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 Trial
Literature - 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
Background
The neutrophil-lymphocyte ratio (NLR) is a biomarker for innate and adaptive immunity [1]. 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 [2]. 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 [3].
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).
Methods
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.
Outcomes
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.
Main results
- 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)).
Conclusion
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 [4].
References
1. Buonacera A, Stancanelli B, Colaci M, Malatino L. Neutrophil to lymphocyte ratio: an emerging marker of the relationships between the immune system and diseases. Int J Mol Sci. 2022 Mar 26;23(7):3636. doi: 10.3390/ijms23073636.
2. Adamstein NH, MacFadyen JG, Rose LM, et al. The neutrophil–lymphocyte ratio and incident atherosclerotic events: analyses from five contemporary randomized trials. Eur Heart J. 2021 Mar 1;42(9):896-903. doi: 10.1093/eurheartj/ehaa1034.
3. Ridker PM, Devalaraja M, Baeres FM, et al. IL-6 inhibition with ziltivekimab in patients at high atherosclerotic risk (RESCUE): a double-blind, randomised, placebo-controlled, phase 2 trial. Lancet. 2021 May 29;397(10289):2060-2069. doi: 10.1016/S0140-6736(21)00520-1.
4. ClinicalTrials.gov identifier: NCT05021835. ZEUS - A research study to look at how ziltivekimab works compared to placebo in people with cardiovascular disease, chronic kidney disease and inflammation (ZEUS). Available at: https://clinicaltrials.gov/ct2/show/NCT05021835. Accessed March 14, 2023.
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