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

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ClinicalTrials.gov Identifier: NCT03288584
Recruitment Status : Recruiting
First Posted : September 20, 2017
Last Update Posted : July 9, 2018
Sponsor:
Information provided by (Responsible Party):
Ignatios Ikonomidis, University of Athens

Brief Summary:
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).

Condition or disease Intervention/treatment
Rheumatoid Arthritis Inflammation Drug: Tocilizumab (Actemra®) Drug: Other biological agent Drug: Corticosteroid and non-biological agents.

Detailed Description:

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.


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Study Type : Observational
Estimated Enrollment : 60 participants
Observational Model: Case-Control
Time Perspective: Prospective
Official Title: The Effect of Inhibition of Interleukin-6 Activity on Vascular, Endothelial and Left Ventricular Function in Patients With Rheumatoid Arthritis
Actual Study Start Date : January 2017
Estimated Primary Completion Date : December 2018
Estimated Study Completion Date : June 2019

Resource links provided by the National Library of Medicine


Group/Cohort Intervention/treatment
Tocilizumab
Inhibition of Interleukin-6 activity by tocilizumab (Actemra®) 150mg od, sc injection
Drug: Tocilizumab (Actemra®)
Inhibition of Interleukin-6 activity by tocilizumab (Actemra®) 150mg od, sc injection

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

Corticosteroid and non-biological agents.
Enhanced treatment with corticosteroid and non-biological agents.
Drug: Corticosteroid and non-biological agents.
Enhanced treatment with corticosteroid and non-biological agents.




Primary Outcome Measures :
  1. Reduction of pulse wave velocity after treatment with tocilizumab [ Time Frame: 3 months after treatment ]
    Reduction of pulse wave velocity (PWV, m/sec) using tonometry after administration of tocilizumab

  2. Increase of global longitudinal strain after treatment with tocilizumab [ Time Frame: 3 months after treatment ]
    Increase of left ventricular global longitudinal strain (GLS, %) using speckle tracking echocardiography after administration of tocilizumab


Secondary Outcome Measures :
  1. Reduction of malondialdehyde after treatment with tocilizumab [ Time Frame: 3 months after treatment ]
    Reduction of malondialdehyde (MDA, nmol/L) using spectrophotometry after treatment with tocilizumab

  2. Reduction of protein carbonyls after treatment with tocilizumab [ Time Frame: 3 months after treatment ]
    Reduction of protein carbonyls (PCs, nmol/mg protein) using spectrophotometry after treatment with tocilizumab

  3. Increased of endothelial glycocalyx thickness after treatment with tocilizumab [ Time Frame: 3 months after treatment ]
    Increased of endothelial glycocalyx thickness as assessed by perfused boundary region (PBR, micrometers) of the sublingual arterial microvessels after treatment with tocilizumab



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Ages Eligible for Study:   18 Years to 80 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Sampling Method:   Probability Sample
Study Population
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.
Criteria

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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03288584


Contacts
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Contact: Ignatios Ikonomidis, MD 00302105832187 ignoik@otenet.gr
Contact: John Lekakis, MD 00302105832187 lekakisster@gmail.com

Locations
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Greece
Attikon Hospital Recruiting
Athens, Haidari, Greece, 12462
Contact: Ignatios Ikonomidis, MD    00302105832187    ignoik@otenet.gr   
Principal Investigator: Ignatios Ikonomidis, MD         
Principal Investigator: Pelagia Katsimbri, MD         
Principal Investigator: Ioanna Andreadou, PhD         
Principal Investigator: George Pavlidis, MD         
Principal Investigator: Dimitrios Boumpas, MD         
Principal Investigator: John Lekakis, MD         
Principal Investigator: Efstathios Iliodromitis, MD         
Sponsors and Collaborators
University of Athens
Investigators
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Principal Investigator: Ignatios Ikonomidis, MD National and Kapodistrain University of Athens

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: Ignatios Ikonomidis, Associate Professor of Cardiology, University of Athens
ClinicalTrials.gov Identifier: NCT03288584     History of Changes
Other Study ID Numbers: RA-IL6-ATTIKON
First Posted: September 20, 2017    Key Record Dates
Last Update Posted: July 9, 2018
Last Verified: July 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Ignatios Ikonomidis, University of Athens:
Arterial stiffness
Endothelial function
Endothelial glycocalyx
Left ventricular function
Apoptosis
Oxidative stress
Additional relevant MeSH terms:
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Arthritis
Arthritis, Rheumatoid
Inflammation
Joint Diseases
Musculoskeletal Diseases
Rheumatic Diseases
Connective Tissue Diseases
Autoimmune Diseases
Immune System Diseases
Pathologic Processes