Background/Purpose:  IL-1 blockade is highly effective for systemic juvenile idiopathic arthritis (sJIA), but clinical observations raise the possibility that initiation of treatment in a “window of opportunity” before chronic arthritis develops may be more effective than in latyers disease. We have hypothesized that sJIA is a biphasic process in which an initial IL-1β-driven systemic phase gives rise to IL-17-driven chronic inflammatory arthritis. We sought to test this hypothesis in the IL-1ra^-/-model, a spontaneous T cell-mediated murine arthritis dependent upon both IL-1β and IL-17.

Methods:  IL-1ra^-/-mice were treated with anti-mIL-1β or isotype-matched IgG (5mg/kg i.p. 2 times per week) for 2 weeks, beginning either 3 days after arthritis onset (early treatment) or 3 weeks after arthritis treatment (late treatment). Arthritis score (0-3/per paw, 0-12 total) and ankle and wrist thickening measured by caliper were followed for 54 days after arthritis onset. Synovial tissue was harvested at day 54 for flow cytometry to characterize lymphocyte surface phenotype and cytokine production.

Results:  Clinical indices were reduced in both treatment groups compared with isotype control, without a difference between groups. However, joint thickening was reduced in early compared with late treatment, although worsening was again noted after anti-IL-1β was discontinued. Histological injury was minimized in the early treatment group, suggesting that early IL-1β antagonism was more efficient. In support of this possibility, early anti-IL-1β abrogated accumulation of lymphocytes expressing IFN-γ and IL-17A, while treatment of established disease resulted only in modest reduction of IL-17A-expressing cells. Consistent with published findings, γδT cells represented on average slightly more than half of all synovial CD3⁺cells. The reduction in IL-17-expressing lymphocytes paralleled the lower abundance of this population after either early or late treatment, with an intriguing trend toward greater reduction in γδT cells in the early treatment group, corresponding to the reduction in synovial lymphocytes expressing IL-17.

Conclusion:  In murine IL-1ra^-/- synovitis, early IL-1β blockade more efficiently reduces tissue injury and lymphocyte accumulation than late blockade, although both are effective. Efficacy correlated with a reduction in IL-17-producting cells, and in particular with fewer IL-17-producing gdT cells. These findings support the hypothesis that early IL-1β blockade could represent an effective strategy to modulate the development of arthritogenic T cells in IL-1-driven arthritis, a result that may inform the understanding and treatment of sJIA.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/enhanced-efficacy-of-early-vs-late-il-1%ce%b2-antagonism-in-murine-arthritis-mediated-by-deficiency-of-the-il-1-receptor-antagonist-il-1ra/