UNIVERSITA’ DEGLI STUDI DI FOGGIA
FACOLTA’ DI MEDICINA E CHIRURGIA
Istituto di Malattie dell’Apparato Respiratorio
Dipartimento di Scienze Mediche e Chirurgiche
Prof.ssa Maria Pia Foschino Barbaro
Lacedonia Donato
Interstiziopatie polmonari
la diagnosi e i principi di terapia
Am J Respir Crit Care Med 2013;188:733-748.
CATEGORY
CLINICAL-RADIOLOGICPATHOLOGIC DIAGNOSES
ASSOCIATED
MORPHOLOGIC
PATTERNS
Idiopathic Pulmonary Fibrosis
Chronic Fibrosing IP
Smoking-related IP
Acute/subacute IP
Usual Interstitial
Pneumonia
Idiopathic Nonspecific Interstitial
Nonspecific
Pneumonia‡
Interstitial
Pneumonia
Respiratory Bronchiolitis Interstitial Respiratory
Lung Disease
Bronchiolitis
Desquamative Interstitial
Desquamative
Pneumonia
Interstitial
Pneumonia
Cryptogenic Organizing Pneumonia Organizing
Pneumonia
Acute Interstitial Pneumonia
Diffuse Alveolar
Damage
Am J Respir Crit Care Med Vol 183. pp 788–824, 2011
DIAGNOSI DI IPF CERTA
HRTC
SURGICAL BIOPSY
UIP
UIP
Probabile
Possibile
Non Classificabile
Possibile
UIP
Probabile
IPF PROBABILE
Possibile
Possibile
Non Classificabile
POSSIBILE
Inconsistente
UIP
NON Diagnosi di IPF
UIP
Non UIP
Inconsistente
Qualsiasi quadro
tranne che UIP
BAL PATTERNS
IPF
NSIP
Sarcoidosi
HP
(+)
+
+
Cell var
(CD4/CD8 > 3.5)
EOS Proteinosi
PNM alveolare
Altro
Macrofagi
Linfociti
Neutrofili
+
(+)
+
+
Asbestosi
fibr var
Eosinofili
(+)
+
ChurgStrauss
Asperg
+
>25%
Altro
Foamy
macr
Foamy
Macr
Milk Fluid
CD1>5%
HS X
Interstitial Lung Diseases –ERJ Monograph 2009
“GOLD STANDARD” FOR IPF DIAGNOSIS
The accuracy of the diagnosis of IPF increases with
multidisciplinary discussion (MDD) between
pulmonologists, radiologists, and pathologists
experienced in the diagnosis of interstitial lung disease.
Am J Respir Crit Care Med 2011; 183: 788-824
“The
multidisciplinary approach does not
lessen the importance of lung biopsy in the
diagnosis of IIPs; rather, it defines the settings
where biopsy is more informative than high
resolution computed tomography (HRCT) and
those where biopsy is not needed”.
Am J Respir Crit Care Med 2013;188:733-748.
PRINCIPI DI TERAPIA
FASI DEL TRATTAMENTO DELLE PID
•
•
•
•
Patologia di Fondo
Sintomi (dispnea, tosse)
Comorbidità (RGE, PH, Depressione)
Trattamento delle riacutizzazioni
Trattamento della Patologia di
Fondo
•
•
•
•
•
•
•
•
Corticosteroidi
Azatioprina
Ciclofosfamide
Micofenolato
NAC
Pirfenidone
TRAPIANTO
FUTURE…..
Am J Respir Crit Care Med 2000; 161: 646-664
Currently there is no evidence to support the routine use of
corticosteroids alone in the management of idiopathic
pulmonary fibrosis.
Richeldi L, Davies HRH R, Spagnolo P, Luppi F. Cochrane Database Syst Rev Issue 4 2010
Corticosteroidi in altre PID
PRED
PRED + AZA (or CYCPH)
PRED+AZA+NAC
NAC
Pirfenidone #
Strong NO
Strong NO
Weak NO
Wear NO
Weak NO
Very Low
Very Low
Low
Low
Low – Mod
# 4 Favorevoli
10 Contrari
17 Astenuti
Am J Respir Crit Care Med Vol 183. pp 788–824, 2011
VC
2
DLCO
2
P = 0.02
0
-2
NAC/Pred/Aza
-4
-6
-8
PBO/Pred/Aza
P = 0.003
0
DLco (% predicted)
Vital capacity (% predicted)
IFIGENIA: Primary Efficacy Results
-2
-4
NAC/Pred/Aza
-6
PBO/Pred/Aza
-8
-10
-10
Baseline
6 Months
12 Months
A:P n 80:75
63:60
55:51
Baseline
6 Months
12 Months
Mortality, P = NS
NAC/Pred/Aza
7/80 (9%)
PBO/Pred/Aza
8/75 (11%)
Demedts M et al. N Engl J Med. 2005;353:2229-2242.
No mortality difference
Placebo
NAC
NAC-Pred-Aza
When approximately 50% of data had been collected, the independent Data and
Safety Monitoring Board recommended termination of the combination-therapy
group at a mean follow-up of 32 weeks.
N Engl J Med 2012; 366: 1968-77
P=0.001
N Engl J Med 2012; 366: 1968-77
Pirfenidone anti-fibrotic activity

Orally available, synthetic molecule that exhibits anti-fibrotic properties
in a variety of in vitro studies and in vivo models
Pirfenidone
Meccanismo d’azione non
completamente identificato
- Riduce la deposizione di colagene
- Riduce il TGF-B
- b-FGF
- Riduzione del TNF-a
CH3
N
O
1. Iyer SN, Gurujeyalakshmi G, Giri SN. J Pharmacol Exp Ther 1999; 291:367-373. 2. Iyer SN, Gurujeyalakshmi G, Giri SN. J Pharmacol Exp Ther 1999; 289:211-218. 3. Gurujeyalakshmi G, Hollinger MA,
Giri SN. Am J Physiol 1999; 276:L311-L318. 4. Oku H, Shimizu T, Kawabata T, et al. Eur J Pharmacol 2008; 590:400-408. 5. Grattendick KJ, Nakashima JM, Fenget L, et al. Int Immunopharmacol 2008; 679687. 6. Lee BS, Margolin SB, Nowak RA. J Clin Endocrinol Metab 1998; 83:219-223. 7. Iyer SN, Wild JS, Schiedt MJ, et al. J Lab Clin Med 1995; 125:779-785. 8 Schelegle ES, Mansoor JK, Giri S. Proc Soc Exp
Biol Med 1997; 216:392-397.
PFN035.EU
24
Percent Predicted FVC Over Time
Studies 004 and 006
Study 004 Pirfenidone 2403 mg/day
Study 006 Pirfenidone 2403 mg/day
Study 004 Placebo
Study 006 Placebo
Mean change from baseline
(% predicted FVC)
0
-5
004 pirfenidone
006 pirfenidone
006 placebo
-10
004 placebo
-15
0
12
24
36
Weeks
P<0.001 for Study 004; P=0.503 for Study 006
48
60
72
Percent Predicted FVC Over Time
Pooled analysis of Studies 004 and 006
Pirfenidone 2403 mg/d (n=345)
Placebo (n=347)
Mean change from baseline
(% predicted FVC)
0
Pirfenidone vs. placebo:
Relative difference: 23%
*p=0.005
-5
*
-10
-15
0
12
24
36
Weeks
Noble PW, Albera C, Bradford WZ, et al. Lancet. 2011;377:1760-1769.
48
60
72
Meta-analysis of pirfenidone
treatment effect
Event driven analysis of either 10% decline in FVC or all cause mortality
(Progression Free Survival)
Spagnolo P, Del Giovane C, Luppi F, et al. Cochrane Database Syst Rev 2010 9: CD003134
28
May 18, 2014,
May 18, 2014,
PRED
PRED + AZA (or CYCPH)
PRED+AZA+NAC
NAC
Pirfenidone
Nintedanib
2011
Strong NO
Strong NO
Weak NO
Wear NO
Weak NO
Next…
Strogn NO
Strong NO
Strong NO
Strong NO
Strong YES
Wear/Strong YES
39
Trapianto e IPF
Trapiantati
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