La Terapia delle Fibrosi
Polmonari
Venerino Poletti
Ospedale GB Morgagni
Forlì (I)
Therapeutic Approaches to ILDs
ILDs treatment is guided by:
•
•
•
•
ILDs Aetiology (Known and Unknown causes)
ILDs Pathology (Inflammatory and Fibrotic)
Severity of disease and Disease Behaviour
The clinical context (age, comorbidities,
complications)
An Official American Thoracic Society/European Respiratory
Society Statement: Update of the International Multidisciplinary
Classification of the Idiopathic Interstitial Pneumonias.
Travis, Am J Respir Crit Care Med 2013
ILDs of known cause
 Drug induced
 Occupational and Environmental Exposure
 Collagen Vascular Diseases Associated
Hypersensitivity pneumonitis (HP)
is a complex syndrome of varying intensity, clinical
presentation, and natural history.
Several different diagnostic criteria for HP have been
proposed. Most apply only to typical, acute cases. No
clear diagnostic criteria exist for subacute or chronic
disease.
HP acute form
HOURS -2 DAYS
begin 2–9 h after exposure,
peak during 6 and 24 h, and last
from hours to days.
influenza-like symptoms
(chills, fever, sweating,
myalgias, lassitude,
headache and
Nausea)
Respiratory symptoms such
as cough and dyspnoea are
common but not universal.
HP subacute form
DAYS-WEEKS
appear gradually over several
days to weeks,
cough and dyspnoea, and
may progress to severe
dyspnoea
and cyanosis, leading to
urgent hospitalization.
HP chronic form
MONTHS
insidious onset over a
period of months,
increasing cough and
exertional dyspnoea,
fatigue , weight loss,
digital clubbing.
Chronic bird fancier's lung: histopathological and clinical
correlation.
group A BOOP-like or cellular NSIP-like
lesions, n = 7;
group B fibrotic NSIP-like lesions, n = 8;
group C UIP-like lesions, n = 11.
Chronic HP Treatment
 Eliminate the causal agent
 Prednisone 20-40 mg, tapered to 10mg/d up to 8
weeks, although fibrotic HP is less likely to
respond.
 In chronic, progressive HP, immunosuppressants
may be added as corticosteroid sparing agents, as
done in other fibrotic ILD.
 There is no antifibrotic treatment for chronic
advanced HP patients and lung transplantation
should be considered.
 Rituximab
CTD-ILDs Prognosis
CTD-ILD have a better prognosis compared
to IIPs.
Survival of RA-UIP does NOT differ from
IPF (3.5y)
Park JH, AJRCCM 2007
CTD-ILDs Treatment
1) DO NOT TREAT trivial ILDs:
Mild (HRCT extension <20% , DLco > 65%, FVC >75%) and stable.
2) TREATMENT FOR SLOWLY PROGRESSIVE CTD-ILDs
Prednisone po 0.5-1mg/Kg tapered to a maintenace dose of 10mg/day
in association with Azathioprine po 150mg/dì. Duration 2-3 years.
Alternatives:
-Mycophenolate po 250mg bd, up to 1000mg twice a day (seems to be better
tolerated, thera are NO clinical trials)
3) SALVAGE TREATMENT: consider Rituximab 1g followed by 1g after 2 weeks
(case series: Jo1+PM, SSc)
MMF DOSE
Daily dose of MMF 3000 mg/day in 65%
In only 4 subjects was the daily dose<2000 mg. None exceeded a dose of
3000 mg/day
MEDIAN DURATION of MMF USE
897 days
SIDE EFFECTS/DISCONTINUATION
In 13 subjects (10%) MMF was discontinuated (2 gastrointestinal intolerance,
2 ILD progression , 2 hepatic transaminase elevation, 1 recurrent infections,
1 cytopenia, 4 non specific symptoms)
Idiopathic ILDs
An Official American Thoracic Society/European Respiratory
Society Statement: Update of the International Multidisciplinary
Classification of the Idiopathic Interstitial Pneumonias.
Travis, Am J Respir Crit Care Med 2013
Pirfenidone
 Pirfenidone:
 Antifibrotic, antioxidant, anti-TNF
 Different experimental models :heart, lung, kidney fibrosis
 A series of four randomized controlled studies: (>1100 patients)
Pirfenidone
dosage
N
Changes in VC
decline/placebo
Ref
Azuma
1800 mg/d
Placebo
72
35
ΔVC 100 ml (9mo)
AJRCCM
2005
Taniguchi
1800 mg/d
1200 mg/d
Placebo
108
55
104
ΔFVC 70 ml (12 mo)
ERJ 2010
PIPF 004
2403 mg/d
1197 mg/d
Placebo
174
174
87
ΔFVC =4% pred.
(12% vs 8%)
72 wks
Noble,
Lancet 2011
PIPF 006
2403 mg/d
Placebo
171
173
NS
Noble,
Lancet 2011
FVC decline
Grouped analysis
% patients with ΔFVC > 10%
2403 mg Placebo
21%
31%
P
0.003
 Progression free survival
RR=0.74 P=0.025
 Distance 6MWT
Δ=24m P=0.009
 Positive trend for mortality
reduction
(Noble, Lancet 2011;377:1760)
L’uso del Pirfenidone nella pratica
clinica: cosa abbiamo imparato?
PROFILO POPOLAZIONE, N = 83 PAZIENTI TRATTATI
maschi (68, 82%), età media 66 anni (range, 46-81). FVC del 74% del predetto
(131-35), DLco 47% (89-20).
EVENTI AVVERSI
- avversi frequentemente osservati (43% dei pazienti) sono stati: astenia,
difficoltà di concentrazione, artralgie, e perdita di peso.
- sintomi gastrointestinali 34%,
- rush cutaneo 20% (11% da fotosensibilità),
- aumento degli enzimi epatici 3%.
L’uso del Pirfenidone nella pratica
clinica: cosa abbiamo imparato?
- Abbiamo osservato in totale 50 eventi avversi di cui :
-
6 (12%) gravi (2 aumentI enzimi epatici, 1 rash cutaneo, 1 reazione da
fotosensibilità, 2 cachessia) che hanno richiesto la definitiva sospensione
del farmaco.
- 19 (38%) lievi e sono stati affrontati senza necessità di modificare la dose
assunta.
- I rimanenti 25 (50%) erano lievi-moderati e sono stati affrontati con approci
diversi: riduzione della dose (5), temporanea interruzione (10) o definitiva
sospensione (10).
- Tutti gli eventi avversi sono stati completamente reversibili.
FOLLOW-UP
- 14 pazienti sono deceduti (10 di esacerbazione acuta diIPF)
- 7 pazienti la malattia è progredita.
0.25
0.50
0.75
1.00
La sopravvivenza libera da progressione di malattia dopo 12 mesi di
trattamento è stata del 87.03% (95% CI 77%-93%) per il Pirfenidone e del
72.05 % (95% CI 65%-78%) per I pazienti trattati con altri farmaci (p=0.0114)
0.00
N
0
Number at risk
N 186
Y 83
Y
6
12
18
24
89
11
68
0
time (months)
152
73
111
35
N Engl J Med 2012;366:1968-77.
Increased mortality in treated patients
N Engl J Med 2012;366:1968-77.
(IPFNet, NEJM 2012)
Increased mortality and hospitalization rate
N Engl J Med 2012;366:1968-77.
(IPFNet, NEJM 2012)
PANTHER trial – Is NAC effective ?
NAC (600 mg x3/d)
N=260
60 weeks
Placebo
Results expected 1q 2014
BIBF 1120 (nintedanib, Vargatef®) :
multi-target Tyrosine Kinase inhibitor
Triple
angiokinase
Inhibitor
Involved
in IPF
pathogenesis
Hilberg, Cancer Res 2008
The TOMORROW study
(Richeldi, NEJM 2011;365:1079)
Placebo
N=85
BIBF 1120-300mg
N=85
FVC 12 mo
- 190 ml
- 60 ml
0,013
Exacerbations
15,7 %
2,4 %
0,02
SGRQ
+5,46
-0,66
0,0007
GI side effects (drug stop)
Diarrhea
11,8% vs 0%
Nausea
4,7% vs 0%
Vomiting
2,4% vs 1,2%
P value
-68%
Two Phase 3 trials (Inpulsis)
Results expected end 2013
A non exhaustive list ot targets
Anti-TGFβ
Anti CTGF
Anti-CCL2
Anti-IL-13
Anti-IL-4, IL-13
JNKi
Anti-αvβ6
Anti LOXL2
SAP
CO inhalé
MMPs
Anti-LTs
Interferon alpha
Aerosolized IFNγ
Collagen V
Octreotide
PI3Kinase
Sirolimus
Serotonin, LPA1, losartan, …
Fresolimumab (Sanofi-Genzyme, Phase1)
FG-3019 (Fibrogen, Phase2)
CNTO 888 (Phase 2)
QAX-576 (Novartis, Phase 2)
Tralokinumab (AZ-MedImmune, Phase 2)
SAR156597 (Sanofi, Phase 2)
CC-930 (Celgene, Phase 2)
STX-100 (Stromedix, Phase 2)
simtuzumab (Gilead, Phase 2)
PRM-151 (Promedior, Phase 2)
Phase 2
minocycline
zileuton
Phase 1 (Thorax 2011)
Phase 2
IW001 (Immuneworks, Phase 1)
FIBROSAND (Phase 2) ERJ 2012
GSK2126458 (GSK, Phase 1)
Is bacterial
Infection/colonization
a target in IPF ?
Apoptosis
cotrimoxazole :
960mg x 2/j
Folic acid: 5mg/j
cotrimoxazole
(Shulgina, Thorax 2012; on line First)
3/53
14/65
Survie
Improvement of
mortality in the
per-protocol
population
HR: 0.21
(IC95%: 0.06-0.78)
p=0.02
Others...
Failure of
monotargeted
therapies
nintedanib
pirfenidone
2013
Next step ?
Should we treat GERD ?
Retrospective analysis of 2 IPF
cohorts
Prolonged survival associated
with :
 FVC ↑
 DLCO ↑
 Anti-GERD Tt
Lee, AJRCCM 2011
Should we treat PHT in IPF ?
 Specific Tts are not recommended
 Hoeper, Int J Cardiol 2011;154S:S45-S53
 Pulmonary edema in case of veno-occlusive component
 Colombat, Hum Pathol 2007;38:60-65
 Ambrisentan increased mortality in a recent trial
 Raghu (ATS 2012)
 Identify the right patient ?
 Sildenafil improves QoL and dyspnea score if RV dysfunction
 IPFNet, NEJM 2010;363:620-8; Han, Chest 2013, on line;
 Riociguat (guanylate cyclase agonist) to be evaluated
 Hoeper, ERJ 2012, on line
Do not forget…
Lung transplant is the only treatment
shown to improve survival in IPF patients
 A treatment of exception (<3%)
 Evaluate patients < 65 years
 Be ready for exacerbation : Evaluate early
rather than late
 DLCO<40%
CVF>10%
or
lung
function
decline
Egan, Thorax 2005; Wells, Interstitial Lung Disease guideline, Thorax 2008;63 Suppl 5
Raghu, AJRCCM 2011;183:788-824
Palliative Care in IPF
 Ravaglia C, et al. J Pall Care 2013
*This approach is recommended in IPF
patients
*NIV/Mechanical ventilation only in very
selected cases
Novel Treatments for other ILDs
Established and experimental medical therapy
of pulmonary sarcoidosis.
Baughman RP, Nunes H, Sweiss NJ, Lower EE.
Eur Respir J. 2013 Jun;41(6):1424-38.
 Standard treatments for pulmonary sarcoidosis, includes
glucocorticoids, and cytotoxic agents, such as methotrexate,
azathioprine and leflunomide,
 Newer biological agents, such as infliximab and adalimumab.
 There is, as yet, no standard assessment for response, there is
a growing consensus that response to treatment may include
improvement of one or more of the following: forced vital
capacity, chest imaging and steroid sparing. Several drugs
used for pulmonary sarcoidosis have demonstrated
improvement in one or more of these measures.
Recommendations can be either strong (1A,
1B, 1C) or weak (2A, 2B, 2C).