IDIOPATHIC PULMONARY FIBROSIS UPDATE

Transcription

1 IDIOPATHIC PULMONARY FIBROSIS UPDATE The Importance of Early Recognition and Referral 1

2 Learning objectives Recognize the importance of early diagnosis and treatment of idiopathic pulmonary fibrosis (IPF) Describe the clinical profile of patients in whom IPF should be suspected Discuss the management of adverse effects of IPF pharmacotherapies to facilitate medication adherence 2

3 Meet the patient: Eric: 65-year old male Non-productive cough 1 year Shortness of breath 1 month Former 20 pack-year smoker; quit 2 years ago Being treated by PCP for COPD Despite inhaled long-acting bronchodilator dyspnea becoming worse Cough not responding to antitussive meds 3

4 Meet the patient: Eric: 65-year old male Auscultation: Late inspiratory Velcro crackles Examination otherwise unremarkable Chest X-ray ordered: Bilateral, peripheral interstitial markings Spirometry: FEV1 87% predicted, d FVC 71% predicted, FEV 1 /FVC ratio: 84% of predicted 4

5 All chronic cough is not COPD! Which of the following suggest that Eric may not have COPD? a) Smoking history b) No benefit from bronchodilator therapy c) Inspiratory crackles on chest ausculation d) Normal FEV1/FVC ratio on spirometry 5

6 All chronic cough is not COPD! Which of the following suggest that Eric may not have COPD? a) Smoking history b) No benefit from bronchodilator therapy c) Inspiratory crackles on chest ausculation d) Normal FEV1/FVC ratio on spirometry 6

7 Common clinical presentation of IPF Older age (>60 years) Male gender Smoking common, in 60 70% Symptoms: Progressive exertional dyspnea Non-productive cough Signs: Bilateral inspiratory Velcro-like crackles Clubbing of fingers Tests: Abnormal pulmonary function test indicating restriction and impaired gas exchange Raghu G et al. Am J Respir Crit Care Med. 2011;183(6):

8 How IPF differs from COPD or asthma Parameter Asthma COPD IPF Age of onset Usually < 40 years Usually > 40 years Usually > 50 years Smoking history Not causal, but worsens control Usually > 10 pack years Typically > 20 pack years Sputum production Infrequent Often Infrequent Allergies Often Infrequent Infrequent Clinical symptoms Intermittent and variable Persistent and progressive Persistent and progressive Disease course Stable (with exacerbations) Progressive worsening Variable; steady worsening (with exacerbations) common Importance of Often important Often important Often important co morbid illnesses Spirometry Often normalizes May improve but never normalizes Restrictive pattern Airway inflammation Eosinophilic Neutrophilic N/A, Airway fibrosis Role of inhaled corticosteriods Essential for optimal control Helpful in patients with moderate to severe disease and frequent AECOPD No value Role of bronchodilators As needed use only Regular therapy usually necessary Unnecessary Role of exercise Rarely formally used Essential therapy Useful for majority of patients training End of life discussions Rarely necessary Often essential Essential Adapted from: O Donnell et al. Can Respir J. 2008; 15(Suppl A):1A 9A 8

9 When to consider ILD? Patients with presumed COPD/HF, not benefiting from treatment Subtle abnormalities on chest X- ray (largely normal in COPD) Middle-aged/elderly patients with unexplained chronic exertional dyspnea or chronic cough 24. Zibrak JD et al. NPJ Prim Care Respir Med. 2014;24:

10 Drug-induced ILD Common causes: Cancer chemotherapy, including methotrexate Nitrofurantoin t i Amiodarone Less common: Tegretol, Flecainide, Tetracycline Schwaiblmair M et al. Open Respir Med J. 2012;6:

11 IPF vs. COPD IPF COPD Physical examination Inspiratory crackles Late, velcro Early Wheezing Finger clubbing +/ Hyperinflation Spirometry Reduction in TLC Reduced FEV1/FVC ratio Others Response to bronchodilators Chest X ray Specific patterns of abnormality Largely normal 24. Zibrak JD. NPJ Prim Care Respir Med. 2014;24:

12 Classification of Interstitial Lung Diseases Interstitial Lung Diseases Exposure related: Occupational Environmental Avocational Medication Idiopathic interstitial pneumonia (IIP) Desquamative interstitial pneumonia (DIP) Connective tissue disease: Scleroderma RA Sjogren Idiopathic pulmonary fibrosis (IPF) Respiratory bronchiolitis interstitial lung dis. (RBILD) Sarcoidosis Other: Vasculitis/Diffuse alveolar hemorrhage (DAH) Langherhans cell histiocytosis (LCH) Eosinophilic pneumonias Neurofibromatosis LAM Acute interstitial pneumonia (AIP) Nonspecific interstitial pneumonia (NSIP) Cryptogenic organizing pneumonia (COP) Lymphocytic interstitial pneumonia (LIP) Am J Respir Crit Care Med 2002;165:

13 Travis WD, et al. Am J Respir Crit Care Med 2013;188(6):

14 Idiopathic pulmonary fibrosis (IPF) 20% of all ILDs; most frequent and severe form of idiopathic interstitial pneumonia (IIP) Unknown cause Primarily occurs in older adults Disease course varies, average survival little better than inoperable lung cancer Delayed diagnosis may negatively impact patients 1. Raghu G et al. Am J Respir Crit Care Med. 2015;192(2):e Sgalla G et al. Respirology. 2016;21(3): Antoniou KM et al. Lancet Respir Med. 2014;2(1):e

15 IPF: abnormal wound healing leads to irreversible fibrosis Three stages of pathogenesis 1 : What initiates this process is unknown 1. Travis WD et al. Am J Respir Crit Care Med. 2013; 188(6): Raghu G et al. Am J Respir Crit Care Med. 2011;183(6): Fibrosis distinguishes IPF from other ILDs, which are mainly inflammatory 2 Distorted alveolar capillary barrier architecture leads to impaired gas exchange, which limits routine physical activity 3 15

16 High rates of IPF in Canada Published studies: Prevalence /100,000 person-years Incidence /100, person-years Higher prevalence/incidence in Canada than in other jurisdictions: Prevalence: /100,000 Incidence: 24-51/100, Ley B, Collard HR. Clin Epidemiol. 2013;5: Charlene DF, et al. Am J Respir Crit Care Med. 2015;191:A2522-A

17 IPF clinical presentation Age: Generally >60 years Sex: Men > women Smoking: Most patients have smoking history No smoking history does not rule out IPF Consider IPF in patients presumed to have COPD or HF, who fail to benefit from treatment for these conditions 2. Sgalla G et al. Respirology. 2016;21(3): Raghu G et al. Am J Respir Crit Care Med. 2011;183(6): Oldham JM et al. Respir Med. 2014;108(6):

18 Chronic cough Most common initial symptom of IPF Cough: Non-productive, often intractable Bibasilar late inspiratory Velcrolike crackles Exertional dyspnea: insidious, progresses steadily Finger clubbing 2. Sgalla G et al. Respirology. 2016;21(3): Raghu G et al. Am J Respir Crit Care Med. 2011;183(6): Kondoh Y et al. Chest. 1993;103(6): Collard HR et al. Am J Respir Crit Care Med. 2007;176(7): Antoniou KM et al. Respiration. 2013;86(4):

19 IPF risk factors Smoking: Strong association, particularly if >20 pack-years GERD: Microaspirationi of gastric contents repetitive lung injury Genes: TERT, TERC,, SPC, SPA2,, ELMOD2, MUC5B Viruses: Role in initiation, progression, exacerbations 5. Ley B et al. Clin Epidemiol. 2013;5: Raghu G et al. Am J Respir Crit Care Med. 2011;183(6): Baumgartner KB et al. Am J Respir Crit Care Med. 1997;155(1): Molyneaux PL et al. Eur Respir Rev. 2013;22(129): Raghu G et al. Euro Respir J. 2006;27(1):

20 Natural history of IPF Progressive disease - at variable rates: Rapid deterioration or slower progression Median survival from diagnosis: 2-3 years Death most frequently from respiratory failure Factors for shorter survival: Older age, smoking history, lower BMI More severe abnormalities on lung function tests and exercise tests, greater radiologic extent of disease Complications (pulmonary arterial hypertension, malignancy) 2. Sgalla G et al. Respirology. 2016;21(3): Ley B et al. Am J Respir Crit Care Med. 2011;183(4):

21 Natural history of IPF Ley B et al. Am J Respir Crit Care Med 2011;183:

22 IPF As lethal as cancer Survival Rates of IPF Compared to Common Cancers Vancheri et al., 2010 ERJ 59. Vancheri C et al. Eur Respir J. 2010;35(3):

23 Chest X-ray in IPF Non-specific findings Symmetric peripheral, bibasilar reticular markings Low lung volumes Heart borders often hazy or poorly defined ~10% patients - normal chest X-rays IPF IPF Normal Normal 13. Oldham JM. Respiratory Med. 2014;108(6): Meltzer EB. Orphanet J Rare Dis. 2008;3:8. 23

24 HRCT in IPF 7. Raghu G et al. Am J Respir Crit Care Med. 2011;183(6):

25 Other investigations Pulmonary function testing (PFT) TLC, FVC (may be normal in early stages) Normal-to-increased FEV1/FVC, DL CO survival if low baseline FVC, FVC, DL CO 6-minute walk test (6MWT) Measure of disease status 6MWD survival Surgical lung biopsy Rarely required (UIP is usually diagnostic) Done if diagnosis remains uncertain despite review of clinical and radiological information 13. Oldham JM et al. Respir Med. 2014;108(6): du Bois RM et al. Am J Respir Crit Care Med. 2011;183(9):

26 Delayed referral poorer survival in IPF Canadian patient survey : Average wait: 20 months from symptom onset to confirmed diagnosis 32% patients received 1 diagnosis other than IPF, 15% received 3 diagnoses Diagnosis may be delayed 5 years PCPs - Key role in early diagnosis, referral to respirologist, and in some cases, ordering HRCT thorax 2. Sgalla G et al. Respirology. 2016;21(3): Zibrak JD et al. NPJ Prim Care Respir Med. 2014;24:

27 Importance of early referral to a specialty centre Delayed access to a tertiary care centre is associated with a higher mortality rate, independent d of disease severity 1.0 <1 year 1 2 years 2 4 years 0.8 >4 years Su urvival P value= Years Lamas DJ et al. Am J Respir Crit Care Med. 2011;184(7):

28 Diagnostic algorithm for IPF 7. Raghu G. Am J Respir Crit Care Med. 2011;183(6):

29 Case study revisited HRCT ordered; shows UIP pattern: Reticular opacities with basal and subpleural predominance, associated with honeycomb appearance Patient referred to respirologist PFT rules out obstructive disease FVC, TLC, and DL CO No cause for UIP pattern of ILD identified Diagnosed as IPF 29

30 Case challenge The most common clinical presentation of IPF involves: a) Productive cough and fever b) Cough, exertional dyspnea, inspiratory crackles, finger clubbing c) Acute respiratory distress d) Dyspnea at rest 30

31 Case challenge The most common clinical presentation of IPF involves: a) Productive cough and fever b) Cough, exertional dyspnea, inspiratory crackles, finger clubbing c) Acute respiratory distress d) Dyspnea at rest 31

32 Case challenge Approved treatment options for IPF are a) Nintedanib and pirfenidone b) Prednisolone and cyclophosphamide c) Azathioprine and N-acetylcysteine d) Bronchodilators 32

33 Case challenge Approved treatment options for IPF are a) Nintedanib and pirfenidone b) Prednisolone and cyclophosphamide c) Azathioprine and N-acetylcysteine d) Bronchodilators 33

34 Treatment of IPF Goals: Slow disease progression, manage comorbidities, prevent exacerbations, optimize QoL, increase survival Shared care Care shared by PCPs and specialists Requires clear roles, good communication, respect for each other s contribution to care 26. Thickett DR et al. Thorax. 2014;69(12): Harrison NK et al. Thorax. 2010;65(6): Virani T. 34

35 Approved pharmacologic therapies for IPF Pirfenidone: Antifibrotic agent with pleiotropic effects Nintedanib: Tyrosine Kinase Inhibitor (inhibits PDGFR, FGFR, VEGFR) 1. Raghu G et al. Am J Respir Crit Care Med. 2015;192(2):e Raghu G et al. Am J Respir Crit Care Med. 2011;183(6): Wells A. Eur Respir J. 2015;45(5):

36 Pirfenidone: Slows Disease Progression in IPF King TE et al. N Engl J Med. 2014;370(22):

37 Nintedanib: Slows Disease Progression in IPF Richeldi L et al. N Engl J Med 2014;370:

38 Nintedanib & Pirfenidone Availability & Dosage Nintedanib Pirfenidone Availability 100, 150 mg capsules 267 mg capsules Dosage 150 mg g( (1 capsule) BD 801 mg g( (3 capsules) TID with food If adverse reaction, temporary Titrate to full dosage (9 dosage reduction to 100 mg, treatment interruption/discontinuation capsules/day) over 14 days: Days 1-7: 1 capsule TID Days 8-14: 2 capsules TID LFT at outset and periodically as clinically necessary Days 15 onward: 3 capsules TID If adverse reaction, temporary dosage reduction, treatment interruption/discontinuation if adverse reactions. LFT at outset, monthly for first 6 months, every 3 months thereafter Prescribing information OFEV, ESBRIET 38

39 Test yourself Corticosteroids are a) first line treatment options in IPF. b) used in combination therapy to reduce the dosage of nintedanib or pirfenidone. c) used for acute exacerbations but not for long term treatment. t t d) not indicated in IPF. 39

40 Test yourself Corticosteroids are a) first line treatment options in IPF. b) used in combination therapy to reduce the dosage of nintedanib or pirfenidone. c) used for acute exacerbations but not for long term treatment. t t d) not indicated in IPF. 40

41 Corticosteroids, immunosuppressants in IPF No role for corticosteroids, immunosuppressants Meta-analysis: No evidence for effect of corticosteroids Medical records (n=487): No difference in survival with prednisone or colchicine PANTHER-IPF: Prednisone, azathioprine, N- acetylcysteine t combination deaths, hospitalizations 1. Raghu G et al. Am J Respir Crit Care Med. 2015;192(2):e Raghu G et al. Am J Respir Crit Care Med. 2011;183(6): Oldham JM et al. Respir Med. 2014;108(6): Richeldi L et al. Cochrane Database Syst Rev. 2003(3):CD Douglas WW et al. Am J Respir Crit Care Med. 2000;161(4): N Engl J Med. 2012;366(21): Woodcock HV et al. F1000Prime Rep. 2014;6:16. 41

42 Anticoagulants in IPF Anticoagulant therapy: Worse survival, shorter interval to disease progression Use for disease-modifying purpose not recommended in IPF 44. Tomassetti S et al. Sarcoidosis Vasc Diffuse Lung Dis. 2013;30(2): Trawinska MA et al. Ther Clin Risk Manag. 2016;12:

43 Oxygen therapy in IPF Hypoxemic at rest impaired QoL No controlled studies of long term oxygen for resting hypoxemia in IPF Indirect evidence from studies showing survival benefit in obstructive lung disease If clinically significant resting hypoxemia long-term oxygen therapy Some evidence for oxygen use in patients who only desaturate during exercise; improved exercise endurance 7. Raghu G et al. Am J Respir Crit Care Med. 2011;183(6): Arizono S et al. Eur Respir J. 2015;46(suppl 59). 43

44 Pulmonary rehabilitation in IPF Pulmonary rehabilitation is a multi-component intervention involving aerobic conditioning, strength & flexibility training, self-management education, nutritional interventions, psychosocial support Improves walk distance, symptoms, QoL 46. Adamali HI et al. Curr Respir Care Rep 2012;1: Nishiyama O et al. Respirology. 2008;13(3): Jastrzebski D et al. J Physiol Pharmacol. 2006;57 Suppl 4:

45 Pulmonary rehab modestly improves functional status and quality of life in ILD patients SF 36: physical summary score 6 minute walk test (points) Δ: 6±1 points 31±1 37± Δ: 46±3 308±6 354±6 Physical summary score MWD (m) P< P<0.001 Admission Discharge Admission Discharge 6MWD, 6 minute walk test distance Huppmann P et al. Eur Respir J. 2013;42(2):

46 Lung transplantation in IPF Improves survival Offered to appropriate patients Adult lung recipients median survival 5.5 years Lung Allocation Score (LAS)* Based on medical urgency and post transplant survival Used to prioritize candidates for transplantation Early referral for evaluation *Although version of LAS is used, it has not been standardized in Canada. 7. Raghu G et al. Am J Respir Crit Care Med. 2011;183(6): Adamali HI et al. Curr Respir Care Rep 2012;1: Thabut G et al. J Thoracic Cardiovasc Surg. 2001;126(2):

47 Management Nutrition; dietary supplements Exercise Vaccines; flu vaccine, pneumonia vaccine Oxygen? Prevention of reflux and recurrent microaspiration may slow disease progression Referral to respirology for further investigations, including bronchoscopy and biopsy 47

48 Acute exacerbations of IPF Acute respiratory deterioration with diffuse airspace changes on chest imaging either triggered (e.g. infection, post-op, drug) or idiopathic High in-hospital mortality associated with exacerbations Need to rule out pulmonary emboli (need CT angiogram) Supportive therapy is mainstay High dose corticosteroids commonly used, but limited data to support efficacy Pirfenidone, nintedanib not used to treat exacerbations Immunosuppressants, anticoagulants inconclusive 7. Raghu G et al. Am J Respir Crit Care Med. 2011;183(6): Kim D. Respir Res. 2013;14(1): Collard HR, et al. Am J Respir Crit Care Med 2016;194: Bhatti H et al. Ann Thorac Med. 2013;8(2):

49 Comorbidities in IPF Impact on QoL, survival GERD: PPIs for patients with GERD symptoms Obstructive sleep apnea: CPAP improves QoL Pulmonary hypertension (PH): No benefit of treating PH on IPF outcomes Mood disturbances: Screening, management recommended Lung cancer: Adversely affects survival 1. Raghu G et al. Am J Respir Crit Care Med. 2015;192(2):e Oldham JM et al. Respir Med. 2014;108(6): Lee JS et al. Am J Respir Crit Care Med. 2011;184(12): Mermigkis C et al. Sleep and Breathing. 2013;17(4): Zisman DA et al. N Engl J Med. 2010;363(7): King TE et al. Am J Respir Crit Care Med. 2011;184(1): Glaspole I et al. A94. New Insights in IPF; 2016:A2606-A Akhtar AA et al. Chron Respir Dis. 2013;10(3): Tomassetti S et al. Chest. 2015;147(1):

50 Revisit the patient Patient advised about treatment options Nintedanib 150 mg twice daily initiated Shared care: PCP monitors patient every 3 months for disease progression and complications, treatment related adverse effects One month later: Feeling better, no exacerbations, but complains of diarrhea 50

51 Case challenge For patients experiencing diarrhea with nintedanib: a) Discontinuation of treatment is the only option. b) Antidiarrheal medication (e.g., loperamide) is not recommended. c) Treatment with an opiate is recommended. d) Consider dosage reduction, treatment interruption, or discontinuation if diarrhea does not respond to conventional antidiarrheal management. 51

52 Case challenge For patients experiencing diarrhea with nintedanib: a) Discontinuation of treatment is the only option. b) Antidiarrheal medication (e.g., loperamide) is not recommended. c) Treatment with an opiate is recommended. d) Consider dosage reduction, treatment interruption, or discontinuation if diarrhea does not respond to conventional antidiarrheal management. 52

53 Monitoring/Follow up of IPF Monitor 3-6 monthly (sooner if needed) for: Disease progression: respiratory symptoms, worsening PFT, progressive fibrosis on HRCT, acute respiratory decline Disease-related complications: DVT, PE, malignancy Treatment-related complications: Related to adverse effects of medications General status: Mood, anxiety, nutrition, oxygenation 7. Raghu G et al. Am J Respir Crit Care Med. 2011;183(6): Raghu G. Eur Respir J 2011;37:

54 Nintedanib & Pirfenidone Common Adverse Reactions Nintedanibc Pirfenidone Most common ( 5%): Most common ( 10%): Diarrhea Nausea Insomnia Nausea Abdominal pain Vomiting Rash Abdominal pain URTI Weight decreased Arthralgia Dizziness Liver enzyme elevation Decreased appetite Headache Diarrhea Fatigue Headache Vomiting Anorexia GERD Weight decreased Hypertension Dyspepsia Sinusitis Source: Prescribing information OFEV, ESBRIET 54

55 Nintedanib & Pirfenidone: Precautions Nintedanib Elevated liver enzymes: Monitor ALT, AST, bilirubin Nausea, vomiting, diarrhea: Treat patients at first signs - adequate hydration and antidiarrheal medicine Discontinue nintedanib if severe diarrhea/nausea/vomiting persists Thromboembolism: Risk of MI; caution in patients at CV risk Pirfenidone Elevated liver enzymes: Monitor ALT, AST, bilirubin. May require temporary dosage reduction/discontinuation Nausea, vomiting, diarrhea, dyspepsia, GERD, abdominal pain: May require temporary dosage reduction/discontinuation Source: Prescribing information OFEV, ESBRIET 55

56 Nintedanib & Pirfenidone: Precautions Nintedanib Bleeding: Use in patients with known bleeding risk only if anticipated benefit outweighs potential risk. GI perforation: Caution in patients with recent abdominal surgery. Discontinue if patient develops GI perforation. Use in patients with known risk of GI perforation only if anticipated benefit outweighs potential risk Pirfenidone Photosensitivity and rash: Avoid exposure to sunlight and sunlamps. Wear sunscreen and protective clothing. May require temporary dosage reduction/discontinuation Pregnancy: Advise of potential hazard to fetus Source: Prescribing information OFEV, ESBRIET 56

57 Management of key adverse effects Pirfenidone Nausea/vomiting: Take with food Photosensitivity: Avoid/minimize exposure to sunlight Nintedanib Diarrhea: Manage at first sign of symptoms; start antidiarrheal (e.g., loperamide) Nausea/vomiting: Treat (e.g., with antiemetics) as needed Source: Prescribing information OFEV, ESBRIET Source: Prescribing information OFEV, ESBRIET 57

58 Nintedanib & Pirfenidone Drug interactions Nintedanib Coadministration of P-gp and CYP3A4 inhibitors (e.g., ketoconazole, erythromycin) may increase nintedanib exposure. Monitor for tolerability. Inducers of P-gp and CYP3A4 (rifampicin, carbamazepine, phenytoin, St. John s wort) can decrease exposure to nintedanib. No data on safety in patients on anticoagulant therapy. Pirfenidone Moderate (e.g., ciprofloxacin) and strong (e.g., fluvoxamine) inhibitors of CYP1A2 increase systemic exposure of pirfenidone and may alter adverse reaction profile of pirfenidone. Discontinue fluvoxamine prior to administration of pirfenidone or reduce to 1 capsule TID. Consider dosage reduction with ciprofloxacin. Inducers of CYPA12 (e.g., omeprazole) may reduce effective levels of pirfenidone and should be avoided. Source: Prescribing information OFEV, ESBRIET 58

59 Nintedanib & Pirfenidone Use in Specific Populations Nintedanib Hepatic impairment: Monitor for adverse reactions, consider dose modification/ discontinuation. Use not recommended in moderate/severe impairment. Renal impairment: i Safety/efficacy not studied Smokers: Decreased exposure, may alter efficacy profile. Nursing mothers: Discontinue nursing or discontinue the drug Pirfenidone Hepatic Impairment: Monitor for adverse reactions, consider dosage modification/ discontinuation. Use not recommended in severe impairment. Renal Impairment: Monitor for adverse reactions, consider dosage modification/discontinuation. Use not recommended in ESRD on dialysis. Smokers: Decreased exposure, may alter efficacy profile. Nursing mothers: Unknown Source: Prescribing information OFEV, ESBRIET 59

60 Palliative care in IPF burden of symptoms Consider referral if significant decline in lung function/functional status requiring assistance for ADL Home care teams can assist in providing symptom relief and advance care planning for end of life 45. Thickett DR et al. Thorax. 2014;69(12): Adamali HI. Curr Respir Care Rep 2012;1:

61 Key learning points Early diagnosis needed; delay in referral to specialist care associated with poorer survival All chronic cough is not COPD; all ILD is not IPF Refer relevant patients to respirologist If unexplained cough/dyspnea and suspect ILD REFER! 61

62 Key learning points (contd.) Approved drugs for IPF: nintedanib, pirfenidone Manage co-morbidities and exacerbations Monitor every 3-6 months (sooner if needed) for progression/complications 62

63 Discussion In your opinion, what are the barriers to the optimal care of IPF patients? How can they be overcome? How will you change your approach to recognition and management of IPF? 63

64 Resources ATS/ERS/JRS/ALAT guidelines Canadian Pulmonary Fibrosis Foundation Canadian Lung Association Living with Pulmonary Fibrosis ca/living-with-pf/ 64