Background/Purpose: Seronegative joint diseases, including psoriatic arthritis and juvenile idiopathic arthritis, are characterized by the lack of autoantibodies, which are relevant biomarkers for predicting disease activity in rheumatoid arthritis. Promising alternative biomarkers are the Damage Associated Molecular Patterns (DAMPs), S100A8, S100A9 and the heterodimer S100A8/A9. These proteins are specifically expressed and released by infiltrating phagocytes and may therefore serve as relevant biomarkers for joint inflammation and destruction in seronegative arthritis. In this study we determined the biomarker potential of serum S100A8/A9 and in vivo imaging of synovial S100A8 to asses joint inflammation and damage in the IL-1 receptor antagonist deficient (IL-1Ra^-/-) mice, a mouse model for seronegative arthritis in which serum autoantibodies are not correlated to disease activity.

Methods: Serum levels of S100A8/A9 and various cytokines were monitored during arthritis development in IL-1Ra^-/- mice using ELISA and Luminex and were correlated to macroscopic and microscopic parameters for joint inflammation and damage. Local S100A9 expression and matrix metalloproteinase (MMP) mediated cartilage damage in the ankle joints were investigated by immunohistochemistry. In addition local S100A8 and activated MMPs were monitored in vivo by optical imaging using anti-S100A8-Cy7 and AF-489-Cy7, a specific tracer for activated MMPs.

Results: Starting at week 8, serum levels of S100A8/A9 were significantly increased (1640 ± 1008 ng/ml at week 16) in IL-1Ra^-/- mice compared to WT BALB/c control mice (429 ± 191 ng/ml, P = 0.005) and strongly correlated to joint swelling (r = 0.766, P < 0.0001), while serum levels of IL-1β, IL-6, TNF-α, IL-17, IL-4 or IFN-α did not. In addition, high serum S100A8/A9 levels at week 10 were predictive for increased joint swelling at week 16 (r = 0.576, P = 0.0002). Next to macroscopic swelling, increased serum S100A8/A9 also correlated to microscopic cell influx (r = 0.794, P < 0.0001) and was reflected by local expression of S100A9 within the synovium, indicating the activated synovial lining as the source of increased serum S100A8/A9. Local expression of S100-DAMPs could also be monitored non-invasively by in vivo optical imaging using anti-S100A8-Cy7. Next to a biomarker for inflammation, S100-DAMPs may also be used for assessing joint damage. Indeed, arthritic IL-1Ra^-/- mice showed increased cartilage damage (r = 0.687, P < 0.0001) which coincided with MMP-mediated neoepitope (VDIPEN) expression and in vivo imaging of activated MMPs.

Conclusion:  These findings underline the potential of S100-DAMPs as a systemic and local biomarker in seronegative arthritis, not only for assessing inflammation but also joint damage.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/s100a8a9-a-potent-serum-and-molecular-imaging-biomarker-for-synovial-inflammation-and-joint-destruction-in-seronegative-experimental-arthritis/