Interstitial Lung Disease -associations with autoantibodies

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 SSc is an uncommon CTD with a prevalence about 50 times less than RA Skin fibrosis is the hallmark but internal organ involvement is also common However distinct organs are involved in a particular patient Common sites of damage include the pulmonary interstitium (causing fibrosis) and the pulmonary vasculature as well as the kidneys and GI tract Often difficult to disentangle particularly breathlessness may be caused by pulmonary fibrosis or vasculature and sensitive markers such as DLCO may be affected by both Would be useful to distinguish who is at risk perhaps when treatment may be more effective One way is extent of cutaneous disease. Skin thickening proximal to the elbows defined as diffuse cutaneous rather than lcSSc. Pts with dcSSc more likely to have PF and renal crisis, lcSSc PAH but can get PF with lcSSc tooSSc is an uncommon CTD with a prevalence about 50 times less than RA Skin fibrosis is the hallmark but internal organ involvement is also common However distinct organs are involved in a particular patient Common sites of damage include the pulmonary interstitium (causing fibrosis) and the pulmonary vasculature as well as the kidneys and GI tract Often difficult to disentangle particularly breathlessness may be caused by pulmonary fibrosis or vasculature and sensitive markers such as DLCO may be affected by both Would be useful to distinguish who is at risk perhaps when treatment may be more effective One way is extent of cutaneous disease. Skin thickening proximal to the elbows defined as diffuse cutaneous rather than lcSSc. Pts with dcSSc more likely to have PF and renal crisis, lcSSc PAH but can get PF with lcSSc too

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 � 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

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 SSc is an uncommon CTD with a prevalence about 50 times less than RA Skin fibrosis is the hallmark but internal organ involvement is also common However distinct organs are involved in a particular patient Common sites of damage include the pulmonary interstitium (causing fibrosis) and the pulmonary vasculature as well as the kidneys and GI tract Often difficult to disentangle particularly breathlessness may be caused by pulmonary fibrosis or vasculature and sensitive markers such as DLCO may be affected by both Would be useful to distinguish who is at risk perhaps when treatment may be more effective One way is extent of cutaneous disease. Skin thickening proximal to the elbows defined as diffuse cutaneous rather than lcSSc. Pts with dcSSc more likely to have PF and renal crisis, lcSSc PAH but can get PF with lcSSc tooSSc is an uncommon CTD with a prevalence about 50 times less than RA Skin fibrosis is the hallmark but internal organ involvement is also common However distinct organs are involved in a particular patient Common sites of damage include the pulmonary interstitium (causing fibrosis) and the pulmonary vasculature as well as the kidneys and GI tract Often difficult to disentangle particularly breathlessness may be caused by pulmonary fibrosis or vasculature and sensitive markers such as DLCO may be affected by both Would be useful to distinguish who is at risk perhaps when treatment may be more effective One way is extent of cutaneous disease. Skin thickening proximal to the elbows defined as diffuse cutaneous rather than lcSSc. Pts with dcSSc more likely to have PF and renal crisis, lcSSc PAH but can get PF with lcSSc too

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

19. Autoantibodies � Antinuclear Antibodies Using Indirect Immunofluorescence on human cell lines, ANA are found in up to 95% of cases of SSc As early as 1980 it was realised that some patterns had clinical associations with the centromere pattern highly associated with the CREST syndrome which is now recognised as a form of lcSSc Other common patterns are of homogeneous nuclear staining and a nucleolar pattern. Despite the patterns it is not always possible to determine the underlying antigen Using Indirect Immunofluorescence on human cell lines, ANA are found in up to 95% of cases of SSc As early as 1980 it was realised that some patterns had clinical associations with the centromere pattern highly associated with the CREST syndrome which is now recognised as a form of lcSSc Other common patterns are of homogeneous nuclear staining and a nucleolar pattern. Despite the patterns it is not always possible to determine the underlying antigen

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

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

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?