NOVEL APPROACHES TO PULMONARY FIBROSIS Gisli Jenkins FRCP PhD Professor of Experimental Medicine University of Nottingham
OVERVIEW Review of ILDs What is pulmonary fibrosis? How should IPF be diagnosed? How should IPF be treated? Is personalised therapy for IPF possible?
ILD OLYMPICS Asbestosis CTD IPF Sarcoidosis NSIP The rest HSP Drugs
ILD OLYMPICS CTD NSIP Asbestosis IPF The rest Drugs HSP RA Sarcoidosis
ILD OLYMPICS Inflammatory Fibrotic Granulomatous
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
DEFINITELY NOT IPF Sarcoid Hypersensitivity Pneumonitis Metzger F et al. Chest 2010;138:724-726 2010 by American College of Chest Physicians
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;19:1679-1685
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* www.thelancet.com/respiratory Published online July 25, 2016 http://dx.doi.org/10.1016/s2213-2600(16)30152-7
MIGHT BE IPF Hunninghake et al NEJM 2013
DO INTERSTITIAL LUNG ABNORMALITIES REPRESENT EARLY PULMONARY FIBROSIS? Putman et al JAMA 2016
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
IPF IS A PROGRESSIVE DISEASE Elicker et al Resp Med 2010 Interstitial Lung Diseases Unit
MORTALITY FROM IPF IN THE UK HAS INCREASED IN THE LAST 40 YEARS 3500 3000 ICD-10 (2000) 2500 2000 1500 ICD-9 (1979) 1000 500 0 1968 1969 1970 1971 1972 1973 1974 1975 1976 1977 1978 1979 1980 1981 1982 1983 1984 1985 1986 1987 1988 1989 1990 1991 1992 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 Navaratnam Thorax. 2011;66(6):462-7.
5 year survival rates from IPF compared with various cancers.. Vancheri ERJ 2010 35(3):496-504
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
A POLYMORPHISM IN THE COMMON VARIANT OF MUC5B PROMOTES SUSCEPTIBILITY TO IPF Fingerlin et al Nat Genet 2013
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
DIAGNOSING IPF HRCT Reticulation Honeycombing Traction Basal Peripheral Subpleural (ATS/ERS Criteria AJRCCM 2011)
LUNG FUNCTION
SHOULD VATS BIOPSIES BE PERFORMED? Leads to acute excarbations Mortality rate between 1.7-2.4% 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
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)
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 < 0.001 Single agent NAC no benefit compared with placebo Raghu et al N Eng J Med 2012 Martinez et al N Eng J Med 2014
DISEASE MODIFYING ANTIFIBROTIC DRUGS Pirfenidone Nintedanib King et al NEJM 2014 Richeldi et al NEJM 2014
BEST SUPPORTIVE CARE Co-morbidities Withdraw ineffective or harmful therapies Symptom relief Dyspnoea Oxygen Cough PPI Prednisolone Thalidomide Opiates
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
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
SAME RADIOLOGICAL APPEARANCE DIFFERENT DISEASE? RA-ILD IPF Walsh et al Thorax 2014;69:216-222
ARE CURRENT CLINICAL STRATA OF FIBROTIC LUNG DISEASE FIT FOR PURPOSE? Ryerson et al ERJ 2013 Kim et al. Chest. 2009
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
MUC5B AND TOLLIP POLYMORPHISMS ARE ASSOCIATED WITH SLOWER PROGRESSION OF IPF Noth et al Lancet Resp Med 2013 Peljto et al JAMA 2013
SERUM BIOMARKERS MAY BE USEFUL IN SCREENING EARLY DISEASE MMP7 SpD Kropski et al Am J Respir Crit Care Med 2015
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
THE PROFILE STUDY
MATRIX NEOEPITOPES Karsdal MA et al Assay Drug Dev Technol 2013
MATRIX NEOEPITOPES CAN DISTINGUISH PROGRESSIVE FROM STABLE IPF Jenkins et al Lancet Respir Med 2015
PATIENTS WITH RISING MATRIX NEOEPITOPES HAVE INCREASED RISK OF MORTALITY Jenkins et al Lancet Respir Med 2015
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
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
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
THE αvβ6 INTEGRIN IS UPREGULATED IN REGIONS OF FIBROSIS IN PATIENTS WITH UIP Xu et al Am J Pathol 2009
HIGH LEVELS OF β6 IMMUNOSTAINING ARE ASSOCIATED WITH A WORSE PROGNOSIS Saini et al Eur Resp J 2015
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
A β6 TARGETING PEPTIDE CO-LOCALISES WITH AREAS OF FIBROSIS FOLLOWING BLEOMYCIN INSTILLATION John et al J Nuc Med 2013
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
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
THE PULMONARY FIBROSIS GROUP
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