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

Abstract

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