Background The IL-36 family of cytokines includes three agonists, IL-36α, IL-36β and IL-36γ, and two established or hypothetical antagonists, respectively IL-36Ra and IL-38. IL-36 agonists are pro-inflammatory cytokines highly expressed in skin and involved in the pathogenesis of psoriasis. A recent study demonstrated that only a subset of patients with rheumatoid arthritis (RA) had an elevated IL-36 agonists/antagonists ratio within the synovium and could potentially respond to IL-36 inhibition strategies but little is known about the expression and biologic functions of the IL-36 axis in synovial tissue of psoriatic arthritis (PsA) so far hardly been studied. Objectives In this study, we aimed to comparatively investigate the expression and role of IL-36 cytokines in synovial tissue of early RA and PsA patients. Methods Synovial tissue samples were collected from patients with early RA and PsA (disease duration Results Gene and protein expression of IL-36 agonists was comparable between RA and PsA synovial tissue; conversely, the antagonists IL-36Ra and IL-38 were significantly lower in PsA compared to RA. Accordingly, the agonists/antagonists ratio was considerably higher in PsA synovium, suggesting an activation of the IL36 pro-inflammatory pathway. Among the immune cells infiltrating the PsA synovium, macrophages (CD68+), T lymphocytes (CD3+) and plasma cells (CD138+) were the primary IL36α-expressing cells. At baseline, the synovial expression of IL-36α was significantly higher in PsA patients who did not respond to DMARDs treatment at 12 months; this differential synovial expression of IL-36α between responders and non-responders was also maintained at six months. In keeping with this observation, we showed that treatment with methotrexate or sulfasalazine did not reduce the expression of IL-36 in PsA cells in vitro. Finally, we observed that PsA-FLS and PsA-PBMCs produced significantly higher levels of IL-8 upon stimulation with IL-36α in comparison with cells isolated from RA patients. Conclusions The expression of the anti-inflammatory IL-36 cytokines antagonists are differently regulated in early RA and PsA, being significantly lower in the latter. Moreover, the pro-inflammatory IL-36α is up-regulated in synovial tissue of PsA non-responders to conventional DMARDs. The impaired balance between agonists and antagonists might contribute to the persistent inflammation characterising the diseased tissue. The exogenous replacement of the IL-36 antagonists may be a novel promising therapeutic target for PsA patients. Disclosure of Interest None declared
