Colorado Pharmacists Society Annual Meeting June 21 st & 22 nd, 2018

Transcription

1 Interstitial Lung Disease: Focus for the pharmacist Susan Tallieu, MSN, APN, ACNP-BC University of Colorado Anschutz Campus Division of Pulmonary Medicine and Critical Care Colorado Pharmacists Society Annual Meeting June 21 st & 22 nd, 2018

2 Conflict of Interest Disclosure I have no conflicts of interest to disclose.

3 Learning Objectives: Define Interstitial Lung Disease (ILD) List the known causes of ILD Describe the subsets of ILD that have treatment options and what those treatment options are Outline various treatment complications and common side effects Review drug induced lung injury and treatment.

4 What is Interstitial Lung Disease? A group of diseases with various etiologies that involves chronic inflammation and fibrosis There are over 200 known causes of ILD Causes a restrictive defect in the lungs There are acute and chronic forms Most of these are rare Is still not well understood and our treatments are limited

5 Causes of Interstitial Lung Disease Interstitial Lung Disease Known Etiology Unknown Etiology Smoking Connective Tissue Disease Organic Exposure Drug Related Inorganic Exposure Granulomatous Non-IPF Idiopathic interstitial pneumonias IPF Rare forms

6 Causes of Interstitial Lung Disease Known cause or association Treatment Related Medications Radiation Connective Tissue Disease Rheumatoid arthritis Systemic Lupus Erythematous Scleroderma Immunologic Sarcoid Hypersensitivity pneumonitis (HP) Genetic Familial Unknown Causes Idiopathic interstitial pneumonias Idiopathic Pulmonary Fibrosis (IPF) Nonspecific interstitial pneumonia Cryptogenic organizing pneumonia (COP) Specific Pathology Lymphangioleiomyomatosis (LAM) Raghu, 2011; Talmadge, 2017

7 Why is this important for you to know? Certain medications have increased risk for pulmonary toxicitypharmacists can help to identify these in the inpatient and outpatient setting Treatments vary depending on the underlying cause making it imperative to diagnose correctly- treating incorrectly may increase mortality in some cases The side effects of many of our therapies can make adherence difficult Patients need to be counseled on side effects and importance of adherence

8 Determining the right diagnosis: Diagnostics Complete H/P Environmental and exposure history Medication history Family History Rule out alternative diagnosis Testing Serologic evaluation ECHO High resolution CT chest Oxygen needs Pulmonary Function Test (PFTs) Bronchoscopy Lung Biopsy Raghu, 2011

9 Drug Induced Interstitial Lung Disease

10 Drug Induced Interstitial Lung Disease Antibiotics- nitrofurantoin Antiarrhythmics- amiodarone Rheumatoid medicationsmethotrexate, DMARDs Chemotherapy- bleomycin Dietary Supplements Oxygen Radiation Pexels.com

11 Mechanism of Injury and Clinical Findings Mechanism of Injury Dependent upon the drug- still not well understood Cytotoxic injury Immune complex mediated injury Cell mediated Histopathologic findings Diffuse alveolar damage Radiographic Findings Nonspecific interstitial pneumonia (NSIP) is the most common on CT Opacification seen on CXR Drug exposure Resolution of symptoms Santiago, 2000; Vahid, 2008; Williams, 2006

12 Nitrofurantoin pulmonary toxicity Incidence: 1 in 5,000 after first time use 1 in 750 chronic users Pathogenesis: Acute and chronic forms Risk Factors: Most often women (85-90%) due to higher incidence of UTI Ages UpToDate, 2018; Camus, 2004 Clinical manifestations: Acute- fever, crackles, cough, rash (1-12 hours) Chronic- dyspnea, cough, fatigue, crackles Treatment: Permanent discontinuation Consider corticosteroids Symptoms should improve in hours

13 Amiodarone pulmonary toxicity Incidence: 1-5% (increases with higher doses) within months of starting therapy Pathogenesis is thought to be from cytotoxic lung injury and/or a hypersensitivity reaction Risk Factors: Doses greater than 400mg/day Duration greater than 2 months 60+ years of age preexisting lung disease, surgery, and pulmonary angiography Clinical manifestations: New onset of dyspnea, nonproductive cough, abnormal breath sounds Abnormal chest imaging Treatment: Permanent discontinuation Severe cases require corticosteroids UpToDate, 2018

14 Rheumatoid Medications-Methotrexate Incidence: 1-8% Pathogenesis: Most often hypersensitivity reaction but multiple types of lung injury are reported Risk Factors: Age 60+ Pleuropulmonary involvement Hypoalbuminemia Prior use of DMARDs Diabetes UpToDate, 2018 Clinical manifestations: Acute, subacute and chronic Dyspnea, cough, fever, crackles Treatment: Drug Discontinuation Symptoms typically resolve in several weeks, there is no data to suggest corticosteroids improve outcomes It is not recommended to rechallange

15 Rheumatoid Medications-DMARDs Incidence: Conflicting data, there are case reports of worsening or induced pulmonary disease; there is also data to show improvement of rheumatoid related lung disease with use of DMARDs Varies among medications Pneumotox.com for reference It is a diagnosis of exclusion Clinical manifestations: dyspnea, cough, abnormal breath sounds Treatment: Drug Discontinuation Talman, 2017

16 Antineoplastic Lung injury Incidence: 10-20% of patient treated with antineoplastic agents Pathogenesis: Suspected to be be from direct cytotoxicity with multiple mechanisms Clinical Presentation: Variable clinical manifestations, timing, imaging and histopathology with non-specific symptoms Treatment: Drug discontinuation Supportive care Glucocorticoids UpToDate, 2016; Vahid, 2008

17 Chemotherapy Induced- Bleomycin Incidence: Well known but the incidence is not well documented Pathogenesis: oxidative injury and cytokine induction Risk Factors: Increased dose, smoking history, renal dysfunction. Sleiifer, 2001; Uptodate, 2017, Vahid, 2008 Clinical manifestations: Monitor pulmonary function tests Prevention: Decreasing the total cumulative dose Consider alternative therapies Treatment: Permanent discontinuation High dose corticosteroids

18 Prednisone Glucocorticoid Form: multiple doses from 1 mg- 20 mg Dose: Between 0.5 mg- 1 mg/kg IBW for induction. Tapering schedule is dependent upon clinical evaluation and if steroid sparing agent will be used Side effects: Weight gain, hypertension, hyperglycemia, gastric reflux, osteoporosis, cataract formation, depression, hyperexcitability, insomnia and myopathy Monitoring: Need PJP prophylaxis (BDS or doxycycline) for doses of 20mg or more Blood and urine glucose monthly Bone mineral density Treatment with calcium and vitamin D

19 Key Points: The first step is always DISCONTINUATION of the suspected agent In some cases treatment may involve steroids depending on the clinical scenario (around 6 months of treatment) Supportive care

20 Connective Tissue Related Interstitial Lung Disease

21 Connective Tissue Disease Related ILD Diseases associated with ILD: Scleroderma Rheumatoid Arthritis Sjogrens syndrome Systemic lupus erythematosus Polymyositis Dermatomyositis Mixed connective tissue disease (50-66% with ILD) Bennett, 2016; Cottin, 2016

22 Connective Tissue Disease Related ILD Incidence: Dependent upon the underlying rheumatologic condition but in some diseases over 75% have pulmonary involvement. Better survival than IPF Pathogenesis: Autoimmune mediated. Multiple pulmonary manifestations: Pleural disease ILD Pulmonary hypertension (PH) Clinical Manifestations: Variable Treatments: Dependent upon the underlying disease and extent of ILD Much of our treatment is extrapolated from other studies Lake, Bennet, 2016; Cottin, 2014

23 Mycophenolate (mycophenolic acid- MPA) Immunosuppressant, purine synthesis inhibitor, glucocorticoid-sparing agent Forms: Mycophenolate mofetil (MMF) Mycophenolate sodium (EC-MPS) Dose: Start at 500 mg twice daily and titrate up every 2 weeks by 500mg to a goal dose of 1000mg-1500mg daily Side effects: Gastrointestinal upset Myelosuppression Pre-menopausal women need counseling on birth control Monitoring: Need appropriate vaccinations Laboratory monitoring Serologic testing Vegh, 2005; Vij, 2013

24 Cyclophosphamide Antineoplastic, immunosuppressant, antirheumatic Forms: IV and oral Dose: Oral, 50 mg daily for 2 weeks then increase by 50 mg increments every two weeks to a treatment dose of 2 mg/kg/day IBW Side effects: Myelosuppression Hepatitis Cystitis Malignancy Premature ovarian failure Monitoring: Laboratory monitoring Urinaylysis Vij, 2013

25 Other Immunologic Related Interstitial Lung Disease

26 Immunologic Environmental Organic (hypersensitivity pneumonitis) Inorganic (occupation exposures) Sarcoid Vasculitis Post-infectious Infectious Treatment is similar to connective tissue related ILD as the underlying cause is driven by abnormal immune response Treatments include: Glucocorticoids MMF Azathioprine Methotrexate Rituximab

27 Hypersensitivity Pneumonitis (Extrinsic allergic alveolitis) Multiple causes (over 200 known) Some common examples include: Birds fanciers lung Farmers Lung Hot tub lung And of course pneumonoultramicroscopicsilico volcanokoniosis (volcano lung) Pexels.com

28 Hypersensitivity Pneumonitis (HP) Incidence: 420 to 3000 in farmers lung, varies greatly in other populations Pathogenesis: Repeated exposure causes an immunopathological response causing inflammation and eventually fibrosis This is the one time smoking may actually benefit youthere is a decreased risk of developing HP in smokers Treatment: Antigen Avoidance Glucocorticoids Azathioprine Mycophenolate mofetil Lung Transplant Selman, 2012

29 Key points CTD Prednisone Long term steroid effects MMF GI symptoms Myelosuppression Infectious risk Cyclophosphamide Increased risk of bladder cancer, this is cumulative.how long has the patient been taking it Immune mediated (HP) MMF Azathioprine Prednisone Long term effects of steroids

30 Idiopathic Pulmonary Fibrosis

31 Idiopathic Pulmonary Fibrosis A subclass of primary idiopathic interstitial lung disorders It is a diagnosis of exclusion Management: Pharmacologic therapy Pulmonary rehab Lung transplantation Palliative care There are two FDA approved therapies for IPF

32 IPF Therapy- Pirfenidone (Esbriet) Anti-fibrotic MOA: Not fully understood Form: 267 mg capsule Dose: goals of 3 capsules three times daily with meals Side effects and monitoring: GI upset, needs to be taken with food Photosensitivity Need to be counseled on sun protection Hepatotoxicity Regular blood work Is reversible with discontinuation or dose reduction

33 ASCEND Primary Primary and and Key Key Secondary Secondary Outcomes Efficacy Outcomes during the Week Study Period. King TE Jr et al. N Engl J Med 2014;370:

34 IPF Therapy- Nintedanib (Ofev) Anti-fibrotic Inhibits fibroblast migration, proliferation, and myoblast transformation Form: 150 mg capsule mg capsule Dose: 150 mg capsule twice a day with meals Side effects and monitoring: GI upset Diarrhea- loperamide Nausea and vomiting Hepatotoxicity Regular blood work Is reversible with discontinuation or dose reduction

35 INPULSIS Primary and Key Secondary Outcomes Richeldi L et al. N Engl J Med 2014;370: d Ch an ge fro m Ba sel ine ov er Ti me in Fo rce d Vit al Ca pai Nci

36 Analysis of Forced Vital Capacity and All-Cause Mortality. Karimi-Shah BA, Chowdhury BA. N Engl J Med 2015;372:

37 Prednisone, Azathioprine, and N-Acetylcysteine for Pulmonary Fibrosis (PANTHER-IPF) Randomized, double-blind, placebo-controlled trial with mild to moderate lung function impairment Randomized into three groups combination of prednisone, azathioprine and NAC, NAC alone, or placebo. Terminated early due to increased rate of death and hospitalization in the combination therapy group

38 Safety End Points. PANTHER Trial The Idiopathic Pulmonary Fibrosis Clinical Research Network. N Engl J Med 2012;366:

39 Kaplan Meier analysis of time to first occurrence of a pirfenidone-related adverse event (AE) as measured from randomisation, irrespective of treatment duration, in the pooled phase III clinical trials. Lisa H. Lancaster et al. Eur Respir Rev 2017;26: by European Respiratory Society

40 Summary- IPF treatment There are two approved therapies for IPF Both slow the rate of progression in IPF Azathioprine, NAC and prednisone are not recommended and showed increased mortality and rate of hospitalization Side effects are can pose difficulty in adherence and can be reduced with slower dose titration

41 Key points Drug induced lung injury Stop the medication Decrease the inflammatory response Long term complications? Connective Tissue Disease/Immunologic Immunosuppression Monitoring of side effects from long term immunosuppressive therapy Idiopathic pulmonary Fibrosis Two FDA approved therapies Side effect profiles decrease adherence Side effects can be decreased with slower titration and symptom management

42 Thank You! Pexels.com

43 Susan Tallieu, ACNP-BC, MSN Colorado Pharmacists Society Annual Meeting

44 References Balk, R. (2018). Methotrexate-induced lung injury. Flaherty (Ed.), UpToDate. Retrieved March 30, 2018, from Baughman, R., Costabel, U., du Bois, R. (2008). Clinic of Chest Medicine. 2008, 29 (3):533. Bennett, R. (2016). Clinical manifestations of mixed connective tissue disease. Axford (Ed.), UpToDate. Retrieved March 30, 2018, from Camus P, Fanton A, Bonniaud P, et al. Interstitial lung disease induced by drugs and radiation. Respiration 2004; 71:301. Chan, E., & King, T. (2017). Amiodarone pulmonary toxicity. Flaherty (Ed.), UpToDate. Retrieved March 30, 2018, from Chan, E., & King, T. (2017). Pulmonary disease induced by cardiovascular drugs. Flaherty (Ed.), UpToDate. Retrieved March 30, 2018, from Cottin, V. (2013). Interstitial lung disease. European Respiratory Review 22: / The Idiopathic Pulmonary Fibrosis Clinical Research Network (2012). New England Journal of Medicine 2012, 366: DOI: /NEJMoa Feldman, D., & Els, N. (2017). Bleomycin-induced lung injury. Kantoff (Ed.), UpToDate. Retrieved March 30, 2018, from Karimi-Shah, B., Chowdhury, B. (2015). Forced Vital Capacity in Idiopathic Pulmonary Fibrosis FDA Review of Pirfenidone and Nintedanib. New England Journal of Medicine, 372: DOI: /NEJMp

45 References Kim YJ, Song M, Ryu JC: Mechanisms underlying methotrexate-induced pulmonary toxicity. Expet Opin Drug Saf. 2009, 8: / L\ Lake, F. (2016). Drug-induced lung disease in rheumatoid arthritis. King, T. (Ed.), UpToDate. Retrieved April 15, 2018, from Lancaster et al. (2017). Pirfenidone safety and adverse event management in idiopathic pulmonary fibrosis. Retrieved April 15, 2018, from Maldonado, F., & Limper, A. (2016). Pulmonary Toxicity associated with systemic antineoplastic therapy: Clinical presentation, diagnosis and treatment. Flaherty (Ed.), UpToDate. Retrieved March 30, 2018, from Paramothayan, S., Lasserson, T. (2008). Treatments for pulmonary sarcoidosis. Respiratory Medicine. 2008; 102:1. Raghu G, Collard HR, Egan JJ, et al. An official ATS/ERS/JRS/ALAT statement: idiopathic pulmonary fibrosis: evidence-based guidelines for diagnosis and management. Am J Respir Crit Care Med 2011; 183:788. Richeldi et al. (2014). Efficacy and Safety of Nintedanib in Idiopathic Pulmonary Fibrosis. New England Journal of Medicine 2014, 370: DOI: /NEJMoa Santiago et al. (2000). Pirfenidone safety and adverse event management in idiopathic pulmonary fibrosis. Pulmonary Drug Toxicity: Radiologic and Pathologic Manifestations. Retrieved June 1, 2018 from Selman et al (2012). Hypersensitivity Pneumonitis Insights in Diagnosis and Pathobiology. American Journal of Respiratory and Critical Care Medicine 2012, 186:

46 References: Sleijfer, S. (2001). Bleomycin-Induced Pneumonitis. Chest. 120: DOI: Tashkin st al. (2006). Cyclophosphamide versus Placebo in Scleroderma Lung Disease. New England Journal of Medicine, : DOI: /NEJMoa Talmadge et al. (2014). A Phase 3 Trial of Pirfenidone in Patients with Idiopathic Pulmonary Fibrosis. New England Journal of Medicine 2014, 370: DOI: /NEJMoa Vahid B., Marik, P. (2008). Pulmonary Complications of Novel Antineoplastic Agents for Solid Tumor. Chest 2008, 3133: Vegh J., Szilasi M., Soos G., et al. (2005). Interstitial lung disease in mixed connective tissue disease. Orv Hetil 2005; 146:2435 Vij S., Strek, M. (2013). Diagnosis and Treatment of Connective Tissue Disease-Associated Interstitial Lung Disease. Chest, : doi: /chest Wikimedia Commons, the free media repository. (2018, March 8). File: Honeycomb Lung. Retrieved 15:09, June 1, 2018 from Williams E. (2006). Recurrent Acute Nitrofurantoin-Induced Pulmonary Toxicity. Pharmacotherapy. 5: DOI: /phco Zeeuw, J., & Gillissen, A. (2018). Nitrofurantoin-induced lung injury. Flaherty (Ed.), UpToDate. Retrieved March 30, 2018, from