Presentation on theme: "Interstitial lung disease in systemic sclerosis"— Presentation transcript:
1Interstitial lung disease in systemic sclerosis Athol WellsRoyal Brompton HospitalLondon, UK
2Cardiopulmonary 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.
3Underlying 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:
4Symptoms of SSc-ILDInclude dyspnoea on exertion, non-productive cough and inspiratory cracklesPrognosis linked to disease extentEarly detection important for best management
5CT findings in SSc closely idiopathic NSIP but not IPF 1008060Ground-glass opacification (%)4020IPFSScNSIPDesai SR, et al. Radiology 2004; 232:560-7.
7Diagnosis 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:
8Biopsy 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
9Bouros D et al. Am J Respir Crit Care Med 2002;165:1581-6
10The 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.
11Sometimes 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
14Clinical 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
15Who should be treated?Shorter duration of systemic disease: studies of SteenObserved progression: not quantifiedMore severe disease ………
16The 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
18The 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?
19Neutrophilia 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:
20Other 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:
21A 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
22In both the Goh and the Strange studies, BAL neutrophil content correlated with disease extent on HRCT This fits nicely with old data
23Wells A. Am J Respir Crit Care Med 1994; 150:462-468
24BAL neutrophil content largely reflects severity It does not reliably separate SSc patients into high and low risk groups Other CTDs less studied
25Alveolitis on HRCT The problem of ground-glass ….
26This is the archetypal SSc HRCT Lots of ground-glass … but only 15% of SSc patients have reversible histology
27When is ground-glass less likely to be inflammatory?
40The 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:
41The 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:
42Limited 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:
43Cyclophosphamide 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
44For the futureAccurate identification of patients at high risk of progressive lung diseaseSafe and effective therapy for ILD