41942.ppt
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1-90 1
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Manifestation of Systemic Diseases in Manifestation of Systemic Diseases in the Lung:the Lung:
Connective Tissue Diseases Connective Tissue Diseases
Ulrich CostabelAbt. Pneumologie/Allergologie
RuhrlandklinikEssen
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INT005-SlideKit
PPulmonary manifestations ulmonary manifestations in rheumatological disordersin rheumatological disorders
• Frequency of detection depends on the applied investigative technique
• Involvement of various anatomic compartments - airways, alveoli, vessels, pleura, diaphragm
• Different histopathologic variants of diffuse parenchymal lung disease vary in frequency, UIP, NSIP, BOOP, AIP etc
• “Rheumatoid lung” is not a precise diagnosis
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INT005-SlideKit
Pulmonary manifestations Pulmonary manifestations in collagen vascular disordersin collagen vascular disorders
Total Main manifestation frequency
Rheumat. Arthritis 50% Bronchiectasis (25%)
System. Sclerosis 90% ILD (NSIP) (20%)
SLE 70% Pleuritis (50%)
Polymyositis 10-45% ILD (NSIP/UIP) (45%)
Sjögren‘s 50-75% Xerotrachea (40%)Syndrome
Sharp Syndrome 40-80% ILD (UIP), Pulm. Hypert.
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INT005-SlideKit
Collagen vascular disease:Collagen vascular disease: diagnostic proceduresdiagnostic procedures
History, clinic, chest radiograph, lung function, serology
Diffuse ILD
HRCTBAL
Echocardiogram
Airways Dis.
HRCT
Pulm. Vasc. Disease
EchocardiogramRight heart catheter
HRCTBAL
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INT005-SlideKit
BronchiolitisBronchiolitis
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BronchiectasisBronchiectasis
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Airway disorders in rheumatological diseaseAirway disorders in rheumatological disease
Rheumatoid Syst. Dermato-/ Sjögren´s arthritis L.E. Polymyositis Syndrome
Bronchitis ++ +
Bronchiectasis ++ ±
Follicular bronchiolitis ± ±
Oblit. bronchiolitis + ± ± BOOP ++ ± ++ ±
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Airway disorders in inflammatory bowel diseaseAirway disorders in inflammatory bowel disease
Ulcerative colitis Crohn‘s disease
Tracheobronchial stenoses ± ±
Chronic bronchitis ++ ++
Chronic bronchial suppuration ++ ++
Bronchiectasis ++ ++
Diffuse panbronchiolitis ± 0
BOOP + +
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INT005-SlideKit
ILD in collagen-vascular diseaseILD in collagen-vascular disease
Common problems• Improved management of systemic disease leads
to increased significance of pulmonary fibrosis.
• Difficult challenge for chest physician - multiorgan diseases.
• High frequency of subclinical involvement -how to deal with?
• Often admixed with other pulmonary pathology (non-ILD).
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INT005-SlideKit
Collagen vascular diseaseCollagen vascular disease- other thoracic involvement- other thoracic involvement
• Pleura RA +++ SLE +++ SS ± PSS ±
• Pulmonary hypertension
PSS +++ SLE +++ PM/DM ± SS ± RA ±
• Respiratory muscle weakness
PM/DM ++ SLE ++ PSS ±
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INT005-SlideKit
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9999
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INT005-SlideKit
Progressive Systemic SclerosisProgressive Systemic Sclerosis
• Multisystem autoimmune disease with life- threatening pulmonary complications
• Wide spectrum of pleuropulmonary involvement: - interstitial lung disease (ILD) - vascular disease - pleural disease - airways disease
• ILD and pulmonary hypertension most common causes of death
• Incidence 1.0-2.0 per 100,000 female/male: 4/1 age peak 30~50 yr
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INT005-SlideKit
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Autoantibodies in PSSAutoantibodies in PSS
Autoantibody Comments
Anticentromere20-40% total systemic sclerosis, wide racial variation, 70-80% limited cutaneous variant with pulmonary hypertension (CREST-syndrome)
Scl-70 28-70% total systemic sclerosis, wide racial variation, >30% diffuse cutaneous disease with interstitial lung disease
PM-Scl
Antinucleolar
Ku
Scleroderma-myositis overlap syndromes
8-20% systemic sclerosis, suggests poorest 10-year survival, renal crisis
Scleroderma-myositis overlap syndromes
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Scleroderma
CREST(Anti-Centromer+)
PSS(Scl 70+)
Pulmonary hypertension
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INT005-SlideKit
Pleuropulmonary involvement in PSSPleuropulmonary involvement in PSS
• Diffuse ILD 40-90%
• Organizing pneumonia (BOOP) rare
• Pulmonay hypertension 40%
• Isolated pulmonary hypertension 20%
• Pleuritis 8%
• Aspiration pneumonia
• Alveolar haemorrhage rare
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INT005-SlideKit
Prevalence of ILD in PSSPrevalence of ILD in PSS
• Restrictive lung function 40%
• Reduced diffusing capacity DLCO 90%
• Plain chest x-ray 40%
• HR-CT 80~90%
• Autopsy 80%
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INT005-SlideKit
Clinical manifestations of ILD in PSSClinical manifestations of ILD in PSS
• Symptoms (dyspnea and cough) and signs (crackles) not different from other forms of diffuse ILD
• Dyspnea may be denied due to limitation of physical activity
• Clubbing uncommon• ILD becomes more frequent with extensive skin
involvement• ILD may precede other manifestations
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Systemic sclerosisSystemic sclerosis
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INT005-SlideKit
Systemic SclerosisSystemic Sclerosis
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INT005-SlideKit
Systemic SclerosisSystemic Sclerosis
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INT005-SlideKit
CT findings in ILD of PSSCT findings in ILD of PSS(n = 40)(n = 40)
• Ground glass 100 %• Irregular linear (reticular) 90 %• Small nodules 70 %• Honeycombing 33 %• Traction bronchiectasis 68 %• Bilateral pleural thickening 45 %
(Kim EA et al, J Comp Assist Tomogr 2001)
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INT005-SlideKit
Scl-70-positive Systemic Sclerosis
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INT005-SlideKit
Thoracoscopic biopsy revealed fibrotic NSIP in PSS
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INT005-SlideKit
Seropositive Rheumatoid Arthritis
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IPF/UIP
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INT005-SlideKit
CT in PSS compared with IPF and idiop. NSIPCT in PSS compared with IPF and idiop. NSIP(Desai et al. Radiology 2004)(Desai et al. Radiology 2004)
• Coarseness of reticular pattern: similar in PSS and idiop. NSIP, but higher in IPF (median scores: PSS 5.5; IPF 8.8)
• Ground glass proportion: similar in PSS and idiop. NSIP, but less in IPF (median: PSS 50 %, IPF 24 %)
• Conclusion: CT in PSS closely resembles idiop. NSIP, and differs from IPF (less extensive, less coarse fibrosis, more ground glass
in PSS)
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INT005-SlideKit
ILD in Rheumatoid ArthritisILD in Rheumatoid Arthritis
Disease prevalence
• In clinical studies 1-5%
• In HRCT studies 20%
Dawson et al. Thorax 2001
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INT005-SlideKit
ILD on HRCT in Rheumatoid ArthritisILD on HRCT in Rheumatoid Arthritis
• 150 consecutive patients irrespective of the presence or absence of chest disease.
• 28 (19%) had ILD on HRCT, 12 (43%) of this group had also emphysematous changes
• Of the 28 patients with ILD: - 82% had reduced DLco - 54% had bilateral crackles - 14% had restriction - 14% had ILD on chest X-ray Dawson, Thorax. 2001
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CT Findings in RA-related Lung DiseasesCT Findings in RA-related Lung Diseases
Four major CT patterns were identified in 63 Patients
• UIP (n= 26)• NSIP (n= 19)• Bronchiolitis (n= 11)• Organizing pneumonia (n= 5)
• DAD (n= 1)• LIP (n= 1)
Dawson, Thorax 2001
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INT005-SlideKit
Wells A, et al.AJRCCM,1994
Survival – IPF vs ILD in PSS
FASSc
CFA
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INT005-SlideKit
Histopathologic patterns of ILD in PSSHistopathologic patterns of ILD in PSS
• NSIP predominant: 78 % (Bouros 2002) (NSIP: n=62) 68 % (Kim DS 2002)
• UIP uncommon: 8 % (Bouros 2002) (UIP: n=6) 26 % (Kim DS 2002)
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INT005-SlideKit
Survival compared between NSIP and UIP/ESL in PSS
Bouros, et al. AJRCCM 2002
NSIP vs UIP/ESL: p>0.05
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INT005-SlideKit
Prognostic FactorsPrognostic Factors
Poorer survival predicted by
• Lower baseline DLCO
• Increased eosinophil count on BAL
• Deterioration in DLCO during 3 yrs of follow-up
Bouros AJRCCM 2002
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INT005-SlideKit
Survival in NSIP of PSS with or without increased BAL percentage eosinophil counts
Bouros, et al. AJRCCM 2002
(n=21)
(n=36)
p=0.03
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INT005-SlideKit
Changes in DLCO at 3 years are predictive of survival (p<0.01)
Bouros, et al. AJRCCM 2002
(n=36)
(n=12)
(n=12)
(n=25)(n=8)
DLCO + :15% change
+/-: marginal
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INT005-SlideKit
Comparison of survival between CVD associated UIP and NSIP
p=0.386
Nakamura Y et al. Sarcoidosis Vasc Diffuse Lung Dis 2003
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Comparison of survival between Comparison of survival between CVD-associated and idiopathic ILD CVD-associated and idiopathic ILD
when classified according to when classified according to histologic patternshistologic patterns
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INT005-SlideKit
Comparison of survival between idiopathic NSIP vs CVD associated NSIP
Nakamura Y et al. Sarcoidosis Vasc Diffuse Lung Dis 2003
p=0.553
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INT005-SlideKit
Comparison of survival between idiopathic UIP vs CVD associated UIP
Nakamura Y et al. Sarcoidosis Vasc Diffuse Lung Dis 2003
UIP-CVD
p=0.028
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INT005-SlideKit
Survival probability CVD-associated UIP vs idiopathic UIP (p=0.005)
Flaherty, et al. AJRCCM 2003
CVD-associated UIP (n=9)
Idiopathic UIP (n=99)
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INT005-SlideKit
Fibroblastic foci score for each lobe: idiopathic UIP vs CVD-associated UIP (p=0.003)
Flaherty, et al. AJRCCM 2003
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INT005-SlideKit
Histopathological Subsets in RA-Histopathological Subsets in RA-associated Lung Diseaseassociated Lung Disease
• Retrospective review of 18 patients with RA who underwent SLB for suspected ILD from Korea
• 10 UIP, 6 NSIP, 2 OP
• RA preceded ILD in 12 patients; concomitant Dx in 3 patients, ILD preceded RA in 3 patients.
• Histo UIP showed CT features of UIP except in one
• 5/10 UIP, but 0/6 NSIP died during follow-up of 4.2 yr and 3.7 yr Lee et al. Chest 2005; 127: 2019
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Histopathologic Patterns in ILD of Histopathologic Patterns in ILD of PolymyositisPolymyositis
NSIP (n=7)
UIP (n=3)
DAD (n=3)
Fujisawa et al. J Rheumatol 2005; 32:58
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INT005-SlideKit
Organizing PneumoniaOrganizing PneumoniaCryptogenic vs secondary variantsCryptogenic vs secondary variants
• Cryptogenic: 37 patients
• Secondary: 27 patients
- CVD 10 patients - malignancy 9 patients - drug 8 patients
• Focal: 10 patients
Lohr et al. 1997
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INT005-SlideKit
Organizing PneumoniaOrganizing PneumoniaCryptogenic vs secondary variantsCryptogenic vs secondary variants
• No difference between cryptogenic and secondary OP
- type or severity of symptoms
- signs
- laboratory
- PFT
- radiology
- pathology Lohr et al. 1997
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Organizing Pneumonia, Survival Organizing Pneumonia, Survival (n=74)(n=74)
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Organizing Pneumonia, Survival Organizing Pneumonia, Survival (n=74)(n=74)
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INT005-SlideKit
BAL in Progressive Systemic Sclerosis
Schwarz / King: Interstitial Lung Disease,2004
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INT005-SlideKit
Percentage lymphocyte counts in NSIP of PSS
cellular vs fibrotic: p=0.007
Bouros, et al. AJRCCM 2002
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INT005-SlideKit
ground-glass mixed reticular
BAL neutrophil percentages in relation to CT appearance in PSS
Wells A, et al.AJRCCM,1994
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INT005-SlideKit
BAL neutrophil percentages in relation to extent of CT involvement in PSS
Wells A, et al.AJRCCM,1994
0 <50% >50%
0 vs <50%: p<0.001
0 vs >50%: p<0.001
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Changes of PFT in scleroderma
White B, et al. Ann Intern Med, 2000
Cyclophosphamide
Cyclophosphamide
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INT005-SlideKit
Survival in patients with scleroderma and alveolitis
cyclophosphamide
untreated
White B, et al. Ann Intern Med, 2000
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INT005-SlideKit
BAL findings and disease progressionBAL findings and disease progression
• BAL lymphocytosis is found in patients without clinical or radiol. disease (subclinical alveolitis): no predictor for development of fibrosis
• BAL neutrophilia is associated with subsequent deterioration in PFT and DLCO (Silver 1984, Behr 1996 Witt 1999, White 2000)
• However, BAL neutrophilia is strongly linked with extensive fibrosis on CT (Wells 1994)
• Unclear: does BAL neutrophilia predict progress independently of the extent of fibrosis on CT?
• Moreover: a subgroup of patients with normal BAL deteriorates (10 – 20 %)
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INT005-SlideKit
BAL for monitoring ILD in PSS?BAL for monitoring ILD in PSS?-- a controversial issue-- a controversial issue
• T.E. King (Textbook of 2003): „BAL analysis appears to be one of the best
methods available for monitoring the pulmonary disease“
• A.U. Wells and R. du Bois (Textbook of 2004): „It would appear that BAL alone does not have a
major prognostic role and has no established place in the monitoring of disease“
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INT005-SlideKit
PrognosisPrognosis
• Prognosis of diffuse ILD in PSS is better than in IPF
• moderate restriction (FVC > 50%): 10 yr survival 70-75%
• severe restriction (FVC < 50%): 10 yr survival 55-60%
(Wells 1994)
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INT005-SlideKit
Isolated restrictive ventilatory defect (RVD)
Isolated pulmonary hypertension(PHTN)
Chang B, et al. J Rheumatol,2003
Retrospective cross-sectional study 619 scleroderma patients
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INT005-SlideKit
TreatmentTreatment
• Current treatment mainly based on uncontrolled and retrospective studies
• Common regimen: prednisone with an immunosuppressant
• Most data available for cyclophosphamide, usually orally (max. 150mg/day)
• Cyclophosphamide i.v. pulse therapy every 4 wk superior? – Unclear.
• Azathioprine may be as effective but no formal comparisons have been made
(Silver 1990, Steen 1994, White 2000)
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Ayathioprine in systemic sclerosisAyathioprine in systemic sclerosis12 months12 months
Dheda et al. 2004
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INT005-SlideKit
Mycophenolate Mofetil (MMF) for CTD-ILDMycophenolate Mofetil (MMF) for CTD-ILD
• Retrospective observational study from Denver
• 28 pt treated with MMF over 35.9 patient-years: scleroderma n=9, PM/DM n=5, Sjögren n=4
• Prednisone reduction from 15 to 10 mg (p=0.09)
• FVC %pred increased by 2.3%, DLCO by 2.6%
Swigris et al, Chest 2006;130:30
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INT005-SlideKit
Clinical trials in ILD of PSSClinical trials in ILD of PSS
• Placebo-controlled oral cyclophosphamide (USA): positive
• Placebo-controlled i.v. cyclophosphamide (UK)
• Bosentan (endothelin-receptor antagonist) for antifibrotic efficacy (BUILD 2 trial): negative
• Anti-TGFß trial
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Cyclophosphamide versus Placebo Cyclophosphamide versus Placebo
in Scleroderma Lung Diseasein Scleroderma Lung Disease
D.P. Tashkin et al. for the Scleroderma Lung Study Research Group
New Engl J Med 2006; 354: 2655-66
Sponsor: NIH
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INT005-SlideKit
Study Design Scleroderma Lung StudyStudy Design Scleroderma Lung Study
• Randomized, double-blind, placebo-controlled, 13 centers in the US.
• 158 patients enrolled - randomized to cyclophosphamide (2mg/kg/day) or placebo - primary endpoint: FVC % pred at 12 mo.
• Patient eligibility - active alveolitis (on BAL or HRCT) - restriction (FVC 45-85%) - grade 2 exertional dyspnea on Mahler dyspnea index
• Exclusion - DLCO < 30% pred - smokers - clinically significant pulmonary hypertension
Tashkin et al. NEJM. 2006
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Results Scleroderma Lung StudyResults Scleroderma Lung Study
Baseline 12 mo. DifferenceCyclophosph
FVC (%pred) 67.6+1.3 66.6+1.7 -1.0+0.92 TLC (%pred) 70.4+2.1 70.5+1.8 -0.3+1.82
Placebo
FVC (%pred) 68.3+1.5 65.6+1.6 -2.6+0.9 TLC (%pred) 67.9+1.9 64.7+1.9 -2.8+1.2
The adjusted mean absolute difference in FVC at 12 mo. was 2.52 (0.28-4.79)% in favor of cyclophosphamide (p<0.03)
Tashkin et al. NEJM. 2006
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INT005-SlideKit
Results (continued)Results (continued)
• Significant effect also on several secondary endpoints:
- Transitional dyspnea index,
- HAQ disability score,
- 2 domains of SF-36 QOL,
- Skin thickness score.
• Drop-out rate at 12 months was 30% (similar to IFIGENIA study)
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Tashkin et al. NEJM. 2006
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INT005-SlideKit
LessonsLessons
• Rate of decline in FVC%pred is different - 2.6% per year in Scleroderma ILD - 5.0% per year in IPF (in IFIGENIA)
• Drop-out rates are high in any ILD treatment trial:
- ~30% per year
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INT005-SlideKit
Interstitial Interstitial lung diseaselung disease in CVD in CVD
• Marker-antibody in PSS: Anti-Scl-70 in >30%• Dominant pattern NSIP (exception RA), LIP very rare (even in
Sjögren Syndrome)
• Course variable, prognosis better than in IPF
• 10-yr-survival PSS: 70-75% with mild restriction 55-60% with severe (VC<50%)
• Treatment indicated, if impairment/deterioration of lung function: Prednisone/cyclophosphamide standard tx; for
azathioprine no formal comparisons
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INT005-SlideKit
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Ruhrlandklinik