Rheumatology 2000; 39: 655-665
© 2000 British Society for Rheumatology
A comparison of the efficacy and safety of leflunomide and methotrexate for the treatment of rheumatoid arthritis
1 Department of Rheumatology and Rehabilitation, University of Leeds School of Medicine, Leeds, UK,
2 Department of Rheumatology, Leiden University Medical Centre, Leiden, The Netherlands,
3 Staatl Rheumakrankenhaus, Baden-Baden,
4 J. W. Goethe-Universität, Frankfurt am Main, Germany,
5 Staffordshire Rheumatology Centre, Stoke-on-Trent, UK,
6 National Institute of Rheumatology and Physiotherapy, Budapest, Hungary,
7 Department of Rheumatology, University Hospital of Ghent, Belgium,
8 Department of Rheumatology, Helsinki University Central Hospital, Helsinki, Finland,
9 Department of Rheumatology, Martina Hansens Hospital, Sandvika, Norway,
10 Department of Internal Medicine, University Hospital, Uppsala, Sweden,
11 Research Laboratory at Medical Department, Hvidovre University Hospital, Copenhagen, Denmark,
12 Hospital Sant Pau, Barcelona, Spain,
13 University College Hospital, Cork, Ireland,
14 Chris Hani Baragwanath Hospital, Johannesburg, South Africa and
15 Hoechst Marion Roussel, Frankfurt, Germany
Objective. To compare the clinical efficacy and safety of leflunomide and methotrexate for the treatment of rheumatoid arthritis (RA).
Methods. In this multicentre, double-blind trial, 999 subjects with active RA were randomized to leflunomide (n = 501; loading dose 100 mg/day for 3 days, maintenance dose 20 mg/day) or methotrexate (n = 498; 10–15 mg/week) for 52 weeks. After 1 yr the subjects could choose to stay for a second year of double-blind treatment. The primary end-points were tender and swollen joint counts and overall physician and patient assessments. Analyses were of the intent-to-treat group.
Results. After 1 yr, the mean changes in the leflunomide and methotrexate groups, respectively, were -8.3 and -9.7 for tender joint count; -6.8 and -9.0 for swollen joint count; -0.9 and -1.2 for physician global assessment; -0.9 and -1.2 for patient global assessment; -14.4 and -28.2 for erythrocyte sedimentation rate. Improvements seen with methotrexate were significantly greater than those with leflunomide. No further improvement occurred after the second year of treatment and the distinction between the two treatments in terms of tender joint count and patient global assessment was lost. During the first year of treatment, a small and equivalent degree of radiographically assessed disease progression was seen with both drugs. After 2 yr, disease progression was significantly less with methotrexate. The most common treatment-related adverse events in both groups were diarrhoea, nausea, alopecia, rash, headache, and elevated plasma liver enzyme levels. Over 2 yr, 21 subjects receiving methotrexate were withdrawn due to elevated plasma liver enzymes vs eight subjects taking leflunomide. Two drug-related deaths from pulmonary causes were recorded with methotrexate vs no drug-related deaths among the subjects receiving leflunomide.
Conclusions. Both leflunomide and methotrexate are efficacious for prolonged treatment of RA. At the doses used, some clinical benefit of methotrexate over leflunomide was observed in the first year of treatment. This benefit must be weighed against the potential toxicity of this drug when used without folate supplementation.
KEY WORDS: Leflunomide, Methotrexate, Clinical trial, Folate supplementation, Rheumatoid arthritis, Radiographic assessment of disease progression.
Correspondence to: P. Emery, Department of Rheumatology and Rehabilitation, University of Leeds School of Medicine, 36 Clarendon Road, Leeds LS2 9NZ, UK.
For a complete list of the Multinational Leflunomide Study Group See Appendix.
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  B. Chikura, S. Lane, and J. K. Dawson Clinical expression of leflunomide-induced pneumonitis Rheumatology, September 1, 2009; 48(9): 1065 - 1068. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. E. Donahue, G. Gartlehner, D. E. Jonas, L. J. Lux, P. Thieda, B. L. Jonas, R. A. Hansen, L. C. Morgan, and K. N. Lohr Systematic Review: Comparative Effectiveness and Harms of Disease-Modifying Medications for Rheumatoid Arthritis Ann Intern Med, January 15, 2008; 148(2): 124 - 134. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 I Tchetverikov, M C Kraan, B van El, R Hanemaaijer, J DeGroot, and T W J Huizinga Leflunomide and methotrexate reduce levels of activated matrix metalloproteinases in complexes with {alpha}2 macroglobulin in serum of rheumatoid arthritis patients Ann Rheum Dis, January 1, 2008; 67(1): 128 - 130. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Metzler, N. Miehle, K. Manger, C. Iking-Konert, K. de Groot, B. Hellmich, W. L. Gross, E. Reinhold-Keller, and for the German Network of Rheumatic Diseases Elevated relapse rate under oral methotrexate versus leflunomide for maintenance of remission in Wegener's granulomatosis Rheumatology, July 1, 2007; 46(7): 1087 - 1091. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Gaffo, K. G. Saag, and J. R. Curtis Treatment of rheumatoid arthritis Am. J. Health Syst. Pharm., December 15, 2006; 63(24): 2451 - 2465. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C P Chung, J L Thompson, G G Koch, I Amara, V Strand, and T Pincus Are American College of Rheumatology 50% response criteria superior to 20% criteria in distinguishing active aggressive treatment in rheumatoid arthritis clinical trials reported since 1997? A meta-analysis of discriminant capacities Ann Rheum Dis, December 1, 2006; 65(12): 1602 - 1607. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K Martin, F Bentaberry, C Dumoulin, M Longy-Boursier, F Lifermann, F Haramburu, J Dehais, T Schaeverbeke, B Begaud, and N Moore Neuropathy associated with leflunomide: a case series Ann Rheum Dis, April 1, 2005; 64(4): 649 - 650. [Full Text] [PDF]
|
|
|
|
|
|
P. Maddison, P. Kiely, B. Kirkham, T. Lawson, R. Moots, D. Proudfoot, R. Reece, D. Scott, R. Sword, A. Taggart, et al. Leflunomide in rheumatoid arthritis: recommendations through a process of consensus Rheumatology, March 1, 2005; 44(3): 280 - 286. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. J. Kinder, A. B. Hassell, J. Brand, A. Brownfield, M. Grove, and M. F. Shadforth The treatment of inflammatory arthritis with methotrexate in clinical practice: treatment duration and incidence of adverse drug reactions Rheumatology, January 1, 2005; 44(1): 61 - 66. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Rajakulendran and C. Deighton Do guidelines for the prescribing and monitoring of leflunomide need to be modified? Rheumatology, November 1, 2004; 43(11): 1447 - 1448. [Full Text] [PDF]
|
|
|
|
 |
|
 L-S Tam, E K Li, C-K Wong, C W. Lam, and C-C Szeto Double-blind, randomized, placebo-controlled pilot study of leflunomide in systemic lupus erythematosus Lupus, August 1, 2004; 13(8): 601 - 604. [Abstract] [PDF]
|
|
|
|
|
|
G. Poor and V. Strand Efficacy and safety of leflunomide 10 mg versus 20 mg once daily in patients with active rheumatoid arthritis: multinational double-blind, randomized trial Rheumatology, June 1, 2004; 43(6): 744 - 749. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. L. Whittle and R. A. Hughes Folate supplementation and methotrexate treatment in rheumatoid arthritis: a review Rheumatology, March 1, 2004; 43(3): 267 - 271. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Metzler, C. Fink, P. Lamprecht, W. L. Gross, and E. Reinhold-Keller Maintenance of remission with leflunomide in Wegener's granulomatosis Rheumatology, March 1, 2004; 43(3): 315 - 320. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Brennan, N. Bansback, A. Reynolds, and P. Conway Modelling the cost-effectiveness of etanercept in adults with rheumatoid arthritis in the UK Rheumatology, January 1, 2004; 43(1): 62 - 72. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D Aletaha, T Stamm, T Kapral, G Eberl, J Grisar, K P Machold, and J S Smolen Survival and effectiveness of leflunomide compared with methotrexate and sulfasalazine in rheumatoid arthritis: a matched observational study Ann Rheum Dis, October 1, 2003; 62(10): 944 - 951. [Abstract] [Full Text]
|
|
|
|
|
|
A. Erra, C. Tomas, P. Barcelo, M. Vilardell, and S. Marsal Is the recommended dose of leflunomide the best regimen to treat rheumatoid arthritis patients? Rheumatology, September 1, 2003; 42(9): 1123 - 1124. [Full Text] [PDF]
|
|
|
|
|
|
P A Ory Interpreting radiographic data in rheumatoid arthritis Ann Rheum Dis, July 1, 2003; 62(7): 597 - 604. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A Hoi and G O Littlejohn Aminotransferase levels during treatment of rheumatoid arthritis with leflunomide in clinical practice Ann Rheum Dis, April 1, 2003; 62(4): 379 - 379. [Full Text] [PDF]
|
|
|
|
|
|
J. S. Smolen, F. C. Breedveld, M. H. Schiff, J. R. Kalden, P. Emery, G. Eberl, P. L. van Riel, and P. Tugwell A simplified disease activity index for rheumatoid arthritis for use in clinical practice Rheumatology, February 1, 2003; 42(2): 244 - 257. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Gause Progress in the treatment of rheumatic disease Nephrol. Dial. Transplant., January 1, 2003; 18(1): 13 - 16. [Full Text] [PDF]
|
|
|
|
|
|
D. Burger, N. Begue-Pastor, S. Benavent, L. Gruaz, M.-T. Kaufmann, R. Chicheportiche, and J.-M. Dayer The active metabolite of leflunomide, A77 1726, inhibits the production of prostaglandin E2, matrix metalloproteinase 1 and interleukin 6 in human fibroblast-like synoviocytes Rheumatology, January 1, 2003; 42(1): 89 - 96. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
V Strand, R Landewe, and D van der Heijde Using estimated yearly progression rates to compare radiographic data across recent randomised controlled trials in rheumatoid arthritis Ann Rheum Dis, November 1, 2002; 61(90002): ii64 - 66. [Full Text] [PDF]
|
|
|
|
|
|
P Geborek, M Crnkic, I F Petersson, and T Saxne Etanercept, infliximab, and leflunomide in established rheumatoid arthritis: clinical experience using a structured follow up programme in southern Sweden Ann Rheum Dis, September 1, 2002; 61(9): 793 - 798. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. L. Scott and V. Strand The effects of disease-modifying anti-rheumatic drugs on the Health Assessment Questionnaire score. Lessons from the leflunomide clinical trials database Rheumatology, August 1, 2002; 41(8): 899 - 909. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. T. Carulli and U. M. Davies Peripheral neuropathy: an unwanted effect of leflunomide? Rheumatology, August 1, 2002; 41(8): 952 - 953. [Full Text] [PDF]
|
|
|
|
|
|
D L Scott, J S Smolen, J R Kalden, L B A van de Putte, A Larsen, T K Kvien, M Schattenkirchner, P Nash, C Oed, and I Loew-Friedrich Treatment of active rheumatoid arthritis with leflunomide: two year follow up of a double blind, placebo controlled trial versus sulfasalazine Ann Rheum Dis, October 1, 2001; 60(10): 913 - 923. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N J Wiles, D G I Scott, E M Barrett, P Merry, E Arie, K Gaffney, A J Silman, and D P M Symmons Benchmarking: the five year outcome of rheumatoid arthritis assessed using a pain score, the Health Assessment Questionnaire, and the Short Form-36 (SF-36) in a community and a clinic based sample Ann Rheum Dis, October 1, 2001; 60(10): 956 - 961. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Davidson and B. Diamond Autoimmune Diseases N. Engl. J. Med., August 2, 2001; 345(5): 340 - 350. [Full Text] [PDF]
|
|
|
|
 |
|
 V. Rozenfeld, L. Chagan, and E. Kleyman The Year in Review: Rheumatology Journal of Pharmacy Practice, February 1, 2001; 14(1): 54 - 69. [Abstract] [PDF]
|
|
|
|
|
|
F C Breedveld and J-M Dayer Leflunomide: mode of action in the treatment of rheumatoid arthritis Ann Rheum Dis, November 1, 2000; 59(11): 841 - 849. [Abstract] [Full Text]
|
|