DIFFERENCES IN FIBROPROLIFERATIVE HEALING IN EXOGENEOUS AND IDIOPATHIC ILDs. ARE THERE ANY?

Transcription

1 NIHR Southampton Respiratory Biomedical Research Unit DIFFERENCES IN FIBROPROLIFERATIVE HEALING IN EXOGENEOUS AND IDIOPATHIC ILDs. ARE THERE ANY? Fibrosing Interstitial Lung Diseases CPFS/WASOG/AIPO/ERS Conference Prague, June 2014 Luca Richeldi MD PhD Professor of Respiratory Medicine Chair of Interstitial Lung Disease Honorary Consultant Physician The NIHR Southampton Respiratory Biomedical Research Unit is funded by the National Institute for Health Research (NIHR) and is a partnership between University Hospital Southampton NHS Foundation Trust and the University of Southampton

2 I HAVE ABSOLUTELY NO IDEA AND PROBABLY NO ONE ELSE DOES

3 FIBROPROLIFERATIVE HEALING

4 Courtesy Martin Kolb

5 Mark Jones, University of Southampton

6 AJRCCM 2013; 188:

7 Interstitial Lung Disease Exposure-related: - Occupational - Environmental - Avocational - Medication Major IIP Idiopathic interstitial pneumonia (IIP) Idiopathic pulmonary fibrosis (IPF) Idiopathic nonspecific interstitial pneumonia (insip) Respiratory bronchiolitis interstitial lung disease (RBILD) Desquamative interstitial pneumonia (DIP) Cryptogenic organizing pneumonia (COP) Acute interstitial pneumonia (AIP) Connective tissue disease: - Scleroderma - Rheum. arthritis - Sjogren Rare IIP Sarcoidosis Idiopathic lymphoid interstitial pneumonia (ilip) Idiopathic pleuroparenchymal fibroelastosis Unclassifiable IIP Other: - Vasculitis/Diffuse alveolar hemorrhage (DAH) - Langherhans cell histiocytosis (LCH) - Eosinophilic pneumonias - Neurofibromatosis - LAM AJRCCM 2013; 188:

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11 The Cigarette Century. Allan M. Brandt, 2007

12 Sarcoidosis - Environmental - Rheum. arthritis - Langherhans cell histiocytosis (LCH) - Eosinophilic pneumonias Idiopathic pulmonary fibrosis (IPF) Respiratory bronchiolitis interstitial lung disease (RBILD) Desquamative interstitial pneumonia (DIP) AJRCCM 2013; 188:

13 Clin Chest Med 2012; 33:

14 PROPOSED CLASSIFICATION OF SMOKING-RELATED ILDs Group 1: chronic ILDs that are very likely caused by cigarette smoking Respiratory bronchiolitis associated ILD (RB-ILD) Desquamative interstitial pneumonia (DIP) Adult pulmonary Langerhans cell histiocytosis (PLCH) Group 2: acute ILDs that may be precipitated by cigarette smoking Acute eosinophilic pneumonia (AEP) Pulmonary hemorrhage syndromes (PHS) Group 3: ILDs that are statistically more prevalent in smokers Idiopathic pulmonary fibrosis (IPF) Rheumatoid arthritis associated ILD (RA-ILD) Group 4: ILDs that are less prevalent in smokers Hypersensitivity pneumonitis (HP) Sarcoidosis Clin Chest Med 2012; 33:

15 PROPOSED CLASSIFICATION OF SMOKING-RELATED ILDs chronic acute Clin Chest Med 2012; 33:

16 AT DIAGNOSIS 3 MOS AFTER SMOKING CESSATION

17 PROPOSED CLASSIFICATION OF SMOKING-RELATED ILDs Idiopathic pulmonary fibrosis (IPF) Clin Chest Med 2012; 33:

18 IDIOPATHIC PULMONARY FIBROSIS King T, Pardo A and Selman M, Lancet 2011

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20 Gene Discovery in Pulmonary Fibrosis Genome-Wide Linkage Scan in Families Fine Mapping Association Studies Cases vs. Controls 8.8 Mb 120 Kb FIP MUC5B (rs ) GG GT TT Controls 272 (82%) 58 (18%) 2 (1%) Familial IPF 35 (41%) 46 (53%) 5 (6%) Whole > 100 genes Courtesy Sporadic Genome David IPF Schwartz 186 (34%) 332 (60%) 37 (7%) GT 6.2 ( ) ( ) genes Odds Ratios MUC5B rs TT 19.4 ( ) 27.0 ( ) Seibold. NEJM 2011; 364:1503

21 MUC5B Promoter SNP (rs ) and Pulmonary Fibrosis Familial and Sporadic IPF General Population OR=6.2 per allele 34.1 Fold P= Fold P= Seibold. NEJM 2011; 364:1503 Helling (submitted) Courtesy David Schwartz WT Variant WT Variant Controls (N=139) IPF (N=203)

22 MUC5B Promoter SNP (rs ) and Pulmonary Fibrosis Familial and Sporadic IPF General Population OR=6.2 per allele MUC5B / Keratin 5 / Distal Airway DAPI Chest CT Abnormalities Honeycomb Cyst Seibold. PLoS One 2013; 8:e58658 Courtesy David Schwartz

23 MUC5B Promoter SNP (rs ) and Pulmonary Fibrosis Familial and Sporadic IPF General Population HR= Prognosis OR=6.2 per allele OR= per allele Chest CT Abnormalities Seibold. NEJM 2011; 364:1503 Hunninghake. NEJM 2013; 368:2192 Peljto. JAMA 2013; 309: % > 50 yrs Courtesy David Schwartz

24 MUC5B Promoter SNP (rs ) and Pulmonary Fibrosis Familial and Sporadic IPF General Population Prognosis Early IPF Chest CT Abnormalities Targeted Treatment 2-7% > 50 yrs Courtesy David Schwartz

25 MUC5B Variant has a Low Penetrance General Population IPF Prevalence < 1% OR=6.2 per allele 50-60% MUC5B SNP 20% MUC5B SNP Courtesy David Schwartz Other Gene Variants Gene x Gene = MUC5B Gene Promoter x Environment SNP

26 -log 10 (P value) Genome Wide Association Study in IIP Host Defense: MUC5B and ATP11A Barrier Function: DSP and DPP9 DNA Repair: TERC, TERT, and OBFC1 TERT DSP MUC5B 30-33% of the disease risk 10 5 TERC FAM13A OBFC1 ATP11A DPP X Courtesy David Schwartz Chromosome Fingerlin. Nat Genet 2013; 45:613

27 GENE-ENVIRONMENT INTERACTION

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29 AJRCCM 2013; 188:

30 REVISED ATS/ERS IIPs CLASSIFICATION: CATEGORIZATION OF MAJOR IIPs CATEGORY Chronic fibrosing IP Smoking-related IP Acute/Subacute IP CLINICAL-RADIOLOGICAL- PATHOLOGICAL DX IPF I-NSIP RB-ILD DIP COP AIP ASSOCIATED MORPHOLOGIC PATTERNS UIP NSIP RB DIP OP DAD AJRCCM 2013; 188:

31 REVISED ATS/ERS IIPS CLASSIFICATION: CLASSIFICATION ACCORDING TO DISEASE BEHAVIOR - 1 CLINICAL BEHAVIOR TREATMENT GOAL MONITORING STRATEGY Reversible and selflimited (e.g. RB-ILD) Reversible with risk of progression (e.g. some NSIP, COP, DIP) Stable with residual disease (e.g. some NSIP) Remove possible cause Initially for a response and then rationalize longer term therapy Maintain status Short-term (3-6 months) observation to confirm disease regression Short-term observation to confirm response: long-term observation to ensure gains are preserved Long-term observation to assess disease course AJRCCM 2013; 188:

32 REVISED ATS/ERS IIPS CLASSIFICATION: CLASSIFICATION ACCORDING TO DISEASE BEHAVIOR - 2 CLINICAL BEHAVIOR TREATMENT GOAL MONITORING STRATEGY Progressive, irreversible with potential for stabilization (e.g. some NSIP) Progressive, irreversible despite therapy (e.g. some NSIP, IPF) To stabilize To slow progression Long-term (3-6 months) observation to assess disease course Long-term observation to assess disease course and need for transplant or effective palliation AJRCCM 2013; 188:

33 Bullshit is unavoidable whenever circumstances require someone to talk without knowing what he is talking about. Thus the production of bullshit is stimulated whenever a person s obligations or opportunities to speak about some topic exceed his knowledge of the facts that are relevant to that topic. Harry G. Frankfurt, On Bullshit. Princeton University Press 2005, page 63

34 NIHR Southampton Respiratory Biomedical Research Unit DIFFERENCES IN FIBROPROLIFERATIVE HEALING IN EXOGENEOUS AND IDIOPATHIC ILDs. ARE THERE ANY? Fibrosing Interstitial Lung Diseases CPFS/WASOG/AIPO/ERS Conference Prague, June 2014 Luca Richeldi MD PhD Professor of Respiratory Medicine Chair of Interstitial Lung Disease Honorary Consultant Physician The NIHR Southampton Respiratory Biomedical Research Unit is funded by the National Institute for Health Research (NIHR) and is a partnership between University Hospital Southampton NHS Foundation Trust and the University of Southampton