PNEUMOTRIESTE 2011

1. PNEUMOTRIESTE 2011 Pulmonary hypertension and diffuse parenchymal diseases: therapeutic options Carlo Albera Università di Torino Facoltà di Medicina e Chirurgia San Luigi Gonzaga Dipartimento di Scienze Cliniche e Biologiche Ambulatorio Interstiziopatie Polmonari / Malattie Rare

2. Pulmonary hypertension and diffuse parenchymal diseases: therapeutic options To date no approved drugs

3. Thank you for your attention

4. Clinical Classification of Pulmonary Hypertension (Dana Point 2008) • Pulmonary Arterial Hypertension • 1.1 Idiopatic • 1.2 Heritable • 1.2.1 BMPR2 • 1.2.2 ALK1, endoglin (+ / - hereditary haemorrhaigc teleangectasia) • 1.2.3 Unknown • 1.3 Drugs and toxins induced • 1.4 Associated with (APAH) • 1.4.1 Connective Tissue Diseases • 1.4.2 HIV infection • 1.4.3 Portal hypertension • 1.4.4 Congenital heart disease • 1.4.5 Schistosomiasis • 1.4.6 Chronic haemolityc anaemia • 1.5 Persistent PH of the newborn 5. PH with unclear and/or multifact mechs 5.1 Haematological dis: myieloproliferative, splenectomy 5.2 Systemic diseases: sarcoidosis, pulmonary Langerhans cell histiocytosis, lymphangioleiomyomatosis 5.3 Metabolic dis: glycogen storage disease. Gaucher disease, thyroid disorders 5.4 Others: tumoral obstruction, fibrosing mediastinitis, CRF on dialysis 3. PH due to lung dis/hypoxiaemia 3.1 COPD 3.2 ILD 3.3 Other pulmonary diseases with mixed restrictive and obstructive pattern 3.4 Sleep-disordered breathing 3.5 Alveolar hypoventilation disorders 3.6 Chronic exposure to high altitude 3.7 Developmental abnormabilities 4. Chronic thromboembolic PH 1’. PVOD and/or Pulm capill Haemang. 2. PH due to left heart disease 2.1 Systolic dysfunction 2.2 Diastolic dysfunction 2.3 Valvular diseases

5. DPLD of known cause or Idiopathic Granulomatous Other forms of IP association e.g. LAM, PLCH, interstitial eosinophilic pneumonia, pneumonias etc. Idiopathic IP other than pulmonary idiopathic fibrosis pulmonary fibrosis Respiratory bronchiolitis Desquamative interstitial pneumonia interstitial lung disease Acute interstitial Cryptogenic pneumonia organising pneumonia Non-specific interstitial Lymphocytic pneumonia interstitial pneumonia Diffuse Parenchymal Lung Disease ATS/ERS International Multidisciplinary Consensus Classification of the Idiopathic Interstitial Pneumonia AJRCCM 2002; 165: 277-304

6. Pulmonary hypertension and ILDs What from guidelines ?

7. ATS/ERS/JRS/ALAT EBM GUIDELINES Am J Respir Crit Care Med 183, 788–824, 2011

8. Treatment ofselectedcomplications and comorbidconditions Thereisanincreasingawarenessofcomplications and comorbidconditionsfrequentlyassociatedwithIPF. These include acute exacerbationofIPF, pulmonaryhypertension, gastroesophagealrefluxdisease, obesity, emphysema, and obstructivesleep apnea. Itisunknowniftreatingthesecomorbiditiesinfluencesclinicaloutcomes. ATS/ERS/JRS/ALAT EBM GUIDELINES Am J Respir Crit Care Med 183, 788–824, 2011

9. Question: Should pulmonary hypertension be treated in patients with IPF ? (1) Recommendation: Pulmonary hypertension should not be treated in the majority of patients with IPF, but treatment may be a reasonable choice in a minority (weak recommendation, very low-quality evidence). Values: This recommendation places a high value on cost and the potential for drug-related morbidity, and a low value on very low-quality data suggesting a possible benefit in selected patients. ATS/ERS/JRS/ALAT EBM GUIDELINES Am J Respir Crit Care Med 183, 788–824, 2011

10. Question: Should pulmonary hypertension be treated in patients with IPF ? (2) Remarks: In patients with moderate to severe pulmonary hypertension documented by right heart catheterization (i.e., mPAP ≥ 35 mm Hg), in line with the interpretation of a weak recommendation, a trial of vasomodulatory therapy may be indicated. The committee recognizes the need for clinical trials of vasomodulatory therapies in this patient population. (Vote: 8 for use, 14 against use, 1 abstention, 8 absent.) ATS/ERS/JRS/ALAT EBM GUIDELINES Am J Respir Crit Care Med 183, 788–824, 2011

11. Monitoring for Complications and Comorbidities: Comorbidities including pulmonary hypertension, pulmonary embolism, lung cancer, and coronary artery disease are known to occur in IPF. While the development of these comorbidities may influence survival, the role of routine screening to identify such complications in patients with IPF is unknown. (???) Thus, a recommendation for routine screening cannot be made ATS/ERS/JRS/ALAT EBM GUIDELINES Am J Respir Crit Care Med 183, 788–824, 2011

12. Monitoring for Complications and Comorbidities: pulmonary hypertension (1) In patients demonstrating progressive disease, the identification of PH may impact consideration for lung transplantation in eligible patients, and evaluation is indicated. Echocardiography is inaccurate in estimating pulmonary hemodynamics in patients with fibrotic lung disease and should not be relied upon to assess the presence and severity of pulmonary hypertension. ATS/ERS/JRS/ALAT EBM GUIDELINES Am J Respir Crit Care Med 183, 788–824, 2011

13. Monitoring for Complications and Comorbidities: pulmonary hypertension (2) BNP levels have been shown to correlate with the presence of moderate to severe PH, but have not been validated as a screening tool At the present time, right heart catheterization is required to confirm the presence of PH. ATS/ERS/JRS/ALAT EBM GUIDELINES Am J Respir Crit Care Med 183, 788–824, 2011

14. European Heart Journal (2009) 30, 2493–2537

15. PH due to lung diseases and/or hypoxaemia (group 3) In COPD the presenceof PH isassociatedwith shortersurvival and frequentepisodesofexacerbation. In interstitiallungdiseases PH is a poorprognosticfactor and PAP is the mostimportantpredictorofmortality. European Heart Journal (2009) 30, 2493–2537

16. PH due to lung diseases and/or hypoxaemia (group 3) Diagnosis echocardiography is the best screening tool for the assessment of PH. its diagnostic value in advanced respiratory diseases is lower than in PAH Echocardiographic estimation of PAPs l ILDs may be inaccurate. European Heart Journal (2009) 30, 2493–2537

17. PH due to lung diseases and/or hypoxaemia (group 3) Diagnosis The specificity of systolic PAP in detecting PH is low The negative predictive value is acceptable. Indications for echocardiography for the screening of PH in COPD and ILDs are: (i) exclusion of significant PH (ii) evaluation of concomitant left heart disease; (iii)selection of patients for RHC European Heart Journal (2009) 30, 2493–2537

18. PH due to lung diseases and/or hypoxaemia (group 3) Diagnosis • A definite diagnosis of PH relies on measurements at RHC. • The indication for RHC in advanced lung disease are: • proper diagnosis of PH incandidates for surgical treatments (transplantation, lung volume reduction); • suspected ‘out of proportion’ PH potentially amenable to be enrolled in RCT with specific PAH drug therapy; • frequent episodes of RV failure; • (iv) inconclusive echocardiographic study in cases with a high level of suspicion European Heart Journal (2009) 30, 2493–2537

19. PH due to lung diseases and/or hypoxaemia (group 3) Therapy Currentlythereisno specifictherapyfor PH associatedwithCOPD or interstitiallungdiseases. Long-term O2 administrationhasbeenshownpartiallytoreduce the progressionof PH in COPD. Nevertheless, withthis treatment PAP rarelyreturnstonormalvalues and the structuralabnormalitiesofpulmonaryvesselsremainunaltered. In interstitiallungdiseases, the roleoflong-term O2 therapy in PH progressionislessclear. European Heart Journal (2009) 30, 2493–2537

20. PH due to lung diseases and/or hypoxaemia (group 3) Therapy • Treatment with conventional vasodilators is not recommended because they may impair gas exchange due to: • the inhibition of hypoxic pulmonary vasoconstriction • lack of efficacy after long-term use. • Published experience with specific PAH drug therapy is scarce and consists of the assessment of acute effects and uncontrolled studies in small series. European Heart Journal (2009) 30, 2493–2537

21. PH due to lung diseases and/or hypoxaemia (group 3) Therapy The treatment of choice for patients with COPD or interstitial lung diseases and associated PH who are hypoxaemic is long-term O2 therapy. Patients with ‘out of proportion’ PH due to lung diseases (dyspnoea insufficiently explained by lung mechanical disturbances and mPAP >40-45mmHg at rest) should be referred to expert centres and enrolled in clinical trials targeting PAH-specific drug therapy. The use of targeted PAH therapy in patients with COPD or interstitial lung diseases and mean PAP <40 mmHg is currently discouraged because there are no systematic data regarding its safety or efficacy. European Heart Journal (2009) 30, 2493–2537

22. Recommendations for PH due to lung diseases a) Class of recommendation. b) Level of evidence. European Heart Journal (2009) 30, 2493–2537

23. Take home message from guidelines Actually there are no EBM-supported therapeutic options for the treatment of PH associated to ILDs The therapy of ILDs is probably the best way to prevent/delay the development of associated PH Effective antifibrotic drug(s) may offer in the next future some new chances The treatment of ILDs-associated PH represent a still unmet medical need ILDs- associated PH if “Out proportion” may be considered and managed in a different way

24. Some additional data on ILDs and PH

25. Report 2010 Registro Malattie Rare Regione Piemonte/Val d’Aosta www.malattierarepiemonte.it

26. Dana Point Group III Dana Point Group V Nathan SD Int J Clin Pract.20081742-1241

27. Idiopathic Other forms of IP Granulomatous e.g. LAM, PLCH, interstitial eosinophilic pneumonia, pneumonias etc. Idiopathic IP other than pulmonary idiopathic fibrosis pulmonary fibrosis Non-specific interstitial pneumonia Diffuse Parenchymal Lung Disease SARCOIDOSIS ATS/ERS International Multidisciplinary Consensus Classification of the Idiopathic Interstitial Pneumonia AJRCCM 2002; 165: 277-304

28. PulmonaryHypertension and Sarcoidosis Dana Point group 5 • PH with unclear and/or multifact mechs • 5.1 Haematological dis: myieloproliferative, splenectomy • 5.2 Systemic diseases: sarcoidosis, pulmonary Langerhans cell histiocytosis, lymphangioleiomyomatosis • 5.3 Metabolic dis: glycogen storage disease. Gaucher disease, thyroid disorders • 5.4Others: tumoral obstruction, fibrosing mediastinitis, CRF on dialysis

29. Prospective, observational study • 246 consecutive sarcoidosis patients • PH defined as estimated sPAP > 40 mm Hg • 212 patients evaluated for sPAP • 12 patients(5.7%) had PH. • Decreased lung volume increases the risk of PH developing in patients with sarcoidosis. Handa,T et al. CHEST 2006; 129:1246–1252

30. Arthritis Research & Therapy 2007, 9(Suppl 2):S8

31. Endothelin-1 / albumin levels in bronchoalveolar lavage fluid (BAL) fluid in sarcoid patients and healthy controls. Endothelin-1 levels in BAL fluid Arthritis Research & Therapy 2007, 9(Suppl 2):S8

32. Suspected if: • unexplained dyspnoea in sarcoidosis • worsening dyspnoea in steroid-refractory sarcoidosis • Pathogenetic mechanism of PH in sarcoidosis appears to be multifactorial: • direct compression of the pulmonary arteries • fibrotic destruction of the lung vasculature • hypoxia and a pulmonary vasculopathy • vasculitis • veno-occlusive PH (ECHO vs RHC !!!) Arthritis Research & Therapy 2007, 9(Suppl 2):S8

33. PulmonaryHypertension and IdiopathicPulmonaryFibrosis (IPF) Dana Point group 3 3.PH due to lung dis/hypoxemia 3.1 COPD 3.2 ILD 3.3 Other pulmonary diseases with mixed restrictive and obstructive pattern 3.4 Sleep-disordered breathing 3.5 Alveolar hypoventilation disorders 3.6 Chronic exposure to high altitude 3.7 Developmental abnormabilities

34. Pulmonary Hypertension in IPF • Pathogenesis • Prevalence, detection, diagnosis • Course and significance • Therapy

35. Pulmonary Hypertension in IPF • Pathogenesis • Prevalence, detection, diagnosis • Course and significance • Therapy

36. IPF- associated PH Genetic predisposition (mutations BMPR-2, ALK-1, 5HT polymorphism, NOS) Risk factors and associated conditions (e.g. HIV, anorexigens) Matrix, platelets, inflammatory cells Endothelial cells Smooth muscle cells Pathogenesis of PAH Hypoxia Local milieu (cytokines,chemokines, growth factors,etc) → fibrosis Loss of capillary and/or angiogenesis, in situ thrombosis PULMONARY VASCULAR INJURY Vasoconstriction – proliferation inflammation – thrombosis Pulmonary vascular disease Clinical syndrome of PAH BMPR-2: bone morphogenetic protein receptor type 2; ALK-1: activin receptor-like kinase 1; 5HT: 5-hydroxytryptamine or seratonin; NOS: nitric oxide synthase 1. Adapted from Gaine S JAMA 2000; 284: 3160–3168

37. (n 376) (n 376) bronchiole-vascular bundle in an area medial + intimal thickening +elastic tissue of relatively nonfibrotic lung tissue duplication . PH in IPFsharespathologicfeaturesofhypoxia-induced PH butalsodemonstratesmarkedintimalchanges, which likelyreflect a local and systemiccytokineeffect. Pulmonary artery/arteriole in a lobule marked medial thickening of relatively nonfibrotic lung tissue. Pulmonary artery branch in an area of dense fibrosis. Medial thickening and significant intimal proliferation. Patel N et al CHEST 2007; 132:998–1006

38. Pulmonary Hypertension in IPF • Pathogenesis • Prevalence, detection, diagnosis • Course and significance • Therapy

40. Diagnosis of P(A)H: a four-stage process 1. Suspicion of pulmonary hypertension 2. Detection of pulmonary hypertension 3. Pulmonary hypertension class identification 4. Pulmonary arterial hypertension evaluation • Symptoms and physical examination • Screening procedures • Incidental findings • Electrocardiogram • Chest radiograph • Transthoracic Doppler echocardiography • Pulmonary function tests and arterial blood gases • Ventilation/perfusion lung scan • High-resolution CT • Spiral CT • Pulmonary angiography • Type (blood tests and immunology, HIV test, abdominal ultrasound) • Exercise capacity (6MWD, peak oxygen consumption) • Haemodynamics (RHC) Nt-pro BNP Angio-RMN Galiè N et al Eur Heart J 2004; 25: 2243–2278

41. Pulmonary Hypertension in IPF • Pathogenesis • Prevalence, detection, diagnosis • Course and significance • Therapy

42. PAH associata a sclerodermia: curve di sopravvivenza 100 Nessun coinvolgimento degli organi interni (es. cuore) (n = 138) 80 60 % di sopravvivenza Coinvolgimentopolmonare (senzaPAH) n = 73) 40 20 PAH associata a sclerodermia (n = 17) 0 0 2 4 6 8 10 12 Anni dalla diagnosi di PAH Koh et al. Br J Rheumatol 1996;35:989-993

43. 5-year survival rates of patients with IPF grouped by mPAP mPAP <17 mm Hg mPAP ≥17 mm Hg Hamada K et al CHEST 2007; 131:650–656

44. Comparison of the survival curves between the patients with sPAP ≥40 mmHg and those with sPAP < 40 mmHg. Song JW et al Respiratory Medicine (2009) 103, 180 186

45. Comparison of the survival curves of subjects stratified to their sPAP and BNP levels. Group 1: sPAP < 40 mmHg and BNP ratio < 1. Group 2: sPAP ≥40 mmHg or BNP ratio ≥ 1. Group 3: sPAP ≥ 40 mmHg and BNP ratio ≥1 Song JW et al Respiratory Medicine (2009) 103, 180 186

46. Reanalysis of 376 patients listed for lung transplantation in the UNOS registry from 2004 to 2005 who underwent catheterization. 28% had PH with PCWP ≤ 15 mm Hg (median mPAP, 31 mm Hg) CHEST 2007; 132:998–1006

47. PH is present in 20% to 40% of patients with IPF who are evaluated for lung transplantation. DlCO% and other indicators of gas diffusion abnormality are predictive of PH in IPF more than other measures of lung function. (n 376) Patel N et al CHEST 2007; 132:998–1006

48. 110 IPF patients wer evaluated. The prevalence of emphysema in the IPF cohort was 28% Pulmonary arterial hypertension (PAH) was evaluated with TTE and defined by an eSPAP > 45 mmHg All IPF patients with emphysema showed PAH IPF with emphysema was highly associated with severe PAH (eSPAP: 82.3 ± 20.2 mmHg versus 56.7± 15.3 mmHg, p < 0.0001).

49. Chest; Prepublished online February 18, 2009;

50. Rossato Silva D et al J Bras Pneumol. 2008;34(10):779-786