1. Interstitial Lung Disease -associations with autoantibodies Dr Felix Woodhead Locum Respiratory Physician UHCW 5 October 2010

2. 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

3. Associations of ILD Inorganic dusts (pneumoconiosis) Organic dusts (Hypersensitivity Pneumonitis) Drugs Rheumatological disease Idiopathic

4. 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

5. Patient 1

6. Patient 1 – Histopathology UIP

7. 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

8. Patient 2

9. Patient 1

10. Patient 2 – Respiratory Bronchiolitis

11. 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

12. 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

13. 2002 ATS/ERS guidelines for Idiopathic Interstitial Pneumonia Am J Respir Crit Care Med 2002Nicholson et al Am J Respir Crit Care Med 2000

14. Patient 3

15. 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

16. 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

17. 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

18. Am J Respir Crit Care Med 2008

19. 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

20. 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

21. 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

22. 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

23. ImmunoblottingImmunoprecipitation 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

24. Radiolabelled protein immunoprecipitation patterns

25. RNA immunoprecipitation

26. 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

27. 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’

28. 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

29. Autoantibodies can predict likelihood of Intersitial Pneumonia in SSc Median % 13 0 0 7 p<0.0001

30. 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

31. Is it important? CTD-associated ILD has better outcome Immunosuppressants ?Lesson from rheumatologists about ‘early synovitis’

32. 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

33. Questions?