Background/Purpose:

Seronegative joint diseases such as psoriatic arthritis and juvenile idiopathic arthritis are characterized by the lack of autoantibodies, potent biomarkers used for predicting disease activity and outcome in seropositive joint diseases. Promising alternative biomarkers for detecting disease activity in seronegative arthritis are the Damage Associated Molecular Patterns (DAMPs) S100A8 and S100A9 proteins specifically expressed and released by infiltrating phagocytes in the inflamed joint. In this study, we explore the biomarker potential of serum S100A8/A9 and in vivo imaging of synovial S100A8 to assess joint inflammation and damage in 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 of IL-1Ra^-/-and WT (BALB/c genetic background) mice was collected every two weeks starting at week 4 until end-point at week 16, and swelling in the hind paws was macroscopically scored on a scale of 0 to 4. Serum levels of IL-1β, IL-6 and TNFα were measured by Luminex technology and S100A8/A9 complex levels by ELISA. Hind paws were isolated and histologically scored for cell influx, cartilage damage and bone erosion. Paraffin sections of the hind paws were also stained for S100A8 expression. Synovial S100A8 was imaged by injection of anti-S100A8-Cy7 antibody and 24 hour p.i. fluorescent images were acquired in the IVIS Lumina optical imaging system.

Results:

Starting at week 8 up to week 16, serum levels of S100A8/A9 in IL-1Ra^-/- mice were significantly  increased (1640 ± 1008 ng/ml at week 16) compared to basal levels in WT mice (429 ± 191 ng/ml, P = 0.005) and strongly correlated to joint swelling (r = 0.740, P < 0.0001). Histological analysis of hind paws showed that joint inflammation but also cartilage and bone destruction (r = 0.672 – 0.770, P < 0.0001) significantly correlated to serum S100A8/A9 levels, in contrast to levels of IL-1β, IL-6, and TNFα. Serum S100A8/A9 levels already correlated to joint swelling (r = 0.410, P = 0.047) as early as week 8 and high serum levels at week 10 were predictive for increased joint swelling at week 16 (r = 0.563, P = 0.004). Local expression of S100A8 within the synovium as detected by immunolocalisation correlated to joint damage and serum S100A8/A9 levels, indicating the activated synovial lining as the source of increased serum S100A8/A9. Imaging of S100A8 using specific anti-S100A8-Cy7 antibody showed a significant uptake in inflamed joints of IL-1Ra^-/- mice when compared to a control isotype (P = 0.044). In non-arthritic IL-1Ra^-/-mice no specific S100A8 targeting was observed.

Conclusion:

High levels of serum S100A8/A9 correlate to joint inflammation and destruction in experimental seronegative arthritis and local synovial expression of S100-DAMPs can be monitored in vivo by molecular imaging. These findings underline the potential of S100-DAMPs as a serum and imaging biomarker for disease severity in seronegative arthritis.

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