Psoriatic arthritis (PsA) is clinically heterogeneous, showing inflammation of the peripheral joints, spine, entheses, fingers and toes, skin or nails. Whilst there is substantial overlap in the underlying immunobiology driving inflammation in any of these sites, there are also marked differences. However, the reasons for these differences are unclear. The BRIGHT consortium hypothesizes that intestinal microbiota shape immune responses in the early stages of PsA thereby driving clinical heterogeneity. To address this, the group will investigate (i) how gut barrier integrity, intestinal dysbiosis, disease subtype and severity relate in patients; (ii) whether there are differences in the cellular sources that produce or respond to IL-23 and IL-17 production, using deep phenotyping of blood, gut, joint and skin; and (iii) whether PsA intestinal microbiota shape IL-23 and/or IL-17-dependent responses and treatment, using animal models of axial and peripheral forms of PsA.
Obj.1: How do gut barrier integrity, intestinal dysbiosis, disease subtype and severity in PsA relate?
Obj.2: Do similar cellular sources produce or respond to IL-23 and IL-17 in different tissues (blood, skin, gut, joint) in PsA?
Obj.3: Do intestinal microbiota shape IL-23/IL-17 dependent responses in axial and peripheral forms of PsA?
M1, months 01 - 12: Serum analysis of GIANT cohort
M2, months 06 – 18: PsA gut histopathology
M3, months 12 – 24: Link to microbiota and PsA phenotype
M4, months 01 – 24: Patient recruitment and sample collection
M5, months 04 – 30: Deep phenotyping by scRNAseq and flow cytometry
M6, months 01 – 36: Experimental animal studies in germ-free, gnotobiotic and knockout models
M7, months 27 – 36: Manuscript submission
M8, months 30 – 36: Symposium
Several million adults in Europe live with PsA, which significantly affects their quality of life. The group hopes that their findings will start to reveal the gut as a potential critical determinant of peripheral versus spinal disease subtype in patients with PsA. This would generate a shift in the way we think about the diagnosis, disease outcome and response to treatment in PsA.