1. Emerging Approaches to Treatment of IPF Gregory P. Cosgrove, MD Associate Professor, Pulmonary Division Assistant Director, Interstitial Lung Disease Program Medical Director, Minimally Invasive Diagnostic Center National Jewish Health Associate Professor Division of Pulmonary Sciences and Critical Care Medicine University of Colorado Denver, Colorado

2. Faculty Disclosure It is the policy of The France Foundation to ensure balance, independence, objectivity, and scientific rigor in all its sponsored educational activities. All faculty participating in this activity will disclose to the participants any significant financial interest or other relationship with manufacturer(s) of any commercial product(s)/device(s) and/or provider(s) of commercial services included in this educational activity. The intent of this disclosure is not to prevent a faculty member with a relevant financial or other relationship from participating in the activity, but rather to provide participants with information on which they can base their own judgments. The France Foundation has identified and resolved any and all faculty conflicts of interest prior to the release of this activity. Gregory P. Cosgrove, MD, has served as a consultant for the Medical Advisory Board and the Pulmonary Fibrosis Foundation.

3. Learning Objective Describe the evidence-based diagnosis and management of IPF recommended in the 2011 ATS/ERS guidelines

4. What is interstitial lung disease and pulmonary fibrosis?

5. Normal Lung Histology

6. Interstitial Lung Disease Inflammation

7. Interstitial Lung Disease Fibrosis

8. Interstitial Lung Disease Combination of inflammation and fibrosis

9. Normal Lung Explant

10. IPF Lung Explant

11. Interstitial Lung Disease

14. Incidence: > 30,000 patients/year Prevalence: > 80,000 current patients Age of onset: most 40–70 years Two-thirds > 60 years old at presentation Males > females ATS/ERS/JRS/ALAT Statement. Am J Respir Crit Care Med. 2011;183:788-824. Raghu G, et al. Am J Respir Crit Care Med. 2006;174:810-816. US Demographics of IPF 0 50 100 150 200 250 300 45-5455-6465-7475+ Male Female 0 20 40 60 80 100 120 45-5455-6465-7475+ Male Female Prevalence Incidence Per 100,000

15. ATS/ERS/JRS/ALAT Statement. Am J Respir Crit Care Med. 2011;183:788-824. Raghu G, et al. Am J Respir Crit Care Med. 2006;174:810-816. Risk Factors for IPF Risk factors – Familial – Smoking Possible associated factors – Environment (eg, wood or metal dust)  Farming, raising birds, hair dressing, stone cutting, exposure to vegetable/animal dust or livestock – Gastroesophageal reflux disease (GERD) – Infectious agents – Gene-x-environment

16. Current Definition of IPF Distinct chronic 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.

17. Current Definition of IPF Exclusion of other known causes of ILD Presence of UIP pattern on HRCT imaging in those patients without a surgical lung biopsy ATS/ERS/JRS/ALAT Statement. Am J Respir Crit Care Med. 2011;183:788-824.

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

19. HRCT Criteria for a UIP Pattern

20. Diagnostic Integration of Radiographic and Pathologic Features ATS/ERS/JRS/ALAT Statement. Am J Respir Crit Care Med. 2011;183:788-824.

21. Conditions Associated With an HRCT Pattern of UIP IPF Toxic drug reactions Chronic hypersensitivity pneumonitis Connective tissue diseases Asbestosis Acute interstitial pneumonia

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

23. Role of Bronchoscopy in the Diagnosis of IPF “Transbronchial biopsy should not be used in the evaluation of IPF in the majority of patients, but may be appropriate in a minority.” (weak) “Recognition of a predominantly inflammatory cellular pattern (increased lymphocytes, eosinophils, or neutrophils) in the BAL differential cell profile frequently helps the clinician narrow the differential diagnosis of ILD, even though such patterns are nonspecific.” ATS/ERS/JRS/ALAT Statement. Am J Respir Crit Care Med. 2011;183:788-824. Meyer KC, et al. Am J Respir Crit Care Med. 2012;185:1004-1014.

24. The Suggested Natural History of Patients with IPF Adapted from ATS/ERS/JRS/ALAT Statement. Am J Respir Crit Care Med. 2011;183:788-824.

25. IPF Prognosis Ley B, et al. Am J Respir Crit Care Med. 2011;183:431-440. Swigris JJ, et al. Chest. 2009;136:841-848 Prasse A, et al. Respirology. 2009;14:788-795. Rosas IO, et al. PLoS Med. 2008;5:e93

26. IPF Prognosis ATS/ERS/JRS/ALAT Statement. Am J Respir Crit Care Med. 2011;183:788-824.

27. Monitoring Patients with IPF Every 3 to 6 months: – Spirometry – Diffusion – 6MWT – QOL (patient questionnaire to assess dyspnea) – O 2 requirement – Comorbidities HRCT should be done only with clinical change

28. Diagnosis Take Home Messages Typical clinical features include age > 50 years, gender (male > female), insidious onset of dyspnea, nonproductive cough, and bibasilar Velcro ® crackles Atypical clinical or HRCT findings in a patient with suspected IPF should prompt consideration of a surgical lung biopsy. With a confident clinical and HRCT diagnosis, a biopsy is not recommended IPF has characteristic UIP histopathologic features that enable definitive diagnosis when clinical and HRCT findings are inconclusive

29. Monitoring Take Home Messages Both baseline and dynamic factors measured during monitoring of IPF are associated with an increased risk of mortality Prognostic indicators do not fully predict the course of disease for an individual patient Patients should be monitored every 3 to 6 months for comorbidities and progression of IPF

30. 46-year-old female presents with 3 months of cough and dyspnea Notices some increase in cough in her home but decreased cough while visiting relatives Exam notable for mid- late inspiratory crackles and squeaks Case 1

33. Diagnostic Algorithm for Patients with Suspected ILD ATS/ERS/JRS/ALAT Statement. Am J Respir Crit Care Med. 2011;183:788-824.

34. Case 1

35. 67-year-old male presents with 2-3 years of cough and progressive dyspnea Exam unremarkable except for mid-late inspiratory crackles and clubbing Case 2

39. Diagnostic Algorithm for Patients with Suspected ILD ATS/ERS/JRS/ALAT Statement. Am J Respir Crit Care Med. 2011;183:788-824.

40. Nonpharmacologic Therapies Long-term oxygen therapy Formal pulmonary rehabilitation programs are preferred for initiation of exercise Lung transplantation – Weight reduction Mechanical ventilation ATS/ERS/JRS/ALAT Statement. Am J Respir Crit Care Med. 2011;183:788-824.

41. Evaluation for Lung Transplantation Early referral SpO 2 ≤ 88% 1 – Defines desaturation on 6MWT – Calls for O 2 supplemented 6MWT – Distinguishes early/advanced disease Lung Allocation Score (LAS) used to prioritize candidates 2 – Survival on list (urgency) – Survival posttransplant (benefit) 1.Lama VN, et al. Am J Respir Crit Care Med. 2003;168:1084-1090. 2.A Guide to Calculating the Lung Allocation Score. http://www.unos.org/docs/lung_allocation_score.pdf. Accessed January 2013.

42. Pulmonary Rehabilitation Objectives Pulmonary Rehabilitation. http://www.pilotforipf.org/resources/PtCounseling_07.pdf. Accessed January 2013. Decrease respiratory symptoms and complications Permit a return to work or leisure activities Increase control over daily functioning Improve physical conditioning and exercise performance Improve emotional well-being

43. Treatment of Comorbidities in IPF Obstructive sleep apnea Gastroesophageal reflux disease (GERD) Smoking Obesity Pulmonary hypertension Exacerbation of IPF ATS/ERS/JRS/ALAT Statement. Am J Respir Crit Care Med. 2011;183:788-824.

44. Offer high standard of care Add to patient empowerment Burdens – May require travel – Frequent visits to research center Clinical Trial Participation Clinicaltrials.gov. http://www.clinicaltrials.gov/ct2/results?term=ipf. Accessed January 2013.

45. Patient Tool: Clinical Trial Participation Clinical trials as a treatment option for IPF. http://www.pilotforipf.org/resources/PILOTPamphlet1.pdf. Accessed January 2013. What is a clinical trial? Questions to ask the physician First steps in participation Benefits and risks

46. Safety and Efficacy Study of Pirfenidone to Treat Idiopathic Pulmonary Fibrosis (IPF) Extension Trial of the Long Term Safety of BIBF 1120 in Patients With Idiopathic Pulmonary Fibrosis Evaluating the Effectiveness of Prednisone, Azathioprine, and N-acetylcysteine in People With Idiopathic Pulmonary Fibrosis (PANTHER-IPF) Phase 3 Clinical Trials at www.ClinicalTrials.gov Clinicaltrials.gov. http://www.clinicaltrials.gov/ct2/results?term=treatment and ipf. Accessed January 2013.