UNDERSTANDING HOW CYSTIC FIBROSIS (CF) PROGRESSES AND ITS IMPACT ON YOUR PATIENTS

Transcription

1 UNDERSTANDING HOW CYSTIC FIBROSIS (CF) PROGRESSES AND ITS IMPACT ON YOUR PATIENTS

2 CF IS A MULTI-ORGAN, PROGRESSIVE, GENETIC DISEASE Many problems with CF may be present at birth and persist and progress throughout the patient s life Lungs Pancreas Liver Age 0-5 years Early mucinous plugging and bronchiectasis 1 Pancreatic exocrine insufficiency; up to 71% of patients with CF are pancreatic insufficient at birth 1,2 Abnormal liver function test results 1 Age 6-10 years Advancing bronchiectasis and pulmonary exacerbations 2 Ongoing degradation, as thickened secretions clog more ducts 3 Age years Bronchiectasis with recurrent exacerbations, requiring nutritional support, supplementary oxygen, and noninvasive ventilatory support 1 CF-related diabetes mellitus in approximately 25% of adolescents 4 Cirrhosis 1 Age 20+ years Bronchiectasis with hemoptysis, pneumothorax; progressive respiratory failure; lung transplant 1 CF-related diabetes mellitus in up to Portal hypertension 40% of adults 1 (5%-10%); liver transplant 1 Additional Considerations Potentially irreversible damage as early as 2 months of age; eventual pulmonary insufficiency responsible for ~80% of CF-related deaths 3 Nutritional/caloric deficiency issue (growth impairment) 5 CF can be associated with biliary cirrhosis (<10%) 1 Not all patients with CF experience all these symptoms or follow this timeline. 2

3 CF IS A MULTI-ORGAN, PROGRESSIVE, GENETIC DISEASE (cont) Many problems with CF may be present at birth and persist and progress throughout the patient s life Age 0-5 years Meconium ileus 1 Gastrointestinal Other Symptoms Chronic rhinosinusitis; nasal polyp; absence of vas deferens 1,3 Age 6-10 years Age years Constant vigilance regarding malnutrition 3 Decreased motility may lead to chronic constipation 3 Arthropathy; CF-related bone disease (osteoporosis); female infertility 1,6 Age 20+ years Distal intestinal obstruction syndrome 1 Additional Considerations Gastrointestinal abnormalities often evident before birth 2 Potential for renal dysfunction in diabetic patients 1 Not all patients with CF experience all these symptoms or follow this timeline. 3

4 EVERYONE WITH CF FACES PROGRESSION AND PROGRESSION SHORTENS LIVES Some genotypes are associated with longer survival than others, but CF remains a life-shortening disease 7 MORTALITY BY CFTR GENOTYPE CLASSIFICATION 7 Percentage of patients still living Genotype Unclassified Lower Risk Higher Risk Age of onset and rate of CF progression vary between and within the genetic mutations known to cause CF 8 However, the range of systemic effects and eventual progression is typically similar across all CF-causing genotypes 8 In a separate analysis of registry data, the median age of death in people with CF was approximately 29 years Age at Death or Discontinuation (years) Adapted from McKone et al. Patients were grouped by genotype, classified as high risk or lower risk of early lung function decline based on the primary functional class of their CFTR mutations, or unclassified if 1 or both alleles were unidentified. 7 CFTR, cystic fibrosis transmembrane conductance regulator. 4

5 PEOPLE NEED AN ADEQUATE QUANTITY OF WELL-FUNCTIONING CFTR PROTEINS TO STAY HEALTHY Maintaining water and salt balance at the epithelial cell surface requires an adequate quantity and function of CFTR proteins 10,11 CFTR proteins are an important regulator of fluid and ion balance in epithelial tissues in organs throughout the body 3,10,12,13 Cell surface Normal CFTR protein Normally, CFTR protein channels transport ions, such as chloride and bicarbonate, through the epithelial cell surface in these organs 3,10,12,13 In normal cells, CFTR proteins are open about 40% of the time 14 This controlled movement of ions helps to regulate water and electrolyte (salt) balance at the cell surface to keep mucus thin and watery 3,10,12,13 Thin, watery mucus is easily moved through organ passages and helps ensure normal organ function Nucleus 5

6 CF IS CAUSED BY DEFECTIVE OR A REDUCED QUANTITY OF CFTR PROTEINS RESULTING FROM MUTATIONS IN THE CFTR GENE 281 known CFTR mutations can result in CF due to too few and/or defective CFTR 8,10,15 REDUCED CFTR QUANTITY 8,10,13,19 CFTR protein Cell surface With too few and/or defective CFTR proteins, water and salt balance at epithelial cell surfaces is disrupted 3,6,10,16 Defective synthesis Defective processing Mucus becomes thick and sticky in organs throughout the body, and it can clog small passages 3,6,10,16 This interferes with the proper function of the lungs, pancreas, gastrointestinal system, sinuses, liver, and reproductive system Nucleus REDUCED CFTR FUNCTION 8,10,13,19 This can lead to potentially irreversible lung damage even before loss of function is detected by spirometry 1,3,17,18 Damage can be cumulative over time Cell surface Defective gating Defective conductance CFTR protein A defect in quantity and/or function of CFTR is the underlying cause of CF 8,19 Nucleus 6

7 CF-CAUSING CFTR MUTATIONS CAN REDUCE TOTAL CFTR ACTIVITY TO VARYING DEGREES C It depends on how the mutations affect the quantity and/or function of CFTR proteins LITTLE TO NO QUANTITY LITTLE TO NO FUNCTION CFTR protein Cell surface Cell surface CFTR protein SOME QUANTITY Cell surface Defective synthesis Defective processing Nucleus Normal CFTR protein Nucleus SOME FUNCTION Cell surface Defective gating Defective conductance Nucleus Nucleus Abnormal CFTR protein With little to no CFTR activity, CF appears early and progresses rapidly 10,20-22 With some CFTR activity, CF can appear later in life, but remains progressive 10,20 Regardless of whether they have only some or little to no CFTR activity, people with 2 CF-causing mutations experience progressive CF disease

8 TOO FEW OR DEFECTIVE CFTR PROTEINS MEANS A CASCADE OF DISEASE AND LUNG DAMAGE THE CFTR DYSFUNCTION CASCADE IN THE LUNGS 1 Plugging of bronchial ducts and passages CFTR dysfunction Ion imbalance Mucus thickening Inflammation, infection, lung damage Susceptibility to infection The cascade of CF in the lungs can result in inflammation, infection, and lung damage, even before loss of lung function is detected by spirometry 1,3,23,24 8

9 A SIMILAR CASCADE OF EFFECTS OCCURS IN OTHER ORGAN SYSTEMS This cascade results in thickening of secretions, blocking of small passages, inflammation, and organ damage 3,6,10,16 As a consequence, CFTR protein dysfunction affects multiple organ systems with progressive signs and symptoms 1,3,25-27 Pancreas Lungs Sinuses Gastrointestinal system Skin/sweat glands Reproductive system 9

10 PATIENTS MAY EXPERIENCE STRUCTURAL LUNG DAMAGE BEFORE A DECLINE IN FEV 1 IS DETECTED HRCT scan shows pulmonary abnormalities in the lungs of a 13-year-old boy with normal pulmonary function tests and a ppfev 1 of 99% Bronchiectasis 2. Peripheral cysts 3. Bronchiectasis 4. Mucus-plugged bronchus 5. Peripheral cysts This was a retrospective study in 25 children with CF with a mean age of 10.7 years and a mean FEV 1 of 76. The purpose of the study was to show correlation of CT score with pulmonary disease. The study was able to show correlation of CT score with pulmonary function tests. The image above was the only instance where CT scan was shown to be more sensitive. 28 CT, computed tomography; FEV 1, forced expiratory volume in 1 second; HRCT, high-resolution computed tomography; ppfev 1, percent predicted FEV 1. Adapted from de Jong et al. 10

11 PULMONARY EXACERBATIONS ARE A HARMFUL FEATURE OF CF AND CONTRIBUTE TO LUNG DAMAGE Pulmonary exacerbations begin early in life and increase in incidence with age 29,30 PULMONARY EXACERBATIONS BY AGE IN YEARS, * Number of individuals Total individuals with or without exacerbations Individuals with 1 or more pulmonary exacerbations Individuals with 2 or more pulmonary exacerbations < Age (years) Adapted from CFF Registry Damaging pulmonary exacerbations can occur early in life 30 Although the incidence of exacerbations is relatively low in young children with CF, it increases as the children age 29,30 By age 12 years, as many as 30% of patients will have at least 1 pulmonary exacerbation per year 9 * Pulmonary exacerbations are a major cause of irreversible lung damage and can have devastating effects, including increased risk of mortality, hospitalizations, and use of intravenous antibiotics; reduced quality of life; and a rapid decline in pulmonary function 9,31 * Source of data: Patients with CF treated at Cystic Fibrosis Foundation (CFF) accredited care centers in the US who consented to have their data entered in 2015 in the CFF Registry. 11

12 POOR NUTRITION IN YOUNGER CHILDREN IS CORRELATED WITH REDUCED LUNG FUNCTION Nutritional deficits due to CF-related pancreatic and digestive problems are associated with decreased lung function When young children are below weight for their age, there is a correlation with reduced future lung function 32 In a study of preschool children, it was found that low weight for age at age 3 was associated with a lower ppfev 1 at age 6 32 MEAN ppfev 1 AT AGE 6 BY WFA PERCENTILE AT AGE 3 (N=931) 32 Mean ppfev 1 predicted at age Patients with CF below the 10th WFA percentile are generally regarded as having poor growth 80 <5th n= th n= th n= th n= th n=155 >75th n=113 WFA percentile at age 3 Adapted from Konstan et al. WFA, weight for age. 12

13 MILESTONES IN THE MANAGEMENT OF CF As advances in detection and management have emerged, median predicted survival has increased from approximately 6 months in 1938 to 42 years in ,9,33,34 Pancreatic enzyme replacement therapy Sweat test developed Antibiotics for CF pathogens Airway clearance CF center care CFTR discovered Tobramycin inhalation solution Dornase alpha Azithromycin Hypertonic saline Aztreonam solution for inhalation CFTR modulation Present 13

14 A WIDE RANGE OF TESTS CAN HELP ASSESS CF PROGRESSION ACROSS ORGAN SYSTEMS Consideration should be given to a method s effectiveness, age-based ease of use, and impact/burden on the patient Lung Pancreas Commonly Used Assessment Tools Imaging with HRCT Spirometry (eg, FEV 1, FVC) Magnetic resonance imaging Lung clearance index (LCI) Body mass index Immunoreactive trypsinogen Fecal elastase-1 Considerations Radiation burden with frequent imaging may be a concern, especially in young children 35 Standard assessment of lung function, specifically large airways 5 Young children (<6 years) may find it difficult to perform 36 May be normal despite underlying small airway structural damage 37 Similar accuracy to CT without radiation risk 38 Relatively new technology; unproven in clinical practice 38 Can detect underlying small airway lung damage even with 5,39 normal FEV 1 May be easier for young children (<6 years) 40 LCI is still considered an exploratory endpoint in clinical trials 41 Standard assessment for the nutritional impact of CF, along with weight and height measurements 5 Increasingly used in neonatal screening for CF 42,43 Easy to use for all ages 44 FVC, forced vital capacity. 14

15 A WIDE RANGE OF TESTS CAN HELP ASSESS CF PROGRESSION ACROSS ORGAN SYSTEMS (cont) Consideration should be given to a method s effectiveness, age-based ease of use, and impact/burden on the patient Liver Gastrointestinal Sinus Bone Commonly Used Assessment Tools Transaminase levels Signs and symptoms (dysmotility, constipation, etc) Nasal endoscopy CT radiographic imaging Dual-energy x-ray absorptiometry Considerations Transaminases vary over time in patients with CF-related liver disease 45 Consistently high transaminase levels occur only with advanced liver disease 46,47 Monitoring may help avoid effects that may compound malnourishment due to pancreatic insufficiency 48 Useful for detecting chronic rhinosinusitis and polyps, which occur in almost all patients and may precede development of CF lung disease 49,50 Radiation burden may be a concern 51 15

16 CF PROGRESSION: UNDERSTANDING THE CAUSE AND ITS IMPACT ON YOUR PATIENTS CF is a multi-organ, progressive, genetic disease that affects the whole body, and many problems with CF may be present at birth 1,10 Onset and progression of CF symptoms can occur in different organs at different ages Multisystemic damage often occurs before symptoms emerge 52 Our ability to detect and monitor CF progression in different organs has increased over time with improved understanding of the disease 33 All patients with CF experience progression; however, CF management has improved over time in concert with scientific and medical discoveries 1,7 BROUGHT TO YOU BY VERTEX, because we believe that knowledge empowers you and your patients. More resources are available for you at CFSourceHCP.com, and for your patients at CFSource.com. 16

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