The Extrapulmonary Effects of Cystic Fibrosis Transmembrane Conductance Regulator Modulators in Cystic Fibrosis

Abstract

The effects of cystic fibrosis (CF) transmembrane conductance regulator (CFTR) modulators on lung function, pulmonary exacerbations, and quality of life have been well documented. However, CF is a multiorgan disease, and therefore an evidence base is emerging on the systemic effects of CFTR modulators beyond the pulmonary system. This is of great clinical importance, as many of these studies provide proof of concept that CFTR modulators might be used one day to prevent or treat extrapulmonary manifestations stemming from CFTR dysfunction. In this concise review of the literature, we summarize the results of key publications that have evaluated the effects of CFTR modulators on weight and growth, pancreatic function, the gastrointestinal and hepatobiliary systems, sinus disease, bone disease, exercise tolerance, fertility, mental health, and immunity. Although many of these studies have reported beneficial extrapulmonary effects related to the use of ivacaftor (IVA) in patients with CF with at least one gating mutation, most of the evidence is low or very low quality, given the limited number of patients evaluated and the lack of control groups. Based on an even smaller number of studies evaluating the extrapulmonary effects of lumacaftor-IVA, the benefits are less clear. Although limited, these studies may provide the basis for future clinical trials to evaluate CFTR modulators on the extrapulmonary manifestations of CF.

Keywords: cystic fibrosis; cystic fibrosis transmembrane conductance regulator; ivacaftor; lumicaftor–ivacaftor; tezacaftor–ivacaftor.

Figure 1.

Cystic fibrosis (CF) transmembrane conductance regulator (CFTR) modulators and extrapulmonary effects. Reported associations between CFTR modulator use and extrapulmonary clinical outcomes graded by quality of evidence according to the American Thoracic Society (75) with reference to the effects of specific CFTR modulators. American Thoracic Society quality of evidence rating based on study methodology: high = randomized controlled trial (RCT); low = well-done observational studies with control groups; moderate = downgraded RCT or upgraded observational study; very low = others (e.g., case reports and case series). *Hepatobiliary complications: as reported by the Cystic Fibrosis Foundation Patient Registry (CFFPR) and UK Cystic Fibrosis Registry (CFR); the U.S. CFFPR includes gallstones, gallstones requiring surgery/procedure, liver disease (cirrhosis), cirrhosis complications (esophageal varices, gastric varices, gastrointestinal bleed, splenomegaly, hypersplenism, and ascites), liver disease (noncirrhosis), hepatic steatosis, liver disease (other), and abnormal liver enzymes (UK CFR only). φ = psychiatric; BMI = body mass index; CNS = central nervous system; CRS = chronic rhinosinusitis; CT = computed tomography; GERD = gastroesophageal reflux disease; GI = gastrointestinal; IVA = ivacaftor; LUM = lumacaftor; PA = Pseudomonas aeruginosa.