Living with Pulmonary Fibrosis

1. Living with Pulmonary Fibrosis Gerard Cox FIRH – SJHH McMaster University Sept 2013

2. What is pulmonary fibrosis?

3. Interstitium Literally what is between (air)spaces Alveolar walls Walls of lobules = septae (septal lines) Lymphatic vessels Bronchovascular tissues Blood vessels Airways Fissures

4. Anatomy Lung: Alveoli-Interstitium-Vasculature

5. Collagen network in the lung Lung collapsed Lung inflated Toshima et al, ArchHistolCytol 2004

6. What is Pulmonary Fibrosis? • Scarring of the lung • Interstitial • Idiopathic

7. Characteristics of ILD Sub-acute to chronic Interference with lung function Airways less involved (↓FEV due to ↓VC) Stiffer lungs = lower VC Blocked blood vessels = impaired oxygenation Symptoms Stiff and small lungs = dyspnea Cough Sputum – less frequent (no bronchitis) Pain – no pain receptors in lung tissue

8. How to Recognize ILD Symptoms Chronic, non-variable, (dyspnea and cough) Signs Bilateral basal crackles (cave sine) Clubbing (<25%) Radiology Increased markings (linear or nodular) Breathing test results Small lungs, no obstruction, ↓gas exchange

9. Pulmonary Function Small lungs ↓ TLC and ↓ VC No obstruction ↓ FEV ≡ ↓ VC ↓ Gas exchange ↓ Diffusing capacity [xs] ↓ SpO2 ↓ Exercise capacity CPET or 6MW

10. What you need to know • How you feel • Vital capacity – expressed as % predicted • Oxygen – home oximeter • Exercise capacity

11. What can I expect • Diagnosis • Treatment • Secondary illnesses • Lung transplantation

12. Pulmonary Fibrosis Diagnostic Process Is there interstitial lung disease? Chest Xray – [exclude CHF, trial of diuretic] High Resolution CT scan – [nature and extent] Is there impairment? Pulmonary Function Test - VC, TLC, DCO reduced Exercise Test - cardiopulmonary, O2, tolerance Is it getting worse? [?MCID? and ?Interval?] Symptoms, Radiology, Physiology

13. Pulmonary Fibrosis in SSc Diagnostic Process If there is interstitial lung disease: - typical (NSIP or UIP) -due to another cause Does it need to be treated? Can it be treated? - Risk/Benefit (Risk = 25% incidence of serious side-effect)

14. Management - ?2’ary? Is disease present? Typical or not? Is it causing a problem? Is it getting worse? Primary (idiopathic) or secondary? Remove cause or Treat = immunosuppression Clx, Xray, HRCT, PFT Ditto Symptoms, PFT, CPET Change in Sx or tests History, blood tests Drugs, dusts, GERD Cyclophosphamide or Azt or MMP +/- pred

16. Organ Specific Mortality

17. Treatment of PF in SSc CYC has been shown to be superior to placebo in SSC-ILD ….D Khanna Clin Exp Rheum 2010;28:S52-S62 2 prospective randomized studies failed to show a major benefit …. Bussone G Autoimmunity Reviews 2010

18. Scleroderma-Related Interstitial Lung Disease (ILD) • Pulmonary involvement, including ILD and pulmonary HTN, develops in 80% of patients with SSc, and is currently the leading cause of death in these patients • 40% of all patients with SSc develop moderate restrictive ventilatory impairment, and 15% develop severe restrictive associated with a 10-year survival rate of only 40-50% • NSIP is much more prevalent (76%) than UIP (11%) in SSc-associated ILD – COP, CLP, PVOD, HsPn • NSIP has a longer course, lower rate of decline in pulmonary function and a better response to therapy than UIP (non-SSc)

19. Treatment of SSc-Related ILD Beware of using steroids alone • Collagen accumulation results from abnormal interactions between endothelial cells, mononuclear cells leading to production of fibrosis-inducing cytokines and stimulation of fibroblasts • Maybe vascular hyperreactivity, obstruction and tissue hypoxia • Inflammatory cells in BAL fluid in SSc-ILD reflects inflammation in the lungs - ?pathogenic? • Corticosteroids and immunosuppressive therapy have been used to treat SSc-associated ILD • No documented efficacy of corticosteroids in placebo-controlled trials: concerns of an increased risk of scleroderma renal crisis(Steen et al. Arthiritis Rheum 1998 41: p1613-19)

20. Adverse EventsTable 3

21. Change in Values from Baseline to Month 12 Table 2 Absolute Difference in FVC (2.53%; p˂0.03) favoring CYC Absolute difference in TLC (4.09; p=0.026) favoring CYC Absolute difference in HAQ-DI (-0.16; p=0.009) favoring CYC Combined endpoint of time to death plus FVC at 12 months favoring CYC (p=0.04) TDI improved by 1.4±0.23 in CYC group and worsened in placebo group -1.5±0.43 (p˂0.001)

22. Adjusted FVC at 24 Months P=0.364 Tashkin et al. Am J Respir Crit Care Med 2007 176: p1026-1034

23. Adjusted Mahler TDI at 24 Months P=0.074 Tashkin et al. Am J Respir Crit Care Med 2007 176: p1026-1034

24. Adjusted Rodnan Skin Score at 24 Months P=0.23 Tashkin et al. Am J Respir Crit Care Med 2007 176: p1026-1034

25. What that means is… • Little or no prednisone • Cyclophosphamide slows deterioration • If not tolerated, try another drug • You never know…..

26. HRCT – BW - 2006

27. HRCT – BW - 2007

28. 2011 2013

29. Lung transplantation • Before kidney • 3 – 6 months to assess • 10% per yr

30. GERD and PF Pepsin and bile salts Found in BAL Reported in patients post-transplant Associated with rejection Frequently found Abstract at ATS 2011

31. Assymmetric PF Tcherakian et al Thorax 2011;66:226-231 Progression of IPF: lessons from asymmetric disease 32 vs 64 matched controls; R>L ⅔ GERD 62 vs 31% Acute exacerbations 47 vs 17% Similar survival (!)

32. JC

33. JC

34. JC

35. JC

36. Pulmonary Hypertension • Screen (CSRG) • Wonder if declining function but breahing tests stable • Definitive test - catheterization • Treat – benefits • Seek specialized care

37. Where are we now? • More aware – community + medics • Advocacy, SSO, CSRG data • Multi-disciplinary teams – Rheumatology+ • Kidney, heart, stomach, lung • New drugs • GI, pirfenidone, • We are in this together

38. VC

39. VC

40. VC

41. VC