PDE4 Inhibition as Potential Treatment of Epidermolysis Bullosa Acquisita

Hiroshi Koga, Andreas Recke, Gestur Vidarsson, Hendri H. Pas, Marcel F. Jonkman, Takashi Hashimoto, Anika Kasprick, Saeedeh Ghorbanalipoor, Hermann Tenor, Detlef Zillikens, Ralf J. Ludwig

Abstract

Pemphigoid diseases such as epidermolysis bullosa acquisita (EBA) may be difficult to treat. In pemphigoid diseases, mucocutaneous blistering is caused by autoantibodies to hemidesmosomal antigens; in EBA the autoantigen is type VII collagen. Despite growing insights into pemphigoid disease pathogenesis, corticosteroids are still a mainstay of treatment. In experimental EBA, myeloid cell activation is a key event leading to blistering. Activation of these cells depends on phosphodiesterase (PDE) 4. We therefore evaluated the potential for PDE4 inhibition in EBA: PDE4 was highly expressed in inflammatory cells and in the epidermis of patients compared with healthy skin samples. PDE4 inhibitors rolipram, roflumilast, and roflumilast N-oxide prevented the release of immune complex-induced reactive oxygen species from polymorphonuclear leukocytes and separation of the dermal-epidermal junction of skin incubated with antibodies to collagen type VII and polymorphonuclear leukocytes. The PDE4 inhibitors also impaired CD62L shedding and decreased CD11b expression on immune complex-stimulated polymorphonuclear leukocytes. For in vivo validation, experimental EBA was induced in mice by transfer of anti-collagen type VII IgG or immunization with collagen type VII. Roflumilast dose-dependently reduced blistering in antibody transfer-induced EBA and also hindered disease progression in immunization-induced EBA. PDE4 inhibition emerges as a new treatment modality for EBA and possibly other neutrophil-driven pemphigoid diseases.
Original languageEnglish
JournalJournal of Investigative Dermatology
Volume136
Issue number11
Pages (from-to)2211-2220
Number of pages10
ISSN0022-202X
DOIs
Publication statusPublished - 01.11.2016

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