Department of Pharmacology and Therapeutics 4th Medical lectures

1
Department of Pharmacology and Therapeutics
4th Medical lectures

• 20/Oct/2005

2
Suspicion of DPLD

• Dyspnoea/Cough
• Symptoms often subtle, non specific and slowly
  progressive
• Long period before diagnosis confirmed
• Some patients are asymptomatic
• Diagnosed on the basis of abnormal radiology
  /PFTs
• Need to maintain an index of suspicion
• Esp if environmental/occupational exposures/
  concomitant medical conditions

3
aetiology

• Incidence
• Males 31.5/100,000
• Females 26.1/100,000
• Pathogenesis
• Injury to the lung coupled with attempts to heal

4
(No Transcript)
5
Classification

• ATS/ERS consensus statement
• DPLD secondary to identificable causes
• Environmental
• Occupational
• Drugs
• CTD/IBD
• DPLD secondary to granulomatous diseases
• Rare DPLD with well defined clinicopathological
  features
• LAM
• Histiocytosis X
• Eosinophilic pneumonia
• Pulmonary alveolar proteinosis
• IIP

6
Inhaled Agents
Inorganic
   Silica
   Asbestos
   Beryllium
Organic
   Animal/bird antigens
   Farm antigens
Drug-Induced
Antibiotics
Antiarrhythmics
Anti-inflammatory agents
Chemotherapeutic agents
Antidepressants
Radiation
Oxygen
Connective Tissue Disease Scleroderma Polymyositi
s/dermatomyositis Systemic lupus
erythematosus Rheumatoid arthritis Mixed
connective tissue disease Ankylosing
spondylitis Primary Sjögren's syndrome Behçet's
syndrome Infectious Atypical
pneumonias Pneumocystis carinii
pneumonia Tuberculosis
7
Idiopathic Sarcoidosis Eosinophilic
granuloma Idiopathic Interstitial Pneumonia
(IIP) Bronchiolitis obliterans organizing
pneumonia (OP) Lymphocytic interstitial pneumonia
(LIP) Usual interstitial pneumonia
(UIP) Nonspecific interstitial pneumonia
(NSIP) Desquamative interstitial pneumonia
(DIP) Respiratory bronchiolitis with interstitial
lung disease (RB-ILD) Acute interstitial
pneumonia (AIP). Malignant Lymphangitic
carcinomatosis Bronchoalveolar cell
carcinoma Miscellaneous Lymphangioleiomyomatosis
Histiocytosis X Adapted from Flaherty and
Martinez.
8
Diagnostic approach

• ATS/ERS
• Integrated clinical, radiological and
  pathological approach
• Essential to diagnosis UIP/IPF
• History
• Examinaton
• Selected lab studies
• Imaging studies
• In selected patients
• TBBX/Surgical Biopsy

9
(No Transcript)
10
(No Transcript)
11
Clinical History

• Sex
• LAM, Tuberosis Sclerosis premenopausal women
• Women with IPF have a better prognosis
• Age
• sarcoidosis, Familial IPF, Eosinophilic Granuloma
• Co morbidity CTD, IBD
• Drug exposure - BPMAN
• Assessment of living and work conditions
• Occupation/ social/leisure
• Risks for HIV

12
Symptoms

• Dyspnoea
• Cough
• Other symptoms
• Haemoptysis
• alveolar hemorrhage syndromes, pulmonary vascular
  diseases, lymphangioleiomyomatosis, tuberous
  sclerosis, and chronic mitral valve disease.
• Pleuritic chest pain
• collagen vascular illness, or a pneumothorax in
  patients with lymphangioleiomyomatosis, tuberous
  sclerosis, or eosinophilic granuloma.
• Onset of symptoms can give clues
• Acute process
• atypical infections, eosinophilic pneumonia,
  pulmonary hemorrhage, Wegener's granulomatosis,
  AIP, initial hypersensitivity reactions, or
  bronchiolitis obliterans organizing pneumonia
  (BOOP).
• Sub-Acute/Chronic process
• IPF, silica- or asbestos-related lung disease,
  long-standing hypersensitivity pneumonitis (HP),
  drug-induced lung diseases

13
Occupational/ Environmental history

• Diagnostic importance
• Therapeutic importance
• Occupational exposure
• Often long latent period
• avian, animal, fish proteins, fungal spores,
  asbestos, silica, cobalt, beryllium, aluminum,
  isocyanates, and copper sulfate.
• Home
• The presence or absence of pets, especially birds

14
Medications

• http//www.pneumotox.com

15
Smoking history

• RBILD, DIP, and eosinophilic granuloma
• Almost exclusively in smokers
• HP/EAA
• Less common in smokers
• If occurs in smokers more severe and chronic

16
Examination

• The physical examination are generally
  nonspecific.
• Dry bibasilar crackles, although inspiratory
  high-pitched rhonchi (squeaks) can be seen with
  bronchiolar disorders.
• Clubbing (most common in IPF)
• Right heart failure
• Signs of underlying connective tissue disorders.

17
Physiology

• Restrictive pattern
• Laboratory features
• FBC
• Electrolytes
• Autoantibody screen
• Inflammatory markers

18
Radiology

• Chest X-Ray (20 Normal)
• HRCT

19
HRCT Findings in IPF

• Bibasal subpleural distribution
• Reticular shadowing
• Honeycombing
• Lack of ground glass opacification
• Widened interlobular septae
• Tractional bronchiectasis

20
(No Transcript)
21
HRCT NSIP/ Path NSIP HRCT NSIP/ Path UIP HRCT
UIP/ Path UIP
22
BAL/TBBX/Lung biopsy

• Depends on clinical suspicion
• Risk v benefit
• Presence of classical clinical and radiological
  features

23
Concordant UIP Discordant UIP NSIP
24
IPF Survival
Daniil ZD et al. Am J Respir Crit Care Med. 1999
160899 Bjoraker JA et al. Am J Respir Crit Care
Med. 1998 157 199
25

• No data exist that adequately documents that any
  of the current treatment approaches
• Improve survival or
• Quality of life for patients
• Until adequate studies are conducted that define
  the best treatment for patients with IPF, this
  committee suggests combined therapy
  (corticosteroid and either azathioprine or
  cyclophosphamide) for patientswho possess
  features consistent with a more likely favourable
  outcome

26
Interferon Gamma (INF-? 1b)

• Rationale for use
• Pilot study, 1999
• Raghu 2004 R, MC, PC, DB 330 patients
• 48 week follow up
• SC TIW
• Failed to reach primary efficacy endpoint

27
Interferon Gamma
Raghu G, et al N Eng J Med, 2004 350 125-33
28
Interferon Gamma
INSPIRE International Study of Survival Outcomes
in Idiopathic Pulmonary Fibrosis with Interferon
Gamma 1-b 2 years, 600 pts, 75 centres, Less
severe disease FVC gt55 DLCO gt35
29
Pirfenidone Rationale for Therapy

• Antifibrotic agent
• Decreases fibroblast proliferation
• Decreases ECM production
• Inhibits TGF-ß collagen synthesis
• Inhibits mitogenic effect of PDGF
• Ameliorated fibrosis in a hamster model of
  bleomycin lung
• Beneficial effect in Hermansky-Pudlak syndrome
• Orally active
• Safe

30
Pirfenidone

• Initial trial Raghu et al, 1999
• Osaka et al, 2004 R, PC, DB, MC trial 107 pts
• Dose titrated to 600 t.i.d.
• 1º endpoint lowest O2 saturation at 6MWT
• 2º endpoints
• Change in baseline pulmonary function
• Events of acute exacerbation of IPF
• QOL score
• Disease progression by HRCT pattern

31
Pirfenidone

• Study aborted by DSMB
• Interim analysis of endpoints
• Acute exacerbations of IPF 5 vs. 0
• p 0.0032
• ADR photosensitivity nausea
• INTERMUNE sponsored larger RCT

32
N-Acetyl Cysteine

• Rationale for use
• Oxidative stress
• Glutathione
• NAC properties
• Restoration of glutathione
• Reduction of fibroblasts
• Decreases ECM components
• Inhibition of proinflammatory profibrotic
  cytokines and signal transducers
• Improves lung function
• Safe

33
N-Acetyl Cysteine

• IFIGENIA trial
• 155 patients NAC Pred AZA
• NAC titrated to 600mg t.i.d
• 1º endpoint at 12 months
• 15 ? VC
• 20 ? DLCO
• Trend toward improved mortality

34
Endothelin Receptor Antagonists

• Rationale for use
• Endothelin promotes expression of smooth muscle,
  fibrboblasts and ECM protein
• Animal models
• Endothelin levels elevated in IPF
• Efficacy in pulmonary arterial hypertension
• 3 drugs currently under evaluation
• Bosentan
• Sitaxsentan Ambrisentan

35
Bosentan

• BUIILD 1 (IPF)
• 132 patients, 32 centres, 9 countries
• 1º endpoint at 12 months 6 MWT
• 2 º endpoint mortality, lung function, QOL
• Ongoing
• Similar dose titration to PAH trials 62.5?125 bid

36
The Evolution of IPF therapy

• Steroids Azathioprine anti-oxidants
  anti-fibrotic ERAs,anti-TNF ??????
• 
  
  
• 1950s 2004

37
Summary What should we do now?

• No FDA therapy approved for IPF
• Multimodality therapy ?
• Supplementary oxygen
• Pulmonary rehabilitation
• Patient with EARLY disease
• Combination therapy
• Prednisolone and Azathioprine (or
  Cyclophosphamide)
• Experimental therapy in a RCT
• Patient with LATE disease
• Lung transplantation
• Experimental therapy in a RCT