Presentation on theme: "Interstitial lung disease in systemic sclerosis"— Presentation transcript:
1 Interstitial lung disease in systemic sclerosis Athol WellsRoyal Brompton HospitalLondon, UK
2 Cardiopulmonary manifestations are serious complications of SSc Causes of death in 1012 SSc patients1Cardiopulmonary manifestations are the commonest causes of death in SSc227% of SSc-related deaths result from PAH225% of SSc-related deaths result from ILD2Other*Heart & lungLungHeart*Kidney, cancer, miscellaneous1.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 proliferation1Epithelial cells produce pro-fibrotic factors, which may initiate fibrosis2Endothelial damage has also been implicated as a possible co-factor1.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-ILDInclude dyspnoea on exertion, non-productive cough and inspiratory cracklesPrognosis linked to disease extentEarly detection important for best management
5 CT findings in SSc closely idiopathic NSIP but not IPF 1008060Ground-glass opacification (%)4020IPFSScNSIPDesai SR, et al. Radiology 2004; 232:560-7.
7 Diagnosis of SSc-ILDCT shows reticular opacities, ground-glass opacity with little honeycombingPulmonary function tests: restrictive impairment, reduced diffusing capacity for CO, arterial hypoxaemia on exerciseLung biopsy not warrantedSelman 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=47UIP n = 6“End-stage lung” n = 6RBILD n = 4Others n = 2Bouros 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 Inactivitywith Cat-like ObservationThe role of the doctor is to amuse the patient while nature takes its courseVoltaire
14 Clinical needsDecisions are dichotomous: treat or not, enrol in treatment trial or notWe need definition of high and low risk diseaseWe 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 SteenObserved progression: not quantifiedMore severe disease ………
16 The definition of “alveolitis” Traditional view that treatment applies to patients with “alveolitis”HRCT “alveolitis” has been definedBAL “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 progressDoes 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 severityGoh NS. Arthritis Rheum 2007; 56:
20 Other outcome analyses BAL neutrophil levels were not predictive of the rapidity of decline in FVC or DLcoBAL lymphocyte and eosinophil content were not linked to any measure of outcomeGoh NS. Arthritis Rheum 2007; 56:
21 A complementary statement The study of Goh: long term follow-up but uncontrolled, variable treatmentThe placebo-controlled SLS oral cyclophosphamide study: one year of follow-upBAL neutrophil content did not predict progression in the placebo armStrange 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?
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 systemAccurate depiction of high and low risk in moderately experienced handsConceptually easy
36 Disease extent determines mortality 10080604020120LimitedDuration of follow-up (months)ExtensiveSurvival (%)UKRSA stagingGoh NS. Am J Respir Crit Care Med. 2008; 177:
37 Disease extent determines rapidity of progression 20406080100120Duration of follow-up (months)Progression-free survival (%)LimitedExtensiveUK/RSA stagingGoh NS. Am J Respir Crit Care Med. 2008; 177:
38 HRCT extent Mild Disease Extensive Disease <20% Indeterminate >20%FVC >70%FVC <70%Mild DiseaseExtensive DiseaseGoh NS, et al. Am J Respir Crit Care Med Mar 27; [Epub]
40 The scleroderma lung study (SLS) Multi-centred, double-blind, randomised, placebo-controlled trialInvestigated the effects of oral cyclophosphamide on lung function and health-related symptoms in patients with active alveolitis and SSc-ILD145 patients completed at least 6 months of treatmentTashkin 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 = 73Placebo n = 72Baseline value (mean ± SE)67.6±1.368.3±1.5Value at 12 months (mean ± SE)66.6±1.765.6±1.6Difference (mean ± SE)−1.0±0.92−2.6±0.9p-valuep <0.05 after adjustment for baseline values in favour of cyclophosphamide*Primary endpointTashkin 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 azathioprineHoyles 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 diseaseTreatment effect may be understated because of selction bias in placebo-controlled studies, leading to preferential enrolment of patients with indolent diseaseKowal-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 futureAccurate identification of patients at high risk of progressive lung diseaseSafe and effective therapy for ILD