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Folsäure zur Reduktion der Methotrexat-Toxizität

Reducing toxicity of methotrexate with folic acid

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Zusammenfassung

Methotrexat (MTX) gilt als das Basismedikament mit der günstigsten Nebenwirkungs-/Wirkungsbeziehung zur Therapie der Rheumatoiden Arthritis. Ein lebensverlängernder Effekt wurde nachgewiesen. Die nebenwirkungsbedingten Abbruchraten liegen jedoch nach 1 Jahr bereits bei 30–60%. In dieser Übersicht wird die Datenlage zur Supplementation mit Folsäure oder Folinat und ihr Effekt auf Nebenwirkungen und Effektivität von Methotrexat ausgewertet.

Methode

Die Datenauswertung erfolgte mittels einer Medline-Recherche mit den Suchbegriffen: „folate“, „folic acid“, „folinic acid“, „homocysteine“, „cardiovascular“, „heart infarction“, „methotrexate“ und „rheumatoid arthritis“. Bei der Sichtung der relevanten Literatur wurden zusätzlich in den jeweiligen Literaturangaben aufgeführte, nicht in Medline enthaltene, Artikel berücksichtigt.

Schlussfolgerung

Folsäure und Folinat reduzieren statitisch signifikant Nebenwirkungen und Therapieabbrüche von MTX. Die MTX-induzierte Hyperhomozysteinämie wird verhindert. Folsäure ist sicherer, kostengünstiger und einfacher im Handling als Folinat. Eine leichte Reduktion der MTX-Effektivität ist möglich, die Vorteile überwiegen jedoch. Bei jeder low-dose MTX-Therapie sollte eine Supplementierung mit Folsäure durchgeführt werden.

Summary

Background

Methotrexate is considered to have the best ratio of efficacy to toxicity of the disease modifying antirheumatic drugs. Recently it has been shown to enhance the life expectancy of patients with rheumatoid arthritis. Some 30–60% of RA patients discontinue MTX treatment within 1 year because of side-effects. In this review, the current data about supplementation with folate or folinic acid and their effect on the toxicity and efficacy of low-dose methotrexate therapy are analysed.

Methods

A Medline search was performed using “folate”, “folic acid”, “folinic acid”, “homocysteine”, “methotrexate”, “cardiovascular”, “heart infarction” and “rheumatoid arthritis” as search terms. The relevant literature was reviewed and other papers referred to as references were explored.

Conclusion

Both folate and folinic acid reduce methotrexate toxicity and the discontinuation rate, and decrease methotrexate-induced hyperhomocysteinemia. Folate is less expensive, more secure and easier to handle than folinic acid. The efficacy of methotrexate probably decreases slightly, but the benefit outweighs the risk. Folate supplementation should, therefore, be routinely prescribed to every patient taking low-dose methotrexate.

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References

  1. American College of Rheumatology ad hoc comittee on clinical guidelines (1996) Guidelines for monitoring drug therapy in rheumatoid arthritis. Arthritis Rheum 39:723–731

    PubMed  Google Scholar 

  2. Andersen LS, Hansen EL, Knudsen JB, Wester JU, Hansen GV, Hansen TM (1997) Prospectively measured red cell folate levels in methotrexate treated patients with rheumatoid arthritis: relation to withdrawal and side effects. J Rheumatol 24:830–837

    CAS  PubMed  Google Scholar 

  3. Bressole F, Kinowski JM, Morel J, Pouly B, Sany J, Combe B (2000) Folic acid alters methotrexate availability in Patients with rheumatoid arthritis. J Rheumatol 27:2110–2114

    PubMed  Google Scholar 

  4. British Society for Rheumatology (2000) National Guidelines for the Monitoring of Second Line Drugs,London

  5. Buckley LM (1991) Reply. J Rheumatol 18:783

    Google Scholar 

  6. Buckley LM (1996) Reply. J Rheumatol 23:403–404

    PubMed  Google Scholar 

  7. Buckley LM, Vacek PM, Cooper SM (1990) Administration of folinic acid after low-dose methotrexate in patients with rheumatoid arthritis. J Rheumatol 17:1158–1161

    CAS  PubMed  Google Scholar 

  8. Choi HK, Hernan MA, Seeger JD, Robins JM, Wolfe F (2002) Methotrexate and mortality in patients with rheumatoid arthritis: a prospective study. Lancet 359:1173–1177

    Article  CAS  PubMed  Google Scholar 

  9. Del Rincon ID, Williams K, Stern MP, Freemann GL, Escalante A (2001) High incidence of cardiovascular events in a rheumatoid arthritis cohort not explained by traditional cardiac risk factors. Arthritis rheuma 44:2737–2745

    Article  CAS  Google Scholar 

  10. Griffith SM, Fisher J, Clarke S, Montgomery B, Jones PW, Saklatvala J, Dawes PT, Shadforth MF, Hothersall TE, Hassel AB, Hay EM (2000) Do patients with rheumatoid arthritis established on methotrexate and folic acid 5 mg daily need to continue folic acid supplements long term? Rheumatology (Oxford) 39:1102–1109

    Article  CAS  PubMed  Google Scholar 

  11. Haagsma CJ, Blom HJ, van Riel PL, van’t Hof MA, Giesenorf BA, van Oppenraaij-Emmerzaal D, van de Putte LB (1999) Influence of sulphasalazine, methotrexate, and the combination of both on plasma homocysteine concentrations in patients with rheumatoid arthritis. Ann Rheum Dis 58:79–84

    Google Scholar 

  12. Hanrahan PS, Russell AS (1988) Concurrent use of folinic acid and methotrexate in rheumatoid arthritis. J Rheumatol 15:1078–1080

    CAS  PubMed  Google Scholar 

  13. Hoekstra M, Van de Laar MA, Bernelot-Moens HJ, Kruijsen MW, Haagsma CJ (2003) Longterm survival study of methotrexate use in a Dutch cohort of 1022 patients with rheumatoid arthritis. J Rheumatol 30:2325–2329

    CAS  PubMed  Google Scholar 

  14. Hoekstra M, Van Ede AE, Haagsma CJ, Van de Laar MA, Huizinga TW, Kruijsen MW, Laan RF (2003) Factors associated with toxicity, final dose, and efficacy of methotrexate in patients with rheumatoid arthritis. Ann Rheum Dis 62:423–426

    Article  CAS  PubMed  Google Scholar 

  15. Hunt PG, Rose CD, McIIvain-Simpson G, Tejani S (1997) The effects of daily intake of folic acid on the efficacy of methotrexate therapy in children with juvenile rheumatoid arthritis. A controlled study. J Rheumatol 24:2230–2232

    CAS  PubMed  Google Scholar 

  16. Jobanputra P, Hunter M, Clark D, Lambert CM, Hurst NP (1995) An audit of methotrexate and folic acid for rheumatoid arthritis. Experience from a teaching centre. Br J Rheumatol 34:971–975

    CAS  PubMed  Google Scholar 

  17. Joyce DA, Will RK, Hoffmann DM, Laing B, Blackburn SJ (1991) Exacerbation of rheumatoid arthritis in patients treated with methotrexate after administration of folinic acid. Ann Rheum Dis 50:913–914

    CAS  PubMed  Google Scholar 

  18. Kitas GD, Erb N (2003) Tackling ischaemic heart disease in rheumatoid arthritis. Rheumatology (Oxford) 42:607–613

    Article  CAS  PubMed  Google Scholar 

  19. Kommission Qualitätssicherung der Deutschen Gesellschaft für Rheumatologie (2000) Methotrexat. In: „Qualitätssicherung in der Rheumatologie“. Verlag Steinkopff, Darmstadt, 5.3.7.1–5.3.7.3

  20. Krause D, Schleusser B, Herborn G, Rau R (2000) Response to methotrexate treatment is associated with reduced mortalitiy in patients with severe rheumatoid arthritis. Arthritis Rheum 43:14–21

    Article  CAS  PubMed  Google Scholar 

  21. Leeb BF, Witzmann G, Ogris E, Studnicka-Benke A, Andel I, Schweitzer H, Smolen JS (1995) Folic acid and cyanocobalamin levels in serum and erythrocytes during low-dose methotrexate therapy of rheumatoid arthritis and psoriatic arthritis patients. Clin Exp Rheumatol 13:459–463

    CAS  PubMed  Google Scholar 

  22. Morgan SL, Baggott JE, Altz-Smith M (1987) Folate status of rheumatoid arthritis patients receiving long-term, low-dose methotrexate therapy. Arthritis Rheum 30:1348–1356

    CAS  PubMed  Google Scholar 

  23. Morgan SL, Baggott JE, Lee JY, Alarcon GS (1998) Folic acid supplementation prevents deficient blood folate levels and hyperhomocysteinemia during longterm, low dose methotrexate therapy for rheumatoid arthritis: implications for cardiovascular disease prevention. J Rheumatol 25:441–446

    CAS  PubMed  Google Scholar 

  24. Morgan SL, Baggott JE, Vaughn WH, Austin JS, Veitch TA, Lee JY, Koopmann WJ, Krumdieck CL, Alarcon GS (1994) Supplementation with folic acid during methotrexate therapy for rheumatoid arthritis. A double-blind placebo-controlled trial. Ann Intern Med 121:833–841

    CAS  PubMed  Google Scholar 

  25. Morgan SL, Baggott JE, Vaughn WH, Young PK, Austin JV, Krumdieck CL, Alarcon GS (1990) The effect of folic acid supplementation on the toxicity of low dose methotrexate in patients with rheumatoid arthritis. Arthritis Rheum 33:9–18

    CAS  PubMed  Google Scholar 

  26. Ortiz Z, Shea B, Suarez Almazor M, Moher D, Wells G, Tugwell P (2000) Folic acid and folinic acid for reducing side effects in patients receiving methotrexate for rheumatoid arthritis. Cochrane Database Syst Rev (2):CD000951

    Google Scholar 

  27. Ravelli A, Migliavacca D, Viola S, Ruperto N, Pistorio A, Martini A (1999) Efficacy of folinic acid in reducing methotrexate toxicity in juvenile idiopathic arthritis. Clin Exp Rheumatol 17:625–627

    CAS  PubMed  Google Scholar 

  28. Schiff MH (1999) Leflunomide versus methotrexate: a comparison of the European and American experience. Scand J Rheumatol 112(Suppl):31–35

    Article  CAS  Google Scholar 

  29. Shiroky JB, Neville C, Esdaile JM, Choquett D, Zummer M, Hazeltine M, Bykerk V, Kanji M, St. Pierre A, Robidoux L (1993) Low dose methotrexate with leucovorin (folinic acid) in the management of rheumatoid arthritis. Results of a multicenter randomized, double blind, placebo controlled trial. Arthritis Rheum 36:795–803

    CAS  PubMed  Google Scholar 

  30. Stone J, Doube A, Dudson D, Wallace J (1997) Inadequate calcium, folic acid, vitamin E, zinc, and selenium intake in rheumatoid arthritis patients: results of a dietary survey. Semin Arthritis Rheum 27:180–185

    Article  CAS  PubMed  Google Scholar 

  31. Suzuki Y, Uehara R, Tajima C (1999) Elevation of serum hepatic aminotransferase during treatment of rheumatoid arthritis with low-dose methotrexate. Risk factors and response to folic acid. Scand J Rheumatol 28:273–281

    Article  CAS  PubMed  Google Scholar 

  32. Tett SE, Triggs EJ (1996) Use of methotrexate in older patients. A risk-benefit assessment. Drugs Aging 9:458–471

    CAS  PubMed  Google Scholar 

  33. Tishler M, Caspi D, Fishel B, Yaron M (1988) The effects of leucovorin (folinic acid) on methotrexate therapy in rheumatoid arthritis patients. Arthritis Rheum 31:906–908

    CAS  PubMed  Google Scholar 

  34. Van Ede AE, Laan RF, Blom HJ, Boers GH, Haagsma CJ, Thomas CM, De Boo TM, Van de Putte LB (2002) Homocysteine and folate status in methotrexate-treated patients with rheumatoid arthritis. Rheumatology (Oxford) 41:658–665

    Article  CAS  PubMed  Google Scholar 

  35. Van Ede, AE, Laan RF, Rood MJ, Huizinga TWJ, van de Laar MA, van Denderen CJ, Westgeest TAA, Romme TC, De Rooij DJRAM, Jacobs MJM, De Boo TM, Van der Wilt GJ, Severens JL; Hartman M, Krabbe PFM, Dijkmans BAC, Breedveld FC, Van de Putte LB (2001) Effect of folic acid supplementation on the toxicity and efficacy of methotrexate in rheumatoid arthritis. Arthritis Rheum 44:1515–1524

    Article  CAS  PubMed  Google Scholar 

  36. Weinblatt ME, Fraser P (1989) Elevated mean corpuscular volume as a predictor of hematologic toxicity due to methotrexate therapy. Arthritis Rheum 32:1592–1596

    CAS  PubMed  Google Scholar 

  37. Weinblatt ME, Maier AL, Coblyn JS (1993) Low dose leucovorin does not interfere with the efficacy of methotrexate in rheumatoid arthritis: an 8 week randomized placebo controlled trial. J Rheumatol 20:950–952

    CAS  PubMed  Google Scholar 

  38. Whittle SL, Hughes RA (2004) Folate supplementation and methotrexate treatment in rheumatoid arthritis: a review. Rheumatology 43:267–271

    Article  CAS  PubMed  Google Scholar 

  39. Wolfe F, Freundlich B, Strauss WL (2003) Increase in cardiovascular disease prevalence in rheumatoid arthritis. J Rheumatol 30:36–40

    PubMed  Google Scholar 

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  1. Sophienblatt 1, 24103, Kiel, Germany

    P. Harten

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Harten, P. Folsäure zur Reduktion der Methotrexat-Toxizität. Z. Rheumatol. 64, 353–358 (2005). https://doi.org/10.1007/s00393-005-0638-3

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