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New Insights in the Treatment of Severe Asthma: Focus Upon Phenotypes Monica Kraft, M.D. Professor of Medicine Director, Duke Asthma, Allergy and Airway Center Division of Pulmonary, Allergy and Critical Care Medicine Duke University Medical Center Durham, North Carolina USA


Disclosures Speakers bureau: n/a Advisory Board/consultant: n/a Other income: Royalties: Elsevier Research (funds provided to institution): National Institutes of Health, Genentech GSK, Novartis, Merck, Boston Scientific


Severe Asthma

• Definition • Phenotypes - Pathologic/Clinical

Therapeutic Options/Personalized Medicine


Emphasizing Control Rather Than Severity Asthma control Good

Poor

Mild

Asthma severity

good control

Severe

We have little influence !

Control reflects the adequacy of treatment

In which we play a significant role !

Severity is a property of the disease

poor control


Approach to Management/Contributing Factors/Co-Morbid Conditions •Examine for concomitant medical disorders, i.e. sinusitis, OSA, VCD •GERD - acid and non-acid reflux •Environmental control •Alternative diagnoses •Review medication technique •Adherence


We have now moved to defining phenotypes of this heterogeneous disease Clinical: Fixed obstruction Obese Adult onset Exacerbation prone Treatment resistant Triggers Occupational Aspirin Exercise Menses

Pathologic: Eosinophilic Non-eosinophilic Pauci-granulocytic


Severe Asthma Clusters

Moore et al. AJRCCM 2010;181:315323


Asthma Clusters • Cluster 1: early onset, atopic, nl lung fxn < 2 controllers, minimal healthcare utilization • Cluster 2: early onset, atopic, > 2 controllers, nl lung fxn, significant health care utilization • Cluster 3: adult onset, obese woman with low lung fxn, high medication requirement and healthcare utilization • Cluster 4: early onset, atopic, severe obstruction with some reversibility (FEV1: 57% to 76% pred), high healthcare utilization • Cluster 5: early onset, severe obstruction, 66% atopic; less reversibility ( FEV1: 43% to 58%), high health care utilization Moore et al. AJRCCM 2010;181:315-323


Association of an IL-6 polymorphism with severe asthma and reduced lung function (clusters 4 and 5)

Hawkins et al. JACI 2012; in press.


Pathological Phenotypes: Can they determine therapeutic choices? •Eosinophilic/TH2 (IL-4, IL-5 and IL-13) •Non-eosinophilic •Pauci-granulocytic •Relevance of location of inflammation/remodeling


Variability in IL-13 Responsive Genes

Woodruff, et al. AJRCCM 2009; 180:388-395


Clinical Features of Asthmatics with “High” and “Low” IL-13 Gene Signatures

Woodruff, et al. AJRCCM 2009; 180:388-395


Interleukin-13 and Non窶的nterleukin-13 Inflammatory Pathways in Asthma.

Kraft M. N Engl J Med 2011.


Biomarkers that identify the Th2 phenotype • • • •

Sputum eosinophils Exhaled nitric oxide Circulating eosinophils periostin


What Are Treatment Options for the Eosinophilic Phenotype?


Omalizumab Significantly Reduces Submucosal Eosinophils Eosinophils (cells/mm2) 80

P=0.033

80

P=0.81

60

60

40

40 P<0.001

20

20 8.0

6.3

6.4

1.5

0

0 Baseline Posttreatment Omalizumab (n=14)

Djukanovic et al. AJRCCM 2004

Baseline

Posttreatment

Placebo (n=14)


Inhibition of IL-13 and Lung Function

Corren et al. NEJM 2011; in press


Mepolizumab for Severe Eosinophilic Asthma

Nair et al. NEJM 2009;360:985


Other therapies (some under development) for eosinophilic asthma

Anti-CRTH2 Anti-IL-9 Anti-TSLP Zileuton â&#x20AC;&#x201C; aspirin sensitive asthma; 25% of severe asthma and eosinophilic


Non-eosinophilic asthma


Neutrophils in Asthma

• Associated with more severe limitation (Woodruff et al. JACI 2001;108:753 Shaw et al. Chest 2007;132:1871)

• Not associated with greater AHR as •

compared to eosinophils predominant inflammation (Woodruff) Observed in fatal asthma, but primary in small airways (Simoes et al. Clin Exp Allergy 2005;35:602)

• Increased during exacerbations (Lamblin et al. AJRCCM 1998;157:394; Fahy et al. JACI 1995;95:843)


Sputum Differential and Clinical Characteristics â&#x20AC;&#x201C; SARP experience

Hastie et al. for SARP. J All Clin Immunol 2010;125:1028


Sputum Differential and Clinical Characteristics

Hastie et al. for SARP. J All Clin Immunol 2010;125:1028


How do the neutrophils get there? IL-17 Ligand

Receptor

Function

IL-17A

IL-17RA

IL-6, 8 Gro-a, GCSF, GMCSF

IL-17F

IL-17RA/C

MUC5A, MUC5B Airway hyperresponsiveness Airway neutrophilia

IL-17E

IL-17RB

IL-4, 5, 13, IgE, eotaxin Mucus secretion AHR, eos, severity


Question: Is neutrophilic asthma a stable phenotype?


Sputum neutrophils and ICS – Cowen et al.

• Subjects with mild to moderate asthma

• •

underwent steroid withdrawal over 28 days; induced sputum with differential performed Fluticasone introduced and repeat sputum performed Exclusions: respiratory infection within 4 weeks, OCS within 3 months


Sputum differential after fluticasone withdrawal

Cowan et al. Thorax 2010;65:384


Sputum differentials before and after fluticasone

Cowan et al. Thorax 2010;65:384


What other mediators are prominent in non-eosinophilic asthma?


BAL TNF-Îą Levels are Increased in the lungs of obese asthmatics

Lugogo et al. JACI 2012; in revision

**p<0.001, *p<0.01, #p<0.05


What are the treatment options for the non-eosinophilic phenotype?


Treatment options for the noneosinophilic phenotype – available now and under developement • • • • •

Anti-TNF zileuton macrolides Anti-IL-17 Anti-IL-22


Pauci-Granulocytic •No definitive cell type noted in examination of endobronchial biopsies •May be treated with oral corticosteroids. •Inflammation may be located distally, but not proven.


Therapies for the pauci-granulocytic phenotype • Small particle size ICS • Bronchial thermoplasty • tiotropium


Airway & Alveolar Tissue Eosinophils 4 am

4 pm

Nv eos 30 x103/mm3

† * (17.7,75.0)

40

40 NNA NA

30

20

20

*

(3.0,26.5)

† 10 (1.9,18.6) (29.1,18.2) (2.7,16.8) 10 0

(0.0,13.3)

Airway Alveolar Tissue

(0.0,0.0)(0.0,1.8)

0

Airway Alveolar Tissue Kraft AJRCCM; 1996


Deposition of BDP in healthy volunteers HFA BDP 40 µg

CFC-BDP 42 µg

Oral 31% 94% Lung 51%

18%

4%

Exhaled

1%

Leach CL et al. Eur Respir J 1998; 12(6): 1346-53


Eosinophils/mm2

Central and Peripheral Airway Eosinophils Before and After Flunisolide HFA 70 60 50 40 30 20 10 0

*

* before

after

before

peripheral airways

after

central airways

Eosinophils (MBP+) before and after HFA-flunisolide in peripheral and central airways. Mean±SEM. *† p < .001 vs pre treatment.

Hauber P et al. JACI 2003


Airway Smooth Muscle

Airway Smooth Muscle

Normal Airway Asthmatic Airway


Bronchial Thermoplasty 80

79

64 57

60 50 40 29

30

18

20 10

Sham

76

0.8

70

Percent of Subjects

1.0

AIR2 Trial Net Benefit = 19% PPS (Alair - Sham) = 100.0%

Events/ Subject/ Year

90

32% 0.7

0.6

* 0.48

23%

0.4 0.36

0.28

**

0.2

² - 0.5

0.07

0.0

0 > -0.5 to <0.5

Sham

³ 0.5

Alair

Net Benefit

0.43

84%

7 3

Alair

Severe Exacerbations

Unsched. Office Visits

ER Visits

0.14 73% 0.13 0.04

0.04 Hospitalizations

*PPS = 95.6%, ** PPS= 95.6%

Castro M et al. Am J Respir Crit Care Med. 2010;181(2):116-24


Tiotropium as Add-On Therapy for Asthma Uncontrolled with ICS

Peters SP and the Asthma Clinical Research Network NEJM 2010;363:1715


Conclusions

• Severe asthma is a spectrum of disease, with different pathologic and clinical phenotypes.

• Defining phenotypes is in its infancy. • Tailoring treatment to phenotypes is the ultimate goal.

• Importance of contributing factors and adherence cannot be overestimated.


955_MonicaKRAFT_SevereasthmaALAT2012Kraft