The irritative response of uninvolved skin is a serious limitation of dithranol therapy in psoriasis. A characterisation in cell biological terms may be helpful in finding an effective counteraction to this well-known irritation. Therefore, we studied the effect of single and repeated applications of dithranol on normal human skin. Besides a clinical evaluation, we studied aspects of epidermal proliferation, differentiation and inflammation. On day 2, after single dithranol challenge, we observed an induction of both the cornified envelope precursor protein involucrin and the cross-linking enzyme transglutaminase I. Subsequently, epidermal hyperproliferation was observed with a maximum on day 8. The epidermal response to dithranol appears to be a reinforcement of the barrier function. Remarkably, however, filaggrin was found to be decreased. Profilaggrin breakdown might be an attempt to compensate for xerosis of uninvolved skin that accompanies dithranol therapy. T lymphocytes and to a lesser extent polymorphonucleocytes were found to be significantly increased. The reduction of Langerhans cells suggests a dose-dependent toxic effect of dithranol or one of its metabolites on Langerhans cells. The dynamics in the induction of changes after repeated challenge are comparable with those after single challenge. However, the induction of hyperproliferation following repeated application appeared to continue between day 8 and 12. Based on the dynamics of dithranol-induced irritation, it may be of interest to study the efficacy of intermittent dithranol treatment. Our results indicate that an optimal timing for biopsies in future dithranol irritation studies lies between 4 and 8 days after the first dithranol challenge.

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