Effects of Interleukin-1 Inhibition on Vascular and Left Ventricular Function in Rheumatoid Arthritis Patients With Coronary Artery Disease

Study Results

Results pending

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Basic Information

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Recruitment Status

COMPLETED

Clinical Phase

NA

Total Enrollment

80 participants

Study Classification

INTERVENTIONAL

Study Start Date

2011-03-31

Study Completion Date

2013-06-30

Brief Summary

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Inhibition of interleukin-1 (IL-1) activity in patients with RA without CAD ameliorates vascular and LV function. Moreover, data from species shows beneficial effect of this treatment on LV function after experimental myocardial infarction. The purpose of this study is to investigate whether anakinra, an IL-1 receptor antagonist, improves vascular and left ventricular (LV) function in patients with coronary artery disease (CAD) and coexistent rheumatoid arthritis (RA).

Detailed Description

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The inflammatory processes observed in patients with rheumatoid arthritis (RA) are strongly linked to enhanced interleukin-1 (IL-1) activity. Increased IL-1 activity causes myocardial cell damage and endothelial dysfunction. The adverse effects of IL-1 on myocardial and endothelial cells are mediated by an enhanced nitrooxidative stress and the promotion of apoptotic cardiomyocyte death through increased nitrooxidative stress and inflammation. Anakinra, a recombinant form of human IL-1 receptor antagonist, is commonly used for the treatment of RA. Experimental data indicates that administration of anakinra after acute myocardial infarction ameliorates cardiac remodeling by reducing cardiomyocyte apoptosis. Moreover, in our previous studies we have shown that treatment with anakinra reduces IL-1-mediated nitrooxidative stress and apoptotic markers leading to an improvement in Tissue Doppler and speckle tracking-derived parameters of left ventricular (LV) function in RA patients. However it has not been defined whether inhibition of IL-1 activity by anakinra shows beneficial effects on endothelial, coronary, arterial and LV systolic and diastolic function in patients with coronary artery disease (CAD).

For this purpose, we studied 60 patients with CAD and coexistent RA (American Rheumatism Association criteria) as well as 20 patients with RA and without CAD. All the above subjects had an inadequate response to disease modifying antirheumatic drugs (DMARDs) and corticosteroids and were going to initiate treatment with IL-1 activity inhibitor (anakinra). All patients were on treatment with statins and cardioactive medications respectively, for the last 6 months. In the 20 patients with only RA, the presence of CAD was excluded with a non-invasive test and/or a negative recent coronary arteriogram.

In a double-blind, placebo-controlled fashion, all patients were randomized to receive a single injection of anakinra(100 mg s.c.) or placebo. After 48-hours patients were crossed over to the alternate treatment (placebo or anakinra) and measurement of the examined markers was repeated. The 48h interval between the 2 consecutive studies was decided to secure a sufficient wash-out period of anakinra in accordance to the drug's half-life time.

Twenty asymptomatic subjects matched for age and sex as the RA patients and with a normal ECG, echocardiogram, and treadmill test were selected as healthy control subjects among subjects attending the cardiology outpatients' clinic.

At baseline in all RA subjects and controls as well as 3-hours after the single injection of anakinra in RA subjects, we assessed by means of echocardiography the following parameters a) the LV dimensions,fractional shortening and wall motion score index (WMSI) b) the systolic (Sm), early diastolic (Em) and late diastolic (Am) myocardial velocities of the mitral annulus by using of tissue Doppler (TDI) as well as the ratio of E wave of the mitral inflow measured by pulsed wave Doppler to the mean Em as an index of LV diastolic filling pressures c) the LV longitudinal, circumferential and radial strain and strain rate, as well as Global Longitudinal strain and Torsion using speckle tracking echocardiography d) the coronary flow reserve (CFR)after adenosine infusion to assess coronary vasomotor function e) the flow-mediated endothelial-dependent dilation of the brachial artery (FMD) to assess peripheral endothelial function f) the diameters of aorta at systole and diastole to calculate the aortic strain as an index of local aortic properties. At the same time periods, we measured in blood samples a) nitrotyrosine (NT), protein carbonyls (PC)and malondialdehyde(MDA)to assess nitrooxidative stress b)soluble Fas and Fas-ligand )to assess apoptosis c) interleukin-1b and tumor necrosis factor-a to assess inflammation

Conditions

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Rheumatoid Arthritis Coronary Artery Disease Inflammation

Study Design

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Allocation Method

RANDOMIZED

Intervention Model

CROSSOVER

Primary Study Purpose

TREATMENT

Blinding Strategy

TRIPLE

Participants Investigators Outcome Assessors

Study Groups

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anakinra

Group Type ACTIVE_COMPARATOR

anakinra

Intervention Type DRUG

Inhibition of Interleukin-1 activity by anakinra (Kineret®) 100mg od, sc injection

placebo

Group Type PLACEBO_COMPARATOR

placebo

Intervention Type DRUG

water for injection

Interventions

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anakinra

Inhibition of Interleukin-1 activity by anakinra (Kineret®) 100mg od, sc injection

Intervention Type DRUG

placebo

water for injection

Intervention Type DRUG

Other Intervention Names

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Kineret® (anakinra) water for injection

Eligibility Criteria

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Inclusion Criteria

* Patients with rheumatoid arthritis and coexistent coronary artery disease or without CAD who had an inadequate response to disease modifying antirheumatic drugs (DMARDs) and corticosteroids and were going to initiate treatment with interleukin-1 inhibitor.

Exclusion Criteria

* Familiar hyperlipidemia
* Diabetes mellitus
* Chronic obstructive pulmonary disease or asthma, moderate or severe valvular heart disease, primary cardiomyopathies,malignant tumors

Minimum Eligible Age

18 Years

Eligible Sex

ALL

Accepts Healthy Volunteers

Yes

Responsible Party

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Ignatios Ikonomidis

Assistant Professor in Cardiology

Responsibility Role PRINCIPAL_INVESTIGATOR