Type I interferon induced differences in exercise adaptations of aerobic capacity and fatigue in systemic lupus erythematosus – A randomised controlled single-centre trial v1.0

Abstract

Impaired exercise capacity and persistent fatigue are common manifestations in patients with systemic lupus erythematosus (SLE) even during disease remission. Knowledge on pathophysiologic mechanisms causing these disease manifestations is limited. SLE is characterised by various immune system dysregulations including an overexpression of type 1 interferons (IFN-I). This study aims to examine whether higher IFN-I activity negatively correlates with improvement in aerobic capacity and fatigue following a 12-week exercise intervention. Sixty adult patients with SLE will be randomised 1:1 stratified for sex to exercise or control. The exercise group will undergo bouts of high intensity interval training (HIIT), 45 minutes 3 times weekly for 12 weeks. The control group is informed to maintain current physical activity during study participation. Clinical, patient-reported, laboratory and imaging data will be collected before, during, and after the study period. The primary outcome is aerobic capacity measured by maximal oxygen uptake (VO2max). The co-primary outcome is fatigue measured by the fatigue severity scale (FSS) questionnaire. Transcriptomic analysis use Nanostring technology to obtain IFN gene signature (IFNGS). The predictive value of the IFNGS on the outcomes will be assessed by regression models including pre-specified covariates of interest. Analysis will be done per protocol (PP) and as intention to treat (ITT).The study has been approved by the ethics committee of the Capital Region of Denmark (H-21039032) and clinicaltrials.gov (NCT05478018). Results from this study will be disseminated through peer-reviewed publications, conference presentations and clinical communications. Strengths and limitations:The first randomised controlled exercise trial of SLE patients investigating the impact of interferon signature on patient-reported and physiological exercise outcomes. A novel approach to gain insight into underlying mechanisms of fatigue and reduced exercise capacity in SLE.Patients enrolling in an exercise study might be healthier than the general SLE population, which may limit the external validity of our results. Due to the nature of exercise therapy blinding of patients to the intervention is not possible, which may introduce performance bias (e.g., regarding patient-reported outcomes)The exercise protocol with short bursts of highly intensive aerobic exercise might impact aerobic capacity more than it influences fatigue and muscle strength.