5. Trat IPF 1.pdf

8/19/2019 5. Trat IPF 1.pdf

1/112

Considerații terapeutice asuprafibrozei pulmonare idiopatice (IPF)

Voicu Tudorache – Clinica de Pneumologie – UMF Timisoara

8/19/2019 5. Trat IPF 1.pdf

2/112

There are more questions than

answers currently exist

8/19/2019 5. Trat IPF 1.pdf

3/112

An Official ATS/ERS/JRS/ALAT Statement: Idiopathic Pulmonary Fibrosis: Evidence-based Guidelines for Diagnosis and Management, Am

J Respir Crit Care Med , 2011.

8/19/2019 5. Trat IPF 1.pdf

4/112

• Inflammation causes fibrosis – Inflammatory concept was dominant in the 1970s and

1980s

• IPF resulted from unremitting inflammatory response

to injury culminating in progressive fibrosis – Role of inflammation remains controversial• Lack of efficacy of corticosteroids

Noble PW, Homer RJ. Clin Chest Med . 2004;25:749-758, vii.Raghu G, Chang J. Clin Chest Med . 2004;25:621-636, v.

Injury Inflammation Fibrosis

Inflammatory Hypothesis

8/19/2019 5. Trat IPF 1.pdf

5/112

Noninflammatory (multiple hit) Hypothesis

Recurrent

pulmonar

y injury

Epithelial/

endothelial

injury and

apoptosis

Loss of basement

membrane

Failure of

re-epithelialization/

re-endothelialization

ECM

deposition

Fibroblast

proliferatio

n

Release of

profibrotic

growth factors

(TGF- , PDGF,IGF-1)

Progressive fibrosis with loss of

lung architecture

TGF-b = transforming growth factor-betaPDGF = platelet derived growth factorIGF-1 = insulin-like growth factor-1

Noble PW, Homer RJ. Clin Chest Med . 2004;25:749-758, vii.Raghu G, Chang J. Clin Chest Med . 2004;25:621-636, v. Selman M, et al. Drugs. 2004;64:405-430.

8/19/2019 5. Trat IPF 1.pdf

6/112

Probabilitatea de diagnostic și instituirea tratamentului

• În diagnosticul de TEP folosim probabilitatea înluarea deciziei terapeutice.

• De ce clasificările de IPF ”definită”, ”probabilă”,”posibilă”, ”nedeterminată”, nu pot funcționa șiele ca probabilități diagnostice ?

• Recomandările de tratament sunt scrise doar

pentru situația de ”IPF definită”. • Pacienții cu IPF ”probabilă” sau ”posibilă” vor

face obiectul diagnosticului diferențial cu NSIP-fibrotică sau pneumonia de hipersensibilitate

(HP).

8/19/2019 5. Trat IPF 1.pdf

7/112

Pharmacologic Agents for IPF

ATS Statement

2011

Pre-ATS

Statement 2011 2011-2013 2014

8/19/2019 5. Trat IPF 1.pdf

8/112

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

Pirfenidone (CAPACITY 2) 435 Change in FVC Positive

Pirfenidone (Ogura) 275 Change in FVC Positive

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

Anticoagulation 56 Survival Positive

N-acetylcysteine (NAC)

(IFIGENIA)184 Change in FVC, DLco Positive

Sildenafil (STEP)29

Change in 6MWD, Borg dyspneaindex Negative

Completed Trials for IPF:

Prior to 2011 Consensus Statement

ATS2011

2011-2013 2014Pre-2011

8/19/2019 5. Trat IPF 1.pdf

9/112

Alte tratamente

• Anticoagulante – nu se recomandă • Colchicină – fără efect

• Ciclosporină A – fără efect • Interferon-ɣ-1b – fără efect • Etanercept (inhibitor al TNFa) – fără efect

• Inhibitori de endotelină-1 (bosentan,macitentan, ambrisentan) – fără efect

8/19/2019 5. Trat IPF 1.pdf

10/112

Imatinib (c-Abl, c-kit and PDGF, TK inhibitor)

treatment for IPF

Craig E.D et al., AJRCCM., 2010

In a randomized, placebo-controlled trial of119 pts with mild to moderate IPF followedfor 96 weeks, Imatinib did not affect

survival or lung function.

8/19/2019 5. Trat IPF 1.pdf

11/112

2011 Guidelines on

Management of IPF

Treatment StrongFor

WeakFor

WeakAgainst

StrongAgainst

Corticosteroid X

Colchicine X

Cyclosporine A X

Interferon γ 1b XBosentan X

Etanercept X

NAC/Azathioprine/Prednisone X

NAC X

Anticoagulation X

Pirfenidone X

Mechanical ventilation X

Pulmonary rehab X

Long-term oxygen X

Lung transplantation X

ATS2011

2011-2013 2014Pre-2011

8/19/2019 5. Trat IPF 1.pdf

12/112

8/19/2019 5. Trat IPF 1.pdf

13/112

Other Completed Trials

for IPF (2011-2013)

Trial NPrimary

EndpointResult

Macitentan FVC Negative

BIBF 1120(nintedanib) 432 FVC Trend (P = 0.06)

Everolimus 89 Progression Negative

Co-trimoxazole 181 FVCNegative, but QOL↑

Mortality 3/53 vs 14/65 (P = 0.02)

ATS2011

2011-2013 2014Pre-2011

8/19/2019 5. Trat IPF 1.pdf

14/112

3 Clinical Trials Presentedat ATS 2014

• PANTHER N-acetylcysteine (NAC)• ASCEND pirfenidone• INPULSIS nintedanib

(BIBF1120)

ATS2011

2011-2013Pre-2011 2014

8/19/2019 5. Trat IPF 1.pdf

15/112

PANTHER N-acetylcysteine (NAC)

8/19/2019 5. Trat IPF 1.pdf

16/112

Possible NAC Mechanisms of Action

• Increase glutathione antioxidation• Downregulate lysyl oxidase (LOX) activity,

(essential for collagen deposition)

Li S, et al. Respiration. 2012;84(6):509-517.

Rushworth GF, et al. Pharmacol Ther . 2014;141(2):150-159.

8/19/2019 5. Trat IPF 1.pdf

17/112

Demedts M, et al. New Engl J Med . 2005;353:2229-2242.

+ azathioprine + steroids

+ azathioprine + steroids

Early Evidence for a NAC Cocktail

Acetylcysteine + azathioprine + steroids

Placebo + azathioprine + steroids

ATS2011

2011-2013 2014Pre-2011

8/19/2019 5. Trat IPF 1.pdf

18/112

PANTHER 2012

Raghu G, et al. N Engl J Med. 2012;366:1968-1977.

ATS2011

2011-2013 2014Pre-2011

8/19/2019 5. Trat IPF 1.pdf

19/112

PANTHER 2012 Interim Results

• Triple therapyhas no benefit

for FVC• Increased risk ofdeath

Primary TripleTherapy

Placebo P-value

FVC(liters)

-0.24 -0.23 0.85


P r o

b a b i l i t y

Time to DeathKaplan –Meier Analysis

Weeks Since Randomization

HR 9.26

(95% CI 1.16-74.1)

P = 0.01

ATS2011

2011-2013 2014Pre-2011

8/19/2019 5. Trat IPF 1.pdf

20/112

PANTHER 2012 Adverse Events

• Triple therapy hashigher incidence of

adverse eventsthan placebo

P-value for each comparison < 0.05

IPFNet writing committee. N Engl J Med 2012;366;1968-77.

P-values < 0.05


P e r c e n t a g e

ATS2011

2011-2013 2014Pre-2011

8/19/2019 5. Trat IPF 1.pdf

21/112

PANTHER 2012 Conclusions

• “Increased risks of death and hospitalizationwere observed in patients with IPF who weretreated with a combination of prednisone,

azathioprine, and NAC, as compared withplacebo.” – Compelling evidence against the use of the triple

combination for patients with mild-to-moderate

IPF• Next steps

– Combination arm terminated

– Two arms of study continued (NAC vs placebo)


8/19/2019 5. Trat IPF 1.pdf

22/112

Martinez FJ, et al. N Engl J Med. 2014;370(22):2093-2101.

PANTHER 2014

ATS2011

2011-2013Pre-2011 2014

8/19/2019 5. Trat IPF 1.pdf

23/112

• Subjects: 264 patients with IPF (2 armcontinuation of PANTHER-IPF)

• Treatment: acetylcysteine (600 mg) or

placebo 3 times daily• Duration: 60 weeks• Primary end point: change in FVC• Secondary end points

– Time to the first acute exacerbation – Change from baseline in the total score on the

St. George’s Respiratory Questionnaire

PANTHER Study Design


8/19/2019 5. Trat IPF 1.pdf

24/112

NAC Does Not Reduce FVC Decline

Martinez FJ, et al. N Engl J Med. 2014;370(22):2093-2101 .

8/19/2019 5. Trat IPF 1.pdf

25/112


PANTHER Summary

Conclusion: NAC offered no significant benefit with

respect to the preservation of FVC in patients withIPF with mild-to-moderate impairment in lungfunction

Endpoint NAC Placebo P- value

ΔFVC (liters) −0.18 −0.19 0.77

Rate of Death 4.9% 2.5% 0.30

AcuteExacerbation 2.3% 2.3% >0.99

8/19/2019 5. Trat IPF 1.pdf

26/112

ASCENDPirfenidone

8/19/2019 5. Trat IPF 1.pdf

27/112

Possible Mechanisms of Pirfenidone

Action

Hilberg O, et al. Clin Respir J. 2012;6:131-143.

TNF-α IL-6

Pirfenidone

TGF-β IL-6

MMPsCollagenas

es

ROIs

Collage

n

• Antifibrotic• Molecular target

unclear

• Active in severalanimal models offibrosis (lung,liver, kidney)

8/19/2019 5. Trat IPF 1.pdf

28/112

Early Pirfenidone Results

FVC at 52 weeks

1800 mg -0.09

1200 mg -0.08

placebo -0.16

P = 0.04 vs placebo

P r o g r e s s i o n - F r e e S u r v i v

a l

Time Days

Taniguchi H, et al. Eur Respir J. 2010;35:821-829.

Pirfenidone

(2 Doses)

ATS2011

2011-2013 2014Pre-2011

Placebo

8/19/2019 5. Trat IPF 1.pdf

29/112

Noble P, et al. Lancet. 2011;377:1760-1769.

CAPACITY 2011

CAPACITY-2 CAPACITY-1

• One pirfenidone trial was positive, one was negative• CAPACITY-1 placebo group FVC declined more slowly than expected

ATS2011

2011-2013 2014Pre-2011

8/19/2019 5. Trat IPF 1.pdf

30/112

CAPACITY Endpoints

Endpoint CAPACITY-2 CAPACITY-1

FVC X

Overall survival X X

Progression-free survival X

Six-minute walk distance X

DLCO

X X

Dyspnea X X

Exertional desaturation X X

Noble P, et al. Lancet. 2011;377:1760-1769.

8/19/2019 5. Trat IPF 1.pdf

31/112

ASCEND 2014

ATS2011

2011-2013Pre-2011 2014

8/19/2019 5. Trat IPF 1.pdf

32/112

• Subjects: 555 patients with IPF• Treatment: oral pirfenidone (801 mg) or placebo 3

times daily• Duration: 52 weeks

• Primary end point: change in FVC or death atweek 52

• Secondary end points – 6-minute walk distance – Progression-free survival – Dyspnea – Death from any cause or from IPF

ASCEND Study Design

King TE, et al. N Engl J Med. 2014;370(22):2083-2092.

8/19/2019 5. Trat IPF 1.pdf

33/112

Primary ASCEND Endpoint Achieved

King TE, et al. N Engl J Med. 2014;370(22):2083-2092 .

P

a t i e n t s w i t h ≥ 1

0 %

F V C

D e c l i n e o r D e a

t h ( % )

Week

Primary

Endpoint

48% Relative

Reduction

8/19/2019 5. Trat IPF 1.pdf

34/112

Pirfenidone Increased

Progression-Free Survival*


*Progression is first occurrence of death,

10% ↓ FVC, or 50 m ↓ 6MWD

8/19/2019 5. Trat IPF 1.pdf

35/112

Pirfenidone Reduces Loss of FVC

8/19/2019 5. Trat IPF 1.pdf

36/112

More Pirfenidone Patients Maintain Walk

Distance or Survive


P

r o p o r t i o n o f P a t i e n t s w i t h

≥

5 0 m D

e c l i n e o r D e a t h ( % )

Week

8/19/2019 5. Trat IPF 1.pdf

37/112


ASCEND Adverse Events

Adverse Event

Pirfenidone

(%)

(N = 278)

Placebo

(%)

(N = 277)

Δ (%)

Nausea 36 13.4 22.6Rash 28.1 8.7 19.4Dyspepsia 17.6 6.1 11.5

Anorexia 15.8 6.5 9.3GERD 11.9 6.5 5.4Weight Loss 12.6 7.9 4.7Insomnia 11.2 6.5 4.7Dizziness 17.6 13 4.6Vomiting 12.9 8.7 4.2

… … … … Dyspnea 14.7 17.7 -3Cough 25.2 29.6 -4.4IPF 9.4 18.1 -8.7

Pirfenidone Associated with Less

8/19/2019 5. Trat IPF 1.pdf

38/112


Pirfenidone Associated with Less

Mortality ASCEND and CAPACITY data

From randomization to 28 days after last dose

Cox proportional hazard model

Log-rank test

8/19/2019 5. Trat IPF 1.pdf

39/112


ASCEND Summary

• Treatment with pirfenidone for 52 weekssignificantly reduced disease progression, asmeasured by – Changes in % predicted FVC (P < 0.001)

– Changes in 6-minute walk distance (P = 0.04) – Progression-free survival (P < 0.001)

• Treatment with pirfenidone reduced all-cause

mortality and treatment emergent IPF-relatedmortality in pooled analyses at week 52

• Pirfenidone was generally safe and well tolerated

8/19/2019 5. Trat IPF 1.pdf

40/112

40

• Pirfenidone, as compared with placebo, reduceddisease progression in patients with IPF

• Treatment was generally safe, had an acceptable

side effect profile, and was associated with fewerdeaths

ASCEND Conclusions

8/19/2019 5. Trat IPF 1.pdf

41/112

INPULSIS Nintedanib

8/19/2019 5. Trat IPF 1.pdf

42/112

Nintedanib (BIBF 1120)

multiple tyrosine kinase inhibitor

8/19/2019 5. Trat IPF 1.pdf

43/112

8/19/2019 5. Trat IPF 1.pdf

44/112

Possible Mechanisms of Nintedanib

Action

• Triple kinase inhibitor• Phosphatase

activator

• Antiangiogenic,antitumor activity

VEGF

Nintedanib

PDGF FGF SHP-1

Hilberg F, et al. Cancer Res. 2008;68(12):4774-4782.

Tai WT, et al. J Hepatol . 2014;61(1):89-97.

Pleiotropic Effects

ATS

8/19/2019 5. Trat IPF 1.pdf

45/112

INPULSIS 2014

ATS2011

2011-2013Pre-2011 2014

8/19/2019 5. Trat IPF 1.pdf

46/112

• Subjects: A total of 1066 patients with IPF• Treatment: oral nintedanib (150 mg) or placebo twice

daily (randomized in a 3:2 ratio)

• Duration: 52 weeks• Primary end point: annual rate of decline in FVC• Secondary end points

– Time to the first acute exacerbation

– Change from baseline in the total score on theSt. George’s Respiratory Questionnaire

Richeldi L, et al. N Engl J Med. 2014;370(22):2071-2082 .

INPULSIS-1 and INPULSIS-2 Study Design

Nintedanib ( 1120)

8/19/2019 5. Trat IPF 1.pdf

47/112

Nintedanib (BIBF 1120): efficacy of a

multiple tyrosine kinase inhibitor in IPF

Richeldi L,Costabel U,Selman M,

et al.,NEJM 2011

Nintedanib ( 1120)

8/19/2019 5. Trat IPF 1.pdf

48/112

Richeldi L,Costabel U,Selman M,

et al.,NEJM 2011

Nintedanib (BIBF 1120): efficacy of a

multiple tyrosine kinase inhibitor in IPF

8/19/2019 5. Trat IPF 1.pdf

49/112

Richeldi L, et al. N Engl J Med. 2014;370(22):2071-2082.

Primary INPULSIS Endpoint AchievedAnnual Rate of Change of FVC

INPULSIS-1 INPULSIS-2

45% Relative

Reduction52% Relative

Reduction

Nintedanib Placebo

Nintedanib Reduces Loss of FVC

8/19/2019 5. Trat IPF 1.pdf

50/112

Nintedanib Reduces Loss of FVC

INPULSIS-

INPULSIS-

M e a n O b s e

r v e d C h a n g e f r o m

B a s e l i n e i n F V C

( m L )


Week

Mixed Findings for Time to First Acute Exacerbation

8/19/2019 5. Trat IPF 1.pdf

51/112

Mixed Findings for Time to First Acute Exacerbation

C u m u l a t i v e

I n c i d e n c e o f F i r s t A c u t e E x a c e r b a t i o n ( % )

INPULSIS-1

INPULSIS-2


Days

8/19/2019 5. Trat IPF 1.pdf

52/112


Common Nintedanib Adverse Events

EventINPULSIS-1 INPULSIS-2

Nintedanib(n = 309)

Placebo(n = 204)

Nintedanib(n = 329)

Placebo(n = 219)

Any (%) 96 89 94 90

Diarrhea(%)

62 19 63 18

Nausea

(%)

23 6 26 7

8/19/2019 5. Trat IPF 1.pdf

53/112

INPULSIS Mortality Rates


Deaths

Nintedanib

150 mg bid

(n = 638)

Placebo

(n = 423)HR P -value

All-cause (%) 5.5 7.8 0.70 0.14

Respiratory (%) 3.8 5.0 0.74 0.34On-treatment (%)* 3.8 6.1 0.68 0.16

* Deaths between randomization and 28 days after last dose

8/19/2019 5. Trat IPF 1.pdf

54/112


INPULSIS Summary

• Nintedanib had significant benefit in adjusted annual rateof change in FVC• INPULSIS-1 Δ = 125.3 ml P < 0.001• INPULSIS-2 Δ = 93.7 ml P < 0.001

• Nintedanib had significant benefit in time to the firstacute exacerbation in INPULSIS-2• INPULSIS-1 HR = 1.15 P = 0.67• INPULSIS-2 HR = 0.38 P = 0.005

• Significant difference in favor of nintedanib for thechange from baseline in the total SGRQ score inINPULSIS-2 but not INPULSIS-1

8/19/2019 5. Trat IPF 1.pdf

55/112


INPULSIS Conclusions

• Nintedanib reduced the decline in FVC,which is consistent with a slowing of diseaseprogression

• Nintedanib was frequently associated withdiarrhea, which led to discontinuation of thestudy medication in less than 5% of patients

A t b ti (AE )

8/19/2019 5. Trat IPF 1.pdf

56/112

Acute exacerbation (AEx)

• Definition:

– Diagnosis of IPF

– Unexplained development of worsening of dyspnoeawithin 30 days; hipoxemia; ± cough, fever, increased

sputum; – HRCT with new ground-glass abnormalities or new

alveolar infiltrates;

– No evidence of pulmonary infection by ET aspirate or

BAL, cardiac failure, pulmonary embolism; – Histologically: acute or organizing diffuse alveolar

damage (DAD).

An official ATS/ERS/JRS/ALAT statement: Idiopathic Pulmonary

Fibrosis: evidence-based Guidlines for Diagnosis and Management.,Am J Respir Crit Care Med , 2011

8/19/2019 5. Trat IPF 1.pdf

57/112

AEx: HRCT patterns

• Three HRCT patterns described;

– Dif fuse and mult i focal associated withunderlying diffuse alveolar damage at biopsy;

– In diffuse disease, mortality is 80-90%;

– Peripheral disease has a better outcome, butshould be interpreted with caution.

ACUTE EXACERBATIONS OF IPF

8/19/2019 5. Trat IPF 1.pdf

58/112

ACUTE EXACERBATIONS OF IPF

Several recent clinical trials have shown that multiplesubclinical and acute exacerbations lead to decline in

pulmonary function

Traditional view: slow, steady decline in lung function respiratory failure

Acute exacerbation would represent:

an inherent acceleration in the pathobiological processes

involved in IPF, or

Unidentified respiratory complication , or

Distinct phenotypes (frequent exacerbators)

Frequency of acute exacerbation:

Analysis of 147 IPF patients demonstrated 2-year frequencyof acute exacerbations was 9.6% (5-10% per year).

Martinez et al, Ann Intern Medicine, 2005., Kim et al, Eur Resp J, 2006

AEx:

8/19/2019 5. Trat IPF 1.pdf

59/112

AEx:Disorder coagulation/fibrinolysis

• In stable IPF, pro-coagulant/antifibrinolyticalveolar environment.

• Similar findings in ARDS.

• ARDS and AEs of IPF have strikingclinical, radiological and histologicalfeatures.

8/19/2019 5. Trat IPF 1.pdf

60/112

Biological parameters at the time of AEx

Parameters n Median (range) % > normal Normalvalues

Neutrophilcount, /mm3

36 8090 (1080 - 15500) 62 1500 - 7000

CRP, mg/L 37 44 (2 - 246) 73 < 10

LDH, IU/L 26 588 (330 - 1077) 89 < 378

Procalcitonin,ng/L

23 0,1 (0,1 - 0,2) 0 < 0,5

D-dimers, ng/ml

29 653 (186 - 7165) 57 < 500

Nt-pro BNP, ng/ 24 625 (34 - 10500) 43 < 900

Simon-Blancal et al., Respiration., 2012

Definition of early evolution of IPF-AEx

8/19/2019 5. Trat IPF 1.pdf

61/112

Definition of early evolution of IPF-AExunder treatment

(determined in the first 10 days after treatment initiation)

Improvement Stabilization Deterioration

Increase in PaO2≥10

mm Hg, or increase in

SaO2≥ 5% or

decrease in

supplemental oxygen

≥3 l/min

Change in PaO2 < 10

mm Hg, and change

in SaO2

8/19/2019 5. Trat IPF 1.pdf

62/112

AEx: Empirical treatment

• High-dose steroid therapy (often intravenous)

• Intravenous cyclophosphamide

• Trial with rituximab is underway

• VM sau NVI la o minoritate (exacerbareinaugurală de IPF sau la cei în iminență detransplant pulmonar.

• Anticoagulation ?

8/19/2019 5. Trat IPF 1.pdf

63/112

Nonpharmacological

• OLD la cei cu hipoxemie severă (SaO2 < 88% lapulsoximetrie) în repaus, la ADL sau la 6MWDT

• Vaccinare antigripală și antipneumococică • Reabilitarea pulmonară (RP):

– Test de mers +46 m, ameliorare la SF-36

– Mai puțin eficientă comparativ cu rezultatele dinBPOC

– Nu-i demonstrat că beneficiile RP ar persista multtimp

8/19/2019 5. Trat IPF 1.pdf

64/112

Transplantul pulmonar (TxP)

TxP ameliorează durata de supraviețuire apacienților ajunși în fază avansată a IPF.

Indicații:

• Vârsta < 65 ani, dar comorbiditățile vor ”decide”;

• DLco < 39%;

• FVC a diminuat 10% în ultimile 6 luni;• Nu se știe dacă beneficiul de supraviețuire este

diferit dacă TxP este uni sau bilateral.

Guideline for Transplantation

8/19/2019 5. Trat IPF 1.pdf

65/112

Guideline for Transplantation[Orens JB et al., J. Heart and Lung Transplantation., 2006]

• Histologic or radiographic evidence of UIP andany of the following: – A DLco < 39% predicted – A 10% decrement in FVC during 6 months of follow-

up – A decrease in pulse oximetry < 88% during 6-MWD – Honeycombing on HRCT (fibrosis score of > 2)

• Histologic evidence of NSIP and any of thefollowing: – A DLco < 35% predicted – A 10% decrement in FVC or 15% decrease in DLco

during 6 months of follow-up

8/19/2019 5. Trat IPF 1.pdf

66/112

8/19/2019 5. Trat IPF 1.pdf

67/112

IPF

George TJ et al.,

Arch Surg., 2011

8/19/2019 5. Trat IPF 1.pdf

68/112

8/19/2019 5. Trat IPF 1.pdf

69/112

Yusen RD, et al., J Heart and lung transplant., 2013.

I t i i t t biditățil

8/19/2019 5. Trat IPF 1.pdf

70/112

Inventarierea și tratarea comorbidităților

• Asocierea emfizem-IPF (CPFE – combinedpulmonary fibrosis and emphysema syndrome);• RGE;• HTAP;

• SAS;• Cancer bronho-pulmonar;• Patologie cardio-vasculară;

• Boală venoasă trombo-embolică; • Depresie;• Diabet zaharat;• Osteoporoză;

Combined pulmonary fibrosis

8/19/2019 5. Trat IPF 1.pdf

71/112

Combined pulmonary fibrosis

and emphysema (CPFE)

• clinical presentation: – severe dyspnea, pulmonary fibrosis, – typically occurs in male smokers (other trigger: agrochemical

compounds)

• PFT: – preserved lung volumes, and a markedly reduced (TLCO).

• characteristic radiographic – upper lobe predominant centrilobular or periseptal emphysema

and lower lobe predominant pulmonary fibrosis• frequently complicated by pulmonary hypertension,

acute lung injury, and lung cancer

• prognosis: worse survival than those with IPF alone

8/19/2019 5. Trat IPF 1.pdf

72/112

IPF + Hipertensiune pulmonară

HTAP este prezentă la 10% din pacienții atinși deIPF în momentul diagnosticului și la 30-45% lamomentul bilanțului pre transplant pulmonar.

Instalarea unei HTAP este sugerată de: • ↑ dispneea • ↓ capacitatea de efort • ↑ hipoxemia și se alterează DLco • Risc de exacerbare acută a IPF • Crește mortalitatea

– A se exclude trombo-embolismul periferic, SAS și oinsuficiență cardiacă stângă

IPF d P l H t i

8/19/2019 5. Trat IPF 1.pdf

73/112

IPF and Pulmonary Hypertension

•Estimates of the prevalence of pulmonary hypertensionin IPF range between 31% - 85%.

• These patients are hypothesized to represent a distinctphenotype having a disproportionate pulmonaryhypertension due to episodic hypoxemia during sleep or

exercise or may have an imbalance of angiogenesis andangiostasis in the lung.

• The incidence and severity of pulmonary hypertensionincreases with time.

• Pulmonary hypertension in IPF is associated with ahigher mortality, especially in patients with combinedemphysema and pulmonary fibrosis.

Shorr AF et al. Eur Respir J 2007. Agarwal R, et al. Indian JChestDis Allied

Sci 2005. Lettieri CJ et al. Chest 2006. Nadrous HF, et al. Chest 2005.NathanSD, et al..Respirat ion 2008

8/19/2019 5. Trat IPF 1.pdf

74/112

IPF + Hipertensiune pulmonară

Diagnosticul de HTAP: – Clinic - sugerat – Eco-doppler cord - sugerat – Dozare BNP - sugerat

– Scanner toracic - sugerat (raport A/P < 1) – Cateterismul cordului drept = fundamentat

Tratament:

– PAPm 35-40 mmHg în repaus nu se recomandă tratamentspecific. – PAPm 35-40 mmHg în repaus Sildenafil – PAPm severă în repaus epoprostenol sau bosentan (nu

ambrisentan)

Gastroeosophageal Reflux Disease (GERD)

8/19/2019 5. Trat IPF 1.pdf

75/112

Gastroeosophageal Reflux Disease (GERD)

• The prevalence of GERD in IPF is estimated to be between 66%-87%.

• Importantly, 33%- 53% of patients with documented acid refluxare asymptomatic.

• Instillation of acid into the tracheobronchial tree produces pulmonaryfibrosis in animal models and aspiration of gastric contents cancause pulmonary fibrosis in humans.

• Recurrent silent aspiration of gastric acid is associated with acuteexacerbations of IPF (high pepsin levels in BAL) .

• The use of GER medications was associated with decreasedradiologic fibrosis and was an independent predictor of longersurvival time in patients with IPF.

Tcherakian C, et al.. Thorax 2011. Raghu G, et al. Eur Respir J 2006. Sweet MP et al.J Thorac Cardiov asc Surg 2007. Lee J, et al. Am J Respir Crit Care Med, 2011,

Cardiovascular Disease and Venous

8/19/2019 5. Trat IPF 1.pdf

76/112

Cardiovascular Disease and VenousThromboembolic Disease

• patients with IPF were shown to have anincreased risk (3,4 x) of angina, atrial fibrillation,

deep venous thrombosis, and stroke.

• patients with deep venous thrombosis andpulmonary embolism have an increased risk

of idiopathic interstitial pneumonia compared

with controls.

Daniels CE, et al. Eur Respir J 2008. Kizer JR, et al. Arc h Intern Med 2004. HubbardRB, et al. Am J Respir Crit Care Med 2008. Sode BF, et al. Am J Respir Crit Care Med

2010. Olson A, et al. Am J Respir Cri t Care Med 2011

8/19/2019 5. Trat IPF 1.pdf

77/112

Indicators of prolonged survival

• Younger pts (

8/19/2019 5. Trat IPF 1.pdf

78/112

8/19/2019 5. Trat IPF 1.pdf

79/112

8/19/2019 5. Trat IPF 1.pdf

80/112

• Inferior post-transplant outcomes in IPF relative to other lung

8/19/2019 5. Trat IPF 1.pdf

81/112

Inferior post transplant outcomes in IPF relative to other lungtransplant recipients.

• Telomerase mutations are the most common identifiable

genetic cause of IPF

Clinical considerations for a) suspecting and b) evaluating patientswith pulmonary fibrosis who may have telomere syndromes.

8/19/2019 5. Trat IPF 1.pdf

82/112

P ti

8/19/2019 5. Trat IPF 1.pdf

83/112

Preventive measures

• Gastro-oesophageal reflux

• Avoidance of exposure to agents known to causepulmonary fibrosis or hypersensitivity pneumonitis:

– drugs, – occupations, – moulds, – domestic environment factors, – avian agents,

especially in poeple genetically predisposed to IPF.

Î iji li ti ă

8/19/2019 5. Trat IPF 1.pdf

84/112

Îngrijirea paliativă

• Tusea invalidantă: corticoizi (prednison10mg/zi) și thalidomidă;

• Dispnee severă și tuse: opiozi

administrați cronic; • Pentru pacienții dependenți de pat

hospice;

• Planificare în perspectivă pentru locațieși opțiune pentru tratamentele finale.

T t t l t l î IPF

8/19/2019 5. Trat IPF 1.pdf

85/112

Tratamentul actual în IPF

Comun recomandat:• NAC• Pirfenidone• Nintedanib

• OLD• Reabilitare pulmonară

• Transplantul pulmonar

• Tratamentul RGE• Tratamentul HTAP

Situații speciale

• Exacerbarea IPF• Paliația

• corticoterapia

Future therapeutic approaches likely will targetl th i lt l ith

8/19/2019 5. Trat IPF 1.pdf

86/112

• In malignant diseases, even with ”personalisedmedicine”, combination therapies are generallyrequired. (oncological perspective)

• It would be naive to suppose that identifying”Group A” and ”Group B” IPF groups willmagically provide efficacy with monotherapy.

• The yield from current drug development, basedon single pathway evaluation is miserable.

• We will still need pleiotropism (because the bodyis highly pleiotropic) and multiple agents to dealwith clusters of coactivated pathways.

several pathways simultaneously withcombinations of interventions

Potential Therapeutic Targets

8/19/2019 5. Trat IPF 1.pdf

87/112

Noble PW, Homer RJ. Clin Chest Med . 2004;25:749-758, vii.Raghu G, Chang J. Clin Chest Med . 2004;25:621-636, v.Selman M, et al. Drugs. 2004; 64:405-430.

Burdick MD, et al. Am J Respir Crit Care Med . 2005;171:261-268.

Aberrant

Vascular

Remodeling

Angiostaticmolecules

Fibroproliferatio

nGrowth factorsinhibitors

Chemokineantagonists

Inflammation

Anti-oxidants

Cytokines

Epithelial

Restoration

Mitogens

Stem cellprogenitors

Host Defense

Interferon-gamma

Prostaglandin-E2

Current Phase 2 Trials for IPF

8/19/2019 5. Trat IPF 1.pdf

88/112

Current Phase 2 Trials for IPFNext Generation Therapy?

Trial Target N Primary Endpoint

Co-trimoxazole (Ph3)

Pneumocystis jiroveci

56Change in FVC or respir.Hospital’n

FG-3019 Anti-CTGF 90 Change in FVC from baseline

Rituximab CD-20 58 Titers of anti-HEp-2autoantibodies

Simtuzumab Anti-LOXL2 500 PFS

GC-1008 TGF-b 25 Safety, tolerability, PK

QAX576 Anti-IL-13 40 Safety, tolerability, FVCTralokinumab Anti-IL-13 302 Change in FVC from baseline

STX-100 αvβ6 32 Adverse events

BMS-986020 LPA Receptor 300 Rate of change in FVC

Linking IPF Pathogenesis to Potential Therapies

8/19/2019 5. Trat IPF 1.pdf

89/112

Ahluwalia N, et al. Am J Respir Crit Care Med . 2014

CONCLUSIONS

8/19/2019 5. Trat IPF 1.pdf

90/112

CONCLUSIONS

•

Currently, no unifying hypothesis explains allthe abnormalities.

• No definitive therapy is known to altersurvival.

• As pharmacotherapy, Pirfenidone andNintedanib seems till now, to offer somehope.

• Combination of intervention that targetseveral pathways simultaneously probably willbe the future treatment.

Vă mulțumesc !Vă lț !

8/19/2019 5. Trat IPF 1.pdf

91/112

Vă mulțumesc !

Vă mulțumesc !Vă mulțumesc !


Vă mulțumesc !

Vă l !

8/19/2019 5. Trat IPF 1.pdf

92/112

Cazuri clinice exemplificative

l

8/19/2019 5. Trat IPF 1.pdf

93/112

Femeie, 53 ani• IMC = 36• Inginer textil (expunere la scame), nefumătoare • Dispnee progresivă de efort (MRC=4) • Tuse iritativă • Astenie/fatigabilitate

Examen clinic

• Raluri in velcro

• Hipocratism digital

Cazul 1

E l

8/19/2019 5. Trat IPF 1.pdf

94/112

Disfuncție ventilatorie restrictivă ușoară.

Reducere moderată a transferului gazos prinmembrana alveolo-capilară pulmonară.

Sindrom restrictiv de natură parenchimatoasă.

Evaluare10.03.2011

6MWT - 492 m (101%); SaO2 nadir 83%

Screening BŢC - negativ (profil ANA, FR, anti-CCP)

Ecocardiografie - HTP ușoară (PAPm estimată = 38 mmHg)

HRCT – UIP ( ̋̋usual interstitial pneumonia˝ )

Honeycombing

8/19/2019 5. Trat IPF 1.pdf

95/112

HoneycombingOpacități reticulare subpleurale

Bronșiectazii

de tracțiune

Honeycombing

Esofag dilatat

• Alternative diagnostice:

8/19/2019 5. Trat IPF 1.pdf

96/112

g- Fibroză pulmonară idiopatică - Boală de țesut conjunctiv

plămân reumatoid - Expunere cronică

pneumonită de hipersensibilitate medicație

- NSIP-fibrotic idiopatică

• Biopsie pulmonară ?

• Tratament- Prednison 40 mg/zi- Azathioprină 150 mg/zi - ACC 1800 mg/zi

- Reabilitare pulmonară

Evoluție

8/19/2019 5. Trat IPF 1.pdf

97/112

Evoluție

la diagnostic după 6 luni

MRC = 4 MRC = 5

6MWT - 492 m (101%) 6MWT - 339 m (68%)

- SaO2 nadir 83% - SaO2 nadir 70%

HRCT după 6 luni – progresie semnificativă

8/19/2019 5. Trat IPF 1.pdf

98/112

Profil evolutiv – comentarii:

8/19/2019 5. Trat IPF 1.pdf

99/112

- Exacerbare IPF ?

Forma difuză → corticoterapie (IV), doze mari

- Progresia bolii?

IPF rapid progresivă (”rapid progressor”) →

transplant pulmonar.

Cercetare biologia telomerică

Profil evolutiv comentarii:

Cazul 2

8/19/2019 5. Trat IPF 1.pdf

100/112

Bărbat, 70 ani

• Ex-fumător 20 PA • Dispnee progresivă de efort (MRC=3)

Evaluare

• Raluri in velcro • SaO2 = 98%•

Parametrii ventilometrici normali.

Reducere ușoară a transferului gazos prin

membrana alveolo-capilară pulmonară.

Sindrom restrictiv de natură parenchimatoasă.

HRCTEmfizem LSS

8/19/2019 5. Trat IPF 1.pdf

101/112

Honeycombing

Distribuție

periferică

Opacități reticulare subpleurale

• Dg: IPF + Emfizem(CPFE – combined pulmonary fibrosis and emphysema)

8/19/2019 5. Trat IPF 1.pdf

102/112

la diagnostic după 6 luni

MRC = 3 MRC = 3

6MWT - 530 m (120%) 6MWT - 540 m (123%)

- SaO2 nadir 92% - SaO2 nadir 91%

(CPFE – combined pulmonary fibrosis and emphysema )

• Tratament - ACC 1800 mg/zi

• Evoluție

Cazul 3

8/19/2019 5. Trat IPF 1.pdf

103/112

Bărbat, 80 ani

• Ex-fumător 35 PA • Cardiopatie ischemică cronică • Dispnee progresivă de efort (MRC=4) • Tuse iritativă

Evaluare• Raluri in velcro• Discret hipocratism digital• SaO2 = 91%

HRCT

8/19/2019 5. Trat IPF 1.pdf

104/112

Predominant bazal, periferic

Opacități reticulare

Honeycombing? Bronșiectazii?

Evoluție

8/19/2019 5. Trat IPF 1.pdf

105/112

la diagnostic după 1 an după 4 ani

SaO2 = 91% SaO2 = 88% SaO2 = 91%

Evoluție

La diagnostic după 4 ani

8/19/2019 5. Trat IPF 1.pdf

106/112

Profil evolutiv

8/19/2019 5. Trat IPF 1.pdf

107/112

Profil evolutiv

• Evoluție lentă/staționară:

– IPF posibilă: fenotip ”slow progressor ?” • Biopsie pulmonară pentru precizare diagnostică.

– Fibroză pulmonară : NSIP fibrotic

• Tratament• - ACC 1800 mg/zi• - OLD

Cazul 4

8/19/2019 5. Trat IPF 1.pdf

108/112

Cazul 4

Bărbat, 62 ani - Fumător 40 PA - Expunere la solvenți (10 ani)

Evoluție fără tratament

8/19/2019 5. Trat IPF 1.pdf

109/112

(după 2 ani)

Profil evolutiv

8/19/2019 5. Trat IPF 1.pdf

110/112

Profil evolutiv

• Rasă (bangladesh) – Fără tratament

– Continuarea expuneriiambientale/ocupaționale

– Continuarea fumatului

• Studiu genetic


8/19/2019 5. Trat IPF 1.pdf

111/112

Vă mulțumesc !



Vă mulțumesc !

Vă l !

Issues in Clinical Trials of IPF

8/19/2019 5. Trat IPF 1.pdf

112/112

Issues in Clinical Trials of IPF

• Which patients should be studied?

IPF

IPF/COPD

IPF rapid

accelerators

IPF/PH

IPF slow

progressorsIPF acute

exacerbators

Clinical Phenotypes

Documents

5. Trat IPF 1.pdf