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 nonpharmacological therapy. We examined whether interleukin-6 (IL-6) inhibition, a common biological 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, nonrandomized study involving 20 postmenopausal women with RA [10 on IL-6 inhibitor (IL-6i), 10 on TNF-α inhibitor (TNF-αi)]. Participants underwent a hyperinsulinemic-euglycemic clamp (HEC) and fluorine-18 fluorodeoxyglucose positron emission tomography and magnetic resonance imaging ([¹⁸F]FDG PET/MRI) to assess whole body and skeletal muscle glucose uptake. Muscle biopsies were performed before and 240 min after a 30-min moderate-to-vigorous intensity aerobic exercise session to analyze molecular responses, including RNA sequencing (RNA-Seq) and protein expression. Participants had a mean age of 57.8 ± 5.1 yr and a mean body mass index (BMI) of 28.2 ± 4.9 kg/m². Disease duration averaged 18.0 ± 7.5 yr, and both groups had comparable clinical characteristics. Acute exercise did not elicit significant between-group differences in insulin sensitivity (<i>M</i> value: 4.51 ± 1.34 vs. 4.28 ± 0.87; <i>P</i> 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 preexercise, IL-6i participants exhibited increased glucose transporter type 4 (GLUT4) expression (<i>P</i> value = 0.01) and distinct cytokine profiles, including elevated IL-8 (<i>P</i> value = 0.04) and IL-10 (<i>P</i> value = 0.02) levels. RNA-Seq analysis showed comparable pathway enrichment between groups, with upregulation of TNF-α and IL-6-Janus kinase-signal transducer and activator of transcription 3 (JAK-STAT3) signaling. IL-6 inhibition does not blunt the acute metabolic benefits of exercise in RA, supporting its safety as a nonpharmacological intervention. Trial registration: Clinicaltrials.gov (NCT04927546).<b>NEW & NOTEWORTHY</b> A single session of aerobic exercise has a similar effect on insulin sensitivity and muscle glucose uptake in women with RA treated with either IL-6i or TNF-αi. The study supports exercise as a safe and complementary strategy for patients with RA on IL-6i or TNF-αi therapy, reinforcing its inclusion in clinical care and the need for further research on long-term outcomes.