PFF Teal = MAIN COLORS PFF Green = Light Green = Red = HIGHLIGHT COLORS Light Grey = Dark Grey = Black = APPROVED DRUGS FOR IPF: SHOULD THEY BE STUDIED FOR NON-IPF PULMONARY FIBROSIS? KEVIN K. BROWN, MD CLINICAL CARE: NEW AND EVOLVING TREATMENT STRATEGIES NOVEMBER 14, 2015
Yes
Questions to consider: 1. Are we treating a single disease, a syndrome or a pathologic mechanism that manifests as progressive pulmonary fibrosis? 2. Is the treatment safe in the population? 3. Is the treatment efficacious in the population?
In 2015 the diagnosis of IPF requires: 1. Exclusion of other known causes of interstitial lung disease (e.g., domestic exposures, connective tissue disease, and drug toxicity). 2. The presence of a UIP chest imaging pattern on HRCT in patients not subjected to surgical lung biopsy. 3. Specific combinations of HRCT chest imaging patterns and pathologic patterns in patients who undergo a surgical lung biopsy.
Screen failures in the recent Pirfenidone trial
Comparison of Selected Inclusion/Exclusion Criteria
Not performed UIP Probable UIP Possible UIP Not UIP UIPIPF Not IPF Possible UIP Unclassifiable IPF Some are IPF, some are not Not IPF Inconsist- ent with UIP Unclassifiable Some are IPF, some are not Not IPF Lung Biopsy HRCT Not IPF per guidelines IPF per guidelines ASCEND INPULSIS Courtesy: Hal Collard
The Problem with Chest Imaging
Trial Design Comparison: ASCEND vs. CAPACITY
Measuring Agreement Among Observers Kappa ValueStrength of Agreement < 0Poor 0–0.2Slight 0.2–0.4Fair 0.4–0.6Moderate 0.6–0.8Substantial 0.8–1.0Almost perfect Sackett DL, et al. Clinical Epidemiology: A basic science for clinical medicine; 1991:29. Landis JR, Koch GG. Biometrics. 1977;33: Clinically useful agreement Actual Agreement Beyond Chance Potential Agreement Beyond Chance Kappa = =
Inter-observer Variation among Radiologists Median (range) w coefficient of agreement IPF0.63 (0.48 – 0.78) NSIP0.51 (0.27 – 0.78) Sarcoidosis0.70 (0.58 – 0.84) Extrinsic allergic alveolitis0.60 (0.36 – 0.78) COP0.49 (0.06 – 0.76) Smoking related ILD0.51 (0.20 – 0.73) Aziz ZA et al, Thorax 2004 For CT diagnosis of pulmonary embolus Kappa = For CT diagnosis of cystic lung disease Kappa =
The Presence of Honeycombing on HRCT = 0.31 ( ) = 0.21 ( ) Agreement among experts and study site Agreement among expert readers Lynch et al, Am J Respir Crit Care Med 2005
The Presence of Honeycombing on HRCT = 0.31 ( ) = 0.21 ( ) Agreement among experts and study site Agreement among expert readers Lynch et al, Am J Respir Crit Care Med 2005
Agreement on the Presence of a UIP Pattern Lynch et al, Am J Respir Crit Care Med 2005 = 0.33 ( ) Agreement among expert readers
Thomeer M et al, Eur Respir J 2008
Weighted Kappa Among HRCT Reviewers Thomeer M et al, Eur Respir J 2008
Weighted Kappa Among HRCT Reviewers Thomeer M et al, Eur Respir J 2008
The Problem with Pathology
Kappa coefficients (k) between lobar and final diagnoses in 48 patients DiagnosisLobar diagnosis (n = 98) Final diagnosis (n = 48) UIP0.40 Moderate0.49 Moderate NSIP0.32 Fair OP HP Sarcoidosis Normal0.07N/A Overall0.39 Fair0.43 Moderate Nicholson AG et al, Thorax. 2004
Weighted Kappas Among 2 Pathologists Nicholson AG et al, Thorax. 2004
NSIP vs. UIP
Jegal. Am J Respir Crit Care Med 2005; 171:639 P=0.007 Kaplan-Meier survival curves of subjects with IPF and fibrotic NSIP
FVC change > 10% p=0.01 Flaherty, Am J Resp Crit Care Med, 2003 Change in FVC predicts survival in IPF and NSIP
Jegal. Am J Respir Crit Care Med 2005; 171:639 Change in FVC predict survival in IPF and NSIP
Baseline Predictors of Survival Jegal et al, Am J Respir Crit Care Med 2005
Predictors of Survival at 6 Months Jegal et al, Am J Respir Crit Care Med 2005
Predictors of Survival at 6 Months Jegal et al, Am J Respir Crit Care Med 2005
IPF vs. Fibrotic HP
UIP NSIP CIP or OP Ohtani et al, Thorax 2005 Pathologic Pattern predicts mortality in HP
Vourlekis et al, Am J Med 2004 Fibrosis predicts mortality in HP p = median survival 7.1 yrs median survival > 20 yrs
Hanak et al, Chest 2008 Presence of CT Fibrosis predicts survival
IPF Mortality is related to CT Disease Extent 3 / 8 (38%) 23 / 93 (25%) 17 / 179 (9%) 1 / 35 (3%) Disease Extent Mortality (%) Lynch et all, Am J Respir Crit Care Med 2005
Extent of CT Fibrosis predicts survival in HP Hanak et al, Chest 2008
Olson et al, Chest 2008
Survival is shortened in RA Solomon JJ et al, Resp Med 2013
ExRA shortens survival in RA Solomon JJ et al, Resp Med 2013
ILD shortens survival in RA Solomon JJ et al, Resp Med 2013
Fibrotic ILD shortens survival in RA Solomon JJ et al, Resp Med 2013
Survival with RA-UIP is Similar to IPF Solomon JJ et al, Resp Med 2013
Moua T et al, Resp Res 2014
Strand et al, Chest 2014 Idiopathic Pulmonary Fibrosis (IPF)
Connective Tissue Disease-UIP Strand et al, Chest 2014
Corte T, et al 2012 Eur Respir 39:
Moua T et al, Mayo Clin Proc 2014 Positive serologies in IPF have no impact on mortality
Park et al, Chest 2007
AE-PF Clinical context and Prognosis Huie et al, Respirology 2010 Underlying Diagnosis IPF CTD-ILD UIP pattern RA UCTD NSIP pattern UCTD SSc Dermatomyositis LIP Drug-induced ILD Unclassified
IPF-like IPF Probable IPF Not IPF IP-AF Fibrotic HP fNSIP ARDS Possible IPF Sarcoidosis CTD-ILD
The diagnosis of IPF remains a challenge and many IPF patients do not meet our current diagnostic criteria The presence of fibrosis in the setting of IPAF, connective tissue disease, and hypersensitivity pneumonitis is associated a similar clinical course and early mortality It is the presence of progressive pulmonary fibrosis that is the problem The rationale and opportunity to study the safety and efficacy of current IPF therapy in non-IPF pulmonary fibrosis exists and is compelling Summary