OA26 Fibrin is associated with worsening clinical parameters and outcomes in a prospective cohort of Juvenile Idiopathic Arthritis patients

Background/Aims Juvenile Idiopathic arthritis (JIA) is the most common rheumatic disease of childhood. In adult-onset arthritis, the presence of fibrin within synovial samples has been linked to severity of disease and worsening clinical outcomes. Furthermore, mice deficient in fibrinogen are protected from joint damage in arthritis. In this study we assessed whether fibrin associates with disease activity in JIA. Methods Synovial tissue sections were obtained from 54 participants with JIA recruited to the Multiomic Analysis of Paediatric Joint and Gut inflammation (MAPJAG) study. These participants underwent minimally-invasive synovial biopsy, the majority (45/54) prior to treatment with disease modifying anti-rheumatic drugs. Sections were stained by Immunohistochemistry (IHC) using an antibody targeting an epitope on the N-terminus of fibrinogen-beta exposed after thrombin activity to allow for polymerisation into fibrin. Staining for insoluble clot material was confirmed, and assessed by two blinded researchers with reference to morphology, proportion of total tissue and staining intensity. Results Two distinct patterns of fibrin distribution were identified: (1) a more “linear” staining pattern followed the edge of the tissue and synovium closely and was observed in 96.3% patients (n = 52/54); and (2), “globular” fibrin represented large fibrin polymers, which were densely stained and did not follow the contours of the synovium, and was observed in 92.6% (n = 50/54) tissues. Further analysis assessed globular fibrin as a proportion of total tissue. Increasing proportions of globular fibrin were associated with worse clinical outcomes for multiple parameters of disease severity (ESR (R = 0.3; p = 0.039), cJADAS10 (R = 0.3; p = 0.03), pain (R = 0.28, p = 0.043), and physician VAS (R = 0.32; p = 0.021); uncorrected p values). We identified a ‘fibrin-high’ phenotype where > 20% of the tissue following IHC staining was globular fibrin. Participants in the fibrin-high category were significantly more likely to need an intervention (joint injection/ biologic/ DMARD by year 1 after baseline ( p = 0.024, Fishers exact test). We focussed on the interaction of globular fibrin with synovial tissue, as in some patients we observed absorption of globular fibrin into the synovial lining layer. In these patients, higher baseline physicians VAS and pain scores were recorded (p = 0.046 and 0.022, Wilcoxon rank sum). Conclusion This study provides the first in-depth assessment of the associations of fibrin and synovial tissue in children with inflammatory arthritis. We show that increasing fibrin in synovial tissue at baseline is associated with worse clinical outcomes in ‘fibrin-high’ individuals. These data suggest that fibrin detection early in disease may be a useful biomarker to predict disease trajectory. Future research should focus on the contribution of fibrin in disease pathogenesis and identify the diagnostic potential of the fibrin-high phenotype. Disclosure E. Clay: None. C. Talbot: None. A. Appadoo: None. H. Adams: None. C.G. Smith: None. C. Bolton: None. G. Neag: None. E. Lawrence: None. J. Kelly: None. K.H. Kupiec: None. B. Barklam: None. C. Foley: None. A. Hodgson: None. P. Chin: None. L. Marsh: None. I. Beh: None. C. Mahony: None. S. Kemble: None. A. Hackland: None. M. Hanlon: None. E. DiCarlo: None. E. Gravallese: None. A. Filer: None. E. Al-Abadi: None. L.R. Wedderburn: None. A. Croft: None.