Inhibition of Interleukin-1 by Anakinra Improves Vascular and Left Ventricular Function in Patients With Rheumatoid Arthritis

Abstract

Background-Interleukin-1 increases nitrooxidative stress. We investigated the effects of a human recombinant interleukin-1a receptor antagonist (anakinra) on nitrooxidative stress and vascular and left ventricular function. Methods and Results-In an acute, double-blind trial, 23 patients with rheumatoid arthritis were randomized to receive a single injection of anakinra (150 mg SC) or placebo and, after 48 hours, the alternative treatment. At baseline and 3 hours after the injection, we assessed (1) coronary flow reserve, aortic distensibility, systolic and diastolic (Em) velocity of the mitral annulus, and E to Em ratio (E/Em) using echocardiography; (2) flow-mediated, endothelium-dependent dilation of the brachial artery; and (3) malondialdehyde, nitrotyrosine, interleukin-6, endothelin-1, and C-reactive protein.In a chronic, nonrandomized trial, 23 patients received anakinra and 19 received prednisolone for 30 days, after which all indices were reassessed. Compared with baseline, there was a greater reduction in malondialdehyde, nitrotyrosine, interleukin-6, and endothelin-1 and a greater increase in flow-mediated dilation, coronary flow reserve, aortic distensibility, systolic velocity of mitral annulus, and E/Em after anakinra than after placebo (malondialdehyde Ϫ25% versus 9%; nitrotyrosine Ϫ38% versus Ϫ11%; interleukin-6 Ϫ29% versus 0.9%; endothelin-1 Ϫ36% versus Ϫ11%; flow-mediated dilation 45% versus Ϫ9%; coronary flow reserve 29% versus 4%; and aortic distensibility 45% versus 2%; PϽ0.05 for all comparisons). After 30 days of treatment, the improvement in biomarkers and in vascular and left ventricular function was greater in the anakinra group than in the prednisolone group (PϽ0.05). Conclusions

Interleukin-1 Blockade With Anakinra to Prevent Adverse Cardiac Remodeling After Acute Myocardial Infarction (Virginia Commonwealth University Anakinra Remodeling Trial [VCU-ART] Pilot Study)

“…26 Owing to the small number of patients or perhaps because of a different inciting event, we did not observe a significant reduction in C-reactive protein. Nevertheless, a significant correlation was seen between the C-reactive protein changes and LV remodeling.…”

Endothelial Dysfunction in Tristetraprolin-deficient Mice Is Not Caused by Enhanced Tumor Necrosis Factor-α Expression

“…Also in synovial fluids obtained from RA patients the levels of RONS including superoxide are significantly raised and positively correlated with higher Nox activity (62). In addition, increased levels of nitrotyrosine, another marker of oxidative stress, were detected in RA patients (63) and also in TTP Ϫ/Ϫ mice (Fig. 4D).…”

Anakinra and Its Rapidly Expanding Role in Management of Nonarthritic Systemic Disorders

“…It decreases necrosis of cardiac tissue following acute myocardial infarctions 2 , and thereby attenuates cardiac remodeling and prevents apoptosis and subsequent postinfarct complications such as cardiac failure. In patients with RA, anakinra increases the coronary flow reserve and decreases endothelin-1 levels, improving left ventricular function in these patients 3 . Similarly, Chada, et al have shown in an animal model that when anakinra is administered as an aerosol to surfactantdepleted lungs it reduces pulmonary inflammation, but also has a negative effect on the pulmonary artery pressure and thus ameliorates associated pulmonary hypertension 4 .…”