Advances in Clinical and Experimental Medicine

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Advances in Clinical and Experimental Medicine

2007, vol. 16, nr 2, March-April, p. 287–295

Publication type: review article

Language: English

Creative Commons BY-NC-ND 3.0 Open Access

Toxicity of Low Dose Methotrexate in Rheumatoid Arthritis

Działania niepożądane w czasie terapii metotreksatem u chorych na reumatoidalne zapalenie stawów

Jerzy Świerkot1,

1 Department of Rheumatology, Silesian Piasts University of Medicine in Wrocław, Poland

Abstract

Methotrexate (MTX) has become in the last 15 years the “gold standard” in the treatment of rheumatoid arthritis. Low−dose MTX has shown to be an effective treatment for rheumatoid arthritis. However during the treatment with low doses MTX (7.5–25 mg weekly) adverse effects occurred frequently – by 37–96% of patients. This article reviews the most common adverse events (gastrointestinal, haematological, neurologic adverse events, cutaneous reactions, hepatotoxicity, pulmonary toxicity, MTX osteopathy, MTX−induced nodulosis) and methods minimizing them. In this review the role of folate supplementation during MTX therapy was described. The factors associated with toxicity, especially the genetic factors were analyzed.

Streszczenie

W ciągu ostatnich 15 lat metotreksat (MTX) stał się „złotym standardem” w leczeniu reumatoidalnego zapalenia stawów (r.z.s.). Skuteczność MTX w leczeniu r.z.s. została potwierdzona w wielu pracach. Często jednak, stosując nawet małe dawki MTX (7,5–25 mg raz w tygodniu), obserwuje się działania niepożądane. Odsetek wszystkich działań niepożądanych podczas długotrwałej terapii małymi dawkami MTX wynosi 37–96%. W artykule przedstawiono najczęstsze działania niepożądane (na przewód pokarmowy, oddechowy, skórę, powikłania hepatologiczne, hematologiczne, nefrologiczne, pochodzące z ośrodkowego układu nerwowego) i sposoby zapobiegania im. Omówiono rolę substytucji kwasu foliowego podczas leczenia MTX. Zwrócono także uwagę na czynniki predysponujące do wystąpienia działań niepożądanych ze szczególnym uwzględnieniem predyspozycji genetycznych.

Key words

methotrexate, polyarthritis rheumatoidea, adverse events

Słowa kluczowe

metotreksat, reumatoidalne zapalenie stawów, objawy uboczne

References (37)

  1. Świerkot J, Szechiński J, Wiland P: Pięcioletnia ocena kliniczna skuteczności leczenia metotreksatem chorych na reumatoidalne zapalenie stawów. Pol Arch Med Wewn 2000, 103, 5–6, 267–275.
  2. Kinder AJ, Hassell AB, Brand J, Brownfield A, Grove M, Shadforth MF: The treatment of inflammatory arthritis with methotrexate in clinical practice: treatment duration and incidence of adverse drug reactions. Rheumatology 2005, 44, 61–66.
  3. Wluka A, Buchbinder R, Mylvaganam A: Long term methotrexate use in rheumatoid arthritis: 12 year follow up of 460 patients treated in community practice. J Rheumatol 2000, 27, 1864–1871.
  4. Hoekstra M, van Ede AE, Haagsma CJ, van de Laar MA, Huizinga TW, Kruijsen MW, Laan RF: Factors associated with toxicity, final dose, and efficacy of methotrexate in patients with rheumatoid arthritis. Ann Rheum Dis 2003, 62, 423–426.
  5. Kremer JM: Toward a better understanding of methotrexate. Arthritis Rheum 2004, 50, 1370–1382.
  6. Lederle FA: Summarized data of the controlled multicenter studies of Ward and Weinblatt, in MethotrexateRheumatoid Arthritis−Expanded clinical Summary. New York 1985.
  7. Weinblatt ME: Toxicity of low dose methotrexate in rheumatoid arthritis. J Rheumatol Suppl 1985, 12 Suppl 12, 35–39.
  8. Bannwarth B, Labat L, Moride Y: Methotrexate in rheumatoid arthritis. Drugs 1994, 47, 25–50.
  9. Fathi NH, Mitros F, Hoffman J, Straniero N, Labreque D, Koehnke R, Furst DE: Longitudinal measurement of methotrexate liver concentrations does not correlate with liver damage, clinical efficacy, or toxicity during a 3.5 year double blind study in rheumatoid arthritis. J Rheumatol 2002, 29, 2092–2098.
  10. Borgquist SR, Felson DT, Prashker MJ: The cost−effectiveness of liver biopsy in rheumatoid arthritis patients treated with methotrexate. Arthritis Rheum 1995, 38, 326–333.
  11. Khanna D, Park GS, Paulus HE, Simpson KM, Elashoff D, Cohen SB, Emery P, Dorrier C, Furst DE: Reduction of the efficacy of methotrexate by the use of folic acid: post hoc analysis from two randomized controlled studies. Arthritis Rheum 2005, 52, 3030–3038.
  12. Khadadah ME, Jayakrishnan B, Al−Gorair S, Al−Mutairi M, Al−Maradni N, Onadeko B, Malaviya AN: Effect of methotrexate on pulmonary function in patients with rheumatoid arthritis – a prospective study. Rheumatol Int 2002, 22, 204–207.
  13. Dawson JK, Graham DR, Desmond J, Fewins HE, Lynch MP: Investigation of the chronic pulmonary effects of low−dose oral methotrexate in patients with rheumatoid arthritis: a prospective study incorporating HRCT scanning and pulmonary function tests. Rheumatology 2002, 41, 262–267.
  14. Miyata M, Sakuma F, Fukaya E, Kobayashi H, Rai T, Saito H, Kasukawa R, Suzuki S: Detection and monitoring of methotrexate−associated lung injury using serum markers KL−6 and SP−D in rheumatoid arthritis. Intern Med 2002, 41, 467–473.
  15. Taniguchi K, Usui Y, Matsuda T, Suzuki S, Fujiki K, Yakusiji F, Tomiyama J, Kinoshita K, Ilzuka H, Kuga Y: Methotrexate−induced acute lung injury in a patient with rheumatoid arthritis. Int J Clin Pharmacol Res 2005, 25, 101–105.
  16. Gutierrez−Urena S, Molina JF, Garcia CO, Cuellar ML, Espinoza LR: Pancytopenia secondary to methotrexate therapy in rheumatoid arthritis. Arthritis Rheum 1996, 39, 272–276.
  17. Kuitunen T, Malmstrom J, Palva E, Pettersson T: Pancytopenia induced by low−dose methotrexate. A study of the cases reported to the Finnish Adverse Drug Reaction Register From 1991 to 1999. Scand J Rheumatol 2005, 34, 238–241.
  18. Lim AY, Gaffney K, Scott DG: Methotrexate−induced pancytopenia: serious and under−reported? Our experience of 25 cases in 5 years. Rheumatology 2005, 44, 1051–1055.
  19. Izzedine H, Launay−Vacher V, Karie S, Caramella C, de Person F, Deray G: Is low−dose methotrexate nephrotoxic? Case report and review of the literature. Clin Nephrol 2005, 64, 315–319.
  20. Boerbooms AM, Kerstens PJ, Loenhout JW, Mulder J: Infections during low−dose methotrexate treatment in rheumatoid arthritis. Semin Arthritis Rheum 1995, 24, 411–421.
  21. Perhala RS, Wilke WS, Clough JD: Local infectious complications following large joint replacement in rheumatoid arthritis patients treated with methotrexate versus those not treated with methotrexate. Arthritis Rheum 1991, 34, 146–152.
  22. Ebeo CT, Grish MR, Byrd RP, Roy TM, Mehta JB: Methotrexate−induced pulmonary lymphoma. Chest 2003, 123, 2150–2153.
  23. 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 Rheum 1992, 35, 138–145.
  24. Di Munno O, Delle Sedie A, Rossini M, Adami S: Disease−modifying antirheumatic drugs and bone mass in rheumatoid arthritis. Clin Exp Rheumatol 2005, 23, 137–144.
  25. Halla JT, Hardin JG: Underrecognized postdosing reactions to methotrexate in patients with rheumatoid arthritis. J Rheumatol 1994, 21, 1224–1226.
  26. Combe B, Guttierrez M, Anaya JM, Sany J: Possible efficacy of hydroxychloroquine on accelerated nodulosis during methotrexate therapy for rheumatoid arthritis. J Rheumatol 1993, 20, 755–756.
  27. Merrill JT, Cronstein BN, Shen C et al.: Reversal of new but not old rheumatoid nodules by colchicine: Evidence from an in vitro model and case reports of 14 patients [Abstract 7]. Arthritis Rheum (Suppl) 1996, 84. 294 J. ŚWIERKOT
  28. Stenger AA, Houtman PM, Bruyn GA: Does folate supplementation make sense in patients with rheumatoid arthritis treated with methotrexate? Ann Rheum Dis 1992, 51, 1019–1020.
  29. Kim YI: 5,10−Methylenetetrahydrofolate reductase polymorphisms and pharmacogenetics: a new role of single nucleotide polymorphisms in the folate metabolic pathway in human health and disease. Nutr Rev 2005, 63, 398–407.
  30. Chiżyński K: Hiperhomocysteinemia – ważny czynnik ryzyka choroby niedokrwiennej serca. Pol Przegl Kardiol 2002, 4, 103–108.
  31. Haagsma CJ, Blom HJ, van Riel PL, van’t Hof MA, Giesendorf BA, van Oppenraaij−Emmerzaal D, van de Putte LB: Influence of sulphasalazine, methotrexate, and the combination of both on plasma homocysteine concentrations in patients with rheumatoid arthritis. Ann Rheum Dis 1999, 58, 79–84.
  32. Berkun Y, Levartovsky D, Rubinow A, Orbach H, Aamar S, Grenader T, Abou Atta I, Mevorach D, Friedman G, Ben−Yehuda A: Methotrexate related adverse effects in patients with rheumatoid arthritis are associated with the A1298C polymorphism of the MTHFR gene. Ann Rheum Dis 2004, 63, 1227–1231.
  33. Van Ede AE, Laan RF, Blom HJ, Huizinga TW, Haagsma CJ, Giesendorf BA, de Boo TM, van de Putte LB: The C677T mutation in the methylenetetrahydrofolate reductase gene: a genetic risk factor for methotrexate−related elevation of liver enzymes in rheumatoid arthritis patients. Arthritis Rheum 2001, 44, 2525–2530.
  34. Herrlinger KR, Cummings JR, Barnardo MC, Schwab M, Ahmad T, Jewell DP: The pharmacogenetics of methotrexate in inflammatory bowel disease. Pharmacogenet Genomics 2005, 15, 705–711.
  35. Choi HK, Hernan MA, Seeger JD, Robins JM, Wolfe F: Methotrexate and mortality in patients with rheumatoid arthritis: a prospective study. Lancet 2002, 6, 359, 1173–1177.
  36. Singer RB: Mortality in rheumatoid arthritis patients treated with or without methotrexate. J Insur Med 2003, 35, 144–149.
  37. Prodanowich S, Ma F, Taylor JR, Pezon C, Fasihi T, Kirsner RS: Methotrexate reduces incidence of vascular diseases in veterans with psoriasis or rheumatoid arthritis. J Am Acad Dermatol 2005, 52, 262–267.