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

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

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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
Pages (from-to)2211-2220
Number of pages10
JournalJournal of Investigative Dermatology
Volume136
Issue number11
DOIs
Publication statusPublished - Nov-2016

Keywords

  • OBSTRUCTIVE PULMONARY-DISEASE
  • DERMAL-EPIDERMAL SEPARATION
  • INDUCED TISSUE-DAMAGE
  • FACTOR-KAPPA-B
  • FC-GAMMA-RIV
  • VII COLLAGEN
  • PHOSPHODIESTERASE-4 INHIBITORS
  • NEUTROPHIL GRANULOCYTES
  • TOPICAL CORTICOSTEROIDS
  • SPONTANEOUS APOPTOSIS

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