Introduction
Manifestation | Definition |
---|---|
Asthma
| Inflammatory disease of the airways characterized by: |
• Infiltration by eosinophils, lymphocytes and neutrophils | |
• Mast cell activation | |
• Epithelial loss | |
Associated reversible airway obstruction, recurrent symptoms and bronchial hyper-responsiveness | |
Gene-by-environment interactions are important | |
Inflammation
| Plays central role in asthma pathophysiology |
Mediated by T cells, lymphocytes, mast cells, eosinophils and epithelium. Other resident cells such as fibroblasts and smooth muscle play a role | |
Airway remodeling
| As inflammation proceeds, other changes evolve leading to reparative or remodeling changes and include: |
• Sub-basement membrane thickening | |
• Subepithelial fibrosis | |
• Smooth muscle hypertrophy | |
• Angiogenesis | |
Mucus gland hyperplasia and hypersecretion | |
Bronchoconstriction
| Airway narrowing resulting in wheezing |
Probably acutely due to release of mast cell mediators such as histamine, leukotrienes, and tryptase | |
Obstruction could be mediated by multiple factors: | |
• Smooth muscle contraction | |
• Airway edema | |
• Airway remodeling and fibrosis | |
Bronchial Hyperresponsiveness
| Exaggerated bronchoconstrictive response to a wide variety of stimuli; best measured clinically by methacholine challenge testing; mediated by inflammation, remodeling and other airway changes that occur in asthma |
Event | Cell types involved | Mediators | Cell type affected | Net effect |
---|---|---|---|---|
Inflammation
|
Antigen-presenting cell
| CSM | T cells, B cells | T cell activation Antibody synthesis |
TNF alpha | Endothelium | Cell adhesion, recruitment | ||
Mast cells
| IL-4 | T cells | Th2 cell polarization | |
IL-4, IL-13 | B cells |
IgE class switching
| ||
IL-13 | Goblet cell | Mucus secretion CAM | ||
TNF-alpha | Endothelium | upregulation | ||
LTs | Smooth muscles | Contraction | ||
LTs, IL-5 | Eosinophils | Chemoattraction, survival | ||
Histamine | Endothelium etc | Edema, bronchospasm | ||
T cells
| IL-4, IL-13 | B cells |
IgE class switching
| |
IL-5 | Eosinophils | Hematopoiesis, survival | ||
IL-9 | Mast cells | BHR, mast cell growth | ||
B cells
|
IgE
| Mast cells, basophil | Early phase response Mediator release | |
Eosinophil
| MBP | Epithelium, mast cells | Injury, histamine release | |
LTs | Smooth muscle | Contraction | ||
Cytokines | Multiple types | Inflammation |
The problem
Omalizumab: historical and molecular aspects
Omalizumab pharmacokinetics
Molecular structure and interactions with IgE
Molecular and clinical effects
Condition | Reference |
---|---|
Allergic rhinitis
| [66,69,85-89] |
Allergic asthma:
| |
• Moderate-severe persistent disease | [55,64,90-94] |
• Steroid-sparing effect | [57,95,96] |
Churg-Strauss syndrome
| [97,98] |
Peanut anaphylaxis*
| [52,70,71,99,100] |
Uticaria
| [78] |
Angioedema
| [101] |
Immunotherapy reactions
| [102] |
Rubber latex allergy
| [79] |
Immunological Effects | |
---|---|
Direct effects
| Binding to constant region of IgE |
Decreased free levels of IgE | |
Decreased mast cell/basophil FcεR1 expression | |
Indirect effects
| Decreased mucosal eosinophils |
Decreased sputum eosinophils | |
Decreased tissue IgE+ mast cells | |
Decreased tissue B and T lymphocytes | |
Inhibition of early and late phase reactions | |
Improved BHR/unchanged BHR | |
Improved response to methacholine challenge | |
Mast cell stabilization: inhibits degranulation | |
Clinical Effects
| |
Effects on asthma
| Decreased exacerbations |
Improved peak flow | |
Small improvement in FEV1 | |
Decreased rescue β2-agonist use | |
Improved quality of life | |
Decreased mean nocturnal clinical score | |
Decreased total asthma clinical score | |
Decreased hospitalizations | |
Improved asthma control | |
Steroid-sparing effect |
Effects of omalizumab in non-asthma conditions
Omalizumab: adverse events and safety
System | Reaction/AE | Frequency | Other aspects |
---|---|---|---|
Systemic
| Malignancy | 20/4127 patients | 0.5% versus 0.2% control Breast, prostate, melanoma Skin cancer, parotid, etc. |
Anaphylaxis | 1/1000 patients | 0.1%–0.2% 60% within 1–3rd dose <2 hrs 14% after 4th dose, <30 mins | |
Viral infection | 23% | Fever, myalgia, etc. 53% versus 42% control | |
Parasitic infection | 36/68 | Odds risk 1.98 Geohelminths | |
Immunogenicity | <0.1% | Antibody to Omalizumab | |
Cutaneous
| Injection site reaction | 45% | Warmth, erythema Bruising, burning |
Skin eruption* | 6% | Dermatitis, urticaria | |
Respiratory
| Infections* | 20% | |
Sinus
| Sinusitis* | 15% | |
CNS
| Headache* | 15% | |
Pharynx
| Pharyngitis* | 11% | |
Platelets
| Thrombocytopenia | ? | Post-marketing observation |
Integument
| Alopecia | ? | Post-marketing observation |
Drug interactions | Unknown |
---|---|
Pregnancy
| Category B |
Nursing
| Excreted in milk* |
Fertility
| Study with monkeys shows no effect |
Pediatric use
| Safety below 12 years unknown |
Geriatric use
| Not enough data |
Immediate treatment | Assessment of breathing, circulation and orientation |
---|---|
Inject epinephrine 0.3 mg intramuscularly in lateral thigh | |
Activate emergency services (911) | |
Patient to be placed in recumbent position | |
Establish and maintain airway Oxygen | |
Establish an intravenous line | |
Use nebulized beta-agonist for bronchospasm +/- corticosteroids and antihistamines | |
Long-term prevention
| Patient education |
Provision of epinephrine autoinjector | |
Anaphylaxis identification (card, bracelet) | |
Xolair information sheet |
Insurance and reimbursement issues
Indications for omalizumab
Omalizumab dosing and duration of therapy
Pre-treatment | Body weight (Kg) | |||
---|---|---|---|---|
Serum IgE Level (IU/mL)
|
30–60
|
>60–70
|
>70–90
|
>90–150
|
>30–100 | 150 | 150 | 150 | 300 |
>100–200 | 300 | 300 | 300 | |
>200–300 | 300 | |||
>300–400* | ||||
>400–500* | ||||
>500–600* |
Pre-treatment | Body weight (Kg) | |||
---|---|---|---|---|
Serum IgE Level (IU/mL)
|
30–60
|
>60–70
|
>70–90
|
>90–150
|
>30–100* | ||||
>100–200* | 225 | |||
>200–300* | 225 | 225 | 300 | |
>300–400 | 225 | 225 | 300 | |
>400–500 | 300 | 300 | 375 | |
>500–600 | 300 | 375 |
DO NOT DOSE
| |
>600–700 | 375 |
DO NOT DOSE
|