The power of fumaric acid esters in psoriasis treatment

Fumarates are derivatives of fumaric acid and have been used empirically in the treatment of psoriasis for decades. We have identified Dimethylfumarate (DMF) as the most effective of all fumarates tested so far. This substance has been shown to be antiproliferative, antiinflammatory and immunomodulatory in many different cells in vitro.

We could show that the effect of DMF in endothelial cells is mediated specifically by inhibiting the NF-κB signaling cascade. DMF inhibits the expression only of NF-κB dependent proteins, by impairing nuclear import of active NF-κB dimers. Although the observed effects are clearly NF-κB dependent, the precise mode of action still remains obscure. Nevertheless, the observed inhibition of NF-κB of DMF might be an attractive new therapeutic option in the treatment of many different malignant and chronic inflammatory diseases.

In subsequent studies we were able to demonstrate DMF as a promising therapeutic substance in animal models for human melanoma; DMF inhibits NF-κB-dependent gene expression, reduces tumor growth and metastasis.

DMF also has been shown to be safe even in the long-term treatment of human psoriasis patients. The characteristics described above justify the initiation of clinical trials in human patients with malignant melanoma; a first trial is currently being planned.

Publications

• Dimethylfumarate inhibits TNF-induced nuclear entry of NF-kappa B/p65 in human endothelial cells.
  Loewe R, Holnthoner W, Gröger M, Pillinger M, Gruber F, Mechtcheriakova D, Hofer E, Wolff K, Petzelbauer P. J Immunol. 2002 May 1;168(9):4781-7.
• Dimethylfumarate inhibits tumor-necrosis-factor-induced CD62E expression in an NF-kappa B-dependent manner.
  Loewe R, Pillinger M, de Martin R, Mrowietz U, Gröger M, Holnthoner W, Wolff K, Wiegrebe W, Jirovsky D, Petzelbauer P. J Invest Dermatol. 2001 Dec;117(6):1363-8.

Team

• Robert Loewe, M.D.
• Teresa Valero, M.D.
• Sylvia Steele, M.Sc.