nterstitial ungdiseases euven Department of pneumology Unit for interstitial lung diseases University Hospitals Leuven March 12 th 2015 Interstitial lung diseases state of the art Treatment of idiopathic interstitial pneumonias Wim Wuyts Unit for interstitial lung diseases Department of pneumology UZ Leuven www.longfibrose.be
Introduction Treatment Pharmacological Non-IPF IPF Non-pharmacological Lung transplantation Pulmonary rehabilitation Challenges Treatment of IIP
Introduction
Classification of Interstitial Lung Disease Known Causes Drugs Collagen Vascular Exposures Genetic IIPs: Idiopathic Interstitial Pneumonias Granulomatous Lung Diseases Sarcoidosis Fungal Mycobacterial Unique Entities PAP EG and EP LAM Capillaritis American Thoracic Society/European Respiratory Society. Am J Respir Crit Care Med 2002;165:277-304. Travis et al. Am J Respir Crit Care Med. 2013: 188: 733-748
Classification of Interstitial Lung Disease Known Causes Drugs Collagen Vascular Exposures Genetic IIPs: Idiopathic Interstitial Pneumonias Granulomatous Lung Diseases Sarcoidosis Fungal Mycobacterial Unique Entities PAP EG and EP LAM Capillaritis IPF: Idiopathic Pulmonary Fibrosis American Thoracic Society/European Respiratory Society. Am J Respir Crit Care Med 2002;165:277-304. Travis et al. Am J Respir Crit Care Med. 2013: 188: 733-748
Classification of Interstitial Lung Disease Known Causes Drugs Collagen Vascular Exposures Genetic IIPs: Idiopathic Interstitial Pneumonias Granulomatous Lung Diseases Sarcoidosis Fungal Mycobacterial Unique Entities PAP EG and EP LAM Capillaritis 55% IPF: Idiopathic Pulmonary Fibrosis 25% insip: Nonspecific Interstitial Pneumonia RB-ILD: Respiratory Bronchiolitis Interstitial Lung Disease 10 15% <2% AIP: Acute Interstitial Pneumonia DIP: Desquamative Interstitial Pneumonia 5% COP: Cryptogenic Organizing Pneumonia American Thoracic Society/European Respiratory Society. Am J Respir Crit Care Med 2002;165:277-304. Travis et al. Am J Respir Crit Care Med. 2013: 188: 733-748
Classification of Interstitial Lung Disease Known Causes Drugs Collagen Vascular Exposures Genetic IIPs: Idiopathic Interstitial Pneumonias Granulomatous Lung Diseases Sarcoidosis Fungal Mycobacterial Unique Entities PAP EG and EP LAM Capillaritis 55% IPF: Idiopathic Pulmonary Fibrosis 25% insip: Nonspecific Interstitial Pneumonia RB-ILD: Respiratory Bronchiolitis Interstitial Lung Disease 10 15% Rare IIPs: ilip IPPFE <2% AIP: Acute Interstitial Pneumonia DIP: Desquamative Interstitial Pneumonia Unclassifiable IIPs 5% COP: Cryptogenic Organizing Pneumonia American Thoracic Society/European Respiratory Society. Am J Respir Crit Care Med 2002;165:277-304. Travis et al. Am J Respir Crit Care Med. 2013: 188: 733-748
prognosis IPF 100 80 Non-specific interstitial pneumonia Other IIPs p < 0.001 rank sum test Survival (%) 60 40 20 0 0 2 4 6 8 10 12 Time after diagnosis (years) 14 16 18 IPF: Idiopathic pulmonary fibrosis IIPs: Idiopathic interstitial pneumonias Bjoraker JA et al. Am J Respir Crit Care Med 1998;157:199-203.
IIP Pharmacological treatment
IIP treatment General approach for ILD Rule out Exposure CTD IPF Non-IPF IIP Mainstay still immunosupressive therapy If no clear effect of immunosupressive agents: consider atypical IPF
IPF Pharmacological treatment
N-Acetyl cysteine IFIGENIA trial Absolute change in FVC: 0.18l Guidelines: weak negative But clinical practice Triple therapy: mainstay Many patients treated with N- Acetylcysteine monotherapy!
NIH starts Panther trial: 3 arms placebo NAC monotherapy CS/AZA/NAC 60 weeks treatment Aim 390 patients N-Acetylcysteine Interim results (238/390 enrolled) placebo CS/AZA/NAC Mortality 11% - 1% Hospital admissions 29% - 8% CS/AZA/NAC stopped 21/10/2011!!! Main message CS/AZA/NAC should no longer be initiated in new patients
N-Acetylcysteine: PANTHER PART II Remaining arms (264 enrolled) placebo NAC Results No difference in change of FVC w60 No differences in secondary outcomes Main message CS/AZA/NAC should no longer be initiated in new patients No evidence for NAC monotherapy Results of PANORAMA trial awaitened
Current IPF treatment: Pirfenidone
Capacity 1 + 2 Baseline Characteristics 004 006 Characteristic* PFD 1197 mg (n=87) PFD 2403 mg (n=174) Placebo (n=174) PFD 2403 mg (n=171) Placebo (n=173) FVC (% predicted) 76.4 74.5 76.2 74.9 73.1 DLCO (% predicted) 47.2 46.4 46.1 47.8 47.4 6MWT distance (m) 418 411 410 378 399 Supplemental O 2 use (%) 17 17 14 28 28 HRCT Definite IPF (%) 95 91 94 87 91 Surgical lung biopsy (%) 37 49 49 55 54 Smoking status (%) Never 31 32 29 35 37 Former 66 63 66 65 58 Current** 3 5 5 0 5 *Values are expressed as the number (%) or mean unless otherwise indicated **According to protocol patients had to stop smoking prior to inclusion in the study Patients in rather early or moderate stage of disease!!! Noble PW, Albera C, Bradford WZ, et al. Lancet. 2011;377:1760-1769.
PIPF-004: % Predicted FVC Change at Week 72 0 Mean change from baseline in %FVC -5-10 Pirfenidone 2403 mg/d Pirfenidone 1197 mg/d Placebo -15 0 12 24 36 48 60 72 Pirfenidone 2403 mg/d vs Placebo Absolute difference, % 1.4 2.5 Weeks 4.6 4.8 4.1 4.4 Relative difference, % 53.5 65.2 63.7 52.3 38.3 35.3 P-value 0.061 0.014 <0.001 <0.001 <0.001 0.001 Noble PW, Albera C, Bradford WZ, et al. Lancet. 2011;377:1760-1769.
PIPF-006: % Predicted FVC Change at Week 72 Pirfenidone 2403 mg/d Placebo Absolute difference, % -0.4 2.8 2.4 1.9 0.6 0.6 Relative difference, % -31.5 62.1 48.2 27.3 7.6 6.5 P-value 0.021 <0.001 0.011 0.005 0.172 0.501 Noble PW, Albera C, Bradford WZ, et al. Lancet. 2011;377:1760-1769.
Current IPF treatment: Pirfenidone 2 Japasese trials: in favour of Pirfenidone 2 Capacity trials: primary end points: secondary endpoints pooled data positive positive EMA: approved Pirfenidone for IPF in Europe FDA: requested new trial: ASCEND trial
T King et al. ATS International Conference 2014 ASCEND Study design
ASCEND: Inclusion criteria HRCT: Confident diagnosis of IPF Definite UIP, or Possible UIP, with confirmation on SLB FVC: 50% and 90% percent of predicted DL CO : 30% and 90% percent of predicted FEV 1 /FVC ratio: 0.80 T King et al. New Engl J Med 2014; 370: 2083-92
T King et al. New Engl J Med 2014; 370: 2083-92 ASCEND Study design
ASCEND: primary efficacy analysis patients with >10% FVC or death Proportion of patients with >10%FVC decline or death T King et al. New Engl J Med 2014; 370: 2083-92
ASCEND: primary efficacy analysis mean change in FVC Mean change in FVC (ml) T King et al. New Engl J Med 2014; 370: 2083-92
ASCEND: primary efficacy analysis patients with >50m in 6MWD or death Proportion of patients with >50m decline in 6MWD or death T King et al. ATS New International Engl J Med 2014; Conference 370: 2083-92 2014
T King et al. New Engl J Med 2014; 370: 2083-92 ASCEND: Adverse events
T King et al. New Engl J Med 2014; 370: 2083-92 ASCEND + CAPACITY trials: pooled all cause mortality
Nintedanib tyrosine kinase inhibitor inhibits 3 RTK s: * vascular endothelial growth factor (VEGF) receptor * platelet derived growth factor (PDGF) receptor * fibroblast growth factor (FGF) receptor Richeldi L et al. N Engl J Med 2011;365(12):1079-87 Richeldi et al. N Engl J Med 2014 29;370(22):2071-82
Richeldi et al. N Engl J Med 2014 29;370(22):2071-82 Impulsis: inclusion criteria
Richeldi et al. N Engl J Med 2014 29;370(22):2071-82 Impulsis: baseline criteria
Richeldi et al. N Engl J Med 2014 29;370(22):2071-82 Impulsis: results Annual rate of decline
Richeldi et al. N Engl J Med 2014 29;370(22):2071-82 Impulsis: results investigator reported AE
Richeldi et al. N Engl J Med 2014 29;370(22):2071-82 Impulsis: adverse events
Richeldi et al. N Engl J Med 2014 29;370(22):2071-82 Impulsis: mortality
IIP Non Pharmacological treatment
3 000 Adult Lung Transplants Major Indications By Year (Number) CF IPF COPD Alpha-1 IPAH Re-Tx 2 500 Number of Transplants 2 000 1 500 1 000 500 0 Transplant Year 2013 JHLT. 2013 Oct; 32(10): 965-978
Adult Lung Transplants Survival by Diagnosis 100 80 Alpha-1 (N=2,624) CF (N=6,164) COPD (N=12,914) IPF (N=8,528) IPAH (N=1,400) Sarcoidosis (N=934) Survival (%) 60 40 20 0 Median survival (years): Alpha-1=6.3; CF=7.8; COPD=5.4; IPF=4.5; IPAH=5.2; Sarcoidosis=5.4 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 Years 2013 JHLT. 2013 Oct; 32(10): 965-978
Survival by Diagnosis and Age Group 100 80 COPD 18-49 (N=1,971) COPD 50-65 (N=10,190) COPD >65 (N=753) IPF 18-49 (N=1,936) IPF 50-65 (N=5,582) IPF >65 (N=1,010) Survival (%) 60 40 20 0 Median survival (years): COPD: 18-49 = 6.4; 50-65 = 5.4; >65 = 3.7 IPF: 18-49 = 5.7; 50-65 = 4.3; >65 = 3.8 0 1 2 3 4 5 6 7 8 9 10 Years 2013 JHLT. 2013 Oct; 32(10): 965-978
Survival according to diagnosis Leuven from 2002 on Actuarial survival 100 75 50 25 COPD ILD CF PAHT Brect redo 6,5y 0 0 365 730 1095 1460 1825 2190 2555 2920 3285 3650 Time (days) Courtesy G Verleden
IPF survival, S vs SSLTx in leuven Percent survival 100 75 50 25 SLTx SSLTx 0 0 365 730 1095 1460 1825 2190 2555 2920 3285 Time P=0.016 Courtesy G Verleden
Double lung do better in IPF 100 IPF/Single lung (N=4,920) 80 IPF/Double lung (N=3,606) Survival (%) 60 40 p < 0.0001 N at risk at 10 years = 125 N at risk = 18 20 N at risk at 10 years = 244 0 N at risk = 43 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 Years 2013 JHLT. 2013 Oct; 32(10): 965-978
ILD: new ISHLT guidelines When to refer? Histological of radiographical evidence for UIP or fnsip FVC < 80% or DLCO <40% Any dyspnea or functional limitation attributable to lung disease Oxygen requirement, even if only during exertion Inflammatory ILD: Medical therapy fails to improve dyspnea oxygen requirement and/or lung function When to transplant? Decline in FVC 10% during 6 months of follow-up 5% decline is associated with poorer prognosis and may warrant listing. Decline in DLCO 15% during 6m Desaturation to <88% or distance <250 m on 6MWD >50 m decline in 6MWD over 6m Pulmonary hypertension Hospitalization because of respiratory decline, pneumothorax, or acute exacerbation Weill D, Benden C, Corris PA, Dark JH et al. A consensus document for the selection of lung transplant candidates. J Heart Lung Transplant. 2015; 34: 1-15.
Pulmonary rehabilitation: goals Pulmonary rehabilitation is evidence-based, multi-disciplinary intervention for patients with chronic respiratory diseases who are symptomatic often have decreased daily life activities Pulmonary rehabilitation aims to reduce symptoms optimize functional status increase participation reduce health care costs www.ersnet.org and www.thoracic.org
COPD: muscle force 150 Healthy COPD % pred 100 50 0 PImax PEmax HF QF 6MWD Control 118cm 2 COPD 79.6cm 2 Bernard S., AJRCCM 1998;158: 629-634
PR feasible in ILD? p= 0,97 p<0,001 15000 150 steps.day -1 10000 5000 QF% 100 50 0 COPD ILD 0 COPD ILD Michielsen Chest 2006
Overview a role 402 (202 foripf) pulm prospective rehabilitation 6MWD in improved DPLD? Study Pt population Design Result Huppmann et al. (2012) SF-36 improved Ferreira et al (2009) 113 (50 IPF) retrospective 6MWD improved UCSD improved Holland et al (2008) 57 ILD (34 IPF) RCT 8 weeks training 6m FU 6MWD improved Max heart rate CRD improved Nishiyama et al (2008) 30 IPF Randomised controlled 6MWD improved SGRQ improved Ferreira et al 330 (43ILD) retrospective 6MWD improved CRDQ improved Jastrzebski et al (2006) 31 ILD Prospective SF-36 improved SGRQ improved Naji et al (2006) 19 ILD retrospective CRDQ improved SGRQ improved Foster et al 1990) 32 (7 ILD) Retrospective 6MWD improved
PR feasible in ILD? Current state of the art Patients with IPF Program Outpatient 9wks 2/wk 30 endurance training (cycling, walking) Functional strength training lower limbs Unsupervised home exercise Holland Thorax 2008
PR feasible in ILD? Current state of the art 6MWD 100 50 0-50 6MWD CRDQ (dys) 25 * * 20 CRDQ dys (points) 15 10 5-100 Base 9wks 26wks 0 Base 9wks 26wks Holland Thorax 2008
PR feasible in ILD? Current state of the art 32 Patients with IPF 2 groups Training Program 12 w 2/w 60 min supervised Control Regular medical treatment But after 11m No significant difference between 2 groups Vainshelboim B e al Respiration 2014; 88: 378-388 Vainshelboim B e al Lung epub march 3 2015
PR in ILD 600 Own experience 6MWD (m) 550 500 450 400 0 3 6 9 12 Time (months) 30 CRDQ (dyspnea) 25 20 15 10 0 3 6 9 12 Time (months) Vainshelboim B e al Respiration 2014; 88: 378-388 Vainshelboim B e al Lung epub march 3 2015
Challenges in pulmonary fibrosis
Case 1 69y old No signs of underlying CTD exposure CT: UIP pattern no biopsy
Case 2 SPIROMETRIE Pred. Meas. %Pred. ----------- ----- ----- ------ FVC (L) 3.91 1.86* 48 FEV1 (L) 3.00 1.67* 56 FEV1/FVC (%) 74.68 90.00* PEF (L/sec) 7.90 5.70* 72 FEF 25% (L/sec) 7.06 5.70 81 FEF 50% (L/sec) 4.12 4.18 102 FEF 75% (L/sec) 1.41 0.88 63 FEF 25-75%(L/sec) 3.09 2.69 87 MIF 50% (L/sec) 3.35 LONGV. PLETHYSMOGR. Pred. Meas. %Pred. ------------------- ----- ----- ------ VC (L) 4.07 1.86* 46 RV (Pleth) (L) 2.60 1.67* 64 TGV (Pleth) (L) 3.65 2.22* 61 TLC (Pleth) (L) 6.90 3.53* 51 DLCO: not possible to measure 6m ago: 31% Possible UIP pattern
if HRCT is non definite UIP biopsy needed But!!! Comorbidities Severe disease Introduction
There is more than the 2011 guidelines Study of 135 patients (IPF, n=97) With biopsy no honeycombing on HRCT Possible UIP on HRCT Age > 65 Ground glass < reticular shadowing 95% likelihood of UIP at biopsy Fell CD et al. Am J Respir Crit Care Med 2010;181:832-7.
Travis et al. Am J Respir Crit Care Med. 2013: 188: 733-748 Unclassifiable IIP
Spectrum of ILD LIP Acute HP ILD-CTD sarcoidosis DIP fnsip IPF COP cnsip AIP RB-ILD Chronic HP Inflammatory type Fibrotic type
Challenges Other relentless fibrotic disorders: fnsip Chronic HP ILD~CTD We need clinical trials Severe IPF? Treatment to reverse fibrosis Many challenges left in IIP
Diagnosis of IIP Rule out exposure Underlying CTD IPF IIP treatment conclusions Non-IPF: mainstay immunosupressive agents IPF: specific treatment available
IPF treatment Pirfenidone conclusions effect proven in 5 major trials Slows down FVC decline Pooled data of CAPACITY and ASCEND: mortality benefit Side effects are manageable in experienced hands Nintedanib Slows down FVC decline No significant effect on acute exacerbations No singificant effect on mortality (yet) Adverse events!
Lung transplantation conclusions Early referral necessary! Histological of radiographical evidence for UIP or fnsip FVC < 80% or DLCO <40% IPF patients seem to have slightly worse outcome Double lung TX do better Pulmonary rehabilitation Seems to be valid option More trials needed
Possible UIP pattern conclusions If Age >65y More fibrosis than inflammation on HRCT Highly likely to find UIP on biopsy Unclassifiable IIP Disease behaviour classification More options should be tested ILD is still a challenging field
Thank you for your attention