Effect of a 12-week high-intensity exercise intervention: a comparison of cardiac exercise adaptations during biological disease-modifying antirheumatic drug treatment (TNF inhibitors vs IL-6 signalling inhibitors) in patients with rheumatoid arthritis - study protocol for a randomised controlled trial

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Introduction The chronic inflammatory state in rheumatoid arthritis (RA) augments the risk of cardiovascular disease (CVD), with pro-inflammatory cytokines tumour necrosis factor (TNF) and interleukin 6 (IL-6) playing a vital role. Consequently, biological disease-modifying antirheumatic drugs (bDMARDs) may attenuate that risk. IL-6 is also a myokine, secreted from exercising skeletal muscles, where IL-6 exhibits anti-inflammatory effects that may ameliorate the risk of CVD. In healthy humans treated with IL-6 signalling inhibitors (IL-6i), exercise induced loss of visceral fat mass and cardiac adaptations were abolished. We hypothesise that IL-6 signalling inhibition will impair the cardiac and metabolic adaptions to exercise training compared with TNF inhibition in RA patients. Methods and analysis 80 RA patients treated with IL-6i (n=40) or TNF inhibitors (n=40) are included in a 12-week randomised investigator-blinded 4×4 min high-intensity interval training (HIIT) study. Patients are stratified for medical treatment and sex and allocated 1:1 to an exercise or a no exercise control group (four groups). The supervised exercise intervention comprises 3 weekly HIIT sessions on an ergometer bicycle. The primary outcome is the change in left ventricular mass (LVM), and key secondary outcome is change in visceral fat mass. Both outcomes are measured by MRI. Primary statistical analysis will evaluate LVM at follow-up in a regression model. Intention-to-treat and per protocol analyses will be conducted. The latter necessitates a minimum attendance rate of 80%, adherence to bDMARDs treatment of ≥80% and minimum 8 min (50%) of maximal heart rate above 85% per session. Ethics and dissemination The study has been approved by the Capital Region Ethics Committee (H-21010559 amendments 86424, 87463 and 88044) and the Danish Medicines Agency (2021-b005287-21). The trial will follow ICH-GCP guidelines. Regardless of outcome, results will be published in relevant peer-reviewed journals.

TidsskriftBMJ Open
Udgave nummer5
Antal sider10
StatusUdgivet - 2023

Bibliografisk note

Funding Information:
PGJ has received lecture fees from Astra Zeneca and Novo Nordisk. MLA has received speaking fees from Novartis. LK has received lecture fees from Novo, Novartis, AstraZeneca, Bayer and Boehringer. LD has received speaking fees from Eli Lilly, Galderma and Janssen and research grant from BMS outside the present work. RHC is currently employed at Novo Nordisk, Denmark. All other authors declare no conflicts of interests.

Funding Information:
This work was supported from Gangstedfonden, grant number A40059, Kong Christian den Tiendes Fund, grant number N/A, Snedkermester Sophus Jacobsen og hustru Astrid Jacobsens, Fund grant number N/A, Gigtforeningen, grant number A7782, The Rigshospital Research Scholarship, grant number N/A, The Capital Region Research Fund, grant number R159-A6993 and Trygfonden, grant number 101390 and 20045.

Publisher Copyright:
© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

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