SAT0024 Il-36 axis is an emerging therapeutic target in psoriatic arthritis synovial tissue

• Published in: Annals of the rheumatic diseases Vol. 77; no. Suppl 2; p. 885
• Main Authors: Boutet, M.-A., Nerviani, A., Lliso-Ribera, G., Goldmann, K., Lewis, M., Pitzalis, C.
• Format: Journal Article
• Language: English
• Published: London BMJ Publishing Group LTD 01.06.2018
• Subjects: Antagonists; Arthritis; Biopsy; CD3 antigen; Cytokines; Drug development; Enzyme-linked immunosorbent assay; Fibroblasts; Immunofluorescence; Immunohistochemistry; Immunosuppressive agents; Inflammation; Interleukin 8; Leukocytes (mononuclear); Lymphocytes T; Macrophages; Methotrexate; Patients; Peripheral blood mononuclear cells; Plasma cells; Psoriasis; Psoriatic arthritis; Rheumatoid arthritis; Ribonucleic acid; RNA; Skin; Steroid hormones; Synovium; T cell receptors; Ultrasound
• ISSN: 0003-4967; 1468-2060
• DOI: 10.1136/annrheumdis-2018-eular.3485

BackgroundThe 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.ObjectivesIn this study, we aimed to comparatively investigate the expression and role of IL-36 cytokines in synovial tissue of early RA and PsA patients.MethodsSynovial tissue samples were collected from patients with early RA and PsA (disease duration <12 months) DMARDs (Disease Modifying Anti-Rheumatic Drugs) and steroids-naïve. All patients underwent an ultrasound-guided synovial biopsy before starting the treatment; the procedure was repeated following six months of treatment with conventional DMARDs. The expression of IL-36 family members was investigated in synovial tissue at gene level by RNA-Sequencing (87 RA, 15 PsA), at protein level by immunohistochemistry (IHC) and immunofluorescence (IF) (20 RA, 26 PsA) and in plasma by ELISA (22 RA, 38 PsA). RA and PsA-fibroblasts-like-synoviocytes (FLS) and peripheral blood mononuclear cells (PBMCs) were treated in vitro to assess their response to IL-36 stimulation.ResultsGene 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.ConclusionsThe 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 InterestNone declared