Dimethylfumarate for psoriasis: more than a dietary curiosity.

Fumaric acid esters (FAEs) have been used for the oral treatment of psoriasis since 1959 and have been registered for this indication in Germany since 1994. Dimethylfumarate (DMF) and its metabolite methylhydrogenfumarate (MHF) are the pharmacologically active compounds, with DMF being the main component of the marketed FAE-mixture. However, the mechanism of action of FAE is yet to be fully understood. It has been shown that DMF inhibits NFkappaB translocation, which leads to (i) the inhibition of pro-inflammatory cytokine production and adhesion molecule expression, (ii) the inhibition of dendritic cell differentiation and, at higher concentrations, (iii) the induction of apoptosis. Recent evidence also shows that these effects are mediated through the interference of the intracellular redox system by DMF. Here, the mode of action of FAE and its clinical use for psoriasis will be discussed.

[1]  H. Perlman,et al.  Macrophages Require Constitutive NF-κB Activation To Maintain A1 Expression and Mitochondrial Homeostasis , 2000, Molecular and Cellular Biology.

[2]  Altmeyer,et al.  Treatment of psoriasis with fumaric acid esters: results of a prospective multicentre study , 1998, The British journal of dermatology.

[3]  J Geysen,et al.  Dimethylfumarate is an inhibitor of cytokine-induced E-selectin, VCAM-1, and ICAM-1 expression in human endothelial cells. , 1997, Biochemical and biophysical research communications.

[4]  P. Altmeyer,et al.  Treatment of severe psoriasis with fumaric acid esters: scientific background and guidelines for therapeutic use , 1999, The British journal of dermatology.

[5]  P. Nibbering,et al.  Monomethylfumarate affects polarization of monocyte‐derived dendritic cells resulting in down‐regulated Th1 lymphocyte responses , 2004, European journal of immunology.

[6]  A. Barchowsky,et al.  Arsenic induces oxidant stress and NF-kappa B activation in cultured aortic endothelial cells. , 1996, Free radical biology & medicine.

[7]  M. Merville,et al.  Constitutive nuclear factor-kappaB activity preserves homeostasis of quiescent mature lymphocytes and granulocytes by controlling the expression of distinct Bcl-2 family proteins. , 2002, Blood.

[8]  J. Prinz.  Psoriasis vulgaris – a sterile antibacterial skin reaction mediated by cross‐reactive T cells? An immunological view of the pathophysiology of psoriasis , 2001, Clinical and experimental dermatology.

[9]  K. Held,et al.  Effect of dimethyl fumarate on the radiation sensitivity of mammalian cells in vitro. , 1988, Radiation research.

[10]  P. Altmeyer,et al.  Verlaufsbeobachtungen der Lymphozytensubpopulationen bei Psoriasis-Patientent unter oraler Therapie mit Fumaraten , 1996 .

[11]  A. Menssen,et al.  Dominant lesional T cell receptor rearrangements persist in relapsing psoriasis but are absent from nonlesional skin: evidence for a stable antigen-specific pathogenic T cell response in psoriasis vulgaris. , 2001, The Journal of investigative dermatology.

[12]  T. Ottenhoff,et al.  Selective stimulation of T helper 2 cytokine responses by the anti‐psoriasis agent monomethylfumarate , 1996, European journal of immunology.

[13]  G. Zupi,et al.  Glutathione Influences c-Myc-induced Apoptosis in M14 Human Melanoma Cells* , 2002, The Journal of Biological Chemistry.

[14]  R. Willemze,et al.  Long‐term safety aspects of systemic therapy with fumaric acid esters in severe psoriasis , 2003, The British journal of dermatology.

[15]  K Wolff,et al.  Dimethylfumarate inhibits tumor-necrosis-factor-induced CD62E expression in an NF-kappa B-dependent manner. , 2001, The Journal of investigative dermatology.

[16]  S. R. Spencer,et al.  Induction of glutathione transferases and NAD(P)H:quinone reductase by fumaric acid derivatives in rodent cells and tissues. , 1990, Cancer research.

[17]  J. Finke,et al.  Inhibition of NF-kappa B activity in human T lymphocytes induces caspase-dependent apoptosis without detectable activation of caspase-1 and -3. , 1999, Journal of immunology.

[18]  Ockenfels,et al.  The antipsoriatic agent dimethylfumarate immunomodulates T‐cell cytokine secretion and inhibits cytokines of the psoriatic cytokine network , 1998, The British journal of dermatology.

[19]  H. Gollnick,et al.  Dimethylfumarat ist unter den Fumaderm®-Inhaltsstoffen der stärkste Induktor von Apoptose-Phänomenen in lympho-histiozytären U-937-Zellen , 2000 .

[20]  U. Mrowietz,et al.  Inhibition of dendritic cell differentiation by fumaric acid esters. , 2001, The Journal of investigative dermatology.

[21]  A. Ormerod,et al.  Fumaric acid esters, their place in the treatment of psoriasis , 2004, The British journal of dermatology.

[22]  T. Zollner,et al.  Pulling the trigger on psoriasis , 1996, Nature.

[23]  K. Wolff,et al.  Dimethylfumarate inhibits TNF-induced nuclear entry of NF-kappa B/p65 in human endothelial cells. , 2002, Journal of immunology.

[24]  J. Geysen,et al.  Dimethylfumarate is an inhibitor of cytokine-induced nuclear translocation of NF-kappa B1, but not RelA in normal human dermal fibroblast cells. , 2001, The Journal of investigative dermatology.

[25]  C. Nieboer,et al.  Systemic therapy with fumaric acid derivates: new possibilities in the treatment of psoriasis. , 1989, Journal of the American Academy of Dermatology.

[26]  Felix Treumer,et al.  Dimethylfumarate is a potent inducer of apoptosis in human T cells. , 2003, The Journal of investigative dermatology.

[27]  T. Murphy,et al.  Activation of Endogenous Antioxidant Defenses in Neuronal Cells Prevents Free Radical‐Mediated Damage , 1998, Journal of neurochemistry.

[28]  P. Altmeyer,et al.  Fumaric acid esters (FAEs) suppress CD 15- and ODP 4-positive cells in psoriasis. , 1994, Acta dermato-venereologica. Supplementum.

[29]  J. Flier,et al.  The antipsoriatic drug dimethylfumarate strongly suppresses chemokine production in human keratinocytes and peripheral blood mononuclear cells , 2001, The British journal of dermatology.

[30]  P. Altmeyer,et al.  Fumaric Acid Esters Suppress Peripheral CD4- and CD8-Positive Lymphocytes in Psoriasis , 1998, Dermatology.

[31]  P. Frosch,et al.  Antipsoriatic effect of fumaric acid derivatives. Results of a multicenter double-blind study in 100 patients. , 1994, Journal of the American Academy of Dermatology.

[32]  R. Blank,et al.  Effect of fumaric acid and dietary buffering capacity on ileal and fecal amino acid digestibilities in early-weaned pigs. , 1999, Journal of animal science.

[33]  James T. Elder,et al.  The genetics of psoriasis 2001: the odyssey continues. , 2001, Archives of dermatology.

[34]  J. Finke,et al.  Inhibition of NF-κB Activity in Human T Lymphocytes Induces Caspase-Dependent Apoptosis Without Detectable Activation of Caspase-1 and -3 , 1999, The Journal of Immunology.

[35]  T. Kavanagh,et al.  Effect of dietary inducer dimethylfumarate on glutathione in cultured human retinal pigment epithelial cells. , 1999, Investigative ophthalmology & visual science.

[36]  T. Pellmar,et al.  Role of glutathione in repair of free radical damage in hippocampus in vitro , 1992, Brain Research.

[37]  P. Nibbering,et al.  Pharmacokinetics of oral fumarates in healthy subjects. , 2004, British journal of clinical pharmacology.

[38]  O. FitzGerald,et al.  Immunolocalization of adhesion molecules in psoriatic arthritis, psoriatic and normal skin , 1995, The British journal of dermatology.

[39]  K. Asadullah,et al.  Influence of monomethylfumarate on monocytic cytokine formation – explanation for adverse and therapeutic effects in psoriasis? , 1997, Archives of Dermatological Research.

[40]  Neil Kaplowitz,et al.  Reduced glutathione depletion causes necrosis and sensitization to tumor necrosis factor‐α–induced apoptosis in cultured mouse hepatocytes , 2002, Hepatology.

[41]  S. Wolffram,et al.  Presystemic metabolism and intestinal absorption of antipsoriatic fumaric acid esters , 2003, Biopharmaceutics & drug disposition.

[42]  C. Haslett,et al.  NF-κB Activation Is a Critical Regulator of Human Granulocyte Apoptosis in Vitro* , 1999, The Journal of Biological Chemistry.

[43]  A. Perl,et al.  Metabolic switches of T-cell activation and apoptosis. , 2002, Antioxidants & redox signaling.

[44]  J. Berth-Jones,et al.  Fumaric acid esters in severe psoriasis, including experience of use in combination with other systemic modalities , 2004, The British journal of dermatology.

[45]  E. Christophers,et al.  Disease concomitance in psoriasis. , 1995, Journal of the American Academy of Dermatology.