1569 A specific inflammatory gene signature in pityriasis rubra pilaris identifies a pathogenic role for keratinocytes

Pityriasis rubra pilaris (PRP) represents a group of rare inflammatory skin disorders of unknown etiology. PRP shows some common clinical and histological features with psoriasis, suggesting a shared underlying pathophysiology. Based solely on these similarities, a role of the IL23-Th17-axis in PRP was suggested and several cases of successful treatment of PRP with psoriasis biologics were reported. However, through molecular profiling of PRP lesions using NanoString technology we have identified a specific signature, which allows accurate differentiation of PRP from other inflammatory skin diseases including psoriasis. Interestingly, PRP-associated inflammation does not demonstrate typical Th1-, Th2-, or Th17-related signatures. Conversely, our data suggest that keratinocytes, rather than T cells, play a pathogenic role in PRP, by producing cytokines such as IL17C, IL1a, IL20, and IL23, and the chemokine ligand CCL20, while IL17A/F and IL22 are absent. In line with these data, we show a clinical case aggravating under anti-IL17A therapy but swiftly going into clinical and molecular remission upon switching to anti-IL12/23 treatment. Combining fluorescentin-situhybridization, single cell sequencing, and digital spatial profiling, we identify superficial keratinocytes, but not immune cells, as cellular source of pathogenic cytokines. Thus, our study identifies a PRP-specific inflammatory signature, thereby 1) providing a novel diagnostic tool and 2) suggesting clearly distinct immunopathogeneses for PRP and psoriasis. While psoriasis is driven by Th17/Tc17 cells infiltrating the epidermis, an aberrant, T cell-independent activation of keratinocytes seems to underlie PRP, which thus reflects an ongoing innate inflammation. These findings should help guiding physicians towards more rational therapeutic choices in the management of PRP.