Non IPF ILDs & Anti-fibrotic agent role

1. Alireza Bagheri,MD. MSc
Pulmonologist,Shariati Hospital
Tehran University of Medical Sciences
Iranian Society of Pulmonology,Webinar on ILDs, march 2021

2. q ILD pathophysiology
q UIP pattern
q iNSIP treatment & outcome
q Progressive fibrosing ILD
q Disease progression definition
q Burden of PF-ILDs
q Antifibrotic RCTs
q Nintedanib in PF-ILD (INBUILD)
q PFT value in prognosis & outcome
q Minimal clinically important difference
q Critique of INBUILD report in NEJM
q End of beginning
q Spectrum of Fibrotic Lung Disease
q Risk factors of PF in ILDs
q Multidisciplinary approach to ILD
q ILD disease progression assessment
q ILD management
q Conclusion
2

3. § Bilateral parenchymal (alveolar walls) infiltrative lung diseases
with variable degrees of tissue inflammation and fibrosis,in
immunocompetent hosts without infection or neoplasm
§ a large group of > 200 parenchymal pulmonary disorders
§ Clinically:
§ DOE, Chronic dry cough,Fatigue,
§ bilateral infiltrates imaging
§ abnormal pulmonary physiology, and gas transfer
3

4. § Varying in :
§ Triggers
§ Susceptibility
§ initial inflammatory responses
§ common mechanisms in later phases
§ profibrotic environment
§ cytokine milieu :TGFβ, connective-
tissue growth factor, PDGF, and WNT
and hedgehog signaling
§ fibroblast activation and
differentiation into myofibroblasts,
which further orchestrate
fibrogenesis
4
Wijsenbeek & cottin. N Engl J Med Sep, 2020

5. §ILDs with known causes
ü pneumoconioses
ü CTD : (RA-ILD, SS-ILD, Sjögren’s,
idiopathic inflammatorymyopathy)
ü Chronic HP
§Unknown cause ILD:
Ø Sarcoidosis
Ø IIP
5

6. § ILDs with known causes
§ pneumoconioses
§ CTD
§ HP
§ Unknown etiology ILD:
Ø Sarcoidosis
ØIIP
§ IPF
§ NSIP
§ DIP
§ RBILD
§ AIP
§ COP
§ LIP
6

7. § ILDs with known causes
§ pneumoconioses
§ CTD
§ HP
§ Unknown ethiology ILD:
Ø Sarcoidosis
ØIIP
§ IPF
§ NSIP
§ DIP
§ RBILD
§ AIP
§ COP
§ LIP
7
ü UIP pattern
ü Poor prognosis
ü Progressive
ü immunosuppressive
resistance
ü may response to
antifibrotic drug

8. 8
Ganesh, etal. American Journal of Respiratory and Critical Care Medicine.2011,183

9. 9
Ganesh, etal. American Journal of Respiratory and Critical Care Medicine.2011,183

10. § UIP
• predominant peripheral and lower-­ lobe reticulation
• Honeycombing
• Traction bronchiectasis 10
Lederer et al. N Engl J Med 2018

11. § non-IPF
Ø predominance of ground-­glass opacities
Ø reticular abnormalities in the lower lung
Ø subpleural sparing 11
Lederer et al. N Engl J Med 2018

12. v sharply defined mosaic attenuation and ground-­glass opacities
12
Lederer et al. N Engl J Med 2018

13. 13
§ 83 iNSIP patients from 1991 to 2006 in Asan Medical Center, Seoul, Korea
§ general trend toward improvement or stability in treated iNSIP patients
§ 40% experienced recurrence after the discontinuation of treatment.
§ a subset of the patients with fibrotic NSIP did not respond to therapy and had a high
mortality rate, similar to IPF.
§ About 10% of the patients developed CVD during follow-up and (younger & higher RF)
§ honeycombing on the initial HRCT, initial PFT and changes in FVC at 12 months have
considerable prognostic value.
§ Cellular NSIP had much better prognosis than fibrotic NSIP , although recurrence may
occur
Park et al. Eur Respir J 2009

14. 14
Nunes et al. Eur Respir J 2015

15. 15
Ø corticosteroid dose?
Ø which immunosuppressive &
dose?
Ø Not only decrease in FVC in
the f/u group, but increase
nonsignificant?
Lee et al. Respiratory Research (2017)
§ 95 iNSIP from 54 University hospitals across the
S.Korea 2003-2007
§ All the other ILDs were excluded.
§ 86 were treated with corticosteroid or
immunosuppressive (mean 11.8 m)
§ 9 f/u for more than a year
§ ↑ FVC (10%),FEV1 (9.8%),Dlco (8.4%) in
treatment group
§ Early treatment and ANA–ve respond better.

16. § Progressive fibrosis of the lung parenchyma is self-sustaining and causes
progressive deterioration in lung function,respiratory symptoms and quality of life
§ It therefore increases the risk of early death.
§ Pulmonary fibrosis is sometimes regarded as an indicator of disease progression,
and the prognosis associated with an ILD is generally worsened by its presence.
§ However, aside from IPF, ILDs with progressive fibrosis may be clinicallystable,
especially if the disease is mild.
§ In addition,a progressive phenotype can exist in the absence of pulmonary fibrosis
16
Cottin, et al. Eur Respir Rev 2018

17. 17
Cottin V, et al. Eur Respir Rev 2018

18. 18
Cottin V, et al. Eur Respir Rev 2018

19. 19
Cottin V, et al. Eur Respir Rev 2018
§There are NO uniformly accepted criteria,
but we suggest patients meeting any of the following criteria
within a 24-month period have experienced disease progression:
§ ↓ FVC > 10% (relative)
§ ↓ DLCO > 15%
§ ↓ FVC :5-10% + worsening symptoms ± HRCT extension

20. 20
Cottin V, et al. Eur Respir Rev 2018

21. 21
Cottin V, et al. Eur Respir Rev 2018
§ Progressive fibrosis is an important characteristic of several ILDs that is
strongly linked with morbidity and mortality.
§ progressive-fibrosing non IPF-ILDs have many overlapping characteristics
that are similar to the classical fibrosing progressive phenotype ILD : IPF
§ Antifibrotic therapy is currently being investigated in these diseases.(2018)
§ Accurate and early diagnosis is challenging but crucial to ensure that each
patient receives treatment that is appropriate for the rate of progression
seen with their particular disease

22. 22
Holze C, et al. Eur Respir Rev 2018
§ up to 34% of ILD patients do not
receive a final diagnosis for ⩾2
years during which time we
anecdotally observe repetition of
diagnostic tests and
consultations.
§ up to 25% of patients remain
unclassifiable following
extensive investigation, which
can be due to conflicting
radiological or histopathological
data or the unavailabilityof a
lung biopsy
§ it was estimated that the total
annual medical costs for ILDs in
2000–2011 were up to USD 3
billion, (1.8 for IPF)

23. 23
Collins and raghu Eur Respir Rev 2019

24. § After review of exposure history, imaging and histopathology by ILD experts :
half of the IPF patients (2011 criteria) were subsequently diagnosed with cHP
§ Since the diagnosis of IPF in the INPULSIS 1 and 2 trials was not ascertained by
histopathology features of UIP in patients who did not have honeycombing (IPF
guidelines 2011),it is possible that up to 32% of patients enrolled in these
trials may not have had true IPF.
§ However,the therapeutic efficacy and safety was similar to IPF
§ This implies that nintedanib may slow disease progression in patients with
pulmonary fibrosis in general (IPF & non-IPF) and raises the question of whether
the same may be true for pirfenidone.
§ The SENSCIS trial Nintedanib in SSc-ILD with fibrotic extent ⩾10% on HRCT and
onset of SSc 7 years before screening : reduced the ↓ FVC over 52weeks
(primary end-point) (−52.4 versus placebo −93.3 mL/year)
24
Collins and raghu Eur Respir Rev 2019
Morell, Lancet Respir Med 2013

25. 25
Richeldi, et al. Eur Respir Rev 2019

26. 26
Richeldi, et al. Eur Respir Rev 2019

27. 27
Richeldi, et al. Eur Respir Rev 2019

28. 28
Flaherty et al. N Engl J Med 2019
BMJ Open Resp Res 2017
§ INBUILD ClinicalTrials. NCT02999178
§ 663 patients at 153 sites in 15 countries, 2017-18

29. 29
Significant pulmonary arterial hypertension
chest wall abnormality, large pleural effusion
Sever HTN (≥ 160/100 mmHg),MI,UA within 6m
Risk of bleeding:genetic predisposition OR requiring
fibrinolysis, full-dose therapeutic anticoagulation or antiplatelet
OR History of haemorrhagic CNS (12 m) OR Haemoptysis or
haematuria, active GIB or ulcers, major injury or surgery (in the
opinion of the investigator) within 3 m of screening OR INR > 2
History of a thrombotic event (CVA,TIA..) in 12 m
Peanut allergy
Life expectancy for disease other than ILD < 2.5 years
(investigator’s assessment)
Planned major surgical procedures
Women who are or willing pregnant, nursing
Active alcohol or drug abuse
Patients not able to understand or follow trial
Exclusion criteria
AST, ALT,Bili > 1.5 × ULN
Chronic liver disease (Child Pugh A, B or C)
Creatinine clearance < 30 mL/min
Previous treatment with nintedanib or pirfenidone
Other investigational therapy received within 1 month or 6 half-
lives
Use of any of the following medications to treat ILD:
azathioprine; cyclosporine;mycophenolate mofetil;
tacrolimus;oral corticosteroids (> 20 mg/day) or the
combination of oral corticosteroids + azathioprine +
NAC(within 4 w of randomisation);cyclophosphamide
(within 8 w of randomisation);or rituximab (within 6 m of
randomisation)
Diagnosis of IPF
Primary obstructive (pre-BD FEV1/FVC < 0.7)
Flaherty et al. N Engl J Med 2019
BMJOpen Resp Res 2017

30. 30
Wollin, Eur Respir J 2015

31. 31
Eur Respir J 2019

32. 32
Flaherty et al. N Engl J Med 2019

33. 33
Flaherty et al. N Engl J Med 2019

34. 34
Flaherty et al. N Engl J Med 2019
-80.8 ??

35. 35
Am J Respir Crit Care Med, 2003

36. § The American College of Occupational and Environmental Medicine
(ACOEM) recommends a longitudinal limit based on an annual decline of
15% which is comparable to LLD using within-person variation of 6%
§ ATS/ERS guidance says within-day differences in FEV1 < 5% , week-to-
week differences <11% , and year-to-year differences <15% for normal
subjects should not be interpreted as clinically meaningful;
§ greater differences apply to COPDs (within-day < 13%; week-to-week < 20%)
36
Townsend, Spirometry in Occupational Health, JOEM 2020
Pellegrino, R., Viegi,. Interpretative strategies for lung function tests. European Respiratory Journal 2005

37. Am J Respir Crit Care Med, 2005 Vol 171
§ 179 patients 1990 -2002 at Asan medical center,
Seoul, S.Korea
§ 131 IPF,41 Fibrotic NSIP,7 cellular NSIP
§ Median f/u:2 y
§ Corticosteroids ± cytotoxic therapy were given to
95% of fibrotic NSIP,and a short-term trial to IPF
§ 5-year survival:fibrotic NSIP =76.2%;IPF= 43.8%
§ predictors of survival after 6 months of followup:
§ older age
§ male sex
§ UIP pattern in pathology
§ lower initial lung function (FVC and DlCO)
§ lower initial PaO2
§ deterioration in FVC
37

38. 38
§ all randomized IPF subjects (1,156) in two placebo-controlled
clinical trials of IFN-g1b (Protocols GIPF- 001 [330] and GIPF-
007 [826]) irrespective of treatment assignment (placebo [443]
or IFN-g1b [713]),given that both of these studies were
negative.
§ Minimal clinically important difference (MCID) : distribution-
based and anchor-based methods
§ In patients who reported that their global health status was
“somewhat better”or“somewhat worse,”:mean change in
percent-predicted FVC at Week 48 vs baseline (MCID) : 2.2%
§ Mean change in percent-predicted FVC between Weeks 12
and 60 and change between Weeks 24 and 72, respectively,
corresponding estimates of MCID were 2.7% and 4.3%
§ Criterion-referencing analyses : Mean (± SD) baseline
percent- predicted FVC in patients who died during the 48-
week follow-up period was 64.9% (± 11.2), compared with
70.7% (± 12.8) in those who survived.Based on this difference,
the estimated MCID was 5.8% (P <0.001)
Am J Respir Crit Care Med. 2011, Vol 184

39. 39
§ Correlation of percent-predicted FVC between measurements (mean interval,18 d) was high (r =0.93; P <0.001).
§ Correlations between FVC and other parameters were generally weak,with the strongest observed correlation
between FVC and Dlco (r =0.38; P < 0.001).
§ Correlations between change in FVC and changes in other parameters were slightly stronger (range,r=0.16–0.37;
P<0.001).
§ Importantly, 1-year risk of death was more than twofold higher (P <0.001) in patients with a 24-week decline in FVC
between 5% and 10%. The estimated MCID was 2–6%.
§ Conclusions: FVC is a reliable, valid, and responsive measure of clinical status in patients with IPF,and a decline of 2–
6%, although small, represents a clinically important difference.
Am J Respir Crit Care Med. 2011, Vol 184

40. 40
PharmacoEconomics - Open (2020)

41. Baseline
FVC
(ml)
Baseline
FVC (%
predicted)
Post
intervention
FVC (ml)
52 weeks
rate of
decline in
FVC (%
predicted)
↓ FVC
(%predicted)
in UIP-like
pattern
(2/3
patients)
MCID Mortality Price
(Drug pack
& Total
yearly)
Nintedanib
2340 68.7% 2259 (-80.8) 3.45%
(-82.9 ml)
3.54% >10 %
> 5 %
> 2-6 % ?
4.8%
€ 28,910.5
€ 102,315.0
Placebo
2321 69.3% 2134 (-187.8) 8.09%
(-211.1 ml)
9.09% 5.1% -
Flaherty et al. N Engl J Med 2019
Rinciog et al. PharmacoEconomics - Open (2020)
Rate of FVC decline:Change in percent predicted OR ml ?
41
§ The absolute treatment effects in these patient
populations were similar in in magnitude to
those observed in pooled data from the INPULSIS
trials in patients with IPF (a between-group
difference of 109.9 ml in the INPULSIS trials)
§ Changes in health-related quality of life, as
measured on the K-BILD questionnaire over the
52-week period, were small in the two treatment
groups (NOT meaningful)
§ higher frequency of diarrhea, nausea, and
vomiting in nintedanib group
😕
4.64 %

42. 1) Neither pirfenidone nor nintedanib is a cure for IPF, and most patients on treatment continue to decline.
2) We do not know whether (and to what extent) these drugs remain effective beyond 52 weeks.
3) There is NO clear mortality benefit,and it remains to be determined to what extent a beneficial effect on
functional decline translates to a significant effect on survival (measuring this outcome appears prohibitive
because of the number of patients and study duration required for an adequately powered study).
4) There is NO consistent effect on quality of life.
5) Clinical trials of both pirfenidone and nintedanib have limited their enrollment to patients with mild to
moderate functional impairment,and we do not know whether the beneficial effects of these drugs also apply
to patients with more advanced disease (FVC < 50%)
6) Clinical trials of both pirfenidone and nintedanib have enrolled highly selected patients, mostly by virtue of
lack of significant morbidity,and it remains to be determined whether their results are generalizable to the
greater population with idiopathic pulmonary fibrosis.
7) When to start? which of the pirfenidone or nintedanib should be used first? (similar treatment effect)
8) Both drugs are substantially expensive (pirfenidone’s and nintedanib’s expected cost will be $100,000/year in
the United States), which might represent a barrier to receiving these therapies and their cost-effectiveness is
unknown, a common scenario in rare/orphan diseases
42
Paolo Spagnolo, amjmed.2015

43. § a large number of conditions, with a wide range of causes, clinical manifestations,
and imaging and pathological features, as well as variable outcomes.
§ Despite the intrinsic heterogeneity of this group of diseases, in most of them, the
pulmonary alveolar walls are infiltrated by various combinations of inflammatory
cells, fibrosis, and proliferation of certain cells that make up the normal alveolar wall.
§ Since these pathologic abnormalities predominate in the lung interstitium, the
disorders are termed interstitial lung diseases (ILDs).
43
Wijsenbeek & cottin. N Engl J Med Sep, 2020

44. §Overall ILD prevalence:74 -76 cases per 100,000 people
§Fibrotic ILDs:(cases per 100,000)
1) Sarcoidosis:30.2
2) CTD–associated ILDs: 12.1
3) IPF : 8.2
§Progressive fibrosing phenotype:
§ IPF: 90-100%
§ Non-IPF ILDs:13-40% (20-28/ 100000)
44
Wijsenbeek & cottin. N Engl J Med Sep, 2020

45. 45
Wijsenbeek & cottin. N Engl J Med Sep, 2020
1) ILDs related to distinct primary diseases : sarcoidosis, PLCH, EP,
LAM, and PAP
2) ILDs related to environmental exposures: pneumoconiosis
(inorganic substances), HP (organic particles)
3) ILDs induced by drugs: illicit drugs, irradiation
4) ILDs associated with CTDs, including RA–ILD and SSc–ILD,
idiopathic inflammatory myopathy, and primary Sjögren’s disease
5) Idiopathic interstitial pneumonias: IPF, idiopathic NSIP

46. Condition Relative
Prevalence (all
ILD patients)
Progressive
Fibrosing
Phenotype (%)
IPF 12 90-100
SSc–ILD 9 40
RA–ILD 8 32
Fibrotic
Sarcoidosis
45 13
Chronic HP 3 21
Unclassifiable
Fibrotic ILDs
8 53
N Engl J Med 2018
46
N Engl J Med Sep, 2020

47. 47
Condition Clinic HRCT Prognosis
(Median survival )
Relative
Prevalence
(all ILD
patients)
Progressive
Fibrosing
Phenotype
(%)
IPF Velcro crackles; clubbing (30–50%); male > female
(3:1); age >50 yr
Definite or probable UIP pattern potential for slowing
progression (3–4 yr)
12 90-100
SSc–ILD Younger age, more women, multisystem, Raynaud’s,
skin thickening, fingertip lesions, telangiectasia,
GERD, vasculopathy, ANA
anti–Scl-70, anticentromere,anti–RNA polymerase III
Fibrotic NSIP > UIP possible stabilization
with treatment
35% of death: ILD
(10 yr mortality: 40%)
9 40
RA–ILD Morning stiffness, symmetric arthritis, synovitis, joint
erosions, rheumatoid nodules
ACPAs, but RF less specific
UIP pattern > NSIP
Airway & pleural involvment
effect of treatment on
lung disease: unknown
(3 yr)
8 32
Fibrotic
Sarcoidosis
(Stage IV)
Younger age; Female= male,
Multisystem disease (skin, eye, heart, liver, lymph
nodes)
lung involvement : 90%
absence of bibasilar crackles, NO clubbing;
noncaseating epithelioid-cell granulomas with giant
cells on pathological evaluation
Upper-lobe,
Peribronchovascular, & lymphatic;
dense perihilar fibrotic or cavitated
masses;
bronchial distortion, reticular
opacities, and traction
bronchiectasis;
UIP-like pattern rare
generally responsive
to immunomodulation
(10 yr mortality: 10%)
45 13
Chronic HP Prolonged exposure to inhaled particles, Offending
inhaled Ag not always identified; recurrent episodes
of symptoms; BAL: lymphocytosis
biopsy: airway- centric lymphocytic infiltration,
loose granulomas, and giant cells
Reticulation and honeycombing,
with peribronchovascular,
Upper & middle-zone distribution;
GGO with mosaicism & air trapping
potential for
improvement or
stabilization with
treatment (5-Yr
survival, 50-80%)
3 21
Unclassifiable
Fibrotic ILDs
Demographic features vary; median age: 60–65 yr;
nonspecific symptoms with dyspnea and cough;
no first choice diagnosis; often subtle autoimmune
features, nondiagnostic CT findings
Major discrepancy among clinical, imaging, and
histologic features;
biopsy results noncontributory
Nonspecific features generally not
meeting criteria for main patterns
variable disease
course
(5-Yr survival, 45–70%)
8 53
Wijsenbeek & cottin. N Engl J Med Sep, 2020

48. 48
Wijsenbeek & cottin. N Engl J Med Sep, 2020
Condition Management Risk Factors for Progressive
Fibrosis or Death
IPF Antifibrotictherapy(pirfenidone,nintedanib) Older age,male,UIP pattern,
FVC< 70%
SSc–ILD Immunosuppressive therapy:MFM,CPM,AZA,RTX,TCL
Antifibrotic therapy (nintedanib)
Stem-cell or lung TRx
Diffuse cutaneous SSc, <7 yr since Dx,
male, Black race, anti–Scl-70,
HRCT >20%,↓ FVC & DLco
RA–ILD Lack of evidence for immunosuppressive therapy;RTX,ABA,or MFM
occasionally used;
antifibrotic therapy (nintedanib) used in cases of progressive
fibrosis; pirfenidone is under investigation
Older age,male,HRCT >20%,
UIP pattern, FVC < 70%
Fibrotic
Sarcoidosis
Monitoring alone or treatment with glucocorticoids;
MTX or AZA as glucocorticoid-sparing agent or second-line therapy;
IFX or ADA as third-line therapy;
lack of evidence for leflunomide and HCQ for lung disease;
benefit of antifibrotic therapy : unclear
Black race, HRCT >20%,PH,female
Chronic HP Exposure avoidance;
limited evidence for glucocorticoidsand (MFM or AZA);
antifibrotic therapy (nintedanib) for progressive fibrosis;
lung TRx in rare cases
Persistent exposure to offending
antigen, UIP pattern
Unclassifiable
Fibrotic ILDs
Limited evidence for glucocorticoids;
immunosuppressive therapy often first-line;
antifibrotic therapy (pirfenidone or nintedanib) in progressive fibrosis
Honeycombing on imaging,
progressive decline in lung function

49. 49
Wijsenbeek & cottin. N Engl J Med Sep, 2020
qPresentation : cough,progressive exertional dyspnea,exercise limitation
qHx: environmental exposures,medication use
qPh/Ex:fine crackles (Velcro rales or crepitations) are indicative of fibrosis
qPremature graying of hair and hematologic abnormalities may be a sign of
telomeropathy-related fibrosis
qHands, joints,and skin should be thoroughly examined

50. 50
Wijsenbeek & cottin. N Engl J Med Sep, 2020
qChest HRCT : diagnostic and may identify patterns..
qreticulation,architectural distortion, and lung volume loss
qUIP pattern:IPF,RA–ILD, and in advanced disease (any condition)
qNSIP:SS-ILD
qExpiratory phase for HP
qSpirometery:restrictive
ü normal lung function does NOT rule out the presence of pulmonary fibrosis
qDLCO ↓
qBAL .. Bronchial & lymph node Bx

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Wijsenbeek & cottin. N Engl J Med Sep, 2020

52. 52
Wijsenbeek & cottin. N Engl J Med Sep, 2020
§ The natural course of untreated IPF : progression to respiratory failure in virtually
every patient with a secure diagnosis.
§ In non-IPF ILDs, more than half have stable,chronic disease or improvement
with immunomodulatory therapy.
§ The longitudinal disease course varies and needs to be identified individually,
since it has implications for management decisions and occasionally may lead to
a reconsideration of the diagnosis.
§ serum biomarker for monitoring disease progression … NOT yet.

53. 53
Wijsenbeek & cottin. N Engl J Med Sep, 2020
§ There is NO standard definition of disease progression
§ In antifibrotic clinical trails:
§ ↓ FVC > 10%
§ ↓ FVC :5-10% + worsening symptoms ± HRCT extension
§ Worsening symptoms + HRCT extensions
§ In clinical practice NO threshold or decline rate have been accepted,but PFT q 3-6 m
§ FVC Measurements errors [& year to year variability..]→ multimodal assessment:
üWorsening symptoms
üExercise intoleramce
üDLCO
üExtension in HRCT
üHypoxemia
üAcute exacerbation

54. 54
Wijsenbeek & cottin. N Engl J Med Sep, 2020
Kolb, Eur Respir Rev 2018
ØLung fibrosis diagnosis:↓ QOL in patients & their family
üTreatment aims:
ü slowing down disease progression
ü ↑ QOL
üEducating patients and sharing decisions
üAvoidance of the offending antigen in CHP, airborne irritants and pollutants
ütobacco cessation
üvaccination (influenza & pneumococcal),hand washing and avoidance of sick contacts
üstrategies to minimize mechanicalVILI
üO2 therapy in resting hypoxemia
üPulmonary rehabilitation
ücoexisting conditions :identified and accurately treated
üLung TRx ?

55. 55
Wijsenbeek & cottin. N Engl J Med Sep, 2020
üIn IPF :pirfenidone or nintedanibis recommended
üin non-IPF ILDs first-line therapy :glucocorticoids,immunosuppressive therapy,or both ..
§ Nintedanib: FDA and EMA approved for patients with SSc–ILD and for patients with
chronic fibrosing ILDs with a progressive phenotype.
§ Nintedanibis NOT associated with an improvement in function but reduces the decline in
FVC by about half [but does NOT effect on mortality & QoL …]
§ So, progressive pulmonaryfibrosis may be amenable to antifibrotic therapy
regardless of the underlying specific disease.
§ Pirfenidone reduces disease progression in patients with progressive, unclassifiable,
fibrotic ILD
§ benefit of long-termpreservation of lung function should be balanced against the risk of
side effects.
§ When to start ??
§ How sequence of these treatments ??

56. 56
Wijsenbeek & cottin. N Engl J Med Sep, 2020

57. 57
§ How much is important: less 100 cc decline in FVC out of 2300 cc in the 7th decade?
§ Is this meaningful change?
ØNO change in the respiratory symptoms
ØNO change in patient reported outcomes
ØNO change in Quality of Life
ØNO change in mortality
§ Does this little change last beyond 52 w?
§ Does it fit to sever ILD patients?
§ Does it cost effective?
vBalance the pros & cons.
vShare decision with patients & their families
INBUILD

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