Clinical Updates in the Management of Severe Asthma

REYNOLD A. Panettieri, Jr., MD

MICHAEL E.

Wechsler, MD, MMSc

This activity is jointly provided by Global Education Group and Integritas Communications.

This activity is supported by an educational grant from AstraZeneca and Genzyme, a Sanofi company, and Regeneron Pharmaceuticals.

CLINICAL UPDATES in the MANAGEMENT of

SEVERE ASTHMA

New Strategies for Individualizing Long-Term Care

This activity is jointly provided by Global Education Group and Integritas Communications.

This activity is supported by an educational grant from AstraZeneca and Genzyme, a Sanofi company, and Regeneron Pharmaceuticals.

iii

TABLE OF CONTENTS Faculty iv Preamble vi Chapter 1 The Causes and Consequences of Severe Asthma

1

Reynold A. Panettieri, Jr., MD

Chapter 2 Comprehensive Assessment of Patients With Severe Asthma

9

Reynold A. Panettieri, Jr., MD

Chapter 3 Biologic Therapies for Severe Asthma

17

Michael E. Wechsler, MD, MMSc

Chapter 4 Nonbiologic Strategies for the Management of Severe Asthma

27

Michael E. Wechsler, MD, MMSc

Severe Asthma 37 Clinical Resource Center™ Severe Asthma 43 Supplemental Video Library

Download this activity and additional tools at

CLINICAL UPDATES in the MANAGEMENT of SEVERE ASTHMA

iv

FACULTY Reynold A. Panettieri, Jr., MD Professor of Medicine Robert Wood Johnson Medical School Vice Chancellor, Clinical & Translational Science Director, Rutgers Institute for Translational Medicine & Science Child Health Institute of New Jersey Rutgers, The State University of New Jersey New Brunswick, New Jersey Reynold A. Panettieri, Jr, MD, is the Director of the Institute for Translational Medicine and Science and Vice Chancellor for Translational Medicine and Science at Rutgers University, and the former Director of the Airways Biology Initiative at the University of Pennsylvania. His interests are in the cellular and molecular mechanisms that regulate airway smooth muscle cell growth and the immunobiology of airway smooth muscle. Consequences of increases in airway smooth muscle growth promote the development of irreversible airflow obstruction and airway remodeling seen in patients with chronic severe asthma. Dr. Panettieri’s lab also focuses on cytosolic signaling pathways that mediate gene expression and alter myocyte function.

Dr. Panettieri also served as the Deputy Director of the Center of Excellence in Environmental Toxicology. He directed the human exposure chamber that defines the molecular mechanisms regulating ozone- and particulate matter-induced airway hyperresponsiveness. In parallel with his basic science interests, Dr. Panettieri managed the comprehensive clinical program for the care of patients with asthma and is actively involved in clinical investigations focused on the management of asthma and chronic obstructive pulmonary disease (COPD).

In addition to his research and clinical interests, Dr. Panettieri served as chairperson of the National Institutes of Health (NIH) Lung Cellular, Molecular, and Immunobiology Study Section, is a member of the NIH Distinguished Editorial Panel, and is a member of both the American Society for Clinical Investigation and Association of American Physicians.

Download this activity and additional tools at

FACULTY

v

Michael E. Wechsler, MD, MMSc Co-Director, The Cohen Family Asthma Institute Professor, Department of Medicine Division of Pulmonary, Critical Care and Sleep Medicine Director, Asthma Program National Jewish Health Denver, Colorado

Michael E. Wechsler is Professor of Medicine and Director of the Asthma Program in the Division of Pulmonary, Critical Care and Sleep Medicine at National Jewish Health in Denver. He is board certified in both Pulmonary and Critical Care Medicine.

Professor Wechsler’s research focuses on clinical and translational asthma with emphasis on clinical trials in asthma, novel asthma therapies, bronchial thermoplasty, asthma pharmacogenomics, and management of eosinophilic granulomatosis with polyangiitis (Churg-Strauss Syndrome, CSS). He has published more than 100 peerreviewed manuscripts relating to asthma, CSS, and eosinophilic lung diseases.

Professor Wechsler is a member of the Steering Committee and site Principal Investigator of the NIH-sponsored Asthma Clinical Research Network (ACRN, now called AsthmaNet), a multicenter asthma clinical trials consortium. He has served as Principal Investigator of the National Heart, Lung, and Blood Institute (NHLBI)sponsored ACRN LARGE trial, Partners Genetics Enters Medicine Initiative-funded GABLE trial and the Agency for Healthcare Research and Quality (AHRQ)-funded Blacks and Exacerbations on LABA or Tiotropium (BELT) trial. He is currently serving as Principal Investigator of an NHLBI sponsored study of asthma therapies in African Americans that examines race-specific differences in response to asthma therapy.

He is also leading an National Institute of Allergy and Infectious Diseases (NIAID)sponsored study exploring anti-interleukin 5 in CSS. A member of the American Society of Clinical Investigation, Professor Wechsler has participated in many different task forces related to the study of eosinophilic lung diseases that were sponsored by the NIH, the US Food and Drug Administration (FDA), the European Respiratory Society and the International Eosinophil Society.

Professor Wechsler also serves as Associate Editor of the Journal Allergy and is on the editorial board of the European Journal of Clinical Investigation. Dr. Wechsler received AB and MMSc degrees from Harvard University in Boston and an MD degree from McGill University in Montreal.

Download this activity and additional tools at

CLINICAL UPDATES in the MANAGEMENT of SEVERE ASTHMA

vi

PREAMBLE Target Audience The educational design of this activity addresses the needs of allergists/clinical immunologists, pulmonologists, and other clinicians involved in the ongoing management of patients with severe asthma.

Statement of Need/Program Overview An estimated 5% to 15% of the more than 25 million Americans with asthma have a severe form of the disease and are burdened by an outsized proportion of asthmarelated morbidity, mortality, and healthcare costs.1,2 Although managing this cohort has historically been challenging, new insights into the heterogeneous clinical features and disease mechanisms among patients with severe asthma have raised the possibility of integrating presenting characteristics with molecular and cellular profiling to identify endotypes—ie, phenotypic descriptions that are matched with underlying mechanistic pathways.3,4 Detailed disease classification, the development of biomarkers, and longitudinal monitoring of symptom control are now being used to guide the use of the growing number of biologic therapies, an important educational topic as pulmonologists and clinical immunologists increasingly seek to personalize treatment for patients with severe asthma.3,5,6 Available in multiple formats, this multimedia eHealth Source™ will cover best practices for assessing disease control in patients with severe asthma, the evidence for current and emerging therapies, and strategies to improve patient education and treatment adherence.

References 1. Levy ML. The national review of asthma deaths: what did we learn and what needs to change?

Breathe (Sheff). 2015;11(1):14-24.

2. Bahadori K, et al. Economic burden of asthma: a systematic review. BMC Pulmonary Medicine.

2009;9:24.

3. Chung KF, et al. International ERS/ATS guidelines on definition, evaluation and treatment of severe asthma. Eur Respir J. 2014;43(2):343-373.

4. Lötvall J, et al. Asthma endotypes: a new approach to classification of disease entities within the asthma syndrome. J Allergy Clin Immunol. 2011;127(2):355-360.

5. Wan XC, Woodruff PG. Biomarkers in severe asthma. Immunol Allergy Clin North Am. 2016;36(3):547-557.

6. Walsh GM. Biologics targeting IL-5, IL-4 or IL-13 for the treatment of asthma—an update.

Expert Rev Clin Immunol. 2016 Aug 2:1-7. [Epub ahead of print]

Download this activity and additional tools at

PREAMBLE

vii

Educational Objectives After completing this activity, the participant should be better able to: • Discuss the pathophysiology of severe asthma, focusing on clinically relevant disease subtypes and molecular targets for new biologic medications • Comprehensively assess patients with symptoms of severe asthma to determine the level of disease control and uncover potential phenotypes that can guide ongoing therapy • Describe the clinical profiles of current and emerging biologic therapies for patients with severe asthma • Individualize long-term management regimens for patients with severe asthma based on current symptoms, past treatment responses, appropriate biomarkers, and exacerbation risks • Educate patients with severe asthma and, when necessary, their caregivers to facilitate shared decision making, encourage self-management, and promote treatment adherence

Physician Accreditation Statement This activity has been planned and implemented in accordance with the accreditation requirements and policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint providership of Global Education Group (Global) and Integritas. Global is accredited by the ACCME to provide continuing medical education for physicians.

Physician Credit Designation Global designates this enduring activity for a maximum of 1.0 AMA PRA Category 1 Credit™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

Nurse Practitioner Continuing Education This activity has been planned and implemented in accordance with the accreditation Standards of the American Association of Nurse Practitioners (AANP) through joint providership of Global and Integritas. Global is accredited by the American Association of Nurse Practitioners as an approved provider of nurse practitioner continuing education.

Provider number: 1561024. This activity is approved for 1.0 contact hour(s) which includes 0 hour(s) of pharmacology.

Activity ID #2103E. This activity was planned in accordance with AANP CE Standards and Policies.

Global Contact Information For information about the accreditation of this program, please contact Global at 303-395-1782 or inquire@globaleducationgroup.com.

Download this activity and additional tools at

CLINICAL UPDATES in the MANAGEMENT of SEVERE ASTHMA

viii

Instructions to Receive Credit In order to receive credit, participants must complete the preactivity questionnaire, postactivity questionnaire, and program evaluation at www.exchangecme.com/ SAehealth. Participants must also score at least a 70% on the posttest.

For information about the accreditation of this program, please contact Global at 303-395-1782 or cme@globaleducationgroup.com

System Requirements PC Microsoft Windows 2000 SE or above.

Flash Player Plugin (v7.0.1.9 or greater) Internet Explorer (v5.5 or greater), or Firefox Adobe Acrobat Reader Mac Mac OS 10.2.8 Flash Player Plugin (v7.0.1.9 or greater) Safari Adobe Acrobat Reader Internet Explorer is not supported on the Macintosh.

Fee Information and Refund/Cancellation Policy There is no fee for this educational activity.

Disclosure of Conflicts of Interest Global requires instructors, planners, managers, and other individuals and their spouse/life partner who are in a position to control the content of this activity to disclose any real or apparent conflict of interest they may have as related to the content of this activity. All identified conflicts of interest are thoroughly vetted by Global for fair balance, scientific objectivity of studies mentioned in the materials or used as the basis for content, and appropriateness of patient care recommendations.

The faculty reported the following financial relationships or relationships to products or devices they or their spouse/life partner have with commercial interests related to the content of this CME activity: Reynold A. Panettieri, Jr, MD Consultant: AstraZeneca, Gilead, Johnson & Johnson, Merck, Teva, NIH; Grant/Research: AstraZeneca, Gilead, Johnson & Johnson, Merck, Roche, Sanofi-Aventis, Teva, NIH Michael E. Wechsler, MD, MMSc Consultant: AstraZeneca, BSCI, Teva, Novartis, Sanofi-Aventis, Vectura Group, Sunovion, Regeneron, Ambit bioscience, Meda, Mylan, Gliacure, Tunitas, Genentech, Theravance

Download this activity and additional tools at

PREAMBLE

The planners and managers reported the following financial relationships or relationships to products or devices they or their spouse/life partner have with commercial interests related to the content of this CME activity: Lindsay Borvansky

Nothing to disclose

Andrea Funk

Nothing to disclose

Kristen Delisi, NP

Nothing to disclose

Jim Kappler, PhD

Nothing to disclose

Rose O’Connor, PhD

Nothing to disclose

Disclosure of Unlabeled Use This educational activity may contain discussion of published and/or investigational uses of agents that are not indicated by the FDA. Global and Integritas do not recommend the use of any agent outside of the labeled indications.

The opinions expressed in the educational activity are those of the faculty and do not necessarily represent the views of any organization associated with this activity.

Please refer to the official prescribing information for each product for discussion of approved indications, contraindications, and warnings.

Disclaimer Participants have an implied responsibility to use the newly acquired information to enhance patient outcomes and their own professional development. The information presented in this activity is not meant to serve as a guideline for patient management. Any procedures, medications, or other courses of diagnosis or treatment discussed in this activity should not be used by clinicians without evaluation of patient conditions and possible contraindications on dangers in use, review of any applicable manufacturer’s product information, and comparison with recommendations of other authorities.

eReader version available at

EXCHANGECME.com/ ASTHMAeHealth

Download this activity and additional tools at

ix

CLINICAL UPDATES in the MANAGEMENT of SEVERE ASTHMA

x

Download this activity and additional tools at

CHAPTER 1

The Causes and Consequences of Severe Asthma Reynold A. Panettieri, Jr., MD

A

sthma is a chronic respiratory disorder characterized by variable limitations in expiratory airflow, wheezing, shortness of breath, chest tightness, and cough.1 It is a common diagnosis, with epidemiologic studies estimating that 25 million Americans and more than 300 million people globally have asthma.2,3 Not surprisingly, the associated medical, psychosocial, and economic burdens are significant.4,5 For example, each year in the United States, asthma-related symptoms and exacerbations result in almost 2 million emergency department visits, many of which lead to inpatient hospital stays.2 An outsized proportion of the associated morbidity, mortality, and healthcare costs is experienced by the estimated 5% to 15% of patients with asthma who have a severe form of the disease.6-9 The World Health Organization has outlined a relatively expansive definition of severe asthma that reflects symptom severity, current therapies, treatment responses, and exacerbation risks.10 Patients who meet these criteria can generally be categorized into 3 groups: 1) untreated individuals with asthma and signs and symptoms of severe disease; 2) patients who remain symptomatic owing to suboptimal management plans, high-risk environmental conditions, poor treatment adherence, or incorrect use of delivery devices; and 3) people with asthma who require high-dose inhaled corticosteroids (ICS) and additional long-acting controller medications.10 The last cohort has been defined by the American Thoracic Society and the European Respiratory Society as a patient with asthma who "require treatment with high-dose ICS plus a second controller (and/or systemic corticosteroids) to prevent it from becoming ‘uncontrolled’ or which remains ‘uncontrolled’ despite this therapy” (Box 1).1,4 This eHealth Source™ activity focuses on these patients, including identifying potential phenotypes, comprehensively evaluating disease manifestations, and individualizing ongoing treatment regimens at times using new targeted biologic medications (see link to supplementary VIDEO 1).

Download this activity and additional tools at

1

CLINICAL UPDATES in the MANAGEMENT of SEVERE ASTHMA

2

BOX 1: Indications of uncontrolled severe asthma in patients aged ≥6 years1 Uncontrolled asthma defined as at least one of the following: 1. Poor symptom control: ACQ consistently >1.5, ACT <20 (or "not well controlled" by NAEPP/GINA guidelines) 2. Frequent severe exacerbations: two or more bursts of systemic CS (>3 days each) in the previous year 3. Serious exacerbations: at least one hospitalization, ICU stay, or mechanical ventilation in the previous year 4. Airflow limitation: after appropriate bronchodilator withhold FEV1 <80% predicted (in the face of reduced FEV1/FVC defined as less than the lower limit of normal) ACQ, Asthma Control Questionnaire; ACT, Asthma Control Test; CS, corticosteroid; FEV1, forced expiratory volume in 1 second; FVC, forced vital capacity; GINA, Global Initiative for Asthma; ICU, intensive care unit; NAEPP, National Asthma Education and Prevention Program.

BURDENS of SEVERE ASTHMA

Large patient networks have been used to examine potential clinical presentations, biopsychosocial consequences, and treatment outcomes associated with severe asthma.7,9 These observational studies have described substantial burdens for affected individuals, gaps in long-term care, and a clear need for additional treatment options. For instance, The Epidemiology and Natural History of Asthma: Outcomes and Treatment Regimens (TENOR) study showed that patients are markedly impaired by severe or difficult-to-treat asthma despite increased use of healthcare services and multiple medications (half of the TENOR patients used ≥3 long-term medications for asthma control).9 In addition, 5% to 10% of TENOR patients from various age groups had been hospitalized during the 3 months prior to enrollment, and up to 22% had recently visited emergency services for asthma-related symptoms.11 These findings are consistent with the results from the Gaining Optimal Control study in which a third of patients with severe asthma did not meet the criteria for well-controlled disease despite combination therapy with ICS and a long-acting β2-agonist.8 Other studies have shown that patients with poorly controlled severe asthma experience high levels of medical and

CHAPTER 1 The Causes and Consequences of Severe Asthma

mental distress are frequently absent from work or school and face increased mortality risks.7,12,13 Together, these data underscore the crucial need to identify and aggressively treat severe asthma to improve long-term patient outcomes.

ASTHMA PATHOPHYSIOLOGY and NEW THERAPEUTIC TARGETS

Ongoing research has elucidated some of the mechanistic underpinnings of asthma development, including key roles for the airway epithelium and dysregulated immune processes.14 Numerous inflammatory triggers can induce structural and functional changes in the lung airways, such as hyperplasia of mucous-producing goblet cells, hypertrophy of local smooth muscle, and subepithelial fibrosis.15 These processes affect airway mechanics.15 Additionally, bronchial tissue becomes hyperresponsive to allergens, pollutants, and/or infectious agents.15 In severe asthma, many of these mechanisms are exacerbated as chronically injured airway epithelium interacts with mesenchymal and immune cell populations.16,17 Crosstalk among these cells results in an inflammatory milieu of cytokines, chemokines, and other signaling factors that create a feedback loop between dysregulated immune processes and airway wall remodeling.17 Evidence for considerable diversity in the underlying inflammatory processes, the range of potential disease manifestations, and documented variability in therapeutic responses illustrate asthmaâ&#x20AC;&#x2122;s heterogeneity.1,18 Thus, it appears that various pathophysiologic processes can lead to the characteristic clinical presentation of variable airflow obstruction.1,18 In some cases, shared demographic, clinical, and/or pathophysiologic parameters have been used to define asthma phenotypes.19 For example, almost 2 decades ago, profiling immune cells in endobronchial tissue samples revealed 2 cohorts.20 One group was characterized by high eosinophil counts despite the use of ICS, whereas samples from the second group showed significant neutrophilic infiltration.20 This and other studies support a pathogenic role for eosinophilia in many patients, while also suggesting that asthma-related airway inflammation can be driven by a range of immune cell populations and molecular factors.20,21 Since that time, various techniques have been used to describe a number of somewhat overlapping severe asthma phenotypes, such as allergic asthma, nonallergic asthma, asthma with obesity, late-onset asthma, and

3

CLINICAL UPDATES in the MANAGEMENT of SEVERE ASTHMA

4

exacerbation-prone asthma.19,22 Additional efforts have been made to integrate these clinical phenotypes with molecular and cellular profiling to identify endotypes—ie, phenotypic descriptions that are matched to underlying pathophysiologic mechanisms.1,23 The overall goal is to enable clinicians to select medications with mechanisms of action that combat the primary etiologic and pathologic processes in each patient.4 This type of research has shown that the T helper (Th)2 and Th17 subsets of helper T cells play key roles in the development of asthma characterized by eosinophilic and neutrophilic bronchial infiltration, respectively (Figure 1).24,25 Furthermore, inflammatory signaling in Th2-mediated (or allergic) asthma is mediated by cytokines produced by these cells, including interleukin-5 (IL-5), IL-4, and IL-13. IL-5 contributes to the proliferation, differentiation, migration, and survival of eosinophils, a cellular population associated with basement membrane zone thickening and an indicator of ICS-responsive disease.26-28 Moreover, IL-5 expression in the airways appears to correlate with the clinical severity of allergic asthma.29 IL-4 and IL-13 have both been linked to airway hyperresponsiveness and the induction of alternatively activated macrophages, which contribute to pulmonary fibrosis.30,31 IL-13 has also been tied to immunoglobulin E synthesis, goblet cell hyperplasia, and mucus hypersecretion.32,33 Other studies have shown that sputum IL-13 levels negatively correlate with asthma control and remain elevated in glucocorticoid-insensitive asthma.34-36 Of note, IL-4 and IL-13 exert some of their effects through the same heterodimer receptor complex comprising IL-4 receptor α and IL-13 receptor α1.36 Together, this research has provided a foundation for the development of targeted biologic therapies designed to inhibit signaling by these Th2 cytokines (see link to supplementary VIDEO 2).

KEY CLINICAL HIGHLIGHTS • Patients with severe asthma suffer from an outsized proportion of disease-related mortality, morbidity, and social burdens • Th2 and Th17 cells play roles in eosinophilic and neutrophilic asthma, respectively • The Th2 cytokines IL-4, IL-5, and IL-13 are thought to contribute to the development of allergic asthma, and can be targeted with current and emerging biologic therapies

CHAPTER 1 The Causes and Consequences of Severe Asthma

5 Th cell differentiation Allergens

MHC class II TCR

IL-4

Th2 cytokine production Th2 cell

Dendritic cell Th0 cell IL-4

IL-5

IL-5

IL-4

IL-13

IL-13

Isotype switching to IgE IL-4

Eosinophil trafficking to tissues

IL-13

Eosinophil differentiation

IgM IL-13

Mucus production Goblet cell hyperplasia

B cell

Allergens IgE Memory B cell

Collagen production by fibroblasts Smooth muscle cell contractility

FcεRI Mast cell

Basophil

FIGURE 1. Pathophysiology of Th2 cell–driven asthma37 FcεRI, high-affinity IgE receptor; IgE, immunoglobulin E; IgM, immunoglobulin M; IL, interleukin; MHC, major histocompatibility complex; TCR, T cell receptor; Th, T helper cell.

Adapted from Gandhi NA, et al. Nat Rev Drug Discov. 2016;15(1):35-50.

CLINICAL UPDATES in the MANAGEMENT of SEVERE ASTHMA

6

REFERENCES 1. Chung KF, et al. International ERS/ATS guidelines on definition, evaluation and treatment of severe asthma. Eur Respir J. 2014;43(2):343-373.

2. Centers for Disease Control and Prevention. Asthma Facts: CDCâ&#x20AC;&#x2122;s National Asthma Control Program Grantees. Centers for Disease Control and Prevention; July 2013.

3. Blackwell DL, et al. Summary health statistics for U.S. adults: National Health Interview Survey, 2012. Vital Health Stat. 2014;10(260):1-161.

4. Lang DM. Severe asthma: epidemiology, burden of illness, and heterogeneity. Allergy Asthma Proc. 2015;36(6):418-424.

5. Barnett SB, Nurmagambetov TA. Costs of asthma in the United States: 2002-2007. J Allergy Clin Immunol. 2011;127(1):145-152.

6. Bahadori K, et al. Economic burden of asthma: a systematic review. BMC Pulm Med. 2009;9:24.

7. Levy ML. The national review of asthma deaths: what did we learn and what needs to change? Breathe (Sheff). 2015;11(1):14-24.

8. Bateman ED, et al. Can guideline-defined asthma control be achieved? The Gaining Optimal Asthma ControL study. Am J Respir Crit Care Med. 2004;170(8):836-844.

9. Chipps BE, et al. Key findings and clinical implications from The Epidemiology and Natural History of Asthma: Outcomes and Treatment Regimens (TENOR) study. J Allergy Clin Immunol. 2012;130(2):332-342.e310.

10. Bousquet J, et al. Uniform definition of asthma severity, control, and exacerbations: document presented for the World Health Organization Consultation on Severe Asthma. J Allergy Clin Immunol. 2010;126(5):926-938.

11. Chipps BE, et al. Assessment of asthma control and asthma exacerbations in the epidemiology and natural history of asthma: outcomes and treatment regimens (TENOR) observational cohort. Curr Respir Care Rep. 2012;1(4):259-269.

12. Sullivan SD, et al. Extent, patterns, and burden of uncontrolled disease in severe or difficultto-treat asthma. Allergy. 2007;62(2):126-133.

13. Strine TW, et al. Risk behaviors and health-related quality of life among adults with asthma: the role of mental health status. Chest. 2004;126(6):1849-1854.

14. Wenzel S. Mechanisms of severe asthma. Clin Exp Allergy. 2003;33(12):1622-1628.

15. Barnes PJ. Pathophysiology of allergic inflammation. Immunol Rev. 2011;242(1):31-50.

16. Walsh GM. An update on biologic-based therapy in asthma. Immunotherapy.

2013;5(11):1255-1264.

17. Davies DE, et al. Airway remodeling in asthma: new insights. J Allergy Clin Immunol.

2003;111(2):215-225; quiz 226.

18. Anderson GP. Endotyping asthma: new insights into key pathogenic mechanisms in a complex, heterogeneous disease. Lancet. 2008;372(9643):1107-1119.

19. Moore WC, et al. Identification of asthma phenotypes using cluster analysis in the Severe Asthma Research Program. Am J Respir Crit Care Med. 2010;181(4):315-323.

20. Wenzel SE, et al. Evidence that severe asthma can be divided pathologically into two inflammatory subtypes with distinct physiologic and clinical characteristics. Am J Respir Crit Care Med. 1999;160(3):1001-1008.

21. Bell MC, Busse WW. Severe asthma: an expanding and mounting clinical challenge. J Allergy Clin Immunol Pract. 2013;1(2):110-121.

22. Global Initiative for Asthma. Global Strategy for Asthma Management and Prevention, 2017. www.ginasthma.org. Accessed April 21, 2017.

23. LĂśtvall J, et al. Asthma endotypes: a new approach to classification of disease entities within the asthma syndrome. J Allergy Clin Immunol. 2011;127(2):355-360.

24. Woodruff PG, et al. T-helper type 2-driven inflammation defines major subphenotypes of asthma. Am J Respir Crit Care Med. 2009;180(5):388-395.

25. Kim MA, et al. Adult asthma biomarkers. Curr Opin Allergy Clin Immunol. 2014;14(1):49-54.

26. Garcia G, et al. Anti-interleukin-5 therapy in severe asthma. Eur Respir Rev. 2013;22(129):251-257.

27. Ying S, et al. Phenotype of cells expressing mRNA for TH2-type (interleukin 4 and interleukin 5) and TH1-type (interleukin 2 and interferon gamma) cytokines in bronchoalveolar lavage and bronchial biopsies from atopic asthmatic and normal control subjects. Am J Respir Cell Mol Biol. 1995;12(5):477-487.

28. Rosenberg HF, et al. Eosinophil trafficking in allergy and asthma. J Allergy Clin Immunol.

2007;119(6):1303-1310; quiz 1311-1302.

29. Humbert M, et al. Relationship between IL-4 and IL-5 mRNA expression and disease severity in atopic asthma. Am J Respir Crit Care Med. 1997;156(3 Pt 1):704-708.

30. Venkayya R, et al. The Th2 lymphocyte products IL-4 and IL-13 rapidly induce airway hyperresponsiveness through direct effects on resident airway cells. Am J Respir Cell Mol Biol. 2002;26(2):202-208.

31. Wynn TA, Ramalingam TR. Mechanisms of fibrosis: therapeutic translation for fibrotic disease.

Nat Med. 2012;18(7):1028-1040.

32. Yasuo M, et al. Relationship between calcium-activated chloride channel 1 and MUC5AC in goblet cell hyperplasia induced by interleukin-13 in human bronchial epithelial cells.

Respiration. 2006;73(3):347-359.

33. Tanabe T, et al. Clarithromycin inhibits interleukin-13-induced goblet cell hyperplasia in human airway cells. Am J Respir Cell Mol Biol. 2011;45(5):1075-1083.

34. Ito K, et al. Update on glucocorticoid action and resistance. J Allergy Clin Immunol.

2006;117(3):522-543.

35. Saha SK, et al. Increased sputum and bronchial biopsy IL-13 expression in severe asthma.

J Allergy Clin Immunol. 2008;121(3):685-691.

36. Rael EL, Lockey RF. Interleukin-13 signaling and its role in asthma. World Allergy Organ J. 2011;4(3):54-64.

37. Gandhi NA, et al. Targeting key proximal drivers of type 2 inflammation in disease.

Nat Rev Drug Discov. 2016;15(1):35-50.

7

CLINICAL UPDATES in the MANAGEMENT of SEVERE ASTHMA

8

In order to receive credit, participants must complete the preactivity questionnaire, posttest, and program evaluation at

EXCHANGECME.com/ SAeHealth

CHAPTER 2

Comprehensive Assessment of Patients With Severe Asthma Reynold A. Panettieri, Jr., MD

I

dentifying patients with severe asthma requires differential diagnoses of milder cases that are suboptimally managed, disorders with similar symptom profiles, â&#x20AC;&#x153;difficultâ&#x20AC;? asthma caused primarily by confounding factors, and refractory asthma that requires relatively aggressive therapy.1 Specialists should always begin by confirming the diagnosis and ruling out other potentially causative conditions (Table 1).2 Patient evaluations must be multidimensional, including a detailed medical history to search for characteristic patterns of respiratory symptoms (eg, wheezing, dyspnea, chest tightness, and/or cough with variable intensities).2 Lung function testing (eg, spirometry) should be used to assess current expiratory airflow limitations and excessive variability at baseline and periodically thereafter.2 Depending on the patient and recent history, providers may choose to perform a bronchodilator reversibility test or a bronchial challenge (eg, with methacholine or histamine). Moreover, comparing initial and subsequent lung function parameters, such as peak expiratory flow or forced expiratory volume in 1 second (FEV1), can help identify and characterize the severity of subsequent disease exacerbations.2 The patient workup often includes chest imaging (eg, X-ray or as-needed computed tomography) and a complete blood count panel, taking note of peripheral eosinophil numbers.2 Depending on the clinical situation and available resources, clinicians may also want to consider allergy tests and measurements of fractional exhaled nitric oxide (FeNO).2 At times, specific tests can be ordered to ensure certain comorbid complications are not the primary cause of symptomsâ&#x20AC;&#x201D;for example, a gastrointestinal evaluation looking for gastroesophageal reflux disease or laryngoscopy in severe cases to rule out vocal cord dysfunction.

Download this activity and additional tools at

9

CLINICAL UPDATES in the MANAGEMENT of SEVERE ASTHMA

10

TABLE 1: Differential Diagnosis of Asthma2 Age Conditions 6-11 • Chronic upper airway years cough syndrome • Inhaled foreign body • Bronchiectasis • Primary ciliary dyskinesia • Congenital heart disease • Bronchopulmonary dysplasia • Cystic fibrosis

Symptoms • Sneezing, itching, blocked nose, throat-clearing • Sudden onset of symptoms, unilateral, wheeze • Recurrent infections, productive cough • Recurrent infections, productive cough, sinusitis • Cardiac murmurs

• Pre-term delivery, symptoms since birth • E xcessive cough and mucus production, gastrointestinal symptoms 12-39 • Chronic upper airway • Sneezing, itching, blocked years cough syndrome nose, throat-clearing • Vocal cord dysfunction • Dyspnea, inspiratory wheezing (stridor) • Hyperventilation, • Dizziness, paresthesia, dysfunctional breathing sighing • Bronchiectasis • Productive cough, recurrent infections • Cystic fibrosis • E xcessive cough and mucus production • Congenital heart • Cardiac murmurs disease • Alpha1-antitrypsin • Shortness of breath, deficiency family history of early emphysema • Inhaled foreign body • Sudden onset of symptoms

Cont’d

CHAPTER 2 Comprehensive Assessment of Patients With Severe Asthma

11

Age Conditions Symptoms 40+ • Vocal cord dysfunction • Dyspnea, inspiratory years wheezing (stridor) • Hyperventilation, • Dizziness, paresthesia, dysfunctional breathing sighing • Chronic obstructive • Cough, sputum, dyspnea pulmonary disease on exertion, smoking or noxious exposure • Bronchiectasis • Productive cough, recurrent infections • Cardiac failure • Dyspnea with exertion, nocturnal symptoms • Medication-related • Treatment with angiotensin cough converting enzyme inhibitor • Parenchymal lung • Dyspnea with exertion, disease nonproductive cough, finger clubbing • Pulmonary embolism • Sudden onset of dyspnea, chest pain • Central airway • Dyspnea, unresponsive to obstruction bronchodilators

EXACERBATIONS and COMPLICATING COMORBIDITIES Each patient should also be assessed for previous exacerbations, which serve as a composite measure of symptoms, lung function, healthcare utilization, and the need for systemic steroid courses.3 Exacerbations are defined by the Global Initiative for Asthma (GINA) as periods of acute or subacute worsening of symptoms and lung function relative to the individual’s usual status such that a change in treatment is required.2 It is important to have a good understanding of patients’ recent and long-term exacerbation history to identify individuals at risk for potentially catastrophic outcomes, shape treatment decisions, and define a baseline to assess future treatment responses.4 For example, patients who have experienced an exacerbation-induced hospitalization

CLINICAL UPDATES in the MANAGEMENT of SEVERE ASTHMA

12

or emergency services visit within the past year are at increased risk for asthma-related death and should understand the urgent need to seek medical care early during any future exacerbation.5 Importantly, many patients fail to report exacerbations even when they lead to hospital stays or emergency care.1,6,7 Thus, healthcare providers must specifically and repeatedly query patients about the occurrence of these events. Part of the confusion may stem from the diversity of terms used to describe these episodes, including acute severe asthma and asthma attacks.8 GINA recommends speaking with patients about flare-ups as a simple term that describes a worsening of asthma symptoms while acknowledging that the disease is present at other times as well.2 In addition to conditions masquerading as asthma, clinicians need to consider confounding comorbidities and other factors that may markedly contribute to the symptom burden or impair quality of life.2 In some cases, comorbidities can increase the frequency and/or severity of exacerbations.9 Some of the most frequently encountered comorbidities include gastroesophageal reflux disease, sinusitis, obesity, respiratory infections, and obstructive sleep apnea.9 Many of these chronic comorbid conditions contribute to increased systemic inflammation, which can enhance asthma-related airway remodeling and associated inflammatory signaling.10 Taken together, it is imperative that comorbid conditions are identified and treated appropriately to reduce the influence of these disorders on asthma symptom severity (see link to supplementary VIDEO 3). Thus, a comprehensive assessment of the patient’s past medical history and current presentation along with identification of comorbid conditions is an essential step in individualizing management plans.11

ASSESSING ASTHMA CONTROL After a diagnosis is confirmed, clinicians should directly question patients on the extent of asthma control initially and at every subsequent opportunity, including explanations of what is meant by “control.” Two domains of asthma control should be considered: 1) a comprehensive evaluation of symptom burden, including effects of current treatments, and 2) the risk of future adverse asthma-related events.2,12 Disease control will be a reflection of the patient’s genetic background, underlying pathophysiologic disease processes, treatment regimen, environment, and psychosocial status.2 GINA recommends focusing on the 4 previous weeks when querying patients about the

CHAPTER 2 Comprehensive Assessment of Patients With Severe Asthma

number of days per week with asthma symptoms, asthma-related functional limitations and awakenings at night, and the number of times the patient used a reliever medication to address symptoms.2 Several clinical assessment tools are available to help translate a multidimensional evaluation into a numeric value, with certain scores or ranges validated against experts’ assessments and assigned to different levels of symptom control.2 Examples include the Asthma Therapy Assessment Questionnaire (ATAQ), Asthma Control Questionnaire (ACQ), Asthma Control Test (ACT), and GINA recommendations on assessing asthma symptom control (Box 1).1,13 The ATAQ is a selfadministered, 4-item questionnaire for adults that allows clinicians to review information about functional effects, patient perspectives, and inhaler use over the last 4 weeks.14 A score of 0 indicates wellcontrolled asthma symptoms, whereas a score ≥1 suggests that

BOX 1: GINA assessment of asthma control in adults, adolescents, and children aged 6–11 years2 Asthma symptom Level of asthma control symptom control In the past 4 weeks, Well Partly Uncontrolled has the patient had: controlled controlled • Daytime asthma  Yes symptoms  No more than twice/week?

• Any night  Yes waking due to  No asthma?

None 1-2 3-4 of these of these of these • Reliever needed for  Yes symptoms  No more than twice/week?

• Any activity  Yes limitation due  No to asthma?

13

CLINICAL UPDATES in the MANAGEMENT of SEVERE ASTHMA

14

further patientâ&#x20AC;&#x201C;clinician discussion and possibly a change in current therapies are needed.14 The 7-question ACQ assesses patients for specific symptoms, functional limitations, sleep disturbances, and rescue bronchodilator use over the last week, as well as FEV1% predicted.15 After each question is ranked from 0 to 6, the final ACQ score is calculated as the average numeric response for all 7 items.15 For patients at least 12 years of age, the 5-question ACT assesses asthma symptoms and control over the prior 4 weeks.16 Threshold scores for the ACQ and ACT have been included in guidelines from the American Thoracic Society (ATS) and European Respiratory Society (ERS) as potential criteria to determine whether a patient with severe asthma has uncontrolled disease (see link to supplementary VIDEO 4).1

USING BIOMARKERS to DEFINE ASTHMA PHENOTYPES and ENDOTYPES As noted previously, asthma is a heterogeneous disorder that can be associated with a wide range of clinical histories, disease manifestations, and underlying pathophysiologic processes.13,17 Thus, an increasingly important aspect of patient management is tailoring mechanistically rational therapy to address specific asthma phenotypes, which can be classified using prominent symptoms and other readily identifiable clinical parameters.18 One long-discussed phenotype is allergic asthma, which historically has been diagnosed based on identifiable allergen triggers and/or the presence of a clear personal or family history of allergic disease. Differences from nonallergic asthma phenotypes have been observed using patientsâ&#x20AC;&#x2122; sputum samples and treatment responses: allergic asthma is associated with eosinophilic airway inflammation and often responds well to inhaled corticosteroids (ICS). On the other hand, various types of nonallergic asthma may have neutrophilic profiles in the sputum, or potentially lack inflammatory cells altogether, leading to reduced responses to ICS. Additional research has focused on characterizing various biomarkers to better define asthma phenotypes and predict responses to various therapies.1,13 As outlined in the recent ERS/ATS guidelines, treatment choices can be shaped by peripheral eosinophil counts or circulating immunoglobulin E (IgE) levels.1 FeNO levels have also been used as a marker of Th2 cell inflammation, although there is some controversy around the utility of this test in daily practice.1 Two other biomarker

CHAPTER 2 Comprehensive Assessment of Patients With Severe Asthma

candidates that have emerged as predictors of responses to anti–IL-13 agents are periostin and dipeptidyl peptidase-4 (DPP-4) (see link to supplementary VIDEO 5).19,20 As more information becomes available about the utility of these and other biomarkers, clinicians may be able to use these parameters to better personalize therapy for patients with severe asthma.

KEY CLINICAL HIGHLIGHTS: • When evaluating a new patient with asthma, it critical to first confirm the diagnosis • Comorbid conditions that contribute to asthma symptoms should be identified and optimally managed • Assessing asthma control requires a multidimensional evaluation of symptoms, functional effects, and risks for future adverse outcomes (eg, exacerbations) • Treatment decisions for severe asthma will increasingly be guided by using biomarkers, such as eosinophil counts, FeNO, or plasma levels of IgE or periostin

REFERENCES 1. Chung KF, et al. International ERS/ATS guidelines on definition, evaluation and treatment of severe asthma. Eur Respir J. 2014;43(2):343-373.

2. Global Initiative for Asthma. Global Strategy for Asthma Management and Prevention, 2017. www.ginasthma.org. Accessed April 21, 2017.

3. Fuhlbrigge A, et al. Asthma outcomes: exacerbations. J Allergy Clin Immunol. 2012;129(suppl 3):S34-S48.

4. Nucala (mepolizumab) [package insert]. Philadelphia, PA: GlaxoSmithKline; 2015.

5. Alvarez GG, et al. A systematic review of risk factors associated with near-fatal and fatal asthma. Can Respir J. 2005;12(5):265-270.

6. Adams JY, et al. The patient with asthma in the emergency department. Clin Rev Allergy Immunol. 2012;43(1-2):14-29.

7. Osborne ML, et al. Lack of correlation of symptoms with specialist-assessed long-term asthma severity. Chest. 1999;115(1):85-91.

8. Blaiss MS, et al. Patient and physician asthma deterioration terminology: results from the 2009 Asthma Insight and Management survey. Allergy Asthma Proc. 2012;33(1):47-53.

9. Boulet LP. Influence of comorbid conditions on asthma. Eur Respir J. 2009;33(4):897-906.

10. Murdoch JR, Lloyd CM. Chronic inflammation and asthma. Mutat Res. 2010;690(1-2):24-39.

11. Levy ML, et al. Diagnostic spirometry in primary care: proposed standards for general practice compliant with American Thoracic Society and European Respiratory Society recommendation.

Prim Care Respir J. 2009;18(3):130-147.

15

CLINICAL UPDATES in the MANAGEMENT of SEVERE ASTHMA

16

12. Reddel HK, et al. An official American Thoracic Society/European Respiratory Society statement: asthma control and exacerbations: standardizing endpoints for clinical asthma trials and clinical practice. Am J Respir Crit Care Med. 2009;180(1):59-99.

13. Lang DM. Severe asthma: Epidemiology, burden of illness, and heterogeneity. Allergy Asthma Proc. 2015;36(6):418-424.

14. Vollmer WM, et al. Association of asthma control with health care utilization and quality of life.

Am J Respir Crit Care Med. 1999;160(5 Pt 1):1647-1652.

15. Juniper EF, et al. Development and validation of a questionnaire to measure asthma control. Eur Respir J. 1999;14(4):902-907.

16. Nathan RA, et al. Development of the asthma control test: a survey for assessing asthma control. J Allergy Clin Immunol. 2004;113(1):59-65.

17. Agache I, et al. Untangling asthma phenotypes and endotypes. Allergy. 2012;67(7):835-846.

18. Wenzel SE. Asthma phenotypes: the evolution from clinical to molecular approaches. Nat Med. 2012;18(5):716-725.

19. Emprm V, et al. Periostin - a novel systemic biomarker for eosinophilic airway inflammation: a case control study. J Clin Diagn Res. 2016;10(2):OC01-OC04.

20. Shiobara T, et al. Dipeptidyl peptidase-4 is highly expressed in bronchial epithelial cells of untreated asthma and it increases cell proliferation along with fibronectin production in airway constitutive cells. Respir Res. 2016;17:28.

In order to receive credit, participants must complete the preactivity questionnaire, posttest, and program evaluation at

EXCHANGECME.com/ SAeHealth

CHAPTER 3

Biologic Therapies for Severe Asthma Michael E. Wechsler, MD

S

ome patients with severe asthma will benefit from biologic therapy, and a growing number of these agents are now available or in latestage clinical development. Biologic treatment options for severe asthma have been designed to target immunoglobulin E (IgE) or interfere with Th2 cytokine signaling mediated by interleukin (IL)-5, IL-13, or IL-4.1 Each of the therapies discussed in this chapter has produced positive clinical trial results in overlapping but not identical cohorts of patients with severe asthma.2 Using these data to identify appropriate candidates for treatment will require comprehensive evaluations of patients and disease manifestations, clinical trial results, and ongoing research into biomarkers that can help predict therapeutic responses.2

ANTI-IgE THERAPY Allergen-specific IgE antibodies are produced by B cells and contribute to atopic sensitization, as found in many patients with allergic asthma.3 In these cases, allergen–IgE binding activates basophils and mast cells to release histamine, lipid mediators, and cytokines, leading to bronchoconstriction, plasma exudation in the lungs, and other downstream inflammatory processes.3,4 The anti-IgE antibody omalizumab is approved by the US Food and Drug Administration (FDA) for the treatment of patients ≥6 years of age with moderateto-severe, persistent allergic asthma, a positive aeroallergen test, and symptoms that are inadequately controlled with inhaled corticosteroids (ICS).3 In the United States, omalizumab’s prescribing information states that patients should be checked for circulating IgE levels, with concentrations between 30 and 700 IU/mL indicating that the individual is an appropriate candidate.5 The subcutaneous (SQ) dosing level and frequency (75-375 mg every 2 or 4 weeks) are then determined based on the patient’s IgE level and body weight.5

Download this activity and additional tools at

17

CLINICAL UPDATES in the MANAGEMENT of SEVERE ASTHMA

18

Numerous clinical trials have shown that omalizumab can reduce exacerbation rates and improve quality of life measures in patients with severe allergic asthma.6,7 Modest improvements in lung function as measured by the forced expiratory volume in 1 second (FEV1) and morning peak expiratory flow have also been noted.7,8 Although adverse effects in clinical trials were generally mild or moderate in severity, there is a small risk of anaphylaxis presenting as bronchospasm, hypotension, syncope, urticaria, and/or angioedema of the throat or tongue (clinical trial incidence, 0.14% in omalizumab-treated patients vs 0.07% in control patients).9 Thus, after omalizumab administration, clinicians should monitor patients closely for an appropriate period and be prepared to manage anaphylaxis should a reaction arise.

INHIBITORS of IL-5 SIGNALING As discussed previously, the Th2 cytokine IL-5 is critical throughout the lifecycle of eosinophils, which often drive asthma-related airway inflammation and produce several factors involved in airway wall remodeling (see link to supplementary VIDEO 6).10,11 The potential contributions of IL-5 to asthma pathophysiology are also supported by clinical studies of various anti-IL-5 therapies. As the first FDA-approved anti-IL-5 biologic agent, mepolizumab is available as add-on maintenance treatment for patients â&#x2030;Ľ12 years old with severe asthma and an eosinophilic phenotype.12 The approved dosing regimen is 100 mg SQ every 4 weeks. In the phase 3 MENSA trial, mepolizumab was administered to patients with severe asthma, â&#x2030;Ľ2 exacerbations in the prior year, and high blood eosinophil counts.13 Compared with placebo, mepolizumab at the approved dosage resulted in significant reductions in the annualized rate of clinically significant asthma exacerbations, airflow limitations as measured by FEV1, and scores on the 5-item Asthma Control Questionnaire (ACQ-5).13 In the SIRIUS study, mepolizumab-treated patients with severe eosinophilic asthma who required daily oral glucocorticoid therapy experienced a decrease in the annual exacerbation rate, an approximate 50% reduction in required glucocorticoid doses, and improvements in ACQ-5 scores.14 The most common adverse events from these clinical trials included headache and injection-site reactions, whereas the prescribing information carries warnings about rarely occurring hypersensitivity reactions (angioedema, bronchospasm, hypotension, urticaria, and rash) and herpes zoster infections.12

CHAPTER 3 Biologic Therapies for Severe Asthma

A second anti-IL-5 antibody, reslizumab, was approved by the FDA in March 2016 as add-on maintenance treatment for severe asthma in patients ≥18 years old with severe asthma and an eosinophilic phenotype.15 Reslizumab is administered once every 4 weeks as an intravenous infusion over 20 to 50 minutes at a dose of 3 mg/kg of body weight. Two phase 3 clinical trials examined patients with asthma inadequately controlled by medium-to-high-dose ICS, blood eosinophil counts ≥400 cells/μL at screening, and a history of ≥1 exacerbation during the previous year.16 Reslizumab significantly reduced the frequency of asthma exacerbations, increased FEV1 values, and improved ACQ-7 (7-item) scores.16 Another study showed that reslizumab did not provide clinically meaningful effects on lung function or symptom control in patients with blood eosinophil counts <400/µL, highlighting the importance of checking baseline eosinophils before proceeding with therapy.17 In the 2 large phase 3 trials, the only adverse event that occurred with an incidence ≥2% and more frequently in the reslizumab arms was oropharyngeal pain.15,16 Similar to omalizumab, the prescribing information for reslizumab includes a warning about postinfusion anaphylaxis, requiring that the medication be administered in a healthcare setting prepared to manage this complication.15 A different approach to inhibiting IL-5 signaling is seen with benralizumab, a therapeutic antibody that targets IL-5 receptor α rather than the cytokine itself.18 Whether this mechanistic distinction translates to clinical differences compared with the other anti-IL-5 therapies has not yet been confirmed.19 Benralizumab has been submitted to the FDA for approval, in part based on results from the phase 3 CALIMA and SIROCCO studies (Box 1).20,21 In both studies, patients with blood eosinophil counts ≥300 cells/µL showed significant improvements in prebronchodilator FEV1 with both dosing regimens, and there were no clear differences between the treatment arms in the rates of any adverse events.20,21 Interestingly, greater benefits for some outcomes (eg, measures of asthma symptoms, asthma control, and quality of life) were observed with benralizumab dosing every 8 weeks compared with every 4 weeks.20,21 Moreover, patients with blood eosinophil counts <300 cells/μL experienced significant reductions in exacerbation rates with treatment every 4 weeks and improved asthma symptoms with dosing every 8 weeks.20,21 This may relate to targeting the receptor rather than the IL-5 cytokine. Benralizumab binding to IL-5 receptor α expressed on

19

CLINICAL UPDATES in the MANAGEMENT of SEVERE ASTHMA

20

BOX 1: Effects on annual exacerbation rates in the phase 3 CALIMA and SIROCCO studies20,21

Treatment Arms

Phase 3 Trial: CALIMA 1. Placebo (n=370) 2. Benralizumab 30 mg every 4 weeks (n=357) 3. Benralizumab 30 mg every 8 weeks (n=364)

Exacerbation rate ratio vs placebo for patients with ≥300 baseline eosinophils/µL

Exacerbation rate ratio vs placebo for patients with <300 baseline eosinophils/µL

4-week dosing: 0.64 (P<0.005) 8-week dosing: 0.72 (P<0.05)

4-week dosing: 0.64 (P<0.05) 8-week dosing: 0.60 (P<0.005)

Phase 3 Trial: SIROCCO 1. Placebo (n=407) 2. Benralizumab 30 mg 4-week dosing: every 4 weeks 0.55 (P<0.0001) (n=399) 8-week dosing: 3. Benralizumab 30 mg 0.49 (P<0.0001) every 8 weeks (n=398)

4-week dosing: 0.70 (P<0.05) 8-week dosing: 0.83 (P=NS)

Patient Population • Patients 12-75 years old with physician-diagnosed asthma • ≥2 exacerbations while on LABA+medium- or high-dose ICSa • FEV1 <80% predicted with ≥12% and ≥200 mL postbronchodilator reversibilityb • ACQ-6 score ≥1.5 at enrollment • Each arm divided into patients with <300 or ≥300 baseline blood eosinophils/µL In SIROCCO, medium-dose ICS was permitted only in patients 12 to 17 years old.

FEV1 <90% predicted was threshold for patients 12 to 17 years old.

ACQ, Asthma Control Questionnaire; FEV1, forced expiratory volume in 1 second; ICS, inhaled corticosteroid; LABA, long-acting β-agonist; NS, not significant. a

b

CHAPTER 3 Biologic Therapies for Severe Asthma

eosinophils blocks IL-5 signaling and may also induce complementmediated antibody-dependent cellular cytotoxicity in eosinophils and other receptor-expressing cells, such as basophils or mast cells.19,22 Additional research, however, is needed to confirm and explain these trial results.

INHIBITORS of IL-13 or IL-13/IL-4 SIGNALING Chapter 1 details some of the roles of the Th2 cytokines IL-13 and IL-4 in asthma pathophysiology. Tralokinumab is a monoclonal antibody that targets IL-13. Recent structural analyses demonstrate that tralokinumab prevents IL-13 from binding to both IL-13 receptor α1 and IL-13 receptor α2, which are thought to mediate pathophysiologic mechanisms that overlap with those induced by IL-4 and specific IL-4-independent effects, respectively.23,24 A phase 2b clinical trial compared 2 dosing schedules for tralokinumab 300 mg SQ in patients with severe asthma who had 2-6 exacerbations in the previous year.25 Tralokinumab every 2 weeks or every 4 weeks was generally safe and well tolerated, with modest improvements in lung function observed with dosing every 2 weeks.25 Exacerbation rates did not significantly improve in either treatment arm compared with the placebo arm.25 However, a post-hoc subgroup analysis found that patients treated with tralokinumab every 2 weeks who had high circulating levels of periostin or dipeptidyl peptidase-4 (DPP-4) showed markedly better responses to the drug, suggesting that these proteins are candidate biomarkers that could be used to select tralokinumab responders (Figure 1).25 Ongoing phase 3 studies are investigating whether biomarkers can be used to identify patients who are more likely to benefit from tralokinumab, and a companion biomarker testing panel may also become available if the drug is approved by the FDA. The monoclonal antibody, dupilumab, targets IL-4 receptor α, which forms a heterodimer with IL-13 receptor α1 to mediate signaling by both IL-4 and IL-13.24 A phase 2b trial examined dupilumab SQ 200 mg or 300 mg every 2 weeks or 4 weeks in patients with poorly controlled asthma and a history of ≥1 severe exacerbation in the prior year despite treatment with medium-to-high-dose ICS and a long-acting β-agonist (LABA).26 Patients in each treatment arm showed a significant improvement in FEV1 compared with placebo.26 This benefit was also observed for both doses administered every 2 weeks in patients with baseline blood eosinophil counts either <300 cells/µL or ≥300 cells/µL.26 Three of the four

21

CLINICAL UPDATES in the MANAGEMENT of SEVERE ASTHMA

Change in Annual Exacerbation Rate Compared With Placebo, %

22 40

32

20

7

0 -20 -40

-44 -60 -80

-57 All (n=33)b

-67a DPP-4â&#x20AC;&#x201C; DPP-4â&#x20AC;&#x201C; Periostin- Periostinhigh low high low (n=24) (n=8) (n=18) (n=15)

FIGURE 1: Asthma exacerbation rates with tralokinumab vs placebo in patients stratified by periostin or DPP-4 levels25 P<0.05 vs placebo ; bData reflects post-hoc subgroup analysis of patients with airway reversibility at baseline, but not on long-term oral corticosteroids who received tralokinumab 300 mg every 2 weeks (n=33) or placebo (n=48). a

DPP-4, dipeptidyl peptidase 4.

dupilumab treatment arms showed significant reductions in the annualized rate of severe exacerbations, a result that was also independent of the baseline blood eosinophil counts for both dosages given every 2 weeks (Figure 2).26 Improvements in various asthma control scores were observed, particularly in the treatment arms in which subjects were treated every 2 weeks.26 The most common adverse effects were upper respiratory tract infections and injection-site reactions, although none of the reported events were consistently more common in the dupilumabtreated groups than in the placebo arm.26

ADDITIONAL BIOLOGIC THERAPIES for VARIOUS SEVERE ASTHMA PHENOTYPES In addition to therapies that are FDA-approved or in late-stage clinical development, a number of other biologic agents are being evaluated

CHAPTER 3 Biologic Therapies for Severe Asthma

Annual Severe Exacerbation Rate

Annual Severe Exacerbation Rate

23 1.2

Patients With Baseline Eosinophils ≥300 cells/µL 1.044

1.0 0.8

0.678

0.6 0.358a

0.4

0.300a

0.2 0.0

1.2

Placebo (n=68)

200 mg 300 mg 200 mg 300 mg every every every every 4 weeks 4 weeks 2 weeks 2 weeks (n=59) (n=66) (n=64) (n=64)

Patients With Baseline Eosinophils <300 cells/µL

1.0 0.8

0.779

0.6

0.445

0.4

0.489 0.253b

0.313a

0.2 0.0

Placebo (n=90)

200 mg 300 mg 200 mg 300 mg every every every every 4 weeks 4 weeks 2 weeks 2 weeks (n=91) (n=91) (n=84) (n=92)

FIGURE 2: Exacerbation rates with dupilumab in patients stratified based on baseline blood eosinophil counts26 a

0.201b

P<0.05 vs placebo; b P<0.005 vs placebo.

CLINICAL UPDATES in the MANAGEMENT of SEVERE ASTHMA

24

as potential treatment options for various severe asthma phenotypes.

Examples include antibodies designed to interrupt signaling by the cytokines IL-6, IL-17, IL-33, or thymic stromal lymphopoietin (TSLP).27-29 IL-6, IL-33, and TSLP are key regulatory factors that promote the development of Th2 responses and therefore may serve as upstream targets that affect signaling by more than 1 of the Th2 cytokines described above.27-29 On the other hand, IL-17 is a proinflammatory cytokine that contributes to late-onset, non-Th2 phenotypes, which often present with incompletely reversible airway obstruction and significant neutrophilic inflammation.27-29 Although clinical trials examining some of these therapies have not been universally positive, ongoing research is attempting to clarify which patients are likely responders based on the primary pathophysiologic mechanisms underlying different disease phenotypes.30 Moreover, optimizing outcomes for some patients with severe asthma may require that more than 1 proinflammatory factor is specifically inhibited. As with other immune-driven pathologic conditions, the ultimate goal would be the induction of persistent immunomodulation or long-term disease remission through a rationally selected combination of targeted therapies.

CONCLUDING COMMENTS As the number of biologic treatment options for severe asthma increases, clinicians will be tasked with determining which agent offers the greatest chance of success for each patient. These decisions are not yet completely evidence-based, and additional research is needed to optimize a personalized approach to therapy across all known severe asthma phenotypes. In particular, the roles of biomarkersâ&#x20AC;&#x201D;eg, blood eosinophil count, circulating levels of IgE, periostin, DPP-4â&#x20AC;&#x201D;need to be better defined. Moreover, engaging in shared decision-making will require clinicians to interpret evolving clinical trial data, while considering patient preferences on mode of administration, dosing frequency, and potential adverse events. Nevertheless, therapeutic options for patients with severe asthma are increasing, and tailored approaches to treatment are becoming increasingly possible.

CHAPTER 3 Biologic Therapies for Severe Asthma

25

KEY CLINICAL HIGHLIGHTS • Asthma research has uncovered immunologic and inflammatory factors that play key pathobiologic roles for various severe asthma cohorts • Numerous antibody-based biologic therapies have been recently approved by the FDA or are in late-stage clinical development for severe asthma • Personalizing biologic therapy for severe asthma will require consideration of disease phenotypes, biomarkers, drug characteristics, and patient preferences

REFERENCES 1. Parulekar AD, et al. Role of biologics targeting type 2 airway inflammation in asthma: what have we learned so far? Curr Opin Pulm Med. 2017;23(1):3-11.

2. Fricker M, et al. Can biomarkers help us hit targets in difficult-to-treat asthma? Respirology.

2017;22(3):430-442.

3. Burrows B, et al. Association of asthma with serum IgE levels and skin-test reactivity to allergens. N Engl J Med. 1989;320(5):271-277.

4. Kawakami T, et al. Histamine-releasing factor and immunoglobulins in asthma and allergy.

Allergy Asthma Immunol Res. 2014;6(1):6-12.

5. Omalizumab [package insert]. Initial US approval 2003. South San Francisco, CA: Genentech USA, Inc.; July 2016.

6. Papathanassiou E, et al. Severe asthma: anti-IgE or anti-IL-5? Eur Clin Respir J. 2016;3:31813.

7. Normansell R, et al. Omalizumab for asthma in adults and children. Cochrane Database Syst Rev. 2014;(1):CD003559.

8. Humbert M, et al. Benefits of omalizumab as add-on therapy in patients with severe persistent asthma who are inadequately controlled despite best available therapy (GINA 2002 step 4 treatment): INNOVATE. Allergy. 2005;60(3):309-316.

9. Corren J, et al. Safety and tolerability of omalizumab. Clin Exp Allergy. 2009;39(6):788-797.

10. Bousquet J, et al. Eosinophilic inflammation in asthma. N Engl J Med. 1990;323(15):1033-1039.

11. Wenzel SE, et al. Evidence that severe asthma can be divided pathologically into two inflammatory sufbtypes with distinct physiologic and clinical characteristics. Am J Respir Crit Care Med. 1999;160(3):1001-1008.

12. Mepolizumab [package insert]. Initial US approval 2015. Philadelphia, PA: GlaxoSmithKline LLC; February 2017.

13. Ortega HG, et al. Mepolizumab treatment in patients with severe eosinophilic asthma. N Engl J Med. 2014;371(13):1198-1207.

14. Bel EH, et al. Oral glucocorticoid-sparing effect of mepolizumab in eosinophilic asthma. N Engl J Med. 2014;371(13):1189-1197.

15. Reslizumab [package insert]. Initial US approval 2016. Frazer, PA: Teva Respiratory LLC; May 2016.

16. Castro M, et al. Reslizumab for inadequately controlled asthma with elevated blood eosinophil counts: results from two multicentre, parallel, double-blind, randomised, placebo-controlled, phase 3 trials. Lancet Respir Med. 2015;3(5):355-366.

17. Corren J, et al. Phase 3 study of reslizumab in patients with poorly controlled asthma: effects across a broad range of eosinophil counts. Chest. 2016;150(4):799-810.

CLINICAL UPDATES in the MANAGEMENT of SEVERE ASTHMA

26

18. Castro M, et al. Benralizumab, an anti-interleukin 5 receptor α monoclonal antibody, versus placebo for uncontrolled eosinophilic asthma: a phase 2b randomised dose-ranging study.

Lancet Respir Med. 2014;2(11):879-890.

19. Castro M, Bacharier LB. Treatment for severe eosinophilic asthma-consistent effect of antiinterleukin-5 antibodies? Lancet. 2016;388(10056):2059-2060.

20. FitzGerald JM, et al. Benralizumab, an anti-interleukin-5 receptor α monoclonal antibody, as add-on treatment for patients with severe, uncontrolled, eosinophilic asthma (CALIMA): a randomised, double-blind, placebo-controlled phase 3 trial. Lancet. 2016;388(10056):2128-2141.

21. Bleecker ER, et al. Efficacy and safety of benralizumab for patients with severe asthma uncontrolled with high-dosage inhaled corticosteroids and long-acting β2-agonists (SIROCCO): a randomised, multicentre, placebo-controlled phase 3 trial. Lancet. 2016;388(10056):2115-2127.

22. Kolbeck R, et al. MEDI-563, a humanized anti-IL-5 receptor α mAb with enhanced antibody-dependent cell-mediated cytotoxicity function. J Allergy Clin Immunol.

2010;125(6):1344-1353.e2.

23. Popovic B, et al. Structural characterisation reveals mechanism of IL-13-neutralising monoclonal antibody tralokinumab as inhibition of binding to IL-13Rα1 and IL-13Rα2. J Mol Biol. 2017;429(2):208-219.

24. Munitz A, et al. Distinct roles for IL-13 and IL-4 via IL-13 receptor α1 and the type II IL-4 receptor in asthma pathogenesis. Proc Natl Acad Sci U S A. 2008;105(20):7240-7245.

25. Brightling CE, et al. Efficacy and safety of tralokinumab in patients with severe uncontrolled asthma: a randomised, double-blind, placebo-controlled, phase 2b trial. Lancet Respir Med. 2015;3(9):692-701.

26. Wenzel S, et al. Dupilumab efficacy and safety in adults with uncontrolled persistent asthma despite use of medium-to-high-dose inhaled corticosteroids plus a long-acting β2 agonist: a randomised double-blind placebo-controlled pivotal phase 2b dose-ranging trial. Lancet.

2016;388(10039):31-44 27. West EE, et al. TSLP: A key regulator of asthma pathogenesis. Drug Discov Today Dis Mech.

2012;9(3-4).

28. Baines KJ, et al. Transcriptional phenotypes of asthma defined by gene expression profiling of induced sputum samples. J Allergy Clin Immunol. 2011;127(1):153-160, 160 e151-159.

29. Chang HS, et al. Neutrophilic inflammation in asthma: mechanisms and therapeutic considerations. Expert Rev Respir Med. 2017;11(1):29-40.

30. Busse WW, et al. Randomized, double-blind, placebo-controlled study of brodalumab, a human anti-IL-17 receptor monoclonal antibody, in moderate to severe asthma. Am J Respir Crit Care Med. 2013;188(11):1294-1302.

In order to receive credit, participants must complete the preactivity questionnaire, posttest, and program evaluation at

EXCHANGECME.com/ SAeHealth

CHAPTER 4

Nonbiologic Strategies for the Management of Severe Asthma Michael E. Wechsler, MD, MMSc

C

linical practice guidelines for asthma recommend that patients with persistent symptoms and/or repeated exacerbations despite adherence to medium-to-high-dose inhaled corticosteroids (ICS) and additional long-acting controllers should be referred for specialist care.

In most cases, the referral is an opening step to a long-term relationship, which should encompass open patient-clinician dialogue, repeated asthma education, ongoing monitoring for asthma control, comorbidity management (see Chapter 2), and tailoring of treatment regimens, when necessary. In addition to the growing number of biologic therapies (see Chapter 3), other medications and modalities can be used to help manage cases of severe asthma.

NEWER TREATMENT MODALITIES for SEVERE ASTHMA Tiotropium Inhaled long-acting muscarinic antagonists (LAMAs) are often used to treat patients with chronic obstructive pulmonary disease, and one of these agents, tiotropium, has been approved by the US Food and Drug Administration (FDA) as long-term, once-daily maintenance therapy in patients ≥6 years of age with asthma (Table 1).1 Registration data for tiotropium were derived from 5 studies examining adults with asthma, and two 12-week and two 48-week parallel-arm design trials that enrolled either adolescents 12-17 years of age or pediatric patients 6-11 years of age.1 As examples of these studies, two replicate, 24-week trials compared tiotropium 5 μg or 2.5 μg once daily, salmeterol 50 μg twice daily, and placebo in patients 18-75 years old with symptomatic asthma despite medium-dose ICS.2 Pooled data showed significant improvements with both tiotropium doses and salmeterol compared with placebo in peak and trough forced expiratory volume in 1 second (FEV1) responses and in a responder rate calculated using the 7-question Download this activity and additional tools at

27

CLINICAL UPDATES in the MANAGEMENT of SEVERE ASTHMA

28

TABLE 1: Tiotropium in Asthma1 Medication class

Long-acting muscarinic antagonist

Route of administration

Oral inhalation

Dosing for asthma

Delivered once-daily via 2 inhalations, each containing 1.25 µg

Warnings and precautions

• Discontinue if a hypersensitivity reaction (eg, angioedema, urticaria, rash, bronchospasm, anaphylaxis) develops postadministration • Discontinue if paradoxical bronchospasm occurs • Use caution in patients with glaucoma as worsening of narrow-angle glaucoma may occur • Use caution in patients with prostatic hyperplasia or bladder-neck obstruction because worsening of urinary retention may occur

Prescribing considerations

• Tiotropium should not be used as a rescue medication for acute asthma exacerbations • Although bronchodilator effects of tiotropium 2.5 µg once daily are apparent after the first dose, maximum bronchodilator effects may not be achieved for 4 to 8 weeks • Because clinical trials showed inconsistent effects on patient-reported symptoms and quality-of-life measures, some experts suggest prescribing tiotropium with an initial 4-week trial, during which lung function, asthma control, and other treatment-related outcomes can be longitudinally assessed

CHAPTER 4 Nonbiologic Strategies for the Management of Severe Asthma

Asthma Control Questionnaire.2 Exacerbation rates also decreased with both tiotropium doses compared with placebo.2 Because improvements in lung function and reductions in exacerbation risks were generally similar, or even more pronounced with tiotropium 2.5 μg than with the 5 μg dose, the lower dosage was approved by the FDA for the asthma indication and included in the drug’s prescribing information.1 Systematic reviews have not identified any significant safety concerns when tiotropium is used as add-on therapy for asthma.3

Allergen Immunotherapy For almost a century, allergists have used subcutaneous immunotherapy to desensitize patients with allergies to specific antigens.4 This treatment modality is based on the administration of increasing amounts of 1 or more allergens at defined intervals using injections of aqueous extracts under the skin (or more recently with tablets placed under the tongue).4 Historically, allergen extracts and immunotherapy protocols were not standardized, study populations were small, and many trials were not specifically designed to examine asthma-related outcomes, such as lung function.5 Moreover, the effects observed across various trials have depended on the administered allergen, and heterogeneity in study designs has somewhat limited the translation of published results into recommendations for real-world practice.5 Nevertheless, most clinical studies and meta-analyses that included patients with allergic asthma (usually concomitant to rhinitis) have shown that immunotherapy delivered subcutaneously or sublingually can significantly control asthma symptoms, reduce medication usage, and/or improve bronchial reactivity.5-7 If performed correctly, administering an allergen as asthma therapy is a safe procedure, with patients potentially experiencing injectionsite reactions, or less commonly, such systemic responses as hives, increased asthma symptoms, or decreases in blood pressure.5 Of note, however, patients with asthma may be at increased risk for rare anaphylactic reactions and should be properly monitored for a short period after the allergen is administered. Before starting allergen immunotherapy, it is also important to ensure that the patient’s asthma is under control as much as possible and that consideration has been given to complicating comorbidities or medications (eg, recent heart conditions or the use of β-blockers). In some published reports, patients have been pretreated with anti-immunoglobulin E (IgE) omalizumab to

29

CLINICAL UPDATES in the MANAGEMENT of SEVERE ASTHMA

30

gain control of allergic asthma, which may reduce some treatmentrelated risks.8 Clinicians may also now consider component-based IgE testing to identify patients with higher levels of allergen-specific IgE; preliminary evidence suggests that these individuals are more likely to respond positively to allergen immunotherapy.9,10

Bronchial Thermoplasty Bronchial thermoplasty delivers thermal energy to the airway wall, ablating smooth muscle cells and possibly certain nerve receptors, thereby reducing airway remodeling processes and asthma-related bronchoconstriction (Table 2).11 Bronchial thermoplasty for severe asthma involves a series of 3 bronchoscopy outpatient procedures performed at 3-week intervals.

The pivotal sham-controlled AIR2 trial examined adult patients who were still symptomatic despite treatment with high-dose ICS and a long-acting β2-agonist (LABA). Compared with patients who underwent the sham procedure, bronchial thermoplasty resulted in better integrated Asthma Quality of Life Questionnaire scores and fewer exacerbations, emergency department visits, and missed work/school days during the follow-up period (6-52 weeks after the first procedure).12 Follow-up studies showed that some of benefits derived from bronchial thermoplasty, such as reduced exacerbation risk and fewer emergency department visits, were

TABLE 2: Bronchial Thermoplasty in Asthma11,15 Mechanism of action

Localized delivery of radiofrequency energy to ablate airway smooth muscle cells, resulting in reduced airway remodeling and decreased bronchoconstriction

Mode of delivery Three bronchoscope-directed insertions of a catheter performed 3 weeks apart to target the right lower lobe, left lower lobe, and bilateral upper lobes For the treatment of severe persistent FDA indication asthma in patients ≥18 years old whose asthma is not well controlled with ICS and LABAs Cont’d

CHAPTER 4 Nonbiologic Strategies for the Management of Severe Asthma

31

Contraindications • Presence of a pacemaker, internal defibrillator, or other implantable electronic devices • Known sensitivity to medications that are required for bronchoscopies, including lidocaine, atropine, and benzodiazepines • Patients with the following conditions should not be treated with bronchial thermoplasty: –– Active respiratory infection –– Asthma exacerbation or a change in systemic corticosteroid dosage in the prior 14 days –– Coagulopathy • Patients should follow physician Procedural considerations guidance on stopping treatment with anticoagulants, antiplatelet agents, aspirin, and nonsteroidal antiinflammatory drugs before the procedure • Bronchial thermoplasty should only be performed by adequately trained clinicians in appropriately equipped settings that include access to resuscitation equipment for hemoptysis, pneumothorax, or other respiratory complications • Patients are generally given oral corticosteroids for 3 days preprocedure, the day of the procedure, and 1 day following the procedure to mitigate potential airway inflammation • Patients previously treated with bronchial thermoplasty should not be retreated in the same areas, because no available data address the safety or effectiveness of repeated use ICS, inhaled corticosteroids; LABA, long-acting β2-agonist.

CLINICAL UPDATES in the MANAGEMENT of SEVERE ASTHMA

32

maintained for up to 5 years.13,14 The procedure is not without risk—in the original AIR2 trial, for example, 8.4% of the patients in the bronchial thermoplasty group were hospitalized for respiratory symptoms during the initial 6-week treatment period, usually on the day that a bronchoscopy was performed.12 Therefore, prophylactic systemic corticosteroids are recommended for a brief period before and after the procedure.15 It is currently difficult to predict which patients with severe asthma will respond best to bronchial thermoplasty.16 There is some evidence to suggest larger biopsy-confirmed effects in patients who have more airway smooth muscle at baseline, although these results have not necessarily translated to greater clinical benefits.17 Some experts suggest considering this modality as an option for patients who are not good candidates for one of the biologic agents or for those with a notable irreversible component to their chronic airway obstruction without significant eosinophilia. Indeed, ongoing trials are seeking to clarify the effectiveness of bronchial thermoplasty for specific asthma phenotypes identified based on imaging, airway histology, or other biomarkers.15

STRENGTHENING the THERAPEUTIC ALLIANCE BETWEEN PATIENTS and PROVIDERS Promoting Patient Education and Shared Decision-Making Educating patients—and, when necessary, caregivers—on the clinical implications of disease pathophysiology, modifiable risk factors contributing to uncontrolled asthma, therapeutic options, and detailed treatment instructions is essential to optimizing long-term outcomes.18 Therapeutic regimens should be tailored to patient preferences and goals, identified through frank and frequent conversations (see link to supplementary VIDEO 7). Unfortunately, the time-limited realities of many healthcare settings can interfere with collaborative patientclinician relationships and the integration of patient perspectives into ongoing management plans. Many national societies have produced resources to assist with these issues, including online patient education materials, decision aids, and structured asthma action plans (Links available at www.ExchangeCME.com/AsthmaeHealth).19 A few key themes should be addressed with patients at each opportunity. For instance, it is important to specifically ask about inhaler use, both to ensure that devices are being used correctly and to

CHAPTER 4 Nonbiologic Strategies for the Management of Severe Asthma

quantify the need for rescue medication as a proxy for asthma control and exacerbation risks.20 Patients should also understand expected medication benefits and potential side effects and have structured action plans that outline how to recognize and react to oncoming exacerbations.21 Targeted education on disease processes and management strategiesâ&#x20AC;&#x201D;potentially delivered by a multidisciplinary health care teamâ&#x20AC;&#x201D;is especially helpful for patients who frequently require emergency service or inpatient admissions (see link to supplementary VIDEO 8). In 1 practice model designed to target patients with relatively high health care utilization rates, a nursing specialist was tasked with providing asthma education and proactive management plans, while coordinating best-practice care with primary care providers and available social service professionals.22 This multipronged approach significantly improved self-management of environmental triggers and reduced hospitalizations, readmissions, lost work/school days, and healthcare costs.22 Clinicians should also be aware of technologies that can facilitate patient education and engagement. An estimated 90% of young adult Americans carry smartphones, providing an almost universal opportunity to reinforce dosing schedules and longitudinally monitor symptoms and lung function in this cohort.23,24 Apps have also been designed to improve the use of asthma action plans and structure selfmanagement responses to potential exacerbations.23,24 Other advances include easier-to-use devices, such as breath-actuated medicationdelivery systems that reduce the required manual dexterity and respiratory coordination.25 Although these strategies can improve the care of all patients with asthma, they may be particularly beneficial for subgroups that have experienced relatively poor outcomes in the past. For example, smartphone-based recommendations can improve outreach to populations such as African Americans who have been traditionally underserved by healthcare systems. On the other hand, new devices may help older patients take their medications properly, even when they have lost some degree of coordination and muscle strength in their hands.

Improving Adherence to Therapeutic Regimens As in any chronic disease, adherence to prescribed regimens is critical to optimizing outcomes in severe asthma. A recent systematic review found that approximately 1 in 4 exacerbations and more than

33

CLINICAL UPDATES in the MANAGEMENT of SEVERE ASTHMA

34

half of asthma-related hospitalizations were primarily caused by poor adherence.26 Unfortunately, clinicians often overestimate the degree to which patients follow agreed-upon treatment plans and at times can be overconfident in their ability to identify individuals who are not adherent.26,27 Clinicians should understand that adherence and persistence with asthma therapy reflect complex interactions among demographic, clinical, and psychosocial factors. Thus, efforts to assess and improve these parameters must account for patient age, cultural background, health literacy, social support networks, and economic status, among other factors.26,28,29 The National Asthma Education and Prevention Program has highlighted a number of strategies that can be used to enhance adherence to asthma therapies (Box 1).30 Importantly, therapeutic goals should be established in collaboration with the patient and relevant caregivers.31 Some evidence

BOX 1: Strategies to enhance adherence to asthma therapies30,32 • Identify factors that interfere with treatment adherence • Clarify patients’ expectations for treatment, while addressing concerns • Develop treatment plans together with patients, family members, and other caregivers • Simplify treatment regimens as much as possible • Explain how each medication works to control or prevent symptoms • Have patients repeat instructions in their own words, or ask patients how they would respond to given clinical scenarios • Consider medication cost and insurance coverage when prescribing • Provide positive reinforcement • Discuss adherence to medication regimens at every follow-up interaction • Encourage patients to seek support from family members, caregivers, friends, and support groups • Introduce patients to other individuals who have had similar experiences

CHAPTER 4 Nonbiologic Strategies for the Management of Severe Asthma

suggests that asking patients to describe desired goals and recommended treatment approaches in their own words can help.32 Other studies have shown promising results with electronic monitoring of controller and rescue inhaler use.33,34 As in other aspects of asthma management, clinicians need to specifically query patients about their medication and personalize efforts to improve adherence whenever necessary.

KEY CLINICAL HIGHLIGHTS: • Tiotropium and bronchial thermoplasty can be used to treat certain patients with uncontrolled, severe asthma • Patients benefit from ongoing education about asthma pathophysiology, modifiable risk factors, and treatment options • Clinicians need to directly and repeatedly assess patients for treatment adherence and inhaler technique

REFERENCES 1. Tiotropium [package insert]. Initial US approval 2004. Ridgefield, CT: Boehringer Ingelheim Pharmaceuticals Inc.; February 2017.

2. Kerstjens HA, et al. Tiotropium or salmeterol as add-on therapy to inhaled corticosteroids for patients with moderate symptomatic asthma: two replicate, double-blind, placebocontrolled, parallel-group, active-comparator, randomised trials. Lancet Respir Med. 2015;3(5):367-376.

3. Befekadu E, et al. Tiotropium in asthma: a systematic review. J Asthma Allergy. 2014;7:11-21.

4. Pipet A, et al. Allergen-specific immunotherapy in allergic rhinitis and asthma. Mechanisms and proof of efficacy. Respir Med. 2009;103(6):800-812.

5. Passalacqua G, et al. Allergen immunotherapy in asthma; what is new? Asthma Res Pract.

2015;1:6.

6. Zielen S, et al. Steroid-sparing effects with allergen-specific immunotherapy in children with asthma: a randomized controlled trial. J Allergy Clin Immunol. 2010;126(5):942-949.

7. Mosbech H, et al. Standardized quality (SQ) house dust mite sublingual immunotherapy tablet (ALK) reduces inhaled corticosteroid use while maintaining asthma control: a randomized, double-blind, placebo-controlled trial. J Allergy Clin Immunol. 2014;134(3):568-575 e567.

8. Lambert N, et al. Pre-treatment by omalizumab allows allergen immunotherapy in children and young adults with severe allergic asthma. Pediatr Allergy Immunol. 2014;25(8):829-832.

9. Fritzsching B. Personalized medicine in allergic asthma: at the crossroads of allergen immunotherapy and “biologicals”. Front Pediatr. 2017;5:31.

10. Tosca MA, et al. Egg allergy: the relevance of molecular-based allergy diagnostics. Clin Exp Allergy. 2014;44(8):1094-1095.

11. Fajt ML, Wenzel SE. Development of new therapies for severe asthma. Allergy Asthma Immunol Res. 2017;9(1):3-14.

12. Castro M, et al. Effectiveness and safety of bronchial thermoplasty in the treatment of severe asthma: a multicenter, randomized, double-blind, sham-controlled clinical trial. Am J Respir Crit Care Med. 2010;181(2):116-124.

13. Castro M, et al; AIR2 Trial Study Group. Persistence of effectiveness of bronchial thermoplasty in patients with severe asthma. Ann Allergy Asthma Immunol. 2011;107(1):65-70.

35

CLINICAL UPDATES in the MANAGEMENT of SEVERE ASTHMA

36

14. Wechsler ME, et al. Bronchial thermoplasty: long-term safety and effectiveness in patients with severe persistent asthma. J Allergy Clin Immunol. 2013;132(6):1295-1302.

15. Laxmanan B, Hogarth DK. Bronchial thermoplasty in asthma: current perspectives. J Asthma Allergy. 2015;8:39-49.

16. Chung KF, et al. International ERS/ATS guidelines on definition, evaluation and treatment of severe asthma. Eur Respir J. 2014;43(2):343-373.

17. Chakir J, et al. Effects of bronchial thermoplasty on airway smooth muscle and collagen deposition in asthma. Ann Am Thorac Soc. 2015;12(11):1612-1618.

18. Wechsler ME. Getting control of uncontrolled asthma. Am J Med. 2014;127(11):1049-1059.

19. Ram FS, McNaughton W. Giving Asthma Support to Patients (GASP): a novel online asthma education, monitoring, assessment and management tool. J Prim Health Care. 2014;6(3):238-244.

20. Cajigal S, et al. Predictive properties of the Asthma Control Test and its component questions for severe asthma exacerbations. J Allergy Clin Immunol Pract. 2017;5(1):121-127.

21. O’Leary F, et al. Improving the quality of care for children with wheeze: the use of electronic asthma action plans and electronic pre-school wheeze action plans. J Paediatr Child Health.

2016;52(9):872-876.

22. Castro M, et al. Asthma intervention program prevents readmissions in high healthcare users.

Am J Respir Crit Care Med. 2003;168(9):1095-1099.

23. Perry TT, et al. Smartphone-based vs paper-based asthma action plans for adolescents.

Ann Allergy Asthma Immunol. 2017;118(3):298-303.

24. Kosse RC, et al. mHealth intervention to support asthma self-management in adolescents: the ADAPT study. Patient Prefer Adherence. 2017;11:571-577.

25. Haidl P, et al. Inhalation device requirements for patients’ inhalation maneuvers. Respir Med. 2016;118:65-75.

26. Barnes CB, Ulrik CS. Asthma and adherence to inhaled corticosteroids: current status and future perspectives. Respir Care. 2015;60(3):455-468.

27. Kardas P, et al. Adherence to treatment in asthma and COPD patients in their doctors’ assessment. Pneumonol Alergol Pol. 2015;83(6):436-444.

28. Apter AJ, et al. The association of health literacy with adherence and outcomes in moderatesevere asthma. J Allergy Clin Immunol. 2013;132(2):321-327.

29. Chapman SC, et al. Changing adherence-related beliefs about ICS maintenance treatment for asthma: feasibility study of an intervention delivered by asthma nurse specialists. BMJ Open.

2015;5(6):e007354.

30. National Asthma Education Prevention Program. Expert Panel Report 3 (EPR-3): guidelines for the diagnosis and management of asthma-summary report 2007. J Allergy Clin Immunol.

2007;120(suppl 5):S94-S138.

31. Wilson SR, et al. Shared treatment decision making improves adherence and outcomes in poorly controlled asthma. Am J Respir Crit Care Med. 2010;181(6):566-577.

32. Global Initiative for Asthma . Global Strategy for Asthma Management and Prevention, 2017.

Available from: www.ginasthma.org. Accessed May 3, 2017.

33. Foster JM, et al. Inhaler reminders improve adherence with controller treatment in primary care patients with asthma. J Allergy Clin Immunol. 2014;134(6):1260-1268 e1263.

34. Foster JM, et al. The reliability and patient acceptability of the SmartTrack device: a new electronic monitor and reminder device for metered dose inhalers. J Asthma. 2012;49(6):657-662.

SEVERE ASTHMA

CLINICAL RESOURCE CENTER™ GUIDELINES Global Strategy for Asthma Management and Prevention Global Initiative for Asthma (GINA) 2017. »» http://ginasthma.org/gina-reports/

International ERS/ATS guidelines on definition, evaluation and treatment of severe asthma.

Chung KF, et al. Eur Respir J. 2014;43(2):343-373. »» http://erj.ersjournals.com/content/erj/43/2/343.full.pdf

PATIENT RESOURCES Asthma and Allergy Foundation of America (AAFA) AAFA is dedicated to improving the quality of life for people with asthma and allergic diseases through education, advocacy, and research. »» http://www.aafa.org/page/asthma.aspx

American College of Allergy, Asthma, and Immunology (ACAAI) The ACAAI fosters a culture of collaboration and congeniality in which members work toward the common goals of patient care, education, advocacy, and research. »» http://acaai.org/

Download this activity and additional tools at

37

CLINICAL UPDATES in the MANAGEMENT of SEVERE ASTHMA

38

American College of Chest Physicians (CHEST Foundation) The mission of CHEST Foundation is to develop resources to champion the prevention, diagnosis, and treatment of chest diseases through education, communication, and research. »» https://www.chestnet.org/Foundation/ Patient-Education-Resources/COPD

American Lung Association The American Lung Association is the leading organization working to save lives by improving lung health and preventing lung disease through education, advocacy, and research. »» http://www.lung.org/lung-disease/copd/living-withcopd/copd-management-tools.html

American Thoracic Society (ATS) The mission of the ATS is to improve health worldwide by advancing research, clinical care, and public health in respiratory disease, critical illness, and sleep disorders. »» https://www.thoracic.org/patients/patient-resources/

Asthma Action Plan This printable reference tool is designed to help patients know when to use their different asthma medications and when to call their healthcare providers. »» http://www.aafa.org/media/asthma-action-plan-aafa.pdf

Asthma and Outdoor Air Pollution This resource provides guidance to patients who are sensitive to air pollution. »» https://www3.epa.gov/airnow/asthma-flyer.pdf

Download this activity and additional tools at

Severe Asthma CLINICAL RESOURCE CENTER™

Asthma Inhalers This is a list of different inhaled asthma medications with key information such as prescribing information and tips for proper inhaler technique. »» http://wipediseases.org/dev3/inhalers/ sort/?type=Asthma

How to Use a Metered-Dose Inhaler Printed instructions and short videos are provided to aid patients in taking their medication correctly. »» https://www.cdc.gov/asthma/inhaler _ video/default.htm

My Asthma Wallet Card This printable card for patients to carry lists important information, such as current medications and health care provider contact information. »» https://catalog.nhlbi.nih.gov/pubstatic//14-5245/ 14-5245.pdf

CLINICAL ASSESSMENT TOOLS Asthma Control Test (ACT) This 5-question test evaluates asthma control over the past 4 weeks on a 5-point Likert scale. A score of <20 on the ACT suggests asthma that is uncontrolled.

Nathan RA, et al. J Allergy Clin Immunol. 2004;113(1):59-65. »» http://pediatrics.iu.edu/files/7214/8807/0220/rpqn-asthma-controltest-act.pdf

Asthma Control Questionnaire (ACQ) This 7-question assessment tool measures asthma control over the past 7 days. Six questions are self-administered by the patient, and 1 question requires a clinician’s input. Mean scores range from 1 (totally controlled) to 6 (severely uncontrolled).

Juniper EF, et al. The Euro Respir J. 1999;14(4):902-907. »» http://www.qoltech.co.uk/acq.html

Download this activity and additional tools at

39

CLINICAL UPDATES in the MANAGEMENT of SEVERE ASTHMA

40

Asthma Therapy Assessment Questionnaire (ATAQ) This 4-question test assesses asthma control over the past 4 weeks.

Each question has a possible score of 0 or 1; if the sum of the 4 question scores is >1, the patient’s asthma may be uncontrolled.

Vollmer WM, et al. Am J Crit Care Med. 1999;160(5 Pt 1):1647-1652. »» https://evidencebasedpractice.osumc.edu/Documents/Guidelines/ ATAQChecklist.pdf

SUGGESTED READING Efficacy and safety of tralokinumab in patients with severe uncontrolled asthma: a randomised, double-blind, placebocontrolled, phase 2b trial.

Brightling CE, et al. Lancet Respir Med. 2015;3(9):692-701. »» www.pubmed.gov/26231288

Efficacy and safety of benralizumab for patients with severe asthma uncontrolled with high-dosage inhaled corticosteroids and long-acting β2-agonists (SIROCCO): a randomised, multicentre, placebo-controlled phase 3 trial.

Bleecker ER, et al. Lancet. 2016;388(10056):2115-2127. »» https://www.ncbi.nlm.nih.gov/pubmed/27609408

Reslizumab for inadequately controlled asthma with elevated blood eosinophil counts: results from two multicentre, parallel, double-blind, randomised, placebo-controlled, phase 3 trials.

Castro M, et al. Lancet Respir Med. 2015;3(5):355-366. »» www.pubmed.gov/25736990

A review of anti-IgE monoclonal antibody (omalizumab) as add on therapy for severe allergic (IgE-mediated) asthma.

D’Amato G, et al. Ther Clin Risk Manag. 2007;3(4):613-619. »» https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2374942/pdf/ tcrm-0304-613.pdf

Download this activity and additional tools at

Severe Asthma CLINICAL RESOURCE CENTER™

Biologics in asthma—the next step toward personalized treatment.

Darveaux J, Busse WW. J Allergy Clin Immunol Pract. 2015;3(2):152-161. »» http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4774509/pdf/nihms759179.pdf

Inflammatory and comorbid features of patients with severe asthma and frequent exacerbations.

Denlinger LC, et al. Am J Respir Crit Care Med. 2017;195(3):302-313. »» https://www.ncbi.nlm.nih.gov/pubmed/?term=27556234

Targeting key proximal drivers of type 2 inflammation in disease.

Gandhi NA, et al. Nat Rev Drug Discov. 2016;15(1):35-50. »» https://www.ncbi.nlm.nih.gov/pubmed/26471366

Benralizumab, an anti-interleukin-5 receptor α monoclonal antibody, as add-on treatment for patients with severe, uncontrolled, eosinophilic asthma (CALIMA): a randomised, double-blind, placebo-controlled phase 3 trial.

FitzGerald JM, et al. Lancet. 2016;388(10056):2128-2141. »» https://www.ncbi.nlm.nih.gov/pubmed/27609406

Efficacy and safety of lebrikizumab in patients with uncontrolled asthma (LAVOLTA I and LAVOLTA II): replicate, phase 3, randomised, double-blind, placebo-controlled trials.

Hanania NA, et al. Lancet Respir Med. 2016;4(10):781-796. »» https://www.ncbi.nlm.nih.gov/pubmed/27616196

Adult asthma biomarkers.

Kim MA, et al. Curr Opin Allergy Clin Immunol. 2014;14(1):49-54. »» www.pubmed.gov/24300416

Mepolizumab treatment in patients with severe eosinophilic asthma.

Ortega HG, et al. N Engl J Med. 2015;371(13):1198-1207. »» http://www.nejm.org/doi/pdf/10.1056/NEJMoa1403290

Download this activity and additional tools at

41

CLINICAL UPDATES in the MANAGEMENT of SEVERE ASTHMA

42

Allergen immunotherapy in asthma; what is new?

Passalacqua G, et al. Asthma Res Pract. 2015;1:6. »» https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4970380/pdf/40733 – 2015 –Article – 6.pdf

Co-morbidities in severe asthma: clinical impact and management.

Porsbjerg C, Menzies-Gow A. Respirology. 2017;22(4):651-661. »» http://onlinelibrary.wiley.com/doi/10.1111/resp.13026/epdf

Bronchial thermoplasty: Long-term safety and effectiveness in patients with severe persistent asthma.

Wechsler ME, et al. J Allergy Clin Immunol. 2013;132(6):1295-1302.e3. »» http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4114404/pdf/ nihms542587.pdf

Dupilumab efficacy and safety in adults with uncontrolled persistent asthma despite use of medium-to-high-dose inhaled corticosteroids plus a long-acting β2 agonist: a randomised double-blind placebo-controlled pivotal phase 2b dose-ranging trial.

Wenzel S, et al. Lancet. 2016;388(10039):31-44. »» https://www.ncbi.nlm.nih.gov/pubmed/27130691

Download this activity and additional tools at

SEVERE ASTHMA

SUPPLEMENTAL VIDEO LIBRARY VIDEO 1: Welcome and Introduction »» www.exchangecme.com/project/savideos

VIDEO 2: Clinical Insights into Severe Asthma Pathophysiology »» www.exchangecme.com/project/savideos

VIDEO 3: Management of Comorbid Conditions »» www.exchangecme.com/project/savideos

VIDEO 4: Clinical Assessment Tools »» www.exchangecme.com/project/savideos

VIDEO 5: Periostin as a Severe Asthma Biomarker »» www.exchangecme.com/project/savideos

Download this activity and additional tools at

43

CLINICAL UPDATES in the MANAGEMENT of SEVERE ASTHMA

44

VIDEO 6: Role of Eosinophils in Severe Asthma Management »» www.exchangecme.com/project/savideos

VIDEO 7: Underserved Populations With Severe Asthma »» www.exchangecme.com/project/savideos

VIDEO 8: Patient Education and Communication »» www.exchangecme.com/project/savideos

In order to receive credit, participants must complete the preactivity questionnaire, posttest, and program evaluation at

EXCHANGECME.com/ SAeHealth Download this activity and additional tools at

45

CLINICAL UPDATES in the MANAGEMENT of SEVERE ASTHMA

46

CLINICAL UPDATES in the MANAGEMENT of SEVERE ASTHMA

iv

Please visit the CLINICAL RESOURCE CENTER for additional information and resources

ExchangeCME.com/ASTHMAeHEALTH

© 2017 Global Education Group and Integritas Communications.

All rights reserved. No part of this syllabus may be used or reproduced in any manner whatsoever without written permission except in the case of brief quotations embedded in articles or reviews.