IL-36γ in enthesitis-related juvenile idiopathic arthritis and its association with disease activity

IL-36 has been implicated in the pathogenesis of spondyloarthropathies (SpA) like psoriasis and inflammatory bowel disease. Enthesitis related arthritis (ERA) category of juvenile idiopathic arthritis is a form of juvenile SpA, however no data is available on the role of IL-36 in this disease. IL-36α, β, γ and IL-36R mRNA expression in blood and synovial fluid mononuclear cells and IL-36α, γ, IL-36Ra, IL-6 and IL-17 levels were measured in serum and synovial fluid (SF). IL-36γ production by fibroblast like synoviocytes (FLS) upon stimulation with pro-inflammatory cytokines and its effect on FLS were also studied. mRNA levels of IL-36α, IL-36γ and IL-36R were increased in PBMCs of ERA patients as compared to healthy controls however only IL-36γ was measurable in serum of one third of patients. In SFMCs, all 4 mRNA were detectable but were lower than RA patients. SF IL-36γ levels correlated with disease activity score (r=0.51, p< 0.0001), SF IL-6 (r=0.4, p= 0.0063) and IL-17 levels (r=0.57, p=0.0018). Pro-inflammatory cytokines increased expression of IL-36γ and IL-6 in FLS cultures. SFs from 5 ERA patients also increased expressions of IL-36γ and IL-6 in FLS which could be blocked by using IL-36Ra. This suggests that pro-inflammatory cytokines aid in upregulation of IL-36γ which in turn may upregulate expression of IL-6. This might lead to a positive feedback loop of inflammation in ERA. Association of SF levels of IL-36γ with disease activity further supports this possibility. IL-36Ra based therapy may have a role in ERA.