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Digestive Diseases and Sciences

, Volume 53, Issue 4, pp 1025–1032 | Cite as

Treatment of Crohn’s Disease with Leflunomide as Second-Line Immunosuppression

A Phase 1 Open-Label Trial on Efficacy, Tolerability and Safety
  • Martin H. Holtmann
  • Anna-Lena Gerts
  • Arndt Weinman
  • Peter R. Galle
  • Markus F. NeurathEmail author
Original Paper

Abstract

The aim of this study was to assess the potential of leflunomide, an immunosuppressant in rheumatoid arthritis, as a second-line immunosuppression treatment of patients with Crohn's disease refractory or intolerant to azathioprine. The study cohort consisted of 24 patients. The primary end point was steroid-free remission, and secondary end points were changes in the Crohn's disease activity index (CDAI) and steroid intake, responsiveness of arthralgias and adverse events. Results were expressed in medians (quartiles). The remission rate increased from 21 to 42% by week 16 (P < 0.05). In the intention-to-treat analysis, the CDAI decreased from 219 to 87 (P = 0.018) and the steroid intake from 25 to 3 mg/day (P = 0.033). In the per-protocol analysis, the CDAI decreased from 182 to 87 (P = 0.0183) and the steroid intake from 45 to 4 mg/day (P = 0.0778). Patients with arthralgias improved significantly. However, adverse side effects were frequent. Leflunomide may improve disease activity, especially in terms of arthralgias, and reduce steroid intake. Adverse events were more frequent in our patients than has been reported in controlled studies for rheumatoid arthritis but corresponded to those found in post-marketing studies.

Keywords

Crohn’s disease Immunosuppression Leflunomide Open-label trial 

References

  1. 1.
    Loftus EV Jr (2004) Clinical epidemiology of inflammatory bowel disease: Incidence, prevalence, and environmental influences. Gastroenterology 126:1504–1517PubMedCrossRefGoogle Scholar
  2. 2.
    Shanahan F (2002) Crohn’s disease. Lancet 359:62–69PubMedCrossRefGoogle Scholar
  3. 3.
    Neurath MF, Finotto S, Glimcher LH (2002) The role of Th1/Th2 polarization in mucosal immunity. Nat Med 8:567–573PubMedCrossRefGoogle Scholar
  4. 4.
    Egan LJ, Sandborn WJ (2004) Advances in the treatment of Crohn’s disease. Gastroenterology 126:1574–1581PubMedCrossRefGoogle Scholar
  5. 5.
    Loftus EV Jr, Silverstein MD, Sandborn WJ, Tremaine WJ, Harmsen WS, Zinsmeister AR (1998) Crohn’s disease in Olmsted County, Minnesota, 1940–1993: incidence, prevalence, and survival. Gastroenterology 114:1161–1168PubMedCrossRefGoogle Scholar
  6. 6.
    Sandborn W, Sutherland L, Pearson D, May G, Modigliani R, Prantera C (2000) Azathioprine or 6-mercaptopurine for inducing remission of Crohn’s disease. Cochrane Database Syst Rev CD000545Google Scholar
  7. 7.
    Sandborn WJ, Sutherland L, Pearson DC, May GR, Modigliani R, Prantera C (1999) Azathioprine or 6-mercaptopurine for inducing remission of Crohn’s disease (Cochrane review). In: The Cochrane Library. John Wiley & Sons, ChichesterGoogle Scholar
  8. 8.
    Connell WR, Kamm MA, Ritchie JK, Lennard-Jones JE (1993) Bone marrow toxicity caused by azathioprine in inflammatory bowel disease: 27 years of experience. Gut 34:1081–1085PubMedCrossRefGoogle Scholar
  9. 9.
    Connell WR, Kamm MA, Dickson M, Balkwill AM, Ritchie JK, Lennard-Jones JE (1994) Long-term neoplasia risk after azathioprine treatment in inflammatory bowel disease. Lancet 343:1249–1252PubMedCrossRefGoogle Scholar
  10. 10.
    Haber CJ, Meltzer SJ, Present DH, Korelitz BI (1986) Nature and course of pancreatitis caused by 6-mercaptopurine in the treatment of inflammatory bowel disease. Gastroenterology 91:982–986PubMedGoogle Scholar
  11. 11.
    Alfadhli AA, McDonald JW, Feagan BG (2005) Methotrexate for induction of remission in refractory Crohn’s disease. Cochrane Database Syst Rev CD003459Google Scholar
  12. 12.
    Neurath MF, Wanitschke R, Peters M, Krummenauer F, Meyer zum Buschenfelde KH, Schlaak JF (1999) Randomised trial of mycophenolate mofetil versus azathioprine for treatment of chronic active Crohn’s disease. Gut 44:625–628PubMedCrossRefGoogle Scholar
  13. 13.
    Mladenovic V, Domljan Z, Rozman B, Jajic I, Mihajlovic D, Dordevic J, Popovic M, Dimitrijevic M, Zivkovic M, Campion G et al. (1995) 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 38:1595–1603PubMedCrossRefGoogle Scholar
  14. 14.
    Weinblatt ME, Kremer JM, Coblyn JS, Maier AL, Helfgott SM, Morrell M, Byrne VM, Kaymakcian MV, Strand V (1999) Pharmacokinetics, safety, and efficacy of combination treatment with methotrexate and leflunomide in patients with active rheumatoid arthritis. Arthritis Rheum 42:1322–1328PubMedCrossRefGoogle Scholar
  15. 15.
    Strand V, Scott DL, Emery P, Kalden JR, Smolen JS, Cannon GW, Tugwell P, Crawford B (2005) Physical function and health related quality of life: analysis of 2-year data from randomized, controlled studies of leflunomide, sulfasalazine, or methotrexate in patients with active rheumatoid arthritis. J Rheumatol 32:590–601PubMedGoogle Scholar
  16. 16.
    Emery P, Breedveld FC, Lemmel EM, Kaltwasser JP, Dawes PT, Gomor B, Van Den Bosch F, Nordstrom D, Bjorneboe O, Dahl R, Horslev-Petersen K, Rodriguez De La Serna A, Molloy M, Tikly M, Oed C, Rosenburg R, Loew-Friedrich I (2000) A comparison of the efficacy and safety of leflunomide and methotrexate for the treatment of rheumatoid arthritis. Rheumatology 39:655–665PubMedCrossRefGoogle Scholar
  17. 17.
    Davis JP, Cain GA, Pitts WJ, Magolda RL, Copeland RA (1996) The immunosuppressive metabolite of leflunomide is a potent inhibitor of human dihydroorotate dehydrogenase. Biochemistry 35:1270–1273PubMedCrossRefGoogle Scholar
  18. 18.
    Fox RI, Herrmann ML, Frangou CG, Wahl GM, Morris RE, Strand V, Kirschbaum BJ (1999) Mechanism of action for leflunomide in rheumatoid arthritis. Clin Immunol 93:198–208PubMedCrossRefGoogle Scholar
  19. 19.
    Prajapati DN, Knox JF, Emmons J, Saeian K, Csuka ME, Binion DG (2003) Leflunomide treatment of Crohn’s disease patients intolerant to standard immunomodulator therapy. J Clin Gastroenterol 37:125–128PubMedCrossRefGoogle Scholar
  20. 20.
    Holtmann M, Krummenauer F, Claas C., Kremeyer K, Lorenz D, Rainer O, Vogel I, Boecker U, Boehm S, Buening C, Duchmann R, Gerken G, Herfarth H., Luegering N, Kruis W, Reinshagen M, Schmidt J, Stallmach A, Stein J, Sturm A, Galle PR, Hommes DW, D’Haens G, Rutgeerts P, Neurath MF (2006) Long-term effectiveness of azathioprin in IBD beyond 4 years: a European multicener study in 1176 patients. Dig Dis Sci 51:1516–1524PubMedCrossRefGoogle Scholar
  21. 21.
    Tiede I, Fritz G, Strand S, Poppe D, Dvorsky R, Strand D, Lehr HA, Wirtz S, Becker C, Atreya R, Mudter J, Hildner K, Bartsch B, Holtmann M, Blumberg R, Walczak H, Iven H, Galle P, Ahmadian MR, Neurath MF (2003) CD28-dependent Rac1 activation is the molecular target of azathioprine in primary human CD4+ T lymphocytes. J Clin Invest 111:1133–1145Google Scholar
  22. 22.
    Choy EH, Panayi GS (2001) Cytokine pathways and joint inflammation in rheumatoid arthritis. N Engl J Med 344:907–916PubMedCrossRefGoogle Scholar
  23. 23.
    Erra A, Tomas C, Barcelo P, Vilardell M, Marsal S (2003) Is the recommended dose of leflunomide the best regimen to treat rheumatoid arthritis patients? Rheumatology 42:1123–1124PubMedCrossRefGoogle Scholar
  24. 24.
    Siva C, Eisen SA, Shepherd R, Cunningham F, Fang MA, Finch W, Salisbury D, Singh JA, Stern R, Zarabadi SA (2003) Leflunomide use during the first 33 months after food and drug administration approval: experience with a national cohort of 3,325 patients. Arthritis Rheum 49:745–751PubMedCrossRefGoogle Scholar
  25. 25.
    Martin K, Bentaberry F, Dumoulin C, Dehais J, Haramburu F, Begaud B, Schaeverbeke T (2005) Effectiveness and safety profile of leflunomide in rheumatoid arthritis: actual practice compared with clinical trials. Clin Exp Rheumatol 23:80–84PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2007

Authors and Affiliations

  • Martin H. Holtmann
    • 1
  • Anna-Lena Gerts
    • 1
  • Arndt Weinman
    • 1
  • Peter R. Galle
    • 1
  • Markus F. Neurath
    • 1
    • 2
    Email author
  1. 1.1st Department of MedicineJohannes Gutenberg-UniversityMainzGermany
  2. 2.I. Medical ClinicUniversity of MainzMainzGermany

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