Trial of atorvastatin in rheumatoid arthritis (TARA): Double-blind, randomised placebo-controlled trial

McCarey, David; McInnes, I.; Madhok, Rajan

doi:10.1016/j.accreview.2004.08.010

Cited by 165 publications

(219 citation statements)

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“…Aufgrund dieser Ergebnisse und der postulierten pleiotropen Effekte scheint es nahe liegend, dass Statine auch bei Patienten mit chronisch-systemischer Inflammation einen günstigen Effekt auf die Endothelfunktion ausüben. Eigene Daten zeigen eine signifikante Verbesserung der FMD durch Simvastatin [65,66] [69,70], was zu einer Erhöhung der Thrombozytenaktivierung, -adhäsion und -aggregation führt. Dies könnte potentiell zu mehr thrombotischen und ischämischen Ereignissen führen.…”

Section: Tnf-α-antagonistenunclassified

Rheumatoide Arthritis, Inflammation und Atherosklerose

Hürlimann¹,

Enseleit²,

Ruschitzka³

2004

Herz

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Patients with rheumatoid arthritis (RA) have a two to five times increased risk of developing premature cardiovascular disease that shortens life expectancy by 5-10 years. Traditional risk factors known to promote and accelerate the progression of atherosclerotic lesions however, are often absent in patients with RA. Many similarities have emerged between the paradigm of inflammation in the pathogenesis of atherosclerosis and the well-established mechanisms of inflammation in the pathogenesis of RA. Hence it is intriguing to speculate that inflammation in RA is not confined to the joints but also present in the vessel wall. Indeed, low-grade inflammation and endothelial dysfunction play pivotal roles in the initiation, progression and propagation of the atherosclerotic process. While the healthy endothelium prevents adhesion of mononuclear cells, the defence mechanisms cease under the influence of cardiovascular risk factors and inflammation and they express adhesion molecules (selectins, vascular adhesion molecule-([VCAM-]1, intercellular adhesion molecule-[ICAM-]1) that promote the adherence of monocytes. This expression is induced by pro-inflammatory cytokines such as interleukin-(IL-)1beta and tumor necrosis factor-(TNF-)alpha, by C-reactive protein (CRP), and CD40/CD40 ligand interactions. As all of these factors are present at increased levels in the systemic circulation in RA, it appears possible that they might impact the endothelium as well. Further similarities include proteolytic enzymes such as matrix metalloproteinases (MMPs) that play a role in joint destruction as well as in destabilization and rupture of vulnerable atherosclerotic plaques. In addition, coagulation factors such as increased levels of tissue factor (TF), van Willebrand factor (vWF) and plasminogen activator inhibitor-(PAI-)1 are important in both, RA and CAD. Endothelial dysfunction has shown to correlate with cardiovascular prognosis in several studies, which indicates its clinical relevance. Endothelial function measurement is performed in the coronary or peripheral circulation (by venous occlusion plethysmography or flow-mediated dilation). Recent studies have demonstrated impaired endothelial function in patients with RA, already at early stages of the disease. Similar results are found in patients with systemic lupus erythematosus (SLE), indicating that inflammation per se may impair altering vascular function. This and more evidence supports the notion that inflammation plays a pivotal role in vascular dysfunction and may by these mechanisms explain at least part of the excess morbidity and mortality observed in RA and SLE. In light of the growing evidence of increased cardiovascular morbidity and mortality mostly independent of traditional risk factors, treatment strategies in RA should not only aim at relieving symptoms and inhibiting joint destruction but should have a beneficial effect on the vasculature to reduce cardiovascular events. Indeed, an improvement in endothelial function in RA was recently demonstrated by anti-...

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Section: Tnf-α-antagonistenunclassified

Rheumatoide Arthritis, Inflammation und Atherosklerose

Hürlimann¹,

Enseleit²,

Ruschitzka³

2004

Herz

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“…Increasing evidence implicates the beneWcial eVect of statins for treatment of RA [20,22,25,26,38]. However, the exact mechanisms by which statins modulate inXammation of RA remain to be established in detail.…”

Section: Discussionmentioning

confidence: 98%

“…Accumulating evidence supports the notion that statins have therapeutic potential for autoimmune diseases such as RA. For instance, several clinical trials demonstrated the beneWcial eVects of statins therapy on patients with RA [24][25][26]. Concordant results of statins therapy were obtained on rodent animal models of RA through inhibiting the pathogenic Th1 and proinXammatory responses [27,28].…”

Section: Introductionmentioning

confidence: 95%

HMG-CoA reductase inhibitor simvastatin suppresses Toll-like receptor 2 ligand-induced activation of nuclear factor kappa B by preventing RhoA activation in monocytes from rheumatoid arthritis patients

et al. 2010

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To investigate whether anti-inflammatory effects of HMG-CoA reductase inhibitor simvastatin (SMV) in rheumatoid arthritis (RA) is mediated by Toll-like receptor-2 (TLR-2) signal via inhibiting activation of RhoA, a small Rho GTPase that plays an important role in inflammatory responses. Peripheral blood monocytes from active RA patients were treated with Staphylococcus aureus peptidoglycan (PG), a ligand of TLR-2, in the presence or absence of SMV. RhoA activity was assessed by a pull-down assay. DNA-binding activity was measured by a sensitive multi-well colorimetric assay. Cytokine secretion was measured by ELISA. PG stimulation increased the level of active GTP-bound RhoA compared with unstimulated monocytes, and the effect of PG on RhoA activity was suppressed with anti-TLR-2 monoclonal antibody. RhoA inhibition either with a specific inhibitor or by siRNA transfection inhibited activation of NF-κB and secretion of TNFα and IL-1β in PG-induced RA monocytes. SMV mitigated PG-induced increase in RhoA activity and NF-κB activation as well as secretion of TNFα and IL-1β. The inhibitory effects of SMV were completely reversed by mevalonate and geranylgeranyl pyrophosphate. Our results indicate the modulation of RhoA on TLR-2-mediated inflammatory signaling in RA and provide a novel evidence for anti-inflammatory effects of statins through influencing TLR-2 signaling via RhoA in RA.

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“…This comorbidity is not fully explained by traditional risk factors. However, clinical evidence indicates that suppression of inXammation reduces the risk of cardiovascular morbidity and mortality in patients with severe RA [36]. The Weld of biomarkers is a growing one, particularly in OA [37].…”

Section: Discussionmentioning

confidence: 99%

White cells count in smokers affected by rheumatic diseases

et al. 2010

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Evidence shows that tobacco smoking interacts with development of rheumatic diseases. Increase in white cells count (leukocytosis) is frequently present, and in smokers, it is considered a biomarker of cardiovascular risk. Aim of the study is to evaluate this biomarker in smokers with rheumatic diagnosis. We carried out an observational study on 115 rheumatic outpatients (26 men and 89 women) divided into two groups according to their smoking habit: one composed of 56 smokers, the other of 59 not smokers. Diagnosis and common routinary clinical parameters were collected. In the total sample, smokers were 48.69%. Most common diagnosis was osteoarthritis (OA) (40.87% of the total); smokers in OA women were 36.11%, smokers in OA men were 54.55%. Second most common diagnosis was rheumatoid arthritis (RA) (23.48% of the total); smokers in RA women were 40.91%; smokers in RA men were 80%. OA smokers showed a significant increase (P < 0.05) in white cells count when compared with OA not smokers. Between RA smokers and not smokers, any clinical difference was found. RA subjects following regular pharmacological treatment in the last 2 months were 84.61%. OA patients treated with drugs in the last 2 months were only 22.2%. Results seem to confirm that smoking habit may influence the development as well as gender distribution of rheumatic diseases. They show also that in absence of pharmacological treatment in smokers affected by OA leukocytosis (biomarker of cardiovascular risk) is observed.

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Trial of atorvastatin in rheumatoid arthritis (TARA): Double-blind, randomised placebo-controlled trial

Cited by 165 publications

References 0 publications

Rheumatoide Arthritis, Inflammation und Atherosklerose

Rheumatoide Arthritis, Inflammation und Atherosklerose

HMG-CoA reductase inhibitor simvastatin suppresses Toll-like receptor 2 ligand-induced activation of nuclear factor kappa B by preventing RhoA activation in monocytes from rheumatoid arthritis patients

White cells count in smokers affected by rheumatic diseases

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