NOVEL APPROACHES TO PULMONARY FIBROSIS. Gisli Jenkins FRCP PhD Professor of Experimental Medicine University of Nottingham

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1 NOVEL APPROACHES TO PULMONARY FIBROSIS Gisli Jenkins FRCP PhD Professor of Experimental Medicine University of Nottingham

2 OVERVIEW Review of ILDs What is pulmonary fibrosis? How should IPF be diagnosed? How should IPF be treated? Is personalised therapy for IPF possible?

3 ILD OLYMPICS Asbestosis CTD IPF Sarcoidosis NSIP The rest HSP Drugs

4 ILD OLYMPICS CTD NSIP Asbestosis IPF The rest Drugs HSP RA Sarcoidosis

5 ILD OLYMPICS Inflammatory Fibrotic Granulomatous

6 CHRONIC PROGRESSIVE FIBROTIC LUNG DISEASE OR INFLAMMATORY INTERSTITIAL LUNG DISEASE Inflammatory Sarcoid CTD-ILD HSP NSIP DIP RBILD LIP Fibrotic IPF Fibrotic HSP Rheumatoid -UIP Asbestosis IPPFE

7 DEFINITELY NOT IPF Sarcoid Hypersensitivity Pneumonitis Metzger F et al. Chest 2010;138: by American College of Chest Physicians

8 NOT IPF AT THE MOMENT NSIP ANA α-dsdna Ribonucleoproteins α-ro and α-la (Sjogrens) α-smith (SLE) α-ro52 (none-specific) α-topoisomerase/scl70 (SSc) α-pm/scl (SSc/PM overlap) α-trna synthetases (PDM) Jo-1 PL-7 PL-12 α-mda5 (CADM) α-igg4 (IG4RD) RA and α CCP (RA) -UIP MPO (Vasculitis) -UIP Marten al Eur Radiol 2009;19:

9 MYCOPHENOLATE MOFETIL VERSUS ORAL CYCLOPHOSPHAMIDE IN SCLERODERMA-RELATED INTERSTITIAL LUNG DISEASE (SLS II):A RANDOMISED CONTROLLED, DOUBLE-BLIND, PARALLEL GROUP TRIAL Donald P Tashkin, Michael D Roth, Philip J Clements, Daniel E Furst, Dinesh Khanna, Eric C Kleerup, Jonathan Goldin, Edgar Arriola, Elizabeth R Volkmann, Suzanne Kafaja, Richard Silver, Virginia Steen, Charlie Strange, Robert Wise, Fredrick Wigley, Maureen Mayes, David J Riley, Sabiha Hussain, Shervin Assassi, Vivien M Hsu, Bela Patel, Kristine Phillips, Fernando Martinez, Jeff rey Golden, M Kari Connolly, John Varga, Jane Dematte, Monique E Hinchcliff, Aryeh Fischer, Jeff rey Swigris, Richard Meehan, Arthur Theodore, Robert Simms, Suncica Volkov, Dean E Schraufnagel, Mary Beth Scholand, Tracy Frech, Jerry A Molitor, Kristin Highland, Charles A Read, Marvin J Fritzler, Grace Hyun J Kim, Chi-Hong Tseng, Robert M Elashoff, for the Sclerodema Lung Study II Investigators* Published online July 25,

10 MIGHT BE IPF Hunninghake et al NEJM 2013

11 DO INTERSTITIAL LUNG ABNORMALITIES REPRESENT EARLY PULMONARY FIBROSIS? Putman et al JAMA 2016

12 IDIOPATHIC PULMONARY FIBROSIS Elderly male ex-smokers Usually 2 year history of: Progressive shortness of breath on exertion Dry non productive cough On examination Bilateral Basal Crepitations Clubbed

13 IPF IS A PROGRESSIVE DISEASE Elicker et al Resp Med 2010 Interstitial Lung Diseases Unit

14 MORTALITY FROM IPF IN THE UK HAS INCREASED IN THE LAST 40 YEARS ICD-10 (2000) ICD-9 (1979) Navaratnam Thorax. 2011;66(6):462-7.

15 5 year survival rates from IPF compared with various cancers.. Vancheri ERJ (3):

16 CAUSES OF IPF Idiopathic (and cryptogenic) means we don t know Genetics responsible for about 30% Other hypotheses include: Viral infection Gastro-Oesophageal Reflux Disease Inhaled dust/smoke

17 A POLYMORPHISM IN THE COMMON VARIANT OF MUC5B PROMOTES SUSCEPTIBILITY TO IPF Fingerlin et al Nat Genet 2013

18 RARE VARIANTS ARE ASSOCIATED WITH FAMILIAL PULMONARY FIBROSIS Telomerase TERT, TERC DKC1, PARN, NAF1 RTEL1, TINF2 Epithelial Cell Function SFTPA1 SFPTA2 SFPTC ABC3 6% patients in UK with IPF have 1 relative Currently we do not recommend genetic screening These patients are eligible for 100k Genome Project

19 DIAGNOSING IPF HRCT Reticulation Honeycombing Traction Basal Peripheral Subpleural (ATS/ERS Criteria AJRCCM 2011)

20 LUNG FUNCTION

21 SHOULD VATS BIOPSIES BE PERFORMED? Leads to acute excarbations Mortality rate between % Hutchinson et al Am J Respir Crit Care Med 2016, Hutchinson Eur Respir J 2016 Ventilation promotes TGFβ activation in the lung. Jenkins et al JCI 2006, John et al Science Signalling 2016 Mechanical stretch of IPF tissue has enhanced TGFβ activation. Froese et al Am J Respir Crit Care Med 2016

22 IPF MANAGEMENT NICE IPF Guidelines (CG163) Put the MDT at the heart of management NICE IPF Quality Standard (QS79) Patients should be diagnosed with IPF by MDT All patients should have access to a Specialist Nurse Should have ambulatory Oxygen assessments Should have access to Pulmonary Rehabilitation Should have access to Palliative Care 2 NICE approved drugs for IPF Pirfenidone (TA282) Nintedanib (TA379)

23 THE PANTHER STUDY Triple therapy with Pred/AZA/NAC for IPF had significantly worse outcome compared with placebo. Death 8 vs 1 p < 0.01 Hospitalisation 23 vs 7 p < Single agent NAC no benefit compared with placebo Raghu et al N Eng J Med 2012 Martinez et al N Eng J Med 2014

24 DISEASE MODIFYING ANTIFIBROTIC DRUGS Pirfenidone Nintedanib King et al NEJM 2014 Richeldi et al NEJM 2014

25 BEST SUPPORTIVE CARE Co-morbidities Withdraw ineffective or harmful therapies Symptom relief Dyspnoea Oxygen Cough PPI Prednisolone Thalidomide Opiates

26 THERE IS STILL CONSIDERABLE PROGRESS NEEDED Strict prescribing criteria for anti-fibrotic therapy IPF only FVC 80-50% Responders only Large number of adverse effects Mechanism of action unclear

27 SAME DISEASE DIFFERENT COURSE Onset of Disease Sub-clinical Period Disease Progression Onset of Symptoms Diagnosis A B C D Pre-diagnosis Period Post-diagnosis Period Death 1 yr 2 yr 3 yr 4 yr 5 yr 6 yr Time Adapted from Ley B et al, Am J Respir Crit Care Med 2011

28 SAME RADIOLOGICAL APPEARANCE DIFFERENT DISEASE? RA-ILD IPF Walsh et al Thorax 2014;69:

29 ARE CURRENT CLINICAL STRATA OF FIBROTIC LUNG DISEASE FIT FOR PURPOSE? Ryerson et al ERJ 2013 Kim et al. Chest. 2009

30 Can Pulmonary Fibrosis be stratified? Protein MicroRNA Transcript Lung Tissue Genome Classical IPF Accelerated IPF Atypical IPF IPF + Emphysema IPF + Lung Cancer IPF + Pulmonary Hypertension IPF + asbestos exposure IPF + RA Interstitial Lung Abnormalities MMP7/ SpD Matrix Neoepitopes mir29 Integrins muc5b Therapy

31 MUC5B AND TOLLIP POLYMORPHISMS ARE ASSOCIATED WITH SLOWER PROGRESSION OF IPF Noth et al Lancet Resp Med 2013 Peljto et al JAMA 2013

32 SERUM BIOMARKERS MAY BE USEFUL IN SCREENING EARLY DISEASE MMP7 SpD Kropski et al Am J Respir Crit Care Med 2015

33 CAN IPF BE STRATIFIED BY RESPONSE TO THERAPY? Responders vs Non-responder The challenge in IPF is defining treatment response We currently use >10% absolute drop in FVC We need more dynamic markers of disease which better reflect disease biology

34 THE PROFILE STUDY

35 MATRIX NEOEPITOPES Karsdal MA et al Assay Drug Dev Technol 2013

36 MATRIX NEOEPITOPES CAN DISTINGUISH PROGRESSIVE FROM STABLE IPF Jenkins et al Lancet Respir Med 2015

37 PATIENTS WITH RISING MATRIX NEOEPITOPES HAVE INCREASED RISK OF MORTALITY Jenkins et al Lancet Respir Med 2015

38 HIGHER RATE OF CHANGE OF MATRIX NEOEPITOPES IS ASSOCIATED WITH INCREASED RISK OF DEATH IN PATIENTS WITH IPF Jenkins et al Lancet Respir Med 2015

39 CAN WE IDENTIFY MOLECULAR ENDOTYPES OF PULMONARY FIBROSIS Identify a subset of pulmonary fibrosis with a specific behaviour Conserved across clinical phenotypes Targetable by specific therapies Identified by specific biomarkers

40 Gq RhoA ROCK X 3 P X P 3 ELK1 4 TGFβ1 X αvβ6 integrin αv integrin P X 3 P Jenkins et al J Clin Invest 2006 Xu et al Am J Pathol 2009 Henderson et al Nat Med 2013 Tatler et al J Biol Chem 2016 Tatler et al Plos One 2016 John et al Science Signalling 2016

41 THE αvβ6 INTEGRIN IS UPREGULATED IN REGIONS OF FIBROSIS IN PATIENTS WITH UIP Xu et al Am J Pathol 2009

42 HIGH LEVELS OF β6 IMMUNOSTAINING ARE ASSOCIATED WITH A WORSE PROGNOSIS Saini et al Eur Resp J 2015

43 THE αvβ6 INTEGRIN IS UPREGULATED FOLLOWING Binding of 111 In-DTPA-A20FMDV2 BLEOMYCIN INDUCED LUNG INJURY (β6 specific peptide) Bleomycin saline bleomycin + anti-αvβ6 αvβ6 Specific peptide Control peptide saline bleo John et al J Nuc Med 2013

44 A β6 TARGETING PEPTIDE CO-LOCALISES WITH AREAS OF FIBROSIS FOLLOWING BLEOMYCIN INSTILLATION John et al J Nuc Med 2013

45 CONCLUSIONS 1 ILDs should be considered inflammatory or fibrotic Inflammatory ILDs can be treated with steroids and immunosuppression Fibrotic ILD should NOT be treated with steroids and immunosuppression

46 CONCLUSIONS 2 Genetics plays a key role in IPF and patients with affected 1 relatives are eligible for 100k genome project The Disease Modifying Anti-fibrotic Drugs pirfenidone and nintedanib slow disease progression but do not cure IPF Serum biomarkers may play a role in monitoring disease progression or therapeutic response Understanding specific endotypes of disease and developing appropriate therapeutics and companion biomarkers will help the majority of patients who are ineligible, intolerant or unresponsive to current therapy

47 THE PULMONARY FIBROSIS GROUP

48 Acknowledgements Nottingham Richard Hubbard Simon Johnson Alan Knox Ian Hall Ian Sayers Bristol Cambridge UCL Ann Millar Helen Parfrey Robin McAnulty Imperial Toby Maher Hull Simon Hart Leicester Queen Mary Martin Tobin Louise Wain Richard Allen John Marshall Edinburgh Nick Hirani Moira Whyte William Wallace Biogen Idec GSK Paul Wienreb Shelia Violette Richard Marshall Andy Blanchard Pauline Lukey