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Selected Publication:
Benezeder, T.
Dithranol in psoriasis and beyond
PhD-Studium (Doctor of Philosophy); Humanmedizin; [ Dissertation ] Medical University of Graz; 2021. pp. 114
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- Authors Med Uni Graz:
- Benezeder Theresa Helena
- Advisor:
- Eller Kathrin
- Strobl Herbert
- Wolf Peter
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- Abstract:
- Recently, treatment of severe psoriasis has improved considerably with targeted therapy using antibodies against key cytokines. However, not much treatment innovation has occurred for mild forms of psoriasis, although these patients account for the majority of cases. Dithranol has been used to treat psoriasis since 1916 and still remains among the most effective topical treatment options, although its exact mechanism of action has never been fully explained. In psoriasis, successful treatment with dithranol or other agents leads to complete clearance of psoriatic lesions, but they are likely to recur at the exact same body sites after treatment cessation. It is still unknown what is left behind at the molecular or cellular level that can potentially trigger psoriasis flare-ups. The aim of this thesis was to scrutinize dithranol’s mechanism of action in psoriasis and to study the skin’s physiologic response to dithranol. Moreover, this thesis combines novel data with existing literature to answer the question what is left behind after clinical resolution of psoriasis. A clinical trial with 15 psoriasis patients subjected to topical dithranol treatment was conducted and several animal models like the c-Jun/JunB and imiquimod psoriasis model were employed. Microarray analysis showed that top differentially expressed genes in the early response to dithranol belonged to epidermal and keratinocyte differentiation pathways and IL-36 family, but not those of the IL-17/IL-23 axis. In psoriasis patients, dithranol led to a fast decrease in expression of keratinocyte differentiation genes, anti-microbial peptides (AMPs), chemoattractants for neutrophils and neutrophil cell counts that was followed with much delay by reduced T cell counts. To study the skin’s physiological response to dithranol, normal murine skin as well as xenografted human skin was analyzed. Here, dithranol increased mRNA expression of AMPs, keratinocyte differentiation markers and inflammatory cytokines. These transcriptional changes were paralleled by inflammation, disturbed skin barrier and epidermal hyperproliferation. Elucidating dithranol’s mechanism of action provided potential new targets for future treatment strategies. Early inhibition of the keratinocyte-neutrophil crosstalk and inhibiting the IL-36 pathway is crucial for dithranol’s fast anti-psoriatic effect. In addition, promising targets are keratinocyte differentiation regulators and AMPs. In healthy skin, dithranol elicits a contact response and disturbed barrier which may lead via anti-microbial peptides and cytokines like IL-1β to an immune suppressive environment. This could be beneficial in treating alopecia areata, a disease with seemingly normal epidermis besides altered hair follicles. Furthermore, extensive literature review revealed that molecular imprints in psoriatic skin do not entirely resolve, even after clearance of lesions is achieved clinically and various different treatment options seem to elicit a similar molecular response. A fast decrease in keratinocyte differentiation genes and epidermal hyperproliferation is paralleled by reduced expression of keratinocyte-derived anti-microbial peptides and chemotactic factors for neutrophils and neutrophil cell counts quickly diminish. Although dithranol suppresses expression of inflammatory genes, there is only a delayed effect on T cell counts in the skin. Thus, inhibition of the crosstalk between keratinocytes and neutrophils is one of the most important early steps of successful anti-psoriatic therapy.