Identification of a cytokine network sustaining neutrophil and Th17 activation in untreated early rheumatoid arthritis

© 2010 Cascão et al.; licensee BioMed Central Ltd. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Introduction: Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease characterized by sustained synovitis. Recently, several studies have proposed neutrophils and Th17 cells as key players in the onset and perpetuation of this disease. The main goal of this work was to determine whether cytokines driving neutrophil and Th17 activation are dysregulated in very early rheumatoid arthritis patients with less than 6 weeks of disease duration and before treatment (VERA). Methods: Cytokines related to neutrophil and Th17 activation were quantified in the serum of VERA and established RA patients and compared with other very early arthritis (VEA) and healthy controls. Synovial fluid (SF) from RA and osteoarthritis (OA) patients was also analyzed. Results: VERA patients had increased serum levels of cytokines promoting Th17 polarization (IL-1b and IL-6), as well as IL-8 and Th17-derived cytokines (IL-17A and IL-22) known to induce neutrophil-mediated inflammation. In established RA this pattern is more evident within the SF. Early treatment with methotrexate or corticosteroids led to clinical improvement but without an impact on the cytokine pattern. Conclusions: VERA patients already display increased levels of cytokines related with Th17 polarization and neutrophil recruitment and activation, a dysregulation also found in SF of established RA. 0 Thus, our data suggest that a cytokine-milieu favoring Th17 and neutrophil activity is an early event in RA pathogenesis.This work was supported by a grant from Sociedade Portuguesa de Reumatologia/Schering-Plough 2005. RAM and RC were funded by Fundação para a Ciência e a Tecnologia (FCT) SFRH/BD/30247/2006 and SFRH/BD/40513/2007, respectively. MMS-C was funded by Marie Curie Intra-European Fellowship PERG-2008-239422 and a EULAR Young Investigator Award

Cartilage oLIGOMERIC mATRIX pROTEIN - Inflammation biomarker in knee osteoarthritis

Chondrocytes and synovial cells synthesize Cartilage Oligomeric Matrix Protein (COMP) when activated by proinflammatory cytokines. The aim of this study was to analyze and compare ultrasound parameters of joint inflammation, effusion and synovitis with the levels of COMP in the serum of patients with primary osteoarthritis. Ultrasound was done and the concentration of COMP (ng/mL was examined in 88 patients. 75% of patients had effusion (size 10.13±4.35 mm), 62.5% had effusion in lateral recessus (LR), 28.4% (size 8.53±2.27 mm) in suprapatelar (SR), and 27.3% (size 11.38±4.44 mm) in medial (MR). 67% of patients had synovitis size 4.84±3.57 mm in SR, 3.15±1.86 mm in MR; and 6.09±2.80 mm in LR. 17.0% of patients had nodular type of synovitis, 30.7% had diffusive, and 19.3% nodular - diffusive. There was a significant link between the size of synovitis and effusion in SR (r=0.966, p=0.000), MR (r=0.812, p=0.009) and LR (r=0.886, p=0.003). The median of COMP concentration was 54 (44.5-58) ng/mL in patients without effusion. In those with effusion it was 57 (48.75-64.25) ng/mL (p=0.030). Without synovitis it was 52 (45.5-58) ng/mL, with synovitis 58 (50-66) ng/mL, (p=0.006), diffusion type synovitis 6o (50-67) ng/mL, nodular 57 (50-62) ng/mL, nodular-diffusion 54 (44.5-66.5) ng/mL (p=0.014). With longer osteophytes the median of COMP was 56 (48-64) ng/mL, with shorter osteophytes 55 (46.5-59) ng/mL (p=0.000). Cartilage oligomeric matrix protein has a moderate significance in the assessment of disturbance of the metabolism of synovial and cartilage tissue in patients with knee osteoarthritis (sensitivity=59%; specificity=5o%; cut off=53.5 ng/mL). © 2011 Association of Basic Medical Sciences of FBIH

Tumor necrosis factor-α blockade treatment decreased CD154 (CD40-ligand) expression in rheumatoid arthritis

CD154 (commonly referred to as CD40-ligand) is a critical T cell factor that participates in the pathogenesis of autoimmune and is over-expressed in rheumatoid arthritis (RA). TNF-α blockade treatment had dramatic efficacy in RA.To investigate whether TNF-α blockade treatment can inhibit CD154 expression in RA.Blood samples were collected from 33 patients with rheumatoid arthritis before and 3 months after TNF-α blockade treatment. Clinical serological data determined by standard assays and T cell CD154 expression levels determined by flow cytometry were statistically analyzed for these two time points.The percentage of CD154 expression on gated CD4+ T cells of PBMCs from RA patients after 3 months TNF-α blockade treatment was significantly lower than before treatment (2.94 ± 3.21% vs. 7.21 ± 5.64%; p = 0.0001). The disease activity and anti-CCP antibody levels were also significantly reduced after TNF-α blockade treatment. The CD154 expression levels were positively correlated with disease activity index DAS28, and CRP. The post-stimulated CD154 expression percentage of purified CD4+ T cells between baseline and after TNF-α blockade treatment was not significantly different (p = 0.221). Baseline CD154 levels were positively correlated with treatment-induced changes in DAS28 (p = 0.014; r2 = 0.187).TNF-α blockade treatment significantly decreased the CD154 expression on CD4+ T cells, disease activity and anti-CCP antibody simultaneously in RA patients. However TNF-α blockade did not impair T cell capacity to express CD154 after stimulation. These results suggest that decreased CD154 expression after TNF-α blockade may be due to decreased RA disease activity but not direct inhibition of CD154 responsiveness of T cells