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
INTERSTITIAL LUNG DISEASES:
FOCUS ON IDIOPATHIC
PULMONARY FIBROSIS (IPF)
Advisory Boards: Boehringer Ingelheim, Genentech,
Mesoblast
Research Grants: Genentech; Lester and Sue Smith
Foundation, Marcus Foundation; NIH
DISCLOSURES
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
FEV1 FVC FEV1/FVC DLCO
February 15 2.42 (84%) 2.80 (64%) 0.86 8.75 (34%)
74-YEAR-OLD MALE EX-SMOKER WITH COUGH & DYSPNEA
HRCT 14 MONTHS LATER
Normal Lung Usual Interstitial Pneumonia
IDIOPATHIC PULMONARY FIBROSIS
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
Pleuroparenchymal Fibroelastosis
MAJOR IIPs
HISTORICAL CLASSIFICATION OF INTERSTITIAL LUNG DISEASES
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.
1970s 2016 Idiopathic
IPs Heterogeneous
group that included
a number of
diseases
IPF
NSIP
DIP RB-
ILD
AIP
Cellular
Fibrotic
Sarcoidosis
Hypersensitivity Pneumonitis
(EAA)
Asbestosis
LAM
BML
LG
COP
ILIP
Unclassifiable
IIPs Rare IIPs
IPF IS THE MOST COMMON
IDIOPATHIC INTERSTITIAL PNEUMONIA
Interstitial lung disease (ILD)
ILD of known cause Idiopathic interstitial
pneumonias Other forms of ILD Granulomatous ILD
Unclassifiable idiopathic interstitial
pneumonias
Rare idiopathic interstitial
pneumonias
Major idiopathic interstitial
pneumonias
Idiopathic nonspecific
interstitial pneumonia
Desquamative interstitial pneumonia
Cryptogenic organizing
pneumonia
Acute interstitial pneumonia
Respiratory
bronchiolitis-interstitial
lung disease
Idiopathic pulmonary fibrosis (IPF)
Idiopathic
pleuroparenchymal
fibroelastosis
Idiopathic lymphoid
interstitial pneumonia
Travis WD et al. Am J Respir Crit Care Med. 2013;188(6):733-748.
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.
DISTINGUISHING DYSPNEA
IPF
COPD
Heart
failure
Million
9 3 15 6 0 18
Disease Prevalence, United States
1
3
2
136,170
15.7 million
5.1 million
12
THE INCIDENCE OF IPF INCREASES WITH AGE
Raghu G et al. Lancet Respir Med. Appendix. 2014;2:566-572.
0
10
20
30
40
50
60
66-69 70-74 75-79 80+
Pe
rce
nta
ge
of
Pa
tie
nts
Age of Incident Medicare Patients with IPF
at Diagnosis in 2011
Age
Male sex
Hispanic ethnicity
Geography
RISK FACTORS/LOCATION OF IPF IN US
Raghu G, et al. Lancet Respir Med. 2014;2(7):566-572.
Highest Medium
Lowest
0
20
40
60
80
100
Lung Cancer IPF Ovarian Cancer PAH Colorectal Cancer Breast Cancer
5-Y
ear
Su
rviv
al R
ate
,a %
SURVIVAL IN IPF IS WORSE THAN MOST
CANCERS
17
44
57
65
89
IPF survival
is comparable
to that of lung
cancer
203
PATIENTS WITH IPF ARE OFTEN MISDIAGNOSED
1-2 Years (average) Disease Onset Diagnosis
Patients are often
misdiagnosed with bronchitis,
asthma, COPD, emphysema,
or heart disease
0
5
10
15
Cellular NSIP Fibrotic NSIP IPF
Mo
nth
s
Duration of Time from Disease Onset to Diagnosis
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
IPF: A DISEASE WITH AN UNPREDICTABLE CLINICAL COURSE
0 1 2 3 4
Years
Resp
irato
ry
Fu
ncti
on
/Sym
pto
ms
Acute exacerbations
Slowly progressive
Kim DS, et al. Proc Am Thorac Soc. 2006; 3: 285-292
Rapidly progressive
0 1 2 2 4 3 6 4 8 6 0 7 2 8 4 9 6 1 0 8 1 2 0
0
2 0
4 0
6 0
8 0
1 0 0D L c o = > 5 0 %
D L c o 3 5 -4 9 %
D L c o < 3 5 %
M o n th s
Pe
rc
en
t s
urv
iva
l
P=0.0001
DIFFUSING CAPACITY PREDICTS SURVIVAL IN IPF
Nathan SD, et al. Chest. 2011;140:221-229.
0 1 2 2 4 3 6 4 8 6 0 7 2 8 4 9 6 1 0 8 1 2 0
0
2 0
4 0
6 0
8 0
1 0 0D L c o = > 5 0 %
D L c o 3 5 -4 9 %
D L c o < 3 5 %
M o n th s
Pe
rc
en
t s
urv
iva
lDLco ≥ 50%
DLco 35-49%
Dlco < 35%
Months
Pe
rce
nt
Su
rviv
al
P=0.0053
FVC PREDICTS SURVIVAL IN IPF
Nathan SD, et al. Chest. 2011;140:221-229.
0 1 2 2 4 3 6 4 8 6 0 7 2 8 4 9 6 1 0 8 1 2 0
0
2 0
4 0
6 0
8 0
1 0 0F V C > o r= 7 0 %
F V C 5 5 -6 9 %
F V C < 5 5 %
M o n th s
Pe
rc
en
t s
urv
iva
l
FVC ≥ 70%
FVC 55-69%
FVC < 55%
Months
Pe
rce
nt
Su
rviv
al
0 1 2 2 4 3 6 4 8 6 0 7 2 8 4 9 6 1 0 8 1 2 0
0
2 0
4 0
6 0
8 0
1 0 0F V C > o r= 7 0 %
F V C 5 5 -6 9 %
F V C < 5 5 %
M o n th s
Pe
rc
en
t s
urv
iva
l
6MWT: PARAMETERS PREDICT SURVIVAL IN IPF
du Bois RM, et al. Eur Respir J. 2014;43(5):1421-1429.
Swigris JJ, et al. Chest. 2009;136:841-848
6MWT distance at 24 weeks Baseline 6MWT distance
Lee JS, et al. Am J Respir Crit Care Med. 2011;184(12):1390-1394.
GERD TREATMENT AND SURVIVAL
Su
rviv
al
Time to Event (days)
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
Lancaster LH, et al. Chest. 2009;136:772-778.
12%
20%
68%
Moderate/Severe
AHI > 15 events/h
Mild AHI 5–15/h
No OSA
AHI 5/h
AHI: apnea-hypopnea index
Clinical presentation:
• Typically affects adults
>50 years of age
• Chronic exertional dyspnea
• Dry, nonproductive cough
• Crackles or rales on
auscultation
• Digital clubbing
Patient presents with
suspected ILD
• Detailed history
• Physical exam
• PFT
DIAGNOSTIC ALGORITHM FOR 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.
• Exposures (environmental,
occupational, pets)1
• Skin, joint, or muscle
findings including arthritis,
pleurisy, skin thickening, and
Raynaud’s phenomenon
may indicate a connective
tissue disorder1
Not IPF
Yes
No
Patient presents with
suspected ILD
• Detailed history
• Physical exam
• PFT
Identifiable cause of
ILD?
Serologic testing to
exclude CTD
Diagnostic Algorithm for 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.
Not IPF
Yes
Positive No
Patient presents with
suspected ILD
• Detailed history
• Physical exam
• PFT
Identifiable cause of
ILD?
Serologic testing to
exclude CTD
Diagnostic Algorithm for 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.
HRCT is critical to making an
accurate diagnosis of IPF1
• UIP
• Possible UIP
• Inconsistent with UIP
Not IPF
Yes
Positive No
Negative
Patient presents with
suspected ILD
• Detailed history
• Physical exam
• PFT
Identifiable cause of
ILD?
HRCT
Serologic testing to
exclude CTD
Diagnostic Algorithm for 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.
• HRCT is critical to making an
accurate diagnosis of IPF1
o UIP
o Possible UIP
o Inconsistent with UIP
UIP
Not IPF IPF
Yes
Positive No
Negative
Definite UIP
Patient presents with
suspected ILD
• Detailed history
• Physical exam
• PFT
Identifiable cause of
ILD?
HRCT
Serologic testing to
exclude CTD Image courtesy of and used with permission from Jonathan
Goldin, MD, PhD.
Diagnostic Algorithm for 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.
Not UIP
Image courtesy of and used with permission from Jonathan
Goldin, MD, PhD.
Not IPF IPF
Yes
Positive
Not UIP
No
Negative
Definite UIP
Patient presents with
suspected ILD
• Detailed history
• Physical exam
• PFT
Identifiable cause of
ILD?
HRCT
Serologic testing to
exclude CTD
Diagnostic Algorithm for 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.
Not UIP
Possible UIP
Image courtesy of and used with permission from Jonathan
Goldin, MD, PhD.
Image courtesy of and used with permission from Jonathan
Goldin, MD, PhD.
Not IPF IPF
Yes
Surgical lung biopsy
Positive
Not UIP
No
Negative
Possible UIP
Definite UIP
Patient presents with
suspected ILD
• Detailed history
• Physical exam
• PFT
Identifiable cause of
ILD?
HRCT
Serologic testing to
exclude CTD
Diagnostic Algorithm for 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.
Possible UIP
Not UIP
Image used with permission from the American Thoracic
Society. © 2015. Raghu G et al.1
Not IPF IPF
Yes
Surgical lung biopsy
Positive
Not UIP
No
Negative
Possible UIP
Definite UIP
Patient presents with
suspected ILD
• Detailed history
• Physical exam
• PFT
Identifiable cause of
ILD?
HRCT
Serologic testing to
exclude CTD
Not UIP
Diagnostic Algorithm for 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.
Image used with permission from the American Thoracic
Society. © 2015. Raghu G et al.1
Image used with permission from the American Thoracic
Society. © 2015. Raghu G et al.1
Not UIP
Not IPF IPF
Yes
Surgical lung biopsy
Positive
Not UIP
No
Negative
Possible UIP
MDD UIP
Definite UIP
Patient presents with
suspected ILD
• Detailed history
• Physical exam
• PFT
Identifiable cause of
ILD?
HRCT
Serologic testing to
exclude CTD
Not UIP
Not UIP
UIP/Probable UIP
Diagnostic Algorithm for 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
Ahluwalia N, et al. Am J Respir Crit Care Med. 2014;190(8):867–78.
INJURY
Angiogenesis
Fibroblast migration and proliferation
Wound clot
Basement
membrane
disruption
Epithelial apoptosis
Epithelial cell injury and activation
Myofibroblast accumulation
Progressive fibrosis and
impaired reepithelialization
Pre-2011
Noth I et al. Am J Respir Crit Care Med. 2012;186:88-95.
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 DLco, 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 89 Progression Negative
PAST NEGATIVE CLINICAL TRIALS IN IPF 2000-PRESENT
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
No infusion related adverse events
Most common adverse event was
bronchitis
Promising exploratory endpoints:
Walk test distance
Lung Function
Oxygen usage
PRELIMINARY SAFETY RESULTS FIRST IN MAN FDA APPROVED
CLINICAL TRIAL COMPLETED DECEMBER 2015
KEY POINTS:
WORK-UP SHORTNESS OF BREATH
WWW.BREATHLESSIPF.COM
REFER EARLY TO SPECIALIST
March 14, 2016