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An update on the management of Idiopathic Pulmonary Fibrosis (IPF)


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Diagnosis and management of idiopathic pulmonary fibrosis based on current guidelines

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  • I have polymyositis, been also Diagnosed with pulmonary fibrosis, and I'm on oxygen at this time. I'm on prednisone, a very high dose! I'm taking a shot three times a week plus I'm to go in once a month to the hospital to give my immune system a boost of new cells. This year my family decided to try natural herbs. Three months ago my son ordered two bottles of IPF herbal remedy from Best Health Herbal Centre, which I only used for six weeks and the result was extremely marvellous. No more use of oxygen, stopped taking prednisone, my lungs function was back to normal and my IPF was completely reversed. Thanks to Best Health Herbal Centre, I will never stop sharing my testimony till the whole world know about this wonderful IPF herbal remedy and Am so happy to see myself living IPF FREE…
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  • My Husband was diagnosed with Idiopathic pulmonary fibrosis 5 years ago and was on minimum daily dosage prednisone (7.5 mg), azathioprine and N-Acetyl. They put him on 6 liters of oxygen and steroids to slow down progression. His symptoms have always been shortness of breath, and coughing badly. the prednisone wasn’t really working and he could not tolerate them for long due to severe side effects, There has been little if any progress in finding a cure or reliable treatment. So this year his primary physician suggested we started him on Natural Herbal Gardens Idiopathic Pulmonary Fibrosis Herbal formula which eased his anxiety a bit,, We ordered their IPF herbal treatment after reading alot of positive reviews, i am happy to report with the help of Natural Herbal Garden natural herbs we have been able to reverse my husband symptoms using herbs, his symptoms totally declined over a 9 weeks use of the Natural Herbal Gardens IPF natural herbal formula. His Idiopathic pulmonary fibrosis is totally reversed! Their official web page is www . naturalherbalgardens . com After the herbal treatment he also finally was able to give up smoking after 20 years. We are thankful to nature, herbs are truly gift from God
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An update on the management of Idiopathic Pulmonary Fibrosis (IPF)

  1. 1. An update on the management of Idiopathic Pulmonary Fibrosis Sarfraz Saleemi MD Pulmonary Medicine King Faisal Specialist Hospital & Research Center Riyadh, Saudi Arabia
  2. 2. Historical aspects of ILD Year/author publication Reference 1872 von Buhl desquamative pneumonia chronic interstitial pneumonia Oldenburg, Munich, 1872: 56-67 1898 Rindfleisch cirrhosis cystica pulmonum Verh Ges Dtsch Nat] Forsch Arzt 1898; 69 1907 Sandoz Necropsy findings in twin sisters - fetal bronchiectasis likely the first description of familial IPF Beitr Pathol Anat Allg Pathol 1907; 41: 495-516 1912 von Hansemann five cases lymphangitis reticularis pulmonum ViIrhows Arch [Pathol Anaq 1912; 220: 311-321 1933 Hamman & Rich first published their observations of IPF acute diffuse interstitial fibrosis Int Clin 1933; 1: 196-231 1945 Eder et al. clubbing of the fingers and toes as a clinical feature of the disease Bull Johns Hopkins Hosp 1945; 76: 163-171 1948 Potter & Gerber Subacute diffuse interstitial fibrosis of the lungs Awrh Intern Med 1948; 82: 113-124 1954 Vanek1 necropsy findings in 16 cases interstitial nonpurulent pneumonia Zentralbl Allg Pathol 1954; 92: 405-416 1952 Rubin et al. First open thoracotomy with lung biopsy Ann Intem Med 1952; 36: 827-844 1964 Livingstone 45 histologically proven cases QJMed 1964; 33: 71-103 1964 Scadding suggested the term Br MedJ 1964; 2: 686 1933 Hamman & Rich first published their observations of IPF acute diffuse interstitial fibrosis Int Clin 1933; 1: 196-231 fibrosing alveolitis
  3. 3. Revised Classification of Interstitial Lung Disease (ILD) ILD of known cause e.g. CTD, drugs, exposure etc. Idiopathic interstitial pneumonia (IIP) Granulomatous interstitial pneumonias e.g. Sarcoidosis Other ILD e.g. LAM, PLCH, PAP etc. Major IIPs Rare IIPs Non-specific interstitial pneumonia (NSIP) Acute interstitial pneumonia (AIP) Desquamatous Interstitial pneumonia (DIP) Respiratory Bronchiolitis ILD (RB-ILD) Lymphoid interstitial pneumonia Cryptogenic organizing pneumonia (COP) Idiopathic pulmonary fibrosis (IPF) Unclassified IIPs 55% 25% Pleuroparenchymal fibroelastosis Travis WD et al. Am J Resp Crti Care Med. 2013;188:733-748.
  4. 4. Major Idiopathic Interstitial Pneumonias Category Clinical Diagnosis Pathologic pattern Chronic fibrosing IPF UIP Idiopathic nonspecific interstitial Pneumonia (iNSIP) NSIP Smoking- related Respiratory bronchiolitis-ILD (RB-ILD) Respiratory bronchiolitis Desquamative interstitial pneumonia (DIP) Desquamative interstitial pneumonia Acute/ subacute Cryptogenic organizing pneumonia (COP) Organizing pneumonia Acute interstitial pneumonia (AIP) Diffuse alveolar damage Travis et al. Am J Respir Crit Care Med. 2013;188:733-748.
  5. 5. Idiopathic Pulmonary Fibrosis (IPF) • Chronic, progressive fibrosing interstitial pneumonia of unknown cause. • Occurring primarily in older adults • limited to the lungs • and associated with the histopathologic and/or radiologic pattern of Usual Interstitial Pneumonia (UIP) Am J Respir Crit Care Med. 2011;183(6):788-824. progressive irreversible lethal disease
  6. 6. Proposed mechanism of lung fibrosis in IPF Growth factors (TGF-β1) and other products of epithelial cell injury Fibroblasts 1. Susceptible host - genetics - Old age 2. Injury to alveolar epithelium - cigarette smoke - industrial dust - GE reflux - viral infection 4. Release of pro- fibrotic cytokines 6. Increased extracellular matrix deposition 5. Recruitment, proliferation and activation of fibroblasts and differentiation of myofibroblasts 7. Impaired gas exchange leading to respiratory failure 3. Aberrant wound healing response - recruitment and activation of immune cells - Increase vascular permeability - increased apoptosis
  7. 7. Risk factors and possible causes of IPF Older age Family history Cigarette smoking Male genderIPF
  8. 8. Genetics of IPF Possible candid gene polymorphisms – SFTPA2 or SFTPC mutations (Surfactant proteins C or A2) – TERT mutations (Telomerase reverse transcriptase) – MUC5B (MUCIN 5B)promoter gene – ABCA3 familial
  9. 9. MUC5B promoter gene • Discovered by genomewide linkage scan • Increased expression of MUC5B on the p-terminus of Chromosome 11 • More associated w/ patients older than >50yrs (Framingham cohort, NEJM 2013) • Associated with IPF but not scleroderma or sarcoidosis fibrosis (Thorax 2013) • Hypothesized Mechanisms: by increased Mucin5B production – Increased epithelial injury – Slowed clearance of airway toxins Nusair 2013
  10. 10. Telomere factor in IPF • Telomere is a repeated sequence of TTAGGG at the end of chromosome. • Telomeres protect genetic information by acting as a buffer against the chromosomal shortening during replication. • Critical shortening of the telomeres leads to cell-cycle arrest. • Maintaining telomere length is necessary for ongoing cell proliferation. • Loss in telomere length can be restored by the ribonucleoprotein telomerase
  11. 11. Telomere length in Interstitial Lung Diseases • 359 patients with various ILD • 173 healthy subjects • TL in all cases of ILD was significantly shorter compared with those of control subjects • TL in patients with idiopathic pulmonary fibrosis (IPF) was significantly shorter than in patients with other ILDs CHEST 2015; 148(4): 1011 - 1018
  12. 12. Effect of telomere length on survival in patients with idiopathic pulmonary fibrosis: An observational cohort study with independent validation • 370 patients • 149 patients with idiopathic pulmonary fibrosis had shorter telomere lengths than did the 195 healthy controls (mean age-adjusted log-transformed ratio of telomere to single copy gene was −0·16 [SD 0·23] vs 0·00 [0·18]; p<0·0001); • The association between telomere length and survival in patients with idiopathic pulmonary fibrosis was independent of age, sex, forced vital capacity, or diffusing capacity of carbon monoxide, and was replicated in the two independent idiopathic pulmonary fibrosis replication cohorts (Chicago cohort, HR 0·11 [0·03– 0·39], p=0·00066; San Francisco cohort, HR 0·25 [0·07–0·87], p=0·029). The Lancet Respiratory Medicine , Volume 2 , Issue 7 , 557 - 565 Telomere length was independently associated with transplant-free survival in patients with IPF (HR 0·22 [95% CI 0·08–0·63]; p=0·0048)
  13. 13. 500 Incidence Prevalence 400 300 200 100 0 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 Time (y) Adapted from Raghu G et al. Lancet Respir Med. 2014;2(7):566-72. Casesper100,000person-years Incidence and Prevalence of IPF
  14. 14. Incidence of IPF Am J Respir Crit Care Med 2006;175: 810-816 0 10 20 30 40 50 60 70 80 90 100 0 1 2 3 4 5 6 7 Male Female 18-34 35-44 45-54 55-64 65-74 >75 Age group (years) Per100,1000
  15. 15. Diagnosis of IPF IPF diagnostic team
  16. 16. Multi-disciplinary approach improves diagnostic agreement and confidence
  17. 17. Survival related to delay in referral to tertiary care center Am J Respir Crit Care Med. 2011;184:842-847
  18. 18. AND Definite UIP pattern on HRCT without surgical biopsy OR Definite/possible UIP pattern on HRCT + surgical lung biopsy showing definite/probable UIP Exclusion of known causes of Interstitial Lung Disease Raghu G, et al. Am J Respir Crit Care Med. 2011;183:788-824. Diagnosis of IPF – current guidelines
  19. 19. CT scan criteria for UIP Raghu G et al. Am J Respir Crit Care Med. 2011;183:788-824. UIP Pattern Possible UIP Pattern Inconsistent With UIP Pattern (All Four Features) (All Three Features) (Any of the Seven Features) Raghu G et al. Am J Respir Crit Care Med. 2011;183:788-824.
  20. 20. Histology criteria of UIP UIP pattern Probable UIP Possible UIP NOT UIP Pattern 1. Evidence of marked fibrosis/architectural distortion +/- honeycombing in a predominantly subpleural/paraseptal distribution 2. Presence of patchy involvement by fibrosis 3. Presence of fibroblast foci 4. Absence of features against a diagnosis of UIP 1. Evidence of marked fibrosis /architectural distortion +/- honeycombing 2. Absence of either patchy involvement or fibroblastic foci, but not both 3. Absence of features against a diagnosis of UIP 1. Patchy or diffuse involvement of lung parenchyma by fibrosis, with or without interstitial inflammation 2. Absence of other criteria for UIP 3. Absence of features against a diagnosis of UIP 1. Hyaline membranes 2. Organizing pneumonia 3. Granulomas 4. Marked interstitial Inflammatory cell Infiltrate away from honeycombing 5. Predominant airway centered changes 6. Other features suggestive of an alternate diagnosis
  21. 21. Histology of IPF (UIP) Normal lung Fibroblastic foci Honeycombing Interstitial fibrosis
  22. 22. Diagnosis of IPF integrating CT and pathology Histopathological pattern UIP Probable UIP Possible UIP Non- classifiable fibrosis Non-UIP HRCT Pattern UIP Yes Yes Yes Yes No Possible UIP Yes Yes Probable Probable No Not consistent with UIP Possible No No No No
  23. 23. Clinical conditions other than IPF associated with usual interstitial pneumonia pattern(UIP) • Collagen vascular disease • Drug toxicity • Chronic hypersensitivity pneumonitis • Asbetosis • Familial idopathic pulmonary fibrosis • Hermansky-Pudlak syndrome
  24. 24. Suspected interstitial lung disease High resolution CT scan of chest IPF IPF/Not IPF NOT IPF MDD Diagnostic Algorithm Raghu G et al. Am J Respir Crit Care Med. 2011;183:788-824. Identifiable Causes for ILD? Surgical Lung biopsy NO UIP pattern Possible UIP Inconsistent with UIP NO UIP UIP Probable/possible UIP Unclassifiable fibrosis YES pulmonologist pathologist radiologist
  25. 25. Disease Progression Time Acute worsening Stable Natural History of IPF At the time of diagnosis it is not possible to predict whether patients will have a slower or faster rate of decline
  26. 26. 5 year survival rate % IPF survival
  27. 27. IPF survival Median survival 3 years from the onset of symptoms
  28. 28. Cause of Death in IPF 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.
  29. 29. Level of dyspnea Increase in level of dyspnea DLCO ≤40% Decrease in FVC≥10% Saturation<88% on 6MWT Decrease in DLco≥15% Extent of honeycombing on HRCT Decrease >50 m in 6MWT Pulmonary hypertension Worsening of fibrosis on HRCT Concomitant Emphysema Indicators of increased risk of mortality in IPF Longitudinal factorsBaseline factors
  30. 30. GAP prognostic Score GAP Index for IPF Factor Points Gender: Male 1 Age: 61-65 1 >65 2 Physiology: FVC 50-75% pred. 1 < 50% pred. 2 DLCO 36-55% pred. 1 < 36% pred. 2 Pt. cannot perform 3 GAP Staging for IPF Mortality (%) Points Stage 1-yr 2-yr 3-yr 0-3 I 5.6 11 16 4-5 II 16 30 42 6-8 III 39 62 77 Eur Respir Rev 2014; 23: 220–224
  31. 31. IPF co-morbidities Extra-pulmonaryPulmonary •Parenchymal (e.g., lung cancer; infections.) • Pulmonary vascular (e.g., pulmonary embolus, PH) •Cardiac (e.g., HFpEF, CAD) • Endocrine (e.g., diabetes mellitus) • Hematologic (e.g., anemia , polycythemia) • GI (e.g., GERD) • Psychiatric • Musculoskeletal (e.g., osteoporosis) • Medications
  32. 32. GERD treatment and survival in IPF
  33. 33. Fundoplication for GERD and survival in IPF
  34. 34. IPF survival in the setting of PH Cumulativeprobabilityofsurvival Years
  35. 35. IPF management Risk stratify Symptom management Pulmonary rehabilitation Oxygen Co-morbidities/complications Pharmacological therapy Enroll in a clinical trial (Where available and appropriate) Lung Transplant (Where available and appropriate)
  36. 36. Timeline: Therapeutic Approaches to IPF Colchicine D-penicillamine Immunomodulation Future NAC Glutathione Warfarin IFN-g 1b Etanercept Imatinib Bosentan FG-3109? Statins? LO Inhibitors? Combo Tx? BIBF 1120? QAX576?? Sirolimus? 1950s 1990s 2005 Anti-inflammatory Immunosuppression Anti-fibrotic Anti-oxidant Antiproliferative Corticosteroids azathioprine cyclophosphamide 2014 Pirfenidone Nintedanib Next?
  37. 37. Traditional treatment of IPF Prednisone Azathioprine N-Acetylcysteine Warfarin
  38. 38. M Turner-Warwick, et al. Thorax. 1980;35:593-599. G. Raghu, et al. ARRD. 1991;144:291-296. 0 3 6 9 12 15 18 100 80 60 40 20 0 % Survival Treated (prednisone alone) Untreated Prednisone + Imuran Time (years) Prednisone +/- Azathioprine in IPF
  39. 39. Clinical trials in the new era 2011 2012 2013 2014 CAPACITY trial I &II (Pirfenidone) PANTHER Part B (NAC) ASCEND (Pirfenidone) INPULSIS I & II (Nintedanib) PANTHER Part A (Pred, Aza, NAC) ACE-IPF (Warfarin)
  40. 40. Noth et al. A placebo controlled randomized trial of warfarin in idiopathic pulmonary fibrosis Am J Respir Crit Care Med 2012;186:88 ACE – IPF (Anticoagulation Effectiveness in IPF) Stopped early for increased mortality risk 14 treatment vs. 3 placebo deaths
  41. 41. Warfarin vs. Placebo: All-cause Mortality and Hospitalization 100 Warfarin Placebo90 Log-rank P values at 48 weeks: 0.034 80 70 60 50 40 30 20 10 0 0 4 8 12 16 20 24 Weeks 35 41 28 32 38 40 44 48 # at Risk Warfarin Placebo 72 73 63 64 46 48 22 29 14 20 3 3 Noth I et al. Am J Respir Crit Care Med. 2012;186(1):88-95. Probability(%)
  42. 42. WARFARIN
  43. 43. PANTHER-IPF • Prednisone, Azathioprine and N-acetylcysteine: A Study That Evaluates Response in IPF NEJM 2012;366:1968 Randomized to NAC, NAC plus prednisone/azathioprine, or placebo for 60 weeks IPF n=341 Placebo n=131 NAC plus P/A n=77 NAC alone n=133 60 weeks 1”ry outcome: FVC decline 2’ry outcome: Acute exacerbation, disease progression
  44. 44. PANTHER-IPF
  45. 45. interim safety analysis In October 2011, when approximately 50% of the data had been collected, enrolment in triple therapy arm was stopped Pred/Aza/ NAC Placebo Mortality 11% 1% Hospitalization 29% 8% Serious adverse events (SAE) 31% 9% PANTHER-IPF
  46. 46. Steroids Azathioprine
  47. 47. PANTHER-IPF (part B) • Prednisone, Azathioprine and N-acetylcysteine: A Study That Evaluates Response in IPF NEJM 2012;366:1968 IPF n=341 Placebo n=131 NAC plus P/A n=77 NAC alone n=133 60 weeks 1”ry outcome: FVC decline 2’ry outcome: Acute exacerbation, disease progression
  48. 48. part B NAC arm completed at 52 weeks PANTHER-IPF
  49. 49. N-Acetylcysteine
  50. 50. New era of anti-proliferative therapy Pirfenidone Nintedanib
  51. 51. Clinical Studies Assessing Pirfenidone in Idiopathic Pulmonary Fibrosis: Research or Efficacy and Safety Outcomes Noble et al. Pirfenidone in patients with idiopathic pulmonary fibrosis (CAPACITY): two randomized trials. Lancet 2011;377:1760 CAPACITY trials
  52. 52. CAPACITY Enrolled patients with FVC ≥ 50%, DLCO ≥ 35% • Randomized to pirfenidone or placebo for 72 weeks • Primary endpoint: Change in FVC IPF n=779 Placebo n=347 Pirfenidone (1197 mg) n=87 Pirfenidone (2403 mg) n=345 72 weeks 1”ry outcome: FVC decline 2’ry outcome: 6-min walk, progression free survival death
  53. 53. CAPACITY
  54. 54. Overall data of both studies show significant slowing in FVC decline CAPACITY
  55. 55. Cochrane Review of Pirfenidone Studies • First licensed treatment in EU in March 2011 for mild to moderate IPF (FVC≥50%, TLCO≥35%, 6MWD ≥150m) FDA did not approve the drug and demanded another trial
  56. 56. ASCEND Assessment of Pirfenidone to Confirm Efficacy and Safety in Idiopathic Pulmonary Fibrosis Performed in response to an FDA request for an additional trial to support approval King et al. A phase 3 trial of pirfenidone in patients with idiopathic pulmonary fibrosis NEJM 2014;370:2083
  57. 57. ASCEND IPF n=555 Placebo n=277 Pirfenidone (2403 mg ) n=278 52 weeks 1”ry outcome: FVC decline 2’ry outcome: 6-min walk, progression free survival dyspnea death
  58. 58. ASCEND
  59. 59. – primary end pointASCEND
  60. 60. Secondary end pointsASCEND (progression free survival)
  61. 61. Pooled analysis CAPACITY and ASCEND trials Primary end-point
  62. 62. Pooled analysis CAPACIT and ASCEND trials Subgroup analysis - Primary end-point
  63. 63. Pooled analysis CAPACIT and ASCEND trials Secondary end-points
  64. 64. Pirfenidone summary
  65. 65. FDA approves Pirfenidone (Esbriet) October 2014
  66. 66. RECAP (Research on Efficacy and Safety Outcomes) study) SARCOIDOSIS VASCULITIS AND DIFFUSE LUNG DISEASES 2014; 31; 198-205
  67. 67. RECAP (Research on Efficacy and Safety Outcomes) study) Kaplan-Meier estimates of overall survival
  68. 68. Vincent Cottin, and Toby Maher Eur Respir Rev 2015;24:58-64 duration of study follow-up for 345 patients randomised to pirfenidone in the CAPACITY trial RECAP (Research on Efficacy and Safety Outcomes) study Long term tolerability and compliance
  69. 69. First author [ref.] Country Patients Patient characteristics Efficacy outcome Adverse events Treatment discontinuation due to adverse events % GI Skin WIJSENBEEK[13] Netherlands 52 Age: 63.4±7.7 years Baseline FVC (% pred): 68.3±18.4 Stable lung function in 17 out of 20 patients treated for >6 months (three out of 20 declined). In 11 out of 19 patients cough score decreased (unchanged: n=7; increased: n=1) NA NA 19 RAVAGLIA[14] Italy 81# Age: 69 (41–81) years Baseline FVC (% pred): 70.8 Stable or significantly improved lung function in 40 (59%) out of 68 patients NA NA 16 NIETOBARBERO[15] Spain 86 Age: NA Baseline FVC (% pred): 70±19 Stable FVC and DLCO in those who had pulmonary function testing (n=20) 35 (41) 11 (13)+ 14 BONELLA[16] Germany 45 Age: 69±7 years Baseline FVC (% pred): 61±15 Stable lung function in 28 (70%) out of 40 patients; subjective improvement in cough in 12 (33%) out of 36 patients 17 (38) 10 (22) 13 OKUDA [17] Japan 76 Age: 70.5±8.3 years Baseline FVC (% pred): 65.3±16.1 Reduction in FVC and DLCO decline 18 (24)§ 19 (25)ƒ 18 ARAI [18] Japan 41 Age: 70 (65.5–75.5) years Baseline FVC (% pred): 66.7 (54.8– 77.8)¶ Significant reduction in vital capacity decline in patients with severity grades I–II (Japanese Respiratory Society criteria) 24 (59)## 5 (12)+ 15 OLTMANNS[19] Germany 63 Age: 68±7 years Baseline FVC (% pred): 70±19 Stable lung function in 62% of patients NA NA 13 CHAUDHURI[20] UK 40 Age: 65.8 (48– 80) years Baseline FVC (% pred): 77.3 (46–146) Reduction in FVC and DLCO decline at 9 months 87 10+ 15 Real world experience with Pirfenidone
  70. 70. INPULSIS I and II Trials NEJM 2014;370:2071 Randomized (3:2) to nintedanib/placebo for 52 wks Nintedanib – An intracellular tyrosine kinase inhibitor IPF n=1066 Placebo n=423 Nintedanib n=638 52 weeks 1”ry outcome: FVC decline 2’ry outcome: Acute exacerbation Quality of life Mortality Nintedanib 300 mg daily
  71. 71. INPULSIS I and II Trials
  72. 72. INPULSIS - primary endpoint
  73. 73. INPULSIS 1 INPULSIS 2 INPULSIS - secondary endpoints
  74. 74. INPULSIS: Conclusions In patients with idiopathic pulmonary fibrosis, Nintedanib reduced the decline in FVC, which is consistent with a slowing of disease progression. Nintedanib slows disease progression by reducing the decline in lung function by 50% in a broad range of IPF patient types. Nintedanib significantly reduced the risk of acute exacerbations by 68%
  75. 75. FDA approves Nintedanib (Ofev) October 2014
  76. 76. The overall results suggest that the treatment effect of nintedanib on slowing disease progression persisted for 2 years open-label extension of INPULSIS 1 & 11 trials. Interim results 734 (91%) were treated in INPULSIS-ON 430 continuing nintedanib treatment 304 initiating nintedanib treatment ERS 2015 INPULSIS-ON “TOMORROW TRIAL”
  77. 77. Combination therapy for IPF Safety and pharmacokinetics of nintedanib and pirfenidone in idiopathic pulmonary fibrosis Ogura T et al. Safety and pharmacokinetics of nintedanib and pirfenidone in idiopathic pulmonary fibrosis. European Respiratory Journal 2015 45: 1382-1392 • A randomised, double-blind, phase II, dose escalation trial • 50 Japanese patients were randomized • Adverse events = 9/17 (53%) nintedanib alone 10/21 (48%) nintedanib + pirfenidone • Nintedanib had no effect on the pharmacokinetics of pirfenidone.
  78. 78. Safety and Tolerability Study of Pirfenidone in Combination With Nintedanib in Participants With Idiopathic Pulmonary Fibrosis (IPF) NCT02598193 Condition idiopathic pulmonary fibrosis Treatments nintedanib, pirfenidone Phase phase 4 Start date January 2016 End date May 2017 Trial size 80 participants
  79. 79. First Multinational Study Initiated to Evaluate OFEV® (nintedanib) with Add-on of pirfenidone in the Treatment of Idiopathic Pulmonary Fibrosis NCT02579603 A 12-week, open-label, randomized, parallel-group study evaluating safety, tolerability and pharmacokinetics (PK) of oral OFEV when taken in combination with oral pirfenidone, compared to treatment with OFEV alone, in people with IPF. 100 patients – multicenter – United States, Canada, Italy, Germany, France and the Netherlands. Ongoing
  80. 80. Effectiveness of combined therapy with pirfenidone and inhaled N‐acetylcysteine for advanced idiopathic pulmonary fibrosis: A case–control study 34 patients 12-month follow-up Treatment was considered ineffective if the decline in FVC was ≥10% and effective if the decline was <10%. Inhaled NAC plus pirfenidone (n = 24) Pirfenidone alone (control; n = 10). Results: Annual rate of change in FVC in NAC plus pirfenidone group = −610 mL pirfenidone group = −1320 mL (P < 0.01) Progression free survival (PFS ) in NAC plus pirfenidone group = 304 days Pirfenidone group = 168 days (P = 0.016) Conclusion: Combination treatment with inhaled NAC and oral pirfenidone reduced the rate of annual FVC decline and improved PFS in patients with advanced IPF. Respirology, April, 2015. 10.1111/resp.12477
  81. 81. Thalidomide for the treatment of cough in idiopathic pulmonary fibrosis. a randomized trial Ann Intern Med. 2012 Sep 18;157(6):398-406 • 98 participants were screened 24 were randomly assigned 23 received treatment 20 completed treatment period • Cough Quality of Life Questionnaire (CQLQ) scores significantly improved with thalidomide (mean difference vs. placebo, -11.4 [95% CI, -15.7 to -7.0] P < 0.001 • Thalidomide also significantly improved scores on the visual analogue scale of cough (mean difference vs. placebo, -31.2 [CI, -45.2 to -17.2] P < 0.001
  82. 82. Strong recommendation Conditional recommendation Level of recommendations as per IPF guidelines Strong recommendation against use Conditional recommendation against use Conditional recommendation for use Issue not addressed or deferred for future discussion 2015 vs. 2011 treatment guidelines for IPF
  83. 83. 2015 vs. 2011 treatment guidelines for IPF Strong recommendation against use Conditional recommendation for use Not addressed or deferred Conditional recommendation against use
  84. 84. 2015 vs. 2011 treatment guidelines for IPF Conditional recommendation for use Conditional recommendation against use Not addressed or deferred
  85. 85. Current Clinical Trials in IPF 116 studies in IPF 22 therapeutic trials • BIBF 1120 • QAX576 • Plasma exchange, rithuximab and steroids for acute exacerbations • Sirolimus • Losartan • Phase I – AB0024 – PRM-151 – STX-100 – CC930 – IW001
  86. 86. Proposed IPF pharmacological management Pirfenidone Nintedanib Clinical trials Assess in 6-12 months Stabilization or Improvement Decrease in FVC<10% DLCO<15% Continue treatment Severe disease FVC <50% DLCO < 35% Worse Decrease in FVC>10% DLCO>15% Lung Transplant Mild – Moderate disease FVC>50% and DLCO >35%
  87. 87. Lung transplantation in idiopathic pulmonary fibrosis Single vs Bilateral Transplant trends 2014 Lung transplant referral guidelines for IPF patients Kistler et al. BMC Pulmonary Medicine 2014, 14:139 • Age limits • Histopathologic or radiographic evidence of usual interstitial pneumonitis (UIP) • Abnormal lung function: FVC <80% predicted or DLCO <40% predicted • Any dyspnea or functional limitation attributable to lung disease • Any oxygen requirement, even if only during exertion Weill D, et al. J Heart Lung Transplant. 2014 Jun 26.
  88. 88. Post transplant survival of patients with IPF Source Yr of transplant No. of IPF patients %age of patients alive ISLT Annual report 3 months 1 yr 3 yr 5 yr 10 yr 1900-2011 8528 85 75 59 47 34 Source Yr of transplant No. of IPF patients %age of patients alive ISLT Annual report SLT/BLT 1 yr 3 yr 5 yr 10 yr 1900-2011 8528 SLT 75 57 43 20 BLT 74 63 49 35 Total Single vs Bilateral transplant Kistler et al. BMC Pulmonary Medicine 2014, 14:139
  89. 89. Pre-transplant mortality on wait list
  90. 90. Kaplan-Meier survival analysis for lung transplants by etiology of end-stage lung disease Arch Surg. 2011;146(10):1204-1209
  91. 91. Acute exacerbation of IPF (AEx-IPF) Diagnostic criteria for AEx-IPF 1. Previous or concurrent diagnosis of IPF 2. Unexplained worsening or development of dyspnea within 30 days 3. HRCT with new bilateral ground-glass abnormality and/or consolidation superimposed on a background reticular or honeycomb pattern consistent with UIP pattern 4. No evidence of pulmonary infection by endotracheal aspirate or BAL 5. Exclusion of alternative causes, including: • Left heart failure • Pulmonary embolism • Identifiable cause of acute lung injury (sepsis, aspiration, trauma, reperfusion pulmonary edema, pulmonary contusion, fat embolization, inhalational injury, cardiopulmonary bypass, drug toxicity, acute pancreatitis, transfusion of blood products, and stem cell transplantation) Am J Respir Crit Care Med 2007
  92. 92. Baseline IPF Exacerbation
  93. 93. Histopathological features • The most common finding is diffuse alveolar damage superimposed on the underlying UIP. Organizing pneumonia and extensive fibroblastic foci have also been reported. Am J Respir Crit Care Med 2007, 176:636–643. Am J Surg Pathol 2007, 31:277–284.
  94. 94. Incidence of AEx-IPF Study IPF Patient Population Reported Incidence Collard et al 461 patients – retrospective review 14.2% at I yr 20.2% at 3 yr Kim et al 147 biopsy-proven cases followed up for 2 yr 8.5% at 1 yr Martinez et al 168 placebo patients in whom IPF was diagnosed clinically or by biopsy followed up for at least 48 wk 4.8% overall with median of 76 wk of follow-up Azuma et al 35 placebo patients in whom IPF was diagnosed clinically or by biopsy followed up for 9 mo 14.3% at 9 mo Taniguchi et al 74 patients – retrospective review 8.6 % at I yr 23.9 % at 3 yr
  95. 95. Mortality in AEx-IPF • Systemic review of 8 studies: pooled mortality rate: 1 month 60% 3 months 67% • Other studies: mortality as high as 85% mean survival 3-13 days Eur J Intern Med 2008;19:227-3 Eur J Intern Med 2008;19:227-3 Intensive Care Med 2001;27:1868-74
  96. 96. Risk factors for AEx-IPF • lower FVC and/or lower DLCO • Higher degree of dyspnea (score>2 on mMRC) • Presence of pulmonary hypertension • Co-existence of emphysema • Invasive procedures – bronchoscopy and thoracoscopic biopsy. • GERD – pepsin presence in BAL • Extent of fibrotic changes on CT scan • Smoking • ?virus infections (a well-controlled study by Wootton et al.found evidence of viral respiratory infection in only 4 of 34 patients who presented with AE-IPF)
  97. 97. International consensus, the American Thoracic Society, the European Respiratory Society, the Japanese Respiratory Society, and the Latin American Thoracic Association (ATS/ERS/JRS/ALAT) guidelines • supportive care – main treatment • corticosteroids “corticosteroids should be used in the majority of patients with AE-IPF, but not using corticosteroids may be a reasonable choice in a minority” recommendation is weak and based on very low quality evidence No specific recommendations regarding the dose, route, and duration of corticosteroid therapy are made Management of AEx-IPF
  98. 98. Use of immunosuppressant drugs and other modalities in AEx-IPF • Treatment of AE-IPF with Direct hemoperfusion with a polymyxin B-immobilized fiber column (PMX-DHP) improved 12-month survival. (31 patients) BMC Pulm Med. 2015 )Feb 22;15:15 • Plasma exchange + rituximab + corticosteroids (6 patients) Am J Respir Crit Care Med 2013;187:A5712 • Cyclophosphamide + corticosteroids (small case series) Eur Respir J 2011;38:1487-9 • Tacrolimus + Corticosteroids (5 patients) Intern Med 2011;50:189-95
  99. 99. Summary • IPF is a rare disease with high mortality. • Median survival is worse than most cancers • Diagnosis is based on HRCT and/or histological evidence of UIP while known causes are ruled out. • Early and accurate diagnosis is important as available treatments are tested on mild to moderate IPF • New evidence suggest efficacy of Pirfenidone and Nintedanib in delaying the decline in lung function and reducing exacerbations.
  100. 100. • There is evidence against the use of steroids and immunosuppressive agents in IPF • Acute exacerbation of IPF should be treated with supportive care and steroid use in this clinical setting may be beneficial. • Non-pharmacological treatment include long term oxygen therapy , pulmonary rehabilitation and supportive care. • Eligible Patients should be referred for lung transplant evaluation as soon as possible. • Screening should be done for pulmonary hypertension, obstructive sleep apnea, gastroesophageal reflux disease, and coronary artery disease. • End-of-life care and palliative care services Summary – cont..
  101. 101. Thank you