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

What is pulmonary fibrosis?

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

Anatomy Lung: Alveoli-Interstitium-Vasculature

Collagen network in the lung Lung collapsedLung inflated Toshima et al, ArchHistolCytol 2004

What is Pulmonary Fibrosis? Scarring of the lung Interstitial Idiopathic

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

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

Pulmonary Function Small lungs ↓ TLC and ↓ VC No obstruction ↓ FEV ≡ ↓ VC ↓ Gas exchange ↓ Diffusing capacity [xs] ↓ SpO 2 ↓ Exercise capacityCPET or 6MW

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

What can I expect Diagnosis Treatment Secondary illnesses Lung transplantation

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

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)

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

Organ Specific Mortality

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

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)

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 : p )No documented efficacy of corticosteroids in placebo-controlled trials: concerns of an increased risk of scleroderma renal crisis (Steen et al. Arthiritis Rheum : p ) Beware of using steroids alone

Adverse Events Table 3

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)

Adjusted FVC at 24 Months Tashkin et al. Am J Respir Crit Care Med : p P=0.364

Adjusted Mahler TDI at 24 Months P=0.074 Tashkin et al. Am J Respir Crit Care Med : p

Adjusted Rodnan Skin Score at 24 Months P=0.23 Tashkin et al. Am J Respir Crit Care Med : p

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

HRCT – BW

HRCT – BW

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

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

Assymmetric PF Tcherakian et al Thorax 2011;66: 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 (!)

JC

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

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

VC