title: The effects of oral liarozole on epidermal proliferation and differentiation in severe plaque psoriasis are comparable with those of acitretin.
abstract: The imidazole derivative liarozole is a potent inhibitor of cytochrome P450-dependent 4-hydroxylation of endogenous all-trans retinoic acid, thereby increasing the levels of all-trans retinoic acid in both plasma and skin. As part of a large, double-blind, randomized clinical study, we investigated the cell biological alterations in uninvolved and lesional skin of 20 patients with severe plaque psoriasis, who were treated with either liarozole or acitretin. The extent and severity of the skin lesions, as recorded by the Psoriasis Area and Severity Index score, was significantly reduced (P </=0.05) after 12 weeks of treatment in both the acitretin- and the liarozole-treated group. A significant decrease in the markers for inflammation (neutrophils), epidermal proliferation (Ki-67-positive cells), normal differentiation (transglutaminase) and abnormal differentiation [cytokeratin 16 and skin-derived antileucoproteinase (SKALP), also known as elafin] was seen in both groups. No significant differences were noted in clinical scores or cell biological scores between the liarozole- and acitretin-treated group. None of the markers returned to the levels seen in uninvolved skin or in normal human skin. The expression of epidermal fatty acid binding protein (E-FABP) was only minimally decreased after 12 weeks of treatment, a substantial part of the stratum spinosum remaining positive. SKALP levels in serum fell in both groups with similar kinetics and showed a statistically significant correlation with clinical scores. A remarkable finding in the uninvolved skin of patients treated with liarozole or acitretin was the distinct focal expression of SKALP in the granular layer and the expression of E-FABP in the spinous layers, which is not found in normal human skin. Although the mechanism of action differs fundamentally, liarozole and acitretin show similar effects with respect to clinical effects and cell biological changes in the lesional and non-lesional skin.
authors.affiliation: Department of Dermatology, University Hospital Nijmegen, The Netherlands. a.kuijpers@derma.azn.nl
authors.forename: A L
authors.initials: AL
authors.lastname: Kuijpers
authors.forename: J P
authors.initials: JP
authors.lastname: Van Pelt
authors.forename: M
authors.initials: M
authors.lastname: Bergers
authors.forename: P J
authors.initials: PJ
authors.lastname: Boegheim
authors.forename: J E
authors.initials: JE
authors.lastname: Den Bakker
authors.forename: G
authors.initials: G
authors.lastname: Siegenthaler
authors.forename: P C
authors.initials: PC
authors.lastname: Van de Kerkhof
authors.forename: J
authors.initials: J
authors.lastname: Schalkwijk
mesh_terms: D017255:Acitretin / Q000627:therapeutic use*; D000284:Administration, Oral; D000328:Adult; D000368:Aged; D002454:Cell Differentiation / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D004311:Double-Blind Method; D004817:Epidermis / Q000187:drug effects* / Q000473:pathology; D005260:Female; D006801:Humans; D007093:Imidazoles / Q000008:administration & dosage* / Q000494:pharmacology; D007124:Immunoenzyme Techniques; D007641:Keratolytic Agents / Q000008:administration & dosage* / Q000494:pharmacology; D007958:Leukocyte Count / Q000187:drug effects; D008297:Male; D008875:Middle Aged; D053491:Proteinase Inhibitory Proteins, Secretory; D011506:Proteins / Q000378:metabolism; D011565:Psoriasis / Q000188:drug therapy* / Q000473:pathology; D015842:Serine Proteinase Inhibitors / Q000097:blood