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 collapsedLung 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] ↓ SpO 2 ↓ Exercise capacityCPET 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, O 2, 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 patientsPulmonary 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%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, HsPnNSIP 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)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 Collagen accumulation results from abnormal interactions between endothelial cells, mononuclear cells leading to production of fibrosis- inducing cytokines and stimulation of fibroblastsCollagen 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 hypoxiaMaybe vascular hyperreactivity, obstruction and tissue hypoxia Inflammatory cells in BAL fluid in SSc-ILD reflects inflammation in the lungs - ?pathogenic?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 ILDCorticosteroids 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)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) Beware of using steroids alone

20. Adverse Events Table 3

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

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

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. 20112013

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

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