diethyl-fumarate and Psoriasis

Psoriasis is an autoimmune disease affecting 2-4% of the Caucasian population. Inflammatory processes induce the migration of interferon (IFN) gamma producing Th1 lymphocytes into the skin. These play a key role in the pathogenesis of psoriasis. These Th1 lymphocytes are responsible for the pathological reactions in psoriatic skin leading to keratinocyte hyperproliferation, small vessel proliferation and neutrophilic infiltration. Antigen-presenting cells activate dermal CD4+ T lymphocytes, and various signals can support the polarization of Th1 responses. The main signal for Th1 development is interleukin (IL) 12. After binding to their receptors both IL-12 and IFN-gamma promote intracellular IFN-gamma production by activating signal transducer and activator of transcription (STAT) 4 or 1. STAT1 activation by IFN-gamma is followed by T-bet activation, a master transcription factor for Th1 lymphocytes. In experimental models of Th1-mediated autoimmune diseases immune deviation of polarized autoreactive Th1 into anti-inflammatory Th2 responses generally improves the disease. Therefore new therapeutic approaches based on immunomodulating molecules have been developed for psoriasis, a prototypical Th1-mediated autoimmune disorder. Recently IL-4, the most effective Th2-inducing cytokine, has been shown to be safe and efficient for treating psoriasis. Improvement was associated with the induction of a Th2 phenotype of skin infiltrating lymphocytes. This review summarizes the IL-4 inducing potential of various conventional and newer systemic therapies for psoriasis. Many of these were thought to be primarily immunosuppressive. A review of the literature reveals that most of them can induce IL-4 and Th2, and that Th2 induction may be an underestimated mode of action in the therapy of Th1-mediated autoimmune disease. Further studies are needed to determine the central role of IL-4 in the control of Th1-induced autoimmune disease, namely psoriasis.

Topics: Cholecalciferol; Cyclosporine; Cytokines; Fumarates; Humans; Inflammation Mediators; Interleukin-4; Methotrexate; Phototherapy; Psoriasis; Th1 Cells; Th2 Cells; Vitamin A

Fumaric acid, fumaric acid dimethylester, and the dithranol derivative C4-lactone were studied in the mouse tail test to evaluate their effects on epidermal cell differentiation compared with other topical antipsoriatic drugs, such as betamethasone, calcipotriol, and dithranol. Mouse tails were treated for 2 weeks and longitudinal histological sections prepared of the tail skin. The length of the orthokeratotic regions (stratum granulosum) was measured on 10 sequential scales per tail and expressed as percentage of the full length of the scale. In addition, epidermal thickness was measured and the efficacy of the various compounds evaluated. In comparison to 2% salicylic acid ointment, all tested compounds except fumaric acid significantly (p < or = 0.05) increased the proportion of the orthokeratotic region. C4-lactone and calcipotriol were less effective than dithranol, fumaric acid dimethylester only moderately influenced cell differentiation, and betamethasone showed the least potent effect. Dithranol was the most potent substance inducing orthokeratosis without increasing epidermal thickness.

Topics: Administration, Topical; Animals; Anti-Inflammatory Agents; Anticarcinogenic Agents; Cell Differentiation; Epidermal Cells; Epidermis; Fumarates; Keratosis; Male; Mice; Psoriasis; Tail

Fumaric acid may not be regarded as an antipsoriatic drug. Beneficial effects on psoriatic lesions may be explained by secondary changes such as the acidification of gastric juice in cases of anacidity or hypacidity . Monoethylfumarate exerts true antipsoriatic activities but is by far too toxic for clinical use. Experimental investigations have confirmed an inhibitory action of the above-mentioned fumarate on nucleic acid synthesis and protein synthesis of PHA-stimulated human lymphocytes.

Topics: DNA; Fumarates; Gastric Acidity Determination; Humans; Proteins; Psoriasis