Mycophenalate

1. The emerging role
of mycophenolate
mofetil in
interstitial lung
diseases

2. Introduction
• Interstitial lung diseases (ILDs) aka diffuse parenchymal
lung diseases encompass more than 200 disorders that
are generally characterized by inflammation
and/fibrosis in the lung parenchyma.
• As per the Global Disease Burden Study report, ILDs
were ranked at the 40th position among all diseases
with respect to global years of life lost in 2013,
representing an increase of 86% compared with 1990.

3. ILD
IIPs Autoimmune ILDS
Idiopathic pulmonary
fibrosis Interstitial pneumonia
with autoimmune
features¶
Idiopathic nonspecific
interstitial pneumonia
Respiratory
bronchiolitis-interstitial
lung disease
Desquamative
interstitial pneumonia
Cryptogenic organising
pneumonia
Acute interstitial
pneumonia
Idiopathic lymphoid
interstitial
pneumonia
Idiopathic
pleuroparenchymal
fibroelastosis
Unclassifiable IIPs
Hypersensitivity
pneumonitis Sarcoidosis# Other ILDS
Rheumatoid arthritis
ILD
Sjögren's syndrome
ILD
Systemic lupus
erythematous ILD
Polymyositis and
dermatomyositis ILD
Mixed connective
tissue disease ILD
Systemic sclerosis
ILD
Other connective
tissue disease ILDs
• Lymphangioleiomyomatosis
• Langerhans cell histiocytosis
• Drug-associated ILD
•ILDs related to other occupationa
exposures+
• Vasculitis/granulomatosis ILDs
• Other rare ILDS

4. Which is the most prevalent ILD you encounter in your practice?
• .
Chronic Hypersensitivity Pneumonitis Connective TissueDisease-ILD Idiopathic PulmonaryFibrosis
Sarcoidosis Unclassifiable ILD

5. Results : IN ILD survey
Commonest ILDs Encountered in Clinical Practice
Chronic hypersensitivity pneumonitis (cHP) was ranked as no. 1 ILD, followed by
idiopathic pulmonary fibrosis (IPF), connective tissue-ILD and sarcoidosis.
Table 1: Interstitial Lung Diseases
Rank 1 represents the most common and rank 5 being the least common ILD encountered in practice
The numbers in the table represents the total number of respondents
N= 320 ILD specialist
Presented at 8th International Workshop on Lung Health 2021 and NAPCON 2021

6. Results : India ILD survey
CHP accounted for 47% of total ILD cases
0%
100%
80%
60%
40%
20% 38%
14%
25%
14%
5%
15%
31%
47%
12%
8%
33% 5%
11% 5%
14%
IPF CTD-ILD HP Sarcoidosis Other ILDs
North India Postgraduate Institute of Medical Education & Research (2018)
India ILD Registry (2016)
Eastern India experience (2014)
Expert Review of Respiratory Medicine, DOI:
10.1080/17476348.2021.2001331
20%

7. Hypersensitivity Pneumonitis

8. Distinguishing IPF from F-HP
IPF and HP are amongst the two commonest causes of ILD in India / globally
The distinction:
- Is difficult
- Has major practical importance for the patient
Important to get it right, up front

9. Clinical history and examination
History
AGE:
- IPF: age > 50
- HP: no predilection
SEX:
- IPF: male > female
- HP: no sex predilection
SMOKING:
- IPF: Risk factor
- HP: Protective
Examination
HP:
- UL predominance
- Squawks distinctive
- Systemic features (acute)
IPF:
- Clubbing and crackles more extensive

10. Exposures and precipitins
An exposure history must be assiduously elicited and is often present in HP:
• Microbial
• Animal protein (including Avian)
• Plant protein
• Chemical
• Drugs
• Metals - -
• Check at home and work place
•A history of exposure does not equal a causal relationship
Pigeon exposure is near universal
• +ve precipitins common: but may be present in those exposed but asymptomatic
• A formal questionnaire to facilitate
identification of a trigger may be ideal
•None validated to date
ATS HP Guidelines 2020

11. Exposures and precipitins
•HP should not be diagnosed solely on the basis of +ve precipitins, nor excluded
because precipitins are negative
- 50% of exposed population may demonstrate antibodies hence cause and effect are
difficult to establish
Antibody testing may be done but
very low confidence in its effects
ATS HP Guidelines 2020

12. •Finding and removing the responsible antigen is associated with significantly better
survival
•Finding and removing such exposures also has important prognostic and therapeutic
implications
• The average survival in a cohort of 142 OLBx cases declined from:
- 18.2 years (if antigen identified)
- To 9.3 years (no antigen found)
- Fernandez Perez et al Chest 2013
Identifying the antigen is pivotal

13. In what percentage of your patients with
HYPERSENSITIVITY PNEUMONITIS
are you unable to identify inciting antigen?

14. Results : IN ILD Survey
38% of respondents reported that in about 41–60% of their HP cases, the inciting
antigen remains unidentifiable
10.16
16.51
32.06
37.77
3.49
0
10
20
30
40
0-10 % 11-20 % 21-40 % 41-60 % I don’t see patients
with
Hypersensitivity
Pneumonitis
% of Respondents unable to identify the inciting antigen in HP
50
%
of
Respondents
Presented at 8th International Workshop on Lung Health 2021 and NAPCON 2021
N= 320 ILD specialist

15. •Immunosuppressants in HP should be initial treatment for most patients
(even chronic HP)
• Immunosuppressants in IPF provide no benefit but increase:
- All-cause mortality
- All-cause hospitalisations
- Treatment related severe adverse events
- Panther study, IPFnet, NEJM, 2012
• We now know anti-fibrotics are effective in both
- Flaherty K, INBUILD NEJM, 2019
Treatment: why does the distinction matter?

16. In ILDs other than IPF, immunosuppression is the
cornerstone of therapy,with varying levels of evidence
for different immunomodulatory agents and for each specific ILD.
Immunomodulatory treatment of interstitial lung disease
Laura van den Bosch, Fabrizio Luppi, Giovanni Ferrara & Marco Muraid
THERAPEUTIC ADVANCES in
Respiratory Disease
Ther Adv Respir Dis
2022, Vol. 16: 1-16
DOI: 10.1177/
17534666221117002
© The Author(s), 2022.
Article reuse guidelines:
sagepub.com/journals-
permissions

17. • Azathioprine
• Cyclophosphamide
• Mycophenolate mofetil
• Methotrexate
• Rituximab
Which steroid sparing agent do you prefer in your ILD patients?

18. Use of Mycophenolate Mofetil or Azathioprine for the Management of Chronic
Hypersensitivity Pneumonitis
Julic Morisset, MD; Kerri A. Johannson, MD; Eric Vittinghoff, PhD; Carlos Aravena, MD; Brett M. Elicker,
MD; Kirk D. Jones, MD; Charlene D. Fell, MD; Helene Manganas, MD; Bruno-Pierre Dubé, MD; Paul J. Wolters,
MD; Harold R. Collard, MD, FCCP; Christopher J. Ryerson, MD; and Brett Ley, MD
i. MMF : n=51
- Daily dose : 1-3 g OR
ii. AZA : n=19
- Daily dose : 100-150 mg
Prednisone dose at MMF or
AZA initiation: 12.33mg/d
Prednisone dose at 6 months
after MMF or AZA initiation:
3.75mg/d
Morisset et al Chest 2017

19. Some were already receiving steroids
but still there was decline in both FVC or DLco
• Dose of Prednisone was 12.33mg/d
•6 months after mycophenolate initiation,
the dose was reduced by 4 fold
( 12.33 mg/d to 3.75mg/d)

20. How does mycophenolate mofetil
scores over azathioprine and steroids in cHP

21. Mycophenolate
mofetil
Azathioprine Inference
Molecular
Properties
Specificity for
activated T-
lymphocytes
Higher specificity for
activated T- lymphocytes
compared to Azathioprine
Lesser
specificity of
activated T-
lymphocytes
This could lead to
better clinical
response in
patients with cHP
Controlling the
autoantibody
production by B-
cells
More effective than
azathioprine in controlling
the autoantibody
production by B-cells
Less effective than
mycophenolate
mofetil in controlling
the autoantibody
production by B-cells
This could lead to
better clinical
response in
patients with
CTD-ILD

22. Mycophenolate mofetil Azathioprine Inference
Efficacy and
Safety
In chronic HP Statistically significant
improvement in DLco of
3.9%, while forced vital
capacity (FVC) improved by
1.3%.
Improved only DLco
with decline in FVC by
- 1.1%
Mycophenolate mofetil
improves and/stabilizes both
FVC and DLco; unlike
azathioprine
In chronic HP with
progressive
breathlessness
Adverse events
reported in 13.6%
Adverse events reported
in 33.3%
Both were effective, 50%
reduction in dose of steroids
16.2 + 9.7 to 8.2 + 4.2 mg daily
Discontinuation rate -
7.5%
Discontinuation rate -
17%
Mycophenolate mofetil was
well tolerated compared to
azathioprine

23. Evidence of mycophenolate mofetil in
CTD-ILDs

24. Randomised placebo controlled trials of immunosuppression
| Systemic Sclerosis-associated ILD
Cyclophosphamide vs Placebo: SLS I trial Cyclophosphamide vs Mycophenolate: SLS II
Tashkin et al Lancet Respir Med Sept 2016
Tashkin et al, NEJM 2006 – Hoyles et al A&R 2006

25. TREATMNT OF SSc-ILD TREATMNT OF RA-ILD
Early / inflammatory
Fibrotic / inflammatory
SSc-ILD
Mycophenolate
Cyclophsphamide
Tocilizumab
Nintedanib and / or
Mycophenolate
inflammatory
Fibrotic
RA-ILD
Mythotrexate
Rituximab
Abatacept
Nintedanib and / or
Mycophenolate
No formal guideline or
Consensus statements
EUROREAN RESOIRATORY SOCIETY INTERNATIONAL CONGRESS 2022
BARCELONA Spain, 4-5 September

26. Mycophenolate Mofetil: Dosing
The optimal daily dose is between 1.5 and 3g in two divided doses.
In patients with end-stage renal disease dose reduction is recommended.
It should be taken either 30 minutes before the meal or 2hrs after the meal.
Use of antacids and mineral supplements should be separated by at least 2 hours
from mycophenolate mofetil.
The optimal duration of mycophenolate mofetil remain unknown; however, it can be
continued until the patient experiences stability (minimum of 12 to 24 months).

27. When should I add mycophenolate mofetil ?
Mycophenolate mofetil takes about 2 months to show its clinical
effectiveness, hence if
i.either start mycophenolate mofetil as upfront with steroids and then slowly taper the
dose of steroids once the lung function stabilized and symptoms are controlled
ii.If patient is started on steroids, then add mycophenolate mofetil once symptoms are
under control and once the lung function is stabilized on steroids then slowly taper
down the steroid dose

28. Conclusion
• MMF is a potent immunosuppressant with anti-proliferative and anti-fibrotic
properties.
• Its use in patients with ILDs has been associated with stabilization of the FVC
and DLco and a significant reduction in the use of systemic CS.
• Compared with other immunosuppressants, MMF exhibits rapid onset of
action with similar efficacy, but a generally better safety profile and lacking
hepatic, renal or pulmonary toxicity.
• Treatment emergent AEs such as gastrointestinal events and leucopaenia were
generally mild to moderate in severity.
Thus, though the evidence supporting the efficacy data is limited, MMF appears to
be a safe and well-tolerated steroid-sparing agent in patients with ILDs.

29. The emerging role of mycophenolate mofetil in
interstitial lung diseases
Kevin K Brown, Sujeet K Rajan, Padmanabha Shenoy, Monali Mehta, Meena
Lopez, Rashmi S Hegde & Jaideep Gogtay
To cite this article: Kevin K Brown, Sujeet K Rajan, Padmanabha Shenoy, Monali Mehta,
Meena Lopez, Rashmi S Hegde & Jaideep Gogtay (2021): The emerging role of mycophenolate
mofetil in interstitial lung diseases, Expert Review of Respiratory Medicine, DOI:
10.1080/17476348.2021.2001331
To link to this article: https://doi.org/10.1080/17476348.2021.2001331

30. THANK YOU

31. Hypersensitivity pneumonitis
(Extrinsic allergic alveolitis)
• A complex syndrome of varying intensity, clinical presentation, and
natural history rather than a single, uniform disease.
• It represents an immunologic reaction to an inhaled agent,
particularly an organic antigen, occurring within the pulmonary
parenchyma.
• Numerous inciting agents have been described, including, but not
limited to, agricultural dusts, bioaerosols, and certain reactive
chemical species
• An association between MUC5B rs35705950 minor alleles and the
risk of chronic hypersensitivity pneumonitis has been identified

32. Environmental source Major causative antigen
Moldy hay, grain, silage
Thermophilic actinomycetes, such as Saccharopolyspora
rectivirgula (also known as Micropolyspora faeni or Faenia rectivirgula)
Fungus, such as Aspergillus umbrosus
Mold on pressed sugar cane (bagassosis, very rare cases) Thermoactinomyces sacchari, T. vulgaris
Tobacco plants (tobacco grower's lung; "Blackfat" tobacco)
Aspergillus spp
Scopulariopsis brevicaulis
Lycoperdonosis Lycoperdon perlatum (puffball spores)
Mushroom worker's lung
Mushroom spores
Thermophilic actinomycetes
Potato riddler's lung (moldy hay around potatoes)
Thermophilic actinomycetes
T. vulgaris
S. rectivirgula
Aspergillus spp
Paprika slicer's lung (moldy paprika pods) Rhixopus stolonifer (also called Mucor stolonifer)
Wine maker's lung (mold on grapes) Botrytis cincrea
Cheese washer's lung (moldy cheese)
Penicillium caseifulvum
Aspergillus clavatus
Coffee worker's lung Coffee-bean dust
Tea grower's lung Tea plants

33. Environmental source Major causative antigen
Chemical worker's lung
Diphenylmethane diisocyanate (MDI)
Toluene diisocyanate (TDI)
Detergent worker's lung (washing powder
lung)
Bacillus subtilis enzymes
Pauli's reagent alveolitis Sodium diazobenzene sulfate
Vineyard sprayer's lung Copper sulfate (bordeaux mixture)
Pyrethrum (pesticide) Pyrethrum
Epoxy resin lung Phthalic anhydride (heated epoxy resin)
Bible printer's lung Moldy typesetting water
Machine operator's lung
Pseudomonas fluorescens
Mycobacterium immunogenum
Aerosolized metal working fluid

34. Classical
classification
Boyd
classification
Cormier
classification
Selman classification
Vasakova
classification
Acute Acute progressive
Active
Active nonprogressive
and intermittent
Acute: Symptom
duration <6
months*; mostly
reversible
Subacute
Acute intermittent
nonprogressive
Acute progressive and
intermittent
Chronic Nonacute Residual
Chronic Chronic-fibrotic:
symptom duration
>6 months*; may be
partially reversible,
but risk of
progression
Nonprogressive
Progressive
Richerson HB, Bernstein IL,
Fink JN, et al. Guidelines for
the clinical evaluation of
hypersensitivity pneumonitis.
Report of the Subcommittee
on Hypersensitivity
Pneumonitis. J Allergy Clin
Immunol 1989; 84:839.
Boyd G, McSharry CP, Banham
SW, Lynch PP. A current view of
pigeon fancier's lung. A model
for pulmonary extrinsic allergic
alveolitis. Clin Allergy 1982; 12
Suppl:53.
Cormier, Y, Lacasse, Y. Keys to
the diagnosis of
hypersensitivity pneumonitis:
The role of serum precipitins,
lung biopsy, and high-
resolution computed
tomography. Clin Pulm Med
1996; 3:72.
Interstitial Lung Disease, Schwarz MI,
King TE Jr, (Eds), 5th ed, Shelton, CT,
People's Medical Publishing House,
2011.
Vasakova M, Morell F, Walsh S, et
al. Hypersensitivity Pneumonitis:
Perspectives in Diagnosis and
Management. Am J Respir Crit Care
Med 2017; 196:680.
Classification systems for hypersensitivity pneumonitis

35. CLINICAL FEATURES
• Dyspnea and cough
• Chest tightness and constitutional symptoms, such as fever, chills,
weight loss, and malaise
• Acute presentation Vs Insidious presentation
• Tachypnea, focal or diffuse crackles, mid inspiratory squeaks (chirping
or squawks)

36. Laboratory tests
• Serologic assays for specific IgG antibodies
• Testing of environmental samples
• Lymphocyte proliferation test
• Skin tests
• Nonspecific tests of inflammation
• Pulmonary function tests

37. High resolution computed tomography
• Two series of images should be obtained with the patient supine: one at deep
inspiration and another at one second after prolonged exhalation
HRCT pattern Typical HP Compatible with HP
Indeterminate
for HP
Nonfibrotic HP pattern
Description
The "typical HP" pattern is suggestive of a
diagnosis of HP. It requires (A) at least one HRCT
abnormality indicative of parenchymal infiltration
and (B) at least one HRCT abnormality indicative
of small airway disease, both in a diffuse
distribution.
"Compatible-with-HP" patterns are
nonspecific patterns that have
been described in HP.
N/A
Relevant
radiological
findings
•HRCT abnormalities indicative of parenchymal
infiltration:GGOs
•Mosaic attenuation
*
•HRCT abnormalities indicative of small airway
disease:Ill-defined, centrilobular nodules
•Air trapping
•Distribution of parenchymal
abnormalities:Craniocaudal: diffuse (with or
without some basal sparing)
•Axial: diffuse
•Parenchymal abnormalities:
Uniform and subtle GGOs
•Airspace consolidation
•Lung cysts
•Distribution of parenchymal
abnormalities:
•Craniocaudal: diffuse (variant:
lower lobe predominance)
•Axial: diffuse (variant:
peribronchovascular)
N/A

38. Fibrotic HP pattern
Description
The "typical HP" pattern is suggestive of a
diagnosis of HP. It requires (A) an HRCT pattern
of lung fibrosis (as listed below) in one of the
distributions and (B) at least one abnormality
that is indicative of small airway disease.
"Compatible-with-HP" patterns exist
when the HRCT pattern and/or
distribution of lung fibrosis varies
from that of the typical HP pattern;
the variant fibrosis should be
accompanied by signs of small airway
disease.
The "indeterminate-for-HP"
pattern exists when the HRCT is
neither suggestive of nor
compatible with a typical and
probable HP pattern.
Relevant radiological
findings
HRCT abnormalities indicative of lung fibrosis
are most commonly composed of irregular
linear opacities/coarse reticulation with lung
distortion; traction bronchiectasis and
honeycombing may be present but do not
predominate.
•The distribution of fibrosis may be:Random
both axially and craniocaudally, or
•Mid lung zone-predominant, or
•Relatively spared in the lower lung zones
•HRCT abnormalities indicative of small airway
disease:Ill-defined, centrilobular nodules
and/or GGOs
•Mosaic attenuation
*
, three-density pattern
¶
,
and/or air trapping (often in a lobular
distribution)
•Variant patterns of lung fibrosis:UIP
pattern: basal and subpleural
distribution of honeycombing
with/without traction bronchiectasis
(per 2018 diagnosis of IPF
guidelines
[1]
)
•Extensive GGOs with superimposed
subtle features of lung fibrosis
•Variant (predominant) distributions
of lung fibrosis:Axial:
peribronchovascular, subpleural
areas
•Craniocaudal: upper lung zones
•HRCT abnormalities indicative of
small airway disease:Ill-defined
centrilobular nodules, or
•Three-density pattern
¶
and/or air
trapping
•Lone patterns (ie, not
accompanied by other findings
suggestive of HP) of:UIP pattern
(as per 2018 IPF diagnosis
guidelines
[1]
)
•Probable UIP pattern (as per 2018
IPF diagnosis guidelines
[1]
)
•Indeterminate pattern for UIP (as
per 2018 IPF diagnosis
guidelines
[1]
)
•Fibrotic NSIP pattern
•Organizing pneumonia-like
pattern
•Truly indeterminate HRCT pattern

40. Bronchoalveolar lavage
• A marked BAL lymphocytosis (greater than 20 percent and often
exceeding 50 percent of the white blood cells recovered) is a
nonspecific, but helpful, finding when the clinical and radiographic
findings suggest subacute HP
• BAL lymphocytosis can also be seen in organizing pneumonia and
nonspecific interstitial pneumonia, but not usually at this high level.

41. Characteristics that help in the diagnosis of HP in patients with respiratory +/– constitutional symptoms (eg, cough,
breathlessness, fever, fatigue) and absence of features to suggest systemic rheumatic disease
1.Known exposure to offending antigen identified by:
1. History of appropriate exposure: Aerobiologic or microbiologic investigations of the environment that confirm the
presence of an inciting antigen
2. The presence of specific IgG antibodies in serum against the identified antigen (serum precipitins, ELISA, or
ImmunoCAP)*
2.Compatible HRCT findings:
2. Acute/subacute: Upper and middle lobe predominant small centrilobular nodules, ground-glass attenuation, and
lobular areas of decreased attenuation and vascularity
3. Chronic/fibrotic: Upper and middle lobe predominant fibrosis, peribronchovascular fibrosis, honeycombing, mosaic
attenuation, air trapping, centrilobular nodules, and relative sparing of bases
3.BAL lymphocytosis: Supports diagnosis of HP if lymphocytosis, but nonspecific and not always needed
3. Lymphocytosis >20%, often >50%
4. Mycobacterial stains and culture negative
4.Positive inhalation challenge testing by:
4. Reexposure to the environment
5. Inhalation challenge to the suspected antigen in a hospital setting (not widely available or standardized)
1.Only performed in selected patients

42. Histopathology
• Nonfibrotic HP
Classic triad :
• Chronic cellular bronchiolitis with a peribronchial infiltration of lymphocytes.
An organizing pneumonia pattern may be present with intraluminal “buds” or
“whorls” of granulation tissue (Masson bodies), as are seen in cryptogenic
organizing pneumonia
• Small, poorly-formed non necrotizing granulomas located near respiratory or
terminal bronchioles. These ill-defined aggregates of epithelioid macrophages
may be associated with multinucleated giant cells. Well-formed granulomas
are not commonly seen
• Chronic cellular pneumonitis with a patchy mononuclear cell infiltration
(predominantly lymphocytes and plasma cells) of the alveolar walls.

43. Histopathology
• Fibrotic HP
Include features of UIP and/or fibrotic nonspecific interstitial
pneumonia (NSIP). Sometimes features such as lymphocytic infiltrates,
organizing pneumonia, poorly-formed granulomas, and multinucleated
giant cells (often isolated) are present in patients with chronic/fibrotic
HP, although the predominant pattern is fibrosis.
Airway-centered fibrotic lesions (peribronchiolar metaplasia) may be
present, but are nonspecific

44. TREATMENT
• Antigen avoidance
• Acute HP with minimal or transient symptoms
• Acute or subacute HP with persistent symptoms

45. Interstitial Lung Diseases…have come a long way
1872 Buhl
chronic interstitial pneumonia
desquamative pneumonia
muscular cirrhosis of the lung
1935 Hamman-Rich syndrome
1892 Osler
• cirrhosis of the lung
1898 Rindfleisch
• cirrhosis cystica pulmonum
1954 Vanek
• interstitial nonpurulent pneumonia
2000 ATS/ERS
• Definition of IPF
1964 Scadding
• CFA
1968 Liebow
• pathologic classification UIP
1997 Müller & Colby
• radio-pathological classification
1998 Katzenstein & Meyer
• pathologic classification
1713 Ramazzini
• disease of grain workers
1932 Towey
• sooty bark disease
1932 Campbell
• formers lung
1816 Laennec
• stethoscope
1895 Röntgen
• X-ray
1968 Ikedo
• flexible bronchoscopy
1971 Hounsfield
• computed tomography
1972 Anderson
• transbronchial biopsy
1983 Davidson
• COP Epler
1985
• BOOP
2000
1800 1900 1950 1975
Fig. 1. Milestones for idiopathic interstitial pneumonias (blue), hypersensitivity pneumonitis (green), organizing pneumonia
(red), and for relevant technical achievements (gray). BOOP, bronchiolitis obliterans organizing pneu- monia; COP, cryptogenic
organizing pneumonia; UIP, usual interstitial pneumonia. Clin Chest Med 42 (2021) 229–239