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
EH Giannini, EJ Brewer, N Kuzmina, A Shaikov, A Maximov, I Vorontsov, CW Fink, AJ Newman, JT Cassidy, and LS Zemel
BACKGROUND. The antimetabolite methotrexate has been shown in placebo-controlled trials to be effective in adults with rheumatoid arthritis. Methotrexate may also be effective in children with resistant juvenile rheumatoid arthritis, but the supporting data are from uncontrolled trials. METHODS. Centers in the United States and the Soviet Union participated in this randomized, controlled, double-blind trial designed to evaluate the effectiveness and safety of orally administered methotrexate. Patients received one of the following treatments each week for six months: 10 mg of methotrexate per square meter of body-surface area (low dose), 5 mg of methotrexate per square meter (very low dose), or placebo. The use of prednisone (less than or equal to 10 mg per day) and two nonsteroidal antiinflammatory drugs was also allowed. RESULTS. The 127 children (mean age, 10.1 years) had a mean duration of disease of 5.1 years; 114 qualified for the analysis of efficacy. According to a composite index of several response variables, 63 percent of the children who received low-dose methotrexate improved, as compared with 32 percent of those in the very-low-dose group and 36 percent of those in the placebo group (P = 0.013). As compared with the placebo group, the low-dose group also had significantly larger mean reductions from base line in the number of joints with pain on motion (-11.0 vs. -7.1), the pain-severity score (-19 vs. -11.5), the number of joints with limited motion (-5.4 vs. -0.7), and the erythrocyte sedimentation rate (-19.0 vs. -6 mm per hour). In the methotrexate groups only three children had the drug discontinued because of mild-to-moderate side effects; none had severe toxicity. CONCLUSIONS. Methotrexate given weekly in low doses is an effective treatment for children with resistant juvenile rheumatoid arthritis, and at least in the short term this regimen is safe.
Source Information
Department of Pediatrics, University of Cincinnati College of Medicine, OH.
This article has been cited by other articles:
KOCHARLA, L., TAYLOR, J., WEILER, T., TING, T. V., LUGGEN, M., BRUNNER, H. I.
(2009). Monitoring Methotrexate Toxicity in Juvenile Idiopathic Arthritis. The Journal of Rheumatology
36: 2813-2818
[Abstract][Full Text]
Beresford, M W, Baildam, E M
(2009). New advances in the management of juvenile idiopathic arthritis--1: Non-biological therapy. EDUCATION AND PRACTICE
94: 144-150
[Abstract][Full Text]
Horneff, G., Ebert, A., Fitter, S., Minden, K., Foeldvari, I., Kummerle-Deschner, J., Thon, A., Girschick, H. J., Weller, F., Huppertz, H. I.
(2009). Safety and efficacy of once weekly etanercept 0.8 mg/kg in a multicentre 12 week trial in active polyarticular course juvenile idiopathic arthritis. Rheumatology (Oxford)
48: 916-919
[Abstract][Full Text]
Horneff, G, De Bock, F, Foeldvari, I, Girschick, H J, Michels, H, Moebius, D, Schmeling, H, and the German and Austrian Paediatric Rheumatolog,
(2009). Safety and efficacy of combination of etanercept and methotrexate compared to treatment with etanercept only in patients with juvenile idiopathic arthritis (JIA): preliminary data from the German JIA Registry. Ann Rheum Dis
68: 519-525
[Abstract][Full Text]
Bell, E. A.
(2009). Pharmacotherapy of Juvenile Idiopathic Arthritis. Journal of Pharmacy Practice
22: 17-28
[Abstract]
Lovell, D. J., Ruperto, N., Goodman, S., Reiff, A., Jung, L., Jarosova, K., Nemcova, D., Mouy, R., Sandborg, C., Bohnsack, J., Elewaut, D., Foeldvari, I., Gerloni, V., Rovensky, J., Minden, K., Vehe, R. K., Weiner, L. W., Horneff, G., Huppertz, H.-I., Olson, N. Y., Medich, J. R., Carcereri-De-Prati, R., McIlraith, M. J., Giannini, E. H., Martini, A., the Pediatric Rheumatology Collaborative Study Gro,
(2008). Adalimumab with or without Methotrexate in Juvenile Rheumatoid Arthritis. NEJM
359: 810-820
[Abstract][Full Text]
Gerloni, V, Pontikaki, I, Gattinara, M, Fantini, F
(2008). Focus on adverse events of tumour necrosis factor {alpha} blockade in juvenile idiopathic arthritis in an open monocentric long-term prospective study of 163 patients. Ann Rheum Dis
67: 1145-1152
[Abstract][Full Text]
Deng, Y., Hou, Z., Wang, L., Cherian, C., Wu, J., Gangjee, A., Matherly, L. H.
(2008). Role of Lysine 411 in Substrate Carboxyl Group Binding to the Human Reduced Folate Carrier, as Determined by Site-Directed Mutagenesis and Affinity Inhibition. Mol. Pharmacol.
73: 1274-1281
[Abstract][Full Text]
Bartoli, M, Taro, M, Magni-Manzoni, S, Pistorio, A, Traverso, F, Viola, S, Magnani, A, Gasparini, C, Martini, A, Ravelli, A
(2008). The magnitude of early response to methotrexate therapy predicts long-term outcome of patients with juvenile idiopathic arthritis. Ann Rheum Dis
67: 370-374
[Abstract][Full Text]
Cespedes-Cruz, A, Gutierrez-Suarez, R, Pistorio, A, Ravelli, A, Loy, A, Murray, K J, Gerloni, V, Wulffraat, N, Oliveira, S, Walsh, J, Calvo Penades, I, Alpigiani, M G, Lahdenne, P, Saad-Magalhaes, C, Cortis, E, Lepore, L, Kimura, Y, Wouters, C, Martini, A, Ruperto, N, for the Pediatric Rheumatology International Trial,
(2008). Methotrexate improves the health-related quality of life of children with juvenile idiopathic arthritis. Ann Rheum Dis
67: 309-314
[Abstract][Full Text]
McCann, L. J, Wedderburn, L. R, Hasson, N.
(2006). JUVENILE IDIOPATHIC ARTHRITIS. EDUCATION AND PRACTICE
91: ep29-ep36
[Full Text]
Killeen, O G, Gardner-Medwin, J M
(2006). In juvenile idiopathic arthritis, is folate supplementation effective against methotrexate toxicity at the expense of methotrexate's efficacy?. Arch. Dis. Child.
91: 537-538
[Full Text]
Hashkes, P. J., Laxer, R. M.
(2005). Medical Treatment of Juvenile Idiopathic Arthritis. JAMA
294: 1671-1684
[Abstract][Full Text]
Silverman, E., Mouy, R., Spiegel, L., Jung, L. K., Saurenmann, R. K., Lahdenne, P., Horneff, G., Calvo, I., Szer, I. S., Simpson, K., Stewart, J. A., Strand, V., the Leflunomide in Juvenile Rheumatoid Arthritis (,
(2005). Leflunomide or Methotrexate for Juvenile Rheumatoid Arthritis. NEJM
352: 1655-1666
[Abstract][Full Text]
Nozaki, Y., Kusuhara, H., Endou, H., Sugiyama, Y.
(2004). Quantitative Evaluation of the Drug-Drug Interactions between Methotrexate and Nonsteroidal Anti-Inflammatory Drugs in the Renal Uptake Process Based on the Contribution of Organic Anion Transporters and Reduced Folate Carrier. J. Pharmacol. Exp. Ther.
309: 226-234
[Abstract][Full Text]
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: 206-208
[Abstract][Full Text]
de Boer, J, Wulffraat, N, Rothova, A
(2003). Visual loss in uveitis of childhood. Br J Ophthalmol
87: 879-884
[Abstract][Full Text]
Wilkinson, N, Jackson, G, Gardner-Medwin, J
(2003). Biologic therapies for juvenile arthritis. Arch. Dis. Child.
88: 186-191
[Abstract][Full Text]
Ramanan, A V, Whitworth, P, Baildam, E M
(2003). Use of methotrexate in juvenile idiopathic arthritis. Arch. Dis. Child.
88: 197-200
[Abstract][Full Text]
Cleary, A G, McDowell, H, Sills, J A
(2002). Polyarticular juvenile idiopathic arthritis treated with methotrexate complicated by the development of non-Hodgkin's lymphoma. Arch. Dis. Child.
86: 47-49
[Full Text]
Gylys-Morin, V. M., Graham, T. B., Blebea, J. S., Dardzinski, B. J., Laor, T., Johnson, N. D., Oestreich, A. E., Passo, M. H.
(2001). Knee in Early Juvenile Rheumatoid Arthritis: MR Imaging Findings. Radiology
220: 696-706
[Abstract][Full Text]
Gerloni, V., Cimaz, R., Gattinara, M., Arnoldi, C., Pontikaki, I., Fantini, F.
(2001). Efficacy and safety profile of cyclosporin A in the treatment of juvenile chronic (idiopathic) arthritis. Results of a 10-year prospective study. Rheumatology (Oxford)
40: 907-913
[Abstract][Full Text]
Schmeling, H, Mathony, K, John, V, KeyBer, 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: 410-412
[Abstract][Full Text]
Brogan, P A, Dillon, M J
(2000). Personal practice: The use of immunosuppressive and cytotoxic drugs in non-malignant disease. Arch. Dis. Child.
83: 259-264
[Full Text]
Lovell, D. J., Giannini, E. H., Reiff, A., Cawkwell, G. D., Silverman, E. D., Nocton, J. J., Stein, L. D., Gedalia, A., Ilowite, N. T., Wallace, C. A., Whitmore, J., Finck, B. K., The Pediatric Rheumatology Collaborative Study Gro,
(2000). Etanercept in Children with Polyarticular Juvenile Rheumatoid Arthritis. NEJM
342: 763-769
[Abstract][Full Text]
Kuis, W., Wulffraat, N. M., Petty, R. E.
(1999). Autologous stem cell transplantation: an alternative for refractory juvenile chronic arthritis. Rheumatology (Oxford)
38: 737-738
[Full Text]
Wulffraat, N. M., Kuis, W.
(1999). Autologous stem cell transplantation: a possible treatment for refractory juvenile chronic arthritis?. Rheumatology (Oxford)
38: 764-766
[Abstract][Full Text]
Nguyen, Q. D., Foster, C. S.
(1998). Saving the Vision of Children With Juvenile Rheumatoid Arthritis-Associated Uveitis. JAMA
280: 1133-1134
[Full Text]
Munro, R, Porter, D R, Sturrock, R D
(1998). Lymphadenopathy in a patient with systemic onset juvenile chronic arthritis. Ann Rheum Dis
57: 513-517
[Full Text]
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: 174-175
[Full Text]
Ruperto, N., Ravelli, A., Falcini, F., Lepore, L., De Sanctis, R., Zulian, F., Buoncompagni, A., Sardella, M. L., Strano, C., Alessio, M., Viola, S., Martini, A.
(1998). Performance of the preliminary definition of improvement in juvenile chronic arthritis patients treated with methotrexate. Ann Rheum Dis
57: 38-41
[Abstract][Full Text]
Ballow, M., Nelson, R.
(1997). Immunopharmacology: Immunomodulation and Immunotherapy. JAMA
278: 2008-2017
[Abstract]
Gottlieb, B. S., Keenan, G. F., Lu, T., Ilowite, N. T.
(1997). Discontinuation of Methotrexate Treatment in Juvenile Rheumatoid Arthritis. Pediatrics
100: 994-997
[Abstract][Full Text]
Sathananthan, R, David, J
(1997). The adolescent with rheumatic disease. Arch. Dis. Child.
77: 355-358
[Abstract][Full Text]
Malleson, P N
(1997). Management of childhood arthritis. Part 2: chronic arthritis. Arch. Dis. Child.
76: 541-544
[Full Text]
Weinblatt, M. E.
(1995). Methotrexate for Chronic Diseases in Adults. NEJM
332: 330-331
[Full Text]
LINDSLEY, C. B.
(1993). Nonsteroidal Anti-inflammatory Drugs and Gastrointestinal Injury in Children-Reply. Arch Pediatr Adolesc Med
147: 1280-1280
[Abstract]
(1992). LOW-DOSE METHOTREXATE FOR JUVENILE RHEUMATOID ARTHRITIS. JWatch General
1992: 5-5
[Full Text]