Slide 3 IPF: Definition and Diagnosis

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NEW APPROACHES TO MANAGING IDIOPATHIC PULMONARY FIBROSIS

BASIC FACTORS AFFECTING CLINICAL DECISION MAKING IN IPF Lack of understanding of disease Epidemiology Pathogenesis Natural history Genetic risk factors Lack of precise understanding of diagnosis Clinical criteria Utility of diagnostic tests Lack of understanding of treatment Benefits and risks Quality of life Survival Mapel DW et al. Chest. 1996;110:1058.

IPF: DEFINITION AND DIAGNOSIS

OVERVIEW Prevalence: 13–20/100,000 in US (approximately 35,000-55,000 cases) Onset: Usually between 50 and 70 yr Clinical presentation Progressive dyspnea on exertion Paroxysmal cough, usually nonproductive Abnormal breath sounds on chest auscultation Abnormal chest x-ray or HRCT Restrictive pulmonary physiology with reduced lung volumes and DLCO and widened AaPO2 Coultas DB et al. Am J Respir Crit Care Med. 1994;150:967. ATS/ERS. Am J Respir Crit Care Med. 2000;161:646.

ATS/ERS. Am J Respir Crit Care Med. 2000;161:646. CLASSIFICATION OF IIP (IMMUNOCOMPETENT HOST) Idiopathic pulmonary fibrosis/Usual interstitial pneumonia (UIP) Desquamative interstitial pneumonia (DIP) Respiratory bronchiolitis- associated interstitial lung disease (RBILD) Acute interstitial pneumonia (AIP) Nonspecific interstitial pneumonia (NSIP) Idiopathic interstitial pneumonia (IIP)

INTERNATIONAL CONSENSUS STATEMENT ON IPF: HISTOLOGY UIP is essential to diagnosis of IPF Idiopathic, progressive, diffuse fibrosing inflammatory process Involves lung parenchyma Surgical lung biopsy recommended in patients with suspected IPF, especially those with atypical clinical or radiographic features Major purpose of histologic examination is to distinguish UIP from other histologic subsets of IIP ATS/ERS. Am J Respir Crit Care Med. 2000;161:646.

DIAGNOSIS OF IPF Major criteria Exclusion of other known causes of ILD Abnormal pulmonary function studies Bibasilar reticular abnormalities on HRCT scan No histologic or cytologic features on transbronchial lung biopsy or BAL analysis supporting another diagnosis Minor criteria Age >50 yr Insidious onset of otherwise unexplained exertional dyspnea Duration of illness 3 mo Bibasilar, dry (“Velcro”) inspiratory crackles ATS/ERS. Am J Respir Crit Care Med. 2000;161:646.

Slide courtesy of KO Leslie, MD. HISTOPATHOLOGIC ELEMENTS OF UIP

Slide courtesy of KO Leslie, MD. TEMPORAL HETEROGENEITY OF UIP

INFLAMMATION AND FIBROSIS IN UIP Slide courtesy of KO Leslie, MD.

CHRONIC INTERSTITIAL INFLAMMATION IN UIP Slide courtesy of KO Leslie, MD.

Slide courtesy of KO Leslie, MD. FIBROBLASTIC FOCI IN UIP

Katzenstein ALA et al. Am J Respir Crit Care Med. 1998;157:1301. Feature UIP DIP/RBILD AIP NSIP Temporal appearance Variegated Uniform Uniform Uniform Interstitial inflammation Scant Scant Scant Usually prominent Collagen fibrosis Patchy Variable, diffuse No Variable, diffuse in DIP; focal, mild in RBILD Fibroblast proliferation Fibroblastic foci No Diffuse Occasional, diffuse, or rare fibroblastic foci Organizing pneumonia No No No Occasional, focal Honeycomb changes Yes No No Rare Intraalveolar macrophage Occasional, focal Diffuse in DIP; No Occasional, patchy accumulation peribronchiolar in RBILD Hyaline membranes No No Occasional, No focal CONTRASTING PATHOLOGIC FEATURES OF IIP

PROGNOSTIC FACTORS IN IPF

SURVIVAL OF PATIENTS WITH IPF 1.00 0.75 0. 50 0.25 0.00 0 20 40 60 80 100 120 Median survival of patients who died (N=41/74) = 28.2 mo Time from Onset of Symptoms (mo) Probability of Survival Schwartz DA et al. Am J Respir Crit Care Med. 1994;149:450.

Daniil ZD et al. Am J Respir Crit Care Med. 1999;160:899. Bjoraker JA et al. Am J Respir Crit Care Med. 1998;157:199. Years SURVIVAL FOR UIP VS NSIP Years 7 6 5 4 3 2 1 0 0 20 40 60 80 100 UIP NSIP 0 2 4 6 8 10 12 14 16 18 0 20 40 60 80 100 UIP NSIP Others % Alive

CAUSE OF DEATH IPF [N=543] 1-7 year FU 60% Died [N=326] Respiratory failure 39% Lung cancer 10% Pulmonary embolism 3% Pulmonary infection 3% Cardiovascular disease 27% Other 18% Panos RJ et al. Am J Med. 1990;88:396.

RISK FACTORS FOR PROGRESSIVE DISEASE Age: >50 yr Gender: male Dyspnea: moderate to severe with exertion History of cigarette smoking Lung function: moderate to severe loss (especially gas exchange with exercise) BAL fluid: neutrophilia or eosinophilia at presentation HRCT scan: reticular opacities or honeycomb changes Response to corticosteroids: poor Pathology: more fibrosis, fibroblastic foci

LUNG FUNCTION AND SURVIVAL 0 25 50 75 100 0 20 40 60 80 100 120 80 72 56 36 18 0 0 25 50 75 100 TLC≥45% TLC<45% ≤50th percentile >50th percentile FEV1/FVC Ratio Months p=0.04 p=0.002 Probability of Survival (%) Tukiainen P et al. Thorax. 1983;38:349. Schwartz DA et al. Unpublished data.

HRCT FINDINGS IN IPF Slide courtesy of G Raghu, MD.

100 75 50 25 0 Frequency of Improvement in Lung Function (%) HRCT Appearance Ground Glass Mixed Reticular N=11 Wells AU et al. Am Rev Respir Dis. 1993;148:1076. HRCT ABNORMALITIES AND CHANGES IN LUNG FUNCTION N=12 N=4

HRCT APPEARANCE VS SURVIVAL IN IPF Survival (%) Time from Presentation (yr) Daniil ZD et al. Am J Respir Crit Care Med. 1999;160:899. CT appearance atypical of CFA CT appearance typical of CFA 100 90 80 70 60 50 40 30 20 10 0 0 1 2 3 4 5 6 7

BAL CELLULARITY AND STEROID RESPONSIVENESS Responders (N=8) Nonresponders (N=19) * p<0.05 Prevalence (%) Rudd RM et al. Am Rev Respir Dis. 1981;124:1. Neutrophils >4% Eosinophils >3% * * * 100 75 50 25 0 Lymphocytes >11%

PATHOGENESIS OF PULMONARY FIBROSIS

Katzenstein ALA et al. Am J Respir Crit Care Med. 1998;157:1301. PATHOGENESIS AND COURSE OF UIP UIP Multiple microscopic foci of injury occurring over many years Focal fibroblast proliferation (fibroblastic foci) Collagen deposition Progressive clinical course Death Recurrent microscopic injury

Cellular phase Fibrotic phase Normal alveoli Cellular phase Homeostasis Fibrotic phase fibroblast ELR+ CXC ELR- CXC ELR+ CXC ELR- CXC ELR+ CXC ELR- CXC ELR+ CXC ELR- CXC Triggering event Slide courtesy of RM Strieter, MD. TNF-a IL-1 Monocyte IL-1 TNF-a MØ IFN-g IL-12 IL-18 Lymphocyte Endothelial cell Angiostasis ELR- CXC Extracellular matrix ELR+ CXC Angiogenesis Endothelial cell MOLECULAR BIOLOGY OF PULMONARY REPAIR

INFLAMMATORY RESPONSE OF THE LUNG Recognition Recruitment Removal Resolution Slide courtesy of RM Strieter, MD. Fixed macrophage Antigen Capillary endothelial cell Circulating leukocyte Capillary Monocyte Infiltrating leukocyte Activated leukocyte Phagocytic leukocyte (macrophage) Chemotactic cytokine wave Fibroblast Fibrous matrix (scar issue)

Th1 AND Th2 RESPONSES Th1 Increased IFN-g Increased IL-2 Increased IL-12 Increased IL-18 Th2 Increased IL-4 Increased IL-5 Increased IL-10 Increased IL-13 Antibody-Mediated Immunity Cell-Mediated Immunity TISSUE RESTORATION FIBROSIS Fibroblast Activation and Matrix Deposition Slide courtesy of RM Strieter, MD.

ROLE OF Th1 AND Th2 RESPONSES IN REPAIR PROCESS Cytokine Activation Phase Fibrotic Phase Fibroblast Slide courtesy of RM Strieter, MD. Th2 Type Th1 Type Resolution Extracellular Matrix (Fibrosis) Chemokines IL-10 (-) IL-4/IL-13 (+) IFN-g IL-12 IL-18 (-)

ROLE OF TGF-b AND IFN-g IN REPAIR PROCESS Ulloa L et al. Nature. 1999;397:710. TGF-b receptor IFN-g receptor Activation of Jak/STAT1 Smad3-4 Smad7 IFN-g inhibits activation of Smad3-Smad4 and induces Smad7 Increase of TGF-b–dependent gene transcription Inhibition of TGF-b–dependent gene transcription

MOLECULAR BIOLOGY OF IPF: SUMMARY Shift to increased production of Th2 cytokines and decreased production of Th1 cytokines resulting from unknown lung injury Overexpression of Th2 cytokine TGF- stimulates angiogenesis, fibroblast activation, deposition of ECM, and fibrogenesis Th1 cytokine IFN- counters effects of TGF-, but IFN- production decreased in IPF  IFN- may have therapeutic role in management of IPF

APPROACHES TO THERAPY

ATS/ERS. Am J Respir Crit Care Med. 2000;161:646 THERAPEUTIC APPROACHES TO IPF Corticosteroids Other immunosuppressives Azathioprine Cyclophosphamide Antifibrotic agents Colchicine D-Penicillamine IFN- IFN- Pirfenidone Antioxidant agents Glutathione N-acetylcysteine Others Agents that block neutrophil adhesion molecules Inhibitors of specific fibrogenic cytokines and growth factors

LIMITATIONS OF CLINICAL TRIALS IN IPF Small number of patients enrolled Variable natural history and clinical course of disease Variable diagnostic criteria leading to heterogeneous patient groups Variable and nonvalidated assessment criteria Variable duration of studies Lack of placebo controls

AZATHIOPRINE PLUS PREDNISONE VS PREDNISONE ALONE IN IPF Survival Probability Years Raghu G et al. Am Rev Respir Dis. 1991;144:291. 1.0 0.8 0.6 0.4 0.2 0 0 1 2 3 4 5 6 7 8 9 Azathioprine + Prednisone Prednisone

COLCHICINE VS PREDNISONE IN IPF Prednisone Colchicine 100 80 60 40 20 0 0 10 20 30 Months “Failure” (%) Douglas WW et al. Mayo Clin Proc. 1997;72:201.

EFFECT OF THERAPY ON SURVIVAL IN IPF 100 80 60 40 20 0 0 10 20 30 40 50 60 70 Months Survival (%) Prednisone Prednisone + Colchicine Prednisone + D-Penicillamine Prednisone + Colchicine + D-Penicillamine Selman M et al. Chest. 1998;114:507.

CLINICAL RESPONSE TO THERAPY IN IPF Johnson MA et al. Thorax. 1989;44:280. 50 Stable or Improved (%) 100 0 Months 1 3 12 24 36 Prednisolone + Cyclophosphamide Prednisolone

NEW TARGETS FOR THERAPEUTIC INTERVENTION Greater insight into pathogenesis of IPF using molecular biological approaches Wide range of potential mediators identified Targets might include Initial injurious agent Earliest pathogenetic event Final common pathway leading to fibrosis

INTERFERON-1b CLINICAL TRIAL

Ziesche R et al. N Engl J Med. 1999;341:1264. PATIENT ELIGIBILITY Histologically verified IPF Predominantly peripheral distribution of lesions without bilateral patchy infiltrates on HRCT 10% decrease in lung function during prior 12 mo despite continuous or repeated treatment with corticosteroids, other immunosuppressive agents, or both for 6 mo Patients excluded if TLC <45% of predicted normal value

9 patients randomized to 200 mg IFN-g1b SC 3 times/wk + 7.5 mg prednisolone PO/day  12 mo 9 patients randomized to 7.5 mg prednisolone PO/day (maximal dose: 50 mg/day)  12 mo 4 patients excluded (end-stage pulmonary fibrosis) 22 patients recruited Ziesche R et al. N Engl J Med. 1999;341:1264. RANDOMIZATION AND TREATMENT 18 patients enrolled 50 mg prednisolone PO daily  4 wk w/o response

Ziesche R et al. N Engl J Med. 1999;341:1264. OUTCOME MEASURES TLC and FVC At baseline After 3, 6, 9, and 12 mo PaO2 at rest and after maximal exertion At baseline After 3, 6, 9, and 12 mo No significant between-group differences at baseline

Ziesche R et al. N Engl J Med. 1999;341:1264. TLC BEFORE AND AFTER TREATMENT 100 90 80 70 60 50 40 30 Day 0 1 Year INF-g1b + Prednisolone

Ziesche R et al. N Engl J Med. 1999;341:1264. PaO2 AT REST BEFORE AND AFTER TREATMENT 100 90 80 70 60 50 40 30 PaO2 at Rest (mm Hg) Day 0 1 Year Prednisolone Alone 100 90 80 70 60 50 40 30 Day 0 1 Year INF-g1b + Prednisolone

Ziesche R et al. N Engl J Med. 1999;341:1264. PaO2 ON MAXIMAL EXERTION BEFORE AND AFTER TREATMENT 100 90 80 70 60 50 40 30 PaO2 on Maximal Exertion (mm Hg) Day 0 1 Year Prednisolone Alone 100 90 80 70 60 50 40 30 Day 0 1 Year INF-g1b + Prednisolone

Ziesche R et al. Unpublished data. 10 1 10-1 10-2 10-3 10-4 10-5 1 2 3 4 5 6 TGF-b1 Range of Transcription (amol/mg RNA) 10 1 10-1 10-2 10-3 10-4 10-5 1 2 3 4 5 6 IL-4 Range of Transcription (amol/mg RNA) Before IFN-g1b Therapy 10 1 10-1 10-2 10-3 10-4 10-5 1 2 3 4 5 6 Range of Transcription (amol/mg RNA) 10 1 10-1 10-2 10-3 10-4 10-5 1 2 3 4 5 6 Range of Transcription (amol/mg RNA) After IFN-g1b Therapy IFN-g1b DOWNREGULATES TGF-b AND IL-4 IN IPF

Raghu G et al. Independent review. March 2000. REANALYSIS OF STUDY RESULTS In collaboration with R. Ziesche, data were reanalyzed by independent panel of experts Pulmonary pathologist Three pulmonologists Each patient’s lung function studies, CT scans, and surgical lung biopsy reviewed to Reconfirm diagnosis of IPF according to ATS/ERS/ACCP criteria Reassess clinical course

Raghu G et al. Independent review. March 2000. REANALYSIS: IPF DIAGNOSIS Controls IFN-treated (n=9) (n=9) Definite IPF/UIP 5 4 Probable IPF* 3 3 Definitely not IPF 1 2 *UIP±NSIP/chronic hypersensitivity pneumonitis/other.

Raghu G et al. Independent review. March 2000. REANALYSIS: CHANGE IN TLC 100 80 60 40 20 0 Baseline 12 mo IFN-g1b + Low-Dose Prednisolone TLC (% Predicted) 100 80 60 40 20 0 Baseline 12 mo Prednisolone Alone TLC (% Predicted) Definite IPF Probable IPF Not IPF

REANALYSIS: CHANGE IN FVC Raghu G et al. Independent review. March 2000. 100 80 60 40 20 0 Baseline 12 mo IFN-g1b + Low-Dose Prednisolone FVC (% Predicted) 100 80 60 40 20 0 Baseline 12 mo Prednisolone Alone FVC (% Predicted) Definite IPF Probable IPF Not IPF

REANALYSIS: CHANGE IN AaPO2 Raghu G et al. Independent review. March 2000. Baseline 12 mo Baseline 12 mo 80 40 20 0 IFN-g1b + Low-Dose Prednisolone AaPO2 60 80 60 40 20 0 Prednisolone Alone AaPO2 Definite IPF Probable IPF Not IPF

Raghu G et al. Independent review. March 2000. Conclusions Patients with steroid-resistant IPF do improve with IFN-1b Definitive phase III clinical trial with large number of well-defined study patients is needed to confirm potential benefits of IFN-1b in steroid-resistant IPF