cancer 1974, 34, 858–866.
Coban, C.D., Sheon, R.P., Kirsner, A.B. Immunosuppressive drugs and acute leukemia. Ann Intern Med 1973, 79, 131–132.
Cooperative Clinics Committee of the American Rheumatism Association: A controlled trial of cyclophosphamide in rheumatoid arthritis. N Engl J Med 1970, 283, 883–889.
Townes, A.S., Sowa, J.M., Shulman, L.E. Controlled trial of cyclophosphamide in rheumatoid arthritis. Arthritis Rheum 1976, 19, 563–573.
Lidsky, M.D., Sharp, J.T., Billings, S. Double-blind study of cyclophosphamide in rheumatoid arthritis. Arthritis Rheum 1973, 16, 148–153.
Wall, R.L., Clansen, K.P. Carcinoma of the urinary bladder in patients receiving cyclophosphamide. N Engl J Med 1975, 293, 271–273.
Tannenbaum, H., Schur, P.H. Development of reticulum cell sarcoma during cyclophosphamide therapy. Arthritis Rheum 1974, 17, 15–18.
Love, R.R., Sowa, J.M. Myelomonocytic leukemia following cyclophosphamide therapy of rheumatoid disease. Ann Intern Med 1977, 86, 199–204.
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.
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.
Weinblatt, M.E. Toxicity of low dose methotrexate in rheumatoid arthritis. J Rheumatol 1985, Suppl. 12, 35–39.
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.
Tolman, K.G., Clegg, D.O., Lee, R.G., Ward, J.R. Methotrexate and the liver. J Rheumatol 1985, Suppl. 12: 29–34.
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.
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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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DOI: https://doi.org/10.1007/BF02114393