1. Interstitial lung disease in systemic sclerosis
Athol Wells
Royal Brompton Hospital
London, UK

2. Cardiopulmonary manifestations are serious complications of SSc
Causes of death in 1012 SSc patients1
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
Other*
Heart & lung
Lung
Heart
*Kidney, cancer, miscellaneous
1.Ferri C, et al. Medicine (Baltimore) 2002; 81:
2.Steen V. Scleroderma Care Res 2006; 3:14-22.

3. 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-factor
1.Kuhn C 3rd, et al. Am Rev Respir Dis 1989; 140:
2.Selman M, et al. Ann Intern Med 2001; 134:

4. 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

5. CT findings in SSc closely idiopathic NSIP but not IPF
100 80 60
Ground-glass opacification (%) 40 20
IPF
SSc
NSIP
Desai SR, et al. Radiology 2004; 232:560-7.

6. UIP
NSIP or SSc lung

7. 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:
Bouros D, et al. Am J Respir Crit Care Med 2002; 165:

8. 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;165:1581-6

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

10. 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.

11. Sometimes the answer is obvious
Intensive treatment vs MICO therapy

12. “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

13. Sometimes the answer is anything but obvious

14. 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

15. Who should be treated?
Shorter duration of systemic disease: studies of Steen
Observed progression: not quantified
More severe disease ………

16. The definition of “alveolitis”
Traditional view that treatment applies to patients with “alveolitis”
HRCT “alveolitis” has been defined
BAL “alveolitis” has been defined

17. “An alveolitis on BAL”
A neutrophilia or granulocytosis on BAL had predicted decline in four studies

18. 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?

19. Neutrophilia in 70/148 cases (47%) HR = 2. 41 [1. 24, 4
Neutrophilia in 70/148 cases (47%) HR = 2.41 [1.24, 4.56] Effect confined to two year mortality on adjustment for severity
Goh NS. Arthritis Rheum 2007; 56:

20. 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:

21. 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
Strange C. Am J Respir Crit Care Med 2008; 177:91-98

22. In both the Goh and the Strange studies, BAL neutrophil content correlated with disease extent on HRCT This fits nicely with old data

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

24. BAL neutrophil content largely reflects severity It does not reliably separate SSc patients into high and low risk groups Other CTDs less studied

25. Alveolitis on HRCT The problem of ground-glass ….

26. This is the archetypal SSc HRCT
Lots of ground-glass … but only 15% of SSc patients have reversible histology

27. When is ground-glass less likely to be inflammatory?

28. Admixed reticular abnormalities matter

29. versus……..

30. Traction bronchiectasis matters
NSIP Gr 1 (cellular)

31. NSIP Gr 3 (fibrotic)

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

33. Often, some ground-glass is clearly fibrotic but some may be inflammatory HRCT is only a rough guide

34. Ground-glass on HRCT is NOT synonymous with inflammation The phrase “alveolitis on CT” should be banned

35. Staging by severity: SSc – what is needed
Simple, user-friendly system
Accurate depiction of high and low risk in moderately experienced hands
Conceptually easy

36. Disease extent determines mortality
100 80 60 40 20
120
Limited
Duration of follow-up (months)
Extensive
Survival (%)
UKRSA staging
Goh NS. Am J Respir Crit Care Med. 2008; 177:

37. Disease extent determines rapidity of progression20 40 60 80
100
120
Duration of follow-up (months)
Progression-free survival (%)
Limited
Extensive
UK/RSA staging
Goh NS. Am J Respir Crit Care Med. 2008; 177:

38. HRCT extent Mild Disease Extensive Disease <20% Indeterminate
>20%
FVC >70%
FVC <70%
Mild Disease
Extensive Disease
Goh NS, et al. Am J Respir Crit Care Med Mar 27; [Epub]

39. Treatment

40. 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, et al. N Engl J Med 2006; 354:

41. The Scleroderma Lung Study Cyclophosphamide vs placebo
Forced vital capacity (FVC) % of predicted*
Cyclophosphamide n = 73
Placebo n = 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, et al. N Engl J Med 2006; 354:

42. 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, et al. Arthritis Rheum 2006; 54:

43. 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

44. For the future
Accurate identification of patients at high risk of progressive lung disease
Safe and effective therapy for ILD