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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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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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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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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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BronchiolitisBronchiolitis

BronchiectasisBronchiectasis

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 ++ ± ++ ±

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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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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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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9999

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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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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

Scleroderma

CREST(Anti-Centromer+)

PSS(Scl 70+)

Pulmonary hypertension

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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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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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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

Systemic sclerosisSystemic sclerosis

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Systemic SclerosisSystemic Sclerosis

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Systemic SclerosisSystemic Sclerosis

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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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Scl-70-positive Systemic Sclerosis

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Thoracoscopic biopsy revealed fibrotic NSIP in PSS

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Seropositive Rheumatoid Arthritis

IPF/UIP

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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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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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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

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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Wells A, et al.AJRCCM,1994

Survival – IPF vs ILD in PSS

FASSc

CFA

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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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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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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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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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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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Comparison of survival between CVD associated UIP and NSIP

p=0.386

Nakamura Y et al. Sarcoidosis Vasc Diffuse Lung Dis 2003

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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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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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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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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Fibroblastic foci score for each lobe: idiopathic UIP vs CVD-associated UIP (p=0.003)

Flaherty, et al. AJRCCM 2003

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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

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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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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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

Organizing Pneumonia, Survival Organizing Pneumonia, Survival (n=74)(n=74)

Organizing Pneumonia, Survival Organizing Pneumonia, Survival (n=74)(n=74)

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BAL in Progressive Systemic Sclerosis

Schwarz / King: Interstitial Lung Disease,2004

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Percentage lymphocyte counts in NSIP of PSS

cellular vs fibrotic: p=0.007

Bouros, et al. AJRCCM 2002

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ground-glass mixed reticular

BAL neutrophil percentages in relation to CT appearance in PSS

Wells A, et al.AJRCCM,1994

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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

Changes of PFT in scleroderma

White B, et al. Ann Intern Med, 2000

Cyclophosphamide

Cyclophosphamide

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Survival in patients with scleroderma and alveolitis

cyclophosphamide

untreated

White B, et al. Ann Intern Med, 2000

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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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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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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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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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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)

Ayathioprine in systemic sclerosisAyathioprine in systemic sclerosis12 months12 months

Dheda et al. 2004

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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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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

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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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

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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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)

Tashkin et al. NEJM. 2006

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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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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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Ruhrlandklinik