Multiomic characterization of entheseal disease in psoriasis and psoriatic arthritis: implication for disease severity

Psoriatic arthritis (PSA), is a chronic inflammatory disease with significant impact on patients disease burden. Its management represents a relevant unmet medical need mainly due to interindividual heterogeneity and few diagnostic and prognostic biomarkers available in routine. Pathophysiology is also unknown, however about 20-30% of Psoriasis (PSO) patients develop PSA. To date, limited prognostic biomarkers identifying PSO at high risk of transition towards PSA are available due to the lack of full knowledge of molecular and cellular mechanisms responsible for this transition. Moreover, PSA, similarly to other immune-mediated inflammatory diseases, is characterized by significant heterogeneity in terms of involvement of different clinical domains leading to inter-individual disease severity and treatment response. Enthesitis, which is one of the primary events in PSA pathogenesis, occurs in 30-50% of patients and is associated with higher disease burden. However, entheseal involvement might be difficult to evaluate and many entheses are explorable only through imaging techniques. Animal models showed that an aberrant immune response involving the entheseal-synovial niche is central in the pathogenesis of PSA hosting innate IL-23 responsive cells that makes this anatomic site a functional IL-23 responsive tissue, similarly to the gut. Indeed, HLA-B27 transgenic rats develop a disease that resembles to human SpA since includes features as colitis, arthritis, psoriasis and uveitis. In humans with PSA, extraarticular manifestations such as gut inflammation are considered a marker of disease severity and it is known that subclinical gut inflammation may initiate zonulin-dependent alterations of gut-epithelial and gut-vascular barriers favouring gut leakage, and supporting the link between gut-entheseal and joint in PSA. To date, no conclusive data are available about the molecular and cellular composition of simultaneously affected tissues (skin, synovial/entheseal tissue and gut) in PSO or PSA and whether the presence of an entheseal disease, alone or in addition to joint and gut involvement may affect disease prognosis, severity and treatment response.
In this scenario, the development of high-resolution technologies for clinical characterization such as imaging has permitted an earlier and more precise evaluation of inflammation even in a pre-clinical phase. In research, high-resolution technologies such as single-cell RNA sequencing have increased our knowledge about the cellular diversity of chronic inflammatory diseases with the identification of novel putative mechanisms triggering the loss of immunological tolerance. Moreover, spatial transcriptomic platforms allowed the identification of location-specific and cell-specific transcriptomic signatures from biorepository tissue-banks. Therefore, understanding the link between entheses, skin, joint and gut in different disease stages might improve the management of PSO/PSA patients identifying their transition phase, the chronicity and severity of disease and choice and moment of drug therapy. In this study proposal we will develop a comprehensive evaluation of inflammation at clinical, imaging and molecular levels through a comprehensive multiomic atlas of inflammatory and stromal cells in multiple biological niches (enthesis, skin, synovial tissue, gut and peripheral blood) of PSO and PSA using high- throughput transcriptomic approaches with single-cell and spatial resolution.