Triple CFTR Modulator Therapy Shows Sustained Reduction in Inflammation in Cystic Fibrosis: Study
Researchers have found in a new study that triple CFTR modulator therapy, or elexacaftor/tezacaftor/ivacaftor (ETI), produces rapid and sustained reductions in systemic inflammation in individuals with cystic fibrosis, with corresponding improvements in lung function. These findings are indicative of the fact that ETI improves not only airway function but also has systemic anti-inflammatory benefits that are maintained over time, though some inflammatory markers may remain slightly above healthy control levels in certain subgroups. The study was published in The European Respiratory Journal by Olga H. and colleagues.
In cystic fibrosis, chronic infection of the airways and sustained inflammation are hallmarks that result in progressive destruction of the lungs and a diminished quality of life. Although ETI and other CFTR modulators have transformed the management of CF by targeting the defective CFTR protein, their long-term impact on systemic inflammation has not been well understood.
This multicenter study enrolled 198 individuals with CF aged 6 years and older who were initiating ETI therapy and 74 age-matched HCs. The researchers assessed systemic inflammation, as reflected by peripheral blood neutrophil counts, CRP, and six pro-inflammatory cytokines-G-CSF, IL-1β, IL-6, IL-8, and MCP-1-at baseline and follow-up visits 3, 12, and 24 months after therapy initiation. The study evaluated both the speed and persistence of systemic anti-inflammatory effects of ETI, as well as their relationship to lung function improvement assessed using percent predicted forced expiratory volume (ppFEV₁).
Key Findings
Within just 3 months from the start of ETI therapy, there were rapid and significant reductions in inflammatory markers:
Neutrophil counts decreased to 71% of baseline levels.
CRP levels decreased to 40% of baseline values.
G-CSF was reduced to 41%, IL-1β to 63%, IL-6 to 46%, and IL-8 to 81% of baseline levels (all p < 0.05).
MCP-1 reached 82% of baseline levels only by 12 months (p < 0.05).
Improvement in inflammation from baseline to 3 months was significantly associated with improved lung function (ppFEV₁) for all markers except IL-8, with Spearman's r ranging from -0.17 to -0.42 (p < 0.05).
By 24 months, levels of all cytokines had reached those seen in healthy controls, reflecting a sustained normalization of systemic inflammation.
While most markers remained low over 24 months, IL-6 demonstrated partial return in some patients, indicating smoldering or episodic low-grade inflammation in certain subgroups.
This large, real-world prospective study showed that elexacaftor/tezacaftor/ivacaftor rapidly and sustainably reduces systemic inflammation in subjects with cystic fibrosis over a period of 24 months. These results confirm that ETI is a game-changing therapy for cystic fibrosis, not only regarding respiratory improvement but also in relation to the systemic modulation of inflammation and improvement of the health trajectory of patients.
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