Abstract
The effects of the new immunomodulating isoxazol derivative leflunomide, in comparison with cyclosporin A, on established antigen-induced arthritis in rats as well as serum antibody levels were determined. When treatment with leflunomide, at concentrations from 2.5 to 10 mg/kg/d, was started on day 3 of arthritis, the acute and chronic phases of arthritis were effectively inhibited. This was demonstrated by decreased joint swelling and reduced histopathological arthritis score at the end of experiment (day 26). Furthermore, the treatment resulted in a significantly reduced level of serum antibodies to the matrix components collagen type I, type II and proteoglycans. Neither leflunomide nor cyclosporin A, at doses of 1 mg/kg/d, had an effect on the severity of arthritis and antibody levels. However, when both drugs were used together, at these non-effective doses, the histopathological score of chronic arthritis was significantly reduced. The results of our experiments demonstrate that leflunomide has a strong suppressive effect on both acute and chronic phases of antigen-induced arthritis and formation of autoantibodies in rats. Furthermore, orally administered doses of leflunomide were as effective as doses of cyclosporin A given intraperitoneally. The combination of sub-effective doses of leflunomide and cyclosporin A resulted in significant inhibition of chronic arthritis.
Article PDF
Similar content being viewed by others
Avoid common mistakes on your manuscript.
References
Bartlett RR, Schleyerbach R. Immunopharmacological profile of a novel isoxazol derivative, HWA 486, with potential antirheumatic activity. I. Disease modifying action on adjuvant arthritis of the rat. Int J Immunopharmacol 1985;7:7–18.
Pasternak RD, Wadopian NS, Wright RN, Siminoff P, Gylys JA, Buyniski JP. Disease modifying activity of HWA 486 in rat adjuvant-induced arthritis. Agents Actions 1987;21:241–3.
Hambleton P, McMahon S. Drug actions on delayed-type hypersensitivity in rats with developing and established adjuvant arthritis. Agents Actions 1990;29:328–32.
Glant TT, Mikecz K, Bartlett RR, Deak F, Thonar EJMA, Williams JM, et al. Immunomodulation of proteoglycan-induced progressive polyarthritis by leflunomide. Immunopharmacology 1992;23:105–16.
Seifert H, Misikic P, Oed C, Löw-Friedrich I, Campion G. Clinical experience with leflunomide in patients with rheumatoid arthritis (RA). In: Bartlett RR, editor. Leflunomide. Proc Vienna Symp. Basel: Birkhäuser, 1993: p A5.
Dumonde DC, Glynn LE. The production of arthritis in rabbits by an immunological reaction to fibrin. Br J Exp Pathol 1962;43:373–83.
Brackertz D, Mitchell GF, Mackay IR. Antigen-induced arthritis in mice. I: Induction of arthritis in various strains of mice. Arthr Rheum 1977;20:841–50.
Dijkstra CD, Döpp EA, Vogels IMC, van Noorden CJF. Macrophages and dentritic cells in antigen-induced arthritis. An immunohistochemical study using cryostat sections of the whole knee joint of rat. Scand J Immunol 1987;26:513–23.
Griffith RJ. Characterisation and pharmacological sensitivity of antigen arthritis induced by methylated bovine serum albumin in the rat. Agents Actions 1992;35:88–95.
van den Berg WB, van de Putte LBA, Zwarts WA, Joosten LAB. Electrical charge of the antigen determines intraarticular antigen handling and chronicity of arthritis in mice. J Clin Invest 1984;74:1850–9.
Bräuer R, Kittlick PD, Thoss K, Henzgen S. Different immunological mechanisms contribute to cartilage destruction in antigen-induced arthritis. Exp Toxic Pathol 1994;46:383–8.
Hunneyball IM. The use of experimental arthritis in the rabbit for the development of antiarthritic drugs. Adv Inflamm Res 1984;7:249–62.
Bartlett RR, Anagnostopulos H, Zielinski T, Mattar T, Schleyerbach R. Effects of leflunomide on immune responses and models of inflammation. Springer Semin Immunopathol 1993;14:381–94.
Feutren G. Cyclosoprin A: recent developments in the mechanism of action and clinical application. Curr Opin Immunol 1989;2:239–45.
Blackham A, Griffith RJ. The effect of FK506 and cyclosporin A on antigen-induced arthritis. Clin Exp Immunol 1991;86: 224–8.
Bräuer R, Kette H, Henzgen S, Thoss K. Influence of cyclosporin A on cytokine levels in synovial fluid and serum of rats with antigen-induced arthritis. Agents Actions 1994;41:96–8.
Williams JW, Xiao F, Foster P, Clardy C, McChesney L, Sankary H, et al. Leflunomide in experimental transplantation. Control of rejection and alloantibody production, reversal of acute rejection, and interaction with cyclosporine. Transplantation 1994;57:1223–31.
McChesney LP, Xiao F, Sankary HN, Foster PF, Sharma S, Haklin M, et al. An evaluation of leflunomide in the canine renal transplantation model. Transplantation 1994;57:1717–22.
Xiao F, Chong AS Foster P, Sankary H, McChesney L, Koukoulis G, et al. Leflunomide controls rejection in hamster to rat cardiac xenografts. Transplantation 1994;58:828–34.
Bräuer R, Thoss K, Henzgen S. Humoral and cell-mediated sensitivity to cartilage constituents in mice with antigen-induced arthritis. In: van den Berg WB, van der Kraan PM, van Lent PLEM, editors. Joint Destruction in Arthritis and Osteoarthritis. Agents and Actions Suppl. Vol. 39. Basel: Birkhäuser, 1993:69–73.
Mattar T, Kochhar K, Bartlett R, Bremer EG, Finnegan A. Inhibition of the epidermal growth factor receptor tyrosine kinase activity by leflunomide. FEBS Letts 1993;334:161–4.
Zielinski T, Zeitter D, Müllner S Bartlett RR. Leflunomide, a reversible inhibitor of pyrimidine biosynthesis? Inflamm Res 1995;44:S207–8.
Cherwinski HM, Byars N, Ballaron SJ, Nakano GM, Young JM, Ransom JT. Leflunomide interferes with pyrimidine nucleotide biosynthesis. Inflamm Res 1995;44:317–22.
Author information
Authors and Affiliations
Additional information
accepted by M. J. Parnham
Rights and permissions
About this article
Cite this article
Thoss, K., Henzgen, S., Petrow, P.K. et al. Immunomodulation of rat antigen-induced arthritis by leflunomide alone and in combination with cyclosporin A. Inflamm Res 45, 103–107 (1996). https://doi.org/10.1007/BF02265123
Received:
Revised:
Accepted:
Issue Date:
DOI: https://doi.org/10.1007/BF02265123