Long-Term Anti-TNF-α Treatments Reverse the Endothelial Dysfunction in Rheumatoid Arthritis: The Biological Coherence between Synovial and Endothelial Inflammation

Abstract

Rheumatoid arthritis (RA) is associated with an excess cardiovascular morbidity and mortality, related to systemic inflammation with endothelial dysfunction (ED) and impaired flow-mediated vasodilation (FMD). We assessed the FMD response to anti-TNF-a treatments in 28 RA patients, aged 49.8±15.3 years: an unpaired FMD was found in 66.7% of our cases and was restored after 6 weeks of anti-TNF-a treatment (13.5±5.3% vs 4.6±4.1 %, p < 0.05). Twenty-five percent of the infliximab patients demonstrated a long term response, compared with 60% of etanercept and 100% of adalimumab patients, after 2 years (p<O.OI). Infections (3 cases), myocardial ischemia (I case) or loss of response (4 cases) were associated with a worsened FMD, restored by shifting to adalimumab. The present study confirms that ED is an RA systemic disease marker, responsive to anti-TNF-a treatment and sensitive to clinical events or to a loss of response, underlying the biological coherence between synovial and endothelial inflammation.

Anti-arthritic effects of clematichinenoside (AR-6) on PI3K/Akt signaling pathway and TNF-α associated with collagen-induced arthritis

“…Several studies have shown that the levels of TNF-α correlated with arthritis severity, and that TNF-α neutralizing therapy using Anti-TNF-α monoclonal antibody and soluble TNF receptor improves clinical symptoms and inhibits (or even reverses) inflammatory bone destruction in RA . In synovial tissue of RA patients, a positive regulatory cycle is produced whereby NF-κB induces the transcription of pro-inflammatory cytokines such as TNF-α, and cell adhesion molecules (Capria et al, 2010). Moreover, our previous study has demonstrated this upon treatment with AR-6 in CIA rats.…”

Inhibition of inflammatory mediators and related signaling pathways by macrophage-stimulating protein in rheumatoid arthritis synovial fibroblasts

“…A broad range of stimuli including the cytokines, TNF-a or IL-1b, and chemokines activate the NF-kB dimers by triggering a signaling pathway that leads to the phosphorylation of IkB. In synovial tissue of RA patients, a positive regulatory cycle is produced whereby NF-jB induces the transcription of pro-inflammatory cytokines, such as IL-1b and TNF-a, chemokines, and cell adhesion molecules and promotes the expression of COX-2, iNOS and MMPs in many cell types [13]. Moreover, the overexpression of inflammatory factors has been shown to induce the activation of NF-jB in the positive feedback loop [13].…”

“…In synovial tissue of RA patients, a positive regulatory cycle is produced whereby NF-jB induces the transcription of pro-inflammatory cytokines, such as IL-1b and TNF-a, chemokines, and cell adhesion molecules and promotes the expression of COX-2, iNOS and MMPs in many cell types [13]. Moreover, the overexpression of inflammatory factors has been shown to induce the activation of NF-jB in the positive feedback loop [13]. In the present study, the expression of p-p65 (activated NF-jB subunit), p-IKBa and p-IKBb was measured to determine whether NF-jB is activated in RASF stimulated by LPS.…”

Targeting inflammation in the prevention of cardiovascular disease in patients with inflammatory arthritis

“…103 Decreased FMD correlates well with invasive tests of coronary endothelial dysfunction and atherosclerosis, and predicts CV events in population-based studies. 104,105 In patients with inflammatory arthritis, most studies revealed transient [106][107][108][109] or even sustained ($12 weeks) [110][111][112][113][114][115] improvement in macrovascular function by anti-TNF treatment, whereas only 3 studies found no improvement. 75,95,116 In a study comparing anti-TNF treatment and traditional DMARDs, more significant improvement in FMD was observed in the anti-TNF group.…”