Effect of phosphodiesterase-4 inhibition on skin and mucosal lesions in experimental anti-laminin 332 mucous membrane pemphigoid

Meeting Abstract: P130 The autoimmune bullous disease mucous membrane pemphigoid (MMP) is characterized by autoantibodies against the dermal-epidermal-junction and a predominant mucosal involvement. Reactivity against laminin 332 (Lam332), a heterotrimer consisting of 3 laminin chains, is found in one third of MMP patients. Major clinical and immunopathological characteristics of the human dis-ease, including both mucosal and skin lesions, are recapitulated in the recently established antibody transfer model for anti-Lam332 MMP in adult mice. As the treatment of MMP patients still relies on high-dose corticosteroids, there is a high unmet need for new and more specific therapies. Phosphodiesterase-4 (PDE4) inhibition has previously been shown to be effective in patients with psoria-sis vulgaris and Behcet’s disease. Here, in the anti-Lam332 MMP mouse model, a specific PDE4 inhibitor, roflumilast, was applied in a prophylactic approach, using 5 mg/kg/day p.o. In two independ-ent and blinded experiments, roflumilast significantly reduced oral lesions compared to vehicle-treated mice as quantified by endos-copy (P = 0.029), whereas, interestingly, a significant increase in skin lesions was observed (P < 0.0001). In line, in lesional biopsies, the number of inflammatory cells was significantly decreased in the buccal mucosa, but not in the skin, of roflumilast-treated com-pared to vehicle-treated mice (P = 0.007, P = 0.1523). A significant decrease of oral lesions could also be seen, when the PDE4 inhibi-tor was applied in a therapeutic approach (P = 0.016), i.e., when le-sions had already developed. To investigate the differential effect of the PDE4 inhibitor observed in the prophylactic approach, a transcriptome analysis by NGS of affected skin and buccal mucosa from roflumilast-treated anti-Lam332 MMP mice (n = 5), vehicle-treated anti-Lam332 MMP mice (n = 5) and mice injected with non-pathogenic rabbit IgG (n = 3) was performed. Differential gene analysis revealed Chil3, Ly9, IL18 bp, integrin alpha-L, and TNF to be upregulated in lesional skin of untreated mice with anti-Lam332 MMP. Among these inflammatory mediators, TNF showed a central role by STRING analysis. In the buccal mucosa of roflumilast-treated mice with anti-Lam332 MMP, Aldh1a2, Ryr1, Tceal7, and Il22ra2 were upregulated. Further validation by Gen Set Variation Analysis, qPCR, and Western Blotting will help to corroborate these findings and uncover pathways responsible for the differential effect of PDE4 inhibition on antibody-mediated tissue destruction in skin and mucosa. Furthermore, our data sup-port PDE4 inhibition as potential novel therapy for mucous mem-brane lesions in patients with MMP