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Rheumatology International

, Volume 25, Issue 3, pp 169–178 | Cite as

Evidence-based use of methotrexate in children with rheumatic diseases: a consensus statement of the Working Groups Pediatric Rheumatology Germany (AGKJR) and Pediatric Rheumatology Austria

  • Tim NiehuesEmail author
  • Gerd Horneff
  • Hartmut Michels
  • Michaela Sailer Höck
  • Lothar Schuchmann
Review Article

Abstract

Juvenile idiopathic arthritis (JIA) is the most common diagnosis in children and adolescents with rheumatic disorders. In many children and adolescents, JIA is successfully treated with non-steroidal anti-inflammatory drugs (NSAID) and physiotherapy. However, in a significant number of cases the disease is resistant to this therapy, and treatment with “second line” disease-modifying antirheumatic drugs (DMARDs) is required. Methotrexate (MTX) is frequently referred to as “first-choice second-line agent” for the treatment of JIA. To increase drug safety, the Working Groups for Children and Adolescents with Rheumatic Diseases in Germany (AGKJR) and Pediatric Rheumatology Austria have initiated the formulation of evidence-based recommendations. Evidence is based on consensus expert meetings, a MEDLINE search with the key words “Methotrexate” and “juvenile arthritis” limited to age 0–18 years, standard textbooks and review articles, data from the central registry of the German Research Center for Rheumatic Diseases (Deutsches Rheumaforschungszentrum Berlin DRFZ), experience with MTX in adults with rheumatoid arthritis (RA), and recommendations of the German Society of Rheumatology (DGRh). Based on these data, evidence and recommendations are graded, and evidence-based recommendations for the use of MTX in children and adolescents with rheumatic disease are presented.

Keywords

Methotrexate Children Evidence-based recommendations Juvenile idiopathic arthritis 

Notes

Acknowledgements

We thank Prof. Dr. H. I. Huppertz (Professor-Hess-Kinderklinik Bremen) for critical reading of the manuscript and Mrs. Petra Knops for the help in preparation of the manuscript.

References

  1. 1.
    Cassidy JT, Petty R (2001) Textbook of pediatric rheumatology, 4th edn. WB Saunders Company, PhiladelphiaGoogle Scholar
  2. 2.
    Wahn V, Oppermann J, Huppertz HI, Zepp F (2001) Rheumatische Erkrankungen im Kindes- und Jugendalter. Hans Marseille Verlag, MunichGoogle Scholar
  3. 3.
    Minden K, Niewerth M, Listing J, Zink A, German Study Group of Pediatric Rheumatologists (2002) Health care provision in pediatric rheumatology in Germany–national rheumatologic database. J Rheumatol 29(3):622–628Google Scholar
  4. 4.
    Olsen NJ, Murray LM (1989) Antiproliferative effects of methotrexate on peripheral blood mononuclear cells. Arthritis Rheum 32:378–385Google Scholar
  5. 5.
    Rosenblatt DS, Whitehead VM, Vera N, Pottier A, Dupont M, Vuchich MJ (1978) Prolonged inhibition of DNA synthesis associated with the accumulation of methotrexate polyglutamates by cultured human cells. Mol Pharmacol 14:1143–1147Google Scholar
  6. 6.
    Cutolo M, Sulli A, Pizzorni C, Seriolo B, Straub RH (2001) Anti-inflammatory mechanisms of methotrexate in rheumatoid arthritis. Ann Rheum Dis 60:729–735CrossRefGoogle Scholar
  7. 7.
    Horneff G, Forster J, Seyberth HW, Michels H (2000) Recommendations by the Pediatric and Adolescent Rheumatology Study Committee on therapy with Etanercept (p75 TNF-alpha receptor immunoglobulin fusion protein, Pharmacotherapy Committee). Z Rheumatol 59:365–369CrossRefGoogle Scholar
  8. 8.
    Onel KB (2000) Advances in the medical treatment of juvenile rheumatoid arthritis. Curr Opin Pediatr 12:72–75CrossRefGoogle Scholar
  9. 9.
    Seeliger S, Niehues T, Harms E, Frosch M, Roth J (2002) Methotrexat in der Behandlung der juvenilen idiopathischen Arthritis. Monatsschr Kinderheilkd 150:452–459CrossRefGoogle Scholar
  10. 10.
    Andersen PA, West SG, O’Dell JR, Via CS, Claypool RG, Kotzin BL (1985) Weekly pulse methotrexate in rheumatoid arthritis. Clinical and immunologic effects in a randomized, double-blind study. Ann Intern Med 103:489–496Google Scholar
  11. 11.
    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
  12. 12.
    Weinblatt ME, Coblyn JS, Fox DA, Fraser PA, Holdsworth DE, Glass DN, Trentham DE (1985) Efficacy of low-dose methotrexate in rheumatoid arthritis. N Engl J Med 312:818–822Google Scholar
  13. 13.
    Williams HJ, Willkens RF, Samuelson CO Jr, Alarcon GS, Guttadauria M, Yarboro C, Polisson RP, Weiner SR, Luggen ME, Billingsley LM et al (1985) Comparison of low-dose oral pulse methotrexate and placebo in the treatment of rheumatoid arthritis. A controlled clinical trial. Arthritis Rheum 28:721–730Google Scholar
  14. 14.
    Petty RE, Southwood TR, Baum J, Bhettay E, Glass DN, Manners P, Maldonado-Cocco J, Suarez-Almazor M, Orozco-Alcala J, Prieur AM (1998) Revision of the proposed classification criteria for juvenile idiopathic arthritis: Durban, 1997. J Rheumatol 25:1991–1994PubMedGoogle Scholar
  15. 15.
    Feldmann W (2000) Evidence-based pediatrics, 1st edn. BC Decker, HamiltonGoogle Scholar
  16. 16.
    Sackett DL, Rosenberg WM, Gray JA, Haynes RB, Richardson WS (1996) Evidence based medicine: what it is and what it isn’t. BMJ 13:71–72Google Scholar
  17. 17.
    Truckenbrodt H, Hafner R (1986) Methotrexate therapy in juvenile rheumatoid arthritis: a retrospective study. Arthritis Rheum 29:801–807Google Scholar
  18. 18.
    Giannini EH, Brewer EJ, Kuzmina N, Shaikov A, Maximov A, Vorontsov I, Fink CW, Newman AJ, Cassidy JT, Zemel LS (1992) Methotrexate in resistant juvenile rheumatoid arthritis. Results of the U.S.A.–U.S.S.R. double-blind, placebo-controlled trial. The Pediatric Rheumatology Collaborative Study Group and The Cooperative Children’s Study Group. N Engl J Med 326:1043–1049PubMedGoogle Scholar
  19. 19.
    Woo P, Southwood TR, Prieur AM, Dore CJ, Grainger J, David J, Ryder C, Hasson N, Hall A, Lemelle I (2000) Randomized, placebo-controlled, crossover trial of low-dose oral methotrexate in children with extended oligoarticular or systemic arthritis. Arthritis Rheum 43:1849–1857CrossRefGoogle Scholar
  20. 20.
    Takken T, Van Der Net J, Helders PJ (2001) Methotrexate for treating juvenile idiopathic arthritis. Cochrane Database Syst Rev 4:CD003129 Google Scholar
  21. 21.
    Ravelli A, Viola S, Migliavacca D, Ruperto N, Pistorio A, Martini A (1999) The extended oligoarticular subtype is the best predictor of methotrexate efficacy in juvenile idiopathic arthritis. J Pediatr 135:316–320Google Scholar
  22. 22.
    Cassidy JT (1999) Medical management of children with juvenile rheumatoid arthritis. Drugs 58:831–850Google Scholar
  23. 23.
    Ravelli A, Martini A (2000) Methotrexate in juvenile idiopathic arthritis: answers and questions. J Rheumatol 27:1830–1833Google Scholar
  24. 24.
    Breit W, Frosch M, Meyer U, Heinecke A, Ganser G (2000) A subgroup-specific evaluation of the efficacy of intraarticular triamcinolone hexacetonide in juvenile chronic arthritis. J Rheumatol 27:2696–2702Google Scholar
  25. 25.
    Padeh S, Passwell JH (1998) Intraarticular corticosteroid injection in the management of children with chronic arthritis. Arthritis Rheum 41:1210–1214CrossRefPubMedGoogle Scholar
  26. 26.
    Ruperto N, Murray KJ, Gerloni V, Wulffraat N, De Oliveira S, Falcinin F, Alessio M, Burgos-Vargas R, Corona F, Vesely R, Foster H, Davidson J, Zulian F, Asplin L, Baildam E, Dolezalova P, Walsh J, Buoncompagni A, Garcia-Consuegra J, Ozdogan H, Saurenmann R, Joos R, Calvo I, Alpigiani LP, Machado C, Lahdenne P, Cortis E, Lepore L, Hall A, Kimura Y, Wouters C, Woo P, Martini A (2002) A randomized trial of Methotrexate in medium versus higher doses in children with juvenile idiopathic arthritis who failed on standard dose. In: EULAR Meeting Stockholm, Abstract Nr. 1384Google Scholar
  27. 27.
    Kremer JM, Galivan J, Streckfuss A, Kamen B (1986) Methotrexate metabolism analysis in blood and liver of rheumatoid arthritis patients. Association with hepatic folate deficiency and formation of polyglutamates. Arthritis Rheum 29:832–835Google Scholar
  28. 28.
    Ravelli A, Di Fuccia G, Molinaro M, Ramenghi B, Zonta L, Regazzi MB, Martini A (1993) Plasma levels after oral methotrexate in children with juvenile rheumatoid arthritis. J Rheumatol 20:1573–1577Google Scholar
  29. 29.
    Albertioni F, Flato B, Seideman P, Beck O, Vinje O, Peterson C, Eksborg S (1995) Methotrexate in juvenile rheumatoid arthritis. Evidence of age-dependent pharmacokinetics. Eur J Clin Pharmacol 47:507–511CrossRefGoogle Scholar
  30. 30.
    Reiff A, Shaham B, Wood BP, Bernstein BH, Stanly P, Szer IS (1995) High dose methotrexate in the treatment of refractory juvenile rheumatoid arthritis. Clin Exp Rheumatol 13:113–118Google Scholar
  31. 31.
    Wallace CA, Bleyer WA, Sherry DD, Salmonson KL, Wedgwood RJ (1989) Toxicity and serum levels of methotrexate in children with juvenile rheumatoid arthritis. Arthritis Rheum 32:677–681PubMedGoogle Scholar
  32. 32.
    Oguey D, Kolliker F, Gerber NJ, Reichen J (1992) Effect of food on the bioavailability of low-dose methotrexate in patients with rheumatoid arthritis. Arthritis Rheum 35:611–614Google Scholar
  33. 33.
    Wallace CA (1998) The use of methotrexate in childhood rheumatic diseases. Arthritis Rheum 41:381–391Google Scholar
  34. 34.
    Balis FM, Mirro J Jr, Reaman GH, Evans WE, McCully C, Doherty KM, Murphy RF, Jeffries S, Poplack DG (1988) Pharmacokinetics of subcutaneous methotrexate. J Clin Oncol 6:1882–1886Google Scholar
  35. 35.
    Balis FM, Savitch JL, Bleyer WA (1983) Pharmacokinetics of oral methotrexate in children. Cancer Res 43:2342–2345Google Scholar
  36. 36.
    Jundt JW, Browne BA, Fiocco GP, Steele AD, Mock D (1993) A comparison of low dose methotrexate bioavailability: oral solution, oral tablet, subcutaneous and intramuscular dosing. J Rheumatol 20:1845–1849Google Scholar
  37. 37.
    Furst DE, Kremer JM (1988) Methotrexate in rheumatoid arthritis. Arthritis Rheum 31:305–314Google Scholar
  38. 38.
    Dupuis LL, Koren G, Silverman ED, Laxer RM (1995) Influence of food on the bioavailability of oral methotrexate in children. J Rheumatol 22:1570–1573Google Scholar
  39. 39.
    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 25:441–446PubMedGoogle Scholar
  40. 40.
    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 (Oxford). Rheumatology 41:658–665CrossRefGoogle Scholar
  41. 41.
    Ortiz Z, Shea B, Suarez-Almazor ME, Moher D, Wells GA, Tugwell P (1998) The efficacy of folic acid and folinic acid in reducing methotrexate gastrointestinal toxicity in rheumatoid arthritis. A metaanalysis of randomized controlled trials. J Rheumatol 25:36–43Google Scholar
  42. 42.
    van Ede AE, Laan RF, Rood MJ, Huizinga TW, van de Laar MA, van Denderen CJ, Westgeest TA, Romme TC, de Rooij DJ, Jacobs MJ, de Boo TM, van der Wilt GJ, Severens JL, Hartman M, Krabbe PF, Dijkmans BA, Breedveld FC, van de Putte LB (2001) Effect of folic or folinic acid supplementation on the toxicity and efficacy of methotrexate in rheumatoid arthritis: a forty-eight week, multicenter, randomized, double-blind, placebo-controlled study. Arthritis Rheum 44:1515–1524CrossRefGoogle Scholar
  43. 43.
    Hunt PG, Rose CD, McIlvain-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 24:2230–2232Google Scholar
  44. 44.
    Dupuis LL, Koren G, Shore A, Silverman ED, Laxer RM (1990) Methotrexate-nonsteroidal antiinflammatory drug interaction in children with arthritis. J Rheumatol 17:1469–1473 Google Scholar
  45. 45.
    Singsen BH, Goldbach-Mansky R (1997) Methotrexate in the treatment of juvenile rheumatoid arthritis and other pediatric rheumatoid and nonrheumatic disorders. Rheum Dis Clin North Am 23:811–840Google Scholar
  46. 46.
    Wallace CA, Smith AL, Sherry DD (1993) Pilot investigation of naproxen/methotrexate interaction in patients with juvenile rheumatoid arthritis. J Rheumatol 20:1764–1768Google Scholar
  47. 47.
    Lafforgue P, Monjanel-Mouterde S, Durand A, Catalin J, Acquaviva PC (1993) Is there an interaction between low doses of corticosteroids and methotrexate in patients with rheumatoid arthritis? A pharmacokinetic study in 33 patients. J Rheumatol 20:263–267Google Scholar
  48. 48.
    O’Dell JR (2001) Combinations of conventional disease-modifying antirheumatic drugs. Rheum Dis Clin North Am 27:415–426Google Scholar
  49. 49.
    Barrera P, Haagsma CJ, Boerbooms AM, Van Riel PL, Borm GF, Van de Putte LB, Van der Meer JW (1995) Effect of methotrexate alone or in combination with sulphasalazine on the production and circulating concentrations of cytokines and their antagonists. Longitudinal evaluation in patients with rheumatoid arthritis. Br J Rheumatol 34:747–755Google Scholar
  50. 50.
    Seitz M, Loetscher P, Dewald B, Towbin H, Rordorf C, Gallati H, Baggiolini M, Gerber NJ (1995) Methotrexate action in rheumatoid arthritis: stimulation of cytokine inhibitor and inhibition of chemokine production by peripheral blood mononuclear cells. Br J Rheumatol 34:602–609Google Scholar
  51. 51.
    Weinblatt ME, Kremer JM, Bankhurst AD, Bulpitt KJ, Fleischmann RM, Fox RI, Jackson CG, Lange M, Burge DJ (1999) A trial of etanercept, a recombinant tumor necrosis factor receptor:Fc fusion protein, in patients with rheumatoid arthritis receiving methotrexate. N Engl J Med 340:253–259CrossRefPubMedGoogle Scholar
  52. 52.
    Schmeling H, Mathony K, John V, Keysser G, Burdach S, Horneff G (2001) A combination of etanercept and methotrexate for the treatment of refractory juvenile idiopathic arthritis: a pilot study. Ann Rheum Dis 60:410–412CrossRefGoogle Scholar
  53. 53.
    Graham LD, Myones BL, Rivas-Chacon RF, Pachman LM (1992) Morbidity associated with long-term methotrexate therapy in juvenile rheumatoid arthritis. J Pediatr 120:468–473Google Scholar
  54. 54.
    Grennan DM, Gray J, Loudon J, Fear S (2001) Methotrexate and early postoperative complications in patients with rheumatoid arthritis undergoing elective orthopaedic surgery. Ann Rheum Dis 60:214–217CrossRefGoogle Scholar
  55. 55.
    Franke J, Hafner R, Lohrs U, Truckenbrodt H (1996) Methotrexate and liver fibrosis in juvenile chronic arthritis retrospective study of 73 liver biopsies. Monatsschrift Kinderheilkunde 144:147–151Google Scholar
  56. 56.
    Hashkes PJ, Balistreri WF, Bove KE, Ballard ET, Passo MH (1997) The long-term effect of methotrexate therapy on the liver in patients with juvenile rheumatoid arthritis. Arthritis Rheum 40:2226–2234Google Scholar
  57. 57.
    Erickson AR, Reddy V, Vogelgesang SA, West SG (1995) Usefulness of the American College of Rheumatology recommendations for liver biopsy in methotrexate-treated rheumatoid arthritis patients. Arthritis Rheum 38:1115–1119Google Scholar
  58. 58.
    Kremer JM, Alarcon GS, Lightfoot RW Jr, Willkens RF, Furst DE, Williams HJ, Dent PB, Weinblatt ME (1994) Methotrexate for rheumatoid arthritis. Suggested guidelines for monitoring liver toxicity. American College of Rheumatology. Arthritis Rheum 37:316–328Google Scholar
  59. 59.
    McKendry RJ (1997) The remarkable spectrum of methotrexate toxicities. Rheum Dis Clin North Am 23:939–954Google Scholar
  60. 60.
    Kremer JM, Alarcon GS, Weinblatt ME, Kaymakcian MV, Macaluso M, Cannon GW, Palmer WR, Sundy JS, St Clair EW, Alexander RW, Smith GJ, Axiotis CA (1997) Clinical, laboratory, radiographic, and histopathologic features of methotrexate-associated lung injury in patients with rheumatoid arthritis: a multicenter study with literature review. Arthritis Rheum 40:1829–1837Google Scholar
  61. 61.
    Salaffi F, Manganelli P, Carotti M, Subiaco S, Lamanna G, Cervini C (1997) Methotrexate-induced pneumonitis in patients with rheumatoid arthritis and psoriatic arthritis: report of five cases and review of the literature. Clin Rheumatol 16:296–304Google Scholar
  62. 62.
    Cron RQ, Sherry DD, Wallace CA (1998) Methotrexate-induced hypersensitivity pneumonitis in a child with juvenile rheumatoid arthritis. J Pediatr 132:901–902Google Scholar
  63. 63.
    Camiciottoli G, Trapani S, Castellani W, Ginanni R, Ermini M, Falcini F (1998) Effect on lung function of methotrexate and non-steroid anti-inflammatory drugs in children with juvenile rheumatoid arthritis. Rheumatol Int 18:11–16CrossRefGoogle Scholar
  64. 64.
    Pelucchi A, Lomater C, Gerloni V, Foresi A, Fantini F, Marazzini L (1994) Lung function and diffusing capacity for carbon monoxide in patients with juvenile chronic arthritis: effect of disease activity and low dose methotrexate therapy. Clin Exp Rheumatol 12:675–679Google Scholar
  65. 65.
    Schmeling H, Stephan V, Burdach S, Horneff G (2002) Pulmonary function in children with juvenile idiopathic arthritis and effects of methotrexate therapy. Z Rheumatol 61:168–172CrossRefGoogle Scholar
  66. 66.
    Mariette X, Cazals-Hatem D, Warszawki J, Liote F, Balandraud N, Sibilia J (2002) Lymphomas in rheumatoid arthritis patients treated with methotrexate: a 3-year prospective study in France. Blood 1(99):3909–3915CrossRefGoogle Scholar
  67. 67.
    Rau R (1994) Treatment of chronic polyarthritis with methotrexate 1994–a review. Z Rheumatol 53:199–229Google Scholar
  68. 68.
    Cleary AG, McDowell H, Sills JA (2002) Polyarticular juvenile idiopathic arthritis treated with methotrexate complicated by the development of non-Hodgkin’s lymphoma. Arch Dis Child 86:47–49CrossRefGoogle Scholar
  69. 69.
    Krugmann J, Sailer-Hock M, Muller T, Gruber J, Allerberger F, Offner FA (2000) Epstein–Barr virus-associated Hodgkin’s lymphoma and Legionella pneumophila infection complicating treatment of juvenile rheumatoid arthritis with methotrexate and cyclosporine A. Hum Pathol 31:253–255Google Scholar
  70. 70.
    Londino AV Jr, Blatt J, Knisely AS (1998) Hodgkin’s disease in a patient with juvenile rheumatoid arthritis taking weekly low dose methotrexate. J Rheumatol 25:1245–1246Google Scholar
  71. 71.
    Munro R, Porter DR, Sturrock RD (1998) Lymphadenopathy in a patient with systemic onset juvenile chronic arthritis. Ann Rheum Dis 57:513–517Google Scholar
  72. 72.
    Padeh S, Sharon N, Schiby G, Rechavi G, Passwell JH (1997) Hodgkin’s lymphoma in systemic onset juvenile rheumatoid arthritis after treatment with low dose methotrexate. J Rheumatol 24:2035–2037Google Scholar
  73. 73.
    Bawle EV, Conard JV, Weiss L (1998) Adult and two children with fetal methotrexate syndrome. Teratology 57:51–55Google Scholar
  74. 74.
    Kozlowski RD, Steinbrunner JV, MacKenzie AH, Clough JD, Wilke WS, Segal AM (1990) Outcome of first-trimester exposure to low-dose methotrexate in eight patients with rheumatic disease. Am J Med 88:589–592CrossRefGoogle Scholar
  75. 75.
    Buckley LM, Bullaboy CA, Leichtman L, Marquez M (1997) Multiple congenital anomalies associated with weekly low-dose methotrexate treatment of the mother. Arthritis Rheum 40:971–973Google Scholar
  76. 76.
    Blackburn WD Jr, Alarcon GS (1989) Impotence in three rheumatoid arthritis patients treated with methotrexate. Arthritis Rheum 32:1341–1342Google Scholar
  77. 77.
    Sussman A, Leonard JM (1980) Psoriasis, methotrexate, and oligospermia. Arch Dermatol 116:215–217CrossRefGoogle Scholar
  78. 78.
    O’Dell JR (1997) Methotrexate use in rheumatoid arthritis. Rheum Dis Cl N Am 23:779–796Google Scholar
  79. 79.
    Aherne GW, Piall E, Marks V, Mould G, White WF (1978) Prolongation and enhancement of serum methotrexate concentrations by probenecid. Br Med J 29:1097–1099Google Scholar
  80. 80.
    Brik R, Berkowitz D, Berant M (1998) Duration of methotrexate treatment until partial and total remission of refractory juvenile rheumatoid arthritis. Ann Rheum Dis 57:174–175Google Scholar
  81. 81.
    Huang JL (1996) Methotrexate in the treatment of children with chronic arthritis–long-term observations of efficacy and safety. Br J Clin Pract 50:311–314Google Scholar
  82. 82.
    Gottlieb BS, Keenan GF, Lu T, Ilowite NT (1997) Discontinuation of methotrexate treatment in juvenile rheumatoid arthritis. Pediatrics 100:994–997CrossRefGoogle Scholar
  83. 83.
    Ravelli A, Viola S, Ramenghi B, Aramini L, Ruperto N, Martini A (1995) Frequency of relapse after discontinuation of methotrexate therapy for clinical remission in juvenile rheumatoid arthritis. J Rheumatol 22:1574–1576Google Scholar
  84. 84.
    Huemer M, Fodinger M, Huemer C, Sailer-Hock M, Falger J, Rettenbacher A, Bernecker M, Artacker G, Kenzian H, Lang T, Stockler-Ipsiroglu S (2003) Hyperhomocysteinemia in children with juvenile idiopathic arthritis is not influenced by methotrexate treatment and folic acid supplementation: a pilot study. Clin Exp Rheumatol 21:249–255Google Scholar
  85. 85.
    Foell D, Frosch M, Schulze zur Wiesch A, Vogl T, Sorg C, Roth J (2004) Methotrexate treatment in juvenile idiopathic arthritis: when is the right time to stop? Ann Rheum Dis 63:206–208CrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2005

Authors and Affiliations

  • Tim Niehues
    • 1
    Email author
  • Gerd Horneff
    • 2
  • Hartmut Michels
    • 3
  • Michaela Sailer Höck
    • 4
  • Lothar Schuchmann
    • 5
  1. 1.Pediatric Immunology and Rheumatology, Department of Pediatric Oncology, Hematology and Immunology, Centre for Child HealthHeinrich-Heine-UniversityDusseldorfGermany
  2. 2.University Children’s Hospital of the Martin-Luther-UniversitätHalle-WittenbergGermany
  3. 3.Children’s Hospital for Rheumatic DiseasesGarmisch-PartenkirchenGermany
  4. 4.University Children’s HospitalInnsbruckAustria
  5. 5.Working group Pediatric RheumatologyFreiburgGermany

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