Abstract
Juvenile idiopathic arthritis (JIA) is one of the most common rheumatic diseases in childhood. In a significant number of JIA cases the disease is resistant to therapy with NSAIDs, intra-articular corticosteroid injections, and physiotherapy, and methotrexate is used as a second-line agent. The efficacy of methotrexate therapy in children with JIA has been demonstrated in prospective controlled trials and this agent appears to have slightly superior efficacy compared with leflunomide. Data from randomized studies indicate a starting dose of 10–15 mg/m2/week orally. The dose of parenteral methotrexate can be increased to 15–20 mg/m2/week. Combination therapy with methotrexate and an NSAID is recommended. However, there are still no data on when to initiate methotrexate in JIA and how long children should be treated.
The most common adverse effects are aversion to the drug and nausea. In the case of minor adverse effects the use of folic acid at a dosage of 1 mg/day is feasible. In JIA, daily folate supplementation has only been studied in one small heterogeneous cohort with a very short observation period and, at present, a general recommendation on daily folate supplementation cannot be made.
In summary, methotrexate is seen by many pediatric rheumatologists as the first-choice, second-line drug; there is good evidence of its efficacy in JIA. However, in light of the recent introduction of biologic agents, the place of methotrexate in the treatment of JIA may have to be redefined in the coming years.
Similar content being viewed by others
References
Cassidy JT, Petty R. Textbook of pediatric rheumatology. 4th ed. Philadelphia (PA): WB Saunders Company, 2001
Wahn V, Oppermann J, Huppertz HI, et al. Rheumatische Erkrankungen im Kindes- und Jugendalter. Hans Marseille Verlag 2001; 1: 156
Minden K, Niewerth M, Listing J, et al. German Study Group of Pediatric Rheumatologists: health care provision in pediatric rheumatology in Germany: national rheumatologic database. J Rheumatol 2002 Mar; 29(3): 622–8
Foeldvari I, Wierk A. Methotrexate is an effective treatment for chronic uveitis associated with juvenile idiopathic arthritis. J Rheumatol 2005 Feb; 32: 362–5
Ramanan AV, Withworth P, Baildam EM. Use of methotrexate in juvenile idiopathic arthritis. Arch Dis Child 2003; 88: 197–200
Kremer JM. Toward a better understanding of methotrexate. Arthritis Rheum 2004; 50: 1370–82
Hou Z, Stapels SE, Haska CL, et al. Localization of a substrate binding domain of the human reduced folate carrier to transmembrane domain 11 by radioaffinity labeling and cysteine-substituted accessibility methods. J Biol Chem 2005; 280: 36206–13
Dolezalova P, Krijt J, Chladek J, et al. Adenosine and methotrexate polyglutamate concentrations in patients with juvenile arthritis. Rheumatology 2005; 44: 74–9
Johnston A, Gudjonsson JE, Sigmundsdottir H, et al. The anti-inflammatory action of methotrexate is not mediated by lymphocyte apoptosis, but by the suppression of activation and adhesion molecules. Clin Immunol 2005; 114: 154–63
Onel KB. Advances in the medical treatment of juvenile rheumatoid arthritis. Curr Opin Pediatr 2000; 12: 72–5
Seeliger S, Niehues T, Harms E, et al. Methotrexate in der Behandlung der juvenilen idiopathischen arthritis. Monatsschr Kinderheilkd 2002; 150: 452–9
Niehues T, Horneff G, Michels H, et al. 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. Rheumatol Int 2005; 25: 169–78
Andersen PA, West SG, O’Dell JR, et al. Weekly pulse methotrexate in rheumatoid arthritis: clinical and immunologic effects in a randomized, double-blind study. Ann Intern Med 1985; 103: 489–96
Thompson RN, Watts C, Edelman J, et al. A controlled two-centre trial of parenteral methotrexate therapy for refractory rheumatoid arthritis. J Rheumatol 1984; 11: 760–3
Weinblatt ME, Coblyn JS, Fox DA, et al. Efficacy of low-dose methotrexate in rheumatoid arthritis. N Engl J Med 1985; 312: 818–22
Williams HJ, Willkens RF, Samuelson Jr CO, 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: 721–30
Canadian Task Force on the Periodic Health Examination. Canadian guide to clinical preventive health care. Ottawa (ON): Canada Communication Group, 1994
U.S. Preventive Services Task Force. Guide to clinical preventive services. 2nd ed. Baltimore (MD): Williams and Wilkins, 1996
Feldmann W. Evidence-based pediatrics. 1st ed. Hamilton (ON): BC Decker, 2000
Sackett DL, Rosenberg WM, Gray JA, et al. Evidence based medicine: what it is and what it isn’t. BMJ 1996; 13: 71–2
Truckenbrodt H, Hafner R. Methotrexate therapy in juvenile rheumatoid arthritis: a retrospective study. Arthritis Rheum 1986; 29: 801–7
Giannini EH, Cassidy JT, Brewer EJ, et al. Comparative efficacy and safety of advanced drug therapy in children with juvenile rheumatoid arthritis. Semin Arthritis Rheum 1993 Aug; 23: 34–46
Giannini EH, Brewer EJ, Kuzmina N, et al. Methotrexate in resistant juvenile rheumatoid arthritis: results of the USA-USSR double-blind, placebo-controlled trial. The Pediatric Rheumatology Collaborative Study Group and the Cooperative Children’s Study Group. N Engl J Med 1992; 326: 1043–9
Woo P, Southwood TR, Prieur AM, et al. Randomized, placebo-controlled, crossover trial of low-dose oral methotrexate in children with extended oligoarticular or systemic arthritis. Arthritis Rheum 2000; 43: 1849–57
Takken T, Van der Net J, Helder PJ. Methotrexate for treating juvenile idiopathic arthritis. Cochrane Database Syst Rev 2001; (4): CD003129
Ravelli A, Viola S, Migliavacca D, et al. The extended oligoarticular subtype is the best predictor of methotrexate efficacy in juvenile idiopathic arthritis. J Pediatr 1999; 135: 316–20
Silverman E, Spiegel L, Hawkins D, et al. Leflunomide or methotrexate for juvenile rheumatoid arthritis. N Engl J Med 2005 Apr; 352: 1655–66
Cassidy JT. Medical management of children with juvenile rheumatoid arthritis. Drugs 1999; 58: 831–50
Ravelli A, Martini A. Methotrexate in juvenile idiopathic arthritis: answers and questions. J Rheumatol 2000; 27: 1830–3
Breit W, Frosch M, Meyer U, et al. A subgroup-specific evaluation of the efficacy of intraarticular triamcinolone hexacetonide in juvenile chronic arthritis. J Rheumatol 2000; 27: 2696–702
Padeh S, Passwell JH. Intraarticular corticosteroid injection in the management of children with chronic arthritis. Arthritis Rheum 1998; 41: 1210–4
Brik R, Berkowitz D, Berant M. Duration of methotrexate treatment until partial and total remission of refractory juvenile rheumatoid arthritis. Ann Rheum Dis 1998; 57: 174–5
Huang JL. Methotrexate in the treatment of children with chronic arthritis: long-term observations of efficacy and safety. Br J Clin Pract 1996; 50: 311–4
Gottlieb BS, Keenan GF, Lu T, et al. Discontinuation of methotrexate treatment in juvenile rheumatoid arthritis. Pediatrics 1997; 100: 994–7
Ravelli A, Viola S, Ramenghi B, et al. Frequency of relapse after discontinuation of methotrexate therapy for clinical remission in juvenile rheumatoid arthritis. J Rheumatol 1995; 22: 1574–6
Foell D, Frosch M, Schulze zur Wiesch A, et al. Methotrexate treatment in juvenile idiopathic arthritis: when is the right time to stop? Ann Rheum Dis 2004; 63: 206–8
Ruperto N, Murray KJ, Gerloni V, et al. A randomized trial of methotrexate comparing an intermediate dose with a higher dose in children with juvenile idiopathic arthritis who failed to respond to standard doses of methotrexate. Arthritis Rheum 2004 Jul; 50: 2192–202
Kremer JM, Galivan J, Streckfuss A, et al. Methotrexate metabolism analysis in blood and liver of rheumatoid arthritis patients: association with hepatic folate deficiency and formation of polyglutamates. Arthritis Rheum 1986; 29: 832–5
Oguey D, Kolliker F, Gerber NJ, et al. Effect of food on the bioavailability of low-dose methotrexate in patients with rheumatoid arthritis. Arthritis Rheum 1992; 35: 611–4
Wallace CA. The use of methotrexate in childhood rheumatic diseases. Arthritis Rheum 1998; 41: 381–91
Balis FM, Mirro Jr J, Reaman GH, et al. Pharmacokinetics of subcutaneous methotrexate. J Clin Oncol 1988; 6: 1882–6
Balis FM, Savitch JL, Bleyer WA. Pharmacokinetics of oral methotrexate in children. Cancer Res 1983; 43: 2342–5
Alsufyani K, Ortiz-Alvarez O, Cabral DA, et al. The role of subcutaneous administration of methotrexate in children with juvenile idiopathic arthritis who have failed oral methotrexate. J Rheumatol 2004; 31: 179–82
Jundt JW, Browne BA, Fiocco GP, et al. A comparison of low dose methotrexate bioavailability: oral solution, oral tablet, subcutaneous and intramuscular dosing. J Rheumatol 1993; 20: 1845–9
Furst DE, Kremer JM. Methotrexate in rheumatoid arthritis. Arthritis Rheum 1988; 31: 305–14
Dupuis LL, Koren G, Silverman ED, et al. Influence of food on the bioavailability of oral methotrexate in children. J Rheumatol 1995; 22: 1570–3
O’Dell JR. Methotrexate use in rheumatoid arthritis. Rheum Dis Clin North Am 1997; 23: 779–96
Aherne GW, Piall E, Marks V, et al. Prolongation and enhancement of serum methotrexate concentrations by probenecid. BMJ 1978; 29: 1097–9
Albertioni F, Flato B, Seideman P, et al. Methotrexate in juvenile rheumatoid arthritis: evidence of age dependent pharmacokinetics. Eur J Clin Pharmacol 1995; 47: 507–11
Reiff A, Shaham B, Wood BP, et al. High dose methotrexate in the treatment of refractory juvenile rheumatoid arthritis. Clin Exp Rheumatol 1995; 13: 113–8
Wallace CA, Bleyer WA, Sherry DD, et al. Toxicity and serum levels of methotrexate in children with juvenile rheumatoid arthritis. Arthritis Rheum 1989; 32: 677–81
Morgan SL, Oster RA, Lee JY, et al. The effect of folic acid and folinic acid supplementation on purine metabolism in methotrexate-treated rheumatoid arthritis. Arthritis Rheum 2004; 50: 3104–11
Cronstein BN. Folic acid and folinic acid supplements and methotrexate therapy: comment on the article by Morgan, et al. Arthritis Rheum 2005 Apr; 52(4): 1338–9
Ortiz Z, Shea B, Suarez-Almazor ME, et al. The efficacy of folic acid and folinic acid in reducing methotrexate gastrointestinal toxicity in rheumatoid arthritis: a metaanalysis of randomized controlled trials. J Rheumatol 1998; 25: 36–43
van Ede AE, Laan RF, Rood MJ, et al. 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 2001; 44: 1515–24
Morgan SL, Baggott JE, Lee JY, et al. Folic acid supplementation prevents deficient blood folate levels and hyperhomocysteinemia during long term, low dose methotrexate therapy for rheumatoid arthritis: implications for cardiovascular disease prevention. J Rheumatol 1998; 25: 441–6
van Ede AE, Laan RF, Blom HJ, et al. Homocysteine and folate status in methotrexate-treated patients with rheumatoid arthritis. Rheumatol (Oxf) 2002; 41: 658–65
Harten P. Folsäure zur Reduktion der Methotrexate-Toxizität. Z Rheumatol 2005; 64: 353–8
Hunt PG, Rose CD, McIlvain-Simpson G, et al. 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 1997; 24: 2230–2
Huemer M, Fodinger M, Huemer C, et al. Hyperhomocysteinemia in children with juvenile idiopathic arthritis is not influenced by methotrexate treatment and folic acid supplementation: a pilot study. Clin Exp Rheumatol 2003; 21: 249–55
Dupuis LL, Koren G, Shore A, et al. Methotrexate-nonsteroidal antiinflammatory drug interaction in children with arthritis. J Rheumatol 1990; 17: 1469–73
Singsen BH, Goldbach-Mansky R. Methotrexate in the treatment of juvenile rheumatoid arthritis and other pediatric rheumatoid and nonrheumatic disorders. Rheum Dis Clin North Am 1997; 23: 811–40
Wallace CA, Smith AL, Sherry DD. Pilot investigation of naproxen/methotrexate interaction in patients with juvenile rheumatoid arthritis. J Rheumatol 1993; 20: 1764–8
Lafforgue P, Monjanel-Mouterde S, Durand A, et al. Is there an interaction between low doses of corticosteroids and methotrexate in patients with rheumatoid arthritis? A pharmacokinetic study in 33 patients. J Rheumatol 1993; 20: 263–7
O’Dell JR. Combinations of conventional disease-modifying antirheumatic drugs. Rheum Dis Clin North Am 2001; 27: 415–26
Weinblatt ME, Kremer JM, Bankhurst AD, et al. A trial of etanercept, a recombinant tumor necrosis factor receptor: Fc fusion protein, in patients with rheumatoid arthritis receiving methotrexate. N Engl J Med 1999; 340: 253–9
Schmeling H, Mathony K, John V, et al. A combination of etanercept and methotrexate for the treatment of refractory juvenile idiopathic arthritis: a pilot study. Ann Rheum Dis 2001; 60: 410–2
Gerloni V, Pontikaki I, Gattinara M, et al. Efficacy of repeated intravenous infusions of an anti-tumor necrosis factor α monoclonal antibody, infliximab, in persistently active, refractory juvenile idiopathic arthritis: results of an open-labeled prospective study. Arthritis Rheum 2005 Feb; 52(2): 548–53
Mariette X, Cazals-Hatem D, Warszawki J, et al. Lymphomas in rheumatoid arthritis patients treated with methotrexate: a 3-year prospective study in France. Blood 2002 Jun 1; 99: 3909–15
Ortiz-Alavarez O, Morishita K, Avery G, et al. Guidelines for blood test monitoring of methotrexate toxicity in juvenile idiopathic arthritis. J Rheumatol 2004; 31: 2501–6
Franke J, Hafner R, Lohrs U, et al. Methotrexate and liver fibrosis in juvenile chronic arthritis retrospective study of 73 liver biopsies. Monatschr Kinderheilkd 1996; 144: 147–51
Hashkes PJ, Balistreri WF, Bove KE, et al. The long-term effect of methotrexate therapy on the liver in patients with juvenile rheumatoid arthritis. Arthritis Rheum 1997; 40: 2226–34
Erickson AR, Reddy V, Vogelgesang SA, et al. Usefulness of the American College of Rheumatology recommendations for liver biopsy in methotrexate-treated rheumatoid arthritis patients. Arthritis Rheum 1995; 38: 1115–9
Kremer JM, Alarcon GS, Lightfoot Jr RW, et al. Methotrexate for rheumatoid arthritis: suggested guidelines for monitoring liver toxicity. American College of Rheumatology. Arthritis Rheum 1994; 37: 316–28
Kremer JM, Alarcon GS, Weinblatt ME, et al. Clinical, laboratory, radiographic, and histopathologic features of methotrexate-associated lung injury in patients with rheumatoid arthritis: a multicenter study with literature review. Arthritis Rheum 1997; 40: 1829–37
Salaffi F, Manganelli P, Carotti M, et al. Methotrexate-induced pneumonitis in patients with rheumatoid arthritis and psoriatic arthritis: report of five cases and review of the literature. Clin Rheumatol 1997; 16: 296–304
Cron RQ, Sherry DD, Wallace CA. Methotrexate-induced hypersensitivity pneumonitis in a child with juvenile rheumatoid arthritis. J Pediatr 1998; 132: 901–2
Camiciottoli G, Trapani S, Castellani W, et al. Effect on lung function of methotrexate and non-steroid anti-inflammatory drugs in children with juvenile rheumatoid arthritis. Rheumatol Int 1998; 18: 11–6
Pelucchi A, Lomater C, Gerloni V, et al. 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 1994; 12: 675–9
Schmeling H, Stephan V, Burdach S, et al. Pulmonary function in children with juvenile idiopathic arthritis and effects of methotrexate therapy. Z Rheumatol 2002; 61: 168–72
Graham LD, Myones BL, Rivas-Chacon RF, et al. Morbidity associated with long-term methotrexate therapy in juvenile rheumatoid arthritis. J Pediatr 1992; 120: 468–73
Kinder AJ, Hassell AB, Brand J, et al. The treatment of inflammatory arthritis with methotrexate in clinical practice: treatment duration and incidence of adverse drug reactions. Rheumatology 2005; 44: 61–6
Grennan DM, Gray J, Loudon J, et al. Methotrexate and early postoperative complications in patients with rheumatoid arthritis undergoing elective orthopaedic surgery. Ann Rheum Dis 2001; 60: 214–7
McKendry RJ. The remarkable spectrum of methotrexate toxicities. Rheum Dis Clin North Am 1997; 23: 939–54
Rackham OJ, Sills JA, Davidson JE. Immunoglobulin levels in methotrexate treated paediatric rheumatology patients. Arch Dis Child 2002; 87: 147–8
Rau R. Treatment of chronic polyarthritis with methotrexate 1994: a review. Z Rheumatol 1994; 53: 199–229
Cleary AG, McDowell H, Sills JA. Polyarticular juvenile idiopathic arthritis treated with methotrexate complicated by the development of non-Hodgkin’s lymphoma. Arch Dis Child 2002; 86: 47–9
Krugmann J, Sailer-Hock M, Muller T, et al. Epstein-Barr virus-associated Hodgkin’s lymphoma and Legionella pneumophila infection complicating treatment of juvenile rheumatoid arthritis with methotrexate and cyclosporine A. Hum Pathol 2000; 31: 253–5
Londino Jr AV, Blatt J, Knisely AS. Hodgkin’s disease in a patient with juvenile rheumatoid arthritis taking weekly low dose methotrexate. J Rheumatol 1998; 25: 1245–6
Munro R, Porter DR, Sturrock RD. Lymphadenopathy in a patient with systemic onset juvenile chronic arthritis. Ann Rheum Dis 1998; 57: 513–7
Padeh S, Sharon N, Schiby G, et al. Hodgkin’s lymphoma in systemic onset juvenile rheumatoid arthritis after treatment with low dose methotrexate. J Rheumatol 1997; 24: 2035–7
Bawle EV, Conard JV, Weiss L. Adult and two children with fetal methotrexate syndrome. Teratology 1998; 57: 51–5
Kozlowski RD, Steinbrunner JV, MacKenzie AH, et al. Outcome of first-trimester exposure to low-dose methotrexate in eight patients with rheumatic disease. Am J Med 1990; 88: 589–92
Buckley LM, Bullaboy CA, Leichtman L, et al. Multiple congenital anomalies associated with weekly low-dose methotrexate treatment of the mother. Arthritis Rheum 1997; 40: 971–3
Blackburn Jr WD, Alarcon GS. Impotence in three rheumatoid arthritis patients treated with methotrexate. Arthritis Rheum 1989; 32: 1341–2
Sussman A, Leonard JM. Psoriasis, methotrexate, and oligospermia. Arch Dermatol 1980; 116: 215–7
Acknowledgements
We dedicate this work to Professor Dr Ulrich Göbel and thank him for his continuous support of our Pediatric Immunology and Rheumatology Division. We thank P. Knops for assistance in the preparation of this manuscript.
No sources of funding were used to assist in the preparation of this review. The authors have no conflicts of interest that are directly relevant to the content of this review.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Niehues, T., Lankisch, P. Recommendations for the Use of Methotrexate in Juvenile Idiopathic Arthritis. Pediatr-Drugs 8, 347–356 (2006). https://doi.org/10.2165/00148581-200608060-00003
Published:
Issue Date:
DOI: https://doi.org/10.2165/00148581-200608060-00003