Interstitial lung disease in systemic sclerosis

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

2. 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 Cardiopulmonary manifestations are serious complications of SSc Causes of death in 1012 SSc patients1 Other* Heart & lung Lung Heart *Kidney, cancer, miscellaneous 1.Ferri C, et al. Medicine (Baltimore) 2002; 81:139-53. 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; 140:1693-703. 2.Selman M, et al. Ann Intern Med 2001; 134:136-51.

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 0 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; 134:136-51. Bouros D, et al. Am J Respir Crit Care Med 2002; 165:1581-6.

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, 4.56]Effect confined to two year mortality on adjustment for severity Goh NS. Arthritis Rheum 2007; 56:205-212

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; 56:205-212

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 HRCTThis fits nicely with old data

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

24. BAL neutrophil content largely reflects severityIt does not reliably separate SSc patients into high and low risk groupsOther CTDs less studied

25. Alveolitis on HRCTThe 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 inflammatoryHRCT is only a rough guide

34. Ground-glass on HRCT is NOT synonymous with inflammationThe 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. 100 Limited 80 60 Extensive Survival (%) 40 20 0 80 20 60 100 40 0 120 Duration of follow-up (months) Disease extent determines mortality UKRSA staging Goh NS. Am J Respir Crit Care Med. 2008; 177:1248-54

37. 100 80 60 Progression-free survival (%) Limited 40 20 Extensive 0 0 20 40 60 80 100 120 Duration of follow-up (months) Disease extent determines rapidity of progression UK/RSA staging Goh NS. Am J Respir Crit Care Med. 2008; 177:1248-54

38. HRCT extent <20% Indeterminate >20% FVC >70% FVC <70% Mild Disease Extensive Disease Goh NS, et al. Am J Respir Crit Care Med. 2008 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; 354:2655-66.

41. The Scleroderma Lung StudyCyclophosphamide vs placebo *Primary endpoint Tashkin DP, et al. N Engl J Med 2006; 354:2655-66.

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; 54:3962-70.

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