Sweat chloride reflects CFTR function and correlates with clinical outcomes following CFTR modulator treatment.

IF 5.4 2区 医学 Q1 RESPIRATORY SYSTEM Journal of Cystic Fibrosis Pub Date : 2025-01-03 DOI:10.1016/j.jcf.2024.12.006
Edith T Zemanick, Bonnie Ramsey, Dorota Sands, Edward F McKone, Isabelle Fajac, Jennifer L Taylor-Cousar, Marcus A Mall, Michael W Konstan, Nitin Nair, Jiaqiang Zhu, Emilio Arteaga-Solis, Fredrick Van Goor, Lisa McGarry, Valentin Prieto-Centurion, Patrick R Sosnay, Carmen Bozic, David Waltz, Nicole Mayer-Hamblett
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Abstract

Background: Highly effective CFTR modulators improve CFTR function and lead to dramatic improvements in health outcomes in many people with cystic fibrosis (pwCF). The relationship between measures of CFTR function, such as sweat chloride concentration, and clinical outcomes in pwCF treated with CFTR modulators is poorly defined. We conducted analyses to better understand the relationships between sweat chloride and CFTR function in vitro, and between sweat chloride and clinical outcomes following CFTR modulator treatment.

Methods: Mean sweat chloride values in healthy people, CF carriers, and pwCF treated with CFTR modulators at different doses were compared to chloride transport in corresponding human bronchial epithelial (HBE) cells. A pooled analysis of phase 3 CFTR modulator studies was performed to evaluate the relationship between attained values of sweat chloride and improvements in lung function, body mass index (BMI), patient reported outcomes, pulmonary exacerbations, and lung function change over time.

Results: Sweat chloride concentrations in vivo correlated strongly with CFTR-dependent chloride current in HBE cells in vitro. Sweat chloride values of <30 mmol/L and ≥30 to <60 mmol/L in pwCF following CFTR modulator treatment were associated with better clinical outcomes than sweat chloride ≥60 to <80 mmol/L and ≥80 mmol/L.

Conclusions: In pwCF treated with CFTR modulators, lower sweat chloride levels (reflecting greater CFTR function) are associated with better clinical outcomes. These results support the therapeutic strategy of further restoring CFTR function towards normal, as reflected in lowering sweat chloride to below the diagnostic threshold for CF (<60 mmol/L) and to normal (<30 mmol/L), with CFTR modulators.

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汗液氯化物反映CFTR功能,并与CFTR调节剂治疗后的临床结果相关。
背景:高效CFTR调节剂可改善许多囊性纤维化(pwCF)患者的CFTR功能并显著改善其健康状况。CFTR功能测量(如汗液氯化物浓度)与CFTR调节剂治疗pwCF的临床结果之间的关系尚不明确。我们进行了分析,以更好地了解汗液氯化物与体外CFTR功能之间的关系,以及CFTR调节剂治疗后汗液氯化物与临床结果之间的关系。方法:比较不同剂量CFTR调节剂处理的健康人、CF携带者和pwCF的平均汗液氯化物值与相应的人支气管上皮(HBE)细胞的氯化物转运。对3期CFTR调节剂研究进行了汇总分析,以评估汗液氯化物的获得值与肺功能、体重指数(BMI)、患者报告的结局、肺恶化和肺功能随时间变化的改善之间的关系。结果:体内汗液氯化物浓度与体外HBE细胞cftr依赖的氯电流密切相关。结论:在CFTR调节剂治疗的pwCF中,较低的汗液氯化物水平(反映更强的CFTR功能)与较好的临床结果相关。这些结果支持进一步恢复CFTR功能的治疗策略,如将汗液氯化物降低到CF的诊断阈值以下(
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来源期刊
Journal of Cystic Fibrosis
Journal of Cystic Fibrosis 医学-呼吸系统
CiteScore
10.10
自引率
13.50%
发文量
1361
审稿时长
50 days
期刊介绍: The Journal of Cystic Fibrosis is the official journal of the European Cystic Fibrosis Society. The journal is devoted to promoting the research and treatment of cystic fibrosis. To this end the journal publishes original scientific articles, editorials, case reports, short communications and other information relevant to cystic fibrosis. The journal also publishes news and articles concerning the activities and policies of the ECFS as well as those of other societies related the ECFS.
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