Plasma levels of chemokines decrease during elexacaftor/tezacaftor/ivacaftor therapy in adults with cystic fibrosis

Westhölter, Dirk; Pipping, Johannes; Raspe, Jonas; Schmitz, Mona; Sutharsan, Sivagurunathan; Straßburg, Svenja; Welsner, Matthias; Taube, Christian; Reuter, Sebastian

doi:10.1016/j.heliyon.2023.e23428

Cited by 2 publications

(1 citation statement)

References 40 publications

(60 reference statements)

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“…For instance, IL-8 and IL-23 levels remained unchanged between baselines, one and three months. While serum IL-8 levels have been reported to fall post ETI, the change is not always significant and measurement have been previously taken after a more prolonged treatment period [19,32]. Changes in IL-8 levels as well as elevation in IL-23 in CF sputum appear to be more marked with IL-6, being potentially, a more sensitive circulating biomarker [20].…”

Section: Plos Onementioning

confidence: 99%

Anti-inflammatory effects of elexacaftor/tezacaftor/ivacaftor in adults with cystic fibrosis heterozygous for F508del

Jarosz-Griffiths,

Gillgrass,

Caley

et al. 2024

PLoS ONE

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Inflammation is a key driver in the pathogenesis of cystic fibrosis (CF). We assessed the effectiveness of elexacaftor/tezacaftor/ivacaftor (ETI) therapy on downregulating systemic and immune cell-derived inflammatory cytokines. We also monitored the impact of ETI therapy on clinical outcome. Adults with CF, heterozygous for F508del (n = 19), were assessed at baseline, one month and three months following ETI therapy, and clinical outcomes were measured, including sweat chloride, lung function, weight, neutrophil count and C-reactive protein (CRP). Cytokine quantifications were measured in serum and following stimulation of peripheral blood mononuclear cells (PBMCs) with lipopolysaccharide (LPS) and adenosine triphosphate and analysed using LEGEND plex™ Human Inflammation Panel 1 by flow cytometry (n = 19). ASC specks were measured in serum and caspase-1 activity and mRNA levels determined from stimulated PBMCs were determined. Patients remained stable over the study period. ETI therapy resulted in decreased sweat chloride concentrations (p < 0.0001), CRP (p = 0.0112) and neutrophil count (p = 0.0216) and increased percent predicted forced expiratory volume (ppFEV1) (p = 0.0399) from baseline to three months, alongside a trend increase in weight. Three months of ETI significantly decreased IL-18 (p< 0.0011, p < 0.0001), IL-1β (p<0.0013, p = 0.0476), IL-6 (p = 0.0109, p = 0.0216) and TNF (p = 0.0028, p = 0.0033) levels in CF serum and following PBMCs stimulation respectively. The corresponding mRNA levels were also found to be reduced in stimulated PBMCs, as well as reduced ASC specks and caspase-1 levels, indicative of NLRP3-mediated production of pro-inflammatory cytokines, IL-1β and IL-18. While ETI therapy is highly effective at reducing sweat chloride and improving lung function, it also displays potent anti-inflammatory properties, which are likely to contribute to improved long-term clinical outcomes.

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Section: Plos Onementioning

confidence: 99%

Anti-inflammatory effects of elexacaftor/tezacaftor/ivacaftor in adults with cystic fibrosis heterozygous for F508del

Jarosz-Griffiths,

Gillgrass,

Caley

et al. 2024

PLoS ONE

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The effect of highly effective modulator therapy on systemic inflammation in cystic fibrosis

Maher,

Cytlak-Chaudhuri,

Aleem

et al. 2024

Preprint

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Background: Despite significant clinical improvements, there is evidence of persisting airway inflammation in people with cystic fibrosis established on Elexacaftor/tezacaftor/ivacaftor (ETI) therapy. As CF is a multi-system disease, systemic immune profiles can reflect local inflammation within the lungs and other organs. Understanding systemic inflammation after ETI therapy may reveal important translational insights. This study aims to profile systemic inflammatory changes and relate these to the well-documented improvements observed with ETI therapy. Methods: We conducted a single-centre longitudinal study with 57 CF subjects initiating ETI therapy. All participants were Phe508del homozygous or Phe508del/minimal function. Blood samples were collected pre-ETI and 3-12 months post-therapy initiation. Analyses included mass spectrometry-based proteomics, a multiplex immunoassay, and flow cytometry for peripheral immune cell counts and phenotype. Controls samples were provided by 29 age- matched healthy controls. Results: Systemic inflammation reduced with ETI therapy; however, the immune profile remained distinct from healthy controls. ETI reduced neutrophil counts and was associated with a more mature, less inflammatory phenotype, as well as a shift toward an immune resolving state associated with increased CD206 expression. Cytokines known to influence neutrophil levels reduced with therapy. Despite ETI therapy, neutrophil and monocyte counts remained elevated compared to healthy controls. There was no obvious association between the ETI-related improvements in systemic inflammation and lung function. Conclusions: Patients with CF show evidence of persisting systemic inflammation despite ETI therapy, this may have long term potentially adverse effects on respiratory and other organ systems.

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Plasma levels of chemokines decrease during elexacaftor/tezacaftor/ivacaftor therapy in adults with cystic fibrosis

Cited by 2 publications

References 40 publications

Anti-inflammatory effects of elexacaftor/tezacaftor/ivacaftor in adults with cystic fibrosis heterozygous for F508del

Anti-inflammatory effects of elexacaftor/tezacaftor/ivacaftor in adults with cystic fibrosis heterozygous for F508del

The effect of highly effective modulator therapy on systemic inflammation in cystic fibrosis

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