interstitial lung disease: focus for the pharmacist · 6/11/2018  · • define interstitial lung...

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

Conflict of Interest Disclosure

• I have no conflicts of interest to disclose.

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.

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…

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

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

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

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

Drug Induced Interstitial Lung Disease

Drug Induced Interstitial Lung Disease

• Antibiotics- nitrofurantoin

• Antiarrhythmics- amiodarone

• Rheumatoid medications- methotrexate, DMARDs

• Chemotherapy- bleomycin

• Dietary Supplements

• Oxygen

• Radiation

Pexels.com

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

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

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

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

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

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

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

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

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

Connective Tissue Related Interstitial Lung Disease

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

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

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

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

Other Immunologic Related Interstitial Lung Disease

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

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

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

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

Idiopathic Pulmonary Fibrosis

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

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

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

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

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

Karimi-Shah BA, Chowdhury BA. N Engl J Med 2015;372:1189-1191.

Analysis of Forced Vital Capacity and All-Cause Mortality.

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

The Idiopathic Pulmonary Fibrosis Clinical Research Network. N Engl J Med 2012;366:1968-1977.

Safety End Points.

PANTHER Trial

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

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

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

Thank You!

Pexels.com

Susan Tallieu, ACNP-BC, MSN

Susan.tallieu@ucdenver.edu

Colorado Pharmacists Society

Annual Meeting

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.

Retrieved March 30, 2018, from https://www.uptodate.com/contents/amiodarone-pulmonary-toxicity

• Chan, E., & King, T. (2017). Pulmonary disease induced by cardiovascular drugs. Flaherty (Ed.), UpToDate.

Retrieved March 30, 2018, from https://www.uptodate.com/contents/pulmonary-disease-induced-by-cardiovascular-drugs

• Cottin, V. (2013). Interstitial lung disease. European Respiratory Review 22:26-32. 10.1183/09059180.00006812

• The Idiopathic Pulmonary Fibrosis Clinical Research Network (2012). New England Journal of Medicine 2012, 366:1968-1977 DOI:10.1056/NEJMoa1113354

• Feldman, D., & Els, N. (2017). Bleomycin-induced lung injury. Kantoff (Ed.), UpToDate.

Retrieved March 30, 2018, from https://www.uptodate.com/contents/bleomycin-induced-lung-injury

• Karimi-Shah, B., Chowdhury, B. (2015). Forced Vital Capacity in Idiopathic Pulmonary Fibrosis – FDA Review of Pirfenidone and Nintedanib. New England Journal of Medicine, 372:1189-1191

DOI: 10.1056/NEJMp1500526

References

• Kim YJ, Song M, Ryu JC: Mechanisms underlying methotrexate-induced pulmonary toxicity. Expet Opin Drug Saf. 2009, 8: 451-458. 10.1517/14740330903066734.L\

• Lake, F. (2016). Drug-induced lung disease in rheumatoid arthritis. King, T. (Ed.), UpToDate.

Retrieved April 15, 2018, from https://www.uptodate.com/contents/drug-induced-lung-disease-in-rheumatoid-arthritis

• Lancaster et al. (2017). Pirfenidone safety and adverse event management in idiopathic pulmonary fibrosis.

Retrieved April 15, 2018, from http://err/ersjournals.com/content/26/146/170057.long

• 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 https://www.uptodate.com/contents/pulmonary-toxicity-associated-with-systemic-antineoplastic-therapy-clinical-presentation-diagnosis-and-treatment

• 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, 370:2071-2081. DOI: 10.1056/NEJMoa1402584

• 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 https://doi.org/10.1148/radiographics.20.5.g00se081245

• Selman et al (2012). Hypersensitivity Pneumonitis Insights in Diagnosis and Pathobiology. American Journal of Respiratory and Critical Care Medicine 2012, 186:314-22.

References:

• Sleijfer, S. (2001). Bleomycin-Induced Pneumonitis. Chest. 120: 617-624 DOI: https://doi.org/10.1378/chest.120.2.617

• Tashkin st al. (2006). Cyclophosphamide versus Placebo in Scleroderma Lung Disease. New England Journal of Medicine, 2006. 354:2655-2666. DOI: 10.1056/NEJMoa055120

• Talmadge et al. (2014). A Phase 3 Trial of Pirfenidone in Patients with Idiopathic Pulmonary Fibrosis. New England Journal of Medicine 2014, 370:2083-2092. DOI: 10.1056/NEJMoa1402582

• Vahid B., Marik, P. (2008). Pulmonary Complications of Novel Antineoplastic Agents for Solid Tumor. Chest 2008, 3133:528-538. https://doi.org/10.1378/chest.07-0851

• 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, 2013. 143: 814-824. doi: 10.1378/chest.12-0741

• Wikimedia Commons, the free media repository. (2018, March 8). File: Honeycomb Lung. Retrieved 15:09, June 1, 2018 from https://commons.wikimedia.org/w/index.php?title=File:Honeycomb_lung_(4840520057).jpg&oldid=291401751.

• Williams E. (2006). Recurrent Acute Nitrofurantoin-Induced Pulmonary Toxicity. Pharmacotherapy. 5:713-718. DOI:10.1592/phco.26.5.713

• Zeeuw, J., & Gillissen, A. (2018). Nitrofurantoin-induced lung injury. Flaherty (Ed.), UpToDate.

Retrieved March 30, 2018, from https://www.uptodate.com/contents/nitrofurantoin-induced-pulmonary-injury