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A unique solution for severe asthma. Dr Talker Olga Pulmonary department. C ase Presentation, 10.2009: . 48 year old lady, teacher at school Married +7 s/p op. d/t scoliosis at age 17 No smoking history Family history of severe asthma Allergy to dust mites

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A unique solution for severe asthma dr talker olga pulmonary department

A unique solution for severe asthma.Dr Talker OlgaPulmonary department


C ase presentation 10 2009
Case Presentation, 10.2009:

48 year old lady, teacher at school

Married +7

s/p op. d/t scoliosis at age 17

No smoking history

Family history of severe asthma

Allergy to dust mites

Severe asthma with recurrent exacerbations, recurrent prolonged courses of oral steroids, prednisone 30-40 mg.


A case 10 2009
A case, 10.2009:

BMI- 23

Normal CXR, normal ECHO, p-ANCA, c-ANCA- normal

High eosinophil count-1100

Stool examination- no parasites

PFT- obstructive pattern with FEV1- 60%

Treatment- Prednisone, Seretide 500, Foradil, Flixonase, Omepradex.



Severe asthma definition
Severe asthma, definition:

Severe asthma- disease that requires high dose inhaled or near continuous oral glucocorticoid treatment to maintain asthma control.


To be excluded
To be excluded:

Ongoing exposure to triggers

Nonadherence

Alternative disorder that mimics asthma

Comorbidities


To be excluded1
To be excluded:

Ongoing exposure to triggers:

allergens, irritants at patient’s home, school, work-laboratory animals, latex, glutaraldehide, toluene diisocyanate, flour, NSAID’s, beta-blockers.

Adherence


To be excluded2
To be excluded:

Conditions that mimic asthma:

Vocal cord dysfunction( combination of inspiratory flow volume loop and laryngoscopy during symptoms), vocal cord paralysis, vocal cord lesions.

Central airway obstruction- tracheal strictures, tracheal copmpression by goiter, thracheal and proximal bronchial tumors, vascular rings( CT, bronchoscopy)

COPD- greater than 20 p.y. smoking history, family history of emphysema or alpha-1 antitrypsin deficiency, irreversible airflow obstruction and low diffusing capacity.


To be excluded3
To be excluded:

Bronchiectasis- copious productive cough, refractory to bronchodilator therapy, HRCT.

ABPA may develop patients with asthma d/t colonization of the airways with aspergillus and typically present with recurrent mucoid impaction and atelectasis, proximal bronchiectasis, skin test positive to aspergillus, elevated IgE (>1000 ng/ml).

Hypersensitivity pneumonitis- exposure to allergens- birds, barns, humidifiers, PFT- mixed obstructive and restrictive pattern, reduced DLCO, fleeting infiltrates.


To be excluded4
To be excluded:

Eosinophilia and respiratory sypmtoms: filariasis, trichinellosis, strongiloides infection- patients from endemic area, blood eosinophilia, elevated IgE, specific IgG to parasites, improvement with specific treatment.

Paranasal sinus disease, skin lesions, peripheral neuropathy, eosynophilia > 10% is common in Churg-Strauss s-me, p-ANCA positive.

Chronic eosinophilic pneumonia- fever, weight loss, night sweats, pulmonary infiltrates.

Endobronchialsarcoidosis- hylaradenopathy and interstitial opacities.

Cardiac disease- echocardiography.


To be excluded5
To be excluded:

Comorbidities:

Chronic rhinosinusitis, allergic rhinitis

GERD

Ongoing smoking

Obesity

OSA

Anxiety , depression.


A case 01 2010
A case, 01.2010:

IgE- 80 u/ml

Started Xolair- monoclonal anti-IgE antibody, 225 mg every two weeks

Prednisone tapering down


A case 11 2010
A case, 11.2010:

Receiving Xolair 225 mg every two weeks

Stopped Seretide

No prednisone

PFT- FEV1- 75%


The ige mediated inflammatory response type i hypersensitivity reaction
The IgE-mediated inflammatory response:type I hypersensitivity reaction

IgE

FceRI

B-cell

Allergen

Mast cell

Histamine

Leukotrienes

Prostaglandins

Cytokines

Atopic

disease

IL-4

IL-13

Th2-cell

IL-5

Antigen-presenting

cell

Eosinophil

Holgate ST. QJM 1998


Xolair omalizumab prevents ige interacting with fc e ri on all cell types
Xolair® (omalizumab)prevents IgE interacting with FceRI on all cell types

IgE

Eosinophil

Macrophage/monocyte

Mast cell

Basophil

Dendritic cell


Omalizumab ige complexes
Omalizumab:IgE Complexes

  • Omalizumab:IgE complexes are either trimers or hexamers, based on Xolair IgE ratio

  • The complexes are of limited size and are eliminated via the reticuloendothelial system

  • No specific organ accumulation, no bigger complexes

Omalizumab (~150 kD)

IgE (~190 kD)

Hexamer

(~1000 kD)

Trimers

(~490 kD- 530 kD)


Reduction in serum free ige following s c administration of xolair
Reduction in serum free IgE following s.c. administration of Xolair®

Median free IgE (ng/mL)

300

  • 300mg administered once monthly for 48 weeks topatients with moderate-to-severe asthma

200

Day 1 post-dose

100

0

0

1

3

7

14

112

168

252

336

Days (not to scale)

Day 0 = screening (n=93)

Source: Extension Study Report 8C


Innovate in vestigatio n of o malizumab in se v ere a sthma t r e atment
INNOVATEINvestigatioN of Omalizumab in seVereAsthma TrEatment

Humbert M, et al. Allergy 2005

  • Patients (aged 12–75 years) with allergic asthma

    • FEV1 40–<80% at randomization

    • Asthma symptoms in the 4 weeks prior to randomization despite high-dose ICS and LABA

    • Clinically meaningful exacerbations in the previous year:

      • Either 2 exacerbations requiring systemic steroids

      • Or a severe exacerbation (PEF or FEV1 <60% personal best) requiring systemic steroids and ER treatment

      • Or hospitalization


Innovate results

Omalizumab

Placebo

* P = 0.04, ** P = 0.002, *** P = 0.038

INNOVATE Results

26 %

50 %

44.2 %


Qol significantly improved overall and across all domains compared with placebo
QoL significantly improved overall and across all domains compared with placebo

Omalizumab

AQLQ score†

Placebo

0.95

**

0.91

***

0.90

***

0.91

***

1.0

0.8

0.6

0.4

0.2

0

0.89

***

Activities Emotions Symptoms Environment Overall

**p<0.01; ***p<0.001

†Change from baseline (least squares mean)

AQLQ = Asthma Quality of Life Questionnaire


Omalizumab was well tolerated
Omalizumab was well tolerated compared with placebo

  • The percentage of patients who experienced adverse events (AEs) was similar in both treatment groups

    • omalizumab, 72.2%; placebo, 75.5%

  • Fewer serious AEs in the omalizumab group

    • omalizumab, 11.8%; placebo, 15.6%

  • AEs were generally mild or moderate in nature and of short duration

Humbert M, et al. Allergy 2005


Gina 2007 guidelines anti ige therapy at step 5
GINA 2007 guidelines* compared with placeboanti-IgE therapy at step 5

*For children older than 5 years, adolescents and adults†Receptor antagonist or synthesis inhibitor

ICS = inhaled corticosteroid; LABA = long-acting β2-agonist

GINA Workshop Report 2007


Summary of dosing strategy for xolair
Summary of dosing strategy for Xolair compared with placebo®

  • Free IgE target ~25ng/mL(10.4 IU/mL)

  • At least 0.016 mg / kg / IU IgE / month

  • Target Xolair®:IgE ratio greater than 15:1

  • Dose to be adjusted for individual’s baseline IgE and body weight

  • Dosing strategy accommodates a wide range of baseline IgE and body weights


Updated dosing table
Updated Dosing Table compared with placebo


Pulmonary outpatients clinic
Pulmonary outpatients clinic compared with placebo


Omalizumab in severe allergic asthma real life experience meir medical center
Omalizumab compared with placebo in Severe Allergic Asthma: Real Life Experience Meir Medical Center

  • 54 patients

  • 47 patients fulfilled the selection criteria (at least 3 months of treatment)

  • Age: 61± 12 years (26-85)

  • Mean Ig E total levels: 281 ± 236 IU/ml


Omalizumab in severe allergic asthma real life experience meir medical center1
Omalizumab compared with placebo in Severe Allergic Asthma: Real Life ExperienceMeir medical center

  • Duration of disease: 25 ±17 years (2-60)

  • Mean monthly Xolair dosage:

    401± 241mg(150-1200).

  • Mean time on Xolair: 28± 18 months



Baseline treatment
Baseline treatment compared with placebo


Asthma exacerbation rate one year
Asthma exacerbation rate compared with placebo(one year)

P=0.007


Lung functions
Lung functions compared with placebo

P=0.002

58.1±13.9


Steroids dosages
Steroids dosages compared with placebo

P=0.027


Steroids reduction
Steroids compared with placeboreduction

  • 4 (8.5%) stopped steroids.

  • 10 (21%) reduced the dosage.


Hospitalizations during xolair tx
Hospitalizations during compared with placeboxolair Tx


Side effects
Side effects compared with placebo

  • Only 1 patient withdrawn

  • 5 patients with musculoskeletal pains.

  • No cardiovascular side effects.

  • No anaphylaxis.

  • No malignancies.


Conclusions
CONCLUSIONS compared with placebo

Omalizumab is effective add-on treatment in patients with moderate to severe allergic asthma and accompany by an acceptable safety profile.


Future
Future? compared with placebo



Mepolizumab a humanized anti il 5 mab as a option for severe asthma
Mepolizumab resistant asthma, a humanized anti-IL-5 mAb, as a option for severe asthma


Thank you
Thank You resistant asthma


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