Faculty Tara Carr, MD Nicola Hanania, MD Linda Rogers, MD The - - PowerPoint PPT Presentation

Faculty

Tara Carr, MD

The University of Arizona Health Sciences

Linda Rogers, MD

Icahn School of Medicine at Mount Sinai

Nicola Hanania, MD

Baylor College

• f Medicine

This activity was made possible by an educational grant supported by

Sanofi Genzyme and Regeneron Pharmaceuticals

Disclosure of Relevant Financial Relationships

In accordance with the ACCME Standards for Commercial Support, The France Foundation (TFF) requires that individuals in a position to control the content of an educational activity disclose all relevant financial relationships with any commercial interest. TFF resolves all conflicts of interest to ensure independence, objectivity, balance, and scientific rigor in all its educational

• programs. Furthermore, TFF seeks to verify that all scientific research referred

to, reported, or used in a CME/CE activity conforms to the generally accepted standards of experimental design, data collection, and analysis. TFF is committed to providing learners with high-quality CME/CE activities that promote improvements in healthcare and not those of a commercial interest.

Faculty Disclosures

• Tara Carr, MD, has served as a consultant for AstraZeneca, Boehringer Ingelheim

Pharmaceuticals, Inc., and Sanofi Genzyme and Regeneron Pharmaceuticals. She has also received research grant support from Aimmune Therapeutics, DBV Technologies, and Roche/Genentech.

• Nicola Hanania, MD, has received honoraria for serving on advisory boards and as a

consultant for AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Novartis, Roche, and Sanofi Genzyme and Regeneron Pharmaceuticals. He has also received research grant support from AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Glaxo SmithKline, and Roche.

• Linda Rogers, MD, has received honoraria for serving as a consultant for AstraZeneca, Sanofi

US, and Teva Pharmaceutical Industries, and for serving on advisory boards for AstraZeneca. She has received research grant support from Sanofi.

Learning Objectives

1 2

Explain how phenotypes and endotypes can help guide a precision medicine approach to severe asthma Summarize mechanisms of action and key efficacy and safety data pertaining to biologics used in severe asthma Apply information on phenotypes and endotypes and biologics to precision therapy, as part of a personalized treatment selection process

3

Historical Perspectives on Severe Asthma

“It must be admitted that the remedies for asthma are of very irregular and uncertain

• peration; that probably there is no single

remedy that is not inoperative in a large number of cases; that that which is useful in one is valueless in another while there are many cases that resist all remedies. If this intractability of asthma were doubtful the large number of remedies that have been suggested would be a sufficient proof of it.” “The success of a remedy given on certain principles proves the correctness of the principles on which it was given, and the known action of a medicine directly implies the nature of the pathological state.”

• Henry Hyde Salter, MD, 1860

Historical Approaches to Asthma Treatment

Asthma Definition Today

Chronic inflammatory disorder of the airways Recurring episodes of wheezing, breathlessness, chest tightness, and coughing, especially at night or early morning Chronically inflamed airways are hyperresponsive; airflow becomes limited (by bronchoconstriction, mucus, increased inflammation) when airways are exposed to various triggers

WHO/NHLBI Workshop Report. 1995. Global strategy for asthma management and prevention. National Institutes of Health, National Heart, Lung, and Blood Institute, Bethesda, MD. Publication No. 95-3659.

Airway inflammation Episodic (reversible) airway limitation —

• bstructive

symptoms Airway hyperresponsiveness

Asthma: More Than Just Allergy

Holt PD, Sly PG. Nature Medicine 2012; 18(5),726-35.

Episodic airway inflammation Tissue damage Tissue repair & remodeling Steady-state respiratory function Transient symptoms Persistent pathological changes Environmental triggers Lung tissue structure-function relationships Time (y) Persistent asthma threshold

Asthma in the US Today

• National data1

– 20.4 million adults (8.3%) – 6.1 million children (8.3%) – 12.4 million acute attacks – 1.7 million ED visits – 3,518 deaths annually (rate: 10/million)

• 1. CDC. https://www.cdc.gov/asthma/most_recent_data.htm. 2015, 2016.
• 2. Nurmagambetov T, et al. Ann Am Thorac Soc. 2018;15(3):348-356.
• Costs: $81.9 billion

in 20132

– Medical – Missed work and school days – Asthma-related mortality

Economic Burden of Asthma in the US

Medical Costs for All Payers† Absenteeism

• Work/school days missed per person per year:
• 1.6 days (for all ages)
• 2.2 days (for children)
• Total annual number of work/school days

missed:

• 22,360 – 1,492,060 days
• Represents indirect costs of $4 million – $345

million

• Combined medical and absenteeism costs
• $65 million – $3,718 million
• From 2015 to 2020, costs are expected to

increase by ~24%

*Medically treated asthma = diagnosis of asthma and at least one of the following: hospitalization, ED visit, office-based provider visit, outpatient hospital visit, or prescription drug.

†Sum of all payments for hospitalizations, ED visits, office-based visits, outpatient visits, and prescription medications made by all payers (Medicare + Medicaid +private insurance).

All costs reported in 2014 dollars. MEPS = Medical Expenditure Panel Survey Nurmagambetov T, et al. J Asthma. 2017;54(4):357-370.

Per person for all ages

Cost analysis of medically treated asthma* using 2008–2012 MEPS data

ERS/ATS Definition of Uncontrolled Asthma

Defined as at least one of the following

• Poor symptom control: ACQ consistently > 1.5, ACT < 20 (or “not well controlled” by

NAEPP/GINA guidelines)

• Frequent severe exacerbations: ≥ 2 bursts of systemic CS (> 3 days each) in the previous year
• Serious exacerbations: at least one hospitalization, ICU stay, or mechanical ventilation in the

previous year

• 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)

Chung KF, et al. Eur Respir J. 2014;43:343-373.

Many patients with severe asthma are not well-controlled with standard therapy

Abbreviations: ACQ: Asthma Control Questionnaire; ACT: Asthma Control Test; NAEPP: National Asthma Education and Prevention Program.

Factors That Can Contribute to Uncontrolled Asthma

14

Uncontrolled Asthma

• Cyclical nature of disease
• Increased disease severity
• Differing asthma phenotypes

Disease-Related Factors

• Medication underprescribing
• Failure to assess adherence
• Failure to assess inhaler technique
• Misdiagnosis
• Lack of asthma action plan
• Absence of specialty care

Physician-Related Factors

• Passive smoking
• Frequent exposure to

traffic or air pollution

• Outdoor and indoor

allergens Environmental Factors

• Comorbidities (eg, GERD,

rhinosinusitis, depression)

• Smoking
• Obesity
• Age
• Psychosocial issues (eg, lower

income, poor health literacy)

• Poor treatment adherence
• Inadequate inhaler technique
• Heterogeneity of treatment

response

• Failure to follow self-management

plan

• Side effects of other medications

(eg, NSAIDs) Patient-Related Factors

GERD = gastroesophageal reflux disease Adapted from Wechsler ME. Am J Med. 2014;127(11):1049-1059.

Gaining Optimal Asthma Control Study (GOAL)

60 47 75 62 20 40 60 80 <500 mcg >500 - 1000 mcg ICS ICS + LABA Percent of Subjects Daily BDP (or Equivalent) Use in the Past 6 months

*P <0.001 BDP = beclomethasone dipropionate; ICS = inhaled corticosteroid; LABA = long-acting beta agonist. Bateman ED, et al. Am J Respir Crit Care Med. 2004;15;170(8):836-844.

25% – 38% were unable to achieve well-controlled asthma despite high-dose ICS, LABA, and oral steroids

 * *

ERS/ATS Definition of Severe Asthma

Asthma requiring treatment with

• Guideline-suggested medications for GINA steps 4–5 asthma

(high-dose ICS*,† and LABA or leukotriene modifier/theophylline) for the previous year OR

• Systemic CS for ≥ 50% of the previous year to prevent it from

becoming “uncontrolled” or which remains “uncontrolled” despite this therapy

Chung KF, et al. Eur Respir J. 2014;43:343-373. *For patients ages ≥ 6 years.

†Definitions of high-dose ICS vary for patients ages 6-12 years vs those ages > 12 years.

ERS = European Respiratory Society; ATS = American Thoracic Society; GINA: Global Initiative for Asthma; ICS = inhaled corticosteroids; LABA: long acting β2-agonists; CS = corticosteroids

Focus Is Shifting Toward Disease Mechanisms

Lotvall J, et al. J Allergy Clin Immunol. 2011;127(2):355–360.

Observable Characteristics (Phenotype) What can be observed and measured clinically? What are the potential drivers of disease? Pathophysiological Mechanism (Endotype)

Phenotype Possible Mechanism (Endotype) Clinical Characteristics Early-onset, allergic IgE-mediated Th2/type 2 inflammation Childhood onset, allergen triggers, allergic rhinitis Early-onset, obesity- exacerbated Eosinophil recruitment, airway remodeling Obesity, childhood onset, allergy Aspirin-exacerbated respiratory disease Eicosanoids Adult onset, severe asthma, nasal polyposis Allergic broncho-pulmonary mycosis Fungal colonization with Th2/type 2 and mixed responses Adult onset, severe asthma, pronounced mucus production Asthma-predictive, index- positive preschool wheezer Th2/type 2 inflammation, eicosanoids >3 episodes of wheeze/y, 1 major

• r 2 minor atopy characteristics

Severe late-onset hypereosinophilic ILC2 activation, dual positive Th2/Th17 inflammation Adult onset, severe exacerbations, less atopic Exacerbation-prone Eosinophil-driven inflammation Frequent exacerbations, sinusitis, GERD

Carr TF, et al. Am J Respir Crit Care Med. 2018: 197(1):22-37.

Asthma Phenotypes

Asthma Phenotypes (cont)

Phenotype Possible Mechanism (Endotype) Clinical Characteristics Exercise-induced Th2/type 2 in some, not clear in

• thers

Symptoms develop with or after exercise—more so in cold, dry air Neutrophilic Lack of Th2/type 2 inflammation Th17, infection, inflammasome Adult onset, variable severity Obesity-induced IL-6, oxidative stress pathways Adult onset, predominantly female, very symptomatic Paucigranulocytic Airway remodeling, increased smooth muscle tone, thickened basement membrane Mild and severe Asthma with smoking Epithelial dysfunction, altered histone deacetylase Current/former tobacco smoke exposure, worse QOL and more symptoms, corticosteroid insensitivity

Carr TF, et al. Am J Respir Crit Care Med. 2018: 197(1):22-37.

GM-CSF Leukotrienes PGD2 Histamine IL-3, IL-4, IL-5, IL-9 Antigens

Type 2 Inflammation

TSLP Th2 cell ILC2 IL-13 GATA3 CRTh2 B cell IgE Eosinophil CRTh2 IL-4 IL-5 IL-4, IL-5, IL-13 GATA3 Mast cell IL-25 Irritants, pollutants, microbes, and viruses

Non-Type 2 Inflammation

IL-33 IL-6 CXCL8 GM-CSF TGF-β IL-23 Th17 cell CRTh2 Neutrophil IL-6 IL-17 IL-8 CXCR2 BLT2 Leukotrienes B4 IFN-γ TNF Th1 cell ALX Lipoxin

Key Mechanisms in Airway Inflammation

ALX = lipoxin A4 receptor; BLT2 = leukotriene B receptor 2; CRTh2 = chemoattractant receptor homologue from Th2 cells; CXCL8 = CXC motif chemokine ligand 8; CXCR2 = CXC motif chemokine receptor 2; GATA3 = GATA binding protein 3; GM-CSF = granulocyte–macrophage colony-stimulating factor; IFN-γ = interferon gamma; ILC2 = innate lymphoid cells; PGD2 = prostaglandin D2; TSLP = thymic stromal lymphopoietin; TGF-β = transforming growth factor β; Th =T helper; TNF = tumor necrosis factor. Adapted from Israel E, Reddel HK. N Engl J Med. 2017;377(10):965-976.

Non-invasive approaches to distinguishing type 2 vs non-type 2 asthma

• FeNO
• IgE and allergy testing
• Sputum or peripheral blood eosinophilia

Type 2 vs Non-Type 2 Asthma

Type 2 Asthma

• More severe
• High expression of Th2-cell cytokines

in the airways

• Airway and systemic eosinophilia
• Responsive to corticosteroids
• Responsive to inhibitors of Type 2

inflammation

Non-Type 2 Asthma

• Less severe
• Low expression of Th2-cell cytokines in

the airways

• Absence of airway and systemic

eosinophilia

• Lack of responsiveness to corticosteroids
• Lack of responsiveness to inhibitors of

type 2 inflammation

FeNO = fractional exhaled nitric oxide. Fahy J. Nat Rev Immunol. 2015;15:57-65. Global Initiative for Asthma (GINA). Difficult-to-Treat & Severe Asthma in Adult and Adolescent Patients. Diagnosis and Management. V 2.0. April 2019. Available at www.ginasthma.org.

Comparison of Type 2 Inflammation Biomarkers in Asthma

Biomarker Type 2 Levels Limitations Low Medium High Total IgE (IU) <30 31–149 >150

• Affected by age
• Poor predictor of response rate to biologic therapy
• Does not correlate well with asthma severity
• Elevations not specific to asthma (also found in atopic

dermatitis, allergic bronchopulmonary aspergillosis, etc.) Blood eosinophils (cells/μL) <150 151–399 >400

• Affected by weight, allergen exposure, steroids, and

infection; optimal cut off value varies per therapy.

• Elevations not specific to asthma (also found in allergic

rhinitis, drug reactions, etc.) Sputum eosinophils – – ≥3%

• Semi-invasive
• Confined to research settings

FeNO (ppb) <25 26–49 >50

• Affected by age, weight, sex, smoking, and respiratory

infections

Parulekar AD, et al. Curr Opin Pulm Med. 2016;22(1):59-68. Peters MC, et al. Curr Allergy Asthma Rep. 2016;16(10).

Phenotype/Endotype-Specific Asthma Treatments

Does the patient have: What are the pathway targets? Consider these therapies: Pipeline therapies:

Atopic phenotype or comorbidities

• Elevated total and/or specific IgE
• Symptoms related to allergen

exposure

• Atopic dermatitis, allergic rhinitis,

nasal polyps

• Elevated FeNO
• IgE
• IL-4
• IL-13
• IL-4Ra
• CRTH2
• Anti-IgE (omalizumab)
• Anti-IL-5 or anti-IL-5Ra

(benralizumab, mepolizumab, reslizumab)

• Anti-IL-4/IL-13 (dupilumab)
• Fevipiprant*
• Tezepelumab*

Eosinophilic phenotype

• Elevated blood and/or sputum

eosinophils

• Severe asthma with exacerbations
• IL-5
• IL-5R
• Anti-IL-5 or anti-IL-5Ra

(benralizumab, mepolizumab, reslizumab)

• Anti-IgE (omalizumab)
• Anti-IL-4/IL-13 (dupilumab)
• Fevipiprant*
• Tezepelumab*

Neutrophilic phenotype

• Lack of atopy or eosinophilia
• Suggestion of chronic

infection/inflammation

• IL-17
• IL-1
• Chronic infection
• Macrolide antibiotics
• Anti IL-17
• Anti IL-6
• Anti-neutrophil

Paucigranulocytic phenotype

• Fixed airflow obstruction
• Lack of benefit from inhaled steroids

–

• Bronchodilators (adrenergic,

muscarinic)

• Bronchial thermoplasty

–

*Investigational (Phase 3); not FDA-approved.

Calvin Coolidge: U.S. President from 1923-1929

• 30th president of the United States
• He took office on August 3, 1923, following the sudden death of President

Warren G. Harding

• He was the only U.S. president to be sworn in by his own father. In 1923, while visiting his childhood

home in Vermont, Coolidge learned of President Warren Harding's death. As it was the middle of the night, Coolidge's father—a notary public—administered the oath by lamp light

• Led the nation through most of the Roaring Twenties, a decade of dynamic social and cultural

change, materialism and excess

• Nicknamed “Silent Cal” for his quiet, steadfast, and frugal nature, Coolidge cleaned up the rampant

corruption of the Harding administration and provided a model of stability and respectability for the American people in an era of fast-paced modernization

Case 1: Calvin Coolidge (1872–1933)

• Allergies throughout life

– Childhood onset – “Sinus trouble” and “irritation” – Severe allergies to pollen, dust, horse dander

• 1890 (age 18): prolonged

episode of bronchitis

Cohen SG. Allergy Asthma Proc.1998;19(1):40-46. Photo source: Coolidge Foundation. https://www.coolidgefoundation.org/presidency/a-biographical-sketch-of-calvin-coolidge.

Calvin Coolidge (1872–1933) (cont)

• 1918 (age 46 years): flu-related “bronchial problem”
• Thereafter, frequent asthma + rhinosinusitis

symptoms

• Sneezing, nasal blockage, coughing, breathlessness
• Worsened with age
• Chronic indigestion
• Cigar smoker
• Distrusted doctors
• Self-medicated
• Chlorine gas in a closed room
• “Spray” of unknown composition

Library of Congress, Prints & Photographs Division Cohen SG. Allergy Asthma Proc.1998; 19(1):40-46.

Calvin Coolidge Today*

• Age 46 years
• ED visit for “extreme difficulty breathing”
• Infectious etiology ruled out
• Asthma suspected
• Treatment: CS + β2-adrenergic bronchodilator
• Discharged with
• Albuterol PRN
• Prednisone: 50 mg/day for 7 days
• Budesonide/formoterol: 160 mcg/4.5 mcg, 2

puffs 2x daily

• Fluticasone nasal spray 1 – 2x daily

Calvin Coolidge, 1918 Library of Congress, Prints & Photographs Division, cph.3g10777 *These details are fictional and intended strictly for educational purposes.

Calvin Coolidge Today: In Your Office for Follow-up*

• Appears anxious
• Reports sleeping poorly due to nighttime

coughing; daytime chest tightness; use of rescue inhaler every day since discharge

• Triggers: “hay fever”
• Other recent symptoms

– Allergies/sneezing – Sinus pain – Heartburn

• ACT score: 13†
• Reports adherence to prescribed

treatment for > 3 months

• Demonstrates proper inhaler use

2 4 2 2 3 13

Nathan RA et al. J Allergy Clin Immunol. 2004;113:59-65. ASTHMA CONTROL TEST *These details are fictional and intended strictly for educational purposes.

†Score of <19 indicates uncontrolled asthma.

Calvin Coolidge: Differential Diagnosis

• Perform a careful history/PE to determine whether symptoms

are typical of asthma or due to another diagnosis or comorbidity

– Dyspnea: COPD, obesity, cardiac disease, deconditioning – Cough: inducible laryngeal obstruction (VCD), upper airway cough syndrome (post-nasal drip), GERD, bronchiectasis, ACE inhibitors – Wheeze: obesity, COPD, tracheobronchomalacia, VCD

• Perform spirometry
• Order labs

COPD: chronic obstructive pulmonary disease; VCD = vocal cord dysfunction. Global Initiative for Asthma (GINA). Difficult-to-Treat & Severe Asthma in Adult and Adolescent Patients. Diagnosis and Management. V 2.0. April 2019. Available at www.ginasthma.org.

Calvin Coolidge: Work-up*

• Pre-/post bronchodilator findings
• Spirometry loop with scooping present; no inspiratory abnormality
• FeNO: 50 ppb
• Eosinophils: 440 cells/μL
• Total IgE: 320 kU/ml
• Specific IgE positive for: dust mites, mold, pollen, horse dander
• Chest x-ray: normal

Parameter Pre-bronchodilator Absolute (L) & %predicted Post-bronchodilator Absolute (L) & %predicted Post-bronchodilator % change FVC 3.08 (72%) 3.14 (73%) +2% FEV1 1.88 (53%) 2.11 (59%) +12% FEV1/FVC 0.61 0.67 NA FEF25-75% 28% 35% +25%

*These details are fictional and intended strictly for educational purposes.

Severe Asthma Decision Tree

31

Adolescents and adults with symptoms and/or exacerbations despite GINA Step 4/5 treatment

REVIEW RESPONSE

(3-6 months later) Is asthma still uncontrolled? Does asthma become uncontrolled? Consider step-down treatment (OCS first) Continue

• ptimizing

management Restore previous dose yes no yes no

Consider partnering with a specialist/severe asthma clinic

Diagnosis: Difficult- to-treat asthma

Confirm the diagnosis Assess symptom control Look for contributing factors Treatment issues Incorrect inhaler technique Suboptimal adherence Patient attitudes/goals Comorbidities Rhinosinusitis/nasal polyps Obesity GERD OSA Anxiety/depression Risk factors Smoking Environmental exposures Meds (-blockers, NSAIDs) Overuse of SABA relievers Blood or sputum eosinophils

ASSESS

Provide asthma education Optimize treatment Correct inhaler technique Address barriers to adherence Switch to ICS-formoterol maintenance + reliever therapy Treat comorbidities/ modifiable risk factors Consider non-pharmacologic interventions Smoking cessation Diet/exercise/weight loss Mucus clearance Influenza vaccination Breathing exercises Allergen avoidance Consider trial of high-dose

ICS, if not used

OPTIMIZE MANAGEMENT

Diagnosis: Severe asthma NSAID = nonsteroidal anti-inflammatory drugs; OCS = oral corticosteroid; OSA = obstructive sleep apnea; SABA = short-acting beta2 agonist. Global Initiative for Asthma. Available from: https://ginasthma.org/wp-content/uploads/2018/04/wms-GINA-2018-report-V1.3-002.pdf; Global Initiative for

• Asthma. Available from: https://ginasthma.org/wp-content/uploads/2018/11/GINA-SA-FINAL-wms.pdf. Accessed April 9, 2019.

GM-CSF Leukotrienes PGD2 Histamine IL-3, IL-4, IL-5, IL-9 Antigens

Type 2 Inflammation

TSLP Th2 cell ILC2 IL-13 GATA3 CRTh2 B cell IgE Eosinophil CRTh2 IL-4 IL-5 IL-4, IL-5, IL-13 GATA3 Mast cell IL-25 Irritants, pollutants, microbes, and viruses

Non-Type 2 Inflammation

IL-33 IL-6 CXCL8 GM-CSF TGF-β IL-23 Th17 cell CRTh2 Neutrophil IL-6 IL-17 IL-8 CXCR2 BLT2 Leukotrienes B4 IFN-γ TNF Th1 cell ALX Lipoxin

Key Mechanisms in Airway Inflammation

ALX = lipoxin A4 receptor; BLT2 = leukotriene B receptor 2; CRTh2 = chemoattractant receptor homologue from Th2 cells; CXCL8 = CXC motif chemokine ligand 8; CXCR2 = CXC motif chemokine receptor 2; GATA3 = GATA binding protein 3; GM-CSF = granulocyte–macrophage colony-stimulating factor; IFN-γ = interferon gamma; ILC2 = innate lymphoid cells; PGD2 = prostaglandin D2; TSLP = thymic stromal lymphopoietin; TGF-β = transforming growth factor β; Th =T helper; TNF = tumor necrosis factor. Adapted from Israel E, Reddel HK. N Engl J Med. 2017;377(10):965-976.

Blood Eosinophil Counts and Risk of Asthma Exacerbations

Price DB, et al. Lancet Respir Med. 2015;3:849-858.

Claims Database Analysis Examining Eosinophil Count and Exacerbations Requiring Systemic CS or ER/Hospital Care

Severe Exacerbations Acute Respiratory Events Overall Asthma Control

Role of Eosinophils and FeNO in Asthma Exacerbations

–80 –60 –40 –20 20 40

FeNO

P=0.45* (n=193) P=0.54* (n=383) P=0.001* (n=201) P=0.005* (n=414)

Mean (95% CI) % Reduction in Protocol-Defined Asthma Exacerbation Rate EOS

<19.5 ppb <260/μL ≥19.5 ppb ≥60/μL

–16 –53 –9 –32 Hanania N, et al. Am J Respir Crit Care Med. 2013:187:804-811. *Exacerbation reduction P values, omalizimab vs. placebo in each biomarker subgroup

Greater prevention of exacerbations with omalizumab was seen in patients with high individual T2 biomarkers (eosinophils, FeNO)†

†Greater prevention of exacerbations was also seen in patients with high periostin (≥50 ng/mL), though the difference compared to patients with low periostin

(<50 ng/mL) was not significant (P = 0.07).

Allergic Rhinitis  Asthma

• Allergic rhinitis is a risk factor for

– Recurrent childhood cough and wheezing – Asthma onset, persistence, severity

• Link: progressive allergen

sensitization and clinical expression of respiratory inflammation during childhood

Lambrecht B, Hammad H. Nature Immunol, 2015;16(1):1529-2908. Burgess JA, et al. J Allergy Clin Immunol. 2007;120(4):863-869.

Childhood Rhinitis and Asthma, Ages 8-32 y

Non-Atopic Atopic HR 95% CI P HR 95%CI P No Rhinitis

Ref 1.0 N/A 1.8 1.0 – 3.2 0.035

Active Rhinitis

2.1 1.2 – 3.4 0.005 3.7 2.2 – 6.1 <0.001

Cox Proportional Hazards Model

Carr TF, et al. Clin Exp Allergy 2019:49(1):35-43.

GINA 2019 Treatment Strategy

LTRA = leukotriene receptor agonist. *Off-label, data only for budesonide-formoterol. †Off-label, separate or combination ICS and SABA inhalers. ‡Low-dose ICS-formoterol is for patients prescribed budesonide-formoterol maintenance and reliever. ¶Consider adding HDM SLIT for sensitized patients with allergic rhinitis and FEV >70% predicted.

• GINA. Global Strategy for Asthma Management and Prevention: 2019 Update. www.ginasthma.org.

As needed low dose ICS- formoterol* Daily low-dose inhaled ICS or as needed low dose ICS-formoterol* Low-dose ICS/LABA Medium dose ICS/LABA High dose ICS/LABA Refer for phenotypic assessment ± add-

• n therapy

(eg, tiotropium, anti-IgE, anti-IL5/5R, anti-IL4R)

STEP 1 STEP 2 STEP 3 STEP 4 STEP 5

Low-dose ICS whenever SABA is taken† LTRA, or Low-dose ICS whenever SABA taken† Medium dose ICS or low dose ICS + LTRA¶ High dose ICS, add-on tiotropium,

• r add-on LTRA¶

Add low dose OCS, but consider side effects

PREFERRED CONTROLLER PREFERRED RELIEVER Other controller

• ptions

As needed low-dose ICS-formoterol* As needed low-dose ICS-formoterol‡ As-needed SABA

Other reliever option

Calvin Coolidge, 6-Month Follow-up*

• Maintained on high dose ICS/LABA
• Modified his environment to reduce triggers
• Symptoms have improved partially but had

another exacerbations requiring a course of OCS

• Continues to use his rescue inhaler daily
• FEV1: 70% predicted with 10% improvement

post-bronchodilator

• FeNO: 42 ppb
• ACT score: 18
• Reports adherence to treatment regimen
• Demonstrates proper inhaler use

*These details are fictional and intended strictly for educational purposes..

3 4 4 3 4 18

Nathan RA et al. J Allergy Clin Immunol. 2004;113:59-65. ASTHMA CONTROL TEST

GINA: Assessing Severe Asthma Phenotype

• Investigate for co-morbidities (and/or

treat/refer as appropriate)

• CBC, CRP, IgG, IgA, fungal precipitins,

CXR and/or chest HRCT, DLCO

• Skin-prick testing or specific IgE for

allergens

• Other directed testing based on clinical

suspicion (eg, ANCA, sinus CT, BNP, ECG)

• Consider need for social/psychological

support

• Involve multi-disciplinary team
• Invite enrollment in registry or clinical trial (if

available) Type 2 Inflammation

• Blood eosinophils† ≥150/µL and/or
• FENO† ≥20 ppb and/or
• Sputum eosinophils ≥ 2% and/or
• Need for maintenance OCS

*Note: these are NOT the criteria for add-on biologics. †Repeat eosinophil and FENO tests up to 3 times in patients on lowest possible OCS. ‡Implement strategies to minimize side effects.

¶Off-label.

• Assess the severe asthma phenotype during

high-dose ICS (or lowest possible OCS)* Yes No

• Consider
• Adherence tests
• Increasing ICS dose for

another 3-6 months

• AERD, ABPA, chronic

rhinosinusitis, nasal polyposis, atopic dermatitis Is add-on type 2 biologic therapy available/ affordable?

• Review the basics
• Avoid exposures
• Consider investigations
• Sputum induction
• Chest HRCT
• Bronchoscopy for other

diagnoses

• Consider add-on treatments
• LAMA or macrolide trial
• Low-dose OCS
• Stop ineffective add-on

therapies

• Consider bronchial thermoplasty

Yes No

• Consider higher dose ICS
• Consider nonbiologic add-on therapy

(eg, LABA, LAMA, leukotriene modifiers, macrolide¶)

• Consider add-on low-dose OCS‡
• Stop any ineffective add-on therapies

STEP 5: Assess phenotype and factors contributing to symptoms, QOL, exacerbations STEP 6a:Consider nonbiologic treatments ABPA = allergic bronchopulmonary aspergillosis; AERD = aspirin-exacerbated respiratory disease; ANCA = antineutrophil cytoplasmic antibodies; BNP = brain natriuretic peptide; DLCO = diffusing capacity of the lungs for carbon monoxide.

• GINA. Global Strategy for Asthma Management and Prevention: 2019 Update. ww.ginasthma.org.

Available and Emerging Targeted Therapies for Severe Asthma

Status Biologic Target Key Trials

Administration

Approved or Studied in Other Diseases Age (years) Route Frequency FDA- approved Omalizumab IgE Study 008/009/ALTO ≥6 SC Q2W / Q4W Urticaria‡ Nasal polyps Mepolizumab IL-5 MENSA, SIRIUS ≥12 SC Q4W EGPA‡ COPD Nasal polyps HES Reslizumab IL-5 BREATH trials ≥18 IV Q4W Sinusitis Eosinophilic Esophagitis Benralizumab IL-5 receptor SIROCCO/CALIMA/ZONDA ≥12 SC Q4W / Q8W COPD Dupilumab IL-4 receptor† LIBERTY/VENTURE/VOYAGE ≥12 SC Q2W Atopic dermatitis‡ Nasal polyps Eosinophilic esophagitis Peanut allergy, grass allergy COPD Phase 3* Tezepelumab TSLP PATHWAY, NAVIGATOR, SOURCE ≥18 SC Q2W/Q4W Atopic dermatitis Fevipiprant DP2 receptor LUSTER ≥18 Oral QD 

*Completed or ongoing, †Inhibits IL-4 and IL-13 signaling pathways, ‡FDA-approved for treatment of this disease. DP2 = prostaglandin D2; EGPA = eosinophilic granulomatosis with polyangiitis; HES = hypereosinophilic syndrome; COPD = chronic obstructive pulmonary disease.

Anti-IgE Mab: Omalizumab

• Reduces exacerbations in

– 50% of patients with moderate- to-severe asthma1 – Adults with severe allergic asthma (25% relative reduction)2 – Urban children with asthma3

• Reduces risk of seasonal viral-

induced exacerbations in children (ICATA3, PROSE4)

http://tmedweb.tulane.edu/pharmwiki/doku.php/treatment_of_asthma

• 1. Rodrigo GJ, et al. Chest. 2011 Jan;139(1):28-35.
• 2. Hanania NA, et al. Ann Intern Med. 20113;154(9):573-82.
• 3. Busse WW, et al. N Engl J Med. 2011;364(11):1005-1015.
• 4. Teach SJ, et al. J Allergy Clin Immunol. 2015;136:1476-85.

Omalizumab for Severe Allergic Asthma

0.28 0.28 0.54 0.66

0.2 0.4 0.6 0.8 Busse et al. 2001 Soler et al. 2001

Omalizumab Placebo

Stable Steroid Phase 16 wks

0.39 0.36 0.66 0.75

0.2 0.4 0.6 0.8

Busse et al. 2001 Soler et al. 2001

Omalizumab Placebo

Steroid Reduction Phase 12 wks

P = 0.006 P = 0.003 P < 0.001 P < 0.001 Busse W, et al. J Allergy Clin Immunol. 2001;108:184-190. Soler M, et al. Eur Respir J. 2001;18:254-261. Mean exacerbations/ patient Mean exacerbations/patient

Omalizumab for Treatment of Severe Allergic Asthma*

Omalizumab Group Placebo Group Frequency of protocol-defined asthma exacerbations, n (%) 275 (64.4) 242 (57.5) 1 94 (22.0) 107 (25.4) 2 31 (7.3) 34 (8.1) 3 16 (3.7) 23 (5.5) ≥4 11 (2.6) 15 (3.6) Rate of protocol-defined asthma exacerbations per patient 0.66 0.88 Incidence rate ratio (95% CI); P value 0.75 (0.61 – 0.92); 0.006

Hanania N, et al. Ann Intern Med. 2011;154:573-582. *Patients had inadequately controlled asthma despite treatment with high-dose ICS + LABAs, with or without other controllers.

Anti-IL-4/IL-13 MAb: Dupilumab

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

Wenzel S, et al. N Engl J Med. 2013;368:2455-2466.

Proportion of Patients with Exacerbations (Primary Endpoint) Time to Exacerbation

Proportion of patients with exacerbation Placebo (n = 52) Dupilumab (n = 52) 44% 6%

87%

P<0.001 60 50 40 30 20 10

Dupilumab in Persistent Asthma with Elevated Eosinophils

50 Cumulative exacerbation rate (%) 40 30 20 10 1 2 3 4 5 6 7 8 9 10 11 12 Dupilumab Placebo HR = 0.10 (95% CI, 0.03–0.34) P<0.001) Dupilumab

• r placebo

monotherapy Tapering

• f IGC

Stable background therapy LA BA withdrawal Week 60

Efficacy of Dupilumab in Patients with Uncontrolled Asthma: LIBERTY ASTHMA Phase 3 Trials

• 1. Castro M, et al. N Engl J Med. 2018;378(26):2486-2496.
• 2. Rabe KF, et al. N Engl J Med. 2018;378(26):2475-2485.

0.87 0.46

0.2 0.4 0.6 0.8 1 1.2 Placebo 1.14 mL Dupilumab 200 mg

QUEST1

1,902 patients ≥ 12 years with uncontrolled, moderate-to-severe asthma

0.39 – 0.53 0.72 – 1.05

48%

*

0.97 0.52

0.2 0.4 0.6 0.8 1 1.2 Placebo 2.00 mL Dupilumab 300 mg

0.45 – 0.61 0.81 – 1.16

46%

*

N= 317 631 321 633

Annualized Rate of Severe Asthma Exacerbations (52 weeks)

• 42
• 70
• 80
• 60
• 40
• 20

Placebo 2.00 mL Dupilumab 300 mg

VENTURE2,†

210 patients ≥ 12 years with oral corticosteroid-dependent severe asthma

Change in OCS Dose from Baseline (24 weeks)

±5% ±5%

N= 107 103

*

Percent Rate *P <0.001.

†In addition, after 24 weeks, 48% of patients on dupilumab no

longer needed OCS vs 25% of patients on placebo (P = 0.002). *P <0.001.

Anti-IL-5/Anti-IL5R MAbs

Benralizumab Mepolizumab Reslizumab

Source: Varicchi G, et al. Curr Opin Allergy Clin Immunol. 2016,16(2):186-200.

Benralizumab in Severe Asthma with Eosinophilia: ZONDA Study

Time to First Asthma Exacerbation Change from Baseline in Oral Glucocorticoid Dose

Nair P, et al. N Engl J Med. 2017;376:2448-2458.

Efficacy of Benralizumab for Patients with Severe Asthma: SIROCCO Trial

Bleecker ER, et al. Lancet. 2016;388:2115-2121.

Eosinophils ≥ 300 cells/μL Eosinophils < 300 cells/μL

• 1. Ortega HG, et al. N Engl J Med 2014;371:1198-1207.
• 2. Bel EH, et al. N Engl J Med. 2014;371(13):1189-1197.

Mepolizumab for Eosinophilic Asthma: MENSA and SIRIUS Studies

MENSA1 SIRIUS2

*P < 0.0001 vs placebo. CAE = clinical asthma exacerbation. Castro M, et al. Lancet Respir Med. 2015;3(5):355-366.

Study 3082

Probability of Not Having a CAE by Week 52, % (95% CI) Placebo Reslizumab Study 3082 44 (38 – 51) 61 (55 – 67)* Study 3083 52 (45 – 58) 73 (67 – 79)*

Reslizumab in Inadequately Controlled Eosinophilic Asthma

Study 3083

Oral Corticosteroid-sparing Strategies

Benralizumab1

• Reduced OCS dose by 75%

(vs 25% with placebo) Dupilumab3

• Reduced OCS dose by 70%

(vs 42% with placebo) Mepolizumab2

• Reduced OCS dose by 50%

(vs 0% with placebo) Omalizumab4

• 79% of patients reduced OCS

dose by ≥ 50% (vs 55% with placebo)

• 1. Nair P, et al. N Engl J Med. 2017;376(25):2448-2458.
• 2. Bel EH, et al. N Engl J Med. 2014;371(25):1189-1197.
• 3. Rabe KF, et al. N Engl J Med. 2018;378(26):2475-2485.
• 4. Soler M, et al. Eur Respir J. 2001;18(2):254-261.

Safety Summary for Available Asthma Biologics

Biologic Key Safety Findings Omalizumab Injection site reactions Anaphylaxis (box warning) Dupilumab Injection-site reactions Hypersensitivity Conjunctivitis Keratitis Benralizumab Hypersensitivity Mepolizumab Injection site reactions Hypersensitivity Reslizumab Anaphylaxis (boxed warning) Increased CPK

CPK = creatine phosphokinase

GINA 2019: Identifying Patients with Severe Asthma and Selecting Treatment

*Baseline IgE levels do not predict likelihood of response Global Initiative for Asthma (GINA). Difficult-to-Treat Severe Asthma in Adolescents and Adult Patients: Diagnosis And Management. 2018. www.ginasthma.org.

Type 2 airway inflammation if:

Meets ≥ 1 of the following criteria while on high-dose ICS (before OCS):

• Blood eosinophils ≥150 cells/µL
• FeNO ≥20 ppb
• Sputum eosinophils ≥2%
• Asthma is clinically allergen-driven
• Need for maintenance OCS

Start with anti-IgE therapy if:

• Ages ≥6 years
• Severe allergic asthma
• Sensitization on skin prick testing or specific IgE
• Total serum IgE* and weight within dosage range
• Exacerbations in the last year

Predictors of good response:

• Blood eosinophils ≥260 cells/µL
• FeNO ≥20 ppb
• Allergen-driven symptoms
• Childhood-onset asthma

Start with anti-IL5 or –IL5R therapy if:

• Ages ≥12 or ≥18 years
• Severe eosinophilic asthma
• Exacerbations in the last year
• Blood eosinophils ≥300 cells/µL

Predictors of good response:

• Higher blood eosinophils
• More exacerbations in previous year
• Adult-onset of asthma
• Nasal polyps
• Ages ≥12 years
• Severe eosinophilic asthma or need for

maintenance OCS

• Exacerbations in last year
• Blood eosinophils ≥150 cells/µL or FeNO ≥25 ppb

Predictors of good response:

• Higher blood eosinophils
• Higher FeNO

May also be used to treat:

• Moderate-to-severe atopic dermatitis
• Nasal polyps (investigational)

Start with anti-IgE therapy if:

• Ages ≥6 years
• Severe allergic asthma
• Sensitization on skin prick testing or specific IgE
• Total serum IgE* and weight within dosage range
• Exacerbations in the last year

Start with anti-IL5 or –IL5R therapy if:

• Ages ≥12 or ≥18 years
• Severe eosinophilic asthma
• Exacerbations in the last year
• Blood eosinophils ≥300 cells/µL

Start with Anti-IL4 if:

• Ages ≥12 years
• Severe eosinophilic asthma or need for

maintenance OCS

• Exacerbations in last year
• Blood eosinophils ≥150 cells/µL or FeNO ≥25 ppb

Theodore “Teddy” Roosevelt: U.S. President from 1901-1909

• 26th president of the United States
• He took office on September 14, 1901 upon the assassination and death of

President William McKinley and won a second term based on his merits.

• Roosevelt had been the Vice President of the United States for only 194 days

when he succeeded to the presidency.

• He was a dedicated conservationist, setting aside some 200 million acres for

national forests, reserves and wildlife refuges during his presidency.

• In the foreign policy arena, Roosevelt won a Nobel Peace Prize for his

negotiations to end the Russo-Japanese War and spearheaded the beginning of construction on the Panama Canal.

Teddy Roosevelt (1858–1919)

• Frequent severe wheezing attacks in childhood

– Weekly – often Sundays

• Stress associated?
• Allergy-associated?

– No apparent seasonal pattern – No apparent allergy to dogs/cats/other animals – Likely smoke exposure

• Frequent colds, fevers, gastroenteritis
• Family history: Sister with asthma

McCullough D. Mornings on Horseback. New York: Simon and Schuster, 2001.

Teddy Roosevelt: Attempted Treatments

• Coffee
• Rhubarb pills
• Mustard plasters
• Ipecac
• Magnesia
• Cigars (!)
• Jimson weed smoke (!)
• “Change of air”
• “Vigorous exercise” advised by AD Rockwell, a neurologist,

when Roosevelt was 12 years old

Cohen SG. Allergy Asthma Proc. 1997;18(6):382-386. Kiell N. Effects of asthma on the character of Theodore Roosevelt. In The Asthmatic Child: Psychosomatic Approach to Problems and Treatment. Schneer HI, (ed). New York: Harper & Row, 84-102, 1963.

Teddy Roosevelt: Adult Experience with Asthma

• Great improvement but periodic attacks

– Stress-associated? – Worsened after the deaths of his wife and mother (FACT: They died on the same day in 1884) – Suspicion of tuberculosis, advised to travel West (1884)

Library of Congress. cph.3b14493. Cohen SG. Allergy Asthma Proc. 1997;18(6):382-386.

Teddy Roosevelt Today*

• Referred by his PCP to your office for

evaluation of “severe allergies” and “asthma recurrence”

• History

– States he had “asthma in childhood” that improved with “exercise and fresh air” – BMI = 27 kg/m2 – Smokes cigars – Prescribed ICS + LABA; states that “the medicines do nothing”

*These details are fictional and intended strictly for educational purposes.

Teddy Roosevelt Today: Work-up*

• Bronchodilator findings
• FeNO: 15 ppb
• Eosinophils = 110 cells/μL
• Total IgE = 21 kU/ml
• Skin testing: negative

Parameter Pre-bronchodilator Absolute (L) and % Predicted Post-bronchodilator Absolute (L) and % Predicted Post-bronchodilator % Change

FVC 4.11 (84%) 4.22 (87%) 2% FEV1 2.89 (79%) 3.26 (88%) 13% FEV1/FVC 0.70 0.77 N/A

*These details are fictional and intended strictly for educational purposes.

Role of Smoke Exposures in Asthma Onset and Progression

Source: Polosa R, Thomson NC. Eur Respir J. 2013; 41: 716–726

Smoking Impairs Response to Oral and Inhaled CS in Asthma1

• Smokers (n = 14), ex-smokers (n = 10),

and never smokers (n = 26) with asthma

• Prednisolone (40 mg/d) or placebo for

2 weeks

• Improvement in FEV1 and ACS in never

smokers; no change in smokers

• Ex-smokers with asthma had improvement

in AM and PM PEF but not FEV1 or ACS

• Similar results with inhaled corticosteroids2
• 1. Chaudhuri R, et al. Am J Respir Crit Care Med. 2003;168:1308-1311.
• 2. Lazarus SC, et al. Am J Respir Crit Care Med. 2007;175(8):783-790.

Closed circles: Placebo Open circles: Prednisolone

Stenius-Aarniala B, et al BMJ. 2000 Mar 25;320(7238):827-32. Hakala K, et al. Chest 2000;118:1315-1321.

Effect of Weight Loss on Asthma

Effects of Bariatric Surgery on Asthma

• Improves ACS and AQL
• Improves AHR, particularly in

non-atopic patients

• Increases lymphocytes in BAL
• Increases cytokine production

(Th1, Th2, Th17) by peripheral CD4 cells

Normal IgE High IgE

N = 23

AHR = airway hyperresponsiveness; AQL = asthma quality of life; BAL = bronchoalveolar lavage. Dixon AE et al. J Allergy Clin Immunol. 2011;128:508-515.

Months from Surgery Months from Surgery PC20 to methacholine (mg/ml) PC20 to methacholine (mg/ml)

Effect of Obesity on Biomarkers and Outcomes of Asthma Before and After Weight Loss in Adults

*Pathway has not been studied or no significant associations have been reported.

Biomarkers

• Leptin []
• Adiponectin []
• Adipose tissue inflammation []
• Serum IL-6  []
• Oxidative stress []
• Exhaled NO [*]

Clinical Findings

• Risk of incident asthma []
• Risk of asthma []
• Exacerbation []
• Asthma severity []
• Asthma control []
• Asthma QOL []
• Treatment response []
• Susceptibility to air pollutants []

Lung Function and Airway Reactivity

• FEV1 []
• Expiratory reserve volume []
• Functional residual capacity []
• Peak expired flow []
• Airway hyperresponsiveness []
• Bronchodilator responsiveness  [*]

Peters U, et al. J Allergy Clin Immunol. 2018;141(4): 1169-1179.

66

Corticosteroid Resistance in Refractory Asthma

Anti-

AP-1 = Activator protein 1; GC = glucocorticoid; GR = glucocorticoid receptor; GRE = glucocorticoid response element; HDAC: histone deacetylase; IKK = IκB kinase; MAPK = mitogen-activated protein kinase; NF-kB = nuclear factor kB; ROS = reactive oxygen species. Adcock IM, et al. Curr Allergy Asthma Rep. 2008;8(2):171-178. Barnes PJ. J Allergy Clin Immunol. 2013;131:636-645.

Sobieraj et al JAMA. 2018;319(14):1473-1484.

Association of ICS and LAMA with Asthma Control in Uncontrolled, Persistent Asthma

• Systematic review and meta-analysis
• LAMA significantly associated with a

significant 47% reduction in risk of exacerbation when added to ICS vs. placebo, with ICS dose held constant

• LAMA was not significantly associated

with the risk of exacerbation compared with

– 2x the dose of ICS – LABA + ICS – Triple therapy with the ICS dose held constant in a population considered highest risk for exacerbations

Excerbations requiring systemic corticosteroid

Gibson PG, et al. Lancet 2017;390(10095):659-668.

AMAZES Study

1.86 1.09

0.2 0.4 0.6 0.8 1 1.2 1.4 1.6 1.8 2 2.2 Category 1

Incidence rate ratio: 0·59 [95% CI 0·47–0·74] P < 0.0001) Placebo Azithromycin

Annual asthma exacerbation rate

Danek CJ, et al. J Appl Physiol. 2004;97:1946-1953.

Bronchial Thermoplasty

• FDA approved for asthma not controlled on

standard therapy

• Most safety data in patients with moderate

lung function impairment (FEV1 > 60%)

• Ongoing controversy about its role
• Reimbursement limitations

Treated Airway (65 C) Untreated Airway

Castro A, et al. Am J Respir Crit Care Med. 2010;181:116-124. Iyer VN, Lim KG. Chest. 2014;146:17-21.

AIR 2 Study

• Primary endpoint: difference in AQLQ scores

from baseline (MID = 0.5) – Difference between BT and sham: 0.19 – 79% of BT vs 63% of sham had > 0.5-point improvement in AQLQ

• No differences observed in lung function,

rescue medicine use, symptom-free days

AQLQ = Asthma Quality of Life Questionnaire; MCID = minimal important difference 4.30 5.66 4.32 5.48 1 2 3 4 5 6 Baseline End of Study

Change from Baseline on AQLQ

BT Sham

AIR2 and PAS-2 Studies: Decreased Exacerbations and Acute Care

Percent Percent

Exacerbations Hospitalizations ED visits

Chupp G, et al. Eur Respir J. 2017; 50:1700017.

Percent

Advances

• Understanding of disease

heterogeneity

• Identification of asthma endotypes
• Move toward precision medicine
• Utility of biomarkers
• Growing number of targeted

therapies

Unmet Needs

• Patients remain uncontrolled
• High healthcare utilization and costs
• Lack of long-term efficacy/safety data
• Comparative value-based

assessments

• Cost/utilization management

programs

Advances and Challenges in Asthma Care

Emerging Targets/Treatments for Severe Asthma

Assaf S, Hanania NA. Curr Opin All Clin Immunology 2019 (in press).

Targeting Alarmins

Macrophage Endothelial cell, Fibroblast Macrophage, Allergies

Arima M, Fukuda T. Korean J Intern Med. 2011;26:8-18.

Tezepelumab: Efficacy in Reducing Asthma Exacerbations

0.67 0.26 0.19 0.22

0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8

Annualized Rate of Asthma Exacerbations over 52 wks

Corren J, et al. N Engl J Med .2017;377:936-946.

P < 0.001 vs placebo for all telezumab doses/dose frequencies

Placebo Tezepelumab 70 mg q 4 wks Tezepelumab 210 mg q 4 wks Tezepelumab 280 mg q 4 wks

Targeting PGD2 (CRTH2 Receptor)

Arima M, Fukuda T. Korean J Intern Med. 2011;26:8-18. PGD2 = prostaglandin D2; DP = D-prostanoid receptor CRTH2 chemoattractant receptor on TH2 cells; MDC = macrophage-derived chemokine

Controlled Asthma?

• Cyclical nature of disease
• Increased disease severity
• Differing asthma phenotypes

Disease-Related Factors

• Medication under-prescribing
• Failure to assess adherence
• Failure to assess inhaler technique
• Misdiagnosis
• Lack of asthma action plan
• Absence of specialty care

Physician-Related Factors

• Passive smoking
• Frequent exposure to

traffic or air pollution

• Outdoor and indoor

allergens

Environmental Factors

• Comorbidities (eg, GERD

rhinosinusitis, depression)

• Smoking
• Obesity
• Age
• Psychosocial issues (eg, lower

income, poor health literacy)

• Poor treatment adherence
• Inadequate inhaler technique
• Heterogeneity of treatment

response

• Failure to follow self-

management plan

• Side effects of other medications

(eg, NSAIDs)

Patient-Related Factors

• Reduce exposure to

allergic triggers

• Assess phenotypes
• Match treatment to asthma

phenotype

• Manage comorbid conditions

– Depression – GERD – Rhinitis – Sinusitis

• Encourage weight loss
• Emphasize treatment adherence
• Educate about correct inhaler

technique

• Smoking cessation
• Assess and address adherence and

inhaler technique

• Refer for specialty care
• Develop an asthma action plan

Key Takeaways: Managing Uncontrolled Asthma

Adapted from Wechsler ME. Am J Med. 2014;127(11):1049-1059.

Key Takeaways: Severe Asthma

• Asthma has long been understood to be a heterogenous disease.
• Asthma can be generally be categorized as T2 or non-T2 and

further characterized as specific phenotypes and endotypes based

• n laboratory findings and known disease pathways.
• About 5–10% of patients with asthma have severe disease; for

many of these patients, asthma is poorly controlled.

• Understanding of disease pathways has led to development of

effective, targeted treatments for patients with severe, uncontrolled, T2 asthma.

• Treatment for severe non-T2 asthma remains an area of unmet

need.