Διάγνωστικη και Θεραπευτική Προσέγγιση IPF

Διάγνωστικη και Θεραπευτική Προσέγγιση IPF ΕΠΕ Refreshing Courses Αργύριος Τζουβελέκης Biomedical Sciences Research Center Alexander Fleming PCCSM Yale School of Medicine Interstitial Lung Disease Unit, SOTIRIA Hospital, University of Athens

CLASSIFICATION OF ILDs CHRONIC WITHOUT SYSTEMIC DISEASE (Idiopathic interstitial Pneumonias, CEP,LAM Alv proteinosis, PVOD) CHRONIC WITH SYSTEMIC DISEASE (vasculitis, CVD Sarcoidosis) ACUTE ( A I P, A EP,H P) ILD > 500 SUBACUTE ( COP,H P) EPISODIC (HP, vasculitis, COP, EOS. PNEUMONIA) CHRONIC KNOWN ETIOLOGY (Environmental, Occupational, Drugs)

AJRCCM 2013 Idiopathic interstitial pneumonias (IIP) Idiopathic pulmonary fibrosis/usual interstitial pneumonia (IPF/UIP) Nonspecific interstitial pneumonia (NSIP) Cryptogenic organizing pneumonia (COP/OP) Desquamative interstitial pneumonia (DIP) Respiratory bronchiolitisassociated interstitial lung disease (RBILD) Acute interstitial Pneumonia (AIP) RARE IIPs 55% 25% 3% 15% 3%

Current Definition of IPF Distinct chronic progressive fibrosing interstitial pneumonia of unknown cause, primarily occurring in older adults, is limited to the lungs, and has typical imaging and pathologic findings of UIP ATS/ERS/JRS/ALAT Statement. Am J Respir Crit Care Med. 2011;183:788-824.

Παθογένεια Alveolar physiological state Usual Interstitial Pneumonia Lesion Recurring microinjuries Epithelial cells apoptosis Epithelial & fibroblast activation Matrix remodeling Cell proliferation and migration Pneumocyte type I Pneumocyte type II Endothelial cell Fibroblast

COMPARATIVE PROGNOSIS AND FUNDING OF IPF

Διάγνωση

Ιστορικό Κλινική εξέταση

Fine end inspiratory basal crackles (velcro).

Drugs eg, Amiodarone, bleomycin, nitrofurantoin www.pneumotox.com Radiation External beam radiation therapy to thorax Connective Tissue Diseases Rheumatoid arthritis Systemic sclerosis (scleroderma) Idiopathic inflammatory myopathies Vasculitis Known Causes of ILD: History & Physical Exam Occupational/Environmental Inorganic antigens (Pneumoconioses) Asbestosis Coal worker s pneumoconiosis Silicosis Organic antigens (Hypersensitivity Pneumonitis) Birds Mold

Ακτινολογικό Πρότυπο

HRCT Criteria for UIP UIP Pattern Possible UIP Pattern Subpleural, basal predominance + + Reticular abnormality + + Honeycombing (+/- traction bronchiectasis) + - Absence of inconsistent features + + Raghu G, et al. Am J Respir Crit Care Med. 2011;183:788-824.

UIP Pattern Hodnett PA, et al. Am J Respir Crit Care Med. 2013;188:141-149.

Possible (undetermined) UIP Pattern traction bronchiectasis Hodnett PA, et al. Am J Respir Crit Care Med. 2013;188:141-149.

HRCT features inconsistent with IPF Inconsistent Features Upper lobe predominant Peribronchovascular predominance Ground-glass > extent of reticular abnormality Profuse micronodules Discrete cysts Diffuse mosaic attenuation/gas-trapping Consolidation Raghu G, et al. Am J Respir Crit Care Med. 2011;183:788-824.

Inconsistent With UIP distinct lobular pattern Hodnett PA, et al. Am J Respir Crit Care Med. 2013;188:141-149.

Ανοσολογικό Προφίλ

Serologic Tests Can Help Identify Other Conditions ATS/ERS/JRS/ALAT Statement. Am J Respir Crit Care Med. 2011;183:788-824. Connective tissue diseases ANA, RF & anti-ccp (ERS/ATS guidelines) CK and aldolase Anti-myositis panel with Jo-1 antibody ENA panel Scl-70, ACA Ro (SSA), La (SSB) MPO/PR3 (ANCA) Smith, RNP ESR, CRP Hypersensitivity pneumonitis Hypersensitivity panel (if exposure history)

Παθολογοανατομικό πρότυπο

Τοπογραφική ετερογένεια Normal Alveolar Structure Usual Interstitial Pneumonia Lesion Pneumocyte type I Pneumocyte type II Endothelial cell Fibroblast

USUAL INTERSTITIAL PNEUMONIA AND IDIOPATHIC PULMONARY FIBROSIS LIP AIP KNOWN ETIOLOGY CVD-PF, DRUGS, HP, Asbestosis etc RB-ILD DIP UIP-IPF COP NSIP Most UIPs are IPF, ALL UIPs ARE NOT IPF Slide courtesy of Demosthenes Bouros

RARE >30% UNCLASSIFIABLE

undetermined 15 combinations

Inconsistent UIP/Unclassifiable ILD

Προβληματικές οι τρέχουσες Κατευθυντήριες Οδηγίες

Αναπάντητα ερωτήματα

Vote: 4 for the use of BAL, 18 against the use of BAL, 1 abstention, 8 absent.)

50% of chp patients were misdiagnosed as IPF BAL provides us vital information on degree of alveolitis treatment response

The new guidelines for IPF diagnosis (ATS/ERS/JRS/ALAT) Transbronchial biopsy (TBB) Desirable effects of TBB Less burdensome More efficient Undesirable effects of TBB 53% lower diagnostic yield 22% less likely to acquire adequate specimen For patients with newly diagnosed ILD of unknown cause who are clinically suspected of having IPF and who have a HRCT pattern other than consistent with UIP, we recommend / suggest that TBB be performed / not be performed.

The new guidelines for IPF diagnosis (ATS/ERS/JRS/ALAT) Cryobiopsy Desirable effects of cryobiopsy Approximately 96% of surgical lung biopsies may be avoided. 5.7% fewer respiratory infections. 1.5% less procedural mortality. Undesirable effects of cryobiopsy 8.5% lower diagnostic yield 4.4% more bleeding 11.5% more pneumothorax 7.5% more prolonged air leak For patients with newly diagnosed ILD of unknown cause who are clinically suspected of having IPF and who have a HRCT pattern other than consistent with UIP, we recommend / suggest that Cryobiopsy be performed / not be performed.

The new guidelines for IPF diagnosis (ATS/ERS/JRS/ALAT) Surgical lung biopsy (SLBx) Desirable effects of SLBx Adequate sample obtained in 100%. Diagnostic yield of 90%. Undesirable effects of SLBx 3.5% overall mortality 1.7% procedural mortality 6.1% develop exacerbations 5% develop pneumothorax 5.9% develop prolonged air leak 6.5% develop a respiratory infection 4.5% develop neuropathic pain 3% have delayed wound healing Biopsy in selected cases = 30% (unclassified IPAF) For patients with newly diagnosed ILD of unknown cause who are clinically suspected of having IPF and who have a HRCT pattern other than consistent with UIP, we recommend / suggest that surgical lung biopsy be performed / not be performed.

The new guidelines for IPF diagnosis (ATS/ERS/JRS/ALAT) Multidisciplinary team discussion (MDD) vs single discipline discussions (SDD) in patients who are clinically suspected of having IPF Favoring MDD over SDD Avoid incorrect therapy, delayed therapy, and unnecessary diagnostic testing or therapy in approximately 30% of patients. Favoring SDD over MDD Less burdensome More efficient Diagnosis should be made based on MDT Walsh et al. Eur Respir J 2017; 50: 1700936

Diagnostic Algorithm for Patients with Suspected IPF ATS/ERS/JRS/ALAT Statement. Am J Respir Crit Care Med. 2011;183:788-824. SEROLOGY? BAL? CRYOBIOPSY? BIOMARKERS?

IPF and comorbidities IPF and emphysema CPFE (30-60%) IPF and Pulmonary Hypertension (10-80%) IPF and Lung cancer (15%) IPF and GERD (80%) IPF and sleep apnea (6-10%) IPF and ischemic heart disease (30%) IPF and hypothyroidism (10%) VitD deficiency (90%) IPF and depression (25%) Raghu et al. Eur Respir J 2015. ;46: 1113-1130

Θεραπεία

Θεραπεία IPF <2000 American Journal Medicine 1981

Θεραπεία IPF 2000-2010 Until adequate studies are conducted combined therapy : corticosteroid The art of medicine consists of amusing the patient, while the nature cures the disease. Voltaire 1694-1778 azathioprine or cyclophosphamide NOT BASED ON SCIENTIFIC DATA EXPERT OPINION, LOW EVIDENCE! MICO- Masterful Inactivity with Cat-like Observation Athol Wells 2008 ATS / ERS consensus statement, AJRCCM 2000;161:646

PANTHER-IPF: prednisone, azathioprine, N-acetylcysteine: A study that evaluates response in IPF Probability 1.0 0.8 0.6 0.4 0.2 0.0 0 15 30 45 60 Time to death Triple therapy Placebo Probability Time to death or disease progression 1.0 1.0 0.8 0.8 0.6 2014 0.6 Triple therapy 0.4 0.4 0.2 0.2 Anno Mirabilis Placebo 0.0 0.0 0 15 30 45 60 0 15 30 45 60 Probability Time to death or hospitalisation Triple therapy Placebo Idiopathic Pulmonary Fibrosis Clinical Research Network. N Engl J Med 2012;366:1968-77.

15/10/2014 ΟΛΑ ΤΑ ΣΤΑΔΙΑ

Μηχανισμοί δράσης πιρφενιδόνης Αντι-ινωτικό Άγνωστος ακριβής μηχανισμός δράσης Ενεργό σε πολλαπλά θεραπευτικά μοντέλα ίνωσης TNF-α IL-6 TGF-β IL-6 Pirfenidone Collagen MMPs Collagenase s ROIs Hilberg O, et al. Clin Respir J. 2012;6:131-143.

Pirfenidone reduces annual rate of FVC decline in 1247 patients from three phase III RCTs Noble et al. Eur Respir J. May 2016

Pirfenidone reduces all-cause mortality in 1247 patients from three phase III RCTs Cumulative risk of death (%) 8 6 4 2 0 0 HR 0.52 (95% CI 0.31 0.87)* P = 0.011 1 3 2 week 6 Placebo (n = 624) Pirfenidone (n = 623) 3 9 5 2 Patients at risk, n Week Pirfenidone Placebo 0 490 624 13 618 619 26 609 603 39 596 586 52 509 490 In the pre-specified pooled analysis of all-cause mortality, pirfenidone reduced the risk of mortality by 48% at Week 52 compared with placebo (P = 0.01) * Cox proportional hazards model; log-rank test. King TE et al. N Engl J Med 2014;370:2083 2092.

Pirfenidone reduces all-cause hospitalizations in 1247 patients from three phase III RCTs Collard et al. Am J Respir Crit Care Med. May 2017

Ανεπιθύμητες Ενέργειες Bouros et al. RECAP N=1058 242 (23%) NA 430 (35.3%) 305 (28.8%) 444 (42%)

Pirfenidone effectiveness in the natural clinical setting

Pirfenidone in Mild-to-Moderate Disease Real World Observational Study Disease Stabilization after 3 yrs of Rx 0.14-0.6-2.4-9.3 Tzouvelekis et al. Frontiers In Med 2017. accepted

Μηχανισμοί δράσης nintedanib Αναστολέας τυροσινικών κινασών Ενεργοποιητής φωσφατασών Αντι-καρκινικό VEGF Nintedanib PDGF FGF SHP-1 Pleiotropic Effects Hilberg F, et al. Cancer Res. 2008;68(12):4774-4782. Tai WT, et al. J Hepatol. 2014;61(1):89-97.

NINTEDANIB-INPULSIS TRIALS Primary efficacy endpoint in pooled data Adjusted annual rate (SE) of decline in FVC (ml/year) 0-50 -100-150 -200-250 -300-113, 6-223, 109.9 ml/year 5 (95% CI: 75.9, 144.0) p<0.0001 Nintedanib 150 mg bid (n=638) Placebo (n=423) Mean (SE) observed change from baseline in FVC (ml) No. of patients Nintedanib Placebo 0 Nintedanib 150 mg bid Placebo 2 4 6 12 24 36 52 Week 626 616 613 604 587 569 519 417 408 407 403 395 383 345 Richeldi et al. NEJM 2014; 370: 2071-82

TIME TO FIRST CONFIRMED OR SUSPECTED ACUTE EXACERBATION PER ADJUDICATION Nintedanib 150 mg bid Placebo HR 0.32 (95% CI; 0.16, 0.65) p=0.0010 Nintedanib 150 mg bid (n=638) Placebo (n=423) Patients with 1 acute exacerbation, n (%) 12 (1.9) 24 (5.7) Richeldi et al. NEJM 2014; 370: 2071-82

Nintedanib Disease stabilization at 1 yr NINTEDANIB START NINTEDANIB START n=83 n=94 n=75 n=94 n=81 n=73 FVC%pred 68.1+18.1 68.7+18.2 67.0+19.6 DLCO%pred 44.5+14.6 44.0+15.3 42.5+14.9 Months 0 6 12 *Deaths (n=14) were considered as censored and excluded from the analysis Months 0 6 12 *Deaths (n=14) were considered as censored and excluded from the analysis

Ανεπιθύμητες Ενέργειες ADVERSE EVENT BOUROS ET AL. INPULSIS/TOMORROW N (%), (TOTAL=94) N (%), (TOTAL=689) Diarrhea 52 (55.3%) 445 (61.5%) Liver toxicity 5 (5.3%) NA Vomiting 12 (12.7%) 85 (11.8%) Fatigue 17 (18.1%) NA Nausea 17 (18.1%) 176 (24.3%) Anorexia 18 (19.1%) 81 (11.2%) Constipation 2 (4.7%) NA Abdominal pain 6 (6.4%) NA Hematochezia 1 (1.1%) NA Dizziness 3 (3.2%) NA Headache 2 (4.7%) NA Upper Respiratory Tract Infection 9 (9.6%) 65 (9.0%) Fatal adverse events 14 (14.8%) 38 (5.3%) Myocardial Infarction 2 (2.1%) 18 (2.7%) IPF progression 12 (12.7%) 68 (9.4%) Adverse event leading to treatment 20 (21.2%) 149 (20.6%) discontinuation Diarrhea 9 (9.6%) 38 (5.3%) Nausea 1 (1.1%) 17 (2.4%) IPF progression 5 (5.3%) 15 (2.1%) Myocardial Infarction 1 (1.1%) NA Patient s decision 4 (4.3%) NA

Αντι-ινωτικά Καθημερινοί Προβληματισμοί Pirfenidone 9 χάπια/day (3*3-μαζί με φαγητό-βελτίωση ανεκτικότητας) συνοσηρότητες? 3 χάπια/day-σκεύασμα Pirfenidone φωτοευαισθησία (Μεσογειακή χώρα) Nintedanib -150 mg 1*2, 3*3-μαζί με φαγητό-βελτίωση ανεκτικότητας διάρροιες αντι-διαρροϊκά (λοπεραμιδη) και τιτλοποιηση δόσης- 100 mg/day αποτελεσματικό? Nintedanib επιφυλακτικοί με Στεφανιαία νόσο (30%) Επιλογή φαρμάκου κατόπιν συζήτησης με τον ασθενή

Tzouvelekis A et al. Pulm Pharm Ther 2017 Παρακολούθηση PFTs/ 3μηνο HRCT low dose /6-12 μηνες Προσοχή σε όζους scarcinoma PET scan U/S καρδιάς /έτος ή σε δυσανάλογο αποκορεσμό βάσει PFTs, χαμηλή DLCO,CPFE Ανοσολογικός έλεγχος/ έτος σε περιπτώσεις IPAF Έλεγχος ηπατικών ενζύμων/γενική αίματος/ μήνα αντι-ινωτικά

Ανάγκη για νέες Θεραπείες 1. Υψηλά ποσοστά αποτυχίας στη διαλογή ασθενών 2. Θεραπεία για όλους τους φαινότυπους ενδότυπους ασθενών (ετερογένεια νόσου) Personalized medicine 3. Θεραπεία για Παροξύνσεις νόσου συνοσηρότητες 4. Λιγότερες παρενέργειες Tzouvelekis A et al. Curr Opin Pulm Med 2017

Νεότερες κλινικές μελέτες στην IPF PHASE I MACITENTAN PRM-151 ILOPROST BOSENTAN STX-100 hmsc AMBRISENTAN ETANERCEPT IMATINIB PHASE II PHASE III REGISTRATION LAUNCHED NINTEDANIB Pirfenidone (Esbriet ) TD139 CC-930 GSK2126458 CNTO 888 SAR156597 CO-TRIMOXAZOLE OMEPRAZOLE GLPG1690 NAC QAX576 LOSARTAN POSITIVE RESULTS NEGATIVE RESULTS ZILEUTON THALIDOMIDE WARFARIN TREPROSTINIL TETRATHIOMOLYBDATE TRIPLE THERAPY SILDENAFIL BMS-986020 SIMTUZUMAB OCTREOTIDE TRALOKINUMAB IFN-γ GC1008 LEBRIKIZUMAB FG-3019 IW001 ONGOING PENDING RESULTS N>30 www.clinicaltrials.gov

Combination clinical trials Agent Clinical Trials.gov registry number 1. Pirfenidone - NAC PANORAMA study Lancet RM-2016 Study design Endpoints Outcome Phase 4 Safety Well tolerable-mild photosensitivity enhancement in NAC group 2. Pirfenidone + Nintedanib NCT02598193 Phase 4, Open label, Non- Randomized, Single group 3. Pirfenidone + Nintedanib NCT02606877 Phase 4, Open label, Non- Randomized, Multiple-dose, Two group Safety and Tolerability Pirfenidone-nintedanib low risk, high synergy 4. Pirfenidone + Sildenafil NCT02951429 Phase 2, Randomized, Placebocontrolled Interaction in Pharmacokinetics Efficacy, safety, and tolerability Ongoing Ongoing Ongoing 5. Pirfenidone + Vismodegib NCT02648048 Phase 1, Open label, Single group 6. Pirfenidone + Lebrikizumab NCT01872689 Phase 2, Randomized, Placebocontrolled 7. Nintedanib + Sildenafil NCT02802345 Phase 2, Randomized, Placebocontrolled Safety, and tolerability Efficacy and safety Efficacy and safety Ongoing Ongoing Ongoing

Thyroid hormone blunts lung fibrosis through improvement of AECIIs mitochondrial function Tzouvelekis A, Yu G et al. Nature Medicine (accepted)

Choosing the right end-points for efficacy trials

Cluster 1 Cluster 2 TFS Chicago IPF cohort TFS Pittsburgh IPF cohort P=0.019 HR:3.30 95%CI:1.16-9.37 HR:1.96 CI:1.01 3.8

Take Home Messages 5-yrs personal view Στόχευση εξωκυτταρίου θεμελίου ουσίας - Η πλειοψηφία τους έχει αποτύχει Θεραπεία για όλους τους φαινότυπους ασθενών- Personalized medicine Πρωτογενή καταληκτικά σημεία βιοχημικοί δείκτες (biomarkers) Ογκολογική θεραπευτική προσέγγιση Οξείες Παροξύνσεις νόσου????? Συνοσηρότητες (καρκίνος, πνευμονική υπέρταση)???? Αταξινόμητες ILDs (30% of total ILDs)????- Pirfenidone Tzouvelekis A et al. Pulm Pharm Ther 2017

Πρόκληση η 1

Ιστορικό Παρούσα Νόσος Άνδρας, 60 ετών, <5p/yrs, 180 cm, 90kg 2007: Ιδιοπαθής Υπερασβεστουρία- chlorothalidone 2007: Θυρεοειδίτιδα Hashimoto 02/01/2017: Μη παραγωγικός βήχας δύσπνοια προσπαθείας (ΙΙ/ΙV), από 6μήνο-δεκατική πυρετική κίνηση από 3ημέρου-ιδιώτης πνευμονολόγος Eργαστηριακές εξετάσεις: Hct: 47.1, Hgb: 14.1, WBCs: 17.450, CRP: 3.4 Aκτινογραφία θώρακος Moxifloxacin-7d Α/Ε: SaO2: 96%-FiO2: 21%, HR: 75bpm, clubbing (-/-), ΜΜΡ +/+,κφ κατά τα λοιπά συστήματα Δεν αναφέρει Raynaud, αρθραλγίες, μυαλγίες, πρωινή δυσκαμψία Σπιρομέτρηση: FVC: 73%, Tif: 81.6, TLC: 48%, DLCO:39% 6MWD: 410m, 98% (start) 88% (end) HRCT

HRCT-Ιανουάριος 2017

HRCT-Ιανουάριος 2017

HRCT-Ιανουάριος 2017 Fibrotic NSIP

Επόμενο βήμα Βρογχοσκόπηση Ανοσολογικός έλεγχος Βρογχοσκόπηση και ανοσολογικός έλεγχος Παρακολούθηση και επανέλεγχος σε 6 μήνες Κανένα από τα παραπάνω

Φεβρουάριος 2017 Βρογχοσκόπηση: MΦ: 52%, Λεμφοκύτταρα:37%, Εωσινόφιλα:8%, Πολυμορφοπύρηνα: 3% Ανοσολογικός έλεγχος: ΑΝΑ:1/640, Ra test, ENA panel: negative

Επόμενο βήμα VATS-Βιοψία Πνεύμονος Cryobiopsy TBB Έναρξη υψηλών δόσεων κορτικοστεροειδών (>20 mg/kg) Παρακολούθηση και επανέλεγχος σε 6 μήνες

??????

VATS

IPAF UIP-HCM

Καταλληλότερη θεραπεία Υψηλές δόσεις κορτικοστεροειδών (>20mg) και κυκλοφωσφαμίδη Χαμηλές δόσεις κορτικοστεροειδών (10-15mg) + αντι-ινωτικό Αντι-ινωτικό Παρακολούθηση

Lancet Respir Med. 2016;4(10):770-772

Possible and definite UIP Συμπεριφέρονται το ίδιο, ανταποκρίνονται το ίδιο Raghu et al. Am J Respir Crit Care Med 2017;195(1):78-85.

Πρόκληση η 2

HRCT PFTs 100 Value FVC 88% predicted FEV1/FVC 89% TLC 84% predicted DLco 78% predicted 90 80 70 60 FVC1 DLCO TLC 50 40 0 months 1 2

Παρακολουθώ και περιμένω? MICO? (Masterful Inactivity with cat-like observation)

Καθυστερημένη έναρξη αγωγής σχετίζεται με δυσμενή πρόγνωση P for trend = 0.04 Lamas et al. Am J Respir Crit Care Med. 2011;184:842-847.

Απρόβλεπτη κλινική πορεία νόσου Slow progressors Rapid progressors Acute exacerbations Ley et al. AJRCCM 2011;183:431-440

HRCT PFTs 100 Value FVC 74% predicted FEV1/FVC 88% TLC 68% predicted DLco 66% predicted 90 80 70 60 FVC1 DLCO TLC 50 40 0 months 20 months 1 2

Η ανταπόκριση στο nintedanib ισχύει και σε ασθενείς με διατηρημένους πνευμονικούς όγκους n=17 ΔFVC%pred -3.2 n=67-4.7 FVC>80% FVC 80% Kolb et al. Thorax 2017;72:340-46 *Deaths (n=14) were considered as censored and excluded from the analysis, 52 weeks

Η ανταπόκριση στην pirfenidone ισχύει και σε ασθενείς με διατηρημένους πνευμονικούς όγκους