Effects of Interleukin-6 Inhibition on Vascular, Endothelial and Left Ventricular Function in Rheumatoid Arthritis

NCT ID: NCT03288584

Last Updated: 2020-04-03

Study Results

Results pending

The study team has not published outcome measurements, participant flow, or safety data for this trial yet. Check back later for updates.

Basic Information

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Recruitment Status

UNKNOWN

Total Enrollment

60 participants

Study Classification

OBSERVATIONAL

Study Start Date

2017-10-27

Study Completion Date

2020-12-31

Brief Summary

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Recent studies show beneficial effect of the inhibition of interleukin-6 (IL-6) activity on vascular and left ventricular (LV) function. The purpose of this study is to investigate whether anakinra, an IL-6 receptor antagonist, improves vascular, endothelial and LV function in patients with 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-6 (IL-6) activity. Increased IL-6 activity causes myocardial cell damage and endothelial dysfunction. The adverse effects of IL-6 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. Tocilizumab, a recombinant form of human IL-6 receptor antagonist, is commonly used for the treatment of RA. However it has not been defined whether inhibition of IL-6 activity by tocilizumab shows beneficial effects on endothelial, coronary, arterial and LV systolic and diastolic function in patients with RA.

For this purpose, we studied 60 patients with RA (American Rheumatism Association criteria). All the above subjects had an inadequate response to disease modifying antirheumatic drugs (DMARDs) and corticosteroids and were going to initiate treatment with IL-6 activity inhibitor (tocilizumab). All patients were on treatment with statins and cardioactive medications respectively, for the last 6 months.

All patients were randomized to receive a single injection of tocilizumab (150 mg s.c.), or other biological agent (TNFa inhibitor, abatacept, rituximab, IL-1Ra) or enhanced treatment with corticosteroid and non-biological agents.

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 months after the single injection of tocilizumab in RA subjects, we assessed the following parameters a)carotid-femoral pulse wave velocity (PWV), b) the LV dimensions,fractional shortening and wall motion score index (WMSI) c) 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 d) the LV longitudinal, circumferential and radial strain and strain rate, as well as Global Longitudinal strain and Torsion using speckle tracking echocardiography e) the coronary flow reserve (CFR)after adenosine infusion to assess coronary vasomotor function f) the flow-mediated endothelial-dependent dilation of the brachial artery (FMD) to assess peripheral endothelial function g) the diameters of aorta at systole and diastole to calculate the aortic strain as an index of local aortic properties, h) perfused boundary region (PBR) of the sublingual arterial microvessels (ranged from 5-25μm) using Sideview, Darkfield imaging (Microscan, Glycocheck). Increased PBR is considered an accurate index of reduced endothelial glucocalyx thickness because of a deeper red blood cells (RBC) penetration in the glucocalyx. At the same time periods, we measured in blood samples a) nitrotyrosine (NT), protein carbonyls (PC) and malondialdehyde (MDA) to assess oxidative stress, b) soluble Fas and Fas-ligand to assess apoptosis, and c) interleukin-6 and tumor necrosis factor-a to assess inflammation.

Conditions

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Rheumatoid Arthritis Inflammation

Study Design

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Observational Model Type

CASE_CONTROL

Study Time Perspective

PROSPECTIVE

Study Groups

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Tocilizumab

Inhibition of Interleukin-6 activity by tocilizumab (Actemra®) 150mg od, sc injection

Tocilizumab (Actemra®)

Intervention Type DRUG

Inhibition of Interleukin-6 activity by tocilizumab (Actemra®) 150mg od, sc injection

Other biological agent

Other biological agent (TNFa inhibitor, abatacept, rituximab, IL-1Ra)

Other biological agent

Intervention Type DRUG

Other biological agent (TNFa inhibitor, abatacept, rituximab, IL-1Ra)

Corticosteroid and non-biological agents.

Enhanced treatment with corticosteroid and non-biological agents.

Corticosteroid and non-biological agents.

Intervention Type DRUG

Enhanced treatment with corticosteroid and non-biological agents.

Interventions

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Tocilizumab (Actemra®)

Inhibition of Interleukin-6 activity by tocilizumab (Actemra®) 150mg od, sc injection

Intervention Type DRUG

Other biological agent

Other biological agent (TNFa inhibitor, abatacept, rituximab, IL-1Ra)

Intervention Type DRUG

Corticosteroid and non-biological agents.

Enhanced treatment with corticosteroid and non-biological agents.

Intervention Type DRUG

Eligibility Criteria

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Inclusion Criteria

* Patients with rheumatoid arthritis who had an inadequate response to disease modifying antirheumatic drugs (DMARDs) and corticosteroids and were going to initiate treatment with interleukin-6 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

Maximum Eligible Age

80 Years

Eligible Sex

ALL

Accepts Healthy Volunteers

Yes

Sponsors

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University of Athens

OTHER

Sponsor Role lead

Responsible Party

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Ignatios Ikonomidis

Associate Professor of Cardiology

Responsibility Role PRINCIPAL_INVESTIGATOR

Principal Investigators

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Ignatios Ikonomidis, MD

Role: PRINCIPAL_INVESTIGATOR

National and Kapodistrain University of Athens

Locations

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Attikon Hospital

Athens, Haidari, Greece

Site Status RECRUITING

Countries

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Greece

Central Contacts

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Ignatios Ikonomidis, MD

Role: CONTACT

00302105832187

John Lekakis, MD

Role: CONTACT

00302105832187

Facility Contacts

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Ignatios Ikonomidis, MD

Role: primary

00302105832187

References

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Ikonomidis I, Pavlidis G, Katsimbri P, Lambadiari V, Parissis J, Andreadou I, Tsoumani M, Boumpas D, Kouretas D, Iliodromitis E. Tocilizumab improves oxidative stress and endothelial glycocalyx: A mechanism that may explain the effects of biological treatment on COVID-19. Food Chem Toxicol. 2020 Nov;145:111694. doi: 10.1016/j.fct.2020.111694. Epub 2020 Aug 18.

Reference Type DERIVED
PMID: 32822775 (View on PubMed)

Ikonomidis I, Pavlidis G, Katsimbri P, Andreadou I, Triantafyllidi H, Tsoumani M, Varoudi M, Vlastos D, Makavos G, Kostelli G, Betaenas D, Lekakis J, Parissis J, Boumpas D, Alexopoulos D, Iliodromitis E. Differential effects of inhibition of interleukin 1 and 6 on myocardial, coronary and vascular function. Clin Res Cardiol. 2019 Oct;108(10):1093-1101. doi: 10.1007/s00392-019-01443-9. Epub 2019 Mar 11.

Reference Type DERIVED
PMID: 30859382 (View on PubMed)

Other Identifiers

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RA-IL6-ATTIKON

Identifier Type: -

Identifier Source: org_study_id

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