Association of Interleukin 6 Inhibition With Ziltivekimab and the Neutrophil-Lymphocyte Ratio: A Secondary Analysis of the RESCUE Clinical Trial

IMPORTANCE: The neutrophil-lymphocyte ratio (NLR) independently predicts atherosclerotic events and is a potential biomarker for residual inflammatory risk. Interleukin (IL) 1β inhibition reduces the NLR, but whether inhibition of IL-6, a cytokine downstream of IL-1, also lowers the NLR is uncertain. OBJECTIVE: To evaluate whether ziltivekimab, a therapeutic monoclonal antibody targeting the IL-6 ligand, associates with a lower NLR compared with placebo. DESIGN, SETTING, AND PARTICIPANTS: This was an exploratory post hoc analysis of Trial to Evaluate Reduction in Inflammation in Patients With Advanced Chronic Renal Disease Utilizing Antibody Mediated IL-6 Inhibition (RESCUE), a double-blind, randomized, placebo-controlled, phase 2 trial conducted from June 17, 2019, to January 14, 2020, with 24 weeks of follow-up. Participants were enrolled at 40 sites in the US and included adults aged 18 or older with moderate to severe chronic kidney disease and high-sensitivity C-reactive protein levels of 2 mg/L or greater. Data were analyzed from September 28, 2021, to October 2, 2022. INTERVENTIONS: Participants were randomly assigned equally to placebo or ziltivekimab, 7.5 mg, 15 mg, or 30 mg, subcutaneously every 4 weeks. MAIN OUTCOMES AND MEASURES: The primary outcome was the change in the NLR at 12 weeks. RESULTS: A total of 264 participants (median [IQR] age, 68 [60-75] years; 135 men [51%]; 129 women [49%]) were enrolled, of which 187 (71%) had diabetes, and 126 (48%) had known atherosclerosis. The median (IQR) change in the NLR at 12 weeks was 1.56% (IQR, −15.7% to 20.0%), −13.5% (IQR, −31.6% to 3.20%), −14.3% (IQR, −26.9% to 4.62%), and −22.4% (IQR, −33.3% to −4.27%) in the placebo, 7.5-mg, 15-mg, and 30-mg groups, respectively. The estimated treatment difference compared with placebo was −14.6% (95% CI, −24.8% to −4.81%; P = .004), −15.3% (95% CI, −25.2% to −5.10%; P = .004), and −23.6% (95% CI, −33.2% to −14.2%; P < .001) in the 7.5-mg, 15-mg, and 30-mg groups, respectively. A similar reduction in the absolute neutrophil count was observed. CONCLUSIONS AND RELEVANCE: Results of this post hoc analysis of the RESCUE trial show that IL-6 ligand inhibition with ziltivekimab associates with a lower NLR, suggesting that it may disrupt multiple atherogenic inflammatory pathways, including those mediated by the myeloid cell compartment. The NLR may have use in monitoring ziltivekimab’s efficacy should it be introduced into clinical practice.