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• W2778023201 abstract "See “Reduction of Recurrence Risk of Pancreatitis in Cystic Fibrosis With Ivacaftor: Case Series” by Carrion et al on page 451. Cystic fibrosis (CF) is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene (1). Over 2000 mutations of the CFTR gene have been described. They vary in residual CFTR protein function and subsequent disease-causing severity (2). CF is a multiorgan disease in which pancreatic involvement is a prominent feature, but the damage to pancreatic function is of variable severity (3). CFTR mutations with none to minimal residual protein function clinically present with exocrine pancreas insufficiency and are classified as severe mutations (4). Already in a early phase of disease development, often already in utero, the exocrine pancreatic tissue is structurally destroyed due to autophagic and autolytic activity leading up to the complete inability to excrete the proteolytic and lipolytic digestive pancreatic enzymes. As a result of the structural nature of the damage, the production and secretion of exocrine pancreatic enzymes are permanently blocked and stopped. Remarkably, however, this inability of CF patients to produce and secrete activated pancreatic digestive enzymes protects them from developing episodes of clinical and biochemical pancreatitis. On the other hand, CF patients with milder CFTR mutations and higher residual protein function do not develop severe structural damage of their pancreas (5). They remain exocrine pancreatic sufficient. The reduced chloride secretion due to partially diminished CFTR protein function, however, results in the reduced secretion of pancreatic ductular secretion. This situation can develop into a temporary ductular stasis of activated pancreatic digestive enzymes and local inflammation. As a consequence, these patients are at high risk of experiencing severe episodes of pancreatitis that present with pain attacks and elevations of serum amylase and lipase (6,7). CF-related recurrent pancreatitis has recently gained renewed interest since the development of the understanding that this form of hereditary pancreatitis is strongly related the so-called milder CFTR mutation with significantly residual CFTR protein function (8). Only 1% to 2% of the residual pancreatic reserve is required to maintain pancreatic sufficiency. This process of pancreatic damage is detectable by the release of the pancreatic protein trypsinogen into the bloodstream, which forms the basis of newborn screening for CF. The era of CFTR potentiators and correctors has resulted in newfound optimism in the treatment of CF. Ivacaftor is one of the new treatments used for CF patients with the so-called “gating” mutation, a specific type of CFTR gene mutation class that is typified by a dysfunctional CFTR protein on the cell surface (9). Ivacaftor improves the dysfunctional chloride ion gating function of the CFTR protein. This results in the improvement of clinical symptoms such as lung function and body weight (10). The in utero damage and chronic fibrocystic changes that affect the pancreas in the majority of CF patients suggests that the new classes of medications may offer little benefit. Previous reports of improved weight gain and body mass index have been largely theorized to be secondary to improved intestinal pH, decreased intestinal inflammation with improved absorption, and normalization of intestinal histopathology changes. Recent findings in the Ivacaftor trials, however, have not only shown improvements in patients’ body mass index z scores but also in their fecal elastase levels. The recent study, involved CF patients aged 2 to 5 years with a so-called CFTR gating mutation (11) who were treated with Ivacaftor. In this study, the first promising results for the potential of exocrine pancreatic insufficiency (EPI) treatment with CFTR modulation were reported. Already in this older pediatric age group, the authors found a mean increase in fecal elastase-1, the surrogate marker for EPI, of almost 100 μg/g after a 24-week treatment period. Even, 23% had fecal elastase-1 measurements of more than 200 μg/g, considered exocrine pancreatic sufficient, at the end of the study period. This observation in the KIWI study demonstrates the potential of CFTR modulation therapies in prevention or recovery of the development EPI and CF-related pancreatic disease in general. This data suggest that the new potentiators and correctors may have more benefit to pancreatic outcomes than previously considered. One of the most anticipated effects of CFTR modulation therapies is the possibility of preventing early disease development. To date, in regions where neonatal heel prick screening has been introduced, most CF patients are diagnosed between the ages of 4 to 6 weeks. By that time, about 50% of patients have, however, already developed complete EPI with clinical evidence of intestinal fat and fat-soluble vitamin malabsorption and growth retardation. Of the remaining patients, roughly 40% will become exocrine pancreatic insufficient in the following months to years. To date, pancreatic insufficiency in CF patients is an irreversible state and requires lifelong pancreatic enzyme replacement therapy with every meal or snack. Cystic fibrosis pancreatic insufficiency is also related to increased incidence and younger presentation of CF-related diabetes. CF-related diabetes is one of the most strongly associated risk factors for decreased survival and early mortality in CF patients. Therefore, the prevention or recovery of the development of pancreatic insufficiency is regarded as one of the most important goals of CFTR modulation. Carrion et al report in this issue (12) a retrospective cohort study into the effects of Ivacaftor on the frequency and severity of symptomatic pancreatitis episodes in CF patients with a history of recurrent pancreatitis. Patients experiencing 1 to 5 episodes of pancreatitis attacks did not suffer from pancreatitis episodes for up to 1 year after starting Ivacaftor. In their case series, they elegantly show the potential of CFTR modulation therapy with Ivacaftor on the clinical symptoms of this crippling disease. Their report is one of the first studies to report a clinically relevant improvement of CFTR protein dysfunction in the gastrointestinal tract. These findings provide valuable information for the clinical and scientific understanding and treatment of CF. To date, the focus of interest in the treatment of the disease and the development of new therapies has been understandably on the CF-related pulmonary diseases as the most severe and life-limiting presentation of the disease. In particular, gastrointestinal diseases can, however, also be serious and potentially life-threatening. Furthermore, lung disease, gastrointestinal disease is often already present at birth or develops in infancy. These factors make CFTR modulation treatment effects in the digestive tract highly relevant. Although relevant, it is evident that this retrospective case series presented by Carrion et al has its shortcomings. The study group is small and the limited follow-up duration period are serious drawbacks. Because only patients on Ivacaftor treatment were included in the study, the lack of case-controls makes the reported observation vulnerable to selection bias. This criticism is strengthened by the fact that it is not evident from the report what indication these patients were selected for with respect to Ivacaftor treatment. Finally, discontinuation of pancreas enzyme replacement therapy as a secondary outcome is questionable. These comments, however, do not diminish the remarkably positive results of this study that were mostly reflected in the number of pancreatitis episodes and the strongly reduced opioid usage that were reported by these patients. Although the study does not provide mechanistic proof for a direct effect of Ivacaftor on the pancreas secretion function, the results are highly suggestive that a direct relationship between pancreatic CFTR protein function correction and the reduced risk of pancreatitis is present. The current study paves the way for future prospective investigations that evaluate the effect of CFTR modulation on recurrent CF-related hereditary pancreatitis. Moreover, this study underlines the need for prospective research during and following the introduction of CFTR modulation therapies on the effect of nonpulmonary clinical outcome measures using phase IV biobanking and patient registries. From these studies, new and potentially highly relevant effects can be identified and evaluated. These results can then be applied in the treatment of CF patients or to develop or recognize other additional indications for CFTR modulation therapies outside of the CF disease field." @default.
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• W2778023201 title "CFTR Protein Function Modulation Therapy Is Finally Targeting Cystic Fibrosis-related Gastrointestinal Disease" @default.
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