IL-6 inhibition reduces neutrophil-lymphocyte ratio in patients with CKD and elevated hsCRP
Association of Interleukin 6 Inhibition With Ziltivekimab and the Neutrophil-Lymphocyte Ratio: A Secondary Analysis of the RESCUE Clinical TrialLiterature - Adamstein NH, Cornel JH, Davidson M, et al. - JAMA Cardiol. 2023 Feb 1;8(2):177-181. doi: 10.1001/jamacardio.2022.4277.
Introduction and methods
The neutrophil-lymphocyte ratio (NLR) is a biomarker for innate and adaptive immunity . NLR, which can be determined from routine blood cell counts, may be relevant for monitoring anti-inflammatory therapies. A recent analysis of 5 contemporary clinical trials that included data from over 60,000 patients demonstrated that NLR predicts CV events and that IL-1β inhibition reduced NLR . The RESCUE (Trial to Evaluate Reduction in Inflammation in Patients With Advanced Chronic Renal Disease Utilizing Antibody Mediated IL-6 Inhibition) trial previously demonstrated that IL-6 inhibition with the monoclonal antibody ziltivekimab reduced several inflammatory and coagulation markers relevant to atherosclerosis (including hsCRP) in patients with CKD and elevated hsCRP .
Aim of the study
In this secondary analysis of the RESCUE trial, the authors evaluated whether ziltivekimab has an effect on 3 cell-based inflammatory biomarkers - NLR, absolute neutrophil count (ANC), and absolute lymphocyte count (ALC).
The RESCUE trial was a double-blind, randomized, placebo-controlled, multicenter, phase 2 trial conducted in the US. 264 adults with CKD (stage 3 to 5) and elevated hsCRP (≥ 2 mg/L) were randomized to subcutaneous administration of ziltivekimab (7.5 mg, 15 mg, or 30 mg) or placebo every 4 weeks up to 24 weeks. Patients with an ANC of less than 2.0x10⁹/L were excluded. In this analysis, a total of 215 patients were included, of whom 187 patients (71%) had diabetes and 126 patients (48%) had known atherosclerosis.
The primary outcome was the change in NLR at 12 weeks after starting treatment. Secondary outcomes were changes in the ANC and ALC at 12 weeks.
- The change in NLR at 12 weeks was greater in the ziltivekimab group compared to the placebo group (difference with placebo -14.6% (95%CI: -24.8% to -4.81%; P=0.004); -15.3% (95%CI: -25.2% to -5.10%; P=0.004); -23.6% (95% CI: -33.2% to -14.2%; P<0.001), for respectively 7.5 mg, 15 mg, and 30 mg). This association of ziltivekimab with lower NLR was present already at 1 week.
- Ziltivekimab reduced the ANC level at 12 weeks compared to placebo (difference 5.41% (IQR: -10.0% to 23.8%) for placebo, -7.92% (IQR: -26.8% to 5.56%) for 7.5 mg, -10.2% (IQR: -21.6% to 6.07%) for 15 mg, and -20.7% (IQR: -36.0% to -10.7%) for 30 mg).
- Ziltivekimab did not change the ALC level.
- There was a modest correlation of a change in NLR at 12 weeks with changes in other biomarkers (hsCRP (Spearman ρ=0.26; P<0.001), fibrinogen (Spearman ρ=0.18; P=0.02), haptoglobin (Spearman ρ=0.17; P=0.03), and Lp(a) (Spearman ρ=0.22;P=0.004)).
This secondary analysis of the RESCUE trial demonstrated that targeted inhibition of IL-6 with the monoclonal antibody ziltivekimab was associated with a dose-dependent reduction in NLR by lowering ANC. These results have potential clinical significance as there is an association of NLR with atherosclerotic risk. The authors are currently conducting a phase 3 trial with 6000 patients with atherosclerosis, CKD, and elevated hsCRP to determine whether the effects of ziltivekimab on inflammation correspond to beneficial outcomes on CV events and kidney function .