A unique solution for severe asthma dr talker olga pulmonary department
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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 OlgaPulmonary department


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:

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.


What is to be done?


Severe asthma, definition:

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


To be excluded:

Ongoing exposure to triggers

Nonadherence

Alternative disorder that mimics asthma

Comorbidities


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 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 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 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 excluded:

Comorbidities:

Chronic rhinosinusitis, allergic rhinitis

GERD

Ongoing smoking

Obesity

OSA

Anxiety , depression.


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:

Receiving Xolair 225 mg every two weeks

Stopped Seretide

No prednisone

PFT- FEV1- 75%


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 FceRI on all cell types

IgE

Eosinophil

Macrophage/monocyte

Mast cell

Basophil

Dendritic cell


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®

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


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


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

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

***

ActivitiesEmotionsSymptomsEnvironmentOverall

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

†Change from baseline (least squares mean)

AQLQ = Asthma Quality of Life Questionnaire


Omalizumab was well tolerated

  • 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

*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®

  • 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


Pulmonary outpatients clinic


Omalizumab 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 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


Real Life Experience: Meir Medical Center: Sex


Baseline treatment


Asthma exacerbation rate(one year)

P=0.007


Lung functions

P=0.002

58.1±13.9


Steroids dosages

P=0.027


Steroids reduction

  • 4 (8.5%) stopped steroids.

  • 10 (21%) reduced the dosage.


Hospitalizations during xolair Tx


Side effects

  • Only 1 patient withdrawn

  • 5 patients with musculoskeletal pains.

  • No cardiovascular side effects.

  • No anaphylaxis.

  • No malignancies.


CONCLUSIONS

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


Future?


Potential targets for selected novel therapies for treatment resistant asthma


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


Thank You


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