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Abstract Number: 957

The Role Of S100A4 As a Biological Marker Of Immune Response In Early Rheumatoid Arthritis

Lucie Andrés Cerezo1, Klára Prajzlerová2, Martina Remáková1, Herman F. Mann3, Michal Tomcík2, Karel Pavelka4, Jiri Vencovsky2 and Ladislav Senolt2, 1Department of Clinical and Experimental Rheumatology, 1st Faculty of Medicine, Charles University, Prague, Czech Republic, Institute of Rheumatology, Prague, Czech Republic, 2Department of Clinical and Experimental Rheumatology, 1st Faculty of Medicine, Charles University, Prague, Institute of Rheumatology, Prague, Czech Republic, 3Institute of Rheumatology and Department of Rheumatology, 1st Faculty of Medicine, Charles University, Prague, Prague, Czech Republic, 4Institute of Rheumatology and Department of Rheumatology, 1st Faculty of Medicine, Charles University in Prague, Prague, Czech Republic

Meeting: 2013 ACR/ARHP Annual Meeting

Keywords: biomarkers and rheumatoid arthritis (RA)

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Session Information

Session Title: Cytokines, Mediators, Cell-cell Adhesion, Cell Trafficking and Angiogenesis I

Session Type: Abstract Submissions (ACR)

Background/Purpose:

We have previously demonstrated that S100A4 is up-regulated in established rheumatoid arthritis (RA) and that S100A4 regulates apoptosis and synthesis of matrix degrading enzymes in synovial fibroblasts. The aim of the present study was to: 1) characterize whether S100A4 reflects disease activity and/or response to treatment in patients with early RA and 2) determine whether S100A4 regulates production of pro-inflammatory cytokines in mononuclear cells.

Methods:

Serum samples were obtained from 59 patients with early RA (symptom duration ≤ 6 months) before and 3 months after treatment with disease modifying anti-rheumatic drugs (DMARDs) and also from 41 healthy individuals. Disease activity score (DAS28-CRP) was assessed at baseline and after 3 and 12 months. S100A4 levels were analyzed by ELISA. Peripheral blood mononuclear cells (PBMCs) and CD3+ T-cells isolated from patients with established RA were stimulated with S100A4, S100A8 and S100A12 proteins (each 1μg/ml). Production of interleukin IL-1β, IL-6 and tumor necrosis factor alpha (TNF-α) was measured by ELISA. Receptor for advanced glycation end products (RAGE) and Toll-like receptor-4 (TLR-4) signalling were examined. For signalling pathway blocking studies, inhibitors of MyD88, NFkB and MAP kinases p38, erk1/2, jnk were used. Activation of MAP kinases was determined by Western blotting.

Results:

S100A4 serum levels were significantly higher in patients with early RA compared with healthy controls (p<0.001) and significantly decreased after 3 months of treatment (p<0.001).

Although S100A4 levels did not correlate with disease activity, in female patients, high S100A4 levels (>1000 ng/ml) at baseline predicted worse response to treatment (DAS28 ≥ 3.2) after 3 and 12 months of therapy (PPV 0.28, OR (95% CI) 2. 846 (1.837, 4.410), p= 0.006 and PPV 0.60, OR (95% CI) 2.700 (0. 992, 7.351), P=0.046). Interestingly, higher S100A4 levels (>1000 ng/ml) at 3 months predicted worse response to treatment (DAS28 ≥ 3.2) in all patients after 12 months (PPV=0.33, OR (95% CI) 2.36 (1.17, 4.74), p=0.04).

Stimulation of PBMCs with S100A4 significantly up-regulated production of IL-1β, IL-6 and TNF-α compared with unstimulated cells (p<0.001). Importantly, production of the cytokines was markedly enhanced in response to S100A4 compared with S100A8 and S100A12 proteins. Extracellular S100A4 induced production of the pro-inflammatory cytokines (p<0.01) also in CD3+ T-cells. Furthermore, enhanced production of pro-inflammatory cytokines in S100A4 stimulated PMBCs was at least partly mediated via TLR-4, but not RAGE, and by the activation of transcription factor NFkB and MAP kinases p38 and erk1/2.

Conclusion:

This is the first study to demonstrate that S100A4 is elevated in patients with early RA and that S100A4 induces inflammatory response mediated by the TLR-4 signalling pathway in mononuclear cells. Taken together, we suggest that high levels of S100A4 may represent a potential biomarker of insufficient treatment response and/or therapeutic target for immune mediated diseases such as RA.

Acknowledgement: This study was supported by Internal Grant Agency of Ministry of Health of the Czech Republic NT/13698-4


Disclosure:

L. Andrés Cerezo,
None;

K. Prajzlerová,
None;

M. Remáková,
None;

H. F. Mann,
None;

M. Tomcík,
None;

K. Pavelka,
None;

J. Vencovsky,
None;

L. Senolt,
None.

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