interstitial lung disease: focus for the pharmacist · 6/11/2018 · • define interstitial lung...
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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 21st & 22nd, 2018
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Conflict of Interest Disclosure
• I have no conflicts of interest to disclose.
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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.
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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…
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Interstitial Lung Disease
Known Etiology
Drug Related
Smoking
Connective
Tissue Disease
Organic Exposure Inorganic
Exposure
Unknown
Etiology
Idiopathic
interstitial pneumonias
IPF Non-IPF
Granulomatous Rare forms
Causes of Interstitial Lung Disease
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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
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Why is this important for you to know?
• Certain medications have increased risk for pulmonary toxicity- pharmacists 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
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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
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Drug Induced Interstitial Lung Disease
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Drug Induced Interstitial Lung Disease
• Antibiotics- nitrofurantoin
• Antiarrhythmics- amiodarone
• Rheumatoid medications- methotrexate, DMARDs
• Chemotherapy- bleomycin
• Dietary Supplements
• Oxygen
• Radiation
Pexels.com
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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
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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 60-70
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 24-
48 hours
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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
UpToDate, 2018
• Clinical manifestations: • New onset of dyspnea, non-
productive cough, abnormal breath sounds • Abnormal chest imaging
• Treatment: • Permanent discontinuation • Severe cases require
corticosteroids
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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
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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
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Antineoplastic Lung injury
• Incidence: 10-20% of patient treated with antineoplastic agents
• Pathogenesis: Suspected to be be from direct cytotoxicity with multiple mechanisms
UpToDate, 2016; Vahid, 2008
• Clinical Presentation: Variable clinical manifestations, timing, imaging and histopathology with non-specific symptoms…
• Treatment:
• Drug discontinuation
• Supportive care
• Glucocorticoids
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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
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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
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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
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Connective Tissue Related Interstitial Lung Disease
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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
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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
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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
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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
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Other Immunologic Related Interstitial Lung Disease
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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
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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… pneumonoultramicroscopicsilicovolcanokoniosis (volcano lung) Pexels.com
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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 you- there is a decreased risk of developing HP in smokers
• Treatment: • Antigen Avoidance
• Glucocorticoids
• Azathioprine
• Mycophenolate mofetil
• Lung Transplant
Selman, 2012
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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
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Idiopathic Pulmonary Fibrosis
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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
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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
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King TE Jr et al. N Engl J Med 2014;370:2083-2092.
Primary and Key Secondary Efficacy Outcomes during the Week Study Period.
ASCEND Primary and Key Secondary Outcomes
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IPF Therapy- Nintedanib (Ofev)
• Anti-fibrotic
• Inhibits fibroblast migration, proliferation, and myoblast transformation
• Form: 150 mg capsule + 100 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
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Richeldi L et al. N Engl J Med 2014;370:2071-2082.
d Change from Baseline over Ti
me in Forced
Vital CapaINcity
INPULSIS Primary and Key Secondary Outcomes
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Karimi-Shah BA, Chowdhury BA. N Engl J Med 2015;372:1189-1191.
Analysis of Forced Vital Capacity and All-Cause Mortality.
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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
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The Idiopathic Pulmonary Fibrosis Clinical Research Network. N Engl J Med 2012;366:1968-1977.
Safety End Points.
PANTHER Trial
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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;26:170057
©2017 by European Respiratory Society
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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
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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
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Thank You!
Pexels.com
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References
• Balk, R. (2018). Methotrexate-induced lung injury. Flaherty (Ed.), UpToDate.
Retrieved March 30, 2018, from https://www.uptodate.com/contents/methotrexate-induced-lung-injury
• 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 https://www.uptodate.com/contents/clinical-manifesations-of-mixed-connective-tissue-disease
• 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.
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