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A unique solution for severe asthma. Dr Talker Olga Pulmonary department

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

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  1. A unique solution for severe asthma.Dr Talker OlgaPulmonary department

  2. 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.

  3. 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.

  4. What is to be done?

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

  6. To be excluded: Ongoing exposure to triggers Nonadherence Alternative disorder that mimics asthma Comorbidities

  7. 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

  8. 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.

  9. 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.

  10. 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.

  11. To be excluded: Comorbidities: Chronic rhinosinusitis, allergic rhinitis GERD Ongoing smoking Obesity OSA Anxiety , depression.

  12. A case, 01.2010: IgE- 80 u/ml Started Xolair- monoclonal anti-IgE antibody, 225 mg every two weeks Prednisone tapering down

  13. A case, 11.2010: Receiving Xolair 225 mg every two weeks Stopped Seretide No prednisone PFT- FEV1- 75%

  14. 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

  15. Xolair® (omalizumab)prevents IgE interacting with FceRI on all cell types IgE Eosinophil Macrophage/monocyte Mast cell Basophil Dendritic cell

  16. 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)

  17. 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

  18. 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

  19. Omalizumab Placebo * P = 0.04, ** P = 0.002, *** P = 0.038 INNOVATE Results 26 % 50 % 44.2 %

  20. 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

  21. 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

  22. 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

  23. 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

  24. Updated Dosing Table

  25. Pulmonary outpatients clinic

  26. 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

  27. 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

  28. Real Life Experience: Meir Medical Center: Sex

  29. Baseline treatment

  30. Asthma exacerbation rate(one year) P=0.007

  31. Lung functions P=0.002 58.1±13.9

  32. Steroids dosages P=0.027

  33. Steroids reduction • 4 (8.5%) stopped steroids. • 10 (21%) reduced the dosage.

  34. Hospitalizations during xolair Tx

  35. Side effects • Only 1 patient withdrawn • 5 patients with musculoskeletal pains. • No cardiovascular side effects. • No anaphylaxis. • No malignancies.

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

  37. Future?

  38. Potential targets for selected novel therapies for treatment resistant asthma

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

  40. Thank You

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