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

Not Applicable

Completed

• Conditions: Rheumatoid Arthritis
• Interventions: Behavioral: No exercise; Behavioral: Exercise

• Registration Number: NCT05215509
• Lead Sponsor: Rigshospitalet, Denmark

Brief Summary

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.

Detailed Description

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 Timeline

• Study Start: 2021-01-01
• Study First Submitted: 2021-11-16
• Study First Submitted QC: 2022-01-28
• Study First Posted: 2022-01-31
• Primary Completion: 2023-08-10
• Study Completion: 2023-12-31
• Status Verified: 2024-02
• Last Update Submitted: 2024-02-01
• Last Update Posted: 2024-02-02

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 69

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

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
RA patients IL-6Rb Control	No exercise	This group will be allocated to "control" and therefore no supervised exercise regimen
RA patients TNFi Control	No exercise	This group will be allocated to "control" and therefore no supervised exercise regimen
RA patients TNFi Exercise	Exercise	The patients will be randomized to 12-week supervised exercise training intervention or no exercise training. The exercise training program includes three supervised sessions per week over a 12-week period. The program consists of high intensity endurance training on ergometer bicycles. The intensity will progress throughout the 12 weeks of training. The training consists of 10 minutes of warm up at 40-60% maximum heart rate (HRmax), followed by 25 minutes of high intensity interval training (4 bouts of 4 min at \>85% HRmax interspaced by 3 minutes of low intensity training at 40-60% Hrmax) and finally a 5 min cool-down of 50% Hrmax
RA patients IL-6Rb Exercise	Exercise	The patients will be randomized to 12-week supervised exercise training intervention or no exercise training. The exercise training program includes three supervised sessions per week over a 12-week period. The program consists of high intensity endurance training on ergometer bicycles. The intensity will progress throughout the 12 weeks of training. The training consists of 10 minutes of warm up at 40-60% maximum heart rate (HRmax), followed by 25 minutes of high intensity interval training (4 bouts of 4 min at \>85% HRmax interspaced by 3 minutes of low intensity training at 40-60% Hrmax) and finally a 5 min cool-down of 50% Hrmax

Primary Outcome Measures

Name	Time	Method
Change in left ventricular mass	12 weeks	measured by MRI scan

Secondary Outcome Measures

Name	Time	Method
Visceral adipose tissue mass	12 weeks	measured by MRI scan
Global longitudinal strain	12 weeks	Functional cardiac parameters: measured by MRI scan and echocardiography
Intramyocardial triglyceride content	12 weeks	Measured by MRI and MR spectroscopy
Blood sample	12 weeks	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.
Left ventricular and atrial end-diastolic volume	12 weeks	Structural cardiac parameter: measured by MRI scan and echocardiography
Left atrial volume index	12 weeks	Structural cardiac parameter: measured by MRI scan and echocardiography
Interventricular septum thickness	12 weeks	Structural cardiac parameter: measured by MRI scan and echocardiography
Whole body plethysmography	12 weeks	Pulmonary function testing
Oral glucose tolerance test	12 weeks	75g of glucose taken while fasting
Axial accelerometer-based physical activity monitors	5 days in week 6 of the intervention/control	Free-living physical activity is measured using axial accelerometer-based physical activity monitors (AX3; Axivity, Newcastle upon Tyne, UK) for a 5-day period
RA disease specific outcomes 6	12 weeks	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
Stroke volume	12 weeks	Structural cardiac parameter: measured by MRI scan and echocardiography
E/A ratio	12 weeks	Functional cardiac parameters: measured by MRI scan and echocardiography
Cardiorespiratory fitness	12 weeks	Measured with an incremental VO2 protocol on exercise bike
Dynamic spirometry	12 weeks	Pulmonary function testing
Body composition	12 weeks	Measured by a DXA scan
Dietary intake	3 days in the week 6 of intervention/control	Self reported intake of all foods and liquids
LVEF	12 weeks	Functional cardiac parameters: measured by MRI scan and echocardiography
E/é	12 weeks	Functional cardiac parameters: measured by MRI scan and echocardiography
Left ventricular and atrial end-systolic volume	12 weeks	Structural cardiac parameter: measured by MRI scan and echocardiography
Aortic and pulmonary distensibility and pulse wave velocity	12 weeks	Functional vascular parameter: measured by MRI
RA disease specific outcomes 3	12 weeks	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.
RA disease specific outcomes 8	12 weeks	Change in response criteria will be assessed according the European League Against Rheumatism (EULAR none/good/moderate response)
Left ventricular posterior wall thickness	12 weeks	Structural cardiac parameter: measured by MRI scan and echocardiography
Subcutaneous, visceral and epicardial adipose tissue	12 weeks	Measured by MRI and MR spectroscopy
Diffusion capacity	12 weeks	Pulmonary function testing
RA disease specific outcomes 5	12 weeks	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
RA disease specific outcomes 1	12 weeks	Change in measures of the international Core Outcome Set for rheumatoid arthritis : 66/68 tender and swollen joint count
RA disease specific outcomes 2	12 weeks	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)
RA disease specific outcomes 7	12 weeks	Change in response criteria will be assessed according the American College of Rheumatology (ACR 20/50/70) response
RA disease specific outcomes 4	12 weeks	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.

Trial Locations

Locations (1)

Rigshospitalet; 🇩🇰 Copenhagen, Denmark