INTERSTITIAL LUNG DISEASES: FOCUS ON IDIOPATHIC PULMONARY FIBROSIS (IPF) Marilyn K. Glassberg Csete, M.D. Professor of Medicine, Surgery, and Pediatrics Director, Interstitial and Rare Lung Disease Program University of Miami Miller School of Medicine April 8, 2016
DISCLOSURES Advisory Boards: Boehringer Ingelheim, Genentech, Mesoblast Research Grants: Genentech; Lester and Sue Smith Foundation, Marcus Foundation; NIH
74-YEAR-OLD MALE EX-SMOKER WITH COUGH & DYSPNEA History: 12 months ago developed productive cough and shortness of breath Referred to pulmonologist with abnormal CXR and had HRCT of chest Hospitalized 14 months later with increased dyspnea and hypoxemia treated with antibiotics and steroids Dyspnea with ADLs Since discharge, requires continuous oxygen therapy Frequent heartburn Reports poor sleep, snoring and daytime fatigue Past Medical/Family/Social History +HTN, Hyperlipidemia Family history of CAD, Former 30 pack year smoker Exam 140/66, 86, 22, SpO2 90% at rest on RA; BMI 27 Bibasilar inspiratory crackles, no wheeze No peripheral edema or signs of CHF
74-YEAR-OLD MALE EX-SMOKER WITH COUGH & DYSPNEA FEV 1 FVC FEV 1 /FVC DL CO February 15 2.42 (84%) 2.80 (64%) 0.86 8.75 (34%)
HRCT 14 MONTHS LATER
IDIOPATHIC PULMONARY FIBROSIS Normal Lung Usual Interstitial Pneumonia
WHERE DOES IPF FIT IN THE CONTEXT OF THE ILDS? The most common ILD: 42,000 new cases per year Definition of IPF: Specific form of chronic, progressive fibrosing interstitial pneumonia of unknown cause Occurring primarily in males above the age of 55 Limited to the lungs 80% are ex-smokers Raghu G, et al, and the ATS/ERS/JRS/ALAT Committee on IPF. Am J Respir Crit Care Med. 2011;183:788-824
HISTORICAL CLASSIFICATION OF INTERSTITIAL LUNG DISEASES MAJOR IIPs Sarcoidosis Hypersensitivity Pneumonitis (EAA) 1970s Idiopathic IPs Heterogeneous group that included a number of diseases IPF DIP AIP NSIP RB- ILD 2016 Cellular Asbestosis LAM BML LG Rare IIPs COP Fibrotic Unclassifiable IIPs Adapted from Ryu JH, et al. Mayo Clin Proc. 1998;73:1085-1101 Adapted from ATS/ERS. Am J Respir Crit Care Med. 2013;188: 733-748. Pleuroparenchymal Fibroelastosis ILIP
IPF IS THE MOST COMMON IDIOPATHIC INTERSTITIAL PNEUMONIA Interstitial lung disease (ILD) ILD of known cause Idiopathic interstitial pneumonias Granulomatous ILD Other forms of ILD Major idiopathic interstitial pneumonias Rare idiopathic interstitial pneumonias Unclassifiable idiopathic interstitial pneumonias Desquamative interstitial pneumonia Idiopathic pulmonary fibrosis (IPF) Idiopathic lymphoid interstitial pneumonia Cryptogenic organizing pneumonia Idiopathic nonspecific interstitial pneumonia Idiopathic pleuroparenchymal fibroelastosis Acute interstitial pneumonia Respiratory bronchiolitis-interstitial lung disease Travis WD et al. Am J Respir Crit Care Med. 2013;188(6):733-748.
DISTINGUISHING DYSPNEA Disease Prevalence, United States IPF 1 136,170 Heart failure 2 5.1 million COPD 3 15.7 million 0 3 6 9 12 15 18 Million 1. Raghu G, 2013; 2. Go AS, et al. Circulation. 2013;127:e6 e245. 3. Wheaton AG, et al. MMWR Morb Mortal Wkly Rep. 2015;64:289 295.
Percentage of Patients THE INCIDENCE OF IPF INCREASES WITH AGE 60 50 40 30 20 10 0 Age of Incident Medicare Patients with IPF at Diagnosis in 2011 66-69 70-74 75-79 80+ Raghu G et al. Lancet Respir Med. Appendix. 2014;2:566-572.
RISK FACTORS/LOCATION OF IPF IN US Age Male sex Highest Lowest Medium Hispanic ethnicity Geography Raghu G, et al. Lancet Respir Med. 2014;2(7):566-572.
SURVIVAL IN IPF IS WORSE THAN MOST CANCERS 5-Year Survival Rate, a % 100 89 80 65 60 40 IPF survival is comparable to that of lung cancer 44 57 20 17 20 3 0 Lung Cancer IPF Ovarian Cancer PAH Colorectal Cancer Breast Cancer
Months PATIENTS WITH IPF ARE OFTEN MISDIAGNOSED Disease Onset 1-2 Years (average) Diagnosis Patients are often misdiagnosed with bronchitis, asthma, COPD, emphysema, or heart disease 15 10 5 0 Duration of Time from Disease Onset to Diagnosis Cellular NSIP Fibrotic NSIP IPF
PROGRESSION OF IPF Normal Progressive destruction of lung architecture 5-year survival rate from diagnosis = 20 to 40% Age of onset : 2/3 over age 60
Respiratory Function/Symptoms IPF: A DISEASE WITH AN UNPREDICTABLE CLINICAL COURSE Slowly progressive Rapidly progressive Acute exacerbations 0 1 2 3 4 Years Kim DS, et al. Proc Am Thorac Soc. 2006; 3: 285-292
P e r c e n t s u r v iv a l Percent Survival P e r c e n t s u r v iv a l DIFFUSING CAPACITY PREDICTS SURVIVAL IN IPF 1 0 01 0 0 8 0 8 0 6 0 6 0 DL co 50% DL co 35-49% Dl co < 35% D L c o = D> 5L 0 c % o = > 5 0 % D L c o 3D5-4 L c9 o% 3 5-4 9 % D L c o < D 3 5 L % c o < 3 5 % 4 0 2 0 4 0 2 0 P=0.0001 0 0 0 1 2 2 4 3 6 4 8 6 0 7 2 8 4 9 6 1 0 8 1 2 0 0 1 2 2 4 3 6M o4n 8th s6 0 7 2 8 4 9 6 1 0 8 1 2 0 M o n th s Months Nathan SD, et al. Chest. 2011;140:221-229.
Percent Survival P e r c e n t s u r v iv a l P e r c e n t s u r v iv a l FVC PREDICTS SURVIVAL IN IPF 1 0 01 0 0 8 0 8 0 6 0 6 0 FVC 70% FVC 55-69% FVC < 55% F V C > o r= F 7V 0 C % > o r= 7 0 % F V C 5 5-6 F V9 C % 5 5-6 9 % F V C < 5 5 F % V C < 5 5 % 4 0 2 0 4 0 2 0 P=0.0053 0 0 0 1 2 2 4 3 6 4 8 6 0 7 2 8 4 9 6 1 0 8 1 2 0 0 1 2 2 4 3 6M o 4n 8th s6 0 7 2 8 4 9 6 1 0 8 1 2 0 Months M o n th s Nathan SD, et al. Chest. 2011;140:221-229.
6MWT: PARAMETERS PREDICT SURVIVAL IN IPF Baseline 6MWT distance 6MWT distance at 24 weeks du Bois RM, et al. Eur Respir J. 2014;43(5):1421-1429. Swigris JJ, et al. Chest. 2009;136:841-848
Survival GERD TREATMENT AND SURVIVAL Time to Event (days) Lee JS, et al. Am J Respir Crit Care Med. 2011;184(12):1390-1394.
OBSTRUCTIVE SLEEP APNEA IS COMMON IN IPF 55 subjects with IPF Sleep apnea evaluation Epworth Sleepiness Scale Sleep Apnea Scale of Sleep Disorders Nocturnal polysomnography Findings that did not correlate with OSA Spirometry Lung volume DLCO ESS 68% No OSA AHI 5/h 12% Moderate/Severe AHI > 15 events/h 20% Mild AHI 5 15/h AHI: apnea-hypopnea index Lancaster LH, et al. Chest. 2009;136:772-778.
DIAGNOSTIC ALGORITHM FOR IPF Patient presents with suspected ILD Detailed history Physical exam PFT Clinical presentation: Typically affects adults >50 years of age Chronic exertional dyspnea Dry, nonproductive cough Crackles or rales on auscultation Digital clubbing Adapted from Raghu G et al. 1 CTD, connective tissue disorder; MDD, multidisciplinary discussion; PFT, pulmonary function testing. 1. Raghu G et al. Am J Respir Crit Care Med. 2011;183:788-824. 2. Flaherty KR, Khanna D. Thorax. 2014;69(3):205-206.
Diagnostic Algorithm for IPF Yes Patient presents with suspected ILD Detailed history Physical exam PFT Identifiable cause of ILD? No Serologic testing to exclude CTD Exposures (environmental, occupational, pets) 1 Skin, joint, or muscle findings including arthritis, pleurisy, skin thickening, and Raynaud s phenomenon may indicate a connective tissue disorder 1 Not IPF Adapted from Raghu G et al. 1 CTD, connective tissue disorder; MDD, multidisciplinary discussion; PFT, pulmonary function testing. 1. Raghu G et al. Am J Respir Crit Care Med. 2011;183:788-824. 2. Flaherty KR, Khanna D. Thorax. 2014;69(3):205-206.
Diagnostic Algorithm for IPF Patient presents with suspected ILD Detailed history Physical exam PFT Yes Positive Identifiable cause of ILD? No Serologic testing to exclude CTD Not IPF Adapted from Raghu G et al. 1 CTD, connective tissue disorder; MDD, multidisciplinary discussion; PFT, pulmonary function testing. 1. Raghu G et al. Am J Respir Crit Care Med. 2011;183:788-824. 2. Flaherty KR, Khanna D. Thorax. 2014;69(3):205-206.
Diagnostic Algorithm for IPF Patient presents with suspected ILD Detailed history Physical exam PFT HRCT is critical to making an accurate diagnosis of IPF 1 UIP Possible UIP Inconsistent with UIP Yes Positive Identifiable cause of ILD? No Serologic testing to exclude CTD Negative HRCT Not IPF Adapted from Raghu G et al. 1 CTD, connective tissue disorder; MDD, multidisciplinary discussion; PFT, pulmonary function testing. 1. Raghu G et al. Am J Respir Crit Care Med. 2011;183:788-824. 2. Flaherty KR, Khanna D. Thorax. 2014;69(3):205-206.
Diagnostic Algorithm for IPF Yes Positive Patient presents with suspected ILD Detailed history Physical exam PFT Identifiable cause of ILD? No Serologic testing to exclude CTD Negative HRCT HRCT is critical to making an accurate diagnosis of IPF 1 o o o UIP Definite UIP Possible UIP Inconsistent with UIP UIP Image courtesy of and used with permission from Jonathan Goldin, MD, PhD. Not IPF IPF Adapted from Raghu G et al. 1 CTD, connective tissue disorder; MDD, multidisciplinary discussion; PFT, pulmonary function testing. 1. Raghu G et al. Am J Respir Crit Care Med. 2011;183:788-824. 2. Flaherty KR, Khanna D. Thorax. 2014;69(3):205-206.
Diagnostic Algorithm for IPF Patient presents with suspected ILD Detailed history Physical exam PFT Not UIP Yes Positive Not UIP Identifiable cause of ILD? No Serologic testing to exclude CTD Negative HRCT Image courtesy of and used with permission from Jonathan Goldin, MD, PhD. Definite UIP Not IPF IPF Adapted from Raghu G et al. 1 CTD, connective tissue disorder; MDD, multidisciplinary discussion; PFT, pulmonary function testing. 1. Raghu G et al. Am J Respir Crit Care Med. 2011;183:788-824. 2. Flaherty KR, Khanna D. Thorax. 2014;69(3):205-206.
Diagnostic Algorithm for IPF Patient presents with suspected ILD Detailed history Physical exam PFT Not UIP Yes Positive Not UIP Identifiable cause of ILD? No Serologic testing to exclude CTD Negative HRCT Possible UIP Surgical lung biopsy Possible UIP Image courtesy of and used with permission from Jonathan Goldin, MD, PhD. Definite UIP Not IPF IPF Adapted from Raghu G et al. 1 CTD, connective tissue disorder; MDD, multidisciplinary discussion; PFT, pulmonary function testing. 1. Raghu G et al. Am J Respir Crit Care Med. 2011;183:788-824. 2. Flaherty KR, Khanna D. Thorax. 2014;69(3):205-206.
Diagnostic Algorithm for IPF Patient presents with suspected ILD Detailed history Physical exam PFT Not UIP Yes Positive Not UIP Not UIP Identifiable cause of ILD? No Serologic testing to exclude CTD Negative HRCT Possible UIP Surgical lung biopsy Possible UIP Image used with permission from the American Thoracic Society. 2015. Raghu G et al. 1 Definite UIP Not IPF IPF Adapted from Raghu G et al. 1 CTD, connective tissue disorder; MDD, multidisciplinary discussion; PFT, pulmonary function testing. 1. Raghu G et al. Am J Respir Crit Care Med. 2011;183:788-824. 2. Flaherty KR, Khanna D. Thorax. 2014;69(3):205-206.
Diagnostic Algorithm for IPF Patient presents with suspected ILD Detailed history Physical exam PFT Not UIP Yes Positive Not UIP Not UIP Identifiable cause of ILD? No Serologic testing to exclude CTD Negative HRCT Possible UIP Surgical lung biopsy Image used with permission from the American Thoracic Society. 2015. Raghu G et al. 1 Definite UIP Not IPF Not UIP UIP/Probable UIP UIP MDD IPF Adapted from Raghu G et al. 1 CTD, connective tissue disorder; MDD, multidisciplinary discussion; PFT, pulmonary function testing. 1. Raghu G et al. Am J Respir Crit Care Med. 2011;183:788-824. 2. Flaherty KR, Khanna D. Thorax. 2014;69(3):205-206.
PATHOGENESIS OF IPF Epithelial cell injury and activation INJURY Epithelial apoptosis Progressive fibrosis and impaired reepithelialization Wound clot Fibroblast migration and proliferation Basement membrane disruption Myofibroblast accumulation Angiogenesis Ahluwalia N, et al. Am J Respir Crit Care Med. 2014;190(8):867 78.
PAST NEGATIVE CLINICAL TRIALS IN IPF 2000-PRESENT Trial n Primary Endpoint Result Interferon-beta (1999) 167 Progression-free survival time Negative Interferon-gamma (GIPF-001) 330 Progression-free survival Negative Interferon-gamma (Inspire) 826 Survival time Negative Pirfenidone (CAPACITY 1) 344 Change in FVC Negative Etanercept 100 Change in DL co, FVC Negative Imatinib Mesylate 120 Progression-free survival Negative Bosentan (BUILD 1 and 2) 132 Change in 6MW Negative Bosentan (BUILD 3) 390 Progression-free survival time Negative Sildenafil (STEP) 29 Change in 6MWD, Borg dyspnea index Negative Ambrisentan (Artemis-IPF) 478 Progression-free survival Stopped Ambrisentan (Artemis-PH) 50 6MWD Stopped Everolimus Noth I et al. Am J Respir Crit Care Med. 89 2012;186:88-95. Progression Negative
PHARMACOLOGIC APPROACHES FDA APPROVED IN OCTOBER 2014 Two drugs: Nintedanib and Pirfenidone Effective in slowing functional decline and disease progression Current evidence supports timely diagnosis and administration of treatment Neither drug cures IPF
MSCS: A UNIQUE IMMUNOPRIVILEGED CELL Williams and Hare. Circ Res 2011; 109:923-40
YOUNG MSCS PREVENT LUNG FIBROSIS Tashiro J., et al. Transl Res. 2015 Dec;166(6):554-67
PRELIMINARY SAFETY RESULTS FIRST IN MAN FDA APPROVED CLINICAL TRIAL COMPLETED DECEMBER 2015 No infusion related adverse events Most common adverse event was bronchitis Promising exploratory endpoints: Walk test distance Lung Function Oxygen usage
KEY POINTS: WORK-UP SHORTNESS OF BREATH WWW.BREATHLESSIPF.COM REFER EARLY TO SPECIALIST
March 14, 2016