Effects of IL-6 and IL-6 blockade on neutrophil function in vitro and in vivo

Wright, Helen L.; Cross, Andrew; Edwards, Steven W.; Moots, Robert J.

doi:10.1093/rheumatology/keu035

Cited by 156 publications

(131 citation statements)

References 23 publications

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“…In MONARCH, changes in laboratory values in the sarilumab group, including neutropenia, liver transaminases and total cholesterol, were expected class effects. While the mechanism of neutropenia remains unclear, studies have shown that blockade of IL-6R does not affect neutrophil function 34. This is consistent with MONARCH and previous sarilumab studies,24 25 demonstrating that decreased neutrophil counts were not associated with a concurrent increase in infection rate.…”

Section: Discussionsupporting

confidence: 85%

Efficacy and safety of sarilumab monotherapy versus adalimumab monotherapy for the treatment of patients with active rheumatoid arthritis (MONARCH): a randomised, double-blind, parallel-group phase III trial

et al. 2016

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ObjectivesTo compare efficacy and safety of sarilumab monotherapy with adalimumab monotherapy in patients with active rheumatoid arthritis (RA) who should not continue treatment with methotrexate (MTX) due to intolerance or inadequate response.MethodsMONARCH was a randomised, active-controlled, double-blind, double-dummy, phase III superiority trial. Patients received sarilumab (200 mg every 2 weeks (q2w)) or adalimumab (40 mg q2w) monotherapy for 24 weeks. The primary end point was change from baseline in 28-joint disease activity score using erythrocyte sedimentation rate (DAS28-ESR) at week 24.ResultsSarilumab was superior to adalimumab in the primary end point of change from baseline in DAS28-ESR (−3.28 vs −2.20; p<0.0001). Sarilumab-treated patients achieved significantly higher American College of Rheumatology 20/50/70 response rates (sarilumab: 71.7%/45.7%/23.4%; adalimumab: 58.4%/29.7%/11.9%; all p≤0.0074) and had significantly greater improvement in Health Assessment Questionnaire-Disability Index (p=0.0037). Importantly, at week 24, more patients receiving sarilumab compared with adalimumab achieved Clinical Disease Activity Index remission (7.1% vs 2.7%; nominal p=0.0468) and low disease activity (41.8% vs 24.9%; nominal p=0.0005, supplemental analysis). Adverse events occurred in 63.6% (adalimumab) and 64.1% (sarilumab) of patients, the most common being neutropenia and injection site reactions (sarilumab) and headache and worsening RA (adalimumab). Incidences of infections (sarilumab: 28.8%; adalimumab: 27.7%) and serious infections (1.1%, both groups) were similar, despite neutropenia differences.ConclusionsSarilumab monotherapy demonstrated superiority to adalimumab monotherapy by improving the signs and symptoms and physical functions in patients with RA who were unable to continue MTX treatment. The safety profiles of both therapies were consistent with anticipated class effects.Trial registration numberNCT02332590.

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Section: Discussionsupporting

confidence: 85%

Efficacy and safety of sarilumab monotherapy versus adalimumab monotherapy for the treatment of patients with active rheumatoid arthritis (MONARCH): a randomised, double-blind, parallel-group phase III trial

et al. 2016

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“…In a primate model of arthritis managed with TCZ, the absence of bone marrow myeloid hyperplasia or hypoplasia when ANC was reduced and the lack of neutrophil morphological abnormalities strongly suggested that neither peripheral sequestration nor incomplete granulopoiesis was the underlying mechanism of the reduced circulating neutrophils [30]. A recent study [7] of neutrophil function and survival, which included RA patients treated with TCZ in an open-label, phase 4 trial, demonstrated that TCZ treatment did not have a direct effect on neutrophil functions, including apoptosis, phagocytosis, respiratory burst, chemotaxis or expression of adhesion molecules. In vitro evidence suggests that IL-6 increases circulating neutrophils by releasing them from marginated pools in bone marrow [8].…”

Section: Discussionmentioning

confidence: 99%

“…Decreased neutrophil counts have been reported in trials of TCZ in RA patients [13, 14]. Blocking IL-6 signalling with TCZ is associated with transient neutropenia, but ex vivo findings show this does not directly affect neutrophil functions associated with host defence [7]. …”

Section: Introductionmentioning

confidence: 99%

Effect of tocilizumab on neutrophils in adult patients with rheumatoid arthritis: pooled analysis of data from phase 3 and 4 clinical trials

et al. 2016

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Objectives. To investigate changes in neutrophil count and occurrences of infection in RA patients treated with the IL-6 receptor-α inhibitor tocilizumab (TCZ). Methods. Data were pooled from patients who received i.v. TCZ (4 mg/kg + MTX, 8 mg/kg ± DMARDs, 10 mg/kg) or placebo + DMARDs in phase 3/4 clinical trials, long-term extensions or a pharmacology study. Neutrophil counts were measured routinely according to the Common Toxicity Criteria for Adverse Events grades; TCZ dosing was adjusted if necessary. Covariates associated with decreased neutrophil counts were assessed with multivariate regression analysis. Infection rates within 30 days of neutrophil count changes were calculated per 100 patient-years of TCZ exposure. Results. In placebo-controlled parts of trials, more TCZ-treated than placebo-treated patients had grade 1/2 or 3/4 neutrophil counts (TCZ: 28.2%/3.1%; placebo: 8.9%/0.2%). In placebo-controlled trials + long-term extensions, 4171 patients provided 16204.8 patient-years of TCZ exposure. Neutrophil counts decreased through week 6 from baseline [mean (s.d.) change, –2.17 (2.16) × 109/l) and remained stable thereafter. Rates (95% CI) of serious infections within 30 days of normal [4.66 (4.31, 5.03)], grade 1/2 [2.48 (1.79, 3.34)] and 3/4 [2.77 (0.34, 10.01)] neutrophil counts were similar. Baseline neutrophil count <2 × 109/l and female gender were associated with grade 3/4 neutrophil counts [odds ratio (OR) (95% CI): 19.02 (6.76, 53.52), 2.55 (1.40, 4.66)]. Patients who stopped TCZ in response to decreased neutrophil count returned more quickly to normal levels than patients who reduced or continued their dose. Conclusion. Decreases in neutrophil counts in patients taking TCZ do not appear to be associated with serious infections and are normalized by current risk mitigation guidelines.

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“…While LPS, GM-CSF, IL-8, and LTB 4 have been found to extend neutrophil lifespan in vitro , PAF, fMLF, and IL-6 show no effect, and TNFα shows a biphasic response where it promotes apoptosis during the first 8 h of exposure, followed by a delayed rate of apoptosis at later times (Klein et al, 2000, 2001; Cowburn et al, 2002; Liu et al, 2005; Wright et al, 2014). Primed neutrophils from patients with multiple sclerosis, ANCA-associated vasculitis, and liver cirrhosis show increased apoptosis (Harper et al, 2001; Klimchenko et al, 2011; Naegele et al, 2012), while neutrophils from patients at risk of multiple-organ failure and individuals presenting with septic peritonitis, severe trauma, or septic trauma show a decrease in apoptosis (Ertel et al, 1998; Biffl et al, 1999, 2001; Nolan et al, 2000; Feterowski et al, 2001).…”

Section: Phenotypic Changes During Primingmentioning

confidence: 99%

Multiple Phenotypic Changes Define Neutrophil Priming

Miralda

Uriarte

McLeish

2017

Front. Cell. Infect. Microbiol.

153

177

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Exposure to pro-inflammatory cytokines, chemokines, mitochondrial contents, and bacterial and viral products induces neutrophils to transition from a basal state into a primed one, which is currently defined as an enhanced response to activating stimuli. Although, typically associated with enhanced generation of reactive oxygen species (ROS) by the NADPH oxidase, primed neutrophils show enhanced responsiveness of exocytosis, NET formation, and chemotaxis. Phenotypic changes associated with priming also include activation of a subset of functions, including adhesion, transcription, metabolism, and rate of apoptosis. This review summarizes the breadth of phenotypic changes associated with priming and reviews current knowledge of the molecular mechanisms behind those changes. We conclude that the current definition of priming is too restrictive. Priming represents a combination of enhanced responsiveness and activated functions that regulate both adaptive and innate immune responses.

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Effects of IL-6 and IL-6 blockade on neutrophil function in vitro and in vivo

Cited by 156 publications

References 23 publications

Efficacy and safety of sarilumab monotherapy versus adalimumab monotherapy for the treatment of patients with active rheumatoid arthritis (MONARCH): a randomised, double-blind, parallel-group phase III trial

Efficacy and safety of sarilumab monotherapy versus adalimumab monotherapy for the treatment of patients with active rheumatoid arthritis (MONARCH): a randomised, double-blind, parallel-group phase III trial

Effect of tocilizumab on neutrophils in adult patients with rheumatoid arthritis: pooled analysis of data from phase 3 and 4 clinical trials

Multiple Phenotypic Changes Define Neutrophil Priming

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