Acute-Phase Serum Amyloid A Regulates Tumor Necrosis Factor alpha 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: 7.87). 04/2012; 64(4):1035-45. DOI: 10.1002/art.33455
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ABSTRACT 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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    • "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; 2013:183653. DOI:10.1155/2013/183653 · 3.24 Impact Factor
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    ABSTRACT: Most notable among the acute phase proteins is serum amyloid A (SAA), levels of which can increase 1000-fold during infections, aseptic inflammation, and/or trauma. Chronically elevated SAA levels are associated with a wide variety of pathological conditions, including obesity and rheumatic diseases. Using a recombinant hybrid of the two human SAA isoforms (SAA1 and 2) that does not exist in vivo, numerous in vitro studies have given rise to the notion that acute phase SAA is a pro-inflammatory molecule with cytokine-like properties. It is however unclear whether endogenous acute phase SAA per se mediates pro-inflammatory effects. We tested this in samples from patients with inflammatory arthritis and in a transgenic mouse model that expresses human SAA1. Endogenous human SAA did not drive production of pro-inflammatory IL-8/KC in either of these settings. Human neutrophils derived from arthritis patients displayed no signs of activation, despite being exposed to severely elevated SAA levels in circulation, and SAA-rich sera also failed to activate cells in vitro. In contrast, two recombinant SAA variants (the hybrid SAA and SAA1) both activated human neutrophils, inducing L-selectin shedding, production of reactive oxygen species, and production of IL-8. The hybrid SAA was approximately 100-fold more potent than recombinant SAA1. Recombinant hybrid SAA and SAA1 activated neutrophils through different receptors, with recombinant SAA1 being a ligand for formyl peptide receptor 2 (FPR2). We conclude that even though recombinant SAAs can be valuable tools for studying neutrophil activation, they do not reflect the nature of the endogenous protein.
    Frontiers in Immunology 04/2013; 4:92. DOI:10.3389/fimmu.2013.00092
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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 · 3.53 Impact Factor
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