3/21/19. Individualizing Asthma Care: Addressing Type 2 Inflammation. Disclosures. Faculty

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1 Individualizing Asthma Care: Addressing Type 2 Inflammation Faculty v Diego J Maselli, MD FCCP Associate Professor of Medicine Division of Pulmonary Diseases & Critical Care Medicine University of Texas Health, San Antonio, Texas Director, Severe Asthma Program, University Health System, San Antonio, Texas v Nicola A Hanania, MD, MS, FRCP(C), FACP, FCCP, FERS Associate Professor of Medicine Director, Airways Clinical Research Center Section of Pulmonary and Critical Care Medicine Baylor College of Medicine, Houston, Texas 2 Disclosures vdiego J Maselli, MD FCCP serves as a consultant for Novartis, Sanofi Regeneron, AstraZeneca and GlaxoSmithKline. He is also a speaker for Sanofi Regeneron, Sunovion and GlaxoSmithKline. vnicola A Hanania, MD, MS, FRCP(C), FACP, FCCP, FERS has received honoraria for serving on advisory boards or as consultant for Novartis, Sanofi Regeneron, GlaxoSmithKline, AstraZeneca, Sunovion, Mylan and Boehringer Ingelheim. His institution received research grant support on his behalf from GlaxoSmithKline, AstraZeneca and Boehringer Ingelheim. 3 1

2 Learning Objectives 1. Describe the newer concepts in the pathophysiology of asthma and type 2 inflammation and the implications of targeted biologic therapies 2. Implement tools for clinical assessment of asthma control and risk factors for poor asthma outcomes 3. Individualize treatment of moderate-to-severe asthma 4. Discuss the impact of comorbid conditions on asthma control and the evidence approach to their treatment 4 Pre-test Questions 5 Pre-test Question 1 Pre-S1: All of the following are Biomarkers that reflect type 2 airway inflammation except: 1. Allergen specific IGE 2. Exhaled Nitric Oxide (FeNO) 3. Blood or Sputum Eosinophils 4. Blood or Sputum Neutrophils 5. I don t know 6 2

3 Pre-test Question 2 Pre-S2: Which of the following tools is an evidence-based instrument for assessing asthma control in adult primary care patients? 1. ACT 2. CARAT 3. CAT 4. PHQ-9 7 Pre-test Question 3 Pre-S3: All of the following comorbidities are common in patients with asthma and can affect asthma control, EXCEPT: 1. Allergic rhinitis 2. GERD 3. Obesity 4. Type 2 diabetes 5. Sleep Apnea 8 Pre-test Question 4 Pre-S4: A 34-year-old woman with a 15-year history of asthma reports daily asthma symptoms and nighttime awakenings 2 nights per week. The symptoms prevent her from exercising most days. She uses albuterol 1-2 times/d and reports daily adherence to high-dose ICS/LABA. Her ACT score is 12 How would you grade this patient s level of asthma control? 1. Controlled 2. Partly controlled 3. Uncontrolled 4. Insufficient information to determine control 9 3

4 Pre-test Question 5 Post-S5: A 41-year-old man presents with severe, uncontrolled asthma. He also has a history of GERD. Current medications include high-dose ICS/LABA, tiotropium, and lansoprazole. His blood work-up shows serum IgE level 15 IU/mL, blood eosinophil count 450 cells/mcl, and Allergen specific IgE (RAST) negative for common aeroallergens. Based on these findings, which of the following is NOT an appropriate biologic agent: 1. Benralizumab (Anti-IL5R) 2. Mepolizumab (Anti-IL5) 3. Omalizumab (Anti-IGE) 4. Dupilumab (Anti-IL4R) 10 Identifying Severe and Uncontrolled Asthma 11 Case #1: Sarah vsarah, a 24-year-old overweight woman (BMI 27.9 kg/m 2 ) with a 10-year history of asthma, presents for a checkup vcurrently using high-dose ICS/LABA v1 asthma exacerbation in last year, treated with oral prednisone vduring the discussion, Sarah reports: vfrequent daytime symptoms and nighttime awakenings vfrequent use of her rescue inhaler vdaily adherence to her medications vno known environmental triggers vwhen asked, she demonstrates correct inhaler technique in the office vwhat would you do? 12 4

5 Assessing Asthma Control: Key Questions to Ask IN THE PAST 4 WEEKS: 1. Daytime asthma symptoms more than twice a week? vchest tightness vdyspnea vcough 2. Night waking due to asthma? 3. Used your rescue inhaler more than twice a week 4. Experienced limitations of daily activities due to asthma symptoms? 0 = controlled 1-2 Partly controlled 3-4 Uncontrolled 13 Asthma Control Test (ACT) 14 Assessment of Asthma Control: Future Risk of Poor Outcomes vfrequent albuterol use vpoor adherence vlow FEV1 (< 60%) vpsychological or social problems vcontinued exposures: smoking vincreased blood eosinophils vcomorbid conditions: obesity, sinusitis vprevious intubations v 2 exacerbations in the past year 15 GINA asthma guidelines,

6 Severe Asthma Definition vpatients on high dose inhaled corticosteroids (ICS) in addition to a long-acting β agonist (LABA) or another controller (GINA 4 5) IN PREVIOUS YEAR vpatients on oral corticosteroids for more than 50% of the time Ø Approximately 5%-10% of all asthmatics meet these criteria 16 Chung KF, et al. International ERS/ATS guidelines on definition, evaluation and treatment of severe asthma. Eur Respir J Feb;43(2): Case #1: Sarah, Cont d vsarah s clinician asks her about the frequency of her symptoms and asks her to complete the ACT vsarah reports: vdaytime symptoms: Every day vnighttime awakenings: Most nights of the week vuse of rescue inhaler: Daily vact score: 9 vwhat would you do? 17 Managing Asthma 18 6

7 Goal of Asthma Management: Achieving Control Reducing Current Impairment and Future Risk Symptom control (daytime symptoms, night-time awakening) Exacerbations Improve Management of Reduce Rescue medication comorbidities Treatment-related AEs Lung Function Emergency visits Effective asthma management requires a partnership between patient and healthcare provider to define and achieve treatment goals GINA. Global strategy for asthma management and prevention, report-global-strategy-forasthma-management-and-prevention/. Accessed March, 2018; 2. NHLBI. NAEPP EPR-3: guidelines for the diagnosis and management of asthma. Full report Accessed March, 2018 Common Causes of Uncontrolled Asthma! Ongoing exposure to asthma triggers 1 Comorbidities and psychosocial factors 1 Nonadherence to therapy 1 Incorrect inhaler technique Global Initiative for Asthma. Global Strategy for Asthma Management and Prevention. Updated gina-report-global-strategy-for-asthma-management-and-prevention/ Accessed August 29, Bourdin A et al. Clin Exp Allergy Nov;42(11): Provide Hands-on Inhaler Skills Training: 4 C s Choose Choose an appropriate device before prescribing. Consider medication options, arthritis, patient skills and cost. For ICS by pmdi, prescribe a spacer Avoid multiple different inhaler types if possible Check Check technique at every opportunity Can you show me how you use your inhaler at present? Identify errors with a device-specific checklist Correct Give a physical demonstration to show how to use the inhaler correctly Check again (up to 2-3 times) Re-check inhaler technique frequently, as errors often recur within 4-6 weeks Confirm Can you demonstrate correct technique for the inhalers you prescribe? Brief inhaler technique training improves asthma control 21 GINA 2017, Box 3-11 (4/4) 7

8 GINA Asthma Guidelines 22 GINA asthma guidelines, 2018 Case #1: Sarah, Cont d vsarah s clinician prescribes tiotropium 2.5 mcg qd, in addition to high-dose ICS/LABA vsix weeks later, Sarah returns for a checkup vshe reports some improvement of her symptoms, but: vpersistent daily symptoms vfrequent nighttime awakenings vuse of rescue inhaler most days vact score: 10 vher clinician recommends oral corticosteroids vis this the right choice? 23 Phenotypes in Asthma Definition: Set of observable characteristics of an individual resulting from the interaction of its genotype with the environment. vasthma is heterogeneous vmany types have been described (particularly in severe asthma) veosinophilic asthma vallergic asthma vobesity associated asthma vneutrophilic and pauci-immune asthma 24 Chung KF, et al. International ERS/ATS guidelines on definition, evaluation and treatment of severe asthma. Eur Respir J Feb;43(2):

9 Revisiting Asthma Pathobiology Eosinophilic asthma Normal Allergic eosinophilic inflammation 25 Nonallergic eosinophilic inflammation Papi A, et al. Lancet ;391(10122): Mixed granulocytic asthma IgE, im m unoglobin E; IL, interleukin; Th2, T helper type 2 cell; TSLP, thymic stromal lym popoietin; PGD2, prostaglandin D2; Th17, T helper cell type 17. Revisiting Asthma Pathobiology Eosinophilic asthma Allergic eosinophilic inflammation Normal Noneosinophilic asthma Paucigranulocytic 26 Nonallergic eosinophilic inflammation Papi A, et al. Lancet ;391(10122): Mixed granulocytic asthma Th1 + Th17 neutrophilic inflammation IgE, im m unoglobin E; IL, interleukin; Th2, T helper type 2 cell; TSLP, thymic stromal lym popoietin; PGD2, prostaglandin D2; Th17, T helper cell type 17. Type 2 Inflammation in Asthma Allergens Pollutants Irritants 27 Robinson, D. Clin Exp Allergy Feb;47(2):

10 Asthma Phenotypes in Clinical Practice vasthma phenotypes may help clinicians identify treatable traits vvery important in severe asthma vsimple and inexpensive testing can identify characteristics to help clinicians select therapy Blood eosinophils (CBC with differential) Serum Immunoglobulin E (IgE) RAST Testing (Allergen Specific IgE) Fractional exhaled nitric oxide (FeNO) 28 The Role of Biologics in Asthma 29 Monoclonal Antibody Therapeutics vmonoclonal antibodies are targeted therapies that neutralize key cytokines or receptors responsible for inflammation in asthma vby using simple biomarkers (eg, IgE, allergy testing, blood eosinophils), clinicians can determine if a patient is a candidate for biologic therapy vbiologics are used for patients who do not respond to high dose ICS/LABA, after comorbid conditions and environmental factors are addressed vcurrently 5 monoclonal antibodies approved for asthma vcurrent biologics are given SQ or IV every 2-8 weeks, depending on the medication 30 10

11 Anti-IgE: Omalizumab vmonoclonal antibody that binds to IgE vinterrupts the pathways activated in allergic inflammation vgiven subcutaneous every 2 4 weeks based on weight and IgE levels vige levels IU/mL in adults vfirst to use a biomarker in clinical practice as a treatable trait 31 Omalizumab [prescribing information]. South San Francisco, CA: Genentech; Type 2 Inflammation in Asthma Omalizumab Allergens Pollutants Irritants 32 Robinson, D. Clin Exp Allergy Feb;47(2): Anti-IL5: Benralizumab, Mepolizumab, Reslizumab vdeveloped to treat the eosinophilic phenotype vcbc with differential can evaluate for eosinophils Benralizumab Mepolizumab Reslizumab Eosinophil level 300 cells/mcl 150 cells/mcl 400 cells/mcl Route of administration SC SC IV Bel et al. N Engl J Med ;371(13):1189; Ortega et al. N Engl J Med. 2014;371(13):1198; Castro et al. Lancet Respir Med 2015;3: 355; Bjermer et al. Chest. 2016;150(4):789; Cinqair [prescribing information]. Frazer, PA: Teva Respiratory, LLC; 2016; Nucala 33 [prescribing information]. Research Triangle Park, NC: GlaxoSmithKline; 2017; Fasenra [prescribing information]. Wilmington, DE: AstraZeneca Pharmaceuticals;

12 Type 2 Inflammation in Asthma Allergens Pollutants Irritants Mepolizumab Reslizumab Benralizumab 34 Robinson, D. Clin Exp Allergy Feb;47(2): Anti-IL4/IL13: Dupilumab vmonoclonal antibody that binds to the receptor of IL4 and IL13. vgiven subcutaneous every 2 weeks. vinterrupts pathways activated by type 2 inflammation. vfirst to be approved for home use. 35 Castro M, et al. N Engl J Med Jun 28;378(26): Rabe KF, et al. N Engl J Med Jun 28;378(26): Type 2 Inflammation in Asthma Allergens Pollutants Irritants Dupilumab 36 Robinson, D. Clin Exp Allergy Feb;47(2):

13 Biologicals in Asthma vconsidered equivalent by most experts vthe key is patient selection vmultiple studies have shown efficacy in: Quality of life Exacerbations Emergency department visits Hospitalizations Steroid requirements Holgate S, et al.. J Allergy Clin Immunol Mar;115(3): Humbert M, et al. Allergy Mar;60(3): Hanania NA, et al. Ann Intern Med May 3;154(9): Bel et al. N Engl J Med ;371(13):1189; Ortega et al. N Engl J Med. 2014;371(13):1198; 37 Castro et al. Lancet Respir Med 2015;3: 355; Bjermer et al. Chest. 2016;150(4):789. Castro M, et al. N Engl J Med Jun 28;378(26): Rabe KF, et al. N Engl J Med Jun 28;378(26): Current FDA-approved Biologic Therapies for Asthma 38 Monoclonal antibody Brand name Target Dosing Treatable traits Omalizumab Xolair IgE Benralizumab Fasenra IL-5 Mepolizumab Nucala IL-5 Reslizumab Cinqair IL-5 Dupilumab Dupixent IL-4 / IL-13 SQ q 2-4 weeks SQ q 4-8 weeks SQ q 4 weeks IV q 4 weeks SQ q 2 weeks (at home) High IgE levels + perennial allergens Eosinophilic phenotype Eosinophilic phenotype Eosinophilic phenotype Eosinophilic phenotype Corticosteroid Dependent Asthma Comorbidities and Asthma 39 13

14 Case #2: Matt vmatt is a 31-year-old man with a 15-year history of asthma. He is obese (BMI 32 kg/m 2 ) and has a history of allergic rhinitis. vreports frequent symptoms of wheezing and shortness of breath, nighttime awakenings, and use of rescue inhaler vnotes that asthma symptoms often worsen after eating vact score: 11 vcurrent medications: vhigh-dose ICS/LABA vtiotropium 2.5 mcg qd vfexofenadine 180 mg qd prn vhis clinician orders testing for eosinophils, IgE levels, RAST for seasonal allergens vwhat would you do? 40 Treating the Whole Patient Comorbidities Commonly Associated With Asthma Atopic dermatitis GERD Obesity Obstructive sleep apnea Rhinosinusitis/ nasal polyposis Vocal cord dysfunction 41 Boulet LP. Eur Respir J. 2009;33(4): ; Galli E, et al. Allergy Asthma Proc. 2007;28(5): ; Porsbjerg C, Menzies-Gow, A. Respirology. 2017;22(4): Effect of Comorbid Conditions on Patients with Asthma Comorbidities More health care utilization Increased frequency/ severity of exacerbations More severe asthma Increased systemic inflammation Greater reductions in HRQoL Identification and treatment of comorbid conditions is critical. 42 HRQoL, health-related quality of life. Boulet LP. Eur Respir J. 2009;33(4): ; Murdoch JR, Lloyd CM. Mutat Res. 2010;690(1-2):24-39.; Sundh J, et al. Respir Med. 2017;132:

15 Allergic Rhinitis and Asthma vallergic rhinitis increases the risk of asthma 3-fold vpresent in 75%-80% of patients with severe asthma vmay add substantial costs for asthma patients p = p = Bousquet J, et al. Clin Exp Allergy Jun;35(6): Allergic Rhinitis and Asthma: Clinical Studies STUDY N DESIGN OBSERVATIONS Adam, Retrospective Crystal-Peters, 2002 Corren, 2004 Dixon, Retrospective Nasal steroids and antihistamines associated with reduced ED visits Asthma ED visits/hospitalizations occurred less often in treated group (6.6% v. 1.3%, p = 0.001) 361 cases Treatment with nasal steroids or 1444 controls Nested case-control antihistamines reduced risk of hospitalization for asthma 237 adults 151 children Prospective double blind PBO-controlled 24 weeks of nasal steroids did not improve asthma control 44 Corren et al. J Allergy Clin Immunol. 2004;113(3):415; Adams et al. J Allergy Clin Immunol. 2002;109(4):636; Crystal-Peters et al. J Allergy Clin Immunol. 2002;109(1):57; Dixon et al. J Allergy Clin Immunol. 2015;135(3):701-9.e5. Obesity and Asthma Symptoms vup to 1/3 of patients are misdiagnosed with asthma when they have coexisting obesity vin extreme obesity (BMI > 40) it is virtually impossible to diagnose asthma vsimilar symptoms: Shortness of breath Exercise-induced dyspnea Chest tightness Treatment vsome evidence of less response to inhaled steroids vadding non-steroidal treatments should be considered vweight loss and exercise has been shown to improve asthma outcomes vencourage weight loss at every visit and refer to weight reduction programs when available (including surgery) 45 Freitas PD et al. Am J Respir Crit Care Med Jan 1;195(1):

16 GERD and Asthma v55% of difficult-to-control asthmatics may have GERD v35% of asthmatic patients with documented GERD by ph monitoring did not have typical symptoms vclinical suspicion: vworsening of asthma symptoms after a meal vheartburn or regurgitation before onset of asthma symptoms 46 Chung KF, et al. International ERS/ATS guidelines on definition, evaluation and treatment of severe asthma. Eur Respir J Feb;43(2): GERD and Asthma: Clinical Studies 16 weeks esomeprazole Therapy Subjects Outcomes N=624 mod-severe asthma +/- GERD +/- nocturnal symptoms Improved PEF only in +GERD/+nocturnal symptoms No dif. Exacerbations 24 weeks esomeprazole Baseline data for Study of Acid Reflux and Asthma N=393 inadequately controlled asthma Minimal or no GERD ~80% using ICS+LABA 53% had reflux by ph (N=304) 38% had proximal reflux (N=242) No differences in asthma control, PFTs, symptoms, nocturnal awakenings or QoL No differences in SABA use, nocturnal awakenings, ICS dose, LABA use, PFTs, or methacholine response +/- prox. or distal reflux 47 Kiljander et al. Am J Respir Crit Care Med. 2006;173(10):1091; Mastronarde et al.n Engl J Med. 2009;360(15):1487; DiMango et al. Am J Respir Crit Care Med. 2009;180(9):809. Case #2: Matt, Cont d vmatt s clinician recommends: Daily use of fexofenadine 8-week trial of PPI Weight-loss strategies vtwo months later, Matt reports: 48 Weight loss of 5 lbs Improved asthma symptoms after meals Persistent daytime and nighttime asthma symptoms Difficulty exercising due to asthma symptoms vcurrent medications: High-dose ICS/LABA Tiotropium 2.5 mcg qd Fexofenadine 180 mg qd Lansoprazole 15 mg qd vwhat would you do now? 16

17 Referring to Specialists When to refer for advanced therapies? v Asthma that is not controlled with high-dose ICS/LABA and a second controller v Frequent exacerbations (more than 2 in 1 year) v > 2 bursts of Oral Corticosteroids in 1 year v Hospitalizations (1 or more) or history of ICU admissions v Daily symptoms despite maximal therapy v Comorbidities that complicate asthma E.g., sinusitis, nasal polyps, aspergillosis, severe rhinitis What testing is helpful? v Complete pulmonary function testing (spirometry and lung volumes) v Serum IgE levels v RAST Testing (regional perennial allergens) v CBC with differential to evaluate eosinophils v Chest X-ray 49 GINA asthma guidelines, 2018 Summary 50 Summary vsevere asthma is a common and uncontrolled disease that is linked to poor clinical outcomes vasthma is heterogeneous, and various phenotypes can be identified with simple testing vtype 2 inflammation involves various cell lines and cytokines (eg, IL-4, IL-5, IL-13) and may be activated by allergic and non-allergic triggers vtargeted therapies, such as monoclonal antibodies, improve asthma outcomes and may be considered in severe asthma not controlled with standard therapies vall patients with severe asthma should be evaluated for comorbidities va multidisciplinary approach is often required in severe asthma, and asthma education should be a component of all asthma care 51 17

18 Post-test Questions 52 Post-test Question 1 Post-S1: All of the following are Biomarkers that reflect type 2 airway inflammation except: 1. Allergen specific IGE 2. Exhaled Nitric Oxide (FeNO) 3. Blood or Sputum Eosinophils 4. Blood or Sputum Neutrophils 5. I don t know 53 Post-test Question 2 Post-S2: Which of the following tools is an evidence-based instrument for assessing asthma control in adult primary care patients? 1. ACT 2. CARAT 3. CAT 4. PHQ

19 Post-test Question 3 Post-S3: All of the following comorbidities are common in patients with asthma and can affect asthma control, EXCEPT: 1. Allergic rhinitis 2. GERD 3. Obesity 4. Type 2 diabetes 5. Sleep Apnea 55 Post-test Question 4 Post-S4: A 34-year-old woman with a 15-year history of asthma reports daily asthma symptoms and nighttime awakenings 2 nights per week. The symptoms prevent her from exercising most days. She uses albuterol 1-2 times/d and reports daily adherence to high-dose ICS/LABA. Her ACT score is 12 How would you grade this patient s level of asthma control? 1. Controlled 2. Partly controlled 3. Uncontrolled 4. Insufficient information to determine control 56 Post-test Question 5 Post-S5: A 41-year-old man presents with severe, uncontrolled asthma. He also has a history of GERD. Current medications include high-dose ICS/LABA, tiotropium, and lansoprazole. His blood work-up shows serum IgE level 15 IU/mL, blood eosinophil count 450 cells/mcl, and Allergen specific IgE (RAST) negative for common aeroallergens. Based on these findings, which of the following is NOT an appropriate biologic agent: 1. Benralizumab (Anti-IL5R) 2. Mepolizumab (Anti-IL5) 3. Omalizumab (Anti-IGE) 4. Dupilumab (Anti-IL4R) 57 19

20 Post-test Question 6 Post-S6: Approximately how many patients with Asthma do you see on a weekly basis, in any clinical setting? 1. None >25 58 Q&A 59 20