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5. Materi WS ILD - Pulmonary Progressive Fibrosis-Cause and treatment dr. Fariz, Sp.P(K).pptx.pdf
1. Progressive Pulmonary Fibrosis: Cause
and Treatment
dr. Fariz Nurwidya, SpP(K), PhD
Chairman
Division of Immunology and Interstitial Lung Disease
Department of Pulmonology and Respiratory Medicine - Universitas Indonesia
2. • Interstitial lung disease (ILD) describes a large group of disorders characterized by progressive scarring of the
lung tissue between and supporting the air sacs.
• ILD is another term for pulmonary fibrosis, which means “scarring” and “inflammation”
• Pulmonary fibrosis is where the tissue in the lungs becomes scarred. Pulmonary fibrosis can be localized,
segmental, lobar, or affect the entirety of the lung (s)
• The scarring associated with interstitial lung disease may cause progressive lung stiffness, eventually affecting
the ability to breathe and get enough oxygen into your bloodstream
1. Denton CP et al. Nat Rev Rheumatol 2018;14:511–27; 2. Difference Between COPD and Pulmonary Fibrosis | Difference
Between http://www.differencebetween.net/science/health/difference-between-copd-and-pulmonary-fibrosis/#ixzz7Rp29GLTV; 3.
https://www.physio-pedia.com/index.php?title=Pulmonary_Fibrosis&veaction=edit§ion=3
Interstitial Lung Disease
3. ILD, interstitial lung disease.
1. Wynn TA. J Exp Med. 2011;208:1339–1350. 2. Cottin V, Hirani N, Hotchkin D, et al. Eur Respir Rev. 2018;27(150):180076. 3. Wynn TA. J Pathol. 2008;214:199–210. 4.
Wells AU, Brown KK, Flaherty KR, et al. Eur Respir J. 2018;51(5). doi: 10.1183/13993003.00692-2018. 5. Travis WD, Costabel U, Hansell DM, et al. Am J Respir Crit Care
Med. 2013:188(6):733–748.
May ultimately lead
to organ malfunction,
disruption of gas
exchange and death
from respiratory failure1
May involve stimuli such
as viral infections,
exposure to toxins, or
autoimmunity1,3
Variable and
unpredictable in its
disease course, ranging
from stable
to quickly
progressing2,4,5
Occurs in a wide variety
of ILDs characterized by
the irreversible, often
progressive, destruction
of lung architecture,
including those
associated with
connective tissue
diseases1,2
Pulmonary fibrosis
5. Pathogenesis and development of ILD
• In genetically susceptible individuals, external
factors such as smoking, environmental
chemicals, infections and gastroesophageal
reflux disease (GERD) can lead to epithelial cell
injury and aberrant repair, alveolar macrophage
activation, neutrophil recruitment, and oxidative
stress.
• Over time, increased ECM turnover will result in
the development of fibrosis. With these
exposures the host's immune tolerance is broken
leading to chronic inflammation from cellular and
humoral autoimmunity, endothelial cell
dysfunction, granuloma formation, and alveolar
macrophage activation thus further aggravating
inflammation.
• As the disease progresses, interstitial
pneumonia changes from an early alveolitis
(increased alveolar space content of
inflammatory products, reflecting inflammatory
ILD pattern) to a transition period (thickened
alveolar septum and the deposition of collagen
fibers, significantly reduced capillary beds), and
eventually ending in alveolar structural
destruction and fibrosis.
Shao et al. Front. Immunol., 07 June 2021 | https://doi.org/10.3389/fimmu.2021.684699
This figure is created with MedPeer
6. Lung function consistently declines in most patients with SSc-ILD, so early
detection and intervention is essential to prevent further deterioration
FVC, forced vital capacity; SSc-ILD, systemic sclerosis-associated interstitial lung disease.
1. Guler SA et al. Ann Am Thorac Soc 2018;15:1427–33.
Progression of FVC (% predicted) in 171 patients with SSc-ILD overall
(complete cohort; A) and when categorized by prognosis (B)1
8
0
7
0
6
0
5
0
2
0
FVC
%
predicted
0 2 4 6 8 1
0
1
2
Years since
diagnosis
4
0
3
0
Complete
cohort
8
0
7
0
6
0
5
0
2
0
FVC
%
predicted
0 2 4 6 8 1
0
1
2
Years since
diagnosis
4
0
3
0
Long-term
survival
(survived >8
years)
Medium-term
mortality
(decreased 4–8
years)
Short-term
mortality
(decreased <4
years)
A
7. Progressive irreversible disease with potential for
stabilisation
Stable with residual disease
Reversible disease with risk of progression
Reversible and self-limited
Progressive irreversible disease
despite therapy
Progressive but responds to immunomodulation,
at least in short term*
Non-progressive
Progressive regardless of treatment considered
appropriate for individual ILDs
ATS/ERS classification for IIPs IPF Consensus working group proposal for
classification of fibrosing ILDs
Classification of ILDs based on disease behaviour
• * If fibrosing ILDs progress after perceived response to immunosuppressive treatment, this disease behavior also contributes to the progressive fibrosing phenotype
1. Travis WD et al. Am J Respir Crit Care Med 2013;188:733–48; 2. Wells AU et al. Eur Respir J 2018;51.pii: 1800692; 3. Flaherty KR et al. BMJ Open Respir Res 2017;4:e000212
Corresponds to progressive fibrosing phenotype
8. What is a progressive fibrosing phenotype?
• ILD, interstitial lung disease
1. Wollin L et al. Eur Respir J 2019;54:1900161; 2. Spagnolo P et al. Ann Rheum Dis 2021;80:143–50; 3. . Kolb M, Vašáková M. Respir Res 2019;20:57; 4. Cottin V et al. Eur Respir Rev
2018:27;180076; 5. Cottin V et al. Eur Respir Rev 2019;28:180100; 6. Flaherty KR et al. N Engl J Med 2019;381:1718–27
There is currently no universally agreed way
to diagnose the progressive fibrosing
phenotype; however progressive fibrosing
ILDs share similar characteristics…
The progressive fibrosing phenotype is a
behavior observed across different autoimmune
ILDs2,3
Regardless of the underlying autoimmune
disease, progressive fibrosing ILDs share
common pathogenic pathways leading to
self-sustaining pulmonary fibrosis
Fibroblast recruitment and activation
Mechano-stimulation
Increased tissue stiffness
Differentiation to myofibroblasts
Extracellular matrix deposition
Self-sustaining progressive
pulmonary fibrosis1
Repetitive alveolar epithelial and/or
vascular endothelial injury
Inflammatory cell recruitment
Profibrotic mediator release
9. Idiopathic interstitial
pneumonias (IIPs)1,2
Idiopathic pulmonary
fibrosis (IPF)
Idiopathic non-specific
interstitial pneumonia
(iNSIP)
Respiratory
bronchiolitis- interstitial
lung disease
Desquamative interstitial
pneumonia
Cryptogenic organising
pneumonia
Acute interstitial
pneumonia
Hypersensitivity
pneumonitis (HP)
Autoimmune ILDs
Rheumatoid arthritis
ILD (RA-ILD)
Sjögren’s syndrome
ILD
Other connective
tissue disease ILDs
Sarcoidosis Other ILDs
Idiopathic lymphoid
interstitial pneumonia
Idiopathic
pleuroparenchymal
fibroelastosis
Unclassifiable IIPs
Interstitial
pneumonia with
autoimmune features
(IPAF)3
Systemic sclerosis
ILD (SSc-ILD)
Polymyositis and
dermatomyositis ILD
Mixed connective
tissue disease ILD
Systemic lupus
erythematosus ILD
ILDs
Examples of types of ILD that may likely be associated
with a progressive fibrosing phenotype
•
1. ATS/ERS. Am J Respir Crit Care Med 2002;165:277–304; 2. Travis WD et al. Am J Respir Crit Care Med 2013;188:733–48; 3. Fischer A et al. Eur Respir J 2015;46:976–87
• lymphangioleiomyomatosis (LAM)
• Langerhans cell histiocytosis (LCH)
• drug-associated ILD
•other exposure ILDs
• vasculitis/granulomatosis ILDs
• other rare ILDs
Yellow boxes/text: examples of ILDs that may be associated with a
progressive fibrosing phenotype. Note that rarely also other ILDs may
have the progressive phenotype.
10. Is it really fibrosis?
• Features indicative of fibrosis :
• Traction bronchiectasis
• Loss of volume
• Distortion of the secondary lobule
• Loss of air-interstitium interface
• Progression of disease
Fibrosing ILD
VS
Non- Fibrosis ILD
• Others :
• Honey combing
• Subpleural cyst
• Reticulation
• Parenchymal band
• Architectural distortion
• Pleural thickening
11. Imaging in progressive fibrosing ILD:
Disease progression (patient 1)
Walsh S et al. Eur Respir Rev 2018;27:180073
Baseline 12 months
Progressive reticulation in both lower lobes
HRCT, high-resolution computed tomography
12. Imaging in progressive fibrosing ILD:
Disease progression (patient 2)
Walsh S et al. Eur Respir Rev 2018;27:180073
Baseline 12 months
Progressive traction dilation of airways
Reticulation in both lower lobes
HRCT, high-resolution computed tomography
13. *Based on systematic review of data published in 1990–2017 and supplemented by physician survey; ^
CTD/MCTD-ILD encompasses a range diseases (RA-ILD, SSc-ILD, SLE-ILD, Sjogren’s ILD, PM/DM-ILD) and 24%
is an average of these aetiologies.
CTD, connective tissue disease; DM-ILD, dermatomyositis-associated interstitial lung disease; HP, hypersensitivity pneumonitis; iNSIP, idiopathic non-specific interstitial pneumonia; IPF, idiopathic pulmonary fibrosis;
MCTD-ILD, mixed connective tissue disease-associated interstitial lung disease; PM-ILD, polymyositis-associated interstitial lung disease; RA-ILD, rheumatoid arthritis-associated interstitial lung disease; SLE-ILD,
systemic lupus erythematosus-associated interstitial lung disease; SSc-ILD, systemic sclerosis-associated interstitial lung disease.
1. Olson A et al. Adv Ther 2021;38(2):854–867.
Adapted from Olson A et al.1
Estimated 13-40% of patients with different types of ILDs develop
a chronic progressive fibrotic phenotype
14. Progression of ILDs are subject to
the judgement of the physician.
To obtain a comprehensive
understanding of the extent of
disease progression, a
multifaceted, multidisciplinary
approach is vital
Disease progression
Global impression
Physician or patient impression
that disease has worsened
Acute exacerbation Acute
respiratory worsening
Symptoms
Worsening of cough and
dyspnea
HRCT
Increase in extent of
radiological abnormalities
Quality of life
Deterioration in health-related
quality of life
PFTs
Decline in FVC and/or DLco
Physical function
Decrease in exercise
capacity
Kolb M, Vašáková M. Respir Res 2019;20:57
HRCT, high-resolution computed tomography; PFTs, pulmonary function tests
15. Worsening respiratory
symptoms2,4,5
Acute exacerbations7
Reduced quality
of life2,7
Early mortality2,6
Emotional distress3
Deterioration of
lung function2,5
Impact of
progressive
fibrosing ILDs
Patients with progressive fibrosing ILDs follow a similar disease
course and prognosis to that observed in patients with IPF
ILD, interstitial lung disease; IPF, idiopathic pulmonary fibrosis.
1. Flaherty KR, et al. BMJ Open Respir Res. 2017;4(1):e000212. 2. Cottin V, et al. Eur Respir Rev. 2018;27(150):180076. 3. Morisset J, et al. Ann Am Thorac Soc.
2016;13(7):1026-1033. 4. Kolb M, Vašáková M. Respir Res. 2019;20(1):57. 5. Maher TM, Wuyts W. Adv Ther. 2019;36(7):1518–1531. 6. Swigris JJ, et al. Eur Respir Rev.
2018;27(150):pii:180075. 7. Kolb M, et al. Eur Respir Rev. 2018;27(150):pii:180071.
16. Update version of ILD progression definition according to 2022
ATS/ERS/JRS/ALAT IPF and PPF guidelines
• In a patient with ILD of known or unknown etiology other than IPF who has radiological
evidence of pulmonary fibrosis, PPF is defined as at least two of the following three
criteria occurring within the past year with no alternative explanation:
worsening respiratory
symptoms
physiological evidence
of disease progression
radiological evidence
of disease progression
• Absolute decline in FVC ≥5% predicted
within 1 year of follow up OR
• Absolute decline in Dlco (corrected for
Hb) ≥10% predicted within 1 year of
follow up
• Increase severity of traction
bronchiectasis or bronchioloectasis
• New GGO with traction
bronchiectasis
• New fine reticulation
• Increase extent or increase
coarseness of reticular abnormality
• New or increased honeycombing
• Increased lobar volume loss
1. Raghu G. et al. Am J Respir Crit Care Med 2022: 205: e18–e47
17. The INBUILD®
criteria provide a possible framework for identifying
progressive fibrosing ILDs
•
FVC, forced vital capacity; HRCT, high-resolution computed tomography; ILD, interstitial lung disease
1. Flaherty KR et al. N Engl J Med 2019;381:1718–27; 2. George PM et al. Lancet Respir Med 2020;8:925–34; 3. Wijsenbeek M. Lancet Respir Med 2020;8:424–5;
4. Wijsenbeek M, Cottin V. N Engl J Med 2020;383:958–68; 2.
INBUILD®
trial criteria1
Any one of the following within the past
24 months despite conventional treatment:
• Relative decline in FVC% predicted of ≥10% OR
• Relative decline in FVC% predicted of 5–<10% and
worsening of respiratory symptoms OR
• Relative decline in FVC% predicted of 5–<10% and
increased extent of fibrosis on HRCT OR
• Worsened respiratory symptoms and an increased
extent of fibrosis on HRCT
There is no universal consensus on
how to define
ILD progression4
The criteria used in the INBUILD®
trial, which included patients with
autoimmune ILDs, may be useful
for identifying patients with
progressive fibrosing ILDs in clinical
practice1–4
18.
19. • Cough can affect sleep, willingness to participate in social activities, and thus,
physical and emotional wellbeing in progressive fibrosing ILD patients
Decreased social
activities
Decreased sleep
Decreased physical and
emotional wellbeing
Cough
“First thing in the morning I cough.
Or when I talk on the telephone…
I cough when I walk. I would have to sit down
and get a hold of myself.”
“I don’t sleep at night. I sleep maybe a half
an hour and then I’m up because all of a
sudden… I’m coughing, you know.”
(Patient with CTD-ILD)
Cough and activity-limiting dyspnea have an immense impact on the
everyday lives of patients with progressive fibrosing ILDs
CTD-ILD, connective tissue disease-associated interstitial lung disease; ILD, interstitial lung disease.
1. Swigris JJ, et al. Eur Respir Rev. 2018;27(150):pii:180075. 2. Khanna D, et al. J Rheumatol. 2015;42(11):2168-2171. 3. Saketkoo LA, et al. Thorax.
2013;69(5):428-436. 4. Mittoo S, et al. Curr Respir Med Rev. 2015;11(2):175-183.
20. • Patients with progressive fibrosing ILDs, such as IPF, hypersensitivity pneumonitis
and CTD-ILD report almost universal symptoms of anxiety and/or depression
Depressive symptoms in ILD are
common, persistent, and strongly
and independently correlated with
dyspnoea, pain, sleep quality and
forced vital capacity
Depression Anxiety
Progressive fibrosing ILDs can place a substantial burden on patients’ daily
lives, severely impacting their functional and emotional wellbeing
CTD-ILD, connective tissue disease-associated interstitial lung disease; ILD, interstitial lung disease; IPF, idiopathic pulmonary fibrosis.
1. Flaherty KR, et al. BMJ Open Respir Res. 2017;4(1):e000212. 2. Morisset J, et al. Ann Am Thorac Soc. 2016;13(7):1026-1033. 3. Hinz A, et al. Sarcoidosis Vasc Diffuse
Lung Dis. 2012;29(2):139-146.
4. Ryerson CJ, et al. Respirology. 2012;17(3):525-532.
21. Role of PFT and HRCT in diagnosis and monitoring
1. Song G, et. al. Acad Radiol. 2012 Jul;19(7):857-64. doi: 10.1016/j.acra.2012.03.007. Epub 2012 Apr 18.; 2. Walsh S et al. Eur Respir Rev 2018;27:180073; Kolb M, Vašáková M. Respir Res
2019;20:57
HRCT, high-resolution computed tomography
• HRCT is central in ILD diagnosis, with observed abnormalities assisting in the initial differentiation between ILDs
• Some image metrics are not only as good discriminators as pulmonary function testing (PFT) for the characterization of ILD
and COPD but are also not redundant when PFT values are provided.
• Image metrics of attenuation histogram statistics and texture descriptions may be valuable for further investigation in
computer-assisted diagnosis
• HRCT may help monitoring disease progression, but other criteria may be equally relevant from a clinician’s perspective
22. Other definitions exist in clinical practice for ILD progression
worsening symptoms
increasing extent of
fibrotic abnormalities
on HRCT
decline in lung
function
1. Goh NS et al. Arthritis Rheumatol 2017;69:1670–8. 2. Cottin V. et al. Eur Respir Rev 2018;27:180076. 3. Distler O. et al. Eur Respir J 2020;55:1902026. 4. Volkmann ER. J Scleroderma Relat
Disord 2020;5:31–40. 5. Hoffmann-Vold A-M et al. Ann Rheum Dis 2020; doi: 10.1136/annrheumdis-2020-217455. 6. Wijsenbeek M, Cottin V. N Engl J Med 2020;383:958-68;
FVC decline ≥10% OR FVC decline 5-10% plus
DLCO decline of 15%, as proposed definition of
progressive fibrosis in SSc-ILD1-4
Absolute FVC% predicted change from baseline
to 12±3 months define subgroups in a EUSTAR
observational study in SSc-ILD5
:
• significant progression (decline of >10%);
• moderate progression (decline of 5% to 10%;
• stable ILD (decline or improvement of < 5%);
• improvement (improvement of ≥5%)
Consistent decline in FVC (without
formally accepted threshold or rate) as
per 3-6- month evaluations6
decline in lung
function
PLUS ANY OF THE
FOLLOWING
OR
• DECREASES DLCO
• NEED FOR OXYGEN SUPPLEMENTATION
• CLINICAL EVENTS PREDICTING EARLY DEATH
1
2
23. Patients with progressive fibrosing ILDs are at risk of further
progression
Brown KK et al. Eur Respir J 2020;55:2000085.
Observed change in FVC over 52 weeks in the placebo groups of the
INPULSIS and INBUILD trials
Mean
(SE)
absolute
change
from
baseline
in
FVC
(mL)
2 4 6 12 24 36
Week
24. • Progressive disease is characterized by
progressive pulmonary fibrosis, worsening
respiratory symptoms and deteriorating lung
function1
• Survival of patients with ILD with a chronic PF
phenotype was similar to those with IPF
(HR, 1.06; 95% CI, 0.84–1.35; p=0.6)2
• Patients with ILD with a chronic PF phenotype
had significantly worse survival compared to
those without PF phenotype
(HR, 3.32; 95% CI, 2.53–4.37; p<0.0001)2
Survival
probability
Time (days)
ILD with a chronic PF phenotype
IPF
ILD without a PF phenotype
p<0.0001 Adapted from Simpson T, et al.2
Data from a retrospective observational study in nine UK tertiary ILD referral centres2
CI, confidence interval; HR, hazard ratio; ILD, interstitial lung disease; IPF, idiopathic pulmonary fibrosis; PF, progressive fibrotic.
1. Flaherty KR et al. BMJ Open Resp Res 2017;4:e000212; 2. Simpson T et al. Eur Respir J 2021;2100221. doi: 10.1183/13993003.00221-2021.
Patients with progressive disease have a significantly higher
mortality compared to those without the PF-phenotype
25. Adapted from Simpson T, et al.2
Decline in FVC is associated with mortality in patients with fibrosing ILDs
other than IPF
Kaplan-Meier estimates. Survival and FVC decline were assessed over the same period.
Krauss E et al. J Clin Med 2020;9:2499.
Survival in patients with unclassifiable ILD (n=140) in the
European IPF Registry by annual rate of decline in FVC % predicted
26. Adapted from Simpson T, et al.2
Initial symptoms
of ILD
Diagnosis of ILD
Development of
progressive
fibrosing ILD
Progressive
fibrosing ILD
detected by
physician
Death
SSc-ILD
Other CTD-ILDs
iNSIP
Unclassifiable IIP
RA-ILD
HP
Sarcoidosis-ILD
Other ILDs
Average time
(months)
33.0
38.3
31.1
29.7
41.6
40.0
45.2
33.7
Average time
(months)
9.3
11.0
9.3
10.3
11.5
8.6
8.8
9.9
Average time
(months)
12.3
13.9
12.0
11.4
15.2
13.6
14.6
12.7
Average time
(months)
9.6
11.2
8.9
9.2
11.0
10.4
11.7
11.1
Adapted from Wijsenbeek M et al. 2019.
The long patient journey in progressive fibrosing ILD
Based on an online survey of 486 physicians from the US, Japan, Germany, France, Italy, Spain, and the UK.
CTD-ILD, connective tissue disease-associated interstitial lung disease; HP, hypersensitivity pneumonitis; IIP, idiopathic interstitial pneumonia; ILD, interstitial lung disease;
iNSIP, idiopathic non-specific interstitial pneumonia; RA-ILD, rheumatoid arthritis-associated interstitial lung disease; SSc-ILD, systemic sclerosis-associated interstitial lung disease.
1. Wijsenbeek M, Kreuter M, Fischer A, et al. Curr Med Res Opin. 2019:1–10. DOI: 10.1080/03007995.2019.1647040.; 2. Snyder LD et al. BMJ Open Respir Res 2020;7(1):e000567; 3. Ley B et al. Am J Respir Crit Care Med 2011;183(4):431–440;
IPF is the prototypical
chronic progressive
fibrotic ILD, with a
median survival from
diagnosis of 2–5
years
and a median time
from onset of
symptoms to
diagnosis of 1.5 years
IPF Non-IPF disease course
27. ILD treatment goal
Wuyts WA, Spyridon Papiris S, Manali E et al. Adv Ther (2020)
37:3246–3264
Prevent lung deterioration
prevent exacerbations
preserve quality of life
Increase survival
28. Inflammation or Fibrosis?
ILD, interstitial lung disease; NSIP, nonspecific interstitial pneumonia.
Mikolasch TA et al. Clin Med (Lond) 2017;17:146–153.
Idiopathic pulmonary
fibrosis
• Sarcoidosis
• Hypersensitivity pneumonitis
• Connective tissue disease
• Cryptogenic organising
pneumonia
• Drug ILD
• Cellular NSIP
• Smoking-related ILD
Fibrosis:
may respond to antifibrotics
Inflammation:
may respond to immunosuppressive/modulatory therapy
Inflammation Fibrosis
29. Treatment options depend on the ILD that the
patient is suffering from but can generally be
classified into various categories as follows:
1. Immune Suppression (MMF, AZA etc.)
2. Isolation from causative exposure
3. Antifibrotics (Nintedanib, pirfenidone)
4. Non-pharmacological treatment
(O2 therapy, etc.)
5. Lung transplant
1. Treatment Options for Pulmonary Fibrosis | Pulmonary Fibrosis Foundation; 2. Johannson, K.A., Chaudhuri, N., Adegunsoye, A. and Wolters, P.J., 2021. Treatment
of fibrotic interstitial lung disease: current approaches and future directions. The Lancet.
What are the treatment options for pulmonary fibrosis?
30. Why antifibrotic is important for pulmonary fibrosis treatment?
1. Finnerty et al. BMC Pulmonary Medicine (2021) 21:411 ; 2. Maher and Strek Respiratory Research (2019) 20:205 https://doi.org/10.1186/s12931-019-1161-4; 3. Respiration
2018;96:514–524 https://doi.org/10.1159/000490667; https://www.karger.com/Article/Abstract/490667
Meta-analysis: benefits of antifibrotics therapy
• offers protection against the rate of decline in FVC in progressive
lung fibrosis
• no significant difference in efficacy whether the underlying
condition was IPF or non-IPF with progressive fibrosis, supporting
the hypothesis of a common pathogenesis
• most individuals can tolerate antifibrotic therapy, and dose
adjustment has been shown to be effective at reducing side
effects without compromising efficacy
Meta-analysis: antifibrotics treatment use remains at ∼60%
Several barriers to antifibrotic treatment, principally reflecting the differing
views and values of patients and physicians were identified, suggesting a
need
• for better patient-physician communication about pharmacological
therapy for IPF
• to educate pulmonologists that IPF is a progressive, irreversible and fatal
disease and that prompt treatment is critical to preserving patients’ lung
function and improving outcomes
31. 1. Lederer DJ, Martinez FJ. Idiopathic pulmonary fibrosis. New England Journal of Medicine. 2018 May 10;378(19):1811-23; 2. Cost Effectiveness of Nintedanib Versus Pirfenidone
Treatment In Idiopathic Pulmonary Fibrosis In Turkey October 2017Value in Health 20(9):A646, DOI:10.1016/j.jval.2017.08.1493
Are all antifibrotics the same?
Only Nintedanib that approved for 3 broader indications (IPF, SSc-ILD and PF-ILD)
Two antifibrotic therapies have been approved for the treatment of IPF: nintedanib and pirfenidone. These drugs slow decline in lung
function and reduce the risk of acute respiratory deteriorations, which are associated with very high morbidity and mortality.
32. Rationale for investigating nintedanib as a treatment for PF-ILD
•Working hypothesis: in patients with PF-ILD, the response to lung injury involves the
development of fibrosis that becomes progressive, self-sustaining and independent
of the trigger
•PF-ILD is characterised by worsening respiratory symptoms, declining lung function,
resistance to immunomodulatory therapies and high mortality
•Nintedanib inhibits fundamental processes in the pathogenesis of lung fibrosis,
irrespective of the trigger,1–4
and has proven efficacy and safety in the treatment of
IPF
•Based on the clinical and mechanistic parallels between IPF and other types of
PF-ILD, nintedanib may be effective in the treatment of PF-ILD beyond IPF
1. Wollin L et al. J Pharmacol Exp Ther 2014;349:209-20; 2. Wollin L et al. Eur Respir J 2015;45:1434-45; 3. Huang J et al. Ann Rheum Dis 2016;75:883-90; 4. Redente EF et al. Am
J Respir Crit Care Med 2016;193:A4170.
33. • Small-molecule tyrosine kinase
inhibitor
• Binds to the receptors
of tyrosine kinases involved in
pathological pathways active in
ILD
• Blocks the downstream
signaling pathways of cells that
contribute to lung fibrosis
• Has anti-inflammatory
and anti-angiogenic activity
Nintedanib is a tyrosine kinase inhibitor
• Mode of action of nintedanib
Nintedanib Summary of Product Characteristics. Available at: http://www.ema.europa.eu
Informasi Produk Lokal OFEV 2022
Kinase
active site
Nintedanib
PDGFR FGFR VEGFR
Fibroblast
Gene
expression
Fibroblast cell
membrane
Inhibits proliferation,
migration, and
transformation
of fibroblasts
Blocks downstream signaling
34. Nintedanib multitargeted tyrosine kinase inhibitor with antifibrotic and
anti-inflammatory effects that inhibit key pathways leading to pulmonary fibrosis
1. Wollin L et al. J Pharmacol Exp Ther 2014;349:209–20; 2. Huang J et al. Ann Rheum Dis 2017;76:1941–48; 3. Tandon K et al. Am J Respir Crit Care Med 2017;195:A2397; 4. Wollin L et al. Am J Respir Crit Care
Med 2017;195:A2450; 5. Wollin L et al. Eur Respir J 2017;50(Suppl 61):PA903; 6. Sato S et al. Respir Res 2017;18:172; 7. Hilberg F et al. Cancer Res 2008;68:4774–82; 8. Sava P et al. JCI Insight 2017;2:pii:96352; 9.
Hostettler KE et al. Respir Res 2014;15:157; 10. Huang J et al. Ann Rheum Dis 2016;75:883–90; 11. Wollin L et al. Am J Respir Crit Care Med 2016;193:A2384
Inhibition of M2
macrophage polarization2,3
Inhibition of
immune-stimulating and
pro-fibrotic mediators4,5
Inhibition of endothelial
cells, vascular smooth
muscle cells and pericytes
and attenuation of pericyte
differentiation7,8
Inhibition of ECM
secretion9,10
Inhibition of receptor
activation1
Inhibition of fibrocyte
activity6
Inhibition of fibroblast
activity1,10,11
35. Proposed management algorithm for PF-ILD
Gibson, C.D., Kugler, M.C., Deshwal, H. et al. Advances in Targeted Therapy for Progressive Fibrosing Interstitial Lung Disease. Lung 198, 597–608 (2020).
https://doi.org/10.1007/s00408-020-00370-1
Increase survival
Prevent lung
deterioration prevent exacerbations
preserve quality of life
PF-ILD treatment goals
36. The INBUILD trial : objective
*Randomisation was stratified by HRCT pattern (UIP-like fibrotic pattern only or other fibrotic patterns) based on central review.
†
Visits occurred every 16 weeks until end of treatment. bid, twice daily; R, randomisation; UIP, usual interstitial pneumonia.
1. Flaherty KR, et al. N Engl J Med 2019; doi: 10.1056/NEJMoa1908681. 2. Patel AS, et al. Thorax 2012;67:804–10.
K-BILD, King’s Brief Interstitial Lung Disease. UIP, usual interstitial pneumonia.
R
Screening
Open-label
nintedanib
(INBUILD-ON)
Double-blind
Nintedanib 150 mg bid (n=332)
Placebo (n=331) Placebo
Nintedanib 150 mg bid
*
Visit 1 2 34 5 6 7 8 9
52
36
24
12
6
4
2
0
Week
PART
A
PART B†
Primary endpoint assessed
Annual rate of decline in FVC (mL/year) assessed over
52 weeks
First database lock
Objective: Aim to investigated the efficacy and safety of Nintedanib 150 mg BID in patients with fibrosing
ILDs with a progressive phenotype (excluding IPF) in 52 weeks
Main secondary endpoints:
Absolute change from baseline in K-BILD
questionnaire2
total score at
week 52
Time to first acute exacerbation of ILD or death
over 52 weeks
Time to death over 52 weeks
37. Of 663 patients, 62.1% had a UIP-like fibrotic pattern
on HRCT
INBUILD®
trial shown that patients who had fibrotic
patterns other than UIP are also at risk of progression
Flaherty KR et al. N Engl J Med 2019;381:1718-1727.
Patients in the INBUILD trial
had a fibrosing ILD other
than IPF and had shown
progression of ILD within
the 24 months prior to
screening
Patients were enrolled
irrespective of fibrotic
pattern on HRCT
UIP-like fibrotic pattern
Other fibrotic
patterns
38. INBUILD: Primary endpoints
• Primary endpoint: rate of decline in FVC (mL/year) assessed over 52 weeks
• Two co-primary analysis populations:
1. Overall population
2. Subjects with a UIP-like fibrotic pattern on HRCT (A+B+C or A+C or B+C)
Flaherty KR et al. N Engl J Med 2019;381:1718-27.
A Definite honeycomb lung destruction with basal and peripheral predominance
B Presence of reticular abnormality and traction bronchiectasis consistent with
fibrosis with basal and peripheral predominance
C Atypical features are absent, specifically nodules and consolidation.
Ground glass opacity, if present, is less extensive than reticular opacity pattern
39. The INBUILD trial : eligible diseases
*Patients with IPF were excluded, as patients with IPF have already been studied.
Flaherty KR et al. BMJ Open Respir Res 2017;4:e000212.
Idiopathic interstitial
pneumonias
Idiopathic pulmonary
fibrosis
Idiopathic non-specific
interstitial pneumonia
Respiratory
bronchiolitis-interstitial
lung disease
Desquamative
interstitial pneumonia
Cryptogenic organizing
pneumonia
Acute interstitial
pneumonia
Hypersensitivity
pneumonitis
Autoimmune
ILDs
Rheumatoid arthritis
ILD
Sjögren’s syndrome
ILD
Other connective
tissue disease ILDs
Sarcoidosis Other ILDs
Idiopathic lymphoid
interstitial
pneumonia
Idiopathic
pleuroparenchymal
fibroelastosis
Unclassifiable IIPs
Interstitial
pneumonia with
autoimmune
features
• Lymphangioleiomyomatosis
• Langerhans cell histiocytosis
• Drug-associated ILD
• Other exposure ILDs
• Vasculitis/granulomatosis ILDs
• Other rare ILDs
Systemic sclerosis
ILD
Polymyositis and
dermatomyositis
ILD
Mixed connective
tissue disease ILD
Systemic lupus
erythematosus ILD
ILDs
INBUILD®
– patients were eligible if they had
progressive fibrosing ILD irrespective of etiology-based
ILD classification
• IPF excluded
• May not be limited to the ILDs
highlighted in orange
40. The INBUILD trial : two co-primary analysis populations
Two co-primary analysis populations
•Overall population
•Patients with a UIP-like fibrotic pattern on HRCT
Flaherty KR, et al. N Engl J Med 2019; doi: 10.1056/NEJMoa1908681.
Disposition of overall population over 52
weeks
41. The INBUILD trial : clinical ILD diagnoses in overall population
*Included rheumatoid arthritis-associated ILD (nintedanib 12.7%; placebo 14.2%), systemic sclerosis-associated ILD (nintedanib 6.9%; placebo 4.8%), mixed connective tissue disease-ILD
(nintedanib 2.1%; placebo 3.6%), and selected other terms in “Other fibrosing ILDs”.
†
Included sarcoidosis, exposure-related ILDs and selected other terms in “Other fibrosing ILDs”. IIP, idiopathic interstitial pneumonia.
Flaherty KR, et al. N Engl J Med 2019; doi: 10.1056/NEJMoa1908681.
Hypersensitivity pneumonitis
Autoimmune ILDs*
Unclassifiable IIP
Other ILDs†
42. Adjusted
annual
rate
(SE)
of
decline
in
FVC
(mL/year)
Difference: 107.0 mL/year
(95% CI: 65.4, 148.5); p<0.001
Relative reduction: 57%
Difference: 128.2 mL/year
(95% CI: 70.8, 185.6); p<0.001
Relative reduction: 61%
Difference: 75.3 mL/year
(95% CI: 15.5, 135.0); p=0.014
Relative reduction: 49%
Nintedanib
(n=332)
Placebo
(n=331)
Nintedanib
(n=206)
Placebo
(n=206)
Nintedanib
(n=126)
Placebo
(n=125)
Overall
population
Patients with UIP-like
fibrotic
pattern on HRCT
Other (non-UIP-like)
fibrotic
patterns on HRCT
Nintedanib effective to reduce FVC declining in all types UIP
patterns
FVC, forced vital capacity; HRCT, high-resolution computed tomography; UIP, usual interstitial pneumonia
Flaherty KR, et al; for the INBUILD Trial Investigators. N Engl J Med 2019;381:1718-27.
INBUILD®
43. Nintedanib delayed time to first acute exacerbation of ILD or death
and time to death over 52 weeks
Flaherty KR, et al; for the INBUILD Trial Investigators. N Engl J Med 2019;381:1718-27.
Overall population Patients with a UIP-like fibrotic
pattern on HRCT
Nintedanib
(n=332)
Placebo
(n=331)
Nintedanib
(n=206)
Placebo
(n=206)
Acute exacerbation of ILD or
death, n (%)
26 (7.8) 32 (9.7) 17 (8.3) 25 (12.1)
Hazard ratio (95% CI) 0.80 (0.48, 1.34) 0.67 (0.36, 1.24)
Nominal p-value2
0.39 0.20
Death, n (%) 16 (4.8) 17 (5.1) 11 (5.3) 16 (7.8)
Hazard ratio (95% CI) 0.94 (0.47, 1.86) 0.68 (0.32, 1.47)
Nominal p-value2
0.85 0.33
INBUILD®
44. Nintedanib delayed time to first acute exacerbation of ILD or death
using data up to first database lock
Flaherty KR, et al; for the INBUILD Trial Investigators. N Engl J Med 2019;381:1718-27.
Nintedanib
Placebo
Hazard ratio: 0.68 (95% CI 0.46, 1.01)
Nominal p=0.06
Nintedanib
Placebo
Hazard ratio: 0.61 (95% CI 0.38, 0.98)
Nominal p=0.04
Overall population Patients with a UIP-like fibrotic pattern on
HRCT
INBUILD®
45. Nintedanib demonstrated consistent efficacy in multi-studies and various ILDs
Difference: 109.9 mL/year
(95% CI: 75.9, 144.0); p<0.001
Relative reduction: 49%
Difference: 41.0 mL/year
(95% CI: 2.9, 79.0); p=0.035
Relative reduction: 44%
Difference: 107.0 mL/year
(95% CI: 65.4, 148.5); p<0.001
Relative reduction: 57%
Adjusted
mean
(SE)
annual
rate
of
decline
in
FVC
(mL/year)
INBUILD (overall population)1
SENSCIS3
INPULSIS (pooled)2
Nintedanib
(n=332)
Nintedanib
(n=638)
Nintedanib
(n=287)
Placebo
(n=331)
Placebo
(n=288)
Placebo
(n=423)
1. Flaherty KR et al. N Engl J Med 2019;381:1718–27; 2. Richeldi L et al. N Engl J Med 2014;370:2071–82; 3. Distler O et al. N Engl J Med 2019;380:2518–28.
Across IPF, PF-ILDs and SSc-ILD, over 52 weeks
46. Reduce acute exacerbations events
INPULSIS®
INPULSIS®
-ON
Nintedanib
(n=638)
Placebo
(n=423)
Continued
Nintedanib
(n=430)
Initiated
Nintedanib
(n=304)
Patients with ≥1 acute exacerbation,
n (%)
31 (4.9) 32 (7.6) 63 (14.7) 37 (12.2)
Total years at risk 601 401 1084 709
Adjusted incidence rate of acute
exacerbations, per 100
patient–years
5.2 8.0 5.8 5.2
Total years at risk = time from start of treatment until start of first event (patients with event) or end of time at risk (patient without event) plus 1 day.
Incidence = (patients with ≥1 acute exacerbation/total years at risk) × 100.
Crestani, B., Lancet Respir Med 2018, http://dx.doi.org/10.1016/S2213-2600(18)30339-4
Consistent in long-term
47. Update version of ILD progression definition according to 2022
ATS/ERS/JRS/ALAT IPF and PPF guidelines
• In a patient with ILD of known or unknown etiology other than
IPF who has radiological evidence of pulmonary fibrosis, PPF is defined as
at least two of the following three criteria occurring within the past year with
no alternative explanation:
worsening respiratory
symptoms
physiological evidence
of disease progression
radiological evidence
of disease progression
• Absolute decline in FVC ≥5% predicted
within 1 year of follow up OR
• Absolute decline in Dlco (corrected for
Hb) ≥10% predicted within 1 year of
follow up
• Increase severity of traction
bronchiectasis or bronchioloectasis
• New GGO with traction bronchiectasis
• New fine reticulation
• Increase extent or increase coarseness
of reticular abnormality
• New or increased honeycombing
• Increased lobar volume loss
48. Suggested future direction and to address the
unmet needs of autoimmune disease-associated
ILD
Autoimmune disease-associated ILD is a combination
of systemic autoimmune disorder and an ILD that can
result in progressive fibrosis and now recognized as a
frequent and serious complication of systemic
autoimmune diseases
• HRCT is essential in the initial evaluation of
any suspected ILD to identify radiologic
pattern and disease extent.
• CHEST and KBILD Questionnaire can help to
screen and monitor ILD
Prevent Lung Deterioration:
Nintedanib slowed the progression of ILD in patient
with PF-ILD, as demonstrated by a lower rate of decline
in FVC across ILDs diagnoses with a consistent
beneficial effect between patients with a UIP-like fibrotic
pattern and other fibrotic patterns on HRCT
Preserve QoL:
Result obtained using the L-PF questionnaire suggested
that Nintedanib may prevent worsening of cough and
reduced worsening of dyspnea
Prevent exacerbation and increase survival:
Nintedanib was associated with a numerically and
significantly reduced risk of acute exacerbation of ILD
or death, and of death in overall population (inc. Asian
population)
INBULD proven Nintedanib efficacy
in patients with PF-ILD
SUMMARY
