Rheumatology International

, Volume 15, Issue 5, pp 195–200

Long-term tolerability of methotrexate at doses exceeding 15 mg per week in rheumatoid arthritis

  • A. Schnabel
  • K. Herlyn
  • C. Burchardi
  • E. Reinhold-Keller
  • W. L. Gross
Original Article

Abstract

The objective of this study was to examie longitudinally the tolerability of methotrexate (MTX) treatment at doses exceeding 15 mg/week in an open-label, prospective study. One hundred and eighty-five patients with rheumatoid arthritis were randomized to receive 15 mg or 25 mg MTX per week initially, and were followed over 30 months. Subsequent dose adjustments according to efficacy and tolerability resulted in levelling off of the mean dose at 18 mg/week, and the original treatment groups were combined for a longitudinal study comparing toxie events during months 1–12 and months 13–30. Withdrawals due to side-effects amounted to 17% during months 1–12 and 4% during months 13–30; dose reductions due to side-effects were 9% and 7%, respectively. The annual incidence of gastrointestinal side-effects increased from 26% to 39% (P=0.05), that of liver enzyme elevation dropped from 43% to 10% (P<0.001) and haemocytopenia remained stable at 5% and 7%. MTX pneumonitis was only observed during the first year, while airway complaints without evidence of parenchymal lung involvement increased to 10% beyond the first year. Fifty-six patients experienced 65 major infectious episodes over the 30-month period, with the respiratory tract being the most frequent site. This study showed that MTX treatment at doses exceeding 15 mg/week is tolerated over extended period of time. Major toxicity and withdrawals due to side-effects occurred predominantly during the first year of treatment and thus showed a decreasing trend over time, while minor toxic events continued throughout the study with a progressive rate of mucous membrane toxicity. MTX-treated RA appears to be a risk situation for major infection.

Key words

Methotrexate Rheumatoid arthritis Side-effects Infection 

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1.
    Schnabel A, Gross WL (1994) Low-dose methotrexate in rheumatic diseases-efficacy, side effects, and risk factors for side effects. Semin Arthritis Rheum 23:310–327Google Scholar
  2. 2.
    Thompson RN, Watts C, Edelman J, Esdaile J, Russell AS (1984) A controlled two-centre trial of parenteral methotrexate therapy for refractory rheumatoid arthritis. J Rheumatol 11:760–763Google Scholar
  3. 3.
    Furst DE, Koehnke R, Burmeister LF, Kohler J, Cargill I (1989) Increasing methotrexate effect with increasing dose in the treatment of resistant rheumatoid arthritis. J Rheumatol 16:313–320Google Scholar
  4. 4.
    Schnabel A, Reinhold-Keller E, Willmann V, Gross WL (1994) Tolerability of methotrexate starting with 15 or 25 mg/week for rheumatoid arthritis. Rheumatol Int 14:33–38Google Scholar
  5. 5.
    Arnett FC, Edworthy SM, Bloch DA, McShane DJ, Fries FJ, Cooper NS, Healey LA, Kaplan SR, Liang MH, Luthra HS, Medsger TA, Mitchell DM, Neustadt DH, Pinals R, Schaller JG, Sharp JT, Wilder RL, Hunder GG (1988) The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis. Arthritis Rheum 31:315–324Google Scholar
  6. 6.
    Furst DE, Erikson N, Clute L, Koehnke R, Burmeister LF, Kohler JA (1990) Adverse experience with methotrexate during 176 weeks of a longterm prospective trial in patients with rheumatoid arthritis. J Rheumatol 17:1628–1635Google Scholar
  7. 7.
    Morand EF, McCloud PI, Littlejohn GO (1992) Life table analysis of 879 treatment episodes with slow acting antirheumatic drugs in community rheumatology practice. J Rheumatol 19:704–708Google Scholar
  8. 8.
    Wolfe F, Hawley D, Cathey MA (1990) Termination of slow acting antirheumatic therapy in rheumatoid arthritis: a 14-year prospective evaluation of 1017 consecutive starts. J Rheumatol 17:994–1002Google Scholar
  9. 9.
    Pincus T, Marcum SB, Callahan LF (1992) Longterm drug therapy for rheumatoid arthritis in seven rheumatology private practices: II. Second line drugs and prednisone. J Rheumatol 19:1885–1894Google Scholar
  10. 10.
    Buchbinder R, Hall S, Sambrook PN, Champion GD, Hartness A, Lewis D, Littlejohn GO, Miller MH, Ryan PFJ (1993) Methotrexate therapy in rheumatoid arthritis: a life table review of 587 patients treated in community practice. J Rheumatol 20: 639–644Google Scholar
  11. 11.
    Fehlauer CS, Carson CW, Cannon GW, Ward JR, Samuelson CO, Williams HJ, Clegg DO (1989) Methotrexate therapy in rheumatoid arthritis: 2-year retrospective follow-up study. J. Rheumatol 16:307–312Google Scholar
  12. 12.
    Sany J, Anaya JM, Lussiez V, Couret M, Combe B, Daures J-P (1991) Treatment of rheumatoid arthritis with methotrexate: a prospective open longterm study of 191 cases. J Rheumatol 18:1323–1327Google Scholar
  13. 13.
    Alarcon GS, Tracy IC, Blackburn WDJ (1989) Methotrexate in rheumatoid arthritis. Toxic effects as the major factor in limiting long-term treatment. Arthritis Rheum 32:671–676Google Scholar
  14. 14.
    Hanrahan PS, Scrivens GA, Russell AS (1989) Prospective longterm follow-up of methotrexate therapy in rheumatoid arthritis: toxicity, efficacy and radiological progression. Br J Rheumatol 28:147–153Google Scholar
  15. 15.
    Tishler M, Caspi D, Yaron M (1993) Long-term experience with low dose methotrexate in rheumatoid arthritis. Rheumatol Int 13:103–106Google Scholar
  16. 16.
    Kremer JM, Lee JK (1988) A long-term prospective study of the use of methotrexate in rheumatoid arthritis. Arthritis Rheum 31:577–584Google Scholar
  17. 17.
    Kremer JM, Phelps CT (1992) Long-term prospective study of the use of methotrexate in the treatment of rheumatoid arthritis. Arthritis Rheum 35:138–145Google Scholar
  18. 18.
    Cannon GW, Ward JR, Clegg DO, Samuelson COJ, Abbott TM (1983) Acute lung disease associated with low-dose pulse methotrexate therapy in patients with rheumatoid arthritis. Arthritis Rheum 26:1269–1274Google Scholar
  19. 19.
    Carroll GJ, Thomas R, Phatouros CC, Atchison MH, Leslie A-L, Cook NJ, D'Souza I (1994) Incidence, prevalence and posible risk factors for pneumonitis in patients with rheumatoid arthritis receiving methotrexate. J Rheumatol 21:51–54Google Scholar
  20. 20.
    Hargreaves MR, Mowat AG, Benson MK (1992) Acute pneumonitis associated with low dose methotrexate treatment for rheumtoid arthritis: report of five cases and review of published reports. Thorax 47:628–633Google Scholar
  21. 21.
    Searles G, McKendry RJR (1987) Methotrexate pneumonitis in rheumatoid arthritis: potential risk factors. Four case reports and a review of the literature. J Rheumatol 14:1164–1171Google Scholar
  22. 22.
    Weinblatt ME, Weissman BN, Holdsworth DE, Fraser PA, Maier AL, Falchuk KR, Coblyn JS (1992) Long-term prospective study of methotrexate in the treatment of rheumatoid arthritis. Arthritis Rheum 35:129–137Google Scholar
  23. 23.
    Wolfe F, Cathey MA (1991) The effect of age on methotrexate efficacy and toxicity. J Rheumatol 18:973–977Google Scholar
  24. 24.
    Van der Veen MJ, van der Heide A, Kruize AA, Bijlsma JWJ (1994) Infection rate and use of antibiotics in patients with rheumatoid arthritis treated with methotrexate. Ann Rheum Dis 53:224–228Google Scholar
  25. 25.
    Antonelli MAS, Moreland LW, Brick JE (1991) Herpes zoster in patients with rheumatoid arthritis treated with weekly, lowdose methotrexate. Am J Med 90:295–298Google Scholar

Copyright information

© Springer-Verlag 1996

Authors and Affiliations

  • A. Schnabel
    • 1
    • 2
  • K. Herlyn
    • 2
  • C. Burchardi
    • 2
  • E. Reinhold-Keller
    • 2
  • W. L. Gross
    • 2
  1. 1.Rheumaklinik Bad BramstedtBad BramstedtGermany
  2. 2.Rheumatologische PoliklinikMedizinische Universität Lübeck and Rheumaklinik Bad Bramstedt, Medizinische KrankenhausabteilungBad BramstedtGermany

Personalised recommendations