Rheumatoide Arthritis, Inflammation und Atherosklerose

Zusammenfassung

Epidemiologische Untersuchungen bestätigten die Relevanz der systemischen Inflammation im Hinblick auf die Prognose atherosklerotischer Folgeerkrankungen. Interessanterweise zeigen sich bei Patienten mit chronischen systemischen Entzündungserkrankungen, z. B. rheumatoider Arthritis (RA) oder systemischem Lupus erythematodes (SLE), eine erhöhte kardiovaskuläre Morbidität und Mortalität, welche durch die klassischen Risikofaktoren allein nicht ausreichend zu erklären sind. In neueren Studien finden sich zudem viele Gemeinsamkeiten zwischen den entzündlichen Mechanismen der Atherosklerose und den bekannten etablierten Entzündungsmechanismen der RA. Unter anderem werden einige der gemeinsamen inflammatorischen Mechanismen, die für die synovialen Erosionen verantwortlich sind, auch für die Entstehung der instabilen Plaques verantwortlich gemacht, was die erhöhte kardiovaskuläre Mortalität der Patienten mit RA erklären könnte.

Interessanterweise zeigen Patienten mit RA oder SLE trotz Fehlens traditioneller Risikofaktoren eine endotheliale Dysfunktion. Verschiedene antiinflammatorische Medikamente, insbesondere Tumor-Nekrose-Faktor-(TNF-)α-Antagonisten, Statine und Celecoxib, die bei Patienten mit RA eingesetzt werden, können die Endothelfunktion verbessern. Wegen der prognostischen Bedeutung der Endothelfunktion könnte dies einen günstigen Einfluss auf die kardiovaskuläre Prognose haben. Ob und wie sich diese antiinflammatorischen Effekte zur Verbesserung der Endothelfunktion in die klinische Praxis übersetzen lassen, können nur große randomisierte, kontrollierte Studien mit klinischen Endpunkten schlüssig beantworten.

Abstract

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-)1β and tumor necrosis factor-(TNF-)α, 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-TNF-α therapy and statins.

Whether and to what degree the effects of anti-inflammatory strategies to improve endothelial function, which although clinically well established is still a surrogate, translate into clinical benefit for our patients with rheumatologic diseases needs to be determined in large-scale clinical trials some of which are now already under way.