Acute-Phase Serum Amyloid A Regulates Tumor Necrosis Factor ␣ and Matrix Turnover and Predicts Disease Progression in Patients With Inflammatory Arthritis Before and After Biologic Therapy

St. Vincent's University Hospital, Dublin Academic Medical Centre, The Conway Institute of Biomolecular and Biomedical Research, Dublin, Ireland.
Arthritis & Rheumatology (Impact Factor: 7.76). 04/2012; 64(4):1035-45. DOI: 10.1002/art.33455
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In this study, we demonstrated a specific relationship between A-SAA and clinical disease activity in inflammatory arthritis, as measured by the SJC. Hepatic induction of acute-phase proteins including CRP is a nonspecific feature of systemic inflammation in response to diverse causes, including trauma, infection, and autoimmune disease (36). In contrast to other hepatic-derived acute-phase proteins, A-SAA at concentrations of up to 1,000 μg/ml has previously been reported in RASFs, which may exceed serum levels obtained in the same subjects (37). Measurement of serum A-SAA levels, which may be partly SF-derived, may therefore be a more accurate indicator of radiographic progression in clinical practice, although further direct comparison with high-sensitivity CRP may be useful. Although heterogeneous by diagnosis, the patients with RA and the patients with PsA in this cohort were indistinguishable in terms of disease duration and baseline radiographic damage prior to biologic therapy. The relatively high incidence of radiographic progression observed in both patients with RA and patients with PsA prior to biologic therapy is likely to be due to a combination of factors, including the high incidence of baseline structural damage, the long history of DMARD-resistant disease, incomplete adherence to therapy, and a relatively high rate of biologic monotherapy, which has been shown to be associated with worse radiographic outcomes (38).

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Available from: Robin Poole, Sep 23, 2014
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    • "Its concentration may increase up to 1000-fold during the acute phase of inflammation in regard to normal condition [10], [11]. Besides its influence on lipid metabolism [12], [13], A-SAA is known to participate to immune cells recruitment at inflammatory sites [14], [15] and to induce expression of pro-inflammatory cytokines [14], [16] and matrix metalloproteinases [17]. Across the last decade, several studies attempted to demonstrate the extra-hepatic production of A-SAA by several tissues and different cell types of patients with atherosclerosis [18], Alzheimer disease [19], obesity [9] or RA [20], [21]. "
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    ABSTRACT: To determine if serum amyloid A (A-SAA) could be detected in human osteoarthritic (OA) joints and further clarify if high A-SAA level in joints result from a local production or from a diffusion process from abnormally elevated plasma concentration. Regulatory mechanism of A-SAA expression and its pro-inflammatory properties were also investigated. A-SAA levels in serum and synovial fluid of OA (n = 29) and rheumatoid arthritis (RA) (n = 27) patients were measured and compared to matched-healthy volunteers (HV) (n = 35). In vitro cell cultures were performed on primary joint cells provided from osteoarthritis patients. Regulatory mechanisms were studied using Western-blotting, ELISA and lentiviral transfections. A-SAA was statistically increased in OA plasma patients compared to HV. Moreover, A-SAA level in OA plasma and synovial fluid increased with the Kellgren & Lauwrence grade. For all OA and RA patients, A-SAA plasma level was higher and highly correlated with its corresponding level in the synovial fluid, therefore supporting that A-SAA was mainly due to the passive diffusion process from blood into the joint cavity. However, A-SAA expression was also observed in vitro under corticosteroid treatment and/or under IL-1beta stimuli. A-SAA expression was down-regulated by PPAR-γ agonists (genistein and rosiglitazone) and up-regulated by TGF-β1 through Alk1 (Smad1/5) pathway. RhSAA induced proinflammatory cytokines (IL-6, IL-8, GRO-α and MCP-1) and metalloproteinases (MMP-1, MMP-3 and MMP-13) expression in FLS and chondrocytes, which expression was downregulated by TAK242, a specific TLR4 inhibitor. Systemic or local A-SAA expression inside OA joint cavity may play a key role in inflammatory process seen in osteoarthritis, which could be counteracted by TLR4 inhibition.
    PLoS ONE 06/2013; 8(6):e66769. DOI:10.1371/journal.pone.0066769 · 3.23 Impact Factor
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    • "IL-1β, IL-6, IL-8, TNF-α, and interferon-γ) in neutrophils [19], [20], monocytes [15], [21] and lymphocytes [22], and is a leukocyte chemoattractant [23], [24]. Several receptors are implicated, including the receptor for advanced glycation end products (RAGE) [16], [25], formyl peptide receptor-like (FPRL)-1 and -2 [20], [26]–[29], toll-like receptor (TLR)-2 and -4 [30]–[32], and scavenger receptors CLA-1/SR-B1 [33]–[35] and CD36 [36] that modulate innate immune responses to several ligands. Recent studies suggest that in macrophages, four signaling pathways involving nuclear factor-κB (NF-κB) and three mitogen-activated protein kinase (MAPK) may contribute to cytokine production (summarized in [36]). "
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    ABSTRACT: S100A12 is elevated in the circulation in patients with chronic inflammatory diseases and recent studies indicate pleiotropic functions. Serum amyloid A induces monocyte cytokines and tissue factor. S100A12 did not stimulate IL-6, IL-8, IL-1β or TNF-α production by human peripheral blood mononuclear cells but low amounts consistently reduced cytokine mRNA and protein levels induced by serum amyloid A, by ∼49% and ∼46%, respectively. However, S100A12 did not affect serum amyloid A-induced monocyte tissue factor. In marked contrast, LPS-induced cytokines or tissue factor were not suppressed by S100A12. S100A12 did not alter cytokine mRNA stability or the cytokine secretory pathway. S100A12 and serum amyloid A did not appear to form complexes and although they may have common receptors, suppression was unlikely via receptor competition. Serum amyloid A induces cytokines via activation of NF-κB and the MAPK pathways. S100A12 reduced serum amyloid A-, but not LPS-induced ERK1/2 phosphorylation to baseline. It did not affect JNK or p38 phosphorylation or the NF-κB pathway. Reduction in ERK1/2 phosphorylation by S100A12 was unlikely due to changes in intracellular reactive oxygen species, Ca(2+) flux or to recruitment of phosphatases. We suggest that S100A12 may modulate sterile inflammation by blunting pro-inflammatory properties of lipid-poor serum amyloid A deposited in chronic lesions where both proteins are elevated as a consequence of macrophage activation.
    PLoS ONE 04/2013; 8(4):e62372. DOI:10.1371/journal.pone.0062372 · 3.23 Impact Factor
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    • "SAA augments the inflammatory response in a cytokine-like fashion by attracting monocytes/macrophages, leukocytes and T lymphocytes, while promoting neutrophil survival and endothelial activation and stimulating the production of the proinflammatory mediators TNF, IL-1, IL-6, IL-8, and IL-17, thus initiating an amplifying loop. Exposure of synovial fibroblasts and chondrocytes to SAA promotes MMP-3 mediated adhesion molecule expression, as well as phagocytosis and chemotaxis of monocytes and neutrophils, thereby contributing to synovial inflammation, hyperplasia, angiogenesis, and joint destruction [9]. SAA has also been implicated in the pathogenesis of atherosclerosis and premature cardiovascular disease, an important aspect in the management of patients with RA, thus making it a potential target for therapy to control both RA and its complications. "
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    ABSTRACT: Matrix metalloproteinase-3 (MMP-3) is involved in the immunopathogenesis of rheumatoid arthritis (RA), but little is known about its relationship to genetic susceptibility and biomarkers of disease activity, especially acute phase reactants in early RA. MMP-3 was measured by ELISA in serum samples of 128 disease-modifying, drug-naïve patients and analysed in relation to shared epitope genotype, a range of circulating chemokines/cytokines, acute phase reactants, autoantibodies, cartilage oligomeric protein (COMP), and the simplified disease activity index (SDAI). MMP-3 was elevated >1.86 ng/ml in 56.25% of patients (P < 0.0001), correlated with several biomarkers, notably IL-8, IL-6, IFN γ, VEGF and COMP (r values = 0.22–0.33, P < 0.014–0.0001) and with CRP and SAA levels (r = 0.40 and 0.41, resp., P < 0.0000) and SDAI (r = 0.29, P < 0.0001), but not with erosions or nodulosis. However, the correlations of CRP and SAA with SDAI were stronger (respective values of 0.63 and 0.54, P < 0.001 for both). COMP correlated with smoking, RF, and MMP-3. MMP-3 is significantly associated with disease activity, inflammatory mediators and cartilage breakdown, making it a potential biomarker of disease severity, but seemingly less useful than CRP and SAA as a biomarker of disease activity in early RA.
    Mediators of Inflammation 04/2013; 2013(4):183653. DOI:10.1155/2013/183653 · 3.24 Impact Factor
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