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. 2005 May 18;64(12):1761–1764. doi: 10.1136/ard.2005.036491

Double blind, randomised, placebo controlled study of leflunomide in the treatment of active ankylosing spondylitis

J C van Denderen 1, M van der Paardt 1, M Nurmohamed 1, Y M M A de Ryck 1, B Dijkmans 1, I E van der Horst-Bru 1
PMCID: PMC1755327  PMID: 15901634

Abstract

Objective: To assess the efficacy and safety of leflunomide in active ankylosing spondylitis (AS) compared with placebo in a 24 week pilot study.

Methods: In a single centre randomised, double blind, placebo controlled study, 45 patients with active AS were randomised to either leflunomide 20 mg daily (n = 30) or placebo (n = 15). Active disease was defined as a score of ⩾4 on the Bath ankylosing spondylitis disease activity index (0–10), and pain of ⩾4 on a visual analogue scale (0–10). The primary efficacy variable at week 24 was the 20% response rate, as recommended by the Assessments in Ankylosing Spondylitis (ASAS) working group. Secondary outcome variables included general wellbeing, metrology index, swollen joint count, erythrocyte sedimentation rate, and C reactive protein.

Results: In all, 13 women and 32 men were studied. Demographic and disease indices were comparable between the two treatment groups at baseline. The rate of ASAS 20% responders was not significantly different: 27% in the leflunomide treated patients and 20% in the placebo group (95% confidence interval, –32% to 19%). No significant differences were found between the treatment groups in mean changes of the secondary outcome variables. Eleven patients were withdrawn prematurely from the study because of adverse events (7), lack of efficacy (3), and non-compliance (1). Most frequently adverse events were gastrointestinal side effects and skin disorders.

Conclusions: In this placebo controlled study, leflunomide treatment did not result in a significant improvement of the ASAS 20% response in active ankylosing spondylitis. No unexpected or severe adverse events occurred.

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Figure 1.

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 Trial profile. Five screened patients are not included because they did not meet the criteria for disease activity, and two patients because they wanted to have a child. AE, adverse events.

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Anderson J. J., Baron G., van der Heijde D., Felson D. T., Dougados M. Ankylosing spondylitis assessment group preliminary definition of short-term improvement in ankylosing spondylitis. Arthritis Rheum. 2001 Aug;44(8):1876–1886. doi: 10.1002/1529-0131(200108)44:8<1876::AID-ART326>3.0.CO;2-F. [DOI] [PubMed] [Google Scholar]
  2. Bollow M., Fischer T., Reisshauer H., Backhaus M., Sieper J., Hamm B., Braun J. Quantitative analyses of sacroiliac biopsies in spondyloarthropathies: T cells and macrophages predominate in early and active sacroiliitis- cellularity correlates with the degree of enhancement detected by magnetic resonance imaging. Ann Rheum Dis. 2000 Feb;59(2):135–140. doi: 10.1136/ard.59.2.135. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Braun J., Brandt J., Listing J., Zink A., Alten R., Burmester G., Golder W., Gromnica-Ihle E., Kellner H., Schneider M. Long-term efficacy and safety of infliximab in the treatment of ankylosing spondylitis: an open, observational, extension study of a three-month, randomized, placebo-controlled trial. Arthritis Rheum. 2003 Aug;48(8):2224–2233. doi: 10.1002/art.11104. [DOI] [PubMed] [Google Scholar]
  4. Braun J., Brandt J., Listing J., Zink A., Alten R., Golder W., Gromnica-Ihle E., Kellner H., Krause A., Schneider M. Treatment of active ankylosing spondylitis with infliximab: a randomised controlled multicentre trial. Lancet. 2002 Apr 6;359(9313):1187–1193. doi: 10.1016/s0140-6736(02)08215-6. [DOI] [PubMed] [Google Scholar]
  5. Calin A., Garrett S., Whitelock H., Kennedy L. G., O'Hea J., Mallorie P., Jenkinson T. A new approach to defining functional ability in ankylosing spondylitis: the development of the Bath Ankylosing Spondylitis Functional Index. J Rheumatol. 1994 Dec;21(12):2281–2285. [PubMed] [Google Scholar]
  6. Clegg D. O., Reda D. J., Weisman M. H., Blackburn W. D., Cush J. J., Cannon G. W., Mahowald M. L., Schumacher H. R., Jr, Taylor T., Budiman-Mak E. Comparison of sulfasalazine and placebo in the treatment of ankylosing spondylitis. A Department of Veterans Affairs Cooperative Study. Arthritis Rheum. 1996 Dec;39(12):2004–2012. doi: 10.1002/art.1780391209. [DOI] [PubMed] [Google Scholar]
  7. Cuchacovich M., Soto L. Leflunomide decreases joint erosions and induces reparative changes in a patient with psoriatic arthritis. Ann Rheum Dis. 2002 Oct;61(10):942–943. doi: 10.1136/ard.61.10.942. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Garrett S., Jenkinson T., Kennedy L. G., Whitelock H., Gaisford P., Calin A. A new approach to defining disease status in ankylosing spondylitis: the Bath Ankylosing Spondylitis Disease Activity Index. J Rheumatol. 1994 Dec;21(12):2286–2291. [PubMed] [Google Scholar]
  9. Gonzalez-Lopez Laura, Garcia-Gonzalez Araceli, Vazquez-Del-Mercado Monica, Muñoz-Valle Jose F., Gamez-Nava Jorge I. Efficacy of methotrexate in ankylosing spondylitis: a randomized, double blind, placebo controlled trial. J Rheumatol. 2004 Aug;31(8):1568–1574. [PubMed] [Google Scholar]
  10. Gorman Jennifer D., Sack Kenneth E., Davis John C., Jr Treatment of ankylosing spondylitis by inhibition of tumor necrosis factor alpha. N Engl J Med. 2002 May 2;346(18):1349–1356. doi: 10.1056/NEJMoa012664. [DOI] [PubMed] [Google Scholar]
  11. Haibel H., Rudwaleit M., Braun J., Sieper J. Six months open label trial of leflunomide in active ankylosing spondylitis. Ann Rheum Dis. 2005 Jan;64(1):124–126. doi: 10.1136/ard.2003.019174. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Jones S. D., Porter J., Garrett S. L., Kennedy L. G., Whitelock H., Calin A. A new scoring system for the Bath Ankylosing Spondylitis Metrology Index (BASMI) J Rheumatol. 1995 Aug;22(8):1609–1609. [PubMed] [Google Scholar]
  13. Jones S. D., Steiner A., Garrett S. L., Calin A. The Bath Ankylosing Spondylitis Patient Global Score (BAS-G). Br J Rheumatol. 1996 Jan;35(1):66–71. doi: 10.1093/rheumatology/35.1.66. [DOI] [PubMed] [Google Scholar]
  14. Kaltwasser J. Peter, Nash Peter, Gladman Dafna, Rosen Cheryl F., Behrens Frank, Jones Peter, Wollenhaupt Jürgen, Falk Franziska G., Mease Philip, Treatment of Psoriatic Arthritis Study Group Efficacy and safety of leflunomide in the treatment of psoriatic arthritis and psoriasis: a multinational, double-blind, randomized, placebo-controlled clinical trial. Arthritis Rheum. 2004 Jun;50(6):1939–1950. doi: 10.1002/art.20253. [DOI] [PubMed] [Google Scholar]
  15. Kraan M. C., Reece R. J., Barg E. C., Smeets T. J., Farnell J., Rosenburg R., Veale D. J., Breedveld F. C., Emery P., Tak P. P. Modulation of inflammation and metalloproteinase expression in synovial tissue by leflunomide and methotrexate in patients with active rheumatoid arthritis. Findings in a prospective, randomized, double-blind, parallel-design clinical trial in thirty-nine patients at two centers. Arthritis Rheum. 2000 Aug;43(8):1820–1830. doi: 10.1002/1529-0131(200008)43:8<1820::AID-ANR18>3.0.CO;2-D. [DOI] [PubMed] [Google Scholar]
  16. Mladenovic V., Domljan Z., Rozman B., Jajic I., Mihajlovic D., Dordevic J., Popovic M., Dimitrijevic M., Zivkovic M., Campion G. Safety and effectiveness of leflunomide in the treatment of patients with active rheumatoid arthritis. Results of a randomized, placebo-controlled, phase II study. Arthritis Rheum. 1995 Nov;38(11):1595–1603. doi: 10.1002/art.1780381111. [DOI] [PubMed] [Google Scholar]
  17. Scott D. L., Smolen J. S., Kalden J. R., van de Putte L. B., Larsen A., Kvien T. K., Schattenkirchner M., Nash P., Oed C., Loew-Friedrich I. Treatment of active rheumatoid arthritis with leflunomide: two year follow up of a double blind, placebo controlled trial versus sulfasalazine. Ann Rheum Dis. 2001 Oct;60(10):913–923. doi: 10.1136/ard.60.10.913. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Smolen J. S., Kalden J. R., Scott D. L., Rozman B., Kvien T. K., Larsen A., Loew-Friedrich I., Oed C., Rosenburg R. Efficacy and safety of leflunomide compared with placebo and sulphasalazine in active rheumatoid arthritis: a double-blind, randomised, multicentre trial. European Leflunomide Study Group. Lancet. 1999 Jan 23;353(9149):259–266. doi: 10.1016/s0140-6736(98)09403-3. [DOI] [PubMed] [Google Scholar]
  19. Strand V., Cohen S., Schiff M., Weaver A., Fleischmann R., Cannon G., Fox R., Moreland L., Olsen N., Furst D. Treatment of active rheumatoid arthritis with leflunomide compared with placebo and methotrexate. Leflunomide Rheumatoid Arthritis Investigators Group. Arch Intern Med. 1999 Nov 22;159(21):2542–2550. doi: 10.1001/archinte.159.21.2542. [DOI] [PubMed] [Google Scholar]
  20. Vandooren Bernard, Kruithof Elli, Yu David T. Y., Rihl Markus, Gu Jieruo, De Rycke Leen, Van Den Bosch Filip, Veys Eric M., De Keyser Filip, Baeten Dominique. Involvement of matrix metalloproteinases and their inhibitors in peripheral synovitis and down-regulation by tumor necrosis factor alpha blockade in spondylarthropathy. Arthritis Rheum. 2004 Sep;50(9):2942–2953. doi: 10.1002/art.20477. [DOI] [PubMed] [Google Scholar]
  21. Zou Jianxiang, Rudwaleit Martin, Brandt Jan, Thiel Andreas, Braun Jürgen, Sieper Joachim. Down-regulation of the nonspecific and antigen-specific T cell cytokine response in ankylosing spondylitis during treatment with infliximab. Arthritis Rheum. 2003 Mar;48(3):780–790. doi: 10.1002/art.10847. [DOI] [PubMed] [Google Scholar]
  22. van Denderen J. Christiaan, van der Horst-Bruinsma Irene, Bezemer P. Dick, Dijkmans Ben A. C. Efficacy and safety of mesalazine (Salofalk) in an open study of 20 patients with ankylosing spondylitis. J Rheumatol. 2003 Jul;30(7):1558–1560. [PubMed] [Google Scholar]
  23. van der Horst-Bruinsma I. E., Clegg D. O., Dijkmans B. A. C. Treatment of ankylosing spondylitis with disease modifying antirheumatic drugs. Clin Exp Rheumatol. 2002 Nov-Dec;20(6 Suppl 28):S67–S70. [PubMed] [Google Scholar]
  24. van der Linden S., Valkenburg H. A., Cats A. Evaluation of diagnostic criteria for ankylosing spondylitis. A proposal for modification of the New York criteria. Arthritis Rheum. 1984 Apr;27(4):361–368. doi: 10.1002/art.1780270401. [DOI] [PubMed] [Google Scholar]
  25. van der Linden S., van Tubergen A., Hidding A. Physiotherapy in ankylosing spondylitis: what is the evidence? Clin Exp Rheumatol. 2002 Nov-Dec;20(6 Suppl 28):S60–S64. [PubMed] [Google Scholar]

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