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

Abstract

Background: Cystic fibrosis (CF) is associated with dysregulated immune responses, exaggerated inflammation and chronic infection. CF transmembrane conductance regulator (CFTR) modulator therapies directly target the underlying protein defects and resulted in significant clinical benefits for people with CF (pwCF). This study analysed the effects of triple CFTR modulator therapy elexacaftor/tezacaftor/ivacaftor (ETI) on CF-associated inflammation, especially systemic chemokines. Methods: A bead-based immunoassay was used to quantify proinflammatory chemokines (IL-8, IP-10, Eotaxin, TARC, RANTES, MIP-1α, MIP-1β, MIP-3α, MIG, ENA-78, GROα, I-TAC) in plasma samples from pwCF collected before, at three, and at six months after starting ETI therapy. Results: Fifty-one pwCF (47 % female; mean age 32 ± 10.4 years) were included. At baseline, 67 % were already receiving CFTR modulator therapy with tezacaftor/ivacaftor or lumacaftor/ivacaftor. After initiation of ETI therapy there was a significant improvement in percent predicted forced expiratory volume in 1 s (+12.7 points, p < 0.001) and a significant decrease in sweat chloride levels (−53.6 %, p < 0.001). After 6 months’ treatment with ETI therapy there were significant decreases in plasma levels of MIP-3α (−68.2 %, p = 0.018), GROα (−17.7 %, p = 0.013), ENA-78 (−16.3 %, p = 0.034) and I-TAC (−3.4 %, p = 0.032). IL-8 exhibited a reduction that did not reach statistical significance (−17.8 %, p = 0.057); levels of other assessed cytokines did not change significantly from baseline. Conclusions: ETI appears to affect a distinct group of chemokines that are predominately associated with neutrophilic inflammation, demonstrating the anti-inflammatory properties of ETI therapy.