Exercise-induced Cardiac Adaptions in Rheumatoid Arthritis Patients During IL-6 vs. TNF Antibody Therapy

Rigshospitalet, Denmark69 enrolled

Overview

The present study will investigative the physiological effects of the cytokines interleukin-6 (IL-6) and tumor necrosis factor (TNF) on the adaptive changes to exercise in patients with rheumatoid arthritis. The investigators hypothesize that blockage of IL-6 receptors will decrease the cardiac and metabolic adaptations to exercise training compared to the inhibition of TNF. 80 patients will be included in a 12-week investigator blinded randomised exercise training intervention study.

80 patients with rheumatoid arthritis who are being treated with either interleukin-6 receptor blockers (IL-6Rb) or tumor necrosis factor inhibitors (TNFi) for a minimum of four months prior to enrollment will be recruited and undergo baseline testing, including examination, biochemistry, ECG, DXA, OGTT, pulmonary function, VO2max, echocardiography, cardiac MRI. After baseline testing, 40 patients in IL-6 receptor blocker treatment and 40 patients in TNF inhibitor treatment.will be randomly allocated into one group receiving standard of care (control group) or a group performing supervised high-intensity interval training three times a week over a period of 12 weeks. The randomization procedure involves a computer-generated block randomization schedule in a ratio of 1:1 stratified by sex by an independent person. Following the 12-week intervention period, all groups will complete a series of follow-up tests (as baseline testing).

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

HEALTH_SERVICES_RESEARCH

Masking

SINGLE

Enrollment

Conditions

Rheumatoid Arthritis

Interventions

ExerciseBEHAVIORAL

Supervised high-intensity interval training for 12 weeks three times per week. The supervision may be physical or online supervision

No exerciseBEHAVIORAL

Control group, therefore no supervised exercise regime

Eligibility

Sex: ALLMin age: 18 YearsMax age: 70 YearsHealthy volunteers:

Medical Language ↔ Plain English

Inclusion Criteria: * Age \>= 18 and \<70 years * Informed consent * Diagnosed RA based on the 2010 American College of Rheumatology/ EULAR criteria. In biological treatment with either IL-6rB og TNFi over four months prior to enrollment * Low RA disease activity, based on the Disease Activity Score-28 ESR for Rheumatoid Arthritis (DAS28) \<=3.2 * An electrocardiogram without features of left ventricular hypertrophy defined by the European Society of Cardiology * Females of childbearing potential have to use one or more of the following highly effective methods for contraception in order to be included: * Vasectomized partner * Bilateral tubal occlusion * Sexual abstinence * Intrauterine device * Hormonal contraception * Females who are considered to have no childbearing potential are * Bilateral tubal ligation * Bilateral oophorectomy * Complete hysterectomy * Postmenopausal defined as 12 months with no menses without an alternative medical cause Exclusion Criteria: * Health conditions that prevent participating in the exercise intervention determined by the Project Coordinator * Subjects who cannot undergo MRI scans (metallic implants or claustrophobia) * Corticosteroid use per os \> 10 mg/day within seven days of study enrollment * Intramuscular corticosteroid within 3 weeks of the study enrollment * Grade 2 hypertension (systolic BP \> 160 mmHg and/or diastolic BP \>100 mmHg) despite the use of antihypertensive drugs. * Pregnancy * Subjects with insulin dependent Diabetes

Locations (1)

Rigshospitalet

Copenhagen, Denmark

Outcomes

Primary Outcomes

Change in left ventricular mass

measured by MRI scan

Time frame: 12 weeks

Secondary Outcomes

Visceral adipose tissue mass

measured by MRI scan

Time frame: 12 weeks

Stroke volume

Structural cardiac parameter: measured by MRI scan and echocardiography

Time frame: 12 weeks

Left ventricular and atrial end-diastolic volume

Structural cardiac parameter: measured by MRI scan and echocardiography

Time frame: 12 weeks

LVEF

Functional cardiac parameters: measured by MRI scan and echocardiography

Time frame: 12 weeks

Global longitudinal strain

Functional cardiac parameters: measured by MRI scan and echocardiography

Time frame: 12 weeks

E/A ratio

Functional cardiac parameters: measured by MRI scan and echocardiography

Time frame: 12 weeks

E/é

Functional cardiac parameters: measured by MRI scan and echocardiography

Time frame: 12 weeks

Left ventricular and atrial end-systolic volume

Structural cardiac parameter: measured by MRI scan and echocardiography

Data from ClinicalTrials.gov

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Time frame: 12 weeks

Left atrial volume index

Structural cardiac parameter: measured by MRI scan and echocardiography

Time frame: 12 weeks

Interventricular septum thickness

Structural cardiac parameter: measured by MRI scan and echocardiography

Time frame: 12 weeks

Left ventricular posterior wall thickness

Structural cardiac parameter: measured by MRI scan and echocardiography

Time frame: 12 weeks

Aortic and pulmonary distensibility and pulse wave velocity

Functional vascular parameter: measured by MRI

Time frame: 12 weeks

Subcutaneous, visceral and epicardial adipose tissue

Measured by MRI and MR spectroscopy

Time frame: 12 weeks

Intramyocardial triglyceride content

Measured by MRI and MR spectroscopy

Time frame: 12 weeks

Cardiorespiratory fitness

Measured with an incremental VO2 protocol on exercise bike

Time frame: 12 weeks

Dynamic spirometry

Pulmonary function testing

Time frame: 12 weeks

Whole body plethysmography

Pulmonary function testing

Time frame: 12 weeks

Diffusion capacity

Pulmonary function testing

Time frame: 12 weeks

Body composition

Measured by a DXA scan

Time frame: 12 weeks

Oral glucose tolerance test

75g of glucose taken while fasting

Time frame: 12 weeks

Axial accelerometer-based physical activity monitors

Free-living physical activity is measured using axial accelerometer-based physical activity monitors (AX3; Axivity, Newcastle upon Tyne, UK) for a 5-day period

Time frame: 5 days in week 6 of the intervention/control

Dietary intake

Self reported intake of all foods and liquids

Time frame: 3 days in the week 6 of intervention/control

Blood sample

Change in fasting total cholesterol, low-density lipoprotein (LDL)-cholesterol and high-density lipoprotein (HDL)-cholesterol (mmol/L). Following an overnight fast (10 hours), blood samples are collected and processed by a trained laboratory technician and analysed according to standard procedures.

Time frame: 12 weeks

Blood sample

Change in triglycerides (mmol/L). Following an overnight fast (10 hours), blood samples are collected and processed by a trained laboratory technician and analysed according to standard procedures.

Time frame: 12 weeks

RA disease specific outcomes 1

Change in measures of the international Core Outcome Set for rheumatoid arthritis : 66/68 tender and swollen joint count

Time frame: 12 weeks

RA disease specific outcomes 2

Change in visual analogue scale (VAS) pain, VAS physician global assessment, VAS patient global assessment The Visual Analogue Scale (VAS) is a self-report measure consisting simply of a 100 mm horixontal line with a statement at each end representing one extreme (0mm = nothing, 100mm = extreme)

Time frame: 12 weeks

RA disease specific outcomes 3

Change in Health Assessment Questionnaire (HAQ-DI) Total score is between 0-3.0. Increasing scores indicate worse functioning with 0 indicating no functional impairment and 3 indicating complete impairment.

Time frame: 12 weeks

RA disease specific outcomes 4

Change in Short Form 36 (SF-36) Health Survey Questionnaire A 8-scale score within 8 domains.All items are scored so that a high score defines a more favorable health state.

Time frame: 12 weeks

RA disease specific outcomes 5

Change in the composite Disease Activity Score-28 ESR for Rheumatoid Arthritis (DAS28). A DAS28 of greater than 5.1 implies active disease, less than 3.2 low disease activity, and less than 2.6 remission

Time frame: 12 weeks

RA disease specific outcomes 6

Change in response criteria will be assessed according the clinical disease activity index (CDAI). The CDAI composite index quantifies disease activity in RA, by utilising four clinical parameters including tender and swollen joints and global assessment from both patient and assessor on a vasual analogue scale. CDAI interpretation score CDAI ≥ 22,1: High Activity CDAI \< 22,1 og ≥10,1: Moderate Activity CDAI \<10,0 og ≥ 2,9: Low Activity CDAI \<2,9: Remission

Time frame: 12 weeks

RA disease specific outcomes 7

Change in response criteria will be assessed according the American College of Rheumatology (ACR 20/50/70) response

Time frame: 12 weeks

RA disease specific outcomes 8

Change in response criteria will be assessed according the European League Against Rheumatism (EULAR none/good/moderate response)

Time frame: 12 weeks