1. Department of Pharmacology and Therapeutics 4 th 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

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 Polymyositis/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

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

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; 160:899 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 patients…who possess features consistent with a more likely favourable outcome”

26. Interferon Gamma (INF-γ 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 >55% DLCO >35%

29. Pirfenidone: Rationale for Therapy Antifibrotic agent Decreases fibroblast proliferation Decreases ECM production Inhibits TGF-β 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% Δ VC –20% Δ 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 ERA’s,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