Interstitial lung disease in systemic

sclerosis

Athol WellsRoyal Brompton Hospital

London, UK

Cardiopulmonary manifestations are serious

complications of SSc

Cardiopulmonary manifestations are the commonest causes of death in SSc2

27% of SSc-related deaths result from PAH2

25% of SSc-related deaths result from ILD2

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Heart

Lung

Heart & lung

1.Ferri C, et al. Medicine (Baltimore) 2002; 81:139-53.2.Steen V. Scleroderma Care Res 2006; 3:14-22.

*Kidney, cancer, miscellaneous

Other*

Causes of death in 1012 SSc patients1

Underlying mechanism of pulmonary fibrosis

Primary sites of injury and repair are regions of fibroblastic proliferation1

Epithelial cells produce pro-fibrotic factors, which may initiate fibrosis2

Endothelial damage has also been implicated as a possible co-factor1.Kuhn C 3rd, et al. Am Rev Respir Dis 1989; 140:1693-

703.2.Selman M, et al. Ann Intern Med 2001; 134:136-51.

Symptoms of SSc-ILD

Include dyspnoea on exertion, non-productive cough and inspiratory crackles

Prognosis linked to disease extent

Early detection important for best management

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IPF SSc NSIP

CT findings in SSc closely idiopathic NSIP but not IPF

Desai SR, et al. Radiology 2004; 232:560-7.

NSIP or SSc lungNSIP or SSc lung

UIPUIP

Diagnosis of SSc-ILD

CT shows reticular opacities, ground-glass opacity with little honeycombing

Pulmonary function tests: restrictive impairment, reduced diffusing capacity for CO, arterial hypoxaemia on exercise

Lung biopsy not warranted

Selman M, et al. Ann Intern Med 2001; 134:136-51.Bouros D, et al. Am J Respir Crit Care Med 2002; 165:1581-6.

Biopsy findings in SSc (n=80)

• NSIP n=62 (78%) - cellular NSIP, n=15 - fibrotic NSIP, n=47

• UIP n = 6• “End-stage lung” n = 6• RBILD n = 4• Others n = 2

Bouros D et al. Am J Respir Crit Care Med 2002;165:1581-6Bouros D et al. Am J Respir Crit Care Med 2002;165:1581-6

Bouros D et al. Am J Respir Crit Care Med 2002;165:1581-6Bouros D et al. Am J Respir Crit Care Med 2002;165:1581-6

The key clinical dilemma

We need to treat major pulmonary inflammation and progressive fibrosis.

But we need to avoid unnecessary treatment in inherently stable disease.

How do we decide? A trend towards routine screening for pulmonary fibrosis in CTD has made this a frequent issue.

Sometimes the answer is obvious

Intensive treatment vs MICO therapy

“Indolent/stable disease”

MICO:

Masterful Inactivity

with Cat-like Observation

The role of the doctor is to amuse the patient while nature takes its course

Voltaire

Sometimes the answer is anything but obvious

Clinical needs

Decisions are dichotomous: treat or not, enrol in treatment trial or not

We need definition of high and low risk disease

We need “Group A and Group B”. We need to STAGE lung disease in the CTD

Who should be treated?

Shorter duration of systemic disease: studies of Steen

Observed progression: not quantified

More severe disease ………

The definition of “alveolitis”

Traditional view that treatment applies to patients with “alveolitis”

HRCT “alveolitis” has been defined

BAL “alveolitis” has been defined

“An alveolitis on BAL”

A neutrophilia or granulocytosis on BAL had predicted decline in four studies

The BAL dilemma: severity or intrinsic progressiveness?

• Severe disease is more likely to progress

• Does BAL simply reflect severity? If so, HRCT and PFT are more user-friendly!

• Does BAL disclose progressiveness, independently of disease severity?

0 10 20 30 40 50 60 70 80 90 1000

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BAL neutrophils > 4.0

p=0.02

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Neutrophilia in 70/148 cases (47%)Neutrophilia in 70/148 cases (47%)

HR = 2.41 [1.24, 4.56]HR = 2.41 [1.24, 4.56]

Effect confined to two year Effect confined to two year mortality on mortality on adjustment for severityadjustment for severity

Goh NS. Arthritis Rheum 2007; 56:205-212Goh NS. Arthritis Rheum 2007; 56:205-212

Other outcome analyses

• BAL neutrophil levels were not predictive of the rapidity of decline in FVC or DLco

• BAL lymphocyte and eosinophil content were not linked to any measure of outcome

Goh NS. Arthritis Rheum 2007; 56:205-212Goh NS. Arthritis Rheum 2007; 56:205-212

Strange C. Am J Respir Crit Care Med 2008; 177:91-98Strange C. Am J Respir Crit Care Med 2008; 177:91-98

A complementary statement

The study of Goh: long term follow-up but uncontrolled, variable treatment

The placebo-controlled SLS oral cyclophosphamide study: one year of follow-up

BAL neutrophil content did not predict progression in the placebo arm

In both the Goh and the Strange studies, BAL neutrophil content correlated with disease extent on HRCT

This fits nicely with old data

Wells A. Am J Respir Crit Care Med 1994; 150:462-468Wells A. Am J Respir Crit Care Med 1994; 150:462-468

BAL neutrophil content largely reflects severity

It does not reliably separate SSc patients into high and low risk groups

Other CTDs less studied

Alveolitis on HRCT

The problem of ground-glass ….

This is the archetypal SSc HRCT

Lots of ground-glass … but only 15% of Lots of ground-glass … but only 15% of SSc patients have reversible histologySSc patients have reversible histology

When is ground-glass less likely to be inflammatory?

Admixed reticular abnormalities matter

versus……..

NSIP Gr 1 (cellular)

Traction bronchiectasis matters

NSIP Gr 3 (fibrotic)

Sometimes you are fairly sure that disease is irreversible…..

Often, some ground-glass is clearly fibrotic but some may be inflammatory

HRCT is only a rough guide

Ground-glass on HRCT is NOT synonymous with inflammation

The phrase “alveolitis on CT” should be banned

Staging by severity: SSc – what is needed

Simple, user-friendly system

Accurate depiction of high and low risk in moderately experienced hands

Conceptually easy

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Limited

Duration of follow-up (months)

Extensive

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Disease extent determines mortality

Goh NSGoh NS. Am J Respir Crit Care Med.. Am J Respir Crit Care Med. 2008; 177:1248-54 2008; 177:1248-54

UKRSA staging

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Duration of follow-up (months)

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Limited

Extensive

Disease extent determines rapidity of progression

Goh NSGoh NS. Am J Respir Crit Care Med.. Am J Respir Crit Care Med. 2008; 177:1248-54 2008; 177:1248-54

UK/RSA staging

HRCT extentHRCT extent

<20%<20% >20%>20% Indeterminate Indeterminate

Mild Mild DiseaseDisease

FVC >70%FVC >70% FVC <70%FVC <70%

Extensive Extensive DiseaseDisease

Goh NS, Goh NS, et al. Am J Respir Crit Care Med.et al. Am J Respir Crit Care Med. 2008 Mar 27; [Epub] 2008 Mar 27; [Epub]

Treatment

The scleroderma lung study (SLS)

Multi-centred, double-blind, randomised, placebo-controlled trial

Investigated the effects of oral cyclophosphamide on lung function and health-related symptoms in patients with active alveolitis and SSc-ILD

145 patients completed at least 6 months of treatment

Tashkin DP, Tashkin DP, et alet al. . N Engl J MedN Engl J Med 2006; 2006; 354:2655-66.354:2655-66.

The Scleroderma Lung Study

Cyclophosphamide vs placeboForced vital capacity (FVC)

% of predicted*Cyclophosphami

den = 73

Placebon = 72

Baseline value (mean ± SE)

67.6±1.3 68.3±1.5

Value at 12 months(mean ± SE)

66.6±1.7 65.6±1.6

Difference (mean ± SE)

−1.0±0.92 −2.6±0.9

p-value p <0.05 after adjustment for baseline values in favour of

cyclophosphamide*Primary endpoint Tashkin DP, Tashkin DP, et alet al. . N Engl J MedN Engl J Med 2006; 354:2655- 2006; 354:2655-

66.66.

Limited support for a cyclophosphamide treatment effect in a subsequent placebo-controlled study of IV cyclophosphamide with low dose prednisolone and subsequent azathioprine

Hoyles RK, Hoyles RK, et alet al. . Arthritis RheumArthritis Rheum 2006; 2006; 54:3962-70. 54:3962-70.

Cyclophosphamide in SSc-ILD

In view of the results from two high quality RCTs and despite its known toxicity, cyclophosphamide should be considered for treatment of SSc-related interstitial lung disease

Treatment effect may be understated because of selction bias in placebo-controlled studies, leading to preferential enrolment of patients with indolent disease

Kowal-Bielecka O, et al. EULAR 2007.

Wells AU, Latsi P, McCune WJ (Editorial). Am J Respir Crit Care Med 2007; 176:952-3

For the future

Accurate identification of patients at high risk of progressive lung disease

Safe and effective therapy for ILD