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 collapsed Lung 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] ↓ SpO2

• ↓ Exercise capacity CPET 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, O2, 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, PFTDittoSymptoms, PFT, CPETChange in Sx or testsHistory, blood tests

Drugs, dusts, GERDCyclophosphamide

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 Scleroderma-Related Interstitial Lung Disease (ILD)Interstitial Lung Disease (ILD)

• Pulmonary involvement, including ILD and pulmonary HTN, develops Pulmonary involvement, including ILD and pulmonary HTN, develops in 80% of patients with SSc, and is currently the leading cause of in 80% of patients with SSc, and is currently the leading cause of death in these patientsdeath in these patients

• 40% of all patients with SSc develop moderate restrictive ventilatory 40% of all patients with SSc develop moderate restrictive ventilatory impairment, and 15% develop severe restrictive associated with a 10-impairment, and 15% develop severe restrictive associated with a 10-year survival rate of only 40-50%year survival rate of only 40-50%

• NSIP is much more prevalent (76%) than UIP (11%) in SSc-NSIP is much more prevalent (76%) than UIP (11%) in SSc-associated ILD – COP, CLP, PVOD, HsPnassociated ILD – COP, CLP, PVOD, HsPn

• NSIP has a longer course, lower rate of decline in pulmonary function NSIP has a longer course, lower rate of decline in pulmonary function and a better response to therapy than UIP (non-SSc)and a better response to therapy than UIP (non-SSc)

Treatment of SSc-Related ILDTreatment of SSc-Related ILD

• Collagen accumulation results from abnormal interactions between endothelial Collagen accumulation results from abnormal interactions between endothelial cells, mononuclear cells leading to production of fibrosis-inducing cytokines and cells, mononuclear cells leading to production of fibrosis-inducing cytokines and stimulation of fibroblastsstimulation 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 - ?Inflammatory cells in BAL fluid in SSc-ILD reflects inflammation in the lungs - ?pathogenic?pathogenic?

• Corticosteroids and immunosuppressive therapy have been used to treat SSc-Corticosteroids and immunosuppressive therapy have been used to treat SSc-associated ILDassociated ILD

• No documented efficacy of corticosteroids in placebo-controlled trials: concerns of No documented efficacy of corticosteroids in placebo-controlled trials: concerns of an an increased risk of scleroderma renal crisisincreased risk of scleroderma renal crisis (Steen et al. Arthiritis Rheum 1998 41: p1613-19)(Steen et al. Arthiritis Rheum 1998 41: p1613-19)

Beware of using steroids alone

Adverse EventsAdverse EventsTable 3Table 3

Change in Values from Baseline to Month 12Change in Values from Baseline to Month 12Table 2Table 2

Absolute difference in HAQ-DI (-0.16; p=0.009) favoring CYC

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 TLC (4.09; p=0.026) favoring CYC

Absolute Difference in FVC (2.53%; p˂0.03) 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)

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)

Combined endpoint of time to death plus FVC at 12 months favoring CYC (p=0.04)

Adjusted FVC at 24 MonthsAdjusted FVC at 24 Months

Tashkin et al. Am J Respir Crit Care Med 2007 176: p1026-1034

P=0.364

Adjusted Mahler TDI at 24 MonthsAdjusted Mahler TDI at 24 Months

P=0.074

Tashkin et al. Am J Respir Crit Care Med 2007 176: p1026-1034

Adjusted Rodnan Skin Score Adjusted Rodnan Skin Score at 24 Monthsat 24 Months

P=0.23

Tashkin et al. Am J Respir Crit Care Med 2007 176: p1026-1034

What that means is…

• Little or no prednisone

• Cyclophosphamide slows deterioration

• If not tolerated, try another drug

• You never know…..

HRCT – BW - 2006

HRCT – BW - 2007

2011 2013

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;66:226-231• 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 (!)

JC

JC

JC

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

VC

VC

VC