A unique solution for severe asthma. Dr Talker Olga Pulmonary department
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Transcript of A unique solution for severe asthma. Dr Talker Olga Pulmonary department
A UNIQUE SOLUTION FOR SEVERE ASTHMA.
DR TALKER OLGAPULMONARY DEPARTMENT
CASE PRESENTATION, 10.2009 :
48 year old lady, teacher at schoolMarried +7s/p op. d/t scoliosis at age 17No smoking historyFamily history of severe asthmaAllergy to dust mitesSevere asthma with recurrent exacerbations, recurrent prolonged courses of oral steroids, prednisone 30-40 mg.
A CASE, 10.2009 :
BMI- 23Normal CXR, normal ECHO, p-ANCA, c-ANCA- normalHigh eosinophil count-1100Stool examination- no parasitesPFT- 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 triggersNonadherenceAlternative disorder that mimics asthmaComorbidities
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.Endobronchial sarcoidosis- hylar adenopathy and interstitial opacities .Cardiac disease- echocardiography .
TO BE EXCLUDED:
Comorbidities:Chronic rhinosinusitis, allergic rhinitisGERDOngoing smokingObesityOSAAnxiety , depression.
A CASE, 01.2010 :
IgE- 80 u/mlStarted Xolair- monoclonal anti-IgE antibody, 225 mg every two weeksPrednisone tapering down
A CASE, 11.2010 :
Receiving Xolair 225 mg every two weeksStopped Seretide No prednisonePFT- FEV1- 75%
Th2-cell
B-cell
Eosinophil
IL-4
IL-13
Mast cell
FceRI
IgE
HistamineLeukotrienesProstaglandinsCytokines
Atopicdisease
IL-5
Antigen-presentingcell
Allergen
THE IGE-MEDIATED INFLAMMATORY RESPONSE:TYPE I HYPERSENSITIVITY REACTION
Holgate ST. QJM 1998
XOLAIR® (OMALIZUMAB) PREVENTS IGE INTERACTING WITH FCERI ON ALL CELL TYPES
Mast cellBasophil
Dendritic cell
IgE
Macrophage/monocyte
Eosinophil
Trimers~(490 kD- 530 kD)
Hexamer~(1000 kD)
Omalizumab )~150 kD(
IgE )~190 kD(
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
300mg administered once monthly for 48 weeks topatients with moderate-to-severe asthma
Day 0 = screening )n=93(
Days )not to scale(
REDUCTION IN SERUM FREE IGE FOLLOWING S.C. ADMINISTRATION OF XOLAIR®
Day 1 post-dose
0
300
200
100
0 1 3 7 14 112 168 252 336
Median free IgE )ng/mL(
Source: Extension Study Report 8C
INNOVATE INVESTIGATION OF OMALIZUMAB IN SEVERE ASTHMA TREATMENT
Patients (aged 12–75 years) with allergic asthma
FEV1 40–<80% at randomizationAsthma 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
Humbert M, et al. Allergy 2005
INNOVATE RESULTS
0.91
0.48 0.43
0.24***0.24**
0.68*
0
0.25
0.5
0.75
1
ExacerbationGeneral
SevereExacerbation
FEV1 < 60
ER visits
Exa
cerb
atio
ns R
ate
*P = 0.04, ** P = 0.002, *** P = 0.038Omalizumab Placebo
26%
50% 44.2%
QOL SIGNIFICANTLY IMPROVED OVERALL AND ACROSS ALL DOMAINS COMPARED WITH PLACEBO
0.46
0.57
0.440.40
0.46
AQLQ score†OmalizumabPlacebo
**p<0.01; ***p<0.001†Change from baseline (least squares mean)
AQLQ = Asthma Quality of Life Questionnaire
0.91***
0.90***
0.95** 0.89
***
0.91***
1.0
0.8
0.6
0.4
0.2
0
ActivitiesEmotionsSymptomsEnvironmentOverall
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 inhibitorICS = inhaled corticosteroid; LABA = long-acting β2-agonist
Step 1 Step 2 Step 3 Step 4 Step 5Asthma education
Environmental controlAs needed rapid-acting β2-agonist
As needed rapid-acting β2-agonist
Controller options
Select one Select one Add one or more Add one or more
Low-dose ICS Low-dose ICS plus LABA
Medium- or
high-dose ICS plus LABA
Oral corticosteroid )lowest dose(
Leukotriene modifier† Medium- or high-dose ICS
Leukotriene modifier
Anti-IgE treatment
Low-dose ICS plus leukotriene
modifierSustained release
theophylline
Low-dose ICS plus sustained
release theophylline
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
14 (30%)
33 (70%)
male
female
BASELINE TREATMENT
ICSCOMBINATION THERAPY
SINGULAIR0
10
20
30
40
50
60
70
80
90
9%
88%
6%
ASTHMA EXACERBATION RATE(ONE YEAR)
020406080
33/47 (70.2%)
18/47 (38.3%)
P=0.007
LUNG FUNCTIONS
FEV1 before
FEV1 affter
55.0
56.0
57.0
58.0
59.0
60.0
61.0
62.0
63.0
64.0
63.9±17
58.1±13.9
P=0.002
STEROIDS DOSAGES
Dose before
Dose after
5.6
5.8
6.0
6.2
6.4
6.6
6.8
7.0
7.2
7.4
6.3±6.8
7.3±8.1
P=0.027
STEROIDS REDUCTION 4 (8.5%) stopped steroids. 10 (21%) reduced the dosage.
HOSPITALIZATIONS DURING XOLAIR TX
45%
25%
17%13%
No hospitalizationOne hospitalizationTwo hospitalizations>3 Hospitalizations
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