Interstitial Lung Disease (ILD) Diagnostic Insights Offered by CTD Serology

Transcription

1 Interstitial Lung Disease (ILD) Diagnostic Insights Offered by CTD Serology Robert G Cooper Prof of Medicine (Muscle and Rheumatology)

2 Normal Alveolar Physiology

3 Contrast with ILD Pathologies Impairing Gas Transfer Parenchymal Inflammation (+/- PF) Parenchymal Fibrosis (+/- inflammation)

4 Background ILD is a heterogeneous spectrum, causing progressive dyspnoea with lethal outcomes from respiratory failure or its cardiac complications. Treatment outcomes variable, and dependant on ILD subgroup phenotype. Problem Differentiating between ILD subgroups can be considerably problematic.

5 The ILD Spectrum Groups Idiopathic (IIP) Granulomatous CTD-ILD Environmental or medicinal exposures Rare causes Idiopathic Pulmonary Fibrosis (IPF), or Usual Interstitial Pneumonia (UIP) Nonspecific Interstitial Pneumonia (NSIP) Cryptogenic Organising Pneumonia (COP) Sarcoidosis Hypersensitivity pneumonitis Rh Arthritis (UIP and non-uip) Systemic sclerosis Myositis spectrum Sjogren s Syndrome Mixed CTD Asbestos Silica Other dusts Nitrofurantoin Bleomycin Vasculitis Langerhans cell histiocytosis Eosinophilic pneumonia Acute Interstitial Pneumonia (AIP) Subgroups Undifferentiated CTD Subgroups Respiratory-bronchiolitisassociated interstitial lung disease (RB-ILD) Desquamative Interstitial Pneumonia (DIP) Lymphoid Interstitial Pneumonia (LIP) A Classification of the ILD Spectrum Adapted from Ryerson CJ, Collard HR. Update on the diagnosis and classification of ILD. Curr Opin Pulm Med 2013; 19:

6 ATS/ERS Classification Guidelines for ILD Subgroup diagnosis made according to occupational and clinical histories and a thorough clinical examination, in combination with routine serology and an HRCT. An idiopathic subgroup diagnosis can only be assigned if other diagnoses have been definitively excluded, but these guidelines did not dictate stringency of serology. Most chest clinics likely only test for RF, CCP and ANA, +/- ENAs Reliable, ILD-specific biomarkers are lacking, representing a major diagnostic issue. American Thoracic Society/European Respiratory Society International Multidisciplinary Consensus Classification of the Idiopathic Interstitial Pneumonias. Am J Respir Crit Care Med 2002; 165(2):

7 ILD Diagnostic Issues Diagnosis easy if a CTD clinically obvious (e.g erosive RA or overt SSc), or an environmental trigger easily identified (e.g silica exposure in a stone mason). But, environmental triggers may be missing and clinical signs absent or very subtle. If history, examination and routine serology give no clue as to the actual diagnosis, this is of necessity assigned radiologically, i.e by HRCT - idiopathic UIP, idiopathic NSIP, idiopathic COP etc.

8 Peripheral reticular changes IPF UIP or Probable UIP Non-Responsive to Immunosuppression

9 CTD-ILD - Ground Glass Changes Responsive to Immunosuppression (not always) Ground glass changes

10 HRCT as Predictor of ILD Mortality IPF vs CTD-ILD Park JH et al. Prognosis of fibrotic interstitial pneumonia: idiopathic versus collagen vascular disease-related subtypes. Am J Respir Crit Care Med 2007; 175(7):

11 HRCT-Specific Problems When history is non diagnostic, CTD signs absent and serology unhelpful, HRCT use can still be problematic: - HRCT images not necessarily ILD subgroup-specific. - HRCT images may vary within ILD subgroups. - Between-assessor variability of image reporting, so MDTs of great importance.

12 Idiopathic Pulmonary Fibrosis (IPF) Fatal in ~ 50% of cases within only 3-4 years. Aggressive corticosteroid immunosuppression is ineffective, and now proven as harmful, so now contra-indicated. Pirfenidone and nintedanib do slow IPF progression, but these drugs are very expensive, so can only be used in tertiary referral ILD clinics, e.g Aintree (Merseyside - NW Coast), Wythenshawe (Gt Manchester) etc.

13 CTD ILD Generally comprise an inflammatory component (i.e ground glass changes) so usually responsive to steroids +/- DMARDS, at least in part. Once Rx initiated, PFTs usually stabilise, though not always. Role of Rituximab unclear. Role of anti-fibrotic drugs also unclear, but trials ongoing or planned in RA-ILD and SSc-ILD.

14 Diagnostic Accuracy Issues Between-subgroup treatment response differences mean that making an accurate diagnosis is crucial in every case, to ensure accurate delivery of either targeted immuno-suppression or targeted fibroinhibition. Lack of reliable, ILD-specific, diagnostic biomarkers means that potentially dangerous diagnostic lung biopsies are still necessary.

15 Therapeutic Difficulties Arising Due to The Lack of ILD- Specific Biomarkers Covert CTD-ILD or IIP? IIP or covert CTD-ILD?

16 How can rheumatology help?

17 Polymyositis Dermatomyositis 1999 Idiopathic Inflammatory Myopathies (IIM) Malignancy Myositis-CTD overlap Juvenile Dermatomyositis

18 Idiopathic Inflammatory Myopathies (IIM) Background in 1999 Myositis is an acquired inflammatory cell infiltration in skeletal muscle, causing myalgia, fatigue and weakness, and thus disability (usually chronic). Death directly due to IIM (i.e ventilatory failure) is rare. Infiltrations with variable numbers of CD8+ and CD4+ T-cells, with some B-cells and fewer macrophages. Multi-system inflammation, and potentially affecting: muscle +/- lungs +/- skin +/- joints Causative mechanisms remains poorly understood, so mechanistic research is still vital.

19 Mechanistic Issues in IIM in 1999 Disease Causation: Genes vs Environment HLA-DRB1*03 (DR3)? Viruses

20 Roles of HLA and cytotoxic T-cells in IIM Klein J & Sato A. N Eng J Med. 2000, 343:702-9 Cytotoxic T-cells cause muscle cell damage and weakness

21 Clinical Difficulties with IIM Many IIM mimics, so only too easy to misdiagnose other myo-pathologies as idiopathic inflammatory myositis. Treatment responses variable, but usually incomplete, so most patients (~75%) never regain normal strength or function. Most UK rheumatologists will only see 8-10 IIM cases in a whole career, so mechanistic research had been very difficult to undertake. So, action needed!!

22 UK Adult Onset Myositis Immunogenetic Collaboration (AOMIC) - Set up by RGC/WERO 2000

23 AOMIC - UKMYONET (RGC/WERO/HC/JL) Case Recruitment Caucasians/Non-Caucasians - Phenotype details, serum and DNA - Myositis probable/definite according to Bohan & Peter Controls (n=537) PM/DM/OL (n >1750) IBM (n >230) JDM* (n >350) *(JDRG collaboration LW/CP)

24 Aims of AOMIC - UKMYONET Immediate - To recruit ethnically homogeneous myositis subgroup cohorts of sufficient size to enable statistically meaningful between-subgroup genetic and serological comparisons. Longer-term - To elucidate disease mechanisms, so as to facilitate future therapeutic developments.

25 % Dermatomyositis Correlation of DM/(DM + PM) with UV exposure Pathogenic role for UV? N = 919, weighted r = 0.94, P < 4 X UV Exposure (Joules/ m 2 ) Guatemala Mexico city Guadalajara New Delhi Santiago Tokyo Seoul Bethesda Barcelona Warsaw Aachen Nijmgen Stockholm Glasgow (Diagram courtesy of Prof Fred Miller, NIH, USA))

26 Interaction between smoking and HLA-DRB1 (SE) in two different subsets of RA Relative risks for eversmokers and neversmokers classified on presence of Shared epitop ACPA-negative compared to neversmokers RA with no shared epitope genes (all cases are anti-citruline an ACPA-positive Relative risks for eversmokers RA and neversmokers classified on presence of Shared epitope genes negative) compared to neversmokers with no shared epitope genes (all cases are anti-citruline anti body positive) 25 40, OR Relative Risk Ever Smokers 0 Ever Smokers No SE Single SE Double SE Never Smokers No SE Single SE Double SE Never Smokers Never Smokers Ever Smokers Never Smokers Ever Smokers Klareskog et al Arthritis Rheum 2006;54:38-46

27 log odds ratio & 95% confidence interval Anti-Jo-1 status by smoking and HLA-DRB1* Index Smoke - Smoke + Smoke - Smoke + DRB1*03 - DRB1*03 - DRB1*03 + DRB1*03 + Chinoy H. et al, Ann Rheum Dis 2012 Jun;71(6):961-5

28 Mechanistic Clues Environmental triggers: E.g infections (viral), UV (light sensitivity in DM), malignancy association (CAM), smoking (Jo-1 and DR3 associated), drugs (statins) etc Genetic and serological factors (associated):

29 Serological Results A large spectrum of myositis autoantibodies, correlating with a large spectrum of IIM subgroups.

30 Myositis-Specific and -Associated Autoantibodies (MSA and MAA) SRP HMGCoAR (DR11) SEVERE MYOPATHY NECROTISING MYOPATHY Jo-1 (DR3) SAE SKIN DISEASE++ Mi-2 (DR7) PmScl (DR3) Ku RNP CTD-IIM (MAA) EIF3 MILD DM Ha EJ PL-7 Anti-synthetase KS LUNG DISEASE autoantibodies LUNG DISEASE++ SINE MYOSITIS OJ PL-12 Zo MDA5 (DR15) CALCINOSIS NXP2 MALIGNANCY TIF1-gamma (DQB1*02) Ro La IBM 5NT1A (DR13)

31 IIM - A Remarkable Disease Spectrum Myositis specific autoantibodies Clinical phenotypes in adults and children Anti-Synthetase (DR3) Anti-SRP Anti-Mi-2 (DR7) Anti-TIF1g etc

32 ANTI-SYNTHETASE SYNDROME (ASS) Anti-synthetase autoantibodies Overall frequency 30% adult IIM patients Myositis (PM or DM) Ha Jo-1 Raynaud s Arthritis (patients often initially misdiagnosed as RA) Zo EJ Anti-synthetase autoantibodies Mechanic s hands Gottron s lesions (DM only) OJ Fever PL-7 KS PL Yoshifuji H. Autoimmunity 2006;39: Gunawardena H. Rheumatology 2009;48: Review. Interstitial Lung Disease (ILD)

33 DM - Heliotrope with Periorbital Oedema

34 DM - Gottron s papules Erythematous to violaceous papules and plaques over the extensor surfaces of MCP and IP joints & other large joints in a symmetric distribution.

35 Mechanics Hands in a Jo-1+ve Myositis Patient with ASS

36 Raynaud s Phenomenon

37 Thermography - Cold Challenge Test

38 Nail-Fold Capillary Abnormalities (As seen by use of ophthalmoscope) (+ 20 D Lens) Magnifying Glass

39 Scleroderma - IIM - ILD Overlap

40 Scoring Scleroderma Skin

41 MSA/MAA are also SURROGATE biomarkers of ILD SRP SEVERE MYOPATHY SAE Mi-2 HMGCR NECROTISING MYOPATHY Jo-1 SKIN DISEASE++ PmScl Ku U1RNP CTD-IIM (MAA) EIF3 Ha EJ PL-7 LUNG DISEASE - ILD Anti-synthetase autoantibodies LUNG DISEASE++ SINE MYOSITIS KS PL-12 OJ Zo MDA5 CALCINOSIS NXP2 MALIGNANCY TIF1-gamma Ro La IBM 5NT1A MILD DM

42 ILD-Specific and ILD-Associated Autoantibodies (ISA and IAA) Clinically Amyopathic CTD-ILD: If ILD is the only clinical feature of a CTD, then an MSA would also represent an ISA Jo-1 Other SSc-specific Abs also associated with ILD PmScl Ku U1RNP CTD-ILD (IAA) EJ Ha LUNG DISEASE - ILD Anti-synthetase autoantibodies CTD-ILD (ISA) Ro La PL-7 KS LUNG DISEASE++ SINE MYOSITIS OJ PL-12 Zo MDA5 Fulminant ILD Especially in Oriental Asians

43 Anti-MDA 5 A myositis specific antibody, usually associates with clinically amyopathic DM (CADM). Also associates with a very fulminant ILD (often lethal within only weeks or months, especially so in Oriental Asians). Little or no response to steroids, cyclophosphamide, MMF, IVIG or Rituximab. Disease mechanisms unknown.

44 Eurimmun Line-Blot Technology Currently Available IIM and SSc Specificities

45 A Growing Clinical Spectrum of ILDs Multiple ISA/IAA autoantibodies Multiple ILD clinical phenotypes Anti-Jo-1 vs PL7 Anti-U1RNP Anti-PMScl Anti-MDA5 etc

46 UK-BILD Aiming to Improve Diagnostic Performance and Provide Mechanistic Insights in ILD Robert G Cooper (Study PI) Prof Medicine & Hon Consultant Rheumatologist

47 UK-BILD: The UK Biomarkers in Interstitial Lung Disease study. A UK-wide cross-sectional recruitment of ILD cases comprehensive across the ILD spectrum. Has recruited ~ 2850 cases to date.

48 UK-BILD National recruitment from 38 centres. Case recruitment comprehensive across the ILD spectrum. Patients must have HRCT-proven ILD, and their investigations must have included routine serology. Samples harvested: Completed 2 page clinical pro forma and whole blood for DNA genotyping (UoM) and EDTA plasma for serotyping by immuno-precipitation (UoB).

49 UK-BILD: Case Accrual by ILD Subgroup to Nov

50 The ILD Spectrum Groups Idiopathic (IIP) Granulomatous CTD-ILD Environmental or medication exposures Rare causes Idiopathic Pulmonary Fibrosis (IPF), or Usual Interstitial Pneumonia (UIP) Nonspecific Interstitial Pneumonia (NSIP) Cryptogenic Organising Pneumonia (COP)? CTD? CTD Acute Interstitial Pneumonia (AIP) Sarcoidosis Hypersensitivity pneumonitis Subgroups Rh Arthritis Systemic sclerosis Myositis spectrum Sjogren s Syndrome Mixed CTD Undifferentiated CTD Asbestos Nitrofurantoin Bleomycin Silica Other dusts Vasculitis Langerhans cell histiocytosis Eosinophilic pneumonia Subgroups Respiratory-bronchiolitisassociated interstitial lung disease (RB-ILD) Desquamative Interstitial Pneumonia (DIP) Lymphoid Interstitial Pneumonia (LIP) Some IIP cases may be reclassified CTD-ILD subgroups Adapted from Ryerson CJ, Collard HR. Update on the diagnosis and classification of ILD. Curr Opin Pulm Med 2013; 19:

51 Other Members of UK-BILD Team Dr Lisa Spencer (Co-I, Chest Physician, Aintree University Hospital, Liverpool, eamil: Mr Paul New (Research Associate, University of Liverpool, Dr Janine Lamb (Co-I, Non-Clinical Scientist heading up the Centre for Integrated Genomic Medical Research (CIGMR), University of Manchester, Prof Neil McHugh (Co-I, Director of Immunoprecipitation National Reference Laboratory, University of Bath, Dr Zoe Betteridge (Non-Clinical Scientist running Immuno-precipitation Laboratory, University of Bath, 38 UK ILD case recruitment sites to date.

52 UoL

53 Institute of Ageing and Chronic Disease Thank you for listening

54 Acknowledgements UoLiverpool Adam Lightfoot Robert Cooper Patients/UoManchester Janine Lamb Simon Rothwell Robert Cooper Hector Chinoy William Ollier Joanna Parkes James Lilleker Alex Oldroyd John Bowes Hazel Platt UoBath/UKMYONET Neil McHugh Zoe Betteridge Patrick Gordon David Isenberg Mike Hanna Pedro Machado Harsha Gunawardena James Miller Paul New EuMyonet/Euromyositis Lucy Wedderburn Gouchun Wang Louise Diedrichson Jens Schmidt Jiri Vencovsky Paula Oakley Olivier Benveniste Ingrid Lundberg MYOGEN/MYONET Ingrid E. Lundberg Frederick W. Miller Peter K. Gregersen Jiri Vencovsky Katalin Danko Lucy R. Wedderburn Vidya Limaye Albert Selva-O'Callaghan Michael G. Hanna Pedro Machado Lauren M. Pachman Ann M. Reed Lisa G. Rider Øyvind Molberg Olivier Benveniste Pernille Mathiesen Timothy Radstake Andrea Doria Jan De Bleecker Boel De Paepe Britta Maurer Leonid Padyukov Terrance P. O'Hanlon Annette Lee