Interstitial Lung Disease-associations with autoantibodiesDr Felix WoodheadLocum Respiratory Physician UHCW5 October 2010

History of Fibrosing Alveolitis

• Corrigan 1838: “on cirrhosis of the lung”

• Hamman-Rich syndrome 1935

• Scadding 1964 – Fibrosing alveolitis

• Idiopathic pulmonary fibrosis in USA

• Averrill Liebow – pathology 1950s

Associations of ILD

• Inorganic dusts (pneumoconiosis)

• Organic dusts (Hypersensitivity Pneumonitis)

• Drugs

• Rheumatological disease

• Idiopathic

Cryptogenic Fibrosing Alveolitis

• Bibasal Crackles

• Restrictive Spirometry or isolated low TLco

• Basally-predominant fibrosis on CXR

• Absence of pneumoconiosis, EAA or known connective tissue disease– RA, SLE

– SSc, PM/DM

Patient 1

Patient 1 – Histopathology UIP

Patient 1 –Idiopathic Pulmonary Fibrosis (IPF)• Not interchangeable term for Idiopathic Interstitial Pneumonia

• ?most common IIP

• Relatively poor prognosis

• Median survival 2 ½ years

• Histology

– Usual Interstitial Pneumonitis (UIP) when biopsied

– Temporal and Spatial heterogeneity, not uniform

• Radiology

– Typical features: basal, peripheral honeycombing, little ground glass

– May have any appearance

– Typical features – don’t need to biopsy, atypical – biopsy helpful

Patient 2

Patient 1

Patient 2 – Respiratory Bronchiolitis

Smoking-related IIP• Respiratory Bronchiolitis

– Histological appearance in ‘healthy smokers’

– Pigmented macrophages in terminal bronchioles

– Clinical condition RB associated ILD (RBILD)

– RBILD radiology similar to Hypersensitivity Pneumonitis (EAA)

– BAL not lymphocytic

• DIP– ‘Desquamative’ due to erroneous belief cells shed into alveoli

– Diffuse collection of pigmented macrophages throughout alveoli

– Radiologically typified by diffuse GGO

• ?smoking related NSIP, Fibrosis and emphysema

The _IPs: Interstitial Pneumonias

• UIP – Usual, the most common, IPF

• NSIP – non-specific

• AIP – acute, Hamman-Rich, ARDS

• DIP – desquamative, ↑macrophages, smoking (RBILD – respiratory bronchiolitis – associated ILD)

• LIP – lymphocytic, HIV and connective tissue disease

2002 ATS/ERS guidelines for Idiopathic Interstitial Pneumonia

Am J Respir Crit Care Med 2002 Nicholson et al Am J Respir Crit Care Med 2000

Patient 3

Cryptogenic Fibrosing Alveolitis

• Bibasal Crackles

• Restrictive Spirometry or isolated low TLco

• Basally-predominant fibrosis on CXR

• Absence of pneumoconiosis, EAA or known connective tissue disease– RA, SLE

– SSc, PM/DM

Systemic Sclerosis

• Scleroderma – skin thickening above MCPs

• Sclerodactyly – skin thickening of fingers

• Digital pitting scars

• Bibasal pulmonary fibrosis

• Major criterion or two or more minor criteria

• Limited cutaneous (lcSSc) vs diffuse cutaneous (dcSSc)

• lcSSc ‘CREST’ syndrome

Interstitial Pneumonia in Systemic Sclerosis

• >50% patients ↓(TLco) in early studies

– Manoussakis et al. Chest 1987

– Steen et al. Arthritis Rheum 1985

• Since Rx for renal crisis, lung disease leading cause of death

– Ferri et al Medicine (Baltimore) 2002

– Scussel-Lonzetti et al Medicine (Baltimore) 2002

– Simeon et al Rheumatology.(Oxford) 2003

• More common in dcSSc

• FA-SSc thought to be indistinguishable from CFA

– Harrison et al. Am Rev Resp Dis 1991

• SSc ILD has a better prognosis than CFA

– Wells et al. AJRCCM 1994

Am J Respir Crit Care Med 2008

Autoantibodies – Antinuclear Antibodies

Centromeric Homogeneous Nucleolar• Diversity of antinuclear antibodies in progressive systemic sclerosis. Anti-centromere

antibody and its relationship to CREST syndrome

– Tan et al. Arthritis Rheum 1980

• 95% SSc Ho & Reveille Arthritis Research & Therapy 2003

• Auto antibodies– Anticentromere

– Anti-topoisomerase 1 (Scl-70)

– Anti RNA polymerase I & III

Anticentromere Antibodies

• Associated with CREST – Tan et al Arthritis Rheum 1980

– Riboldi et al Clinical and Experimental Rheumatology 1985

• Less likely than ACA neg to have pulmonary fibrosis– Steen et al Arthritis Rheum 1988

– Kane et al Respiratory Medicine 1996

• Defined by IIF pattern

• Antigen not soluble

• 6 defined antigens

• ELISA available but not widely used

Anti-topoisomerase 1 antibodies

• 2/3 ATA dcSSc– Steen et al Arthritis Rheum 1988

• Associated with pulmonary fibrosis– Cassani et al Clin Exp Rheumatol 1987

– Manoussakis et al Chest 1987

– Steen et al Arthritis Rheum 1988

Antibody characterisation

• IIF pattern Anticentromere (ACA)

• ENA Anti-topoisomerase 1(ATA)– Double immunodiffusion (Ouchterlony)

– Counterimmunoelectrophoresis (CIE)

• ELISA Anti-RNA polymerase I&III (ARA)

• Immunoblot

• Radiolabelled protein / RNA immunoprecipitation Th/To,others

Immunoblotting Immunoprecipitation

Cell lysate (radiolabelled) Cell lysate

SDS protein acrylamide gel electrophoresis

Separated denatured proteins

Precipitation of soluble antigens by

patient serum

Probing of denatured antigens by patient

serum

Precipitated native proteins

SDS protein acrylamide gel electrophoresis

Detection of antibodies with anti-human antibodies

Detection of antigens by autoradiography

Radiolabelled protein immunoprecipitation patterns

RNA immunoprecipitation

Autoantibodies in Systemic Sclerosis

• Anti-centromere: lcSSc and pulmonary hypertension

• Anti-topoisomerase 1: dcSSc and interstitial pneumonia

• Anti-RNA polymerase I & III: dcSSc, renal crisis, ‘watermelon stomach’

• Anti-PMScl: scleroderma/polymyositis overlap

• Th/To: ‘scleroderma sine scleroderma’

• Anti-U3 RNP: dcSSc, African American ethnicity

• Other SSc-associated AAs: U1-RNP, Ro, La etc

Polymyositis/Dermatomyositis

• Symmetrical proximal muscle weakness

• Elevated serum muscle enzymes

• EMG changes

• Abnormal muscle biopsy

• ± skin rash (Heliotrope rash, Gottron rash)

• 4 criteria ‘definite’, 3 ‘probable’, 2 ‘possible’

Autoantibodies in Idiopathic Inflammatory Myopathies – PM/DM

• Jo-1: histidyl tRNA synthetase– 6 other tRNA synthetase antibodies

– Anti-synthetase syndrome 20% IIM

– High incidence interstitial pneumonia,

– Arthritis, Raynaud’s, ‘mechanic’s hands’

• Mi-2: 5% IIM, predominantly DM, negative assoc IP

• Anti-Signal recognition particle: bad myopathy

• ‘Clinically amyopathic dermatomyositis’- CADM

Autoantibodies can predict likelihood of Intersitial Pneumonia in SSc

Median % 13 0 0 7

p<0.0001

ATA ARA ACA Other0

10

20

30

40

50

60

70

80

90E

xten

t (%

)

Are Autoantibodies useful in Idiopathic Disease?

• Useful in phenotyping connective tissue disease

• ANAs occur in 37% ‘CFA’ (Turner-Warwick)

• 22% my studied patients

• CTD – associated AAs found in IPF cohorts

• CTD-like symptoms common in idiopathic patients, biopsies NSIP > UIP

Is it important?

• CTD-associated ILD has better outcome

• Immunosuppressants

• ?Lesson from rheumatologists about ‘early synovitis’

Coventry and Warwickshire ILD service

• Established by David Parr/Christine O’Brien

• Monthly multidisciplinary meeting

• Thoracic surgeon present

• Future developments– Bronchoalveolar lavage

– Antinuclear antibody testing

– Research/Trials

– Specialist nurse

Questions?