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Pirfenidone for IPF: Data from Three Multinational Phase III Trials

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Pirfenidone for IPF: Data from Three Multinational Phase III Trials Thank you for viewing this presentation. We would like to remind you that this material is the property of the author. It is provided to you by the ERS for your personal use only, as submitted by the author. 2016 by the author UNIVERSITY OF CRETE SCHOOL OF MEDICINE Lung Fibrosis and Sarcoidosis: Diagnostic and therapeutic standards Katerina M. Antoniou, MD, PhD ERS 1.5 Group Chair Dept of Thoracic Medicine Faculty of Medicine, ERS International Congress Heraklion, Crete 1-6 September, London 2016 2 Conflict of interest disclosure I have no real or perceived conflicts of interest that relate to this presentation. I have the following real or perceived conflicts of interest that relate to this presentation: This event is accredited for CME credits by EBAP and EACCME and speakers are required to disclose their potential conflict of interest. The intent of this disclosure is not to prevent a speaker with a conflict of interest (any significant financial relationship a speaker has with manufacturers or providers of any commercial products or services relevant to the talk) from making a presentation, but rather to provide listeners with information on which they can make their own judgments. It remains for audience members to determine whether the speaker’s interests, or relationships may influence the presentation. The ERS does not view the existence of these interests or commitments as necessarily implying bias or decreasing the value of the speaker’s presentation. Drug or device advertisement is forbidden. “Fibrosis and resultant organ failure account for at least one third of deaths worldwide. Since fibrosis is common and has adverse effects in all organs, it is an attractive therapeutic target. Contrary to the widely held perception that scar tissue is permanent, the available evidence points to the highly plastic nature of organ fibrosis.” NEJM 2015; 372: 1138-494 NEJM 2015; 372: 1138-495 Definition The IIPs are a heterogeneous group of non neoplastic disorders resulting from damage to the lung parenchyma by varying patterns and combinations of inflammation, immune dysregulation and fibrosis. Am J Respir Crit Care Med 2002; 165: 277-304 6 Am J Respir Crit Care Med Vol 188, Iss. 6, pp 733–748, Sep 15, 2013 7 IPF is the most common type of idiopathic interstitial pneumonia Interstitial lung disease (ILD) ILD of known causes Granulomatous ILDs Idiopathic interstitial Unique entities (drugs, collagen vascular (sarcoidosis, fungal, pneumonias (IIPs) (PAP, LCH, EP, LAM) disease, exposures) mycobacterial) Major IIPs Rare IIPs Unclassifiable 1. Inadequate data* LIP: lymphocytic Chronic fibrosing Smoking-related Acute / sub-acute 2. Major discordance interstitial pneumonia between findings* PPFE: IPF: idiopathic RB-ILD: respiratory COP: cryptogenic pleuroparenchymal pulmonary fibrosis bronchiolitis ILD organising pneumonia fibroelastosis NSIP: non-specific DIP: desquamative AIP: acute interstitial interstitial pneumonia interstitial pneumonia pneumonia *Clinical, radiological, pathological EP, eosinophilic pneumonia; Adapted from: American Thoracic Society / European Respiratory Society; LAM, lymphangioleiomyomatosis; Am J Respir Crit Care Med 2002;165:277-304 LCH, Langerhans’ cell histiocytosis; Ryerson CJ et al. Curr Opin Pulm Med 2013;19:453-459 PAP, pulmonary alveolar proteinosis Travis WD et al. Am J Respir Crit Care Med 2013;188:733-748 8 9 10 IPF overview • The most prevalent and lethal type of chronic, progressive, fibrosing, interstitial pneumonia • While the cause is unknown, IPF is thought to result from repeated micro-injury and abnormal wound repair, leading to progressive fibrotic change and irreversible loss of function • Annual European incidence estimated at 0.22–7.4 / 100 000 person-years – Predominance in older patients; mean age at diagnosis being 65 years • Prognosis typically extremely poor – Median survival time of 2–5 years from diagnosis – Estimated 5-year survival rate is 20–40%, worse than for many leading cancer Raghu G et al. Am J Respir Crit Care Med 2011;183:788-824 Nalysnyk L et al. Eur Respir Rev 2012;21:355-361 du Bois RM. Eur Respir Rev 2012;21:141-146 Valeyre D. Eur Respir Rev 2011;20:108-113 Kim DS et al. Proc Am Thorac Soc 2006;3:285-292 11 Is screening realistic in IPF? • Based on current outcome data and prevalence, no • A clinical renaissance based on the stethoscope is appealing (but may not be enough) Cottin V, Cordier JF. Eur Respir J 2013;41:250-1 • However, early detection of IPF might be piloted as an ‘add-on’ to existing screening programmes • Spirometric screening and CT screening for lung cancer are two programmes that might be attractive Antoniou KM et al. Lancet Respir Med 2014;2:e1 12 Natural history of IPF: disease progression is inevitable yet unpredictable Patient at baseline Unknown disease course before progression Slowly progressive Episodes of acute Rapidly progressive respiratory worsening Respiratory function / symptoms / function Respiratory 0 1 2 3 4 Median survival following diagnosis (years) Modified from Kim DS et al. Proc Am Thorac Soc 2006;3:285-292 13 IPF: poor prognosis in advanced disease 100 UIP/IPF Nonspecific interstitial pneumonia 80 Other IIPs 60 40 Survival (%) Survival 20 0 0 2 4 6 8 10 12 14 16 18 Time after diagnosis (years) Bjoraker JA et al. Am J Respir Crit Care Med 1998;157:199-203 14 Presenting features • Physicians should be aware of IPF when assessing a patient with the following clinical features and when considering requesting a chest X-ray or referring to a specialist1 Unexplained Persistent chronic cough1 exertional dyspnea1,2 Bilateral inspiratory Age over 50 crackles when years2 listening to the base of the lung1 Normal or impaired spirometry with a Clubbing of IPF? restrictive or the fingers1 occasionally, obstructive pattern1 1. NICE Clinical Guidelines 163: Idiopathic Pulmonary Fibrosis June 2013; 2. Raghu G et al. Am J Respir Crit Care Med 2011;183:788–824. 15 Am J Respir Crit Care Med 2011; 183: 788 The guidelines are now broken because there is no clear answer to ……….. 16 Diagnosis of IPF The diagnosis requires: Exclusion of known causes of interstitial lung diseases: domestic/occupational environmental exposures, connective tissue disorders or drug toxicity The presence of a UIP pattern on HRCT, defined by the following four features, will give a confident IPF diagnosis - Sub-pleural basal predominance - Reticular abnormality - Honeycombing with or without traction bronchiectasis - Absence of features inconsistent with UIP pattern When all these features are confirmed by HRCT, a surgical lung biopsy is not essential for confirmation of IPF diagnosis In the absence of a UIP pattern on HRCT, a surgical lung biopsy is required for confident diagnosis Raghu G, Collard HR, Egan JJ, et al. Am J Respir Crit Care Med 2011;183:788-824. 17 SuspectedSuspected IPFIPF IdentifiableIdentifiable causecause forfor ILD?ILD? YES (CTD,(CTD, drugs, drugs, exposures, exposures, ...) ...) NO Chest HRCT Not UIP Possible UIP UIP Inconsistent with UIP Surgical lung biopsy Not UIP UIP Possible UIP / Probable UIP Non classifiable fibrosis MDD IPF Not IPF IPF / Not IPF 18 HRCT: Criteria for UIP pattern UIP pattern1 Possible UIP pattern1 Inconsistent with UIP pattern1 (All four features) (All three features) (Any of the seven features) • Subpleural, basal predominance • Subpleural, basal predominance • Upper or mid-lung predominance • Reticular abnormality • Reticular abnormality • Peribronchovascular predominance • Honeycombing with or without • Absence of features listed as • Extensive ground-glass abnormality traction bronchiectasis inconsistent with UIP pattern • Profuse micronodules • Absence of features listed as • Discrete cysts inconsistent with UIP pattern • Diffuse mosaic attenuation/air- trapping • Consolidation in bronchopulmonary segment(s)/lobe(s) Definite UIP pattern2 Possible UIP pattern2 Inconsistent with UIP pattern2 HRCT: high-resolution computed tomography; UIP: usual interstitial pneumonia. 1. Raghu G et al. Am J Respir Crit Care Med 2011;183:788–824; 2. Sverzellati N. Respir Res 2013;14:S3. 19 The CT spectrum of IPF 55% Definite UIP Inconsistent Possible UIP with UIP 40% 5–10% 20 Contraindications to biopsy • Severity • Age • Comorbidity • Lack of timely access • Patient disinclination • The ATS / ERS / JRS / ALAT recommendation to biopsy ‘possible UIP’ can be carried out in perhaps 15% of cases ALAT, Latin American Thoracic Association; ATS, American Thoracic Society; ERS, European Respiratory Society; JRS, Japanese Respiratory Society Wells AU et al. Respir Res 2013;14:S2 21 IPF- Comorbidities • IPF is associated with a number of comorbidities including PAH,1 emphysema,2 lung cancer,2 coronary artery disease,3 diastolic dysfunction,4 GERD,5 sleep disorders,6 endocrine disorders and psychiatric disturbances7 • These conditions can develop as a result of IPF (e.g. PAH), common risk factors (such as smoking) or, in the case of GERD, may be a causative factor in IPF • These conditions affect quality of life and in some studies have been linked to mortality1–3 • However their impact on outcomes in patients with IPF is not well understood 1. Lettieri CJ, et al. Chest.2006; 129:746–52; 2. Tomassetti S et al. Chest. 2015; 147:157–64; 3. Nathan SD et al. Respir Med. 2010; 104:1035–41; 4. Papadopoulos CE et al. Eur Respir J. 2008; 31:701–6; 5. Lee JS et al. Am J Respir Crit Care Med. 2011; 184:1390–4; 6. Mermigkis C et al. Lung. 2007; 185:173–8; 7. De Vries J et al. Eur Respir J. 2001; 17:954–61. 22 GERD, gastro-esophageal reflux disease; IPF, idiopathic pulmonary fibrosis; PAH, pulmonary arterial hypertension. 22 23 Results Comorbidities • Mean number of comorbidities per patient was 2.68±1.83 • 157 patients (57.7%) had CV comorbidity, 21 (7.7%) had CNS comorbidity, 133 (48.9%) had pulmonary comorbidities and 60 (22.1%) had cancers 20.6% 18.4% 18.8% 12.5% 11.4% 10.3% 4.4% 3.3% 24 CNS, central nervous system; CV, cardiovascular. 24 IPF comorbidome • Nine comorbidities had an overall prevalence >10% Red = CV Green = pulmonary Orange = others Circle size relates to prevalence.
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