Thomas B' Casale, MD

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Thomas B. Casale, MD
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Optimizing The Treatment Of Allergic Asthma

• Thomas B. Casale, MD
• Professor of Medicine
• Chief, Allergy/Immunology
• Creighton University
• Omaha, NE

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Todays QuestionHow do we optimize the
treatment of allergic asthma?

• Use Effective Treatments!

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What Is An Effective Asthma Treatment?

• Effective asthma treatment
• Does not necessarily mean complete control
• Should have a positive effect on 1 or more of the
  following
• Symptoms
• Airway obstruction
• Inflammation
• Airway hyperresponsiveness
• May not be beneficial for BOTH clinical and
  disease parameters

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Asthma Is Not A Static DiseaseClinical Control
Good control
Poor control
Wheezing
Dyspnea
Cough
Use of rescue medication
FEV1
PEF variability
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Asthma Is Not A Static DiseaseDisease Control
Good control
Poor control
Eosinophils
Neutrophils
FeNO
AHR (methacholine)
AHR (indirect)
FEV1, post-BD
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What Are The Potential Approaches For Optimizing
Asthma Treatment?

• Adherence
• Environmental control
• Education on medications and the disease
• Matching the correct drug to the patient
• LT modifiers
• Inhaled corticosteroids
• Anti- IgE

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Case study

• A 45 y/o patient was diagnosed by you with
  moderate persistent asthma. The patient contacts
  you complaining of significant asthma symptoms.
  What is the likelihood that the patient has
  continued to take the controller medications you
  prescribed last year?
• A. 75
• B. 50
• C. 33
• D. 20

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What Of Patients Refill Controller Medications?
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Case Study of cat

• A 30 y/o male walks into a cat house and
  begins to wheeze. Which of the following could
  be useful in acutely preventing these episodes?
• A. Remove the cat just before coming
• B. Use an antihistamine 30 minutes prior
• C. Avoid places where cats reside
• D. Stick to only dating your wife

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Effective Allergen Control Improves Symptoms
Cat Remediation Machine
Allergen Control
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Which of the following patients are using their
inhaler properly?
A B
C
D
Actual photo taken from Dr Naclerios Clinic
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The Complexity of Using Asthma Inhalers
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Matching the correct drug to the patient

• LT modifiers
• Inhaled corticosteroids
• Anti- IgE

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Leukotrienes Are Important Targets

• Synthesized by many lung and inflammatory cells
• Released after spontaneous and induced asthma
  episodes
• Biologic actions mimic important pathophysiologic
  events in asthma
• Especially important in ASA-sensitive asthma
• Antagonists are effective therapeutically

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Rationale for Leukotriene Modifiers in Asthma
Therapy

• Scientific Rationale Sound
• Biological Effects, CytLTs in Asthma
• Advantages of Systemic Therapy
• Demonstrated Anti-Inflammatory Effects
• Decrease blood AW eos, eNO
• Different From/Complementary to ICS
• Demonstrated Clinical Effects
• Monotherapy Mild Asthma
• Combination Tx
• AW obstruction, Symptoms, Exacerbations

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Problem of Asthma Non-Responders
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Which of the following factors might favor the
response rate of patients on LTRA vs. ICS?

• Genetics
• Obesity
• Cigarette Smoking
• All of the above

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Influence Of Genotype On Montelukast Responses
At 6 Months Comparison By Genotypes
n61
Lima et al, AJRCCM Nov 2005
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Effects Of Genotype And Frequencies On Asthma
Exacerbations In Whites Taking Montelukast For 6
Months
Lima et al, AJRCCM Nov 2005
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Are there other considerations for variable
responses to LTRAs or other controllers?
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Obesity and Asthma

• People with a diagnosis of asthma are more likely
  to be obese than people without asthma
• Ford ES. The epidemiology of obesity and asthma.
  J Allergy Clin Immunol. 2005115897-909
• Pulmonary Perspective
• Am J Respir Crit Care Med Vol 174. pp 112119,
  2006
• David A. Beuther, Scott T. Weiss, and E. Rand
  Sutherland
• National Jewish Medical and Research Center and
  Harvard Medical School

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Effects Of Obesity On Lung Physiology
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Visceral Adiposity Is Associated With Local And
Systemic Inflammation
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Asthma Control Days By BMIComparison Of
Montelukast Vs. Budesonide
Bud
Mont
Pl
Peters-Golden, ERJ, 2006
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• LT modifiers are effective therapies for asthma
• Need to treat the right patients

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CS Receptor ICS

• ICS are the most effective therapies for chronic
  persistent asthma
• Many anti-inflammatory effects
• Improve multiple clinical outcomes

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Analysis of Inhaled Corticosteroid Partial- and
Non-Responders
Patients ()
FEV1 Change from Baseline
1Malmstrom K, et al. Arch Intern Med.
1999130487-95. 2Tantisira KG, et al. Hum Mol
Genet 20041313539.
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Dose Response for FP-MDI FEV1
Szefler SJ, et al. J Allergy Clin Immunol 2002
109 410-8
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Predictors For Favorable Response To Inhaled
Steroids

• Increased serum IgE and eosinophil counts

2. Reactive to lower levels of methacholine PC20
3. High levels of exhaled nitric oxide
4. Increased serum eosinophil cationic protein
Szefler, et al
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What Are Some Of The Reasons For Variable
Responses To ICS?

• Obesity
• Cigarette smoke
• GR variants
• GRb
• Genetic polymorphisms

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Cigarette Smoking and Asthma Variability Reduced
Response to Oral Corticosteroids
Chaudhuri R et al. Am J Respir Crit Care Med.
200316813081311.
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Human GR?, A Potential Endogenous Inhibitor Of
Glucocorticoid Action
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GCR-Beta Expression in BAL
Steroid Resistant Asthmatic
Am J Resp Crit Care Med 19991591600-4
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Increased Expression of GCR? in BAL Macrophages
of GC Insensitive Asthmatics
Goleva E et al. Am J Respir Crit Care Med.
2006173607616
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Response To ICS May Be Genetically Determined
Effects Of CRHR1 Genotype
CAMP study
Adult study
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21.8
20
15
13.7
Change in FEV1 with 8 Wks ICS Therapy ()
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7.4
5.5
5
0
Non-GAT Haplotype
GAT/GAT Homozygous Haplotype
Plt0.02 vs non-GAT. Plt0.01 vs non-GAT.
Tantisira KG, et al. Hum Mol Genet.
20041313531359.
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TBX21 A Functional Variant Predicts Improvement
In Asthma With Use Of ICS
Tantisira, et al PNAS Dec 28, 2004, Vol.
1011809918104
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Patient Responsiveness to ICS and LTRA Is Highly
Variable
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22 Patients respond to montelukast
Montelukast alone (5)
Both meds (17)
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20
10
0
40 Patients respond to fluticasone
FEV1 change with montelukast
10
20
Fluticasone alone (23)
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Line of identity
Neither medication (55)
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50
10
50
40
30
20
0
10
20
30
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FEV1 change with fluticasone

Szefler SJ,
et al. J Allergy Clin Immunol. 2005115233-242.
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ICS

• As with LT modifiers, ICS are effective ..
• for the right patients

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IgE and Respiratory Disease

• Epidemiologic and empirical evidence confirms a
  clear relationship between IgE and both
  pathogenesis and symptoms of respiratory
  disease1,2
• Increased serum IgE associated with
• Asthma prevalence
• Persistent wheezing in children
• Airway hyper-responsiveness (observed in vitro)3
• Strategies aimed at inhibiting IgE are important
  for treatment of asthma

1Burrows B, et al. N Engl J Med
1989320271-7. 2Oettgen HC, Geha, RS. J Allergy
Clin Immunol 2000107429-41. 3Schmidt D, et al.
Clin Exp Allergy 200030233-41.
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Strategies To Modulate IgE

• Regulate IgE synthesis
• 1. Transcription factors
• A. Block GATA-3 (essential in Th2)
• B. Promote T-Bet (essential in Th1)
• 2. Inhibition of essential IgE-promoting
  cytokines
• A. Anti-IL-4/IL13 strategies
• B. IL-12/IFN?
• C. IL-10
• 3. Reduce IgE production by B cells
• Anti-CD23 (low-affinity IgE receptor)
• Remove IgE omalizumab

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Targeting IgE Omalizumab

• Reduces serum IgE levels and IgE receptor
  expression on key inflammatory cells involved in
  asthma
• Decreases airway inflammation
• Improves clinical outcomes

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Effects Of Omalizumab On Airway Inflammation In
Mild Atopic Asthmatics

• 5-center, double blind , placebo-controlled,
  parallel-group, 16-week study (n44)
• Reduction in submucosal eos 8.0 to 1.5
• 10-fold reduction in IgEcells
• - Decreases in FCeRI cells
• Decreases in B cells, and CD3, CD4, and
  CD8 cells

Djukanovic R, et al. Am J Respir Crit Care Med
2004170-583-93.
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Clinical Effects Of Omalizumab

• In patients on ICS alone, or in combination with
  other agents. (addition of omalizumab1,2)
• Reduced number of exacerbations
• Reduced symptom scores
• Reduced need for inhaled corticosteroids
• Reduced use of rescue medication
• Improved asthma-related quality of life

1Busse W et al. J Allergy CLin Immunol
2001108184-90. 2Soler M et al. Eur Respir J
200118254-61. 3Humbert M, et al. Allergy
200560309-16.
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Factors Predictive of Response to Omalizumab
Bousquet J, et al. Chest. 20041251378-1386.
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Effective Asthma Treatments
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Is Targeting A Single Molecule An Effective
Asthma Treatment Strategy?

• A) Yes
• B) No
• C) Depends
• D) All of the above
• - As long as you match the correct target
  molecule to the correct patient
  Genetics/environment/etc.
• LT modifiers
• ICS
• IgE

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Cant Win The Battle When You Dont Have The
Right Tools For Victory
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What Would THE Dream Molecule Look Like That
Would Optimize Asthma Treatment?

• Inhibits AW Inflammation
• Decreases AW Hyperresponsiveness
• Inhibits Ag Spread
• Inhibits the development of AW remodeling
• Reverses AW remodeling
• Easy to use and Cheap!

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Optimizing Asthma Care Requires An Individualized
Approach With The Correct Treatment Matched To
The Patient
Ahh, A Single Effective Treatment!!