1220 friday difficult to treat asthma (bakakos) · § salmeterol/fluticasone 50/500 1 x 2,...

ATHENS 2019GREECE | 27-29 JUNE

DIFFICULT TO TREAT ASTHMA

PETROS BAKAKOS


ASSOC. PROFESSOR IN RESPIRATORY MEDICINENATIONAL AND KAPODISTRIAN UNIVERSITY OF ATHENS

§Conflict of interest

§ Advisory board at Astra-Zeneca, Chiesi, GSK, Elpen, Novartis, Menarini, Pfizer

§ Honorarium for being an invited speaker in Astra-Zeneca, Chiesi, GSK,Elpen, Novartis, Menarini, Pfizer


CASE § 54 y.o male, smoker-40py, ΒΜΙ=37

§ Visits the outpatient clinic for the first time – Asthma diagnosis for more than 10 years

§ Arterial hypertension

§ Salmeterol/fluticasone 50/500 1 x 2, Montelukast 10mg 1 x 1, Aerolin p.r.n almost daily

§ 3 exacerbations in the pervious year requiring OCS

§ ACT: 17

§ FVC 80%, FEV1 59%, FEV1/FVC 60% - reversibility 12% - 180ml


QUESTION: DOES THIS PATIENT HAS SEVERE ASTHMA?

§ YES

§ NO

§ DO NOT KNOW


ABOUT TERMINOLOGY - SEVERITY§ How?

§ Asthma severity is assessed retrospectively from the level of treatment required to control

symptoms and exacerbations

§ When?

§ Assess asthma severity after patient has been on controller treatment for several months

§ Categories of asthma severity

§ Mild asthma: well-controlled with Steps 1 or 2 (as-needed SABA or low dose ICS)

§ Moderate asthma: well-controlled with Step 3 (low-dose ICS/LABA)

§ Severe asthma: requires Step 4/5 (moderate or high dose ICS/LABA ± add-on), or remains

uncontrolled despite this treatment


UNCONTROLLED ASTHMA

Asthma control - two domains§ Assess symptom control over the last 4 weeks

§ Assess risk factors for poor outcomes

Uncontrolled asthma§ Poor symptom control (frequent symptoms or reliever use, limitation of activities,

night waking)

§ Frequent exacerbations (≥2/year) requiring OCS or serious exacerbations (≥1/year) requiring hospitalization)


DIFFICULT-TO-TREAT ASTHMA

§ Uncontrolled despite GINA step 4 or 5 treatment (e.g medium or high dose

ICS with a second controller; maintenance OCS) or that requires such

treatment to maintain good symptom control and reduce the risk of

exacerbations.

§ In many cases asthma seems difficult-to-treat due to modifiable factors

such as incorrect inhaler technique, poor adherence, smoking or

comorbidities or because the diagnosis is incorrect


SEVERE ASTHMA§ A subset of difficult-to-treat asthma


CONFIRM ASTHMA DIAGNOSIS§ It is recommended that patients presenting with “difficult asthma” have their asthma diagnosis confirmed and

be evaluated and managed by an asthma specialist for more than 3 months.

§ 1034 asthma patients were screened, of whom 175 (16.9%) had difficult-to-control asthma. 117 of these accepted

inclusion, and completed systematic assessment. Asthma diagnosis was objectively confirmed in 88%.

von Bülow A et al, Respir Med 2018


CONFIRM ASTHMA DIAGNOSIS§ Systematic evaluation of difficult asthma is useful as it can identify alternative or additional

diagnoses, psychiatric illness or nonconcordance with therapy in a substantial proportion of cases

Robinson D et al, Eur Respir J 2003


DETERMINING THAT THE PATIENT HAS ASTHMA

OR WHAT ELSE ?

Chung KF et al, Eur Respir J 2014


ADHERENCE AND INHALER TECHNIQUE§ Non-adherence to treatment should be considered in all difficult-to-control patients,

as reports show that non-adherence can be as high as 32–56%. Poor inhaler technique is also common and should be addressed.



ASSESSING COMORBIDITIES AND CONTRIBUTORY FACTORS§ Difficult-to-control and severe asthma are often associated with coexisting conditions



ASSESSING COMORBIDITIES AND CONTRIBUTORY FACTORS

Diagnosis and Management of Difficult-to-treat and Severe Asthma in adolescent and adult patients GINA 2019


§ Systematically assessing patients with potentially severe asthma for co-morbidities is important in order to achieve treatment results


Porsbjerg C & Menzies Gow A, Respirology 2017


§ The majority of patients had unmanaged comorbidities.


von Bülow A et al, Respir Med. 2018


§ Patients with difficult asthma and CRS report more symptoms, particularly of sputum and cough and have an

increased risk of asthma exacerbation. CRS with nasal polyps (CRSwNP) in particular is a feature of severe

asthma typically associated with late-onset eosinophilic asthma. Diagnosis requires CT of sinuses and

endoscopy (ENT assessment).


Porsbjerg C & Menzies Gow A, Respirology 2017


ASTHMA DEFINITION

Asthma is a heterogeneous disease, usually characterized by chronic airway inflammation.

It is defined by the history of respiratory symptoms such as wheeze, shortness of breath, chest tightness and cough that vary over time and in intensity, together with variable expiratory airflow limitation.


HOW HETEROGENEOUS?

ONE SIZE FITS ALL

§ Most patients with mild-to-moderate asthma respond satisfactorily to usual treatment

§ Accordingly, mild asthma is a homogeneous disease with no need for special treatments


SEVERE ASTHMA

Agustí A et al. Eur Respir J 2017


QUESTION: IS EVERY PATIENT WITH SEVERE ASTHMA A CANDIDATE FOR BIOLOGIC TREATMENT?

§ YES

§ NO


SEVERE ASTHMA PHENOTYPES

THAT S WHERE TARGETED TREATMENT STARTS


ASSESS PHENOTYPE



ELIGIBLE FOR BIOLOGIC TREATMENT



DEFINE PREDOMINANT PHENOTYPE

A. Allergic predominant asthma B. Eosinophilic predominant asthma

1. Early onset 1. Late onset

2. SPT/RAST (+) with clinically significant allergies*

2. SPT/RAST (-) or (+) with no clinically significant allergies

3. IgE > 100 IU/ml 3. IgE < 100 IU/ml

4. Allergic rhinitis 4. Nasal Polyps

5. High FeNO (30-50 ppb) 5. Very high FeNO > 50 ppb

6. Blood eosinophils < 300 cells/µl 6. Blood eosinophils > 300 cells/µl *

Using the approach in everyday clinical practice,the vast majority of patients can be allocated ineither allergic or eosinophilic predominant T2-high asthma.

• In allergic predominant severe asthma,omalizumab is the treatment of choice, while

• in eosinophilic predominant asthma anti-IL-5treatment (mepolizumab - benralizumab s.c.and reslizumab i.v. are the 3 currentlyapproved representatives in this category) isthe reasonable therapeutic approach

Zervas E. et al, ERJ Open Res. 2018

Mechanism of Action: IL-5 Cytokine Targeted versus Eosinophil Targeted

MepolizumabReslizumab MOA1-

4

indirect

Benralizumab MOA5-7

Enhanced Antibody-Dependent Cell-mediated Cytotoxicity (ADCC)

NK Cell

ADCC

IL-5Ra

NK CellFcγRIIIa

Afucosylated Fc region

Anti-IL-5Ra

ACTIVEEosinophil Apoptosis

IL-5

PASSIVEEosinophil Apoptosis

Anti-IL-5


ZONDA: Benralizumab reduced significantly the dose of OCS at week 28 and the rate of exacerbations

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


PREDICTORS OF RESPONSE(Pooled SIROCCO and CALIMA; ≥300 EOS)

Bleecker ER, Wechsler ME, Mark FitzGerald J, et al. Eur Respir J 2018; Oct 18;52(4)


NEW MONOCLONAL ANTIBODIES

Corren J et al. N Engl J Med 2017

Αnti-TSLP Αnti-IL-4


CONCLUSIONS§ Confirm diagnosis – assess comorbidities and modifiable factors

§ Severe asthma: endotypes – clinical phenotypes – treatable traits

§ Biologic therapies are for a subgroup of asthmatics with difficult-to-treat asthma

§ The choice of the proper biologic is of utmost importance for the benefit of the patient and for public health

§ With many more biologics to come, it would become more important to phenotype properly in order to make the

best choice

§ It is also extremely and equally important to understand the underlying mechanisms


THANK YOU

1220 friday difficult to treat asthma (bakakos) · § salmeterol/fluticasone 50/500 1 x 2,...

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