Interleukin-6 Blockade Does Not Impair Exercise-Induced Glucose Uptake and Insulin Sensitivity in Rheumatoid Arthritis

Patients with rheumatoid arthritis (RA) are at increased risk of insulin resistance and cardiovascular disease, and exercise is a key non-pharmacological therapy. We examined whether IL-6 inhibition, a common biologic treatment for RA, impairs the acute metabolic benefits of exercise, given IL-6’s proposed role as a mediator of exercise-induced glucose metabolism. This was a single-center, non-randomized study involving 20 postmenopausal women with RA (10 on IL-6i, 10 on TNF-αi). Participants underwent a hyperinsulinemic-euglycemic clamp (HEC) and Fluorine-18 Fluorodeoxyglucose Positron Emission Tomography and Magnetic Resonance Imaging ([ 18 F] FDG PET/MRI) to assess whole-body and skeletal muscle glucose uptake. Muscle biopsies were performed before and 240 minutes after a 30-minute moderate-to-vigorous intensity aerobic exercise session to analyze molecular responses, including RNA sequencing and protein expression. Participants had a mean age of 57.8 ± 5.1 years and a mean BMI of 28.2 ± 4.9 kg/m². Disease duration averaged 18.0 ± 7.5 years, and both groups had comparable clinical characteristics. Acute exercise did not elicit significant between-group differences in insulin sensitivity (M-value: 4.51 ± 1.34 vs. 4.28 ± 0.87; p-value >0.05) or skeletal muscle glucose uptake, indicating that IL-6 inhibition does not impair the metabolic responses to acute exercise. Comparing post to pre-exercise, IL-6i participants exhibited increased GLUT4 expression ( p-value = 0.01) and distinct cytokine profiles, including elevated IL-8 ( p-value = 0.04) and IL-10 ( p-value = 0.02) levels. RNA-seq analysis showed comparable pathway enrichment between groups, with upregulation of TNF-α and IL-6-JAK-STAT3 signaling. IL-6 inhibition does not blunt the acute metabolic benefits of exercise in RA, supporting its safety as a non-pharmacological intervention. Trial registration: Clinicaltrials.gov (NCT04927546).